Category Archive Anatomy A – Z

Fifth Through Eighth Weeks of Stages Fetal Development

Fifth Through Eighth Weeks of Stages Fetal Development /Weeks five through eight of gestation are characterized by the development of the major organ systems, including the circulatory, nervous, lymphatic, and gastrointestinal systems. During this time, the embryo is extremely susceptible to the effects of teratogens.

Development

Cardiovascular System

The first organ system to develop during organogenesis is the cardiovascular system. The heart has established its four chambers by four weeks of development, whereas week six involves cardiac outflow separation and descent of the heart (and lungs) into the thorax. The separation divides the truncus arteriosus into the ascending aorta and pulmonary artery; this occurs via spiraling of the aorticopulmonary septum. Anatomically, the aorta and pulmonary appear to wrap around each other superior to the heart. That appearance is the result of embryologic spiraling. The aorticopulmonary septum may also be referred to as the spiral or conotruncal septum.

Lung Development 

Lung development occurs from the embryonic period through the fetal period and continues up to birth. In particular, lung growth begins in early embryonic development when right and left lung buds are formed from an initial outpouching, the respiratory diverticulum. The buds enlarge and branch to form the respiratory tree. The appearance of the visceral and parietal pleura takes place during weeks five through seven.  Both types of pleura arise from mesoderm. The visceral pleura covers the developing bronchial tree, and the parietal pleura covers the internal chest wall. Pleuroperitoneal membranes form and fuse with the diaphragm, which separates the pleural and peritoneal body cavities. Closure of the pleuroperitoneal canal by these membranes takes place by approximately week seven.

Gastrointestinal System

Weeks six through eight are also critical for the development of the gastrointestinal system. The midgut undergoes physiologic herniation through the umbilicus around week six, but this event may be delayed up until week ten. This physiologic process happens because the size of the abdominal cavity is too small to accommodate the enlarging gastrointestinal tract. Herniation provides ample space for the rapidly enlarging midgut. After herniation, the midgut undergoes three rotational events totaling 270 degrees of rotation. The first rotation consists of 90 degrees in a counterclockwise direction around the superior mesenteric artery. This helps establish the appropriate arrangement and placement of the bowel; the ileum is brought to the right side of the body. The second rotation occurs during 10 weeks of gestation and consists of 180 degrees in a counterclockwise direction. The midgut returns to the body cavity at the end of 10 weeks. Finally, the third rotation of 180 degrees in a counterclockwise direction places the cecum on the right side.

In early embryonic development, the lumen of the duodenum is occluded by epithelium. Weeks six through eight are important for establishing the lumen’s patency as the duodenum expands in size. The anal opening is established by the breakdown of the cloacal membrane during week seven.

The pancreas is endodermal in origin and develops by growing dorsal and ventral pancreatic buds. The buds begin as outgrowths of the duodenum. Week seven is significant because the dorsal and ventral buds fuse at this time. Additionally, the ventral pancreatic bud undergoes rotation around the duodenum by week six. It rotates for 180 degrees in a clockwise direction. These embryologic mechanisms are important for proper pancreatic development; congenital malformations may occur in the absence of such processes, which will be discussed later.

Furthermore, the liver undergoes rapid growth during this time. Its first appearance is during the third week of gestation; it undergoes rapid growth during weeks five through ten. The hepatic artery appears at week eight. The liver is endodermal in origin.

Central Nervous System

The neural tube closes around week four and is the early derivative of the brain and spinal cord.  During weeks five through eight, the CNS undergoes the development of its vesicles, which are embryologic precursors to different structures of the brain. The forebrain, midbrain, and hindbrain all develop from vesicles. These three structures are also known as the prosencephalon, mesencephalon, and rhombencephalon, respectively. The prosencephalon later develops into the diencephalon and telencephalon. The diencephalon gives rise to the thalami, hypothalamus, optic cups, and neurohypophysis, while the telencephalon grows to surround the diencephalon, midbrain, and hindbrain. The mesencephalon forms the aqueduct of Sylvius, superior and inferior colliculi, and tegmentum. The rhombencephalon gives rise to the fourth ventricle as well as the metencephalon, a structure that eventually develops into the pons and cerebellum.

Other Organs

Many other organs develop during weeks six through eight, including the pituitary gland, thymus, and adrenal cortex. At week seven, the embryo assumes a characteristic C-shape. At week seven, the ocular retina also begins to develop. The upper and lower limbs continue to grow. Also, facial structures such as the nostrils, eyelids, outer ears, lip, and palate develop, and at week seven, the head and face contours begin to emerge.

Cellular

Cellular processes are highly regulated throughout organogenesis. For example, the CNS requires precise cellular pathways to be followed for proper organ system development. Part of the dorsal ectoderm becomes the neural ectoderm, and their columnar appearance distinguishes the cells. The neural tube forms during early development and serves as an embryonic precursor to the CNS. The process by which the neural tube is formed from the neural plate is called neurulation. The neural tube has closed by four weeks of development, and the first neurons of the human body begin to appear. The neural tube forms the brain anteriorly and thespinal cord posteriorly.

During week seven, cells of the ventricular zone of the brain start making neurons of the cortical plate. The ventricular zone is a proliferative cell layer in the brain that surrounds the ventricles and contains neural stem cells for neurogenesis. Neurogenesis describes the formation of new neurons and their incorporation into the CNS. After new neurons are made, they undergo specific pathways of migration and differentiation. These pathways allow for the creation of new structures and continued CNS growth and development.

Fifth Through Eighth Weeks of Development

Weeks five to eight of gestation develops the major organs, including the circulatory, nervous, and gastrointestinal systems.

Key Points

Being susceptible to the effects of teratogens is high during embryonic development.

At week five, the brain, spinal cord, vertebrae, heart, vasculature, and gastrointestinal tract begin to develop.

During weeks six to seven, the embryo grows from 4 mm in length to 9 mm and begins to curve into a C-shape. The fetal heart bulges, develops further, and begins to beat in a regular rhythm. Rudimentary blood begins to move through the blood vessels. The neural tube, which forms the brain, closes.

During weeks six and seven, the limb buds form. The eyes, mouth, and ear structures begin to form. The initial differentiation of the tissues that will become the spleen, gallbladder, pancreas, liver, kidneys, stomach, and lungs occurs.

By week eight of gestation, the lungs begin to form, as well as the lymphatic system. The main development of the external genitalia begins, and the brain continues to develop. The arms and legs have grown longer, and the foot and hand areas can be clearly distinguished.

Key Terms

  • chorionic membrane: One of the membranes that exist during pregnancy between the developing fetus and mother. The chorionic villi emerge from the chorion, invade the endometrium, and allow transfer of nutrients from maternal blood to fetal blood.
  • Gestational age: The time that has passed since the onset of the last menstruation.
  • Embryonic age: Measures the actual age of the embryo or fetus from the time of fertilization.
  • teratogens: An agent, such as a virus, a drug, or radiation, that causes a malformation of an embryo or fetus.

Weeks five through eight of gestation are characterized by the development of the major organ systems, including the circulatory, nervous, lymphatic, and gastrointestinal systems. During this time, the embryo is extremely susceptible to the effects of teratogens.

Gestational age is the time that has passed since the onset of the last menstruation, which occurs two weeks before the actual fertilization. Embryonic age measures the actual age of the embryo or fetus from the time of fertilization. Thus, the first week of embryonic age is already week three counting with gestational age. The number of the week (used here) is one more than the actual age of the embryo/fetus. For example, the embryo is 0 whole weeks old during the first week after fertilization.

Week 5

At week five, the brain, spinal cord, vertebrae, heart, vasculature, and gastrointestinal tract begin to develop.

Week 6–7

This is a scan of a human embryo at seven weeks—an embryo from an ectopic pregnancy, still in the oviduct. This embryo is about five weeks old (or from the seventh week of menstrual age). The heart is the dark spot at the center of the image, bulging out of the embryo.

Human embryo at seven weeks: An embryo from an ectopic pregnancy, still in the oviduct. This embryo is about five weeks old (or from the seventh week of menstrual age). The heart is the dark spot at the center of the image, bulging out of the embryo.

During weeks six and seven, the embryo grows from four millimeters in length to nine millimeters and begins to curve into a C-shape. The fetal heart bulges, develops further, and begins to beat in a regular rhythm. Rudimentary blood begins to move through the main embryonic blood vessels, connecting to the yolk sac and the chorionic membrane of the placenta.

The arm and leg buds, which will grow into the full limbs over the rest of development, become visible. The neural tube, which forms the brain, closes. The brain then develops into five areas and some cranial nerves are visible.

The eyes, mouth, and ear structures begin to form. The initial differentiation of the tissues that will become the spleen, gallbladder, pancreas, liver, kidneys, stomach, and lungs occurs.

Week 8

By week eight of gestation, the embryo measures 13 millimeters in length. The lungs begin to form, as well as the lymphatic system. The main development of the external genitalia begins, and the brain continues to develop.

The arms and legs have grown longer, and the foot and hand areas can be clearly distinguished. The hands and feet have fingers and toes, but may still be webbed.

This is a color scan of an embryo from an ectopic pregnancy, located in the part of the uterus to which the fallopian tube is attached. The features are consistent with a developmental age of seven weeks (ninth week of menstrual age).

Human embryo from an ectopic pregnancy: An embryo from an ectopic pregnancy, located in the part of the uterus to which the fallopian tube is attached. The features are consistent with a developmental age of seven weeks (the ninth week of menstrual age).

References

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Fourth Week of Development of Embryo

Fourth Week of Development of Embryo (the embryonic disc) will grow from about 2 to about 6 mm. The processes of the third week (neural tube formation, development of blood circulation) continue in the fourth week. At the same time, the amnion increases enormously in size, while the yolk sac does not. This is the cause of a great change in the form.

This is primarily due to the folding of the germinal disk, to the differentiation of the somites and to the rapid development of the nervous system. In the fourth week the embryo has a length of 1.5 to 3.5 mm. At the beginning of the week it is almost straight.

Fourth Week of Development of Embryo

The fourth week of gestation is characterized by the flexion of the superior portion of the neural tube to create the mesencephalon.

Key Points

Neural tube flexion patterns determine neural development, including the positioning and differentiation of the prosencephalon and rhombencephalon, as well as the optical vesicle.

Important changes occur to the embryonic heart as well, including development of the pharyngeal arches.

At the end of the fourth week, the yolk sac presents the appearance of a small pear-shaped vesicle (the umbilical vesicle) that opens into the digestive tube by a long, narrow tube—the vitelline duct.

Key Terms

  • mesencephalon: A part of the brain located rostral to the pons and caudal to the thalamus and the basal ganglia, composed of the tectum (dorsal portion) and the tegmentum (ventral portion).
  • mandibular arch: The first pharyngeal arch, also called the mandibular arch, is the first of six aortic arches that develops in fetal life during the fourth week of development.
  • optical vesicle: The eyes begin to develop as a pair of diverticula from the lateral aspects of the forebrain. These diverticula make their appearance before the closure of the anterior end of the neural tube; after the closure of the tube they are known as the optic vesicles.

Placentation

Trophoblast cells surrounding the embryonic cells proliferate and invade deeper into the uterine lining. They will eventually form the placenta and embryonic membranes. At the end of the fourth week the yolk sac presents the appearance of a small pear-shaped vesicle (the umbilical vesicle) opening into the digestive tube by a long narrow tube, the vitelline duct.

The chorion undergoes rapid proliferation and forms numerous processes. The chorionic villi, which invade and destroy the uterine decidua and at the same time absorb from it nutritive materials for the growth of the embryo. Until about the end of the second month of pregnancy the villi cover the entire chorion, and are almost uniform in size, but after this they develop unequally.

Mesencephalon Development

Late in the fourth week of gestation, the superior part of the neural tube flexes at the level of the future midbrain, the mesencephalon. Superior to the mesencephalon is the prosencephalon (future forebrain) and inferior to it is the rhombencephalon (future hindbrain). The optical vesicle (which will eventually become the optic nerve, retina, and iris) forms at the basal plate of the prosencephalon.

This is a drawing of an embryo brain at four weeks that shows how it differentiated. The embryo's brain is differentiated into the proscephalon, mesencephalon, and rhombencephalon. A white circle represents the area of the optical vesicle. 

Embryo brain at four weeks: At four weeks the embryo’s brain can be differentiated into the proscephalon, mesencephalon, and rhombencephalon. A white circle represents the area of the optical vesicle.

Pharyngeal Arch Development

The embryonic heart attains functionality and starts beating at 22 days after conception (about five weeks after the last menstrual period). It can sometimes be seen as flickering in the embryonic chest by an ultrasound performed during the fourth week after conception.

During the fourth week of development, the first pharyngeal arch, also called the mandibular arch, is the first of six pharyngeal arches that begins to develop. It is located between the stomodeum and the first pharyngeal groove.

This is a schematic, anatomical drawing of a developing fetus with its first, second, and third arches labeled. 

Developing fetus: A schematic of a developing fetus with the first, second, and third arches labeled.

The growth of the amnion

In the third week, the embryonic disc got thickness and a symmetry-axis. The tissues of the embryonic disc extend into the tissues of the peripheral organs: ectoderm into the amnion membrane, entoderm into the wall of the yolk sac and mesoderm into the extra-embryonic mesoderm and the connective stalk. The embryo is still an open disc on all sides, with ectoderm on the backside and entoderm on the breastside.

In order to let an independent body come into being, a skin has be formed around the entire embryo. This happens by a dramatic growth of the amnion, that is pushed to the outside through the pressure of the amniotic fluid. The yolk sac is not growing and its liquid does not give pressure, which results in a yolk sac that hangs loose. By these growth-movements, the amnion enfolds around the embryonic disc. This happens all around: at the head, the tail and on both lateral sides. It happens faster at the head side than at the tail side.

In figures 28 to 31 this enfolding process is shown. It is difficult to imagine this three-dimensional process. It is advisable to compare the drawn sections, copy them and draw other cross-sections (eg. through the heart) in order to understand the process better.

What happens?

  • With the growth of the amnion the relatively large heart is moved from its cranial position above the head to its destination in the chest.
  • A little later the connective stalk is pushed towards the belly, to a place somewhat caudal from the heart. The umbilical cord will eventually develop around it.
  • The neural tube thickens quickly on the cranial end, causing the cranial end to fold inside.
  • The amnion pushes the yolk sac to the inside on the cranial and caudal as well as the lateral sides. The solidity that the notochord gives to the embryonic disc causes the embryonic disc to stay more or less straight. Ectoderm and entoderm are joined together at the mouth membrane and at the cloacal membrane by hinging points. This leads to the formation of the digestive tract.
  • The formation of the digestive tract goes from the tips to the centre.
  • The umbilical cord is created in the centre. It attaches the embryo to the chorion and it transports nutrients and waste products.
  • In the umbilical cord the connective stalk, the yolk sac and allantois are found.
  • In the enclosing of the embryonic disc by the amnion, a part of the chorion is included in the embryo as the body cavity (the intra-embryonic coelom; .
  • The embryo becomes more or less cylindrical, and later it makes a wrapping movement in longitudinal direction .
  • Once it is formed, the digestive tract grows rapidly.

Shows two side views of the embryo in the fourth week. In the drawing from the middle of the fourth week, the 24th day  the amnion surrounds the embryonic disc and the cylindrical embryo is created. Visible is the large hump of the heart that has been pushed from its cranial position above the head to a location in the chest. The neural tube is still open on both sides. The connective stalk and the yolk sac are visible.

At the end of the fourth week, the 28th day, the complete enclosure of the amnion and the umbilical cord (containing blood vessels, connective stalk, yolk sac and allantois) are visible. The heart has grown and descended a bit more and now lies on its final place adjacent to the umbilical cord. The embryo has a short tail and has become rounder. The head and tail are bent to the inside. The head is large; the headside develops faster then the tailside. At the head folds have appeared, caused by the fast thickening of the tissue of the neural tube that thereby bends the head downward. The first arch is the mandibulary arch, from which the upper jaw grows. The last two folds are called branchial (gill) arches, similar to the folds in fish. The beginning of an eye and an ear are visible. The limbs grow, the first beginnings of an arm and a leg can be seen (see the next page for the development of the limbs).


Figure 32. Left: an embryo on day 24, right on 28 days, respectively. 2 and 5 mm long.

Neural tube and digestive tract

The neural tube arises from the centre, the digestive tract from the extremities. In the neural tube there is clear amniotic fluid, which exerts pressure on the wall. In the digestive tract is turbid yolk liquid, which does not. The neural tube is mainly a straight tube, the digestive tract is a tube that winds in and out (the intestines). The neural tube consists of ectoderm, the digestive tract of entoderm. Ectoderm comes from the back, which may be called the antipathy-side of the body (to turn your back on someone). Entoderm comes from the front side, the sympathy-side of our body. With ectoderm we demarcate ourselves and create distance (observing), with entoderm we create connections (digestion of food).

neural tube digestive tract
arises from the middle the extremities
fluid clear amniotic fluid, exerts pressure trouble yolk fluid, no pressure
tissue ectoderm entoderm
form straight winding
where backside = antipathy-side frontside = sympathy-side

Differences between the neural tube and the digestive tract

Characteristics

The processes of the third week gave the embryo volume, but did not give the embryonic disc a boundary. At the beginning of the fourth week, the embryonic disc extends into the enclosing tissues of amnion, chorion and yolk sac. The enclosing movement of the amnion separates the embryo from the enclosing tissues and emancipates the embryonic disc. It still takes a long time before the embryo is independent, but the beginning is there, now that the body gets its first form and is connected to the nourishing tissues by the umbilical cord. Steiner called this stage “Paradise Man”, by which he meant to say that this is the first separation of man from his environment.

Now the body is apart and three-dimensional. The body bends and is directed towards a centre (Fig. 32). Hartmann uses the name “Animal Man”.

The enveloping movement of the amnion has as a result, that the back-side is now on the outside and what was on the ventral side now lies within. It is an enveloping gesture.

The umbilical cord is on the ventral side of the embryo. It started as the connective stalk at the backside, then it moved to the tail and now it shifts to the abdomen. The nourishment came from behind in the stage of the “Plant Man”; from the front in the stage of the “Animal Man”.


Figure 33. Animal Man (from Van der Wal, by Hartmann)

Indicated is that an animal is an organism with content or volume. It is focused inwardly on a centre.

The three tissues of the embryonic disc and what arises from them

The embryonic disc consists of three germ layers:
  • Ectoderm
  • Entoderm
  • Mesoderm
From the ectoderm arise:
  • The skin
  • The nervous system
  • The senses
From the entoderm arise:
  • The digestive tract and digestive organs (liver, pancreas)
  • The lungs
  • The bladder (from the allantois)
The mesoderm can create three types of tissues:
  • It can concentrate and grow inward to form muscles, tendons, ligaments and bones;
  • And the kidneys, spleen and reproductive organs.
  • It can go to the periphery to form body cavities, such as the pericardium, the lung cavity, the abdominal cavity, etc.
  • It can do both at once and form blood cells, blood vessels and the heart.

References

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Third Week of Development – Anatomy, Types, Functions

Third Week of Development/The third week is concerned with establishing left and right handedness, the craniocaudal axis, as well as the conversion of the bilaminar disc into a trilaminar embryo. Additionally, there is further specialization of the extraembryonic structures that will continue to support the embryo during the intrauterine phase.

Gastrulation

During gastrulation, the embryo develops three germ layers (endoderm, mesoderm, and ectoderm) that differentiate into distinct tissues.

Key Points

Gastrulation takes place after cleavage and the formation of the blastula. Formation of the primitive streak is the beginning of gastrulation. It is followed by organogenesis—when individual organs develop within the newly-formed germ layers.

The ectoderm layer will give rise to neural tissue, as well as the epidermis.

The mesoderm develops into somites that differentiate into skeletal and muscle tissues, the notochord, blood vessels, dermis, and connective tissues.

The endoderm gives rise to the epithelium of the digestive and respiratory systems and the organs associated with the digestive system, such as the liver and pancreas.

Key Terms

  • somite: One of the paired masses of mesoderm, distributed along the sides of the neural tube, that will eventually become dermis, skeletal muscle, or vertebrae.
  • gastrulation: The stage of embryonic development at which a gastrula is formed from the blastula by the inward migration of cells.
  • notochord: A structure found in the embryos of vertebrates from which the spine develops.
  • epiboly: One
    of many movements in the early embryo that allow for dramatic physical restructuring and is characterized
    by a thinning and spreading of cell layers.

Gastrulation is a phase early in the embryonic development of most animals during which the single-layered blastula is reorganized into a trilaminar (three-layered) structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.

This is a diagram of the formation of the three primary germ layers—ectoderm, mesoderm, and endoderm—that occurs during the first two weeks of development. The embryo at this stage is only a few millimeters in length.

Gastrulation: Formation of the three primary germ layers occurs during the first two weeks of development. The embryo at this stage is only a few millimeters in length.

Gastrulation takes place after cleavage and the formation of the blastula and the primitive streak. It is followed by organogenesis, when individual organs develop within the newly-formed germ layers. Each layer gives rise to specific tissues and organs in the developing embryo.

In amniotes such as humans, gastrulation occurs in the following sequence

  • The embryo becomes asymmetric.
  • The primitive streak forms.
  • Cells from the epiblast at the primitive streak undergo an epithelial to mesenchymal transition and ingress at the primitive streak to form the germ layers.

The ectoderm gives rise to the epidermis, and also to the neural crest and other tissues that will later form the nervous system. The mesoderm is found between the ectoderm and the endoderm, giving rise to somites.

The somites form muscle, the cartilage of the ribs and vertebrae, the dermis, the notochord, blood and blood vessels, bone, and connective tissue.

The endoderm gives rise to the epithelium of the digestive and respiratory systems, and the organs associated with the digestive system, such as the liver and pancreas. Following gastrulation, the cells in the body are either organized into sheets of connected cells (as in epithelia), or as a mesh of isolated cells, such as mesenchyme.

The molecular mechanism and timing of gastrulation is different in different organisms. However, some common features of gastrulation across triploblastic organisms include:

  • A change in the topological structure of the embryo, from a simply connected surface (sphere-like), to a non-simply connected surface (torus-like)
  • The differentiation of cells into one of three types (endodermal, mesodermal, or ectodermal).
  • The digestive function of a large number of endodermal cells.

Although gastrulation patterns exhibit enormous variation throughout the animal kingdom, they are unified by the five basic types of cell movements that occur during gastrulation:

  • Invagination
  • Involution
  • ingression
  • Delamination
  • Epiboly

Neurulation

Following gastrulation, the neurulation process develops the neural tube in the ectoderm, above the notochord of the mesoderm.

Key Points

The notochord stimulates neurulation in the ectoderm after its development.

The neuronal cells running along the back of the embryo form the neural plate, which folds outward to become a groove.

During primary neurulation, the folds of the groove fuse to form the neural tube. The anterior portion of the tube forms the basal plate, the posterior portion forms the alar plate, and the center forms the neural canal.

The ends of the neural tube close at the conclusion of the fourth week of gestation.

Key Terms

  • basal plate: In the developing nervous system, this is the region of the neural tube ventral to the sulcus limitans. It extends from the rostral mesencephalon to the end of the spinal cord and contains primarily motor neurons.
  • neurulation: The process that forms the vertebrate nervous system in embryos.
  • alar plate: The alar plate (or alar lamina) is a neural structure in the embryonic nervous system, part of the dorsal side of the neural tube, that involves the communication of general somatic and general visceral sensory impulses. The caudal part later becomes the sensory axon part of the spinal cord.
  • notochord: Composed of cells derived from the mesoderm, this provides
    signals to the surrounding tissue during development.

Neurulation is the formation of the neural tube from the ectoderm of the embryo. It follows gastrulation in all vertebrates. During gastrulation cells migrate to the interior of the embryo, forming the three germ layers: the endoderm (the deepest layer), the mesoderm (the middle layer), and the ectoderm (the surface layer) from which all tissues and organs will arise.

In a simplified way, it can be said that the ectoderm gives rise to skin and the nervous system, the endoderm to the intestinal organs, and the mesoderm to the rest of the organs.

After gastrulation, the notochord—a flexible, rod-shaped body that runs along the back of the embryo—is formed from the mesoderm. During the third week of gestation the notochord sends signals to the overlying ectoderm, inducing it to become neuroectoderm.

This results in a strip of neuronal stem cells that runs along the back of the fetus. This strip is called the neural plate, and it is the origin of the entire nervous system.

The neural plate folds outwards to form the neural groove. Beginning in the future neck region, the neural folds of this groove close to create the neural tube (this form of neurulation is called primary neurulation).

The anterior (ventral or front) part of the neural tube is called the basal plate; the posterior (dorsal or rear) part is called the alar plate. The hollow interior is called the neural canal. By the end of the fourth week of gestation, the open ends of the neural tube (the neuropores) close off.

This is a series of illustrations of transverse sections that show the progression of the neural plate into the neural tube. The first illustration shows the neural plate as flat, laying atop the mesoderm and notochord. The second shows the neural plate bending down, with the tow tends joining at the neural plate borders, which are now referred to as the neural crest. The third shows the closure of the neural tube and how this disconnects the neural crest from the epidermis. The neural crest cells differentiate to form most of the peripheral nervous system. Finally, the notochord degenerates and other mesoderm cells differentiate into the somites.

Neurulation: Transverse sections that show the progression of the neural plate into the neural tube.

Secondary neurulation of vertebrates occurs when primary neurulation terminates. It is the process by which the neural tube at the lower levels and the caudal to the mid-sacral region is formed.

In general, it entails the cells of the neural plate forming a cord-like structure that migrates inside the embryo and hollows to form the tube. Each organism uses primary and secondary neurulation to varying degrees (except fish, which use only secondary neurulation).

CLINICAL EXAMPLE

Spina bifida is a developmental congenital disorder caused by the incomplete closing of the neural tube during neurulation.

This is an illustration of a child with spina bifida. An open defect is seen at the base of the child's spine. 

Spina bifida: An illustration of a child with spina bifida

Somite Development

Somites develop from the paraxial mesoderm and participate in the facilitation of multiple developmental processes.

Key Points

The paraxial mesoderm is distinct from the mesoderm found more internally in the embryo.

Alongside the neural tube, the mesoderm develops distinct paired structures called somites that develop into dermis, skeletal muscle, and vertebrae.

Each somite has four compartments: the sclerotome, myotome, dermatome, and the syndetome. Each becomes a specific tissue during development.

Key Terms

  • neural crest cells: A transient, multipotent, migratory cell population that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage, bone, smooth muscle, peripheral and enteric neurons, and glia.
  • conceptus: The fetus or embryo, including all the surrounding tissues protecting and nourishing it during pregnancy.
  • somite: One of the paired masses of mesoderm, distributed along the sides of the neural tube, that will eventually become dermis, skeletal muscle, or vertebrae.

Intraembryonic Coelom Development

In the development of the human embryo the intraembryonic coelom (or somatic coelom) is a portion of the conceptus that forms in the mesoderm. During the second week of development the lateral mesoderm splits into a dorsal somatic mesoderm (somatopleure) and a ventral splanchnic mesoderm (splanchnopleure).

By the third week of development, this process gives rise to a cavity between the somatopleure and splanchnopleure referred to as the intraembryonic celom. This space later gives rise to both the thoracic and abdominal cavities.

Somite Development

In the developing vertebrate embryo, somites are masses of mesoderm that can be found distributed along the two sides of the neural tube. They will eventually become dermis (dermatome), skeletal muscle (myotome), vertebrae (sclerotome), and tendons and cartilage (syndetome).

The mesoderm found lateral to the neural tube is called the paraxial mesoderm. It is separate from the chordamesoderm underneath the neural tube. The paraxial mesoderm is initially called the unsegmented
mesoderm in vertebrates, but is called the segmented mesoderm in chick embryos.

This is drawing of a dorsal view of a human embryo. The repetitive somites are marked with the older term primitive segments.

Somites: A dorsal view of a human embryo. The repetitive somites are marked with the older term primitive segments.

As the primitive streak regresses and the neural folds gather preceding the formation of the neural tube, the paraxial mesoderm divides into blocks called somites. Somites play a critical role in early development by participating in the specification of the migration paths of neural crest cells and spinal nerve axons.

Later in development, somites separate into four compartments:

Dermatome

The dermatome is the dorsal portion of the paraxial mesoderm somite. In the human embryo it arises in the third week of embryogenesis.

The dermatomes contribute to the skin, fat, and connective tissue of the neck and of the trunk, though most of the skin is derived from the lateral plate mesoderm.

Myotome

The myotome is that part of a somite that forms the muscles. Each myotome divides into an epaxial part (epimere), at the back, and a hypaxial part (hypomere) at the front.

The myoblasts from the hypaxial division form the muscles of the thoracic and anterior abdominal walls. The epaxial muscle mass loses its segmental character to form the extensor muscles of the neck and trunk of mammals.

Sclerotome

The sclerotome forms the vertebrae and the rib cartilage and part of the occipital bone. It forms the musculature of the back, the ribs, and the limbs.

Syndetome

The syndetome forms the tendons and some blood vessels.

Development of the Cardiovascular System

The circulatory system develops initially via vasculogenesis, with the arterial and venous systems developing from distinct embryonic areas.

Key Points

The aortic arches are a series of six, paired, embryological vascular structures that give rise to several major arteries. The first and second arches disappear early. The third arch becomes the carotid artery.

The fourth right arch forms the right subclavian artery, while the fourth left arch forms the arch of the aorta. The fifth arch disappears on both sides.The proximal part of the sixth right arch persists as the proximal right pulmonary artery. The sixth left arch gives off the left pulmonary artery.

Approximately 30 posterolateral branches arise off the dorsal aortae and will form the intercostal arteries, the upper and lower extremity arteries, the lumbar arteries, and the lateral sacral arteries. The lateral branches of the aorta form the definitive renal, suprarenal, and gonadal arteries.

The ventral branches consist of the vitelline and umbilical arteries. The vitelline arteries form the celiac, and superior and inferior mesenteric arteries of the gastrointestinal tract. After birth, the umbilical arteries will form the internal iliac arteries.

The venous system develops from the vitelline veins, umbillical veins, and the cardinal veins, all of which empty into the sinus venosus.

Key Terms

  • sinus venosus: A large quadrangular cavity that precedes the atrium on the venous side of the chordate heart. In humans, it exists distinctly only in the embryonic heart, where it is found between the two venae cavae.
  • aortic arches: Also known as pharyngeal arch arteries, this is a series of six, paired, embryological vascular structures that give rise to several major arteries. They are ventral to the dorsal aorta.
  • cardinal vein: The precardinal veins or anterior cardinal veins contribute to the formation of the internal jugular veins and, together with the common cardinal vein, form the superior vena cava. In an anastomosis by anterior cardinal veins, the left brachiocephalic vein is produced.

Vasculogenesis

The human arterial system originates from the aortic arches and from the dorsal aortae starting from week 4 of embryonic life.
The development of the circulatory system initially occurs by the process of vasculogenesis, the formation of new blood vessels when there are no preexisting ones.

This is a drawing of a profile view of a human embryo estimated at twenty or twenty-one days old. The six aortic arches are identified.

Embryonic cardiovascular system: A profile view of a human embryo estimated at twenty or twenty-one days old.

Vasculogenesis is when endothelial precursor cells (angioblasts) migrate and differentiate in response to local cues (such as growth factors and extracellular matrix) to form new blood vessels. The human arterial and venous systems develop from different embryonic areas.

Aortic Arches

The aortic arches—or pharyngeal arch arteries—are a series of six, paired, embryological vascular structures that give rise to several major arteries. They are ventral to the dorsal aorta and arise from the aortic sac.

Arches 1 and 2

This is a schematic drawing of the aortic arches and their arterial destinations.

Aortic arches: A schematic of the aortic arches and their arterial destinations.

The first and second arches disappear early, but the dorsal end of the second gives origin to the stapedial artery, a vessel that atrophies in humans, but persists in some mammals. It passes through the ring of the stapes and divides into supraorbital, infraorbital, and mandibular branches that follow the three divisions of the trigeminal nerve.

The infraorbital and mandibular branches arise from a common stem, the terminal part of which anastomoses with the external carotid. On the obliteration of the stapedial artery, this anastomosis enlarges and forms the internal maxillary artery; the branches of the stapedial artery are now branches of this vessel.

The common stem of the infraorbital and mandibular branches passes between the two roots of the auriculotemporal nerve and becomes the middle meningeal artery. The original supraorbital branch of the stapedial artery is represented by the orbital branches of the middle meningeal artery.

Arches 3 and 4

The third aortic arch constitutes the commencement of the internal carotid artery, and is named the carotid arch. The fourth right arch forms the right subclavian artery as far as the origin of its internal mammary branch. The fourth left arch constitutes the arch of the aorta between the origin of the left carotid artery and the termination of the ductus arteriosus.

Arches 5 and 6

The fifth arch disappears on both sides.The proximal part of the sixth right arch persists as the proximal part of the right pulmonary artery, while the distal section degenerates. The sixth left arch gives off the left pulmonary artery and forms the ductus arteriosus.

This duct remains during fetal life, but closes within the first few days after birth due to increased O2 concentration. This causes the production of bradykinin which causes the ductus to constrict, occluding all flow. Within one to three months, the ductus is obliterated and becomes the ligamentum arteriosum.

Aortic Branches

The dorsal aortae are initially bilateral and then fuse to form the definitive dorsal aorta. Approximately 30 posterolateral branches arise off the aorta and will form the intercostal arteries, upper and lower extremity arteries, lumbar arteries, and the lateral sacral arteries.

The lateral branches of the aorta form the definitive renal, suprarenal, and gonadal arteries. Finally, the ventral branches of the aorta consist of the vitelline arteries and umbilical arteries.

The vitelline arteries form the celiac, and superior and inferior mesenteric arteries of the gastrointestinal tract. After birth, the umbilical arteries will form the internal iliac arteries.

The human venous system develops mainly from the vitelline, umbilical, and cardinal veins, all of which empty into the sinus venosus. The venous system arises during the fourth to eighth weeks of human development.

CLINICAL EXAMPLE

Most defects of the great arteries arise as a result of the persistence of aortic arches that normally should regress or due to the regression of arches that normally should not.

A double aortic arch occurs with the development of an abnormal right aortic arch, in addition to the left aortic arch, forming a vascular ring around the trachea and esophagus, which usually causes difficulty breathing and swallowing.

Occasionally, the entire right dorsal aorta abnormally persists and the left dorsal aorta regresses. In this case, the right aorta will have to arch across from the esophagus, causing difficulty breathing or swallowing.

Chorionic Villi and Placental Development

In the placenta, chorionic villi develop to maximize surface-area contact with the maternal blood for nutrient and gas exchange.

Key Points

Chorionic villi invade and destroy the uterine decidua while at the same time they absorb nutritive materials from it to support the growth of the embryo.

The villi begin primary development in the fourth week, becoming fully vascularized between the fifth and sixth weeks.

Placental development begins with implantation of the blastocyst; this leads to its differentiation into several layers that allow nutrient, gas, and waste exchange to the developing embryo and fetus —as well as forming a protective barrier.

Key Terms

  • chorion: The protective and nutritive membrane that attaches higher vertebrate fetuses to the uterus.
  • uterine decidua: The term for the uterine lining (endometrium) during a pregnancy, which forms the maternal part of the placenta. It is formed under the influence of progesterone and forms highly characteristic cells.
  • chorionic villi: These sprout from the chorion in order to give a maximum area of contact with the maternal blood.
  • placenta: A vascular organ present only in the female during gestation. It supplies food and oxygen from the mother to the fetus, and passes back waste. It is implanted in the wall of the uterus and links to the fetus through the umbilical cord. It is expelled after birth.

Chorionic Villi

Chorionic villi sprout from the chorion after their rapid proliferation in order to give a maximum area of contact with the maternal blood. These villi invade and destroy the uterine decidua while at the same time they absorb nutritive materials from it to support the growth of the embryo.

This is a schematic drawing of a chorionic artery. It shows the chorionic villi connecting to the maternal vessels.

Chorionic artery: An image showing the chorionic villi and the maternal vessels.

During the primary stage (the end of fourth week), the chorionic villi are small, nonvascular, and contain only the trophoblast. During the secondary stage (the fifth week), the villi increase in size and ramify, while the mesoderm grows into them; at this point the villi contain trophoblast and mesoderm.

During the tertiary stage (fifth to sixth week), the branches of the umbilical vessels grow into the mesoderm; in this way, the chorionic villi are vascularized. At this point, the villi contain trophoblast, mesoderm, and blood vessels.

Embryonic blood is carried to the villi by the branches of the umbilical arteries. After circulating through the capillaries of the villi, it is returned to the embryo by the umbilical veins. Chorionic villi are vital in pregnancy from a histomorphologic perspective and are, by definition, products of conception.

Placenta

The placenta is a fetally derived organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother’s blood supply. The placenta begins to develop upon implantation of the blastocyst into the maternal endometrium.

The placenta functions as a fetomaternal organ with two components: the fetal placenta (chorion frondosum), which develops from the same blastocyst that forms the fetus; and the maternal placenta (decidua basalis), which develops from the maternal uterine tissue.

The outer layer of the blastocyst becomes the trophoblast, which forms the outer layer of the placenta. This layer is divided into two further layers: the underlying cytotrophoblast layer and the overlying syncytiotrophoblast layer.

The latter is a multinucleated, continuous cell layer that covers the surface of the placenta. It forms as a result of the differentiation and fusion of the underlying cytotrophoblast cells, a process that continues throughout placental development. The syncytiotrophoblast (otherwise known as syncytium) thereby contributes to the barrier function of the placenta.

This is a color image illustrating the placenta and chorionic villi. The umbilical cord is seen connecting the fetus to the placenta.

Placenta: Image illustrating the placenta and chorionic villi. The umbilical cord is seen connected to the fetus and the placenta.

Gastrulation

Embryo
Embryo

Like many other phases of embryological development, gastrulation is a complex, biochemically dependent process by which the bilaminar embryo acquires a third layer to become a trilaminar disc. It is not uncommon to hear some individuals refer to the embryo as a gastrula during this developmental phase. During this process, the embryo also develops axial inclination. This process also contributes significantly to the morphological changes that the embryo will go through in order to acquire a human shape.

Steps and processes

Gastrulation begins when a linear region of cells of the epiblast layer become thicker at the caudal aspect of the embryo. This primitive (Spemann’s) streak develops as epiblast cells replicate and migrate to the midline of the bilaminar disc under the influence of nodal. Nodal is a transformation growth factor β (TGF β) protein that not only initiates, but also maintains the primitive streak. The streak is comprised of totipotent stem cells from the epiblast that grow in a caudocranial manner. As cells are added to the caudal end of the primitive streak, the cranial end begins to enlarge and forms a primitive (Hensen’s) node.

The primitive node (and streak) is maintained by the hepatocyte nuclear factor 3β (HNF-3 β; a product of the FOXA2 gene). The presence of this protein is also crucial for the formation of forebrain and midbrain structures as well. Simultaneously, a slender depression develops within the streak that is continuous with the sunken area at the primitive node (i.e. the primitive groove and primitive pit, respectively). The establishment of these structures allow identification of the cranial (near the primitive node) and caudal (towards the tail of the primitive streak) poles of the embryo. It also facilitates the identification of the left and right sides, as well as dorsal and ventral surfaces of the embryo.

Germ layers

Formation

The cells of the primitive streak synthesize and secrete fibroblast growth factor 8 (FGF8). FGF8 downregulates the expression of E-cadherin, which is intended to promote cellular adhesion. As a result, epiblast cells that have lost their adhesion molecules will subsequently undergo invagination. Not only does this give rise to the previously described depressions (primitive groove and pit), but it also results in migration of epiblast cells between the epiblast and the hypoblast layers. These cells lose their tall columnar appearance and become loosely arranged spindle-shaped cells suspended in collagenous reticular fibers known as mesenchyme. The mesenchyme is made up of pluripotent cells that will provide structural support for the embryo. They also have the ability to differentiate into osteoblasts, chondroblasts, and fibroblasts, in addition to participating in vasculogenesis and angiogenesis.

FGF8 stimulates the expression of another protein, called Bachyury T, which regulates the transformation of other mesenchyme cells to the middle embryonic layer known as the mesoderm. As other epiblast and primitive streak cells migrate deeper, they eventually displace cells of the hypoblast to form the embryonic endoderm. The cells remaining in the epiblast are subsequently referred to as the ectoderm. Therefore, all three germ layers of the gastrula are epiblast derivatives. The mesoderm will eventually separate the ectoderm from the endoderm, except at the points where the two layers are fused (i.e. caudally at the cloacal membrane, and cranially at the prechordal plate). The cloacal membrane is a circular structure that marks the future location of the anus. On the other hand, the prechordal plate gives rise to the oropharyngeal membrane (also a bilaminar region), which will form the future mouth and pharynx.

Function

The three germ layers are responsible for forming all tissues within the body. The fate of each layer is as follows:

  • The embryonic ectoderm, which is located on the dorsal surface of the embryo, is subdivided into neural ectoderm and surface ectoderm. The neural ectoderm will give rise to the sensory organs (eyes, internal ears). It also subdivides into the neural tube (which will form the brain and spinal cord) and the neural crest (which differentiates into the head mesenchyme and the peripheral nervous system). The surface ectoderm develops into the epidermis.
  • Embryonic mesoderm is a bit more diverse and gives rise to paraxial, intermediate, and lateral plate mesoderm. The lateral plate mesoderm has cardiac, haematological, vascular, and smooth muscle fates. It also gives rise to the spleen, lymphatics, and adipose tissue. Intermediate mesoderm is responsible for the formation of the lower urinary tract, kidneys, and the reproductive system.  The paraxial mesoderm first form somites. The somites then differentiate into the rigid structural components of the body (i.e. bone, ligaments and tendons, cartilage and skeletal muscle). They also give rise to the dermis.
  • The embryonic endoderm gives rise to the aero-digestive epithelium, as well as the glandular cells of the gastrointestinal tract and its associated organs. The lungs, thymus, thyroid, and prostate glands are also derived from endoderm.

Primitive streak cells continue to migrate and differentiate into mesoderm up until the beginning of the 4th gestational week. As mesoderm production declines, the primitive streak also begins to regress, becoming a small structure in the sacrococcygeal part of the embryo. Eventually, it completely disappears by the end of week 4.

Notochord formation

Steps and processes

As the primitive node and streak are formed, invaginating mesodermal cells migrate cranially through the structure. They become prenotochordal cells that travel cranially towards the prechordal plate, in the midline. The primitive pit then projects into the notochordal process, giving rise to the notochordal canal. The notochordal process is now a tubular structure occupying the space between the primitive node to the prechordal plate. The prenotochordal cells of the notochordal process interdigitate with the cells of the hypoblast layer, prior to the invasion of the endoderm. The fused layer subsequently becomes perforated, allowing communication between the notochordal canal and the umbilical vesicle. As these perforations coalesce, the floor of the notochordal canal is lost. This is followed by flattening of the remaining notochordal process to form the notochordal plate.

Proliferation of the notochordal cells at the cranial end of the notochordal plate results in infolding of the tubular structure. Subsequently, a solid cord of cells that is definitively the notochord arises. At the area where the primitive pit descends into the epiblast, the notochordal canal persists; giving rise to a neurenteric canal that provides temporary communication between the amniotic cavity above and the umbilical vesicle below. This communication is obliterated as the notochord detaches from the endoderm.

The notochord projects from the primitive node to the oropharyngeal membrane. As the primitive streak extends caudally, the notochord also follows. Therefore, a craniocaudal growth pattern of the notochord is observed. Also, note that at this stage of development, prechordal mesoderm arises from neural crest cells, just rostral to the notochord. Therefore, the cloacal and oropharyngeal membranes are the only bilaminar regions of the embryo that remain. Notochordal migration is also associated with movement of pluripotent mesoderm that also move cranially, bilaterally with respect to the notochord process and prechordal plate. Once they have established a cranial position in the cardiogenic area of the embryo, the heart primordium is formed from the cardiogenic mesoderm by the end of week 3.

Functions of the notochord

The functions of the notochord in the development of the embryo are as follows:

  • It defines the primitive longitudinal axis of the embryo.
  • It provides some rigidity to the fragile developing human.
  • It contributes to the formation of the intervertebral discs. Fragments of the notochord persist into adulthood as the nucleus pulposus of the intervertebral disc.
  • It plays an important role in the formation of the axial musculoskeletal system.
  • It is important in the development of the central nervous system.

Neural tube development

Steps and processes

Not only does the notochord influence the epiblast to migrate and form the two deeper layers, but it also stimulates regions of the ectoderm to form the neural plate. This thick, elongated area of epithelial cells is a midline structure is adjacent to the midline and is superficially related – and equal in length – to the notochord. Growth of the notochord corresponds with an increase in width of the neural plate. The plate also grows cranially and meets the oropharyngeal membrane until it eventually outgrows the notochord. There is a prominent invagination along the long axis of the neural plate called the neural groove.

Development of the Notochord
Development of the notochord

There are raised neural folds on either side of the groove that appear more pronounced at the cranial pole; indicating early brain development has commenced. Inward migration and subsequent fusion of the neural folds occur as the third week comes to a close. The neural plate has now become a neural tube, which serves as the primitive spinal cord and brain vesicles. Some neural crest cells that were not incorporated in the neural tube transform from epithelium to mesenchyme, after which they move away from the fusing neural folds. The underlying neural tube separates from the ectoderm and the non-neural edges of the ectoderm fuse to close the dorsum of the embryo; forming the epidermis.

During the closure of the neural tube, there is dissociation of some underlying neuroectodermal cells at the inner border of the folds. The neural crest cells completely separate from both the surface ectoderm and neural tube during this migration process. They aggregate as flat, irregular cells known as the neural crest that lies between the neural tube and surface ectoderm. The neural crest divides into left and right halves and migrates laterally, to the dorsal region of the embryo (relative to the neural tube).

Functions

They then develop into sensory ganglia of cranial (CN V, VII, IX, and X) and spinal (dorsal root) nerves. Other structures that are derived from the neural crest include, but are not limited to:

  • Neurilemma sheaths of peripheral nerves
  • Leptomeninges of the arachnoid mater and pia mater
  • Pigment cells
  • The medulla of the suprarenal glands

Importantly, the neural tube contributes significantly to lateralization. The floor of the neural tube expresses the LEFTY protein on the left side of the embryo. Studies suggest that it restricts crossing over of left-sided signals to the right.

Lateralization and body axis formation

While the human body has some amount of symmetry to it (with several organs being paired; each occurring on one side of the body), there are other organs that possess a certain degree of asymmetry and only exist on one side. Lateralization refers to the establishment of left and right sidedness of the body. It occurs as a result of particular genes only being expressed on the left side, and others being silenced on the right.

These events begin prior to the gastrulation phase. The activity of anterior visceral endoderm (AVE) is an example of axial development that precedes gastrulation. The AVE is located at the cranial aspect of the embryonic disc and is integral in the formation of the head. It regulates the expression of LIM homeobox 1 (LHX1), homeobox expressed in ES cells 1 (HESX1), and orthodenticle homeobox 2 (OTX2); which, along with other factors establish the cranial region of the disc. The protein nodal (mentioned previously) also stimulates the production of other gene products that help to define the dorsoventral mesoderm, as well as other cranial and caudal structures.

Bone morphogenetic protein 4 (BMP4) also works in conjunction with fibroblast growth factors to shift mesodermal cells to the ventral region of the body cavity. This ensures that structures such as the body wall mesoderm, blood mesoderm (arising from lateral plate mesoderm) and the kidneys (originating from intermediate mesoderm) will be formed in the ventral area. The impact of BMP4 on the mesoderm is regulated by other genes (noggin, follistatin and Goosecoid) expressed in the primitive node; otherwise, all mesodermal structures would be ventralized.

The Bachyury T gene also participates in the formation of dorsal mesoderm in both the midline and tail region of the embryo. Its gene products are transcription factors that bind to DNA binding domains (T-box), which aid in dorsal and caudal mesoderm formation.

Earlier it was mentioned that nodal is important for the formation of the primitive node and streak. Additionally, these structures also secrete the nodal protein under the influence of FGF8, but only of the embryo’s left side. This is an important factor in the lateralization process. FGF8 induced nodal expression also persists later in embryonal development in the lateral plate mesoderm in addition to the LEFTY-2 (left-right determination factor 2) protein. Both LEFTY-2 and nodal proteins work synergistically to upregulate the expression of another homeobox transcription factor, PITX2 (paired like homeodomain 2) that aids in defining left sidedness. It should be noted that organs found predominantly on the left side of the body (i.e. the primordia of the gut, stomach, heart) are particularly exposed to these left sided proteins.

Allantois

By the 16th day of gestation, an outpouching extending from the wall of the umbilical vesicle that is adjacent to the connecting stalk develops. This diverticulum is referred to as the allantois. In humans, it is a rudimentary structure that may be linked to pathological processes of the urinary bladder.

The allantoic mesoderm spreads out deep to the chorion and expresses vasculogenic potential; giving rise to the umbilical artery that will supply the placenta (the umbilical vein arises from another source). Proximally, the allantois persists throughout development as the urachus. This structure connects the urinary bladder to the anterior abdominal. In adults, the urachus is known as the median umbilical ligament.

Medial umbilical ligament
Medial umbilical ligament

Somite formation

Primitive node tissues are also responsible for the formation of paraxial mesoderm. These are longitudinal blocks of cells that are medially related to the intermediate mesoderm. For completion, the lateral mesoderm is lateral to the intermediate mesoderm, but medial to the extraembryonic mesoderm of the umbilical vesicle and amnion. Under the influence of forkhead transcription factors (FoxC1 and FoxC2), along with NOTCH and HOX genes, condensation and conformational changes of the paraxial mesoderm cells at the end of week three gives rise to paired cube-like bodies of cells called somites.

This development takes place craniocaudally – thanks to the Delta-Notch signalling pathway – on either side of the neural tube. By week four, the embryo will enter the somite period, where around 38 pairs of somites can be observed. This number increases to about 44 pairs by the end of week 5. Somites are unique because they produce marked elevations on the dorsal surface of the embryo. Their prominence also aids in aging the embryo during the fourth and fifth gestational weeks.

Intraembryonic coelom

coelom refers to a body cavity. Therefore the intraembryonic coelom is the primitive body cavity within the embryo. Initially, they appear as solitary coelomic spaces in the lateral and cardiogenic mesoderm layers. Subsequent fusion of the spaces forms a solitary, horseshoe-like space that partitions the lateral mesoderm into two layers:

  • The splanchnic lateral mesoderm is the visceral layer that is adjacent to the endoderm layer and communicates laterally with the extraembryonic mesoderm of the umbilical vesicle. Together, the two structures will form the splanchnopleure; which is the embryonic gut.
  • The somatic lateral mesoderm is the parietal layer that is just deep to the ectoderm and communicates laterally with the extraembryonic mesoderm of the amnion. The two layers combine to form the somatopleure; also known as the embryonic body wall.

The intraembryonic coelom undergoes further division from the 5th gestational week, onwards. At that time, it is divided into the pericardial cavityperitoneal cavity, and the pleural cavities.

Primitive cardiovascular system

The conversion of a bilaminar embryonic disc to a trilaminar one reduces the efficacy of diffusion as the principal mode of nutrient delivery to the developing cells. Consequently, during the third week, the embryo initiates a more efficient mechanism for nutrient transport and waste disposal. Blood vessels arise by two major mechanisms: vasculogenesis and angiogenesis. The former refers to the formation of new blood vessels via a de novo pathway (i.e. induction and assembly of angioblasts). The latter, however, speaks to the formation of new blood vessels by budding from previously formed vessels. The development of blood itself is referred to as hematogenesis.

Blood and blood vessel formation

Fibroblast growth factor 2 (FGF2) is the primary instigator for vasculogenesis. By binding to fibroblast growth factor receptors (FGFR) on mesoderm, it induces their differentiation into hemangioblasts. These pluripotent cells then aggregate in the yolk sac and give rise to blood islands. With the action of vascular endothelial growth factor (VEGF) acting on vascular endothelial growth factor receptors (VEGF-R2), hemangioblasts eventually differentiate into endothelial cells. VEGF then acts on VEGF-R1 in order to stimulate the characteristic tubular arrangement of the endothelial cells in the blood vessels.The hemangioblasts that did not contribute to vasculogenesis will have one of two options:

  • The peripheral cells can give rise to angioblasts that will participate in angiogenesis.
  • Centrally located cells can become hematopoietic stem cells that will differentiate into all blood cells.

Vasculogenesis commences in the extraembryonic mesoderm of the connecting stalk, umbilical vesicle and chorion. It is followed briskly by embryonic vasculogenesis.

Primitive heart formation

As the blood and blood vessels begin to form, there is a concomitant establishment of the cardiogenic area. A pair of longitudinal tubes with endothelium called the endocardial heart tubes are formed during this time. They eventually fuse to form the primordial heart tube. It merges with embryonic and extraembryonic blood vessels to establish the primordial cardiovascular system. In most cases, heartbeats commence at the end of week three, making the heart the first functional organ of the embryo. However, this heartbeat is not readily appreciated until the 5th week of gestation.

Chorionic villi

The primary chorionic villi first appear as the 2nd week ended. Following this event, they are invaded by mesenchymal tissue as they began to arborize. The now secondary chorionic villi extend across the entire chorionic sac. These mesenchymal cells also have vasculogenic and hematogenic potential and subsequently differentiate into capillaries and blood cells. Once the blood vessels become visible, the structures are called tertiary chorionic villi. There is subsequent fusion of the capillaries that gives rise to the arterio-capillary network. These networks will eventually communicate with the primordial heart tube by the end of week . Fetomaternal exchange of nutrients and waste material can now be facilitated at the villous interface instead of the previous diffusion gradients. The trophoblast also continues to grow such that proliferation of the cytotrophoblast results in projection of the villi through the syncytiotrophoblast. This gives rise to an extravillous cytotrophoblastic shell that encircles the chorionic sac and further embeds into the endometrium.

Gross morphological changes of the embryonic disc

Not only does the embryonic disc now have three layers, but it has also increased in length and (in some areas) width. The previously flat circular disc elongates and becomes broad at the cephalic pole, but slender at the caudal region. The increased width at the cephalic end is attributed to the constant cellular migration to this area.

Trilaminar Embryo
Trilaminar embryo

The invagination migration sequence occurring at the primitive streak continues to progress into the 4th gestational week. It is interesting to note that while there is cessation of gastrulation cranially, the process persists in the caudal region. This phenomenon is related to the fact that cellular specialization in the cranial region precedes that same process caudally. Therefore, the primitive streak continues to undergo growth and promote gastrulation in the caudal segment of the embryo.

References

 

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Trophoblast Development – Anatomy, Mechanism

Trophoblast Development/Week 2 is often referred to as the week of twos. It’s the week when the embryoblast, extraembryonic mesoderm and trophoblast each separate into two distinct .

Trophoblast Development

Trophoblasts are the outer layer of cells that provide nutrients to the embryo and form part of the placenta.

Key Points

The trophoblast is subdivided into two layers, the inner cytotrophoblast, which proliferates upon implantation, and the outer syncytiotrophoblast, which supports cytotrophoblast proliferation through contact with the maternal blood.

The cytotrophoblast, at the edges of the villi in the placenta, further differentiates into extravillous trophoblasts, which penetrate into the uterus and attach to the placenta and the mother to promote placental vasculature.

Some trophoblasts replace endothelial cells in the uterine spiral arteries and remodel them into wide-bore conduits that are independent of maternal vasoconstriction. This ensures the fetus receives a steady supply of blood, and that the placenta is not sensitive to damaging fluctuations in oxygen.

Key Terms

  • decidualization: The changes in the endometrial lining after ovulation, characterized by its transformation into a secretory lining in preparation to accept an embryo.
  • extravillous trophoblast: These grow out from the placenta and penetrate into the decidualized uterus.
  • trophoblast: The membrane of cells that forms the wall of a blastocyst during early pregnancy, and also provides nutrients to the embryo and later develops into part of the placenta.

Trophoblasts

Trophoblasts (from the Greek words trephein, to feed, and blastos, germinator) are cells that form the outer layer of a blastocyst. These cells provide nutrients to the embryo and develop into a large part of the placenta.

They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg. This layer of trophoblasts is also collectively referred to as the trophoblast, or, after gastrulation, the trophectoderm, as it is then contiguous with the ectoderm of the embryo.

Trophoblast Function

Trophoblasts play an important role in embryo implantation and interaction with the endometrium of the maternal uterus following decidualization. The trophoblast is composed of two layers: an inner cytotrophoblast and an outer syncytiotrophoblast.

The syncytiotrophoblast is non-proliferative and thus relies on fusion of the underlying cytotrophoblast cells to expand. The syncytiotrophoblast are the cells in direct contact with the maternal blood that reaches the placental surface, and thus facilitates the exchange of nutrients, wastes, and gases between the maternal and fetal systems.

Cytotrophoblast in the tips of villi can differentiate into another type of trophoblast called the extravillous trophoblast. Extravillous trophoblasts grow out from the placenta and penetrate into the decidualized uterus.

This process is essential not only for physically attaching the placenta to the mother, but also for altering the vasculature in the uterus to allow it to provide an adequate blood supply to the growing fetus as pregnancy progresses.

Some of the trophoblast even replaces the endothelial cells in the uterine spiral arteries as they remodel these vessels into wide bore conduits that are independent of maternal vasoconstriction. This ensures the fetus receives a steady supply of blood, and the placenta is not sensitive to fluctuations in oxygen that could cause it damage.

This is a drawing of the extraembryonic coelom or chorionic cavitiy It depicts a blastocyst embedded in the uterine decidua. Also identified are the amniotic cavity, blood clot, body stalk, embryonic ectoderm, entoderm, mesoderm, maternal vessels, trophoblast, uterine epithelium, uterine glands, and yolk-sac.

Extraembryonic coelom or chorionic cavitiy: A blastocyst embedded in the uterine decidua. (am. Amniotic cavity, b.c. Blood clot., b.s. Body stalk., etc Embryonic ectoderm, ent. Entoderm., mes. Mesoderm, m.v. Maternal vessels., tr. Trophoblast., u.e. Uterine epithelium, u.g. Uterine glands., y.s. Yolk-sac.)

Clinical Example

Intrauterine growth restriction (IUGR) can result in an undersized fetus with poor organ development or even death. The primary factor in IUGR is placental dysfunction caused by a failure of the extravillous trophoblasts to penetrate and modify the uterine spiral arteries. The result is a poorly-oxygenated environment and reduced fetal growth.

Bilaminar Embryonic Disc Development

The floor of the amniotic cavity is formed by the embryonic disc.

Key Points

In humans, the formation of the embryonic disc occurs after implantation and prior to embryonic folding (between about day 14 to day 21 post-fertilization).

The embryonic disc is derived from the epiblast layer, which lies between the hypoblast layer and the amnion. The epiblast layer is derived from the inner cell mass.

The formation of the bilaminar embryonic disc precedes gastrulation.

Key Terms

  • optic disc: The location where ganglion cell axons exit the eye to form the optic nerve.
  • bilaminar: Formed of, or having, two laminae, or thin plates.

The floor of the amniotic cavity is formed by the embryonic disc, which is composed of a layer of prismatic cells and the embryonic ectoderm. It is derived from the inner cell mass and lies adjacent to the endoderm.

In humans, the formation of the embryonic disc occurs after implantation and prior to embryonic folding (between about day 14 to day 21 post-fertilization). The embryonic disc is derived from the epiblast layer, which lies between the hypoblast layer and the amnion. The epiblast layer is derived from the inner cell mass.

Embryonic Disc Development

A drawing of a rabbit embryo that identifies the embryonic disc and the primitive streak on it.

Surface view of a rabbit embryo: A drawing of a rabbit embryo that identifies the embryonic disc and the primitive streak (arg—embryonic disc; pr—primitive streak).

The embryonic disc forms during early development. By the blastocyst stage, the embryo is a hollow ball of cells with the inner cell mass (embryoblast) off to one side, and the blastocystic cavity fills the remainder of the sphere.

As the embryo progresses in implantation, a small space appears in the embryoblast and forms the amniotic cavity. Simultaneously, morphological changes occur in the embryoblast that result in the formation of a flat, almost circular bilaminar plate of cells that include the epiblast and the hypoblast—the embryonic disk.

The epiblast forms the floor of the amniotic cavity and is continuous with the amnion. The hypoblast forms the roof of the exocoelomic cavity and is continuous with the thin exocoelomic membrane.

The formation of the bilaminar embryonic disc precedes gastrulation. As gastrulation progresses, the embryonic disc becomes trilaminar and the notochord is formed. Through the process of neurulation, the notochord induces the formation of the central nervous system in the embryonic disc.

Amnion Development

The amnion contains the fluid that cushions and protects the fetus.

Key Points

In humans, the amnion is present in the earliest observed embryonic stage, appearing as a cavity within a mass of cells.

The amniotic cavity is roofed in by a single stratum of flattened, ectodermal cells, called the amniotic ectoderm, while the floor is composed of the prismatic ectoderm of the embryonic disk.

Outside the amniotic ectoderm, a thin layer of mesoderm is connected by the body stalk with the mesodermal lining of the chorion.

By approximately the fourth to fifth week, amniotic fluid (liquor amnii) begins to accumulate in the amnion, which increases in quantity and expands to contact the chorion.

During the later stages of pregnancy, the amniotic fluid allows easier and more fluid movements of the fetus and diminishes the risk of injury.

Key Terms

  • amniotic fluid: In placental mammals, a fluid contained within the amnion membrane that surrounds a developing embryo or fetus (also called liquor amnii).
  • embryonic disk: The floor of the amniotic cavity is formed by the embryonic disk (or disc), which is composed of a layer of prismatic cells.
  • amnion: The innermost membrane of the fetal membranes of reptiles, birds, and mammals; the sac in which the embryo is suspended.
  • chorion: One of the membranes that exist during pregnancy between the developing fetus and mother.

This is a cutaway drawing showing a human fetus in a womb. The fetus is seen enclosed within the amnion.

Amnion: The human fetus is enclosed within the amnion.

The amnion is a closed sac appearing in the inner cell mass as a cavity. This cavity is roofed in by a single stratum of flattened, ectodermal cells called the amniotic ectoderm. Its floor consists of the prismatic ectoderm of the embryonic disk.

The continuity between the roof and the floor is established at the margin of the embryonic disk. Outside the amniotic ectoderm is a thin layer of mesoderm (continuous with that of the somatopleure), which is connected by the body stalk with the mesodermal lining of the chorion.

When first formed, the amnion is in contact with the body of the embryo, but by about the fourth or fifth week, amniotic fluid (liquor amnii) begins to accumulate within it. This fluid increases in quantity, causing the amnion to expand and ultimately to adhere to the inner surface of the chorion so that the extra-embryonic part of the coelom is obliterated.

This increase continues up to the sixth or seventh month of pregnancy, after which it diminishes somewhat. At the end of pregnancy, it amounts to about one liter.

The amniotic fluid allows some free movement for the fetus during the later stages of pregnancy and also diminishes the risk of injury. It contains less than two percent solids, and consists mainly of urea and other extractives, inorganic salts, a small amount of protein, and, frequently, a trace of sugar.

Note: That some of the liquor amnii is swallowed by the fetus is proved by the fact that epidermal debris and hairs have been found among the contents of the fetal alimentary canal.

Yolk Sac Development

The yolk sac is vascularized and contributes nutrients to the embryo.

Key Points

The yolk sac is the earliest visible portion of the gestational sac and is situated on the ventral portion of the embryo, arising from extra-embryonic endoderm.

The blood to and from the yolk sac is conveyed via the primitive aorta and vitelline circulation.

At approximately the end of the fourth week, the yolk sac is connected to the primitive digestive system, which allows the yolk sac to contribute nutrients to the embryo.

Key Terms

  • yolk sac: A membranous sac attached to an embryo that provides early nourishment in the form of yolk in bony fishes, sharks, reptiles, birds, and mammals. It functions as the developmental circulatory system of the human embryo before internal circulation begins.
  • vitelline circulation: The system of blood flowing from the embryo to the yolk sac and back again.
  • gestational sac: The gestational sac (or gestation sac) is the only available intrauterine structure that can be used to determine if an intrauterine pregnancy (IUP) exists until the embryo is identified.
  • Heuser’s membrane: Also called the exocoelomic membrane, it is a short lived combination of hypoblast cells and extracellular matrix.
  • mesenchyme: A type of tissue characterized by loosely associated cells that lack polarity and are surrounded by a large extracellular matrix.

The yolk sac is the first element seen in the gestational sac during pregnancy. In humans, it is usually visible at five weeks of gestation. Identifying a true gestation sac is a critical landmark, and is reliably seen in early pregnancy through ultrasound. The yolk sac, situated on the ventral aspect of the embryo, is lined by extra-embryonic endoderm, outside of which is a layer of extra-embryonic mesenchyme derived from the mesoderm.

Blood is conveyed to the wall of the sac by the primitive aorta. After circulating through a wide-meshed capillary plexus, it is returned by the vitelline veins to the tubular heart of the embryo. This vitelline circulation absorbs nutritive material from the yolk sac that is conveyed to the embryo.

The yolk sac is a membranous sac attached to the embryo that provides nourishment in the form of yolk. In this drawing the yolk sac is off to the right side of the amnion, heart, and body stalk.

Yolk sac: The yolk sac is a membranous sac attached to the embryo that provides nourishment in the form of yolk.

At the end of the fourth week, the yolk sac has the appearance of a small, pear-shaped vesicle (umbilical vesicle) opening into the digestive tube by a long, narrow tube, the vitelline duct. The vesicle can be seen in the afterbirth as a small, somewhat oval-shaped body whose diameter varies from 1 mm to 5 mm. It is situated between the amnion and the chorion and may lie on or at a varying distance from the placenta.

As a rule, the vitelline duct undergoes complete obliteration during the seventh week. In about 2% of the cases, its proximal portion persists as a diverticulum from the small intestine (Meckel’s diverticulum), which is situated about 60 cm proximal to the ileocecal valve. It may be attached by a fibrous cord to the abdominal wall at the umbilicus. Sometimes, a narrowing of the lumen of the ileum is seen opposite the site of attachment of the duct.

The yolk sac starts forming during the second week of embryonic development, at the same time of the shaping of the amniotic sac. The hypoblast starts proliferating laterally and descending. In the meantime Heuser’s membrane, located on the opposite pole of the developing vesicle, starts its upward proliferation and meets the hypoblast.

Sinusoid Development

The sinusoids are capillaries that develop after implantation to allow the exchange of gas and nutrients with the mother.

Key Points

The vitelline veins drain blood from the yolk sac. Portions of the veins above the upper ring become interrupted by the developing liver and broken up by it into a plexus of small capillary -like vessels termed sinusoids.

Sinusoids are found in the liver, lymphoid tissue, endocrine organs, and hematopoietic organs such as the bone marrow and the spleen. Sinusoids found within the terminal villi of the placenta are not comparable to these because they possess a continuous endothelium and complete basal lamina.

The invasion of endometrial sinusoids by the trophoblast
allows maternal blood flow into the trophoblastic lacunae; this forms
uteroplacental blood circulation.

Key Terms

  • sinusoid: Any of several channels through which venous blood passes in various organs.
  • trophoblastic lacunae: Spaces in the early syncytiotrophoblastic layer of the chorion present prior to the development of the villi.
  • vitelline veins: Veins that drain blood from the yolk sac.

The vitelline veins drain blood from the yolk sac. At first, they run upward in front on either side of the intestinal canal and, subsequently, unite on the ventral aspect of the canal. Beyond this, they are connected to one another by two anastomotic branches, one on the dorsal and the other on the ventral aspect of the duodenal portion of the intestine.

Thus, it is encircled by two venous rings. The superior mesenteric vein opens into the middle or dorsal anastomosis. The portions of the veins above the upper ring become interrupted by the developing liver and broken up by it into a plexus of small, capillary-like vessels termed sinusoids.

This is a drawing of the liver and veins of a human embryo, 24 or 25 days old, as seen from the ventral surface. The drawing shows the vitelline veins surrounding the stomach and the connection points of the vitelline veins to the left and right umbilical veins.

Vitelline veins: The liver and veins of a human embryo, 24 or 25 days old, as seen from the ventral surface. (The vitelline veins are visible at the center bottom.)

A sinusoid is a small blood vessel that is a type of capillary similar to a fenestrated endothelium. Sinusoids are actually classified as a type of open pore capillary (that is, discontinuous) as opposed to fenestrated.

Fenestrated capillaries have diaphragms that cover the pores, whereas open pore capillaries lack a diaphragm, having just an open pore. The open pore endothelial cells greatly increase their permeability.

Permeability is also increased by large intercellular clefts and fewer tight junctions. The level of permeability can allow small and medium-sized proteins, such as albumin, to readily enter and leave the blood stream.

Sinusoids are found in the liver, lymphoid tissue, endocrine organs, and hematopoietic organs, such as the bone marrow and the spleen. Sinusoids found within the terminal villi of the placenta are not comparable to these because they possess a continuous endothelium and complete basal lamina.

The invasion of endometrial sinusoids by the trophoblast allows maternal blood flow into the trophoblastic lacunae; this forms the uteroplacental blood circulation.

Development of the Extraembryonic Coelom

The extra-embryonic coelom is a cavity that contains the chorion. It is located between Heuser’s membrane and the trophoblast.

Key Points

The extra-embryonic coelom develops at the same time as the primitive yolk sac through the proliferation and differentiation of hypoblast cells into mesenchymal cells that fill the area between Heuser’s membrane and the trophoblast. The entire structure is enclosed by the chorionic plate.

The extra-embryonic mesoderm is subdivided into two layers: the extra-embryonic splanchnopleuric mesoderm, which is outside the primitive yolk sac; and the extra-embryonic somatopleuric mesoderm, which is adjacent to the cytotrophoblast.

The chorion is one of the membranes that exist during pregnancy between the developing fetus and mother.

Key Terms

  • chorion: The protective and nutritive membrane that attaches higher vertebrate fetuses to the uterus.
  • Heuser’s membrane: Heuser’s membrane (or the exocoelomic membrane) is a short-lived combination of hypoblast cells and extracellular matrix.
  • coelum: Also called the chorionic cavity, this is a portion of the conceptus that consists of a cavity between Heuser’s membrane and the trophoblast.

Development of the Extra-Embryonic Coelom

This is an artificially colored image of the contents in the cavity of the uterus seen at approximately 5 weeks of gestational age by obstetric ultrasonography. It shows the gestational sac, yolk sac, and embryo.

Gestational sac: An artificially colored image of the contents in the cavity of the uterus seen at approximately 5 weeks of gestational age by obstetric ultrasonography.

The extra-embryonic coelom (or chorionic cavity) is a portion of the conceptus consisting of a cavity between Heuser’s membrane and the trophoblast. During the formation of the primitive yolk sac, some of the migrating hypoblast cells transdifferentiate into mesenchymal cells that fill the space between Heuser’s membrane and the trophoblast to form the extra-embryonic mesoderm.

As development progresses, small lacunae begin to form within the extra-embryonic mesoderm that become larger and form the extra-embryonic coelom.

The extra-embryonic mesoderm is divided into two layers: the extra-embryonic splanchnopleuric mesoderm, which lies adjacent to Heuser’s membrane around the outside of the primitive yolk sac; and the extra-embryonic somatopleuric mesoderm, which lies adjacent to the cytotrophoblast layer of the embryo.

The extra-embryonic coelomic cavity is also called the chorionic cavity—it is enclosed by the chorionic plate. The chorionic plate is composed of an inner layer of somatopleuric mesoderm and an outer layer of trophoblast cells. It is the fetal
aspect of the placenta that gives rise to chorionic villi.

Chorion Development

The chorion is one of the membranes that exist during pregnancy between the developing fetus and the mother. It consists of an extra-embryonic mesoderm and two layers of trophoblast and surrounds the embryo and other membranes.

Villi emerge from the chorion, which invade the endometrium, destroy the uterine decidua, and allow the transfer of nutrients from maternal blood to fetal blood.

Chorionic villi are at first small and nonvascular, and consist of only trophoblast, but they increase in size and branch. Blood is carried to the villi by the paired umbilical arteries, which branch into chorionic arteries and enter the chorionic villi as cotyledon arteries.

After circulating through the capillaries of the villi, the blood is returned to the embryo by the umbilical veins. Until about the end of the second month of pregnancy, the villi cover the entire chorion, and are almost uniform in size; but, after this stage, they develop unequally.

2nd weeks

Following all the excitement associated with the first gestational week, the newly formed blastocyst is ready to settle into a supportive environment and continue the growth process. Week 2 is often referred to as the week of twos. It’s the week when the embryoblast, extraembryonic mesoderm and trophoblast each separate into two distinct layers. Additionally, there are two cavities that develop within the embryonic unit at this time as well.

While every step is integral for adequate foetal development, one of the most important features of the second week is the completion of implantation and establishment of fetomaternal interactions. This article will follow the developing embryo through the completion of implantation and development of the non-embryonic components of the conceptus. It will also discuss some complications associated with implantation.

Implantation of the blastocyst

Implantation is a complex biochemical and mechanical process that begins in the first week of gestation and extends into the second week. There are many influencing factors that affect the process. These can be grouped into maternal and embryonal factors. However, both entities work synchronously in order to effectively achieve implantation. The process of implantation can be subdivided into three phases:

  • There is a period of apposition where the blastocyst establishes weak interactions with the uterine wall.
  • The attachment phase occurs when definitive binding of the blastocyst to the uterine epithelium is more established, such that the blastocyst cannot be flushed from the uterine cavity.
  • Finally invasion occurs when the blastocyst begins to burrow into the endometrium.

This period usually occurs between the 19th and 24th day of the menstrual cycle. This coincides roughly with the 6th to 10th day following ovulation.

Maternal factors affecting implantation

In anticipation for successful fertilization each month, the inner uterine wall (endometrium) undergoes a series of changes in order to facilitate the blastocyst. Recall that there are three layers of the endometrium – the strata basalis, spongiosum and compactum.

The deepest layer is the stratum basalis, which functions as the regenerative layer and proliferates to form the stratum spongiosum and stratum compactum. Stratum compactum is the most superficial and the stratum spongiosum resides between the two. Together, the strata compactum and spongiosum form the stratum functionalis; which is the functional layer of the endometrium that facilitates implantation.

The development of the stratum functionalis is mitigated by surges in estrogen (which are released from the maturing ovarian follicle, under the influence of follicle stimulating hormone). If fertilization did not occur during the previous menstrual cycle, the fall in reproductive hormones result in the degeneration of the stratum functionalis. The shedding of this layer during the menstrual phase of the cycle accounts for the vaginal bleeding known as menstruation.

In the subsequent cycle, as follicle stimulating hormone levels rise and stimulate maturation of another ovarian follicle, the resultant increase in estrogen levels leads to proliferation of the stratum basalis. This is known as the proliferative phase, during which time there is thickening of the endometrium. Following an increase in luteinizing hormone and the release of a secondary oocyte, the remaining corpus luteum continues to release estrogen and progesterone to maintain the stratum functionalis. The spiral arteries of the uterus become longer and more tortuous under the influence of the sex hormones.

Endometrium - dorsal view
Endometrium (posterior view)

Following successful fertilization the uterine epithelia, which is characterized by ciliated columnar cells with microvilli, undergoes morphological changes to accommodate the growing embryo. The expression of these cilia (extended processes located at the apical aspect of the cells) is regulated by both progesterone and estrogen. The underlying motile microtubules allow the cilia to move the developing embryo toward a favourable site on the uterine wall. This process usually starts around the end of the first gestational week, when the conceptus is classified as a blastocyst.

The process of bringing the conceptus close to the uterine wall is referred to as adplantation (apposition). As the blastocyst rolls along the surface of the uterus, the pole of the blastocyst with the inner cell mass is adjacent to the uterine wall. Early attachments to the microvilli (short, non-motile, apical epithelial processes) also facilitate the initiation of implantation.

Once the uterine lining is receptive for implantation, the endometrium is said to be in the implantation window. However, this is a complex process that depends on the presence of numerous cytokines, immunomodulators, and increased binding capacity of the epithelium in order for implantation to work. Recall from the first week of gestation that the resulting conceptus is genetically unique when compared with its parents. Therefore, the mother’s immune system should identify the blastocyst as a parasitic entity that should be destroyed.

A key element in the implantation phase that is thought to modify this anticipated immune response (and other parts of implantation) is known as leukaemia inhibitory factor (LIF). This is a member of the interleukin – 6 (IL-6) family that has the ability to influence several unrelated gene expressions (i.e. it’s a pleiotropic entity). Within the reproductive system, it is produced by both the endometrial epithelium as well as the developing blastocyst. Leukaemia inhibitory factor has the following functions with regards to endometrial receptivity:

  • The decidualization of the stromal cells (discussed below) is by LIF. This response is generated by way of a cyclic adenosine monophosphate (cAMP) pathway that activates a biochemical cascade involving estrogen and progesterone, IL-5, IL-6, prostaglandins, and cyclooxygenase 2 (COX-2). The resultant cellular morphological change creates a more favourable implantation environment. This particular reaction is important because it plays a significant role in immunomodulation. It is particularly difficult for thymocytes (T-cells) to invade decidual tissue; similarly, decidual cells have a hard time recruiting T-cells from the percolating blood. Therefore, the probability of the maternal immune system mounting a cytotoxic T-lymphocyte (CTL) response against the allogeneic conceptus is markedly reduced.
  • In addition, LIF upregulates numerous epidermal growth factors such as heparin – binding epidermal growth factor like protein (HB-EGF), epiregulin (EPR), and amphiregulin (AREG). These proteins act as ligands for the epidermal growth factor receptors and subsequently stimulate the proliferation of the endometrial epidermis.
  • LIF also stimulates the activity of implantation genes, including members of the Wnt family (Wnt 4, 5a, and others) and MutS homolog homebox 1 gene (MSX 1). These and other implantation genes result in differentiation of the luminal and glandular epithelia (decidualization), proliferation of the stromal cells, and decrease in the polarity of the epithelium to foster adhesion.
  • Uterodomes (also known as pinopods) are micro-protrusions of the luminal surface of the uterine epithelium that interdigitate with the blastocyst during adplantation and attachment. While they are present throughout the luteal phase of the menstrual cycle, they increase in number under the influence of LIF. In lower other mammals, pinopods are thought to play a significant role in pinocytosis (cell drinking). However, this is not its primary role in humans. As a result, they are referred to as uterodomes based on their appearance.
  • Under normal circumstances, the luminal surface of the uterus is coated with a thick layer of glycocalyx. This is a carbohydrate, glycoprotein rich layer that promotes repulsion of foreign entities from the cell membranes. It also has a large quantity of mucins (MUC-1 and MUC-4). LIF mediates significant local downregulation of MUC-1 in the area of the epithelium adjacent to the hatched blastocyst, which reduces repulsion of the blastocyst. However, relatively high levels of mucins are normally present in unfavourable implantation sites to prevent attachment.
  • Finally, the presence and activity of a member of the junctional adhesion molecule family (JAM-2) is also noted to be increased within the uterus during the 1st to 2nd gestational weeks. Junctional adhesion molecules have the ability to interact within the family (i.e. JAM-JAM binding) as well as with other integrins on non-uterine cells. They therefore promote cellular attachment to the epithelial membrane. Both LIF and progesterone have been shown to upregulate the expression of these adhesion molecules.

As mentioned earlier, the luminal uterine stroma undergoes morphological transformation under the influence of LIF, estrogen and progesterone. This process – known as decidualization – involves accumulation of lipids and glycogen at a cellular level. The cells (i.e. decidual cells) subsequently acquire a polyhedral shape (as opposed to their previous columnar appearance). The process begins locally at the site of fetomaternal attachment, but gradually radiates until the entire endometrium has been transformed. On a molecular level, bone morphogenetic protein 2 (BMP-2) is needed for this transformation to occur; its deficiency is a known cause of infertility. The decidua provides an immunologically safe space for the embryo, in addition to providing nutrition for its development.

Fetal factors affecting implantation

As the blastocyst is hatched from the zona pellucida, it comes into contact with the endometrium. Surface proteins on the trophoblast known as trophinin interact with similar trophinin molecules on the endometrial surface. This plays a role in the differentiation of the trophoblast into two distinct layers:

  • In the periphery, there are multinucleated cells that have no discernible cell walls. This area is referred to as the syncytiotrophoblast. There is no mitotic activity in this area.
  • Deep to the syncytiotrophoblast is a cluster of mitotically active cells known as the cytotrophoblast. This cluster of cells rapidly replicates and migrates to the periphery in order to support the growing syncytiotrophoblast.

Of note, by the end of week 2, the bilaminar disc develops a localized region of thickened cells in the hypoblast. This area is referred to as the prechordal plate. Not only does the prechordal plate help with the organization of the head region during development, but it also indicates the future head region and the location of the mouth.

The syncytiotrophoblast is a highly invasive structure that penetrates the endometrium in order for the blastocyst to become embedded. The trophinin-trophinin binding also induces endometrial epithelial apoptosis in the mother in order to accommodate the invading cell mass. The blastocyst then utilizes the nutrients from the recently destroyed maternal cells as it continues to grow. Furthermore, the syncytiotrophoblast (under the influence of LIF) begins to produce human chorionic gonadotropin hormone (β-hCG). The presence of β-hCG prevents corpus luteum degeneration, resulting in the continued release of estrogen and progesterone. The detection of the glycoprotein in maternal circulation and urine also forms the basis of the pregnancy test.

Another recently discovered element that contributes to implantation is the protein preimplantation factor. It is derived from the embryo and has been shown to aid in maternal immunomodulation, embryo-endometrial adhesion, and endometrial apoptosis.

Review of the initial sequence of implantation

Let’s recap the initial implantation sequence:

  • Endometrial development occurs each month in anticipation of successful fertilization.
  • Successful fertilization occurs and the zygote develops into a blastocyst.
  • The blastocyst roles along the endometrium towards a favourable implantation site.
  • Concurrently, there is maternal immunomodulation, downregulation of repelling entities and upregulation of adhesion moieties.
  • The blastocyst hatches from the zona pellucida.
  • Adplantation occurs when weak carbohydrate binding occurs between the embryo and the glycocalyx.
  • As the embryo gets closer to the endometrium, stronger bonds are formed. These involve interactions with integrins, L-selectin, osteopontin, cadherins, trophinin, as well as CD44 and CD98.
  • Attachment stimulates maternal decidualization and embryonal trophoblast differentiation.
  • Trophoblastic invasion coincides with desmosomal detachment of maternal cells, as well as apoptosis of adjacent decidua.
Blastocyst implantation
Blastocyst implantation

Amniotic cavity

While implantation ensues, the embryoblast also undergoes differentiation to form a bilaminar disc. The flat, circular disc is comprised of a thicker epiblast with high columnar cells and a thinner hypoblast with small cuboidal cells. A small space develops relative to the epiblast; it is the precursor of the amniotic cavity.

Epiblastic cells forming the floor of the cavity subsequently separate to form amnioblasts that will form the amnion (surrounding the amniotic cavity). The sac and cavity will eventually become filled with amniotic fluid later on in the pregnancy. They provide shock absorption and facilitate movement of the foetus during development.

Umbilical vesicle

Peripherally, the hypoblast is continuous with another structure known as the exocoelomic (Heuser’s) membrane. It also forms the roof of the enclosed exocoelomic cavity. Combined, the membrane and the hypoblast form the visceral lining of the yolk sac. However, since the human embryo does not possess a yolk, it is more appropriate to refer to it as the primary umbilical vesicle.

Endodermal cells arising from the exocoelomic membrane extends circumferentially to enclose the embryonic disc and both cavities. It is subsequently referred to as the extraembryonic mesoderm. Both cavities facilitate embryonic folding as growth and morphological changes occur. The umbilical vesicle may play a role in nutrient transfer to the embryo. Furthermore, it is an important source of primordial germ cells.

Early fetomaternal circulation

While the aforementioned cavities and bilaminar disc develop, the syncytiotrophoblast began to lacunate (I.e. form lacunae). The lacunae are filled with an amalgam of cellular debris and maternal blood, known as the embryotroph. This fluid gains access to the embryonic disc via diffusion and delivers nutrients as well as oxygen to the embryo. The lacunae subsequently become confluent, forming lacunar networks, which serves as the primordial uteroplacental circulation. As the networks continue to fuse, the syncytiotrophoblast has a sieve-like appearance, particularly around the embryonic pole of the conceptus. This will subsequently give rise to the intervillous spaces of the placenta.

The capillaries around the implanted embryo become engorged, dilated and their walls become thin. From here onwards, they are known as sinusoids. The syncytiotrophoblast continues to erode the walls of the sinusoids, resulting in more maternal blood flowing freely into the lacunar networks. Much of the derived nutrients is conveyed to the embryo by the trophoblast. However, the trophoblast grows a lot faster than the embryo in the early phases. As such, it is likely to have a higher nutritional requirement than the embryo.

Chorionic sac

As time progresses, the extraembryonic mesoderm increases in size. Numerous cavities known as the extraembryonic coelomic spaces begin to appear deep to the cytotrophoblast and superficial to the exocoelomic membrane. These spaces coalesce to form the extraembryonic coelom. This coincides with a decrease in the volume of the primary umbilical vesicle; which is then referred to as the secondary umbilical vesicle. The cells of the secondary umbilical vesicle arise from migratory extraembryonic endodermal cells of the hypoblast. There is a remnant of the primary umbilical vesicle within the extraembryonic coelom that is referred to as an exocoelomic cyst.

Cellular columns, lined with syncytial coverings, extending into the syncytiotrophoblast indicate the ending of the second gestational week. This phenomenon marks the formation of the primary chorionic villi. Splanchnic and somatic derivatives of the extraembryonic mesoderm line the umbilical vesicles, and the trophoblast and amnion, respectively. The somatic extraembryonic mesoderm, along with both trophoblastic layers, gives rise to the chorion. The space enclosed by the chorion is the chorionic sac; it contains the embryo, as well as the amniotic sac and umbilical vesicle. The latter three structures are attached to the chorion by the connecting stalk. The former extraembryonic coelom is now referred to as the chorionic cavity.

Implantation completed

By the 10th day following fertilization, the embryo is completely embedded in the endometrium. There is a small defect in the epithelium that is sealed by a fibrin-based blood clot known as the closing plug. By day 12, the area is completely healed. The 14 day embryo maintains the form of a flat bilaminar embryonic disc at the end of second week. The thickened prechordal plate develops as a localized thickening of hypoblast and indicates the future site of mouth and organizer of the head region.

Summary of 2nd Week

Here is a simplified summary of the events of the second week:

  • The hatched blastocyst moves along the endometrium towards a favourable point of implantation.
  • The endometrium is converted into an immunologically privileged site with optimum blood supply
  • Weak attachments are strengthened.
  • Differentiation of the trophoblast and endometrial stroma facilitate invasion of the endometrium.
  • Several cavities and membranes are formed.
  • β-hCG production is stimulated.
  • Complete implantation with endometrial scarring is achieved by day 10.
  • Complete regeneration around the scar results around day 12.
  • At the end of week 2, the chorionic cavity is formed.

References

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Female Reproductive System

Oogenesis is the maturation of the female gametes through meiotic division.

Key Points

  • Oogenesis starts with the process of developing oogonia via the transformation of primordial follicles into primary oocytes, a process called oocytogenesis.
  • Oocytogenesis is complete either before or shortly after birth in humans. During the menstrual cycle primary oocytes complete maturation through further meiotic divisions.
  • The first meiotic division is coordinated by hormones: follicle-stimulating hormone (FSH), estrogen, luteinizing hormone (LH), and progesterone.
  • The oocyte is arrested in cell division prior to the second meiotic division, which only occurs after fertilization.

Key Terms

  • polar body: A small haploid cell formed concomitantly as an egg cell during oogenesis, but which does not have the ability to be fertilized.
  • ootid: A nearly mature ovum that results from
    meiotic division of a secondary oocyte.
  • luteinizing hormone: A hormone produced by the anterior pituitary gland. In females, an acute rise of LH triggers ovulation and development of the corpus luteum.
  • follicle: A small cavity or sac that is the site of oocyte development in the ovary.
  • follicle-stimulating hormone: A gonadotropic glycoprotein hormone, secreted in part of the pituitary gland that stimulates the growth of ovarian follicles in female mammals and induces spermatogenesis in male mammals.

The menstrual cycle begins with the maturation of oocytes through the process of oogenesis, as well as concurrent follicle development that stimulates ovulation. Oogenesis starts with the process of developing oogonia via the transformation of primordial follicles into primary oocytes, a process called oocytogenesis. Oocytogenesis is complete either before or shortly after birth in humans. During the menstrual cycle primary oocytes complete maturation through further meiotic divisions.

Follicle development signals the beginning of the menstrual cycle. At the start of the menstrual cycle, some 12-20 primary follicles begin to develop under the influence of elevated levels of follicle-stimulating hormone (FSH) to form secondary follicles. The primary follicles form from primordial follicles, which develop in the ovary as a fetus during conception and are arrested in the prophase state of the cellular cycle.

By around day 9 of the menstrual cycle, only one healthy secondary follicle remain. The rest are reabsorbed into the ovary. The remaining follicle, called the dominant follicle, is responsible for producing large amounts of estrogen during the late follicular phase.

On day 14 of the cycle, a luteinizing hormone surge is triggered by the positive feedback of estrogen. This causes the secondary follicle to develop into a tertiary follicle, which then leaves the ovary 24–36 hours later. An important event in the development of the tertiary follicle occurs when the primary oocyte completes the first meiotic division, resulting in the formation of a polar body and a secondary oocyte. The empty follicle then forms a corpus luteum which later releases progesterone to maintain a potential pregnancy.

Immediately after meiosis I, the haploid secondary oocyte initiates meiosis II. However, this process is also halted at the metaphase II stage until fertilization occurs. When meiosis II has completed, an ootid and another polar body is created.

Both polar bodies disintegrate at the end of meiosis II, leaving only the ootid, which eventually develops into a mature ovum. The formation of polar bodies serves to discard the extra haploid sets of chromosomes that have resulted as a consequence of meiosis.

Diagram showing maturation of the ovum, including oogonium, mitosis, primary oocyte, meiosis I, meiosis arrests in prophase I, meiosis I resumes, secondary oocyte, first polar body, second polar bodies, mature ovum.

The Oogenesis Process: Diagram showing maturation of the ovum.

Ovarian Cycle

The menstrual cycle is the physiological process that fertile women undergo for the purposes of reproduction and fertilization.

LEARNING OBJECTIVES

Differentiate among the phases of the menstrual cycle

KEY TAKEAWAYS

Key Points

  • The ovarian cycle refers to the series of changes in the ovary during which the follicle matures, the ovum is shed, and the corpus luteum develops.
  • The follicular phase describes the development of the follicle in response to follicle stimulation hormone ( FSH ). As luteinizing hormone ( LH ) and FSH levels increase they stimulate ovulation, or the release of a mature oocyte into the fallopian tubes.
  • In the luteal phase, the corpus luteum forms on the ovary and secretes many hormones, most significantly progesterone, which makes the endometrium of the uterus ready for implantation of an embryo.
  • If implantation does not occur, the corpus luteum will be degraded, resulting in menstruation.
  • If implantation occurs the corpus luteum is maintained.

Key Terms

  • ischemic phase: The final part of the secretory phase. The endometrium becomes
    pale and arteries constrict due to lower hormone release by the disintegrating corpus
    luteum.
  • granulosa cells: These cells produce
    hormones and growth factors that interact with the oocyte during its
    development.
  • menstrual cycle: The recurring cycle of physiological changes in the females of some animal species that is associated with reproductive fertility.
  • luteal phase: The latter part of the menstrual cycle that occurs after ovulation, in which the corpus luteum secretes progesterone to prepare the endometrium for the implantation of an embryo.
  • follicular phase: The phase of the estrous cycle that involves follicular maturation within the ovary and, controlled by the hormone estradiol.

The menstrual cycle is the scientific term for the physiological changes that occur in fertile women for the purpose of sexual reproduction.The menstrual cycle is controlled by the endocrine system and commonly divided into three phases: the follicular phase, ovulation, and the luteal phase. However, some sources define these phases as menstruation, proliferative phase, and secretory phase. Menstrual cycles are counted from the first day of menstrual bleeding.

The Follicular Phase

The follicular phase (or proliferative phase) is the phase of the menstrual cycle in humans and great apes during which follicles in the ovary mature, ending with ovulation. The main hormone controlling this stage is estradiol. During the follicular phase, follicle-stimulating hormone (FSH) is secreted by the anterior pituitary gland. FSH levels begin to rise in the last few days of the previous menstrual cycle and peak during the first week of the follicular phase. The rise in FSH levels recruits five to seven tertiary-stage ovarian follicles (also known as Graafian or antral follicles) for entry into the menstrual cycle. These follicles compete with each other for dominance.

FSH induces the proliferation of granulosa cells in the developing follicles and the expression of luteinizing hormone (LH) receptors on these granulosa cells. Two or three days before LH levels begin to increase, usually by day seven of the cycle, one or occasionally two of the recruited follicles emerges as dominant. Many endocrinologists believe that estrogen secretion of the dominant follicle increases to a level that indirectly lowers the levels of LH and FSH. This slowdown in LH and FSH production leads to the atresia (death) of most of the recruited follicles, though the dominant follicle continues to mature.

These high estrogen levels initiate the formation of a new layer of endometrium in the uterus. Crypts in the cervix are also stimulated to produce fertile cervical mucus that reduces the acidity of the vagina, creating a more hospitable environment for sperm. In addition, basal body temperature may lower slightly under the influence of high estrogen levels. Ovulation normally occurs 30 (± 2) hours after the beginning of the LH surge (when LH is first detectable in urine).

Ovulation

Ovulation is the phase in which a mature ovarian follicle ruptures and discharges an ovum (also known as an oocyte, female gamete, or egg). Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle. The time immediately surrounding ovulation is referred to as the ovulatory phase or the periovulatory period.

The Luteal Phase

The luteal phase (or secretory phase) is the latter part of the menstrual or estrous cycle. It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis. The main hormone associated with this stage is progesterone, which is significantly higher during the luteal phase than in other phases of the cycle. Some sources define the end of the luteal phase as a distinct ischemic phase.

After ovulation, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow for some time after ovulation and produces significant amounts of hormones, particularly progesterone, and to a lesser extent, estrogen. Progesterone plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy. It also raises the woman’s basal body temperature. The hormones produced by the corpus luteum suppress production of the FSH and LH, causing the corpus luteum will atrophy. The death of the corpus luteum results in falling levels of progesterone and estrogen. This in turn causes increased levels of FSH, leading to recruitment of follicles for the next cycle. Continued drops in estrogen and progesterone levels trigger the end of the luteal phase, menstruation, and the beginning of the next cycle.

The loss of the corpus luteum can be prevented by implantation of an embryo. After implantation, human embryos produce human chorionic gonadotropin (hCG), which is structurally similar to LH and can preserve the corpus luteum. Because the hormone is unique to the embryo, most pregnancy tests look for the presence of hCG. If implantation occurs, the corpus luteum will continue to produce progesterone (and maintain high basal body temperatures) for eight to twelve weeks, after which the placenta takes over this function.

This diagram of the ovarian cycle shows the cortex, primary follicle, developing follicle, ovum, mature follicle, fluid-filled cavity, ruptured follicle, ovulation, corpus luteum, and degenerating corpus luteum.

The ovarian cycle: The ovarian cycle is the series of changes that occur in the ovary during the menstrual cycle that cause maturation of a follicle, ovulation, and development of the corpus luteum.

Uterine (Menstrual) Cycle

The uterine cycle describes a series of changes that occur to the lining of the uterus, or endometrium, during a typical menstrual cycle.

LEARNING OBJECTIVES

Outline the process of the uterine cycle

KEY TAKEAWAYS

Key Points

  • The uterine cycle includes the increase in the endometrium in preparation for implantation and the shedding of the lining following lack of implantation, termed menstruation.
  • Menstrual cycles are counted from the first day of menstrual bleeding.
  • Endometrial thickening is stimulated by the increasing amount of estrogen in the follicular phase.
  • If implantation does not occur, progesterone and estrogen levels drop, which stimulates menstruation.

Key Terms

  • endometrium: The mucous membrane that lines the uterus in mammals, in which fertilized eggs are implanted.
  • menstrual cycle: In the females of some animal species, the recurring cycle of physiological changes associated with reproductive fertility.
  • decidua: A mucous membrane that lines the uterus: it is shed during menstruation and modified during pregnancy.

Several changes to the uterine lining (endometrium) occur during the menstrual cycle, also called the uterine cycle. The endometrium is the innermost glandular layer of the uterus. During the menstrual cycle, the endometrium grows to a thick, blood vessel-rich tissue lining, representing an optimal environment for the implantation of a blastocyst upon its arrival in the uterus. Menstrual cycles are counted from the first day of menstrual bleeding and are typically 28 days long.

During menstruation, the body begins to prepare for ovulation again. The levels of estrogen gradually rise, signalling the start of the follicular, or proliferation, phase of the menstrual cycle. The discharge of blood slows and then stops in response to rising hormone levels and the lining of the uterus thickens, or proliferates. Ovulation is triggered by a surge in luteinizing hormone. The sudden change in hormones at the time of ovulation sometimes causes minor changes in the endometrium and light midcycle blood flow.

After ovulation, under the influence of progesterone, the endometrium changes to a secretory lining in preparation for the potential implantation of an embryo to establish a pregnancy. If a blastocyst implants, then the lining remains as the decidua. This becomes part of the placenta and provides support and protection for the embryo during gestation.

If implantation does not occur within approximately two weeks, the progesterone-producing corpus luteum in the ovary will recede, causing sharp drops in levels of both progesterone and estrogen. This hormone decrease causes the uterus to shed its lining and the egg in menstruation. The cessation of menstrual cycles at the end of a woman’s reproductive period is termed menopause. The average age of menopause in women is 52 years, but it can occur anytime between 45 and 55.

image

The Uterine Cycle: High estrogen and progesterone levels stimulate increased endometrial thickness, but following their decline from a lack of implantation, the endometrium is shed and menstruation occurs.

Normal menstrual flow can occur although ovulation does not occur. This is referred to as an anovulatory cycle. Follicular development may start but not be completed although estrogen will still stimulate the uterine lining. Anovulatory flow that results from a very thick endometrium caused by prolonged, continued high estrogen levels is called estrogen breakthrough bleeding. However, if it is triggered by a sudden drop in estrogen levels, it is called withdrawal bleeding. Anovulatory cycles commonly occur before menopause and in women with polycystic ovary syndrome.

Hormonal Regulation of the Female Reproductive Cycle

The menstrual cycle is controlled by a series of changes in hormone levels, primarily estrogen and progesterone.

LEARNING OBJECTIVES

Differentiate among the phases of the menstrual cycle

KEY TAKEAWAYS

Key Points

  • The follicular phase begins with an increase in follicle -stimulation hormone ( FSH ), which causes increases in luteinizing hormone ( LH ) and gonadotropin-releasing hormone ( GnRH ). Concurrent increases in estrogen levels cause increases in progesterone, stimulating proliferation of the endometrium.
  • A spike in LH and FSH (“LH surge”) causes ovulation, following a suppression of GnRH.
  • Estrogen levels continue to rise following ovulation and the corpus luteum forms, which secretes progesterone in significant levels and causes decreases in LH and FSH levels.
  • Without implantation, estrogen and progesterone levels will fall and the corpus luteum will degrade.

Key Terms

  • estrogen: A hormone responsible for the appearance of secondary sex characteristics of human females at puberty and the maturation and maintenance of the reproductive organs in their functional state.
  • cumulus: A cluster of cells that surround the oocyte both in the ovarian follicle and after ovulation. These cells
    coordinate follicular development and oocyte maturation.
  • progesterone: A steroid hormone secreted by the ovaries that prepares the uterus for the implantation of a fertilized ovum and subsequent pregnancy.
  • theca cells: A group of endocrine cells in the ovary made
    up of connective tissue surrounding the follicle. They provide
    androgen synthesis and signal transduction between granulosa cells
    and oocytes during development.
  • luteinizing hormone surge: Acute rise of LH levels that triggers ovulation and development of the corpus luteum.

The menstrual cycle is the physiological change that occurs under the control of the endocrine system in fertile women for the purposes of sexual reproduction and fertilization.

This chart of the menstrual cycle indicates the follicular phase and luteal phase, basal body temperature, levels of LH, FSH, progesterone, and estrogen, the ovarian cycle, ovum, ovulation, and the menses, proliferative, and secretory phases of the uterine cycle.

The Menstrual Cycle: The menstrual cycle is controlled by the endocrine system, with distinct phases correlated to changes in hormone concentrations.

Phases of the Menstrual Cycle

The menstrual cycle is divided into three stages: follicular phase, ovulation, and the luteal phase.

Follicular Phase

During the follicular phase (or proliferative phase), follicles in the ovary mature under the control of estradiol. Follicle-stimulating hormone (FSH) is secreted by the anterior pituitary gland beginning in the last few days of the previous menstrual cycle. Levels of FSH peak during the first week of the follicular phase. The rise in FSH recruits tertiary-stage ovarian follicles (antral follicles) for entry into the menstrual cycle.

Follicle-stimulating hormone induces the proliferation of granulosa cells in the developing follicles and the expression of luteinizing hormone (LH) receptors on these cells. Under the influence of FSH, granulosa cells begin estrogen secretion. This increased level of estrogen stimulates production of gonadotropin-releasing hormone (GnRH), which increases production of LH. LH induces androgen synthesis by theca cells, stimulates proliferation and differentiation, and increases LH receptor expression on granulosa cells.

Throughout the entire follicular phase, rising estrogen levels in the blood stimulate growth of the endometrium and myometrium of the uterus. This also causes endometrial cells to produce receptors for progesterone, which helps prime the endometrium to the late proliferative phase and the luteal phase. Two or three days before LH levels begin to increase, one or occasionally two of the recruited follicles emerge as dominant. Many endocrinologists believe that the estrogen secretion of the dominant follicle lowers the levels of LH and FSH, leading to the atresia (death) of most of the other recruited follicles. Estrogen levels will continue to increase for several days.

High estrogen levels initiate the formation of a new layer of endometrium in the uterus, the proliferative endometrium. Crypts in the cervix are stimulated to produce fertile cervical mucus that reduces the acidity of the vagina, creating a more hospitable environment for sperm. In addition, basal body temperature may lower slightly under the influence of high estrogen levels.

Ovulation

Estrogen levels are highest right before the LH surge begins. The short-term drop in steroid hormones between the beginning of the LH surge and ovulation may cause mid-cycle spotting or bleeding. Under the influence of the preovulatory LH surge, the first meiotic division of the oocytes is completed. The surge also initiates luteinization of theca and granulosa cells. Ovulation normally occurs 30 (± 2) hours after the beginning of the LH surge.

Ovulation is the process in a female’s menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum (oocyte). The time immediately surrounding ovulation is referred to as the ovulatory phase or the periovulatory period. In the preovulatory phase of the menstrual cycle, the ovarian follicle undergoes cumulus expansion stimulated by FSH. The ovum then leaves the follicle through the formed stigma. Ovulation is triggered by a spike in the amount of FSH and LH released from the pituitary gland.

Luteal Phase

The luteal phase begins with the formation of the corpus luteum stimulated by FSH and LH and ends in either pregnancy or luteolysis. The main hormone associated with this stage is progesterone, which is produced by the growing corpus luteum and is significantly higher during the luteal phase than other phases of the cycle. Progesterone plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy. It also raises the woman’s basal body temperature.

Several days after ovulation, the increasing amount of estrogen produced by the corpus luteum may cause one or two days of fertile cervical mucus, lower basal body temperatures, or both. This is known as a secondary estrogen surge. The hormones produced by the corpus luteum suppress production of the FSH and LH, which leads to its atrophy. The death of the corpus luteum results in falling levels of progesterone and estrogen, which triggers the end of the luteal phase. Increased levels of FSH start recruiting follicles for the next cycle.

Alternatively, the loss of the corpus luteum can be prevented by implantation of an embryo: after implantation, human embryos produce human chorionic gonadotropin (hCG). Human chorionic gonadotropin is structurally similar to LH and can preserve the corpus luteum. Because the hormone is unique to the embryo, most pregnancy tests look for the presence of hCG. If implantation occurs, the corpus luteum will continue to produce progesterone (and maintain high basal body temperatures) for eight to 12 weeks, after which the placenta takes over this function.

Extrauterine Effects of Estrogens and Progesterone

Estrogen and progesterone have several effects beyond their immediate roles in the menstrual cycle, pregnancy, and labor.

LEARNING OBJECTIVES

Describe the functions of progesterone and estrogen

KEY TAKEAWAYS

Key Points

  • Estrogen promotes female secondary sex characteristics and has structural and metabolic functions, including bone formation, salt and water retention, and increased cortisol levels.
  • The effects of progesterone are largely amplified by estrogen and include increases in core temperature, anti-inflammatory effects, increased use of fat for energy, and regulation of insulin release.
  • Progesterone is sometimes called the ” hormone of pregnancy” as it has many roles relating to the fetal development, including preparing the uterus for implantation, increasing the amount of cervical mucus, and decreasing the maternal immune response.

Key Terms

  • estrogen: A hormone responsible for the appearance of secondary sex characteristics of human females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state.
  • aldosterone: A mineralocorticoid hormone secreted by the adrenal cortex that regulates the balance of sodium and potassium in the body.
  • progesterone: A steroid hormone secreted by the ovaries that prepares the uterus for the implantation of a fertilized ovum and subsequent pregnancy.

Both estrogens and progesterone serve functions in the body beyond their roles in menstruation, pregnancy, and childbirth.

Estrogens Overview

image

Estradiol: One of the estrogens produced in the human body, predominant during a woman’s reproductive years.

Estrogens are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones, although they are found in males as well. The three major naturally occurring forms of estrogen in women are estrone (E1), estradiol (E2), and estriol (E3). Estetrol (E4) is produced only during pregnancy.

Natural estrogens are steroid hormones, while some synthetic versions are non-steroidal. Estrogens are synthesized in all vertebrates as well as some insects, and their presence in both suggests that they have an ancient evolutionary history. Like all steroid hormones, estrogen readily diffuses across the cell membrane. Once inside the cell, it binds to and activates estrogen receptors which in turn modulate the expression of many genes.

Functions of Estrogens

image

Estriol: Another one of the three main estrogens produced in humans.

While estrogens are present in both men and women, they are usually at significantly higher levels in women of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, pubic hair, and female fat distribution. They are also involved in the thickening of the endometrium and other aspects of menstrual cycle regulation.

Other functions of and structural changes induced by estrogen include:

  • Formation of female secondary sex characteristics
  • Accelerating metabolism
  • Increasing fat stores
  • Stimulating endometrial growth
  • Increasing uterine growth
  • Increasing vaginal lubrication
  • Thickening the vaginal wall
  • Maintaining blood vessels and skin
  • Reducing bone resorption, increasing bone formation
  • Reducing muscle mass

Effect on Libido

Sex drive is dependent on androgen levels only in the presence of estrogen. Without estrogen, free testosterone levels actually decrease sexual desire, as demonstrated in women who have hypoactive sexual desire disorder. The sexual desire in these women can be restored by administration of estrogen through oral contraceptives.

Mental Health

Estrogen plays a significant role in women’s mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained low levels of estrogen correlate with significant mood changes. Restoration or stabilization of estrogen levels is clinically effective for recovery from postpartum, perimenopause, and postmenopause depression.

Progesterone Overview

image

Progesterone: Belongs to the progestogen class of hormones and is the predominant example in the human body.

Progesterone is a steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation ), and embryogenesis of humans and other species.

Progesterone belongs to a class of hormones called progestogens and is the major naturally-occurring human form in this category. Progesterone exerts its primary action through the intracellular progesterone receptor, although a distinct, membrane-bound progesterone receptor has also been postulated.

Functions of Progesterone

Progesterone has a number of physiological effects that are amplified in the presence of estrogen. Estrogen, through estrogen receptors, upregulates the expression of progesterone receptors. Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production. This combats the blockade of the mineralocorticoid receptor by the previously-elevated level of progesterone.

Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilization occurs, though the receptor(s) as yet remain unidentified. Detailed characterization of the events occurring in sperm in response to progesterone has shed light on intracellular calcium transients, maintained changes, and slow calcium oscillations, now thought to possibly regulate motility.

Progesterone is sometimes called the “hormone of pregnancy” and has many roles relating to fetal development. It converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time, it affects the vaginal epithelium and cervical mucus, making them thick and impenetrable to sperm.

If pregnancy does not occur, progesterone levels will decrease, leading to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, its levels may be low, leading to anovulatory dysfunctional uterine bleeding. During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy and decrease contractility of the uterine smooth muscle.

In addition, progesterone inhibits lactation during pregnancy. A drop in its levels is facilitates the onset of labor. Another drop following delivery is one of the triggers for milk production. The fetus metabolizes placental progesterone in the production of adrenal steroids.

Female Sexual Response

Female sexual arousal causes physiological changes including increased blood flow to the genitals and enlargement and lubrication of the vagina.

LEARNING OBJECTIVES

Explain the process of female sexual response

KEY TAKEAWAYS

Key Points

  • Responses specific to females include engorgement of several tissues including the nipples, vulva, clitoris, and vaginal walls.
  • Further changes include changes to the shape of the vagina and the positioning of the uterus in the pelvis, as well as increases in blood pressure and heart rate.
  • Experienced by males and females, orgasms are controlled by the involuntary or autonomic nervous system.
  • Age-related changes in sexual responsiveness may be associated with changes in estrogen.

Key Terms

  • vulva: The vaginal opening to the uterus.
  • estrogen: A hormone responsible for the appearance of secondary sex characteristics of females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state.
  • clitoris: A small, sensitive, and elongated erectile organ at the anterior part of the vulva in females and homologous with the penis.

Sexual arousal is caused by sexual desire during or in anticipation of sexual activity. A number of physiological changes occur in the body and mind in preparation for sex and continue during the act. For women, these changes include increased blood flow to the nipples, vulva, clitoris, and vaginal walls, and increased vaginal lubrication.

Physiological Response

This diagram of the clitoris indicates the labia majora and minora, retracted clitoral hood, and glans.

Features of the vulva: The clitoris and labial folds are labelled.

The beginnings of sexual arousal in a woman’s body is usually marked by vaginal lubrication, engorgement of the external genitals, and internal enlargement of the vagina. Further stimulation can lead to more vaginal wetness and further engorgement and swelling of the clitoris and the labia, along with increased redness or darkening of the skin in these areas. Changes also occur to the internal shape of the vagina and to the position of the uterus within the pelvis.

Other bodily changes include an increase in heart rate and blood pressure, as well as flushing across the chest and upper body. If sexual stimulation continues, then sexual arousal may peak into orgasm, resulting in rhythmic muscular contractions in the pelvic region characterized by an intense sensation of pleasure. Experienced by males and females, orgasms are controlled by the involuntary or autonomic nervous system.

As women age, estrogen levels decrease. Reduced estrogen levels may be associated with increased vaginal dryness and less clitoral erection when aroused, but are not directly related to other aspects of sexual interest or arousal. In older women, decreased pelvic muscle tone may prolong the time to reach orgasm, diminish the intensity of orgasms, and cause more rapid resolution. In some women, the uterine contracts that occur during orgasm may cause pain or discomfort.

Psychological Response

Mental and physical stimuli such as touch and the internal fluctuation of hormones influence sexual arousal. Cognitive factors like sexual motivation, perceived gender role expectations, and sexual attitudes play important roles in women’s self-reported levels of sexual arousal. Basson suggests that women’s need for intimacy prompts them to engage with sexual stimuli, leading to an experience of sexual desire and psychological sexual arousal.

Research by Goldey and van Anders showed that sexual cognition impacts hormone levels in women. For instance, sexual thoughts result in a rapid increase in testosterone in women who were not using hormonal contraception. Inconsistent study results indicate that, although testosterone is involved in libido and sexuality of some women, its effects can be obscured by the coexistence of psychological factors in others.

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 Female Reproductive System – Anatomy, Organ, Functions

The female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. In humans, the female reproductive system is immature at birth and develops to maturity at puberty to be able to produce gametes and to carry a fetus to full term. The internal sex organs are the uterus, Fallopian tubes, and ovaries. The uterus or womb accommodates the embryo which develops into the fetus. The uterus also produces vaginal and uterine secretions which help the transit of sperm to the Fallopian tubes. The ovaries produce the ova (egg cells). The external sex organs are also known as the genitals and these are the organs of the vulva including the labia, clitoris, and vaginal opening. The vagina is connected to the uterus at the cervix.[rx]

At certain intervals, the ovaries release an ovum, which passes through the Fallopian tube into the uterus. If in this transit, it meets with sperm, a single sperm (1-cell) can enter and merge with the egg or ovum (1-cell), fertilizing it into a zygote (1-cell).

Anatomy of the Female Reproductive System

The human female reproductive system contains two main parts: the uterus and the ovaries, which produce a woman’s egg cells.

Key Points

A female’s internal reproductive organs are the vagina, uterus, fallopian tubes, cervix, and ovary.

External structures include the mons pubis, pudendal cleft, labia majora and minora, vulva, Bartholin’s gland, and the clitoris.

The female reproductive system contains two main parts: the uterus, which hosts the developing fetus, produces vaginal and uterine secretions, and passes the anatomically male sperm through to the fallopian tubes; and the ovaries, which produce the anatomically female egg cells.

Key Terms

  • ovary: A female reproductive organ, often paired, that produces ova and in mammals secretes the hormones estrogen and progesterone.
  • oviduct: A duct through which an ovum passes from an ovary to the uterus or to the exterior (called fallopian tubes in humans).
  • vulva: The consists of the female external genital organs.
  • oogenesis: The formation and development of an ovum.

The human female reproductive system (or female genital system) contains two main parts:

  1. Uterus
    • Hosts the developing fetus
    • Produces vaginal and uterine secretions
    • Passes the anatomically male sperm through to the fallopian tubes
  2. Ovaries
    • Produce the anatomically female egg cells.
    • Produce and secrete estrogen and progesterone

These parts are internal; the vagina meets the external organs at the vulva, which includes the labia, clitoris, and urethra. The vagina is attached to the uterus through the cervix, while the uterus is attached to the ovaries via the fallopian tubes. At certain intervals, the ovaries release an ovum, which passes through the fallopian tube into the uterus.

If in this transit, it meets with sperm, the sperm penetrates and merges with the egg, fertilizing it. The fertilization usually occurs in the oviducts, but can happen in the uterus itself. The zygote then implants itself in the wall of the uterus, where it begins the process of embryogenesis and morphogenesis. When developed enough to survive outside the womb, the cervix dilates and contractions of the uterus propel the fetus through the birth canal (vagina).

The ova are larger than sperm and have formed by the time an anatomically female infant is born. Approximately every month, a process of oogenesis matures one ovum to be sent down the fallopian tube attached to its ovary in anticipation of fertilization. If not fertilized, this egg is flushed out of the system through menstruation.

An anatomically female’s internal reproductive organs are the vagina, uterus, fallopian tubes, cervix, and ovary.
The external components include the mons pubis, pudendal cleft, labia majora, labia minora, Bartholin’s glands, and clitoris.

Illustrated sagittal view of the female reproductive system. 

Female Repro: Illustrated sagittal view of the female reproductive system.

Ovaries

The ovaries are the ovum-producing organs of the internal female reproductive system.

Key Points

In addition to producing ova, the ovaries are endocrine organs and produce hormones that act during the female menstrual cycle and pregnancy.

Ovaries secrete estrogen and progesterone.

Each ovary is located in the lateral wall of the pelvis in a region called the ovarian fossa.

The ovaries are attached to the uterus via the ovarian ligament (which runs in the broad ligament).

Usually, the ovaries take turns releasing eggs every month; however, if one ovary is absent or dysfunctional then the other ovary releases eggs every month.

There are two extremities to the ovary, the tubal extremity and the uterine extremity.

Key Terms

  • intraperitoneal: Located within the inner layer of the peritoneum (the serous membrane that forms the lining of the abdominal cavity).
  • corpus luteum: A temporary endocrine structure in female ovaries that is essential for establishing and maintaining pregnancy.
  • libido: A person’s overall sexual drive.
  • follicle: A spheroid cellular aggregation found in the ovaries that secrete hormones that influence the stages of the menstrual cycle.
  • ovary: A female reproductive organ, often paired, that produces ova and in mammals secretes the hormones estrogen and progesterone.

The ovary is an ovum-producing reproductive organ, typically found in pairs as part of the vertebrate female reproductive system. Ovaries in females are analogous to testes in males in that both are gonads and endocrine glands. Ovaries secrete both estrogen and progesterone. Estrogen is responsible for the appearance of secondary sex characteristics of females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state. Progesterone functions with estrogen by promoting menstrual cycle changes in the endometrium.

Anatomical Features

The ovaries are located in the lateral wall of each side of the pelvis in a region called the ovarian fossa. The fossa usually lies beneath the external iliac artery and in front of the ureter and internal iliac artery.

In humans, the paired ovaries lie within the pelvic cavity on either side of the uterus, to which they are attached via a fibrous cord called the ovarian ligament. The ovaries are tethered to the body wall via the suspensory ligament of the ovary. The part of the broad ligament of the uterus that covers the ovary is known as the mesovarium. The ovary is the only organ in the human body that is totally invaginated into the peritoneum, making it the only intraperitoneal organ.

There are two extremities to the ovary, the tubal extremity, and the uterine extremity. The tubal extremity is the end to which the Fallopian tube attaches via the infundibulopelvic ligament. The uterine extremity points downward and is attached to the uterus via the ovarian ligament.

This diagram of the female reproductive system indicates the ovary, Fallopian tube, uterus, broad ligament, endometrium, myometrium, internal os, external os, cervix, and vagina. 

Ovary: A pictorial illustration of the female reproductive system

Physiology and Function

The ovaries are the site of egg cell production and also have a specific endocrine function.

Oogenesis

The ovaries are the site of gamete (egg cell, oocyte) production. The developing egg cell (or oocyte) grows within the environment provided by ovarian follicles. Follicles are composed of different types and numbers of cells according to their maturation stage, which can be determined by their size. When oocyte maturation is completed, a luteinizing hormone ( LH ) surge secreted by the pituitary gland stimulates follicle rupture and oocyte release.

This oocyte development and release process is referred to as ovulation. The follicle remains functional and transforms into a corpus luteum, which secretes progesterone to prepare the uterus for possible embryo implantation. Usually, each ovary takes turns releasing eggs each month. However, this alternating egg release is random. When one ovary is absent or dysfunctional, the other ovary will continue to release eggs each month.

Endocrine Function

Ovaries secrete estrogen, progesterone, and testosterone. Estrogen is responsible for the secondary sex characteristics of females at puberty. It is also crucial for the maturation and maintenance of mature and functional reproductive organs. Progesterone prepares the uterus for pregnancy and the mammary glands for lactation. The co-actions of progesterone and estrogen promote menstrual cycle changes in the endometrium. In women, testosterone is important for the development of muscle mass, muscle, and bone strength, and for optimal energy level. It also has a role in libido in women.

Uterus

The uterus is the largest and major organ of the female reproductive tract that is the site of fetal growth and is hormonally responsive.

Key Points

The body of the uterus is connected to the ovaries via the fallopian tubes, and opens into the vagina via the cervix.

Two Müllerian ducts
usually form initially in a female fetus, but in humans, they completely fuse into a single uterus during gestation.

The uterus is essential in sexual response by directing blood flow to the pelvis and to the external genitalia, including the ovaries, vagina, labia, and clitoris.

The reproductive function of the uterus is to accept a fertilized ovum that passes through the utero-tubal junction from the fallopian tube.

The lining of the uterine cavity is called the endometrium.

Key Terms

  • linea terminalis: Part of the pelvic brim, which is the edge of the pelvic inlet.
  • adenomyosis: A condition characterized by the breaking through of the endometrium into the muscle wall of the uterus.
  • uterus: An organ of the female reproductive system in which the young are conceived and develop until birth; the womb.
  • endometrium: The mucous membrane that lines the uterus in mammals and in which fertilized eggs are implanted.
  • fallopian tubes: The fallopian tubes, also known as oviducts, uterine tubes, and salpinges (singular salpinx) are two very fine tubes lined with ciliated epithelia, and lead from the ovaries of female mammals into the uterus via the utero-tubal junction.

The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species. It is within the uterus that the fetus develops during gestation, usually developing completely in placental mammals such as humans.

Two Müllerian ducts usually form initially in a female fetus and, in humans, they completely fuse into a single uterus depending on the species. The uterus consists of a body and a cervix. The cervix protrudes into the vagina. The uterus is held in position within the pelvis by condensations of endopelvic fascia, which are called ligaments. These ligaments include the pubocervical, transverse, cervical, cardinal, and uterosacral ligaments. It is covered by a sheet-like fold of peritoneum, the broad ligament.

The uterus is essential in sexual response by directing blood flow to the pelvis and to the external genitalia, including the ovaries, vagina, labia, and clitoris. The reproductive function of the uterus is to accept a fertilized ovum that passes through the utero-tubal junction from the fallopian tube. It implants into the endometrium and derives nourishment from blood vessels that develop exclusively for this purpose.

image 

Uterus: Vessels of the uterus and its appendages, rearview.

The fertilized ovum becomes an embryo, attaches to a wall of the uterus, creates a placenta, and develops into a fetus (gestates) until childbirth. Due to anatomical barriers such as the pelvis, the uterus is pushed partially into the abdomen due to its expansion during pregnancy. Even during pregnancy, the mass of a human uterus amounts to only about a kilogram (2.2 pounds).

The uterus is located inside the pelvis immediately dorsal (and usually somewhat rostral) to the urinary bladder and ventral to the rectum. The human uterus is pear-shaped and about three inches (7.6 cm) long. The uterus can be divided anatomically into four segments: The fundus, corpus, cervix, and internal os.

A pictorial illustration of the female reproductive system. 

Ovary: A pictorial illustration of the female reproductive system.

The uterus is in the middle of the pelvic cavity in the frontal plane (due to ligament latum uteri). The fundus does not surpass the linea terminalis. The fundus of the uterus is the top, rounded portion, opposite from the cervix. The vaginal part of the cervix does not extend below the interspinal line. The uterus is mobile and moves under the pressure of the full bladder or full rectum anteriorly, whereas if both are full it moves upwards. Increased intra-abdominal pressure pushes it downwards. The mobility is conferred to it by musculo-fibrous apparatus that consists of a suspensory and sustentacular part. Under normal circumstances, the suspensory part keeps the uterus in anteflexion and anteversion (in 90% of women) and keeps it “floating” in the pelvis. In cases where the uterus is “tipped,” also known as the retroverted uterus, women may have symptoms of pain during sexual intercourse, pelvic pain during menstruation, minor incontinence, urinary tract infections, difficulty conceiving, and difficulty using tampons. A pelvic examination by a doctor can determine if a uterus is tipped.

The lining of the uterine cavity is called the endometrium. It consists of the functional endometrium and the basal endometrium from which the former arises. Damage to the basal endometrium results in adhesion formation and/or fibrosis (Asherman’s syndrome). In all placental mammals, including humans, the endometrium builds a lining periodically which is shed or reabsorbed if no pregnancy occurs. Shedding of the functional endometrial lining is responsible for menstrual bleeding (known colloquially as a “period” in humans, with a cycle of approximately 28 days, +/- 7 days of flow, and +/- 21 days of progression) throughout the fertile years of a female and for some time beyond.

Depending on the species and attributes of physical and psychological health, weight, environmental factors of circadian rhythm, photoperiodism (the physiological reaction of organisms to the length of day or night), the effect of menstrual cycles to the reproductive function of the uterus is subject to hormone production, cell regeneration, and other biological activities. The menstrual cycles may vary from a few days to six months but can vary widely even in the same individual, often stopping for several cycles before resuming.

The uterus mostly consists of smooth muscle, known as myometrium. The innermost layer of the myometrium is known as the junctional zone, which becomes thickened in adenomyosis. The parametrium is the loose connective tissue around the uterus. The perimetrium is the peritoneum covering the fundus and ventral and dorsal aspects of the uterus. The uterus is primarily supported by the pelvic diaphragm, perineal body, and urogenital diaphragm. Secondarily, it is supported by ligaments and the peritoneum (broad ligament of uterus).

Female Duct System

The Fallopian tubes, or oviducts, connect the ovaries to the uterus.

Key Points

The Fallopian tube allows passage of the egg from the ovary to the uterus.

The lining of the Fallopian tubes is ciliated and has several segments, including the infundibulum, ampullary, isthmus, and interstitial regions.

Interspersed between the ciliated cells are peg cells, which contain apical granules and produce the tubular fluid that contains nutrients for spermatozoa, oocytes, and zygotes.

Occasionally, the embryo implants into the Fallopian tube instead of the uterus, creating an ectopic pregnancy.

Key Terms

  • oviduct: A duct through which an ovum passes from an ovary to the uterus or to the exterior.
  • fallopian tubes: Also known as oviducts, uterine tubes, and salpinges (singular salpinx), two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus via the uterotubal junction.
  • ovarian follicle: The basic units of female reproductive biology, each composed of roughly spherical aggregations of cells found in the ovary.

The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges (singular salpinx), are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus via the uterotubal junction. In non-mammalian vertebrates, the equivalent structures are the oviducts. These tubes allow the passage of the egg from the ovary to the uterus.

The different segments of the fallopian tube are ( lateral to medial):

  • The infundibulum with associated fimbriae near the ovary
  • The ampullary region that represents the major portion of the lateral tube
  • The isthmus, which is the narrower part of the tube that links to the uterus
  • The interstitial (intramural) part that transverses the uterine musculature

The tubal ostium is the point at which the tubal canal meets the peritoneal cavity, while the uterine opening of the Fallopian tube is the entrance into the uterine cavity, the uterotubal junction.

Illustrative drawing of the anterior view of the uterus showing the uterine segments, indicating the uterine tube (oviduct), infundibulum, ampulla, isthmus, fundus, broad ligament, ovarian ligament, endometrium, myometrium, perimetrium, uterine isthmus, cervix, vagina, vaginal artery, uterine artery and vein, suspensory ligament, ovarian artery and vein, fimbriae, tunica albuginea, ovarian cortex, and edge of follicle. 

Uterine Segments: Illustrative drawing of the anterior view of the uterus showing the uterine segments

There are two types of cells within the simple columnar epithelium of the Fallopian tube. Ciliated cells predominate throughout the tube but are most numerous in the infundibulum and ampulla. Estrogen increases the production of cilia on these cells.

Interspersed between the ciliated cells are peg cells, which contain apical granules and produce the tubular fluid. This fluid contains nutrients for spermatozoa, oocytes, and zygotes. The secretions also promote capacitation of the sperm by removing glycoproteins and other molecules from the plasma membrane of the sperm. Progesterone increases the number of peg cells, while estrogen increases their height and secretory activity. Tubal fluid flows against the action of the ciliary, toward the fimbriated end.

When an ovum is developing in an ovary, it is encapsulated in a sac known as an ovarian follicle. On maturation, the follicle and the ovary’s wall rupture, allowing the ovum to escape. The egg is caught by the fimbriated end and travels to the ampulla where typically the sperm are met and fertilization occurs. The fertilized ovum, now a zygote, travels towards the uterus aided by the tubal cilia and tubal muscle. After about five days, the new embryo enters the uterine cavity and implants about a day later. Occasionally, the embryo implants into the Fallopian tube instead of the uterus, creating an ectopic pregnancy.

Vagina

The vagina is the female reproductive tract and has two primary functions: sexual intercourse and childbirth.

Key Points

The vagina is situated between the cervix of the uterus and the external genitalia, primarily the vulva.

Although there is wide anatomical variation, the length of the unaroused vagina of a woman of child-bearing age is approximately 6 to 7.5 cm (2.5 to 3 in) across the anterior wall (front), and 9 cm (3.5 in) long across the posterior wall (rear).

During sexual arousal, the vagina expands in both length and width.

A series of ridges produced by the folding of the wall of the outer third of the vagina is called the vaginal rugae.

Vaginal lubrication is provided by the Bartholin’s glands near the vaginal opening and the cervix.

The hymen is a membrane of tissue that surrounds or partially covers the external vaginal opening.

Key Terms

  • vulva: The vaginal opening to the uterus.
  • clitoris: A small, sensitive, and elongated erectile organ at the anterior part of the vulva in female mammals, homologous with the penis.
  • Skene’s glands: Glands located on the anterior wall of the vagina, around the lower end of the urethra, that drain into the urethra and near the urethral opening. These may be near or part of the G-spot.
  • vagina: A fibromuscular tubular tract which is the female sex organ and has two main functions, sexual intercourse, and childbirth.

The vagina, a female sex organ, is a fibromuscular tubular tract that has two main functions: sexual intercourse and childbirth. In humans, this passage leads from the opening of the vulva to the uterus, but the vaginal tract ends at the cervix.

Anatomy of the Vagina

image 

Vagina: The vagina is the most immediate internal female reproductive organ. This diagram also indicates the ovaries, uterus, and cervix.

The vaginal opening is much larger than the urethral opening. During arousal, the vagina gets moist to facilitate the entrance of the penis. The inner texture of the vagina creates friction for the penis during intercourse.

The vaginal opening is at the caudal end of the vulva behind the opening of the urethra. The upper quarter of the vagina is separated from the rectum by the rectouterine pouch. The vagina and the inside of the vulva are a reddish-pink color, as are most healthy internal mucous membranes in mammals. A series of ridges produced by the folding of the wall of the outer third of the vagina is called the vaginal rugae. These transverse epithelial ridges and provide the vagina with increased surface area for extension and stretching.

Vaginal lubrication is provided by the Bartholin’s glands near the vaginal opening and the cervix. The membrane of the vaginal wall also produces moisture, although it does not contain any glands. Before and during ovulation, the cervix’s mucus glands secrete different variations of mucus, which provides an alkaline environment in the vaginal canal that is favorable to the survival of sperm.

The hymen is a membrane of tissue that surrounds or partially covers the external vaginal opening. The tissue may or may not be ruptured by vaginal penetration. It can also be ruptured by childbirth, a pelvic examination, injury, or sports. The absence of a hymen may not indicate prior sexual activity. Similarly, its presence may not indicate a lack of prior sexual activity.

The function of the Vagina

The vagina’s primary functions are sexual arousal and intercourse as well as childbirth.

Sexual Arousal and Intercourse

The concentration of the nerve endings close to the entrance of a woman’s vagina (the lower third) can provide pleasurable sensations during sexual activity when stimulated. Ninety percent of the vagina’s nerve endings are in this area. However, the vagina as a whole has insufficient nerve endings for sexual stimulation and orgasm; this lack of nerve endings makes childbirth significantly less painful.

Research indicates that clitoral tissue extends considerably into the vulva and vagina. During sexual arousal and particularly clitoral stimulation, the vaginal walls lubricate to reduce friction caused by sexual activity. With arousal, the vagina lengthens rapidly to an average of about 4 in. (10 cm) and can continue to lengthen in response to pressure. As the woman becomes fully aroused, the vagina tents (expands in length and width), while the cervix retracts. The walls of the vagina are composed of soft elastic folds of mucous membrane which stretch or contract (with support from pelvic muscles) to the size of the inserted penis or another object, stimulating the penis and helping the male to experience orgasm and ejaculation, thus enabling fertilization.

An erogenous zone commonly referred to as the G-Spot (also known as the Gräfenberg Spot) is located at the anterior wall of the vagina, about five centimeters in from the entrance. Some women experience intense pleasure if the G-Spot is stimulated appropriately during sexual activity. A G-Spot orgasm may be responsible for female ejaculation, leading some doctors and researchers to believe that G-Spot pleasure comes from the Skene’s glands, a female homolog of the prostate, rather than any particular spot on the vaginal wall. Other researchers consider the connection between the Skene’s glands and the G-Spot to be weak. They contend that the Skene’s glands do not appear to have receptors for touch stimulation and that there is no direct evidence for their involvement. The G-Spot’s existence as a distinct structure, is still under dispute, as its location can vary from woman to woman and is sometimes nonexistent.

The Vagina and Childbirth

The vagina provides the channel to deliver the baby from the uterus to its independent life outside the mother’s body. During birth, the elasticity of the vagina allows it to stretch to many times its normal diameter. The vagina is often referred to as the birth canal in the context of pregnancy and childbirth.

Vulva

The vulva is the external genitalia of the female reproductive tract, situated immediately external to the genital orifice.

Key Points

Major structures of the vulva include the labia major and minor, mons pubis, clitoris, bulb of vestibule, vulva vestibule, vestibular glands, and the genital orifice (or opening of the vagina ).

The vulva is rich in nerves that are stimulated during sexual activity and arousal.

The vulva also contains the opening of the female urethra and thus serves the vital function of passing urine.

Key Terms

  • labia minora: The two inner folds of skin within the cleft of the labia majora.
  • vulva: The vaginal opening to the uterus.
  • mons pubis: A fleshy protuberance over the pubic bones that becomes covered with hair during puberty.
  • labia majora: The two outer rounded folds of adipose tissue that lie on either side of the opening of the vagina.

The vulva consists of the external genital organs of the female mammal. Its development occurs during several phases, chiefly during the fetal and pubertal periods.

As the outer portal of the human uterus or womb, the vulva protects its opening with a “double door”: the labia majora (large lips) and the labia minora (small lips). The vulva also contains the opening of the female urethra, and thus serves the vital function of passing urine.

In human beings, major structures of the vulva are:

  • The mons pubis
  • The labia majora and the labia minora
  • The external portion of the clitoris and the clitoral hood
  • The vulval vestibule
  • The pudendal cleft
  • The frenulum labiorum pudendi or fourchette
  • The opening (or urinary meatus) of the urethra
  • The opening (or introitus) of the vagina
  • The hymen

Other notable structures include:

  • The perineum
  • The sebaceous glands on labia majora
  • The vaginal glands (Bartholin’s glands and paraurethral or Skene’s, glands)
Labeled image of a vulva, showing external and internal views. This diagram indicates the prepuce, glans clitoris, labia minora, corpus cavernosum, bulb of vestibule, urethral opening, labia majora, vaginal opening, Bartholin's glands, opening of right Bartholin's gland, and anus. 

Vulva: The labeled image of a vulva, showing external and internal views.

The soft mound at the front of the vulva, the mons pubis, is formed by fatty tissue covering the pubic bone. The mons pubis separates into two folds of skin called the labia majora, literally “major (or large) lips.” The cleft between the labia majora is called the pudendal cleft, or cleft of Venus, and it contains and protects the other, more delicate structures of the vulva. The labia majora meet again at the perineum, a flat area between the pudendal cleft and the anus. The color of the outside skin of the labia majora is usually close to the individual’s overall skin color although there is considerable variation.

The inside skin and mucus membrane are often pink or brownish. After the onset of puberty, the mons pubis and the labia majora become covered by pubic hair. This hair sometimes extends to the inner thighs and perineum, but the density, texture, color, and extent of pubic hair coverage vary considerably due to both individual variation and cultural practices of hair modification or removal. The labia minora are two soft folds of skin within the labia majora.

The clitoris is located at the front of the vulva where the labia minora meet. The visible portion of the clitoris is the clitoral glans, roughly the size and shape of a pea. The clitoral glans is highly sensitive, containing as many nerve endings as the analogous organ in males, the glans penis. The point where the labia minora attach to the clitoris is called the frenulum clitoridis. A prepuce, the clitoral hood, normally covers and protects the clitoris; however, in women with particularly large clitorises or small prepuces, the clitoris may be partially or wholly exposed. The clitoral hood is the female equivalent of the male foreskin and may be partially hidden inside of the pudendal cleft.

The area between the labia minora is called the vulval vestibule, and it contains the vaginal and urethral openings. The urethral opening (meatus) is located below the clitoris and just in front of the vagina. This is where urine passes from the urinary bladder.

The opening of the vagina is located at the bottom of the vulval vestibule toward the perineum. The term introitus is more technically correct than “opening,” since the vagina is usually collapsed, with the opening closed unless something is inserted. The introitus is sometimes partly covered by a membrane called the hymen. The hymen will rupture during the first episode of vigorous sex, and the blood produced by this rupture has been traditionally seen as a sign of virginity. However, the hymen may also rupture spontaneously during exercise or be stretched by normal activities such as the use of tampons. Slightly below and to the left and right of the vaginal opening are two Bartholin glands that produce a waxy, pheromone-containing substance, the purpose of which is not yet fully known.

Perineum

The perineum is the region between the genitals and the anus, including the perineal body and surrounding structures.

Key Points

The perineum refers to both external and deep structures.

Perineal tears and episiotomy often occur in childbirth with first-time deliveries, but the risk of these injuries can be reduced by preparing the perineum through massage.

The perineum is an erogenous zone for both males and females.

Key Terms

  • lower rabbis: The term for perineum is often used in the UK.
  • perineum: The region of the body inferior to the pelvic diaphragm and between the legs. It is a diamond-shaped area on the inferior surface of the trunk which includes the anus and, in females, the vagina.
  • episiotomy: A surgical incision through the perineum made to enlarge the vagina and assist childbirth.
  • perineal body: A pyramid-shaped fibromuscular mass in the middle line of the perineum at the junction between the urogenital triangle and the anal triangle.

In human anatomy, the perineum is the surface region between the pubic symphysis and coccyx in both males and females, including the perineal body and surrounding structures. The boundaries vary in classification but generally include the genitals and anus. It is an erogenous zone for both males and females.

Illustrated drawing of the muscles of the female perineum, including the clitoris, bulbocavernosus, ischiocavernosus, external sphincter, and gluteus maximus. 

Perineum Illustration: Illustrated drawing of the muscles of the female perineum.

The term perineum may refer to only the superficial structures in this region or be used to include both superficial and deep structures. The term lower rabbis is used colloquially in the UK to describe this structure. Perineal tears and episiotomy often occur in childbirth with first-time deliveries, but the risk of these injuries can be reduced by preparing the perineum through massage.

The perineum corresponds to the outlet of the pelvis. Its deep boundaries are:

  • The pubic arch and the arcuate ligament of the pubis
  • The tip of the coccyx
  • he inferior rami of the pubis and ischial tuberosity, and the sacrotuberous ligament

The perineum includes two distinct regions separated by the pelvic diaphragm. Its structures include:

  • Superficial and deep perineal pouches
  • Ischioanal fossa, a fat-filled space at the lateral sides of the anal canal bounded laterally by obturator internus muscle, medially by the pelvic diaphragm, and the anal canal.
  • Anal canal
  • Pudendal canal, which contains the internal pudendal artery and the pudendal nerve

Mammary Glands

A mammary gland is an organ in female mammals that produces milk to feed young offspring.

Key Points

Mammary glands are not associated with the female reproductive tract but develop as secondary sex characteristics in reproductive-age females.

The basic components of a mature mammary gland are the alveoli, hollow cavities, a few millimeters large lined with milk-secreting cuboidal cells, and surrounded by myoepithelial cells.

Alveoli join up to form groups known as lobules and each of which has a lactiferous duct that drains into openings in the nipple.

Secretory alveoli develop mainly in pregnancy, when rising levels of prolactin, estrogen, and progesterone cause further branching, together with an increase in adipose tissue and a richer blood flow.

Key Terms

  • Want: Morphogenic signaling proteins that regulate cell-cell interactions.
  • beta-1 integrin: One of the regulators of mammary epithelial cell growth and
    differentiation.
  • mammary gland: A gland that secretes milk for suckling an infant or offspring.
  • lactiferous duct: The components that form a branched system connecting the lobules of the mammary gland to the tip of the nipple.

A mammary gland is an organ in female mammals that produces milk to feed young offspring.

Anatomy of the Mammary Gland

The basic components of a mature mammary gland are the alveoli, hollow cavities, a few millimeters large lined with milk-secreting cuboidal cells, and surrounded by myoepithelial cells. These alveoli join to form groups known as lobules, and each lobule has a lactiferous duct that drains into openings in the nipple. The myoepithelial cells can contract under the stimulation of oxytocin, excreting milk secreted from alveolar units into the lobule lumen toward the nipple where it collects in the sinuses of the ducts. As the infant begins to suck, the hormonally (oxytocin) mediated “let-down reflex” ensues, and the mother’s milk is secreted into the baby’s mouth.

Drawing of the cross-section of the mammary-gland. 

Mammary Gland: Cross-section of the mammary gland. 1. Chest wall 2. Pectoralis muscles 3. Lobules     4. Nipple 5. Areola 6. Milk duct 7. Fatty tissue 8. Skin EndFragment

All the milk-secreting tissue leading to a single lactiferous duct is called a simple mammary gland; a complex mammary gland is all the simple mammary glands serving one nipple. Humans normally have two complex mammary glands, one in each breast, and each complex mammary gland consists of 10–20 simple glands. The presence of more than two nipples is known as polythelia and the presence of more than two complex mammary glands as polymastia.

Development of the Mammary Glands

Mammary glands develop during different growth cycles. They exist in both sexes during the embryonic stage, forming only a rudimentary duct tree at birth. In this stage, mammary gland development depends on systemic (and maternal) hormones but is also under the local regulation of paracrine communication between neighboring epithelial and mesenchymal cells by parathyroid hormone-related protein. This locally secreted factor gives rise to a series of outside-in and inside-out positive feedback between these two types of cells so that mammary bud epithelial cells can proliferate and sprout down into the mesenchymal layer until they reach the fat pad to begin the first round of branching.

Lactiferous duct development occurs in females in response to circulating hormones, first during pre-and postnatal stages and later during puberty. Estrogen promotes branching differentiation, which is inhibited by testosterone in males. A mature duct tree reaching the limit of the fat pad of the mammary gland is formed by bifurcation of duct terminal end buds, secondary branches sprouting from primary ducts, and proper duct lumen formation.

The Process of Milk Production

Secretory alveoli develop mainly in pregnancy, when rising levels of prolactin, estrogen, and progesterone cause further branching, together with an increase in adipose tissue and a richer blood flow. In gestation, serum progesterone remains at a high concentration so signaling through its receptor is continuously activated. As one of the transcribed genes, Wnts secreted from mammary epithelial cells act paracrine to induce branching of neighboring cells. When the lactiferous duct tree is almost ready, alveoli are differentiated from luminal epithelial cells and added at the end of each branch. In late pregnancy and for the first few days after giving birth, colostrum is secreted.

Milk secretion (lactation) begins a few days after birth, caused by a reduction in circulating progesterone and the presence of prolactin, which mediates further amelogenesis and milk protein production and regulates osmotic balance and tight junction function.
The binding of laminin and collagen in the myoepithelial basement membrane with beta-1 integrin on the epithelial surface ensures correct placement of prolactin receptors on the basal lateral side of alveoli cells and directional secretion of milk into lactiferous ducts. Suckling of the baby causes the release of the hormone oxytocin which stimulates contraction of the myoepithelial cells. With combined control from the extracellular matrix (ECM) and systemic hormones, milk secretion can be reciprocally amplified to provide enough nutrition for the baby.

During weaning, decreased the prolactin, lack of mechanical stimulation through suckling, and changes in osmotic balance caused by milk stasis and leaking of tight junctions cause cessation of milk production. In some species there is a complete or partial involution of alveolar structures after weaning; however, in humans, there is only partial involution, which widely varies among individuals. Shrinkage of the mammary duct tree and ECM remodeling by various proteinase is under the control of somatostatin and other growth-inhibiting hormones and local factors. This structure change leads to loose fat tissue filling the empty space. However, a functional lactiferous duct tree can be reformed when a female is pregnant again.

What Is the Female Reproductive System?

The external part of the female reproductive organs is called the vulva, which means covering. Located between the legs, the vulva covers the opening to the vagina and other reproductive organs inside the body.

The fleshy area located just above the top of the vaginal opening is called the mons pubis. Two pairs of skin flaps called the labia (which means lips) surround the vaginal opening. The clitoris, a small sensory organ, is located toward the front of the vulva where the folds of the labia join. Between the labia are openings to the urethra (the canal that carries pee from the bladder to the outside of the body) and vagina. When girls become sexually mature, the outer labia and the mons pubis are covered by pubic hair.

A female’s internal reproductive organs are the vagina, uterus, fallopian tubes, and ovaries.

The vagina is a muscular, hollow tube that extends from the vaginal opening to the uterus. Because it has muscular walls, the vagina can expand and contract. This ability to become wider or narrower allows the vagina to accommodate something as slim as a tampon and as wide as a baby. The vagina’s muscular walls are lined with mucous membranes, which keep it protected and moist.

The vagina serves three purposes:

  1. It’s where the penis is inserted during sexual intercourse.
  2. It’s the pathway (the birth canal) through which a baby leaves a woman’s body during childbirth.
  3. It’s the route through which menstrual blood leaves the body during periods.

A very thin piece of skin-like tissue called the hymen partly covers the opening of the vagina. Hymens are often different from female to female. Most women find their hymens have stretched or torn after their first sexual experience, and the hymen may bleed a little (this usually causes little, if any, pain). Some women who have had sex don’t have much of a change in their hymens, though. And some women’s hymens have already stretched even before they have sex.

The vagina connects with the uterus, or womb, at the cervix (which means neck). The cervix has strong, thick walls. The opening of the cervix is very small (no wider than a straw), which is why a tampon can never get lost inside a girl’s body. During childbirth, the cervix can expand to allow a baby to pass.

The uterus is shaped like an upside-down pear, with a thick lining and muscular walls — in fact, the uterus contains some of the strongest muscles in the female body. These muscles are able to expand and contract to accommodate a growing fetus and then help push the baby out during labor. When a woman isn’t pregnant, the uterus is only about 3 inches (7.5 centimeters) long and 2 inches (5 centimeters) wide.

At the upper corners of the uterus, the fallopian tubes connect the uterus to the ovaries. The ovaries are two oval-shaped organs that lie to the upper right and left of the uterus. They produce, store, and release eggs into the fallopian tubes in the process called ovulation (pronounced: av-yoo-LAY-shun).

There are two fallopian (pronounced: fuh-LO-pee-un) tubes, each attached to a side of the uterus. Within each tube is a tiny passageway no wider than a sewing needle. At the other end of each fallopian tube is a fringed area that looks like a funnel. This fringed area wraps around the ovary but doesn’t completely attach to it. When an egg pops out of an ovary, it enters the fallopian tube. Once the egg is in the fallopian tube, tiny hairs in the tube’s lining help push it down the narrow passageway toward the uterus.

The ovaries (pronounced: OH-vuh-reez) are also part of the endocrine system because they produce female sex hormones such as estrogen (pronounced: ESS-truh-jun) and progesterone (pronounced: pro-JESS-tuh-rone).

How Does the Female Reproductive System Work?

The female reproductive system enables a woman to:

  • produce eggs (ova)
  • have sexual intercourse
  • protect and nourish a fertilized egg until it is fully developed
  • give birth

Sexual reproduction couldn’t happen without the sexual organs called the gonads. Most people think of the gonads as the male testicles. But both sexes have gonads: In females, the gonads are the ovaries, which make female gametes (eggs). The male gonads make male gametes (sperm).

When a baby girl is born, her ovaries contain hundreds of thousands of eggs, which remain inactive until puberty begins. At puberty, the pituitary gland (in the central part of the brain) starts making hormones that stimulate the ovaries to make female sex hormones, including estrogen. The secretion of these hormones causes a girl to develop into a sexually mature woman.

Toward the end of puberty, girls begin to release eggs as part of a monthly period called the menstrual cycle. About once a month, during ovulation, an ovary sends a tiny egg into one of the fallopian tubes.

Unless the egg is fertilized by a sperm whale in the fallopian tube, the egg leaves the body about 2 weeks later through the uterus — this is menstruation. Blood and tissues from the inner lining of the uterus combine to form the menstrual flow, which in most girls lasts from 3 to 5 days. A girl’s first period is called menarche (pronounced: MEH-nar-kee).

It’s common for women and girls to have some discomfort in the days leading to their periods. Premenstrual syndrome (PMS) includes both physical and emotional symptoms that many girls and women get right before their periods, such as:

  • acne
  • bloating
  • tiredness
  • backaches
  • sore breasts
  • headaches
  • constipation
  • diarrhea
  • food cravings
  • depression
  • irritability
  • trouble concentrating or handling stress

PMS is usually at its worst during the 7 days before a girl’s period starts and disappears after it begins.

Many girls also have belly cramps during the first few days of their periods caused by prostaglandins, chemicals in the body that make the smooth muscle in the uterus contract. These involuntary contractions can be dull or sharp and intense.

It can take up to 2 years from menarche for a girl’s body to develop a regular menstrual cycle. During that time, her body is adjusting to the hormones puberty brings. On average, the monthly cycle for an adult woman is 28 days, but the range is from 23 to 35 days.

What Happens If an Egg Is Fertilized?

If a female and male have sex within several days of the female’s ovulation, fertilization can happen. When the male ejaculates (when semen leaves the penis), a small amount of semen is deposited into the vagina. Millions of sperm are in this small amount of semen, and they “swim” up from the vagina through the cervix and uterus to meet the egg in the fallopian tube. It takes only one sperm to fertilize the egg.

About 5 to 6 days after the sperm fertilizes the egg, the fertilized egg (pronounced: zygote) has become a multicelled blastocyst. A blastocyst (pronounced: BLAS-tuh-sist) is about the size of a pinhead, and it’s a hollow ball of cells with fluid inside. The blastocyst burrows itself into the lining of the uterus, called the endometrium. The hormone estrogen causes the endometrium (pronounced: en-doh-MEE-tree-um) to become thick and rich with blood. Progesterone, another hormone released by the ovaries, keeps the endometrium thick with blood so that the blastocyst can attach to the uterus and absorb nutrients from it. This process is called implantation.

As cells from the blastocyst take in nourishment, another stage of development begins. In the embryonic stage, the inner cells form a flattened circular shape called the embryonic disk, which will develop into a baby. The outer cells become thin membranes that form around the baby. The cells multiply thousands of times and move to new positions to eventually become the embryo (pronounced: EM-bree-oh).

After about 8 weeks, the embryo is about the size of a raspberry, but almost all of its parts — the brain and nerves, the heart and blood, the stomach and intestines, and the muscles and skin — have formed.

During the fetal stage, which lasts from 9 weeks after fertilization to birth, development continues as cells multiply, move, and change. The fetus (pronounced: FEE-tis) floats in amniotic (pronounced: am-nee-AH-tik) fluid inside the amniotic sac. The fetus gets oxygen and nourishment from the mother’s blood via the placenta (pronounced plush-SEN-tuh). This disk-like structure sticks to the inner lining of the uterus and connects to the fetus via the umbilical (pronounced: um-BIL-ih-Kul) cord. The amniotic fluid and membrane cushion the fetus against bumps and jolts to the mother’s body.

Pregnancy lasts an average of 280 days — about 9 months. When the baby is ready for birth, its head presses on the cervix, which begins to relax and widen to get ready for the baby to pass into and through the vagina. Mucus has formed a plug in the cervix, which now loosens. It and amniotic fluid come out through the vagina when the mother’s water breaks.

When the contractions of labor begin, the walls of the uterus contract as they are stimulated by the pituitary hormone oxytocin (pronounced: ahk-see-TOE-sin). The contractions cause the cervix to widen and begin to open. After several hours of this widening, the cervix is dilated (opened) enough for the baby to come through. The baby is pushed out of the uterus, through the cervix, and along the birth canal. The baby’s head usually comes first. The umbilical cord comes out with the baby. It’s clamped and cut close to the navel after the baby is delivered.

The last stage of the birth process involves the delivery of the placenta, which at that point is called afterbirth. After it has separated from the inner lining of the uterus, contractions of the uterus push it out, along with its membranes and fluids.

References

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Male Sexual Response Cycle – Anatomy, Structure, Functions

The Male sexual response cycle is a four-stage model of physiological responses to sexual stimulation, which, in order of their occurrence, are the excitement, plateau, orgasmic, and resolution phases. This physiological response model was first formulated by William H. Masters and Virginia E. Johnson, in their 1966 book Human Sexual Response.[rx][rx] Since that time, other models regarding human sexual response have been formulated by several scholars who have criticized certain inaccuracies in the human sexual response cycle model.

Male Sexual Response

Physiological changes occur to male genitalia during sexual arousal.

Key Points

Male sexual response is demonstrated by vasodilation and blood engorgement of the penis, leading to an erection.

The testes rise and grow larger and warmer as blood pressure rises.

The muscles of the pelvic floor, the vesicles, and the prostrate contract, injecting sperm into the urethra of the penis and resulting in the onset of orgasm.

Ejaculation continues with orgasm.

Following orgasm, there is a gradual loss of erection and a feeling of relaxation known as the refractory period.

Cognitive factors involving visual stimuli and high levels of activity in the amygdala and hypothalamus contribute to sexual arousal and sexual response in males.

Key Terms

  • erection: The physiological process by which a penis becomes engorged with blood.
  • sexual arousal: Changes that occur during or in anticipation of sexual activity.
  • refractory period: The period after excitation, during which a membrane recovers its polarization and is not able to respond to a second stimulus.
  • sex flush: Increased blood flow leading to reddening of the skin in response to sexual arousal or orgasm.
  • tumescence: The normal engorgement of the erectile tissue with blood.
  • genitalia: Sex organs.

The erect penis is commonly correlated with male sexual arousal.

Physiological Effects of Arousal

Physical and/or psychological stimulation leads to vasodilation and subsequently increased blood flow into the three spongy areas that run along the length of the penis (the two corpora cavernosa and the corpus spongiosum). The penis grows enlarged and firm, the skin of the scrotum is pulled tighter, and the testes are pulled up against the body.

As sexual arousal and stimulation continue, the glans of the erect penis will swell wider. As the genitals become further engorged with blood, their color deepens and the testes can grow up to 50% larger. As the testes continue to rise, a feeling of warmth may develop around them and the perineum. With further sexual stimulation, the heart rate increases, blood pressure rises, and breathing becomes more rapid. The increase in blood flow in the genitals and other regions may lead, in some men, to a sex flush.

The muscles of the pelvic floor, the ductus deferens (between the testes and the prostate), the seminal vesicles, and the prostate gland may begin to contract in a way that forces sperm and semen into the urethra inside the penis. This is the onset of orgasm and once this has started, the man likely will continue to ejaculate and orgasm fully, with or without further stimulation. If sexual stimulation stops before orgasm, the physical effects of the stimulation, including the vasocongestion, will subside in a short time. Repeated or prolonged stimulation without orgasm and ejaculation can lead to discomfort in the testes that is sometimes called “blue balls.”

Nonarousal-Related Erection

The relationship between erection and arousal is not one-to-one. Some men are older than age 40 report that they do not always have an erection when sexually aroused. A male erection can occur during sleep (nocturnal penile tumescence) without conscious sexual arousal or due to mechanical stimulation (e.g. rubbing against a bed sheet) alone. A young man or one with a strong sexual drive may experience enough sexual arousal for an erection with a passing thought or just the sight of a passerby. Once erect, his penis may gain enough stimulation from contact with the inside of his clothing to maintain the erection for more time.

Post-Orgasm Response

After orgasm and ejaculation, a refractory period usually ensues, characterized by loss of erection, a decline in any sex flush, decreased interest in sex, and a feeling of relaxation associated with the action of the neurohormones oxytocin and prolactin. The intensity and duration of the refractory period can be very short in a highly aroused young man in a highly arousing situation, perhaps without even a noticeable loss of erection. It can be as long as a few hours or days in mid-life and older men.

Hormonal Responses

Several hormones affect sexual arousal, including testosterone, cortisol, and estradiol. However, the specific roles of these hormones are not clear. Testosterone is the most commonly studied hormone involved with sexuality, and it plays a key role in sexual arousal in males, with strong effects on central arousal mechanisms.

Sperm

Sperm are the male “seeds,” germ cells, or gametes.

Key Points

Sperm fertilizes the oocyte, donate the paternal chromatin, and provide the centrosome that maintains the zygote’s microtubule system.

Sperm have three parts: a head, which holds the chromatin, a midpiece filled with mitochondria to provide energy, and a flagellum or tail to move the sperm from the vagina to the oocyte.

Sperm with one tail, such as human sperm, are referred to as spermatozoa.

Sperm quality and quantity decrease with age.

Key Terms

  • anisogamy: The form of sexual reproduction that involves the union or fusion of two gametes that differ in size and/or form.
  • spermatozoa: A motile sperm cell or moving form of the haploid cell that is the male gamete.
  • acrosome: A caplike structure over the anterior half of the sperm’s head.
  • ATP: An acronym for adenosine triphosphate, which transports chemical energy within cells for metabolism.
  • oogamy: A form of anisogamy (heterogamy) in which the female gamete (oocyte) is significantly larger than the male gamete (sperm) and is non-motile. The male gametes are highly motile and compete for the fertilization of the immotile oocyte.

EXAMPLE

The term sperm is derived from the Greek word for seed and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there are marked differences in the size of the gametes, with the smaller termed the “male” or sperm cells. Sperm cells cannot divide and have a limited lifespan. After fusion with egg cells during fertilization, a new organism forms, beginning as a totipotent zygote. The human sperm cell is haploid so that its 23 chromosomes can join the 23 chromosomes of the female egg to form a diploid cell. During fertilization, the sperm provides the following three essential parts to the oocyte:

  • Signaling or activating factor that causes the metabolically dormant oocyte to activate
  • The haploid paternal genome
  • The centrosome, which is responsible for maintaining the microtubule system

Sperm Anatomy

Closeup of Mammalian Fertilization

Closeup of Mammalian Fertilization: Micrograph of a sperm poised to enter an ovum

Sperm develop in the testes and consist of a head, a midpiece, and a tail. The head contains the nucleus with densely coiled chromatin fibers, surrounded anteriorly by an acrosome that contains enzymes for penetrating the female egg. The midpiece has a central filamentous core with many mitochondria spiraled around it.

Sperm Physiology and Function

In animals, most of the energy (ATP) for sperm motility is derived from the metabolism of fructose carried in the seminal fluid. This takes place in the mitochondria located in the sperm’s midpiece. This energy is used for the journey through the female cervix, uterus, and uterine tubes.

Motile sperm cells typically move via flagella and require a water medium in order to swim toward the egg for fertilization. These cells cannot swim backward due to the nature of their propulsion. The uniflagellated sperm cells (with one flagellum) of animals are referred to as spermatozoa.

This sperm diagram indicates the acrosome, plasma membrane, nucleus, centriole, mitochondria, terminal disc, axial filament, head, midpiece, tail, endpiece, periacrosomal space, cell membrane, acrosome, nuclear vacuoles, nucleus, nuclear envelope, subacrosomal space, outer acrosome membrane, ecuatorial segment, postacrosomal region, postacrosomal sheet, posterior ring, connecting piece, redundant nuclear envelope, mitochondrial sheath, outer dense fibers, central pair, and axoneme.

Human Sperm: Detailed and labeled diagram of a human spermatozoa

Fertility Factors

Sperm quantity and quality are the main parameters in semen quality, a measure of the ability of semen to accomplish fertilization. The genetic quality of sperm, as well as its volume and motility, all typically decrease with age.

Spermatogenesis

Male gametes (sperm cells) are haploid cells produced via spermatogenesis.

Key Points

Spermatogenesis begins with a diploid spermatogonium in the seminiferous tubules, which divides mitotically to produce two diploid primary spermatocytes.

The primary spermatocyte then undergoes meiosis I to produce two haploid secondary spermatocytes.

The haploid secondary spermatocytes undergo meiosis II to produce four haploid spermatids.

Each spermatid begins to grow a tail and a mitochondrial-filled midpiece, while the chromatin is tightly packaged into an acrosome at the head.

Maturation removes excess cellular material, turning spermatids into inactive, sterile spermatozoa that are transported via peristalsis to the epididymis.

The spermatozoa gain motility in the epididymis but do not use that ability until they are ejaculated into the vagina.

Spermatogenesis requires optimal environmental conditions.

Key Terms

  • spermatozoa: A motile sperm cell, or moving form of the haploid cell that is the male gamete.
  • spermatocyte: A male gametocyte, from which a spermatozoon develops.
  • axoneme: Cytoskeletal inner core structure of eukaryotic flagella.
  • spermatid: A haploid cell produced by meiosis of a spermatocyte that develops into a spermatozoon.
  • spermatogonium: Any of the undifferentiated cells in the male gonads that become spermatocytes.

Spermatogenesis is the process by which male primary sperm cells undergo meiosis and produce a number of cells calls spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes and each secondary spermatocyte into two spermatids or young spermatozoa. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, which in turn produce four spermatozoa.

Male Gametogenesis

Spermatozoa are the mature male gametes in many sexually reproducing organisms. Spermatogenesis is the male version of gametogenesis and results in the formation of spermatocytes possessing half the normal complement of genetic material.

In mammals, it occurs in the male testes and epididymis in a stepwise fashion that takes approximately 64 days.

Spermatogenesis, essential for sexual reproduction is highly dependent upon optimal conditions to occur correctly. DNA methylation and histone modification have been implicated in the regulation of this process. It starts at puberty and usually continues uninterrupted until death, although a slight decrease can be discerned in the quantity of sperm produced with an increase in age.

Steps in Spermatogenesis

Step 1: Spermatocytogenesis

 

Spermatocytogenesis

Spermatocytogenesis: Diagram of the steps of spermatocytogenesis, including type Ad spermatogonium, type Ap Spermatogonium, type B spermatogonium, primary spermatocyte, and secondary spermatocyte.

Mitotic division of a diploid spermatogonium that resides in the basal compartment of the seminiferous tubules, resulting in two diploid intermediate cells called primary spermatocytes.

Each primary spermatocyte then moves into the adluminal compartment of the seminiferous tubules, duplicates its DNA, and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes.

Secondary spermatocytes later divide into haploid spermatids. During this division, random inclusion of either parental chromosome and chromosomal crossover both increase the genetic variability of the gamete.

Each cell division from a spermatogonium to a spermatid is incomplete; the cells remain connected to one another by bridges of cytoplasm to allow synchronous development. Not all spermatogonia divide to produce spermatocytes; otherwise, the supply would run out. Instead, certain types of spermatogonia divide to produce copies of themselves, thereby ensuring a constant supply of gametogonia to fuel spermatogenesis.

Step 2: Spermatogenesis

The creation of spermatids from secondary spermatocytes. Secondary spermatocytes produced earlier rapidly enter meiosis II and divide to produce haploid spermatids. The brevity of this stage means that secondary spermatocytes are rarely seen in histological preparations.

Step 3: Spermiogenesis

At this stage, each spermatid begins to grow a tail and develop a thickened midpiece where the mitochondria gather and form an axoneme. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. The Golgi apparatus surrounds the now condensed nucleus, becoming the acrosome. One of the centrioles of the cell elongates to become the tail of the sperm.

The non-motile spermatozoa are transported to the epididymis in testicular fluid secreted by the Sertoli cells with the aid of peristaltic contraction. While in the epididymis, the spermatozoa gain motility and become capable of fertilization. However, transport of the mature spermatozoa through the remainder of the male reproductive system is achieved via muscle contraction rather than the spermatozoon’s recently acquired motility.

Physiology of Spermatogenesis

 

Maturation takes place under the influence of testosterone, which removes the remaining unnecessary cytoplasm and organelles. The excess cytoplasm, known as residual bodies, is phagocytosed by surrounding Sertoli cells in the testes. The resulting spermatozoa are now mature but lack motility, rendering them sterile. The mature spermatozoa are released from the protective Sertoli cells into the lumen of the seminiferous tubule in a process called spermiation.

Spermatogenesis is highly sensitive to fluctuations in the environment, particularly hormones and temperature. The seminiferous epithelium is sensitive to elevated temperature in humans and is adversely affected by temperatures as high as normal body temperature. Consequently, the testes are located outside the body in a sack of skin called the scrotum. The optimal temperature is maintained at 2 °C below body temperature in human males. This is achieved by regulation of blood flow and positioning towards and away from the heat of the body by the cremaster muscle and the dartos smooth muscle in the scrotum. Dietary deficiencies (such as vitamins B, E, and A), anabolic steroids, metals (cadmium and lead), x-ray exposure, dioxin, alcohol, and infectious diseases will also adversely affect the rate of spermatogenesis.

Spermatozoon: Diagram of parts of a spermatozoon, including the acrosome, plasma membrane, nucleus, centriole, mitochondria, terminal disc, axial filament, tail, endpiece, midpiece, and head.

Semen

Semen is a fluid produced by the seminal vesicles.

Key Points

Seminal fluid mixes with fluids produced by the prostate and bulbourethral glands.

The seminal fluid provides nutrition and protection for sperm during its journey through the female reproductive tract.

Semen initially coagulates in the vagina, then liquefies to allow the sperm to move.

Key Terms

  • seminal vesicle: One of two simple tubular glands located behind the male urinary bladder, responsible for the production of about sixty percent of the fluid that ultimately becomes semen.
  • seminal fluid: Semen is a fluid that helps in promoting the survival of spermatozoa and provides a medium through which they can move.
  • semen: The fluid produced in the male reproductive organs of an animal that contains the reproductive cells.

Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads (sexual glands) and can fertilize female ova. In humans, seminal fluid contains several components besides spermatozoa, including enzymes (proteolytic and others) and fructose. These elements promote the survival of spermatozoa and provide a medium for motility. Semen is produced and originates from the seminal vesicles, located in the pelvis. The process that results in the discharge of semen is called ejaculation.

Semen Production and Secretion

During the process of ejaculation, sperm passes through the ejaculatory ducts and mix with fluids from the seminal vesicle, the prostate, and the bulbourethral glands to form semen. The seminal vesicles produce a yellowish viscous fluid rich in fructose, amino acids, and other substances that make up about 70% of human semen. The prostatic secretion, influenced by dihydrotestosterone, is a whitish (sometimes clear), thin fluid containing proteolytic enzymes, citric acid, acid phosphatase, and lipids. The bulbourethral glands secrete a clear fluid to lubricate the lumen of the urethra.

Sperm Protection and Transport

Sertoli cells, which nurture and support developing spermatocytes, secrete a fluid into seminiferous tubules that help transport sperm to the genital ducts. The ductules efferents possess cuboidal cells with microvilli and lysosomal granules that modify the semen by reabsorbing some fluid. Once the semen enters the ductus epididymis, the principal cells (which contain pinocytotic vessels indicating fluid reabsorption) secrete glycerophosphocholine, which most likely inhibits premature capacitation.

The seminal plasma provides a nutritive and protective medium for the spermatozoa during their journey through the female reproductive tract. The normal environment of the vagina is a hostile one for sperm cells, as it is acidic (from the native microflora producing lactic acid), viscous, and patrolled by immune cells. The components in the seminal plasma attempt to compensate for this hostile environment. Basic amines such as putrescine, spermine, spermidine, and cadaverine are responsible for the smell and flavor of semen. These alkaline bases counteract the acidic environment of the vaginal canal and protect DNA inside the sperm from acidic denaturation.

Characteristics of Ejaculate

According to the World Health Organization, normal human semen has a volume of 2 ml or greater, pH of 7.2 to 8.0, sperm concentration of 20×106 spermatozoa/ml or more, a sperm count of 40×106 spermatozoa per ejaculate or more, and motility of 50% or more within 60 minutes of ejaculation. After ejaculation, the latter part of the semen coagulates immediately, forming globules. After about 15–30 minutes, a prostate-specific antigen present in the semen causes the de coagulation of the seminal coagulum. It is postulated that the initial clotting helps keep the semen in the vagina, while liquefaction frees the sperm to make their journey to the ova.

Semen quality is a measure of the ability of semen to accomplish fertilization and thus a measure of a man’s fertility. Semen can be preserved for long-term storage by cryopreservation. For human sperm, the longest reported successful storage with this method is 21 years.

Hormonal Regulation of the Male Reproductive System

The male reproductive system is regulated by the production, stimulation, and feedback of specific hormones.

Key Points

GnRH is made in the hypothalamus and travels to the pituitary where it stimulates FSH and LH secretion.

FSH is necessary for sperm maturation.

LH binds to Leydig cells to stimulate testosterone secretion and androgen production.

Testosterone stimulates sex drive.

Inhibin acts as negative feedback to slow the release of FSH and GnRH.

Key Terms

  • GnRH: Gonadotropin-releasing hormone is a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.
  • LH: Luteinizing hormone is produced by the anterior pituitary gland and in males causes the synthesis and secretion of testosterone and androgen.
  • FSH: Follicle-stimulating hormone stimulates both the production of androgen-binding protein by Sertoli cells and the formation of the blood-testis barrier.

Hormonal control of spermatogenesis varies among species. In humans, the mechanisms are not completely understood. However, it is known that the initiation of spermatogenesis occurs at puberty due to the interaction of the hypothalamus, pituitary gland, and Leydig cells. If the pituitary gland is removed, spermatogenesis can still be initiated by follicle-stimulating hormone (FSH) and testosterone.

The Role of Hormones in Male Reproduction

Studies from rodent models suggest that gonadotropin hormones (both LH and FSH) support the process of spermatogenesis by suppressing the proapoptotic signals and thus promoting spermatogenic cell survival. The Sertoli cells themselves mediate parts of spermatogenesis through hormone production. They are capable of producing the hormones estradiol and inhibin. The Leydig cells are also capable of producing estradiol in addition to their main product, testosterone.

Gonadotropin-Releasing Hormone

Gonadotropin-releasing hormone (GnRH) is mainly made in the preoptic area of the hypothalamus before traveling to the pituitary gland. There it stimulates the synthesis and secretion of the gonadotropins, FSH, and luteinizing hormone (LH).

Follicle-Stimulating Hormone

Follicle-stimulating hormone (FSH)  is released by the anterior pituitary gland. Its presence in males is necessary for the maturation of spermatozoa. Follicle-stimulating hormone stimulates both the production of androgen-binding protein by Sertoli cells and the formation of the blood-testis barrier. Increasing the levels of FSH increases the production of spermatozoa by preventing the apoptosis of type A spermatogonia.

Luteinizing Hormone

Luteinizing hormone (LH) is released by the anterior pituitary gland. In the testes, LH binds to receptors on Leydig cells, which stimulates the synthesis and secretion of testosterone.

Testosterone

Testosterone is made in the interstitial cells of the testes. It stimulates the sex drive and is associated with aggression. Androgen-binding protein is essential to concentrating testosterone in levels high enough to initiate and maintain spermatogenesis, which can be 20-50 times higher than the concentration found in the blood. The sequestering of testosterone in the testes is initiated by FSH, and only testosterone is required to maintain spermatogenesis.

Inhibin

Inhibin is secreted by the Sertoli cells and acts to decrease the levels of FSH. The hormone is released into the circulation when the sperm count is too high.

Hormonal Influence

Hormonal Influence: This flowchart details the steps involved in the hormonal control of male reproduction.

This diagram depicts the hormonal regulation of male reproduction, including the following steps: hypothalamus, GnRH secretion, anterior pituitary, FSH and LH secretion, negative feedback, Leydig cells, Sertoli cells, testosterone secretion, inhibit secretion, spermatogenesis, various target tissues, maintenance of accessory reproductive organs and secondary sex characteristics, sex drive, protein synthesis in skeletal muscle, and bone growth in adolescents.

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Male Reproductive System – Anatomy, Mechanism, Functions

The male reproductive system consists of the internal structures: the testes, epididymis, vas deferens, prostate, and the external structures: the scrotum and penis. These structures are well-vascularized with many glands and ducts to promote the formation, storage, and ejaculation of sperm for fertilization, and to produce important androgens for male development.[rx] The major male androgen is testosterone, which is produced from Leydig cells in the testes. Testosterone can be converted in the periphery to a more active form, dihydrotestosterone via 5-alpha-reductase, or estradiol via aromatase. Other key hormones include the inhibin B and Mullerian inhibiting substance (MIS) hormone, both produced by the Sertoli cells in the testes. Important hormones that modulate these include follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are released from the anterior pituitary gland and are regulated by gonadotropin-releasing hormone (GnRH), produced by the hypothalamus. Together, these hormones form the hypothalamic-pituitary-gonadal axis that promotes and maintains sexual development and function in the male.[rx]

Anatomy of the Male Reproductive System

The male reproductive system includes external (penis, scrotum, epididymis, and testes) and internal (accessory) organs.

Key Points

The functions of the male reproductive system include producing and transporting sperm, ejaculating sperm into the female reproductive tract, and producing and secreting male hormones.

Most of the male reproductive system is located outside of the body. These external structures are the penis, scrotum, epididymis, and testes.

The internal organs of the male reproductive system are called accessory organs. They include the vas deferens, seminal vesicles, prostate gland, and bulbourethral glands.

Key Terms

  • semen: Contains spermatozoa, proteolytic and other enzymes, and
    fructose that promotes spermatozoa survival. It also provides a medium for sperm
    motility.
  • spermatogenesis: The process of sperm production within the seminiferous tubules in the testes.
  • testosterone: Steroid hormone produced primarily in the male testes and responsible for the development of male secondary sex characteristics.

The organs of the male reproductive system are specialized for three primary functions:

  • To produce, maintain, transport, and nourish sperm (the male reproductive cells), and protective fluid ( semen ).
  • To discharge sperm within the female reproductive tract.
  • To produce and secrete male sex hormones.

External Male Sex Organs

Most of the male reproductive system is located outside of the man’s body. These external structures are the penis, scrotum, epididymis, and testes.

This diagram of the male reproductive system indicates the bladder, pubic bone, puboprostatic ligament, suspensory ligament of penis, perineal membrane, penis, external urethral sphincter, glans penis, foreskin, urethral opening, corpus cavernosum, scrotum, testes, vas deferens, anus, Cowper's gland, epididymis, prostate gland, ejaculatory duct, seminal vesicle, rectum, and sigmoid colon.

Male Reproductive System: Lateral view of male reproductive system with organs labeled.

The penis is the male organ for sexual intercourse and urination. Semen and urine leave the penis through the urethra. The scrotum is a loose, pouch-like sack of skin that hangs behind the penis, containing the testes.

The scrotum has a protective function, including the maintenance of optimal temperatures for sperm survival and function. For sperm development, the testes must maintain a temperature slightly cooler than normal body temperature. Special muscles in the wall of the scrotum contract and relax in order to move the testes near the body.

The epididymis is located at the back of the testis and connects it to the vas deferens. Its function is to store and carry sperm. The testis is the location for testosterone production. The coiled collection of tubes within the testes are the seminiferous tubules. Within these tubules, spermatogenesis takes place.

Accessory Sex Organs

The internal organs of the male reproductive system are called accessory organs. They include the vas deferens, seminal vesicles, prostate gland, and bulbourethral (Cowper’s) glands.

  • Vas deferens: Transports mature sperm to the urethra in preparation for ejaculation.
  • Seminal vesicles: Sac-like pouches that attach to the vas deferens near the base of the bladder. The vesicles produce molecules such as fructose that serve as energy sources for sperm. The seminal vesicle fluid makes up most of the volume of a man’s ejaculate.
  • Prostate gland: A walnut-sized structure located below the urinary bladder in front of the rectum. It contributes additional fluid to the ejaculate that serves as nourishment for sperm.
  • Bulbourethral (Cowper’s) glands: Pea-sized structures located on the sides of the urethra just below the prostate gland. These glands produce a clear, slippery fluid that empties directly into the urethra. Fluid produced by these glands lubricates the urethra and neutralizes acidity associated with residual urine.

Scrotum

The purpose of the scrotum is to provide the testes with a chamber of appropriate temperature for optimal sperm production.

Key Points

Moving the testes away from the abdomen and increasing the exposed surface area allows a faster dispersion of excess heat.

If testes were in the abdomen, constant pressure from abdominal muscles would possibly empty the testes and epididymis before sperm were sufficiently mature for fertilization.

The function of the scrotum appears to be to keep the temperature of the testes slightly lower than that of the rest of the body.

Key Terms

  • scrotum: The bag of skin and muscle that contains the testes in mammals.
  • testosterone: A steroid hormone that plays a key role in male reproductive development including the promotion of secondary sexual characteristics.
  • epididymis: A narrow, tightly-coiled tube where sperm are stored during maturation. It connects the efferent ducts from the rear of each testicle to its vas deferens.

Anatomical Considerations

The scrotum is a dual-chambered suspended sack of skin and smooth muscle that contains the testes and is homologous to the labia majora in females. It is an extension of the perineum and is located between the penis and anus. In humans and some other mammals, increased testosterone secretion during puberty causes the darkening of the skin and the development of pubic hair on the scrotum. The left testis is usually lower than the right, which may function to avoid compression in the event of an impact. This asymmetry may also allow more effective cooling of the testes.

Function

The function of the scrotum appears to be to keep the temperature of the testes slightly lower than that of the rest of the body. For human beings, the temperature should be one or two degrees Celsius below body temperature (around 35 degrees Celsius or 95 degrees Fahrenheit); higher temperatures may be damaging to sperm count.

The temperature is controlled by the scrotal movement of the testes away or towards the body depending on the environmental temperatures. Moving the testes away from the abdomen and increasing the exposed surface area allows a faster dispersion of excess heat. This is done by means of contraction and relaxation of the cremaster muscle and the dartos fascia in the scrotum.

However, temperature regulation may not be the only function of the scrotum. It has been suggested that if testes were situated within the abdominal cavity, they would be subjected to the regular changes in abdominal pressure that are exerted by the abdominal muscles, resulting in the more rapid emptying of the testes and epididymis of sperm before the spermatozoa were matured sufficiently for fertilization. Some mammals (elephants and marine mammals, for example) do keep their testes within the abdomen where there may be mechanisms to prevent this inadvertent emptying.

External view of the scrotum includes the raphe. Muscle layer of the scrotum includes the scrotal septum, the cremaster muscles, and the dartos muscles. Deep tissues layer of the scrotum includes the plexus of testicular veins, the ductus deferens, the spermatic cord, the testicular artery, the autonomic nerve, the lymphatic vessel, the testis, and the epididymis.

The scrotum: Image of the external, muscle, and deep-tissue views of the scrotum.

Testes

The testis is homologous to the ovary in that it produces the male gamete (sperm) while the ovary produces the female gamete (egg).

Key Points

The testes produce the hormones testosterone and other androgens.

Sperm are produced within seminiferous tubules.

Leydig cells produce and secrete male hormones.

Sertoli cells help in the process of spermatogenesis.

Key Terms

  • Leydig cells: Also known as interstitial cells of Leydig, these are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of the luteinizing hormone.
  • follicle-stimulating hormone: Stimulates the growth and recruitment of immature ovarian follicles in females. In males, it is critical for spermatogenesis as it stimulates primary spermatocytes to form secondary spermatocytes.
  • Sertoli cells: Part of the seminiferous tubule that helps in the process of spermatogenesis.
  • Luteinizing hormone: A hormone produced by gonadotropic cells of the anterior pituitary gland. It triggers ovulation and development of the corpus luteum in females and stimulates Leydig cell production of testosterone in males.
  • testes: Also referred to as testicles, the male gonads in animals.
image

Testicle: A diagram of the major components of an adult human testis, including the following numbered items: 1. Tunica albuginea, 2. Septula testis, 3. Lobulus testis, 4. Mediastinum testis, 5. Tubuli seminiferi contorti, 6. Tubuli seminiferi recti, 7. Rete testis, 8. Ductuli efferentes testis, 9a. Head of the epididymis, 9b. Body of epididymis, 9.c Tail of epididymis,10. Vas deferens, 11a. Tunica vaginalis (parietal lamina), 11b. Tunica vaginalis (visceral lamina), and 12. The cavity of tunica vaginalis.

The testis is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system. The testes produce sperm (spermatogenesis) and androgens, primarily testosterone. Both functions of the testis are influenced by gonadotropic hormones produced by the anterior pituitary gland. Luteinizing hormone results in testosterone release. The presence of both testosterone and follicle-stimulating hormone (FSH) is needed to support spermatogenesis.

Almost all healthy male vertebrates have two testes. In mammals, the testes are often contained within an extension of the abdomen called the scrotum. In mammals with external testes, it is most common for one testicle to hang lower than the other. While the size of the testis varies, it is estimated that 21.9% of men have one higher-positioned testis, while 27.3% of men have reported equally-positioned testicles.

The tough membranous shell called the tunica albuginea contains very fine coiled tubes called seminiferous tubules. These are lined with a layer of germ cells that develop into sperm cells (also known as spermatozoa or male gametes) from puberty into old age. The developing sperm travels through the seminiferous tubules to the rete testis located in the mediastinum testis, to the efferent ducts, and then to the epididymis where newly created sperm cells mature. The sperm moves into the vas deferens and is eventually expelled through the urethra, via the urethral orifice through muscular contractions.

Leydig cells located between seminiferous tubules produce and secrete testosterone and other androgens important for sexual development and puberty, including secondary sexual characteristics such as facial hair and sexual behavior. They also support libido, spermatogenesis, and erectile function. In addition, testosterone controls testicular volume. The Sertoli cells are the testes’ somatic cells, necessary for testis development and spermatogenesis.

This diagram of the male reproductive organs indicates the vas deferens, spermatic artery, nerve filaments of spermatic plexus, deferential artery, epididymis, infundibuliform fascia, parietal layer of tunica vaginalis, testicle, scrotum, raphe, dartos, cremaster muscle, septum of scrotum, spermatic cord, accessory slip of origin of cremaster muscle, and external abdominal ring.

Inside the Human Testes: Diagram illustrates the scrotum with a portion of the covering removed to display the testis.

Penis

In human males, the penis serves as both a reproductive organ and a urinal duct.

Key Points

  • The major structure of the penis is formed by columns of corpus cavernosum and spongiosum tissue.
  • The head of the penis, called the glans, contains the opening for the urethral duct, the passage for urine, and seminal fluid.
  • The penis and clitoris (found in women) are homologous organs.
  • Blood engorgement of penile tissue causes the penis to become erect, facilitating sexual intercourse.
  • Ejaculation is the release of sperm, which propels the sperm into the vaginal canal when it occurs during intercourse.

Key Terms

  • glans: The vascular body which forms the apex of the penis.
  • penis: The male sexual organ for copulation and urination; the tubular portion of the male genitalia (excluding the scrotum).
  • intromittent organ: A term for a male external organ that delivers sperm during copulation.
  • clitoral glans: Highly innervated part of the clitoris that exists at the tip of the clitoral body as a fibrovascular cap.
  • ejaculation: The forcible ejection of semen from the mammalian urethra, a reflex in response to sexual stimulation.

The penis is an intromittent organ of male animals with reproductive and urinary functions. Unlike many other species, the human penis has no baculum or erectile bone. Instead, it relies entirely on engorgement with blood to achieve an erection. The human penis cannot be withdrawn into the groin, and
is larger than that of any other primate, particularly in regards to proportion to body mass.

This diagram of the human penis indicates the glans penis, corpus cavernosum, cavernous branch, dorsal artery, bulb, bulbous branch, bulbourethral artery, internal pudic artery, anterior branch, and corpus spongiosum.

Human Penis: This is a diagram of a human penis with its parts labeled.

Parts of the Penis

The human penis is made up of three columns of tissue: two corpora cavernosa that lie next to each other on the dorsal side and a corpus spongiosum that lies between the corpora cavernosa on the ventral side. The glans penis is the bulbous end of the penis formed by the corpus spongiosum. It supports the foreskin (prepuce) that retracts to expose the glans. The area on the underside of the penis, where the foreskin is attached, is called the frenum (or frenulum). The rounded base of the glans is called the corona. The perineal raphe is the noticeable line along the underside of the penis.

The urethra is the last part of the urinary tract and traverses the corpus spongiosum. The urethral opening is called the meatus and lies on the tip of the glans penis. It serves as a passage both for urine and semen. Sperm are produced in the testes and stored in the attached epididymis. Sperm are propelled through the vas deferens during ejaculation. Fluids are added by the seminal vesicles before the vas deferens carry the sperm to the ejaculatory ducts, which join the urethra inside the prostate gland. The prostate as well as the bulbourethral glands add further secretions, then the semen is expelled through the penis. The raphe is the noticeable ridge between the halves of the penis. It is located on the ventral aspect of the penis and runs from the meatus and across the scrotum to the perineum (area between scrotum and anus).

Homology to the Clitoris

The various parts of the male penis are homologous to parts of the female clitoris:

  • Glans of the penis: homologous to the clitoral glans
  • Corpora cavernosa: homologous to the body of the clitoris
  • Corpus spongiosum: homologous to vestibular bulbs beneath the labia minora
  • Scrotum: homologous to the labia minora and labia majora
  • Foreskin: homologous to the clitoral hood

This diagram comparing the penis to the clitoris indicates the foreskin, corona, corpus spongiosum, urethra, corpura cavernosa, glans, and clitoral hood.

Penile and Clitoral Structure: This diagram compares the structure of the penis to the clitoris.

The Penis As a Sexual Organ

An erection is the stiffening and rising of the penis that facilitates sexual arousal, though it can also happen in non-sexual situations. The primary physiological mechanism that brings about an erection is the autonomic dilation of arteries supplying blood to the penis. This allows more blood to fill the three spongy erectile tissue chambers in the penis, causing it to lengthen and stiffen.

The engorged erectile tissue presses against and constricts the veins that carry blood away from the penis. More blood enters than leaves the penis until an equilibrium is reached where an equal volume of blood flows into the dilated arteries and out of the constricted veins; a constant erectile size is achieved at this equilibrium. Although many erect penises point upwards, it is common and normal for the erect penis to point nearly vertically upwards, nearly vertically downwards, or even horizontally forward, depending on the tension of the suspensory ligament that holds it in position.

Ejaculation is the ejection of semen from the penis and is usually accompanied by orgasm. A series of muscular contractions delivers semen, containing sperm cells or spermatozoa, from the penis. It is usually the result of sexual stimulation, including prostate stimulation. Ejaculation may occur spontaneously during sleep (known as a nocturnal emission or “wet dream”).

Ejaculation has two phases: emission and ejaculation proper. The emission phase of the ejaculatory reflex is under control of the sympathetic nervous system, while the ejaculatory phase is under the control of a spinal reflex at the level of spinal nerves S2 to S4 via the pudendal nerve. A refractory period succeeds the ejaculation, and sexual stimulation precedes it. Anejaculation is the condition of being unable to ejaculate.

Testes Ducts

Testes ducts, which include the seminiferous tubules and vas deferens, are involved in the creation or transportation of sperm.

Key Points

The creation of sperm occurs in the seminiferous tubules of the testes.

The efferent ducts maintain proper fluid concentration in the testes and propel sperm to the epididymis.

The vas deferens carry the sperm from the epididymis to the urethra.

A vasectomy cuts the vas deferens to prevent sperm from entering the urethra and being ejaculated.

Key Terms

  • vasectomy: The surgical removal of all or part of the vas deferens, usually as a means of male sterilization.
  • peristalsis: A radially symmetrical contraction and relaxation of muscles that propagates in an anterograde (forward) wave down a tube.
  • vas deferens: The duct in the testes that carries semen from the epididymis to the ejaculatory duct.
  • rete testis: An anastomosing network of tubules located in the hilum of the testicle (mediastinum testis) that carries sperm from the seminiferous tubules to the efferent ducts.
image

Inside the Human Testes: Diagram of a cross-section of testes: 1: Testicular septa 2: Convoluted seminiferous tubules 3: Testicular lobules 4: Straight seminiferous tubules 5: Efferent ductules 6: Rete testis.

Seminiferous tubules, located in the testes, are where meiosis occurs and the gametes (spermatozoa) are created. The seminiferous tubules are formed from primitive sex cords from the gonadal ridge. The epithelium of the tubule consists of tall, columnar cells called Sertoli cells. Between the Sertoli cells are spermatogenic cells, which differentiate through meiosis to become sperm cells. There are two types of seminiferous tubules: convoluted, located toward the lateral side, and straight, as the tubule comes medially to form ducts that will exit the testis.

Efferent Ducts

The efferent ducts connect the rete testis with the initial section of the epididymis. There are two basic types of efferent ductule structures.

  • Multiple entries into the epididymis: This type is seen in most large mammals. In humans and other large mammals, there are approximately 15–20 efferent ducts that occupy nearly one-third of the head of the epididymis.
  • Single entry: This type is seen in most small animals such as rodents. This is characterized by three to six ductules that merge into a single small ductule prior to entering the epididymis.

The ductuli are unilaminar and composed of columnar ciliated and nonciliated (absorptive) cells. The ciliated cells stir the luminal fluids, which may help ensure homogeneous absorption of water from the fluid produced by the testis. This results in an increase in the concentration of luminal sperm. The epithelium is surrounded by a band of smooth muscle that helps to propel the sperm toward the epididymis.

image

Histological Representation of Seminiferous Tubules: Seminiferous tubule in cross-section (large tubular structure: center of image) with sperm (black, tiny, ovoid bodies furthest from the outer edge of the tubular structure).

The ductus (vas) deferens, also called the sperm duct, extend from the epididymis on each side of the scrotum into the abdominal cavity through the inguinal canal, an opening in the abdominal wall for the spermatic cord. The spermatic cord is a connective tissue sheath that contains the vas deferens, testicular blood vessels, and nerves.

The smooth muscle layer of the vas deferens contracts in waves of peristalsis during ejaculation. Two ducts connect the left and right epididymis to the ejaculatory ducts in order to move sperm. In humans, each tube is about 30 centimeters (a foot) long,
3 to 5 mm in diameter, and surrounded by smooth muscle. The sperm are transferred from the vas deferens into the urethra, collecting secretions from the male accessory sex glands such as the seminal vesicles, prostate gland, and bulbourethral glands, which provide the bulk of semen.

The procedure of deferentectomy, also known as vasectomy, is a method of contraception in which the vas deferens are permanently cut, though in some cases it can be reversed. A modern procedure that does not include cutting the ducts involves injecting an obstructive material into the ductus to block the flow of sperm. Research in male contraception has focused primarily on the vas deferens with the use of the intra-vas device and reversible inhibition of sperm under guidance.

Accessory Sex Glands

The accessory sex glands produce seminal fluid and clean and lubricate the urethra.

Key Points

Seminal glands contain seminal vesicles that produce 50–70% of the seminal fluid.

The excretory duct of the seminal gland opens into the vas deferens as it enters the prostate gland.

Sperm are not in contact with the seminal fluid produced by the seminal vesicles, possibly to block the progress of sperm from other males.

The prostate secretes 20–30% of the seminal fluid which carries the sperm in the ejaculate.

The prostate surrounds the urethra below the bladder and can be felt in a rectal exam.

Bulbourethral glands produce a pre-ejaculate secretion that lubricates and flushes out the urethra in preparation for the sperm.

Key Terms

  • bulbourethral gland: An exocrine gland that secretes a clear fluid upon sexual arousal as pre-ejaculate (or Cowper’s fluid).
  • Lipofuscin: Yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion.
  • prostate: A compound tubuloalveolar exocrine gland of the male reproductive system in most mammals.
  • seminal gland: A pair of simple tubular glands located within the pelvis
    that secrete fluid that partly composes semen.

The accessory sex glands, including the seminal, prostate glands, and bulbourethral glands, produce seminal fluid and clean and lubricate the urethra.

Seminal Gland Anatomy

Each seminal gland forms as an outward growth of the wall of the ampulla of each vas deferens. They are curled and folded within the gland and can spread out to approximately 5 cm, but the unfolded length is approximately 10 cm. The excretory duct of the seminal gland opens into the vas deferens as it enters the prostate gland.

Seminal Gland Physiology and Function

The seminal vesicles secrete a significant proportion of the fluid that ultimately becomes semen. Lipofuscin granules from dead epithelial cells give the secretion its yellowish color. About 50–70% of seminal fluid in humans originates from the seminal vesicles but is not expelled in the first ejaculate fractions which are dominated by spermatozoa and zinc-rich prostatic fluid. Seminal vesicle fluid is alkaline, resulting in human semen with a mildly alkaline pH. This helps neutralize the acidity of the vaginal tract, prolonging the lifespan of sperm. Acidic ejaculate (pH <7.2) may be associated with ejaculatory duct obstruction. The vesicle produces a substance that causes the semen to become sticky after ejaculation, thought to help keep the semen near the cervix.

The thick seminal vesicle secretions contain proteins (including enzymes), mucus, fructose, vitamin C, flavins, phosphorylcholine, and prostaglandins. The high fructose concentrations provide nutrient energy for the spermatozoa when stored in semen in the laboratory. Spermatozoa ejaculated into the vagina are not likely to have contact with seminal vesicular fluid, but transfer directly from the prostatic fluid into the cervical mucus as the first step on their travel through the female reproductive system.

Seminal vesicle fluid is expelled under the sympathetic contraction of the muscular muscle coat. In vitro studies have shown that sperm expelled together with seminal vesicular fluid show poor motility and survival and less-protected chromatin. Thus, the exact physiological importance of seminal vesicular fluid is unclear. It may be a developmental rest, such as in some rodents where the last part of the ejaculate forms a spermicidal plug to reduce the chances for sperm from a later-arriving male to proceed to the oocyte.

Prostate Gland Anatomy

 

image

Prostate: Prostate with seminal vesicles and seminal ducts, viewed from the front and above, including the urethra, seminal vesicle, vas deferens, ampulla, ejaculatory duct, and isthmus.

The prostate surrounds the urethra just below the urinary bladder and can be felt during a rectal exam. It is the only exocrine organ located in the midline in humans and similar animals. Within the prostate, the urethra coming from the bladder is called the prostatic urethra and merges with the two ejaculatory ducts. The prostate is sheathed in the muscles of the pelvic floor, which contract during the ejaculatory process.

Prostate Gland Physiology and Function

The prostate secretes a slightly acidic fluid, milky or white in appearance, that usually constitutes 20–30% of the volume of the semen along with spermatozoa and seminal vesicle fluid. The prostatic fluid is expelled in the first ejaculate fractions, together with most of the spermatozoa. In comparison with the few spermatozoa expelled in seminal vesicular fluid, those expelled in prostatic fluid have better motility, longer survival, and better protection of the genetic material. The prostate also contains some smooth muscles that help expel semen during ejaculation.

To work properly, the prostate needs male hormones (e.g., testosterone), which are produced mainly by the testes. Some male hormones are produced in small amounts by the adrenal glands. However, dihydrotestosterone regulates the prostate. A healthy human prostate is slightly larger than a walnut in adult males, with a weight ranging between 7 and 16 grams.

Bulbourethral Glands

This diagram of the prostate indicates the deep and dorsal arteries of the penis, artery of urethral bulb, internal pudendal artery, bulbourethral gland, sphincter, and rectum.

Bulbourethral Gland: The image shows an internal view of the penis and male sexual anatomy. The bulbourethral gland is labeled at center-left.

Bulbourethral glands are located posterior and lateral to the membranous portion of the urethra at the base of the penis, between the two layers of the fascia of the urogenital diaphragm in the deep perineal pouch. They are enclosed by transverse fibers of the sphincter urethrae membranacea muscle. The bulbourethral glands are compound tubuloalveolar glands, each approximately the size of a pea. They are composed of several lobules held together by a fibrous covering. Each lobule opens into a duct that joins with the ducts of other lobules to form a single excretory duct. This duct is approximately 2.5 cm long and opens into the urethra at the base of the penis. The glands gradually diminish in size with advancing age.

During sexual arousal, each gland produces a clear, salty, viscous secretion known as pre-ejaculate. This fluid helps to lubricate the urethra for spermatozoa to pass through, neutralizes traces of acidic urine in the urethra, and helps flush out any residual urine or foreign matter. It is possible for this fluid to pick up sperm remaining in the urethral bulb from previous ejaculations and carry them out prior to the next ejaculation.

References

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Meiosis – Anatomy, Structure, Functions

Meiosis is a special type of cell division of germ cells in sexually reproducing organisms used to produce the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilization, the haploid cells produced by meiosis from a male and female will fuse to create a cell with two copies of each chromosome again, the zygote. Errors in meiosis resulting in aneuploidy (an abnormal number of chromosomes) are the leading known cause of miscarriage and the most frequent genetic cause of developmental disabilities.[rx]

Meiosis is a special type of cell division of germ cells in sexually reproducing organisms used to produce the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome.

Introduction to Meiosis

Meiosis is the nuclear division of diploid cells into haploid cells, which is a necessary step in sexual reproduction.

Key Points

Sexual reproduction is the production of haploid cells and the fusion of two of those cells to form a diploid cell.

Before sexual reproduction can occur, the number of chromosomes in a diploid cell must decrease by half.

Meiosis produces cells with half the number of chromosomes as the original cell.

Haploid cells used in sexual reproduction, gametes, are formed during meiosis, which consists of one round of chromosome replication and two rounds of nuclear division.

Meiosis I is the first round of meiotic division, while meiosis II is the second round.

Key Terms

  • haploid: of a cell having a single set of unpaired chromosomes
  • gamete: a reproductive cell, male (sperm) or female (egg), that has only half the usual number of chromosomes
  • diploid: of a cell, having a pair of each type of chromosome, one of the pair being derived from the ovum and the other from the spermatozoon

Introduction: Meiosis and Sexual Reproduction

The ability to reproduce in kind is a basic characteristic of all living things. In-kind means that the offspring of any organism closely resemble their parent or parents. Sexual reproduction requires fertilization: the union of two cells from two individual organisms. Haploid cells contain one set of chromosomes. Cells containing two sets of chromosomes are called diploids. The number of sets of chromosomes in a cell is called its ploidy level. If the reproductive cycle is to continue, then the diploid cell must somehow reduce its number of chromosome sets before fertilization can occur again or there will be a continual doubling in the number of chromosome sets in every generation. Therefore, sexual reproduction includes a nuclear division that reduces the number of chromosome sets.

image

Offspring Closely Resemble Their Parents: In-kind means that the offspring of any organism closely resemble their parent or parents. The hippopotamus gives birth to hippopotamus calves

  • (a). Joshua trees produce seeds from which Joshua tree seedlings emerge
  • (b). Adult flamingos lay eggs that hatch into flamingo chicks
  • (c). Sexual reproduction is the production of haploid cells (gametes) and the fusion (fertilization) of two gametes to form a single, unique diploid cell called a zygote. All animals and most plants produce these gametes, or eggs and sperm. In most plants and animals, through tens of rounds of mitotic cell division, this diploid cell will develop into an adult organism.

Haploid cells that are part of the sexual reproductive cycle are produced by a type of cell division called meiosis. Meiosis employs many of the same mechanisms as mitosis. However, the starting nucleus is always diploid and the nuclei that result at the end of a meiotic cell division are haploid, so the resulting cells have half the chromosomes as the original. To achieve this reduction in chromosomes, meiosis consists of one round of chromosome duplication and two rounds of nuclear division. Because the events that occur during each of the division stages are analogous to the events of mitosis, the same stage names are assigned. However, because there are two rounds of division, the major process and the stages are designated with an “I” or a “II.” Thus, meiosis I am the first round of meiotic division and consists of prophase I, prometaphase I, and so on. Meiosis II, the second round of meiotic division, includes prophase II, prometaphase II, and so on.

Comparing Meiosis and Mitosis

Mitosis and meiosis share some similarities, but also some differences, most of which are observed during meiosis I.

Key Points

For the most part, in mitosis, diploid cells are partitioned into two new diploid cells, while in meiosis, diploid cells are partitioned into four new haploid cells.

In mitosis, the daughter cells have the same number of chromosomes as the parent cell, while in meiosis, the daughter cells have half the number of chromosomes as the parent.

The daughter cells produced by mitosis are identical, whereas the daughter cells produced by meiosis are different because crossing over has occurred.

The events that occur in meiosis but not mitosis include homologous chromosomes pairing up, crossing over, and lining up along the metaphase plate in tetrads.

Meiosis II and mitosis are not reduction divisions like meiosis I because the number of chromosomes remains the same; therefore, meiosis II is referred to as equatorial division.

When the homologous chromosomes separate and move to opposite poles during meiosis I, the ploidy level is reduced from two to one, which is referred to as a reduction division.

Key Terms

  • reduction division: the first of the two divisions of meiosis, a type of cell division
  • ploidy: the number of homologous sets of chromosomes in a cell
  • equatorial division: a process of nuclear division in which each chromosome divides equally such that the number of chromosomes remains the same from parent to daughter cells

Comparing Meiosis and Mitosis

Mitosis and meiosis are both forms of division of the nucleus in eukaryotic cells. They share some similarities, but also exhibit distinct differences that lead to very different outcomes. The purpose of mitosis is cell regeneration, growth, and asexual reproduction, while the purpose of meiosis is the production of gametes for sexual reproduction. Mitosis is a single nuclear division that results in two nuclei that are usually partitioned into two new daughter cells. The nuclei resulting from a mitotic division are genetically identical to the original nucleus. They have the same number of sets of chromosomes, one set in the case of haploid cells and two sets in the case of diploid cells. In most plants and all animal species, it is typically diploid cells that undergo mitosis to form new diploid cells. In contrast, meiosis consists of two nuclear divisions resulting in four nuclei that are usually partitioned into four new haploid daughter cells. The nuclei resulting from meiosis are not genetically identical and they contain one chromosome set only. This is half the number of chromosome sets in the original cell, which is diploid.

image

Comparing Meiosis and Mitosis: Meiosis and mitosis are both preceded by one round of DNA replication; however, meiosis includes two nuclear divisions. The four daughter cells resulting from meiosis are haploid and genetically distinct. The daughter cells resulting from mitosis are diploid and identical to the parent cell.

The main differences between mitosis and meiosis occur in meiosis I. In meiosis I, the homologous chromosome pairs become associated with each other and are bound together with the synaptonemal complex. Chiasmata develop and crossover occurs between homologous chromosomes, which then line up along the metaphase plate in tetrads with kinetochore fibers from opposite spindle poles attached to each kinetochore of a homolog in a tetrad. All of these events occur only in meiosis I.

When the tetrad is broken up and the homologous chromosomes move to opposite poles, the ploidy level is reduced from two to one. For this reason, meiosis I am referred to as a reduction division. There is no such reduction in ploidy level during mitosis.

Meiosis II is much more similar to a mitotic division. In this case, the duplicated chromosomes (only one set, as the homologous pairs, have now been separated into two different cells) line up on the metaphase plate with divided kinetochores attached to kinetochore fibers from opposite poles. During anaphase II and mitotic anaphase, the kinetochores divide and sister chromatids, now referred to as chromosomes, are pulled to opposite poles. The two daughter cells of mitosis, however, are identical, unlike the daughter cells produced by meiosis. They are different because there has been at least one crossover per chromosome. Meiosis II is not a reduction division because, although there are fewer copies of the genome in the resulting cells, there is still one set of chromosomes, as there was at the end of meiosis I. Meiosis II is, therefore, referred to as equatorial division.

Functions of Meiosis

The origin and function of meiosis are currently not well understood scientifically and would provide fundamental insight into the evolution of sexual reproduction in eukaryotes. There is no current consensus among biologists on the questions of how sex in eukaryotes arose in evolution, what basic function sexual reproduction serves, and why it is maintained, given the basic two-fold cost of sex. It is clear that it evolved over 1.2 billion years ago, and that almost all species that are descendants of the original sexually reproducing species are still sexual reproducers, including plants, fungi, and animals.

Meiosis is a key event of the sexual cycle in eukaryotes. It is the stage of the life cycle when a cell gives rise to haploid cells (gametes) each having half as many chromosomes as the parental cell. Two such haploid gametes, ordinarily arising from different individual organisms, fuse by the process of fertilization, thus completing the sexual cycle.

Meiosis is ubiquitous among eukaryotes. It occurs in single-celled organisms such as yeast, as well as in multicellular organisms, such as humans. Eukaryotes arose from prokaryotes more than 2.2 billion years ago[rx] and the earliest eukaryotes were likely single-celled organisms. To understand sex in eukaryotes, it is necessary to understand (1) how meiosis arose in single-celled eukaryotes, and (2) the function of meiosis.

Origin of Meiosis

There are two conflicting theories on how meiosis arose. One is that meiosis evolved from prokaryotic sex (bacterial recombination) as eukaryotes evolved from prokaryotes.[rx][rx] The other is that meiosis arose from mitosis.[rx]

From prokaryotic sex

In prokaryotic sex, DNA from one prokaryote is taken up by another prokaryote, and its information is integrated into the DNA of the recipient prokaryote. In extant prokaryotes, the donor DNA can be transferred either by transformation or conjugation.[rx][rx] Transformation in which DNA from one prokaryote is released into the surrounding medium and then taken up by another prokaryotic cell may have been the earliest form of sexual interaction. One theory on how meiosis arose is that it evolved from transformation.[rx] According to this view, the evolutionary transition from prokaryotic sex to eukaryotic sex was continuous.

Transformation, like meiosis, is a complex process requiring the function of numerous gene products. A key similarity between prokaryotic sex and eukaryotic sex is that DNA originating from two different individuals (parents) joins up so that homologous sequences are aligned with each other, and this is followed by an exchange of genetic information (a process called genetic recombination). After the new recombinant chromosome is formed it is passed on to progeny.

When genetic recombination occurs between DNA molecules originating from different parents, the recombination process is catalyzed in prokaryotes and eukaryotes by enzymes that have similar functions and that are evolutionarily related. One of the most important enzymes catalyzing this process in bacteria is referred to as RecA, and this enzyme has two functionally similar counterparts that act in eukaryotic meiosis, RAD51, and DMC1.[rx]

Support for the theory that meiosis arose from prokaryotic transformation comes from the increasing evidence that early diverging lineages of eukaryotes have the core genes for meiosis. This implies that the precursor to meiosis was already present in the prokaryotic ancestor of eukaryotes. For instance the common intestinal parasite Giardia intestinalis, a simple eukaryotic protozoan was, until recently, thought to be descended from an early diverging eukaryotic lineage that lacked sex. However, it has since been shown that G. intestinalis contains within its genome a core set of genes that function in meiosis, including five genes that function only in meiosis.[rx] In addition, G. intestinalis was recently found to undergo a specialized, sex-like process involving meiosis gene homologs.[rx] This evidence, and other similar examples, suggest that a primitive form of meiosis was present in the common ancestor of all eukaryotes, an ancestor that arose from an antecedent prokaryote.[rx][rx]

From mitosis

Mitosis is the normal process in eukaryotes for cell division; duplicating chromosomes and segregating one of the two copies into each of the two daughter cells, in contrast with meiosis. The mitosis theory states that meiosis evolved from mitosis.[rx] According to this theory, early eukaryotes evolved mitosis first, became established, and only then did meiosis and sexual reproduction arise.

Supporting this idea are observations of some features, such as the meiotic spindles that draw chromosome sets into separate daughter cells upon cell division, as well as processes regulating cell division that employ the same, or similar molecular machinery. Yet there is no compelling evidence for a period in the early evolution of eukaryotes, during which meiosis and accompanying sexual capability did not yet exist.

In addition, as noted by Wilkins and Holliday,[rx] there are four novel steps needed in meiosis that are not present in mitosis. These are

  • (1) pairing of homologous chromosomes,
  • (2) extensive recombination between homologs;
  • (3) suppression of sister chromatid separation in the first meiotic division; and
  • (4) avoiding chromosome replication during the second meiotic division. Although the introduction of these steps seems to be complicated, Wilkins and Holliday argue that only one new step, homolog synapsis, was particularly initiated in the evolution of meiosis from mitosis. Meanwhile, two of the other novel features could have been simple modifications, and extensive recombination could have evolved later.[rx]

Coevolution with mitosis

If meiosis arose from prokaryotic transformation, during the early evolution of eukaryotes, mitosis and meiosis could have evolved in parallel. Both processes use shared molecular components, where mitosis evolved from the molecular machinery used by prokaryotes for DNA replication and segregation, and meiosis evolved from the prokaryotic sexual process of transformation. However, meiosis also made use of the evolving molecular machinery for DNA replication and segregation.

Function

Stress-induced sex

Abundant evidence indicates that facultative sexual eukaryotes tend to undergo sexual reproduction under stressful conditions. For instance, the budding yeast Saccharomyces cerevisiae (a single-celled fungus) reproduces mitotically (asexually) as diploid cells when nutrients are abundant, but switches to meiosis (sexual reproduction) under starvation conditions.[rx] The unicellular green alga, Chlamydomonas reinhardtii grows as vegetative cells in a nutrient-rich growth medium, but depletion of a source of nitrogen in the medium leads to gamete fusion, zygote formation, and meiosis.[rx] The fission yeast Schizosaccharomyces pombe, treated with H2O2 to cause oxidative stress, substantially increases the proportion of cells that undergo meiosis.[rx] The simple multicellular eukaryote Volvox carteri undergoes sex in response to oxidative stress[rx] or stress from heat shock.[rx] These examples, and others, suggest that, in simple single-celled and multicellular eukaryotes, meiosis is an adaptation to respond to stress.

Prokaryotic sex also appears to be an adaptation to stress. For instance, transformation occurs near the end of logarithmic growth, when amino acids become limiting in Bacillus subtilis,[rx] or in Haemophilus influenzae when cells are grown to the end of a logarithmic phase.[rx] In Streptococcus mutants and other streptococci, transformation is associated with high cell density and biofilm formation.[rx] In Streptococcus pneumoniae, transformation is induced by the DNA damaging agent mitomycin C.[rx] These, and other, examples indicate that prokaryotic sex, like meiosis in simple eukaryotes, is an adaptation to stressful conditions. This observation suggests that the natural selection pressures maintaining meiosis in eukaryotes are similar to the selective pressures maintaining prokaryotic sex. This similarity suggests continuity, rather than a gap, in the evolution of sex from prokaryotes to eukaryotes.

Stress is, however, a general concept. What is it specifically about the stress that needs to be overcome by meiosis? And what is the specific benefit provided by meiosis that enhances survival under stressful conditions?

DNA repair

In one theory, meiosis is primarily an adaptation for repairing DNA damage. Environmental stresses often lead to oxidative stress within the cell, which is well known to cause DNA damage through the production of reactive forms of oxygen, known as reactive oxygen species (ROS). DNA damages, if not repaired, can kill a cell by blocking DNA replication, or transcription of essential genes.

When only one strand of the DNA is damaged, the lost information (nucleotide sequence) can ordinarily be recovered by repair processes that remove the damaged sequence and fill the resulting gap by copying from the opposite intact strand of the double helix. However, ROS also causes a type of damage that is difficult to repair, referred to as double-strand damage. One common example of double-strand damage is the double-strand break. In this case, genetic information (nucleotide sequence) is lost from both strands in the damaged region, and proper information can only be obtained from another intact chromosome homologous to the damaged chromosome. The process that the cell uses to accurately accomplish this type of repair is called recombinational repair.

Meiosis is distinct from mitosis in that a central feature of meiosis is the alignment of homologous chromosomes followed by recombination between them. The two chromosomes that pair are referred to as non-sister chromosomes since they did not arise simply from the replication of a parental chromosome. Recombination between non-sister chromosomes at meiosis is known to be a recombinational repair process that can repair double-strand breaks and other types of double-strand damage.[rx] In contrast, recombination between sister chromosomes cannot repair double-strand damages arising prior to the replication which produced them. Thus on this view, the adaptive advantage of meiosis is that it facilitates recombinational repair of DNA damage that is otherwise difficult to repair, and that occurs as a result of stress, particularly oxidative stress.[rx][rx] If left unrepaired, this damage would likely be lethal to gametes and inhibit the production of viable progeny.

Even in multicellular eukaryotes, such as humans, oxidative stress is a problem for cell survival. In this case, oxidative stress is a byproduct of oxidative cellular respiration occurring during metabolism in all cells. In humans, on average, about 50 DNA double-strand breaks occur per cell in each cell generation.[rx] Meiosis, which facilitates recombinational repair between non-sister chromosomes, can efficiently repair these prevalent damages in the DNA passed on to germ cells, and consequently prevent loss of fertility in humans. Thus with the theory that meiosis arose from prokaryotic sex, the recombinational repair is the selective advantage of meiosis in both single-celled eukaryotes and multicellular eukaryotes, such as humans.

An argument against this hypothesis is that adequate repair mechanisms including those involving recombination already exist in prokaryotes.[rx] Prokaryotes do have a DNA repair mechanism enriched with recombinational repair,[rx] and the existence of prokaryotic life in severe environments indicates the extreme efficiency of this mechanism to help them survive many DNA damages related to the environment. This implies that an extra costly repair in the form of meiosis would be unnecessary. However, most of these mechanisms cannot be as accurate as meiosis and are possibly more mutagenic than the repair mechanism provided by meiosis. They primarily do not require a second homologous chromosome for the recombination that promotes a more extensive repair. Thus, despite the efficiency of recombinational repair involving sister chromatids, the repair still needs to be improved, and another type of repair is required.[rx] Moreover, due to the more extensive homologous recombinational repair in meiosis in comparison to the repair in mitosis, meiosis as a repair mechanism can accurately remove any damage that arises at any stage of the cell cycle more than mitotic repair mechanism can do [rx] and was, therefore, naturally selected. In contrast, the sister chromatid in mitotic recombination could have been exposed to a similar amount of stress, and, thus, this type of recombination, instead of eliminating the damage, could actually spread the damage[rx] and decrease fitness.

Phases

Meiosis is divided into meiosis I and meiosis II which are further divided into Karyokinesis I and Cytokinesis I and Karyokinesis II and Cytokinesis II respectively. The preparatory steps that lead up to meiosis are identical in pattern and name to interphase of the mitotic cell cycle.[rx] Interphase is divided into three phases:

  • Growth 1 (G1) phase: In this very active phase, the cell synthesizes its vast array of proteins, including the enzymes and structural proteins it will need for growth. In G1, each of the chromosomes consists of a single linear molecule of DNA.
  • Synthesis (S) phase: The genetic material is replicated; each of the cell’s chromosomes duplicates to become two identical sister chromatids attached at a centromere. This replication does not change the ploidy of the cell since the centromere number remains the same. The identical sister chromatids have not yet condensed into the densely packaged chromosomes visible with the light microscope. This will take place during prophase I in meiosis.
  • Growth 2 (G2) phase: G2 phase as seen before mitosis is not present in meiosis. Meiotic prophase corresponds most closely to the G2 phase of the mitotic cell cycle.

Interphase is followed by meiosis I and then meiosis II. Meiosis I separates replicated homologous chromosomes, each still made up of two sister chromatids, into two daughter cells, thus reducing the chromosome number by half. During meiosis II, sister chromatids decouple and the resultant daughter chromosomes are segregated into four daughter cells. For diploid organisms, the daughter cells resulting from meiosis are haploid and contain only one copy of each chromosome. In some species, cells enter a resting phase known as interkinesis between meiosis I and meiosis II.

Meiosis I and II are each divided into prophase, metaphase, anaphase, and telophase stages, similar in purpose to their analogous subphases in the mitotic cell cycle. Therefore, meiosis includes the stages of meiosis I (prophase I, metaphase I, anaphase I, telophase I) and meiosis II (prophase II, metaphase II, anaphase II, telophase II).

Diagram of the meiotic phases

During meiosis, specific genes are more highly transcribed.[rx][rx] In addition to the strong meiotic stage-specific expression of mRNA, there are also pervasive translational controls (e.g. selective usage of preformed mRNA), regulating the ultimate meiotic stage-specific protein expression of genes during meiosis.[rx] Thus, both transcriptional and translational controls determine the broad restructuring of meiotic cells needed to carry out meiosis.

Meiosis I

Meiosis I segregates homologous chromosomes, which are joined as tetrads (2n, 4c), producing two haploid cells (n chromosomes, 23 in humans) which each contain chromatid pairs (1n, 2c). Because the ploidy is reduced from diploid to haploid, meiosis I am referred to as a reductional division. Meiosis II is an equational division analogous to mitosis, in which the sister chromatids are segregated, creating four haploid daughter cells (1n, 1c).[rx]

Meiosis Prophase I in mice. In Leptotene (L) the axial elements (stained by SYCP3) begin to form. In Zygotene (Z) the transverse elements (SYCP1) and central elements of the synaptonemal complex are partially installed (appearing as yellow as they overlap with SYCP3). In Pachytene (P) it’s fully installed except on the sex chromosomes. In Diplotene (D) it disassembles revealing chiasmata. CREST marks the centromeres.

Schematic of the synaptonemal complex at different stages of prophase I and the chromosomes arranged as a linear array of loops.

Prophase I

Prophase I is by far the longest phase of meiosis (lasting 13 out of 14 days in mice[rx]). During prophase I, homologous maternal and paternal chromosomes pair, synapse, and exchange genetic information (by homologous recombination), forming at least one crossover per chromosome.[rx] These crossovers become visible as chiasmata (plural; singular chiasma).[rx] This process facilitates stable pairing between homologous chromosomes and hence enables accurate segregation of the chromosomes at the first meiotic division. The paired and replicated chromosomes are called bivalents (two chromosomes) or tetrads (four chromatids), with one chromosome coming from each parent. Prophase I is divided into a series of substages which are named according to the appearance of chromosomes.

Leptotene

The first stage of prophase I am the leptotene stage, also known as leptonema, from Greek words meaning “thin threads”.[rx] In this stage of prophase I, individual chromosomes—each consisting of two replicated sister chromatids—become “individualized” to form visible strands within the nucleus.[rx] [rx] .The chromosomes each form a linear array of loops mediated by cohesin, and the lateral elements of the synaptonemal complex assemble forming an “axial element” from which the loops emanate.[rx] Recombination is initiated in this stage by the enzyme SPO11 which creates programmed double-strand breaks (around 300 per meiosis in mice).[rx] This process generates single-stranded DNA filaments coated by RAD51 and DMC1 which invade the homologous chromosomes, forming inter-axis bridges, and resulting in the pairing/co-alignment of homologs (to a distance of ~400 nm in mice).[rx][rx]

Zygotene

Leptotene is followed by the zygotene stage, also known as zygonema, from Greek words meaning “paired threads”,[rx]  which in some organisms is also called the bouquet stage because of the way the telomeres cluster at one end of the nucleus.[rx] In this stage the homologous chromosomes become much more closely (~100 nm) and stably paired (a process called synapsis) mediated by the installation of the transverse and central elements of the synaptonemal complex.[rx] Synapsis is thought to occur in a zipper-like fashion starting from a recombination nodule. The paired chromosomes are called bivalent or tetrad chromosomes.

Pachytene

The pachytene stage is also known as pachynema, is from Greek words meaning thick threads is the stage at which all autosomal chromosomes have synapsed. In this stage homologous recombination, including chromosomal crossover (crossing over), is completed through the repair of the double-strand breaks formed in leptotene.[rx] Most breaks are repaired without forming crossovers resulting in gene conversion.[rx] However, a subset of breaks (at least one per chromosome) form crossovers between non-sister (homologous) chromosomes resulting in the exchange of genetic information.[25] Sex chromosomes, however, are not wholly identical, and only exchange information over a small region of homology called the pseudoautosomal region.[rx] The exchange of information between the homologous chromatids results in a recombination of information; each chromosome has the complete set of information it had before, and there are no gaps formed as a result of the process. Because the chromosomes cannot be distinguished in the synaptonemal complex, the actual act of crossing over is not perceivable through an ordinary light microscope, and chiasmata are not visible until the next stage.

Diplotene

During the diplotene stage, also known as diplonema, from Greek words meaning two threads [rx]the synaptonemal complex disassembles and homologous chromosomes separate from one another a little. However, the homologous chromosomes of each bivalent remain tightly bound at chiasmata, the regions where crossing-over occurred. The chiasmata remain on the chromosomes until they are severed at the transition to anaphase I to allow homologous chromosomes to move to opposite poles of the cell.

In human fetal oogenesis, all developing oocytes develop to this stage and are arrested in prophase I before birth.[rx] This suspended state is referred to as the dictyotene stage or dictyate. It lasts until meiosis is resumed to prepare the oocyte for ovulation, which happens at puberty or even later.

Diakinesis

Chromosomes condense further during the diakinesis stage, from Greek words meaning moving through.[rx] This is the first point in meiosis where the four parts of the tetrads are actually visible. Sites of crossing over entangle together, effectively overlapping, making chiasmata clearly visible. Other than this observation, the rest of the stage closely resembles prometaphase of mitosis; the nucleoli disappear, the nuclear membrane disintegrates into vesicles, and the meiotic spindle begins to form.

Meiotic spindle formation

Unlike mitotic cells, human and mouse oocytes do not have centrosomes to produce the meiotic spindle. In mice, approximately 80 Microtubule Organizing Centers (MTOCs) form a sphere in the ooplasm and begin to nucleate microtubules that reach out towards chromosomes, attaching to the chromosomes at the kinetochore. Over time the MTOCs merge until two poles have formed, generating a barrel-shaped spindle.[rx] In human oocytes spindle microtubule nucleation begins on the chromosomes, forming an aster that eventually expands to surround the chromosomes.[rx] Chromosomes then slide along the microtubules towards the equator of the spindle, at which point the chromosome kinetochores from end-on attachments to microtubules.[rx]

Metaphase I

Homologous pairs move together along the metaphase plate: As kinetochore microtubules from both spindle poles attach to their respective kinetochores, the paired homologous chromosomes align along an equatorial plane that bisects the spindle, due to continuous counterbalancing forces exerted on the bivalents by the microtubules emanating from the two kinetochores of homologous chromosomes. This attachment is referred to as a bipolar attachment. The physical basis of the independent assortment of chromosomes is the random orientation of each bivalent along with the metaphase plate, with respect to the orientation of the other bivalents along the same equatorial line.[17] The protein complex cohesin holds sister chromatids together from the time of their replication until anaphase. In mitosis, the force of kinetochore microtubules pulling in opposite directions creates tension. The cell senses this tension and does not progress with anaphase until all the chromosomes are properly bi-oriented. In meiosis, establishing tension ordinarily requires at least one crossover per chromosome pair in addition to cohesion between sister chromatids

Anaphase I

Kinetochore microtubules shorten, pulling homologous chromosomes (which each consist of a pair of sister chromatids) to opposite poles. Nonkinetochore microtubules lengthen, pushing the centrosomes farther apart. The cell elongates in preparation for division down the center.[17] Unlike in mitosis, only the cohesin from the chromosome arms is degraded while the cohesin surrounding the centromere remains protected by a protein named Shugoshin (Japanese for “guardian spirit”), which prevents the sister chromatids from separating.[31] This allows the sister chromatids to remain together while homologs are segregated.

Telophase I

The first meiotic division effectively ends when the chromosomes arrive at the poles. Each daughter cell now has half the number of chromosomes but each chromosome consists of a pair of chromatids. The microtubules that make up the spindle network disappear, and a new nuclear membrane surrounds each haploid set. The chromosomes uncoil back into chromatin. Cytokinesis, the pinching of the cell membrane in animal cells or the formation of the cell wall in plant cells, occurs, completing the creation of two daughter cells. However, cytokinesis does not fully complete resulting in “cytoplasmic bridges” which enable the cytoplasm to be shared between daughter cells until the end of meiosis II.[rx] Sister chromatids remain attached during telophase I.

Cells may enter a period of rest known as interkinesis or interphase II. No DNA replication occurs during this stage.

Meiosis II

Meiosis II is the second meiotic division, and usually involves equational segregation or separation of sister chromatids. Mechanically, the process is similar to mitosis, though its genetic results are fundamentally different. The end result is the production of four haploid cells (n chromosomes, 23 in humans) from the two haploid cells (with n chromosomes, each consisting of two sister chromatids) produced in meiosis I. The four main steps of meiosis II are prophase II, metaphase II, anaphase II, and telophase II.

In prophase II, we see the disappearance of the nucleoli and the nuclear envelope again as well as the shortening and thickening of the chromatids. Centrosomes move to the polar regions and arrange spindle fibers for the second meiotic division.

In metaphase II, the centromeres contain two kinetochores that attach to spindle fibers from the centrosomes at opposite poles. The new equatorial metaphase plate is rotated by 90 degrees when compared to meiosis I, perpendicular to the previous plate.[rx]

This is followed by anaphase II, in which the remaining centromeric cohesin, not protected by Shugoshin anymore, is cleaved, allowing the sister chromatids to segregate. The sister chromatids by convention are now called sister chromosomes as they move toward opposing poles.[rx]

The process ends with telophase II, which is similar to telophase I and is marked by decondensation and lengthening of the chromosomes and the disassembly of the spindle. Nuclear envelopes reform and cleavage or cell plate formation eventually produce a total of four daughter cells, each with a haploid set of chromosomes.

Meiosis is now complete and ends up with four new daughter cells.

Prophase I arrest

Female mammals and birds are born possessing all the oocytes needed for future ovulations, and these oocytes are arrested at the prophase I stage of meiosis.[rx] In humans, as an example, oocytes are formed between three and four months of gestation within the fetus and are therefore present at birth. During this prophase I arrested stage (dictyate), which may last for many years, four copies of the genome are present in the oocytes. The arrest of oocytes at the four genome copy stage was proposed to provide the informational redundancy needed to repair damage in the DNA of the germline.[rx] The repair process used likely involves homologous recombinational repair.[rx][rx] Prophase arrested oocytes have a high capability for efficient repair of DNA damages.[rx] The adaptive function of the DNA repair capability during meiosis appears to be a key quality control mechanism in the female germline and a critical determinant of fertility.[rx]

Genetic diversity

Another hypothesis to explain the function of meiosis is that stress is a signal to the cell that the environment is becoming adverse. Under this new condition, it may be beneficial to produce progeny that differs from the parent in their genetic makeup. Among these varied progeny, some may be more adapted to the changed condition than their parents. Meiosis generates genetic variation in the diploid cell, in part by the exchange of genetic information between the pairs of chromosomes after they align (recombination). Thus, on this view,[rx] an advantage of meiosis is that it facilitates the generation of genomic diversity among progeny, allowing adaptation to adverse changes in the environment.

However, in the presence of a fairly stable environment, individuals surviving to reproductive age have genomes that function well in their current environment. This raises the question of why such individuals should risk shuffling their genes with those of another individual, as occurs during meiotic recombination? Considerations such as this have led many investigators to question whether genetic diversity is a major adaptive advantage of sex.

References

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Reproductive System – Anatomy, Structure, Functions

The reproductive system in females is responsible for producing gametes (called eggs or ova), certain sex hormones, and maintaining fertilized eggs as they develop into mature fetuses and become ready for delivery. A female’s reproductive years are between menarche (the first menstrual cycle) and menopause (cessation of menses for 12 consecutive months). During this period, cyclical expulsion of ova from the ovary occurs, with the potential to become fertilized by male gametes (sperm). This cyclic expulsion of eggs is a normal part of the menstrual cycle.

Overview of the Male and Female Reproductive Systems

The human reproductive system functions to produce human offspring, with the male providing sperm and the female providing the ovum.

Key Points

The male reproductive system consists of external organs. The testes in the scrotum produce the male gamete, sperm, which is ejaculated in seminal fluid by the penis.

The female reproductive system primarily consists of internal organs. The female gamete, ovum, is produced in the ovaries and is released monthly to travel to the uterus via the Fallopian tubes.

Fertilization can occur if the penis is inserted through the vulva into the vagina and sperm is ejaculated towards the cervix. If an ovum is currently in the uterus, it can then be fertilized by sperm that manage to enter the cervix.

Once fertilized, an ovum becomes a zygote and if all goes well, develops into a fetus in the uterus.

Natural birth occurs when the fetus is pushed from the vagina after nine months in the uterus.

Key Terms

  • fallopian tubes: The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges (singular salpinx) are two very fine tubes lined with ciliated epithelia leading from the ovaries of female mammals into the uterus, via the utero-tubal junction.
  • penis: The male sexual organ for copulation and urination; the tubular portion of the male genitalia (excluding the scrotum).
  • vagina: A fibromuscular tubular tract which is the female sex organ and has two main functions: sexual intercourse and childbirth.

EXAMPLES

While the ultimate purpose of the human reproductive system is to produce offspring, the proximate purpose is to produce pleasure and induce bonding. This can be seen in our closest relatives, the bonobo chimpanzees, who have sex for a wide variety of reasons including pleasure, bonding, and alleviating tension in addition to producing offspring.

The reproductive system or genital system is a set of organs within an organism that work together to produce offspring. Many non-living substances, such as fluids, hormones, and pheromones, are important accessories to the reproductive system. Unlike most organ systems, the sexes of differentiated species often have significant differences. These differences allow for a combination of genetic material between two individuals and thus the possibility of greater genetic fitness of the offspring.

The Reproductive Process

Human reproduction takes place as internal fertilization by sexual intercourse. During this process, the erect penis of the male is inserted into the female’s vagina until the male ejaculates semen, which contains sperm, into the vagina. The sperm travels through the vagina and cervix into the uterus for potential fertilization of an ovum. Upon successful fertilization and implantation, the gestation of the fetus occurs within the female’s uterus for approximately nine months (pregnancy). Gestation ends with labor resulting in birth. In labor, the uterine muscles contract, the cervix dilates, and the baby passes out through the vagina. Human babies and children are nearly helpless and require high levels of parental care for many years. One important type of parental care is the use of the mammary glands in the female breasts to nurse the baby.

The Male Reproductive System

The human male reproductive system is a series of organs located outside of the body and around the pelvic region. The primary direct function of the male reproductive system is to provide the male gamete or spermatozoa for fertilization of the ovum. The major reproductive organs of the male can be grouped into three categories. The first category is sperm production and storage. Production takes place in the testes, housed in the temperature-regulating scrotum. Immature sperm then travel to the epididymis for development and storage. The second category, the ejaculatory fluid-producing glands, includes the seminal vesicles, prostate, and vas deferens. The final category, used for copulation and deposition of the spermatozoa (sperm) within the female, includes the penis, urethra, vas deferens, and Cowper’s gland.

This diagram of the male reproductive organs indicates the bladder, pubic bone, penis, corpus cavernosum, penis glands, foreskin, urethral opening, scrotum, testis, epididymis, vas deferens, anus, Cowper's gland, prostate gland, ejaculatory duct, seminal vesicle, rectum, and sigmoid colon.

Organ Systems Involved

The hypothalamic-pituitary-gonadal axis plays a major role in promoting sexual maturity, sperm production and the development of secondary sex characteristics. It maintains spermatogenesis and sexual function throughout the male’s lifetime. The hypothalamus secretes GnRH into the hypothalamo-hypophyseal portal system to stimulate the anterior pituitary. GnRH is a peptide hormone released by hypothalamic neurons in a pulsatile fashion. It acts on the gonadotrophs of the anterior pituitary via the binding and activation of a G protein receptor, which stimulates the anterior pituitary through inositol 1,4,5-triphosphate (IP3) activation (which increases intracellular calcium) to release FSH and LH. GnRH is inhibited by testosterone, estrogen, estradiol, and prolactin.[rx]

In response, the anterior pituitary secretes LH and FSH into the blood. These gonadotropic hormones act on membrane receptors in the Leydig and Sertoli cells of the testes respectively. Both hormones come from the same glycoprotein family and consist of identical alpha subunits, but their different beta-subunit differentiates their functions. Both exert their physiologic effects by binding and activating a G protein receptor, which activates adenylyl cyclase and increases cellular cAMP levels, to stimulate Sertoli and Leydig cells. LH stimulates Leydig cells in the interstitium of the testes to produce testosterone from cholesterol. LH promotes desmolase, which is the initial rate-limiting enzyme that converts cholesterol into pregnenolone. This goes on to produce two key weak androgen intermediates: dehydroepiandrosterone (DHEA) and androstenedione. The enzyme 17-beta-hydroxysteroid dehydrogenase completes the conversion of androstenedione to testosterone. Testosterone acts on the hypothalamus and anterior pituitary via negative feedback to decrease the secretion of LH and FSH. Testosterone can also exert some effect on Sertoli cells, found in the periphery of the seminiferous tubules of testes. FSH and testosterone can stimulate Sertoli cells to release androgen-binding protein (ABP), which provides testosterone to germ cells during spermatogenesis. FSH stimulates Sertoli cells to promote sperm production and release inhibin B and MIS. Inhibin serves as the negative feedback control that Sertoli cells exert on the hypothalamic-pituitary system to decrease FSH release.[rx]

Before puberty, the levels of androgens and gonadotropins typically remain low and constant. Once puberty occurs, the hypothalamus releases GnRH in a pulsatile fashion every one to two hours to maintain amounts of FSH, LH, and plasma testosterone, all of which regulate each other to maintain hormonal balance. In the third decade of life, testosterone levels are found to decline.[rx][rx][rx]

Although a majority of testosterone production in men comes from the Leydig cells in the testes, the adrenal cortex contributes some androgen production. Similar to the hypothalamic-pituitary-gonadal axis, the adrenal glands are also controlled by the hypothalamus and anterior pituitary to form the hypothalamic-pituitary-adrenal axis. The hypothalamus releases corticotrophin-releasing hormone (CRH), which stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH stimulates the enzyme desmolase to convert cholesterol into pregnenolone in the adrenals, similar to testosterone synthesis in the testes. Specifically, the zona reticularis of the adrenal medulla is responsible for generating the weak androgens DHEA and androstenedione, which go on to be converted to testosterone or estradiol peripherally.[rx]

Function

The function of the male reproductive system is to produce androgens such as testosterone that maintain male reproductive function and to promote spermatogenesis and transport into the female reproductive system for fertilization. The testes act as both endocrine and exocrine organs in that they are responsible for androgen production and sperm production and transport.

Mechanism

Spermatogenesis starts at puberty with the germ cells found in the basement membrane of the seminiferous tubules of the testes. Sertoli cells stimulated by FSH help regulate spermatogenesis. One cycle of spermatogenesis begins approximately every 13 days; however, spermatogenesis is not consistently synchronous throughout all seminiferous tubules. The first stage of spermatogenesis begins with mitosis of diploid spermatogonia into primary spermatocytes. These spermatocytes undergo meiosis I to produce haploid secondary spermatocytes, which undergo meiosis II to form haploid spermatids. The most primitive spermatocytes are found peripherally in the seminiferous tubules and mature by migrating towards the lumen. Spermatids transform into spermatozoa by reducing cytoplasm. These spermatozoa are still immotile and are released into the tubules to travel to the epididymis for maturation. The epididymis is a coiled structure consisting of a head, body, and tail. The tail eventually joins with the vas deferens, providing an outlet for mature sperms to ejaculate. In the epididymis, the sperm takes about twelve days to mature and develop motility. They are then stored in the tail of the epididymis until ejaculation occurs. A mature sperm consists of a head, midpiece, and tail. The head contains the nucleus with very little cytoplasm. An acrosome or cap covers the head and is filled with lysosomes, which aids with fertilization. The midpiece contains abundant mitochondria to provide energy for the flagellum or tail of the sperm.

During sexual arousal (physical or psychological), vasodilation brings blood to the penis. The penis contains corpora cavernosa and a corpus spongiosum where blood flows along to enlarge and erect the penis. As sexual stimulation continues, blood continues to flow to the genitals, and the testes enlarge in preparation for ejaculation.

When ejaculation occurs, smooth muscle contractions of the epididymis push sperm into the ductus deferens (vas deferens), which sit in the spermatic cord. The ductus deferens deliver the sperm to the ejaculatory duct by joining with the seminal vesicle duct near the prostate. The seminal vesicles produce fructose, which provides the energy for sperm motility. It is released within a fluid that mixes with the sperm to form semen. Once in the ejaculatory duct, the semen passes through the prostate, which secretes an alkaline fluid that helps thicken the semen so sperm can better stay within the female reproductive system. The semen then passes the bulbourethral glands or Cowper’s glands, which release a thick fluid that lubricates the urethral opening and clears the urethra of any urine residue. The semen then can enter the female vaginal canal, allowing the sperm to travel to and fertilize a potential egg within the female reproductive system.[rx][rx][rx]

The Human Male Reproductive System: Cross-sectional diagram of the male reproductive organs.

Only our species has a distinctive mushroom-capped glans, which is connected to the shaft of the penis by a thin tissue of frenulum (the delicate tab of skin just beneath the urethra). One of the most significant features of the human penis is the coronal ridge underneath the gland around the circumference of the shaft. Magnetic imaging studies of heterosexual couples having sex reveal that during coitus, the typical penis expands to fill the vaginal tract, and with full penetration can even reach the woman’s cervix and lift her uterus. This combined with the fact that human ejaculate is expelled with great force and considerable distance (up to two feet if not contained), suggests that men are designed to release sperm into the uppermost portion of the vagina. This may be an evolutionary adaptation to expel the semen left by other males while at the same time increasing the possibility of fertilization with the current male’s semen.

The Female Reproductive System

The human female reproductive system is a series of organs primarily located inside the body and around the pelvic region. It contains three main parts: the vagina, which leads from the vulva, the vaginal opening, to the uterus; the uterus, which holds the developing fetus; and the ovaries, which produce the female’s ova. The breasts are also a reproductive organ during parenting but are usually not classified as part of the female reproductive system. The vagina meets the outside at the vulva, which also includes the labia, clitoris, and urethra. During intercourse, this area is lubricated by mucus secreted by the Bartholin’s glands. The vagina is attached to the uterus through the cervix, while the uterus is attached to the ovaries via the Fallopian tubes. At certain intervals, approximately every 28 days, the ovaries release an ovum that passes through the Fallopian tube into the uterus.
If the ova are fertilized by sperm, it attaches to the endometrium and the fetus develops. In months when fertilization does not occur, the lining of the uterus called the endometrium, and unfertilized ova are shed each cycle through a process known as menstruation.

Organ Systems Involved

Female Reproductive Organs

Ovaries

  • The ovaries are female gonads, the site of gametogenesis, and the secretion of sex hormones. The outer cortex of each ovary is the site of follicular development, while the inner medulla of each contains blood vessels and connective tissue.

Fallopian Tubes

  • The vulva describes the external female genitalia: labia majora, labia minora, clitoris, vulvar vestibule, urethrethral meatus, vaginal orifice. The labia majora are lateral to the labia minora, fusing anteriorly to make up the mons pubis (a layer overlying the pubic symphysis). The vulvar vestibule is the area medial to the labia minora and is the location of the urethra and vaginal openings. Bartholin’s glands open lateral to the vaginal opening.
  • The vagina is a flexible, fibromuscular tubular structure extending from the vulvar vestibule to the uterine cervix. The distal vagina is the introitus. The anterior vagina abuts the posterior bladder wall while the posterior vagina abuts the anterior rectum.
  • The uterus consists of the corpus (body) and cervix. The superior aspect of the uterine corpus is the fundus, while the inferior portion adjacent to the cervix is called the isthmus/lower uterine segment. The uterine walls contain three distinct layers: the endometrium, myometrium, and the serosa. The endometrium lines the uterine cavity; its thickness and structure vary with hormonal stimulation. The myometrium consists of smooth muscle fibers and is the middle and thickest layer of the uterine wall. The serosa is the outermost lining of the uterus.
  • The uterine cervix is a tubular structure contiguous with the uterine cavity and the vagina, acting as a conduit between the two. The inferior cervix opens into the upper vagina at the cervical os. The lining of the cervix that protrudes into the vagina is called the ectocervix and consists of columnar epithelium. The lining of the inside of the cervical canal is the endocervix, composed of stratified squamous epithelium. The region where the ecto- and endocervix meet, characterized by the transformation from columnar to squamous epithelium, is the transformation zone. The transformation zone is the most frequent location for cervical dysplasia and malignant transformation.
  • Fallopian tubes provide a passageway for oocytes to travel from the ovaries into the uterine cavity. The part of each tube closest to the ovary contains fimbria: finger-like projections that help move the expelled oocyte further into the tube—the fimbria transition into the ampulla, the part of the tube with the widest lumen. The ampulla becomes the isthmus as the lumen narrows and projects towards the uterus. The tube then passes into the uterus, where it becomes the interstitial portion. This opening is where the traveling oocyte exits the tube and enters the uterine cavity.

Uterus

  • The uterus consists of the corpus (body) and cervix. The superior aspect of the uterine corpus is the fundus while the inferior portion adjacent to the cervix is called the isthmus/lower uterine segment. The uterine walls contain three distinct layers: the endometrium, myometrium, and the serosa. The endometrium lines the uterine cavity; its thickness and structure vary with hormonal stimulation. The myometrium consists of smooth muscle fibers and is the middle and thickest layer of the uterine wall. The serosa is the outermost lining of the uterus.
  • The uterine cervix is a tubular structure contiguous with the uterine cavity and the vagina, acting as a conduit between the two. The inferior cervix opens into the upper vagina at the cervical os. The lining of the cervix that protrudes into the vagina is called the ectocervix and consists of columnar epithelium. The lining of the inside of the cervical canal is the endocervix, composed of stratified squamous epithelium. The region where the ecto- and endocervix meet, characterized by the transformation from columnar to squamous epithelium, is the transformation zone. The transformation zone is the most frequent location for cervical dysplasia and malignant transformation.

Vagina

  • The vagina is a flexible, fibromuscular tubular structure extending from the vulvar vestibule to the uterine cervix. The distal vagina is the introitus. The anterior vagina abuts the posterior bladder wall while the posterior vagina abuts the anterior rectum.

Vulva

  • The vulva describes the external female genitalia: labia majora, labia minora, clitoris, vulvar vestibule, urethrethral meatus, vaginal orifice. The labia majora are lateral to the labia minora, fusing anteriorly to make up the mons pubis (a layer overlying the pubic symphysis). The vulvar vestibule is the area medial to the labia minora and is the location of the urethra and vaginal openings. Bartholin’s glands open lateral to the vaginal opening.

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Acid-Base Balance – Anatomy, Mechanism, Functions

Acid-base balance is the homeostatic regulation of the pH of the body’s extracellular fluid (ECF).[1] The proper balance between the acids and bases (i.e. the pH) in the ECF is crucial for the normal physiology of the body—and for cellular metabolism.[1] The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.

The body’s balance between acidity and alkalinity is referred to as acid-base balance. The blood’s acid-base balance is precisely controlled because even a minor deviation from the normal range can severely affect many organs. The body uses different mechanisms to control the blood’s acid-base balance.

The three-dimensional structures of many extracellular proteins, such as the plasma proteins and membrane proteins of the body’s cells, are very sensitive to the extracellular pH.[rx][rx] Stringent mechanisms, therefore, exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3-D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.

pH, Buffers, Acids, and Bases

Henderson–Hasselbalch equation

The Henderson–Hasselbalch equation when applied to the carbonic acid-bicarbonate buffer system in the extracellular fluids, states that:[rx]

{\displaystyle \mathrm {pH} =\mathrm {p} K_{\mathrm {a} ~\mathrm {H} _{2}\mathrm {CO} _{3}}+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{[\mathrm {H} _{2}\mathrm {CO} _{3}]}}\right),}

where:

  • pH is the negative logarithm (or cologarithm) of molar concentration of hydrogen ions in the ECF.
  • pKa H2CO3 is the cologarithm of the acid dissociation constant of carbonic acid. It is equal to 6.1.
  • [HCO
    3]
     is the molar concentration of bicarbonate in the blood plasma
  • [H2CO3] is the molar concentration of carbonic acid in the ECF.

However, since the carbonic acid concentration is directly proportional to the partial pressure of carbon dioxide ({\displaystyle P_{{\mathrm {CO} }_{2}}}) in the extracellular fluid, the equation can be rewritten as follows:[rx][rx]{\displaystyle \mathrm {pH} =6.1+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{0.0307\times P_{\mathrm {CO} _{2}}}}\right),}

where:

  • pH is the negative logarithm of molar concentration of hydrogen ions in the ECF.
  • [HCO
    3]
     is the molar concentration of bicarbonate in the plasma
  • PCO2 is the partial pressure of carbon dioxide in the blood plasma.

The pH of the extracellular fluids can thus be controlled by the regulation of PCO2 and other metabolic acids.

Acids dissociate into H+ and lower pH, while bases dissociate into OH and raise pH; buffers can absorb these excess ions to maintain pH.

Key Points

A basic solution will have a pH above 7.0, while an acidic solution will have a pH below 7.0.

Buffers are solutions that contain a weak acid and its a conjugate base; as such, they can absorb excess H+ ions or OH ions, thereby maintaining an overall steady pH in the solution.

pH is equal to the negative logarithm of the concentration of H+ ions in solution: pH = −log[H+].

Key Terms

  • alkaline: having a pH greater than 7; basic
  • acidic: having a pH less than 7
  • buffer: a solution composed of a weak acid and its conjugate base that can be used to stabilize the pH of a solution

Self-Ionization of Water

Hydrogen ions are spontaneously generated in pure water by the dissociation (ionization) of a small percentage of water molecules into equal numbers of hydrogen (H+) ions and hydroxide (OH) ions. The hydroxide ions remain in solution because of their hydrogen bonds with other water molecules; the hydrogen ions, consisting of naked protons, are immediately attracted to un-ionized water molecules and form hydronium ions (H30+). By convention, scientists refer to hydrogen ions and their concentration as if they were free in this state in liquid water.

2H2O⇋H3O++OH−

The concentration of hydrogen ions dissociating from pure water is 1 × 10−7 moles H+ ions per liter of water. The pH is calculated as the negative of the base 10 logarithm of this concentration:

pH = −log[H+]

The negative log of 1 × 10−7 is equal to 7.0, which is also known as neutral pH. Human cells and blood each maintain near-neutral pH.

pH Scale

The pH of a solution indicates its acidity or basicity (alkalinity). The pH scale is an inverse logarithm that ranges from 0 to 14: anything below 7.0 (ranging from 0.0 to 6.9) is acidic, and anything above 7.0 (from 7.1 to 14.0) is basic (or alkaline ). Extremes in pH in either direction from 7.0 are usually considered inhospitable to life. The pH in cells (6.8) and the blood (7.4) are both very close to neutral, whereas the environment in the stomach is highly acidic, with a pH of 1 to 2.

The pH scale: The pH scale measures the concentration of hydrogen ions (H+) in a solution.

Non-neutral pH readings result from dissolving acids or bases in water. Using the negative logarithm to generate positive integers, high concentrations of hydrogen ions yield a low pH, and low concentrations a high pH.

An acid is a substance that increases the concentration of hydrogen ions (H+) in a solution, usually by dissociating one of its hydrogen atoms. A base provides either hydroxide ions (OH) or other negatively-charged ions that react with hydrogen ions in solution, thereby reducing the concentration of H+ and raising the pH.

Strong Acids and Strong Bases

The stronger the acid, the more readily it donates H+. For example, hydrochloric acid (HCl) is highly acidic and completely dissociates into hydrogen and chloride ions, whereas the acids in tomato juice or vinegar do not completely dissociate and are considered weak acids; conversely, strong bases readily donate OH and/or react with hydrogen ions. Sodium hydroxide (NaOH) and many household cleaners are highly basic and give up OH rapidly when placed in water; the OH− ions react with H+ in solution, creating new water molecules and lowering the amount of free H+ in the system, thereby raising the overall pH. An example of a weak basic solution is seawater, which has a pH near 8.0, close enough to neutral that well-adapted marine organisms thrive in this alkaline environment.

Buffers

How can organisms whose bodies require a near-neutral pH ingest acidic and basic substances (a human drinking orange juice, for example) and survive? Buffers are the key. Buffers usually consist of a weak acid and its conjugate base; this enables them to readily absorb excess H+ or OH, keeping the system’s pH within a narrow range.

Maintaining a constant blood pH is critical to a person’s well-being. The buffer that maintains the pH of human blood involves carbonic acid (H2CO3), bicarbonate ion (HCO3), and carbon dioxide (CO2). When bicarbonate ions combine with free hydrogen ions and become carbonic acid, hydrogen ions are removed, moderating pH changes. Similarly, excess carbonic acid can be converted into carbon dioxide gas and exhaled through the lungs; this prevents too many free hydrogen ions from building up in the blood and dangerously reducing its pH; likewise, if too much OH is introduced into the system, carbonic acid will combine with it to create bicarbonate, lowering the pH. Without this buffer system, the body’s pH would fluctuate enough to jeopardize survival.

image

Buffers in the body: This diagram shows the body’s buffering of blood pH levels: the blue arrows show the process of raising pH as more CO2 is made; the purple arrows indicate the reverse process, lowering pH as more bicarbonate is created.

Antacids, which combat excess stomach acid, are another example of buffers. Many over-the-counter medications work similarly to blood buffers, often with at least one ion (usually carbonate) capable of absorbing hydrogen and moderating pH, bringing relief to those that suffer “heartburn” from stomach acid after eating.

Chemical Buffer Systems

Chemical buffers, such as bicarbonate and ammonia, help keep the blood’s pH in the narrow range that is compatible with life.

Key Points

The body’s acid-base balance is tightly regulated to keep the arterial blood pH between 7.38 and 7.42. Buffer solutions keep the pH constant in a wide variety of chemical actions.

A buffer solution is a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid.

The bicarbonate buffering system maintains optimal pH levels and regulates the carbon dioxide concentration that, in turn, shifts any acid-base imbalance.

Renal physiology controls pH levels through several powerful mechanisms that excrete excess acid or base.

Key Terms

  • bicarbonate: An alkaline, vital component of the pH buffering system of the human body that maintains acid-base homeostasis.
  • buffer: A solution used to stabilize the pH (acidity) of a liquid.
  • pH: In chemistry, a measure of the activity of the hydrogen ion concentration.

EXAMPLES

Anything that adversely affects an individual’s bloodstream will have a negative impact on that individual’s health since the blood acts as a chemical buffer solution to keep all the body’s cells and tissues properly balanced.

Acid-Base Homeostasis

Acid-base homeostasis concerns the proper balance between acids and bases; it is also called body pH. The body is very sensitive to its pH level, so strong mechanisms exist to maintain it. Outside an acceptable range of pH, proteins are denatured and digested, enzymes lose their ability to function, and death may occur.

Buffer Solution

A buffer solution is an aqueous solution of a weak acid and its conjugate base, or a weak base and its conjugate acid. Its pH changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications.

Many life forms thrive only in a relatively small pH range, so they utilize a buffer solution to maintain a constant pH. One example of a buffer solution found in nature is blood. The body’s acid-base balance is normally tightly regulated, keeping the arterial blood pH between 7.38 and 7.42.

Several buffering agents that reversibly bind hydrogen ions and impede any change in pH exist. Extracellular buffers include bicarbonate and ammonia, whereas proteins and phosphates act as intracellular buffers.

The bicarbonate buffering system is especially key, as carbon dioxide (CO2) can be shifted through carbonic acid (H2CO3) to hydrogen ions and bicarbonate (HCO3−):

H2O+CO2⇋H2CO3⇋H++CO3−

Acid–base imbalances that overcome the buffer system can be compensated in the short term by changing the rate of ventilation. This alters the concentration of carbon dioxide in the blood and shifts the above reaction according to Le Chatelier’s principle, which in turn alters the pH.

Renal Physiology

The kidneys are slower to compensate, but renal physiology has several powerful mechanisms to control pH by the excretion of excess acid or base. In response to acidosis, the tubular cells reabsorb more bicarbonate from the tubular fluid, and the collecting duct cells secrete more hydrogen and generate more bicarbonate, and ammonia genesis leads to an increase of the NH3 buffer.

In its responses to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells, and lower the rates of glutamine metabolism and ammonium excretion.

This chart shows the pH range of a variety of common fluids. Buffering agents keep blood pH between 7.38 and 7.42. Sulfuric acid (batter acid) has the highest acidity on the chart; distilled water and saliva are neutral; and lye has the highest alkalinity on the chart.

pH range: Buffering agents keep blood pH between 7.38 and 7.42.

Regulation of H+ by the Lungs

Acid-base imbalances in the blood’s pH can be altered by changes in breathing to expel more COand raise pH back to normal.

Key Points

Hydrogen ions (H+) are carried in the blood along with oxygen and carbon dioxide.

Sixty percent of the carbon dioxide is carried as dissolved bicarbonate.

A small amount of carbon dioxide is carried on the hemoglobin as carbaminohemoglobin, which is transported to the lungs for removal.

Following Le Chatelier’s principle, an imbalance in pH is returned to normal by increasing the rate of ventilation in the lungs.

To compensate for acidemia, more CO2 is expelled, while the opposite occurs for alkalemia.

Key Terms

  • carbaminohemoglobin: A compound of hemoglobin and carbon dioxide. It is one of the forms in which carbon dioxide exists in the blood.
  • Le Chatelier’s principle: A principle that states that if a chemical system at equilibrium experiences a change in concentration, temperature, or total pressure, the equilibrium will shift in order to minimize that change.

EXAMPLES

Since maintaining normal pH is vital for life, and since the lungs play a critical role in maintaining normal pH, smokers have yet another reason to quit smoking.

Acid-base imbalance occurs when a significant insult causes the blood pH to shift out of its normal range (7.35 to 7.45). An excess of acid in the blood is called acidemia and an excess of base is called alkalemia.

The process that causes the imbalance is classified based on the etiology of the disturbance (respiratory or metabolic) and the direction of change in pH ( acidosis or alkalosis). There are four basic processes and one or a combination may occur at any given time.

  • Metabolic acidosis
  • Respiratory acidosis
  • Metabolic alkalosis
  • Respiratory alkalosis

Blood carries oxygen, carbon dioxide, and hydrogen ions (H+) between tissues and the lungs. The majority of CO2 transported in the blood is dissolved in plasma (60% is dissolved bicarbonate).

This is a diagram of expiration that shows a person exhaling. When blood pH drops too low, the body compensates by increasing breathing to expel more carbon dioxide.

Expiration: When blood pH drops too low, the body compensates by increasing breathing to expel more carbon dioxide.

A smaller fraction is transported in the red blood cells that combine with the globin portion of hemoglobin as carbaminohemoglobin. This is the chemical portion of the red blood cell that aids in the transport of oxygen and nutrients around the body, but, this time, it is carbon dioxide that is transported back to the lung.

Acid-base imbalances that overcome the buffer system can be compensated in the short term by changing the rate of ventilation. This alters the concentration of carbon dioxide in the blood, shifting the above reaction according to Le Chatelier’s principle, which in turn alters the pH. The basic reaction governed by this principle is as follows:

H2O+CO2⇋H2CO3⇋H++CO3−

When the blood pH drops too low (acidemia), the body compensates by increasing breathing to expel more CO2; this shifts the above reaction to the left such that less hydrogen ions are free; thus, the pH will rise back to normal. For alkalemia, the opposite occurs.

The Role of the Kidneys in Acid-Base Balance

The kidneys help maintain the acid–base balance by excreting hydrogen ions into the urine and reabsorbing bicarbonate from the urine.

Key Points

The kidneys maintain homeostasis through the excretion of waste products.

Acidosis causes more bicarbonate to be reabsorbed from the tubular fluid, while the collecting ducts secrete more hydrogen to generate more bicarbonate, and more NH3 buffer is formed.

Alkalosis causes the kidney to excrete more bicarbonate as there is reduced secretion of hydrogen ions and more ammonium is excreted.

Key Terms

  • base: Any of a class of generally water-soluble compounds, that have a bitter taste, turn red litmus paper blue, and react with acids to form salts.
  • renal: Pertaining to the kidneys.

EXAMPLES

Urine testing is important because it can detect acid-base imbalances. For instance, uncontrolled diabetes results in highly acidic urine. If diabetes remains uncontrolled, the kidneys could become over-stressed and malfunction, which could lead to coma or death.

Within the human body, fluids such as blood must be maintained within the narrow range of 7.35 to 7.45, making it slightly alkaline. Outside that range, pH becomes incompatible with life; proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself.

To maintain this narrow range of pH the body has a powerful buffering system. Acid-base imbalances that overcome this system are compensated in the short term by changing the rate of ventilation.

Kidneys and Acid-Base Balance

The kidneys have two very important roles in maintaining the acid-base balance:

  1. They reabsorb bicarbonate from urine.
  2. They excrete hydrogen ions into urine.

The kidneys are slower to compensate than the lungs, but renal physiology has several powerful mechanisms to control pH by the excretion of excess acid or base. The major, homeostatic control point for maintaining a stable pH balance is renal excretion.

Bicarbonate (HCO3−) does not have a transporter, so its reabsorption involves a series of reactions in the tubule lumen and tubular epithelium. In response to acidosis, the tubular cells reabsorb more bicarbonate from the tubular fluid, and the collecting duct cells secrete more hydrogen and generate more bicarbonate, and ammonia genesis leads to an increase in the formation of the NH3 buffer.

In response to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells, and lowering the rates of glutamine metabolism and ammonium excretion.

Organ Systems Involved

Every organ system of the human body relies on pH balance; however, the renal system and the pulmonary system are the two main modulators. The pulmonary system adjusts pH using carbon dioxide; upon expiration, carbon dioxide is projected into the environment. Due to carbon dioxide forming carbonic acid in the body when combining with water, the amount of carbon dioxide expired can cause pH to increase or decrease. When the respiratory system is utilized to compensate for metabolic pH disturbances, the effect occurs in minutes to hours.

The renal system affects pH by reabsorbing bicarbonate and excreting fixed acids. Whether due to pathology or necessary compensation, the kidney excretes or reabsorbs these substances which affect pH. The nephron is the functional unit of the kidney. Blood vessels called glomeruli transport substances found in the blood to the renal tubules so that some can be filtered out while others are reabsorbed into the blood and recycled. This is true for hydrogen ions and bicarbonate. If bicarbonate is reabsorbed and/or acid is secreted into the urine, the pH becomes more alkaline (increases). When bicarbonate is not reabsorbed or acid is not excreted into the urine, pH becomes more acidic (decreases). The metabolic compensation from the renal system takes longer to occur: days rather than minutes or hours.

Function

The physiological pH of the human body is essential for many processes necessary to life including oxygen delivery to tissues, correct protein structure, and innumerable biochemical reactions that rely on the normal pH to be in equilibrium and complete.

Oxygen Delivery to Tissues

The oxygen dissociation curve is a graph depicting the relationship of the partial pressure of oxygen to the saturation of hemoglobin. This curve relates to the ability of hemoglobin to deliver oxygen to tissues. If the curve is shifted to the left, there is a decreased p50, meaning that the amount of oxygen needed to saturate hemoglobin 50% is lessened and that there is an increased affinity of hemoglobin for oxygen. A pH in the alkalotic range induces this left shift. When there is a decrease in pH, the curve is shifted to the right, denoting a decreased affinity of hemoglobin for oxygen.

Protein Structure

It would be hard to overstate the importance of proteins in the human body. They makeup ion channels, carry necessary lipophilic substances throughout our mostly lipophobic body, and participate in innumerable biological processes. For proteins to complete necessary functions, they must be in the proper configuration. The charges on proteins are what allow their proper shape to exist. When pH is altered outside of the physiological range, these charges are altered. The proteins are denatured leading to detrimental changes in architecture that cause a loss of proper function.

Biochemical Processes

Throughout the human body, many chemical reactions are in equilibrium. One of the most important was previously mentioned with the equation:

  • H20 + CO2 <-> H2CO3<-> H+ + HCO3-

The Le Chatelier Principle states that when the variables of concentration, pressure, or temperature are changed, a system in equilibrium will react accordingly to restore a new steady state. The reaction above, states that if more hydrogen ions are produced, the equation will shift to the left so that more reactants are formed, and the system can remain in equilibrium. This is how compensatory pH mechanisms work; if there is metabolic acidosis present, the kidneys are not excreting enough hydrogen ions and/or not reabsorbing enough bicarbonate. The respiratory system reacts by increasing minute ventilation (often by increasing respiratory rate) and expiring more CO2 to restore equilibrium.[rx]

What’s normal?

A normal range for arterial pH is 7.35 to 7.45. Acidosis is a pH less than 7.35; alkalosis is a pH greater than 7.45. Because pH is measured in terms of hydrogen (H+) ion concentration, an increase in H+ ion concentration decreases pH and vice versa. Changes in H+ ion concentration can be stabilized through several buffering systems: bicarbonate-carbonic acid, proteins, hemoglobin, and phosphates.

Acidosis, therefore, can be described as a physiologic condition caused by the body’s inability to buffer excess H+ ions. At the other end, alkalosis results from a deficiency in H+ ion concentration. Acidemia and alkalemia refer to the process of acidosis or alkalosis, respectively, occurring in arterial blood.

Body acids are formed as end products of cellular metabolism. Under normal physiologic conditions, a person generates 50 to 100 mEq/day of acid from the metabolism of carbohydrates, proteins, and fats. In addition, the body loses base in the stool. In order to maintain acid-base homeostasis, acid production must balance the neutralization or excretion. The lungs and kidneys are the main regulators of acid-base homeostasis. The lungs release CO2, an end product of carbonic acid (H2CO3). The renal tubules, with the regulation of bicarbonate (HCO3), excrete other acids produced from the metabolism of proteins, carbohydrates, and fats.

Reference values for arterial blood

Women Men
cH+P 36.3–41.7 nmol l−1 (pH: 7.38–7.44) 37.2–42.7 nmol l−1 (pH: 7.37–7.43)
ctH+Ecf −2.3–+2.7 mmol l−1 −3.2–+1.8 mmol l−1
pCO2 4.59–5.76 kPa (33.8–42.4 mmHg) 4.91–6.16 kPa (36.8–46.2 mmHg)
cHCO3P 21.2–27.0 mmol l−1 22.2–28.3 mmol l−1

cH+P: conc. of (free) hydrogen ion in plasma; ctH+Ecf: conc. of titratable hydrogen ion in extracellular fluid (also called standard base deficit, SBD); pCO2: tension of carbon dioxide; cHCO3P: conc. of bicarbonate in plasma.

Related Testing

Arterial blood gas (ABG) sampling, is a test often performed in an inpatient setting to assess the acid-base status of a patient. A needle is used to draw blood from an artery, often the radial and the blood is analyzed to determine parameters such as pH, pC02, pO2, HCO3, oxygen saturation, and more. This allows the physician to understand the status of the patient better. ABGs are especially important in the critically ill. They are the main tool utilized in adjusting to the needs of a patient on a ventilator. The following are the most important normal values on an ABG:

  • pH = 7.35 to 7.45
  • pCO2 = 35 to 45 mmHg
  • pO2 = 75 to 100 mmHg
  • HCO3- = 22 to 26 mEq/L
  • O2 Sat = greater than 95%

The ability to quickly and efficiently read an ABG, especially in reference to inpatient medicine, is paramount to quality patient care.

  • Look at the pH
  • Decide whether it is acidotic, alkalotic, or within the physiological range
  • PaCO2 level determines respiratory contribution; a high level means the respiratory system is lowering the pH and vice versa.
  • HCO3- level denotes metabolic/kidney effect. An elevated HCO3- is raising the pH and vice versa.
  • If the pH is acidotic, look for the number that corresponds with a lower pH. If it is a respiratory acidosis, the CO2 should be high. If the patient is compensating metabolically, the HCO3- should be high as well. Metabolic acidosis will be depicted with an HCO3- that is low.
  • If the pH is alkalotic, again, determine which value is causing this. A respiratory alkalosis will mean the CO2 is low; a metabolic alkalosis should lend an HCO3- that is high. Compensation with either system will be reflected oppositely; for a respiratory alkalosis the metabolic response should be a low HCO3- and for metabolic alkalosis, the respiratory response should be a high CO2.
  • If the pH level is in the physiological range but the PaCO2 and/or bicarb are not within normal limits, there is likely a mixed disorder. Also, compensation does not always occur; this is when clinical information becomes paramount.
  • Sometimes it is difficult to ascertain whether a patient has a mixed disorder. This is discussed later.

Other tests that are important to perform when analyzing the acid-base status of a patient include those that measure electrolyte levels and renal function. This helps the clinician gather the information that can be used to determine the exact mechanism of the acid-base imbalance as well as the factors contributing to the disorders.[rx][rx]

References

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Body Fluids – Physiology, Mechanism, Functions

Body fluidsbodily fluids, or biofluids are liquids within the human body. In lean healthy adult men, the total body water is about 60% (60–67%) of the total body weight; it is usually slightly lower in women (52-55%).[rx][rx] The exact percentage of fluid relative to body weight is inversely proportional to the percentage of body fat. A lean 70 kg (160 pound) man, for example, has about 42 (42–47) liters of water in his body.

The total body of water is divided into fluid compartments,[rx] between the intracellular fluid (ICF) compartment (also called space, or volume) and the extracellular fluid (ECF) compartment (space, volume) in a two-to-one ratio: 28 (28–32) liters are inside cells and 14 (14–15) liters are outside cells.

The ECF compartment is divided into the interstitial fluid volume – the fluid outside both the cells and the blood vessels – and the intravascular volume (also called the vascular volume and blood plasma volume) – the fluid inside the blood vessels – in a three-to-one ratio: the interstitial fluid volume is about 12 liters, the vascular volume is about 4 liters.

Water Content in the Body

A significant percentage of the human body is water, which includes intracellular and extracellular fluids.

Key Points

On average, body water can account for 50% of the total human body weight and it is significantly higher in newborns. Obesity decreases the percentage of water in the body.

Body water is regulated by hormones, including anti-diuretic hormone (ADH), aldosterone, and atrial natriuretic peptide.

Water content in the body can be evaluated using bioelectrical impedance and mass spectrometry.

Important functions of water in the body including supporting the cellular metabolism, molecular transport, biochemical reactions, and the physical properties of water, such as surface tension.

Key Terms

  • hydrolysis: A biochemical reaction in which water molecules are used to break down a molecule into smaller molecules.
  • bioelectrical impedance analysis: A commonly used method for estimating body composition, by measuring resistance to the flow of electricity in the body, which is associated with hydration levels.

Water Content

In physiology, body water is the water content of the human body. It makes up a significant percentage of the total composition of a body. Water is a necessary component to support life for many reasons. All cells in the human body are made mostly of water content in their cytoplasm.

This is a 3-dimensional model of hydrogen bonds (labeled 1 on the model) between molecules of water.

Water molecule: A 3-dimensional model of hydrogen bonds (labeled 1) between molecules of water.

Water also provides a fluid environment for extracellular communication and molecular transport throughout the body. Water itself is also a key component of biochemical reactions involved in physiology, such as hydrolysis. Many organ systems depend on the physical properties of water, such as the surface tension of water in the alveoli of the lungs.

Overall Water Content

The total amount of water in a human of average weight (70 kilograms) is approximately 40 liters, averaging 57 percent of his total body weight. In a newborn infant, this may be as high as 79 percent of the body weight, but it progressively decreases from birth to old age, with most of the decrease occurring during the first 10 years of life.

Also, obesity decreases the percentage of water in the body, sometimes to as low as 45 percent. The water in the body is distributed among various fluid compartments that are interspersed in the various cavities of the body through different tissue types. In diseased states where body water is affected, the fluid compartments that have changed can give clues to the nature of the problem.

Water Content Regulation and Measurement

Body water is regulated largely by the renal and neuroendocrine systems. Water content regulation is one of the most important parts of homeostasis due to its influence on blood pressure and cardiac output. Much of this regulation is mediated by hormones, including anti-diuretic hormone (ADH), renin, angiotensin II, aldosterone, and atrial natriuretic peptide (ANP).

These hormones act as messengers between the kidneys and the hypothalamus; however, the lungs and heart are also involved in the secretion of some of these hormones, such as an angiotensin-converting enzyme (ACE) and ANP respectively.

There are many clinical methods to determine body water. One way to get an uncertain estimate is by calculation based on body weight and urine output. Another way to measure body water is through dilution and equilibration using mass spectrometry, which measures the abundance of water in breath samples from an individual.

In bioelectrical impedance analysis, a person’s hydration level is calculated from high-precision measurements of the opposition to the flow of an electric current through body tissues. Since water conducts electricity, a lower hydration level will cause a greater amount of resistance to electrical flow through the body.

Fluid Compartments

The major body-fluid compartments include intracellular fluid and extracellular fluid (plasma, interstitial fluid, and transcellular fluid).

Key Points

The intracellular fluid of the cytosol or intracellular fluid (or cytoplasmic matrix) is the liquid found inside cells.

The cytosol is a complex mixture of substances that include proteins, ions, and organelles dissolved in water.

Extracellular fluid (ECF) or extracellular fluid volume (ECFV) usually denotes all body fluid outside of cells, and consists of plasma, interstitial, and transcellular fluid.

An extracellular matrix is an extracellular fluid space containing cell-excreted molecules, and they vary in their type and function.

Plasma also serves as an extracellular matrix (ECM) for the cells and molecules of the blood.

Interstitial fluid (or tissue fluid) is a solution that bathes and surrounds the cells of multicellular animals.

Transcellular fluid is the portion of total body water contained within epithelial-lined spaces.

Key Terms

  • intracellular fluid: The liquid found inside cells, between the endomembrane and the membrane-bound organelles.
  • interstitial fluid: A solution that bathes and surrounds the cells of multicellular animals; also called tissue fluid.
  • plasma: The straw-colored/pale-yellow, liquid component of blood that normally holds the blood cells of whole blood in suspension.

Fluid Compartments

The fluids of the various tissues of the human body are divided into fluid compartments. Fluid compartments are generally used to compare the position and characteristics of fluid in relation to the fluid within other compartments.

While fluid compartments may share some characteristics with the divisions defined by the anatomical compartments of the body, these terms are not one in the same. Fluid compartments are defined by their position relative to the cellular membrane of the cells that make up the body’s tissues.

Intracellular Fluid

The intracellular fluid of the cytosol or intracellular fluid (or cytoplasm ) is the fluid found inside cells. It is separated into compartments by membranes that encircle the various organelles of the cell. For example, the mitochondrial matrix separates the mitochondrion into compartments.

The contents of a eukaryotic cell within the cell membrane, excluding the cell nucleus and other membrane-bound organelles (e.g., mitochondria, plastides, lumen of endoplasmic reticulum, etc.), is referred to as the cytoplasm.

This is an illustration of a cytosol encompassing a variety of molecules in its fluid. The cytosol is the fluid within the plasma membrane of a cell and contains the organelles. The cytosol includes dissolved molecules and water.

The cytosol: The cytosol (11) is the fluid within the plasma membrane of a cell and contains the organelles. The cytosol includes dissolved molecules and water.

The cytosol is a complex mixture of substances dissolved in water. Although water forms the large majority of the cytosol, it mainly functions as a fluid medium for intracellular signaling (signal transduction ) within the cell, and plays a role in determining cell size and shape.

The concentrations of ions, such as sodium and potassium, are generally lower in the cytosol compared to the extracellular fluid; these differences in ion levels are important in processes such as osmoregulation and signal transduction. The cytosol also contains large amounts of macromolecules that can alter how molecules behave, through macromolecular crowding.

Extracellular Fluid

Extracellular fluid (ECF) or extracellular fluid volume (ECFV) usually denotes all the body fluid that is outside of the cells. The extracellular fluid can be divided into two major subcompartments: interstitial fluid and blood plasma.

The extracellular fluid also includes the transcellular fluid; this makes up only about 2.5% of the ECF. In humans, the normal glucose concentration of extracellular fluid that is regulated by homeostasis is approximately 5 mm. The pH of extracellular fluid is tightly regulated by buffers and maintained around 7.4.

The volume of ECF is typically 15L (of which 12L is interstitial fluid and 3L is plasma). The ECF contains extracellular matrices (ECMs) that act as fluids of suspension for cells and molecules inside the ECF.

This is a diagram of the extracellular matrix. It shows the spatial relationship between the blood vessels, basement membranes, and interstitial space between structures.

Extracellular matrix: Spatial relationship between the blood vessels, basement membranes, and interstitial space between structures.

Blood Plasma

Blood plasma is the straw-colored/pale-yellow, liquid component of blood that normally holds the blood cells in whole blood in suspension, making it a type of ECM for blood cells and a diverse group of molecules. It makes up about 55% of total blood volume.

It is the intravascular fluid part of the extracellular fluid. It is mostly water (93% by volume) and contains dissolved proteins (the major proteins are fibrinogens, globulins, and albumins), glucose, clotting factors, mineral ions (Na+, Ca++, Mg++, HCO3- Cl-, etc.), hormones, and carbon dioxide (plasma is the main medium for excretory product transportation). It plays a vital role in intravascular osmotic effects that keep electrolyte levels balanced and protects the body from infection and other blood disorders.

Interstitial Fluid

Interstitial fluid (or tissue fluid) is a solution that bathes and surrounds the cells of multicellular animals. The interstitial fluid is found in the interstitial spaces, also known as the tissue spaces.

On average, a person has about 11 liters (2.4 imperial gallons or about 2.9 U.S. gal) of interstitial fluid that provide the cells of the body with nutrients and a means of waste removal. The majority of the interstitial space functions as an ECM, a fluid space consisting of cell-excreted molecules that lies between the basement membranes of the interstitial spaces. The interstitial ECM contains a great deal of connective tissue and proteins (such as collagen) that are involved in blood clotting and wound healing.

Transcellular Fluid

Transcellular fluid is the portion of total body water contained within the epithelial-lined spaces. It is the smallest component of extracellular fluid, which also includes interstitial fluid and plasma. It is often not calculated as a fraction of the extracellular fluid, but it is about 2.5% of the total body water.

Examples of this fluid are cerebrospinal fluid, ocular fluid, joint fluid, and the pleaural cavity that contains fluid that is only found in their respective epithelium-lined spaces.

The function of the transcellular fluid is mainly lubrication of these cavities, and sometimes electrolyte transport.

Body Fluid Composition

The composition of tissue fluid depends upon the exchanges between the cells in the biological tissue and the blood.

Key Points

The cytosol or intracellular fluid consists mostly of water, dissolved ions, small molecules, and large, water-soluble molecules (such as proteins).

Enzymes in the cytosol are important for cellular metabolism.

The extracellular fluid is mainly cations and anions.

Plasma is mostly water and dissolved proteins, but also contains metabolic blood gasses, hormones, and glucose.

The composition of transcellular fluid varies, but some of its main electrolytes include sodium ions, chloride ions, and bicarbonate ions.

Key Terms

  • electrolyte: Any of the various ions (such as sodium or chloride) that regulate the electric charge on cells and the flow of water across their membranes.
  • transcellular fluid: The portion of total body water contained within epithelial-lined spaces, such as the cerebrospinal fluid, and the fluid of the eyes and joints.
  • ion: An atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge.

Body Fluid Composition

The composition of tissue fluid depends upon the exchanges between the cells in the biological tissue and the blood. This means that fluid composition varies between body compartments.

Intracellular Fluid Composition

The cytosol or intracellular fluid consists mostly of water, dissolved ions, small molecules, and large, water-soluble molecules (such as proteins). This mixture of small molecules is extraordinarily complex, as the variety of enzymes that are involved in cellular metabolism is immense.

This is a diagram of ions in a solution.

Ions: Ions in solution.

These enzymes are involved in the biochemical processes that sustain cells and activate or deactivate toxins. Most of the cytosol is water, which makes up about 70% of the total volume of a typical cell. The pH of the intracellular fluid is 7.4. The cell membrane separates cytosol from extracellular fluid but can pass through the membrane via specialized channels and pumps during passive and active transport.

The concentrations of the other ions in the cytosol or intracellular fluid are quite different from those in extracellular fluid. The cytosol also contains much higher amounts of charged macromolecules, such as proteins and nucleic acids, than the outside of the cell.

In contrast to extracellular fluid, cytosol has a high concentration of potassium ions and a low concentration of sodium ions. The reason for this specific sodium and potassium ion concentrations are Na+/K ATPase pumps that facilitate the active transport of these ions. These pumps to transport ions against their concentration gradients to maintain the cytosol fluid composition of the ions.

Extracellular Fluid Composition

The extracellular fluid is mainly cations and anions. The cations include: sodium (Na+ = 136-145 mEq/L), potassium (K+ = 3.5-5.5 mEq/L) and calcium (Ca2+ = 8.4-10.5 mEq/L). Anions include: chloride ( mEq/L) and hydrogen carbonate (HCO3- 22-26 mM). These ions are important for water transport throughout the body.

Plasma is mostly water (93% by volume) and contains dissolved proteins (the major proteins are fibrinogens, globulins, and albumins), glucose, clotting factors, mineral ions (Na+, Ca++, Mg++, HCO3- Cl- etc.), hormones and carbon dioxide (plasma being the main medium for excretory product transportation). These dissolved substances are involved in many varied physiological processes, such as gas exchange, immune system function, and drug distribution throughout the body.

Transcellular Fluid Composition

Due to the varying locations of transcellular fluid, the composition changes dramatically. Some of the electrolytes present in the transcellular fluid are sodium ions, chloride ions, and bicarbonate ions.

Cerebrospinal fluid is similar in composition to blood plasma but lacks most proteins, such as albumins, because they are too large to pass through the blood-brain barrier. Ocular fluid in the eyes contrasts with cerebrospinal fluid by containing high concentrations of proteins, including antibodies.

Movement of Fluid Among Compartments

How fluid moves through compartments depends on several variables described by Starling’s equation.

Key Points

Interstitial fluid is formed when hydrostatic pressure generated by the heart pushes the water out of the capillaries. The water passes from a high concentration outside of the vessels to a low concentration inside of the vessels, but equilibrium is never reached because of the constant blood flow.

Osmotic pressure works opposite to hydrostatic pressure to hold water and substances in the capillaries.

Hydrostatic pressure is stronger in the arterial ends of the capillaries, while osmotic pressure is stronger at the venous ends of the capillaries.

Interstitial fluid is removed through the surrounding lymph vessels and eventually ends up rejoining the blood. Sometimes the removal of tissue fluid does not function correctly and there is a buildup, called edema.

The Starling equation describes the pressure gradients that drive the movement of water across fluid compartments.

Key Terms

  • Starling equation: An equation that illustrates the role of hydrostatic and oncotic forces in the movement of fluid across capillary membranes.
  • interstitial fluid: A solution that bathes and surrounds the cells of multicellular animals.

Fluid Movement

Extracellular fluid is separated among the various compartments of the body by membranes. These membranes are hydrophobic and repel water; however, there a few ways that fluids can move between body compartments. There are small gaps in membranes, such as the tight junctions, that allow fluids and some of their contents to pass through membranes by way of pressure gradients.

Formation of Interstitial Fluid

Hydrostatic pressure is generated by the contractions of the heart during systole. It pushes water out of the small tight junctions in the capillaries. The water potential is created due to the ability of the small solutes to pass through the walls of capillaries.

This buildup of solutes induces osmosis. The water passes from a high concentration (of water) outside of the vessels to a low concentration inside of the vessels, in an attempt to reach an equilibrium. The osmotic pressure drives water back into the vessels. Because the blood in the capillaries is constantly flowing, equilibrium is never reached.

The balance between the two forces differs at different points on the capillaries. At the arterial end of a vessel, the hydrostatic pressure is greater than the osmotic pressure, so the net movement favors water and other solutes being passed into the tissue fluid.

At the venous end, the osmotic pressure is greater, so the net movement favors substances being passed back into the capillary. This difference is created by the direction of the flow of blood and the imbalance in solutes created by the net movement of water that favors the tissue fluid.

Removal of Interstitial Fluid

The lymphatic system plays a part in the transport of tissue fluid by preventing the buildup of tissue fluid that surrounds the cells in the tissue. Tissue fluid passes into the surrounding lymph vessels and eventually rejoins the blood.

Sometimes the removal of tissue fluid does not function correctly and there is a buildup, which is called edema. Edema is responsible for the swelling that occurs during inflammation, and in certain diseases where the lymphatic drainage pathways are obstructed.

Starling Equation

Capillary permeability can be increased by the release of certain cytokines, anaphylatoxins, or other mediators (such as leukotrienes, prostaglandins, histamine, bradykinin, etc.) that are released by cells during inflammation. The Starling equation defines the forces across a semipermeable membrane to calculate the net flux.

The solution to the equation is known as the net filtration or net fluid movement. If positive, fluid will tend to leave the capillary (filtration). If negative, fluid will tend to enter the capillary (absorption). This equation has a number of important physiologic implications, especially when disease processes grossly alter one or more of the variables.

This is a diagram of capillary dynamics. The oncotic pressure exerted by the proteins in blood plasma tends to pull water into the circulatory system. The illustration shows a capillary with blood flow in it. As the blood moves to the venous end of the capillary, hydrostatic pressure removes fluid from the blood, and osmotic pressure puts fluid into the blood flow.

Capillary dynamics: Oncotic pressure exerted by the proteins in blood plasma tends to pull water into the circulatory system.

This is a diagram of the Starling model. Note how the concentration of interstitial solutes increases proportionally to the distance from the arteriole.

According to Starling’s equation, the movement of fluid depends on six variables:

  • Capillary hydrostatic pressure (Pc)
  • Interstitial hydrostatic pressure (Pi)
  • Capillary oncotic pressure (πz)
  • Interstitial oncotic pressure (πi)
  • Filtration coefficient (Kf)
  • Reflection coefficient (σ)

The Starling Equation is mathematically described as Flux=Kf[(Pc-Pi)-σ (πz-πi)

Clinical Significance

A variety of pathological conditions induce abnormalities in fluid balance. Fluid balance abnormalities are either an overload of fluid or a decrease in effective fluid. Fluid overload is clinically known as edema. Edema occurs most commonly in soft tissues of the extremities; however, it is possible to occur in any tissue. Decreases in fluid load are commonly referred to as dehydration.

Edema manifests as swelling in the soft tissues of the limbs and face with a subsequent increase in size and tightness of the skin. Peripheral edema is reducible by increasing the pressure in the interstitial space and is measured by pressing a finger into the tissue, creating a dimple in the edematous skin temporarily. Likewise, wearing compression stockings can reduce peripheral edema by increasing interstitial hydrostatic pressure, forcing fluid back into the capillaries.

Pulmonary edema is a condition when excess fluid swells into interstitial tissues of the lung. Symptoms include shortness of breath and chest pain. Orthopnea, or impaired respiration while lying flat, may also be present as the excess fluid is distributed across the entire lung. Pulmonary edema is life-threatening as it compromises gas exchange in the lungs and conditions can quickly decompensate. Pulmonary edema is associated with cardiac failure and renal failure. Classically, cardiac failure causes pulmonary edema through decreased pumping efficiency and capacity of the left atrium and left ventricle. This creates a back pressure in the pulmonary veins, increasing pressure in the vessels. Subsequently, hydrostatic pressures in the pulmonary capillaries are increased, “pushing” fluid into the interstitial lung space following the Starling equation. Renal failure causes edema through a failure to remove fluids and osmotic components from the body. The net result is increased osmotic pull into tissues and increased hydrostatic push out of capillaries.[5]

Liver disease is also capable of inducing edema. This is due to a failure to produce osmotically active proteins. Specifically, a failure to produce albumin. Albumin is found physiologically primarily in the plasma of the extracellular blood. It is typically not found in the interstitial space. As such, a decrease in body albumen directly decreases the “pull” of osmotic pressure into the capillaries. According to Starling forces, this results in the fluid moving into the interstitial spaces.[rx]

Additionally, fluid overload can be iatrogenically induced by excessive fluid replacement via intravenous (IV) access.

Edema is treated for symptomatic relief using a variety of medications including diuretics to remove fluid from the body via the renal system. Diuretics are closely associated with inducing contraction metabolic alkalosis. Albumin may be supplemented in cases of low plasma albumin. Lifestyle changes can include reducing sodium intake, restricting fluid intake, and wearing compression stockings. However, targeting the underlying pathology to improve cardiac, hepatic, or renal function offers better results than symptomatic treatment by simply removing fluid, replacing osmotic components, or other lifestyle changes.

Dehydration is largely due to inadequate water intake to meet the body’s metabolic needs. The average adult has an obligatory intake requirement of 1600 mL per day. This value increases depending on activity and metabolism. Primary sources of normal fluid loss include urine, sweat, respiration, and stool. Pathological causes include diarrhea, vomiting, infection, and increased urination secondary to SIADH, diabetes mellitus, or diabetes insipidus. Dehydration manifests clinically as decreased urine output, dizziness, fatigue, tachycardia, increased skin turgidity, and fatigue or confusion in severe cases. Whenever possible, oral fluid replacement should be attempted. In more urgent situations, IV fluid replenishment should be based on bolus supplementation of the deficit of fluids and a maintenance replenishment of obligatory intake requirements. The fluid deficit can be calculated when the pre-dehydration weight and post-dehydration weight are known. The equation in males is:

  • Deficit = 0.6 X weight in kilograms X [1-(140/measured Na)]

In females, the equation is:

  • Deficit = 0.5 X weight in kilograms X [1-(140/measured Na)]

This equation is highly useful in determining the initial fluid deficit. However, it has limitations in accuracy and can underestimate total fluid loss by more than 40%. While the above equation can be useful in initial fluid resuscitation, a more accurate approach uses plasma osmolarity instead of sodium, using 290 mmol/kg as the standard value. In pediatric patients, the fluid deficit is directly correlated to bodyweight loss from pre-illness compared to post-illness. One liter of free water weighs 1 kg. Therefore, a 10-kg pre-illness child that weighs 9 kg in illness has a fluid deficit of 1 L. In emergency scenarios, a bolus volume of 30 mL/kg is used to replace the loss. In obese patients, however, this leads to over-repletion of free water. Therefore, it is recommended to base bolus fluid resuscitation on adjusted ideal body weight (AIBW) in obese patients. This is derived from the ideal body weight (IBW) and the actual body weight (ABW).

  • AIBW = IBW + 0.4 (ABW – IBW)

Where ideal body weight is calculated as:

  • Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet

Maintenance fluid is also determined using a formula based on weight.  Fluid should be replaced at a rate of:

  • 4 mL/kg/hr for kg 1-10 + 2 mL/kg/hr for kg 10-20 + 1 mL/kg/hr above 20 kg

In other words, a patient who weighs 55 kilograms would require:

  • 40 mL/hr + 20 mL/hr + 35 mL = 95 mL/hr of free water

IV fluid replacement options include normal saline (0.9% NaCl), one-half normal saline (0.45% NaCl), Dextrose 5% in either normal saline or one-half normal saline, and lactated Ringer’s solution. The choice of replacement fluids is patient scenario-specific and dependent on the electrolyte status of laboratory evaluation.[rx]

Burn patients require specialized increases in fluid replacement secondary to the immense loss of free water through their wounds. The needed fluid resuscitation in adults is calculated using Parkland’s formula and Brooke’s formula. The modified Brooke formula is:

  • 2 mL/kg/% body surface area burned

The modified Parkland formula is:

  • 4 mL/kg/% body surface area burned

Both formulas estimate the first 24-hour fluid requirements from the time of the burn, with half the amount to be given in the first 8 hours. While both formulas give widely different values, they give equivalent outcomes. Final fluid needs should be based on the urine output rate.[rx]

Diabetic ketoacidosis is a complication of diabetes mellitus that results when the body fails to utilize glucose for energy production. Glucose is an osmotically active substance that is excreted in the urine at high concentrations. This leads to extreme fluid loss through the urine and dehydration. This necessitates large volume resuscitation of 6 to 9 L of normal saline on average.

Hyperosmolar hyperglycemic non-ketotic acidosis is a similar illness to diabetic ketoacidosis, except it lacks ketone production. It requires a similar fluid resuscitation.

In hypernatremic patients who undergo fluid replacement with rapid subsequent correction of hypernatremia are at an increased risk for developing cerebral edema. This develops due to increased intracellular and extracellular fluid loads and increased pressure within the brain space. This leads to neurological deficits and ultimately death. This condition can be avoided by slowly infusing fluids such that sodium levels are reduced at an initial rate of 2 to 3 mEq/L per hour for a maximum total change of 12 mEq/L per day until sodium is in a normal range.

Conversely, rapid correction of hyponatremia may lead to central pontine myelinolysis syndrome. Brain cells adapt to chronic states of hyponatremia by shifting organic osmoles, such as amino acids, from the intracellular compartment to the extracellular compartment. This allows the cells to maintain their original volume. When hyponatremia is rapidly corrected, brain cells shrink and the tight junctions of the blood-brain barrier are disrupted, leading to cell damage and demyelination of neurons.[rx] This can lead to what is known as “locked-in syndrome,” which is characterized by paralysis, dysphagia, and dysarthria. The serum sodium should be increased by approximately 1 to 2 mEq/L per hour until the neurologic symptoms of hyponatremia subside or until plasma sodium concentration is over 120 mEq/L.

Crystalloid fluid resuscitation offers complications as they alter the ionic load of the serum. Specifically, normal saline replacement may lead to non-gap hyperchloremic metabolic acidosis. One-half normal saline, if not monitored closely, may dilute ionic components, leading to hyponatremia or, less often, hypokalemia. Abdominal compartment syndrome in septic shock patients is possibly secondary to fluid overload with the subsequent leak of fluid from capillaries into extravascular spaces.

Colloid fluid resuscitation has its risks as well. The two major colloids used are albumen and hydroxyethyl starch. In the SAFE trial, which compared 4% albumin fluid with 0.9% normal saline, it was determined that outcomes are equivalent. However, in specific cases involving neurological injury, 4% albumin has an increased mortality rate compared to normal saline. As such, albumin should be avoided in this situation. Hydroxyethyl starch was studied in comparison and found to carry an increased risk of death or end-stage renal failure when compared to lactated Ringer’s solution when used in sepsis patients.[rx][rx][rx]

References

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