Hormones – Types, Functions, Clinical Feature, Significance

Hormones are chemical messengers that are secreted directly into the blood, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’ which carries them to organs and tissues of the body to exert their functions. There are many types of hormones that act on different aspects of bodily functions and processes.

Hormones are used to communicate between organs and tissues. Invertebrates, hormones are responsible for the regulation of many physiological processes and behavioral activities such as digestion, metabolism, respiration, sensory perception, sleep, excretion, lactation, stress induction, growth and development, movement, reproduction, and mood manipulation.^[rx][rx] In plants, hormones modulate almost all aspects of development, from germination to senescence.^[rx]

Some of these include

• Development and growth
• Metabolism of food items
• Sexual function and reproductive growth and health
• Cognitive function and mood
• Maintenance of body temperature and thirst

Hormones of the endocrine system are a vast topic with numerous hormones involved, affecting virtually every organ in the human body. Human physiologic processes such as homeostasis, metabolic demand, development, and reproduction are all possible because of hormones and the processes mediated by their actions. This review will elaborate on the organs that secret the specific hormone, the actions of the hormone, and where these actions occur. Also, it will review several of the most common endocrine diseases involving hormones. The number of diseases covered is not comprehensive due to the extensive number of diseases and ongoing research in this area. It is important to understand the physiology of hormones and how they result in pathological conditions.

Types of Hormones

• Adrenaline
• Adrenocorticotropic hormone
• Aldosterone
• Androstenedione
• Angiotensin
• Anti-diuretic hormone
• Anti-Müllerian hormone
• Calcitonin
• Cholecystokinin
• Corticotrophin-releasing hormone
• Cortisol
• Dehydroepiandrosterone
• Dihydrotestosterone
• Erythropoietin
• Follicle stimulating hormone
• Gastrin
• Ghrelin
• Glucagon
• Glucagon-like peptide 1
• Glucose-dependent insulinotropic peptide
• Gonadotrophin-releasing hormone
• Growth hormone
• Growth hormone-releasing hormone
• Human chorionic gonadotrophin
• Insulin
• Kisspeptin
• Leptin
• Luteinising hormone
• Melanocyte-stimulating hormone
• Melatonin
• Oestradiol
• Oestriol
• Oestrone
• Oxytocin
• Parathyroid hormone
• Peptide YY
• Progesterone
• Prolactin
• Prostaglandins
• Relaxin
• Somatostatin
• Testosterone
• Thyroid stimulating hormone
• Thyrotropin-releasing hormone
• Thyroxine
• Triiodothyronine
• Vitamin D

Classification by chemical nature of hormones

Hormones	Source	Example
Steroid hormones	Derived from cholesterol which belong to a chemical compounds known as steroids	sex hormones, adrenal cortex hormones
Amine hormones	Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a COOH, or carboxyl, group is removed, whereas the NH3 +, or amine group remains. Amine hormones are synthesized from the amino acids tryptophan or tyrosine.	An example of a hormone derived from tryptophan is melatonin, while tyrosine derivatives include thyroid hormones and catecholamines
Peptide hormones	These hormones are made up of only few amino acid residues and they are usually present themselves in form of a linear chains	Oxytocin and vasopressin
Protein hormones	These hormones are build up from large number of amino acid residues	Insulin, glucagon, somatotropins
Glycoprotein hormones	These are conjugated protein bound to carbohydrate which include galactose, mannose, fructose	luteinizing hormones follicle stimulating hormones, thyroid stimulating hormones
Eicosanoid hormones	Made up of small fatty acid derivatives with a variety of arachidonic acid	Prostaglandins

Clinical Signifence of Hormones

Posterior Pituitary

• Hypothalamus – Posterior Pituitary (neurohypophysis) Hormones. The posterior pituitary is an extension of axonal projections from the supraoptic and paraventricular nuclei of the hypothalamus nervous tissue, where oxytocin and anti-diuretic hormone are stored in the axonal ends or Herring bodies.[rx]
• Oxytocin – secretion results in a positive feedback loop during childbirth, resulting in increasing contractions. Oxytocin also affects lactation. Oxytocin is discussed in detail in this article.[rx]
• Anti-diuretic hormone (ADH) – or vasopressin is important in regulating blood volume and electrolyte levels, especially sodium. Its primary function is to regulate serum osmolarity. When the osmolality is below 280 mOsm/kg in a normal individual, the ADH levels will be lower. This results in water excretion. Conversely, when the plasma osmolality rises above 280 mOsm/kg, the ADH levels increase, resulting in water reabsorption. In addition to osmoreceptor stimulation, volume-sensitive receptors can also trigger ADH release.[rx] Volume-sensitive receptors will only increase ADH if there is a sudden and significant drop in pressure. Small incremental decreases will be insufficient to activate ADH – renin and norepinephrine handle these smaller changes instead.[rx][rx] ADH acts to increase water retention and raise blood pressure via two different receptors. In the distal nephron, V2 receptors help increase water reabsorption by increasing the number of aquaporin channels in the principal cells of the collecting duct. Increased ADH also stimulates V1 receptors, which increase vascular resistance throughout the body.[rx][rx] It is discussed in detail in this article.[rx]
• Anterior Pituitary Affecting Hormones – The hypothalamic-pituitary-adrenal (HPA) axis is a blood portal system connecting the hypothalamus and anterior pituitary, allowing control of several hormones. The hypothalamus is connected anatomically to the pituitary gland via the infundibulum. Within the infundibulum are capillaries that pour into portal veins, flowing directly to the anterior pituitary. This system ensures that the hormones released from the hypothalamus circulate directly into the anterior pituitary gland, never entering the general circulation. The hormones released from the hypothalamus include corticotropin-releasing hormone, thyrotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, somatostatin, prolactin-releasing hormone, and dopamine.[rx]
• Gonadotropin-releasing hormone (GnRH) –  is a hormone released from the hypothalamus and acts on the pituitary to control reproductive functions. There are two important factors for proper GnRH function, including proper neuron migration during development and pulsatile secretion.[rx] A small number of hypothalamic neurons release GnRH, the fetal cells migrate to the olfactory bulb and olfactory tract, from where they continue to the mediobasal hypothalamus in the preoptic area as well as the arcuate nucleus. Fetal cells in the olfactory area have the capability of detecting odorant stimuli and releasing GnRH. The importance of GnRH neuron migration received confirmation in the case of an aborted fetus diagnosed with Kallmann syndrome.[rx] The fetus had an older brother with the same X chromosome deletion; however, further neuropathologic examination revealed GnRH neurons had been arrested at the cribriform plate. The fetus was old enough that these neurons should have already migrated to the hypothalamus.[rx] Additionally, the belief is that anosmia presents in GnRH deficient patients due to the close association of GnRH neurons with the olfactory bulb and tract. The pulsatile property of GnRH neurons was demonstrated when immortalized in vitro tissue continued to release GnRH in a pulsatile fashion – not only implicating a possible intrinsic hypothalamic pulse generator but emphasizes the importance of the pulse itself.[rx] The pulse generator secretes GnRH in very discrete, random, but still regular bursts. It is now well established that GnRH pulsation results in appropriate physiologic gonadotropin levels. However, when GnRH is given continuously, serum gonadotropins will increase initially, but quickly decrease due to desensitization.[rx][rx][rx] This has important clinical implications for various cancers and gynecological pathology. With the discontinuation of continuous GnRH, spontaneous GnRH pulses will return, restoring the gonadotropin response.
• GnRH – has a very short half-life, only 2 to 4 minutes, and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) – the two hormones are commonly referred to as gonadotropins.[rx] Gonadotropins and sex steroids have both negative and positive feedback loops on GnRH pulsation. How these loops work is not fully understood. However, not only sex hormones impact GnRH, multiple other molecules have been found to influence GnRH. Some of these molecules include opiates, gonadal steroids, kisspeptin, neurokinin B, catecholamines, neuropeptide Y, corticotropin-releasing hormone, galanin, dynorphin, and prolactin. GnRH, LH, and FSH regulate various functions important to human sexual development, sex production, and fertility.[rx][rx] For more information, see the sections on LH and FSH. It is discussed in detail in this article.[17]
• Corticotropin-releasing hormone (CRH) – is another hormone involved in the hypothalamic-pituitary-adrenal (HPA) axis. CRH is produced in the paraventricular nucleus of the hypothalamus (PVH), which is released and stimulates the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH).[rx]
• Growth hormone-releasing hormone (GHRH) – is a hypothalamic hormone that binds to pituitary receptors to stimulate growth hormone (GH) release. Binding to its receptor results in the activation of a linked G protein, which stimulates cAMP production. This intracellular signaling results in the actual release of GH and somatotroph proliferation. It is suspected GHRH is released in a pulsatory manner since GH is pulsatory. However, this is not yet fully understood.[rx]
• Somatostatin – has two biologically active forms – somatostatin-14 (S14) and somatostatin-28 (S28) – they are 14 and 28 amino acids, respectively. It is synthesized by delta cells of the islets of Langerhans within the pancreas and by paracrine cells scattered throughout the gastrointestinal tract. Somatostatin is found throughout the body but is notably abundant in the nervous tissue of the spinal cord, brainstem, hypothalamus, and cortex.[rx] When released, somatostatin has a very short half-life. After IV administration, 50% will be removed from circulation in less than three minutes. As a result, the somatostatin concentration found within the blood is quite low, usually in sub-picomolar amounts. Somatostatin receptors are G protein-coupled receptors that, when activated, reduce cAMP levels. Five receptor subtypes exist, subtype 1-5. All five are present within the brain; however, each receptor has tissue specificity. Subtype 1 is present in the brain, lung, pancreas, liver, and GI tract. Subtype 2 is found in the brain and kidney. Subtype 3 is in the brain and pancreas. Subtype 4 is present in the brain and lungs. Subtype 5 occurs in the brain, skeletal muscle, GI tract, heart, adrenals, and pituitary.[21]
• Somatostatin – binds to its receptor, it inhibits GH release from the pituitary.[rx] In addition to inhibiting GH, somatostatin has additional physiologic properties in multiple organs. Within the brain, it has antinociception properties. In the liver/gallbladder, somatostatin decreases blood flow, inhibits gallbladder contraction, and inhibits bile duct secretion. The pancreas will have both endocrine and exocrine secretions in It is discussed in detail in this article inhibited. Finally, somatostatin will inhibit salivary amylase, gastric acid, and gastrointestinal hormone secretions within the gastrointestinal system. It also delays gastric emptying, slows motility, inhibits absorption, and decreases splanchnic blood flow.[rx][rx] It is discussed in detail in this article.[rx]
• Dopamine is an important molecule in the human body; it plays role in many different organs. It is most commonly discussed in psychiatric and neurological settings due to its role as a neurotransmitter. However, dopamine also serves as an endocrine hormone, secreted from the hypothalamus to the pituitary. The primary role regarding endocrine hormone physiology is to inhibit the secretion of prolactin. It has been well established and studied that pathology or medication side effects of decreased dopamine lead to hyperprolactinemia and the pathophysiology associated with this state.[rx] It is discussed in detail in this article.[rx]
• Thyrotropin-releasing hormone (TRH) is composed of three peptides, pyroglutamic-histidyl-proline amide. TRH begins as pro-TRH, and through a process of peptization and cyclization of glutamine, forms a pyroglutamic residue. [10] The metabolization of TRH is rapid, with a plasma half-life of approximately three minutes. TRH is another hormone involved in the HPA axis, helping determine the regulation of TSH secretion. Specifically, TRH is found in the highest concentrations in the PVH and median eminence of the hypothalamus. However, it is also present in the central nervous system, gastrointestinal tract, pancreatic islets, pituitary gland, and reproductive tracts – TRH function at these sites is not known. Lastly, either high levels or exogenous administration of TRH will stimulate additional hormones besides TSH, especially prolactin.[rx][rx][rx][rx]

Anterior Pituitary

• Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) – Follicle stimulating hormone is one of the hormones essential to pubertal development and the function of women’s ovaries and men’s testes. In women, this hormone stimulates the growth of ovarian follicles in the ovary before the release of an egg from one follicle at ovulation. It also increases oestradiol production.
• Prolactin – is a hormone produced by lactotrophs found in the anterior pituitary gland.  Prolactin regulation is by the hypothalamus in an inhibitory manner – that is, dopamine is released from the hypothalamus to decrease prolactin secretion. All other hormones depend on a stimulation signal from the hypothalamus to be synthesized and released. This explains why with the severing of the HPA axis, prolactin levels will increase, whereas other hormone levels will decrease.[rx]
• Prolactin – is secreted, it stimulates milk production in the mammary glands. During pregnancy, elevated estrogen acts on the anterior pituitary to further increase prolactin secretion, preparing the mammary glands for breastfeeding. However, progesterone levels also become elevated, which acts at the breast to inhibit prolactin. This is why milk secretion does not begin until after birth, because postpartum physiology results in drastically decreased progesterone levels, resulting in loss of prolactin inhibition.[rx] It is discussed in detail here.[rx]
• Primary hypothyroidism – TRH will elevate in attempts to increase TSH levels. TRH can act on the anterior pituitary to increase prolactin levels. Anti-psychotics are dopamine antagonists, meaning the usual inhibitory hormone is lost – resulting in elevated prolactin. In either of the above scenarios, in addition to several others (prolactinoma, for example), hyperprolactinemia will be present. Elevated prolactin results in inhibition of GnRH, decreased pulsation leads to decreased levels of FSH and LH. Commonly exhibited symptoms include amenorrhea and infertility in both males and females.[rx][rx][rx][rx]
• Thyroid-stimulating hormone (thyrotropin) (TSH) – TSH is synthesized and released from cells within the anterior pituitary gland, known as thyrotrophin. This hormone is composed of two subunits: 1 alpha and 1 beta. TSH is one of the four hormones which share the same alpha unit. The beta unit is what makes TSH unique and determines its specificity within the human body. Due to the physiologic effects of thyroxine (T4) and triiodothyronine (T3), these two hormones will help tightly control the levels of TSH released into the body.[rx] Minute increases in serum T3 and T4 will result in TSH inhibition. Conversely, small decreases in serum T3 and T4 result in increased TSH. T3 and T4 levels will also work to increase/decrease TRH through a negative feedback look, another mechanism for modulating TSH levels.[rx]
• TSH – is an essential hormone for the thyroid. It stimulates each step in hormone synthesis within the thyroid, affects the expression of multiple genes, and can cause thyroid hyperplasia or hypertrophy. The action begins when TSH binds to a plasma membrane receptor, activating adenylyl cyclase, which increases cyclic adenosine monophosphate (cAMP), resulting in the activation of several protein kinases. Via the same receptor, TSH stimulates phospholipase C, increasing phosphoinositide turnover, protein kinase C activity, and intracellular calcium concentration. How the above steps specifically link to T3 and T4 synthesis, release, and other thyroid metabolic processes are not fully understood.[rx][rx]
• Growth hormone (GH) – is a hormone synthesized by pituitary somatotroph cells. It has five distinct genes which influence the final spliced mRNA hormone.[rx] The predominant form is a 22 kDa GH; the other form is a 20 kDa GH (only 10%). Many factors influence the production and release of GH, the two primary factors being GHRH and somatostatin – stimulating and inhibiting, respectively. However, gender, age, nutrition, and insulin-like growth factor-1 (IGF-1) all modulate GH levels.[rx] Its production begins in the fetus. Maternal GH levels will actually decline due to the increasing placental GH, which replaces maternal levels. GH levels peak during puberty, the time of extensive growth, at about 150 mcg/kg. As aging continues, GH levels decline, paralleling the decline in body mass index. Every seven years, GH levels decrease by about 50%. By the age of 55 years, GH levels will be roughly 25 mcg/kg.[rx]
• GH release is pulsatile – suspected from the reduced tonic inhibition of somatostatin, and possibly bursts of GHRH. Each day there are ten pulsations, lasting 90 minutes, each one separated by 128 minutes. As previously mentioned, gender influences GH levels. In men, GH pulsations are more notable, whereas, in women, the GH secretion appears to be more continuous. Peak GH secretions occur within one hour of deep sleep onset. The average nighttime serum GH level is 1.0 ± 0.2 ng/mL. In contrast, average daytime GH levels are only 0.6 +/- 0.1 ng/mL. IGF-1, leptin, age, obesity, and hyperglycemia are all factors that act to inhibit GH release. Conversely, ghrelin, insulin-induced hypoglycemia, estrogen, dopamine, alpha-adrenergic agonists, and beta-adrenergic antagonists all stimulate GH. While many different factors modulate GH levels, it is important to remember that GHRH and somatostatin will primarily determine GH levels.[rx][rx][rx] It is discussed in more detail here.[rx]
• Adrenocorticotrophic hormone (ACTH) – is a hormone secreted from the anterior pituitary in response to CRH. ACTH travels through the systemic circulation to act upon the adrenal glands, specifically the zona fasciculata and zona reticularis of the adrenal cortex. ACTH primarily acts directly in the zona fasciculata to release cortisol. ACTH stimulates the enzyme cholesterol desmolase, which is the first enzyme involved in converting cholesterol into several steroid hormones. ACTH also stimulates androgen production in the zona reticularis, a byproduct of cortisol synthesis (see adrenal androgens below for more information).[rx][rx]

Pineal Gland

• Melatonin – is a hormone synthesized within the pineal gland from the amino acid tryptophan.[rx] Tryptophan is hydroxylated and then decarboxylated to form 5-hydroxytryptamine or serotonin. When there is sunlight, serotonin is stored within pinealocytes, making it unavailable to monoamine oxidase, the enzyme that converts serotonin to melatonin. In the absence of light, sympathetic input increases, causing a release of epinephrine. This causes the serotonin within pinealocytes to be released. Simultaneously, norepinephrine activates monoamine oxidase, serotonin-N-acetyltransferase, and hydroxy indole-O-methyltransferase.[rx][rx][rx] The result is a rapid increase in melatonin from 2 to 10 pg/mL to 100 to 200 pg/mL.[rx] Melatonin is highly lipid-soluble, allowing it to diffuse freely across cell membranes and the blood-brain barrier.[rx] Its release sends messages throughout the body, primarily the brain, affecting the synthesis of secondary messengers. Melatonin has three receptors identified M1, M2, and M3. All three express within the suprachiasmatic nucleus (SCN) of the hypothalamus. The three receptors are expressed variably, depending on the tissue. However, within the SCN, M1 will inhibit SCN neuron firing during nighttime.
• M2 within the SCN inhibits SCN’s circadian rhythm – These effects may contribute to the sleep-promoting effects of melatonin. M1 and M2 are easily desensitized, so when exogenous melatonin is given chronically, higher doses may be required to achieve the same effect.[rx][rx] The melatonin cascade primarily influences sleep and circadian rhythms. Melatonin is suspected to be one of the primary drivers of sleep induction and maintenance due to its marked increase in the evening. As alluded to earlier, the circadian rhythm is characterized by the low daylight melatonin levels and markedly increased levels at night – peaking between the hours of 11 PM to 3 AM – rapidly decreasing again before the hours of sunrise.[rx] Light from the environment has strong links with circadian rhythm; however, the rhythm will persist when people remain in a dark room for several days.[rx]

Thyroid Gland

• General T3/4 actions – thyroid hormones are crucial throughout the entire life of an individual. In childhood development, thyroid hormones help develop several body systems, particularly the brain. In adulthood, the thyroid hormones help drive metabolic activity and function of nearly all organs. Since it is necessary for so many different systems, a constant thyroid hormone supply is required, yet the total serum levels are always tightly controlled; if not, pathology will occur. Two mechanisms control the production of thyroid hormones. The first is through hormonal pathways and negative feedback loops. Levels of TRH, TSH, T4, and T3 will signal the thyroid whether to increase or decrease thyroid hormone levels. The second is via hormone consumption by extrathyroidal tissues based on nutritional, hormonal, and illness-related factors – the effect varies depending on the tissue.
• Thyroxine (T4) – T4 is less metabolically active and produced exclusively within the thyroid. The daily production rate is 80 to 100 mcg and degraded at roughly 10% per day. Approximately 80% is deiodinated – of this, 40% converts to T3, the other 40% converts to reverse T3 (rT3). The final 20% conjugates to tetraiodothyroacetic. The conversion of in the periphery of T4  to T3 is mediated via the enzyme 5’-deiodinase. T3 is the primary metabolite of T4, which has physiologic activity; other T4 metabolites are inactive. This conversion process is regulated in extrathyroidal tissue. Thus, T3 production may change independently of the pituitary-thyroid state.[rx]
• Tri-iodothyronine (T3) – T3 – is the primary metabolic hormone from the thyroid and is the driver behind metabolic and organ processes. About 80% of T3 production is in extrathyroid tissue from the deiodination of T4. The remaining 20% gets synthesized within the thyroid. Daily production is 30 to 40 mcg, but the extrathyroidal reserve of T3 is roughly 50 mcg. The fraction of T3 produced throughout the body from T4 varies considerably from tissue to tissue. Certain tissues like the anterior pituitary and liver contain high levels of T3 nuclear receptors, making them more responsive to serum T3.[rx][rx]

Different tissues have one of 3 deiodinases within the periphery that convert the prohormone T4 to active T3. Of which three enzymes will be expressed depend on a specific pattern of development and tissue type.[rx][rx]

• Type 1 5’-deiodinase (Dio1) – is found primarily in the liver, kidneys, and muscle. Dio1 was found to have reduced activity in hypothyroid subjects.
• Type 2 5’-deiodinase (Dio2) – was studied in rodents and displayed a higher prevalence in the cerebral cortex, brown fat, and the pituitary. In humans, Dio2 also expresses in skeletal muscle, heart, and thyroid. Within humans, Dio2 produces the majority of circulating T3. Dio2 was found to increase in hypothyroid and iodine-deficient subjects.
• Type 3 5’-deiodinase (Dio3) – actually inactivates T4 and is found primarily in the placenta, skin, skeletal muscle, and the developing brain. It is essential for sensory development, particularly within the inner ear. During human development, Dio3 is expressed first; as Dio1 and Dio2 increase, Dio3 expression will decrease.

It is well known that T4 and T3 have wide-reaching effects and can influence nearly every organ system within the body; specifically, three major areas include bones, heart, and metabolism regulation.

• Bones – Patients in infancy who were born with congenital hypothyroidism and are not treated with hormone replacement will have delayed epiphyseal development and poor growth. This same finding was present in patients with thyroid hormone resistance [18, page 6]. All TR isoforms are expressed in bones. However, TR-alpha and alpha/beta knockout mice showed abnormal bone development.[rx][rx]
• Heart – Patients who have T3 resistance will demonstrate elevated T3 levels, resulting in tachycardia. This likely demonstrates that patients who are resistant to T3 will not have cardiac resistance. Patients who have TR-beta mutations will phenotypically present this way, a concept supported by T3-beta knockout mice that also do not have cardiac resistance to T3.[rx]
• Metabolism regulation – T3 regulates the metabolic rate and can influence modest body weight changes. Humans with TR-beta mutations and T3 resistance demonstrate increased T3-alpha activity—this stimulation results in increased feeding and increased fatty acid oxidation. T3 also influences glucose metabolism, increasing its uptake. When Dio2 is not functioning properly, an association with glucose intolerance is evident. It is not yet well studied, but patients with impaired mitochondrial oxidative metabolism (seen in metabolic syndrome and type 2 diabetics) may have reduced T3 hormone action. The complications of improper metabolism will be discussed in Thyroid hormone pathology.[rx][rx][rx]

Parathyroid

• Parathyroid hormone (PTH) – PTH is the primary regulator of calcium and phosphate homeostasis in the human body. PTH gets synthesized as pre-pro-PTH, which is 115 amino acids long. Within parathyroid cells, it is cleaved to pro-PTH, 90 amino acids, and finally to PTH, 84 amino acids. The 84 amino acid version of PTH is the primary stored, secreted, and active form of the hormone. The short-term control of serum calcium is mediated exclusively by PTH. On a long-term basis, PTH is responsible for converting calcidiol to calcitriol, which occurs within renal tubular cells.[rx][rx][rx]

Pancreas

• Insulin – directly and indirectly, insulin affects several tissues; however, this article focuses on adipose tissue, muscle, and the liver. Insulin is a 51-amino acid peptide that is synthesized and secreted by the beta cells of the pancreas. Its action begins when it binds a cell membrane heterotetrameric receptor. The receptor has two alpha subunits that function to bind insulin, the two beta subunits which transduce the signal. Through a cascade of cell signaling, insulin is a powerful regulator of metabolic action. When there is a breakdown in cell signaling, resistance, or decrease in insulin, many different pathologies can occur – see pathology section for more information. Several factors may act to either further stimulate insulin release or inhibit. Glucose, mannose, leucine, and vagal stimulation will all increase insulin secretion. Alpha-adrenergic effects, somatostatin, and several drugs can inhibit insulin secretion.
• Ketone and insulin dynamics – Under physiologic states which result in deficient insulin levels, such as prolonged fasting or uncontrolled diabetes mellitus, fat is mobilized to meet metabolic demands. The liver is unable to handle all the fatty acids being shuttled its way, resulting in ketone body production. This is a result of incomplete beta-oxidation of the long-chain fatty acids which are oversupplied to the liver. Ketoacids can be employed as fuel in extrahepatic tissue, such as skeletal muscle and the heart. However, under very prolonged periods of fasting, the brain will also use ketoacids for energy. Insulin acts to keep the levels of ketone bodies low; it potently drops circulating levels via three mechanisms. First, insulin inhibits lipolysis, so the fatty acids needed to make ketone bodies are not available. Second, insulin will act within the liver to directly inhibit ketogenesis. Thirdly, insulin helps increase the peripheral clearance of ketone bodies.
• Protein metabolism and paracrine effects – As previously mentioned, insulin inhibits gluconeogenesis, this keeps amino acids readily available for protein synthesis. Insulin expedites the transportation of amino acids into the liver and skeletal muscle. Also, insulin escalates the amount and efficiency of ribosomes. Lastly, insulin inhibits protein breakdown; roughly 40% of proteolysis is influenced by insulin. The net result is increased protein synthesis. Insulin has many influences on other hormones within the body. The pancreatic islet cells have alpha, beta, and delta cells. Alpha secretes glucagon, beta secrets insulin, and delta secretes somatostatin. When these hormones get secreted, they have paracrine effects on the surrounding cells. Insulin specifically will reach alpha cells first and inhibit the release of glucagon, which causes an increased effect of its metabolic actions. In hyperglycemic states, somatostatin will also be secreted, inhibiting alpha cells from releasing glucagon to reduce glucose levels.[rx][rx][rx][rx][rx]
• Glucagon – is a 29 amino acid peptide secreted from the alpha cells of the islets of Langerhans. It opposes the action of insulin, functioning to increase glucose levels within the body. Ingestion of protein, hypoglycemia, and exercise results in glucagon secretion to raise glucose levels. Glucagon can raise glucose levels within the body by increasing glycogenolysis, the end product being glucose. It also promotes gluconeogenesis, which is the production of glucose by using precursor molecules like amino acids and glycerol within the liver.[rx][rx]

Adrenal Glands

The adrenal gland is located just above the kidney and produces several hormones such as aldosterone, cortisol, DHEA, norepinephrine, and epinephrine. Different regions of the adrenal gland produce these hormones. The cortex has three layers: zona glomerulosa, zona fasciculata, and zona reticularis – which secrete aldosterone, cortisol, and DHEA, respectively. The medulla of the adrenal gland is composed of chromaffin cells and is responsible for synthesizing and release of norepinephrine and epinephrine.

• Cortisol – is a glucocorticoid hormone synthesized in the zona fasciculate of the adrenal gland, and ACTH stimulates its production. Cortisol primarily acts to increase glucose levels in the body, which occurs via increased gluconeogenesis, lipolysis, and proteolysis. To keep glucose levels high, cortisol also increases insulin resistance, which is why high levels of cortisol can lead to diabetes mellitus. Since cortisol is a glucocorticoid, it has additional properties, so it has utility as a medication in hospitalized patients. It can increase appetite, raise blood pressure, decrease bone formation, and, most importantly – decrease inflammatory and immune responses. Cortisol has a negative feedback loop that acts on the hypothalamus, anterior pituitary, and adrenal gland to inhibit CRH release, ACTH, and cortisol, respectively.[rx][rx]
• Aldosterone – Aldosterone is a crucial mineralocorticoid hormone in the renin-angiotensin system (RAS) – which is important for regulating cardiac, renal, and vascular physiology. The RAS pathway begins with renin cleaving angiotensinogen into the inactive angiotensin I, which then converts via the angiotensin-converting enzyme (ACE) action angiotensin II (primarily in the lungs). Angiotensin II mediates aldosterone release from the zona glomerulosa of the adrenal gland via angiotensin II type 1 receptor (AT1Rs).[rx]
• Adrenal Androgens – are primarily dehydroepiandrosterone (DHEA) and DHEA sulfate. The production of these androgens within the adrenal gland is a byproduct of the synthesis of cortisol. As a result, the primary stimulant of DHEA and DHEA sulfate is ACTH. These two hormones have minimal, if any, inherent androgenic properties. However, it is well established that the excess secretion of DHEA and DHEA sulfate are hallmarks of congenital adrenal hyperplasia (CAH).  A small percentage will be converted to androstenedione, and then to testosterone (and potentially estrogen) in both the adrenals and peripheral tissue. Once this conversion has occurred, physiologic effects of androgens will occur (see endocrine sex hormones for more information). Therefore, it is not DHEA and DHEA sulfate, which causes virilization in young females; rather, the elevated levels are converted to more potent androgens, which cause the classic phenotype seen in CAH.
• Epinephrine (adrenaline) and norepinephrine (noradrenaline) – these two hormones will be discussed together since they are both produced from the medulla of the adrenal glands and have many similarities. This discussion will explain the different effects of stimulation of alpha-1, beta-1, and beta-2 receptors. Understanding what happens when certain receptors are activated will make it easier to understand the effects of epinephrine and norepinephrine. In clinical settings, epinephrine and norepinephrine have several different uses depending on dose and patient indication.[rx][rx]
• Alpha-1 – stimulation results in the utilization of the IP3-DAG cascade, resulting in increased intracellular calcium. Activation in peripheral arteries results in vasoconstriction, resulting in increased resistance, producing an elevated mean arterial pressure (MAP). Alpha-1 constricts not only arteries but also veins. Venoconstriction results in an increased venous return to the heart. Some additional random effects of alpha-1 include mydriases (pupil dilation) and urine retention via contraction of the urethral sphincter and prostatic smooth muscle.
• Beta-1 – these receptors are primarily present in the heart, and when stimulated, produce increased inotropy and chronotropic without influencing vessels. Beta-1 can also increase renin release, resulting in increases in blood pressure.
• Beta-2 – stimulation of these receptors within blood vessels will result in vasodilation, decreasing the systemic vascular resistance (SVR), resulting in decreased diastolic blood pressure. Within the lungs, beta-2 results in bronchodilation, in the liver, it promotes gluconeogenesis, and in the eye, it can increase aqueous humor production.
• Epinephrine – will bind and stimulate all three receptors. The predominance of the receptor affected depends on the dose administrated. At lower doses, the beta receptor action predominates, resulting in increased cardiac output (CO) from the inotropic and chronotropic effects of beta-1. The stimulation of alpha-1, which would usually cause vasoconstriction, is offset by the vasodilation of beta-2. The result of all three receptors being stimulated is increased CO, decreased SVR, and variable effect on the MAP. High-dose epinephrine results in predominant alpha-1 stimulation. This results in increased SVR and CO. Epinephrine is released into the bloodstream under times of great stress, like “fight or flight” scenarios, or simply stress from life (school, sports, etc.). Strong emotions, including anger or fear, can also stimulate secretion. It was aptly named adrenaline because when you need a surge of energy (facilitated by the above physiologic effects), epinephrine is released.[rx][rx][rx]
• Norepinephrine – has an action on both alpha-1 and beta-1 receptors, with the predominant action coming from alpha-1 stimulation. As a result, there is a potent vasoconstriction and a mild increase in cardiac output. A mild chronotropic effect is noted, but due to the reflex bradycardia from increased MAP, the effect is canceled. Norepinephrine is often secreted in tandem with epinephrine because the stressors that induce epinephrine also cause a release of norepinephrine. However, there are times when these two hormones will be secreted independently of each other. Norepinephrine and epinephrine have other functions; however, these are outside the scope of endocrine hormones and will not be discussed here.[113]

Endocrine Sex Hormones

• Endocrine sex hormones –  due to their intricate and overlapping properties in both genders, will be explained and discussed from a gender standpoint, rather than by organ. Each of the sex hormones is expressed and active in both male and females; it is the levels and concentrations which help develop and define the external and internal function of the human body. Studies and patient cases have shown mutations in classical male hormones, or classical female hormones can still lead to pathology when absent in either gender.
• Female Sexual Development and Hormone Expression and Activity – Physiologist Alfred Jost formulated a simple model of normal sexual development. Chromosomal sex (XX or XY) dictates gonadal sex, which, in turn, determines phenotypic sex (male or female).[rx] Based on this module, three interdependent yet sequential steps must occur. First, the establishment of the chromosomal sex, within the first six weeks of gestation, male and female development is identical. After six weeks, the gonad will develop into the appropriate tissue, testes if male or an ovary if female. The testes will begin to secrete hormones around week six; the ovary is hormonally silent.[rx] Finally, at week 12, the male phenotype will be complete; the female completion occurs a little later than males. The anatomic structures include both the internal urogenital tract – Müllerian or Wolffian ducts – and external genitalia. The female Müllerian ducts become the upper vagina, fallopian tubes, and uterus.

The menstrual cycle divides into two phases, follicular and luteal, determined by endocrine hormones that drive the cycle.

• Follicular Phase – The follicular phase begins with the initiation of menses and ends one day before the luteinizing hormone (LH) surge. Early in the phase, the ovary has little hormone activity, resulting in low estradiol and progesterone levels. However, LH pulsation increases from once every several hours in the late luteal to once every 90 minutes. The mid-follicular phase increases follicle-stimulating hormone (FSH), stimulating folliculogenesis, and increased estradiol. FSH continues to increase estradiol levels by stimulating aromatase for the follicles to continue developing. The increase in estradiol eventually leads to a negative feedback loop on both LH and FSH. Late in the follicular phase, FSH and LH remain low, but FSH does active LH receptors in the ovary, resulting in the secretion of intrauterine growth factors.[rx][rx]
• Luteal Phase – From the follicular into the luteal phase, estradiol continues to rise, peaking one day prior to ovulation. At this time, a unique endocrine phenomenon occurs a switch from negative feedback to positive feedback – resulting in the midcycle surge. There is a 10-fold increase in LH and a smaller surge of FSH as well. The LH surge cannot be simulated in women by administering high estrogen and progesterone levels, indicating that other factors are involved. Roughly 36 hours after the LH surge, the follicle will release the oocyte, and it makes its way through the fallopian tube to the uterine cavity. Progesterone begins to rise due to secretions from the corpus luteum. Progesterone raises body temperature, relaxes uterine smooth muscle, and prevents endometrial hyperplasia. In simple terms, estrogen stimulates the proliferation of the endometrium in preparation for implantation, and progesterone maintains the endometrium as a suitable environment for fertilization and implantation. Late in the luteal phase, if the oocyte does not undergo fertilization, LH levels will decrease, and progesterone and estrogen levels will decrease – sloughing off the outer layer of the endometrium, resulting in menses. If the oocyte does get fertilized, it will implant in the endometrium. The embryo will begin secreting human chorionic gonadotropin (hCG), which sustains the corpus luteum and progesterone levels.[rx][rx][rx]

Male Sexual Development and Hormone Expression and Activity

As mentioned previously in the female section, the default development will be female from an embryological standpoint. Males genetically are XY – the region on the Y chromosome critical to testicular development is the SRY (sex-determining region of the Y chromosome) gene. This is the gene causing neutral gonads to develop into testes. Fetal testes secrete three hormones: anti-Müllerian hormone (AMH), testosterone, and 5-alpha-dihydrotestosterone (DHT). AMH primarily causes the regression of the Müllerian ducts – testosterone and DHT (androgens) are the hormones on which we will primarily focus.[rx][rx]

• The internal urogenital tract – driver is initially by human chorionic gonadotropin (hCG) and later in development by luteinizing hormone (LH) secreted by the fetal anterior pituitary gland. Depending on the development stage, either hCG or LH will cause the fetal testes to secrete testosterone – this propagates the differentiation of the Wolffian ducts into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts.[rx]
• The external urogenital tract – is driven by the conversion of testosterone into DHT by the enzyme 5-alpha-reductase. DHT regulates the fetal development of the prostate and external genitalia, which completely form by the twelfth week of gestation. By studying 5-alpha-reductase deficient animals and humans, the conclusion is that testosterone is responsible for internal sexual development, while DHT is necessary for external development. Patients with 5-alpha-reductase will have normal internal male anatomy but will have ambiguous external genitalia and lack secondary male sex characteristics. This is due to the normal function of testosterone but low levels of DHT. Androgens, in addition to sexual development, affect body composition – there has been a direct correlation of birth weight to the degree of androgenization rather than chromosomal sex.[rx][rx]
• The negative feedback loop of LH – secretion works via two mechanisms. Estradiol inhibits GnRH by inhibition at the level of the hypothalamus, while testosterone and DHT inhibit the pituitary gland directly.[rx] The negative feedback loop of FSH is mediated via two molecules: inhibin B (testicular peptide) and estradiol – inhibin B being the more important regulatory molecule.[rx][rx][rx]
• Estradiol – is produced normally in men when testosterone undergoes aromatization, approximately 20% of estradiol synthesis is in the testes. The remaining 80% is produced in adipose, skin, brain, and bone tissue – adipose being the most notable site of estradiol production in men. When estradiol is deficient, men may have the following problems: increased body fat delayed epiphyseal closure, and decreased bone density. Rats and mice with ER-alpha deficiency have been studied and been shown to be infertile. The testes of these rodents which lack ER-alpha have dilated seminiferous tubules containing no sperm. ER-alpha is not necessary for sperm function, but it is necessary for sperm maturation. ER-alpha, ER-alpha, and ER-beta, or aromatase-deficient mice have been shown to have abnormal mating behavior. ER-beta only deficient mice will exhibit normal mating. While it is not fully understood, it is suspected ER-alpha and estradiol are necessary for normal mating and the aggressive behaviors seen in the male genotype.[rx][rx][rx]
• GnRH  – causes the regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  GnRH’s pulsatile secretions from the hypothalamus cause a similar pulsatile appearance of LH and FSH – the half-life of LH is significantly shorter than FSH. The secretion of GnRH acts upon the gonadotrophic cells of the anterior pituitary, resulting in the release of FSH and LH.[rx]
• LH – acts primarily on Leydig cells by binding to receptors on the cell membrane. This results in the stimulation and release of cAMP, which activates protein kinase A, resulting in Leydig cells producing its primary hormonal product, testosterone. Production of testosterone averages 5 to 7 mg each day.[rx]
• FSH – binds to the cell membrane of Sertoli cells, causing stimulation and release of cAMP, activating protein kinase A. The result of intracellular signaling increases gene expression and protein levels to support spermatogenesis.[rx]

These are the primary roles of FSH and LH. In a broad overview, it can be summarized: LH acts on Leydig cells to secrete testosterone, and FSH acts on Sertoli cells to promote spermatogenesis. Testosterone, like all steroid hormones, originates from cholesterol. Once testosterone is produced, it can be metabolized further via aromatization to become estradiol or reduced by 5-alpha-reductase to DHT. Cells with androgen receptors (AR) can be bound and activated by testosterone or DHT, the latter having a much higher binding affinity. Regardless of which molecule stimulates the AR, a conformational change is induced, allowing translocation to the nucleus. Within the nucleus, a homodimer forms by combining with a second hormone-AR molecule. This creates an active molecule that can bind to androgen response elements – inducing upregulation/downregulation of transcription genes and, ultimately, protein synthesis.[rx] The physiologic action of testosterone is mediated via the hormone itself and its active metabolites – DHT and estradiol, resulting in the following major functions in males[rx][rx]:

• Development of the male phenotype in embryological development (as discussed above)
• Feedback communication on the gonadotropic hypothalamic-pituitary axis
• Provocation of sexual maturity at puberty and maintenance throughout adulthood
• Sexual function (libido, sexual satisfaction, and erectile function)
• Muscle and bone mass at puberty and throughout adulthood
• Maintenance of lower fat mass, initiation, and maintenance of spermatogenesis
• Maintenance of erythropoiesis and hematocrit levels

Appetite Regulation

• Ghrelin – Classically considered the “hunger hormone” due to its stimulation of appetite. It is a 28 amino-acid peptide synthesized predominantly in the stomach, specifically the gastric fundus where oxyntic gland P/D1 cells are found.[rx] These cells come in two types. The open type has exposure to the lumen of the stomach and is secreted directly into the stomach to intermix with gastric contents. The closed type is found close to the lamina propria and is secreted directly into the vasculature.[rx] Ghrelin is also present in the pancreas, placenta, kidney, and pituitary, but at much lower levels.[rx] Ghrelin receptors (growth hormone secretagogue receptor [GHS-R]) have two forms
• GHS-R1a and GHS-R1b -GHS-R1a is found in both the central nervous system and peripheral tissue and mediates food intake and satiety. GHS-R1b has a wider distribution, but its function is unknown since it has no links to the same G protein complex that GHS-R1a is.[rx][rx] Ghrelin levels increase during fasting, starvation, and anorexia – surges are also noted before meals. Nutrients suppress ghrelin, carbohydrates having the greatest inhibitory effect, followed by protein and lipids. The decrease in ghrelin occurs via non-vagal signals from the stomach and intestines.[rx]
• Ghrelin stimulates primarily GH secretion and possibly GHRH itself – further stimulating GH secretion. The resultant effect is increased appetite and a positive energy balance, in addition to the effects of GH (see GH section for more information).  Ghrelin acts locally in the stomach to increase gastric contraction and potentiate stomach emptying. GH is known to affect bone formation and mass, but interestingly osteoblasts express GHS-R1a suggesting a possible direct effect. Defects in GHS-R have been linked to short stature, further implicating its impact on bone formation.[rx][rx]
• Leptin – Conversely, leptin is classically considered the “satiety hormone” due to its suppression of appetite. It is a 167 amino acid protein produced from the ob gene and expressed primarily in adipocytes.[rx] It mediates its actions by binding leptin receptors (LEPRs), of which six isoforms exist LEPR-a, to LEPR-f. The longest form is LEPR-b, is found in many organs, but importantly it is found in the brain – specifically the hypothalamic and brainstem nuclei. Mutations in this isoform result in severe obesity.[rx][rx]

References