Category Archive Endocrinology

Pancreas – Anatomy, Types, Structure, Functions

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas has both an endocrine and a digestive exocrine function. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin, and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins, and fats in food entering the duodenum from the stomach.

The pancreas is an extended, accessory digestive gland that is found retroperitoneally, crossing the bodies of the L1 and L2 vertebra on the posterior abdominal wall. The pancreas lies transversely in the upper abdomen between the duodenum on the right and the spleen on the left. It is divided into the head, neck, body, and tail. The head lies on the inferior vena cava and the renal vein and is surrounded by the C loop of the duodenum. The tail of the pancreas extends up to the splenic hilum. The pancreas produces an exocrine secretion (pancreatic juice from the acinar cells) which then enters the duodenum through the main and accessory pancreatic ducts and endocrine secretions (glucagon and insulin from the pancreatic islets of Langerhans) that enter the blood.

Structure

The Parts of the Pancreas

Your doctor may refer to the parts of the pancreas when discussing your disease. The tumor’s location in the pancreas is important since it affects the symptoms and treatment of your disease.
FOUR MAIN PARTS
  • Head – The head is the widest part of the pancreas. The head of the pancreas is found in the right side of abdomen, nestled in the curve of the duodenum (first part of the small intestine).
  • Neck – The neck is the thin section of the gland between the head and the body of the pancreas.
  • Body – The body is the middle part of the pancreas between the neck and the tail. The superior mesenteric artery and vein run behind this part of the pancreas.
  • Tail – The tail is the thin tip of the pancreas in the left side of the abdomen, in close proximity to the spleen.

[Uncinate process – The uncinate is the part of the head that hooks towards the back of the abdomen around two very important blood vessels—the superior mesenteric artery and the superior mesenteric vein.

The pancreas (shown here in pink) sits behind the stomach, with the body near the curvature of the duodenum, and the tail stretching to touch the spleen.

The pancreas is an organ that in humans lies in the abdomen, stretching from behind the stomach to the left upper abdomen near the spleen. In adults, it is about 12–15 centimeters (4.7–5.9 in) long, lobulated, and salmon-colored in appearance.

Anatomically, the pancreas is divided into the headneckbody, and tail. The pancreas stretches from the inner curvature of the duodenum, where the head surrounds two blood vessels: the superior mesenteric artery, and vein. The longest part of the pancreas, the body, stretches across behind the stomach, and the tail of the pancreas ends adjacent to the spleen.[rx]

Two ducts, the main pancreatic duct, and a smaller accessory pancreatic duct, run through the body of the pancreas, joining with the common bile duct near a small ballooning called the ampulla of Vater. Surrounded by a muscle, the sphincter of Oddi, this opens into the descending part of the duodenum.[rx]

Parts

The head of the pancreas sits within the curvature of the duodenum and wraps around the superior mesenteric artery and vein. To the right sits the descending part of the duodenum and between these travel the superior and inferior pancreaticoduodenal arteries. Behind rests the inferior vena cava, and the common bile duct. In front sits the peritoneal membrane and the transverse colon.[rx] A small uncinate process emerges from below the head, situated behind the superior mesenteric vein and sometimes the artery.[rx]

The neck of the pancreas separates the head of the pancreas, located in the curvature of the duodenum, from the body. The neck is about 2 cm (0.79 in) wide and sits in front of where the portal vein is formed. The neck lies mostly behind the pylorus of the stomach and is covered with the peritoneum. The anterior superior pancreaticoduodenal artery travels in front of the neck of the pancreas.[rx]

The body is the largest part of the pancreas and mostly lies behind the stomach, tapering along its length. The peritoneum sits on top of the body of the pancreas, and the transverse colon in front of the peritoneum.[rx] Behind the pancreas are several blood vessels, including the aorta, the splenic vein, and the left renal vein, as well as the beginning of the superior mesenteric artery.[rx] Below the body of the pancreas sits some of the small intestines, specifically the last part of the duodenum and the jejunum to which it connects, as well as the suspensory ligament of the duodenum which falls between these two. In front of the pancreas sits the transverse colon.[rx]

The pancreas narrows towards the tail, which sits near to the spleen.[rx] It is usually between 1.3–3.5 cm (0.51–1.38 in) long, and sits between the layers of the ligament between the spleen and the left kidney. The splenic artery and vein, which also passes behind the body of the pancreas, pass behind the tail of the pancreas.[rx]

Blood supply

The pancreas has a rich blood supply, with vessels originating as branches of both the coeliac artery and the superior mesenteric artery.[rx] The splenic artery runs along the top of the pancreas and supplies the left part of the body and the tail of the pancreas through its pancreatic branches, the largest of which is called the greater pancreatic artery.[rx] The superior and inferior pancreaticoduodenal arteries run along the back and front surfaces of the head of the pancreas adjacent to the duodenum. These supply the head of the pancreas. These vessels join together (anastomose) in the middle.[rx]

The body and neck of the pancreas drain into the splenic vein, which sits behind the pancreas.[rx] The head drains into, and wraps around, the superior mesenteric and portal veins, via the pancreaticoduodenal veins.[rx]

The pancreas drains into lymphatic vessels that travel alongside its arteries and has a rich lymphatic supply.[rx] The lymphatic vessels of the body and tail drain into splenic lymph nodes, and eventually into lymph nodes that lie in front of the aorta, between the coeliac and superior mesenteric arteries. The lymphatic vessels of the head and neck drain into intermediate lymphatic vessels around the pancreaticoduodenal, mesenteric and hepatic arteries, and from there into the lymph nodes that lie in front of the aorta.[rx]

Arterial Supply

Branches of the splenic artery (a branch of the celiac trunk), superior mesenteric artery (SMA), and the common hepatic artery provide blood supply to the pancreas .

  • Pancreatic head: The gastroduodenal artery (a branch of the common hepatic artery) supplies the head and the uncinate process of the pancreas in the form of the pancreaticoduodenal artery (PDA). Part of the inferior portion of the head is supplied by the inferior PDA which arises from the SMA.
  • Body and the tail: The splenic artery and its branches supply these.

Venous Supply

  • Pancreatic head: The head drains into the superior mesenteric vein (SMV).
  • Body and the neck: The splenic vein drains these.

The SMV and splenic vein merge to form the portal vein.

Nerves

The pancreas has a complex network of parasympathetic, sympathetic, and sensory innervations . It also has an intrinsic nerve plexus. Sympathetic and parasympathetic fibers are dispersed to pancreatic acinar cells. The parasympathetic fibers arise from the posterior vagal trunk and are secretomotor, but the secretions from the pancreas are predominantly mediated by cholecystokinin and secretin, which are hormones produced by the epithelial cells of the duodenum and proximal intestinal mucosa regulated by acidic compounds from the stomach. Sympathetic innervation is via the T6-T10 thoracic splanchnic nerves and the celiac plexus.

Overview of Pancreatic Islets

Pancreatic islets, also called the islets of Langerhans, are regions of the pancreas that contain its hormone-producing endocrine cells.

Key Points

The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the bloodstream by five different types of cells.

The alpha cells produce glucagon and makeup 15–20% of total islet cells. The beta cells produce insulin and amylin and makeup 65–80% of the total islet cells. The delta cells produce somatostatin and makeup 3–10% of the total islet cells.

The gamma cells produce pancreatic polypeptide and makeup 3–5% of the total islet cells. The epsilon cells produce ghrelin and make up less than 1% of the total islet cells.

The feedback system of the pancreatic islets is paracrine and is based on the activation and inhibition of the islet cells by the endocrine hormones produced in the islets.

Key Terms

endocrine: Produces internal secretions that are transported around the body by the bloodstream.

paracrine: Describes a hormone or other secretion released from endocrine cells into the surrounding tissue rather than into the bloodstream.

exocrine: Produces external secretions that are released through a duct.

The pancreas serves two functions, endocrine and exocrine. The exocrine function of the pancreas is involved in digestion, and these associated structures are known as the pancreatic acini.

The pancreatic acini are clusters of cells that produce digestive enzymes and secretions and make up the bulk of the pancreas. The endocrine function of the pancreas helps maintain blood glucose levels, and the structures involved are known as the pancreatic islets, or the islets of Langerhans.

This is an illustration of the pancreas with a detailed view of a pancreatic islet with endocrine cells. The islet is surround by the pancreatic acini and pancreatic duct.

Pancreatic islets or islets of Langerhans: The islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells.

The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the blood flow by five different types of cells.

This is a photo taken through a microscope of pancreatic tissue. The small cells in the middle are beta cells, and the surrounding larger cells are alpha, delta, gamma, and epsilon cells.

Pancreatic tissue: The small cells in the middle are beta cells, and the surrounding larger cells are alpha, delta, gamma, and epsilon cells.

The endocrine cell subsets are:
  • Alpha cells produce glucagon and make up 15–20% of total islet cells. Glucagon is a hormone that raises blood glucose levels by stimulating the liver to convert its glycogen into glucose.
  • Beta cells produce insulin and amylin and makeup 65–80% of the total islet cells. Insulin lowers blood glucose levels by stimulating cells to take up glucose out of the bloodstream. Amylin slows gastric emptying, preventing spikes in blood glucose levels.
  • Delta cells produce somatostatin and makeup 3–10% of the total islet cells. Somatostatin is a hormone that suppresses the release of the other hormones made in the pancreas.
  • Gamma cells produce pancreatic polypeptide and makeup 3–5% of the total islet cells. Pancreatic polypeptide regulates both the endocrine and exocrine pancreatic secretions.
  • Epsilon cells produce ghrelin and make up less than 1% of the total islet cells. Ghrelin is a protein that stimulates hunger.

The feedback system of the pancreatic islets is paracrine—it is based on the activation and inhibition of the islet cells by the endocrine hormones produced in the islets. Insulin activates beta cells and inhibits alpha cells, while glucagon activates alpha cells, which activates beta cells and delta cells. Somatostatin inhibits the activity of alpha cells and beta cells.

Types of Cells in the Pancreas

The islets of Langerhans are the regions of the pancreas that contain many hormone-producing endocrine cells.

Key Points

The pancreas reveals two different types of parenchymal tissue: exocrine acini ducts and the endocrine islets of Langerhans.

The hormones produced in the islets of Langerhans are insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin.

The pancreatic hormones are secreted by alpha, beta, delta, gamma, and epsilon cells.

Key Terms

somatostatin: A polypeptide hormone, secreted by the pancreas, that inhibits the production of certain other hormones.

insulin: A polypeptide hormone that regulates carbohydrate metabolism.

glucagon: A hormone, produced by the pancreas, that opposes the action of insulin by stimulating the production of sugar.

Pancreatic Cells

The pancreas is a glandular organ that belongs to both the digestive and the endocrine systems of vertebrates. It is an endocrine gland that produces several important hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide.

It is also a digestive, exocrine organ, that secretes pancreatic juice that contains digestive enzymes to assist with digestion and the absorption of nutrients in the small intestine. These enzymes help to further break down the carbohydrates, proteins, and lipids in the chyme.

Under a microscope, stained sections of the pancreas reveal two different types of parenchymal tissue. The light-stained clusters of cells are called islets of Langerhans, which produce hormones that underlie the endocrine functions of the pancreas.

The dark-stained cells form acini, connected to ducts. Acinar cells belong to the exocrine pancreas and secrete digestive enzymes into the gut via a system of ducts.

Islets of Langerhans

This is a microscope photograph of a porcine islet of Langerhans. On the left is a brightfield image created using hematoxylin stain; nuclei are dark circles and the acinar pancreatic tissue is darker than the islet tissue. The right image is the same section stained by immunofluorescence against insulin, indicating beta cells.

Islets of Langerhans: A porcine islet of Langerhans. On the left is a brightfield image created using hematoxylin stain; nuclei are dark circles and the acinar pancreatic tissue is darker than the islet tissue. The right image is the same section stained by immunofluorescence against insulin, indicating beta cells.

The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the blood flow by five different types of cells. The endocrine cell subsets are:

  • Alpha cells produce glucagon and make up 15–20% of total islet cells. Glucagon is a hormone that raises blood glucose levels by stimulating the liver to convert its glycogen into glucose.
  • Beta cells produce insulin and amylin, and makeup 65–80% of the total islet cells. Insulin lowers blood glucose levels by stimulating cells to take up glucose out of the bloodstream. Amylin slows gastric emptying, preventing spikes in blood glucose levels.
  • Delta cells produce somatostatin and makeup 3–10% of the total islet cells. Somatostatin is a hormone that suppresses the release of the other hormones made in the pancreas.
  • Gamma cells produce pancreatic polypeptide and makeup 3–5% of the total islet cells. Pancreatic polypeptide regulates both the endocrine and exocrine pancreatic secretions.
  • Epsilon cells that produce ghrelin, and make up less than 1% of the total islet cells. Ghrelin is a protein that stimulates hunger.

The islets of Langerhans can influence each other through paracrine and autocrine communication. The paracrine feedback system is based on the following correlations:

  • The insulin hormone activates beta cells and inhibits alpha cells.
  • The hormone glucagon activates alpha cells which then activate beta cells and delta cells.
  • Somatostatin hormone inhibits alpha cells and beta cells.

Insulin Secretion and Regulation of Glucagon

Glucagon is a peptide hormone that works in conjunction with insulin to maintain a stable blood glucose level.

Key Points

Glucagon and insulin are peptide hormones secreted by the pancreas that plays a key role in maintaining a stable blood glucose level.

Glucagon is produced by alpha cells in the pancreas and acts to raise blood sugar levels.

Insulin is produced by beta cells in the pancreas and acts to lower blood sugar levels.

Key Terms

insulin: A polypeptide hormone that regulates carbohydrate metabolism.

glycogen: A polysaccharide that is the main form of carbohydrate storage in animals and also converts to glucose as needed.

glucagon: A hormone, produced by the pancreas, that opposes the action of insulin by stimulating the production of sugar.

Glucagon and insulin are peptide hormones secreted by the pancreas that play a key role in maintaining a stable blood glucose level. The blood glucose level is carefully monitored by cells within the pancreas that respond by secreting key hormones.

Glucagon

This is an image from a microscope stained for glucagon.

Glucagon staining: This is an image from a microscope stained for glucagon.

Glucagon is produced by alpha cells in the pancreas and elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis. Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan.

Liver cells have glucagon receptors and when glucagon binds to the liver cells they convert glycogen into individual glucose molecules and release them into the bloodstream—this process is known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon also turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis that can induce lipolysis to produce glucose from fat.

Insulin

Insulin is produced by beta cells in the pancreas and acts to oppose the functions of glucagon. It’s main role is to promote the conversion of circulating glucose into glycogen via glycogenesis in the liver and muscle cells.

Insulin also inhibits
gluconeogenesis and promotes the storage of glucose in fat through lipid synthesis and also by inhibiting lipolysis.

In Disease

When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus.

Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally.

Patients with type 2 diabetes are often insulin resistant and, because of such resistance, they may suffer from a relative insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately.

Pancreatic enzymes

Your pancreas creates natural juices called pancreatic enzymes to break down foods. These juices travel through your pancreas via ducts. They empty into the upper part of your small intestine called the duodenum. Each day, your pancreas makes about 8 ounces of digestive juice filled with enzymes. These are the different enzymes:

  • Lipase. This enzyme works together with bile, which your liver produces, to break down fat in your diet. If you don’t have enough lipase, your body will have trouble absorbing fat and the important fat-soluble vitamins (A, D, E, K). Symptoms of poor fat absorption include diarrhea and fatty bowel movements.
  • Protease. This enzyme breaks down proteins in your diet. It also helps protect you from germs that may live in your intestines, like certain bacteria and yeast. Undigested proteins can cause allergic reactions in some people.
  • Amylase. This enzyme helps break down starches into sugar, which your body can use for energy. If you don’t have enough amylase, you may get diarrhea from undigested carbohydrates.

Pancreatic hormones

Many groups of cells produce hormones inside your pancreas. Unlike enzymes that are released into your digestive system, hormones are released into your blood and carry messages to other parts of your digestive system. Pancreatic hormones include:

  • Insulin. This hormone is made in cells of the pancreas known as beta cells. Beta cells make up about 75% of pancreatic hormone cells. Insulin is the hormone that helps your body use sugar for energy. Without enough insulin, your sugar levels rise in your blood and you develop diabetes.
  • Glucagon. Alpha cells make up about 20% of the cells in your pancreas that produce hormones. They produce glucagon. If your blood sugar gets too low, glucagon helps raise it by sending a message to your liver to release stored sugar.
  • Gastrin and amylin. Gastrin is primarily made in the G cells in your stomach, but some is made in the pancreas, too. It stimulates your stomach to make gastric acid. Amylin is made in beta cells and helps control appetite and stomach emptying.

Common pancreatic problems and digestion

Diabetes, pancreatitis, and pancreatic cancer are three common problems that affect the pancreas. Here is how they can affect digestion:

  • Diabetes. If your pancreatic beta cells do not produce enough insulin or your body can’t use the insulin your pancreas produces, you can develop diabetes. Diabetes can cause gastroparesis, a reduction in the motor function of the digestive system. Diabetes also affects what happens after digestion. If you don’t have enough insulin and you eat a meal high in carbohydrates, your sugar can go up and cause symptoms like hunger and weight loss. Over the long term, it can lead to heart and kidney disease among other problems.
  • Pancreatitis. Pancreatitis happens when the pancreas becomes inflamed. It is often very painful. In pancreatitis, the digestive enzymes your pancreas make attack your pancreas and cause severe abdominal pain. The main cause of acute pancreatitis is gall stones blocking the common bile duct. Too much alcohol can cause pancreatitis that does not clear up. This is known as chronic pancreatitis. Pancreatitis affects digestion because enzymes are not available. This leads to diarrhea, weight loss, and malnutrition. About 90% of the pancreas must stop working to cause these symptoms.
  • Pancreatic cancer. About 95% of pancreatic cancers begin in the cells that make enzymes for digestion. Not having enough pancreatic enzymes for normal digestion is very common in pancreatic cancer. Symptoms can include weight loss, loss of appetite, indigestion, and fatty stools.

Your pancreas is important for digesting food and managing your use of sugar for energy after digestion. If you have any symptoms of pancreatic digestion problems, like loss of appetite, abdominal pain, fatty stools, or weight loss, call your healthcare provider.

Function

Pancreatic Hormones and Their Function[1][2][3]

Insulin

Source: Beta cells of islets of the pancreas.

Synthesis: Insulin is a peptide hormone. The insulin mRNA is translated as a single-chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases, which excise the C peptide (one of three domains of proinsulin), thereby generating the mature form of insulin. Insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C-peptide is also secreted into the blood in a 1:1 molar ratio with insulin. Although C-peptide has no established biological action, it is used as a useful marker for insulin secretion.

Transport: insulin circulates entirely in unbound form (T1/2 = 6 min).

Main Target cells: hepatic, muscle and adipocyte cells (i.e., cells specialized for energy storage).

Mechanism of action: Insulin binds to a specific receptor tyrosine kinase on the plasma membrane and increases its activity to phosphorylate numerous regulatory enzymes and other protein substrates.

Regulation of its secretion: Plasma glucose level is the main regulator of insulin secretion. The change in the concentration of plasma glucose that occurs in response to feeding or fasting is the main determinant of insulin secretion. Modest increases in plasma glucose level provoke a marked increase in plasma insulin concentration. Glucose is taken up by beta cells via glucose transporters (GLUT2). The subsequent metabolism of glucose increases cellular adenosine triphosphate (ATP) concentrations and closes ATP-dependent potassium (KATP) channels in the beta cell membrane, causing membrane depolarization and an influx of calcium. Increased calcium intracellular concentration results in an increase of insulin secretion. Increased plasma amino acid and free fatty acid concentrations induce insulin secretion as well. Glucagon is also known to be a strong insulin secretagogue.

Physiological functions: Insulin plays an important role to keep plasma glucose values within a relatively narrow range throughout the day (glucose homeostasis). Insulin’s main actions are

  • (1) In the liver, insulin promotes glycolysis and storage of glucose as glycogen (glycogenesis), as well as the conversion of glucose to triglycerides,
  • (2) In muscle, insulin promotes the uptake of glucose and its storage as glycogen, and
  • (3) in adipose tissue, insulin promotes the uptake of glucose and its conversion to triglycerides for storage.

Amylin (diabetes-associated peptide)

Source: Beta cells of islets of the pancreas. It is co-secreted with insulin in response to caloric intake (feeding state).

Target cells: Alpha cells of islets of pancreas and hypothalamus.

Physiological functions: it suppresses glucagon secretion from the alpha cells of the islets in the pancreas via paracrine interaction between beta cells and alpha cells. Amylin also slows gastric emptying which delays the absorption of glucose from the small intestine into the circulation. Also, it stimulates the satiety center of the brain to limit food consumption.

Glucagon

Source: Alpha cells of islets of the pancreas.

Synthesis: The initial gene product is the mRNA encoding preproglucagon. A peptidase removes the signal sequence of preproglucagon during translation of the mRNA in the rough endoplasmic reticulum to yield proglucagon. Proteases in the alpha cells subsequently cleave the proglucagon into the mature glucagon molecule.

Target cells: Hepatic cells.

Mechanism of action: glucagon binds to a receptor that activates the heterotrimeric G protein Gas, which stimulates membrane-bound adenylyl cyclase. The cAMP formed by adenylyl cyclase, in turn, activates PKA, which phosphorylates numerous regulatory enzymes and other protein substrates.

Regulation of its secretion: The amino acids released by digestion of a protein meal appear to be the main determinant of glucagon secretion.

Physiological functions: Glucagon acts exclusively on the liver to antagonize insulin effects on hepatocytes. It enhances glycogenolysis and gluconeogenesis. It also promotes the oxidation of fat, which can lead to the formation of ketone bodies.

Somatostatin

Source: Delta cells of the islets of the pancreas, hypothalamus, and D cells of gastric glands.

Target cells: Beta cells of islets of the pancreas, somatotroph cells in the anterior pituitary gland, and the G cells of the gastric glands.

Mechanism of action: Somatostatin binds to a receptor that activates the heterotrimeric inhibitory G protein, which inhibits membrane-bound adenylyl cyclase and cAMP formation.

Regulation of its secretion: Glucagon stimulates somatostatin secretion via paracrine interaction between alpha cells and delta cells of the islets of the pancreas.

Physiological functions: Somatostatin inhibits the secretion of multiple hormones, including growth hormone, insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP), and thyroid-stimulating hormone.

Ghrelin

Source: Epsilon cells of the islets of the pancreas, endocrine cells in the stomach and hypothalamus.

Target cells: Beta cells of the islets of the pancreas and somatotroph cells in the anterior pituitary gland.

Physiological functions:  ghrelin inhibits the secretion of insulin from Beta cells of the islets of the pancreas via paracrine interaction between delta cells and beta cells of the islets of the pancreas. It also stimulates appetite and growth hormone secretion.

Pancreatic Polypeptide (PP)

Pancreatic polypeptide is secreted from upsilon (F) cells of the islets of the pancreas. Dietary intake of nutrients alters the secretion of the pancreatic polypeptide. Its function is not decidedly understood yet.

Paracrine Interaction Between Pancreatic Endocrine Cells

Insulin secreted by beta cells acts as a prime hormone of glucose homeostasis. Insulin and amylin inhibit glucagon secretion by alpha cells. Whereas glucagon activates insulin and somatostatin secretion, somatostatin secreted by delta cells and ghrelin by epsilon cells inhibits insulin secretion.

WHY IS THIS IMPORTANT?

Understanding the two functions of the pancreas is important because

Large tumors of the pancreas will interfere with both of these important bodily functions.

  • Exocrine: when tumors block the exocrine system, patients can develop pancreatitis and pain from the abnormal release of digestive enzymes into the substance of the pancreas instead of into the bowel, and they can develop digestive problems, such as diarrhea, from the incomplete digestion of food.
  • Endocrine: when tumors destroy the endocrine function of the pancreas, patients can develop sugar diabetes (abnormally high blood sugar levels).

Tumors can arise in either component, exocrine or endocrine.

  • Exocrine: the vast majority of tumors of the pancreas arise in the exocrine part and these cancers look like pancreatic ducts under the microscope. These tumors are therefore called ductal adenocarcinomas, or simply adenocarcinoma, or even more simply pancreatic cancer.
  • Endocrine: less commonly, tumors arise from the endocrine component of the pancreas and these endocrine tumors are called “pancreatic neuroendocrine tumors,” or “islet cell tumors” for short.

References

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Adrenal Insufficiency – Causes, Symptoms, Treatment

Adrenal insufficiency is a disorder that occurs when the adrenal glands don’t make enough of certain hormones. The adrenal glands are located just above the kidneys. Adrenal insufficiency can be primary, secondary, or tertiary. Primary adrenal insufficiency is often called Addison’s disease.

Adrenal insufficiency is a serious pathologic condition characterized by decreased production or action of glucocorticoids and/or mineralocorticoids and adrenal androgens. This life-threatening disorder may be classified as primary, secondary, or tertiary, resulting from diseases affecting the adrenal cortex, the anterior pituitary gland or the hypothalamus, respectively. The clinical manifestations of adrenal insufficiency include anorexia, abdominal pain, weakness, weight loss, fatigue, hypotension, salt craving, and hyperpigmentation of the skin in case of primary adrenal insufficiency.

Types of Adrenal Insufficiency 

There are three major types of adrenal insufficiency.

  • Primary adrenal insufficiency – is due to impairment of the adrenal glands.
    • 80% are due to an autoimmune disease called Addison’s disease or autoimmune adrenalitis.
    • One subtype is called idiopathic, meaning of unknown cause.
    • It can also be due to congenital adrenal hyperplasia or an adenoma (tumor) of the adrenal gland.
    • Other causes include; Infections (TB, CMV, histoplasmosis, paracoccidioidomycosis), vascular (hemorrhage from sepsis, adrenal vein thrombosis, HIT), deposition disease (hemochromatosis, amyloidosis, sarcoidosis), drugs (azole antifungals, etomidate (even one dose), rifampin, anticonvulsants)
  • Secondary adrenal insufficiency – is caused by impairment of the pituitary gland or hypothalamus.[rx] Its principal causes include pituitary adenoma (which can suppress the production of adrenocorticotropic hormone (ACTH) and lead to adrenal deficiency unless the endogenous hormones are replaced); and Sheehan’s syndrome, which is associated with impairment of only the pituitary gland.
  • Tertiary adrenal insufficiency – is due to hypothalamic disease and a decrease in the release of corticotropin-releasing hormone (CRH).[rx] Causes can include brain tumors and sudden withdrawal from long-term exogenous steroid use (which is the most common cause overall).[rx]

Causes of Adrenal Insufficiency

Causes of Primary Adrenal Insufficiency

The etiology of primary adrenal insufficiency has changed over time. Prior to 1920, the most common cause of primary adrenal insufficiency was tuberculosis, while since 1950, the majority of cases (80-90%) have been ascribed to autoimmune adrenalitis, which can be isolated (40%) or in the context of an autoimmune polyendocrinopathy syndrome (60%).

  • Autoimmune adrenalitis (Addison’s disease) – This condition is characterized by the destruction of the adrenal cortex by cell-mediated immune mechanisms. Antibodies that react against steroid 21-hydroxylase are detected in approximately 90% of patients with autoimmune Addison’s disease, but only rarely in patients with other causes of adrenal insufficiency or normal subjects. Considerable progress has been made in identifying genetic factors that predispose to the development of autoimmune adrenal insufficiency. In addition to the major histocompatibility complex (MHC) haplotypes DR3-DQ2 and DR4-DQ8, other genetic factors, such as protein tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T lymphocyte antigen 4 (CTLA-4), and the major histocompatibility complex class II transactivator (CIITA) have been associated with this condition. Primary adrenal insufficiency may also present as part of autoimmune polyendocrinopathy syndromes. Patients with autoimmune polyendocrinopathy syndrome type 1 (APS1) or APECED (Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy) syndrome may present with chronic mucocutaneous candidiasis, adrenal insufficiency, hypoparathyroidism, hypoplasia of the dental enamel, and nail dystrophy, while type 1 Diabetes Mellitus (T1DM) or pernicious anemia, may develop later in life. Clinical manifestations of autoimmune polyendocrinopathy syndrome type 2 (APS2) include autoimmune adrenal insufficiency, autoimmune thyroid disease, and/or T1DM, whereas autoimmune polyendocrinopathy syndrome type 4 (APS4) is characterized by autoimmune adrenal insufficiency and one or more other autoimmune diseases, such as atrophic gastritis, hypogonadism, pernicious anemia, celiac disease, myasthenia gravis, vitiligo, alopecia, and hypophysitis, but without any autoimmune disorders of APS1 or APS2.
  • Adrenoleukodystrophy – This is an X-linked recessive disorder affecting 1 in 20.000 males (2). The molecular basis of this condition has been ascribed to mutations in the ABCD1 gene, which result in defective beta-oxidation of very-long-chain fatty acids (VLCFAs) within peroxisomes. The abnormally high concentrations of VLCFAs in affected organs, including the adrenal cortex, resulting in the clinical manifestations of this disorder, which include neurological impairment due to white-matter demyelination and primary adrenal insufficiency, with the latter presenting in infancy or childhood.
  • Hemorrhagic infarction – Bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis may also lead to adrenal insufficiency. The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen shows bilateral adrenal enlargement. Several coagulopathies and the heparin-induced thrombocytopenia syndrome have been associated with adrenal vein thrombosis and hemorrhage, while the primary antiphospholipid syndrome has been recognized as a major cause of adrenal hemorrhage. Adrenal hemorrhage has been mostly associated with meningococcemia (Waterhouse-Friderichsen syndrome) and Pseudomonas aeruginosa infection.
  • Infectious adrenalitis – Many infectious agents may attack the adrenal gland and result in adrenal insufficiency, including tuberculosis (tuberculous adrenalitis), disseminated fungal infections, and HIV-associated infections, such as adrenalitis due to cytomegalovirus and mycobacterium avium complex.
  • Drug-induced adrenal insufficiency Drugs that may cause adrenal insufficiency by inhibiting cortisol biosynthesis, particularly in individuals with limited pituitary and/or adrenal reserve, include aminoglutethimide (antiepileptic), etomidate (anesthetic-sedative), ketoconazole (antimycotic), and metyrapone. Drugs that accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes, such as phenytoin, barbiturates, and rifampicin can also cause adrenal insufficiency in patients with limited pituitary or adrenal reserve, as well as those who are on replacement therapy with glucocorticoids. Furthermore, some of novel tyrosine kinase-targeting drugs (e.g. sunitinib) have been shown in animal studies to cause adrenal dysfunction and hemorrhage.

Causes of Primary Adrenal Insufficiency

Disease Pathogenetic Mechanism
Autoimmune adrenalitis
Isolated Associations with HLA-DR3-DQ2, HLADR4-DQ8, MICA, CTLA-4, PTPN22,
CIITA, CLEC16A, Vitamin D receptor
APS type 1 (APECED) AIRE gene mutations
APS type 2 Associations with HLA-DR3, HLA-DR4,
CTLA-4
APS type 4 Associations with HLA-DR3, CTLA-4
Infectious adrenalitis
Tuberculous adrenalitis Tuberculosis
AIDS HIV-1, cytomegalovirus
Fungal adrenalitis Histoplasmosis, cryptococcosis,
coccidiodomycosis
Syphilis Treponema pallidum
African Trypanosomiasis Trypanosoma brucei
Bilateral adrenal hemorrhage Meningococcal sepsis (Waterhouse-
Friderichsen syndrome), primary
antiphospholipid syndrome
Bilateral adrenal metastases Primarily lung, stomach, breast, and colon
cancer
Bilateral adrenal infiltration Primary adrenal lymphoma, amyloidosis,
hemochromatosis
Bilateral adrenalectomy Unresolved Cushing’s syndrome,
bilateral adrenal masses, bilateral pheochromocytoma
Drug-induced adrenal insufficiency
Anticoagulants (heparin, warfarin),
tyrosine kinase inhibitors (sunitinib)
Hemorrhage
Aminoglutethimide Inhibition of P450 aromatase (CYP19A1)
Trilostane Inhibition of 3β-hydroxysteroid
dehydrogenase type 2 (HSD3B2)
Ketoconazole, fluconazole, etomidate Inhibition of mitochondrial cytochrome
P450-dependent enzymes (e.g. CYP11A1,
CYP11B1)
Phenobarbital Induction of P450-cytochrome enzymes
(CYP2B1, CYP2B2), which enhance
cortisol metabolism
Phenytoin, rifampin, troglitazone Induction of P450-cytochrome enzymes
(primarily CYP3A4), which enhance
cortisol metabolism
Genetic disorders
Adrenoleukodystrophy or
adrenomyeloneuropathy
ABCD1 and ABCD2 gene mutations
Congenital adrenal hyperplasia
21-Hydroxylase deficiency CYP21A2 gene mutations
11β-Hydroxylase deficiency CYP11B1 gene mutations
3β-hydroxysteroid dehydrogenase
type 2 deficiency
HSD3B2 gene mutations
17α-Hydroxylase deficiency CYP17A1 gene mutations
P450 Oxidoreductase deficiency POR gene mutations
P450 side-chain cleavage deficiency CYP11A1 gene mutations
Congenital lipoid adrenal hyperplasia StAR gene mutations
Smith-Lemli-Opitz syndrome DHCR7 gene mutations
Adrenal hypoplasia congenital
X-linked NR0B1 gene mutations
Xp21 contiguous gene syndrome Deletion of the Duchenne muscular
dystrophy, glycerol kinase and NR0B1
genes
SF-1 linked NR5A1 gene mutations
IMAGe syndrome CDKN1C gene mutations
Kearns-Sayre syndrome Mitochondrial DNA deletions
Wolman’s disease LIPA gene mutations
Sitosterolaimia (also known as
phytosterolemia)
ABCG5 and ABCG8 gene mutations
Familial glucocorticoid deficiency
(FGD, or ACTH insensitivity syndromes)
Type 1 MC2R gene mutations
Type 2 MRAP gene mutations
Variant of FGD MCM4 gene mutations
FGC – Deficiency of mitochondrial ROS detoxification NNTTXNRD2GPX1PRDX3 gene mutations
Primary Generalized Glucocorticoid
Resistance or Chrousos syndrome
NR3C1 gene mutations
Sphingosine-1-phosphate lyase 1 deficiency SPGL1 gene mutations
Infantile Refsum disease PHYH, PEX7 gene mutations
Zellweger syndrome PEX1 and other PEX gene mutations
Triple A syndrome (Allgrove’s syndrome) AAAS gene mutations

Causes of Secondary and Tertiary Adrenal Insufficiency

Secondary adrenal insufficiency may be caused by any disease process that affects the anterior pituitary and interferes with ACTH secretion. The ACTH deficiency may be isolated or occur in association with other pituitary hormone deficits.

Tertiary adrenal insufficiency can be caused by any process that involves the hypothalamus and interferes with CRH secretion. The most common cause of tertiary adrenal insufficiency is chronic administration of synthetic glucocorticoids that suppress the hypothalamic-pituitary-adrenal (HPA) axis (50).

Causes of Secondary Adrenal Insufficiency.

Disease Pathogenetic Mechanism
Space occupying lesions or trauma
Pituitary tumors (adenomas, cysts,
craniopharyngiomas, ependymomas,
meningiomas, rarely carcinomas) or
trauma (pituitary stalk lesions)
Decreased ACTH secretion
Pituitary surgery or irradiation for pituitary
tumors, tumors outside the HPA axis or
leukemia
Decreased ACTH secretion
Infections or Infiltrative processes
(lymphocytic hypophysitis,
hemochromatosis, tuberculosis, meningitis,
sarcoidosis, actinomycosis, histiocytosis X,
Wegener’s granulomatosis)
Decreased ACTH secretion
Pituitary apoplexy Decreased ACTH secretion
Sheehan’s syndrome (peripartum pituitary
apoplexy and necrosis)
Decreased ACTH secretion
Genetic disorders
Transcription factors involved in pituitary
development
HESX homeobox 1 HESX1 gene mutations
Orthodentical homeobox 2 OTX2 gene mutations
LIM homeobox 4 LHX4 gene mutations
PROP paired-like homeobox 1 PROP1 gene mutations
SRY (sex-determining region Y) – box 3 SOX3 gene mutations
T-box 19 TBX19 gene mutations
Congenital Proopiomelanocortin (POMC)
deficiency
POMC gene mutations
Prader-Willi Syndrome (PWS) Deletion or silencing of genes in the
imprinting center for PWS

Causes of Tertiary Adrenal Insufficiency.

Disease Pathogenetic Mechanism
Space occupying lesions or trauma
Hypothalamic tumors
(craniopharyngiomas or metastasis from
lung, breast cancer)
Decreased CRH secretion
Hypothalamic surgery or irradiation for
central nervous system or nasopharyngeal
tumors
Decreased CRH secretion
Infections or Infiltrative processes
(lymphocytic hypophysitis,
hemochromatosis, tuberculosis, meningitis,
sarcoidosis, actinomycosis, histiocytosis X,
Wegener’s granulomatosis)
Decreased CRH secretion
Trauma, injury (fracture of the skull base) Decreased CRH secretion
Drug-induced adrenal insufficiency
Glucocorticoid therapy (systemic or topical) or endogenous glucocorticoid
hypersecretion (Cushing’s syndrome)
Decreased CRH and ACTH secretion
Mifepristone Tissue resistance to glucocorticoids
through impairment of glucocorticoid
signal transduction
Antipsychotics (chlorpromazine),
antidepressants (imipramine)
Inhibition of glucocorticoid-induced gene
transcription

Symptoms of Adrenal Insufficiency 

  • Signs and symptoms include hypoglycemia, dehydration, weight loss, and disorientation.
  • Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea.
  • These problems may develop gradually and insidiously. Addison’s disease can present with tanning of the skin that may be patchy or even all over the body.
  • Characteristic sites of tanning are skin creases (e.g. of the hands) and the inside of the cheek (buccal mucosa). Goiter and vitiligo may also be present.[rx] Eosinophilia may also occur.[rx]

Diagnosis of Adrenal Insufficiency

The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder.

  • Basal morning serum cortisol concentrations – The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (06:00h – 08:00h), ranging between 10 – 20 mcg/dL (275 – 555 nmol/L) than at other times of the day. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency, while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Simultaneous measurements of cortisol and ACTH concentrations confirm in most cases the diagnosis of primary adrenal insufficiency.
  • Morning salivary cortisol concentrations – Adrenal insufficiency is excluded when salivary cortisol concentration at 08:00his higher than 5.8 ng/mL (16 nmol/L), whereas the diagnosis, is more possible for values lower than 1.8 ng/mL (5 nmol/L).
  • Urinary free cortisol (UFC) – Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may below-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency.
  • Basal plasma ACTH, renin, and aldosterone concentrations – Basal plasma ACTH concentration at 08:00h, when determined simultaneously with the measurement of basal serum cortisol concentration, may both confirm the diagnosis of adrenal insufficiency and establish the cause. The normal values of basal 08:00h plasma ACTH concentrations range between 20-52 pg/mL (4.5-12 pmol/L). In primary adrenal insufficiency, the 08:00h plasma ACTH concentration is elevated and is coupled with increased concentration or activity of plasma renin, low aldosterone concentrations, hyperkalemia and hyponatremia. In the cases of secondary or tertiary adrenal insufficiency, plasma ACTH concentrations are low or low normal, associated with normal values of plasma concentrations of renin and aldosterone.
  • Standard dose ACTH stimulation test – Adrenal insufficiency is usually diagnosed by the standard-dose ACTH test, which determines the ability of the adrenal glands to respond to 250 mcg intravenous or intramuscular administration of ACTH(1-24) by measurement of serum cortisol concentrations at 0, 30 and 60 min following stimulation. The test is defined as normal if peak cortisol concentration is higher than 18–20 mcg/dL (500–550 nmol/L), thereby excluding the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency. However, if secondary adrenal insufficiency is of recent onset, the adrenal glands will have not yet atrophied, and will still be capable of responding to ACTH stimulation normally. In these cases, a low-dose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis.
  • Low-Dose ACTH stimulation test This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. This test should be performed at 14:00h when the endogenous secretion of ACTH is at its lowest. The results might not be valid if it is performed at another time. At 14:00h, a blood sample is collected for the determination of basal cortisol concentrations. The low dose of ACTH(1-24) (500 nanograms ACTH(1-24)/1.73 m2 ) is then administered as an intravenous bolus. In normal subjects, this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia. Subsequently, blood samples are collected at +10 min, +15 min, +20 min, +25 min, +30 min, +35 min, +40 min, and +45 min after stimulation for determination of serum cortisol concentrations. A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard-dose test. The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency.
  • Prolonged ACTH Stimulation Tests – Prolonged stimulation with exogenous administration of ACTH helps differentiate between primary and secondary or tertiary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH. The prolonged ACTH test consists of the intravenous administration of 250 μg of ACTH as an infusion over eight hours (8-hour test) or over 24 hours on two (or three) consecutive days (two-day test), and the measurement of serum cortisol, and 24-hour urinary cortisol and 17-hydroxycorticoid (17-OHCS) concentrations before and after the infusion.
  • Insulin-induced hypoglycemia test – This test provides an alternative choice for confirmation of the diagnosis when secondary adrenal insufficiency is suspected. The insulin tolerance test helps in the investigation of the integrity of the HPA axis and has the ability to assess growth hormone reserve. Insulin, at a dose of 0.1-0.15 U/kg, is administered to induce hypoglycemia, and measurements of cortisol concentrations are determined at 30 min intervals for at least 120 min. This test is contraindicated in patients with cardiovascular disease or a history of seizures and requires a high degree of supervision.
  • Corticotropin-releasing hormone (CRH) test – This test is used to differentiate between secondary and tertiary adrenal insufficiency. It consists of intravenous administration of CRH (1 mcg/kg up to a maximum of 100 mcg) and determination of serum cortisol and plasma ACTH concentrations at 0, 15, 30, 45, 60, 90, and 120 min following stimulation. Patients with secondary adrenal insufficiency demonstrate little or no ACTH response, whereas patients with tertiary adrenal insufficiency show an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response.
  • Autoantibody screen – Adrenocortical antibodies or antibodies against 21-hydroxylase can be detected in more than 90% of patients with recent-onset autoimmune adrenalitis. Furthermore, antibodies that react against other enzymes involved in steroidogenesis and anti-steroid-producing cell antibodies are present in some patients.
  • Very long-chain fatty acids – To exclude adrenoleukodystrophy, plasma very-long-chain fatty acids should be determined in male patients with isolated Addison’s disease and negative autoantibodies.
  • Imaging – Patients without any associated autoimmune disease and negative autoantibody screen should undergo computed tomography (CT) scan of the adrenal glands. In cases of tuberculous adrenalitis, the CT scan shows initially hyperplasia of the adrenal glands and subsequently spotty calcifications during the late stages of the disease. Bilateral adrenal lymphoma, adrenal metastases or adrenal infiltration (sarcoidosis, amyloidosis, hemochromatosis) may also be detected by CT scan. If central adrenal insufficiency is suspected, a magnetic resonance imaging (MRI) scan of the hypothalamus and pituitary gland should be performed. This may detect any potential disease process, such as craniopharyngiomas, pituitary adenomas, meningiomas, metastases, and infiltration by Langerhans cell histiocytosis, sarcoidosis, or other granulomatous diseases. It should be noted that imaging is not required when adrenal cortex autoantibodies are detected.

Treatment of Adrenal Insufficiency

Treatment of Chronic Primary Adrenal Insufficiency

1. Glucocorticoid replacement (one of the given regimens)

  • Hydrocortisone 15 to 25 mg orally in two or three divided doses (the largest dose is taken early in the  morning; typically 10 mg upon awakening in the morning, 5 mg early afternoon, 2.5 mg late afternoon), or
  • Prednisone 5 mg (2.5 to 7.5 mg) orally at bedtime, or
  • Dexamethasone 0.75 mg (0.25 to 0.75 mg) orally at bedtime
  • Monitor clinical symptoms and morning plasma ACTH as needed.

2. Mineralocorticoid replacement

  • Fludrocortisone 0.1 mg (range: 0.05 to 0.2 mg) orally. Hydrocortisone 20 mg and prednisone 50 mg provide a mineralocorticoid effect that is almost equivalent to 0.1 mg of fludrocortisone. Therefore, fludrocortisone replacement (if needed) must be decreased accordingly. Dexamethasone, however, lacks a mineralocorticoid effect and would require a full dose of fludrocortisone.
  • Liberal salt intake.
  • Monitor supine and standing blood pressure as well as pulse, edema, serum potassium, and plasma renin activity

3. Androgen replacement

  • Dehydroepiandrosterone (DHEA) initially 25 to 50 mg orally (only in women for psychological well-being, if needed, after optimal glucocorticoid and mineralocorticoid replacement).

4. Patient education

  • Educate the patient about the illness, how to manage stresses, and inject dexamethasone or other glucocorticoids intramuscularly or subcutaneously.

5. Emergency precautions

  • Patients should have a medical alert bracelet/necklace, an emergency medical information card on their phone or inside their wallet, and prefilled syringes containing 4 mg of dexamethasone 1 mL saline.

6. Treatment of minor febrile illness or stress

  • Increase glucocorticoid dose two to three times for the few days of illness. Do not change the mineralocorticoid dose (3×3 rule).
  • The patient should contact the clinician if the condition worsens or persists for more than three days.
  • No extra dose is required for most uncomplicated, outpatient dental procedures under local anesthesia.
  • Glucocorticoid supplement for surgical stress:
  • Minor: hydrocortisone 25 mg IV (or equivalent) on the day of the procedure
  • Moderate: hydrocortisone 50 to 75 mg IV (or equivalent) on day of surgery and postoperative day 1
  • Major: hydrocortisone 100 to 150 mg IV (or equivalent) in two or three divided doses on the day of surgery and postoperative days 1 and 2

7. Emergency treatment of severe stress or trauma

  • Each patient should have an injectable as well as vials of sterile 0.9% normal saline and syringes.

Treatment of Adrenal Crisis

Measures to stabilize the patient

  • Intravenous access with one or two large-gauge needles
  • Laboratory analysis, including serum electrolytes, glucose, and routine measurement of plasma cortisol and ACTH.
  • Infusion of 2 to 3 liters of isotonic saline or 5% dextrose in isotonic saline as urgently as possible. Periodic hemodynamic monitoring and measurement of serum electrolytes.
  • Give hydrocortisone (100 mg intravenous bolus), followed by 50 mg intravenously every 6 hours (or 200 mg/24 hours as a continuous intravenous infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include prednisolone, prednisone, and dexamethasone.
  • Correct any ongoing electrolyte abnormalities. Hyponatremia is often corrected by cortisol and volume repletion.

Subacute measures after stabilization of the patient

  • Intravenous isotonic saline infusion at a slower rate for the next 24 to 48 hours.
  • Diagnosis and treatment of possible infectious precipitating causes of the adrenal crisis.
  • If the patient does not have known adrenal insufficiency, a short ACTH stimulation test should establish the diagnosis and determine its type and cause.
  • 4. Tapering of parenteral glucocorticoid over 1 to 3 days to the oral glucocorticoid maintenance dose, if there are no ongoing contraindications.
  • Initiating mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily after stopping the saline infusion.

Treatment By specific condition

Adrenal insufficiency is one of the most life-threatening disorders. Treatment should be administered to the patients as soon as the diagnosis is established, or even sooner if an adrenal crisis occurs.

  • Treatment of Chronic Adrenal Insufficiency – One of the most important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy, the need to increase the dose of glucocorticoid during minor or major stress, and to inject hydrocortisone, methylprednisolone, or dexamethasone in emergencies.
  • Emergency precautions – Patients should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card, which should provide information on the diagnosis, the medications, and daily doses, and the physician involved in the patient’s management. Patients should also have supplies of dexamethasone sodium phosphate and should be educated about how and when to administer them.
  • Glucocorticoid replacement therapy – Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid, or cortisone acetate if hydrocortisone is not available. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be administered in two to three divided doses with one-half to two-thirds of the total daily dose being given in the morning. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses, as well as impaired quality of life were observed in patients treated with hydrocortisone. A longer-acting synthetic glucocorticoid, such as prednisone, prednisolone, or dexamethasone, should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess, such as loss of lean body mass and bone density, and gain of visceral fat. Recently, preparations of hydrocortisone that lead to both delayed and sustained release of this compound have been developed and are under clinical investigation. These formulations maintain stable cortisol concentrations during 24 hours and physiologic circadian rhythmicity with the cortisol peak occurring during the early morning after oral intake of the preparation at bedtime. Furthermore, a novel once-daily (OD) dual-release hydrocortisone tablet has been developed to maintain more physiologic circadian-based serum cortisol concentrations. Compared to the conventional treatment, the OD dual-release hydrocortisone improved glucose metabolism, cardiovascular risk factors, and quality of life. Regardless of the type of formulation used, glucocorticoid replacement should be monitored clinically, evaluating weight gain/loss, arterial blood pressure, annualized growth velocity, and presence of Cushing features.
  • Glucocorticoid replacement during minor illness or surgery – During minor illness or surgical procedures, glucocorticoids should be given at a dosage up to three times the usual maintenance dosage for up to three days. Depending on the nature and severity of the illness, additional treatment may be required.
  • Glucocorticoid replacement during major illness or surgery – During major illness or surgery, high doses of glucocorticoid analogs (10 times the daily production rate) are required to avoid an adrenal crisis. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. This dose can be halved on the second postoperative day, and the maintenance dose can be resumed on the third postoperative day.
  • Mineralocorticoid replacement therapy – Mineralocorticoid replacement therapy is required to prevent intravascular volume depletion, hyponatremia, and hyperkalemia. For these purposes, fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.05 – 0.2 mg daily should be taken in the morning. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range, while patients receiving hydrocortisone, which has some mineralocorticoid activity, may require lower doses. The mineralocorticoid dose may have to be increased in the summer, particularly if patients are exposed to temperatures above 29ºC (85ºF). If patients receiving mineralocorticoid replacement develop hypertension, the dose of fludrocortisone should be reduced accordingly. In case of uncontrolled blood pressure, patients should be encouraged to continue fludrocortisone and initiate antihypertensive therapy, such as angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or dihydropyridine calcium blockers.
  • Androgen replacement – In women, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Treatment with DHEA enhances mood and general well-being both in adult patients and in children and adolescents with adrenal insufficiency. A single oral morning dose of DHEA of 25-50 mg may be sufficient to maintain normal serum androgen concentrations in premenopausal women with primary adrenal insufficiency, who present with decreased libido, anxiety, depression, and low energy levels. If symptoms are still present during a period of 6 months, patients are advised to discontinue DHEA replacement. Naturally, women should be encouraged to report any side effects of androgen therapy. Finally, DHEA replacement should be monitored by determining serum DHEA concentrations in the morning before the patient receives her daily DHEA dose.
  • Treatment of adrenal crisis – The aim of initial management in an adrenal crisis is to treat hypotension, hyponatremia, and hyperkalemia, and to reverse glucocorticoid deficiency. Treatment should be started with immediate administration of 100 mg hydrocortisone i.v. and rapid rehydration with normal saline infusion under continuous cardiac monitoring, followed by 100–200 mg hydrocortisone in glucose 5% per 24-hour continuous iv infusion; alternatively, hydrocortisone could be administered iv or im at a dose of 50-100 mg every 6 hours depending on body surface area and age. With daily hydrocortisone doses of 50 mg or more, mineralocorticoids in patients with primary adrenal insufficiency can be discontinued or reduced because this dose is equivalent to 0.1 mg fludrocortisone. Once the patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy.
  • Treatment of chronic secondary and tertiary adrenal insufficiency – In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary.

References

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Graves’ Disease – Causes, Symptoms, Treatment

Graves’ disease is an autoimmune disorder that causes hyperthyroidism or overactive thyroid. With this disease, your immune system attacks the thyroid and causes it to make more thyroid hormone than your body needs. The thyroid is a small, butterfly-shaped gland in the front of your neck. Thyroid hormones control how your body uses energy, so they affect nearly every organ in your body—even the way your heartbeats.

Graves’ disease is the most common cause of hyperthyroidism. It is a disorder with systemic manifestations that primarily affect the heart, skeletal muscle, eyes, skin, bone, and liver. Failure to diagnose Graves’ disease in a timely manner can predispose to thyroid storm which carries high morbidity and mortality. Clinicians ought to be aware of systemic manifestations of Graves’ disease and the different modalities available for treatment. Early diagnosis and management of Graves’ disease can also prevent severe cardiac complications such as atrial flutter, atrial fibrillation, and high output cardiac failure. This activity reviews the evaluation and treatment of Graves’ disease and highlights the role of the interprofessional team in reducing morbidity and improving care for affected patients.

Graves’ disease is an autoimmune disease that primarily affects the thyroid gland. It may also affect multiple other organs including eyes and skin. It is the most common cause of hyperthyroidism. In this chapter, we attempt to review different aspects of Graves’ disease.

Causes of Graves’ Disease

Like all autoimmune diseases, it occurs more commonly in patients with a positive family history. It is more common in monozygotic twins than in dizygotic twins. It is precipitated by environmental factors like stress, smoking, infection, iodine exposure, and postpartum, as well as after highly active antiretroviral therapy (HAART) due to immune reconstitution.

Genetics

A genetic predisposition for Graves’ disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role.[10] To date, no clear genetic defect has been found to point to a single-gene cause.

Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte–associated antigen 4, among others.[rx]

Infectious trigger

Since Graves’ disease is an autoimmune disease that appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies that cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.[rx]

The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor[rx] and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. In the 1990s, it was suggested that Y. enterocolitis may be associated with Graves’ disease.[rx] More recently, the role for Y. enterocolitis has been disputed.[rx]

Epstein–Barr virus (EBV) is another potential trigger.[rx]

Pathophysiology

Graves’ disease is caused by thyroid-stimulating immunoglobulin (TSI), also known as a thyroid-stimulating antibody (TSAb). B lymphocytes primarily synthesize Thyroid stimulating immunoglobulin within the thyroid cells, but it can also be synthesized in lymph nodes and bone marrow. B lymphocytes are stimulated by T lymphocytes which get sensitized by antigen in the thyroid gland. Thyroid-stimulating immunoglobulin binds with thyroid-stimulating hormone (TSH) receptor on the thyroid cell membrane and stimulates the action of the thyroid-stimulating hormone. It stimulates both, thyroid hormone synthesis and thyroid gland growth, causing hyperthyroidism and thyromegaly.

Several environmental factors including pregnancy (mainly postpartum), iodine excess, infections, emotional stress, smoking, and interferon alfa trigger immune responses on susceptible genes to eventually cause Graves’ disease.

Graves’ orbitopathy (ophthalmopathy) is caused by inflammation, cellular proliferation, and increased growth of extraocular muscles and retro-orbital connective and adipose tissues due to the actions of thyroid-stimulating antibodies and cytokines released by cytotoxic T lymphocytes (killer cells). These cytokines and thyroid-stimulating antibodies activate periorbital fibroblasts and preadipocytes, causing the synthesis of excess hydrophilic glycosaminoglycans (GAG) and retro-orbital fat growth. Glycosaminoglycans cause muscle swelling by trapping water. These changes give rise to proptosis, diplopia, congestion, and periorbital edema. If left untreated, it eventually leads to irreversible fibrosis of the muscles.

Pathogenesis of other rare manifestations of Graves disease like pretibial myxedema and thyroid acropachy are poorly understood and are believed to be due to cytokines-mediated stimulation of fibroblasts. Many symptoms of hyperthyroidism like tachycardia, sweating, tremors, lid lag, and stare are thought to be related to increased sensitivity to catecholamine.

Symptoms

Common signs and symptoms of Graves’ disease include:

  • Anxiety and irritability
  • A fine tremor of the hands or fingers
  • Heat sensitivity and an increase in perspiration or warm, moist skin
  • Weight loss, despite normal eating habits
  • Enlargement of the thyroid gland (goiter)
  • Change in menstrual cycles
  • Erectile dysfunction or reduced libido
  • Frequent bowel movements
  • Bulging eyes (Graves’ ophthalmopathy)
  • Fatigue
  • Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
  • Rapid or irregular heartbeat (palpitations)
  • Sleep disturbance

Additional Symptoms

  • Goitre (enlarged thyroid). If the thyroid grows large enough, it may compress the recurrent laryngeal nerve, producing vocal cord paralysis, dysphonia, and even respiratory stridor. Compression of the sympathetic chain may result in Horner’s syndrome.
  • Graves’ ophthalmopathy (protrusion of one or both eyes)
  • Pretibial myxedema
  • Cardiovascular features may include hypertension, and heart rate that may be rapid or irregular in character; these may be perceived as palpitations. Less common findings include left ventricular hypertrophy, premature atrial and ventricular contractions, atrial fibrillation, congestive heart failure, angina, myocardial infarction, systemic embolization, death from cardiovascular collapse and resistance to some drug effects (digoxin, coumadin).
  • Hyperreflexia, with a rapid relaxation phase.
  • A distinctly excessive reaction to all sorts of stimuli.
  • A marked increase in fatigability, or asthenia, is often prominent. This increased weariness may be combined with hyperactivity; patients remark that they are impelled to incessant activity, which, however, causes great fatigue.
  • Insomnia
  • Tremor (usually fine shaking; tremor of the outstretched fingers). In a small study of newly diagnosed hyperthyroid patients, tremor was observed in 76% of them. Some studies lay the cause for hyperthyroid tremor with a heightened beta-adrenergic state, others suggest an increased metabolism of dopamine.
  • Weight loss despite normal or increased appetite. Some patients (especially younger ones) gain weight due to excessive appetite stimulation that exceeds the weigh loss effect.
  • Increased appetite.
  • Weakness or muscle weakness (especially in the large muscles of the arms and legs). This latter occurs in 60 to 80 percent of patients with untreated hyperthyroidism. Muscle weakness is rarely the chief complaint. The likelihood and degree of muscle weakness is correlated with the duration and severity of the hyperthyroid state, and become more likely after the age of 40. Muscle strength returns gradually over several months after the hyperthyroidism has been treated.
  • Muscle degeneration
  • Shortness of breath
  • Increased sweating
  • Heat intolerance
  • Warm and moist skin
  • Thin and fine hair
  • Redness of the elbows is frequently present. It is probably the result of the combination of increased activity, an exposed part, and a hyperirritable vasomotor system.
  • Chronic sinus infections
  • Brittle nails
  • Plummer’s nail
  • Abnormal breast enlargement in men
  • Gastrointestinal symptoms. This includes increased bowel movements, but malabsorption is unusual.
  • Augmented calcium levels in the blood (by as much as 25% – known as hypercalcemia). This can cause stomach upset, excessive urination, and impaired kidney function.
  • Diabetes may be activated or intensified, and its control worsened. The diabetes is ameliorated or may disappear when the thyrotoxicosis is treated
  • Evidence of mild or severe liver disease may be found.
  • Reproductive symptoms in men may include reduced free testosterone (due to the elevation of testosterone-estrogen binding globulin level), diminished libido, erectile dysfunction and (reversible) impaired sperm production with lower mean sperm density, a high incidence of sperm abnormalities, and reduced mobility of the sperm cells. Women may experience infrequent menstruation or irregular and scant menstrual flow along with difficulty conceiving, infertility, and recurrent miscarriage.
  • Neurological seizures, neuropathy from nerve entrapment by lesions of pretibial myxedema, and hypokalemic periodic paralysis may occur. Athetoid, choreia, and corticospinal tract damage are rare. An acute thyrotoxic encephalopathy is very rare.

Diagnosis of Graves’ Disease

Most patients with Graves disease present with classic signs and symptoms of hyperthyroidism. Initial presentation of Graves disease with only Graves orbitopathy or pretibial myxedema is rare. Presentation depends on the age of onset, severity, and duration of hyperthyroidism. In the elderly population, symptoms may be subtle or masked, and they may present with non-specific signs and symptoms like fatigue, weight loss, and new-onset atrial fibrillation. Atypical presentation of hyperthyroidism in elderly is also referred as apathetic thyrotoxicosis.

In younger patients, common presentations include heat intolerance, sweating, fatigue, weight loss, palpitation, hyper defecation, and tremors. Other features include insomnia, anxiety, nervousness, hyperkinesia, dyspnea, muscle weakness, pruritus, polyuria, oligomenorrhea or amenorrhea in the female, loss of libido, and neck fullness. Eye symptoms include lids swelling, ocular pain, conjunctival redness, double vision. Palpable goiter is more common in the younger population, age younger than 60 years.  Up to 10 % of patients may have weight gain.

Physical signs of hyperthyroidism include tachycardia, systolic hypertension with increased pulse pressure, signs of heart failure (like edema, rales, jugular venous distension, tachypnea), atrial fibrillation, fine tremors, hyperkinesia, hyperreflexia, warm and moist skin, palmar erythema and onycholysis, hair loss, diffuse palpable goiter with thyroid bruit and altered mental status.

Signs of extrathyroidal manifestations of Graves’ disease include ophthalmopathy like eyelid retraction, proptosis, periorbital edema, chemosis, scleral injection, exposure keratitis. Thyroid dermopathy causes marked thickening of the skin, mainly over tibia which is rare, seen in 2% to 3% of cases. The thickened skin has peau d’orange appearance and is difficult to pinch. Bone involvement includes subperiosteal bone formation and swelling in the metacarpal bones which is called osteopathy or thyroid acropachy. Onycholysis (Plummer nails) and clubbing are very rare.

Evaluation

Diagnosis of Graves disease starts with a thorough history and physical examination. History should include a family history of Graves’ disease. 

  • Blood tests. Blood tests can help your doctor determine your levels of thyroid-stimulating hormone (TSH) — the pituitary hormone that normally stimulates the thyroid gland — and your levels of thyroid hormones. People with Graves’ disease usually have lower than normal levels of TSH and higher levels of thyroid hormones.Your doctor may order another lab test to measure the levels of the antibody known to cause Graves’ disease. It’s usually not needed to diagnose the disease, but results that don’t show antibodies might suggest another cause of hyperthyroidism.
  • Radioactive iodine uptake. Your body needs iodine to make thyroid hormones. By giving you a small amount of radioactive iodine and later measuring the amount of it in your thyroid gland with a specialized scanning camera, your doctor can determine the rate at which your thyroid gland takes up iodine. The amount of radioactive iodine taken up by the thyroid gland helps determine if Graves’ disease or another condition is the cause of the hyperthyroidism. This test may be combined with a radioactive iodine scan to show a visual image of the uptake pattern.
  • Ultrasound. Ultrasound uses high-frequency sound waves to produce images of structures inside the body. It can show if the thyroid gland is enlarged. It’s most useful in people who can’t undergo radioactive iodine uptake, such as pregnant women.
  • Imaging tests. If the diagnosis of Graves’ disease isn’t clear from a clinical assessment, your doctor may order special imaging tests, such as a CT scan or MRI.
  • Thyroid function tests to diagnose hyperthyroidism – The initial test for diagnosis of hyperthyroidism is the thyroid-stimulating hormone (TSH) test. If TSH is suppressed, one needs to order Free T4 (FT4) and Free T3 (FT3). If free hormone assays are not available, total T4 (Thyroxine) and total T3 (Triiodothyronine) can be ordered. Suppressed TSH with high FT4 or FT3 or both will confirm the diagnosis of hyperthyroidism. In subclinical hyperthyroidism, only TSH is suppressed, but FT4 and FT3 are normal.
  • Tests to differentiate Graves from other causes of hyperthyroidism – Graves’s diagnosis can be obvious with a careful history and physical examination. Features suggestive of Graves disease include a positive family history of Graves disease, the presence of orbitopathy, diffusely enlarged thyroid with or without bruit, and pretibial myxedema.

Measurement of TSH receptor antibody (TRAb) –  There are two available assays, the thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibiting (TBI) immunoglobulin or thyrotropin-binding inhibitory immunoglobulin (TBII). Measurement of TRAb with third-generation assay has sensitivity and specificity of 97% and 99% for the diagnosis of Graves disease. TRAb measurement is indicated in the following conditions:

  • Hyperthyroidism during pregnancy when thyroid uptake scan is contraindicated
  • Pregnant women with h/o Graves disease to determine possible fetal and neonatal hyperthyroidism as these antibodies cross the placenta
  • Patients with possible Graves’ orbitopathy without biochemical hyperthyroidism
  • Patients with recent h/o large iodine load where thyroid uptake scan cannot be reliable, e.g., recent amiodarone use, recent imaging studies with iodinated contrast
  • To determine the prognosis of hyperthyroidism who are being treated.

 Radioactive iodine uptake scan with I-123 or I-131:  In Graves disease, the uptake will be high and diffuse whereas, in a toxic nodule, the uptake will be focal known as a hot nodule. Toxic multinodular goiter will have heterogeneous uptake. The radioactive iodine uptake in subacute or silent thyroiditis, factitious hyperthyroidism, and recent iodine load will be low.

Thyroid Ultrasonogram with Doppler: The thyroid gland in Graves disease is usually hypervascular. T3/T4 ratio greater than20 (ng/mcg) or FT3/FT4 ratio greater than 0.3 (SI unit) suggests Graves disease and can be used to differentiate Graves’ disease from thyroiditis induced thyrotoxicosis.

Other Tests – CT or MRI of orbits can be performed to diagnose Graves orbitopathy in patients who present with orbitopathy without hyperthyroidism. Patients with hyperthyroidism can have microcytic anemia, thrombocytopenia, bilirubinemia, high transaminases, hypercalcemia, high alkaline phosphatase, low LDL and HDL cholesterol.

Treatment of Graves’ Disease

Treatment for Graves’ disease depends on its presentation. Treatment consists of rapid symptoms control and reduction of thyroid hormone secretion.

A beta-adrenergic blocker should be started for symptomatic patients, specifically for patients with a heart rate of more than 90 beats/min, patients with a history of cardiovascular disease, and elderly patients. Atenolol 25 mg to 50 mg orally once daily may be considered the preferred beta-blocker due to its convenience of daily dosing, and it is cardioselective (beta-1 selective). Some prescribers recommend Propranolol 10 mg to 40 mg orally every six to eight hours, due to its potential effect to block peripheral conversion of T4 to T3. If a beta-blocker after that, calcium channel blockers like diltiazem and verapamil can be used to control heart rate.

There are three options to reduce thyroid hormone synthesis. These options are:

  • Antithyroid drugs block thyroid hormone synthesis and release
  • Radioactive iodine (RAI) treatment of the thyroid gland
  • Total or subtotal thyroidectomy.

All three options have pros and cons, and there is no consensus on which one is the best option. It is very important to discuss all three options in detail with the patients and make an individualized decision.

Anti-thyroid Drugs (Thionamides)

Methimazole (MMI) and propylthiouracil (PTU) are two anti-thyroid drugs available in the USA. Outside USA, carbimazole, a derivative of methimazole that is rapidly metabolized to methimazole, is also available. These thioamides inhibit Thyroid Peroxidase (TPO) mediated iodination of thyroglobulin in the thyroid gland, blocking the synthesis of T4 and T3. To some extent, Propylthiouracil also blocks the peripheral conversion of T4 to T3.

In nonpregnant patients, methimazole is the drug of choice due to its less frequent side effects (especially hepatotoxicity), once-daily dosing, and more rapid achievement of normal thyroid function. During the first trimester of pregnancy, propylthiouracil must be used due to its less teratogenic side effects. We can start methimazole from the second trimester of pregnancy. American Thyroid Association (ATA) recommends propylthiouracil for patients with thyroid storm and for patients with minor reactions to methimazole therapy who refuses surgery or RAIA.

Before starting ethionamide treatment, patients should be informed about possible side effects including allergic reactions, neutropenia, and hepatotoxicity. A complete blood count with differentials and liver function tests should be obtained. Ethionamide should not be started if the baseline transaminase level is more than five times the upper limit of normal or if absolute neutrophil count (ANC) is less than 1000/ml.

Dosage: Initiate methimazole 5 mg to 10 mg oral daily if FT4 is 1 to 1.5 times the upper limit of normal (ULN), 10 mg to 20 mg oral daily if FT4 is 1.5 to 2 times ULN, 30 mg to 40 mg oral daily if FT4 is more than two to three times ULN.  Start PTU 50 mg t0 150 mg orally three times daily based on the severity of hyperthyroidism. Once thyroid function improves, the thioamide dose can be tapered and continued at maintenance doses once TFTs become euthyroid. Methimazole is usually maintained at 5 mg to 10 mg daily, and propylthiouracil is maintained at 50 mg two to three times a day.

Adverse effects: Minor side-effects include pruritus and rash (3% to 6%), and major side effects include hepatocellular injury (2.7% propylthiouracil, 0.4% Methimazole), agranulocytosis (0.7%, ANC  less than 500/ml), and vasculitis (rarely lupus and pANCA-positive small vessel vasculitis; more with propylthiouracil than methimazole). Rarely hypoglycemia has been reported with methimazole therapy.

Follow-up and monitoring: Monitor thyroid function tests (TFTs) every four to six weeks for the ethionamide dose adjustment. Once TFTs improve, we can reduce the ethionamide dose by 30% to 50% until a maintenance dose is achieved. Once on a maintenance dose, TFTs can be checked every three months for up to 18 months, thereafter every six months is acceptable. Monitor for adverse effects and perform blood tests as needed based on clinical information. Stop the thioamide if the transaminase level is more than three times of ULN.  Routine monitoring of liver function tests and complete blood count is not necessary. Thionamides can be continued for minor cutaneous reactions with or without concurrent use of antihistamines, but if the problem persists, alternative treatment options including surgery or RAI therapy should be considered.

Duration of treatment: For patients on long-term, thionamide therapy who are on maintenance doses, we can consider stopping the therapy after 12 to 8 months, if TSH and TRAb levels normalize during follow-up. If patients remain clinically and biochemically euthyroid, we can repeat TFTs every two to three months during the first six months after stopping the treatment, then every four to six months for another six months, then every six to 12 months. If TSH remains normal for one year without treatment, annual monitoring with TSH is enough.

RAI Therapy

It is preferred for non-pregnant adult patients older than 21 years, patients not planning to get pregnant within the next six to 12 months after treatment, patients with risky comorbid conditions for surgery, and patients with contraindications for thioamides. It is contraindicated during pregnancy, lactation, coexisting thyroid cancer, in patients with moderate to severe Graves orbitopathy, and for individuals who cannot follow radiation safety guidelines.

Preparation: Beta-adrenergic blockade and pretreatment with methimazole (propylthiouracil pretreatment has a high failure rate for RAI treatment) should be considered for patients with an increased risk of complications from hyperthyroidism and patients with very high thyroid hormone levels. If methimazole is started, it should be stopped three to five days before RAI treatment. It can be restarted for high-risk patients three to seven days after treatment. A pregnancy test is required before RAI treatment.

Dosage: I-131 is administered as a capsule or liquid. The I-131 dose can be calculated or one may use a fixed-dose. The calculated dose is based on thyroid volume, uptake of RAI, and local factors. A fixed-dose can be 10 to 25 mCi of I-131. The patient should be provided with a written radiation safety precautions after RAI treatment to avoid exposure to household members or community members, especially children, and pregnant women.

Follow-up and monitoring: TFTs should be monitored every four to six weeks for six months or until the patient becomes hypothyroid. Once the patient is on a stable levothyroxine dose, TFTs can be repeated every six to 12 months. If hyperthyroidism persists after six months of RAI therapy, it can be considered a treatment failure, and repeat treatment with RAI may be needed.

Thyroidectomy

Thyroidectomy is preferred for patients with very large goiter (more than 80 grams), anterior neck compressive symptoms, co-existing suspicious thyroid cancer, large thyroid nodules (greater than 4 cm), cold nodules, co-existing parathyroid adenoma, very high TRAb, and moderate to severe Graves orbitopathy.

Preparation: 

  • Use thioamides to achieve a near or complete euthyroid state before surgery
  • Use Beta-blockers as needed
  • Use potassium iodide, five to seven drops of Lugol’s solution, or one to two drops of SSKI, mixed in water or juices three times a day, starting seven to ten days before surgery to reduce vascularity
  • Assess calcium and Vitamin D levels and replace if needed

Post-op follow-up:

Thionamides should be stopped after surgery and beta-blockers should be weaned off. Levothyroxine is started at 1.6 micrograms per kg body weight, and the dose is adjusted based on TSH level every six to eight weeks.

Other Adjunct Treatment for Graves Hyperthyroidism

Iodinated contrast agents, sodium iodate, and iopanoic acid inhibit the peripheral conversion of T4 to T3. They are used with methimazole but not as a solo agent as they can cause resistant hyperthyroidism. They are not available in the United States. Iodide (SSKI drops) can be used for mild hyperthyroidism especially after RAI treatment. Glucocorticoid, cholestyramine, lithium, carnitine are other agents that have also been tried. Rituximab may induce remission in patients with Graves disease, but it is costly. 

Treatment of Graves Orbitopathy (GO)

Rapid achievement of euthyroid level should be sought in patients with Graves orbitopathy. Patients should be advised to quit smoking if they do.  Treatment depends on the severity of orbitopathy. For patients with mild orbitopathy who undergo RAI treatment, prednisone 0.4 mg/kg/day to 0.5 mg/kg/day should be started one to three days after treatment and continued for one month. It should be tapered slowly over two months. Mild active Graves orbitopathy should be treated with artificial tears, and glucocorticoid therapy can be considered. Elevation of the head during sleep reduces orbital congestion. Selenium treatment has doubtful benefits. Prompt ophthalmology referral should be considered for all cases of Graves orbitopathy.

Treatment of moderate to severe active Graves orbitopathy requires up to 100 mg of oral prednisone daily for one to two weeks, then tapered over six to 12 weeks or intravenous (IV) methylprednisolone 500 mg/wk for six weeks followed by 250 mg/wk for six weeks. Other options include orbital irradiation, rituximab, and emergency orbital decompression.

Treatment of inactive Graves orbitopathy involves interval close clinical monitoring, elective orbital decompression, strabismus repair and eyelid repair depending upon severity.

Treatment of Dermopathy and Acropachy

Graves dermopathy usually does not need treatment. If treatment is considered, topical high potency glucocorticoid with occlusive dressing can be considered. Rituximab treatment to reduce B-cell may be beneficial, but it remains experimental. There is no treatment available for acropachy.

References

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Secondary Hyperparathyroidism – Causes, Symptoms, Treatment

Secondary Hyperparathyroidism/Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. A basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients. A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Types

Primary hyperparathyroidism

Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:

  • A noncancerous growth (adenoma) on a gland is the most common cause.
  • Enlargement (hyperplasia) of two or more parathyroid glands accounts for most other cases.
  • A cancerous tumor is a very rare cause of primary hyperparathyroidism.

Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder.

Secondary hyperparathyroidism

Secondary hyperparathyroidism is the result of another condition that lowers calcium levels. This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:

  • Severe calcium deficiency. Your body may not get enough calcium from your diet, often because your digestive system doesn’t absorb the calcium from it.
  • Severe vitamin D deficiency. Vitamin D helps maintain appropriate calcium levels in the blood. It also helps your digestive system absorb calcium from your food. Your body produces vitamin D when your skin is exposed to sunlight. You also consume some vitamin D in food. If you don’t get enough vitamin D, then calcium levels may drop.
  • Chronic kidney failure. Your kidneys convert vitamin D into a form that your body can use. If your kidneys work poorly, usable vitamin D may decline and calcium levels drop, causing parathyroid hormone levels to go up. Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Some medical treatments, such as vitamin D, bisphosphonates and cinacalcet, will lower PTH levels. In some people with long-term end-stage kidney disease, the parathyroid glands enlarge and begin to release PTH on their own, and PTH doesn’t go down with medical treatment. This is called tertiary hyperparathyroidism, and people with this condition may require surgery to remove parathyroid tissue.

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia.

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

Causes of Primary Hyperparathyroidism

PTH-dependent Causes of Hypercalcemia

  • Primary Hyperparathyroidism
    • Single adenoma
    • Multigland disease
      • Familial causes of hyperparathyroidism
        • Multiple endocrine neoplasia Type 1
        • Multiple endocrine neoplasia Type 2
        • Familial hyperparathyroidism
        • Hyperparathyroidism-jaw tumor syndrome
    • Parathyroid carcinoma
  • Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor
  • Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

  • Malignancy
  • Granulomatous diseases
  • Hyperthyroidism
  • Thiazide therapy
  • Vitamin D intoxication
  • Milk-alkali syndrome
  • Adrenal insufficiency
  • Vitamin A intoxication
  • Genetic associations include:
OMIM Name Gene
145000 HRPT1 MEN1HRPT2
145001 HRPT2 HRPT2
610071 HRPT3 unknown at 2p13.3-14[rx]

In all cases, the disease is idiopathic but is thought to involve the inactivation of tumor suppressor genes (Menin gene in MEN1) or involve gain of function mutations (RET proto-oncogene MEN 2a).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.[rx]

What are the symptoms of primary hyperparathyroidism?

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by “stones, bones, abdominal groans, thrones, and psychiatric overtones”.

  • “Stones” refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to kidney failure.
  • “Bones” refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
  • “Abdominal groans” refers to gastrointestinal symptoms of constipation, indigestion, nausea, and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.
  • “Thrones” refers to polyuria and constipation
  • “Psychiatric overtones” refer to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

These are the most common symptoms of primary hyperparathyroidism. However, each person may experience symptoms differently. Symptoms of too much calcium in the blood may include:

  • Constipation
  • Frequent urination
  • Increased thirst
  • Joint pain
  • Kidney pain (due to the presence of kidney stones)
  • Lethargy and fatigue
  • Loss of appetite
  • Muscle weakness

Other serious symptoms may include:

  • Abdominal pain
  • Depression
  • Memory loss
  • Nausea
  • Vomiting

The symptoms of primary hyperparathyroidism may look like other medical problems. Always talk with your healthcare provider for a diagnosis.

Diagnosis of Primary Hyperparathyroidism

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia. A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.

Bone mineral density test

Dual-energy x-ray absorptiometry, also called a DXA or DEXA scan uses low-dose x-rays to measure bone density. During the test, you will lie on a padded table while a technician moves the scanner over your body. A bone expert or radiologist will read the scan.

A woman lying on a table with a DXA scanner positioned over her abdomen.During a DXA scan, you will lie on a padded table while a technician moves the scanner over your body.

Kidney imaging tests

Doctors may use one of the following imaging tests to look for kidney stones.

Ultrasound. Ultrasound uses a device called a transducer that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician does the procedure. A radiologist reads the images, which can show kidney stones.

Abdominal x-ray. An abdominal x-ray is a picture of the abdomen that uses low levels of radiation and is recorded on film or on a computer. During an abdominal x-ray, you lie on a table or stand up. A technician positions the x-ray machine close to your abdomen and asks you to hold your breath so the picture won’t be blurry. A radiologist reads the x-ray, which can show the location of kidney stones in the urinary tract. Not all stones are visible on an abdominal x-ray.

Computed tomography (CT) scans. CT scans use a combination of x-rays and computer technology to create images of your urinary tract. CT scans sometimes use a contrast medium—a dye or other substance that makes structures inside your body easier to see. A contrast medium isn’t usually needed to see kidney stones. For the scan, you’ll lie on a table that slides into a tunnel-shaped machine that takes the x-rays. A radiologist reads the images, which can show the size and location of a kidney stone.

Vitamin D blood test – Health care professionals test for vitamin D levels because low levels are common in people with primary hyperparathyroidism. In patients with primary hyperparathyroidism, the low vitamin D level can further stimulate the parathyroid glands to make even more parathyroid hormone. Also, a very low vitamin D level may cause a secondary form of hyperparathyroidism, which resolves when vitamin D levels are returned to normal.

List of tests for primary hyperparathyroidism: 

  • Total calcium
  • Albumin
  • Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
  • Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
  • Parathyroid hormone
  • Phosphorus
  • BUN and creatinine
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • Urine calcium and creatinine
  • Imaging to screen for renal calcifications or urolithiasis
  • Bone densitometry (DXA) including measurement at the distal 1/3 radius
  • EKG
  • Genetic testing in selected individuals if there is suspicion of a genetic syndrome
  • Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false-negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing the enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.

Treatment of Primary Hyperparathyroidism

Drugs

Medications to treat hyperparathyroidism include the following:

  • Calcimimetics. A calcimimetic is a drug that mimics calcium circulating in the blood. The drug may trick the parathyroid glands into releasing less parathyroid hormone. This drug is sold as a cinacalcet (Sensipar). Some doctors may prescribe cinacalcet to treat primary hyperparathyroidism, particularly if surgery hasn’t successfully cured the disorder or a person isn’t a good surgery candidate. The most commonly reported side effects of cinacalcet are joint and muscle pain, diarrhea, nausea, and respiratory infection.
  • Hormone replacement therapy. For women who have gone through menopause and have signs of osteoporosis, hormone replacement therapy may help bones retain calcium. This treatment doesn’t address the underlying problems with the parathyroid glands. Prolonged use of hormone replacement therapy can increase the risk of blood clots and breast cancer. Work with your doctor to evaluate the risks and benefits to help you decide what’s best for you. Some common side effects of hormone replacement therapy include breast pain and tenderness, dizziness, and headaches.
  • Bisphosphonates. Bisphosphonates also prevent the loss of calcium from bones and may lessen osteoporosis caused by hyperparathyroidism. Some side effects associated with bisphosphonates include low blood pressure, fever and vomiting. This treatment doesn’t address the underlying problems with the parathyroid glands

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:

  • Serum calcium is more than 1 mg/dL greater than the upper limit of normal
  • Age younger than 50 years
  • Osteoporosis
  • GFR less than 60 mL/min
  • Urine calcium greater than 400 mg/24 hours
  • Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or the development of complications, then surgery should be recommended.

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

  • Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
  • Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.

Surgery

Surgery to remove the overactive parathyroid gland or glands is the only sure way to cure primary hyperparathyroidism. Doctors recommend surgery for people with clear symptoms or complications of the disease. In people without symptoms, doctors follow the above guidelines to identify who might benefit from parathyroid surgery.2 Surgery can lead to improved bone density and can lower the chance of forming kidney stones.

When performed by experienced surgeons, surgery almost always cures primary hyperparathyroidism.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive gland or glands.

Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.

Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

  • don’t have symptoms
  • have only slightly high blood calcium levels
  • have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want to be answered.
  • Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your healthcare provider if you have questions.

Parathyroid Quick Facts

  • There are 4 parathyroids glands. We all have 4 parathyroids glands.
  • Except in rare cases, parathyroid glands are in the neck behind the thyroid.
  • Parathyroids are NOT related to the thyroid (except they are neighbors in the neck).
  • The thyroid gland controls much of your body’s metabolism, but the parathyroid glands control body calcium. They have no relationship except they are neighbors.
  • Parathyroid glands make a hormone, called “Parathyroid Hormone”.
  • Doctors and labs abbreviate Parathyroid Hormone as “PTH”.
  • Just like calcium, PTH has a normal range in our blood…we can measure it to see how good or bad a job the parathyroid glands are doing.
  • All four parathyroid glands do the exact same thing.
  • Parathyroid glands control the amount of calcium in your blood.
  • Parathyroid glands control the amount of calcium in your bones.
  • You can easily live with one (or even 1/2) parathyroid gland.
  • Removing all 4 parathyroid glands will cause very bad symptoms of too little calcium (hypoparathyroidism). HypOparathyroidism is the opposite of hypERparathyroidism and it is very rare… only one page of this entire site is about hypoparathyroidism disease.
  • When parathyroid glands go bad, it is just one gland that goes bad about 91% of the time–it just grows big (develops a benign tumor) and makes too much hormone. About 8% of the time people with hyperparathyroidism will have two bad glands. It is quite uncommon for 3 or 4 glands to go bad.
  • When one of your parathyroid glands goes bad and makes too much hormone, the excess hormone goes to the bones and takes calcium out of the bones, and puts it in your blood. It’s the high calcium in the blood that makes you feel bad.
  • Everybody with a bad parathyroid gland will eventually develop bad osteoporosis–unless the bad gland is removed.
  • Parathyroids almost never develop cancer–so stop worrying about that!
  • However, not removing the parathyroid tumor and leaving the calcium high for a number of years will increase the chance of developing other cancers in your body (breast, colon, kidney, and prostate).
  • There is only ONE way to treat parathyroid problems–Surgery.
  • Mini-Surgery is now available that almost everyone can/should have. You should educate yourself about the new surgical treatments available. Do not have an “exploratory” operation to find the bad parathyroid tumor–this old-fashioned operation is too big and dangerous.

References

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Primary Hyperparathyroidism – Causes, Symptoms, Treatment

Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. A basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients. A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Types

Primary hyperparathyroidism

Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:

  • A noncancerous growth (adenoma) on a gland is the most common cause.
  • Enlargement (hyperplasia) of two or more parathyroid glands accounts for most other cases.
  • A cancerous tumor is a very rare cause of primary hyperparathyroidism.

Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder.

Secondary hyperparathyroidism

Secondary hyperparathyroidism is the result of another condition that lowers calcium levels. This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:

  • Severe calcium deficiency. Your body may not get enough calcium from your diet, often because your digestive system doesn’t absorb the calcium from it.
  • Severe vitamin D deficiency. Vitamin D helps maintain appropriate calcium levels in the blood. It also helps your digestive system absorb calcium from your food. Your body produces vitamin D when your skin is exposed to sunlight. You also consume some vitamin D in food. If you don’t get enough vitamin D, then calcium levels may drop.
  • Chronic kidney failure. Your kidneys convert vitamin D into a form that your body can use. If your kidneys work poorly, usable vitamin D may decline and calcium levels drop, causing parathyroid hormone levels to go up. Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Some medical treatments, such as vitamin D, bisphosphonates and cinacalcet, will lower PTH levels. In some people with long-term end-stage kidney disease, the parathyroid glands enlarge and begin to release PTH on their own, and PTH doesn’t go down with medical treatment. This is called tertiary hyperparathyroidism, and people with this condition may require surgery to remove parathyroid tissue.

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia.

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

Causes of Primary Hyperparathyroidism

PTH-dependent Causes of Hypercalcemia

  • Primary Hyperparathyroidism
    • Single adenoma
    • Multigland disease
      • Familial causes of hyperparathyroidism
        • Multiple endocrine neoplasia Type 1
        • Multiple endocrine neoplasia Type 2
        • Familial hyperparathyroidism
        • Hyperparathyroidism-jaw tumor syndrome
    • Parathyroid carcinoma
  • Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor
  • Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

  • Malignancy
  • Granulomatous diseases
  • Hyperthyroidism
  • Thiazide therapy
  • Vitamin D intoxication
  • Milk-alkali syndrome
  • Adrenal insufficiency
  • Vitamin A intoxication
  • Genetic associations include:
OMIM Name Gene
145000 HRPT1 MEN1HRPT2
145001 HRPT2 HRPT2
610071 HRPT3 unknown at 2p13.3-14[rx]

In all cases, the disease is idiopathic but is thought to involve the inactivation of tumor suppressor genes (Menin gene in MEN1) or involve gain of function mutations (RET proto-oncogene MEN 2a).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.[rx]

What are the symptoms of primary hyperparathyroidism?

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by “stones, bones, abdominal groans, thrones, and psychiatric overtones”.

  • “Stones” refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to kidney failure.
  • “Bones” refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
  • “Abdominal groans” refers to gastrointestinal symptoms of constipation, indigestion, nausea, and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.
  • “Thrones” refers to polyuria and constipation
  • “Psychiatric overtones” refer to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

These are the most common symptoms of primary hyperparathyroidism. However, each person may experience symptoms differently. Symptoms of too much calcium in the blood may include:

  • Constipation
  • Frequent urination
  • Increased thirst
  • Joint pain
  • Kidney pain (due to the presence of kidney stones)
  • Lethargy and fatigue
  • Loss of appetite
  • Muscle weakness

Other serious symptoms may include:

  • Abdominal pain
  • Depression
  • Memory loss
  • Nausea
  • Vomiting

The symptoms of primary hyperparathyroidism may look like other medical problems. Always talk with your healthcare provider for a diagnosis.

Diagnosis of Primary Hyperparathyroidism

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia. A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.

Bone mineral density test

Dual-energy x-ray absorptiometry, also called a DXA or DEXA scan uses low-dose x-rays to measure bone density. During the test, you will lie on a padded table while a technician moves the scanner over your body. A bone expert or radiologist will read the scan.

A woman lying on a table with a DXA scanner positioned over her abdomen.During a DXA scan, you will lie on a padded table while a technician moves the scanner over your body.

Kidney imaging tests

Doctors may use one of the following imaging tests to look for kidney stones.

Ultrasound. Ultrasound uses a device called a transducer that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician does the procedure. A radiologist reads the images, which can show kidney stones.

Abdominal x-ray. An abdominal x-ray is a picture of the abdomen that uses low levels of radiation and is recorded on film or on a computer. During an abdominal x-ray, you lie on a table or stand up. A technician positions the x-ray machine close to your abdomen and asks you to hold your breath so the picture won’t be blurry. A radiologist reads the x-ray, which can show the location of kidney stones in the urinary tract. Not all stones are visible on an abdominal x-ray.

Computed tomography (CT) scans. CT scans use a combination of x-rays and computer technology to create images of your urinary tract. CT scans sometimes use a contrast medium—a dye or other substance that makes structures inside your body easier to see. A contrast medium isn’t usually needed to see kidney stones. For the scan, you’ll lie on a table that slides into a tunnel-shaped machine that takes the x-rays. A radiologist reads the images, which can show the size and location of a kidney stone.

Vitamin D blood test – Health care professionals test for vitamin D levels because low levels are common in people with primary hyperparathyroidism. In patients with primary hyperparathyroidism, the low vitamin D level can further stimulate the parathyroid glands to make even more parathyroid hormone. Also, a very low vitamin D level may cause a secondary form of hyperparathyroidism, which resolves when vitamin D levels are returned to normal.

List of tests for primary hyperparathyroidism: 

  • Total calcium
  • Albumin
  • Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
  • Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
  • Parathyroid hormone
  • Phosphorus
  • BUN and creatinine
  • Alkaline phosphatase
  • 25-hydroxyvitamin D
  • Urine calcium and creatinine
  • Imaging to screen for renal calcifications or urolithiasis
  • Bone densitometry (DXA) including measurement at the distal 1/3 radius
  • EKG
  • Genetic testing in selected individuals if there is suspicion of a genetic syndrome
  • Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false-negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing the enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.

Treatment of Primary Hyperparathyroidism

Drugs

Medications to treat hyperparathyroidism include the following:

  • Calcimimetics. A calcimimetic is a drug that mimics calcium circulating in the blood. The drug may trick the parathyroid glands into releasing less parathyroid hormone. This drug is sold as a cinacalcet (Sensipar). Some doctors may prescribe cinacalcet to treat primary hyperparathyroidism, particularly if surgery hasn’t successfully cured the disorder or a person isn’t a good surgery candidate. The most commonly reported side effects of cinacalcet are joint and muscle pain, diarrhea, nausea, and respiratory infection.
  • Hormone replacement therapy. For women who have gone through menopause and have signs of osteoporosis, hormone replacement therapy may help bones retain calcium. This treatment doesn’t address the underlying problems with the parathyroid glands. Prolonged use of hormone replacement therapy can increase the risk of blood clots and breast cancer. Work with your doctor to evaluate the risks and benefits to help you decide what’s best for you. Some common side effects of hormone replacement therapy include breast pain and tenderness, dizziness, and headaches.
  • Bisphosphonates. Bisphosphonates also prevent the loss of calcium from bones and may lessen osteoporosis caused by hyperparathyroidism. Some side effects associated with bisphosphonates include low blood pressure, fever and vomiting. This treatment doesn’t address the underlying problems with the parathyroid glands

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:

  • Serum calcium is more than 1 mg/dL greater than the upper limit of normal
  • Age younger than 50 years
  • Osteoporosis
  • GFR less than 60 mL/min
  • Urine calcium greater than 400 mg/24 hours
  • Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or the development of complications, then surgery should be recommended.

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

  • Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
  • Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.

Surgery

Surgery to remove the overactive parathyroid gland or glands is the only sure way to cure primary hyperparathyroidism. Doctors recommend surgery for people with clear symptoms or complications of the disease. In people without symptoms, doctors follow the above guidelines to identify who might benefit from parathyroid surgery.2 Surgery can lead to improved bone density and can lower the chance of forming kidney stones.

When performed by experienced surgeons, surgery almost always cures primary hyperparathyroidism.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive gland or glands.

Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.

Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

  • don’t have symptoms
  • have only slightly high blood calcium levels
  • have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want to be answered.
  • Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your healthcare provider if you have questions.

Parathyroid Quick Facts

  • There are 4 parathyroids glands. We all have 4 parathyroids glands.
  • Except in rare cases, parathyroid glands are in the neck behind the thyroid.
  • Parathyroids are NOT related to the thyroid (except they are neighbors in the neck).
  • The thyroid gland controls much of your body’s metabolism, but the parathyroid glands control body calcium. They have no relationship except they are neighbors.
  • Parathyroid glands make a hormone, called “Parathyroid Hormone”.
  • Doctors and labs abbreviate Parathyroid Hormone as “PTH”.
  • Just like calcium, PTH has a normal range in our blood…we can measure it to see how good or bad a job the parathyroid glands are doing.
  • All four parathyroid glands do the exact same thing.
  • Parathyroid glands control the amount of calcium in your blood.
  • Parathyroid glands control the amount of calcium in your bones.
  • You can easily live with one (or even 1/2) parathyroid gland.
  • Removing all 4 parathyroid glands will cause very bad symptoms of too little calcium (hypoparathyroidism). HypOparathyroidism is the opposite of hypERparathyroidism and it is very rare… only one page of this entire site is about hypoparathyroidism disease.
  • When parathyroid glands go bad, it is just one gland that goes bad about 91% of the time–it just grows big (develops a benign tumor) and makes too much hormone. About 8% of the time people with hyperparathyroidism will have two bad glands. It is quite uncommon for 3 or 4 glands to go bad.
  • When one of your parathyroid glands goes bad and makes too much hormone, the excess hormone goes to the bones and takes calcium out of the bones, and puts it in your blood. It’s the high calcium in the blood that makes you feel bad.
  • Everybody with a bad parathyroid gland will eventually develop bad osteoporosis–unless the bad gland is removed.
  • Parathyroids almost never develop cancer–so stop worrying about that!
  • However, not removing the parathyroid tumor and leaving the calcium high for a number of years will increase the chance of developing other cancers in your body (breast, colon, kidney, and prostate).
  • There is only ONE way to treat parathyroid problems–Surgery.
  • Mini-Surgery is now available that almost everyone can/should have. You should educate yourself about the new surgical treatments available. Do not have an “exploratory” operation to find the bad parathyroid tumor–this old-fashioned operation is too big and dangerous.

References

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Hormone Secretion – Anatomy, Types, Functions

Hormone Secretion/Hormones are secreted from the glands of the endocrine system, they are specific in that each hormone causes a response in a specific target organ or group of cells, rather than on the body as a whole. Exocrine hormones are secreted via a duct into the blood and usually affect a distant organ or tissue hormone secretion in birds is inhibited by peripheral hormones. If GH is acting via IGF-I, then negative feedback by IGF-I on GH release would seem to be likely. IGF-I has been found to inhibit GH release in vitro and in vivo in chicks (Perez et al., 1985; Buonomo et al., 1987). Similarly, as GH increases the circulating concentration of the active thyroid hormone, T3, then it is probable that T3 would inhibit GH secretion. This is the case. The presence of elevated levels of T3 reduces GH release from the chicken pituitary gland in vivo (e.g. Scanes and Harvey, 1987b) and in vitro (Donoghue and Scanes, 1991).

Control of Hormone Secretion

A hormone is a molecule released by a cell or a gland in one part of the body that exerts effects via specific receptors at other sites.

Key Points

The endocrine system relies on feedback mechanisms to control the hormone levels in the circulatory system.

Negative feedback systems prevent deviation from an ideal mean to maintain homeostasis.

Positive feedback systems facilitate deviation from the mean.

Key Terms

negative feedback: A system that prevents deviation from a mean value.

positive feedback: A system that promotes deviation from a mean value.

The physiological activity of a hormone depends largely on its concentration within the circulatory system. The effects of too high or too low a concentration of hormones can be damaging—this level must be tightly controlled.

The endocrine system relies on feedback systems to regulate hormone production and secretion.

Negative Feedback

Most endocrine glands are under negative feedback control that acts to maintain homeostasis, i.e., prevent deviation from an ideal value. A key example of a negative feedback system is the regulation of the thyroid hormone thyroxine, which regulates numerous key metabolic processes.

Briefly, neurons in the hypothalamus secrete a thyroid-releasing hormone that stimulates cells in the anterior pituitary to secrete thyroid-stimulating hormone. The thyroid-stimulating hormone then stimulates the release of thyroxine from the thyroid gland.

When the blood concentration of thyroxine rises above the ideal value as detected by sensory neurons, the hypothalamus is signaled to stop thyroid-releasing hormone production, which eventually lowers the levels of thyroxine in the blood. When these drop below the ideal value the hypothalamus is signaled to begin secreting thyroid-releasing hormone again.

Positive Feedback

Positive feedback mechanisms control self-perpetuating events, that is, they encourage deviation from the mean. Positive feedback systems are much less common although they do exist. A key example occurs during childbirth.

The hormone oxytocin is produced by the posterior pituitary that stimulates and enhances contractions during labor. During birth, as the baby moves through the birth canal, pressure receptors within the cervix signal the hypothalamus to stimulate the pituitary to secrete oxytocin.

Oxytocin travels to the uterus through the bloodstream, stimulating the muscles in the uterine wall to contract which in turn increases the activation of the pressure receptors and stimulates the further release of oxytocin. The strength of muscle contractions intensifies until the baby is born and the stimulation of the pressure receptors is removed, which stops the release of oxytocin.

The Endocrine system (along with the nervous system) controls and regulates the complex activities of the body. The Endocrine system regulates the activities of the body by secreting complex chemical substances (hormones) into the bloodstream. These secretions come from a variety of glands that control various organs of the body. The key functions are:

  • To regulate the metabolic functions of the body.
  • To regulate the rate of chemical reactions in various cells.
  • To influence the ability of substances to transport themselves through cell membranes.

About Hormones

  • Hormones are secreted from the glands of the endocrine system, they are specific in that each hormone causes a response in a specific target organ or group of cells, rather than on the body as a whole. Exocrine hormones are secreted via a duct into the blood and usually affect a distant organ or tissue. Endocrine hormones are secreted within the tissue (rather than via a duct) and enter the bloodstream via capillaries.

Hormones can be grouped into three main types

  • amines, these are simple molecules
    • proteins and peptides which are made from chains of amino acids
    • steroids which are derived from cholesterol.
  • Glands – discharge hormones directly into the bloodstream. They have built-in feedback mechanisms that maintain a proper balance of hormones, and prevent excess hormone secretion. Low concentrations of a hormone will often trigger the gland to secrete. Once the concentrations of the hormone in the blood rise this may cause the gland to stop secreting until once again hormone concentrations fall. This feedback mechanism (which is characteristic of most glands) causes a cycle of hormone secretions.
  •  Disposal of waste – Once hormones have served their function on their target organs/tissues they are destroyed. They are either destroyed by the liver or the actual tissues of the target organs. They are then removed by the kidneys.

The Pituitary Gland

This is known as the “master gland” because it exerts control over all of the other glands of the endocrine system. Despite its importance, the pituitary gland is no larger than a small pea. The Pituitary gland is made up of two separate glands: the Anterior lobe which is an outgrowth of the pharynx, and the

  • The posterior lobe is an outgrowth of the brain composed of neural (nerve) tissue.
  • The Anterior Lobe of the pituitary plays the ‘master’ role secreting six major hormones that affect most of the body, including the other Endocrine glands:
  • ACTH (Adrenocorticotrophic hormone) stimulates the adrenal glands to secrete their hormones.
  • HGH (Human growth hormone) also known as the somatotrophic hormone is responsible for the growth of long bones, muscles, and viscera.
  • TSH (Thyroid-stimulating hormone) influences the structure of the thyroid and causes it to secrete thyroid hormone.
  • FSH (Follicle-stimulating hormone) stimulates female egg production or male sperm production.
  • PRL (Prolactin) in females causes the corpus luteum the area around the mature follicle to produce two important hormones: Oestrogen and Progesterone. During pregnancy, PRL is also responsible for the development of the glandular tissues of the breast which produce milk.
  • LH (Luteinizing hormone) works in conjunction with FSH in females to cause ovulation and prepares the uterus for pregnancy, in males the testes to secrete testosterone.
  • The Posterior Lobe of the Pituitary Gland (or neurohypophysis) stores and releases hormones secreted by the hypothalamus section of the brain including:
  • ADH (Antidiuretic hormone) stimulates the smooth muscles, blood vessels, and intestine. ADH increases the kidney’s permeability to water allowing the body to re-absorb water that would otherwise escape in urine.
  • OT (Oxytocin) stimulates the smooth muscles of the uterus during pregnancy, causing it to contract during labor. It also stimulates the lacteals (milk ducts) in the breast.

The Thyroid gland

The thyroid is a butterfly-shaped gland which is located at the base of the throat. It has two lobes separated in the middle by a strip of tissue (the isthmus). The Thyroid itself secretes three main hormones:

  • Thyroxine contains iodine which is essential for the body’s normal growth and metabolism. Thyroxine helps control body size, regulating not only the growth of tissues but also the differentiation or specialization of tissues.
  • Triiodothyronine has similar functions to thyroxine.
  • Calcitonin causes a decrease in the concentration of calcium in the blood. Calcitonin works with secretions from the parathyroid glands to maintain the balance of calcium necessary for the body to function.

People who have surgery to remove the thyroid gland (thyroidectomy) for cancer or other thyroid problems usually need to take thyroxine supplements in order to maintain normal weight and body functions.

The Parathyroids

There are four Parathyroid glands which are small and rounded, arranged in two pairs usually located above and below the thyroid. Each Parathyroid is small, yellow, and smooth, sometimes they imbed themselves in the thyroid itself.

Parathyroid hormone increases the blood concentrations of calcium and phosphorous, working to balance the Calcitonin which is secreted by the thyroid to maintain the body’s balance of calcium.

The Pancreas

The pancreas is a long, narrow, lobed gland located behind the stomach. The Pancreas has two types of cells: exocrine and endocrine cells. The exocrine cells secrete Pancreatic juices which are used in the duodenum as an important part in the digestive system. The endocrine cells are arranged in clusters throughout the Pancreas, these known as Islets of Langerhans. There are three types of endocrine cells; alpha cells which secrete glucagon, beta cells which secrete insulin, and delta cells which inhibit the secretion of glucagon and insulin:

  • Glucagon increases the blood glucose level by stimulating the liver causing convert Glycogen into Glucose (sugar).
  • Insulin increases the permeability of the cell to glucose, which the cells use for energy. By promoting the utilization of glucose by the tissue cells, insulin causes a decrease in the concentration of glucose in the blood. Insulin also promotes the storage of glycogen in the liver.

The Adrenal Glands

The adrenal glands resemble small caps perched on top of each kidney. The Adrenal is actually a combination of two glands the adrenal cortex and the adrenal medulla.

  • The adrenal cortex is essential for life, as opposed to the adrenal medulla which is important but not indispensable. The anterior pituitary controls the adrenal cortex by secreting the hormone ACTH. All of the secretions of the adrenal cortex are known as steroids, many of which can now be manufactured synthetically. The adrenal cortex is made up of three layers associated with three classes of hormones:
  • Mineralocorticoids are produced by the outer layer of the adrenal cortex, the most important of which is aldosterone. Aldosterone promotes the retention of sodium (Na+) and the excretion of potassium (K+). This helps to maintain both the electrolyte and water content of the body.
  • Glucocorticoids are produced by the middle cortex. These affect almost every cell in the body regulating the metabolism of fats, proteins, and carbohydrates. Cortisone is one such glucocorticoid.
  • Gonadal hormones are produced by the inner cortex, there are roughly even amounts of two types of hormones secreted: Androgen (male) and Estrogen (female). The adrenal gland is not the only gland to secrete sex hormones.
  • The Adrenal Medulla is the inner part of the adrenal gland. The hormones secreted affect the structures in the body that are under the control of the sympathetic nervous system, aiding the body to deal with stressful situations such as fright, attack or pursuit. They are both associated with an increased heartbeat, higher blood pressure, and higher blood glucose levels, thus preparing the body for quick action.
  • Adrenalin (or epinephrine) affects both alpha and beta receptors in the nervous system.
  • Noradrenalin (Norepinephrine) affects only the alpha receptors of the nervous system.

The Gonads

The gonads consist of ovaries in the female and testes in the male. These glands produce hormones important in the development and functioning of the reproductive organs. they are under the control of the pituitary gland and produce secondary sexual traits.

  • Male testes are egg-shaped glands located in the sac-like scrotum, and serve two main functions: (i) The production of sperm cells, and (ii) The secretion of testosterone. Testosterone is the masculizing hormone inducing male secondary sexual characteristics after puberty.
  • Female ovaries are two almond-shaped glands on each side of the uterus. They have three main functions; (i) Containing immature ova (eggs), (ii) secretion of estrogen and (ii) secretion of progesterone.
  • Estrogen is secreted by the adrenal cortex as well as the ovaries and is present in the blood of all females from puberty through to menopause. estrogen acts on the structure of the reproductive organs, especially during the menstrual cycle. This induces and maintains female secondary sexual characteristics. Progesterone works on the uterus to prepare it for the implantation of a fertilized ovum (egg). It causes the development of the breasts and is essential for the complete development of the maternal proportion of the placenta.
  • Giantism too much HGH is secreted before puberty.
  • Dwarfism is caused by a lack of HGH before puberty.
  • Diabetes Mellitus is a condition with under-secretion of insulin, causing the cells to lose their permeability to glucose preventing them from getting sugar needed for energy. Sugar remains in the blood and often the body will try and remove this leading to high sugar content in the urine, causing polyuria (passing of large volumes of urine) and polydipsia (excessive thirst).

Roots, suffixes, and prefixes

Most medical terms are comprised of a root word plus a suffix (word ending) and/or a prefix (beginning of the word). Here are some examples related to the Endocrine System.

component meaning example
A-, AN- without, lack muscular atrophy = ‘wasting away’ of muscles
ADEN- gland adenoma = tumor with gland-like structure
END-, Endo- within endocrine = secreting within
EXO- away from exocrine = secreting outwardly or away from
GLYCO-, GLUCO- sugar, sweet hyperglycemia = excessive blood sugar levels
PARA- near, beside parathyroid = beside the thyroid
POLY- much, many polyadenitis = inflammation of many glands
THYROID- thyroid hypoplasia = defective growth of the thyroid
-CRIME to secrete endocrine = endo (within) crime (secrete)
-TROPHY growth hypertrophy = excessive growth of an organ or part
-MAGALY enlargement hepatomegaly = enlarged liver with hepatitis
-PHYSIS growth a growth or outcropping (as opposed to a trophy where something is physically growing)

References

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Mechanisms of Hormone Action – All About You Can Know

Mechanisms of Hormone Action/Hormones are the messenger molecules of the endocrine system. Endocrine hormones travel throughout the body in the blood. However, each hormone affects only certain cells, called target cells. A target cell is the type of cell on which a hormone has an effect. A target cell is affected by a particular hormone because it has receptor proteins that are specific to that hormone. A hormone travels through the bloodstream until it finds a target cell with a matching receptor it can bind to. When the hormone binds to a receptor, it causes a change within the cell. Exactly how this works depends on whether the hormone is a steroid hormone or a non-steroid hormone.

 Mechanisms of Hormone Action

Protein and peptide hormones, catecholamines like epinephrine, and eicosanoids such as prostaglandins find their receptors decorating the plasma membrane of target cells.

The binding of the hormone to the receptor initiates a series of events which leads to the generation of so-called second messengers within the cell (the hormone is the first messenger). The second messengers then trigger a series of molecular interactions that alter the physiologic state of the cell. Another term used to describe this entire process is signal transduction.

Structure of Cell Surface Receptors

Cell surface receptors are integral membrane proteins and, as such, have regions that contribute to three basic domains:

  • Extracellular domains: Some of the residues exposed to the outside of the cell interact with and bind the hormone – another term for these regions is the ligand-binding domain.
  • Transmembrane domains: Hydrophobic stretches of amino acids are “comfortable” in the lipid bilayer and serve to anchor the receptor in the membrane.
  • Cytoplasmic or intracellular domains: Tails or loops of the receptor that are within the cytoplasm react to hormone binding by interacting in some way with other molecules, leading to the generation of second messengers. Cytoplasmic residues of the receptor are thus the effector region of the molecule.

Several distinctive variations in receptor structure have been identified. As depicted below, some receptors are simple, single-pass proteins; many growth factor receptors take this form. Others, such as the receptor for insulin, have more than one subunit. Another class, which includes the beta-adrenergic receptor, is threaded through the membrane seven times.

Receptor molecules are neither isolated by themselves nor fixed in one location of the plasma membrane. In some cases, other integral membrane proteins interact with the receptor to modulate its activity. Some types of receptors cluster together in the membrane after binding hormones. Finally, as elaborated below, the interaction of the hormone-bound receptor with other membrane or cytoplasmic proteins is the key to the generation of second messengers and transduction of the hormonal signal.

Second Messenger Systems

Consider what would happen if, late at night, you noticed a building on fire. Hopefully, you would dial 911 or a similar emergency number. You would inform the dispatcher of the fire, and the dispatcher would, in turn, contact and “activate” a number of firemen. The firefighters would then rapidly go to work pouring water on the fire, setting up roadblocks, and the like. They would also probably activate other “players”, such as police and fire investigators that would come in later to try and determine the cause of the fire. Importantly, once the fire is out (or the building totally destroyed), the firemen go back to the station and to sleep.

The community response to a fire is, at least in some ways, analogous to a second messenger system involved in a hormone’s action. In the scenario described, you are the “first messenger”, the dispatcher is the “receptor”, the firefighters are the “second messengers”.

Currently, four-second messenger systems are recognized in cells, as summarized in the table below. Note that not only do multiple hormones utilize the same second messenger system, but a single hormone can utilize more than one system. Understanding how cells integrate signals from several hormones into a coherent biological response remains a challenge.

Second Messenger Examples of Hormones Which Utilize This System
Cyclic AMP Epinephrine and norepinephrine, glucagon, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, calcitonin, parathyroid hormone, antidiuretic hormone
Protein kinase activity Insulin, growth hormone, prolactin, oxytocin, erythropoietin, several growth factors
Calcium and/or phosphoinositides Epinephrine and norepinephrine, angiotensin II, antidiuretic hormone, gonadotropin-releasing hormone, thyroid-releasing hormone.
Cyclic GMP Atrial natriuretic hormone, nitric oxide

In all cases, the seemingly small signal generated by hormone binding its receptor is amplified within the cell into a cascade of actions that changes the cell’s physiologic state. Presented below are two examples of second messenger systems commonly used by hormones. The examples used are of glucagon and insulin, both of which ultimately work through a molecular switch involving protein phosphorylation. Be aware that in both cases, a very complex system is being simplified considerably.

Cyclic AMP Second Messenger Systems

Cyclic adenosine monophosphate (cAMP) is a nucleotide generated from ATP through the action of the enzyme adenylate cyclase. The intracellular concentration of cAMP is increased or decreased by a variety of hormones and such fluctuations affect a variety of cellular processes. One prominent and important effect of elevated concentrations of cAMP is the activation of a cAMP-dependent protein kinase called protein kinase A.

Protein kinase A is nominally in a catalytically inactive state but becomes active when it binds cAMP. Upon activation, protein kinase A phosphorylates a number of other proteins, many of which are themselves enzymes that are either activated or suppressed by being phosphorylated. Such changes in enzymatic activity within the cell clearly alter its state.

Now, let’s put this information together to understand the mechanism of action of a hormone-like glucagon

  • Glucagon binds its receptor in the plasma membrane of target cells (e.g. hepatocytes).
  • Bound receptor interacts with and, through a set of G proteins, turns on adenylate cyclase, which is also an integral membrane protein.
  • Activated adenylate cyclase begins to convert ATP to cyclic AMP, resulting in an elevated intracellular concentration of cAMP.
  • High levels of cAMP in the cytosol make it probable that protein kinase A will be bound by cAMP and therefore catalytically active.
  • Active protein kinase A “runs around the cell” adding phosphates to other enzymes, thereby changing their conformation and modulating their catalytic activity – – – abracadabra, the cell has been changed!
  • Levels of cAMP decrease due to destruction by cAMP-phosphodiesterase and the inactivation of adenylate cyclase.

In the above example, the hormone’s action was to modify the activity of pre-existing components in the cell. Elevations in cAMP also have important effects on the transcription of certain genes.

Tyrosine Kinase Second Messenger Systems

The receptors for several protein hormones are themselves protein kinases which are switched on by the binding of hormones. The kinase activity associated with such receptors results in the phosphorylation of tyrosine residues on other proteins. Insulin is an example of a hormone whose receptor is a tyrosine kinase.

The hormone binds to domains exposed on the cell’s surface, resulting in a conformational change that activates kinase domains located in the cytoplasmic regions of the receptor. In many cases, the receptor phosphorylates itself as part of the kinase activation process. The activated receptor phosphorylates a variety of intracellular targets, many of which are enzymes that become activated or are inactivated upon phosphorylations was seen with cAMP second messenger systems, activation of receptor tyrosine kinases leads to rapid modulation in a number of target proteins within the cell. Interestingly, some of the targets of receptor kinases are protein phosphatases which, upon activation by receptor tyrosine kinase, become competent to remove phosphates from other proteins and alter their activity. Again, a seemingly small change due to hormone binding is amplified into a multitude of effects within the cell.
In some cases, the binding of the hormone to a surface receptor induces a tyrosine kinase cascade even though the receptor is not itself a tyrosine kinase. The growth hormone receptor is one example of such a system – the interaction of growth hormone with its receptor leads to activation of cytoplasmic tyrosine kinases, with results conceptually similar to that seen with receptor kinases.

Steroid Hormones

Steroid hormones are made of lipids, such as phospholipids and cholesterol. They are fat-soluble, so they can diffuse across the plasma membrane of target cells and bind with receptors in the cytoplasm of the cell. The steroid hormone and receptor form a complex that moves into the nucleus and influences the expression of genes, essentially acting as a transcription factor. Examples of steroid hormones include cortisol and sex hormones.

Asteroid hormone crosses the plasma membrane of a target cell and binds with a receptor inside the cell.

Non-Steroid Hormones

Non-steroid hormones are made of amino acids. They are not fat-soluble, so they cannot diffuse across the plasma membrane of target cells. Instead, a non-steroid hormone binds to a receptor on the cell membrane. The binding of the hormone triggers an enzyme inside the cell membrane. The enzyme activates another molecule, called the second messenger, which influences processes inside the cell. Most endocrine hormones are non-steroid hormones, including insulin and thyroid hormones.

Direct Gene Activation and the Second-Messenger System

Nuclear receptors function as transcription factors because they can bind to DNA and regulate gene expression.

Key Points

Receptors that can directly influence gene expression are termed nuclear receptors.
Type I nuclear receptors (found in cytosol) are modified to translocate to the nucleus upon hormone binding.

Type II nuclear receptors remain in the nucleus where they often create a complex with co-repressor proteins, which are released upon hormone binding.

Secondary messengers relay signals from receptors on the cell surface to the target molecules.

The secondary messenger systems bind hormones to a receptor that causes a cascade of changes that leads to actions.

Key Terms

nuclear receptor: A class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules, as well as influencing gene expression upon activation.

secondary messenger: Molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus.

hormone response element: A short sequence of DNA within the promoter of a gene that is able to bind a specific hormone-receptor complex and therefore regulate gene expression.

Hormones can alter cell activity by binding with a receptor. Receptors can either directly influence gene expression and thus cell activity, or induce a secondary signaling cascade that will in turn influence cell activity.

Direct Gene Activation

Receptors that can directly influence gene expression are termed nuclear receptors. Located within the cytosol or nucleus, nuclear receptors are the target of steroid and thyroid hormones that are able to pass through the cell membrane. Nuclear receptors can bind directly to DNA to regulate specific gene expressions and are, therefore, classified as transcription factors.

Nuclear receptors can be classified into two broad classes according to their mechanism of action and their sub-cellular distribution in the absence of ligand. Type I nuclear receptors are located in the cytosol. Upon binding to a hormone the receptor and hormone translocate into the nucleus, and bind to specific sequences of DNA known as hormone response elements (HREs).

Type II receptors are retained in the nucleus. In the absence of ligand, type II nuclear receptors often form a complex with co-repressor proteins. Hormone binding to the nuclear receptor results in dissociation of the co-repressor and the recruitment of co-activator proteins.

This figure depicts the mechanism of a class I nuclear receptor (NR) that, in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE).

Lipid soluble hormones directly regulate gene expression: This figure depicts the mechanism of a class I nuclear receptor (NR) that, in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE).

Secondary Messengers

For lipophobic hormones that cannot pass the cellular membrane, activity is mediated and amplified within a cell by the action of second messenger mechanisms (molecules that relay signals from receptors on the cell surface to target molecules inside the cell in the cytoplasm or nucleus).

Most hormone receptors are G protein-coupled receptors. Upon hormone binding, the receptor undergoes a conformational change and exposes a binding site for a G-protein. The G-protein is bound to the inner membrane of the cell and consists of three sub-units: alpha, beta, and gamma.

Upon binding to the receptor, it releases a GTP molecule, at which point the alpha sub-unit of the G-protein breaks free from the beta and gamma sub-units and is able to move along the inner membrane until it contacts another membrane-bound protein: the primary effector.

The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the secondary messenger. The secondary messenger may then activate a secondary effector, whose effects depend on the particular secondary messenger system.

This is a general schematic diagram of second messenger generation following the activation of membrane-bound receptors. 1. The agonist activates the membrane-bound receptor. 2. G-protein is activated and produces an effector. 3. The effector stimulates a second messenger synthesis. 4. The second messenger activates an intercellular process.

Second messenger mechanisms: General schematic of second messenger generation following activation of membrane-bound receptors. 1. The agonist activates the membrane-bound receptor. 2. G-protein is activated and produces an effector. 3. The effector stimulates a second messenger synthesis. 4. The second messenger activates an intercellular process.

Target Cell Specificity

Hormones target a limited number of cells (based on the presence of a specific receptor) as they circulate in the bloodstream.

Key Points

Target cells are cells that are receptive to a secreted hormone.

Target cell activation is
dependent on three factors; the hormone levels in the blood, the receptor levels on the target cell, and hormone–receptor affinity.

Key Terms

target cell: A cell that is receptive to a secreted hormone.

EXAMPLES

An XY fetus will develop along a female pathway if the target cells fail to respond to androgen. This androgen insensitivity occurs when the receptors on the target cells are unable to accept the hormone due to an impairment in receptor shape.

In endocrinology, target cells can refer to the cells where hormones have an effect. Target cells are capable of responding to hormones because they display receptors to which the circulating hormone can bind. In this way, hormones only affect a limited number of cells even though they are transported in the bloodstream throughout the body.

Target cell activation is dependent on three factors:

  • The levels of hormones in the blood.
  • The relative number of hormone receptors on the target cell.
  • The hormone–receptor affinity.

Modulation of these factors can control target cell response. For example, after receptor stimulation, the signaling target cell often sends feedback to the hormone-secreting tissue to down-regulate hormone expression.

Additionally, the target cell can up or down-regulate receptor expression to make it more or less sensitive to the same hormone. Finally, hormone–receptor affinity can be altered by the expression of associated inhibitory or co-activating factors.

In some instances, alterations of receptor structure due to a genetic mutation can lead to a reduction in hormone–receptor affinity, as in the case of androgen insensitivity.

Onset, Duration, and Half-Life of Hormone Activity

A hormone’s half-life and duration of activity are limited and vary from hormone to hormone.

Key Points

The hormone receptors are dynamic structures that vary in number and sensitivity, that depend on the levels of the stimulating hormone.

The blood levels of hormones reflect a balance between secretion and degradation/excretion by the liver and kidneys.

The biological half- life of a hormone is the time it takes for the hormone to lose half of its physiological activity.

The duration of hormone activity refers to the duration of altered cellular behavior triggered by hormone binding.

Key Terms

hormone receptor: A molecule that binds to a specific hormone that triggers alterations in cell activity.

half-life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacological, physiological, or radiological activity.

EXAMPLES

Vitamin D is a hormone that has a half-life of one to two months. If one obtains vitamin D solely through sun (UVB) exposure during the summer months, serum vitamin D levels will be critically low by late winter. This is one reason why current recommendations are to take vitamin D supplements in order to maintain serum vitamin D levels throughout the year.

The number of hormone molecules available for complex formation is usually the key factor that determines the level at which signal transduction pathways are activated. The number of hormone molecules that are available is determined by the concentration of circulating hormones.

Half-Life

The blood levels of hormones reflect a balance between synthesis/secretion and degradation/excretion. The liver and kidneys are the major organs that degrade hormones with breakdown products excreted in urine and feces.

A hormone’s half-life and duration of activity are limited and vary from hormone to hormone. For instance, the biological half-life of luteinizing hormone is 20 minutes, which is shorter than that of a follicle-stimulating hormone (three to four hours), and of human chorionic gonadotropin (24 hours).

A biological half-life or elimination half-life is the time it takes for a substance such as a hormone or a drug to lose half of its pharmacologic or physiologic activity. In a medical context, the half-life may also describe the time it takes for the blood plasma concentration of a substance to halve (plasma half-life) its steady state.

The relationship between the biological and plasma half-lives of a substance can be complex, due to factors including their accumulation in tissues, active metabolites, and receptor interactions.

Duration

The duration of hormone activity refers to the duration of events that were stimulated by hormone-receptor binding. While typically relatively short and measured in minutes or hours, certain events, such as the onset of puberty, are much longer-lasting.

This image depicts the levels of certain hormones during the menstrual cycle, as they correspond to follicular growth and ovulation. Once ovulation starts, the hormone progesterone overtakes the follicle-stimulating hormone, the hormone estrogen, and the luteinizing hormone that were present earlier.

Hormone levels during the menstrual cycle: This image depicts the levels of certain hormones during the menstrual cycle (B), as they correspond to follicular growth and ovulation (A). 1. Follicle-stimulating hormone 2. Estrogen 3. Luteinizing hormone 4. Progesterone.

Mechanism

Growth Hormone

Growth Hormone has a direct and indirect mechanism of action. The direct effect of growth hormone involves growth hormone directly binding to its receptors on target cells to stimulate a response. The indirect effect is mediated by the action of insulin-like growth factor-1(IGF-1), which is secreted by the liver hepatocytes in response to growth hormone. Insulin-like growth factor-1 binds to its receptor, IGF-1R, on the cellular surface and activates a tyrosine kinase-mediated intracellular signaling pathway that phosphorylates various proteins intracellularly leading to increased anabolism, cellular replication and division, and metabolism.

Prolactin

Prolactin initiates its effect by binding to the prolactin receptor found on various tissues across the body, including but not limited to mammillary glands, ovaries, skeletal muscle, uterus, and thymus. Upon the binding of prolactin to its receptor, Jannu kinase 2, a tyrosine kinase is activated that furthermore initiates the JAK-STAT pathway.

FSH & LH

Both LH & FSH bind to G protein-coupled receptors. Upon binding to the receptor, adenylyl cyclase, an enzyme is activated, which goes on to produce cyclic-AMP. The intracellular concentrations of cyclic-AMP rise, which further activates a kinase molecule called protein kinase A. Protein kinase A primarily functions to phosphorylate specific intracellular proteins that then subsequently complete the physiological actions of FSH and LH.

Adrenocorticotropic Hormone

ACTH interacts with G protein-coupled receptors found on the extracellular membranes of the zona fasciculata and zona reticularis of the adrenal cortex. cAMP is the secondary messenger system. Activation of the g-couple receptor activates adenylyl cyclase, thus increase cAMP production and subsequent activation of Protein Kinase A.

Thyroid Stimulating Hormone (TSH)

TSH binds and activates the TSH receptor (TSHR) found on the basolateral surface of thyroid follicle cells. This binding site is a G-protein coupled receptor (GPCR), which couples to both Gs and Gq G-proteins, and hence activating both the cAMP pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second messenger signaling cascades. The Gs pathway activates iodide uptake,  increases thyroid hormone production, and enhances gland growth and differentiation. The Gq pathway is rate-limiting for hormone production by stimulating iodide organification.

Vasopressin

Two regulating receptors, the subfornical organ and the organum vasculum in the hypothalamus, since water deprivation and signal for ADH secretion. A small concentration of vasopressin is sufficient to generate water conservation in the renal tubules. The renal tubules are divided into the proximal, descending, ascending, distal regions, and the collecting duct. The most ADH-dependent segment of the renal tubule is the collecting duct, which has ADH receptors on its basolateral side for ADH to bind and stimulate the Gs protein. The Gs protein stimulates adenylyl cyclase, which further converts ATP into cAMP. High levels of cAMP cause the phosphorylation of protein kinase A, subsequently opening water channels known as aquaporins to allow passage of water from the luminal side to the basolateral side.

Oxytocin

Oxytocin binds to its extracellular receptor present in the myometrium of the uterus, which then activates the Gq protein further leading to activation of phospholipase C. The phospholipase C functions to break down the phosphoinositol diphosphate into two components, Inositol triphosphate (IP3) which will release calcium from the sarcoplasmic reticulum and diacylglycerol (DAG) which will activate protein kinase C. The protein kinase C phosphorylates proteins specifically on the cell membrane to allow calcium entry from the extracellular space. The increased intracellular calcium generates enough energy to cause the contraction of the uterus.

During lactation, when the newborn suckles, it transmits signals to the central nervous system to release oxytocin, a process known as the “milk letdown reflex.” The oxytocin binds to the breast myoepithelial cell receptors and initiates the same Gq cascade similar to uterine contraction, and ejects milk into the baby’s oral cavity.

References

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What are the symptoms of thyroid in females?

What are the symptoms of thyroid in females?/Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. 

The thyroid gland produces three hormones:

  • Triiodothyronine, also known as T3
  • Tetraiodothyronine also called thyroxine or T4
  • Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Thyroid Hormone - Types, Functions, Clinical Significance

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation.

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

  • Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
  • Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
  • Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
    • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
    • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
    • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
  • Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
  • Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
    • Thyrocytes uptake iodinated thyroglobulin via endocytosis
    • Lysosome fuse with the endosome containing iodinated thyroglobulin
    • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
    • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. 
    • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. 

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

  • Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
  • Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
  • Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
  • Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
  • Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.

Thyroid Hormone - Types, Functions, Clinical Significance

Functions

The physiological effects of thyroid hormones are listed below

  • Increases the basal metabolic rate
  • Depending on the metabolic status it can induce lipolysis or lipid synthesis
  • Stimulate the metabolism of carbohydrates
  • Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
  • Permissive effect on catecholamines
  • In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
  • The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
  • Thyroid hormone affects fertility, ovulation, and menstruation
  • Regulate the rate at which calories are burned, affecting weight loss or weight gain.
  • Can slow down or speed up the heartbeat.
  • Can raise or lower body temperature.
  • Influence the rate at which food moves through the digestive tract.
  • Control the way muscles contract.
  • Control the rate at which dying cells are replaced.


Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. 

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. 

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

  • Feeling cold when other people do not
  • Constipation
  • Muscle weakness
  • Weight gain, even though you are not eating more food
  • Joint or muscle pain
  • Feeling sad or depressed
  • Feeling very tired
  • Pale, dry skin
  • Dry, thinning hair
  • Slow heart rate
  • Less sweating than usual
  • A puffy face
  • A hoarse voice
  • More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

  • Bradycardia
  • Fatigue
  • Cold intolerance
  • Weight gain
  • Poor appetite
  • Hair loss
  • Cold and dry skin
  • Constipation
  • Myopathy, stiffness, cramps, entrapment syndromes
  • Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

  • Myxedematous heart disease
  • Puffy appearance with doughy skin texture
  • Hoarse voice with difficulty articulate words
  • Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

  • Amenorrhea or menorrhagia
  • Galactorrhea
  • Erectile dysfunction, infertility in men
  • Decreased libido

Other symptoms:

  • Depression
  • Impaired concentration and memory
  • Goiter
  • Hypertension

Congenital hypothyroidism:

  • Umbilical hernia
  • Hypotonia
  • Prolonged neonatal jaundice
  • Poor feeding, absence of thirst (adipsia)
  • Decreased activity
  • Pot-belly, puffy-face, protuberant tongue
  • Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

  • Heat intolerance
  • Weight loss
  • Increased appetite
  • Increased sweating from cutaneous blood flow increase
  • Weakness
  • Fatigue
  • Onycholysis (separation of nails from nail beds)
  • Pretibial myxedema
  • Weight loss, even if you eat the same or more food (most but not all people lose weight)
  • Eating more than usual
  • Rapid or irregular heartbeat or pounding of your heart
  • Feeling nervous or anxious
  • Feeling irritable
  • Trouble sleeping
  • Trembling in your hands and fingers
  • Increased sweating
  • Feeling hot when other people do not
  • Muscle weakness
  • Diarrhea or more bowel movements than normal
  • Fewer and lighter menstrual periods than normal
  • Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

  • Lid lag (when looking down, sclera visible above cornea)
  • Lid retraction (when looking straight, sclera visible above the cornea)
  • Graves ophthalmopathy

Goiter

  • Diffuse, smooth, non-tender goiter
  • The audible bruit can be heard at the superior poles

Cardiovascular

  • Tachycardia (can be masked by patients taking beta-blockers)
  • Palpitations
  • An irregular pulse from atrial fibrillation
  • Hypertension
  • Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
  • Heart failure (elderly patients)
  • Chest pain
  • Abnormal heart rhythms

Musculoskeletal

  • Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
  • Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
  • Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

  • Restlessness
  • Anxiety
  • Depression
  • Emotional instability
  • Insomnia
  • Tremoulousness
  • Hyperreflexia

Conditions associated with hypothyroidism

  • Iodine deficiency 
  • Cretinism 
  • Wolff-Chaikoff effect 
  • Subacute thyroiditis 
  • Postpartum thyroiditis 
  • Riedel thyroiditis 
  • Hashimoto thyroiditis 
  • Drug-induced 

Conditions associated with hyperthyroidism

  • Graves disease 
  • Iodine excess 
  • Struma ovarii 
  • Thyrotropic pituitary adenoma 
  • Job-Basedow phenomenon
  • Drug-induced: amiodarone, lithium 
  • Thyrotoxicosis and thyroid storm 
  • Toxic multinodular goiter 
  • Thyroid adenoma 

Antithyroid drugs that work in the thyroid gland 

  • Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
  • Thionamides – inhibits TPO – block thyroid hormone synthesis
  • Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
  • Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

  • Propylthiouracil (ethionamide)
  • Dexamethasone
  • Amiodarone
  • Propranolol

Thyroid Conditions

  • Goiter – A general term for thyroid swelling. Goiters can be harmless or can represent iodine deficiency or a condition associated with thyroid inflammation called Hashimoto’s thyroiditis.
  • Thyroiditis – Inflammation of the thyroid, usually from a viral infection or autoimmune condition. Thyroiditis can be painful or have no symptoms at all. This disorder can be either painful or not felt at all. In thyroiditis, the thyroid releases hormones that were stored there. This can last for a few weeks or months.
  • Hyperthyroidism – Excessive thyroid hormone production. Hyperthyroidism is most often caused by Graves disease or an overactive thyroid nodule.
  • Hypothyroidism – low production of thyroid hormone. Thyroid damage caused by autoimmune disease is the most common cause of hypothyroidism.
  • Graves disease – An autoimmune condition in which the thyroid is overstimulated, causing hyperthyroidism.
  • Thyroid cancer – An uncommon form of cancer, thyroid cancer is usually curable. Surgery, radiation, and hormone treatments may be used to treat thyroid cancer.
  • Thyroid nodule – A small abnormal mass or lump in the thyroid gland. Thyroid nodules are extremely common. Few are cancerous. They may secrete excess hormones, causing hyperthyroidism, or cause no problems.
  • Thyroid storm – A rare form of hyperthyroidism in which extremely high thyroid hormone levels cause severe illness.
  • Nodules – Hyperthyroidism can be caused by nodules that are overactive within the thyroid. A single nodule is called a toxic autonomously functioning thyroid nodule, while a gland with several nodules is called a toxic multi-nodular goiter.
  • Excessive iodine – When you have too much iodine (the mineral that is used to make thyroid hormones) in your body, the thyroid makes more thyroid hormones than it needs. Excessive iodine can be found in some medications (amiodarone, a heart medication) and cough syrups.
  • Hashimoto’s thyroiditis – A painless disease, Hashimoto’s thyroiditis is an autoimmune condition where the body’s cells attack and damage the thyroid. This is an inherited condition.
  • Postpartum thyroiditis – This condition occurs in 5% to 9% of women after childbirth. It’s usually a temporary condition.
  • Iodine deficiency – Iodine is used by the thyroid to produce hormones. An iodine deficiency is an issue that affects several million people around the world.
  • A non-functioning thyroid gland – Sometimes, the thyroid gland doesn’t work correctly from birth. This affects about 1 in 4,000 newborns. If left untreated, the child could have both physical and mental issues in the future. All newborns are given a screening blood test in the hospital to check their thyroid function.

Thyroid Tests

  • Anti-TPO antibodies – In autoimmune thyroid disease, proteins mistakenly attack the thyroid peroxidase enzyme, which is used by the thyroid to make thyroid hormones.
  • Thyroid ultrasound – A probe is placed on the skin of the neck, and reflected sound waves can detect abnormal areas of thyroid tissue.
  • Thyroid scan – A small amount of radioactive iodine is given by mouth to get images of the thyroid gland. Radioactive iodine is concentrated within the thyroid gland.
  • Thyroid biopsy – A small amount of thyroid tissue is removed, usually to look for thyroid cancer. A thyroid biopsy is typically done with a needle.
  • Thyroid-stimulating hormone (TSH) – secreted by the brain, TSH regulates thyroid hormone release. A blood test with high TSH indicates low levels of thyroid hormone (hypothyroidism), and low TSH suggests hyperthyroidism. It is produced in the pituitary gland and regulates the balance of thyroid hormones — including T4 and T3 — in the bloodstream. This is usually the first test your provider will do to check for thyroid hormone imbalance. Most of the time, thyroid hormone deficiency (hypothyroidism) is associated with an elevated TSH level, while thyroid hormone excess (hyperthyroidism) is associated with a low TSH level. If TSH is abnormal, measurement of thyroid hormones directly, including thyroxine (T4) and triiodothyronine (T3) may be done to further evaluate the problem. Normal TSH range for an adult: 0.40 – 4.50 mIU/mL (milli-international units per liter of blood).
  • T4 Thyroxine tests – for hypothyroidism and hyperthyroidism, and used to monitor treatment of thyroid disorders. Low T4 is seen with hypothyroidism, whereas high T4 levels may indicate hyperthyroidism. Normal T4 range for an adult: 5.0 – 11.0 ug/dL (micrograms per deciliter of blood).
  • FT4 Free T4 or free thyroxine is a method of measuring T4 that eliminates the effect of proteins that naturally bind T4 and may prevent accurate measurement. Normal FT4 range for an adult: 0.9 – 1.7 ng/dL (nanograms per deciliter of blood)
  • T3 Triiodothyronine tests–  help diagnose hyperthyroidism or to show the severity of hyperthyroidism. Low T3 levels can be observed in hypothyroidism, but more often this test is useful in the diagnosis and management of hyperthyroidism, where T3 levels are elevated. Normal T3 range: 100 – 200 ng/dL (nanograms per deciliter of blood).
  • FT3 Free T3 or free triiodothyronine – is a method of measuring T3 that eliminates the effect of proteins that naturally bind T3 and may prevent accurate measurement. Normal FT3 range: 2.3 – 4.1 pg/mL (picograms per milliliter of blood)
  • T3 and T4 (thyroxine) – The primary forms of thyroid hormone, checked with a blood test.
  • Thyroglobulins – A substance secreted by the thyroid that can be used as a marker of thyroid cancer. It is often measured during follow-up in patients with thyroid cancer. High levels indicate recurrence of the cancer.
  • Other imaging tests – If thyroid cancer has spread (metastasized), tests such as CT scans, MRI scans, or PET scans can help identify the extent of spread.

Related Testing

  • Hypothalamus releases thyrotropin-releasing hormone (TRH) – which stimulates the secretion of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH through a negative feedback loop. As a result, T3 and T4 secretion, and iodine uptake are reduced. Other hormones, such as somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and exercise increase TRH release.
  • TSH and free thyroxine (free T4) test – These determine whether the abnormality arises centrally from the thyroid gland (primary), peripherally from the pituitary (secondary), or hypothalamus (tertiary). In primary hypothyroidism is suspected, the thyroid gland is not releasing enough thyroid hormones. Therefore, TSH levels will be appropriately elevated, while free T4 levels will be lower. In primary hyperthyroidism, free T4 levels abnormally increased, and TSH levels will be appropriately decreased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis, respectively.
  • Thyroid-binding globulin production – is increased because of estrogen and beta-human chorionic gonadotropin (beta-HCG). More free T4 will be bound to TGB, leading to increased production of T4. TSH levels and free T4 levels will normalize, and total T4 will increase. Therefore, laboratory values will show normal TSH, normal free T4, and elevated total T4. 

Additional blood tests might include

  • Thyroid antibodies – These tests help identify different types of autoimmune thyroid conditions. Common thyroid antibody tests include microsomal antibodies (also known as thyroid peroxidase antibodies or TPO antibodies), thyroglobulin antibodies (also known as TG antibodies), and thyroid receptor antibodies (includes thyroid-stimulating immunoglobulins [TSI] and thyroid blocking immunoglobulins [TBI]).
  • Calcitonin – This test is used to diagnose C-cell hyperplasia and medullary thyroid cancer, both of which are rare thyroid disorders.
  • Thyroglobulin – This test is used to diagnose thyroiditis (thyroid inflammation) and to monitor the treatment of thyroid cancer.

Thyroid Treatments

  • Thyroid surgery (thyroidectomy) – A surgeon removes all or part of the thyroid in an operation. Thyroidectomy is performed for thyroid cancer, goiter,  or hyperthyroidism.
  • Antithyroid medications – Drugs can slow down the overproduction of thyroid hormone in hyperthyroidism. Two common antithyroid medicines are methimazole and propylthiouracil.
  • Radioactive iodine – Iodine with radioactivity that can be used in low doses to test the thyroid gland or destroy an overactive gland. Large doses can be used to destroy cancerous tissue.
  • External radiation – A beam of radiation is directed at the thyroid, on multiple appointments. The high-energy rays help kill thyroid cancer cells.
  • Thyroid hormone pills – Daily treatment that replaces the amount of thyroid hormone you can no longer make. Thyroid hormone pills treat hypothyroidism and are also used to help prevent thyroid cancer from coming back after treatment.
  • Recombinant human TSH – Injecting this thyroid-stimulating agent can make thyroid cancer show up more clearly on imaging tests
  • Anti-thyroid drugs (methimazole and propylthiouracil) – Are medications that stop your thyroid from making hormones.
  • Levothyroxine – is the standard of care in thyroid hormone replacement therapy and treatment of hypothyroidism. Levothyroxine (also called LT4) is equivalent to the T4 form of naturally occurring thyroid hormone and is available in generic and brand name forms. To optimize absorption of your thyroid medication, it should be taken with water at a regular time each day. Multiple medications and supplements decrease absorption of thyroid hormone and should be taken 3-4 hours apart, including calcium and iron supplements, proton pump inhibitors, soy, and multivitamins with minerals. Because of the way levothyroxine is metabolized by the body, your doctor may ask you to take an extra pill or skip a pill on some days of the week. This helps us to fine-tune your medication dose for your body and should be guided by an endocrinologist.
  • Liothyronine – is a replacement T3 (triiodothyronine) thyroid hormone. This medication has a short half-life and is taken twice per day or in combination with levothyroxine. Liothyronine alone is not used for the treatment of hypothyroidism long term.
  • Other formulations of thyroid hormone replacement include natural or desiccated thyroid hormone extracts from animal sources. Natural or desiccated thyroid extract preparations have greater variability in the dose of thyroid hormone between batches and imbalanced ratios if T4 vs T3. Natural or animal sources of thyroid hormone typically contain 75% T4 and 25% T3, compared to the normal human balance of 95% T4 and 5% T3. Treatment with a correct balance of T4 and T3 is important to replicate normal thyroid function and prevent adverse effects of excess T3, including osteoporosis, heart problems, and mood and sleep disturbance. An endocrinologist can evaluate symptoms and thyroid tests to help balance thyroid hormone medications.


A LISTING OF THE FDA-APPROVED MEDICINES
PRODUCT
FDA RATING
MANUFACTURER
Unithroid®
AB
(Stevens)*+
L-Thyroxin
AB
(Mylan) *#
Levo-T®
BX
(Alara)
Levoxyl®
BX
(Jones)*
Novothyrox®
BX
(GenPharm)
Synthroid®
BX
(Abbott)*
Levothroid®
BX
(Forest/ Lloyd)*
Levolet®
BX
(Vintage)
Tirosint®
None
(IBSA)
LEGEND:
AB = interchangeable
BX = not interchangeable
* = currently available
+ = This is BX rated vs the other name brand LT4s
# = This is AB rated only to Unithroid and is considered the only “generic”.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones – While not strictly necessary for life, thyroid hormones have profound effects on many “big time” physiologic processes, such as development, growth, and metabolism, and deficiency in thyroid hormones is not compatible with normal health. Additionally, many of the effects of thyroid hormone have been delineated by the study of deficiency and excess states, as discussed briefly below.

Metabolism – Thyroid hormones stimulate diverse metabolic activities in most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smoldering fire. A few examples of specific metabolic effects of thyroid hormones include:

  • Lipid metabolism – Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance the oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels – one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
  • Carbohydrate metabolism – Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth – Thyroid hormones are clearly necessary for normal growth in children and young animals, as evidenced by the growth-retardation observed in thyroid deficiency. Not surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone, a clear indication that complex physiologic processes like growth depend upon multiple endocrine controls.

Development – A classical experiment in endocrinology was the demonstration that tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain.

Other Effects – As mentioned above, there do not seem to be organs and tissues that are not affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

  • Cardiovascular system Thyroid hormones increase heart rate, cardiac contractility, and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs.
  • Central nervous system – Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.
  • Reproductive system –  Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility.


How long does it take to recover from thyroid surgery (thyroidectomy)?

It will take your body a few weeks to recover after your thyroid is surgically removed (thyroidectomy). During this time you should avoid a few things, including:

  • Submerging your incision underwater.
  • Lifting an object that’s heavier than 15 pounds.
  • Doing more than light exercise.

This generally lasts for about two weeks. After that, you can return to your normal activities.

How long after my thyroid is removed will my tiredness go away?

Typically, you will be given medication to help with your symptoms right after surgery. Your body actually has thyroid hormone still circulating throughout it, even after the thyroid has been removed. The hormones can still be in your body for two to three weeks. Medication will reintroduce new hormones into your body after the thyroid has been removed. If you are still feeling tired after surgery, remember that this can be a normal part of recovering from any type of surgery. It takes time for your body to heal. Talk to your healthcare provider if you are still experiencing fatigue and other symptoms of thyroid disease after surgery.

If part of my thyroid is surgically removed, will the other part be able to make enough thyroid hormones to keep me off of medication?

Sometimes, your surgeon may be able to remove part of your thyroid and leave the other part so that it can continue to create and release thyroid hormones. This is most likely in situations where you have a nodule that’s causing your thyroid problem. About 75% of people who have only one side of the thyroid removed are able to make enough thyroid hormone after surgery without hormone replacement therapy.

Can I check my thyroid at home?

You can do a quick and easy self-exam of your thyroid at home. The only tools you need to do this self-exam are a mirror and a glass of water.

To do the thyroid self-exam, follow these steps:

  • Start by identifying where your thyroid is located. Generally, you’ll find the thyroid on the front of your neck, between your collar bone and Adam’s apple. In men, Adam’s apple is much easier to see. For women, it’s usually easiest to look from the collar bone up.
  • Tip your head back while looking in a mirror. Look at your neck and try to hone in on the space you will be looking for once you start the exam.
  • Once you’re ready, take a drink of water while your head is tilted back. Watch your thyroid as you swallow. During this test, you’re looking for lumps or bumps. You may be able to see them when you swallow the water.

Repeat this test a few times to get a good look at your thyroid. If you see any lumps or bumps, reach out to your healthcare provider.

Should I exercise if I have thyroid disease?

Regular exercise is an important part of a healthy lifestyle. You do not need to change your exercise routine if you have thyroid disease. Exercise does not drain your body’s thyroid hormones and it shouldn’t hurt you to exercise. It is important to talk to your healthcare provider before you start a new exercise routine to make sure that it’s a good fit for you.

Can I live a normal life with thyroid disease?

Thyroid disease is often a life-long medical condition that you will need to manage constantly. This often involves a daily medication. Your healthcare provider will monitor your treatments and make adjustments over time. However, you can usually live a normal life with a thyroid disease. It may take some time to find the right treatment option for you and control your hormone levels, but then people with these types of conditions can usually live life without many restrictions.

References

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What is the main function of thyroid hormone?

What is the main function of the thyroid hormone? Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. 

The thyroid gland produces three hormones:

  • Triiodothyronine, also known as T3
  • Tetraiodothyronine also called thyroxine or T4
  • Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Thyroid Hormone - Types, Functions, Clinical Significance

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation.

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

  • Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
  • Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
  • Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
    • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
    • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
    • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
  • Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
  • Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
    • Thyrocytes uptake iodinated thyroglobulin via endocytosis
    • Lysosome fuse with the endosome containing iodinated thyroglobulin
    • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
    • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. 
    • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. 

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

  • Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
  • Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
  • Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
  • Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
  • Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.

Thyroid Hormone - Types, Functions, Clinical Significance

Functions

The physiological effects of thyroid hormones are listed below

  • Increases the basal metabolic rate
  • Depending on the metabolic status it can induce lipolysis or lipid synthesis
  • Stimulate the metabolism of carbohydrates
  • Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
  • Permissive effect on catecholamines
  • In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
  • The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
  • Thyroid hormone affects fertility, ovulation, and menstruation
  • Regulate the rate at which calories are burned, affecting weight loss or weight gain.
  • Can slow down or speed up the heartbeat.
  • Can raise or lower body temperature.
  • Influence the rate at which food moves through the digestive tract.
  • Control the way muscles contract.
  • Control the rate at which dying cells are replaced.


Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. 

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. 

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

  • Feeling cold when other people do not
  • Constipation
  • Muscle weakness
  • Weight gain, even though you are not eating more food
  • Joint or muscle pain
  • Feeling sad or depressed
  • Feeling very tired
  • Pale, dry skin
  • Dry, thinning hair
  • Slow heart rate
  • Less sweating than usual
  • A puffy face
  • A hoarse voice
  • More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

  • Bradycardia
  • Fatigue
  • Cold intolerance
  • Weight gain
  • Poor appetite
  • Hair loss
  • Cold and dry skin
  • Constipation
  • Myopathy, stiffness, cramps, entrapment syndromes
  • Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

  • Myxedematous heart disease
  • Puffy appearance with doughy skin texture
  • Hoarse voice with difficulty articulate words
  • Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

  • Amenorrhea or menorrhagia
  • Galactorrhea
  • Erectile dysfunction, infertility in men
  • Decreased libido

Other symptoms:

  • Depression
  • Impaired concentration and memory
  • Goiter
  • Hypertension

Congenital hypothyroidism:

  • Umbilical hernia
  • Hypotonia
  • Prolonged neonatal jaundice
  • Poor feeding, absence of thirst (adipsia)
  • Decreased activity
  • Pot-belly, puffy-face, protuberant tongue
  • Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

  • Heat intolerance
  • Weight loss
  • Increased appetite
  • Increased sweating from cutaneous blood flow increase
  • Weakness
  • Fatigue
  • Onycholysis (separation of nails from nail beds)
  • Pretibial myxedema
  • Weight loss, even if you eat the same or more food (most but not all people lose weight)
  • Eating more than usual
  • Rapid or irregular heartbeat or pounding of your heart
  • Feeling nervous or anxious
  • Feeling irritable
  • Trouble sleeping
  • Trembling in your hands and fingers
  • Increased sweating
  • Feeling hot when other people do not
  • Muscle weakness
  • Diarrhea or more bowel movements than normal
  • Fewer and lighter menstrual periods than normal
  • Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

  • Lid lag (when looking down, sclera visible above cornea)
  • Lid retraction (when looking straight, sclera visible above the cornea)
  • Graves ophthalmopathy

Goiter

  • Diffuse, smooth, non-tender goiter
  • The audible bruit can be heard at the superior poles

Cardiovascular

  • Tachycardia (can be masked by patients taking beta-blockers)
  • Palpitations
  • An irregular pulse from atrial fibrillation
  • Hypertension
  • Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
  • Heart failure (elderly patients)
  • Chest pain
  • Abnormal heart rhythms

Musculoskeletal

  • Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
  • Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
  • Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

  • Restlessness
  • Anxiety
  • Depression
  • Emotional instability
  • Insomnia
  • Tremoulousness
  • Hyperreflexia

Conditions associated with hypothyroidism

  • Iodine deficiency 
  • Cretinism 
  • Wolff-Chaikoff effect 
  • Subacute thyroiditis 
  • Postpartum thyroiditis 
  • Riedel thyroiditis 
  • Hashimoto thyroiditis 
  • Drug-induced 

Conditions associated with hyperthyroidism

  • Graves disease 
  • Iodine excess 
  • Struma ovarii 
  • Thyrotropic pituitary adenoma 
  • Job-Basedow phenomenon
  • Drug-induced: amiodarone, lithium 
  • Thyrotoxicosis and thyroid storm 
  • Toxic multinodular goiter 
  • Thyroid adenoma 

Antithyroid drugs that work in the thyroid gland 

  • Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
  • Thionamides – inhibits TPO – block thyroid hormone synthesis
  • Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
  • Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

  • Propylthiouracil (ethionamide)
  • Dexamethasone
  • Amiodarone
  • Propranolol

Thyroid Conditions

  • Goiter – A general term for thyroid swelling. Goiters can be harmless or can represent iodine deficiency or a condition associated with thyroid inflammation called Hashimoto’s thyroiditis.
  • Thyroiditis – Inflammation of the thyroid, usually from a viral infection or autoimmune condition. Thyroiditis can be painful or have no symptoms at all. This disorder can be either painful or not felt at all. In thyroiditis, the thyroid releases hormones that were stored there. This can last for a few weeks or months.
  • Hyperthyroidism – Excessive thyroid hormone production. Hyperthyroidism is most often caused by Graves disease or an overactive thyroid nodule.
  • Hypothyroidism – low production of thyroid hormone. Thyroid damage caused by autoimmune disease is the most common cause of hypothyroidism.
  • Graves disease – An autoimmune condition in which the thyroid is overstimulated, causing hyperthyroidism.
  • Thyroid cancer – An uncommon form of cancer, thyroid cancer is usually curable. Surgery, radiation, and hormone treatments may be used to treat thyroid cancer.
  • Thyroid nodule – A small abnormal mass or lump in the thyroid gland. Thyroid nodules are extremely common. Few are cancerous. They may secrete excess hormones, causing hyperthyroidism, or cause no problems.
  • Thyroid storm – A rare form of hyperthyroidism in which extremely high thyroid hormone levels cause severe illness.
  • Nodules – Hyperthyroidism can be caused by nodules that are overactive within the thyroid. A single nodule is called a toxic autonomously functioning thyroid nodule, while a gland with several nodules is called a toxic multi-nodular goiter.
  • Excessive iodine – When you have too much iodine (the mineral that is used to make thyroid hormones) in your body, the thyroid makes more thyroid hormones than it needs. Excessive iodine can be found in some medications (amiodarone, a heart medication) and cough syrups.
  • Hashimoto’s thyroiditis – A painless disease, Hashimoto’s thyroiditis is an autoimmune condition where the body’s cells attack and damage the thyroid. This is an inherited condition.
  • Postpartum thyroiditis – This condition occurs in 5% to 9% of women after childbirth. It’s usually a temporary condition.
  • Iodine deficiency – Iodine is used by the thyroid to produce hormones. An iodine deficiency is an issue that affects several million people around the world.
  • A non-functioning thyroid gland – Sometimes, the thyroid gland doesn’t work correctly from birth. This affects about 1 in 4,000 newborns. If left untreated, the child could have both physical and mental issues in the future. All newborns are given a screening blood test in the hospital to check their thyroid function.

Thyroid Tests

  • Anti-TPO antibodies – In autoimmune thyroid disease, proteins mistakenly attack the thyroid peroxidase enzyme, which is used by the thyroid to make thyroid hormones.
  • Thyroid ultrasound – A probe is placed on the skin of the neck, and reflected sound waves can detect abnormal areas of thyroid tissue.
  • Thyroid scan – A small amount of radioactive iodine is given by mouth to get images of the thyroid gland. Radioactive iodine is concentrated within the thyroid gland.
  • Thyroid biopsy – A small amount of thyroid tissue is removed, usually to look for thyroid cancer. A thyroid biopsy is typically done with a needle.
  • Thyroid-stimulating hormone (TSH) – secreted by the brain, TSH regulates thyroid hormone release. A blood test with high TSH indicates low levels of thyroid hormone (hypothyroidism), and low TSH suggests hyperthyroidism. It is produced in the pituitary gland and regulates the balance of thyroid hormones — including T4 and T3 — in the bloodstream. This is usually the first test your provider will do to check for thyroid hormone imbalance. Most of the time, thyroid hormone deficiency (hypothyroidism) is associated with an elevated TSH level, while thyroid hormone excess (hyperthyroidism) is associated with a low TSH level. If TSH is abnormal, measurement of thyroid hormones directly, including thyroxine (T4) and triiodothyronine (T3) may be done to further evaluate the problem. Normal TSH range for an adult: 0.40 – 4.50 mIU/mL (milli-international units per liter of blood).
  • T4 Thyroxine tests – for hypothyroidism and hyperthyroidism, and used to monitor treatment of thyroid disorders. Low T4 is seen with hypothyroidism, whereas high T4 levels may indicate hyperthyroidism. Normal T4 range for an adult: 5.0 – 11.0 ug/dL (micrograms per deciliter of blood).
  • FT4 Free T4 or free thyroxine is a method of measuring T4 that eliminates the effect of proteins that naturally bind T4 and may prevent accurate measurement. Normal FT4 range for an adult: 0.9 – 1.7 ng/dL (nanograms per deciliter of blood)
  • T3 Triiodothyronine tests–  help diagnose hyperthyroidism or to show the severity of hyperthyroidism. Low T3 levels can be observed in hypothyroidism, but more often this test is useful in the diagnosis and management of hyperthyroidism, where T3 levels are elevated. Normal T3 range: 100 – 200 ng/dL (nanograms per deciliter of blood).
  • FT3 Free T3 or free triiodothyronine – is a method of measuring T3 that eliminates the effect of proteins that naturally bind T3 and may prevent accurate measurement. Normal FT3 range: 2.3 – 4.1 pg/mL (picograms per milliliter of blood)
  • T3 and T4 (thyroxine) – The primary forms of thyroid hormone, checked with a blood test.
  • Thyroglobulins – A substance secreted by the thyroid that can be used as a marker of thyroid cancer. It is often measured during follow-up in patients with thyroid cancer. High levels indicate recurrence of the cancer.
  • Other imaging tests – If thyroid cancer has spread (metastasized), tests such as CT scans, MRI scans, or PET scans can help identify the extent of spread.

Related Testing

  • Hypothalamus releases thyrotropin-releasing hormone (TRH) – which stimulates the secretion of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH through a negative feedback loop. As a result, T3 and T4 secretion, and iodine uptake are reduced. Other hormones, such as somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and exercise increase TRH release.
  • TSH and free thyroxine (free T4) test – These determine whether the abnormality arises centrally from the thyroid gland (primary), peripherally from the pituitary (secondary), or hypothalamus (tertiary). In primary hypothyroidism is suspected, the thyroid gland is not releasing enough thyroid hormones. Therefore, TSH levels will be appropriately elevated, while free T4 levels will be lower. In primary hyperthyroidism, free T4 levels abnormally increased, and TSH levels will be appropriately decreased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis, respectively.
  • Thyroid-binding globulin production – is increased because of estrogen and beta-human chorionic gonadotropin (beta-HCG). More free T4 will be bound to TGB, leading to increased production of T4. TSH levels and free T4 levels will normalize, and total T4 will increase. Therefore, laboratory values will show normal TSH, normal free T4, and elevated total T4. 

Additional blood tests might include

  • Thyroid antibodies – These tests help identify different types of autoimmune thyroid conditions. Common thyroid antibody tests include microsomal antibodies (also known as thyroid peroxidase antibodies or TPO antibodies), thyroglobulin antibodies (also known as TG antibodies), and thyroid receptor antibodies (includes thyroid-stimulating immunoglobulins [TSI] and thyroid blocking immunoglobulins [TBI]).
  • Calcitonin – This test is used to diagnose C-cell hyperplasia and medullary thyroid cancer, both of which are rare thyroid disorders.
  • Thyroglobulin – This test is used to diagnose thyroiditis (thyroid inflammation) and to monitor the treatment of thyroid cancer.

Thyroid Treatments

  • Thyroid surgery (thyroidectomy) – A surgeon removes all or part of the thyroid in an operation. Thyroidectomy is performed for thyroid cancer, goiter,  or hyperthyroidism.
  • Antithyroid medications – Drugs can slow down the overproduction of thyroid hormone in hyperthyroidism. Two common antithyroid medicines are methimazole and propylthiouracil.
  • Radioactive iodine – Iodine with radioactivity that can be used in low doses to test the thyroid gland or destroy an overactive gland. Large doses can be used to destroy cancerous tissue.
  • External radiation – A beam of radiation is directed at the thyroid, on multiple appointments. The high-energy rays help kill thyroid cancer cells.
  • Thyroid hormone pills – Daily treatment that replaces the amount of thyroid hormone you can no longer make. Thyroid hormone pills treat hypothyroidism and are also used to help prevent thyroid cancer from coming back after treatment.
  • Recombinant human TSH – Injecting this thyroid-stimulating agent can make thyroid cancer show up more clearly on imaging tests
  • Anti-thyroid drugs (methimazole and propylthiouracil) – Are medications that stop your thyroid from making hormones.
  • Levothyroxine – is the standard of care in thyroid hormone replacement therapy and treatment of hypothyroidism. Levothyroxine (also called LT4) is equivalent to the T4 form of naturally occurring thyroid hormone and is available in generic and brand name forms. To optimize absorption of your thyroid medication, it should be taken with water at a regular time each day. Multiple medications and supplements decrease absorption of thyroid hormone and should be taken 3-4 hours apart, including calcium and iron supplements, proton pump inhibitors, soy, and multivitamins with minerals. Because of the way levothyroxine is metabolized by the body, your doctor may ask you to take an extra pill or skip a pill on some days of the week. This helps us to fine-tune your medication dose for your body and should be guided by an endocrinologist.
  • Liothyronine – is a replacement T3 (triiodothyronine) thyroid hormone. This medication has a short half-life and is taken twice per day or in combination with levothyroxine. Liothyronine alone is not used for the treatment of hypothyroidism long term.
  • Other formulations of thyroid hormone replacement include natural or desiccated thyroid hormone extracts from animal sources. Natural or desiccated thyroid extract preparations have greater variability in the dose of thyroid hormone between batches and imbalanced ratios if T4 vs T3. Natural or animal sources of thyroid hormone typically contain 75% T4 and 25% T3, compared to the normal human balance of 95% T4 and 5% T3. Treatment with a correct balance of T4 and T3 is important to replicate normal thyroid function and prevent adverse effects of excess T3, including osteoporosis, heart problems, and mood and sleep disturbance. An endocrinologist can evaluate symptoms and thyroid tests to help balance thyroid hormone medications.


A LISTING OF THE FDA-APPROVED MEDICINES
PRODUCT
FDA RATING
MANUFACTURER
Unithroid®
AB
(Stevens)*+
L-Thyroxin
AB
(Mylan) *#
Levo-T®
BX
(Alara)
Levoxyl®
BX
(Jones)*
Novothyrox®
BX
(GenPharm)
Synthroid®
BX
(Abbott)*
Levothroid®
BX
(Forest/ Lloyd)*
Levolet®
BX
(Vintage)
Tirosint®
None
(IBSA)
LEGEND:
AB = interchangeable
BX = not interchangeable
* = currently available
+ = This is BX rated vs the other name brand LT4s
# = This is AB rated only to Unithroid and is considered the only “generic”.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones – While not strictly necessary for life, thyroid hormones have profound effects on many “big time” physiologic processes, such as development, growth, and metabolism, and deficiency in thyroid hormones is not compatible with normal health. Additionally, many of the effects of thyroid hormone have been delineated by the study of deficiency and excess states, as discussed briefly below.

Metabolism – Thyroid hormones stimulate diverse metabolic activities in most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smoldering fire. A few examples of specific metabolic effects of thyroid hormones include:

  • Lipid metabolism – Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance the oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels – one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
  • Carbohydrate metabolism – Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth – Thyroid hormones are clearly necessary for normal growth in children and young animals, as evidenced by the growth-retardation observed in thyroid deficiency. Not surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone, a clear indication that complex physiologic processes like growth depend upon multiple endocrine controls.

Development – A classical experiment in endocrinology was the demonstration that tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain.

Other Effects – As mentioned above, there do not seem to be organs and tissues that are not affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

  • Cardiovascular system Thyroid hormones increase heart rate, cardiac contractility, and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs.
  • Central nervous system – Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.
  • Reproductive system –  Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility.


How long does it take to recover from thyroid surgery (thyroidectomy)?

It will take your body a few weeks to recover after your thyroid is surgically removed (thyroidectomy). During this time you should avoid a few things, including:

  • Submerging your incision underwater.
  • Lifting an object that’s heavier than 15 pounds.
  • Doing more than light exercise.

This generally lasts for about two weeks. After that, you can return to your normal activities.

How long after my thyroid is removed will my tiredness go away?

Typically, you will be given medication to help with your symptoms right after surgery. Your body actually has thyroid hormone still circulating throughout it, even after the thyroid has been removed. The hormones can still be in your body for two to three weeks. Medication will reintroduce new hormones into your body after the thyroid has been removed. If you are still feeling tired after surgery, remember that this can be a normal part of recovering from any type of surgery. It takes time for your body to heal. Talk to your healthcare provider if you are still experiencing fatigue and other symptoms of thyroid disease after surgery.

If part of my thyroid is surgically removed, will the other part be able to make enough thyroid hormones to keep me off of medication?

Sometimes, your surgeon may be able to remove part of your thyroid and leave the other part so that it can continue to create and release thyroid hormones. This is most likely in situations where you have a nodule that’s causing your thyroid problem. About 75% of people who have only one side of the thyroid removed are able to make enough thyroid hormone after surgery without hormone replacement therapy.

Can I check my thyroid at home?

You can do a quick and easy self-exam of your thyroid at home. The only tools you need to do this self-exam are a mirror and a glass of water.

To do the thyroid self-exam, follow these steps:

  • Start by identifying where your thyroid is located. Generally, you’ll find the thyroid on the front of your neck, between your collar bone and Adam’s apple. In men, Adam’s apple is much easier to see. For women, it’s usually easiest to look from the collar bone up.
  • Tip your head back while looking in a mirror. Look at your neck and try to hone in on the space you will be looking for once you start the exam.
  • Once you’re ready, take a drink of water while your head is tilted back. Watch your thyroid as you swallow. During this test, you’re looking for lumps or bumps. You may be able to see them when you swallow the water.

Repeat this test a few times to get a good look at your thyroid. If you see any lumps or bumps, reach out to your healthcare provider.

Should I exercise if I have thyroid disease?

Regular exercise is an important part of a healthy lifestyle. You do not need to change your exercise routine if you have thyroid disease. Exercise does not drain your body’s thyroid hormones and it shouldn’t hurt you to exercise. It is important to talk to your healthcare provider before you start a new exercise routine to make sure that it’s a good fit for you.

Can I live a normal life with thyroid disease?

Thyroid disease is often a life-long medical condition that you will need to manage constantly. This often involves a daily medication. Your healthcare provider will monitor your treatments and make adjustments over time. However, you can usually live a normal life with a thyroid disease. It may take some time to find the right treatment option for you and control your hormone levels, but then people with these types of conditions can usually live life without many restrictions.

References

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Thyroid Hormone – Types, Functions, Clinical Significance

Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. 

The thyroid gland produces three hormones:

  • Triiodothyronine, also known as T3
  • Tetraiodothyronine also called thyroxine or T4
  • Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Thyroid Hormone - Types, Functions, Clinical Significance

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation.

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

  • Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
  • Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
  • Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
    • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
    • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
    • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
  • Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
  • Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
    • Thyrocytes uptake iodinated thyroglobulin via endocytosis
    • Lysosome fuse with the endosome containing iodinated thyroglobulin
    • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
    • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. 
    • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. 

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

  • Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
  • Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
  • Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
  • Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
  • Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.

Thyroid Hormone - Types, Functions, Clinical Significance

Functions

The physiological effects of thyroid hormones are listed below

  • Increases the basal metabolic rate
  • Depending on the metabolic status it can induce lipolysis or lipid synthesis
  • Stimulate the metabolism of carbohydrates
  • Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
  • Permissive effect on catecholamines
  • In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
  • The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
  • Thyroid hormone affects fertility, ovulation, and menstruation
  • Regulate the rate at which calories are burned, affecting weight loss or weight gain.
  • Can slow down or speed up the heartbeat.
  • Can raise or lower body temperature.
  • Influence the rate at which food moves through the digestive tract.
  • Control the way muscles contract.
  • Control the rate at which dying cells are replaced.


Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. 

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. 

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

  • Feeling cold when other people do not
  • Constipation
  • Muscle weakness
  • Weight gain, even though you are not eating more food
  • Joint or muscle pain
  • Feeling sad or depressed
  • Feeling very tired
  • Pale, dry skin
  • Dry, thinning hair
  • Slow heart rate
  • Less sweating than usual
  • A puffy face
  • A hoarse voice
  • More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

  • Bradycardia
  • Fatigue
  • Cold intolerance
  • Weight gain
  • Poor appetite
  • Hair loss
  • Cold and dry skin
  • Constipation
  • Myopathy, stiffness, cramps, entrapment syndromes
  • Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

  • Myxedematous heart disease
  • Puffy appearance with doughy skin texture
  • Hoarse voice with difficulty articulate words
  • Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

  • Amenorrhea or menorrhagia
  • Galactorrhea
  • Erectile dysfunction, infertility in men
  • Decreased libido

Other symptoms:

  • Depression
  • Impaired concentration and memory
  • Goiter
  • Hypertension

Congenital hypothyroidism:

  • Umbilical hernia
  • Hypotonia
  • Prolonged neonatal jaundice
  • Poor feeding, absence of thirst (adipsia)
  • Decreased activity
  • Pot-belly, puffy-face, protuberant tongue
  • Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

  • Heat intolerance
  • Weight loss
  • Increased appetite
  • Increased sweating from cutaneous blood flow increase
  • Weakness
  • Fatigue
  • Onycholysis (separation of nails from nail beds)
  • Pretibial myxedema
  • Weight loss, even if you eat the same or more food (most but not all people lose weight)
  • Eating more than usual
  • Rapid or irregular heartbeat or pounding of your heart
  • Feeling nervous or anxious
  • Feeling irritable
  • Trouble sleeping
  • Trembling in your hands and fingers
  • Increased sweating
  • Feeling hot when other people do not
  • Muscle weakness
  • Diarrhea or more bowel movements than normal
  • Fewer and lighter menstrual periods than normal
  • Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

  • Lid lag (when looking down, sclera visible above cornea)
  • Lid retraction (when looking straight, sclera visible above the cornea)
  • Graves ophthalmopathy

Goiter

  • Diffuse, smooth, non-tender goiter
  • The audible bruit can be heard at the superior poles

Cardiovascular

  • Tachycardia (can be masked by patients taking beta-blockers)
  • Palpitations
  • An irregular pulse from atrial fibrillation
  • Hypertension
  • Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
  • Heart failure (elderly patients)
  • Chest pain
  • Abnormal heart rhythms

Musculoskeletal

  • Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
  • Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
  • Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

  • Restlessness
  • Anxiety
  • Depression
  • Emotional instability
  • Insomnia
  • Tremoulousness
  • Hyperreflexia

Conditions associated with hypothyroidism

  • Iodine deficiency 
  • Cretinism 
  • Wolff-Chaikoff effect 
  • Subacute thyroiditis 
  • Postpartum thyroiditis 
  • Riedel thyroiditis 
  • Hashimoto thyroiditis 
  • Drug-induced 

Conditions associated with hyperthyroidism

  • Graves disease 
  • Iodine excess 
  • Struma ovarii 
  • Thyrotropic pituitary adenoma 
  • Job-Basedow phenomenon
  • Drug-induced: amiodarone, lithium 
  • Thyrotoxicosis and thyroid storm 
  • Toxic multinodular goiter 
  • Thyroid adenoma 

Antithyroid drugs that work in the thyroid gland 

  • Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
  • Thionamides – inhibits TPO – block thyroid hormone synthesis
  • Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
  • Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

  • Propylthiouracil (ethionamide)
  • Dexamethasone
  • Amiodarone
  • Propranolol

Thyroid Conditions

  • Goiter – A general term for thyroid swelling. Goiters can be harmless or can represent iodine deficiency or a condition associated with thyroid inflammation called Hashimoto’s thyroiditis.
  • Thyroiditis – Inflammation of the thyroid, usually from a viral infection or autoimmune condition. Thyroiditis can be painful or have no symptoms at all. This disorder can be either painful or not felt at all. In thyroiditis, the thyroid releases hormones that were stored there. This can last for a few weeks or months.
  • Hyperthyroidism – Excessive thyroid hormone production. Hyperthyroidism is most often caused by Graves disease or an overactive thyroid nodule.
  • Hypothyroidism – low production of thyroid hormone. Thyroid damage caused by autoimmune disease is the most common cause of hypothyroidism.
  • Graves disease – An autoimmune condition in which the thyroid is overstimulated, causing hyperthyroidism.
  • Thyroid cancer – An uncommon form of cancer, thyroid cancer is usually curable. Surgery, radiation, and hormone treatments may be used to treat thyroid cancer.
  • Thyroid nodule – A small abnormal mass or lump in the thyroid gland. Thyroid nodules are extremely common. Few are cancerous. They may secrete excess hormones, causing hyperthyroidism, or cause no problems.
  • Thyroid storm – A rare form of hyperthyroidism in which extremely high thyroid hormone levels cause severe illness.
  • Nodules – Hyperthyroidism can be caused by nodules that are overactive within the thyroid. A single nodule is called a toxic autonomously functioning thyroid nodule, while a gland with several nodules is called a toxic multi-nodular goiter.
  • Excessive iodine – When you have too much iodine (the mineral that is used to make thyroid hormones) in your body, the thyroid makes more thyroid hormones than it needs. Excessive iodine can be found in some medications (amiodarone, a heart medication) and cough syrups.
  • Hashimoto’s thyroiditis – A painless disease, Hashimoto’s thyroiditis is an autoimmune condition where the body’s cells attack and damage the thyroid. This is an inherited condition.
  • Postpartum thyroiditis – This condition occurs in 5% to 9% of women after childbirth. It’s usually a temporary condition.
  • Iodine deficiency – Iodine is used by the thyroid to produce hormones. An iodine deficiency is an issue that affects several million people around the world.
  • A non-functioning thyroid gland – Sometimes, the thyroid gland doesn’t work correctly from birth. This affects about 1 in 4,000 newborns. If left untreated, the child could have both physical and mental issues in the future. All newborns are given a screening blood test in the hospital to check their thyroid function.

Thyroid Tests

  • Anti-TPO antibodies – In autoimmune thyroid disease, proteins mistakenly attack the thyroid peroxidase enzyme, which is used by the thyroid to make thyroid hormones.
  • Thyroid ultrasound – A probe is placed on the skin of the neck, and reflected sound waves can detect abnormal areas of thyroid tissue.
  • Thyroid scan – A small amount of radioactive iodine is given by mouth to get images of the thyroid gland. Radioactive iodine is concentrated within the thyroid gland.
  • Thyroid biopsy – A small amount of thyroid tissue is removed, usually to look for thyroid cancer. A thyroid biopsy is typically done with a needle.
  • Thyroid-stimulating hormone (TSH) – secreted by the brain, TSH regulates thyroid hormone release. A blood test with high TSH indicates low levels of thyroid hormone (hypothyroidism), and low TSH suggests hyperthyroidism. It is produced in the pituitary gland and regulates the balance of thyroid hormones — including T4 and T3 — in the bloodstream. This is usually the first test your provider will do to check for thyroid hormone imbalance. Most of the time, thyroid hormone deficiency (hypothyroidism) is associated with an elevated TSH level, while thyroid hormone excess (hyperthyroidism) is associated with a low TSH level. If TSH is abnormal, measurement of thyroid hormones directly, including thyroxine (T4) and triiodothyronine (T3) may be done to further evaluate the problem. Normal TSH range for an adult: 0.40 – 4.50 mIU/mL (milli-international units per liter of blood).
  • T4 Thyroxine tests – for hypothyroidism and hyperthyroidism, and used to monitor treatment of thyroid disorders. Low T4 is seen with hypothyroidism, whereas high T4 levels may indicate hyperthyroidism. Normal T4 range for an adult: 5.0 – 11.0 ug/dL (micrograms per deciliter of blood).
  • FT4 Free T4 or free thyroxine is a method of measuring T4 that eliminates the effect of proteins that naturally bind T4 and may prevent accurate measurement. Normal FT4 range for an adult: 0.9 – 1.7 ng/dL (nanograms per deciliter of blood)
  • T3 Triiodothyronine tests–  help diagnose hyperthyroidism or to show the severity of hyperthyroidism. Low T3 levels can be observed in hypothyroidism, but more often this test is useful in the diagnosis and management of hyperthyroidism, where T3 levels are elevated. Normal T3 range: 100 – 200 ng/dL (nanograms per deciliter of blood).
  • FT3 Free T3 or free triiodothyronine – is a method of measuring T3 that eliminates the effect of proteins that naturally bind T3 and may prevent accurate measurement. Normal FT3 range: 2.3 – 4.1 pg/mL (picograms per milliliter of blood)
  • T3 and T4 (thyroxine) – The primary forms of thyroid hormone, checked with a blood test.
  • Thyroglobulins – A substance secreted by the thyroid that can be used as a marker of thyroid cancer. It is often measured during follow-up in patients with thyroid cancer. High levels indicate recurrence of the cancer.
  • Other imaging tests – If thyroid cancer has spread (metastasized), tests such as CT scans, MRI scans, or PET scans can help identify the extent of spread.

Related Testing

  • Hypothalamus releases thyrotropin-releasing hormone (TRH) – which stimulates the secretion of TSH in the pituitary gland. Increased free T4 and T3 inhibit the release of TRH and TSH through a negative feedback loop. As a result, T3 and T4 secretion, and iodine uptake are reduced. Other hormones, such as somatostatin, glucocorticoids, and dopamine, also inhibit TSH production. Cold, stress, and exercise increase TRH release.
  • TSH and free thyroxine (free T4) test – These determine whether the abnormality arises centrally from the thyroid gland (primary), peripherally from the pituitary (secondary), or hypothalamus (tertiary). In primary hypothyroidism is suspected, the thyroid gland is not releasing enough thyroid hormones. Therefore, TSH levels will be appropriately elevated, while free T4 levels will be lower. In primary hyperthyroidism, free T4 levels abnormally increased, and TSH levels will be appropriately decreased. Other lab tests such as TSH receptor antibodies or antibodies to thyroid peroxidase can help aid in the diagnosis of Graves disease or Hashimoto thyroiditis, respectively.
  • Thyroid-binding globulin production – is increased because of estrogen and beta-human chorionic gonadotropin (beta-HCG). More free T4 will be bound to TGB, leading to increased production of T4. TSH levels and free T4 levels will normalize, and total T4 will increase. Therefore, laboratory values will show normal TSH, normal free T4, and elevated total T4. 

Additional blood tests might include

  • Thyroid antibodies – These tests help identify different types of autoimmune thyroid conditions. Common thyroid antibody tests include microsomal antibodies (also known as thyroid peroxidase antibodies or TPO antibodies), thyroglobulin antibodies (also known as TG antibodies), and thyroid receptor antibodies (includes thyroid-stimulating immunoglobulins [TSI] and thyroid blocking immunoglobulins [TBI]).
  • Calcitonin – This test is used to diagnose C-cell hyperplasia and medullary thyroid cancer, both of which are rare thyroid disorders.
  • Thyroglobulin – This test is used to diagnose thyroiditis (thyroid inflammation) and to monitor the treatment of thyroid cancer.

Thyroid Treatments

  • Thyroid surgery (thyroidectomy) – A surgeon removes all or part of the thyroid in an operation. Thyroidectomy is performed for thyroid cancer, goiter,  or hyperthyroidism.
  • Antithyroid medications – Drugs can slow down the overproduction of thyroid hormone in hyperthyroidism. Two common antithyroid medicines are methimazole and propylthiouracil.
  • Radioactive iodine – Iodine with radioactivity that can be used in low doses to test the thyroid gland or destroy an overactive gland. Large doses can be used to destroy cancerous tissue.
  • External radiation – A beam of radiation is directed at the thyroid, on multiple appointments. The high-energy rays help kill thyroid cancer cells.
  • Thyroid hormone pills – Daily treatment that replaces the amount of thyroid hormone you can no longer make. Thyroid hormone pills treat hypothyroidism and are also used to help prevent thyroid cancer from coming back after treatment.
  • Recombinant human TSH – Injecting this thyroid-stimulating agent can make thyroid cancer show up more clearly on imaging tests
  • Anti-thyroid drugs (methimazole and propylthiouracil) – Are medications that stop your thyroid from making hormones.
  • Levothyroxine – is the standard of care in thyroid hormone replacement therapy and treatment of hypothyroidism. Levothyroxine (also called LT4) is equivalent to the T4 form of naturally occurring thyroid hormone and is available in generic and brand name forms. To optimize absorption of your thyroid medication, it should be taken with water at a regular time each day. Multiple medications and supplements decrease absorption of thyroid hormone and should be taken 3-4 hours apart, including calcium and iron supplements, proton pump inhibitors, soy, and multivitamins with minerals. Because of the way levothyroxine is metabolized by the body, your doctor may ask you to take an extra pill or skip a pill on some days of the week. This helps us to fine-tune your medication dose for your body and should be guided by an endocrinologist.
  • Liothyronine – is a replacement T3 (triiodothyronine) thyroid hormone. This medication has a short half-life and is taken twice per day or in combination with levothyroxine. Liothyronine alone is not used for the treatment of hypothyroidism long term.
  • Other formulations of thyroid hormone replacement include natural or desiccated thyroid hormone extracts from animal sources. Natural or desiccated thyroid extract preparations have greater variability in the dose of thyroid hormone between batches and imbalanced ratios if T4 vs T3. Natural or animal sources of thyroid hormone typically contain 75% T4 and 25% T3, compared to the normal human balance of 95% T4 and 5% T3. Treatment with a correct balance of T4 and T3 is important to replicate normal thyroid function and prevent adverse effects of excess T3, including osteoporosis, heart problems, and mood and sleep disturbance. An endocrinologist can evaluate symptoms and thyroid tests to help balance thyroid hormone medications.


A LISTING OF THE FDA-APPROVED MEDICINES
PRODUCT
FDA RATING
MANUFACTURER
Unithroid®
AB
(Stevens)*+
L-Thyroxin
AB
(Mylan) *#
Levo-T®
BX
(Alara)
Levoxyl®
BX
(Jones)*
Novothyrox®
BX
(GenPharm)
Synthroid®
BX
(Abbott)*
Levothroid®
BX
(Forest/ Lloyd)*
Levolet®
BX
(Vintage)
Tirosint®
None
(IBSA)
LEGEND:
AB = interchangeable
BX = not interchangeable
* = currently available
+ = This is BX rated vs the other name brand LT4s
# = This is AB rated only to Unithroid and is considered the only “generic”.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones – While not strictly necessary for life, thyroid hormones have profound effects on many “big time” physiologic processes, such as development, growth, and metabolism, and deficiency in thyroid hormones is not compatible with normal health. Additionally, many of the effects of thyroid hormone have been delineated by the study of deficiency and excess states, as discussed briefly below.

Metabolism – Thyroid hormones stimulate diverse metabolic activities in most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production, which seems to result, at least in part, from increased oxygen consumption and rates of ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a smoldering fire. A few examples of specific metabolic effects of thyroid hormones include:

  • Lipid metabolism – Increased thyroid hormone levels stimulate fat mobilization, leading to increased concentrations of fatty acids in plasma. They also enhance the oxidation of fatty acids in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated with thyroid hormone levels – one diagnostic indiction of hypothyroidism is increased blood cholesterol concentration.
  • Carbohydrate metabolism – Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth – Thyroid hormones are clearly necessary for normal growth in children and young animals, as evidenced by the growth-retardation observed in thyroid deficiency. Not surprisingly, the growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone, a clear indication that complex physiologic processes like growth depend upon multiple endocrine controls.

Development – A classical experiment in endocrinology was the demonstration that tadpoles deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in mammals is the fact that normal levels of thyroid hormone are essential to the development of the fetal and neonatal brain.

Other Effects – As mentioned above, there do not seem to be organs and tissues that are not affected by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

  • Cardiovascular system Thyroid hormones increase heart rate, cardiac contractility, and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs.
  • Central nervous system – Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.
  • Reproductive system –  Normal reproductive behavior and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly associated with infertility.


How long does it take to recover from thyroid surgery (thyroidectomy)?

It will take your body a few weeks to recover after your thyroid is surgically removed (thyroidectomy). During this time you should avoid a few things, including:

  • Submerging your incision underwater.
  • Lifting an object that’s heavier than 15 pounds.
  • Doing more than light exercise.

This generally lasts for about two weeks. After that, you can return to your normal activities.

How long after my thyroid is removed will my tiredness go away?

Typically, you will be given medication to help with your symptoms right after surgery. Your body actually has thyroid hormone still circulating throughout it, even after the thyroid has been removed. The hormones can still be in your body for two to three weeks. Medication will reintroduce new hormones into your body after the thyroid has been removed. If you are still feeling tired after surgery, remember that this can be a normal part of recovering from any type of surgery. It takes time for your body to heal. Talk to your healthcare provider if you are still experiencing fatigue and other symptoms of thyroid disease after surgery.

If part of my thyroid is surgically removed, will the other part be able to make enough thyroid hormones to keep me off of medication?

Sometimes, your surgeon may be able to remove part of your thyroid and leave the other part so that it can continue to create and release thyroid hormones. This is most likely in situations where you have a nodule that’s causing your thyroid problem. About 75% of people who have only one side of the thyroid removed are able to make enough thyroid hormone after surgery without hormone replacement therapy.

Can I check my thyroid at home?

You can do a quick and easy self-exam of your thyroid at home. The only tools you need to do this self-exam are a mirror and a glass of water.

To do the thyroid self-exam, follow these steps:

  • Start by identifying where your thyroid is located. Generally, you’ll find the thyroid on the front of your neck, between your collar bone and Adam’s apple. In men, Adam’s apple is much easier to see. For women, it’s usually easiest to look from the collar bone up.
  • Tip your head back while looking in a mirror. Look at your neck and try to hone in on the space you will be looking for once you start the exam.
  • Once you’re ready, take a drink of water while your head is tilted back. Watch your thyroid as you swallow. During this test, you’re looking for lumps or bumps. You may be able to see them when you swallow the water.

Repeat this test a few times to get a good look at your thyroid. If you see any lumps or bumps, reach out to your healthcare provider.

Should I exercise if I have thyroid disease?

Regular exercise is an important part of a healthy lifestyle. You do not need to change your exercise routine if you have thyroid disease. Exercise does not drain your body’s thyroid hormones and it shouldn’t hurt you to exercise. It is important to talk to your healthcare provider before you start a new exercise routine to make sure that it’s a good fit for you.

Can I live a normal life with thyroid disease?

Thyroid disease is often a life-long medical condition that you will need to manage constantly. This often involves a daily medication. Your healthcare provider will monitor your treatments and make adjustments over time. However, you can usually live a normal life with a thyroid disease. It may take some time to find the right treatment option for you and control your hormone levels, but then people with these types of conditions can usually live life without many restrictions.

References

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Low Estrogen Symptoms – Causes, Symptoms

Low Estrogen Symptoms/Estrogen Hormone is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in the management of symptoms associated with menopause. Furthermore, this activity will highlight the mechanism of action, adverse event profile, off-label uses, administration and dosing, monitoring, and relevant interactions pertinent for members of the interprofessional team.

Types of Estrogen Hormone

There are different types of estrogen:

  • Estrone – This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary.
  • Estradiol – Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels can increase the risk of uterine and breast cancer. However, low levels can result in weight gain and cardiovascular disease.
  • Estriol – levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth.

Normal estrogen levels in women

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for women:

Estrone Estradiol
Prepubescent female Undetectable–29 pg/mL Undetectable–20 pg/ml
Pubescent female 10–200 pg/mL Undetectable–350 pg/ml
Premenopausal adult female 17–200 pg/mL 15–350 pg/ml
Postmenopausal adult female 7–40 pg/mL <10 pg/ml

In premenopausal girls and women, estradiol levels vary widely throughout the menstrual cycle.

Normal estrogen levels in men

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for men

Estrone Estradiol
Prepubescent male Undetectable–16 pg/ml Undetectable–13 pg/ml
Pubescent male Undetectable–60 pg/ml Undetectable–40 pg/ml
Adult male 10–60 pg/ml 10–40 pg/ml

Mechanism of Action

Estrogen enters the systemic circulation as a free hormone or protein-bound, either as sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. The initiation of cellular physiological response to estrogen begins in the cell cytoplasm with the binding of estrogen to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce transcription of DNA by binding to nucleotide sequences known as estrogen response elements (ERE) to enact a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle. Estrogen metabolic activity primarily takes place within the liver hepatocytes CYP3A4 and excreted from the body in the urine.

The effects of estrogen on various systems of the body are described below

  • Breast – Estrogen is responsible for the development of mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty, and during pregnancy, functions to secrete breast milk in postpartum lactation.
  • Uterus – In the uterus, estrogen helps to proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
  • Contraception – Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamus release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
  • Vagina – Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin and presents with symptoms of dryness known as vulvovaginal atrophy.
  • Bone – During puberty, estrogen aids in the development of long bones and fusion of the epiphyseal growth plates. Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.
  • Cardiovascular – Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reduce the risk of coronary artery disease in early use in postmenopausal women.

Indications of Estrogen Hormone

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to in the following structures as either estrone, estradiol, and estriol.

  • According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality. Later studies conducted by the Women’s Health Initiative concluded that risk was greater than the benefit of hormone replacement therapy in postmenopausal women.
  • The Women’s Health Initiative ended clinical studies prematurely because of participants in the study developed an increased risk of breast cancer and coronary artery disease. Newer studies contradict the finding of the Women’s Health Initiative, with evidence of the improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when women start estrogen hormone replacement therapy at the onset of menopause.
  • The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include Ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA. Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.
  • Conjugated estrogen therapy is indicated in the treatment of moderate to severe vasomotor symptoms due to menopause.
  • Conjugated estrogen therapy is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
  • Conjugated estrogen therapy is indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  • Conjugated estrogen therapy is indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
  • Conjugated estrogen therapy is indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
  • The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration.

Clinically, the use of estrogen includes the following FDA-approved indications

  • Primary ovarian insufficiency
  • Female hypogonadism
  • Symptoms associated with menopause including vulvovaginal atrophy, dyspareunia, hot flashes and night sweats, and prevention of osteoporosis
  • Oral contraceptive pill (OCP) to prevent pregnancy
  • Moderate acne vulgaris
  • Prostate cancer with advanced forms of metastasis

Estrogen/synthetic estrogen has the following non-FDA-approved indication for polycystic ovarian syndrome for the relief of symptoms of hyperandrogenism and amenorrhea.

Contraindications of Estrogen Hormone

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:

  • Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
  • Coronary arterial disease
  • History of thromboembolism or thrombophlebitis
  • History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies and metastatic disease)
  • History of ischemic stroke
  • Migraine headaches
  • Seizure disorder
  • History of dementia or neurocognitive disorders
  • Hypertension
  • Uterine leiomyomas
  • Endometriosis
  • Urinary incontinence
  • Hyperlipidemia
  • Gallbladder disease
  • Liver disease
  • History of tobacco use
  • Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens are contraindicated for use during pregnancy

Dosage of Estrogen Hormone

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevention of osteoporosis, prevention of pregnancy, hypoestrogenism, and metastatic breast and advance prostate cancers.

Available Estrogen Preparations

Oral

  • Estrogen: Conjugated may be prescribed in the dosage of 0.3-mg, 0.625-mg, 0.9-mg, and 1.25-mg tablets
  • Estradiol may be prescribed in the dosage of 0.5-mg, 1-mg, and 2-mg tablets
  • Norethindrone/Ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

  • Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.
  • Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day

Intramuscular Injection

  • Estradiol valerate administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy,  and hypoestrogenism. Recommendations for advanced prostate cancer palliative treatment is more than 30-mg intramuscular injection.
  • Estradiol cypionate administered as an intramuscular injection in the dosage of 5 mg per mL for treatment of moderate-to-severe symptoms of menopause.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

  • Estradiol topical gel (0.006%): 0.52 mg per pump
  • Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation
  • Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10-mcg, 25-mcg tablet
  • Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally
  • Estradiol transdermal patches may be prescribed at the following dosage: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Estrogen Treatment: Pills

  • What are they? Oral medication is the most common form of ERT. Examples are conjugated Estrogens (Premarin), estradiol (Estrace), and Estratab. Follow your doctor’s instructions for dosing. Most estrogen pills are taken once a day without food. Some have more complicated dosing schedules.
  • Pros. Like other types of estrogen therapy, estrogen pills can reduce or resolve troublesome symptoms of menopause. They can also lower the risk of osteoporosis. While there are newer ways of getting ERT, oral estrogen medicines are the best-studied type of estrogen therapy.
  • Cons. The risks of this type of estrogen therapy have been well-publicized. On its own, estrogen causes a slight increase in the risk of strokes, blood clots, and other problems. When combined with the hormone progestin, the risks of breast cancer and heart attack may rise as well. Oral estrogen-like any estrogen therapy — can also cause side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea.
    Because oral estrogen can be hard on the liver, people with liver damage should not take it. Instead, they should choose a different way of getting estrogen.

Estrogen Treatment: Skin Patches

What are they?

  • Skin patches are another type of ERT – Examples are Alora, Climara, Estraderm, and Vivelle-Dot. Combination estrogen and progestin patches — like Climara Pro and Combipatch — are also available. Menostar has a lower dose of estrogen than other patches, and it’s only used for reducing the risk of osteoporosis. It doesn’t help with other menopause symptoms.
    Usually, you would wear the patch on your lower stomach, beneath the waistline. You would then change the patch once or twice a week, according to the instructions.
  • Pros – In addition to offering the same benefits as an oral therapy, this type of estrogen treatment has several additional advantages. For one, the patch is convenient. You can stick it on and not worry about having to take a pill each day. While estrogen pills can be dangerous for people with liver problems, patches are OK, because the estrogen bypasses the liver and goes directly into the blood. A 2007 study also showed that the patch does not pose a risk of blood clots in postmenopausal women like oral estrogen does, though more studies are needed before making definitive conclusions on whether patches are safer than pills. Right now, all estrogens carry the same black-box warning with respect to clot formation.
  • Cons – While some experts believe that estrogen patches may be safer than oral estrogen in other ways, it’s too early to know. So, for now, assume that estrogen patches pose most of the same risks a very small increase in the risk of serious problems, like cancer and stroke. They also have many similar although perhaps milder — side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea. The patch itself might irritate the skin where you apply it.
    Estrogen patches should not be exposed to high heat or direct sunlight. Heat can make some patches release the estrogen too quickly, giving you too high a dose at first and then too low a dose later. So don’t use tanning beds or saunas while you’re wearing an estrogen patch.

Estrogen Treatment: Topical Creams, Gels, and Sprays

What are they?

  • Estrogen gels (like Estrogen and Divigell) – creams (like Estrasorb), and sprays (like Evamist) offer another way of getting estrogen into your system. As with patches, this type of estrogen treatment is absorbed through the skin directly into the bloodstream. The specifics on how to apply these creams vary, although they’re usually used once a day. Estrogel is applied on one arm, from the wrist to the shoulder. Estrasorb is applied to the legs. Evamist is applied to the arm.
  • Pros – Because estrogen creams are absorbed through the skin and go directly into the bloodstream, they’re safer than oral estrogen for people who have liver and cholesterol problems.
  • Cons – Estrogen gels, creams, and sprays have not been well-studied. While they could be safer than oral estrogen, experts aren’t sure. So assume that they pose the same slight risk of serious conditions, like cancer and stroke.
    One potential problem with using this type of estrogen treatment is that the gel, cream or spray can rub or wash off before it’s been fully absorbed. Make sure you let the topical dry before you put on clothes. Always apply it after you bathe or shower.

Side Effects of Estrogen Hormone

  • Natural estrogen and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding also known as breakthrough bleeding, and anaphylaxis.
  • Weight gain may be a reported adverse effect of the oral contraceptive pill (OCP) containing Ethinyl estradiol, but studies conducted on short-term and long-term use of OCPs resulted in no weight gain association.
  • More severe side effects of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Tell your doctor right away if you have any serious side effects, including mental, mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged, recurrent bleeding), increased or new vaginal irritation, itching, odor, discharge, severe stomach, abdominal pain, persistent nausea, vomiting, yellowing eyes, skin, dark urine, swelling hands, ankles, feet, increased thirst, urination.

Box Warnings

The use of estrogen without progestins increased the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years old) and an increased risk of invasive breast cancer in postmenopausal women (50 to 79 years old) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age have been established by the Women’s Health Initiative Memory Study.

US Preventive Services Task Force (USPSTF) Score: D

Using estrogen-alone or combined estrogen and progestin use to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, ospemifene, raloxifene, tamoxifen, toremifene, tranexamic acid.

This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Why is estrogen important?

Estrogen helps bring about the physical changes that turn a girl into a woman. This time of life is called puberty. These changes include:

  • Growth of the breasts
  • Growth of pubic and underarm hair
  • Start of menstrual cycles

Estrogen helps control the menstrual cycle and is important for childbearing.

Estrogen also has other functions

  • Keeps cholesterol in control
  • Protects bone health for both women and men
  • Affects your brain (including mood), bones, heart, skin, and other tissues

How does estrogen work?

The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue. Estrogen moves through your blood and acts everywhere in your body.

What can go wrong with estrogen levels?

  • For many reasons, your body can make too little or too much estrogen. Or, you can take in too much estrogen, such as through birth control pills or estrogen replacement therapy. You might want to keep track of your symptoms (changes you feel) by writing them down each day. Bring this symptom journal to your doctor.

Estrogen and your menstrual cycle

  • Your estrogen levels change throughout the month. They are highest in the middle of your menstrual cycle and lowest during your period. Estrogen levels drop at menopause.
  • How do you know what your estrogen level is? You will need to give a blood or urine sample to test your estrogen. Ask your doctor what your test results mean.

Low Estrogen

Women

The most common reason for low estrogen in women is menopause or surgical removal of the ovaries. Symptoms of low estrogen include:

  • Menstrual periods that are less frequent or that stop
  • Hot flashes (suddenly feeling very warm) and/or night sweats
  • Trouble sleeping
  • Dryness and thinning of the vagina
  • Low sexual desire
  • Mood swings
  • Dry skin

Some women get menstrual migraines, a bad headache right before their menstrual period, because of the drop in estrogen.

Men – Low estrogen in men can cause excess belly fat and low sexual desire.

High Estrogen in Women

Excess estrogen can lead to these problems, among others:

  • Weight gain, mainly in your waist, hips, and thighs
  • Menstrual problems, such as light or heavy bleeding
  • Worsening of premenstrual syndrome
  • Fibrocystic breasts (non-cancerous breast lumps)
  • Fibroids (noncancerous tumors) in the uterus
  • Fatigue
  • Loss of sex drive
  • Feeling depressed or anxious
  • bloating
  • swelling and tenderness in your breasts
  • fibrocystic lumps in your breasts
  • decreased sex drive
  • irregular menstrual periods
  • increased symptoms of premenstrual syndrome (PMS)
  • mood swings
  • headaches
  • anxiety and panic attacks
  • weight gain
  • hair loss
  • cold hands or feet
  • trouble sleeping
  • sleepiness or fatigue
  • memory problems

Men. High estrogen in men can cause

  • Infertility – Estrogen is partly responsible for creating healthy sperm. When estrogen levels are high, sperm levels may fall and lead to fertility issues.
  • Gynecomastia – Estrogen may stimulate breast tissue growth. Men with too much estrogen may develop gynecomastia, a condition which leads to larger breasts.
  • Erectile dysfunction (ED) – Men with high levels of estrogen may have difficulty getting or maintaining an erection.
  • Enlarged breasts (gynecomastia)
  • Poor erections
  • Infertility

Levels of estrogen

Estrogen levels vary among individuals. They also fluctuate during the menstrual cycle and over a female’s lifetime. This fluctuation can sometimes produce effects such as mood changes before menstruation or hot flashes in menopause.

Factors that can affect estrogen levels include

  • pregnancy, the end of pregnancy, and breastfeeding
  • puberty
  • menopause
  • older age
  • overweight and obesity
  • extreme dieting or anorexia nervosa
  • strenuous exercise or training
  • the use of certain medications, including steroids, ampicillin, estrogen-containing drugs, phenothiazines, and tetracyclines
  • some congenital conditions, such as Turner’s syndrome
  • high blood pressure
  • diabetes
  • primary ovarian insufficiency
  • an underactive pituitary gland
  • polycystic ovary syndrome (PCOS)
  • tumors of the ovaries or adrenal glands

Estrogen imbalance

An imbalance of estrogen leads to:

  • irregular or no menstruation
  • light or heavy bleeding during menstruation
  • more severe premenstrual or menopausal symptoms
  • hot flashes, night sweats, or both
  • noncancerous lumps in the breast and uterus
  • mood changes and sleeping problems
  • weight gain, mainly in the hips, thighs, and waist
  • low sexual desire
  • vaginal dryness and vaginal atrophy
  • fatigue
  • mood swings
  • feelings of depression and anxiety
  • dry skin
  • infertility
  • erectile dysfunction
  • larger breasts, known as gynecomastia

Males with low estrogen levels may have excess belly fat and low libido.

Estrogen sources and uses

If a person has low levels of estrogen, a doctor may prescribe supplements or medication.

Estrogen products include

  • synthetic estrogen
  • bioidentical estrogen
  • Premarin, which contains estrogens from the urine of pregnant mares

Estrogen therapy

  • Estrogen therapy can help manage menopause symptoms as part of hormone therapy, which people usually refer to as hormone replacement therapy.
  • The treatment may consist solely of estrogen (estrogen replacement therapy, or ERT), or it may involve a combination of estrogen and progestin, a synthetic form of progesterone.
  • Hormone treatment is available as a pill, nasal spray, patch, skin gel, injection, vaginal cream, or ring.


It can help manage

  • hot flashes
  • vaginal dryness
  • painful intercourse
  • mood changes
  • sleep disorders
  • anxiety
  • decreased sexual desire

It may also help reduce the risk of osteoporosis, which increases when people enter menopause.

Side effects include

  • bloating
  • breast soreness
  • headaches
  • leg cramps
  • indigestion
  • nausea
  • vaginal bleeding
  • fluid retention, leading to swelling

Some types of hormone therapy can also increase the risk of a stroke, blood clots, and uterine and breast cancer. A doctor can advise a person on whether estrogen therapy is suitable for them.

In addition to menopause, estrogen therapy can also help resolve

  • primary ovarian insufficiency
  • other ovarian issues
  • some types of acne
  • some cases of prostate cancer
  • delayed puberty[rx], for example, in Turner’s syndrome

High levels of estrogen can increase the risk and progression of some types of breast cancer. Some hormone treatments block the action[rx] of estrogen as a way of slowing or stopping cancer development. Hormonal therapy is not for everyone. A family history of breast cancer or thyroid issues may contradict using hormones. People who are unsure can speak to a doctor.

Transitioning to female

A doctor can prescribe estrogen[rx] as part of the therapy for a person assigned male at birth who wishes to transition to a female. The person may also need anti-androgenic treatment.

  • Estrogen can help a person develop female secondary sexual characteristics, such as breasts, and reduce male pattern hair formation.
  • Estrogen therapy will be part of a broader treatment approach. A healthcare professional can advise the individual on the best course of treatment.

Birth control

Birth control pills contain either synthetic estrogen and progestin or progestin-only.

  • Some types prevent pregnancy by stopping ovulation, and they do this by ensuring that hormone levels do not fluctuate throughout the month.
  • They also make the mucus in the cervix thick so that any sperm cannot reach the egg. Other uses include decreasing premenstrual symptoms and reducing the severity of hormone-related acne.

Birth control pills may increase the risk of

  • heart attack
  • stroke
  • blood clots
  • pulmonary embolism
  • nausea and vomiting
  • headaches
  • irregular bleeding
  • weight changes
  • breast tenderness and swelling

Oral birth control presents more risk for women who smoke or are over the age of 35 years. Long-term use may also lead to a higher risk of breast cancer.

Food sources of estrogen

Some foods contain phytoestrogens, which are plant-based substances that resemble estrogen. Some studies suggest that these may affect levels[rx] of estrogen in the body. However, there is not enough evidence to confirm this.

Foods that contain phytoestrogens include

  • cruciferous vegetables
  • soy and some foods containing soy protein
  • berries
  • seeds and grains
  • nuts
  • fruit
  • wine

Some people believe that foods containing phytoestrogens can help manage hot flashes and other effects of menopause, but this does not have scientific backing. In addition, eating whole soy foods, for example, is unlikely to have the same effect as taking extracts from soy as a supplement.


Supplements

Some herbs and supplements contain phytoestrogens, which act in a similar way to estrogen. These may help regulate estrogen and treat symptoms of menopause.

Examples are

  • black cohosh
  • red clover
  • soy isoflavones

However, it is unclear exactly how these compounds affect estrogen and estrogen-related activity in the body, and there is not enough evidence to confirm that they are safe and effective, especially in the long term. Researchers have called for further studies.

In addition, the Food and Drug Administration (FDA) does not regulate herbal and nonmedicinal supplements. As a result, it is not possible to know exactly what a product contains.

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patient’s risk of breast cancer, endometrial cancer, the risk of cardiovascular disease including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should be continued to be monitored for the development of hypertension while taking estrogen. Routine women’s wellness exams including mammography and pap smear should be continued during the use of hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of use of OCPs due to tobacco use having an increased risk of venous thrombosis.

The Endocrine Society recommends monitoring patients’ improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of the start of therapy, then re-evaluated at 6 to 12 months of therapy, then annually after the first year.

References

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Estrogen Pills – Uses, Indications, Contraindications

Estrogen Pills/Estrogen Hormone is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in the management of symptoms associated with menopause. Furthermore, this activity will highlight the mechanism of action, adverse event profile, off-label uses, administration and dosing, monitoring, and relevant interactions pertinent for members of the interprofessional team.

Types of Estrogen Hormone

There are different types of estrogen:

  • Estrone – This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary.
  • Estradiol – Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels can increase the risk of uterine and breast cancer. However, low levels can result in weight gain and cardiovascular disease.
  • Estriol – levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth.

Normal estrogen levels in women

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for women:

Estrone Estradiol
Prepubescent female Undetectable–29 pg/mL Undetectable–20 pg/ml
Pubescent female 10–200 pg/mL Undetectable–350 pg/ml
Premenopausal adult female 17–200 pg/mL 15–350 pg/ml
Postmenopausal adult female 7–40 pg/mL <10 pg/ml

In premenopausal girls and women, estradiol levels vary widely throughout the menstrual cycle.

Normal estrogen levels in men

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for men

Estrone Estradiol
Prepubescent male Undetectable–16 pg/ml Undetectable–13 pg/ml
Pubescent male Undetectable–60 pg/ml Undetectable–40 pg/ml
Adult male 10–60 pg/ml 10–40 pg/ml

Mechanism of Action

Estrogen enters the systemic circulation as a free hormone or protein-bound, either as sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. The initiation of cellular physiological response to estrogen begins in the cell cytoplasm with the binding of estrogen to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce transcription of DNA by binding to nucleotide sequences known as estrogen response elements (ERE) to enact a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle. Estrogen metabolic activity primarily takes place within the liver hepatocytes CYP3A4 and excreted from the body in the urine.

The effects of estrogen on various systems of the body are described below

  • Breast – Estrogen is responsible for the development of mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty, and during pregnancy, functions to secrete breast milk in postpartum lactation.
  • Uterus – In the uterus, estrogen helps to proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
  • Contraception – Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamus release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
  • Vagina – Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin and presents with symptoms of dryness known as vulvovaginal atrophy.
  • Bone – During puberty, estrogen aids in the development of long bones and fusion of the epiphyseal growth plates. Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.
  • Cardiovascular – Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reduce the risk of coronary artery disease in early use in postmenopausal women.

Indications of Estrogen Hormone

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to in the following structures as either estrone, estradiol, and estriol.

  • According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality. Later studies conducted by the Women’s Health Initiative concluded that risk was greater than the benefit of hormone replacement therapy in postmenopausal women.
  • The Women’s Health Initiative ended clinical studies prematurely because of participants in the study developed an increased risk of breast cancer and coronary artery disease. Newer studies contradict the finding of the Women’s Health Initiative, with evidence of the improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when women start estrogen hormone replacement therapy at the onset of menopause.
  • The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include Ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA. Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.
  • Conjugated estrogen therapy is indicated in the treatment of moderate to severe vasomotor symptoms due to menopause.
  • Conjugated estrogen therapy is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
  • Conjugated estrogen therapy is indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
  • Conjugated estrogen therapy is indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
  • Conjugated estrogen therapy is indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
  • The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration.

Clinically, the use of estrogen includes the following FDA-approved indications

  • Primary ovarian insufficiency
  • Female hypogonadism
  • Symptoms associated with menopause including vulvovaginal atrophy, dyspareunia, hot flashes and night sweats, and prevention of osteoporosis
  • Oral contraceptive pill (OCP) to prevent pregnancy
  • Moderate acne vulgaris
  • Prostate cancer with advanced forms of metastasis

Estrogen/synthetic estrogen has the following non-FDA-approved indication for polycystic ovarian syndrome for the relief of symptoms of hyperandrogenism and amenorrhea.

Contraindications of Estrogen Hormone

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:

  • Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
  • Coronary arterial disease
  • History of thromboembolism or thrombophlebitis
  • History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies and metastatic disease)
  • History of ischemic stroke
  • Migraine headaches
  • Seizure disorder
  • History of dementia or neurocognitive disorders
  • Hypertension
  • Uterine leiomyomas
  • Endometriosis
  • Urinary incontinence
  • Hyperlipidemia
  • Gallbladder disease
  • Liver disease
  • History of tobacco use
  • Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens are contraindicated for use during pregnancy

Dosage of Estrogen Hormone

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevention of osteoporosis, prevention of pregnancy, hypoestrogenism, and metastatic breast and advance prostate cancers.

Available Estrogen Preparations

Oral

  • Estrogen: Conjugated may be prescribed in the dosage of 0.3-mg, 0.625-mg, 0.9-mg, and 1.25-mg tablets
  • Estradiol may be prescribed in the dosage of 0.5-mg, 1-mg, and 2-mg tablets
  • Norethindrone/Ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

  • Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.
  • Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day

Intramuscular Injection

  • Estradiol valerate administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy,  and hypoestrogenism. Recommendations for advanced prostate cancer palliative treatment is more than 30-mg intramuscular injection.
  • Estradiol cypionate administered as an intramuscular injection in the dosage of 5 mg per mL for treatment of moderate-to-severe symptoms of menopause.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

  • Estradiol topical gel (0.006%): 0.52 mg per pump
  • Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation
  • Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10-mcg, 25-mcg tablet
  • Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally
  • Estradiol transdermal patches may be prescribed at the following dosage: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Estrogen Treatment: Pills

  • What are they? Oral medication is the most common form of ERT. Examples are conjugated Estrogens (Premarin), estradiol (Estrace), and Estratab. Follow your doctor’s instructions for dosing. Most estrogen pills are taken once a day without food. Some have more complicated dosing schedules.
  • Pros. Like other types of estrogen therapy, estrogen pills can reduce or resolve troublesome symptoms of menopause. They can also lower the risk of osteoporosis. While there are newer ways of getting ERT, oral estrogen medicines are the best-studied type of estrogen therapy.
  • Cons. The risks of this type of estrogen therapy have been well-publicized. On its own, estrogen causes a slight increase in the risk of strokes, blood clots, and other problems. When combined with the hormone progestin, the risks of breast cancer and heart attack may rise as well. Oral estrogen-like any estrogen therapy — can also cause side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea.
    Because oral estrogen can be hard on the liver, people with liver damage should not take it. Instead, they should choose a different way of getting estrogen.

Estrogen Treatment: Skin Patches

What are they?

  • Skin patches are another type of ERT – Examples are Alora, Climara, Estraderm, and Vivelle-Dot. Combination estrogen and progestin patches — like Climara Pro and Combipatch — are also available. Menostar has a lower dose of estrogen than other patches, and it’s only used for reducing the risk of osteoporosis. It doesn’t help with other menopause symptoms.
    Usually, you would wear the patch on your lower stomach, beneath the waistline. You would then change the patch once or twice a week, according to the instructions.
  • Pros – In addition to offering the same benefits as an oral therapy, this type of estrogen treatment has several additional advantages. For one, the patch is convenient. You can stick it on and not worry about having to take a pill each day. While estrogen pills can be dangerous for people with liver problems, patches are OK, because the estrogen bypasses the liver and goes directly into the blood. A 2007 study also showed that the patch does not pose a risk of blood clots in postmenopausal women like oral estrogen does, though more studies are needed before making definitive conclusions on whether patches are safer than pills. Right now, all estrogens carry the same black-box warning with respect to clot formation.
  • Cons – While some experts believe that estrogen patches may be safer than oral estrogen in other ways, it’s too early to know. So, for now, assume that estrogen patches pose most of the same risks a very small increase in the risk of serious problems, like cancer and stroke. They also have many similar although perhaps milder — side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea. The patch itself might irritate the skin where you apply it.
    Estrogen patches should not be exposed to high heat or direct sunlight. Heat can make some patches release the estrogen too quickly, giving you too high a dose at first and then too low a dose later. So don’t use tanning beds or saunas while you’re wearing an estrogen patch.

Estrogen Treatment: Topical Creams, Gels, and Sprays

What are they?

  • Estrogen gels (like Estrogen and Divigell) – creams (like Estrasorb), and sprays (like Evamist) offer another way of getting estrogen into your system. As with patches, this type of estrogen treatment is absorbed through the skin directly into the bloodstream. The specifics on how to apply these creams vary, although they’re usually used once a day. Estrogel is applied on one arm, from the wrist to the shoulder. Estrasorb is applied to the legs. Evamist is applied to the arm.
  • Pros – Because estrogen creams are absorbed through the skin and go directly into the bloodstream, they’re safer than oral estrogen for people who have liver and cholesterol problems.
  • Cons – Estrogen gels, creams, and sprays have not been well-studied. While they could be safer than oral estrogen, experts aren’t sure. So assume that they pose the same slight risk of serious conditions, like cancer and stroke.
    One potential problem with using this type of estrogen treatment is that the gel, cream or spray can rub or wash off before it’s been fully absorbed. Make sure you let the topical dry before you put on clothes. Always apply it after you bathe or shower.

Side Effects of Estrogen Hormone

  • Natural estrogen and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding also known as breakthrough bleeding, and anaphylaxis.
  • Weight gain may be a reported adverse effect of the oral contraceptive pill (OCP) containing Ethinyl estradiol, but studies conducted on short-term and long-term use of OCPs resulted in no weight gain association.
  • More severe side effects of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Tell your doctor right away if you have any serious side effects, including mental, mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged, recurrent bleeding), increased or new vaginal irritation, itching, odor, discharge, severe stomach, abdominal pain, persistent nausea, vomiting, yellowing eyes, skin, dark urine, swelling hands, ankles, feet, increased thirst, urination.

Box Warnings

The use of estrogen without progestins increased the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years old) and an increased risk of invasive breast cancer in postmenopausal women (50 to 79 years old) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age have been established by the Women’s Health Initiative Memory Study.

US Preventive Services Task Force (USPSTF) Score: D

Using estrogen-alone or combined estrogen and progestin use to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, ospemifene, raloxifene, tamoxifen, toremifene, tranexamic acid.

This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Why is estrogen important?

Estrogen helps bring about the physical changes that turn a girl into a woman. This time of life is called puberty. These changes include:

  • Growth of the breasts
  • Growth of pubic and underarm hair
  • Start of menstrual cycles

Estrogen helps control the menstrual cycle and is important for childbearing.

Estrogen also has other functions

  • Keeps cholesterol in control
  • Protects bone health for both women and men
  • Affects your brain (including mood), bones, heart, skin, and other tissues

How does estrogen work?

The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue. Estrogen moves through your blood and acts everywhere in your body.

What can go wrong with estrogen levels?

  • For many reasons, your body can make too little or too much estrogen. Or, you can take in too much estrogen, such as through birth control pills or estrogen replacement therapy. You might want to keep track of your symptoms (changes you feel) by writing them down each day. Bring this symptom journal to your doctor.

Estrogen and your menstrual cycle

  • Your estrogen levels change throughout the month. They are highest in the middle of your menstrual cycle and lowest during your period. Estrogen levels drop at menopause.
  • How do you know what your estrogen level is? You will need to give a blood or urine sample to test your estrogen. Ask your doctor what your test results mean.

Low Estrogen

Women

The most common reason for low estrogen in women is menopause or surgical removal of the ovaries. Symptoms of low estrogen include:

  • Menstrual periods that are less frequent or that stop
  • Hot flashes (suddenly feeling very warm) and/or night sweats
  • Trouble sleeping
  • Dryness and thinning of the vagina
  • Low sexual desire
  • Mood swings
  • Dry skin

Some women get menstrual migraines, a bad headache right before their menstrual period, because of the drop in estrogen.

Men – Low estrogen in men can cause excess belly fat and low sexual desire.

High Estrogen in Women

Excess estrogen can lead to these problems, among others:

  • Weight gain, mainly in your waist, hips, and thighs
  • Menstrual problems, such as light or heavy bleeding
  • Worsening of premenstrual syndrome
  • Fibrocystic breasts (non-cancerous breast lumps)
  • Fibroids (noncancerous tumors) in the uterus
  • Fatigue
  • Loss of sex drive
  • Feeling depressed or anxious
  • bloating
  • swelling and tenderness in your breasts
  • fibrocystic lumps in your breasts
  • decreased sex drive
  • irregular menstrual periods
  • increased symptoms of premenstrual syndrome (PMS)
  • mood swings
  • headaches
  • anxiety and panic attacks
  • weight gain
  • hair loss
  • cold hands or feet
  • trouble sleeping
  • sleepiness or fatigue
  • memory problems

Men. High estrogen in men can cause

  • Infertility – Estrogen is partly responsible for creating healthy sperm. When estrogen levels are high, sperm levels may fall and lead to fertility issues.
  • Gynecomastia – Estrogen may stimulate breast tissue growth. Men with too much estrogen may develop gynecomastia, a condition which leads to larger breasts.
  • Erectile dysfunction (ED) – Men with high levels of estrogen may have difficulty getting or maintaining an erection.
  • Enlarged breasts (gynecomastia)
  • Poor erections
  • Infertility

Levels of estrogen

Estrogen levels vary among individuals. They also fluctuate during the menstrual cycle and over a female’s lifetime. This fluctuation can sometimes produce effects such as mood changes before menstruation or hot flashes in menopause.

Factors that can affect estrogen levels include

  • pregnancy, the end of pregnancy, and breastfeeding
  • puberty
  • menopause
  • older age
  • overweight and obesity
  • extreme dieting or anorexia nervosa
  • strenuous exercise or training
  • the use of certain medications, including steroids, ampicillin, estrogen-containing drugs, phenothiazines, and tetracyclines
  • some congenital conditions, such as Turner’s syndrome
  • high blood pressure
  • diabetes
  • primary ovarian insufficiency
  • an underactive pituitary gland
  • polycystic ovary syndrome (PCOS)
  • tumors of the ovaries or adrenal glands

Estrogen imbalance

An imbalance of estrogen leads to:

  • irregular or no menstruation
  • light or heavy bleeding during menstruation
  • more severe premenstrual or menopausal symptoms
  • hot flashes, night sweats, or both
  • noncancerous lumps in the breast and uterus
  • mood changes and sleeping problems
  • weight gain, mainly in the hips, thighs, and waist
  • low sexual desire
  • vaginal dryness and vaginal atrophy
  • fatigue
  • mood swings
  • feelings of depression and anxiety
  • dry skin
  • infertility
  • erectile dysfunction
  • larger breasts, known as gynecomastia

Males with low estrogen levels may have excess belly fat and low libido.

Estrogen sources and uses

If a person has low levels of estrogen, a doctor may prescribe supplements or medication.

Estrogen products include

  • synthetic estrogen
  • bioidentical estrogen
  • Premarin, which contains estrogens from the urine of pregnant mares

Estrogen therapy

  • Estrogen therapy can help manage menopause symptoms as part of hormone therapy, which people usually refer to as hormone replacement therapy.
  • The treatment may consist solely of estrogen (estrogen replacement therapy, or ERT), or it may involve a combination of estrogen and progestin, a synthetic form of progesterone.
  • Hormone treatment is available as a pill, nasal spray, patch, skin gel, injection, vaginal cream, or ring.


It can help manage

  • hot flashes
  • vaginal dryness
  • painful intercourse
  • mood changes
  • sleep disorders
  • anxiety
  • decreased sexual desire

It may also help reduce the risk of osteoporosis, which increases when people enter menopause.

Side effects include

  • bloating
  • breast soreness
  • headaches
  • leg cramps
  • indigestion
  • nausea
  • vaginal bleeding
  • fluid retention, leading to swelling

Some types of hormone therapy can also increase the risk of a stroke, blood clots, and uterine and breast cancer. A doctor can advise a person on whether estrogen therapy is suitable for them.

In addition to menopause, estrogen therapy can also help resolve

  • primary ovarian insufficiency
  • other ovarian issues
  • some types of acne
  • some cases of prostate cancer
  • delayed puberty[rx], for example, in Turner’s syndrome

High levels of estrogen can increase the risk and progression of some types of breast cancer. Some hormone treatments block the action[rx] of estrogen as a way of slowing or stopping cancer development. Hormonal therapy is not for everyone. A family history of breast cancer or thyroid issues may contradict using hormones. People who are unsure can speak to a doctor.

Transitioning to female

A doctor can prescribe estrogen[rx] as part of the therapy for a person assigned male at birth who wishes to transition to a female. The person may also need anti-androgenic treatment.

  • Estrogen can help a person develop female secondary sexual characteristics, such as breasts, and reduce male pattern hair formation.
  • Estrogen therapy will be part of a broader treatment approach. A healthcare professional can advise the individual on the best course of treatment.

Birth control

Birth control pills contain either synthetic estrogen and progestin or progestin-only.

  • Some types prevent pregnancy by stopping ovulation, and they do this by ensuring that hormone levels do not fluctuate throughout the month.
  • They also make the mucus in the cervix thick so that any sperm cannot reach the egg. Other uses include decreasing premenstrual symptoms and reducing the severity of hormone-related acne.

Birth control pills may increase the risk of

  • heart attack
  • stroke
  • blood clots
  • pulmonary embolism
  • nausea and vomiting
  • headaches
  • irregular bleeding
  • weight changes
  • breast tenderness and swelling

Oral birth control presents more risk for women who smoke or are over the age of 35 years. Long-term use may also lead to a higher risk of breast cancer.

Food sources of estrogen

Some foods contain phytoestrogens, which are plant-based substances that resemble estrogen. Some studies suggest that these may affect levels[rx] of estrogen in the body. However, there is not enough evidence to confirm this.

Foods that contain phytoestrogens include

  • cruciferous vegetables
  • soy and some foods containing soy protein
  • berries
  • seeds and grains
  • nuts
  • fruit
  • wine

Some people believe that foods containing phytoestrogens can help manage hot flashes and other effects of menopause, but this does not have scientific backing. In addition, eating whole soy foods, for example, is unlikely to have the same effect as taking extracts from soy as a supplement.


Supplements

Some herbs and supplements contain phytoestrogens, which act in a similar way to estrogen. These may help regulate estrogen and treat symptoms of menopause.

Examples are

  • black cohosh
  • red clover
  • soy isoflavones

However, it is unclear exactly how these compounds affect estrogen and estrogen-related activity in the body, and there is not enough evidence to confirm that they are safe and effective, especially in the long term. Researchers have called for further studies.

In addition, the Food and Drug Administration (FDA) does not regulate herbal and nonmedicinal supplements. As a result, it is not possible to know exactly what a product contains.

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patient’s risk of breast cancer, endometrial cancer, the risk of cardiovascular disease including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should be continued to be monitored for the development of hypertension while taking estrogen. Routine women’s wellness exams including mammography and pap smear should be continued during the use of hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of use of OCPs due to tobacco use having an increased risk of venous thrombosis.

The Endocrine Society recommends monitoring patients’ improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of the start of therapy, then re-evaluated at 6 to 12 months of therapy, then annually after the first year.

References

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