Ignore this, it's research, pointless research.
The Pituitary Gland
Anatomy of the pituitary gland:
The pituitary gland is sometimes called the "master" gland of the endocrine system, because it controls the functions of the other endocrine glands. The pituitary gland is no larger than a pea, and is located at the base of the brain. The gland is attached to the hypothalumus (a part of the brain that affects the pituitary gland) by nerve fibers. The pituitary gland itself consists of three sections:
· the anterior lobe
· the intermediate lobe
· the posterior lobe
Functions of the pituitary gland:
Each lobe of the pituitary gland produces certain hormones.
anterior lobe:
· growth hormone
· prolactin - to stimulate milk production after giving birth
· ACTH (adrenocorticotropic hormone) - to stimulate the adrenal glands
· TSH (thyroid-stimulating hormone) - to stimulate the thyroid gland
· FSH (follicle-stimulating hormone) - to stimulate the ovaries and testes
· LH (luteinizing hormone) - to stimulate the ovaries or testes
intermediate lobe:
· melanocyte-stimulating hormone - to control skin pigmentation
posterior lobe:
· ADH (antidiuretic hormone) - to increase absorption of water into the blood
by the kidneys
· oxytocin - to contract the uterus during childbirth and stimulate milk production
Hormones of the Pituitary
The pituitary gland is pea-sized structure located at the base of the brain. In humans, it consists of two lobes:
· the Anterior Lobe and
· the Posterior Lobe
Link to graphic showing the locationof the pituitary and other endocrineglands (92K).
The Anterior Lobe
The anterior lobe contains six types of secretory cells, all but one of which (#2 above) are specialized to secrete only one of the anterior lobe hormones. All of them secrete their hormone in response to hormones reaching them from the hypothalamus of the brain.
Thyroid Stimulating Hormone (TSH)
TSH (also known as thyrotropin) is a glycoprotein consisting of:
· a beta chain of 112 amino acids and
· an alpha chain of 89 amino acids. The alpha chain is identical to that found in two other pituitary hormones, FSH and LH. Thus it is its beta chain that gives TSH its unique properties.
The secretion of TSH is
· stimulated by the arrival of thyrotropin releasing hormone (TRH) from the hypothalamus.
· inhibited by the arrival of somatostatin from the hypothalamus.
As its name suggests, TSH stimulates the thyroid gland to secrete its hormone thyroxine (T4). It does this by binding to transmembrane G-protein-coupled receptors (GPCRs) on the surface of the cells of the thyroid.
Some people develop antibodies against their own TSH receptors. When these bind the receptors, they "fool" the cell into making more T4 causing hyperthyroidism. The condition is called thyrotoxicosis or Graves' disease.
Hormone deficiencies
A deficiency of TSH causes hypothyroidism: inadequate levels of T4 (and thus of T3 [Link]). Recombinant human TSH has recently become available to treat patients with TSH deficiency.
Some people inherit mutant TSH receptors. This, too, results in hypothyroidism.
A deficiency of TSH, or mutant TSH receptors, have also been implicated as a cause of osteoporosis. Mice, whose TSH receptors have been knocked out, develop increased numbers of bone-reabsorbing osteoclasts.
Follicle-Stimulating Hormone (FSH)
FSH is a heterodimer of
· the same alpha chain found in TSH (and LH)
· a beta chain of 115 amino acids, which gives it its unique properties.
Synthesis and release of FSH is triggered by the arrival from the hypothalamus of gonadotropin-releasing hormone (GnRH). The effect of FSH depends on one's sex
FSH in females
In sexually-mature females, FSH (assisted by LH) acts on the follicle to stimulate it to release estrogens.
FSH in males
In sexually-mature males, FSH acts on spermatogonia stimulating (with the aid of testosterone) the production of sperm.
Luteinizing Hormone (LH)
LH is synthesized within the same pituitary cells as FSH and under the same stimulus (GnRH). It is a heterodimeric glycoprotein consisting of
· the same 89-amino acid alpha subunit found in FSH and TSH
· a beta chain of 115 amino acids that is responsible for its properties.
The effects of LH also depend on sex.
LH in females
In sexually-mature females, LH
· stimulates the follicle to secrete estrogen in the first half of the menstrual cycle
· a surge of LH triggers the completion of meiosis I of the egg and its release (ovulation) in the middle of the cycle
· stimulates the now-empty follicle to develop into the corpus luteum,which secretes progesterone during the latter half of the menstrual cycle.
LH in males
LH acts on the interstitial cells of the testes stimulating them to synthesize and secrete the male sex hormone, testosterone.
LH in males is also known as interstitial cell stimulating hormone (ICSH).
Prolactin (PRL)
Prolactin is a protein of 198 amino acids. During pregnancy it helps in the preparation of the breasts for future milk production.
After birth, prolactin promotes the synthesis of milk.
Prolactin secretion is
· stimulated by TRH
· repressed by estrogens and dopamine.
In pregnant mice, prolactin stimulates the growth of new neurons in the olfactory center of the brain.
Growth Hormone (GH)
Human growth hormone (also called somatotropin) is a protein of 191 amino acids. The GH-secreting cells are stimulated to synthesize and release GH by the intermittent arrival of growth hormone releasing hormone (GHRH) from the hypothalamus. GH promotes body growth by:
· binding to receptors on the surface of liver cells
· this stimulates them to release insulin-like growth factor-1 (IGF-1; also known as somatomedin)
· IGF-1 acts directly on the ends of the long bones promoting their growth
Things that can go wrong.
· In childhood,
o hyposecretion of GH produces the stunted growth of a dwarf. Dwarfism can also result from an inability to respond to GH. This can result from inheriting two mutant genes encoding the receptors for
§ GHRH or
§ GH
or homozygosity for a disabling mutation in STAT5b, which is part of the "downstream" signaling process after GH binds its receptor.
o hypersecretion leads to gigantism
· In adults, a hypersecretion of GH leads to acromegaly.
Hormone-replacement therapy
GH from domestic mammals like cows and pigs does not work in humans. So for many years, the only source of GH for therapy was that extracted from the glands of human cadavers. But this supply was shut off when several patients died from a rare neurological disease attributed to contaminated glands. Now, thanks to recombinant DNA technology, recombinant human GH (rHGH) is available. While a great benefit to patients suffering from GH deficiency, there has also been pressure to use it to stimulate growth in youngsters who have no deficiency but whose parents want them to grow up tall. And so, in the summer of 2003, the U.S. FDA approved the use of human growth hormone (HGH) for
· boys predicted to grow no taller than 5′3″ and
· for girls, 4′11″
even though otherwise perfectly healthy.
ACTH - the adrenocorticotropic hormone
ACTH is a peptide of 39 amino acids. It is cut from a larger precursor proopiomelanocortin (POMC).
ACTH acts on the cells of the adrenal cortex, stimulating them to produce
· glucocorticoids, like cortisol
· mineralocorticoids, like aldosterone
· androgens (male sex hormones, like testosterone
· in the fetus, ACTH stimulates the adrenal cortex to synthesize a precursor of estrogen called dehydroepiandrosterone sulfate (DHEA-S) which helps prepare the mother for giving birth.
Production of ACTH depends on the intermittent arrival of corticotropin-releasing hormone (CRH) from the hypothalamus.
Hypersecretion of ACTH is a frequent cause of Cushing's disease.
Alpha Melanocyte-Stimulating Hormone (α-MSH)
Alpha MSH is also a cleavage product of proopiomelanocortin (POMC). In fact, α-MSH is identical to the first 13 amino acids at the amino terminal of ACTH.
MSH is discussed in a separate page. Link to it.
The Posterior Lobe
The posterior lobe of the pituitary releases two hormones, both synthesized in the hypothalamus, into the circulation.
· Antidiuretic Hormone (ADH).
ADH is a peptide of 9 amino acids. It is also known as arginine vasopressin.
ADH acts on the collecting ducts of the kidney to facilitate the reabsorption of water into the blood. This it acts to reduce the volume of urine formed (giving it its name of antidiuretic hormone).
Link to discussion of kidney physiology.
o A deficiency of ADH or
o inheritance of mutant genes for its receptor (called V2)
leads to excessive loss of urine, a condition known as diabetes insipidus. The most severely-afflicted patients may urinate as much as 30 liters (almost 8 gallons!) of urine each day. The disease is accompanied by terrible thirst, and patients must continually drink water to avoid dangerous dehydration.
Another type of receptor for arginine vasopressin (designated V1a) is found in the brain, e.g., in voles and mice (rodents) and in primates like monkeys and humans.
o Male prairie voles (Microtus pinetorum) and marmoset monkeys
§ have high levels of the V1a receptor in their brains,
§ tend to be monogamous, and
§ help with care of their young.
o Male meadow voles (Microtus montanus) and rhesus monkeys
§ have lower levels of the V1a receptor in their brains,
§ are promiscuous, and
§ give little or no help with the care of their young.
Meadow voles whose brains have been injected with a vector causing increased expression of the V1a receptor become more like prairie voles in their behavior. (See Lim, M. M. et al., Nature, 17 June 2004.)
Changes in the regulatory region of the human gene for the V1a receptor have been linked to autism.
· Oxytocin
Oxytocin is a peptide of 9 amino acids. Its principal actions are:
o stimulating contractions of the uterus at the time of birth
o stimulating release of milk when the baby begins to suckle
Oxytocin is often given to prospective mothers to hasten birth.
The hypothalamus is a region of the brain. It secretes a number of hormones.
· Thyrotropin-releasing hormone (TRH)
· Gonadotropin-releasing hormone (GnRH)
· Growth hormone-releasing hormone (GHRH)
· Corticotropin-releasing hormone (CRH)
· Somatostatin
· Dopamine
All of these are released into the blood, travel immediately to the anterior lobe of the pituitary, where they exert their effects.
All of them are released in periodic spurts. In fact, replacement hormone therapy with these hormones does not work unless the replacements are also given in spurts.
Two other hypothalamic hormones:
· Antidiuretic hormone (ADH) and
· Oxytocin
travel in neurons to the posterior lobe of the pituitary where they are released into the circulation.
Link to diagram of the endocrine glands (92K)
Thyrotropin-releasing hormone (TRH)
TRH is a tripeptide (GluHisPro).
When it reaches the anterior lobe of the pituitary it stimulates the release there of
· thyroid-stimulating hormone (TSH)
· prolactin (PRL)
Gonadotropin-releasing hormone (GnRH)
GnRH is a peptide of 10 amino acids. Its secretion at the onset of puberty triggers sexual development.
Primary Effects Secondary Effects
FSH and LH Up estrogen and progesterone Up (in females)
testosterone Up (in males)
After puberty, a hyposecretion of GnRH may result from
· intense physical training
· anorexia nervosa
Synthetic agonists of GnRH are used to treat
· inherited or acquired deficiencies of GnRH secretion.
· prostate cancer. In this case, high levels of the GnRH agonist
o reduces the number of GnRH receptors in the pituitary, which
o reduces its secretion of FSH and LH, which
o reduces the secretion of testosterone, which
o reduces the stimulation of the cells of the prostate.
Growth hormone-releasing hormone (GHRH)
GHRH is a mixture of two peptides, one containing 40 amino acids, the other 44.
As its name indicates, GHRH stimulates cells in the anterior lobe of the pituitary to secrete growth hormone (GH).
Corticotropin-releasing hormone (CRH)
CRH is a peptide of 41 amino acids.
As its name indicates, its acts on cells in the anterior lobe of the pituitary to release adrenocorticotropic hormone (ACTH)
CRH is also synthesized by the placenta and seems to determine the duration of pregnancy.
Description of the mechanism.
It may also play a role in keeping the T cells of the mother from mounting an immune attack against the fetus. [Discussion]
Somatostatin
Somatostatin is a mixture of two peptides, one of 14 amino acids, the other of 28.
Somatostatin acts on the anterior lobe of the pituitary to
· inhibit the release of growth hormone (GH)
· inhibit the release of thyroid-stimulating hormone (TSH)
Somatostatin is also secreted by cells in the pancreas and in the intestine where it inhibits the secretion of a variety of other hormones.
Dopamine
Dopamine is a derivative of the amino acid tyrosine. Its principal function in the hypothalamus is to inhibit the release of prolactin (PRL) from the anterior lobe of the pituitary.
Antidiuretic hormone (ADH) and Oxytocin
These peptides are released from the posterior lobe of the pituitary and are described in the page devoted to the pituitary.
ADH
Oxytocin
What is it?
Anatomy
The hypothalamus is an integral part of the substance of the brain. A small cone-shaped structure, it projects downward, ending in the pituitary (infundibular) stalk, a tubular connection to the pituitary gland. The round bony cavity containing the pituitary gland is called the sella turcica. The posterior portion of the hypothalamus, called the median eminence, contains many neurosecretory cells. Important adjacent structures include the mammillary bodies, the third ventricle, and the optic chiasm, the last being of particular concern to physicians because pressure from expanding tumours or inflammations in the hypothalamus or pituitary gland may result in severe visual defects or total blindness. Above the hypothalamus is the thalamus. (For discussion of the function of these surrounding structures, see the nervous system.)
Regulation of hormone secretion
The hypothalamus regulates homeostasis. It has regulatory areas for thirst, hunger, body temperature, water balance, and blood pressure, and links the nervous system to the endocrine system.
The hypothalamus, like the rest of the brain, consists of interconnecting nerve cells ( neurons) with a rich blood supply. To understand hypothalamic function it is necessary to define the various forms of neurosecretion. First, there is neurotransmission, which occurs throughout the brain and is the process by which one nerve cell communicates with another at an intimate intermingling of projections from the two cells (a synapse). This transmission of an electrical impulse from one cell to another requires the secretion of a chemical substance from a long projection from one nerve cell body (the axon) into the synaptic space. The chemical substance that is secreted is called a neurotransmitter. The process of synthesis and secretion of neurotransmitters is similar to that shown in Figure 1 with the exception that neurosecretory granules migrate through lengths of the axon before being discharged into the synaptic space.
Figure 1: Intracellular structure of a typical endocrine cell.
Neurologists have long been aware of four classical neurotransmitters: epinephrine, norepinephrine, serotonin, and acetylcholine, but recently there have emerged a large number of additional neurotransmitters, of which an important group is the neuropeptides. While bioamines and neuropeptides function as neurotransmitters, some of them also perform the role of neuromodulators; they do not act directly as neurotransmitters but rather as inhibitors or stimulators of neurotransmission. Well-known examples are the opioids (for example, enkephalins), so named because they are the naturally occurring peptides with a strong affinity to the receptors that bind opiate drugs such as morphine and heroin. In effect, they are the body's opiates.
Thus the brain, and indeed the entire central nervous system, consists of an extraordinary network of neurons interconnected by neurotransmitters. The secretion of specific neurotransmitters, modified by neuromodulators, lends an organized, directed function to the overall system. These neural connections extend upward from the hypothalamus into other key areas, including the cerebral cortex. The result is that intellectual and functional activities as well as external influences, including stresses, can be funneled into the hypothalamus and thence to the endocrine system, from which they may exert effects on the body.
In addition to secreting neurotransmitters and neuromodulators, the hypothalamus synthesizes and secretes a number of neurohormones. The neurons secreting neurohormones are true endocrine (neurohemal) cells in the classical sense since secretory granules containing neurohormones travel from the cell body through the axon to be extruded, where they enter directly a capillary network, thence to be transported through the hypophyseal-portal circulation to the anterior pituitary gland.
Finally, the neurohypophysis, or posterior lobe of the pituitary gland, provides the classical example of neurohormonal activity. The secretory products, mainly vasopressin and oxytocin, are extruded into a capillary network, which feeds directly into the general circulation.
The existence of hormones of the hypothalamus was predicted well before they were detected and chemically characterized, and they have been studied intensively by many investigators. Two groups of American investigators, led by Andrew Schally and Roger Guillemin, respectively, shared the Nobel Prize for Physiology or Medicine for 1977 for their research on pituitary hormones.
These neurohormones are known as releasing hormones because the major function generally is to stimulate the secretion of hormones originating in the anterior pituitary gland. They consist of simple peptides (chains of amino acids) ranging in size from only three amino acids (thyrotropin-releasing hormone) to 44 amino acids (growth hormone-releasing hormone).
Hormones
Thyrotropin-releasing hormone
Thyrotropin-releasing hormone (TRH), a neurohormone, is the simplest of the hypothalamic neuropeptides. It consists essentially of three amino acids in the sequence glutamic acid-histidine-proline. The simplicity of this structure is deceiving for TRH is involved in an extraordinary array of functions. Not only is it a neurohormone that stimulates the secretion of thyroid-stimulating hormone from the pituitary, and, quite independently, the secretion of another pituitary hormone called prolactin, but it also subserves other central nervous system activities because it is a widespread neurotransmitter or neuromodulator within the brain and spinal cord. There is evidence that TRH is involved in the control of body temperature and that it has psychological and behavioral effects, at least in animals. It may also have therapeutic value. There are studies suggesting that it mitigates the damage induced by spinal cord injury and that it leads to some improvement in the nervous disease known as amyotrophic lateral sclerosis (Lou Gehrig's disease).
These multiple effects are less surprising when it is considered that TRH appeared very early in the evolutionary scale of vertebrates and that, while the concentration of TRH is greatest in the hypothalamus, the total amount of TRH in the remainder of the brain far exceeds that of the hypothalamus. The TRH-secreting cells are subject to stimulatory and inhibitory influences from higher centres in the brain and they also are inhibited by circulating thyroid hormone. In this way TRH forms the topmost segment of the hypothalamic-pituitary-thyroid axis.
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH), a neurohormone also known as luteinizing hormone-releasing hormone (LHRH), is a peptide chain of 10 amino acids. It stimulates the synthesis and release of the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While some investigators hold that there are two types of GnRH, most evidence supports the conclusion that only one type of neuropeptide stimulates the release of the two gonadotropins and that the variations in levels of both gonadotropins in the circulation are due to other modulating factors.
Characteristic of all releasing hormones and most striking in the case of GnRH is the phenomenon of pulsatile secretion. In normal individuals, GnRH is released in spurts at intervals of about 80 minutes. The pulsatile administration of GnRH in large doses results in an ever-increasing concentration of gonadotropins in the blood. In striking contrast, the constant infusion of GnRH suppresses gonadotropin secretion. This phenomenon is advantageous for persons for whom suppression is important. Such persons include children with precocious puberty, and elderly men with cancer of the prostate. On the other hand, pulsatile administration of GnRH is efficacious in men or women in whom deficiency of gonadal function is due to impaired secretion of GnRH. A potential application of this phenomenon is the synthetic modifications of GnRH as a male as well as a female contraceptive.
Neurons that secrete GnRH have connections to an area of the brain known as the limbic system, which is heavily involved in the control of emotions and sexual activity. Studies in rats deprived of pituitary glands and ovaries but maintained on physiological amounts of female hormone (estrogen) have demonstrated that the injection of GnRH results in complex and striking changes in posture characteristic of the receptive female stance for sexual intercourse.
Some individuals have hypogonadism (in which the functional activity of the gonads is decreased and sexual development is inhibited) due to a congenital deficiency of GnRH, which responds to treatment with GnRH. Most of these people also suffer from hypothalamic disease and are deficient in other releasing hormones as well, but there are also individuals in whom GnRH deficiency is isolated and associated with a loss of the sense of smell (anosmia). Abnormalities in the pulses of GnRH secretion result in subnormal fertility, abnormal or absent menstruation, and possibly cystic disease of the ovary or even ovarian cancer
Corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH), a neurohormone, is a large peptide consisting of a single chain of 41 amino acids. It stimulates not only secretion of corticotropin in the pituitary gland but also the synthesis of corticotropin in the corticotropin-producing cells (corticotrophs) of the anterior lobe of the pituitary gland. Many factors, both neurogenic and hormonal, regulate the secretion of CRH, since CRH is the final common element directing the body's response to all forms of stress, whether physical or emotional, external or internal. (This key role of CRH in the hypothalamic-pituitary-adrenal axis is discussed below in connection with the adrenal gland.) Among the hormones that play an important role in modulating the influence of CRH is cortisol, the major hormone secreted by the adrenal cortex, which, as part of the negative feedback servomechanism (exerting control over another system through negative feedback), blocks the secretion of CRH. Vasopressin, the major regulator of the body's excretion of water, has an additional ancillary role in stimulating the secretion of CRH.
Excessive secretion of CRH leads to an increase in the size and number of corticotrophs in the pituitary gland, often resulting in a pituitary tumour. This, in turn, leads to excessive stimulation of the adrenal cortex, resulting in high circulating levels of adrenocortical hormones, the clinical manifestations of which are known as Cushing's syndrome. Conversely, a deficiency of CRH-producing cells can, by a lack of stimulation of the pituitary and adrenal cortical cells, result in adrenocortical deficiency. (These conditions are discussed below.
Growth hormone-releasing hormone
Like CRH, growth hormone-releasing hormone (GHRH) is a large peptide. A number of forms have been described that differ from one another only in minor detail and in the number of amino acids (varying from 37 to 44). Unlike the other neurohormones, GHRH is not widely distributed in other parts of the brain. It is stimulated by stresses, including physical exercise, and secretion is blocked by a powerful inhibitor called somatostatin (see below Somatostatin). Negative feedback control of GHRH secretion is mediated largely through compounds called somatomedins, growth-promoting hormones that are generated when tissues are exposed to growth hormone itself.
An excess of circulating growth hormone in adults leads to a condition called acromegaly. Rarely, a benign tumour, called a hamartoma, located in the hypothalamus may produce excessive amounts of GHRH, leading to acromegaly. Equally rare are tumours arising in the islets of Langerhans of the pancreas that may secrete excessive quantities of GHRH. Indeed, GHRH was first successfully isolated and analyzed from such an ectopic (abnormally positioned) hormone-producing tumour. Isolated deficiency of GHRH (in which there is normal functioning of the hypothalamus except for this deficiency) may be the cause of one form of dwarfism, a general term applied to all individuals with abnormally small stature.
Somatostatin
Somatostatin refers to a number of polypeptides consisting of chains of 14 to 28 amino acids. The name was coined when its discoverers found that an extract of the hypothalamus strongly inhibited the release of growth hormone from the pituitary gland. Somatostatin is also a powerful inhibitor of pituitary TSH secretion. Somatostatin, like TRH, is widely distributed in the central nervous system and in other tissues. It serves an important paracrine function in the islets of Langerhans, by blocking the secretion of both insulin and glucagon from adjacent cells. Somatostatin has emerged not only as a powerful blocker of the secretion of GH, insulin, glucagon, and other hormones but also as a potent inhibitor of many functions of the gastrointestinal tract, including the secretion of stomach acid, the secretion of pancreatic enzymes, and the process of intestinal absorption. Despite these multiple, widespread actions, the term somatostatin has persisted because of its major role as a regulator of GH secretion, and impaired somatostatin secretion may cause some forms of hypersecretion of growth hormone.
No examples of somatostatin deficiency have been found, but a tumour called a somatostatinoma has been well characterized in a number of patients. Persons with a somatostatinoma have cramping abdominal pain, persistent diarrhea, a mild elevation of blood glucose levels, and sudden flushing of the skin.
Prolactin-inhibiting and releasing hormones
The hypothalamic regulation of prolactin secretion from the pituitary is different from the hypothalamic regulation of other pituitary hormones in two respects. First, the hypothalamus primarily inhibits rather than stimulates the release of prolactin from the pituitary (the hypothalamus stimulates the release of all other pituitary hormones). Thus, if pituitary cells are removed from the influence of the hypothalamus, few or none of the pituitary hormones are secreted, except for prolactin, which continues to be secreted by the prolactin-secreting cells (lactotrophs). Second, this major inhibiting factor is not a neuropeptide, but rather the neurotransmitter dopamine, a fact exploited in afflicted persons by physicians who are able to reduce abnormally high concentrations of prolactin by using drugs that mimic the prolactin-inhibiting effects of dopamine. Another prolactin-inhibiting factor (PRF) comes into play primarily during pregnancy and lactation. Prolactin-stimulating factors also exist, among them TRH.
Prolactin deficiency is known to occur, but only rarely. Excessive prolactin production (hyperprolactinemia) is a common endocrine abnormality, and the prolactinoma is the most frequently encountered pituitary tumour.
Gastrointestinal neuropeptides
Although modern endocrinology began with the discovery that a substance, secretin, secreted into the blood from the cells lining the gastrointestinal tract stimulates the secretion of pancreatic juices, little attention was subsequently paid to gastrointestinal hormones. When investigators began to examine the distribution of neuropeptides within the body, however, there emerged a bewildering variety of these hormones, not only within the brain but also in the lining of the gastrointestinal tract and in other organs. The list includes glucagon, the enkephalins, secretin, cholecystokinin, gastrin, calcitonin, angiotensin, substance P, pancreatic polypeptide, neuropeptide Y (a human variant of a peptide called bombesin), delta-sleep-inducing peptide, and vasoactive intestinal peptide. The actions and interactions of these hormones both in the intestinal tract and in the brain are complex and are the subject of continuing investigations. Briefly, these peptides play important roles in the transmission and inhibition of pain stimuli, in eating and drinking behaviour, in memory and learning, in the regulation of body temperature, in the induction of sleep, and in sexual behaviour.
Hypothalamus
The hypothalamus is a part of the brain. It controls part of the autonomic nervous system, which is the part of the nervous system that controls the body organs. The hypothalamus releases substances (hormones) that help control the endocrine and nervous systems, regulate body temperature and sleep, and affect other body functions.
The hypothalamus produces a hormone called thyrotropin-releasing hormone (TRH), which stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH). TSH, in turn, regulates the amount of thyroid hormone produced and released into the bloodstream by the thyroid gland. A problem in the hypothalamus can result in decreased release of thyroid hormone by the thyroid gland.
Your Thyroid Gland
What is Your Thyroid Gland?
Your thyroid gland is one of the endocrine glands, which make hormones to regulate physiological functions in your body. The thyroid gland manufactures thyroid hormone, which regulates the rate at which your body carries on its necessary functions. Other endocrine glands are the pancreas, the pituitary, the adrenal glands, the parathyroid glands, the testes, and the ovaries.
The thyroid gland is located in the middle of the lower neck, below the larynx (voice box) and just above your clavicles (collarbones). It is shaped like a "bow tie," having two halves (lobes): a right lobe and a left lobe joined by an "isthmus.". You can't always feel a normal thyroid gland.
When Is a Thyroid Gland Abnormal?
Diseases of the thyroid gland are very common, affecting millions of Americans. The most common diseases are an over- or under-active gland. These conditions are called hyperthyroidism (e.g., Grave's disease) and hypothyroidism. Sometimes the thyroid gland can become enlarged from over-activity (as in Grave's disease) or from under-activity (as in hypothyroidism). An enlarged thyroid gland is often called a "goiter." Sometimes an inflammation of the thyroid gland (Hashimoto's disease) will cause enlargement of the gland.
Patients may develop "lumps" or "masses" in their thyroid glands. They may appear gradually or very rapidly. Patients who had radiation therapy to the head or neck as children for acne, adenoids, or other reasons are more prone to develop thyroid malignancy. A doctor should evaluate all thyroid "lumps" (nodules).
How Does Your Doctor Make the Diagnosis?
The diagnosis of a thyroid abnormality in function or a thyroid mass is made by taking a medical history and a physical examination. Specifically, your doctor will examine your neck and ask you to lift up your chin to make your thyroid gland more prominent. You may be asked to swallow during the examination, which helps to feel the thyroid and any mass in it. Other tests your doctor may order include:
1. An ultrasound examination of your neck and thyroid
2. Blood tests of thyroid function
3. A radioactive thyroid scan
4. A fine needle aspiration biopsy
5. A chest X-ray
6. A CT or MRI scan
Fine Needle Aspiration
If a lump in your thyroid is diagnosed, your doctor may recommend a fine needle aspiration biopsy. This is a safe, relatively painless procedure. A hypodermic needle is passed into the lump, and samples of tissues are taken. Often several passes with the needle are required. There is little pain afterward and very few complications from the procedure occur. This test gives the doctor more information on the nature of the lump in your thyroid gland and specifically will help to differentiate a benign from a malignant thyroid mass.
Treatment of Thyroid Disease
Abnormalities of thyroid function (hyper or hypothyroidism) are usually treated medically. If there is insufficient production of thyroid hormone, this may be given in a form of a thyroid hormone pill taken daily. Hyperthyroidism is treated mostly by medical means, but occasionally it may require the surgical removal of the thyroid gland.
If there is a lump of the thyroid or a diffused enlargement (goiter), your doctor will propose a treatment plan based on the examination and your test results. Most thyroid "lumps" are benign. Often they may be treated with thyroid hormone, and this is called "suppression" therapy. The object of this treatment is to attempt shrinkage of the mass over time, usually three-six months. If the lump continues to grow during treatment when you are taking the medication, most doctors will recommend removal of the affected lump.
If the fine needle aspiration is reported as suspicious for or suggestive of cancer, then thyroid surgery is required.
What Is Thyroid Surgery?
Thyroid surgery is an operation to remove part or all of the thyroid gland. It is performed in the hospital, and general anesthesia is usually required. Usually the operation removes the lobe of the thyroid gland containing the lump and possibly the isthmus. A frozen section (an immediate microscopic reading) may or may not be used to determine if the rest of the thyroid gland should be removed. Sometimes, based on the result of the frozen section, the surgeon may decide to stop and remove no more thyroid tissue, or proceed to remove the entire thyroid gland, and/or other tissue in the neck. This is a decision usually made in the operating room by the surgeon, based on findings at the time of surgery. Your surgeon will discuss these options with you preoperatively.
After surgery, you may have a drain (a tiny piece of plastic tubing), which prevents fluid from building up in the wound. This is removed after the fluid accumulation is minimal. Most patients are discharged one to three days after surgery. Complications after thyroid surgery are rare. They include bleeding, a hoarse voice, difficulty swallowing, numbness of the skin on the neck, and low blood calcium. Most complications go away after a few weeks. Patients who have all of their thyroid gland removed have a higher risk of low blood calcium post-operatively.
Patients who have thyroid surgery may be required to take thyroid medication to replace thyroid hormones after surgery. Some patients may need to take calcium replacement if their blood calcium is low. This will depend on how much thyroid gland remains, and what was found during surgery. If you have any questions about thyroid surgery, ask your doctor and he or she will answer them in detail.
Hormones of the Pancreas
The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. [Discussion]
Link to graphic showing the locationof the pancreas and other endocrine glands (92K).
However, scattered through the pancreas are several hundred thousand clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are the:
· beta cells, which secrete insulin and amylin;
· alpha cells, which secrete glucagon;
· delta cells, which secrete somatostatin, and
· gamma cells, which secrete a polypeptide of unknown function.
Beta Cells
Insulin is a small protein consisting of
· an alpha chain of 21 amino acids linked by two disulfide (S-S) bridges to a
· beta chain of 30 amino acids.
Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose ("blood sugar").
Insulin affects many organs. It
· stimulates skeletal muscle fibers to
o take up glucose and convert it into glycogen;
o take up amino acids from the blood and convert them into protein.
· acts on liver cells
o stimulating them to take up glucose from the blood and convert it into glycogen while
o inhibiting production of the enzymes involved in breaking glycogen back down ("glycogenolysis").
· acts on fat (adipose) cells to stimulate the uptake of glucose and the synthesis of fat.
In each case, insulin triggers these effects by binding to the insulin receptor - a transmembrane protein embedded in the plasma membrane of the responding cells.
Taken together, all of these actions result in:
· the storage of the soluble nutrients absorbed from the intestine into insoluble, energy-rich products (glycogen, protein, fat)
· a drop in the level of blood sugar
Diabetes Mellitus
Diabetes mellitus is an endocrine disorder characterized by many signs and symptoms. Primary among these are:
· a failure of the kidney to reclaim glucose so that glucose spills over into the urine
· a resulting increase in the volume of urine because of the osmotic effect of this glucose (it reduces the return of water to the blood).
Diabetes mellitus is a disorder quite distinct from the similarly-named diabetes insipidus. They both result in the production of large amounts of urine (diabetes), but in one the urine is sweet while in the other (caused by ADH deficiency) it is not. Before the days of laboratory tests, a simple taste test ("mellitus" or "insipidus") enabled the doctor to make the correct diagnosis.
There are three categories of diabetes mellitus:
· Insulin-Dependent Diabetes Mellitus (IDDM) [also called "Type 1" diabetes] and
· Non Insulin-Dependent Diabetes Mellitus (NIDDM)["Type 2"]
· Inherited Forms of Diabetes Mellitus
Insulin-Dependent Diabetes Mellitus (IDDM)
IDDM (also called Type 1 diabetes)
· is characterized by little (hypo) or no circulating insulin;
· most commonly appears in childhood.
· It results from destruction of the beta cells of the islets.
· The destruction results from a cell-mediated autoimmune attack against the beta cells.
· What triggers this attack is still a mystery, although a prior viral infection may be the culprit.
IDDM is controlled by carefully-regulated injections of insulin. (Insulin cannot be taken by mouth because, being a protein, it would be digested.)
For many years, insulin extracted from the glands of cows and pigs was used. However, pig insulin differs from human insulin by one amino acid; beef insulin by three. Although both work in humans to lower blood sugar, they are seen by the immune system as "foreign" and induce an antibody response in the patient that blunts their effect and requires higher doses.
Two approaches have been taken to solve this problem:
· Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. This approach is expensive, so now the favored approach is to
· Insert the human gene for insulin into E. coli and grow recombinant human insulin in culture tanks. Insulin is not a glycoprotein so E. coli is able to manufacture a fully-functional molecule (trade name = Humulin). Yeast is also used (trade name = Novolin).
Injections of insulin must be done carefully. Injections after vigorous exercise or long after a meal may drive the blood sugar level down to a dangerously low value causing an insulin reaction. The patient becomes irritable, fatigued, and may lose consciousness. If the patient is still conscious, giving a source of sugar (e.g., candy) by mouth usually solves the problem quickly. Injections of glucagon are sometimes used.
Non Insulin-Dependent Diabetes Mellitus (NIDDM)
Many people develop diabetes mellitus without an accompanying drop in insulin levels (at least at first).
In many cases, the problem appears to be a failure to express a sufficient number of glucose transporters in the plasma membrane (and T-system) of their skeletal muscles.
Normally when insulin binds to its receptor on the cell surface, it initiates a chain of events that leads to the insertion in the plasma membrane of increased numbers of a transmembrane glucose transporter.
Discussion of how transmembrane proteins are moved to the surface of the cell in which they are synthesized.
This transporter forms a channel that permits the facilitated diffusion of glucose into the cell.
Skeletal muscle is the major "sink" for removing excess glucose from the blood (and converting it into glycogen). In NIDDM, the patient's ability to remove glucose from the blood and convert it into glycogen may be only 20% of normal. This is called insulin resistance. Curiously, vigorous exercise seems to increase the expression of the glucose transporter (called GLUT-4) on skeletal muscle and this may explain why IDDM is more common in people who live sedentary lives.
NIDDM (also called Type 2 diabetes mellitus) usually strikes in adults and, particularly often, in overweight people. However, over the last few years in the U. S., the incidence of NIDDM in children has grown to the point where they now account for 20% of all newly-diagnosed cases (and, like their adult counterparts, are usually overweight).
Several drugs, all of which can be taken by mouth, are useful in restoring better control over blood sugar in patients with NIDDM.
However, late in the course of disease, patients may have to begin to take insulin. It is as though after years of pumping out insulin in an effort to overcome the patient's insulin resistance, the beta cells become exhausted.
Inherited Forms of Diabetes Mellitus
Some cases of diabetes result from mutant genes inherited from one or both parents. Examples:
· mutant genes for one or another of the transcription factors needed for transcription of the insulin gene (5 mutant versions have been identified).
· mutations in one or both copies of the gene encoding the insulin receptor. These patients usually have extra-high levels of circulating insulin but defective receptors. The mutant receptors
o may fail to be expressed properly at the cell surface or
o may fail to transmit an effective signal to the interior of the cell.
· a mutant version of the gene encoding glucokinase, the enzyme that phosphorylates glucose in the first step of glycolysis.
· mutations in the gene encoding part of potassium channels in the plasma membrane of the beta cell. The channels fail to close properly causing the cell to become hyperpolarized and blocking insulin secretion.
· mutations in several mitochondrial genes which reduce insulin secretion by beta cells. These diseases are inherited from the mother as only her mitochondria survive in the fertilized egg.
While symptoms usually appear in childhood or adolescence, patients with inherited diabetes differ from most children with NIDDM in
· having a history of diabetes in the family and
· not being obese.
Amylin
Amylin is a peptide of 37 amino acids, which is also secreted by the beta cells of the pancreas.
Some of its actions:
· inhibits the secretion of glucagon;
· slows the emptying of the stomach;
· sends a satiety signal to the brain.
All of its actions tend to supplement those of insulin, reducing the level of glucose in the blood.
Alpha Cells
The alpha cells of the islets secrete glucagon, a polypeptide of 29 amino acids.
Glucagon acts principally on the liver where it stimulates the conversion of glycogen into glucose ("glycogenolysis") which is deposited in the blood.
Glucagon secretion is
· stimulated by low levels of glucose in the blood;
· inhibited by high levels, and
· inhibited by amylin.
The physiological significance of this is that glucagon functions to maintain a steady level of blood sugar level between meals.
Injections of glucagon are sometimes given to diabetics suffering from an insulin reaction in order to speed the return of normal levels of blood sugar.
Delta Cells
The delta cells secrete somatostatin. This consists of two polypeptides, one of 14 amino acids and one of 28.
Somatostatin has a variety of functions. Taken together, they work to reduce the rate at which food is absorbed from the contents of the intestine.
Somatostatin is also secreted by the hypothalamus and by the intestine. Further information about somatostatin can be found by following the links.
Gamma Cells
The gamma cells of the islets secrete pancreatic polypeptide. No function has yet been found for this peptide of 36 amino acids.
The gonads, the primary reproductive organs, are the testes in the male and the ovaries in the female. These organs are responsible for producing the sperm and ova, but they also secrete hormones and are considered to be endocrine glands.
Testes
Male sex hormones, as a group, are called androgens. The principal androgen is testosterone, which is secreted by the testes. A small amount is also produced by the adrenal cortex. Production of testosterone begins during fetal development, continues for a short time after birth, nearly ceases during childhood, and then resumes at puberty. This steroid hormone is responsible for:
· The growth and development of the male reproductive structures
· Increased skeletal and muscular growth
· Enlargement of the larynx accompanied by voice changes
· Growth and distribution of body hair
· Increased male sexual drive
Testosterone secretion is regulated by a negative feedback system that involves releasing hormones from the hypothalamus and gonadotropins from the anterior pituitary.
Ovaries
Two groups of female sex hormones are produced in the ovaries, the estrogens and progesterone. These steroid hormones contribute to the development and function of the female reproductive organs and sex characteristics. At the onset of puberty, estrogens promotes:
· The development of the breasts
· Distribution of fat evidenced in the hips, legs, and breast
· Maturation of reproductive organs such as the uterus and vagina
Progesterone causes the uterine lining to thicken in preparation for pregnancy. Together, progesterone and estrogens are responsible for the changes that occur in the uterus during the female menstrual cycle.
The Adrenal Glands
The adrenal glands are two small structures situated one atop each kidney.
Both in anatomy and in function, they consist of two distinct regions:
· an outer layer, the adrenal cortex, which surrounds
· the adrenal medulla.
Link to graphic showing the location and structure of the adrenal glands (92K).
The Adrenal Cortex
Using cholesterol as the starating material, the cells of the adrenal cortex secrete a variety of steroid hormones. These fall into three classes:
· glucocorticoids (e.g., cortisol)
· mineralocorticoids (e.g., aldosterone)
· androgens (e.g., testosterone)
Production of all three classes is triggered by the secretion of ACTH from the anterior lobe of the pituitary.
All these hormones achieve their effects by:
· diffusing from the blood into all cells
· binding to their receptor - a protein present in the cytoplasm and/or nucleus of "target" cells
· The hormone-receptor complex binds to a second to form a dimer.
· The dimer migrates into the nucleus (if it did not form there).
· The hormone-receptor dimer binds to specific hormone response elements in DNA.
· These are specific DNA sequences in the promoter of genes that will be turned on (sometimes off) by the interaction.
· Other transcription factors are recruited to the promoter and gene transcription begins.
Select this link for a stereo view of a steroid receptor (the glucocorticoid receptor) dimer bound to the DNA of its response element.
Glucocorticoids
The glucocorticoids get their name from their effect of raising the level of blood sugar (glucose). One way they do this is by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose.
The most abundant glucocorticoid is cortisol (also called hydrocortisone).
Cortisol and the other glucocorticoids also have a potent anti-inflammatory effect on the body. They depress the immune response, especially cell-mediated immune responses. [Discussion of mechanism]
For this reason glucocorticoids are widely used in therapy:
· to reduce the inflammatory destruction of rheumatoid arthritis and other autoimmune diseases
· to prevent the rejection of transplanted organs
· to control asthma
Mineralocorticoids
The mineralocorticoids get their name from their effect on mineral metabolism. The most important of them is the steroid aldosterone.
Aldosterone acts on the kidney promoting the reabsorption of sodium ions (Na+) into the blood. Water follows the salt and this helps maintain normal blood pressure.
Link to discussion.
Aldosterone also
· acts on sweat glands to reduce the loss of sodium in perspiration;
· acts on taste cells to increase the sensitivity of the taste buds to sources of sodium.
The secretion of aldosterone is stimulated by:
· a drop in the level of sodium ions in the blood;
· a rise in the level of potassium ions in the blood;
· angiotensin II
· ACTH (as is that of cortisol)
Androgens
The adrenal cortex secretes precursors to androgens such as testosterone.
In sexually-mature males, this source is so much lower than that of the testes that it is probably of little physiological significance. However, excessive production of adrenal androgens can cause premature puberty in young boys.
In females, the adrenal cortex is a major source of androgens. Their hypersecretion may produce a masculine pattern of body hair and cessation of menstruation.
Addison's Disease: Hyposecretion of the adrenal cortices
Addison's disease has many causes, such as
· destruction of the adrenal glands by infection;
· their destruction by an autoimmune attack;
· an inherited mutation in the ACTH receptor on adrenal cells.
The essential role of the adrenal hormones means that a deficiency can be life-threatening. Fortunately, replacement therapy with glucocorticoids and mineralocorticoids can permit a normal life.
Cushing's Syndrome: Excessive levels of glucocorticoids
In Cushing's syndrome, the level of adrenal hormones, especially of the glucocorticoids, is too high.
It can be caused by:
· excessive production of ACTH by the anterior lobe of the pituitary;
· excessive production of adrenal hormones themselves (e.g., because of a tumor), or (quite commonly)
· as a result of glucocorticoid therapy for some other disorder such as
o rheumatoid arthritis or
o preventing the rejection of an organ transplant.
The Adrenal Medulla
The adrenal medulla consists of masses of neurons that are part of the sympathetic branch of the autonomic nervous system. Instead of releasing their neurotransmitters at a synapse, these neurons release them into the blood. Thus, although part of the nervous system, the adrenal medulla functions as an endocrine gland.
The adrenal medulla releases:
· adrenaline (also called epinephrine) and
· noradrenaline (also called norepinephrine)
Both are derived from the amino acid tyrosine.
Release of adrenaline and noradrenaline is triggered by nervous stimulation in response to physical or mental stress. The hormones bind to adrenergic receptors - transmembrane proteins in the plasma membrane of many cell types.
Some of the effects are:
· increase in the rate and strength of the heartbeat resulting in increased blood pressure;
· blood shunted from the skin and viscera to the skeletal muscles, coronary arteries, liver, and brain;
· rise in blood sugar;
· increased metabolic rate;
· bronchi dilate;
· pupils dilate;
· hair stands on end ("gooseflesh" in humans);
· clotting time of the blood is reduced;
· increased ACTH secretion from the anterior lobe of the pituitary.
All of these effects prepare the body to take immediate and vigorous action.
What is the Liver?
The liver is the largest glandular organ of the body. It weighs about 3 lb (1.36 kg). It is reddish brown in color and is divided into four lobes of unequal size and shape. The liver lies on the right side of the abdominal cavity beneath the diaphragm. Blood is carried to the liver via two large vessels called the hepatic artery and the portal vein. The heptic artery carries oxygen-rich blood from the aorta (a major vessel in the heart). The portal vein carries blood containing digested food from the small intestine. These blood vessels subdivide in the liver repeatedly, terminating in very small capillaries. Each capillary leads to a lobule. Liver tissue is composed of thousands of lobules, and each lobule is made up of hepatic cells, the basic metabolic cells of the liver.
What is its major function?
The liver has many functions. Some of the functions are: to produce substances that break down fats, convert glucose to glycogen, produce urea (the main substance of urine), make certain amino acids (the building blocks of proteins), filter harmful substances from the blood (such as alcohol), storage of vitamins and minerals (vitamins A, D, K and B12) and maintain a proper level or glucose in the blood. The liver is also responsible fore producing cholesterol. It produces about 80% of the cholesterol in your body.
Diseases of the Liver?
Several diseases states can affect the liver. Some of the diseases are hepatitis (an inflammation of the liver), liver cancer, and cirrhosis (a chronic inflammation that progresses ultimately to organ failure). Alcohol alters the metabolism of the liver, which can have overall detrimental effects if alcohol is taken over long periods of time.
Hemochromatosis can cause liver problems.
Medications that negatively effect the liver?
Medications have side effects that may harm your liver. Some of the medications that can damage your liver are: serzone, anti-cancer drugs (tagfur, MTX, and cytoxan), and medications used to treat diabetes.
Serzone is a prescription drug manufactured by Bristol-Myers Squibb for the treatment of depression.
The possible side effects of Serzone® are: agitation, dizziness, clumsiness or unsteadiness, difficulty concentrating, memory problems, confusion, severe nausea, gastroenteritis, abdominal pain, unusually dark urine, difficult or frequent urination, fainting, skin rash or hives yellowing of the skin or whites of the eyes (jaundice) or a prolonged loss of weight or loss of appetite.
If you or a family member have suffered serious side effects or a fatal injury after taking Serzone®, you or the family member may be eligible to file a claim against the manufacturer. You should contact an attorney that specializes in class action lawsuits immediately.
To help prevent liver damage, let your doctor know about your liver condition when being treated for other conditions. Medications come in many forms and it is best to find out what is in them and what it can do to your liver.
Thymus
The thymus gland lies in the upper part of the mediastinum behind the sternum and extends upwards into the root of the neck. It weighs about 10 to 15 g.(about half an ounce) at birth and begins to grow until the individual reaches puberty when it begins to atrophy. It’s maximum weight is around 30 - 40g (around 1 to 1.5 ounces) by the age of 40 it has returned to it’s weight at birth. The thymus consists of two lobes connected by areolar tissue. The lobes are enclosed in a fibrous capsule which dips into their substance dividing them into lobules that consist of an irregular branching framework of epithelial cells and lymphocytes.
Function
Lymphocytes originate from haemocytoblasts (stem cells) in red bone marrow. Those that enter the thymus mature and develop into activated T-lymphocytes i.e. able to respond to antigens encountered elsewhere in the body. They then divide into two groups :
those that enter the blood, some of which remain in circulation and some lodge in other lymphoid tissue
those that remain in the thymus gland and are the source of future generations of T-lymphocytes.
The maturation of the thymus and other lymphoid tissue is stimulated by thymosin, a hormone secreted by the epithelial cells that form the framework of the thymus gland. Involution of the gland begins in adolescence and, with increasing age the effectiveness of T- lymphocyte response to antigens declines.
Anatomy of the pituitary gland:
The pituitary gland is sometimes called the "master" gland of the endocrine system, because it controls the functions of the other endocrine glands. The pituitary gland is no larger than a pea, and is located at the base of the brain. The gland is attached to the hypothalumus (a part of the brain that affects the pituitary gland) by nerve fibers. The pituitary gland itself consists of three sections:
· the anterior lobe
· the intermediate lobe
· the posterior lobe
Functions of the pituitary gland:
Each lobe of the pituitary gland produces certain hormones.
anterior lobe:
· growth hormone
· prolactin - to stimulate milk production after giving birth
· ACTH (adrenocorticotropic hormone) - to stimulate the adrenal glands
· TSH (thyroid-stimulating hormone) - to stimulate the thyroid gland
· FSH (follicle-stimulating hormone) - to stimulate the ovaries and testes
· LH (luteinizing hormone) - to stimulate the ovaries or testes
intermediate lobe:
· melanocyte-stimulating hormone - to control skin pigmentation
posterior lobe:
· ADH (antidiuretic hormone) - to increase absorption of water into the blood
by the kidneys
· oxytocin - to contract the uterus during childbirth and stimulate milk production
Hormones of the Pituitary
The pituitary gland is pea-sized structure located at the base of the brain. In humans, it consists of two lobes:
· the Anterior Lobe and
· the Posterior Lobe
Link to graphic showing the locationof the pituitary and other endocrineglands (92K).
The Anterior Lobe
The anterior lobe contains six types of secretory cells, all but one of which (#2 above) are specialized to secrete only one of the anterior lobe hormones. All of them secrete their hormone in response to hormones reaching them from the hypothalamus of the brain.
Thyroid Stimulating Hormone (TSH)
TSH (also known as thyrotropin) is a glycoprotein consisting of:
· a beta chain of 112 amino acids and
· an alpha chain of 89 amino acids. The alpha chain is identical to that found in two other pituitary hormones, FSH and LH. Thus it is its beta chain that gives TSH its unique properties.
The secretion of TSH is
· stimulated by the arrival of thyrotropin releasing hormone (TRH) from the hypothalamus.
· inhibited by the arrival of somatostatin from the hypothalamus.
As its name suggests, TSH stimulates the thyroid gland to secrete its hormone thyroxine (T4). It does this by binding to transmembrane G-protein-coupled receptors (GPCRs) on the surface of the cells of the thyroid.
Some people develop antibodies against their own TSH receptors. When these bind the receptors, they "fool" the cell into making more T4 causing hyperthyroidism. The condition is called thyrotoxicosis or Graves' disease.
Hormone deficiencies
A deficiency of TSH causes hypothyroidism: inadequate levels of T4 (and thus of T3 [Link]). Recombinant human TSH has recently become available to treat patients with TSH deficiency.
Some people inherit mutant TSH receptors. This, too, results in hypothyroidism.
A deficiency of TSH, or mutant TSH receptors, have also been implicated as a cause of osteoporosis. Mice, whose TSH receptors have been knocked out, develop increased numbers of bone-reabsorbing osteoclasts.
Follicle-Stimulating Hormone (FSH)
FSH is a heterodimer of
· the same alpha chain found in TSH (and LH)
· a beta chain of 115 amino acids, which gives it its unique properties.
Synthesis and release of FSH is triggered by the arrival from the hypothalamus of gonadotropin-releasing hormone (GnRH). The effect of FSH depends on one's sex
FSH in females
In sexually-mature females, FSH (assisted by LH) acts on the follicle to stimulate it to release estrogens.
FSH in males
In sexually-mature males, FSH acts on spermatogonia stimulating (with the aid of testosterone) the production of sperm.
Luteinizing Hormone (LH)
LH is synthesized within the same pituitary cells as FSH and under the same stimulus (GnRH). It is a heterodimeric glycoprotein consisting of
· the same 89-amino acid alpha subunit found in FSH and TSH
· a beta chain of 115 amino acids that is responsible for its properties.
The effects of LH also depend on sex.
LH in females
In sexually-mature females, LH
· stimulates the follicle to secrete estrogen in the first half of the menstrual cycle
· a surge of LH triggers the completion of meiosis I of the egg and its release (ovulation) in the middle of the cycle
· stimulates the now-empty follicle to develop into the corpus luteum,which secretes progesterone during the latter half of the menstrual cycle.
LH in males
LH acts on the interstitial cells of the testes stimulating them to synthesize and secrete the male sex hormone, testosterone.
LH in males is also known as interstitial cell stimulating hormone (ICSH).
Prolactin (PRL)
Prolactin is a protein of 198 amino acids. During pregnancy it helps in the preparation of the breasts for future milk production.
After birth, prolactin promotes the synthesis of milk.
Prolactin secretion is
· stimulated by TRH
· repressed by estrogens and dopamine.
In pregnant mice, prolactin stimulates the growth of new neurons in the olfactory center of the brain.
Growth Hormone (GH)
Human growth hormone (also called somatotropin) is a protein of 191 amino acids. The GH-secreting cells are stimulated to synthesize and release GH by the intermittent arrival of growth hormone releasing hormone (GHRH) from the hypothalamus. GH promotes body growth by:
· binding to receptors on the surface of liver cells
· this stimulates them to release insulin-like growth factor-1 (IGF-1; also known as somatomedin)
· IGF-1 acts directly on the ends of the long bones promoting their growth
Things that can go wrong.
· In childhood,
o hyposecretion of GH produces the stunted growth of a dwarf. Dwarfism can also result from an inability to respond to GH. This can result from inheriting two mutant genes encoding the receptors for
§ GHRH or
§ GH
or homozygosity for a disabling mutation in STAT5b, which is part of the "downstream" signaling process after GH binds its receptor.
o hypersecretion leads to gigantism
· In adults, a hypersecretion of GH leads to acromegaly.
Hormone-replacement therapy
GH from domestic mammals like cows and pigs does not work in humans. So for many years, the only source of GH for therapy was that extracted from the glands of human cadavers. But this supply was shut off when several patients died from a rare neurological disease attributed to contaminated glands. Now, thanks to recombinant DNA technology, recombinant human GH (rHGH) is available. While a great benefit to patients suffering from GH deficiency, there has also been pressure to use it to stimulate growth in youngsters who have no deficiency but whose parents want them to grow up tall. And so, in the summer of 2003, the U.S. FDA approved the use of human growth hormone (HGH) for
· boys predicted to grow no taller than 5′3″ and
· for girls, 4′11″
even though otherwise perfectly healthy.
ACTH - the adrenocorticotropic hormone
ACTH is a peptide of 39 amino acids. It is cut from a larger precursor proopiomelanocortin (POMC).
ACTH acts on the cells of the adrenal cortex, stimulating them to produce
· glucocorticoids, like cortisol
· mineralocorticoids, like aldosterone
· androgens (male sex hormones, like testosterone
· in the fetus, ACTH stimulates the adrenal cortex to synthesize a precursor of estrogen called dehydroepiandrosterone sulfate (DHEA-S) which helps prepare the mother for giving birth.
Production of ACTH depends on the intermittent arrival of corticotropin-releasing hormone (CRH) from the hypothalamus.
Hypersecretion of ACTH is a frequent cause of Cushing's disease.
Alpha Melanocyte-Stimulating Hormone (α-MSH)
Alpha MSH is also a cleavage product of proopiomelanocortin (POMC). In fact, α-MSH is identical to the first 13 amino acids at the amino terminal of ACTH.
MSH is discussed in a separate page. Link to it.
The Posterior Lobe
The posterior lobe of the pituitary releases two hormones, both synthesized in the hypothalamus, into the circulation.
· Antidiuretic Hormone (ADH).
ADH is a peptide of 9 amino acids. It is also known as arginine vasopressin.
ADH acts on the collecting ducts of the kidney to facilitate the reabsorption of water into the blood. This it acts to reduce the volume of urine formed (giving it its name of antidiuretic hormone).
Link to discussion of kidney physiology.
o A deficiency of ADH or
o inheritance of mutant genes for its receptor (called V2)
leads to excessive loss of urine, a condition known as diabetes insipidus. The most severely-afflicted patients may urinate as much as 30 liters (almost 8 gallons!) of urine each day. The disease is accompanied by terrible thirst, and patients must continually drink water to avoid dangerous dehydration.
Another type of receptor for arginine vasopressin (designated V1a) is found in the brain, e.g., in voles and mice (rodents) and in primates like monkeys and humans.
o Male prairie voles (Microtus pinetorum) and marmoset monkeys
§ have high levels of the V1a receptor in their brains,
§ tend to be monogamous, and
§ help with care of their young.
o Male meadow voles (Microtus montanus) and rhesus monkeys
§ have lower levels of the V1a receptor in their brains,
§ are promiscuous, and
§ give little or no help with the care of their young.
Meadow voles whose brains have been injected with a vector causing increased expression of the V1a receptor become more like prairie voles in their behavior. (See Lim, M. M. et al., Nature, 17 June 2004.)
Changes in the regulatory region of the human gene for the V1a receptor have been linked to autism.
· Oxytocin
Oxytocin is a peptide of 9 amino acids. Its principal actions are:
o stimulating contractions of the uterus at the time of birth
o stimulating release of milk when the baby begins to suckle
Oxytocin is often given to prospective mothers to hasten birth.
The hypothalamus is a region of the brain. It secretes a number of hormones.
· Thyrotropin-releasing hormone (TRH)
· Gonadotropin-releasing hormone (GnRH)
· Growth hormone-releasing hormone (GHRH)
· Corticotropin-releasing hormone (CRH)
· Somatostatin
· Dopamine
All of these are released into the blood, travel immediately to the anterior lobe of the pituitary, where they exert their effects.
All of them are released in periodic spurts. In fact, replacement hormone therapy with these hormones does not work unless the replacements are also given in spurts.
Two other hypothalamic hormones:
· Antidiuretic hormone (ADH) and
· Oxytocin
travel in neurons to the posterior lobe of the pituitary where they are released into the circulation.
Link to diagram of the endocrine glands (92K)
Thyrotropin-releasing hormone (TRH)
TRH is a tripeptide (GluHisPro).
When it reaches the anterior lobe of the pituitary it stimulates the release there of
· thyroid-stimulating hormone (TSH)
· prolactin (PRL)
Gonadotropin-releasing hormone (GnRH)
GnRH is a peptide of 10 amino acids. Its secretion at the onset of puberty triggers sexual development.
Primary Effects Secondary Effects
FSH and LH Up estrogen and progesterone Up (in females)
testosterone Up (in males)
After puberty, a hyposecretion of GnRH may result from
· intense physical training
· anorexia nervosa
Synthetic agonists of GnRH are used to treat
· inherited or acquired deficiencies of GnRH secretion.
· prostate cancer. In this case, high levels of the GnRH agonist
o reduces the number of GnRH receptors in the pituitary, which
o reduces its secretion of FSH and LH, which
o reduces the secretion of testosterone, which
o reduces the stimulation of the cells of the prostate.
Growth hormone-releasing hormone (GHRH)
GHRH is a mixture of two peptides, one containing 40 amino acids, the other 44.
As its name indicates, GHRH stimulates cells in the anterior lobe of the pituitary to secrete growth hormone (GH).
Corticotropin-releasing hormone (CRH)
CRH is a peptide of 41 amino acids.
As its name indicates, its acts on cells in the anterior lobe of the pituitary to release adrenocorticotropic hormone (ACTH)
CRH is also synthesized by the placenta and seems to determine the duration of pregnancy.
Description of the mechanism.
It may also play a role in keeping the T cells of the mother from mounting an immune attack against the fetus. [Discussion]
Somatostatin
Somatostatin is a mixture of two peptides, one of 14 amino acids, the other of 28.
Somatostatin acts on the anterior lobe of the pituitary to
· inhibit the release of growth hormone (GH)
· inhibit the release of thyroid-stimulating hormone (TSH)
Somatostatin is also secreted by cells in the pancreas and in the intestine where it inhibits the secretion of a variety of other hormones.
Dopamine
Dopamine is a derivative of the amino acid tyrosine. Its principal function in the hypothalamus is to inhibit the release of prolactin (PRL) from the anterior lobe of the pituitary.
Antidiuretic hormone (ADH) and Oxytocin
These peptides are released from the posterior lobe of the pituitary and are described in the page devoted to the pituitary.
ADH
Oxytocin
What is it?
Anatomy
The hypothalamus is an integral part of the substance of the brain. A small cone-shaped structure, it projects downward, ending in the pituitary (infundibular) stalk, a tubular connection to the pituitary gland. The round bony cavity containing the pituitary gland is called the sella turcica. The posterior portion of the hypothalamus, called the median eminence, contains many neurosecretory cells. Important adjacent structures include the mammillary bodies, the third ventricle, and the optic chiasm, the last being of particular concern to physicians because pressure from expanding tumours or inflammations in the hypothalamus or pituitary gland may result in severe visual defects or total blindness. Above the hypothalamus is the thalamus. (For discussion of the function of these surrounding structures, see the nervous system.)
Regulation of hormone secretion
The hypothalamus regulates homeostasis. It has regulatory areas for thirst, hunger, body temperature, water balance, and blood pressure, and links the nervous system to the endocrine system.
The hypothalamus, like the rest of the brain, consists of interconnecting nerve cells ( neurons) with a rich blood supply. To understand hypothalamic function it is necessary to define the various forms of neurosecretion. First, there is neurotransmission, which occurs throughout the brain and is the process by which one nerve cell communicates with another at an intimate intermingling of projections from the two cells (a synapse). This transmission of an electrical impulse from one cell to another requires the secretion of a chemical substance from a long projection from one nerve cell body (the axon) into the synaptic space. The chemical substance that is secreted is called a neurotransmitter. The process of synthesis and secretion of neurotransmitters is similar to that shown in Figure 1 with the exception that neurosecretory granules migrate through lengths of the axon before being discharged into the synaptic space.
Figure 1: Intracellular structure of a typical endocrine cell.
Neurologists have long been aware of four classical neurotransmitters: epinephrine, norepinephrine, serotonin, and acetylcholine, but recently there have emerged a large number of additional neurotransmitters, of which an important group is the neuropeptides. While bioamines and neuropeptides function as neurotransmitters, some of them also perform the role of neuromodulators; they do not act directly as neurotransmitters but rather as inhibitors or stimulators of neurotransmission. Well-known examples are the opioids (for example, enkephalins), so named because they are the naturally occurring peptides with a strong affinity to the receptors that bind opiate drugs such as morphine and heroin. In effect, they are the body's opiates.
Thus the brain, and indeed the entire central nervous system, consists of an extraordinary network of neurons interconnected by neurotransmitters. The secretion of specific neurotransmitters, modified by neuromodulators, lends an organized, directed function to the overall system. These neural connections extend upward from the hypothalamus into other key areas, including the cerebral cortex. The result is that intellectual and functional activities as well as external influences, including stresses, can be funneled into the hypothalamus and thence to the endocrine system, from which they may exert effects on the body.
In addition to secreting neurotransmitters and neuromodulators, the hypothalamus synthesizes and secretes a number of neurohormones. The neurons secreting neurohormones are true endocrine (neurohemal) cells in the classical sense since secretory granules containing neurohormones travel from the cell body through the axon to be extruded, where they enter directly a capillary network, thence to be transported through the hypophyseal-portal circulation to the anterior pituitary gland.
Finally, the neurohypophysis, or posterior lobe of the pituitary gland, provides the classical example of neurohormonal activity. The secretory products, mainly vasopressin and oxytocin, are extruded into a capillary network, which feeds directly into the general circulation.
The existence of hormones of the hypothalamus was predicted well before they were detected and chemically characterized, and they have been studied intensively by many investigators. Two groups of American investigators, led by Andrew Schally and Roger Guillemin, respectively, shared the Nobel Prize for Physiology or Medicine for 1977 for their research on pituitary hormones.
These neurohormones are known as releasing hormones because the major function generally is to stimulate the secretion of hormones originating in the anterior pituitary gland. They consist of simple peptides (chains of amino acids) ranging in size from only three amino acids (thyrotropin-releasing hormone) to 44 amino acids (growth hormone-releasing hormone).
Hormones
Thyrotropin-releasing hormone
Thyrotropin-releasing hormone (TRH), a neurohormone, is the simplest of the hypothalamic neuropeptides. It consists essentially of three amino acids in the sequence glutamic acid-histidine-proline. The simplicity of this structure is deceiving for TRH is involved in an extraordinary array of functions. Not only is it a neurohormone that stimulates the secretion of thyroid-stimulating hormone from the pituitary, and, quite independently, the secretion of another pituitary hormone called prolactin, but it also subserves other central nervous system activities because it is a widespread neurotransmitter or neuromodulator within the brain and spinal cord. There is evidence that TRH is involved in the control of body temperature and that it has psychological and behavioral effects, at least in animals. It may also have therapeutic value. There are studies suggesting that it mitigates the damage induced by spinal cord injury and that it leads to some improvement in the nervous disease known as amyotrophic lateral sclerosis (Lou Gehrig's disease).
These multiple effects are less surprising when it is considered that TRH appeared very early in the evolutionary scale of vertebrates and that, while the concentration of TRH is greatest in the hypothalamus, the total amount of TRH in the remainder of the brain far exceeds that of the hypothalamus. The TRH-secreting cells are subject to stimulatory and inhibitory influences from higher centres in the brain and they also are inhibited by circulating thyroid hormone. In this way TRH forms the topmost segment of the hypothalamic-pituitary-thyroid axis.
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH), a neurohormone also known as luteinizing hormone-releasing hormone (LHRH), is a peptide chain of 10 amino acids. It stimulates the synthesis and release of the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While some investigators hold that there are two types of GnRH, most evidence supports the conclusion that only one type of neuropeptide stimulates the release of the two gonadotropins and that the variations in levels of both gonadotropins in the circulation are due to other modulating factors.
Characteristic of all releasing hormones and most striking in the case of GnRH is the phenomenon of pulsatile secretion. In normal individuals, GnRH is released in spurts at intervals of about 80 minutes. The pulsatile administration of GnRH in large doses results in an ever-increasing concentration of gonadotropins in the blood. In striking contrast, the constant infusion of GnRH suppresses gonadotropin secretion. This phenomenon is advantageous for persons for whom suppression is important. Such persons include children with precocious puberty, and elderly men with cancer of the prostate. On the other hand, pulsatile administration of GnRH is efficacious in men or women in whom deficiency of gonadal function is due to impaired secretion of GnRH. A potential application of this phenomenon is the synthetic modifications of GnRH as a male as well as a female contraceptive.
Neurons that secrete GnRH have connections to an area of the brain known as the limbic system, which is heavily involved in the control of emotions and sexual activity. Studies in rats deprived of pituitary glands and ovaries but maintained on physiological amounts of female hormone (estrogen) have demonstrated that the injection of GnRH results in complex and striking changes in posture characteristic of the receptive female stance for sexual intercourse.
Some individuals have hypogonadism (in which the functional activity of the gonads is decreased and sexual development is inhibited) due to a congenital deficiency of GnRH, which responds to treatment with GnRH. Most of these people also suffer from hypothalamic disease and are deficient in other releasing hormones as well, but there are also individuals in whom GnRH deficiency is isolated and associated with a loss of the sense of smell (anosmia). Abnormalities in the pulses of GnRH secretion result in subnormal fertility, abnormal or absent menstruation, and possibly cystic disease of the ovary or even ovarian cancer
Corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH), a neurohormone, is a large peptide consisting of a single chain of 41 amino acids. It stimulates not only secretion of corticotropin in the pituitary gland but also the synthesis of corticotropin in the corticotropin-producing cells (corticotrophs) of the anterior lobe of the pituitary gland. Many factors, both neurogenic and hormonal, regulate the secretion of CRH, since CRH is the final common element directing the body's response to all forms of stress, whether physical or emotional, external or internal. (This key role of CRH in the hypothalamic-pituitary-adrenal axis is discussed below in connection with the adrenal gland.) Among the hormones that play an important role in modulating the influence of CRH is cortisol, the major hormone secreted by the adrenal cortex, which, as part of the negative feedback servomechanism (exerting control over another system through negative feedback), blocks the secretion of CRH. Vasopressin, the major regulator of the body's excretion of water, has an additional ancillary role in stimulating the secretion of CRH.
Excessive secretion of CRH leads to an increase in the size and number of corticotrophs in the pituitary gland, often resulting in a pituitary tumour. This, in turn, leads to excessive stimulation of the adrenal cortex, resulting in high circulating levels of adrenocortical hormones, the clinical manifestations of which are known as Cushing's syndrome. Conversely, a deficiency of CRH-producing cells can, by a lack of stimulation of the pituitary and adrenal cortical cells, result in adrenocortical deficiency. (These conditions are discussed below.
Growth hormone-releasing hormone
Like CRH, growth hormone-releasing hormone (GHRH) is a large peptide. A number of forms have been described that differ from one another only in minor detail and in the number of amino acids (varying from 37 to 44). Unlike the other neurohormones, GHRH is not widely distributed in other parts of the brain. It is stimulated by stresses, including physical exercise, and secretion is blocked by a powerful inhibitor called somatostatin (see below Somatostatin). Negative feedback control of GHRH secretion is mediated largely through compounds called somatomedins, growth-promoting hormones that are generated when tissues are exposed to growth hormone itself.
An excess of circulating growth hormone in adults leads to a condition called acromegaly. Rarely, a benign tumour, called a hamartoma, located in the hypothalamus may produce excessive amounts of GHRH, leading to acromegaly. Equally rare are tumours arising in the islets of Langerhans of the pancreas that may secrete excessive quantities of GHRH. Indeed, GHRH was first successfully isolated and analyzed from such an ectopic (abnormally positioned) hormone-producing tumour. Isolated deficiency of GHRH (in which there is normal functioning of the hypothalamus except for this deficiency) may be the cause of one form of dwarfism, a general term applied to all individuals with abnormally small stature.
Somatostatin
Somatostatin refers to a number of polypeptides consisting of chains of 14 to 28 amino acids. The name was coined when its discoverers found that an extract of the hypothalamus strongly inhibited the release of growth hormone from the pituitary gland. Somatostatin is also a powerful inhibitor of pituitary TSH secretion. Somatostatin, like TRH, is widely distributed in the central nervous system and in other tissues. It serves an important paracrine function in the islets of Langerhans, by blocking the secretion of both insulin and glucagon from adjacent cells. Somatostatin has emerged not only as a powerful blocker of the secretion of GH, insulin, glucagon, and other hormones but also as a potent inhibitor of many functions of the gastrointestinal tract, including the secretion of stomach acid, the secretion of pancreatic enzymes, and the process of intestinal absorption. Despite these multiple, widespread actions, the term somatostatin has persisted because of its major role as a regulator of GH secretion, and impaired somatostatin secretion may cause some forms of hypersecretion of growth hormone.
No examples of somatostatin deficiency have been found, but a tumour called a somatostatinoma has been well characterized in a number of patients. Persons with a somatostatinoma have cramping abdominal pain, persistent diarrhea, a mild elevation of blood glucose levels, and sudden flushing of the skin.
Prolactin-inhibiting and releasing hormones
The hypothalamic regulation of prolactin secretion from the pituitary is different from the hypothalamic regulation of other pituitary hormones in two respects. First, the hypothalamus primarily inhibits rather than stimulates the release of prolactin from the pituitary (the hypothalamus stimulates the release of all other pituitary hormones). Thus, if pituitary cells are removed from the influence of the hypothalamus, few or none of the pituitary hormones are secreted, except for prolactin, which continues to be secreted by the prolactin-secreting cells (lactotrophs). Second, this major inhibiting factor is not a neuropeptide, but rather the neurotransmitter dopamine, a fact exploited in afflicted persons by physicians who are able to reduce abnormally high concentrations of prolactin by using drugs that mimic the prolactin-inhibiting effects of dopamine. Another prolactin-inhibiting factor (PRF) comes into play primarily during pregnancy and lactation. Prolactin-stimulating factors also exist, among them TRH.
Prolactin deficiency is known to occur, but only rarely. Excessive prolactin production (hyperprolactinemia) is a common endocrine abnormality, and the prolactinoma is the most frequently encountered pituitary tumour.
Gastrointestinal neuropeptides
Although modern endocrinology began with the discovery that a substance, secretin, secreted into the blood from the cells lining the gastrointestinal tract stimulates the secretion of pancreatic juices, little attention was subsequently paid to gastrointestinal hormones. When investigators began to examine the distribution of neuropeptides within the body, however, there emerged a bewildering variety of these hormones, not only within the brain but also in the lining of the gastrointestinal tract and in other organs. The list includes glucagon, the enkephalins, secretin, cholecystokinin, gastrin, calcitonin, angiotensin, substance P, pancreatic polypeptide, neuropeptide Y (a human variant of a peptide called bombesin), delta-sleep-inducing peptide, and vasoactive intestinal peptide. The actions and interactions of these hormones both in the intestinal tract and in the brain are complex and are the subject of continuing investigations. Briefly, these peptides play important roles in the transmission and inhibition of pain stimuli, in eating and drinking behaviour, in memory and learning, in the regulation of body temperature, in the induction of sleep, and in sexual behaviour.
Hypothalamus
The hypothalamus is a part of the brain. It controls part of the autonomic nervous system, which is the part of the nervous system that controls the body organs. The hypothalamus releases substances (hormones) that help control the endocrine and nervous systems, regulate body temperature and sleep, and affect other body functions.
The hypothalamus produces a hormone called thyrotropin-releasing hormone (TRH), which stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH). TSH, in turn, regulates the amount of thyroid hormone produced and released into the bloodstream by the thyroid gland. A problem in the hypothalamus can result in decreased release of thyroid hormone by the thyroid gland.
Your Thyroid Gland
What is Your Thyroid Gland?
Your thyroid gland is one of the endocrine glands, which make hormones to regulate physiological functions in your body. The thyroid gland manufactures thyroid hormone, which regulates the rate at which your body carries on its necessary functions. Other endocrine glands are the pancreas, the pituitary, the adrenal glands, the parathyroid glands, the testes, and the ovaries.
The thyroid gland is located in the middle of the lower neck, below the larynx (voice box) and just above your clavicles (collarbones). It is shaped like a "bow tie," having two halves (lobes): a right lobe and a left lobe joined by an "isthmus.". You can't always feel a normal thyroid gland.
When Is a Thyroid Gland Abnormal?
Diseases of the thyroid gland are very common, affecting millions of Americans. The most common diseases are an over- or under-active gland. These conditions are called hyperthyroidism (e.g., Grave's disease) and hypothyroidism. Sometimes the thyroid gland can become enlarged from over-activity (as in Grave's disease) or from under-activity (as in hypothyroidism). An enlarged thyroid gland is often called a "goiter." Sometimes an inflammation of the thyroid gland (Hashimoto's disease) will cause enlargement of the gland.
Patients may develop "lumps" or "masses" in their thyroid glands. They may appear gradually or very rapidly. Patients who had radiation therapy to the head or neck as children for acne, adenoids, or other reasons are more prone to develop thyroid malignancy. A doctor should evaluate all thyroid "lumps" (nodules).
How Does Your Doctor Make the Diagnosis?
The diagnosis of a thyroid abnormality in function or a thyroid mass is made by taking a medical history and a physical examination. Specifically, your doctor will examine your neck and ask you to lift up your chin to make your thyroid gland more prominent. You may be asked to swallow during the examination, which helps to feel the thyroid and any mass in it. Other tests your doctor may order include:
1. An ultrasound examination of your neck and thyroid
2. Blood tests of thyroid function
3. A radioactive thyroid scan
4. A fine needle aspiration biopsy
5. A chest X-ray
6. A CT or MRI scan
Fine Needle Aspiration
If a lump in your thyroid is diagnosed, your doctor may recommend a fine needle aspiration biopsy. This is a safe, relatively painless procedure. A hypodermic needle is passed into the lump, and samples of tissues are taken. Often several passes with the needle are required. There is little pain afterward and very few complications from the procedure occur. This test gives the doctor more information on the nature of the lump in your thyroid gland and specifically will help to differentiate a benign from a malignant thyroid mass.
Treatment of Thyroid Disease
Abnormalities of thyroid function (hyper or hypothyroidism) are usually treated medically. If there is insufficient production of thyroid hormone, this may be given in a form of a thyroid hormone pill taken daily. Hyperthyroidism is treated mostly by medical means, but occasionally it may require the surgical removal of the thyroid gland.
If there is a lump of the thyroid or a diffused enlargement (goiter), your doctor will propose a treatment plan based on the examination and your test results. Most thyroid "lumps" are benign. Often they may be treated with thyroid hormone, and this is called "suppression" therapy. The object of this treatment is to attempt shrinkage of the mass over time, usually three-six months. If the lump continues to grow during treatment when you are taking the medication, most doctors will recommend removal of the affected lump.
If the fine needle aspiration is reported as suspicious for or suggestive of cancer, then thyroid surgery is required.
What Is Thyroid Surgery?
Thyroid surgery is an operation to remove part or all of the thyroid gland. It is performed in the hospital, and general anesthesia is usually required. Usually the operation removes the lobe of the thyroid gland containing the lump and possibly the isthmus. A frozen section (an immediate microscopic reading) may or may not be used to determine if the rest of the thyroid gland should be removed. Sometimes, based on the result of the frozen section, the surgeon may decide to stop and remove no more thyroid tissue, or proceed to remove the entire thyroid gland, and/or other tissue in the neck. This is a decision usually made in the operating room by the surgeon, based on findings at the time of surgery. Your surgeon will discuss these options with you preoperatively.
After surgery, you may have a drain (a tiny piece of plastic tubing), which prevents fluid from building up in the wound. This is removed after the fluid accumulation is minimal. Most patients are discharged one to three days after surgery. Complications after thyroid surgery are rare. They include bleeding, a hoarse voice, difficulty swallowing, numbness of the skin on the neck, and low blood calcium. Most complications go away after a few weeks. Patients who have all of their thyroid gland removed have a higher risk of low blood calcium post-operatively.
Patients who have thyroid surgery may be required to take thyroid medication to replace thyroid hormones after surgery. Some patients may need to take calcium replacement if their blood calcium is low. This will depend on how much thyroid gland remains, and what was found during surgery. If you have any questions about thyroid surgery, ask your doctor and he or she will answer them in detail.
Hormones of the Pancreas
The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. [Discussion]
Link to graphic showing the locationof the pancreas and other endocrine glands (92K).
However, scattered through the pancreas are several hundred thousand clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are the:
· beta cells, which secrete insulin and amylin;
· alpha cells, which secrete glucagon;
· delta cells, which secrete somatostatin, and
· gamma cells, which secrete a polypeptide of unknown function.
Beta Cells
Insulin is a small protein consisting of
· an alpha chain of 21 amino acids linked by two disulfide (S-S) bridges to a
· beta chain of 30 amino acids.
Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose ("blood sugar").
Insulin affects many organs. It
· stimulates skeletal muscle fibers to
o take up glucose and convert it into glycogen;
o take up amino acids from the blood and convert them into protein.
· acts on liver cells
o stimulating them to take up glucose from the blood and convert it into glycogen while
o inhibiting production of the enzymes involved in breaking glycogen back down ("glycogenolysis").
· acts on fat (adipose) cells to stimulate the uptake of glucose and the synthesis of fat.
In each case, insulin triggers these effects by binding to the insulin receptor - a transmembrane protein embedded in the plasma membrane of the responding cells.
Taken together, all of these actions result in:
· the storage of the soluble nutrients absorbed from the intestine into insoluble, energy-rich products (glycogen, protein, fat)
· a drop in the level of blood sugar
Diabetes Mellitus
Diabetes mellitus is an endocrine disorder characterized by many signs and symptoms. Primary among these are:
· a failure of the kidney to reclaim glucose so that glucose spills over into the urine
· a resulting increase in the volume of urine because of the osmotic effect of this glucose (it reduces the return of water to the blood).
Diabetes mellitus is a disorder quite distinct from the similarly-named diabetes insipidus. They both result in the production of large amounts of urine (diabetes), but in one the urine is sweet while in the other (caused by ADH deficiency) it is not. Before the days of laboratory tests, a simple taste test ("mellitus" or "insipidus") enabled the doctor to make the correct diagnosis.
There are three categories of diabetes mellitus:
· Insulin-Dependent Diabetes Mellitus (IDDM) [also called "Type 1" diabetes] and
· Non Insulin-Dependent Diabetes Mellitus (NIDDM)["Type 2"]
· Inherited Forms of Diabetes Mellitus
Insulin-Dependent Diabetes Mellitus (IDDM)
IDDM (also called Type 1 diabetes)
· is characterized by little (hypo) or no circulating insulin;
· most commonly appears in childhood.
· It results from destruction of the beta cells of the islets.
· The destruction results from a cell-mediated autoimmune attack against the beta cells.
· What triggers this attack is still a mystery, although a prior viral infection may be the culprit.
IDDM is controlled by carefully-regulated injections of insulin. (Insulin cannot be taken by mouth because, being a protein, it would be digested.)
For many years, insulin extracted from the glands of cows and pigs was used. However, pig insulin differs from human insulin by one amino acid; beef insulin by three. Although both work in humans to lower blood sugar, they are seen by the immune system as "foreign" and induce an antibody response in the patient that blunts their effect and requires higher doses.
Two approaches have been taken to solve this problem:
· Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version. This approach is expensive, so now the favored approach is to
· Insert the human gene for insulin into E. coli and grow recombinant human insulin in culture tanks. Insulin is not a glycoprotein so E. coli is able to manufacture a fully-functional molecule (trade name = Humulin). Yeast is also used (trade name = Novolin).
Injections of insulin must be done carefully. Injections after vigorous exercise or long after a meal may drive the blood sugar level down to a dangerously low value causing an insulin reaction. The patient becomes irritable, fatigued, and may lose consciousness. If the patient is still conscious, giving a source of sugar (e.g., candy) by mouth usually solves the problem quickly. Injections of glucagon are sometimes used.
Non Insulin-Dependent Diabetes Mellitus (NIDDM)
Many people develop diabetes mellitus without an accompanying drop in insulin levels (at least at first).
In many cases, the problem appears to be a failure to express a sufficient number of glucose transporters in the plasma membrane (and T-system) of their skeletal muscles.
Normally when insulin binds to its receptor on the cell surface, it initiates a chain of events that leads to the insertion in the plasma membrane of increased numbers of a transmembrane glucose transporter.
Discussion of how transmembrane proteins are moved to the surface of the cell in which they are synthesized.
This transporter forms a channel that permits the facilitated diffusion of glucose into the cell.
Skeletal muscle is the major "sink" for removing excess glucose from the blood (and converting it into glycogen). In NIDDM, the patient's ability to remove glucose from the blood and convert it into glycogen may be only 20% of normal. This is called insulin resistance. Curiously, vigorous exercise seems to increase the expression of the glucose transporter (called GLUT-4) on skeletal muscle and this may explain why IDDM is more common in people who live sedentary lives.
NIDDM (also called Type 2 diabetes mellitus) usually strikes in adults and, particularly often, in overweight people. However, over the last few years in the U. S., the incidence of NIDDM in children has grown to the point where they now account for 20% of all newly-diagnosed cases (and, like their adult counterparts, are usually overweight).
Several drugs, all of which can be taken by mouth, are useful in restoring better control over blood sugar in patients with NIDDM.
However, late in the course of disease, patients may have to begin to take insulin. It is as though after years of pumping out insulin in an effort to overcome the patient's insulin resistance, the beta cells become exhausted.
Inherited Forms of Diabetes Mellitus
Some cases of diabetes result from mutant genes inherited from one or both parents. Examples:
· mutant genes for one or another of the transcription factors needed for transcription of the insulin gene (5 mutant versions have been identified).
· mutations in one or both copies of the gene encoding the insulin receptor. These patients usually have extra-high levels of circulating insulin but defective receptors. The mutant receptors
o may fail to be expressed properly at the cell surface or
o may fail to transmit an effective signal to the interior of the cell.
· a mutant version of the gene encoding glucokinase, the enzyme that phosphorylates glucose in the first step of glycolysis.
· mutations in the gene encoding part of potassium channels in the plasma membrane of the beta cell. The channels fail to close properly causing the cell to become hyperpolarized and blocking insulin secretion.
· mutations in several mitochondrial genes which reduce insulin secretion by beta cells. These diseases are inherited from the mother as only her mitochondria survive in the fertilized egg.
While symptoms usually appear in childhood or adolescence, patients with inherited diabetes differ from most children with NIDDM in
· having a history of diabetes in the family and
· not being obese.
Amylin
Amylin is a peptide of 37 amino acids, which is also secreted by the beta cells of the pancreas.
Some of its actions:
· inhibits the secretion of glucagon;
· slows the emptying of the stomach;
· sends a satiety signal to the brain.
All of its actions tend to supplement those of insulin, reducing the level of glucose in the blood.
Alpha Cells
The alpha cells of the islets secrete glucagon, a polypeptide of 29 amino acids.
Glucagon acts principally on the liver where it stimulates the conversion of glycogen into glucose ("glycogenolysis") which is deposited in the blood.
Glucagon secretion is
· stimulated by low levels of glucose in the blood;
· inhibited by high levels, and
· inhibited by amylin.
The physiological significance of this is that glucagon functions to maintain a steady level of blood sugar level between meals.
Injections of glucagon are sometimes given to diabetics suffering from an insulin reaction in order to speed the return of normal levels of blood sugar.
Delta Cells
The delta cells secrete somatostatin. This consists of two polypeptides, one of 14 amino acids and one of 28.
Somatostatin has a variety of functions. Taken together, they work to reduce the rate at which food is absorbed from the contents of the intestine.
Somatostatin is also secreted by the hypothalamus and by the intestine. Further information about somatostatin can be found by following the links.
Gamma Cells
The gamma cells of the islets secrete pancreatic polypeptide. No function has yet been found for this peptide of 36 amino acids.
The gonads, the primary reproductive organs, are the testes in the male and the ovaries in the female. These organs are responsible for producing the sperm and ova, but they also secrete hormones and are considered to be endocrine glands.
Testes
Male sex hormones, as a group, are called androgens. The principal androgen is testosterone, which is secreted by the testes. A small amount is also produced by the adrenal cortex. Production of testosterone begins during fetal development, continues for a short time after birth, nearly ceases during childhood, and then resumes at puberty. This steroid hormone is responsible for:
· The growth and development of the male reproductive structures
· Increased skeletal and muscular growth
· Enlargement of the larynx accompanied by voice changes
· Growth and distribution of body hair
· Increased male sexual drive
Testosterone secretion is regulated by a negative feedback system that involves releasing hormones from the hypothalamus and gonadotropins from the anterior pituitary.
Ovaries
Two groups of female sex hormones are produced in the ovaries, the estrogens and progesterone. These steroid hormones contribute to the development and function of the female reproductive organs and sex characteristics. At the onset of puberty, estrogens promotes:
· The development of the breasts
· Distribution of fat evidenced in the hips, legs, and breast
· Maturation of reproductive organs such as the uterus and vagina
Progesterone causes the uterine lining to thicken in preparation for pregnancy. Together, progesterone and estrogens are responsible for the changes that occur in the uterus during the female menstrual cycle.
The Adrenal Glands
The adrenal glands are two small structures situated one atop each kidney.
Both in anatomy and in function, they consist of two distinct regions:
· an outer layer, the adrenal cortex, which surrounds
· the adrenal medulla.
Link to graphic showing the location and structure of the adrenal glands (92K).
The Adrenal Cortex
Using cholesterol as the starating material, the cells of the adrenal cortex secrete a variety of steroid hormones. These fall into three classes:
· glucocorticoids (e.g., cortisol)
· mineralocorticoids (e.g., aldosterone)
· androgens (e.g., testosterone)
Production of all three classes is triggered by the secretion of ACTH from the anterior lobe of the pituitary.
All these hormones achieve their effects by:
· diffusing from the blood into all cells
· binding to their receptor - a protein present in the cytoplasm and/or nucleus of "target" cells
· The hormone-receptor complex binds to a second to form a dimer.
· The dimer migrates into the nucleus (if it did not form there).
· The hormone-receptor dimer binds to specific hormone response elements in DNA.
· These are specific DNA sequences in the promoter of genes that will be turned on (sometimes off) by the interaction.
· Other transcription factors are recruited to the promoter and gene transcription begins.
Select this link for a stereo view of a steroid receptor (the glucocorticoid receptor) dimer bound to the DNA of its response element.
Glucocorticoids
The glucocorticoids get their name from their effect of raising the level of blood sugar (glucose). One way they do this is by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose.
The most abundant glucocorticoid is cortisol (also called hydrocortisone).
Cortisol and the other glucocorticoids also have a potent anti-inflammatory effect on the body. They depress the immune response, especially cell-mediated immune responses. [Discussion of mechanism]
For this reason glucocorticoids are widely used in therapy:
· to reduce the inflammatory destruction of rheumatoid arthritis and other autoimmune diseases
· to prevent the rejection of transplanted organs
· to control asthma
Mineralocorticoids
The mineralocorticoids get their name from their effect on mineral metabolism. The most important of them is the steroid aldosterone.
Aldosterone acts on the kidney promoting the reabsorption of sodium ions (Na+) into the blood. Water follows the salt and this helps maintain normal blood pressure.
Link to discussion.
Aldosterone also
· acts on sweat glands to reduce the loss of sodium in perspiration;
· acts on taste cells to increase the sensitivity of the taste buds to sources of sodium.
The secretion of aldosterone is stimulated by:
· a drop in the level of sodium ions in the blood;
· a rise in the level of potassium ions in the blood;
· angiotensin II
· ACTH (as is that of cortisol)
Androgens
The adrenal cortex secretes precursors to androgens such as testosterone.
In sexually-mature males, this source is so much lower than that of the testes that it is probably of little physiological significance. However, excessive production of adrenal androgens can cause premature puberty in young boys.
In females, the adrenal cortex is a major source of androgens. Their hypersecretion may produce a masculine pattern of body hair and cessation of menstruation.
Addison's Disease: Hyposecretion of the adrenal cortices
Addison's disease has many causes, such as
· destruction of the adrenal glands by infection;
· their destruction by an autoimmune attack;
· an inherited mutation in the ACTH receptor on adrenal cells.
The essential role of the adrenal hormones means that a deficiency can be life-threatening. Fortunately, replacement therapy with glucocorticoids and mineralocorticoids can permit a normal life.
Cushing's Syndrome: Excessive levels of glucocorticoids
In Cushing's syndrome, the level of adrenal hormones, especially of the glucocorticoids, is too high.
It can be caused by:
· excessive production of ACTH by the anterior lobe of the pituitary;
· excessive production of adrenal hormones themselves (e.g., because of a tumor), or (quite commonly)
· as a result of glucocorticoid therapy for some other disorder such as
o rheumatoid arthritis or
o preventing the rejection of an organ transplant.
The Adrenal Medulla
The adrenal medulla consists of masses of neurons that are part of the sympathetic branch of the autonomic nervous system. Instead of releasing their neurotransmitters at a synapse, these neurons release them into the blood. Thus, although part of the nervous system, the adrenal medulla functions as an endocrine gland.
The adrenal medulla releases:
· adrenaline (also called epinephrine) and
· noradrenaline (also called norepinephrine)
Both are derived from the amino acid tyrosine.
Release of adrenaline and noradrenaline is triggered by nervous stimulation in response to physical or mental stress. The hormones bind to adrenergic receptors - transmembrane proteins in the plasma membrane of many cell types.
Some of the effects are:
· increase in the rate and strength of the heartbeat resulting in increased blood pressure;
· blood shunted from the skin and viscera to the skeletal muscles, coronary arteries, liver, and brain;
· rise in blood sugar;
· increased metabolic rate;
· bronchi dilate;
· pupils dilate;
· hair stands on end ("gooseflesh" in humans);
· clotting time of the blood is reduced;
· increased ACTH secretion from the anterior lobe of the pituitary.
All of these effects prepare the body to take immediate and vigorous action.
What is the Liver?
The liver is the largest glandular organ of the body. It weighs about 3 lb (1.36 kg). It is reddish brown in color and is divided into four lobes of unequal size and shape. The liver lies on the right side of the abdominal cavity beneath the diaphragm. Blood is carried to the liver via two large vessels called the hepatic artery and the portal vein. The heptic artery carries oxygen-rich blood from the aorta (a major vessel in the heart). The portal vein carries blood containing digested food from the small intestine. These blood vessels subdivide in the liver repeatedly, terminating in very small capillaries. Each capillary leads to a lobule. Liver tissue is composed of thousands of lobules, and each lobule is made up of hepatic cells, the basic metabolic cells of the liver.
What is its major function?
The liver has many functions. Some of the functions are: to produce substances that break down fats, convert glucose to glycogen, produce urea (the main substance of urine), make certain amino acids (the building blocks of proteins), filter harmful substances from the blood (such as alcohol), storage of vitamins and minerals (vitamins A, D, K and B12) and maintain a proper level or glucose in the blood. The liver is also responsible fore producing cholesterol. It produces about 80% of the cholesterol in your body.
Diseases of the Liver?
Several diseases states can affect the liver. Some of the diseases are hepatitis (an inflammation of the liver), liver cancer, and cirrhosis (a chronic inflammation that progresses ultimately to organ failure). Alcohol alters the metabolism of the liver, which can have overall detrimental effects if alcohol is taken over long periods of time.
Hemochromatosis can cause liver problems.
Medications that negatively effect the liver?
Medications have side effects that may harm your liver. Some of the medications that can damage your liver are: serzone, anti-cancer drugs (tagfur, MTX, and cytoxan), and medications used to treat diabetes.
Serzone is a prescription drug manufactured by Bristol-Myers Squibb for the treatment of depression.
The possible side effects of Serzone® are: agitation, dizziness, clumsiness or unsteadiness, difficulty concentrating, memory problems, confusion, severe nausea, gastroenteritis, abdominal pain, unusually dark urine, difficult or frequent urination, fainting, skin rash or hives yellowing of the skin or whites of the eyes (jaundice) or a prolonged loss of weight or loss of appetite.
If you or a family member have suffered serious side effects or a fatal injury after taking Serzone®, you or the family member may be eligible to file a claim against the manufacturer. You should contact an attorney that specializes in class action lawsuits immediately.
To help prevent liver damage, let your doctor know about your liver condition when being treated for other conditions. Medications come in many forms and it is best to find out what is in them and what it can do to your liver.
Thymus
The thymus gland lies in the upper part of the mediastinum behind the sternum and extends upwards into the root of the neck. It weighs about 10 to 15 g.(about half an ounce) at birth and begins to grow until the individual reaches puberty when it begins to atrophy. It’s maximum weight is around 30 - 40g (around 1 to 1.5 ounces) by the age of 40 it has returned to it’s weight at birth. The thymus consists of two lobes connected by areolar tissue. The lobes are enclosed in a fibrous capsule which dips into their substance dividing them into lobules that consist of an irregular branching framework of epithelial cells and lymphocytes.
Function
Lymphocytes originate from haemocytoblasts (stem cells) in red bone marrow. Those that enter the thymus mature and develop into activated T-lymphocytes i.e. able to respond to antigens encountered elsewhere in the body. They then divide into two groups :
those that enter the blood, some of which remain in circulation and some lodge in other lymphoid tissue
those that remain in the thymus gland and are the source of future generations of T-lymphocytes.
The maturation of the thymus and other lymphoid tissue is stimulated by thymosin, a hormone secreted by the epithelial cells that form the framework of the thymus gland. Involution of the gland begins in adolescence and, with increasing age the effectiveness of T- lymphocyte response to antigens declines.