Hormones

Hormonal communication systems augment the nervous communcation systems within the body. Hormones are chemical signaling molecules (peptides, proteins or steroids) produced in one site of the body that then travel to another site to have an effect. In this way one cell can effect other distantly located cells. The endocrine system displays an elegant system of checks and balances in the form of feedback loops to facilitate the normal funtioning of all bodily systems. Hormones may be made and have an action locally or may be made in one endocrine gland and have an effect at a distant site.  Glands are functional units of hormone secreting cells located in various regions of the body making up the endocrine system. Each gland has specific functions that help to maintain the normal internal environment and promote the survival of the organism.  Although there are some diffuse endocrine tissues, as in the gastrointestinal epithelium, there are several major glands or control centers within the endocrine system, including:

  • pituitary gland
  • anterior pituitary
  • intermediate lobe
  • posterior pituitary
  • hypothalamus
  • suprarenal (adrenal) gland
  • thyroid
  • parathyroid
  • pancreas
  • testes
  • ovary
  • pineal

“The Master Gland”
The pituitary gland, which lies is a small depression in the sphenoid bone of the skull called the sella turcica, has often been termed the ‘Master Gland’ because many of the hormones it releases effect the release of other hormones. However, the pituitary is really not the master. It is controlled by a brain region called the hypothalamus via the release of releasing factors into a special blood vessel network (hypothalamic-hypophyseal portal system) that feeds the pituicytes. These releasing factors then cause or inhibit the release of pituitary hormones which travel via the circulatory sytem to the target organ.  For example, as a woman’s menstrual cycle progresses toward ovulation, the hypothalamus releases LHRH (luteinizing hormone releasing hormone) that travels via the hypophyseal portal system to the pituitary where it stimulates the production and release of LH (luteinizing hormone). LH then travels to the ovaries where it causes ovulation and the subsequent development of a progesterone secreting corpus luteum.

Anatomically and functionally the pituitary can be divided into three portions:

1) anterior pituritary (adenohypophysis)
Six peptide hormones are secreted by the adenohypophysis: Growth hormone (somatotropin), corticotropin (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and prolactin. All except growth hormone and prolactin regulate the activities of other glands.  Somatotropin, PRL and ACTH are polypeptide hormones and LH, FSH, and TSH are glycoproteins having very similar structures.

  • Growth hormone has no specific target tissue. All cells of the human body are affected by this hormone. It is very important in the growing child but it remains essential to many bodily functions throughout life. GH has effects on the growth of bone and cartilage, protein metabolism, RNA formation, electrolyte balance, fat and glucose metabolism.
  • ACTH    This trophic hormone stimulates the production and release of suprarenal steroids. Normally the amount of circulating ACTH is controlled by the levels of cortisol in the blood, individual biorhythms and stress.
  • TSH    This hormone stimulates the synthesis and secretion of thyroid homones. It is a glycoprotein hormone controlled by feedback from thyroid homones.
  • FSH    The target organs for FSH are the testes, in men, and the ovaries in women. The hormone stimulates the germinal epithelium in the testes to cause and facilitate the making of sperm. In women it stimulates the growth and development of the follicle. It stimulates the production of testosterone in men and estrogen and progesterone in women. Its release from the pituitary is governed by a negative feedback mechanism involving these steroids.
  • LH    The male target organ is the testes and the testosterone producing interstitial cells of Leydig in particular. In women the target of LH is the developing follicle within the ovary where it is necessary for ovulation to occur and a corpus luteum to develop.
  • Prolactin    This hormone is involved in breast development and lactation. In concert with estrogen, it prepares the mammary gland for lactation and then causes the synthesis of milk. Secretion is regulated by a release inhibiting factor and suckling may cause the release of prolactin from the pituitary.

2) intermediate lobe (pars intermedia)
In the adult human this lobe is diminished with poor vascular and neural connections such that secretion is not facilitated. Cells in the pars intermedia may secrete MSH (melanocyte stimulating hormone) which stimulates the activity of melanocytes in the skin.

3) posterior pituitary (neurohypophysis)
This portion of the pituitary is really an extension of the hypothalamus. Neurons with their cell bodies in the hypothalamus and their terminal protions in the neurohypophysis release two hormones. Antidiuretic hormone (ADH) and oxytocin are stored there within the terminal processes of neurons until the signal to release them is received.

  • ADH    In the presence of ADH, the kidneys reabsorb more water from the forming urine within the renal tubules. Without ADH the kidney tubules are almost completely impermeable to water such that a very dilute urine is excreted (diabetes insipidus). ADH has a direct effect on vascular smooth muscle causing vasoconstriction and an increase in blood pressure when present in large doses. The hypothalamus has osmoreceptors that sense the concentration of the blood. They are stimulated by a high blood osmolarity (increased concentration) causing the release of ADH. The hormone then causes the kidney tubules to reabsorb more water to return osmolarity to normal. Volume receptors also play a role when they sense a low blood pressure. Alcohol inhibits ADH secretion.
  • Oxytocin    A major role of this hormone is the stimulation of smooth muscle cells in the pregnant uterus. When labor begins, stretching of the cervix and vagina stimulates a reflex production and release of oxytocin. Oxytocin then travels in the blood to the uterus where it causes more forceful contraction of the smooth muscle. This hormone is also involved in lactation. It causes milk ejection by acting on the smooth muscle surrounding the milk producing cells. Again its production and release is mediated by a neural reflex, the suckling reflex. Emotion, anxiety and pain can inhibit oxytocin release.

Hypothalamus
Anterior pituitary functions are controlled by the region of the brain called the hypothalamus via the secretion of  releasing and inhibiting factors. Specialized neurons in the hypothalamus, controlled by feedback and other communication methods release factors that cause the release of hormones from the anterior pituitary. The pituitary trophic hormones then control the release of other hormones from a target gland. With the exception of prolactin, release promoting factors are more important to the release of pituitary hormones. Somatostatin (inhibits GH release),  prolactin inhibiting factor (PIF), LH releasing factor (LHRF), FSH releasing factor (FSHRF), prolactin releasing factor (PRF), corticotropin releasing factor (CRF), thyrotropin releasing hormone (TRH) are all hormones that control the release of anterior pituitary hormones. The release of these factors is controlled by feedback from the target organ hormone to maintain the proper hormonal balance.

Suprarenal (adrenal) Gland
The suprarenal glands are located on top of each of the kidneys. The adrenal cortex (outer portions) produce the corticosteroids: the mineralcorticoids and the glucocorticoids which are steroid hormones. The cortex also produces some male sex steroids. Cholesterol is the starting place for the biosynthesis of all these steroid hormones.

The adrenal medulla is actually an extension of the nervous system. The adrenal medulla produces norepinephrine and epinepherine (adrenaline) that are released in response to stress or a fright.

Mineralcorticoids
The major mineralcorticoid, which is secreted almost independently of ACTH from the pitutitary, is aldosterone. Aldosterone secretion is controlled mostly by the levels of potassium and sodium in serum and a blood pressure control system called the renin-angiotensin system. The principle action of aldosterone is the retention of sodium. Where sodium goes, so goes associated ions and water. Therefore, aldosterone profoundly effects fluid balance by effecting intracellular and extracellular fluid volume.
Aldosterone has the opposite effect on serum levels of potassium as it is lost in the urine in exchange for sodium in the renal tubules. Salivary and sweat glands are also influenced by aldosterone to save sodium and the intestine increases the absorption of sodium in response to aldosterone.

Aldosterone levels increase and cause fluid retention in diseases such as congestive heart failure and liver cirrhosis. Certain diruetics act by antagonizing aldosterone. In contrast to most diruretics that cause potassium loss, the aldosterone antagonists increase blood potassium and are sometimes used for this effect.

Glucocorticoids
The major glucocorticoid is cortisol. Cortisol has important actions in the control and metabolism of carbohydrates, lipids, and proteins and assists in the metabolic reaction to stress, especially chronic stress. It causes glucose to be liberated from the liver by  increasing glucose production from fatty acids (by-products of lipid breakdown) and amino acids. Cortisol causes the tissues to take up less glucose from the blood and mobilizes fat breakdown. The net effect is to increase serum glucose concentrations which is protective for the brain in that it cannot use any other fuel source than glucose. It also stimulates protein breakdown for glucose formation in all tissues except the liver where it stimulates protein synthesis.

At high concentrations (greater than physiologic) glucocorticoids (such as hydrocortisone or prednisone) are useful for the treatment of allergies and inflammation. Each step of the inflammatory process is blocked by glucocorticoids when given systemically (an IV injection or orally). Topical application of glucocorticoids have anti-inflammatory effects for the local area. The anti-inflammatory activity of glucocorticoids is thought to be due primarily to the stabilization of cell membranes. The immune response can also be suppressed by the use of glucocorticoids. Eosinophils and lymphocytes decrease in the circulation affecting both cellular and humoral immunity. The glucocorticoids are used for many other conditions including asthma, renal diseases, rheumatic disorders such as lupus and inflammatory bowel disease.

Thyroid
The thyroid is a large endocrine organ that functions mostly to control metabolism. It is located in the neck between the trachea and laynx and is bi-lobed with a connecting isthmus. The gland is composed of many tiny follicles, that are in effect, each a separately functioning gland with a single-layer epithelial lining. Each follicle accumulates a storage form of the circulating thyroid hormones, thyroglobin. Thyroglobin is a large protein molecule that contains multiple copies of the amino acid tyrosine. The thyroid hormones are very simple modifications of the amino acid tyrosine. Iodide is added to one or two spots on the amino acid and then two of the modified tyrosines are combined to form one of the two thyroid hormones, thyroxin (T4) or triiodothyronine (T3).  The thyroid hormones are then cut off the thyroglobin as needed and released into the circulation. The thyroid follicles accumulate iodine by extracting it from the blood and trapping it within the lumen of the follicle. This ability to store homone in a large molecule is unique to the thyroid.

Both T4 and T3 enter cells and bind to an intracellular receptors whereby they increase the metabolic capabilities of the cell. Mitochondria and mitochondrial enzymes are increased thereby influencing cellular metabolism. Thyroid hormones are necessary for normal growth and development. They have metabolic effects on protein synthesis, lipid metabolosm and carbohydrate metabolism.

Also produced by parafollicular cells within the thyroid is the polypeptide hormone calcitonin. It funtions in calcium maintainence to decrease the levels of calcium in the blood. When serum calcium levels are excessive, calcitonin is released. It inhibits bone resorption (by inhibiting osteoclast activity), allows the loss of calcium in the urine and therefore decreases calcium in the blood. It opposes the action of parathyroid hormone and has been used clinically for the treatment of osteoporosis.

Parathyroid
The four parathyroid glands lie on top of the thyroid gland in seperate nodes spread out to the four quandrants of the thyroid. Parathyroid homone is under direct feedback control of circulating levels of calcium. If calcium levels fall, then parathyroid hormone is released. As calcium levels rise, release of the hormone is reduced. Parathyroid homone acts on bones, the kidneys and the intestines to reabsorb calcium.

Pancreas
The pancreas is a mixed exocrine and endocrine gland. The exocrine portion makes many of the digestive enzymes necessary for gastrointestinal function. The endocrine portion is comprised of discrete islands of cells called the islets of Langerhans. Cells within the islets produce two hormones that regulate the concentration of glucose in the blood. Insulin is a polypeptide hormone produced by the beta cells that reduces the level of circulating glucose. It is the only hormone that reduces circulating glucose levels, is secreted in response to high glucose levels and is subject to negative feedback control. Insulin causes cells to take up glucose, stimulates the storage of glucose, and inhibits the making of glucose. Abnormalities in the secretion or response of cells to insulin cause the condition diabetes mellitus.

Glucagon is a small protein produced by alpha cells within the islets that causes the level of blood glucose to increase. Its release is controlled by blood levels of glucose. As levels fall, glucagon release is increased causing the release of stored glucose and the synthesis of glucose until levels are increased and glucagon release is then reduced via negative feeedback. Glucagon opposes the metabolic actions of insulin. This opposition plus the negative feedback control of glucose levels maintains very tight control on blood glucose levels.

Testes
Testosterone is the principle hormone of the testes and is synthesized from cholesterol by the Leydig cells. The secretion of testosterone is under the control of LH from the pituitary. LH secretion is decreased by increased levels of testosterone in the blood via negative feedback. Testosterone develops and maintains the male secondary sex characteristics, is anabolic and growth promoting and participates in the formation of sperm. It also causes aggressive behavior and increased libido. Body hair is increased by androgens while scalp hair is decreased.

Like other steroids, testosterone enters cells and binds to an intracellular receptor and then causes the production of mRNA coding for proteins that manifest the changes induced by testosterone. In some target tissues a form of testosterone, DHT, is produced that has greater stability in combination with the receptor and therefore produces a longer lasting effect. DHT is needed for the maturation of the accessory glands and external genitalia, while testosterone is more important in the growth of muscle mass, development of the internal genitalia and maintainence of the male libido and sex drive.

Another hormone produced by the testes is the polypeptide hormone, inhibin, produced by the Sertoli cells. It inhibits FSH secretion by a direct action on the pituitary.

Ovary
The ovaries produce the steroid hormones (estrogens and progesterone) that cause the development of secondary sexual characteristics and develop and maintain the reproductive function in the female. Specifically the estrogens are secreted by the theca interna cells and the granulosa cells of the ovarian follicle, the corpus luteum and the placenta. LH from the anterior pituitary binds to receptors on theca interna or granulosa cells to cause the production of estradiol from cholesterol or a downstream precursor androstenedione that is passed from the thecal cells to the granulosa cells. Progesterone is secreted mostly by the corpus luteum and the placenta but some is made by the developing follicle. Negative feedback from progesterone decreases LH secretion and large doses can prevent ovulation.

Estridiol is the most potent and major secreted estrogen although estrone and estriol can be found in circulation as well. Like other steroid hormones, estrogens enter target cells, combine with a nuclear receptor and cause the production of mRNAs that, when translated into proteins, modify cell function. Estrogens are metabolized by the liver and secreted in bile where some is reabsorbed back into the body. Metabolites of estridiol are excreted in the urine.

Estrogens in the blood stream inhibit the release of FSH and LH, in some circumstances, via negative feedback. At other times, as in the preovulatory LH surge, estrogens increase the release of LH, via positive feedback. Estrogen also increases the excitability of uterine smooth muscle, myometrial sensitivity to oxytocin and increases the libido in women by a direct action on hypothalamic neurons.

Estrogens lower plasma cholesterol, inhibit atherogenesis (plaque formation in blood vessels), and are protective against myocardial infarction as suggested by the lower incidence of heart attacks and atherosclerosis in premenopausal women.

Progesterone has the principal targets of the uterus, breasts and the brain. It promotes the development of breast tissue, causes changes in the endometrial lining during the luteal phase of the cycle, decreases the excitability of myometrial cells and decreases uterine sensitivity to oxytocin.

Cells of the developing follicle also produce the polypeptide hormone inhibin which inhibits FSH secretion by a direct action on the pituitary.

Pineal
The pineal gland can be found deep in the brain at the top of the third ventricle where it is is close communication with the cerebrospinal fluid. In the adult, the pineal gland can often be seen in x-rays of the brain because of the accumulation of radiopaque calcium phosphate and carbonate into small granules called pineal sand. The cells of the pineal gland secrete the hormone melatonin in a diurnal cycle (the amount changes throughout a 24 hr period) where the amount remains low during the daylight hours but increases during the dark hours. This diurnal variation is controlled by norepinephrine from sympathtic nevous input that is regulated by the light-dark cycle in the environment.

Although some people use melatonin supplements to treat insomnia, this effect has not been proven in scientific trials. There have been reports of increased insomnia and depression as well as other side effects associated with its use.

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