THE ENDOCRINE SYSTEM - AN INTRODUCTION

      The endocrine system consists of the ductless glands.  These glands produce chemical messengers called hormones which pass into the bloodstream for circulation throughout the body.  Hormones will excite or inhibit the activity of target organs or tissues.  Whether or not a target tissue will be affected by a hormone depends upon the presence of specific receptor molecules on the membranes or in the cytoplasm of the target cells.

     When a hormone is present in excess the number of receptor molecules on the target cells will decrease.  This "down regulation" will reduce the responsiveness of the target cells to the hormone.  However, when a hormone is at a very low level in the blood, the number of receptor molecules on the target cells may increase.  This is known as "up regulation".  As a result, the target tissue becomes more sensitive to the lower levels of that hormone. 

     Basically there are three types of hormone molecules:

   1.  Protein hormones are large, complex molecules made up of many amino acids  joined together.  These molecules range in size from those hormones composed of 8 to 10 amino acids, e.g., oxytocin and vasopressin (ADH) to the very large molecules of insulin and growth hormone.

    2.  Amine hormones are derived from a single modified amino acid, e.g., the catecholamines (epinephrine and dopamine) are produced from tyrosine.

    3.  Steroid hormones are manufactured from cholesterol, a fat soluble substance.

      The glands of internal secretion (endocrine) are concerned with the control and coordination of processes which are widespread in the body, such as, Metabolism, Growth, Homeostasis, Adaptation to Stress and Sexual Reproduction.  Although each endocrine gland has specific functions, all are interdependent.  The activity or lack of activity of one gland usually influences the rest of the system.

     Control of Hormone Secretions

      Hormone secretion is stimulated and inhibited by three types of signals:

   1.  Neuronal signals are basically nerve impulses which control hormone secretion.  For example, sympathetic nerve stimulation of the adrenal medulla causes the release of epinephrine into the blood.

   2.  Hormonal signals - Hormones can stimulate other endocrine tissues to release their hormones.  ACTH from the anterior pituitary stimulates the release of steroids from the adrenal cortex.

   3.  Humoral signals - The presence or absence of a particular chemical substance in the blood can bring on the release of a given hormone from an endocrine gland.  An example of this type of mechanism can be seen in the effect of high blood calcium producing the release of calcitonin from the thyroid.

 Negative and Positive Feedback

      The most common method of controlling endocrine secretions is through negative feedback.  When a stress, such as low blood sugar, triggers the release of a hormone (glucagon in this case) a response is produced in the body, i.e., an increase in blood sugar.  If the response reduces the stress, then the secretion of hormone will also be reduced - negative feedback.  Less often, the effect of the hormone will enhance or intensify the original stress.  In this positive feedback condition, the mechanism is usually shut off by an outside event.  For example, the release of the hormone oxytocin increases during labor due to the increased pressure on the uterine wall.  The birth of the baby shuts down the mechanism.

 PITUITARY GLAND - The Anterior Lobe

      The pituitary gland is attached to the median eminence of the hypothalamus by the stalk-like infundibulum.  The anterior lobe of this gland accounts for about 75% of the weight of the pituitary and is derived from a pocket in the roof of the embryonic mouth (Rathke's pouch).  In addition to a direct arterial supply, the anterior lobe of the pituitary receives blood through the hypothalamic-hypophyseal portal system from the hypothalamus.  Secretion of the hormones produced by the anterior pituitary is controlled by Releasing and Inhibiting factors released from the hypothalamus into the hypothalamic portal vessels.  The principal hormones produced by the anterior lobe of the pituitary are:

    1.  Corticotropin (ACTH) - is released in response to all forms of stress, i.e., pain, trauma, cold, hypoglycemia, fear and anger.  It targets the cells of the adrenal cortex.  Under the influence of ACTH, the adrenal cortex (zona reticularis) releases cortisol along with some aldosterone.  Over-production of ACTH leads to Cushing's disease.

    2.  Somatotropin (Growth hormone) - is released during the active growth years and throughout life.  A powerful stimulant for its release is the condition of hypoglycemia.  Growth hormone has a wide variety of metabolic effects.  In general, it operates through two pathways.  First, it has a direct effect on the metabolism of proteins, fats and carbohydrates.  These activities lead to an increase in blood sugar, cellular uptake of amino acids and lipolysis.  Indirectly, growth hormone stimulates the liver to release a class of growth stimulating substances called Somatomedins.  The somatomedins target the growing tissues of the body, especially the skeletal system.

     Hyposecretion of growth hormone during childhood leads to dwarfism.  Oversecretion during childhood produces unchecked body growth - giantism.  Oversecretion during adulthood produces the condition called acromegaly in which the victim exhibits overgrowth of the mandible ("lantern jaw") and brow ridges.

    3.  Thyrotropin (Thyroid Stimulating Hormone) - acts on the thyroid gland to stimulate the synthesis and secretion of thyroxine.  A major factor leading to the release of TSH would be a hypothermic condition in the body.  An autoimmune condition which prevents the thyrotropic cells of the anterior pituitary from recognizing the level of TSH in the blood leads to oversecretion of TSH.  This is Grave's disease, a condition marked by overproduction of thyroxine, exophthalmia and goiter.

    4.  Prolactin or lactogenic hormone initiates and maintains milk secretion.  It also seems to be responsible for the stability of the ovarian corpus luteum.  Prolactin release is triggered by a releasing factor from the hypothalamus.  The inhibiting factor for prolactin appears to be dopamine.  During the late secretory phase of the menstrual cycle, a drop in the blood level of estrogens and progesterone leads to an increased release of prolactin.  The resulting increase in lactogenic activity may be responsible for the breast tenderness many women experience at this time.

    5.  Gonadotropic hormones - The anterior pituitary releases two hormones which target the gonads:
     a.  Follicle Stimulating Hormone (FSH) - facilitates the development of ovarian follicles and sperm production.  Its release is controlled partly by blood levels of gonadal steroids.
      b.  Luteinizing hormone (LH) - controls ovulation, the development of the corpus luteum and estrogen secretion in the female.  In the male, this hormone is called Interstitial Cell Stimulating hormone and stimulates the testis to produce testosterone from the cells located between the semeniferous tubules (interstitial cells).

 Pituitary Gland - The Posterior Lobe

      The posterior pituitary or neurohypophysis derives from the hypothalamus of the embryonic brain.  The activity of the posterior lobe is controlled directly by nerve cells whose cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus.  The posterior pituitary secretes the hormones vasopressin (ADH) and oxytocin.  Vasopressin is released under the conditions of low blood volume (hypovolemia) and increased osmotic pressure of the blood.  The latter condition may be due 

to:
   1. loss of body water from sweat, expired air, feces (especially during
   diarrhea), excessive urine production (diabetes).

   2. Lack of fluid intake.

   3. Increased intake of salt.

      Vasopressin is produced in cells of hypothalamic nuclei and travels within the axons of these cells through the infundibular stalk.  It is stored and released from the posterior lobe and causes an increased reabsorption of water by the kidney tubule cells into the blood.

      Oxytocin is also produced by the hypothalamic nuclei and released from the posterior pituitary.  The stimuli for this release include sensory nerve impulses from the uterus during the last stages of pregnancy.  This will result in a reflexive contraction of uterine muscle leading to the birth of the child.  Another source of stimuli for the release of this hormone originates from the nipples of a women who is nursing a child.  Oxytocin will cause a contraction of the myoepithelial tissue in a lactating mammary gland forcing milk into the baby's mouth (milk letdown)

 THYROID GLAND

    The thyroid gland consists of a right and left lobe joined by a middle region called the isthmus.  The thyroid is located on the anterior surface of the trachea just below the larynx.

   Histologically, the interior of the gland consists of hollow balls of cuboidal cells called follicles.  Inside the follicles there is a space within which is stored a product of the follicular cells called thyroglobin. Thyroglobin is an incomplete form of thyroid hormone. Thyroid hormone can be stored temporarily in follicles.

This represents the only example of extracellular storage of a hormone in endocrine tissue.

   The production of thyroid hormone is regulated by the release of hormones from the hypothalamus and anterior pituitary.  The chief stress leading to the increased release of thyroid hormone is a low basal metabolic rate usually accompanied by lower than normal body temperature.

   Hyposecretion of thyroid hormone during the growth years can lead to cretinism (dwarfism with retardation). Hyposecretion during adulthood leads to myxedema, which is characterized by a low BMR, low body temperature and muscular weakness.  If the hyposecretion is due to a lack of iodine in the diet, the individual may also develop an enlargement of the thyroid called simple goiter.  Overactivity of the thyroid in an adult is often associated with an enlarged thyroid and eyes that appearto bulge from their orbits (exophthalmia).  This condition is called Grave's disease.                                                         

 PARATHYROID GLANDS

    The parathyroids consist of four, small masses of tissue located on the posterior aspect of the lobes of the thyroid gland.  The principal product of the parathyroid gland is parathyroid hormone (PTH).  It acts to increase the blood level of calcium by:

   1. increasing the activity of the bone reabsorbing osteoclasts.

   2. increasing the absorption of calcium from the food by the gut wall.

   3. decreasing the excretion of calcium by the kidney.

      PTH release is stimulated by hypocalcemia and inhibited by hypercalcemia.  Overproduction of PTH is usually caused by a tumor of the parathyroid gland and produces a severe depletion of calcium salts from the bones called Osteitis Fibrosa Cystica.  As a result, cavities form in the bone making them more susceptible to fracture.  In postmenapausal women, osteoclasts become more sensitive to PTH.  This leads to the bone-weakening disorder called osteoporosis.

 THE PANCREAS

 The Pancreas - is a mixed or compound gland consisting of acinar (exocrine) tissue specialized to manufacture digestive secretions.  This tissue makes up most of the gland.  In addition, about 2,000,000  islets of endocrine tissue (Islets of Langerhans) produce and secrete a variety of hormones.

   The beta cells of the pancreatic islets are stimulated to release insulin due to hyperglycemia, high plasma levels of amino acids and fatty acids.  Hypersecretion of glucagon, epinephrine, growth hormone, thyroxine and cortisol will also stimulate insulin release.    After release from the beta cell, insulin is carried to the liver by the blood where about 50% is removed and inactivated.  The remainder of the hormone passes into the general circulation, where it remains active for about 15 to 35 minutes.  Insulin increases the uptake of glucose by body cells.  It stimulates glycogen synthesis in liver and skeletal muscle cells.  In adipose tissue, insulin favors lipogenesis.                                                            The primary effect of insulin is to reduce blood glucose levels.  Another effect of insulin release would be the increased uptake of amino acids by body cells.  This leads to increased protein synthesis and growth.

   The alpha cells of the pancreatic islet release the hormone glucagon.  The chief factors triggering this release are hypoglycemia and high levels of amino acids in the blood.  Glucagon causes increased glycogenolysis in liver and skeletal muscle cells.  This leads to the release of glucose into the circulation. Glucagon also produces an increased formation of glucose from amino acids and fatty acids by liver cells.  Glucagon is the chief antagonist to the action of insulin.

 Disorders of Pancreatic Hormones

 Diabetes mellitus - is due to a hyposecretion of insulin or a hypoactivity of insulin.  The are three primary effects of this disorder:

   1.  Hyperglycemia - The lack of insulin leads to an accumulation of glucose in the blood.  Most of the cells of the body require insulin to take up glucose.  The result is that in these tissues alternate sources of energy are utilized, e.g., fatty acids and amino acids undergo gluconeogenesis under the influence of cortisol and glucagon.  At the same time, glucagon and epinephrine increase the breakdown of glycogen in the liver (glycogenolysis).  Both of these activities only exacerbate the problem of hyperglycemia.

    2.  Ketosis - Another complication results from the accumulation of Ketone bodies in the blood.  These compounds result from the increased reliance on fat for energy.  Ketones are organic acids.  Their accumulation lowers the pH of the blood and reduces the oxygen-carrying capacity of the blood.  Unchecked, this will eventually lead to coma and death.

    3.  Dehydration - The presence of high levels of glucose in the glomerular filtrate interferes with the reabsorption of water by the kidney tubules.

 Hypoglycemia - This symptom  may be produced by several conditions not all of them related to islet function.  Established causes of hypoglycemia include:

   a. Beta cell tumor - "hyperinsulinism"

   b. Poor glucagon production and release

   c. Defective glucose release by the liver

   d. Addison's disease

   e. Hyposecretion of growth hormone 

 THE ADRENAL GLANDS

Adrenal glands  are located retroperitoneal on the superior surface of the kidney.  Each gland is compound structure composed of an outer, steroid-producing cortex of mesodermal origin and an inner catecholamine-synthesizing medulla derived from the neural crest.  The medulla is very similar, histologically, to the sympathetic ganglia.  Its cells contain dark-staining granules (chromaffin cells).

 Adrenal Cortex - The outer region of the gland is divided into three fairly distinct region:

 1.  Zona glomerulosa - is a thin, outer area responsible for the manufacture of the mineralocorticoids.  The most important of these is aldosterone (95% of this group).  These steroids regulate the levels of certain electrolytes in the body fluids, i.e., Na+ and K+.  Specifically, they cause the reabsorption of Na+ by the kidney tubules and the elimination of K+.

 2.  Zona fasciculata - is a fairly thick middle zone which synthesizes the glucocorticoids, a group of steroids which help to regulate glucose metabolism.  Cortisol is the most important of these steroids.  This group of hormones is essential for life as they permit adaptation to various stresses - psychological, as well as, physiological.

 3.  Zona reticularis - is the most innermost layer of the cortex.  These cells manufacture glucocorticoids and small amounts of adrenal sex steroids (gonadocorticoids).  The latter are androgens, for the most part.

 Adrenal Medulla - The major products of this gland are epinephrine (most abundant product) and norepinephrine.  Small amounts of the precursor dopamine are also produced.  We refer to these hormones as "sympathomimetic" meaning that they mimic the effects of the sympathetic nervous system, i.e., increased heart rate, construction of blood vessels in the skin and viscera, inhibition of smooth muscle in viscera, dilation of bronchioles, increased respiratory rate and hyperglycemia.

 Disorders of Cortical Hormones

 Cushing's Syndrome - is the result of a hypersecretion of Cortisol.  There are number of causes of this hypersecretion:

1.  Excessive secretion of ACTH - is usually due to a tumor of the anterior pituitary (60 to 70% of the cases).  This condition is referred to as Cushing's disease.

 2.  Adrenal Cushing's syndrome - is the result of an adrenal adenoma, a tumor of the adrenal cortex.  In this condition, there are low levels of ACTH.  About 20% of the cases are due to this cause.

 3.  Paraneoplastic Cushing's syndrome - results from the production of ACTH by a non-endocrine tumor, e.g., Bronchogenic carcinoma.

 4.  Iatrogenic Cushing's syndrome - due to the long term use of glucocorticoids to suppress inflammation or immune response.

Symptoms of Cushing's disease or syndrome:
1.  Hyperglycenia and hypertension
2.  Catabolysis of protein and fat
3.  Immunosuppression
4.  Fat accumulation in the face and upper back
           
Addison's Disease - is an uncommon disorder that requires the destruction of about 90% of both adrenal cortexes before becoming clinically apparent.  The chief causes are believed to be:

1.  Tuberculosis - responsible for about 25% of the cases.

 2.  Autoimmune disease - is suggested by the infiltration of cartical tissue with lymphocytes and the presence of antibodies in the victim's plasma to his own adrenal glands.

 3.  Insufficiency of ACTH - due to a lesion of the hypothalamus or pituitary.

          Symptoms of Addison's disease:

1.  Hypoglycenia and hypotension
2.  Dehydration and hypovolemia
3.  Atrophy of the heart
4.  Anorexia, nausea and diarrhea

THE OVARY

     The ovaries are a pair of bean-shaped structures located in the lower pelvic portion of the abdominopelvic cavity.  Each ovary is associated with the funnel-shaped opening of an oviduct (Fallopian tube) and held in place by supporting ligaments.  The ovary contains a large number of immature sex cells.  During the ovarian cycle, a group of these immature oocytes continues through the process of oogenesis. 

     In the first half of the ovarian cycle, the oocytes become surrounded by an increasing number of follicle or nurse cells.  The growth and storage of food by the oocyte are due to the activities of these cells.  The follicle cells also produce increasing amounts of estrogens during this growth or proliferative stage.  The most important of these hormones is estradiol.  The estrogens induce ovulation and cause growth of the uterus, uterine tubes and mammary tissue.  They also bring on the expression of female traits, such as, fat deposition in the breasts, thighs and buttocks.      Progesterone is secreted by the corpus luteum.  This structure develops from the remnants of the follicle wall remaining in the ovary after ovulation.  Luteinizing hormone is chiefly responsible for the development of the corpus luteum.  The most important function of progesterone is to prepare the lining of the uterus for the implantation of the embryo following fertilization.  It also stimulates milk formation during pregnancy, as well as, the inhibition of ovulation during gestation.

 THE TESTIS

     The testes lie in the scrotal sac which is suspended outside the male's abdominopelvic cavity.  During most of fetal development, the testes are found in the abdominopelvic cavity.  Towards the end of the fetal period, the testes migrate through the inguinal canal into the scrotum.  If this migration does not occur (cryptorchidism) then at the time of puberty the slightly higher temperature of the body cavity will lead to a destruction of the testicular tissue and sterility.

     The principal secretory product of the testis is the steroid testosterone.  This hormone is secreted by the interstitial cells under the influence of luteinizing hormone from the anterior pituitary.  The chief actions of testosterone lead to the virilization of the male, i.e., facial hair, deepening of the voice, increase in the strength of muscles and bone growth.  Later on, this hormone produces the closure of the epiphyseal growth plates in long bones and the cesession of growth in height.  Red blood cell production and hemoglobin synthesis are also enhanced.