THE ENDOCRINE SYSTEM

Prof. Atsma © 2005-2014

The following is a narrative summary of the topic. Click here for the endocrine system "Classroom Notes" that you can print out and bring to class to save yourself a lot of note-taking.

Introduction

Like the nervous system, the Endocrine system is a communication system which uses chemical messengers. The difference is that the message is carried by the blood rather than traveling along an axon. For this reason, the endocrine system's effects are generally somewhat slower to induce, and are longer lasting than those produced by nervous stimulation.

Endocrine glands are stimulated one of three ways: 1) by nervous impulses, usually from the hypothalamus; 2) hormones, usually from the hypothalamus or the adenohypophysis; and 3) humoral stimulation, where it is usually a chemical regulated by the hormone (i.e. calcium, glucose) which induces or suppresses hormone release.

[Note: There are some hormones which are produced by endocrine tissues rather than distinct endocrine glands. Others, usually referred to as paracrines (or sometimes "local hormones"), simply diffuse to nearby cells. For this course, the main focus is the major endocrine glands and their hormones .]

Mechanisms of Hormone Action

There are two basic classes of hormones, each with very different modes of action. Although, most of the human body's hormones are amino acid based ones. What they have in common is that they follow the basic pathway outlined below:

Endocrine gland --------> Hormone --------> Blood --------> Target cell receptor

Steroid hormones are based on the cholesterol molecule. Therefore, they are lipid-soluble, and thus can easily pass through the plasma membrane and combine with receptors inside the cell. The hormone-receptor combination directly affects the cell's DNA, and can either directly initiate or inhibit some cell function. This is called direct gene activation, which should sound familiar from your study of the nervous system as the indirect method of opening sodium channels to induce depolarization. Estrogen stimulating the growth of the uterine lining would be an example of a steroid hormone. Although thyroid hormone is an amino acid based hormone, it does enter the cell and work through direct gene activation.

Amino acid or peptide based hormones usually are unable to directly enter cells, and must instead bind to membrane bound receptors. [Note: Some of the smaller amino acid hormones are able to penetrate the plasma membrane, but this is the exception, not the rule.]  The hormone binding to the receptor in the plasma membrane allows for activation of G-proteins within the membrane. The G-proteins, in turn, activate or deactivate enzymes typically found attached to the membrane on the inside of the cell. In many cases, the enzyme is adenylate cyclase, which converts ATP into cyclic AMP (cAMP). A second messenger such as cAMP (the hormone is the "first messenger") modifies the cytoplasmic biochemistry in a way that signals the cell to take some action (growth, metabolic changes, protein synthesis, etc.). In the case of cAMP, it typically works by activating enzymes in the cytoplasm.

Stimulatory hormones (and their related stimulatory G-proteins) usually activate the enzyme in question, which will then produce a chemical referred to as a second messenger. Inhibitory hormones (and their related stimulatory G-proteins) usually inactivate this enzyme, bringing the production of the second messenger to a halt. Antagonistic stimulatory and inhibitory hormones are not found in all second messenger systems, but are present wherever tight control of homeostasis is necessary. Insulin and glucagon would be an example of an antagonistic hormone system in this category.

However, cyclic AMP is not always the 2nd messenger. In some cells, G- proteins stimulate an enzyme called phospholipase that eventually produces molecules called IP3 and DAG (diacylglycerol). These 2nd messengers work in different ways. DAG works pretty much like cAMP and activates enzymes. IP3  triggers the release of Ca++ ("3rd messenger") from the ER, and calcium activates enzymes. [Note: the textbook refers to calcium as playing a second messenger role. Note that I am using the term informally as a descriptive term, not a technical term.]

There are also some rare cases (e.g. insulin) where the hormone's receptor itself is the enzyme to be activated, so the extra steps of using G-proteins aren't part of the story.  

Factors Affecting Hormone Action

Since hormones and their receptors finding each other is random, concentration of the hormone will affect how strongly a target cell can be stimulated. The amount produced and its half-life are the biggest factors in concentration. If a target cell has enzymes to intentionally destroy the hormone once it has delivered its message, it has a very short half life (could be seconds). Other hormones are only lost when removed by the kidneys, and would have a longer half life (hours).

Interaction with other hormones is a consideration, as some hormones require the action of another hormone to have significant affects ("permissiveness"), like when sex hormones AND thyroid hormone are required for proper growth and development of reproductive system structures. Others may have an amplified affect when another hormone enters the picture ("synergism"), like when glucagon and epinephrine force significantly more sugar release from liver cells.

Finally, Up-regulation and Down-regulation, where the target cell increases or decreases its number of receptors can magnify or suppress the affect of a hormone. Clearly, having more receptors makes it easier for the hormone to find a place to plug in, and enhances the hormone's effect. The increase in uterine oxytocin receptors in the third trimester is a classic example of up-regulation.

The Neuro-Endocrine Link: The Hypothalamus

Control of the neurohypophysis: The hypothalamus directly controls release of hormones stored in the neurohypophysis. Impulses travel down the hypothalamic-hypophyseal tract, which is the trunk of axons connecting the cell bodies in the hypothalamus with storage bulbs of the axons in the neurohypophysis. Just as they do in a typical neuron, the action potential reaching the end of the axon signals the release of the "neurotransmitter" stored there.  Since the neurotransmitter is released for pick up by the blood rather than for diffusion across a synapse, the chemical messenger is instead called a hormone.

Control of the adenohypophysis: The hypothalamus is indirectly connected to the adenohypophysis by a short blood vessel system called the hypophyseal portal system. A set of capillaries in the hypothalamus picks up hypothalamic inhibiting and/or releasing hormones, and then merge to form the hypophyseal portal vein, which then branches into a second set of capillaries in the anterior pituitary.  When they diffuse out into the anterior pituitary, these inhibiting and releasing hormones from the hypothalamus control the release of adenohypophyseal hormones.

The Neurohypophysis (Posterior Pituitary)

Seemingly a simple outgrowth of the hypothalamus specialized for release of chemicals into the blood, the neurohypophysis releases only two hormones (which are actually made in the hypothalamus). Technically, the neurohypophysis also includes the infundibulum, the thin connecting stalk (containing mostly axons) between the hypothalamus and the pituitary.

Oxytocin (made in the paraventricular nucleus of the hypothalamus) causes contraction of the smooth muscle of the uterus and around the myoepithelial cells of the mammary glands (milk let-down). It also has receptors in the brain and seems to influence human behavior, promoting "bonding" of people to each other (couples or parent-child bonding).

Antidiuretic hormone (ADH, aka vasopressin), made in the supraoptic nucleus of the hypothalamus, activates water reabsorption of certain kidney tubules (you'll learn exactly which tubules and how when we cover the urinary system), which is an anti-diuretic effect. The term diuretic or diuresis refers to increased urine output, and this process does the opposite (more water reabsorbed back into the body means less going in to form urine).  It also causes smooth muscle contraction of arterioles in the systemic circulation. In addition to helping the body conserve water, these effects are important in maintaining blood pressure. Hyposecretion causes Diabetes insipidus or high urine output. Hypersecretion causes excess water retention.

The Adenohypophysis (Anterior Pituitary)

The truly glandular portion of the pituitary who's embryonic derivation is the epithelium of the oropharynx, the adenohypophysis is comprised of highly effective secretory cells. Several tropic hormones (control function of other endocrine glands), and three hormones with different target tissues, are produced here.

Growth hormone (GH) (aka somatotropin) encourages growth of most body cells, but particularly sensitive are muscle, nerve, and cartilage/bone-forming tissues (such as the epiphyseal plate). Also helps cells to use available energy sources (carbohydrates and fats) and encourages protein synthesis. It also affects metabolism and can increase blood sugar levels. Hyposecretion can produce Dwarfism (often called pituitary dwarfism to distinguish if from other things that may cause short stature). Hypersecretion can produce Gigantism when it occurs before the fusion of the epiphyseal plate (as excessive longitudinal growth occurs), or in adults, it can cause acromegaly (abnormal thickening of the bones by appositional growth).

Prolactin (Prl) prepares the mammary glands (which should already have been developed by estrogen and progesterone) for active milk production/secretion. Prl release is controlled by hypothalamic prolactin inhibiting hormone (PIH) which is secreted most of the time, and can be stimulated by high estrogen levels. This is one of those times where it it proper to use a "double negative" in writing. Inhibiting PIH while estrogen levels are high increases prolactin output. Tactile stimulation of the breast and the high levels of estrogen found late in pregnancy promote this. Although hyposecretion isn't all that common, it can make it difficult to produce enough milk for a nursing mother. Hypersecretion can cause excess milk production and breast enlargement. Although it is not fully understood why, prolactin seems to reduce fertility - perhaps mother nature's way of making it more difficult to conceive another child until the current one is a little older and not quite so dependent on mom for survival. 

Melanocyte stimulating hormone (MSH) causes melanocytes to release more melanin.

The remaining hormones are tropic hormones (stimulate another endocrine gland) who's names usually define their function. Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex (not the medulla) to release glucocorticoids (i.e. cortisone & cortisol). Follicle stimulating hormone (FSH) stimulates follicular cells in the ovary to produce estrogen and up-regulates these cells to become more sensitive to LH. It also promotes spermatogenesis in males. Luteinizing hormone (LH) stimulates the follicle cells to induce ovulation, and converts the exploded follicle into the corpus luteum, a powerful progesterone/estrogen producing tissue. LH is called ICSH in males, where it stimulates testosterone release. Thyroid stimulating hormone (TSH, aka thyrotropin) stimulates thyroid follicular cells to produce and release thyroxin. As would logically follow, the effects of hyper/hyposecretion for each of the above will mirror those of the gland/hormone they target.

Thyroid Gland

The thyroid gland is located just inferior to the larynx. Follicular cells are stimulated by TSH from the pituitary, and secrete mainly T4 (Thyroid Hormone or Thyroxine) and triiodothyronine (T3) which is produced in lesser amounts but has more potent effects on target cells. TH is a pretty simple molecule - just two tyrosine amino acids bonded together. The number 3 or 4 just refers to the number of iodine atoms are attached. Actually, T4 is converted to T3 by target tissues, so one could argue that it is really T3 that is the active form of thyroid hormone. These hormones have chemical properties that let them penetrate the cell membrane for direct gene activation, just like steroidal hormones.

The feedback loop may be summarized as:

1) Dropping levels of thyroid hormone stimulates the release of thyrotropin releasing hormone from the hypothalamus, resulting in TSH release from the adenohypophysis. This stimulates:
2) Uptake of thyroid hormone precursors (tyrosine amino acids and the iodine needed as a cofactor), and their storage in the open spaces or follicles in the form of a "colloid" made largely of thyroglobulin (a globular protein made of lots of tyrosine amino acids linked together). In the storage follicles, iodine is attached to the tyrosine amino acids. And then:
3) Under the stimulus of TSH, thyroglobulin molecules are chopped up and reformed into into two amino acid fragments (T3 and T4), which are prepared for secretion.

Conversely:

1) Elevated blood thyroxin levels inhibit the release of thyrotropin releasing hormone from the hypothalamus, resulting in:
2) A reduction in pituitary release of TSH, and
3) Subsequent reduction in thyroid activity.

Other stimuli (e.g. low temperature) can affect this feedback loop.  

The difference in how T3 and T4 are made is really quite simple. Enzymes in the colloid usually attach two iodines to each tyrosine amino acid. So when the thyroglobulin is chopped up into two amino acid fragments, each thyroxine molecule has 4 iodines (2+2=4). More rarely, only one iodine is attached to a tyrosine amino acid. So when that tyrosine is attached to another that has two iodines, that hormone molecule only has 3 (1+2=3).

T3 and T4 promote normal metabolic activity (breakdown of carbohydrate and lipid energy sources and increased protein synthesis) in most cells in the body. Because nearly all cells have TH receptors (except the adult brain and a few organs regulated otherwise), TH has widespread effects. The most obviously important effects are in stimulating proper metabolism (burns calories and stimulates protein/fat/cholesterol synthesis). But because TH is involved in "permissiveness" relationships with other hormones as described earlier, thyroid hormone is important in proper development of most body systems in fetal and childhood development. Hyposecretion may cause weight gain, low body temp., weakness, and reduced mental function in adults (and cretinism in children when their nervous systems don't develop properly). Hypersecretion produces the logical effects of elevated metabolism: weight loss, wasting of tissues (e.g. muscle), and hyperexcitability. This is called Graves disease in adults. Goiter (enlargement of the thyroid gland) can occur due to tumors of the thyroid, or tumors of the pituitary that result in excess TSH production. Although itis rare in most developed countries where adequate nutrition is available, dietary deficiency of iodine can also cause goiters as the follicles swell with unusable colloid and TSH levels stay high.

Parafollicular cells of the thyroid secrete the protein hormone calcitonin (encourages osteoblastic activity). High blood Ca++ levels trigger release of calcitonin from the parafollicular cells (the cells NOT directly bordering the follicles). Interestingly, recent evidence suggests that calcitonin's effect on lowering blood calcium is minimal at most. Instead most calcium regulation occurs through the normal loss of calcium in the urine and regulation by the next gland/hormone.  

Parathyroid Glands

The Parathyroid Glands are small rounded pieces of tissue (4-6) protruding posterior-laterally from the thyroid in most mammals, but tend to be embedded in the thyroid of humans. Parathyroid hormone (PTH) is the antagonist of calcitonin and encourages osteoclast activity in bone cells, also tends to increase production of vitamin D (enhances absorption of Ca++ form the gut). It also activates kidney reabsorption of Ca++. The simple feedback loop is triggered by drop in blood Ca++ levels.

Adrenal Glands

As with the hypophysis, the adrenals are an embryological hybrid, derived from nervous tissue (medulla) and mesodermal tissue (cortex). The two portions of the adrenals also are vastly different in terms of their mechanism of stimulation. The cortex is stimulated by ACTH from the pituitary, and the medulla is directly stimulated by nervous impulses from the hypothalamus.

The Adrenal cortex secretes steroid-based hormones and has three obvious tissue layers:

The outer zona glomerulosa (rounded clumps of cells) secretes mineralocorticoids, essentially aldosterone (the main "mineralocorticoid"), which turns on Na+/k+ pumps in the kidney tubules in order to reabsorb sodium and excrete potassium. Several things cause aldosterone release: 1) high K+; 2) low BP triggers release of rennin from specialized kidney cells, and rennin begins a process of converting a plasma protein called angiotensinogen (made in the liver) into angiotensin I, and then angiotensin II (it is angiotensin II that triggers aldosterone release as well as vasoconstriction); 3) ACTH stimulation; 4) low Na+ (a weaker trigger of aldosterone release). The important role these hormones play should suggest to you why the adrenal glands are essential. Blood pressure and electrolyte balance is heavily dependent on the regulation provided by aldosterone.

The middle zona fasciculata (long strands of cells) secretes glucocorticoids (cortisone, cortisol, corticosterone), which increase glucose production (for example from amino acids) and encourage hyperglycemia. Adipose cells are stimulated to breakdown lipids for energy. They also have anti-inflammatory properties and suppress the immune system. Triggered by ACTH from the adenohypophysis (triggered by corticotropic releasing hormone from the hypothalamus, triggered by the brain's perception of danger, stress, adverse conditions).

Hypersecretion causes Cushing’s disease and is usually caused by brain tumors causing excess ACTH production.  High glucocorticoid levels keep blood sugar too high (causing adipose tissue growth/redistribution), and immune suppression. Hyposecretion causes Addison’s disease, and usually results from low ACTH productionBlood sugar runs low, and weight loss can occur from this imbalance in metabolism.

The cortex's innermost layer, the zona reticularis is an area with irregular strands of cells that secrete androgens, important to females who would not otherwise get the low levels of androgens needed for proper development of certain tissues. The effects of hypersecretion are pretty obvious - masculine characteristics in females. The effects of hyposecretion are "controversial." Although these androgens may contribute to things in females like maintaining muscle mass, sex drive, etc., there is little evidence as to if lower levels do any harm and if supplements do any good.

Note: there is a little crossover of job responsibilities in the last two zones, whereby they may produce each other's hormones. But the vast majority of the hormones are produced as described above.

Adrenal medulla secretes amino acid-based hormones collectively referred to as the catecholamines. Both epinephrine and norepinephrine dilate the coronary arteries and increase BP by vasoconstriction in the peripheral circulation. Epinephrine (the majority of the adrenal medulla's hormone production) increases heart rate and dilates the bronchial tree, and norepinephrine is the more potent vasoconstrictor (and effector of BP). The medulla is derived from nervous tissue and is directly connected to the hypothalamus by nerves for prompt triggering of  catecholamine release during the fight or flight response. Since these hormones mainly synergize the sympathetic response, hyposecretion is unlikely to have much effect. And perhaps due to its origin as embryonic nervous tissue, hypersecretion doesn't seem to happen.

Pancreas

Mostly an exocrine gland carrying enzymes to the duodenum, the pancreas is dotted with clumps of hormone-producing cells called the pancreatic islets or islets of Langerhans. Beta cells in the islets secrete insulin, which stimulates many cells to absorb glucose from the blood. In particular, liver, muscle, and adipose cells absorb large amounts of glucose for processing. The liver and muscles are stimulated to store the glucose as the starch glycogen (glycogenesis); adipose cells are also stimulated to store glucose as fat. Breakdown of glycogen and fat is inhibited. A simple feedback loop stimulates insulin release when blood glucose levels are high. Alpha cells secrete glucagon, the antagonist of insulin, which stimulates the liver to break-up glycogen (glycogenolysis) and release of glucose into the blood. Synthesis of new glucose molecules is also encouraged (gluconeogenesis).

Diabetes mellitus and hypoglycemia are the main disorders associated with improper secretion of these hormones. Type I Diabetes mellitus is insulin deficit diabetes due to autoimmune disease that destroys beta cells. It is treated with insulin replacement therapy. Type II is non-insulin-dependent diabetes, and usually is caused by genetic predisposition to insulin receptors (or the 2nd messenger systems) malfunctioning when other risk factors contributing to speeding up the malfunction (obesity, high carbohydrate diet, etc.). 

Hypoglycemia (low blood sugar) can have two very different contributing factors. Too little glucagon released (or released too slowly) when blood sugar levels drop can allow blood sugar to stay dangerously low for too long. Or, rapid hypersecretion of insulin when blood sugar levels rise can cause blood sugar to plummet down well below normal. While many body cells can use other molecules for energy, most of the nervous system can't. That's why fainting can occur easily for those with hypoglycemia.

The graphics below help explain normal blood sugar regulation, and what goes wrong in diabetes and hypoglycemia. It's worth repeating that diabetes is a term that just means increased urine output, and that it is the all-important "mellitus" part of the name that tells you that sugar is the cause of it. You'll learn about how malfunctioning sugar regulation causes this increased urine output when we cover the urinary system.

 

Normal Blood Sugar Regulation:

Diabetes Mellitus:

BloodSugar2

Hypoglycemia:

BloodSugar3

Gonads

Hormones produced by the gonads are of the steroid variety. Both testis and ovaries are stimulated by the pituitary hormones LH and FSH. LH mainly stimulates hormone production in the gonads, whereas FSH is primarily involved in gamete production.

Testis: The seminiferous tubules are the exocrine (sperm-producing) portion of the testes, and the testosterone-producing interstitial cells (aka cells of Leydig) lie in small clumps between the seminiferous tubules. Testosterone is responsible for the fetal development of the male accessory structures, and during puberty, the development of the secondary sex characteristics such as facial hair, (and with GH) additional muscle growth.

Ovaries: The ovaries work in cycles to produce oocytes ("egg cells") and the female hormones estrogen and progesterone. Although the do not play a role in fetal development, the estrogens are responsible for the female secondary sex characteristics such as breast development and the typical female subcutaneous fat deposition pattern. Progesterone is also secreted during the female cycle, and plays a major role in preparing the uterus for pregnancy.

I know the above seems a little brief considering the importance of the sex hormones, but that it intentionally so. It makes more sense to cover the sex hormones and their feedback loops in detail when we get to the reproductive system.

MISCELLANEOUS

The Thymus secretes thymosin which activates T-lymphocytes during late fetal and early childhood development. Atrophies after early development. The Pineal body secretes melatonin, but more importantly, may be part of biological clock that initiates puberty. Not widely known to be an endocrine gland, the Kidney contains juxtaglomerular cells which produce rennin. Rennin  converts angiotensinogen to angiotensin (see ADH). The Atria of the heart produce atrial natriuretic factor (ANF) antagonist/inhibitor of aldosterone that promotes Na+ secretion by the kidney tubules (may be triggered when blood pressure is elevated).

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