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 major endocrine glands and their hormones are the main focus.]

There are two basic classes of hormones, each with very different modes of action. What they have in common is that they follow the basic pathway outlined below:

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

Steroid hormones are lipid-soluble, and thus can easily pass through the plasma membrane and combine with receptors inside the cell. The hormone-receptor combination seems to directly affect the cell's DNA, and either directly initiate or inhibit some cell function. Estrogen stimulating the growth of the uterine lining would be an example.

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. 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. A second messenger such as cAMP modifies the cytoplasmic biochemistry in a way that signals the cell to take some action (growth, metabolic changes, protein synthesis, etc.). 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. Most of the human body's hormones are peptide based ones. Insulin and glucagon would be an example of an antagonistic hormone system in this category.

Factors Affecting Hormone Action

Considering that 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. Interaction with other hormones is a consideration, as some hormones require the action of another hormone to have significant affects ("permissiveness"), and others may have an amplified affect when another hormone enters the picture ("synergism"). 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. The increase in uterine oxytocin receptors in the third trimester is a classic example of up-regulation.

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.

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). 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). Antidiuretic hormone (ADH, aka vasopressin), made in the supraoptic nucleus of the hypothalamus, activates water reabsorption of the kidney tubules, and 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.

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. 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 often, and prolactin releasing hormone (PRH) which tends to be released in significant amounts only in late pregnancy. Melanocyte stimulating hormone (MSH) causes melanocytes to release more melanin.

The remaining hormones are tropic hormones 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.

The thyroid gland is located just inferior to the larynx. Follicular cells are stimulated by TSH from the pituitary, and secrete mainly t4 and triiodothyronine (t3) which is produced more slowly but has more potent effects on target cells. These hormones are small enough (two amino acids) that they penetrate the cell membrane as do 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 and the iodine needed as a cofactor), and their storage in the open spaces or follicles in the form of a "colloid" (thyroglobulin). In the storage follicles, iodine is attached to the tyrosine amino acids. And then
3) Under the stimulus of TSH, colloid molecules are chopped up and reformed into T3 and T4, which are reabsorbed into the follicular cells where the hormones 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.

T3 and T4 (collectively referred to as TH for simplicity) promote normal metabolic activity (breakdown of carbohydrate and lipid energy sources and increased protein synthesis) in most cells in the body.

Parafollicular cells of the thyroid secrete the protein hormone calcitonin (encourages osteoblastic activity). The humoral feedback loop is more straightforward for calcitonin: high blood Ca++ levels trigger release of calcitonin from the parafollicular cells.

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 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 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).

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.

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 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.

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).

Normal Blood Sugar Regulation:

Diabetes Mellitus:

Hypoglycemia:

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.

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 of aldosterone that promotes Na+ secretion by the kidney tubules (may be triggered when blood pressure is elevated).