The Endocrine System: An Overview

Endocrine glands are ductless glands that produce and release hormones to the blood through diffusion.

Endocrine glands may be strictly endocrine, such as the pituitary, thyroid, parathyroid, adrenal, pineal and thymus; or they may be organs that have hormone production as one of many functions, such as the pancreas, gonads, hypothalamus, and others.


Chemistry of Hormones

Hormones are long-distance chemical signals that are secreted by the cells to the extracellular fluid and regulate the metabolic functions of other cells.

Most hormones are amino acid based, but gonadal and adrenocortical hormones are steroids, derived from cholesterol.

Mechanisms of Hormone Action

Hormones typically produce changes in membrane permeability or potential, stimulate synthesis of proteins or regulatory molecules, activate or deactivate enzymes, induce secretory activity, or stimulate mitosis.

Water-soluble hormones (all amino acid-based hormones except thyroid hormone) exert their effects through an intracellular second messenger that is activated when a hormone binds to a membrane receptor.

Second messenger systems, activated when a hormone binds to a plasma membrane receptor, activate G-proteins within the cell that alter enzyme activity.

Lipid-soluble hormones (steroids and thyroid hormone) diffuse into the cell, where they bind to intracellular receptors, migrate to the nucleus, and activate specific target sequences of DNA.

Direct gene activation occurs when a hormone binds to an intracellular receptor, which activates a specific region of DNA, causing the production of mRNA, and intitiation of protein synthesis.

Target Cell Specificity

Cells must have specific membrane or intracellular receptors to which hormones can bind.

Target cell response depends on three factors: blood levels of the hormone, relative numbers of target cell receptors, and affinity of the receptor for the hormone.

Target cells can change their sensitivity to a hormone by changing the number of receptors. 

Half-Life, Onset, and Duration of Hormone Activity

The concentration of a hormone reflects its rate of release, and the rate of inactivation and removal from the body.

The half-life of a hormone is the duration of time a hormone remains in the blood, and is shortest for water-soluble hormones.

Target organ response and duration of response vary widely among hormones.

Interaction of Hormones at Target Cells

Permissiveness occurs when one hormone cannot exert its full effect without another hormone being present (reproductive hormones need thyroxine to properly stimulate development of reproductive organs).

Synergism occurs when more than one hormone produces the same effects in a target cell, and their combined effects are amplified (glucagon + epinephrine together stimulate more glucose release from the liver than when each acts alone).

Antagonism occurs when one hormone opposes the action of another hormone (glucagon antagonizes insulin).

Control of Hormone Release

Most hormone synthesis and release is regulated through negative feedback mechanisms.

Endocrine gland stimuli may be humoral, neural, or hormonal.

Nervous system modulation allows hormone secretion to be modified by the nervous stimulation in response to changing body needs.

Major Endocrine Organs

The Pituitary Gland (Hypophysis)

The pituitary gland is connected to the hypothalamus via a stalk, the infundibulum, and consists of two lobes: the anterior pituitary, or adenohypophysis, and the posterior pituitary, or neurohypophysis.

Two neurohormones are synthesized by the hypothalamus and secreted by the posterior pituitary.

Oxytocin acts on the smooth muscle of the uterus and breast to cause uterine contractions during childbirth and contraction of mammary myoepithelial cells, resulting in milk expulsion (let-down reflex) during nursing. Oxytocin also promotes pair-bonding between mother and child.

Oxytocin is also released during orgasm but whether or not it promotes pair bonding between partners is debatable. The fact that release is inhibited by lack of appropriate neural stimuli may speak to that.

Antidiuretic hormone (ADH) acts on kidney tubules to promote increased water reabsorption when blood volume or pressure is low, osmolality is high, and sometimes pain. Adequate hydration inhibits release.

Both oxytocin and ADH release are also inhibited by alcohol, which can lead to speculation about delaying delivery with martinis, renting beer, and coyote love.

There are six adenohypophyseal hormones and one prohormone.

Growth hormone (GH) indirectly (through insulin-like growth factors, IGFs) stimulates body cells to increase in size and divide.

Direct effects are insulin-sparing: mobilization of fatty acids for fuel, inhibition of insulin activity, release of glucose from liver to blood, and stimulation of amino acid uptake by cells.

GHRH, secreted from the hypothalamus, is the stimulus for GH release. The stimulus for GHRH release is low blood levels of GH as well as hypoglycemia, low blood levels of fatty acids, and high blood levels of amino acids.

Hyposecretion of GH results in pituitary dwarfism in children. Hypersecretion of GH in childhood results in gigantism; in adulthood hypersecretion of GH causes acromegaly (increase in size of flat bones after epiphyseal plates of long bones have sealed).

Thyroid stimulating hormone (TSH) is a tropic hormone that stimulates normal development and secretion of the thyroid gland. Thryroid releasing hormone (TRH) from the hypothalamus stimulates TSH release; Thyroid hormone (Thyroxine) exerts negative feedback control of both TRH and TSH.

Adrenocorticotropic hormone (ACTH) is a tropic hormone stimulates the adrenal cortex to release corticosteroid hormones.

Pro-opiomelanocortin (POMC) is a prohormone that is the source of adrenocorticotropic hormone, melanocyte stimulating hormone (which, at normal levels acts in the CNS) and two opiates.

Follicle-stimulating hormone (FSH) is a tropic hormone that stimulates gamete production.

Leutinizing hormone (LH) is a tropic hormone that promotes ovulation in females and production of gonadal hormones.

Prolactin stimulates milk production in females, and may enhance testosterone in males.


The Thyroid Gland

The thyroid gland consists of hollow follicles with follicle cells that produce thyroglobulin, and parafollicular cells that produce calcitonin.


Thyroid hormone consists of two amine hormones: thyroxine (T4) and triiodothyronine (T3), that act on all body cells to increase basal metabolic rate and body heat production.

Hypothyroidism may result from inadequate TRH release, inadequate TSH release, dysfunction of the thyroid gland itself, inadequate dietary iodine, or autoimmune destruction (Hashimoto's autoimmune throiditis).

Full blown hypothyroidism in adults is known as myxedema (mucous swelling). If myxedema results from lack of iodine the thyroid gland continues to make thyroglobulin but can't iodinate it, resulting in an enlarged thyroid, or colloidal/endemic goiter (figure 16a, below).

Treatment typically involves iodine supplementation, thyroid hormone supplementation, and sometimes ablation of the thyroid followed by thyroid hormone replacement. Ablation, which is also the treatment for Graves' disease, is typically accomplished by administration of radioactive iodine.

The most common cause of hyperthyroidism is an autoimmune disease (Graves' disease) in which anti-TSH receptor antibodies bind to TSH receptors on the thyroid and stimulate continuous thyroid hormone release. The feedback mechanism is short-circuited because the production and release of thyroid hormone is not dependent on TSH.

Exopthalmos may occur, indicating edema and fibrosis of tissue behind the eyes (figure 16b, below).

Calcitonin (produced by parafollicular or "C" cells) is a peptide hormone that can lower blood calcium by inhibiting osteoclast activity and stimulating Ca2+ uptake and incorporation into the bone matrix ( at pharmacological doses, otherwise it has no physiological effect in humans).


The Parathyroid Glands

The parathyroid glands contain chief cells that secrete parathyroid hormone, or parathormone.

PTH increases blood calcium levels by accessing stored Ca++, increasing absorbtion of Ca++, and inhibiting loss of Ca++.

PTH increases blood calcium levels by mobilizing Ca++ and PO43+ from bone, like the figure says, but what it doesn't say is that when PTH stimulates Ca++ reabsorption at the kidney it also stimulates the excretion of PO43+. The figure does point out that PTH increases Ca++ absorption by stimulating renal activation of vitamin D3.


The Adrenal (Suprarenal) Glands

The adrenal glands, or suprarenal glands, consist of two regions: an inner adrenal medulla and an outer adrenal cortex.

The adrenal cortex produces corticosteroids from three distinct regions: the zona glomerulosa, the zona fasciculata, and the zona reticularis.

Glomerulosa: primarily mineralocorticoids, mostly aldosterone, are essential to regulation of electrolyte concentrations of extracellular fluids (Na+ & K+).

Aldosterone secretion is regulated by the renin-angiotensin mechanism, fluctuating blood concentrations of sodium and potassium ions (increased sodium levels/decreased potassium levels), and secretion of ACTH.

Fasiculata: primarily glucocorticoids are released in response to stress through the action of ACTH. Glucocorticoids, like cortisol, are glucose sparing stress related hormones.

Reticularis: primarily gonadocorticoids are mostly weak androgens, which are converted to testosterone and estrogens in the tissue cells.

Cushing's syndrome/disease is caused by an excess of glucocorticoids. The disease may be caused by a glucocorticoid producing tumor but in most cases administration of glucocorticoids clinically results in the syndrome. Cushing's syndrome is characterized by elevated blood glucose, loss of muscle and protein from bone, and hypertension and edema due to salt and water retention. Anti-inflammatory effects can cause increased susceptibility to disease and poor wound healing.

The signs include "moon" face (due to edema), and redistribution of fat to the back of the neck (buffalo hump) and abdomen.

Addison's disease is a disease of cortical insufficiency, resulting in weight loss, low plasma glucose and sodium levels, and an in crease in plasma potassium levels. Common signs are severe dehydration and hypotension. Disruption of the feedback mechanism that controls POMC release may result in over production of MSH and a general bronzing/darkening of the skin.

The adrenal medulla contains chromaffin cells that synthesize epinephrine and norepinephrine (stimulus is acetylcholine released by preganglionic sympathetic fibers).


The Pancreas

The pancreas is a mixed gland that contains both endocrine and exocrine gland cells.

Insulin lowers blood sugar levels by enhancing membrane transport of glucose into body cells, inhibiting glycogenolysis, and inhibiting gluconeogenesis. (Brain, kidney and liver don't need insulin to take up glucose from blood.)

Insulin is an anabolic hormone and will stimulate not only glucose uptake but also storage in the form of glycogen (glycogenesis), fat (lipogenesis) and amino acid incorporation into proteins (inhibits amino acid breakdown by liver to form new glucose molecules - gluconeogenesis).

Stimuli for insulin release are primarily high blood glucose levels but insulin release is also potentiated by rising blood levels of amino acids and fatty acids and release of acetylcholine by parasympathetic neurons (all of these things happen after a meal).

Glucagon is released by the pancreas in response to low blood glucose levels (primarily) and raises blood glucose levels back to within normal range by stimulating glycogenolysis, gluconeogenesis, and release of glucose to the blood by the liver. Additional stimuli are sympathetic nervous system stimulation and rising blood amino acid levels.

Diabetes mellitus is a disease of insulin insufficiency (type I) or insulin resistance (type II), resulting in elevated blood glucose levels.

Glucose spilling into the urine results in osmotic diuresis, giving rise to dehydration and increased thirst. Inability of cells to utilize glucose leads to hunger, all of which give rise to the three classic signs of diabetes, polyuria, polydipsia, and polyphagia.

To meet energy needs of the body fats are mobilized and proteins broken down to utilize amino acids for fuel, resulting in hyperlipidemia and metabolic acidosis. Excretion of ketoacids (with their negative charge) by the kidney is accompanied by loss of cations, particularly K+ and Na+.

Long-term complications include decreased circulatory efficiency, peripheral neuropathy, hypertension, and acceleration of atherosclerosis.

Type I diabetes results from destruction of pancreatic beta cells and subsequent loss of insulin production.

Autoimmune destruction of pancreatic beta cells appears to be linked to certain viral infections and correlates with HLA haplotypes (more in the immune system chapter).

Type II diabetes results from insulin resistance and is associated with obesity and genetic factors.

Adipocyte-derived adiponectin is an insulin-sensitizing and anti-atherosclerotic hormone, and recent studies have demonstrated that adiponectin level is a good predictor of developing type II diabetes and coronary artery disease. Decreasing adiponectin levels are linked to an interaction between genetic factors, such as mutations in the adiponectin gene, and environmental factors, such as high-fat diet.

Other candidates for involvement include PC-1, which inhibits phosphorylation of the insulin receptor, and inhibition or mutations in glucose transporter proteins (glut-4 for example).

The Gonads

The ovaries produce estrogens and progesterone.

The testes produce testosterone.

The Pineal Gland

Secretes melatonin, a hormone derived from serotonin, in a diurnal cycle.

Indirectly receives input from the visual pathways in order to determine the timing of day and night.

Lower light levels (onset of night) stimulate melatonin secretion, which results in drowsiness. Bright light stimulates the breakdown of melatonin (levels are lowest around midday) and helps regulate our diurnal cycle.

Melatonin secretion is also affected by the length of night and day, with levels being higher in the winter months and shorter in the summer.

In some animals mating behavior is mediated by melatonin levels (however sexual response/activity in humans is a complex process...) and is responsible for the "winter blues" (Seasonal Affective Disorder, S.A.D.) some people experience.

The Thymus

The thymus produces thymopoietin, thymic factor, and thymosin, which are essential for the development of T-lymphocytes and the immune response.

Thymopoietin - growth factor for immature T-cells

Thymic factor (thymulin) - T-cell differentiation and enhancement of T and NK cell actions, neuroendocrine activity (positive correlation between thymulin plasma levels and ACTH levels), and seems to have an effect on pro-inflammatory cytokines. Analgesic and anti-inflammatory effects in the CNS.

Thymosin - promotes differentiation of T0 cells to T1 and late T2 differentiation, accelerates proliferation of mature and immature lymphoid cells.

Other Hormone-Producing Structures

Adipose tissue produces leptin, which acts on the CNS to produce a feeling of satiety; secretion is proportional to fat stores.

Adipocytes also produce adiponectin, which enhances insulin activity, and resistin, an insulin antagonist. Secretion of resistin is proportional to fat stores; secretion of adiponectin is inversely proportional to fat stores.

The atria of the heart contain specialized cells that secrete atrial natriuretic peptide (or factor, or hormone - ANP or ANF or ANH, depending on the text) resulting in decreased blood volume, blood pressure, and blood sodium concentration.

ANP inhibits aldosterone secretion and antagonizes its activity at the kidney.

The gastrointestinal tract contains enteroendocrine cells throughout the mucosa that secrete hormones to regulate digestive functions.

The placenta secretes estrogens, progesterone, and human chorionic gonadotropin, which act on the uterus to influence pregnancy.

The kidneys produce erythropoietin, which signals the bone marrow to produce red blood cells.

Osteoblasts in bone produce osteocalcin, which stimulates pancreatic beta cells to divide and secrete more insulin. It also inhibits fat storage and stimulates adipocytes to produce adiponectin. Insulin promotes conversion of inactive osteocalcin to active osteocalcin.

Adiponectin levels are low in type II diabetes, suggesting higher levels may help reverse the insulin resistance characteristic of type II diabetes.

The skin produces cholecalciferol, an inactive form of vitamin D3.



Developmental Aspects of the Endocrine System

Endocrine glands derived from mesoderm produce steroid hormones; those derived from ectoderm or endoderm produce amines, peptides, or protein hormones.

Environmental pollutants have been demonstrated to have effects on sex hormones, thyroid hormone, and glucocorticoids.

Old age may bring about changes in rate of hormone secretion, breakdown, excretion, and target cell sensitivity.