Hormones

It seems like a farfetched notion that a small chemical can enter the bloodstream and cause an action at a very distant location in the body. Yet this scenario occurs everyday. The ability to maintain homeostasis and respond to stimuli is largely due to hormones secreted within your body. Without hormones, you could not grow, maintain a constant temperature, produce offspring, or perform the basic actions that are essential for life.

The endocrine system produces hormones that are instrumental in maintaining homeostasis and regulating reproduction and development. A hormone is a chemical messenger produced by a cell that effects specific change in the cellular activity of other cells (target cells). Unlike exocrine glands (which produce substances such as saliva, milk, stomach acid, and digestive enzymes), endocrine glands do not secrete substances into ducts (tubes). Instead, endocrine glands secrete their hormones directly into the surrounding extracellular space. The hormones then diffuse into nearby capillaries and are transported throughout the body in the blood.

The endocrine and nervous systems often work toward the same goal—both influence other cells with chemicals (hormones and neurotransmitters). However, they attain their goals differently. Neurotransmitters act immediately (within milliseconds) on adjacent muscle, gland, or other nervous cells, and their effect is short-lived. In contrast, hormones take longer to produce their intended effect (seconds to days), may affect any cell, nearby or distant, and produce effects that last as long as they remain in the blood (up to several hours).

Hormones can be chemically classified into four groups:

Amino acid-derived hormones are modified amino acids. Polypeptide and protein hormones are chains of amino acids of less than or more

than about 100 amino acids, respectively. Some protein hormones are actually glycoproteins, containing glucose or other carbohydrate groups.

Steroid hormones are lipids that are synthesized from cholesterol. Steroids are characterized by four interlocking carbohydrate rings.

Eicosanoids are lipids that are synthesized from the fatty acid chains of phospholipids found in plasma membrane.

Mechanisms of hormone action

Hormones circulating in the blood diffuse into the interstitial fluids surrounding the cell. Cells with specific receptors for a hormone respond with an action that is appropriate for the cell. Because of the specificity of hormone and target cell, the effects produced by a single hormone may vary among different kinds of target cells.

Hormones activate target cells by one of two methods, depending upon the chemical nature of the hormone:

Lipid-soluble hormones (steroid hormones and hormones of the thyroid gland) diffuse through the cell membranes of target cells. The lipid-soluble hormone then binds to a receptor protein that, in turn, activates a DNA segment that turns on specific genes. The proteins produced as result of the transcription of the genes and subsequent translation of mRNA act as enzymes that regulate specific physiological cell activity.

Water-soluble hormones (polypeptide, protein, and most amino acid hormones) bind to a receptor protein on the plasma membrane of the cell. The receptor protein, in turn, stimulates the production of one of the following second messengers:

Cyclic AMP (cAMP) is produced when the receptor protein activates another membrane-bound protein called a G protein. The G protein activates adenylate cyclase, the enzyme that catalyzes the production of cAMP from ATP. Cyclic AMP then triggers an enzyme that generates specific cellular changes.

Inositol triphosphate (IP3) is produced from membrane phospholipids. IP3, in turn, triggers the release of Ca2+ from the endoplasmic reticulum, which then activates enzymes that generate cellular changes.

Control of hormone production

Endocrine glands release hormones in response to one (or more) of the following stimuli:

Hormones form other endocrine glands. Chemical characteristics of the blood (other than hormones).

Neural stimulation.

Most hormone production is regulated by a negative feedback system. The nervous system and certain endocrine tissues monitor various internal conditions of the body. If action is necessary to maintain homeostasis, hormones are released, either directly by an endocrine gland or indirectly though the action of the hypothalamus of the brain, which stimulates other endocrine glands to release hormones. The hormones activate target cells, which initiate physiological changes that adjust body conditions. When normal conditions have been restored, the corrective action—the production of hormones—is discontinued. Thus, in negative feedback, when the original (abnormal) condition has been repaired, or negated, corrective actions decrease (or are discontinued). For example, the amount of glucose in the blood regulates the secretion of insulin and glucagons through negative feedback.

The production of some hormones is regulated by positive feedback. In such a system, hormones cause a condition to intensify (rather than decrease). As the condition

intensifies, hormone production increases. Such positive feedback is uncommon but does occur during childbirth (hormone levels build with increasingly intense labor contractions) and lactation (where hormone levels increase in response to nursing, which causes milk production to increase).

The Hypothalamus and Pituitary Glands

The hypothalamus makes up the lower region of the diencephalons and lies just above the brain stem. The pituitary gland (hypophysis) is attached to the bottom of the hypothalamus by a slender stalk called the infundibulum. The pituitary gland consists of two major regions—the anterior pituitary gland (anterior lobe or adenohypophysis) and the posterior pituitary gland (posterior lobe or neurohypophysis).

The hypothalamus oversees many internal body conditions. It receives nervous stimuli from receptors throughout the body and monitors chemical and physical characteristics of the blood, including temperature, blood pressure, and nutrient, hormone, and water content. When deviations from homeostasis occur or when certain developmental changes are required, the hypothalamus stimulates cellular activity in various parts of the body by directing the release of hormones from the anterior and posterior pituitary glands. The hypothalamus communicates directives to these glands by one of the following two pathways:

Communication between the hypothalamus and the anterior pituitary occurs through chemicals (releasing hormones and inhibiting hormones) that are produced by the hypothalamus and delivered to the anterior pituitary through blood vessels. The releasing and inhibiting hormones are produced by specialized neurons of the hypothalamus called neurosecretory cells. The hormones are released into a capillary network (primary plexus) and transported through veins (hypophyseal portal veins) to a second capillary network (secondary plexus) that supplies the anterior pituitary. The hormones then diffuse from the secondary plexus into the anterior pituitary, where they initiate the production of specific hormones by the anterior pituitary. The releasing and inhibiting hormones secreted by the hypothalamus and the hormones produced in response by the anterior pituitary are listed in Table 1 . Many of the hormones produced by the anterior pituitary are tropic hormones (tropins), hormones that stimulate other endocrine glands to secrete their hormones.

TABLE 1 Hormone Functions

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH)

Chemical Form*

Target Action

Hypothalamus

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

GHRH growth hormone RH PP anterior pituitary

inhibits release of hGH

GHIH growth hormone IH (somatostatin)

PP anterior pituitary

stimulates release of hGH

TRH thyrotropin RH PP anterior pituitary

stimulates release of TSH and hGH

GnRH gonadotropin RH PP anterior pituitary

stimulates release of LH and FSH

PRH prolactin RH PP anterior pituitary

stimulates release of PRL

PIH prolactin IH (dopanmine)

PP anterior pituitary

inhibits release of PRL

CRH corticotropin RH PP anterior pituitary

stimulates release of ACTH

Anterior pituitary (tropic hormones)

TSH thyroid stimulating H (thyrotropin)

GP thyroid stimulates secretion of T3 and T4

ACTH adrenocortico-tropic hormone

PP adrenal cortex

stimulates secretion of glucocorticoids

FSH follicle-stimulating hormone

GP ovary, testes regulates oogenesis & spermatogenesis

LH luteinizing hormone GP ovary, testes regulates oogenesis &

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

spermatogenesis

Anterior pituitary (hormones)

PRL prolactin PR mammary glands

stimulates production of milk

hGH human growth H (somatotropin)

PR bone, muscle, various

stimulates growth

Posterior pituitary

OT oxytocin PP uterus, mammary glands

uterine contractions, release of milk

ADH antidiuretic H (vasopressin)

PP kidneys, sweat glands

increases water retention

Thyroid gland

T4 thyroxine AA most body cells

increases rate of cellular metabolism

T3 triiodothyronine AA bone increases rate of cellular metabolism

calcitonin PP bone decreases blood Ca2+

Parathyroid gland

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

PTH parathyroid hormone PP bone, kidneys, intestine

increases blood Ca2+

Adrenal medulla

NE epinephrine (adrenaline) AA blood vessels, liver, heart

increases blood sugar, constricts blood vessels (fight-or-flight response)

NE norepinephrine (noradrenaline)

AA blood vessels, liver, heart

increases blood sugar constricts blood vessels (fight or flight response)

Adrenal cortex

mineralocorticoids (e.g., aldosterone)

S kidneys increase reabsorption of Na+, excretion of K+

glucocorticoids (e.g., cortisol)

S most body cells

increase blood sugar

androgens (e.g., DHEA) S general stimulate onset of puberty, female sex drive

Pancreas

glucagon (secreted by alpha cells)

PP liver increases blood glucose

insulin (secreted by beta PP liver, decreases blood glucose

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

cells) muscle, adipose

somatostatin (secreted by delta cells)

PP alpha & beta cells

inhibits insulin & glucagon release

pancreatic polypeptide (from F cells)

PP delta cells inhibits somato-statin & pancreatic enzymes

Ovaries

estrogen S uterus, general

menstrual cycle, secondary sex characteristics

progesterone S uterus regulates menstrual cycle, pregnancy

relaxin PP pelvis, cervix

dilates cervix & birth canal

inhibin PR anterior pituitary

inhibits FSH release

Testes

testosterone S testes, general

spermatogenesis, secondary sex characteristics

inhibin PR anterior pituitary

inhibits FSH release

Pineal

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

melatonin AA various regulates biological clock

Kidney

erythropoietin GP bone marrow

increases blood cell production

calcitriol (Vitamin d) S intestine increases Ca2+ absorption

Placenta

estrogen S uterus maintains pregnancy, mammary glands

progesterone S uterus maintains pregnancy, mammary glands

hCG GP ovary stimulates release of estrogen & progesterone

hCS PR mammary glands

prepares mammary glands for lactation

Gastrointestinal tract

gastrin PP stomach stimulates HCI release

GIP gastrin inhibitory peptide

PP stomach, pancreas

inhibits gastric juice release, increases insulin

Source

Hormone (H), Releasing Hormone (RH), Or

Inhibiting Hormone (IH) Chemical

Form* Target Action

secretin PP pancreas, liver

stimulates release of enzymes & bile

CCK cholecystokinin PP pancreas, liver

stimulates release of enzymes & bile

serotonin AA stomach stimulates stomach muscle contraction

Heart

ANP atrial natriuretic peptide PP kidney, adrenal cortex

decreases blood pressure

Most cells

PG prostaglandins E all cells except red blood cells

various

LT leukotrienes E all cells except red blood cells

various

Communication between the hypothalamus and the posterior pituitary occurs through neurosecretory cells that span the short distance between the hypothalamus and the posterior pituitary. Hormones produced by the cell bodies of the neurosecretory cells are packaged in vesicles and transported through the axon and stored in the axon terminals that lie in the posterior pituitary. When the neurosecretory cells are stimulated, the action potential generated triggers the release of the stored hormones from the axon terminals to a capillary network within the posterior pituitary. Two hormones, oxytocin and antidiuretic hormone (ADH), are produced and released in this way. Their functions are summarized in Table 1 .

Merck Manual

The endocrine system coordinates functioning between different organs through hormones, which are released into the bloodstream from specific types of cells within endocrine (ductless) glands. Once in circulation, hormones affect function of the target tissue. Some hormones exert an effect on cells of the organ from which they were released (paracrine effect), some even on the same cell type (autocrine effect). Hormones can be peptides of various sizes, steroids (derived from cholesterol), or amino acid derivatives.

Hormones bind selectively to receptors located inside or on the surface of target cells. Receptors inside cells interact with hormones that regulate gene function (eg, corticosteroids, vitamin D, thyroid hormone). Receptors on the cell surface bind with hormones that regulate enzyme activity or affect ion channels (eg, growth hormone, thyrotropin-releasing hormone).

Hypothalamic-Pituitary Relationships

Peripheral endocrine organ functions are controlled to varying degrees by pituitary hormones. Some functions (eg, secretion of insulin by the pancreas, primarily controlled by the plasma glucose level) are controlled to a minimal extent, whereas many (eg, secretion of thyroid or gonadal hormones) are controlled to a great extent. Secretion of pituitary hormones is controlled by the hypothalamus.

The interaction between the hypothalamus and pituitary (hypothalamic-pituitary axis) is a feedback control system. The hypothalamus receives input from virtually all other areas of the CNS and uses it to provide input to the pituitary. In response, the pituitary releases various hormones that stimulate certain endocrine glands throughout the body. Changes in circulating levels of hormones produced by these endocrine glands are detected by the hypothalamus, which then increases or decreases its stimulation of the pituitary to maintain homeostasis.

The hypothalamus modulates the activities of the anterior and posterior lobes of the pituitary in different ways. Neurohormones synthesized in the hypothalamus reach the anterior pituitary (adenohypophysis) through a specialized portal vascular system and regulate synthesis and release of the 6 major peptide hormones of the anterior pituitary. These anterior pituitary hormones regulate peripheral endocrine glands (the thyroid, adrenals, and gonads) as well as growth and lactation. No direct neural connection exists between the hypothalamus and the anterior pituitary. In contrast, the posterior pituitary (neurohypophysis) comprises axons originating from neuronal cell bodies located in the hypothalamus. These axons serve as storage sites for 2 peptide hormones synthesized in the hypothalamus; these hormones act in the periphery to regulate water balance, milk ejection, and uterine contraction.

Virtually all hormones produced by the hypothalamus and the pituitary are released in a pulsatile fashion; periods of such release are interspersed with periods of inactivity. Some hormones (eg, adrenocorticotropic hormone [ACTH], growth hormone, prolactin) have definite circadian rhythms; others (eg, luteinizing hormone and follicle-stimulating

hormone during the menstrual cycle) have month-long rhythms with superimposed circadian rhythms.

Hypothalamic Controls

Thus far, 7 physiologically important hypothalamic neurohormones have been identified (see Table 1: Principles of Endocrinology: Hypothalamic Neurohormones). Except for the biogenic amine dopamine, all are small peptides. Several are produced in the periphery as well as in the hypothalamus and function in local paracrine systems, especially in the GI tract. Vasoactive intestinal peptide, which also stimulates the release of prolactin, is one. Neurohormones may control the release of multiple pituitary hormones. Regulation of most anterior pituitary hormones depends on stimulatory signals from the hypothalamus; the exception is prolactin, which is regulated by inhibitory stimuli. If the pituitary stalk (which connects the pituitary to the hypothalamus) is severed, prolactin release increases, whereas release of all other anterior pituitary hormones decreases.

Table 1

Hypothalamic Neurohormones

Neurohormone Hormones Affected Effect

Thyrotropin-releasing hormoneTSH

Prolactin

Stimulate

Stimulate

Gonadotropin-releasing hormoneLH

FSH

Stimulate*

Stimulate*

Dopamine Prolactin

LH

FSH

TSH

Inhibit

Inhibit

Inhibit

Inhibit

Corticotropin-releasing hormone ACTH Stimulate

Growth hormone–releasing hormone GH Stimulate

Prolactin-releasing hormone Prolactin Stimulate

SomatostatinGH

TSH

Inhibit

Inhibit

Insulin Inhibit

TSH = thyroid-stimulating hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; ACTH = adrenocorticotropic hormone (corticotropin); GH = growth hormone.

*Under physiologic conditions and when administered exogenously in intermittent pulses. Continuous infusion inhibits the release of LH and FSH.

Many hypothalamic abnormalities (including tumors and encephalitis and other inflammatory lesions) can alter the release of hypothalamic neurohormones. Because neurohormones are synthesized in different centers within the hypothalamus, some disorders affect only one neuropeptide, whereas others affect several. The result can be undersecretion or oversecretion of neurohormones. Clinical syndromes that result from the ensuing pituitary hormone dysfunction (eg, diabetes insipidus, acromegaly, Cushing's syndrome, hypogonadism, hypopituitarism) are discussed in Pituitary Disorders: Introduction.

Anterior Pituitary Function

The cells of the anterior lobe (which constitutes 80% of the pituitary by weight) synthesize and release several hormones necessary for normal growth and development and also stimulate the activity of several target glands.

Adrenocorticotropic hormone (ACTH):

ACTH is also known as corticotropin. Corticotropin-releasing hormone (CRH) is the primary stimulator of ACTH release, but antidiuretic hormone plays a role during stress. ACTH induces the adrenal cortex to release cortisol and several weak androgens, such as dehydroepiandrosterone (DHEA). Circulating cortisol and other corticosteroids (including exogenous corticosteroids) inhibit the release of CRH and ACTH. The CRH-ACTH-cortisol axis is a central component of the response to stress. Without ACTH, the adrenal cortex atrophies and cortisol release virtually ceases.

Thyroid-stimulating hormone (TSH):

TSH regulates the structure and function of the thyroid gland and stimulates synthesis and release of thyroid hormones. TSH synthesis and release are stimulated by the hypothalamic hormone thyrotropin-releasing hormone (TRH) and suppressed (by negative feedback) by circulating thyroid hormones.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH):

LH and FSH control the production of the sex hormones. Synthesis and release of LH and FSH are stimulated by gonadotropin-releasing hormone (GnRH) and suppressed by estrogen and testosterone. In women, LH and FSH stimulate ovarian follicular development and ovulation. In men, FSH acts on Sertoli cells and is essential for spermatogenesis; LH acts on Leydig cells of the testis to stimulate testosterone biosynthesis.

Growth hormone (GH):

GH stimulates somatic growth and regulates metabolism. Growth hormone–releasing hormone (GHRH) is the major stimulator and somatostatin is the major inhibitor of the synthesis and release of GH. GH controls synthesis of insulin-like growth factor 1 (IGF-1, also called somatomedin-C), which largely controls growth. Although IGF-1 is produced by many tissues, the liver is the major source. A variant of IGF-1 occurs in muscle, where it plays a role in enhancing muscle strength. It is less under control of GH than is the liver variant.

The metabolic effects of GH are biphasic. GH initially exerts insulin-like effects, increasing glucose uptake in muscle and fat, stimulating amino acid uptake and protein synthesis in liver and muscle, and inhibiting lipolysis in adipose tissue. Several hours later, more profound anti–insulin-like metabolic effects occur. These include inhibition of glucose uptake and use, causing plasma glucose and lipolysis to increase, which increases plasma free fatty acids. GH levels increase during fasting, maintaining plasma glucose levels and mobilizing fat as an alternative metabolic fuel. Production of GH decreases with aging. Ghrelin, a hormone produced in the fundus of the stomach, promotes GH release from the pituitary, increases food intake, and improves memory.

Prolactin:

Prolactin is produced in cells called lactotrophs that constitute about 30% of the cells of the anterior pituitary. The pituitary doubles in size during pregnancy, largely because of hyperplasia and hypertrophy of lactotrophs. In humans, the major function of prolactin is stimulating milk production. Also, prolactin release occurs during sexual activity and stress. Prolactin may be a sensitive indicator of pituitary dysfunction; prolactin is the hormone most frequently produced in excess by pituitary tumors, and it may be one of the hormones to become deficient from infiltrative disease or tumor compression of the pituitary.

Other hormones:

Several other hormones are produced by the anterior pituitary. These include pro-opiomelanocortin (POMC, which gives rise to ACTH), α- and β-melanocyte-stimulating hormone (MSH), β-lipotropin (β-LPH), the enkephalins, and the endorphins. POMC and MSH can cause hyperpigmentation of the skin and are only significant clinically in disorders in which ACTH levels are markedly elevated (eg, Addison's disease, Nelson syndrome). The function of β-LPH is

unknown. Enkephalins and endorphins are endogenous opioids that bind to and activate opioid receptors throughout the CNS.

Posterior Pituitary Function

The posterior pituitary releases antidiuretic hormone (also called vasopressin or arginine vasopressin) and oxytocin. Both hormones are released in response to neural impulses and have half-lives of about 10 min.

Antidiuretic hormone (ADH):

ADH acts primarily to promote water conservation by the kidney by increasing the permeability of the distal tubular epithelium to water. At high concentrations, ADH also causes vasoconstriction. Like aldosterone, ADH plays an important role in maintaining fluid homeostasis and vascular and cellular hydration. The main stimulus for ADH release is increased osmotic pressure of water in the body, which is sensed by osmoreceptors in the hypothalamus. The other major stimulus is volume depletion, which is sensed by baroreceptors in the left atrium, pulmonary veins, carotid sinus, and aortic arch, and then transmitted to the CNS through the vagus and glossopharyngeal nerves. Other stimulants for ADH release include pain, stress, emesis, hypoxia, exercise, hypoglycemia, cholinergic agonists, β-blockers, angiotensin, and prostaglandins. Inhibitors of ADH release include alcohol, α-blockers, and glucocorticoids.

A lack of ADH produces central diabetes insipidus; an inability of the kidneys to respond normally to ADH causes nephrogenic diabetes insipidus. Removal of the pituitary gland usually does not result in permanent diabetes insipidus because some of the remaining hypothalamic neurons produce small amounts of ADH. Copeptin is coproduced with ADH in the posterior pituitary. Measuring it may be useful in distinguishing the cause of hyponatremia.

Oxytocin:

Oxytocin has 2 major targets: the myoepithelial cells of the breast, which surround the alveoli of the mammary gland, and the smooth muscle cells of the uterus. Suckling stimulates the production of oxytocin, which causes the myoepithelial cells to contract. This contraction causes milk to move from the alveoli to large sinuses for ejection (ie, the milk letdown reflex of nursing mothers). Oxytocin stimulates contraction of uterine smooth muscle cells, and uterine sensitivity to oxytocin increases throughout pregnancy. However, plasma levels do not increase sharply during parturition, and the role of oxytocin in the initiation of labor is unclear. There is no recognized stimulus for oxytocin release in men, although men have extremely low levels.

Endocrine Organs and Tissues

Although their major function is not the secretion of hormones, some organs contain specialized cells that produce hormones. These organs include the heart, the gastrointestinal tract, the placenta, the kidneys, and the skin.

In addition, all cells (except red blood cells) secrete a class of hormones called eicosanoids. These hormones are paracrines, or local hormones, that primarily affect neighboring cells. Two groups of eicosanoids, the prostaglandins (PGs) and the leukotrienes (LTs), have a wide range of varying effects that depend upon the nature of the target cell. Eicosanoid activity, for example, may impact blood pressure, blood clotting, immune and inflammatory responses, reproductive processes, and the contraction of smooth muscles.

Antagonistic Hormones

Maintaining homeostasis often requires conditions to be limited to a narrow range. When conditions exceed the upper limit of homeostasis, specific action, usually the production of a hormone is triggered. When conditions return to normal, hormone production is discontinued. If conditions exceed the lower limit of homeostasis, a different action, usually the production of a second hormone is triggered. Hormones that act to return body conditions to within acceptable limits from opposite extremes are called antagonistic hormones.

The regulation of blood glucose concentration (through negative feedback) illustrates how the endocrine system maintains homeostasis by the action of antagonistic hormones. Bundles of cells in the pancreas called the islets of Langerhans contain two kinds of cells, alpha cells and beta cells. These cells control blood glucose concentration by producing the antagonistic hormones insulin and glucagon:

Beta cells secrete insulin. When the concentration of blood glucose rises (after eating, for example), beta cells secret insulin into the blood. Insulin stimulates the liver and most other body cells to absorb glucose. Liver and muscle cells convert the glucose to glycogen (for short-term storage), and adipose cells convert the glucose to fat. In response, glucose concentration decreases in the blood, and insulin secretion discontinues (through negative feedback from declining levels of glucose).

Alpha cells secrete glucagon. When the concentration of blood glucose drops (during exercise, for example), alpha cells secrete glucagon into the blood. Glucagon stimulates the liver to release glucose. The glucose in the liver originates from the breakdown of glycogon and the conversion of amino acids and fatty acids into glucose. When blood glucose levels return to normal, glucagon secretion discontinues (negative feedback).

Another example of antagonistic hormones occurs in the maintenance of Ca2+ concentration in the blood. Parathyroid hormone (PTH) from the parathyroid glands increases Ca2+ in the blood by increasing Ca2+ absorption in the intestines and reabsorption in the kidneys and stimulating Ca2+ release from bones. Calcitonin (CT)

produces the opposite effect by inhibiting the breakdown of bone matrix and decreasing the release of calcium into the blood.