CLASSIFICATION OF HORMONES

Multicellular organisms have developed complex mechanisms to ensure regulation of metabolism. Although the nervous system and endocrine system were classically considered to play crucial and largely independent roles in this process, studies over several decades demonstrated that these systems converge to maintain homeostasis and various physiological functions. In its simplest form, the endocrine system may be viewed as consisting of an endocrine gland: that is, a collection of specialized cells that synthesize and secrete a hormone and a target tissue that responds to this hormone. Hormones are chemical substances, produced by endocrine organs or cells dispersed in major organ systems, that act at distant tissues through the blood to exert their biological actions.

Hormones are often classified according to structure or function. Peptide or protein hormones, such as gut and anterior pituitary hormones, are typically synthesized as larger precursor proteins (preprohormones) on ribosomes attached to the rough endoplasmic reticulum. The signal (“pre-”) peptide is cleaved by a peptidase on the inner membrane of the rough endoplasmic reticulum, resulting in a prohormone that is released into the rough endoplasmic reticulum lumen and transported to the Golgi apparatus. Here, the prohormone undergoes further cleavage and, in some instances, formation of disulfide bonds and other modifications such as glycosylation. The resulting hormone product is typically stored in secretory vesicles and released through exocytosis. The latter may occur constitutively in addition to being regulated by an endogenous chemical signal: for example, elevated glucose level in the case of insulin; a tropic hormone, such as adrenocorticotropic hormone (ACTH), in regulation of cortisol; or a neural stimulus, as is the case of vagal regulation of gastrointestinal hormones. Exocytosis is energetically dependent, requiring an influx of calcium and an intact cytoskeleton.

Steroid hormones are derived from enzymatic processing of a cholesterol precursor (Fig. 118-1). Conversion of cholesterol to pregnenolone through side-chain cleavage is the first step in the steroidogenic pathway and occurs in all steroidogenic tissues (i.e., adrenal cortex, testes, ovaries, and placenta). Further metabolism is determined by specific enzymes that mediate hydroxylation, methylation, and demethylation. Corticosteroids and progestins contain 21 carbons; androgens, 19 carbons; and estrogens, 18 carbons and aromatic A-ring. Because 11- and 21-hydroxylases are expressed only in the adrenal cortex, the production of glucocorticoids and mineralocortiocoids occurs only in this gland. Cortisol, the principal glucocorticoid, is synthesized mostly by zona fasciculata cells and hydroxylated at the 17-carbon position and exerts major effects on glucose and various metabolic processes. Aldosterone, the principal mineralocorticoid, is a 17-deoxycorticosteroid produced in the zona glomerulosa of the adrenal cortex. Progesterone is the main steroid secreted by the placenta and ovaries and also serves as a precursor for corticosteroids and other sex steroid hormones.

Figure 118-1 Biosynthesis of steroid hormones.

Catecholamines, named for the catechol ring derived from tyrosine, are the best-known hormones derived from amino acids and secreted from chromaffin cells in the adrenal medulla. Epinephrine is the principal hormone secreted by the adrenal medulla, which occupies the innermost part of the adrenal gland. Although the predominant source of norepinephrine in the blood is the sympathetic nerve terminal, the adrenal medulla derived from the neuroectoderm receives preganglionic sympathetic innervation and has the ability to produce and secrete norepinephrine. Catecholamines can be synthesized from phenylalanine; however, the majority are generated from tyrosine. Oxidation of tyrosine to dihydroxyphenylalanine is catalyzed by tyrosine hydroxylase and represents the rate-limiting step in catecholamine synthesis. Dihydroxyphenylalanine is converted to dopamine by L-aromatic amino acid decarboxylase, followed by conversion to norepinephrine by dopamine-β-hydroxylase. Unlike tyrosine hydroxylase and L-aromatic amino acid decarboxylase, dopamine-β-hydroxylase is located in the cytosol of the chromaffin cell. Phenylethanolamine-N-methyltransferase catalyzes the conversion of norepinephrine to epinephrine. These catecholamines are stored in different granules and carried by specific transporter proteins. The secretion of catecholamines occurs through exocytosis in response to stimulation by preganglionic cholinergic fibers innervating the adrenal medulla, as well as by nutrient or peptide signals. Interestingly, the chromaffin granules contain various peptides, such as neuropeptide Y and enkephalins, which modulate catecholamine secretion.

MECHANISMS OF HORMONE ACTION

Hormones by definition are transported in the blood, although the methods for transporting peptides, steroids, and catecholamines vary, depending on solubility. Peptide and protein hormones are hydrophilic and dissolve directly or associate with albumin in the plasma. Insulin circulates as monomeric and polymeric forms, whereas some anterior pituitary hormones circulate as dissociated subunits. Steroid and thyroid hormones, in contrast, are insoluble and bind to transport proteins (corticosteroid-binding globulin in the case of cortisol and thyroid-binding globulin and transthyretin in the case of thyroxine). The hormone bound to the carrier protein cannot interact with the receptor, but it serves as a reserve to replenish the free (bioactive) form. Nonetheless, the bound hormone exists in equilibrium with free hormone and receptor-bound fractions. The free hormone level increases as the rate of hormone degradation and clearance rises. On the other hand, conditions that increase the amount of carrier proteins, such as pregnancy and liver disease, elevate total hormone levels, although the balance between free and bound hormone is preserved.

In view of the fact that hormone concentrations are very low, in the range of 10⁻¹⁵ to 10⁻⁹ M, and more than 100-fold lower than levels of similar sterols, amino acids, and polypeptides, how do target cells identify hormones to initiate specific biological effects? In general, receptors for peptide, amine, and steroid hormones have a domain that recognizes and binds the hormone, with subsequent activation of a signaling mechanism that transduces the information into an intracellular action. Steroid and thyroid hormones and retinoic acid are lipophilic; associate with transport proteins in the blood, which prolongs their plasma half-life; and readily cross the plasma membrane in target tissues and bind to receptors in the nucleus or cytoplasm (Table 118-1; Fig. 118-2).^1,2 The hormone-receptor complex undergoes activation, which leads to changes in chromatin, binding to specific regions of DNA, and transcription or inactivation of target genes. Studies since the 1980s have led to greater understanding of steroid-regulated genes, hormone response elements (i.e., short DNA segments that bind to specific steroid receptor-hormone complexes), and how these cis-acting DNA elements interact with transacting factors.^3–5 Transacting factors include coactivator and corepressor molecules that modulate transcription.⁵ For example, in the absence of hormone, thyroid and retinoic acid receptors associate with NcoR, SMRT and other proteins, which results in repression of target genes. Binding by thyroxine dissociates the complex culminating in gene activation. Members of the p160 family of coactivators (e.g., SRC-1, NCoA-1, GRIP 1, TIF2, and p/CIP) have been implicated in the function of corticosteroids and other steroids.

TABLE 118-1 Classification of Hormone Receptors

Figure 118-2 Steroid receptor signaling. Most steroid receptors under basal conditions exist in the cytoplasm as complexes with heat-shock proteins (HSPs). The steroid (H) crosses the plasma membrane into the cytoplasm and associates with the receptor (R)–HSP complex, resulting in dissociation of HSPs. This exposes a nuclear translocation signal, leading to transport of the hormone-receptor complex into the nucleus, where it binds to a hormone response element (HRE) in the DNA and associates with various transcription proteins to regulate gene expression. AAAA, mRNA, messenger RNA; TATA.

Polypeptides, glycoprotein hormones, and catecholamines are water soluble, have no transport proteins, and possess a relatively short half-life. These hormones bind to surface receptors on the plasma membrane and generate second-messenger molecules (Fig. 118-3). Epinephrine, as well as several neuropeptides and gut and pituitary hormones, including neuropeptide Y, cholecystokinin, vasopressin, glucagon, ACTH, thyroid-stimulating hormone (TSH), and luteinizing hormone, bind to their respective membrane receptors, stimulate adenylate cyclase located on the inner plasma membrane, and catalyze the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate.⁶ Activation or inactivation of adenylate cyclase occurs through the guanosine triphosphate–dependent regulator proteins (e.g. G_s [stimulatory] and G_i [inhibitory]).⁷ Changes in cAMP exert diverse effects on metabolism through various substrates, such as the transcription factor cAMP response element binding protein (CREB). CREB phosphorylation by cAMP leads to interaction with the coactivator CREB-binding protein, which results in stimulation of gene transcription.⁸ These effects can be terminated by hydrolysis of cAMP by phosphodiesterases or dephosphorylation by phosphoprotein phosphatases.⁹

Figure 118-3 Examples of membrane-associated hormone receptors. AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; IL-6, interleukin-6; NPY, neuropeptide Y; TRH, thyrotropin-releasing hormone.

Some polypeptide hormones produced by vascular tissues, such as atrial natriuretic factor, stimulate guanosine triphosphate by guanylate cyclase and increase cyclic guanosine monophosphate (cGMP), which leads to activation of cGMP-dependent protein kinase, phosphorylation, and alteration in the of smooth muscle proteins.¹⁰ This effect is terminated by specific cGMP phosphodiesterase. Other hormones signal through phosphatidylinositides and calcium. The actions of ACTH in the adrenal cortex, luteinizing hormone in the ovaries and Leydig cells of the testes, and angiotensin II in vascular tissues have been associated with activation of phospholipase C, which mediates the hydrolysis of phosphatidylinositol-4,5-biphosphate (PIP₂) to 1,4,5-triphosphate (PIP₃) and diacylglycerol. Binding of PIP₃ to organelles increases intracellular Ca²⁺.⁹ Diacylglycerol activates protein kinase C, which phosphorylates various substrates involved in metabolism.

Cytokine receptors lack intrinsic tyrosine kinase activity but associate with proteins that are tyrosine kinases.^11,12 For example, growth hormone, prolactin, inflammatory cytokines, and leptin bind to their receptors, which activate cytoplasmic protein tyrosine kinases, such as Jak1 and Jak2.^11–13 These then phosphorylate other proteins, such as signal transducers and activators of transcription (STAT) proteins and docking proteins containing Src homology 2 (SH2) domains, culminating in transcriptional activation of neuropeptides and various target genes. In contrast, the insulin receptor possesses intrinsic tyrosine kinase activity in the cytoplasmic domain that is activated upon binding of insulin to the extracellular domain of the receptor. This autophosphorylation of insulin receptor leads to phosphorylation of insulin receptor substrates, activation of PI-3 kinase, and a cascade of biochemical events underlying insulin’s effects on glucose uptake, lipid and protein metabolism, and growth.¹⁴

REGULATION OF HORMONE LEVELS AND RHYTHMS

Hormones generally regulate existing reactions instead of initiating de novo reactions. In contrast to the rapid time course of nervous activity, which lasts from milliseconds to seconds, the action of hormones is often prolonged and may persist for some time after the hormone is withdrawn. However, as discussed in detail later, the neurosecretory system allows the neural pathways in the hypothalamus, brainstem, and other regions of the central nervous system to interact with peripheral endocrine tissues, such as the thyroid, adrenal gland, and gonads.

Hormone concentrations in the blood vary, depending on the rate of synthesis, secretion, and clearance. In the case of clearance, steroids undergo a series of reductions and conversion into water-soluble metabolites excreted by the liver or kidneys. Peptide hormones are often degraded by specific peptidases, whereas catecholamines undergo enzymatic conversion into inactive metabolites by deamination and 3-O-methylation or uptake by neurons and extraneuronal tissues. Epinephrine, norepinephrine, dopamine, and their metabolites are excreted by the kidneys.

Hormone systems are subject to principles of homeostasis. A controlled variable, often the circulating hormone or related chemical signal, determines the rate of release of the hormone. The negative feedback loop, in which the hormone acts to inhibit its output, is fundamental to most endocrine systems and best exemplified by the interactions among the hypothalamus, trophic hormones from the pituitary gland, and hormones produced by peripheral endocrine glands. The positive feedback loop is less common and involves a stimulation of hormone by the controlled variable. For example, a rise in estrogen level boosts luteinizing hormone secretion, which leads to a further rise in estrogen level. Oscillation of hormone concentration is minimized to a “set point,” probably as a result of proportional coupling between hormone production and the function of the effector systems. In some cases, hormones produced by the same endocrine organ are regulated in opposite directions. For example, blood glucose rises after a meal, stimulates insulin secretion by pancreatic β cells, which then activates glucose uptake by muscle and fat and by lowering glucose and insulin levels. In contrast, glucagon is increased in response to falling glucose levels during fasting and stimulates glucose production via gluconeogenesis. Although these feedback mechanisms are often restricted to the interacting organs—that is, they are in closed loops—they are also subject to influences from the nervous and other systems, as open loops.

As with virtually all functions of animals, the endocrine system is subject to cyclic changes. The most common endocrine rhythm has a period of approximately 24 hours (i.e., circadian), which follows an intrinsic program driven by a “biological clock,” the suprachiasmatic nucleus. In contrast, diurnal rhythms can be circadian or influenced by shifts in light and dark. Diurnal rhythm is an example of entrainment of a free running rhythm by an external cue, the zeitgeber. Meal patterns also entrain the rhythms of gut hormones. Cortisol levels peak in the morning between 2:00 and 4:00 A.M. and reach a nadir at night. In contrast, growth hormone and prolactin levels peak at night. TSH secretion is lowest between 9:00 A.M. and 12:00 noon and maximal at night. It is well known that the cortisol rhythm can be altered by light and dark, feeding, and stress.

In addition to diurnal rhythms, hormones are secreted in bursts, known as an ultradian rhythm. For example, luteinizing hormone is secreted in rapid, high-amplitude pulses at night in adolescents; in adults, in contrast, luteinizing hormone pulses are lower and occur throughout the 24-hour period. Episodic hormone pulses have also been described for growth hormone, corticotropin, and prolactin, and loss of these rhythms has been linked to hypothalamic dysfunction. Infradian rhythms last longer than a day and best exemplified by the menstrual cycle.