Mechanisms of Hormonal Regulation

Water-soluble hormone binding with plasma membrane receptors initiates a complex cascade of intracellular effects. In this cascade, the hormone is termed the first messenger. The hormone-receptor interaction initiates a signal that generates a small molecule inside the cell, called the second messenger. The second messenger conveys the signal from the receptor to the cytoplasm and nucleus of the cell and mediates the effect of the hormone on the target cell. Second messengers include cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), calcium, inositol triphosphate (IP₃), and the tyrosine kinase system (Table 21.2).

The second messenger cAMP increases when first messengers from the anterior pituitary gland, such as adrenocorticotropic hormone (ACTH) and TSH, bind to a cell membrane receptor. Increased levels of intracellular cAMP activate protein kinases, leading to activation or deactivation of intracellular enzymes (Fig. 21.5). cGMP also functions as a second messenger following receptor binding of first messengers (e.g., atrial natriuretic peptide and nitric oxide). These hormones and signaling molecules play crucial roles in cardiovascular and pulmonary health and disease. Drugs, such as phosphodiesterase inhibitors that sustain the action of cGMP are used in the treatment of erectile dysfunction and are being explored for the treatment of vascular and pulmonary hypertension and cognitive dysfunction.^3,4

The second messenger IP₃ is increased in response to angiotensin II and antidiuretic hormone (ADH) receptor binding and triggers a release of intracellular calcium. This leads to the formation of the calcium-calmodulin complex, which mediates the effects of calcium on intracellular activities that are crucial for cell metabolism, growth, and smooth muscle contraction.

Some hormone first messengers, such as insulin, growth hormone (GH), and prolactin, bind to surface receptors that directly activate second messengers of the tyrosine kinase family. These tyrosine kinases include the Janus family of tyrosine kinases (JAK) and signal transducers and activators of transcription (STAT). They regulate a wide range of intracellular processes that contribute to cellular metabolism, immunity, growth, apoptosis, and oncogenesis. They can be targeted for inhibition in treatments aimed at moderating immune-mediated responses, as in rheumatoid arthritis and cancer.5,6

With the exception of thyroid hormones, the lipid-soluble hormones are synthesized from cholesterol (giving rise to the term “steroid”) (see Table 21.1). Receptors for lipid-soluble hormones are in the cytosol and nucleus, and directly modulate gene expression without complex second messengers (Fig. 21.6). Because these are relatively small, lipophilic, hydrophobic molecules, lipid-soluble hormones can cross the lipid plasma membrane by simple diffusion (see Chapter 1). They bind with cytosolic or nuclear receptors, which keeps them from diffusing back out of the cell. The effects of lipid-soluble hormones on cytosol and nuclear receptors can take hours to days. However, lipid hormone receptors for estrogen, thyroid hormone, and aldosterone are located in the plasma membrane and are associated with rapid responses (seconds or minutes) (see Fig. 21.6). These receptors, when activated, have primarily intracellular nongenomic (membrane-initiated steroid signaling) effects. Through crosstalk, nongenomic responses and gene transcription modulate each other, allowing cells to adapt rapidly to environmental changes.^7,8

The hypothalamus is located at the base of the brain. It is connected to the pituitary gland by the infundibulum (pituitary stalk) (Fig. 21.8). The hypothalamus is connected to the anterior pituitary through hypophysial portal blood vessels (Fig. 21.9) and to the posterior pituitary via a nerve tract referred to as the hypothalamohypophysial tract (Fig. 21.10). These connections are vital to the functioning of the hypothalamic–pituitary system. The hypothalamus contains special neurosecretory cells that synthesize and secrete the hypothalamic-releasing hormones that regulate the release of hormones from the anterior pituitary. In addition, these cells synthesize the hormones ADH (also called vasopressin) and oxytocin, which are stored and released from the posterior pituitary gland. ADH and oxytocin travel to the posterior pituitary by way of the hypothalamohypophysial nerve tract. Releasing and inhibitory hormones are synthesized in the hypothalamus and are secreted into the portal blood vessels, through which they travel to their target tissues within the anterior pituitary and control the release of tropic hormones. These releasing/inhibitory hormones from the hypothalamus include prolactin-inhibiting hormone (PIH), prolactin-releasing hormone (PRH), TRH, gonadotropin-releasing hormone (GnRH), hypothalamic somatostatin, growth hormone-releasing hormone (GHRH), corticotropin-releasing hormone (CRH), and substance P. These hormones are summarized in Table 21.3.

Illustration A shows the anterior pituitary (adenohypophysis) and labels the following structures: hypothalamus, neurons, and blood capillaries (hypothalamic-hypophyseal portal system). The capillaries release neurons into circulation. Illustration B shows the posterior pituitary (neurohypophysis) and labels the following structures: hypothalamus, infundibulum, and neurons. The capillaries release neurons into circulation.

An illustration of the pituitary gland (anterior and posterior) shows and labels the following structures: hypothalamus, mammillary body, median eminence, primary capillary plexus, hypothalamic-hypophysial portal vessels, sinuses, vein, artery, and optic chiasm.

An illustration shows the frontal lobe, thalamus, hypothalamus, and the pituitary gland. The following structures in the illustration are labeled from the top to the bottom: supraoptic nucleus, paraventricular nucleus, supraopticohypophysial tract, optic chiasm, tuberohypophysial tract, mammillary body, pituitary stem, pituitary stalk, hypothalmohypophysial tract, connective tissue (trabecula), pars distalis, pars intermedia, pars nervosa, posterior lobe, cleft, anterior lobe.

The pituitary gland is located in the sella turcica (a saddle-shaped depression of the sphenoid bone at the base of the skull). It weighs approximately 0.5 g, except during pregnancy, when its weight increases by about 30%. It is composed of two distinctly different lobes: (1) the anterior pituitary, or adenohypophysis, and (2) the posterior pituitary, or neurohypophysis (see Fig. 21.8). These two lobes differ in their embryonic origins, cell types, and functional relationship to the hypothalamus.

The anterior pituitary secretes tropic hormones that affect the physiologic function of specific target organs (see Fig. 21.7). These hormones can be grouped into three categories: corticotropin-related hormones, glycoproteins, and somatotropins (Table 21.4). Corticotropin-related hormones include melanocyte-stimulating hormone (MSH), which promotes the pituitary secretion of melanin to darken skin color, and adrenocorticotropic hormone (ACTH), which regulates the release of cortisol from the adrenal cortex. Also included in the corticotropic hormones are β-lipotropin, which plays a role in fat catabolism, and β-endorphins, which impact pain perception, body temperature, and food and water intake.

The glycoprotein hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH) influence reproductive function and are discussed in Chapter 24. Thyroid-stimulating hormone (TSH), also a glycoprotein hormone, regulates the activity of the thyroid gland. The roles of ACTH and TSH are discussed later in this chapter.

The somatotropic hormones have diverse effects on body tissues and include GH and prolactin. Growth hormone secretion is controlled by two hormones from the hypothalamus: GHRH, which increases GH secretion; and somatostatin, which inhibits GH secretion. GH is essential to normal tissue growth and maturation and also impacts aging, sleep, nutritional status, stress, and reproductive hormones. In the bone, GH stimulates epiphyseal growth and increases osteoclast and osteoblast activity, resulting in increased bone mass. GH also increases amino acid transport in muscles. Other functions of GH include lipolysis and enhancement of hepatic protein synthesis.

Many of the anabolic functions of GH are mediated, at least in part, by the insulin-like growth factors (IGFs), also known as the somatomedins. There are two primary forms of IGF, IGF-1 and IGF-2, of which IGF-1 is the most biologically active. They both circulate bound to a group of IGF-binding proteins (IGFBPs) modulating their availability. IGF-1 binds to IGF-1 receptors, mediating the anabolic effects of GH. IGF-1 also binds to insulin receptors, providing an insulin-like effect on skeletal muscle. IGF-2 has important effects on fetal growth but suppresses GH in the adult. Because of the anabolic effects of GH and IGF-1, they can be used to treat growth disorders, increase muscle mass, and potentially slow the aging process; however, there are concerns about their safety, with potential links to increased rates of cancer.⁹

Prolactin primarily functions to induce milk production during pregnancy and lactation. It has immune stimulatory effects and modulates immune and inflammatory responses with both physiologic and pathologic reactions. Its synthesis and release are increased by stimulation of the nipples and mammary gland during nursing. Vasoactive intestinal polypeptide, serotonin, and growth factors also stimulate the synthesis of prolactin. Release of prolactin is inhibited by dopamine.

The embryonic posterior pituitary (neurohypophysis) is derived from the hypothalamus and is comprised of three parts: (1) the median eminence, located at the base of the hypothalamus; (2) the pituitary stalk; and (3) the infundibular process, also known as the pars nervosa or neural lobe. The median eminence is composed largely of the nerve endings of axons from the ventral hypothalamus. It often is designated as part of the posterior pituitary and contains at least 10 biologically active hypothalamic releasing hormones, as well as the neurotransmitters dopamine, norepinephrine, serotonin, acetylcholine, and histamine. The pituitary stalk contains the axons of neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus and connects the pituitary gland to the brain. Axons originating in the hypothalamus terminate in the pars nervosa, which secretes the hormones of the posterior pituitary (see Fig. 21.10).

The posterior pituitary secretes two polypeptide hormones: (1) ADH, also called arginine vasopressin; and (2) oxytocin. These hormones differ by only two amino acids. They are synthesized—along with their binding proteins, the neurophysins—in the supraoptic and paraventricular nuclei of the hypothalamus (see Fig. 21.10). They are packaged in secretory vesicles and are moved down the axons of the pituitary stalk to the pars nervosa for storage. The posterior pituitary thus can be seen as a site for both storing and releasing hormones synthesized in the hypothalamus. The release of ADH and oxytocin is mediated by cholinergic and adrenergic neurotransmitters. The major stimulus to both ADH and oxytocin release is glutamate, whereas the major inhibitory input is through gamma-aminobutyric acid (GABA). Before release into the circulatory system, ADH and oxytocin are split from the neurophysins and are secreted in unbound form.

The pineal gland is located near the center of the brain (see Fig. 21.1) and is composed of photoreceptive cells that secrete melatonin. It is innervated by noradrenergic sympathetic nerve terminals controlled by pathways within the hypothalamus. Melatonin release is stimulated by exposure to dark and inhibited by light exposure. It is synthesized from tryptophan, which is first converted to serotonin and then to melatonin. Melatonin regulates circadian rhythms and reproductive systems, including the secretion of the GnRHs and the onset of puberty. It also plays an important role in immune regulation and is postulated to impact the aging process. Further effects of melatonin include increasing nitric oxide release from blood vessels, removing toxic oxygen free radicals, and decreasing insulin secretion. Melatonin has been used therapeutically in humans to help with sleep disturbances, jet lag, and psychological and inflammatory disorders. Its utility for numerous other disorders is being explored.

Two lobes of the thyroid gland lie on either side of the trachea, inferior to the thyroid cartilage and joined by a small band of tissue termed the isthmus (see Fig. 21.11). The pyramidal lobe is superior to the isthmus. The normal thyroid gland is not visible on inspection, but it may be palpated on swallowing, which causes it to be displaced upward.

The thyroid gland consists of follicles that contain follicular cells surrounding a viscous substance called colloid (Fig. 21.12). The follicular cells synthesize and secrete the thyroid hormones. Neurons terminate on blood vessels within the thyroid gland and on the follicular cells themselves, so neurotransmitters (acetylcholine, catecholamines) may directly affect the secretory activity of follicular cells and thyroid blood flow. Approximately a 2-month supply of thyroid hormone is stored in the gland.

A photomicrograph of thyroid follicle cells. The colloid (retracted after fixation) is labeled. Other structures labeled and described are as follows. • Blood vessels are found around the follicles. • Follicular epithelium. In the inactive follicle, the follicular epithelium is simple low cuboidal, or squamous. During their active secretory phase, the cells become columnar. • Area of colloid resorption. • A C cell can be distinguished from surrounding follicular cells by its pale cytoplasm. Two more effective identification approaches are: 1. Immunocytochemistry, using an antibody to calcitonin. 2. Electron microscopy, to visualize calcitonin-containing cytoplasmic granules.

Also found in the thyroid are parafollicular cells, or C cells (see Fig. 21.12). C cells secrete various regulatory peptides, including calcitonin and, in much smaller quantities, the neuropeptides ghrelin, serotonin, and somatostatin. At high levels, calcitonin, also called thyrocalcitonin, lowers serum calcium levels by inhibiting bone-resorbing osteoclasts. However, in humans the metabolic consequences of calcitonin deficiency or excess do not appear to be significant. (Bone resorption is explained in Chapter 43). Calcitonin can be used therapeutically to treat a number of bone disorders, including osteogenesis imperfecta, osteoporosis, osteoarthritis, hypercalcemia, Paget bone disease, and metastatic cancer of the bone. The precursor molecule to calcitonin, called procalcitonin, is a stress hormone that is elevated in infectious and inflammatory disorders, and its measurement can aid in the diagnosis of these serious diseases.^10,11

Normally, two pairs of small parathyroid glands are present behind the upper and lower poles of the thyroid gland (see Fig. 21.11). However, their number may range from two to six. The parathyroid glands produce parathyroid hormone (PTH), which is the single most important factor in the regulation of the serum calcium concentration. The overall effect of PTH secretion is to increase serum calcium concentration and decrease the concentration of serum phosphate. A decrease in serum-ionized calcium level stimulates PTH secretion. On release, PTH enters the circulation in unbound form and attaches to plasma membrane receptors in target tissues. To achieve regulation of serum calcium concentration, PTH acts directly on bone with at least two effects. In acute hypocalcemia, PTH secretion stimulates osteoblasts to release factors that cause osteoclast proliferation, maturation, and release of acidic enzymes, such as cathepsin. These enzymes mobilize calcium release from bone (bone resorption), which increases the serum calcium level (Fig. 21.13). There is bone remodeling with chronic stimulation by PTH, a process in which bone is broken down and re-formed. Paradoxically, when PTH is administered intermittently and at a low dose, it stimulates bone formation. This observation led to the use of synthetic PTH for treatment of osteoporosis.¹²

A flowchart shows the role of parathyroid hormone and vitamin D in calcium metabolism. • Decreased serum calcium leads to increased P T H secretion. • Increased P T H secretion affects bone and kidney. • Bone stimulates osteoclast action leading to mobilization of calcium from bone. • Kidney activates vitamin D leading to increased vitamin D, affecting the gut, which leads to increased absorption of calcium ions in the intestines. • Kidney increases reabsorption of calcium ions and decreases reabsorption of phosphate. Mobilization of calcium from bone, increased absorption of calcium ions in the intestines, and increased reabsorption of calcium ions and decreased reabsorption of phosphate leads to increased serum calcium and decreased serum phosphate.

PTH also acts on the kidney to increase calcium reabsorption in the distal tubules of the nephron while phosphate and bicarbonate reabsorption are decreased in the proximal tubules. The resultant increase in the serum calcium concentration inhibits PTH secretion. 1,25-Dihydroxy-vitamin D3 (the active form of vitamin D) is activated by the kidney and works as a cofactor with PTH to promote calcium and phosphate absorption in the gut and enhance bone mineralization. Vitamin D also plays an important role in metabolic processes and controlling inflammation. It has been found to be deficient in the majority of individuals in the United States (see Emerging Science Box: Vitamin D Deficiency).

Phosphate and magnesium concentrations also affect PTH secretion. An increase in the serum phosphate level decreases the serum calcium level by causing calcium-phosphate precipitation into soft tissue and bone, which indirectly stimulates PTH secretion. Hypomagnesemia in persons with normal calcium levels acts as a mild stimulant to PTH secretion; however, in persons with hypocalcemia, hypomagnesemia decreases PTH secretion.

Another hormone that plays an important role in calcium and bone physiology is parathyroid hormone–related protein (PTHrP). This hormone is synthesized in many adult and fetal tissues and affects tissues around it in a paracrine fashion with multiple metabolic effects. It has similar biologic properties to PTH and uses the same receptors but has other actions mediated by different regions within the molecule. It is important for endochondral bone formation and bone remodeling.¹³

Insulin is an anabolic hormone that promotes glucose uptake, primarily in liver, muscle, and adipose tissue. It also increases the synthesis of proteins, carbohydrates, lipids, and nucleic acids. The net effect of insulin in these tissues is to stimulate protein and fat synthesis and decrease blood glucose level. Insulin also facilitates the intracellular transport of potassium (K⁺), phosphate, and magnesium. Table 21.6 summarizes the actions of insulin. Insulin is metabolized in the liver and kidney by enzymes that split disulfide bonds. Very little insulin is excreted unchanged in the urine.

At the target cell, insulin signaling is initiated when insulin binds and activates its cell surface receptor tyrosine kinase. These receptors are found on cells throughout the body.⁴ Insulin receptor binding sends a cascade of signals to activate glucose transporters (GLUT) for entry of glucose into the cell. The primary GLUT is called GLUT4. It is stored in cellular vesicles until activated by the insulin receptor and is then translocated to the cell surface where it facilitates the diffusion of glucose into the cell. Translocation of GLUT4 to the cell surface is associated with a 10- to 21-fold increase in glucose diffusion into the cell, particularly in skeletal and cardiac muscle, liver, and adipose cells (Fig. 21.15). The brain, red blood cells, kidney, and lens of the eye do not require insulin for glucose transport.

An illustration shows a plasma membrane of lipid bilayers. Potassium ions, phosphate, and magnesium ions pass through an uniport and into the cell. Amino acids pass through a second uniport and undergo protein synthesis. Insulin is attached to the alpha receptors on the plasma membrane. Tyrosine kinase from the beta channels undergo autophosphorylation. M A P kinase signaling cascade, amplified by phosphorylation cascades, lead to cell growth and differentiation ang gene expression. Insulin receptor substrates 1 to 4, amplified by phosphorylation cascades, leading to the following: • Glucose transport. • Fatty acid synthesis. • Protein synthesis. • Glycogen synthesis. • Cell growth and survival. • Amino acid and electrolyte transport. Glucose passes through the transport protein (G L U T 4) in the G L U T 4 vesicle that translocate to the plasma membrane.

The sensitivity of the insulin receptor is a key component in maintaining normal cellular function. Insulin sensitivity is affected by age, weight, abdominal fat, and physical activity. Insulin resistance has been implicated in numerous diseases, including hypertension, heart disease, and type 2 diabetes mellitus. Adipocytes release a number of hormones and cytokines that are altered in obesity and have an important impact on insulin sensitivity (see Chapter 23). The most effective measures shown to improve insulin sensitivity in humans are weight loss and exercise.

Glucagon is antagonistic to the effects of insulin, acting to increase blood glucose during fasting, exercise, and hypoglycemia. Glucagon release is stimulated by low glucose levels and sympathetic stimulation and is inhibited by high glucose levels. Amino acids, such as alanine, glycine, and asparagine, also stimulate glucagon secretion. A protein-rich meal has the same effect. Glucagon is produced by the alpha cells of the pancreas and by cells lining the gastrointestinal tract. Glucagon acts primarily in the liver and increases the blood glucose concentration by stimulating glycogenolysis and gluconeogenesis in muscle and lipolysis in adipose tissue. The lypolysis has a ketogenic effect caused by the metabolism of free fatty acids in the liver. These effects have led to the hypothesis that increased glucagon secretion is as important as insulin insufficiency in the pathogenesis of type 2 diabetes mellitus.14

Pancreatic gastrin stimulates the secretion of gastric acid. It is postulated that fetal pancreatic gastrin secretion is necessary for adequate islet cell development. Ghrelin stimulates GH secretion, controls appetite, and plays a role in obesity and the regulation of insulin sensitivity. Pancreatic polypeptide is released in response to hypoglycemia and protein-rich meals. It decreases pancreatic secretion of fluid and bicarbonate, promotes gastric secretion, antagonizes cholecystokinin, and is frequently increased in pancreatic tumors and in diabetes.15

The adrenal cortex accounts for 80% of the weight of the adult gland. The cortex is histologically subdivided into the following three zones:

The cells of the adrenal cortex are stimulated by ACTH from the pituitary gland. All hormones of the adrenal cortex are synthesized from low-density lipoprotein cholesterol. The best-known pathway of steroidogenesis involves the conversion of cholesterol to pregnenolone, which is then converted to the major corticosteroids.

Glucocorticoids

Functions of the glucocorticoids

The glucocorticoids are steroid hormones that have metabolic, neurologic, anti-inflammatory, and growth-suppressing effects (Fig. 21.17). These functions have direct effects on carbohydrate metabolism. These hormones increase the blood glucose concentration by promoting gluconeogenesis in the liver and by decreasing uptake of glucose into muscle cells, adipose cells, and lymphatic cells and by suppressing insulin secretion. They are released under stress conditions, which results in increased glucose for the brain.³⁴ In extrahepatic tissues, the glucocorticoids stimulate protein catabolism and inhibit amino acid uptake and protein synthesis. In extrahepatic tissues, the glucocorticoids stimulate protein catabolism and inhibit amino acid uptake and protein synthesis. The ultimate long-term effect of chronic stress on the body is protein catabolism and muscle wasting, increased lipolysis, insulin resistance, and hyperglycemia.¹⁶

An illustration of the anterior view of a human figure shows and labels its different parts with corresponding effects. • Brain and C N S: depression and psychosis. • Endocrine system: decreased L H and F S H release, decreased T S H release, and decreased G H secretion. • Eye: Glaucoma (increased intraocular pressure). • G I tract: peptic ulcerations. • Carbohydrate or lipid metabolism: increased hepatic glycogen deposition, increased peripheral insulin resistance, increased glucogenesis, increased free fatty acid production, and overall diabetogenic effect. • Cardiovascular or renal: salt and water retention and hypertension. • Adipose tissue distribution: promotes visceral obesity. • Bone and calcium metabolism: decreased bone formation and decreased bone mass and osteoporosis. • Skin or muscle or connective tissue: protein catabolism or collagen breakdown, skin thinning, and muscular atrophy. • Growth and development: decreased linear growth. • Immune system: anti-inflammatory action and immunosuppression.

The glucocorticoids act at several sites to suppress immune and inflammatory reactions. Adaptive immunity is affected by a glucocorticoid-mediated inhibitory effect on the proliferation of T lymphocytes, primarily T-helper lymphocytes. There is a greater adverse effect on T-helper 1 cell cytokine production (including antiviral interferons) than there is on T-helper 2 cell cytokine production, and therefore, greater depression of cellular immunity than humoral immunity (see Chapter 8). They affect innate immunity through several pathways, including inhibition of antigen presentation by dendritic cells and decreased activity of pattern recognition receptors on the surface of macrophages (see Chapter 7). Glucocorticoids also decrease immune and inflammatory responses by decreasing natural killer cell activity; by blocking phospholipase A and the synthesis of prostaglandins, thromboxanes, and leukotrienes; and by inhibiting inflammatory gene expression. In addition, glucocorticoids suppress the synthesis, secretion, and actions of chemical mediators involved in inflammatory and immune responses, including histamine, adhesion molecules, inducible cyclooxygenase, and inducible nitric oxide synthase.¹⁷

Glucocorticoids increase resistance to the severe inflammatory response to lipopolysaccharide (LPS, a bacterial endotoxin) through the inhibition of cytokines, chemokines, certain hormones, and neurotransmitters. In addition, glucocorticoids stimulate anti-inflammatory cytokines. Lysosomal membranes are also stabilized, decreasing the release of proteolytic enzymes. This suppression of innate and adaptive immunity by glucocorticoids means that infection and poor wound healing are some of the most problematic complications of the use of glucocorticoids in the treatment of disease. Similarly, psychologic and physiologic stress increases glucocorticoid production, which provides a pathway for the well-described decrease in immunity seen in both acute and chronic stress conditions (see Chapter 11).^18,19

Glucocorticoids appear to potentiate the effects of catecholamines, including sensitizing the arterioles to the vasoconstrictive effects of norepinephrine, thus increasing the blood pressure. Thyroid hormone and GH effects on adipose tissue are also potentiated by glucocorticoids. Other effects of glucocorticoids include inhibition of bone formation, inhibition of ADH secretion, and stimulation of gastric acid secretion. A metabolite of cortisol may act like a barbiturate and depress nerve cell function in the brain, accounting for the noted effects on mood, such as anxiety and depression, associated with steroid level fluctuation in disease or stress. Pathologically high levels of glucocorticoids increase the number of circulating erythrocytes (leading to polycythemia), increase the appetite, promote fat deposition in the face and cervical areas, increase uric acid excretion, decrease serum calcium levels, suppress the secretion and synthesis of ACTH, and interfere with the action of GH so that somatic growth is inhibited.²⁰

Cortisol

The most potent naturally occurring glucocorticoid is cortisol. It is the main secretory product of the adrenal cortex and is needed to maintain life and protect the body from stress (see Fig. 11.2). Cortisol circulates in bound form attached to albumin but is primarily bound to the plasma protein transcortin. A smaller amount circulates in free form and diffuses into cells with specific intracellular receptors for cortisol. Cortisol has a biologic half-life of approximately 90 minutes. It is primarily metabolized by the liver.

Cortisol secretion is regulated primarily by the hypothalamus and the anterior pituitary gland (Fig. 21.18). Corticotropin-releasing hormone (CRH) is produced by several nuclei in the hypothalamus and stored in the median eminence. Once released, CRH travels through the portal vessels to stimulate the production of ACTH, which is the main regulator of cortisol secretion.

A flowchart shows the feedback control of glucocorticoid synthesis and secretion. The hypothalamus generates corticotropin-releasing hormone (C R H), triggering the anterior pituitary. Adrenocorticotropic hormone (A C T H) from the anterior pituitary triggers the adrenal cortex. Glucocorticoids (especially cortisol) from the adrenal cortex results in the following effects. • Metabolic effects: increased gluconeogenesis, increased glycogenolysis, increased proteolysis, and increased lipolysis. • Cardiovascular effects: increased myocardial contractility, increased cardiac output, and increased blood pressure. The feedback mechanisms are as follows. • Hypothalamus receives positive feedback from hypoxia, hypoglycemia, exercise, cortisol deficiency, and stress. • Hypothalamus receives negative feedback from diurnal rhythms, somatostatin, hypothalamic lesions, and glucocorticoids. • Anterior pituitary receives positive feedback from hypoxia, hypoglycemia, hyperthermia, exercise, cortisol insufficiency, and stress. • Anterior pituitary receives negative feedback from somatostatin, hypothalamic lesions, and glucocorticoids.

Three factors appear to be primarily involved in regulating the secretion of ACTH: (1) negative-feedback effects of high circulating levels of cortisol; (2) diurnal rhythms, with peak levels during sleep; and (3) psychological and physiologic stress increases ACTH secretion, leading to increased cortisol levels. (Neurologic mechanisms regulating sleep are discussed in Chapter 16.)

There also is evidence that there is synthesis and secretion of glucocorticoids from extra-adrenal tissue including the thymus, lung, intestine, skin, brain, and possibly heart in response to immune stimulation. This is thought to provide autocrine and paracrine immune regulation and control of inflammation. Dysregulation of extra-adrenal glucocorticoid production can contribute to autoimmune and inflammatory diseases.²¹

Once ACTH is secreted, it binds to specific plasma membrane receptors on the cells of the adrenal cortex and on other extra-adrenal tissues. Because both adrenal and extra-adrenal tissues have ACTH receptors, a number of effects result from stimulation by ACTH (Box 21.1). ACTH stimulates the cells of the adrenal cortex to immediately synthesize and secrete cortisol. In healthy people, the secretory patterns of ACTH and cortisol are nearly identical. After secretion, 10% to 15% of cortisol circulates unbound, while the rest is bound to albumin or a plasma glycoprotein called transcortin. The levels of transcortin play a role in the HPA feedback system controlling cortisol secretion. Transcortin levels are significantly elevated by increased estrogen levels that occur with pregnancy and hormone therapy. The unbound portion is free to diffuse into cells, but only those cells with specific intracellular glucocorticoid receptors respond to cortisol stimulation. ACTH is rapidly inactivated in the circulation, and the liver and kidneys eliminate the deactivated hormone.

Box 21.1

Effects of Adrenocorticotropic Hormone

Adrenal

• Maintenance of gland size
• Depletion of ascorbic acid
• Activation of adenylyl cyclase
• Conversion of cholesterol to pregnenolone
• Accumulation of cholesterol for steroid hormone synthesis
• Secretion of cortisol and adrenal androgens

Extra-Adrenal

• Stimulation of melanocytes
• Activation of tissue lipase

Mineralocorticoids: aldosterone

Mineralocorticoid steroids directly affect ion transport by epithelial cells, causing sodium retention and potassium and hydrogen loss. Aldosterone is the most potent naturally occurring mineralocorticoid and conserves sodium by increasing the activity of the sodium pump of epithelial cells in the nephron. (The sodium pump is described in Chapter 1.)

The initial stages of aldosterone synthesis occur in the adrenal zona fasciculata and zona reticularis. The final conversion of corticosterone to aldosterone occurs in the zona glomerulosa. Aldosterone synthesis and secretion is regulated primarily by the renin-angiotensin system (described in Chapter 37). The renin-angiotensin system is activated by sodium and water depletion, increased potassium levels, and a diminished effective blood volume (Fig. 21.19). Angiotensin II is the primary stimulant of aldosterone synthesis and secretion; however, sodium and potassium levels also may directly affect aldosterone secretion. ACTH acutely stimulates aldosterone secretion but is secondary to angiotensin II and potassium.

A flowchart shows the feedback mechanisms in regulating aldosterone secretion. The general loop in the regulating process I as follows. • Renin released by juxtaglomerular cells of nephron cleaves angiotensinogen. • Angiotensinogen. • Angiotensin 1. • Angiotensin 2 (also from angiotensin 1-converting enzyme in lung). • Increased aldosterone levels. • Increased sodium and water reabsorption by nephron collecting duct. • Increased effective blood volume to correct initial stimulus to the system. • Increased renal arterial mean pressure. The positive feedback mechanisms impacting the first stage of the regulation are as follows. • Stimulating variables: nitric oxide from macula densa, c A M P, diuretics, epinephrine, norepinephrine, early part of day, and erect posture. • Decreased renal blood flow. • Sympathetic input. The negative feedback mechanisms (inhibiting variables) impacting the first stage of the regulation are as follows. • Adenosine from macula densa. • Angiotensin 2. • Adrenergic blocking agents. • Aldosterone. • Recumbent posture. • Later part of day. The positive feedback mechanisms impacting the increased aldosterone levels are as follows. • Hyponatremia. • Hyperkalemia. • A C T H levels. Hypokalemia is the negative feedback mechanisms impacting the increased aldosterone levels.

When sodium and potassium levels are within normal limits, approximately 50 to 250 mg of aldosterone is secreted daily. Of the secreted aldosterone, 50% to 75% binds to plasma proteins. The proportion of unbound aldosterone contributes to its rapid metabolic turnover in the liver, its low plasma concentration, and its short half-life (about 15 minutes). Aldosterone is metabolized in the liver and is excreted by the kidney.

Aldosterone maintains extracellular volume and blood pressure by acting on distal nephron epithelial cells to increase reabsorption of sodium and excretion of potassium and hydrogen. This renal effect takes 90 minutes to 6 hours. Fluid and electrolyte regulation is addressed in more detail in Chapter 3. Other effects of aldosterone include enhancement of cardiac muscle contraction, stimulation of ectopic ventricular activity through secondary cardiac pacemakers in the ventricles, stiffening of blood vessels with increased vascular resistance, and decrease in fibrinolysis. Pathologically elevated levels of aldosterone have been implicated in the myocardial changes associated with heart failure.²²

The adrenal medulla, together with the sympathetic division of the autonomic nervous system, is embryonically derived from neural crest cells. The chromaffin cells (pheochromocytes) of the adrenal medulla secrete and store the catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline). Both are synthesized from the amino acid phenylalanine (Fig. 21.20). Only 30% of circulating epinephrine comes from the adrenal medulla (the other 70% is released from nerve terminals), and the medulla is only a minor source of norepinephrine. The adrenal medulla functions as a sympathetic ganglion without postganglionic processes. Sympathetic cholinergic preganglion fibers terminate on the chromaffin cells and secrete catecholamines directly into the bloodstream. The catecholamines acting in the blood are therefore hormones and not neurotransmitters.

An illustration depicts the pathway of catecholamine biosynthesis accompanied by the chemical structures of the compounds. 1. Phenylalanine converted to tyrosine by hydroxylase. 2. Tyrosine is converted to Dopa by hydroxylase. 3. Dopa is converted to Dopamine by beta-hydroxylase. 4. Dopamine is converted to norepinephrine by N-methyltransferase. 5. Norepinephrine is converted to epinephrine. 6. The rate-limiting step is indicated by the sublimation of dopamine and norepinephrine by tyrosine hydroxylase.

Physiologic stress to the body (e.g., traumatic injury, hypoxia, hypoglycemia) triggers the exocytosis of the storage granules from chromaffin cells, with release of epinephrine and norepinephrine into the bloodstream. Secretion of adrenal catecholamines is also increased by ACTH and the glucocorticoids. Once released, the catecholamines remain in the plasma for only seconds to minutes. The catecholamines exert their biologic effects after binding to plasma membrane receptors (α₁, α₂, β₁, β₂, and β₃) in target cells. This binding activates the adenylyl cyclase system (an intracellular second messenger system). Catecholamines have diverse effects on the entire body. Their release and the body's response have been characterized as the “fight or flight” response (stress response) (see Figs. 11.2 and 11.4 and Tables 11.3 and 11.4). Metabolic effects of catecholamines promote hyperglycemia through a variety of mechanisms, including interference with the usual glucose regulatory feedback mechanisms. Catecholamines are rapidly removed from the plasma by neuron absorption for storage in new cytoplasmic granules, or metabolically inactivated and excreted in the urine. Catecholamines also directly inhibit secretion by decreasing the formation of the enzyme tyrosine hydroxylase (the rate-limiting step, see Fig. 21.20).