Endocrine Physiology

Chapter 3 Endocrine Physiology

1. The primary function of hormones is to maintain homeostasis (e.g., regulate plasma glucose and electrolyte balance) and coordinate physiologic processes such as development, metabolism, and reproduction.

Hormones maintain homeostasis by regulating processes such as development, metabolism, and reproduction.

2. A “master” list of hormones is shown in Table 3-1, and a schematic is shown in Figure 3-1.

3. Hormones maintain homeostasis by using various feedback mechanisms.

TABLE 3-1 Hormones

Hormones	Physiologic Actions	Pathophysiology
Hypothalamic Hormones
Corticotropin-releasing hormone (CRH)	Stimulates adrenocorticotropic hormone (ACTH) secretion from anterior pituitary	Increase in adrenal insufficiency due to loss of negative feedback
Gonadotropin-releasing hormone (GnRH)	Stimulates gonadotropin secretion from anterior pituitary	Hypothalamic hypogonadotrophic hypogonadism due to hyperprolactinemia → infertility Increase in hypothyroidism → ↓ dopamine secretion due to ↑ TRH → hyperprolactinemia
Thyrotropin-releasing hormone (TRH)	Stimulates thyroid-stimulating hormone (TSH) secretion from anterior pituitary	Decrease in primary or secondary hyperthyroidism due to feedback inhibition
Growth hormone-releasing hormone (GHRH)	Stimulates growth hormone secretion from anterior pituitary	Decrease in growth hormone (GH)-secreting tumor of anterior pituitary
Somatostatin	Inhibits GH secretion from anterior pituitary	Synthetic version (octreotide) used in GH-secreting pituitary adenomas
Dopamine	Inhibits prolactin secretion from anterior pituitary	Hypothyroidism → hyperprolactinemia Antipsychotics → hyperprolactinemia
Anterior Pituitary Hormones
Adrenocorticotropic harmone (ACTH)	Stimulates glucocorticoid and androgen synthesis in adrenal medulla	Cushing disease ↓ Cushing syndrome Paraneoplastic secretion (e.g., small cell lung carcinoma) Cushing disease: ACTH-hypersecreting pituitary
Thyroid stimulating harmone (TSH)	Stimulates thyroid hormone synthesis in the thyroid gland	TSH-secreting pituitary adenoma (secondary hyperthyroidism) ↓ in panhypopituitarism
Luteinizing hormone (LH)	Stimulates testosterone secretion by Leydig cells in testes Stimulates progesterone synthesis in women Stimulates ovulation and corpus luteum development	Elevated levels: polycystic ovary syndrome (PCOS), testicular failure, premature menopause, Turner syndrome Decreased levels: hyperprolactinemia, Kallman syndrome, eating disorders (anorexia), hypopituitarism
Follicle-stimulating hormone (FSH)	Stimulates spermatogenesis in testes Stimulates estrogen synthesis by granulosa cells in ovarian follicles	Elevated levels: testicular failure, premature menopause, Turner syndrome Decreased levels: Kallman syndrome, PCOS, hypopituitarism
Growth hormone (GH)	Anabolic hormone with multiple anabolic and insulin-antagonizing metabolic effects	Gigantism: excess GH before fusion of epiphyseal plates Acromegaly: excess GH after fusion of epiphyseal plates Pituitary dwarfism: GH deficiency resulting in dwarfism with normal body proportions
Prolactin	Stimulates breast maturation and milk letdown	Prolactinoma: hypersecreting prolactinoma resulting in galactorrhea and infertility in women
Posterior Pituitary Hormones
Antidiuretic hormone (ADH)	Stimulates water absorption from the distal nephron	Syndrome of inappropriate antidiuretic hormone (SIADH) Central diabetes insipidus Nephrogenic diabetes insipidus
Oxytocin	Stimulates uterine contraction during labor
Thyroid Hormones
Thyroxine (T₄)	Prohormone that becomes bioactive on peripheral conversion to T₃	Hyperthyroidism: ↑ thyroid gland synthesis of thyroid hormone Thyrotoxicosis: any cause for ↑ thyroid hormones (e.g., gland destruction, exogenous intake, ↑ synthesis) Hypothyroidism: ↓ thyroid gland synthesis of thyroid hormone Thyroiditis: destruction of thyroid gland; can transiently cause hyperthyroidism but ultimately causes hypothyroidism Euthyroid sick syndrome: impaired peripheral conversion of T₄ to T₃
Triiodothyronine (T₃)	Increases basal metabolic rate by up-regulating expression and insertion of Na⁺,K⁺-ATPase pump
Adrenal Cortex Hormones
Aldosterone	Promotes renal Na retention and expands plasma volume	Hypersecreted in primary aldosteronism → hypertension with hypokalemic metabolic alkalosis
Cortisol	Helps maintain glucose for glucose-dependent tissues during fasting state by promoting hepatic gluconeogenesis, peripheral resistance to insulin, and lipolysis in adipose tissue	Cushing disease: ACTH-hypersecreting pituitary adenoma Cushing syndrome: hypercortisolism of any etiology Adrenal insufficiency: can be primary, secondary, or (rarely) tertiary; most commonly iatrogenic from long-term use of steroids
Dehydroepiandrosterone (DHEA)	Converted to testosterone in peripheral tissues	Congenital adrenal hyperplasia: oversecretion of androgens results in virilization, precocious puberty, ambiguous genitalia
Adrenal Medulla Hormones
Epinephrine	Too numerous to list: Liver: ↑ glycogenolysis, gluconeogenesis Skeletal muscle: ↑ anaerobic metabolism, ↑ insulin resistance Adipose: ↑ lipolysis	Pheochromocytoma: autonomously catecholamine-hypersecreting adrenal tumor (most common location) Levels ↑ in congestive heart failure
Ovarian Hormones
Estrogen	Development of female secondary sexual characteristics Follicular phase of menstrual cycle Bone maturation → fusion of epiphyseal plates in adolescent females	Osteoporosis Breast cancer Endometrial cancer
Testicular Hormones
Testosterone	Development of seminal vesicles, epididymis, vas deferens during embryogenesis Increasing lean muscle mass and bone density	Benign prostatic hyperplasia (BPH) Prostate cancer Androgen insensitivity syndrome (testicular feminization)
Dihydrotestosterone (DHT)	Development of the male external genitalia (penis, scrotum) and prostate gland	BPH Male-pattern baldness
Pancreatic Hormones
Insulin	Promotes peripheral uptake of glucose in nonfasting (fed) state	Hypoglycemia (factitious, insulinoma, medication induced) Type 1 diabetes mellitus: absolute deficiency of insulin due to β cells Type 2 diabetes mellitus: relative deficiency of insulin (initially) due to peripheral resistance; later in course may have absolute insulin deficiency
Glucagon	Promotes hyperglycemia and insulin resistance	Glucagonoma
Somatostatin	Inhibits pituitary GH secretion Inhibits various intestinal secretions	Used to treat GH-secreting pituitary adenomas
Vasoactive-intestinal peptide (VIP)	Promotes smooth muscle relaxation and dilation throughout intestines Promotes watery/bicarbonate-rich secretions from pancreas Inhibits gastrin-stimulated HCL secretion in stomach Promotes pepsinogen secretion by gastric chief cells Promotes intestinal motility	Vasoactive intestinal polypeptide-secreting tumor (VIPoma); may be associated with multiple endocrine neoplasia type 1 WDHA (watery diarrhea and resultant dehydration, hypokalemia, achlorhydria) syndrome

3-1 Schematic of the hypothalamic-pituitary-endocrine organ axis. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone; TSH, thyroid-stimulating hormone.

(From Kumar P, Clark M: Kumar and Clark’s Clinical Medicine, 5th ed. Philadelphia, Saunders, 2002, Fig. 18-7.)

Hormones: maintain homeostasis through feedback loops

4. Hormones act slowly relative to the nervous system.

Hormones: act slowly relative to nervous system

B. Mechanism of action of hormones

1. All hormones must interact with a cellular receptor, which then transduces a signal and generates a cellular response.

2. The effectiveness of a given hormone, therefore, depends on the concentration of free hormone (that which is available for binding), the concentration of hormone receptor, and the effectiveness of the transduction mechanism.

3. All endocrine diseases are due to a quantitative or qualitative defect in hormone synthesis or altered tissue sensitivity to hormone, usually manifesting as a disruption of a well-characterized homeostatic control system.

Endocrinopathies: due to qualitative or quantitative defect in hormone synthesis and/or tissue sensitivity to hormone

C. Types of hormones and their individual effector mechanisms

1. Steroid hormones

• Steroid hormones are lipid-soluble compounds derived from cholesterol that are able to enter all cells of the body by diffusing through the lipid-rich plasma membrane.

• They produce their effects by binding to receptors in either the cytosol or nucleus of cells in target tissues, and this hormone-receptor complex then activates transcription of specific genes (Fig. 3-2).

• Because steroid hormones can diffuse freely through lipid membranes, they cannot be stored within intracellular vesicles.

a. They are therefore produced continually, and synthesis and secretion increase on demand.

3-2 After diffusing through the plasma membrane, most steroid hormones bind to a cytoplasmic receptor. This hormone-receptor complex then undergoes a conformational change, which uncovers a nuclear localization site that allows access to the nucleus. The complex then binds to and activates genes that contain the appropriate steroid response element within their sequence. HR, Hormone receptor; NLS, nuclear localization sequence; SRE, steroid response element.

Steroid hormones: produced continuously, cannot be stored, synthesis and secretion ↑ on demand

• Furthermore, because steroid hormones are lipid soluble, they must circulate bound to plasma proteins.

Steroid hormones: circulate bound to proteins, diffuse freely through cell membranes

a. Because they are protein-bound they are not freely filtered by the kidney, which contributes to their long half-life relative to most peptide hormones; they are primarily metabolized by the liver.

• The principal steroid hormones include the sex steroids—testosterone, progesterone, and estrogen—and the adrenal steroids—cortisol and aldosterone.

Sex steroids: testosterone, progesterone, estrogen

Adrenal steroids: aldosterone, cortisol

2. Thyroid hormones

• Are unique in that they are derived from the amino acid tyrosine rather than cholesterol

• Have a mechanism of action similar to steroid hormones (i.e., they diffuse into a cell, bind to a receptor, and alter gene expression)

Thyroid hormones: derived from amino acid tyrosine, not cholesterol

3. Proteoglycan, protein, peptide, and amino acid hormones

• These polar compounds bind to membrane-associated receptors on target cells.

• The signal transduction mechanism used by these agents varies, depending on the receptor type.

• Because they are hydrophilic, they can be stored in cytoplasmic vesicles within endocrine cells and released on demand.

Protein, peptide, amino acid hormones: hydrophilic, stored in vesicles, released on demand, bind membrane-bound receptors

• Some travel free as soluble compounds in the blood, whereas others travel mainly bound, associated with specific binding proteins.

a. In general, free hormones that are not associated with carrier proteins have shorter half-lives than bound hormones.

• Figure 3-3 shows the mechanism underlying G protein signal transduction.

3-3 G protein signal transduction cascade. The first step (A) is the binding of hormone (triangle) to a G protein–associated membrane receptor. This hormone binding stimulates the receptor to undergo a conformational change (B), which causes the α-subunit of the G protein to release guanosine diphosphate (GDP) and bind guanosine triphosphate (GTP). This causes the α-subunit to dissociate from the β-γ complex. The α-subunit and the β-γ complex are then free to diffuse laterally within the lipid bilayer and activate or inhibit the activity of various effector molecules, such as adenylate cyclase (C). After several seconds, intrinsic GTPase activity of the α-subunit degrades the GTP to GDP. The GDP-bound α-subunit is inactive and also binds to the β-γ complex (D), restoring the system to its original condition. The intrinsic adenosine triphosphatase (ATPase) activity of the α-GTP complex limits the duration of the response.

Membrane-spanning receptors: kinase receptors, ligand-gated ion channels, receptor-linked kinases, G protein–coupled receptors

D. Hormone-binding proteins

1. Certain hormones circulate bound to hormone-binding proteins.

2. These binding proteins serve several important physiologic functions:

• They provide a reservoir of hormone, which exists in equilibrium with the free hormone and buffers any moment-to-moment changes in free hormone concentration.

• They extend the half-life of the bound hormone considerably because it is the free hormone that is excreted by the liver or kidneys.

3. All steroid hormones and a few peptide hormones have plasma binding proteins (Table 3-2).

TABLE 3-2 Hormone Binding in Some Plasma Proteins

Plasma Protein	Hormone
Albumin	Multiple lipophilic hormones
Transthyretin	Thyroxine (T₄)
Transcortin	Cortisol, aldosterone
Thyroxine-binding globulin	Triiodothyronine (T₃), T₄
Sex hormone–binding globulin	Testosterone, estrogen

Hormone-binding proteins: extend half-life of bound hormone, levels often ↑ in pregnancy

Clinical note: In pregnancy, plasma levels of the hormone-binding protein thyroid-binding globulin and transcortin increase because of the effects of estrogen on the liver, which increases their synthesis. This increases plasma levels of total thyroid hormone and total cortisol hormone but does not affect levels of free thyroid hormone or free cortisol hormone. Therefore, despite elevated levels of total thyroid hormone and cortisol, these women do not manifest symptoms of hyperthyroidism or hypercortisolism. Note, however, that pregnant women can still experience gestational hyperthyroidism and Cushing syndrome, but the pathophysiology of these endocrinopathies is unrelated to altered hormone-binding protein synthesis.

E. Hierarchical control of hormone secretion

1. For several hormonal control systems, a hierarchical axis exists, consisting of the hypothalamus, the anterior pituitary (adenohypophysis), and a specific endocrine gland (Fig. 3-4A).

2. The hypothalamus, at the top of the axis, secretes releasing (and inhibitory) hormones into a capillary bed that converges on the pituitary and then re-expands into another capillary bed within the anterior pituitary (hypothalamic-hypophyseal portal system) (Table 3-3; Fig. 3-4B).

3-4 A, Hierarchical control of hormone secretion. B, Hypothalamic-hypophyseal portal system.

TABLE 3-3 Effect of Hormones Released by the Hypothalamus on the Anterior Pituitary

Hormone	Effect on Anterior Pituitary
Growth hormone–releasing hormone (GHRH)	Stimulates growth hormone (GH) secretion
Prolactin-inhibitory factor (dopamine)	Inhibits prolactin secretion
Somatostatin	Inhibits GH secretion
Gonadotropin-releasing hormone (GnRH)	Stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion
Corticotropin-releasing hormone (CRH)	Stimulates adrenocorticotropic hormone (ACTH) secretion
Thyrotropin-releasing hormone (TRH)	Stimulates thyroid-stimulating hormone (TSH) secretion

Hypothalamic-hypophyseal portal system: targets delivery of hypothalamic hormones to adenohypophysis with minimal systemic distribution

3. The releasing hormones then stimulate specific cell types of the anterior pituitary and stimulate (or inhibit) pituitary hormone secretion.

4. The pituitary hormone, in turn, may act directly on target tissues (e.g., prolactin) or stimulate an endocrine gland to produce an effector hormone (e.g., thyroid-stimulating hormone).

5. The hypothalamus also controls the secretion of the hormones of the posterior pituitary (neurohypophysis), but in a different fashion.

6. Posterior pituitary hormones are synthesized by neurons in the hypothalamus and transported along axons into the posterior pituitary.

7. There they are released into the bloodstream as neurosecretory granules in response to appropriate stimuli.

Posterior pituitary: composed of axonal extensions originating from hypothalamus

F. Classification of endocrine diseases

1. A hormone deficiency or excess can occur as the result of a defect anywhere along the hypothalamic-pituitary-target organ axis.

2. It is important to determine the location of the defect to make an accurate diagnosis.

3. In primary endocrine diseases, the defect is in the endocrine organ.

• For example, if a defect renders the thyroid gland unable to produce thyroid hormone effectively, the disease is known as primary hypothyroidism.

4. In secondary endocrine diseases, the defect is in the pituitary gland.

• For example, decreased pituitary thyroid-stimulating hormone secretion causes secondary hypothyroidism.

5. In tertiary endocrine diseases, the defect is in the hypothalamus.

• For example, decreased hypothalamic thyrotropin-releasing hormone secretion (extremely rare) causes tertiary hypothyroidism.

Location of defect: primary disease: endocrine gland; secondary disease: pituitary; tertiary disease: hypothalamus

II. Hormonal Control Systems of the Anterior Pituitary

A. Hypothalamic-pituitary-adrenal axis

1. Overview

• Functions to maintain physiologically appropriate plasma levels of the hormone cortisol.

• Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary through activation of corticotroph cells.

• ACTH then acts on the adrenal cortex to stimulate the synthesis and secretion of glucocorticoids and androgens but not the mineralocorticoid aldosterone (see pathology note below).

• Note that androgens do not feedback-inhibit ACTH secretion.

Androgens: do not feedback-inhibit ACTH secretion

Pathology note: In certain types of congenital adrenal hyperplasias (CAH), specific enzyme blocks (e.g., 21- and 11-hydroxlase) lead to impaired cortisol synthesis and shunting of proximally located precursors (e.g., 17-hydroxypregnenolone, 17-hydroxyprogesterone) into the androgen biosynthetic pathway. Because androgens do not feedback-inhibit the pituitary, ACTH levels markedly increase. The result is further pathologic androgen production, resulting in precocious puberty in males later in childhood or ambiguous genitalia in female neonates (e.g., clitoris looks like a penis). In severe forms of CAH, salt wasting (hypotension) from insufficient mineralocorticoid production distal to the enzyme block may occur (e.g., 21-hydroxylase deficiency), or salt retention (hypertension) results from increased weak mineralocorticoids like 11-deoxycorticosterone that are proximal to the enzyme block (e.g., 11-hydroxylase deficiency).

• The primary glucocorticoid is cortisol, and the primary adrenal androgen is dehydroepiandrosterone (DHEA), a precursor of testosterone.

Primary glucocorticoid: cortisol

Primary androgen: DHEA

2. Regulation of the hypothalamic-pituitary-adrenal axis

• As shown in Figure 3-5, cortisol secretion is stimulated by hypoglycemia or stressful conditions (e.g., surgery), when the sympathetic nervous system is also activated.

a. This is why cortisol is sometimes referred to as the stress hormone.

• Cortisol secretion is normally inhibited by increased plasma levels of cortisol because of the negative-feedback effect of cortisol on the pituitary and hypothalamus.

• Note from the figure that androgens do not inhibit CRH or ACTH secretion, as discussed in the pathology note above.

3-5 Main determinants of hypothalamic-pituitary-adrenal axis. ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone.

Cortisol secretion: stimulated by physiologic stressors

Pathology note: A tumor of the adrenal gland that autonomously hypersecretes cortisol exerts negative feedback on the hypothalamus and pituitary and decreases the secretion of ACTH secretion. In this circumstance, the patient will be hypercortisolemic with a low ACTH level, implying the etiology of the hypercortisolism is adrenal in origin.

• Cortisol has a diurnal pattern of secretion that is based on the daily pattern of ACTH secretion from the pituitary.

Cortisol secretion: diurnal pattern, highest in morning

• Cortisol levels are highest in the early morning, owing to the early-morning surge of ACTH (Fig. 3-6).

3. Biosynthetic pathway of adrenal corticosteroids

• The rate-limiting step in adrenal steroid synthesis is the conversion of cholesterol to pregnenolone (Fig. 3-7).

3-6 Diurnal secretion of adrenocorticotropic hormone and cortisol. ACTH, Adrenocorticotropic hormone.

3-7 Pathways of adrenal steroidogenesis. Note that the primary dehydroepiandrosterone (DHEA) produced by the adrenal is DHEA sulfate, whereas the key DHEA produced by the gonads is DHEA. This is important in working up the cause of hirsutism and virilization. Note also the stimulatory effects of angiotensin II and plasma K⁺ on aldosterone synthesis.

Rate-limiting step in steroid hormone synthesis: conversion of cholesterol to pregnenolone

• The synthetic pathway for each adrenal steroid occurs in a specific region of the adrenal gland.

a. Mineralocorticoid synthesis occurs in the zona glomerulosa.

b. Cortisol synthesis primarily occurs in the zona fasciculata.

c. Androgen synthesis occurs in the zona reticularis.

Layers of adrenal cortex: “GFR” for zona glomerulosa, fasciculata, and reticularis

• Although the principal mineralocorticoid aldosterone is synthesized in the adrenal cortex, its synthesis is only slightly affected by ACTH.

a. Rather, its secretion is primarily regulated by plasma concentrations of K⁺ and angiotensin II, the latter increasing conversion of corticosterone to aldosterone by stimulation of 18-hydroxylase.

Aldosterone synthesis: regulated by K⁺ and angiotensin II rather than ACTH

• Note: The gonads (ovaries and testes) and the adrenals are the only tissues that convert cholesterol to steroid hormones.

5. Physiologic actions of cortisol (Fig. 3-8)

• Fuel metabolism

a. In the fasting state, cortisol helps maintain adequate plasma levels of glucose for glucose-dependent tissues such as the central nervous system (CNS).

3-8 Metabolic actions of cortisol. Note also some of the pathologic affects from prolonged exposure to supraphysiologic concentration.

Clinical note: The CNS is primarily dependent on glucose for a fuel source because it is unable to metabolize fatty acids and proteins to any great extent. Therefore, in patients who experience hypoglycemia (e.g., diabetic patient who takes his pre-meal insulin and then forgets to eat), CNS dysfunction can occur. Symptoms can range from mild confusion and somnolence to coma. Fortunately, unless the hypoglycemia is prolonged, it is rare for brain damage to occur.

b. It accomplishes this by inhibiting the peripheral utilization of glucose by muscle and adipose tissue while simultaneously stimulating hepatic gluconeogenesis.

c. Cortisol exerts catabolic actions on most tissues, with the exception of the liver, on which it exerts anabolic actions.

d. Cortisol stimulates hepatic gluconeogenesis in several ways:

• It promotes muscle breakdown, which releases amino acids (e.g., alanine, aspartate) into the gluconeogenic pathway.

• It stimulates synthesis of hepatic gluconeogenic enzymes.

• It potentiates the actions of glucagon and catecholamines on the liver.

• Cortisol additionally stimulates lipolysis in adipose tissue, which helps maintain plasma levels of glycerol and fatty acids during the fasting state.

• These substrates can then be used as alternative fuel sources in various tissues (e.g., muscle), thereby sparing plasma glucose for the CNS.

• In the liver, these substrates can be used as an energy source to support gluconeogenesis.

Metabolic actions of cortisol: generally catabolic, stimulates gluconeogenesis, preserves plasma glucose

Clinical note: Because of the propensity of cortisol to increase plasma glucose levels, prolonged exposure to supraphysiologic levels of cortisol will often cause glucose intolerance and may lead to frank diabetes mellitus in a significant number of patients.

• Effects on blood pressure and plasma volume

b. This stimulates renal sodium reabsorption and causes plasma volume expansion.

Cortisol: exerts mineralocorticoid effects at higher plasma concentrations

Clinical note: Ordinarily, cortisol is degraded by intracellular enzymes in the cells of mineralocorticoid-responsive tissues such as the colon and kidney. However, at higher levels, these enzymes become saturated, at which point cortisol may bind to mineralocorticoid receptors and exert pathologic effects, such as hypertension and electrolyte abnormalities (e.g., hypokalemia).

• Effects on inflammatory and immune responses

a. Cortisol has powerful anti-inflammatory effects.

b. It inhibits activity of the enzyme phospholipase and also inhibits the transcription of various inflammatory cytokines.

c. As shown in Figure 3-9, inhibition of phospholipase leads to decreased arachidonic acid production and, therefore, to decreased production of prostaglandins and leukotrienes, both potent inflammatory mediators.

3-9 Anti-inflammatory action of cortisol. NSAIDs, Nonsteroidal anti-inflammatory drugs.

Cortisol: potent anti-inflammatory but with myriad acute and chronic side effects

• Effects on bone

a. At supraphysiologic levels, cortisol weakens bones by inhibiting bone-forming cells (osteoblasts) and stimulating bone-degrading cells (osteoclasts).

Cortisol: inhibits osteoblasts, stimulates osteoclasts

Avascular necrosis: steroids may precipitate; most commonly occurs in hip

b. Cortisol also acts to decrease plasma calcium by reducing calcium absorption by the intestines as well as inhibiting the production of 1,25-(OH)₂-D (calcitriol) by the kidneys; these actions tend to increase parathyroid hormone secretion, which can promote further bone breakdown.

Cortisol: inhibits intestinal Ca²⁺ absorption; inhibits calcitriol synthesis

Pathology note: Increased levels of glucocorticoids can severely compromise the blood supply to certain susceptible bones, resulting in avascular necrosis of the bone. Avascular necrosis most commonly occurs in the femoral head of the hip joint in patients treated with long-term glucocorticoids.

5. Pathophysiology of the CRH-ACTH-cortisol axis

• Hypercortisolism (Cushing syndrome)

a. Cushing syndrome refers to the constellation of signs and symptoms associated with hypercortisolism, irrespective of the etiology of the hypercortisolism.

b. Recall that cortisol promotes hyperglycemia, muscle breakdown, bone loss, and plasma volume expansion.

• Hypercortisolic states may therefore result in diabetes mellitus, muscle wasting, osteoporosis, and hypertension.

Manifestations of chronic hypercortisolism: diabetes mellitus, muscle atrophy, osteoporosis, hypertension

c. Hypercortisolism is most commonly physician induced (iatrogenic).

Cushing syndrome: most often iatrogenic

d. The most common endogenous source of elevated cortisol is an ACTH-hypersecreting tumor of the pituitary (pituitary Cushing), a condition formerly referred to as Cushing disease.

Pituitary Cushing: most common pathologic cause of Cushing syndrome; caused by ACTH-hypersecreting pituitary adenoma

e. Other causes of Cushing syndrome (Fig. 3-10) include cortisol-hypersecreting adrenal tumors and ectopic (paraneoplastic) production of ACTH by tumors (e.g., small cell lung cancer).