1 What is the cellular mechanism of action of the steroid hormones?

Steroid hormones are lipophilic. Therefore, they diffuse across the plasma membrane and form complexes with cytosolic or nuclear receptors; the bound complexes then activate transcription of various genes. Because steroid hormones rely on the intermediary process of gene expression and protein translation, it can take hours to days for their effects to manifest. Examples of steroid hormones are testosterone, estrogen, progesterone, cortisol, and aldosterone. Cholesterol is the precursor to all steroid hormones. Although thyroid hormone is not a steroid hormone, it uses the same cellular mechanism as the steroids (Fig. 8-1).

Figure 8-1 Mechanisms by which peptide and steroid hormones signal. Ca²⁺, calcium; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; mRNA, messenger RNA; Tyr-P, phosphorylated tyrosine residue.

(From Goldman L, Ausiello D: Cecil Textbook of Medicine, 22nd ed. Philadelphia, WB Saunders, 2004.)

2 What is the cellular mechanism of action of the peptide hormones and the catecholamines?

The peptide hormones and catecholamines are not highly lipid-diffusible and thus cannot cross the plasma membrane. They bind to cell surface receptors (see Fig. 8-1), which initiate a variety of biochemical events, including activation or inhibition of enzymes, alteration of membrane proteins, and mediation of cellular trafficking. These processes can occur within seconds to minutes. Nevertheless, the peptide hormones can stimulate gene expression as well, and this effect is delayed as it is with the steroid hormones. Examples of peptide hormones are insulin, parathyroid hormone (PTH), vasopressin (antidiuretic hormone), and oxytocin. Table 8-1 shows a comparison of polypeptide and steroid hormones.

Table 8-1 Comparison of the Different Types of Hormones

3 Why is the total serum hormone level not an accurate reflection of hormone activity?

Many of the hormones in the serum are inactive because they are attached to serum binding proteins. It is only the free hormone that is biologically active. Another important factor that affects hormone activity is the concentration of cellular hormone receptors available for binding a specific hormone and mediating its action.

Note: Free hormone is in equilibrium with bound hormone:

4 How does a hormone’s binding to the same type of receptor have different effects in different cell types?

Different tissues are different because they express different genes (i.e., differential transcription). Therefore, although different target tissues may express the same hormone receptor, they may also express entirely different downstream protein targets. For example, by binding the same β₂-adrenergic receptors, epinephrine is able to elicit a host of different physiologic responses depending on the tissue location of that receptor (e.g., glycogenolysis in the liver, lipolysis in adipose tissue).

5 What are the four primary classes of membrane-spanning receptors to which peptide hormones bind?

The four primary classes of membrane-spanning receptors to which peptide hormones bind are (1) tyrosine and serine kinase receptors, (2) receptor-linked kinases, (3) G protein–coupled receptors, and (4) ligand-gated ion channels (Fig. 8-2 and Table 8-2). As a gross simplification, the “prototypical” agonists for these receptor types can be considered to be growth factors, growth hormones (GHs), peptide hormones, and neurotransmitters, respectively.

Figure 8-2 The four major classes of membrane receptors for hormones and neurotransmitters. cAMP, cyclic adenosine monophosphate; E, effector enzyme; G, G protein; IP₃, inositol triphosphate; R, receptor.

(From Brown TA, Brown D: USMLE Step 1 Secrets. Philadelphia, Hanley & Belfus, 2004.)

Table 8-2 Classes of Receptors Used by Various Hormones

6 How do the tyrosine kinase receptors transduce their messages?

As depicted in Figure 8-3, binding of peptide hormone to the extracellular domain of the receptor initiates a signal transduction cascade by promoting autophosphorylation of the kinase receptor and subsequent phosphorylation of downstream target proteins, thereby activating or inhibiting these proteins.

Figure 8-3 Mechanism of activation of a tyrosine kinase receptor.

(From Meszaros JG, Olson ER, Naugle JE, et al: Crash Course: Endocrine and Reproductive Systems. Philadelphia, Mosby, 2006.)

7 How do the ligand-gated ion channels work?

Activation of ligand-gated ion channels results in an influx (or efflux) of ions into (or out of) the cell. The nicotinic receptor on skeletal muscle is an example of such a receptor. Binding of acetylcholine to this receptor results in an influx of principally sodium ions into the cell.

8 How do the G proteins transduce their signals?

Binding of hormone/agonist to G protein–coupled receptors causes an αβγ subunit complex to exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Once GTP is bound to the subunit complex, it dissociates into the α subunit and a separate βγ subunit. These dissociated subunits then activate or inhibit enzymes (adenylate cyclase, phospholipase) and ion channels (Ca²⁺ channels) (Fig. 8-4).

Figure 8-4 Signal transduction by G proteins. βARK, β-adrenergic receptor kinase; GAP, GTPase-activating protein; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanosine triphosphate; Pi, inorganic phosphate, PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLCβ, phospholipase Cβ; Raf1, effector protein; Ral GDS, Ras-related GTPase guanine nucleotide dissociation stimulator; RTK, receptor tyrosine kinase.

(From Mann DL: Heart Failure: A Companion to Braunwald’s Heart Disease. Philadelphia, WB Saunders, 2004.)

Note: Adenylate cyclase synthesizes cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), and the cAMP activates various target proteins. G_s receptors stimulate adenylate cyclase, whereas G_i receptors inhibit adenylate cyclase.

9 How do endocrine, paracrine, and autocrine mechanisms of cell communication differ?

Endocrine secretions (i.e., hormones) affect their target organs at considerable distance from their site of secretion, so they must be carried by the bloodstream. Paracrine secretions act locally on adjacent cells and tissues. Paracrine communication seems particularly important in endocrine tissues, such as the pancreatic islets, where constant communication between adjacent cells (e.g., α and δ cells) is critical for optimal functioning. Autocrine secretions are secretions from a cell that bind to receptors on that same cell and exert regulatory actions on that cell. Neuroendocrine secretions involve the secretion of peptides into the blood from specialized neurons (hence the term neuroendocrine). Hypothalamic peptides released into the blood from the terminal boutons of axons located in the posterior pituitary are one example of this mechanism of regulation (Fig. 8-5).

Figure 8-5 The routes by which chemical signals are delivered to cells.

(From Meszaros JG, Olson ER, Naugle JE, et al: Crash Course: Endocrine and Reproductive Systems. Philadelphia, Mosby, 2006.)

10 Describe the concept of negative feedback. What is a feedback loop?

Hormone synthesis and release are governed at multiple levels. Hormone synthesis/release from an organ of interest typically involves regulation by a pituitary hormone, which itself is regulated by a hypothalamic hormone. This general pathway structure is commonly referred to as a hypothalamic-pituitary-(organ) axis (e.g., HPO axis refers to the ovary, HPA axis refers to the adrenal gland). Negative feedback occurs when a product downstream of an axis inhibits production of a reactant by which it is regulated; for example, thyroid hormone inhibition of thyroid-stimulating hormone (TSH). These relationships are often depicted using feedback loops. An example of the thyroid hormone feedback loop is depicted in Figure 8-6.

Figure 8-6 Thyroid hormone physiology. Under normal conditions, thyrotropin-releasing hormone (TRH) is released from the hypothalamus, which causes the release of thyroid-stimulating hormone (TSH) from the anterior pituitary. TSH then causes the release of triiodothyronine (T₃) and thyroxine (T₄) by the thyroid gland, which act on various peripheral organs. T₃ and T₄ also regulate TRH and TSH secretion through negative feedback mechanisms. In primary hypothyroidism (due to thyroid dysfunction), T₃ and T₄ are low despite high TSH levels. In secondary hypothyroidism (due to pituitary or hypothalamic dysfunction), the levels of TSH, T₃, and T₄ are all low.

(From Goldman L, Ausiello D: Cecil Textbook of Medicine, 22nd ed. Philadelphia, WB Saunders, 2004.)

1 What is the diagnosis?

She has Sheehan’s syndrome (or postpartum necrosis), which is an infarction of the anterior pituitary.

2 Why is the pituitary more susceptible to infarction in postpartum hemorrhage than in hemorrhagic shock unrelated to pregnancy?

During pregnancy, there is hyperplasia of the lactotrophs (prolactin-secreting cells) in the anterior pituitary (adenohypophysis) without proportional increase in blood supply, which increases this tissue’s minimal perfusion needs. During postpartum hemorrhage, blood supply to the anterior pituitary can become sufficiently inadequate to meet this increased need, causing infarction.

3 Why is the posterior pituitary typically spared in Sheehan’s syndrome?

The posterior pituitary (neurohypophysis) differs in embryologic origin from the anterior pituitary and therefore has a different blood supply. Remember, the embryologic origin of the anterior pituitary is Rathke’s pouch (an endodermal evagination from the roof of the mouth), whereas the posterior pituitary is derived from a ventral outgrowth from the primitive hypothalamus. Table 8-3 shows a review of the functions of the posterior pituitary hormones.

Table 8-3 Hormones Secreted by the Posterior Pituitary and their Effects

4 Secretion of which pituitary hormones may be affected in this woman?

The hormones secreted by the anterior pituitary include FSH, LH, ACTH, TSH, prolactin, and GH. FLAT P(i)G is a useful mnemonic to remember these hormones.

Depending on the extent of the infarction, all the anterior pituitary hormones may be affected (Fig. 8-7). This patient is unable to lactate, which is consistent with decreased prolactin secretion. (Whenever you see a patient who is unable to lactate shortly after delivery, consider Sheehan’s syndrome!) Note that her axillary and pubic hair is sparse, which is consistent with decreased gonadotropin (FSH, LH) secretion. The patient is also weak and lethargic, which is consistent with hypocortisolism due to decreased ACTH secretion.

Figure 8-7 Hormones of the anterior pituitary gland and their respective target organs. ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

(From Meszaros JG, Olson ER, Naugle JE, et al: Crash Course: Endocrine and Reproductive Systems. Philadelphia, Mosby, 2006.)

5 Why may hypothalamic releasing hormone secretion increase because of an infarction of the anterior pituitary?

The loss of pituitary hormone secretion will decrease negative feedback on the hypothalamic hormones both from low pituitary hormone levels and from low target organ hormone production. Table 8-4 reviews the hypothalamic releasing hormones.

Table 8-4 Hormones Synthesized and Secreted by the Anterior Pituitary and their Effects

6 Why wouldn’t hypothalamic dopamine secretion be elevated from an anterior pituitary infarction?

In contrast with the other hypothalamic hormones, dopamine is inhibitory in nature and reduces the secretion of prolactin by the lactotrophs. Because serum prolactin normally stimulates dopamine secretion from the hypothalamus, in a setting of hypoprolactinemia secondary to pituitary infarction, we would expect decreased secretion of hypothalamic dopamine.

1 What is the diagnosis?

Prolactinoma is a pituitary adenoma caused by abnormal proliferation of lactotrophs; it is the most common type of hypersecreting pituitary adenoma. Note that the pituitary is situated in the sella turcica. Table 8-5 reviews pituitary adenomas.

Table 8-5 Disorders Caused by the Deficiency or Excess of Anterior Pituitary Hormones

2 What are the normal physiologic functions of prolactin preceding, during, and following pregnancy?

Figure 8-8 outlines the other physiologic functions of prolactin.

Figure 8-8 Physiologic actions of prolactin. TRH, thyrotropin-releasing hormone.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007.)

3 Why does this patient have galactorrhea, whereas pregnant women with similar levels of serum prolactin generally do not have this problem?

Although prolactin stimulates milk production, the high concentrations of estrogen and progesterone that are present during pregnancy inhibit lactation, and therefore, galactorrhea. In contrast, this patient has hyperprolactinemia in the absence of elevated levels of estrogen and progesterone, which is causing her galactorrhea.

Note: Milk letdown occurs after childbirth because, during pregnancy, the placenta makes most of the estrogen and progesterone. Levels of both hormones decrease after this structure is expelled in delivery. Additionally, oxytocin is secreted in response to suckling, and this hormone stimulates contraction of myoepithelial cells around the glandular tissue of the breast, causing milk ejection.

4 Hyperprolactinemia can also occur in men. What symptoms might be expected in men?

In men, inhibition of GnRH secretion by prolactin decreases gonadotropin-mediated testosterone, production and low testosterone may lead to erectile dysfunction (impotence) and the loss of sex drive (libido). Galactorrhea can also rarely occur in men in response to certain stimuli such as severe stress and prolonged starvation. Of note, be suspicious of hyperprolactinemia in men presenting with malaise and depression. This correlation is a board favorite.

5 How does elevated prolactin prevent pregnancy (i.e., what is the mechanism of infertility and amenorrhea in this patient)?

Prolactin inhibits the hypothalamic release of GnRH, which is a stimulus for FSH and LH secretion. The consequent reduction of FSH and LH eliminates the ovulatory cycle, resulting in infertility and amenorrhea. Note that hyperprolactinemia in men can cause impotence and infertility through a similar mechanism, except in this case testosterone is lowered as a result of the decreased LH.

6 Why is asking about a history of schizophrenia and use of antipsychotic medications a relevant question in the diagnostic workup of this patient?

Several antipsychotics (particularly the typical antipsychotics) can cause hyperprolactinemia. This is not a fact you have to memorize if you simply recall that antipsychotics are dopamine antagonists, and that hypothalamic dopamine is the major inhibitor of pituitary prolactin secretion. The USMLE loves these types of correlations!

7 What is the mechanistic basis for using bromocriptine (used to treat Parkinson’s disease) in the treatment of a prolactinoma?

Bromocriptine is a dopamine agonist (recall that Parkinson’s disease is caused by a lack of dopamine) that inhibits prolactin secretion by the anterior pituitary.

8 How can head trauma with a severed pituitary stalk cause a similar increase in prolactin (assuming the anterior pituitary itself was not damaged)?

This increase is due to disruption of the tuberoinfundibular tract, which runs from the hypothalamus through the pituitary stalk and is the source of dopamine, which inhibits prolactin release.

Note: Plasma levels of all other anterior pituitary hormones (e.g., TSH, ACTH) will decrease with a severed pituitary stalk.

9 Why does hypothyroidism need to be considered in the evaluation of hyperprolactinemia?

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the secretion of both TSH and prolactin by the anterior pituitary. Because hypothyroidism causes elevated levels of TRH, it should be ruled out as a potential cause of hyperprolactinemia.

1 What is the diagnosis?

Acromegaly (from the Greek roots akros [extremities] and megalos [large]: large extremities) is caused by a GH-secreting tumor of the anterior pituitary. It most commonly affects middle-aged adults.

Note: One good way to diagnose this disorder is to look at an old picture of the patient and compare it with the patient’s current appearance. Because the physical changes take place over decades, family members and friends often do not recognize them.

2 Why is hyperglycemia commonly associated with this disease?

GH increases serum glucose levels, and its release in response to decreasing glucose concentration is one of the body’s mechanisms for preventing serious hypoglycemia. The elevation of blood glucose can be significant enough in acromegaly that many of these patients will have frank diabetes. In normal individuals, a glucose load will cause almost complete suppression of GH secretion, but it will not suppress GH secretion as much or at all by an independently functioning pituitary adenoma that is secreting GH.

3 What are the normal physiologic functions of growth hormone and how is its secretion regulated?

GH secretion occurs primarily at night and in response to various stressors such as starvation and hypoglycemia. When released during a good night of sleep, its anabolic actions on muscle and bone are of primary importance. When released in response to physiologic stressors such as starvation and hypoglycemia, its metabolic actions to conserve carbohydrate fuels (for use by the central nervous system [CNS] and other glucose-dependent tissues) and maintain protein stores (to preserve muscle strength needed for mobility) take center stage.

GH secretion is inhibited by elevated somatostatin, glucose levels, emotional stress, illness, malnutrition, obesity, glucocorticoids, and decreased thyroid hormone. Triiodothyronine (T₃) is required for normal function of GH.

4 Given the normal physiology of growth hormone, how can we explain this patient’s presentation?

The enlarged mass in the sella turcica is explained by a pituitary adenoma composed of proliferating somatotrophs. The enlarged hands and feet result from the anabolic effects of GH and insulin-like growth factor-1 (IGF-1) on the bones. As discussed previously, failure of GH suppression by a glucose load is typically seen in acromegaly. We were not told that this patient had hyperglycemia, but one would expect it in acromegaly because of the insulin-antagonizing (“diabetogenic”) actions of GH on the liver and skeletal muscle, as well as stimulation of lipolysis in adipose tissue.

Note: Most of the metabolic effects of GH are mediated through IGF-1, which is secreted by the liver. IGF-1 acts on bone to stimulate linear and lateral bone growth. IGF-1 also promotes the growth of cartilage and other soft tissues (Fig. 8-9).

Figure 8-9 Physiologic actions of growth hormone. GH, growth hormone; GHRH, growth hormone–releasing hormone; IGFs, insulin-like growth factors.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007.)

5 Why is octreotide, a somatostatin analog, useful in the treatment of acromegaly?

Somatostatin is a peptide hormone secreted by the hypothalamus. It inhibits GH secretion by the anterior pituitary. Its analog octreotide is also effective in inhibiting GH secretion.

Note: Somatostatin is also synthesized by pancreatic islets and gastric mucosa and inhibits intestinal activity and gastrointestinal motility.

6 If this patient developed a growth hormone–secreting tumor in his early teens, how might the clinical manifestations differ?

GH stimulates bone growth, and if the epiphyseal plates have not yet closed, excess GH can cause patients to attain extremes of body height. When this occurs, the disease is called gigantism. “André the Giant,” a professional wrestler and actor, suffered from this disease.

7 What growth abnormality results from deficient secretion of growth hormone during the growing years?

Pituitary dwarfism is the most common result of this deficiency.

Note: The dwarfism caused by deficient GH secretion is proportional (i.e., the limbs and trunk are of normal relative proportions), as opposed to the comparatively shorter limbs characteristic of dwarfism caused by achondroplasia. Of note, achondroplasia is caused by mutations of the fibroblast growth factor receptor gene 3 (FGFR3), which inhibit bone growth.

1 What are the general causes of the hormonal abnormality most likely present in this woman?

This woman has hypercortisolism (Cushing syndrome), as indicated by her symptoms (muscle weakness, amenorrhea, deepening voice), classic examination findings (central obesity, abdominal striae, dorsocervical fat pad or “buffalo hump,” acanthosis nigricans), and laboratory findings (hyperglycemia, elevated random cortisol).

Perhaps the most common cause of Cushing syndrome is the iatrogenic prescription of glucocorticoids for inflammatory conditions. Other causes include a cortisol-hypersecreting adrenal adenoma (common) or carcinoma (rare), ACTH-secreting pituitary adenoma (Cushing disease), and ectopic (paraneoplastic) secretion (think small cell carcinoma of the lung for boards).

The hirsutism and deepening voice in this patient are suggestive of an ACTH-dependent cause of Cushing syndrome, in which shunting of glucocorticoid precursors into the androgenic pathway occurs, but further workup is clearly needed.

2 What is the cause of the hypercortisolism in this patient?

Cushing disease is due to the elevated cortisol and ACTH. One would expect suppressed ACTH levels if the adrenal glands were hypersecreting cortisol. Paraneoplastic ACTH secretion (e.g., small cell carcinoma) is suggested by the increased ACTH level, but ectopic ACTH secretion occurs independently of the HPA (hypothalamic-pituitary-adrenal) axis and does not normally suppress in response to glucocorticoids such as dexamethasone. In contrast, pituitary adenomas, which are well differentiated, typically retain some feedback responsiveness to glucocorticoids; thus, ACTH secretion may not suppress with low-dose dexamethasone but typically will with high-dose dexamethasone (Table 8-6).

Table 8-6 Features of Cushing Syndrome

3 Why are the results of a dexamethasone suppression test read at a specific time of day?

Cortisol secretion has a wide circadian rhythm, with plasma levels varying several-fold throughout a 24-hour period (normal range 5-20 μg/dL) and peaking in the morning hours. The morning upsurge is necessarily preceded by an upsurge in ACTH, so ACTH levels should also be measured at a specific time (usually 5 AM).

4 Why has hirsutism developed in this woman?

Hirsutism is the presence of excess facial and body hair in women, especially in a male pattern, and typically reflects elevated androgens. Elevated androgens in this woman are due to increased levels of ACTH, which in addition to stimulating cortisol synthesis by the adrenals also promotes “shunting” of the glucocorticoid precursors to the androgen pathway,.

5 Why isn’t hyperaldosteronism typically seen in Cushing disease?

Although aldosterone is secreted by the adrenal cortex, its synthesis and secretion are influenced only minimally by ACTH levels. Rather, the principal regulators of aldosterone secretion are angiotensin II and serum potassium.

6 What morphologic feature of the adrenal glands would you expect to see in this woman?

Bilateral adrenal hyperplasia (with widening of the zona fasciculata and reticularis, specifically) is typically seen because ACTH is trophic for the adrenal glands. This feature is also present in ectopic production of ACTH.

7 How is hypercortisolism contributing to hyperglycemia in this patient?

Cortisol promotes hyperglycemia by stimulating hepatic gluconeogenesis and inhibiting the peripheral utilization of glucose (similar to GH). The increase in gluconeogenesis is due to stimulation of the synthesis of gluconeogenic enzymes by cortisol and also to greater mobilization of amino acids from skeletal muscle to participate in gluconeogenesis (hence the muscle wasting) (Fig. 8-10).

Figure 8-10 Metabolic actions of cortisol.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007.)

8 How is hypercortisolism contributing to hypertension and hypokalemia in this patient?

At higher plasma levels, cortisol exerts mineralocorticoid effects similar to those of aldosterone. This causes sodium retention and an ensuing plasma volume expansion that contributes to hypertension. The sodium is retained in exchange for secreting more potassium, which explains this patient’s hypokalemia. Another contributing factor to this patient’s hypertension is that cortisol stimulates the expression of adrenergic receptors in vascular smooth muscle.

9 Why doesn’t cortisol have mineralocorticoid actions in the normal physiologic setting?

Cortisol can bind mineralocorticoid receptors with an affinity similar to that of aldosterone, but cells in mineralocorticoid-sensitive tissues (kidneys, colon, salivary glands) produce 11β-hydroxysteroid dehydrogenase (11β-HSD), which breaks down cortisol into cortisone. Cortisone cannot bind to the aldosterone receptor. When the plasma cortisol is significantly elevated, 11β-HSD becomes saturated, thereby allowing intracellular cortisol to exert its mineralocorticoid effects in these tissues. This explains the plasma volume expansion and hypertension discussed previously.

Note: Licorice candy (if it contains licorice root from the licorice plant) also increases plasma cortisol levels by decreasing the activity of 11β-HSD, thereby potentially causing hypertension.

10 What would an x-ray study of her bones likely reveal?

An x-ray study of her bones would likely show a loss of bone density due to osteoporosis. Cortisol inhibits osteoblasts and stimulates osteoclasts, a double whammy. As a result, this promotes bone resorption, leading to osteoporosis. Osteoporosis is an especially significant side effect in patients taking steroids chronically.

11 What are the three layers of the adrenal cortex, and which one is responsible for the excess production of cortisol in this patient?

Just think of glomerular filtration rate (GFR) for the three layers—zona glomerulosa, fasciculata, and reticularis—which secrete mineralocorticoids (e.g., aldosterone), glucocorticoids (e.g., cortisol), and androgens (e.g., dehydroepiandrosterone [DHEA]), respectively (Fig. 8-11).

Figure 8-11 Main determinants of hypothalamic-pituitary-adrenal axis. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007.)

12 One treatment for Cushing disease is to remove both adrenal glands (bilateral adrenalectomy). What might happen to the pituitary gland following such a surgery?

The removal of both adrenal glands will stop the production of cortisol. Lacking the negative feedback of cortisol, the pituitary will synthesize ACTH and melanocyte-stimulating hormone (MSH) unchecked, leading to enlargement of the preexisting pituitary adenoma with resulting headache and diffuse hyperpigmentation. This is known as Nelson’s syndrome.

Note: MSH production is elevated when ACTH production is increased because both are produced from the same precursor polypeptide (pro-opiomelanocortin [POMC]).

Summary Box: Hypercortisolism

Hypercortisolism regardless of cause is termed Cushing syndrome. The most common cause of Cushing syndrome is the iatrogenic administration of steroids.

Hypercortisolism from a hypersecreting pituitary adenoma is termed Cushing disease.

Classic signs and symptoms of Cushing syndrome include:

Central obesity: Cortisol stimulates protein breakdown in the extremities, but the hyperinsulinemia from the cortisol-induced hyperglycemia promotes fat deposition.

Purple abdominal striae are the result of weight gain and capillary fragility or rupture from the effects of hypercortisolism.

Hypertension is due to mineralocorticoid actions of cortisol at the kidney.

Hirsutism is due to adrenocorticotropic hormone (ACTH)–induced shunting of glucocorticoid precursors to the androgenic pathway.

Osteoporosis is due to cortisol-induced bone breakdown.

Bilateral adrenalectomy for Cushing disease (rarely done!) can cause Nelson’s syndrome, which is characterized by diffuse hyperpigmentation as a result of increased melanocyte-stimulating hormone (MSH) production.

1 What do you suspect at this point?

Vague symptoms (fatigue, weakness), hypotension, and the metabolic disturbances in this case are all concerning for adrenal insufficiency.

Recall that aldosterone (and cortisol at high levels) stimulates sodium retention and potassium excretion from the kidneys. Recall also that cortisol and epinephrine antagonize the actions of insulin. Given these physiologic functions, one can see how a lack of mineralocorticoid, glucocorticoid, and catecholamines can result in hypotension, hyponatremia (see following note), and hyperkalemia.

There are many causes of adrenal insufficiency but the hyperpigmentation observed in this patient suggests elevated ACTH levels (recall that MSH is a byproduct of ACTH synthesis). We can deduce from this that the “problem” exists at the level of the adrenals (low cortisol levels decrease negative feedback on the pituitary, leading to elevated ACTH levels).

2 What are some general causes of primary adrenal insufficiency (Addison’s disease)?

Autoimmune destruction is perhaps the most common cause of Addison’s disease. Tubercular invasion of the adrenals in miliary (disseminated) tuberculosis is a common cause of Addison’s disease in developing countries. Metastatic invasion of the adrenals, which occurs frequently with lung cancer, is another cause. Other rarer causes include disseminated fungal infections (e.g., histoplasmosis) and drugs such as ketoconazole and metyrapone, which selectively inhibit the steroidogenesis pathway.

3 What was the cause of adrenal insufficiency in this patient?

All we can say with the given information is that this young man has primary adrenal insufficiency due to the elevated ACTH and lack of response to cosyntropin. Because there are no clues to suggest malignancy or infection, and we are not told that he is taking any medications, the likely cause is autoimmune destruction of the adrenals.