Cushing Syndrome Case File

Cushing Syndrome Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 50

A 32-year-old woman presents to her obstetrician/gynecologist with complaints of irregular periods, hirsutism, and mood swings. She also reports weight gain and easy bruising. On examination, she is found to have truncal obesity, a round “moon” face, hypertension, ecchymoses, and abdominal striae. The patient is given a dexamethasone suppression test which reveals an elevated level of cortisol.

◆ What is the likely diagnosis?

◆ What would an elevated adrenocorticotropic hormone (ACTH) level indicate?

ANSWERS TO CASE 50: CUSHING SYNDROME

Summary: A 32-year-old female with irregular menses, hirsutism, mood swings, weight gain, truncal obesity, hypertension, abdominal striae, ecchymoses, and elevated cortisol levels.

◆ Diagnosis: Cushing Syndrome

◆ Elevated ACTH level: Likely cause of adrenal hyperplasia from. ACTH-producing tumor

CLINICAL CORRELATION

This patient presents with many of the classic findings of Cushing syndrome. Adrenal hyperplasia can be caused by excessive stimulation from ACTH (pituitary or ectopic production) or from a primary adrenal problem such as adenomas/ carcinomas. In addition to above symptoms, patients with Cushing syndrome are also at risk for osteoporosis and diabetes mellitus (DM). The diagnosis is confirmed with elevated cortisol levels after a dexamethasone suppression test. Treatment depends on the underlying etiology and is often surgical.

Definitions

Abdominal striae: Stretch marks of the abdominal region.

ACTH (adrenocorticotropic hormone or corticotropin): Hormone produced in the anterior pituitary, which stimulates adrenal production of cortisol.

Adenoma: Any benign tumor of glandular origin; typically found in the adrenal, pituitary, and thyroid glands (note: once an adenoma has progressed to malignancy, it is referred to as an adenocarcinoma).

CRH (corticotropin-releasing hormone): Hormone produced in the hypothalamus, which stimulates release of ACTH from the anterior pituitary.

Cushing disease: A specific form of Cushing syndrome, which is caused by an ACTH-secreting pituitary adenoma; represents approximately 66 percent of all cases of Cushing syndrome. Because of structural similarities with melanocyte-stimulating hormone (MSH), excess ACTH from pituitary adenomas can induce dermal hyperpigmentation.

Dexamethasone suppression test: An overnight test used to screen patients for Cushing syndrome by administering dexamethasone to a patient. Positive results for this test are indicated by a patient’s inability to reduce cortisol levels after dexamethasone treatment—usually because the patient’s feedback loop mechanism is ineffective at inhibiting cortisol release.

Ecchymosis: Bruise or contusion; normally comes from damage to the capillaries at the site of injury, allowing blood to seep out into the surrounding tissue, presenting initially as a blue or purple color.

Ectopic ACTH syndrome: Form of Cushing syndrome in which benign or malignant tumors arise in places other than the pituitary, leading to excessive release of ACTH and subsequently, cortisol into the bloodstream; represents approximately 10 to 15 percent of Cushing syndrome cases.

Hirsutism: Increased presence of hair in women on body regions where hair does not normally grow.

Hypercortisolism: A condition in which the body is exposed to an excess of cortisol for an extended period of time.

Iatrogenic Cushing syndrome: Condition in which all symptoms of Cushing syndrome are brought on by administration of synthetic forms of cortisol, such as prednisone and dexamethasone. “Iatrogenic” originates from Greek and literally translates to mean “born from” the “healer.”

Pseudo-Cushing syndrome: Condition in which alcohol induces symptoms of Cushing syndrome without the tumor that leads to increased cortisol levels.

DISCUSSION

Cortisol is a stress hormone released in response to trauma—physical and emotional—that leads to several physiologic changes aimed at reducing the stress associated with this trauma. This process is helpful to the body because the activity of cortisol can limit the harmful effects of stress. However, if too much cortisol is secreted (hypercortisolism) symptoms of Cushing syndrome may appear.

Cortisol is secreted from the adrenal glands of the kidneys (“adrenal” literally means near or at the kidney). All steroid hormones are synthesized from cholesterol, with the rate-limiting step in steroid biosynthesis being the cleavage of the cholesterol side chain. This is done by several enzymes that make up the cytochrome P450 side-chain cleavage complex. High levels of Ca²⁺ and protein phosphorylation—due to increased cAMP in the cytosol—increase the rate of cholesterol side-chain cleavage in the mitochondria. First, cholesterol is mobilized into the mitochondria of the adrenal cortex cells, where its side chain is cleaved by the cytochrome P450 cleavage complex (CYP11A1) to yield pregnenolone (Figure 50-1). Pregnenolone is oxidized by 3β- hydroxysteroid dehydrogenase to form progesterone, which is then converted

Figure 50-1. Biosynthesis of cortisol. Cholesterol is the starting material for all steroid synthesis. Cortisol synthesis involves a series of oxidation reactions catalyzed by cytochrome P450 enzymes (1) The cleavage of cholesterol’s sixcarbon side chain is catalyzed by CYP11A1—the rate-limiting step in steroid synthesis. (2) This is followed by dehydrogenation of the hydroxyl group in pregnenolone, which is catalyzed by 3β-hydroxysteroid dehydrogenase. (3) This molecule is then oxygenated at carbons 17, 21, and 11 by CYP17, CYP21A2, and CYP11B1, respectively, to yield cortisol. All structure modifications are indicated by dashed lines.

into cortisol by the action of three cytochrome P450 enzymes, CYP17, CYP21A2, and CYP11B1. After synthesis is complete, cortisol is released from the zona fasciculata in the adrenal cortex via free diffusion into the blood stream for distribution to its target organs, such as liver and kidney.

The adrenal gland produces cortisol in response to intermediate hormones, called adrenocorticotropin hormone (ACTH) and corticotropin-releasing hormone (CRH) via the humoral stress pathway, which extends from the brain to the adrenals (Figure 50-2). Once the body has received an environmental stress signal, it is detected by neurons in the cerebral cortex and transmitted to the hypothalamus. The hypothalamus then releases CRH via the classic secretory pathway into the anterior pituitary. CRH stimulates release of

Figure 50-2. Induction of the humoral stress pathway. Once an environmental stress is detected by the CNS, this signals the hypothalamus to release CRH into the anterior pituitary. ACTH is then released from the pituitary into the blood and eventually binds membrane receptors in cells of the adrenal cortex. Cortisol is synthesized and leaves the cell via free diffusion into the blood and is eventually distributed to the hypothalamus and pituitary to inhibit release of CRH and ACTH, respectively, through a negative feedback loop.

ACTH, which then moves into the blood and down to the adrenal glands. Once in the zona fasciculata of the adrenal cortex, ACTH binds membrane receptors stimulating transfer of cholesterol to the mitochondria for cleavage events leading to synthesis and release of cortisol. After diffusing out of the cell into the blood stream, cortisol binds corticosteroid-binding globulin (CBG), also known as transcortin. Cortisol then moves to receptors back in the pituitary to signal reduction of ACTH and CRH production, thus regulating cortisol synthesis by a negative feedback mechanism.

As the major stress hormone, cortisol has many functions. For example, in trabecular bone, cortisol inhibits synthesis of new bone by osteoblasts and decreases absorption of Ca²⁺ in the GI tract, leading to osteopenia. However, the two principal influences of cortisol are on metabolism and the immune system.

Metabolism: Cortisol is catabolic and carries out lipolysis and muscle tissue degradation. Muscle catabolism provides a source of amino acids used by the liver to fuel gluconeogenesis and increases blood glucose levels. Proteolysis of collagen can lead to skin fragility, easy bruising, and striae. Lipolysis, or lipid degradation, generates free fatty acids in the blood, which when degraded by β-oxidation in the liver provide an alternative energy source, decreasing the demand for glucose. Increased lipolysis in Cushing syndrome is also thought to cause the redirection of fat deposition away from the limbs toward the trunk, leading to symptoms, such as “buffalo hump” and “moon face.” In addition to increasing blood glucose levels, too much cortisol can inhibit insulin activity and exacerbate diabetic complications. Cortisol and cAMP induce two enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), both of which lead to increased glucose levels. The effect of cortisol is to induce PEPCK and G6Pase gene expression through a glucocorticoid response element (GRE) upstream of each gene. PEPCK and G6Pase both increase the rate of gluconeogenesis and antagonize insulin response activity, leading to increased blood glucose.

Immune System: Cortisol also has immunosuppressive effects and can reduce inflammation. For example, other synthetic forms of cortisol, such as hydrocortisone, are used medicinally to reduce inflammation. Cortisol’s immunosuppressive effects are partly a result of its ability to sequester lymphocytes in the spleen, thymus, and bone marrow. Most other immunosuppressive effects come from cortisol’s ability to modulate gene transcription. Cortisol diffuses into the cell and binds glucocorticoid receptors, which disaggregate into single, or monomer, proteins. Now that the activated receptor, or transcription factor, has a free DNA binding domain it will translocate to the nucleus to alter gene expression. This activity induces transcription of several immunosuppressive genes that inhibit expression of target genes, such as IL-2.

Cushing syndrome is a rare condition in which elevated levels of cortisol are present in the patient for an extended period of time (hypercortisolism). Typically, it affects those between the ages of 20 and 50 years. On rare occasions, this disease may result from an inherited condition, which leads to growth of adenomas in endocrine glands, such as the adrenal, parathyroid, pancreas or pituitary glands.

Benign tumors in the pituitary or adrenal glands can lead to excess release of ACTH or cortisol into the blood, causing the symptoms of Cushing syndrome. Typically, excess levels of endogenous cortisol—not synthetic forms of cortisol—can cause hypertension, most likely because of its weak binding capacity with mineralocorticoid receptors (i.e., aldosterone receptors).

Typically, hypercortisolism comes from: (1) A pituitary adenoma, which secretes excess ACTH, thus causing release of cortisol from the adrenals; (2) an adrenal adenoma, which secretes excess cortisol; (3) a lung tumor, which secretes excess ACTH; or (4) administration of synthetic forms of cortisol (i.e., dexamethasone, prednisone, etc.) due to previously diagnosed diseases, such as rheumatoid arthritis. In the case of a pituitary adenoma, the location of the adenoma makes the pituitary gland insensitive to the negative feedback mechanism brought on by excess cortisol in the blood. Sixty-six percent of all cases of Cushing syndrome are derived from pituitary adenomas. When hypercortisolism is due to exogenous administration of steroids it is referred to as iatrogenic Cushing syndrome.

Also, because cortisol is a stress hormone, people who suffer a great deal of stress, such as athletes, alcoholics, and pregnant women may have high blood cortisol levels and exhibit symptoms of Cushing syndrome (also known as pseudo-Cushing syndrome).

Treatment of Cushing syndrome is intended to return cortisol levels back to normal and usually occurs through surgery. In some cases medications, such as mitotane, which lower blood and urine cortisol levels, can be used alone or in combination with radiation therapy.

COMPREHENSION QUESTIONS

A 45-year-old female patient presents with hirsutism, striae, bruising, acne, and hyperpigmentation of the skin. After a thorough physical examination the physician notes that she also suffers from hypertension and shows signs of a “buffalo hump” on her back between the shoulders. Cushing syndrome is suspected and after laboratory tests show elevated blood cortisol levels she is given a dexamethasone suppression test. Her results are positive.

[50.1] Following administration of dexamethasone, this patient exhibits elevated cortisol levels (a positive result) because of which of the following?

A. The humoral stress pathway can no longer regulate cortisol levels via a negative feedback loop.

B. There is a deficiency in the enzyme that breaks down dexamethasone, leading to excess amounts of glucocorticoid in the blood

C. The anterior pituitary is nonresponsive to excess cortisol and is aberrantly producing excess CRH

D. A CRH-secreting tumor of the adrenal glands is stimulating cortisol synthesis and is no longer responding to the negative feedback loop

[50.2] The hirsutism observed in the patient above is best explained by which of the following?

A. ACTH stimulating synthesis of adrenal androgens

B. CRH stimulating synthesis of adrenal androgens

C. Cortisol activating aldosterone receptors

D. Cortisol stimulating expression of adrenal androgen biosynthetic enzymes

[50.3] The characteristic accumulation of adipose tissue in the facial, truncal, and cervical regions of the body in patients with Cushing syndrome is best explained by which of the following?

A. Excess adrenal androgens due to adrenal tumor

B. Excess cortisol over long periods of time

C. Cross stimulation of mineralocorticoid receptors by cortisol

D. Increased production of MSH

E. Increased proteolysis

[50.4] The most common cause of hypercortisolism is which of the following?

A. Adrenal tumor that secretes excess cortisol and mineralocorticoid hormones.

B. Lung tumor that secretes excess ACTH that leads to excess cortisol in the blood.

C. Administration of synthetic cortisol by physician

D. Pituitary adenoma that secretes excess ACTH, leading to excess cortisol in the blood.

Answers

[50.1] A. The body’s humoral stress pathway can no longer regulate cortisol levels via a negative feedback loop. By administering a synthetic form of cortisol (dexamethasone), the physician is testing the body’s natural ability to reduce cortisol production. However, a patient with Cushing syndrome produces excess cortisol from one of several major sources, such as an ACTH-secreting pituitary adenoma, an ACTH-secreting lung tumor, or a cortisol-secreting adrenal tumor. Either one of these sources will be unaffected by the dexamethasone suppression test, thus exhibiting no change in blood cortisol levels. If the stress humoral pathway is intact, the test will show a drop in cortisol levels.

[50.2] A. Androgenic phenotypes are commonly seen in Cushing syndrome because ACTH, frequently in excess, stimulates synthesis of adrenal androgens in addition to cortisol.

[50.3] B. While the exact mechanism is not known, excess cortisol over long periods of time mobilizes lipids and redirects fat deposition away from the peripheral regions to the truncal region creating a “buffalo hump” appearance between the shoulders and a “moon face.”

[50.4] D. While all of the choices can lead to hypercortisolism, about twothirds of all cases are due to a pituitary adenoma that secretes excess ACTH, leading to excess cortisol in the blood.

References

Boron WF, Boulpaep EL. Medical Physiology: A Cellular and Molecular Approach. Philadelphia, PA: Elsevier Science, 2003; 1319. 

Lin B, Morris DW, Chou JY. Hepatocyte nuclear factor 1alpha is an accessory factor required for activation of glucose-6-phosphatase gene transcription by glucocorticoids. DNA Cell Biol 1998;17:967–4. 

Mahmoud-Ahmed AS, Suh JH. Radiation therapy for Cushing’s disease: a review. Pituitary 2002;5:175–80. 

Muller OA, von Werder K. Ectopic production of ACTH and corticotropin-releasing hormone (CRH). J Steroid Biochem Mol Biol 1992;43:403–8. 

Petersen DD, Magnuson MA, Granner DK. Location and characterization of two widely separated glucocorticoid response elements in the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 1988;8:96–104. 

Phillips PJ, Weightman W. Skin and Cushing syndrome. Aust Fam Physician 2007;36:545–7.

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