Endocrine dysfunction has not been prominent in HIV infection. Nonetheless, all glands of the endocrine system may be infiltrated with opportunistic infections or malignancies or may be affected by drugs used to treat HIV-related disorders. More recently, hyperlipidemia and lipodystrophy have been associated with the use of highly active antiretroviral therapy, especially with certain protease inhibitors. The specific etiology of these disorder remains unclear. The subtle presentations of endocrine diseases create difficult diagnostic challenges.

Adrenal Gland Dysfunction
The adrenal gland is the endocrine gland most commonly affected in AIDS patients examined at autopsy, although clinical evidence of adrenal insufficiency is observed in <8% of AIDS patients. Widespread lipid depletion and varying degrees of adrenal necrosis are the most prevalent pathologic findings in postmortem examinations. Adrenal invasion by CMV is noted in up to 50% of patients with adrenal pathology. Mycobacterium avium complex, Kaposi’s sarcoma, C. neoformans, and Histoplasma capsulatum involve the adrenal glands in 5 to 12% of cases. Drug therapy, with agents such as ketoconazole (adrenal dysfunction) or rifampin (increased clearance of cortisol) may also result in adrenal insufficiency. Fatigue, anorexia, nausea, vomiting, orthostatic hypotension, and hyponatremia are symptoms frequently noted in many HIV-infected patients; however, only a few with these symptoms are actually adrenal insufficient when evaluated using standard laboratory criteria.

Basal 8 _A.M. plasma cortisol levels are usually higher in patients with advanced HIV disease than in asymptomatic patients and uninfected healthy controls. However, other ACTH-dependent steroids, such as desoxycorticosterone (DOC), compound B, and 18-hydroxy-DOC, are not elevated and show a blunted response to corticotropin (ACTH) stimulation, implying subnormal adrenal reserves. Patients who fail to achieve plasma cortisol levels >20 mug per deciliter 60 minutes after ACTH stimulation should be considered to have, or be at high risk of developing, adrenal insufficiency. Plasma ACTH levels are frequently normal or subnormal even when plasma cortisol levels are depressed, suggesting that adrenal insufficiency in some HIV-infected patients is due to a primary pituitary or CNS disorder. Treatment of adrenal insufficiency in HIV-infected patients is the same as in other individuals with abnormal adrenal function.

Hypogonadism
The most common abnormality of endocrine function noted clinically is hypogonadism. Decreased libido occurs in over one half of male patients with AIDS, and impotence, usually associated with low serum testosterone levels, is reported in up to 30% of AIDS patients. Serum gonadotropin levels may be below normal or inappropriately within normal limits in hypogonadal men with AIDS. When pituitary responsiveness to gonadotropin-releasing hormone is assessed in these hypogonadotropic males, normal release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) has been observed, suggesting a hypothalamic basis for the central hypogonadotropism.

Other studies have demonstrated appropriately elevated levels of LH and FSH in hypogonadal men, implying primary testicular dysfunction. Drugs, such as ketoconazole, ganciclovir, and acyclovir have been associated with low testosterone levels or decreased spermatogenesis. Chronic use of megesterol acetate is invariably associated with suppression of testosterone levels in men. Studies of gonadal function in women are limited, although menstrual irregularities are common in women with advanced HIV disease.

Thyroid Disease
Thyroid function remains remarkably normal throughout the course of HIV disease. Low levels of thyroxine (T₄ ), triiodothyronine (T₃ ), and free-thyroxine index (FTI) in the setting of low concentrations of thyrotropin (TSH), the so-called euthyroid sick syndrome, is remarkably uncommon among ambulatory HIV-infected patients. Decreased levels of T₃ resin uptake and elevated levels of T₄ -binding globulin are frequently noted in ambulatory patients with advanced disease; however, concentration of T₃ and T₄ are most often within normal limits. Invasive disease due to CMV, P. carinii, C. neoformans, Kaposi’s sarcoma, and lymphoma have all been described in the thyroid. Remarkably, even patients with infiltrating opportunistic diseases of the thyroid gland usually remain euthyroid throughout the course of their disease. Nonetheless, despite the relative infrequency of clinical disease, hypothyroidism represents a potentially reversible cause of fatigue, malaise, altered mental status, and “failure to thrive” in HIV-Infected individuals and should be routinely evaluated.

Less common causes of hypothyroidism in HIV-infected patients include adverse effects of medications. Ketoconazole has been associated with primary hypothyroidism on rare occasions. In addition, drugs that are strong inducers of hepatic microsomal enzymes, such as rifampin, may lead to increased clearance of T₄.

Metabolic Abnormalities
Hyponatremia is the most common electrolyte disturbance noted in HIV-infected individuals (see discussion in renal section). Disorders of carbohydrate metabolism have been reported in association with direct pancreatic invasion by opportunistic processes and with drug therapy. Pancreatic lesions caused by CMV, toxoplasmosis, Kaposi’s sarcoma, and lymphoma are noted in up to 35% of cases at autopsy. Yet the development of type I diabetes mellitus has been reported in only a few instances.

Hypoglycemia is the most common alteration in glucose metabolism. Direct toxic effects of drugs may induce premature release of insulin by beta cells, resulting in hypoglycemic episodes that may be severe and prolonged. Pentamidine isothionate is the most common cause of hypoglycemia, occurring in 4 to 33% of treated patients. Renal insufficiency is a predisposing factor in the development of pentamidine-induced hypoglycemia. Although most hypoglycemic episodes result from parenteral administration of pentamidine, several cases have been reported in patients receiving aerosolized drug.

Disorders of calcium metabolism are relatively uncommon but do occur. Hypercalcemia is associated with HIV-related leukemia and lymphoma. Hypocalcemia usually is the result of drug therapy with agents, such as amphotericin B and foscarnet, which induce magnesium wasting and decrease levels of ionized calcium, respectively. CMV has been observed in parathyroid tissue, however, CMV-induced hypoparathyroidism is extremely rare.

Hyperlipidemia is noted commonly in HIV-infected patients. Isolated elevation of triglycerides is reported in up to 50% of patients with either asymptomatic HIV disease or AIDS. Although hypertriglyceridemia is routinely noted among patients with HIV wasting syndrome, no relationship has been noted between the serum triglyceride level and the degree of wasting. Elevation of cachectin (tumor necrosis factor), inhibition of lipoprotein lipase, and decreased clearance of circulating lipoproteins have all been proposed as potential mechanisms of hypertriglyceridemia, but no clear association of any of these factors has been established.

In the era of highly active antiretroviral therapy (HAART), patients receiving protease inhibitor therapy have been noted to have elevated plasma triglyceride and cholesterol levels. Initial reports identified ritonavir as the most likely cause of these metabolic abnormalities, but more recently, indinavir, nelfinavir, and saquinavir have also been implicated. Sporadic reports of nonprotease inhibitor-containing regimens causing this syndrome have also appeared. In addition to hyperlipidemia, glucose intolerance and frank diabetes mellitus have been associated with HAART regimens. Insulin resistance appears to play a role in the development of this entry, but the precise mechanism remains unclear. To complete the syndrome, abnormalities in body fat distribution have been observed in some individuals on HAART regimens.

Loss of peripheral body fat in the extremities and excess accumulation of fat in the abdominal region (so-called “protease paunch”) and breasts have been reported, to some degree, in up to 80% of patient on HAART; severe manifestations are observed in 10% of patients. Dorsocervical fat pad enlargement (buffalo hump) among HAART recipients has been reported in 55 patients in the published literature. These patients have normal cortisol levels and varying degrees of hypertriglyceridemia or lipodystrophy. No specific therapeutic approaches for this syndrome have been elucidated. In severe cases, the HAART regimen must be modified.