Disturbances of adrenal, thyroid, growth hormone, and gonadal function are commonly seen in HIV disease and may contribute to the loss of muscle and lean body mass in advanced HIV disease. Increasingly, anabolic hormonal therapies are being considered to reverse the loss of lean body mass in both men and women. In this article, we will review the most common endocrine manifestations of HIV disease and discuss potential endocrine mechanisms and therapeutic strategies for the AIDS wasting syndrome.
Gonadal function and androgen levels
Gonadal dysfunction is common in both men and women with HIV disease, particularly in the advanced stages and among patients with significant weight loss. In a study by Dobs et al,(1) 6 percent, 44 percent, and 50 percent of men with asymptomatic disease, AIDS-related complex, and AIDS, respectively, exhibited decreased total testosterone levels. However, sex-hormone binding globulin levels are increased in 35 to 50 percent of men with AIDS,(1,2) suggesting that total testosterone levels may less accurately reflect the bioavailable androgen levels in this population. In a recent study of 75 men with AIDS wasting screened for gonadal dysfunction, the serum free testosterone level was below the age-adjusted reference range in 49 percent of patients, demonstrating the utility of the free testosterone level as a marker of gonadal dysfunction in this population (Figure 1).(2)
The mechanisms of gonadal dysfunction in men with HIV disease may relate to an effect of severe acute illness on gonadotropin production, anatomic destruction of testicular tissue, and/or medication effects. In our own studies, 65 percent of HIV-infected men with hypogonadism exhibit gonadotropin levels that are either low or inappropriately normal for the degree of hypogonadism.(2) Weight loss and caloric deprivation may also contribute to hypogonadotropic hypogonadism among subjects with the wasting syndrome. Hypothalamic and/or pituitary destruction causing panhypopituitarism and gonadal failure have been reported in a small number of patients, but is too infrequent to account for the more generalized disturbance in gonadal function seen in HIV-infected patients. Finally, megestrol acetate can result in decreased gonadotropin production and gonadal failure because of its glucocorticoid-like properties.
With regard to the potential causes of primary hypogonadism in AIDS, testicular destruction due to opportunistic infections or lymphoma are seen in HIV-infected men. In approximately one quarter of all HIV-infected men with systemic infections or secondary neoplasms, the infection or neoplasm was also found in testicular tissue on autopsy. Cytomegalovirus is the most commonly seen pathogen, but toxoplasmosis and Kaposi's sarcoma have also been reported.(3) However, these mechanisms are unlikely to explain the relatively high percentage of primary gonadal failure in asymptomatic men with a normal testicular examination and without a predisposing history of primary hypogonadism.
The clinical implications of gonadal failure in men with HIV disease relate primarily to loss of muscle mass, fatigue, and decreased quality of life. In non-HIV-infected men with acquired hypogonadism, lean body mass is lost and fat mass increased.(4) Similarly, advanced HIV disease is often accompanied by a wasting syndrome characterized by weight loss and a disproportionate decrease in lean body mass with relative fat sparing. This pattern is even more pronounced among hypogonadal men with AIDS wasting syndrome, in whom loss of muscle mass often greatly exceeds weight loss. For example, in a recent study, Grinspoon et al(2) found a 10 percent weight loss but 23 percent loss of expected muscle mass among a cohort of hypogonadal men with wasting syndrome. Furthermore, serum androgen levels are highly correlated with lean body mass and exercise functional capacity among hypogonadal men with AIDS wasting syndrome (Figure 2).(2) These data suggest a clinically relevant association between the loss of lean body mass, reduced exercise functional capacity, and serum androgen levels in hypogonadal men with AIDS wasting syndrome.
Recent studies also suggest a relatively high prevalence of amenorrhea and gonadal dysfunction among HIV-infected women. Although earlier studies found no increased prevalence of menstrual dysfunction and no correlation of menstrual function with disease indices such as CD4+ counts,(5,6) two recent studies suggest that 20 to 25 percent of women with HIV infection are amenorrheic.(7,8) Of note, the prevalence of amenorrhea is further increased to 38 percent among HIV-infected women with more significant weight loss (<90 percent of ideal body weight).(7) Interestingly, decreased muscle mass is also associated with amenorrhea, but the cause of muscle loss in this subpopulation is unknown.
One potential mechanism of decreased muscle mass in HIV-infected women is androgen deficiency. In a recent study, significant androgen deficiency was noted in HIV-infected women compared with healthy female controls. In 66 percent of women with AIDS wasting, free testosterone levels were decreased below the normal range for healthy women. In addition, low serum testosterone and dehydro-epiandrosterone sulfate levels correlated with the loss of muscle mass in this population (Figure 3).(7) Although the mechanisms of androgen deficiency remain unknown in this population, the use of gonadal steroids to reverse wasting syndrome in women with AIDS is now being studied.
Increased resting energy expenditure is a hallmark of HIV-infected patients and may contribute to wasting syndrome in this population.(9) Although the exact mechanisms responsible for increased resting energy expenditure in HIV-infected patients are not known, it is thought that increased energy expenditure in association with decreased food intake during episodes of acute illness may, in part, be responsible for the severe weight loss often associated with advanced disease. Grunfeld et al(10) demonstrated increased resting energy expenditure (+18 percent) among men with AIDS and secondary infection compared with HIV-positive subjects free of secondary infection (Figure 4). Furthermore, among patients with active secondary infection, caloric intake was only 83 percent of resting energy expenditure (Figure 5).(10) Macallan et al(11) recently demonstrated among HIV-infected men that food intake decreases during secondary infection out of proportion to any change in energy expenditure, suggesting a further mechanism to explain the imbalance in energy expenditure in this population. In a study of ambulatory HIV-positive women, resting energy expenditure measured by indirect calorimetry was also increased to 118 percent of that predicted by the Harris-Benedict equation.(7) These data suggest that altered energy metabolism occurs in both men and women with HIV infection and may contribute to wasting syndrome in such patients.
Growth hormone-insulin-like growth factor I axis
Preliminary data suggest multiple abnormalities in the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis among patients with AIDS, the most common of which is a pattern of acquired GH resistance. IGF-I levels are low in patients with AIDS and correlate with serum albumin levels. These data are consistent with acquired GH resistance, resulting in decreased hepatic production of IGF-I. The most likely cause of acquired GH resistance is protein calorie malnutrition. In a recent cross-sectional study of men with AIDS, mean overnight GH levels derived from sampling every 20 minutes were elevated and IGF-I levels decreased compared with age-matched healthy controls (Figure 6).(2) Growth hormone levels were inversely correlated with caloric intake and percent fat mass by dual energy x-ray absorptiometry, again suggesting a link with overall nutritional status. In contrast, less GH resistance was observed in HIV-positive women.(7) Potential mechanisms to explain this observation in women may relate to differences in the sex-steroid milieu and estrogen levels between men and women.
The clinical implications of GH resistance relate to the observation that lean body mass declines disproportionately to weight and correlates with survival in patients with AIDS. In non-HIV infected patients, GH deficiency is associated with decreased lean body mass.(12) In addition, a recent study by Schambelan et al(13) examined the clinical efficacy of recombinant human growth hormone in this population. Growth hormone administration increased lean body mass and improved exercise functional capacity over a short term (three months) at pharmacologic doses, but was associated with side effects including arthralgias and fluid retention in a significant number of patients.(13) Further studies are needed to define the role of this potent therapy with respect to AIDS wasting syndrome.
Other anabolic agents
Other anabolic therapies in the treatment of AIDS wasting syndrome include nandrolone decanoate, an oral 17-alkylated anabolic steroid that has been used to treat postmenopausal osteoporosis and cancer cachexia. HIV-positive patients receiving nandrolone decanoate in a recent 16-week open label study demonstrated an average weight gain of 2.3 kg.(14) However, total body water as well as lean body mass were increased. Further randomized studies are needed to judge the efficacy of nandrolone in this population.
Oxandrolone is another anabolic agent considered for the treatment of HIV-related sarcopenia. In a 16-week double-blind, placebo-controlled study of oxandrolone, a modest weight gain of 1.8 kg was seen in the treatment group who received 15 mg/d.(15) However, no data concerning body composition were collected.
At the current time, the use of oral anabolic steroids in men with AIDS wasting syndrome can not be fully endorsed because of potential safety considerations, including liver toxicity. Studies are now underway to assess the efficacy of oral anabolic agents, natural testosterone derivatives, and growth hormone in this population.
The adrenal axis is often affected in HIV disease due to medication effects or, more rarely, anatomic destruction from opportunistic infection of the adrenal glands or anterior pituitary. Clinical adrenal insufficiency is important to recognize because it is associated with increased morbidity and mortality. Adrenal insufficiency is often suspected in patients presenting with progressive HIV infection, fatigue, and inanition. Clinical adrenal insufficiency was demonstrated in 4 percent of patients with AIDS or symptomatic HIV in a recent study.(16) Conversely, 30 percent of patients with hyponatremia and other clinical signs of adrenal insufficiency exhibit inadequate cortisol levels on stimulation with cosyntropin (synthetic a1-24-corticotropin), demonstrating the utility of testing in this subset of patients.(17)
The most common cause of adrenal insufficiency in subjects with HIV infection is tissue destruction of the adrenal glands by cytomegalovirus, which is present in the adrenal glands of 33 to 88 percent of patients with AIDS at autopsy.(18) However, glandular destruction does not typically exceed more than 50 percent of adrenal tissue and is therefore not likely to result in hormonal dysfunction in most cases.(19) More rarely, hypothalamic or pituitary destruction may occur from opportunistic infections such as Toxoplasma gondii, cytomegalovirus, and Cryptococcus neoformans.
Assessment of adrenal function in patients with AIDS should be made in patients exhibiting severe fatigue, weight loss, hyponatremia, or hyperkalemia and is best performed with cosyntropin testing (0.25 mg). The cosyntropin test is reliable in almost all cases except those in which secondary adrenal insufficiency of relatively acute onset has occurred such that the adrenal glands are still capable of responding to exogenous corticotropin. In these cases, a random cortisol level, metyrapone, or insulin tolerance test is indicated. Stress doses of hydrocortisone (100 mg every six hours) should be administered immediately after testing and adequate volume support given to acutely ill patients. Administration of the glucocorticoid derivative, dexamethasone, is preferable if a cosyntropin stimulation test is planned. A cortisol level of 18 µg/dL or higher, drawn as a random value or at any time during the cosyntropin test, is evidence of adequate adrenal function. To further distinguish primary from secondary adrenal insufficiency, a corticotropin level drawn prior to steroid administration is useful. The corticotropin level is invariably elevated to 100 pg/mL or more in primary adrenal insufficiency. Therapy for adrenal insufficiency includes glucocorticoid replacement in all cases and the addition of mineralocorticoid replacement in primary adrenal insufficiency. Medications may also affect adrenal function in patients with HIV infection (Table 1). Megestrol acetate is a synthetic progestational agent approved for use as an appetite stimulant in patients with AIDS wasting. Megestrol acetate suppresses adrenal function through a steroid-like effect on the hypothalamic-pituitary-adrenal axis and may result in adrenal insufficiency if tapered rapidly.(20) Ketoconazole decreases cortisol synthesis in a dose-dependent manner. In the setting of known hypoadrenalism or decreased adrenal reserve, rifampin can also precipitate adrenal insufficiency by increasing cortisol metabolism.
|Table 1. Endocrine effects of HIV-related therapies|
|Foscarnet||Decreased ionized calcium; nephrogenic diabetes insipidus|
|Ketoconazole||Decreased cortisol, vitamin D, and testosterone levels|
|Megestrol acetate||Hyperglycemia; adrenal insufficiency on abrupt discontinuation|
|Phenytoin||Increased cortisol metabolism|
|Pentamidine||Hyperglycemia, hypoglycemia, hypomagnesemia|
|Rifampin||Increased cortisol metabolism|
|Protease inhibitors||Diabetes mellitus|
Clinical thyroid disease is relatively rare in patients with HIV disease. Pneumocystis carinii has been shown to cause a syndrome of painful thyroiditis in which hyperthyroidism is followed by hypothyroidism in association with decreased uptake on scanning and a firm tender gland, much like that associated with subacute painful autoimmune thyroiditis.(21) The increasing incidence of Pneumocystis thyroiditis may be related to the increased use of inhaled pentamidine, which is associated with extrapulmonary Pneumocystis infections. In addition, clinically apparent thyroid masses from Aspergillus have been reported but are not associated with a thyroiditis-like picture. Intrathyroidal foci of cytomegalovirus, Mycobacterium avium-intracellulare, Cryptococcus, and Kaposi's sarcoma have also been demonstrated at autopsy but have not yet been implicated in clinical thyroid disease among patients with AIDS. Secondary hypothyroidism from panhypopituitarism has also been reported to result from central nervous system toxoplasmosis and cytomegalo-virus (see section on gonadal function). Note that medications such as rifampin may alter the hepatic clearance of thyroxine in this population.
Electrolytes and fluid balance
Sodium and water balance are often disturbed in HIV infection secondary to endocrine dysfunction. Approximately 40 to 60 percent of hospitalized patients with AIDS and 20 percent of ambulatory patients exhibit hyponatremia. Hyponatremia is related to the syndrome of inappropriate antidiuretic hormone in nearly half of all hyponatremic patients with AIDS. Such patients appear euvolemic, demonstrate inappropriately elevated urine osmolarity for the degree of serum hypo-osmolarity, and are without adrenal or thyroid dysfunction. In contrast, among patients exhibiting volume depletion and hyponatremia, 30 percent are adrenally insufficient.(22) Decreased free water clearance due to HIV nephropathy and volume depletion with excessive free water intake may also contribute to hyponatremia in this population. In addition, hyporeninemic hypoaldosteronism should be suspected in patients with hyponatremia, hyperkalemia, normal renal function, and normal glucocorticoid function.(23) Finally, certain medications such as vidarabine, miconazole, and pentamidine are associated with hyponatremia of unknown origin. In contrast, hypernatremia and nephrogenic diabetes insipidus have been associated with foscarnet therapy and with cytomegalovirus infection of the hypothalamus.(17) Disorders of potassium regulation are seen occasionally in patients with AIDS. The most common clinical scenario is an increased serum potassium level related to treatment with trimethoprim-sulfa-methoxazole. Trimethoprim is structurally similar to the potassium-sparing diuretic, amiloride, and may contribute to hyperkalemia, especially in patients with azotemia.(24) Other potential causes of hyperkalemia in this population include pentamidine-associated tubular nephropathy, HIV nephropathy, primary adrenal insufficiency, and hyporeninemic hypoaldosteronism, have been described in four patients with AIDS.(23)
Hypocalcemia is prevalent among patients with AIDS, occurring in as many as 18 percent of such patients.(25) The most common causes include calcium malabsorption and vitamin D deficiency. The mechanism of malabsorption is unclear but may be related to AIDS enteropathy or specific opportunistic infections of the small intestine. Decreased calcium levels may also be seen in severe illness. Hypocalcemia may also result from the effects of certain medications. For example, foscarnet complexes with calcium to decrease the ionized calcium level, and ketoconazole inhibits 1,25-dihydroxyvitamin D synthesis. In addition, pentamidine may cause severe magnesium wasting, which is often associated with hypocalcemia. In this clinical situation, the hypocalcemia improves with the correction of the hypomagnesemia.
In contrast, hypercalcemia is a rare endocrine manifestation of AIDS. Excessive 1,25-dihydroxyvitamin D production from granulomatous disease, ie, tuberculosis or lymphoma, can result in hypercalcemia. In addition, local osteoclast-mediated bone resorption has been reported with disseminated cytomegalo-virus.
Hypoglycemia results frequently from intravenous pentamidine administration secondary to islet cell inflammation and insulin release. This phenomenon is common especially with high-dose therapy in the setting of azotemia.(26) Hypoglycemia may be followed by chronic hyperglycemia in rare cases, resulting from pancreatic islet beta cell destruction and fibrosis. Islet cell antibody-negative diabetes mellitus has been reported rarely in patients with AIDS. Autopsy data showing nonspecific islet cell inflammation have led to speculation that HIV may have a direct effect on the pancreas. Hyperglycemia is also associated with the use of megestrol acetate because of its potent glucocorticoid activity. Intravenous pentamidine therapy for the treatment of acute Pneumocystis pneumonia has been known to cause diabetes mellitus because of the toxic effect of the drug on pancreatic beta cells. Initially, severe hypoglycemia is seen secondary to an excess release of insulin because of the destruction of the beta cells; eventually this develops into hyperglycemia secondary to insulin deficiency.(17)
Diabetes mellitus has also recently been associated with the use of protease inhibitors. In May 1997, the Food and Drug Administration released information to healthcare providers regarding postmarketing reports suggesting that a small percentage of patients using newly approved protease inhibitors developed hyperglycemia or diabetes mellitus, or experienced a worsening of preexisting diabetes. The potential mechanisms of protease-induced glucose intolerance are not known.(27)
Lipid metabolism is characterized by increased triglyceride and decreased cholesterol and high-density lipoprotein levels in patients with AIDS. Hypertriglyceridemia appears to be independent of the degree of wasting. The mechanism of elevated triglyceride levels relates to decreased lipoprotein lipase activity and decreased hepatic clearance of triglyceride.(28) Of note, increased triglyceride levels correlate with serum interferon levels, but the clinical significance of the hypertriglyceridemia remains unclear.
Endocrine dysfunction is not uncommon in HIV disease. Gonadal dysfunction is highly prevalent, affecting nearly half of all men with AIDS and is most often associated with low gonadotropin levels. Women with HIV disease also have altered gonadal function and an associated loss of muscle mass. Furthermore, acquired growth hormone resistance, related in part to undernutrition, is also seen in HIV-infected patients and may further contribute to the loss of lean body mass in this population. Clinical adrenal disease is seen primarily in patients with disseminated cytomegalo-virus or those who take medications that predispose to adrenal insufficiency. In addition to adrenalopathy, organ-specific disease secondary to opportunistic infection can result in testicular, thyroid, pituitary, and hypothalamic destruction. The clinical importance of these associated disorders relates primarily to the detection and treatment of adrenal insufficiency and the potential use of anabolic hormonal replacement to reverse hypogonadism and increase weight and lean body mass.
Colleen P. Corcoran, MSN, ANP, and Steven Grinspoon, MD, are with the Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
1. Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 1988;84:611-616.
2. Grinspoon S, Corcoran C, Lee K, et al. Loss of lean body mass and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab 1996;81:4051-4058.
3. Chabon AB, Stenger RJ, Grabstald H. Histopathology of testis in acquired immune deficiency syndrome. Urology 1987;29:658-663.
4. Katznelson L, Finkelstein J, Shoenfeld D, et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1997;81:4358-4365.
5. Ellerbock T, Wright T, Bush T. Characteristics of menstruation in women infected with the human immunodeficiency virus. Obstet Gynecol 1996;87:1030-1034.
6. Shah P, Smith J, Wells C. Menstrual symptoms in women infected by the human immunodeficiency virus. Obstet Gynecol 1994;83:397-400.
7. Grinspoon S, Corcoran C, Miller K, et al. Body composition and endocrine function in women with AIDS wasting. J Clin Endocrinol Metab 1997;82:1332-1337.
8. Widi-Wirski R, Berkley S, Downing R, et al. Evaluation of the WHO clinical case definition for AIDS in Uganda. JAMA 1988;87:1030-1034.
9. Suttmann U, Ockenga J, Hoogestraat O, et al. Resting energy expenditure and weight loss in human immunodeficiency virus-infected patients. Metabolism 1993;42:1173-1179.
10. Grunfeld C, Pang M, Shimizu L, et al. Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr 1992;55:455-460.
11. Macallan D, Noble C, Baldwin C, et al. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 1995;333:83-88.
12. Baum H, Biller B, Finkelstein J, et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. Ann Intern Med 1996;125:883-890.
13. Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting. Ann Intern Med 1996;125:873-882.
14. Gold J, High H, Li Y, et al. Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS 1996;10:745-752.
15. Berger J, Pall L, Hall C, et al. Oxandrolone in AIDS-wasting myopathy. AIDS 1996;10:1657-1662.
16. Membreno L, Irony I, Dere W, et al. Adrenocortical function in acquired immune deficiency syndrome. J Clin Endocrinol Metab 1987;65:482-487.
17. Grinspoon S, Donovan D, Bilezikian J. Aetiology and pathogenesis of hormonal and metabolic disorders in HIV infection. In: Norbiato G, ed. The Endocrinology and Metabolism of HIV Infection. London, England: Bailliere Tindall; 1994:735-755.
18. Grinspoon SK, Bilezikian JB. HIV disease and the endocrine system. N Engl J Med 1992;327:1360-1365.
19. Glasgow BJ, Steinsapir KD, Anders K, Layfield LJ. Adrenal pathology in the acquired immune deficiency syndrome. Am J Clin Pathol 1985;84:594-597.
20. Leinung MC, Liporace R, Miller CH. Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med 1995;122:843-845.
21. Lambert M. Thyroid dysfunction in HIV infection. In: Norbiato G, ed. The Endocrinology and Metabolism of HIV Infection. London, England: Bailliere Tindall; 1994:825-836.
22. Tang W, Kaptein E, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Am J Med 1993;94:169-174.
23. Kalin MF, Poretsky L, Seres DS, Zumoff B. Hyporeninemic hypoaldosteronism associated with acquired immune deficiency syndrome. Am J Med 1987;82:1035-1038.
24. Choi MJ, Fernandez PC, Patnaik A, et al. Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS. Ann Intern Med 1993;328:703-706.
25. Peter SA. Disorders of serum calcium in acquired immunodeficiency syndrome. J Natl Med Assoc 1992;84:626-628.
26. Perrone C, Bricaire F, Leport C, Assan D, Vilde JL, Assan R. Hypoglycemia and diabetes mellitus following parenteral pentamidine mesylate administration in AIDS patients. Diabetic Med 1990;7:585-589.
27. Ferri R, Witt R, Sharp V. Protease inhibitors linked to diabetes? Clin Rev 1997;7:121-122.
28. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992;74:1045-1052.
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