- Email: [email protected]
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
NEUROENDOCRINOLOGY
0889-8529/01 $15.00
+ .OO
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION Shalender Bhasin, MD, Atam B. Singh, MD, and Majan Javanbakht, MPH
Functional derangement of every endocrine organ system has been reported in association with HIV infection. The changes in endocrine function may be related to the viral infection of the gland, to systemic effects of HIV or an opportunistic infection, to infiltration by a neoplasm such as Kaposi's sarcoma, to a complication of treatment, or to generation of cytokines. A wide spectrum of endocrine abnormalities is observed in HIV-infected patients. Some of these abnormalities are similar to those seen in other systemic illness, whereas others are unique to HIV infection. The clinical significance of many of these endocrine abnormalities is not well understood. The paucity of data makes it difficult to make general recommendations about hormone replacement therapy in all HIV-infected patients with diminished circulating levels of a particular hormone; however, in some circumstances, hormonal deficiencies can have significant clinical impact, affecting growth and development in HIV-infected children, and affecting sexual function, preservation of muscle mass and function, fat distribution, and quality of life in HIVinfected men and women. The evaluation and management of HIVinfected patients with endocrine abnormalities should be individualized and guided by the patient's clinical presentation.
From the Department of Medicine, University of California Los Angeles School of Medicine (SB); and the Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science (SB, ABS, MJ), Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 30 NUMBER 3 SEI'TEMBER 2001
749
750
BHASIN et a1
ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-GONADAL AXIS IN HIV-INFECTED INDIVIDUALS
Androgen deficiency defined solely in terms of low testosterone levels is a common complication of HIV infection in men and women.* In a survey of 148 HIV-infected men who attended the authors’ clinic, approximately one third had serum total and free testosterone levels in the hypogonadal range.3 Other investigators have reported a similar prevalence of hypogonadism in HIV-infected men.* With the advent of highly active antiretroviral therapy (HAART), the prevalence of hypogonadism has decreased; however, recent surveys of HIV-infected men indicate that androgen deficiency continues to be a frequent metabolic complication that affects approximately 20% of patients on antiretroviral therapy.54 It has been difficult to determine the prevalence of androgen deficiency in HIV-infected women because sensitive assays for the measurement of total and free testosterone levels with precision and accuracy in the low range prevalent in women are not readily available. In addition, because of the paucity of normative data, there is no agreement on what thresholds of testosterone levels define androgen deficiency in women. Using sensitive assays for the measurement of total and free testosterone the authors found that 90% of HIV-infected women had serum total and free testosterone levels below the median for healthy menstruating women (<31 ng/dL); in fact, 80% of HIV-infected women had serum testosterone levels below the tenth percentile for healthy controls. GogginZ6and G r i n ~ p o o nand ~ ~ their co-workers have reported similar high prevalence rates of androgen deficiency in HIV-infected women. The pathophysiology of hypogonadism in HIV infection is complex and involves abnormalities at all levels of the hypothalamic-pituitarygonadal axis. In the authors’ survey of HIV-infected men, 20% of the patients with low testosterone levels had elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and hypergonadotropic hypogonadi~m.~ These patients presumably had primary testicular dysfunction. The remaining 80% of HIV-infected men with low testosterone levels had either normal or low LH and FSH levels; these men with hypogonadotropic hypogonadism had either a central defect at the hypothalamic or pituitary site or a dual defect involving the testis and the hypothalamic-pituitary centers. Testicular involvement is common in HIV infection (Table 1).In a study of 57 autopsy the pathologic findings included tubular scarring, thickening of the basement membrane, interstitial fibrosis, interstitial inflammation, a thickened vessel wall, alteration in Leydig cell number, and decreased spermatogenesis. These data indicate that the pathophysiology of hypogonadism in HIV infection is most likely multifactorial and involves defects at multiple levels of the hypothalamic-pituitary testicular axis. Malnutrition, media*References 3, 14, 15, 17, 18, 29, 30, 45, 50, 54, and 61.
NEUROENDOCFUNE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
751
Table 1. HISTOLOGIC FEATURES OF THE TESTIS IN HIV-INFECTED PATIENTS
Histologic Features
Tubular scarring Thickening of basement membrane Interstitial fibrosis Interstitital inflammation Thickened vessel wall Specific infection Leydig cells Increased Decreased Sperm score Mean Range
AIDS (n = 57)
Control (n = 55)
97 29 16 8 18
90 3 13 5 6 0
8 3
6 1
3.94 1.22-8.99
6.22 1.55-8.96
4
Adapted from Paepe ME, Waxman M Testicular atrophy in AIDS A study of 57 autopsy cases. Hum Pathol 20210, 1989; with permission. Note: The pertinent clinical data and histologic features of the testis in 57 autopsies of patients with acquired immunodeficiency syndrome (AIDS) were analyzed and compared with those of 55 aged-matched controls. The testis of AIDS patients showed a lower degree of spermatogenesis (determined by testicular score count), as well as more prominent thickening of basement membrane and interstitial fibrosis when compared with controls. Infection was found more often in AIDS patients than controls. Microorganisms were Mycobacterium aviurn-intracellulare in six cases and Toxoplasma in five cases.
tors and products of the systemic inflammatory response, drugs such as ketoconazole, weight loss, infectious agents, and metabolic derangement produced by the systemic illness all contribute to a decline in testosterone production. Is Androgen Deficiency an Adaptive or a Maladaptive Response in HIV-Infected Individuals?
It is not known whether the androgen deficiency observed in association with HIV infection is an adaptive response that is beneficial or a maladaptive response that needs to be corrected. Two approaches have been used to address this issue. First, in cross-sectional studies, serum testosterone levels have been correlated with disease outcomes. Second, in intervention studies, the effects of testosterone replacement on disease outcomes have been studied in a number of clinical trials. Low Testosterone Levels Correlate with Poor Disease Outcome in HIV-Infected Men
Low testosterone levels correlate with adverse disease outcome in HIV-infected men. Serum testosterone levels are lower in HIV-infected men who have lost weight when compared with men who have not.13 The authors’ survey revealed that serum testosterone levels correlate
752
BHASIN et a1
inversely with weight loss and Karnofsky performance score^.^ Longitudinal follow-up of HIV-infected homosexual men reveals a progressive decrease in serum testosterone levels.58This decrease is much greater in HIV-infected men who progress to acquired immunodeficiency syndrome (AIDS) than in men who do not. It is not known whether the decrease in testosterone levels is a consequence of weight loss or is a contributory factor that precedes muscle wasting. In a longitudinal study, Dobs and co-~orkers'~ reported that serum testosterone levels declined early in the course of events that culminated in wasting. Testosterone levels correlate with muscle mass and exercise capacity in HIVinfected leading to speculation that hypogonadism may contribute to muscle wasting and debility. Although patients with HIV infection may lose fat and lean tissue, the loss of lean body mass is an important aspect of the weight loss associated with wasting. The magnitude of the depletion of nonfat tissues is an important determinant of the time of death in AIDS.38,39 There is a high prevalence of sexual dysfunction in HIV-infected men46;decreased testosterone levels are only one component of the multifactorial pathophysiology of sexual dysfunction in these patients. With the increasing life expectancy of HIV-infected men, frailty and sexual dysfunction have emerged as important quality of life issues. Effects of Testosterone Replacement in HIV-Infected Men
Several studies of the effects of androgen supplementation in HIVinfected men have been reported*; however, many of these studies were not controlled clinical trials. Most of the studies were of short duration, ranging from 12 to 24 weeks. Several androgenic steroids have been studied in a limited fashion, including nandrolone decanoate, oxandrolone, oxymetholone, stanozolol, testosterone cypionate, and testosterone enanthate. Of the five placebo-controlled studies of testosterone replacement in HIV-infected men with weight loss, three9,lo,28 demonstrated an increase in fat-free mass and two'2,16did not. The three ~ t u d i e s ~ that ,'~,~~ showed gains in fat-free mass selected patients with low testosterone levels. Coodley and Coodley12examined the effects of 200 mg of testosterone cypionate given every 2 weeks for 3 months to 40 HIV-seropositive patients with weight loss of greater than 5% of usual body weight and CD4 cell counts less than 2 x lo5 /L in a double-blind, placebocontrolled study. Among the 35 patients who completed the first 3 months of treatment, there was no significant difference between the effects of testosterone and placebo treatment on weight gain; however, testosterone supplementation improved the overall sense of well-being ( P = 0.03). Body composition was not assessed. In a placebo-controlled, double-blind, clinical trial, the authors examined the effects of physiologic testosterone replacement by means of *References 7, 9, 10, 12, 16, 21, 27, 28, 34, 49, 57, 59, and 64
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
753
the nongenital patch.9 A total of 41 HIV-positive men with serum testosterone levels less than 400 ng/dL were randomly assigned to receive either two placebo patches nightly or two testosterone patches, designed to release 5 mg of testosterone over a 24-hour period. Testosterone replacement was associated with a 1.34-kg increase in lean body mass (P = 0.02) and a significantly greater reduction in fat mass than that achieved with placebo treatment alone. There were no significant changes in liver enzymes, plasma HIV RNA copy number, and CD4 and CD8 + T-cell counts. Placebo and testosterone treatment were associated with a significant increase in muscle strength. Because most of the participants in this study had no prior weight-lifting experience, it was hypothesized that the apparent increase in muscle strength in the placebo group reflected learning effect. Most other studies of testosterone replacement in HIV-infected men have also failed to demonstrate significant increases in muscle strength.12,16,28 In a subsequent studylo the authors had the subjects come back to the exercise laboratory on two or more occasions until they were familiar with the equipment and technique, achieving stability of measurement. This study determined the effects of testosterone replacement, with or without a program of resistance exercise, on muscle strength and body composition in androgen-deficient, HIV-infected men with weight loss and low testosterone levels. In this placebo-controlled, double-blind, randomized clinical trial, HIV-infected men with serum testosterone less than 350 ng/dL and weight loss of 5% or more in the previous 6 months were randomly assigned to one of four groups: (1)placebo, no exercise; (2) testosterone, no exercise; (3) placebo plus exercise; or (4) testosterone plus exercise. Placebo or 100 mg of testosterone enanthate were given intramuscularly weekly for 16 weeks. The exercise program was a thriceweekly, progressive, supervised strength-training program. Effort-dependent muscle strength in five different exercises was measured by the one-repetition maximum method. In the placebo alone group, muscle strength did not change in any of the five exercises (-0.3% to -4.O%), indicating that this strategy was effective in minimizing the influence of the learning effect. Men treated with testosterone alone, exercise alone, or combined testosterone and exercise experienced significant increases in maximum voluntary muscle strength in the leg press ( + 22%to So%), leg curls (+18% to 36%), bench press (+19% to 33%), and latissimus pulls (+17% to 33%) exercises. The gains in strength in all of the exercises were greater in men receiving testosterone or performing exercise alone when compared with men receiving placebo alone. The change in leg press strength was correlated with the change in muscle volume (R = 0.44, P = 0.003) and the change in fat-free mass (R = 0.55, P
754
BHASIN et a1
strength.l0f57 Supraphysiologicdoses of androgens augment the anabolic effects of resistance exercise on lean body mass and maximal voluntary strength.59, The previous data suggest that testosterone can promote weight gain and increase lean body mass and muscle strength in HIV-infected men with low testosterone levels. Nevertheless, it is not known whether physiologic androgen replacement can produce meaningful changes in the quality of life, the use of health care resources, or physical function in HIV-infected men. Testosterone replacement does not affect HIV copy number, but its effects on virus shedding in the genital tract are not known. Potential Adverse Effects of Androgen Therapy
The long-term risks of testosterone administration are poorly understood. Short-term testosterone administration is relatively safe in young androgen-deficient men. Common side effects associated with testosterone replacement in young men are acne, oiliness of skin, and breast tenderness. Testosterone administration can induce breast enlargement owing to testosterone conversion to estradiol, although this effect is an uncommon complication. Additional potential adverse effects of testosterone supplementation include erythrocytosis, the induction or exacerbation of sleep apnea, and breast tenderness or enlargement.s,23 The two major areas of concern are the effects of long-term testosterone administration on prostate cancer and the progression of atherosclerotic heart disease.8,23 Although it is generally agreed that testosterone does not cause prostate cancer, this cancer is a common androgen-dependent tumor, and androgen administration may promote tumor growth. Testosterone administration is absolutely contraindicated in men with history of prostate cancer. Many older men have microscopic foci of cancer in their prostates. It is not known whether testosterone administration will make these subclinical foci of cancer grow and become clinically overt. Serum prostate-specific antigen (PSA) levels are lower in testosterone-deficient men and are restored to normal following testosterone replacemen@@; however, serum PSA levels do not increase progressively in healthy hypogonadal men with replacement doses of testosterone. The increase in PSA levels during testosterone replacement might trigger evaluation and biopsy in some patients. More intensive PSA screening and followup of men receiving testosterone replacement might lead to an increased number of prostate biopsies and the detection of subclinical prostate cancers that would have otherwise remained undetected.s*23 Senim PSA levels tend to fluctuate when measured repeatedly in the same individual over time; therefore, when serum PSA levels in androgen-deficient men on testosterone replacement therapy show a change from a previously measured value, the clinician must decide whether the change warrants detailed evaluation of the patient for prostate cancer, or whether it is simply the result of test-to-test variability.
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
755
Recommendations
Because the beneficial effects of testosterone supplementation on health-related outcomes in HIV-infected men have not been clearly demonstrated and the long-term risks remain unknown, therapeutic decisions about testosterone replacement in HIV-infected men must be individualized and should follow an explicit discussion of the uncertainties about potential risks and benefits. ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-THYROIDAXIS
Clinically significant infections of the thyroid are uncommon in patients infected with HIV. Nevertheless, HIV-infected individuals, especially those with AIDS or opportunistic infections, often have abnormalities of thyroid function tests that are distinct from those associated with nonthyroidal illness in patients without HIV infection. Infections of the Thyroid Gland
Numerous case reports describe thyroid gland infection with Pneumocystis carinii, presenting as a neck mass with hypothyroidism5,19, 51, 63 and hyperthyroidism in the initial phase of infection.33,42 Pneumocystis carinii thyroiditis currently represents the most common HIV-associated thyroid infection. Patients may present with a neck mass, neck pain, diffuse goiter, hypothyroidism, and suppressed radioiodine uptake. These patients may go through an initial transient phase of hyperthyroidism, presumably owing to release of thyroid hormone. In a review of autopsy findings in 36 cases of AIDS, Welch and co-workers'j6found cytomegalovirus inclusions in 14%; however, the clinical significance of this finding remains unclear. Mycobacterium avium, Mycobacterium tuberculosis, Cryptococcus neoformans, and Pneumocystis carinii, as well as Kaposi's sarcoma, have been described.35,66 Abnormalities of Thyroid Function
In asymptomatic HIV-infected individuals who are free of concomitant infections or hepatic dysfunction, serum total thyroxine and triiodothyronine (T3)concentrations are typically normal when compared with the values in healthy age- and weight-matched controls (Table 2), whereas thyroid-binding globulin (TBG) concentrations are on average higher in HIV-infected patients than in age-matched healthy controls.17, 50, Consequently, HIV-infected patients have a lower thyroid hormonebinding index (THBI),free thyroxine index, and free thyroxine concentrations. In contrast to patients with nonthyroidal illness without HIV
756
BHASIN et a1
Table 2. ABNORMALITIES OF THYROID HORMONE LEVELS IN HIV-INFECTED INDIVIDUALS IN COMPARISON WITH SERONEGATIVE PATIENTS WITH NONTHYROIDAL ILLNESS
Hormone T3
rT3 TBG T4 TSH
Seronegative, Severe Nonthyroidal Illness
Markedly decreased Increased Increased Normal or decreased Normal, may be increased in recovery
HIVInfected, Stable
HIV-Infected, 111
Normal Decreased Increased Normal Normal
Decreased Decreased or normal Increased Normal Normal
T3 = triiodothyronine; rT, = reverse T3; TBG = thyroxine-binding globulin; T, = thyroxine; TSH thyroid-stimulating hormone. Adaptedfrom Sellmayer DE, Grunfield C: Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 17518,1996. =
infection who have higher reverse T, levels, HIV-infected patients typically have lower serum reverse T, levels.17,50* Although serum T3 concentrations are either normal or slightly reduced in patients with AIDS who are weight stable, the occurrence of secondary infection in these patients is characterized by a significant fall in T, levels in association with weight loss and anorexia.,l In a prospective study of serum thyroid hormone indices in patients with HIV infection, LoPresti and co-workers41 found that the T, level remained normal despite progression of HIV disease. In HIV-infected patients hospitalized with Pneumocystis carinii pneumonia, serum T, values generally remained normal until hospitalization and declined during hospitalization. A low serum T3on admission correlated with mortality. Serum TBG values rose and reverse T, levels declined with progression of HIV infection. It was speculated that the persistence of a normal T3 level despite progression of HIV infection might contribute to weight loss in HIV-infected i n d i v i d ~ a l s . ~ ~ Although serum thyroid-stimulating hormone (TSH) concentrations in HIV-infected patients are within the normal range, studies using intensive 24-hour sampling have reported higher mean 24-hour TSH concentrations in HIV-infected patients when compared with healthy controls.36Mean TSH pulse amplitude is also increased in HIV-infected patients, whereas the mean number of TSH pulses over the 24-hour period is not altered.36The peak TSH response to thyrotropin-releasing hormone (TRH) is higher in HIV-infected patients than in healthy cont r o l ~ . TSH , ~ sialylation is not altered.31 Recommendations
Thyroid hormone replacement in patients with low T3 or T4 related solely to nonthyroidal illness is not currently justified. Beneficial effects
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
757
of thyroid hormone replacement in HIV-infected patients in nonthyroidal illness have not been demonstrated, and there are concerns about inducing a catabolic response with thyroid hormone administration in patients who are already in negative nitrogen balance. ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-ADRENAL GLAND
Although pathologic involvement of the adrenal gland is commonly observed at autopsy in HIV-infected individuals,2°, 66 clinically significant adrenal insufficiency is uncommon. Abnormalities of the adrenal gland found at autopsy in HIV-infected individuals are as follows:35 257
Necrotizing adrenalitis in association with an infectious agent Cytomegalovirus
Mycobacteriurn tuberculosis Cyptococcus neoformans Toxoplasma gondii Mycobacterium avium-intracellulare Pneumocystis carinii Histoplasma capsulatum Lymphoma Hemorrhage Cortical lipid depletion It is not known whether altered sensitivity to glucocorticoids contributes to the pathophysiology of fat redistribution syndrome. Pathologic involvement of the adrenal gland by opportunistic infection or by neoplastic infiltration is often observed at autopsy. Welch and co-workers66reported adrenal gland involvement in 35 of 36 autopsy cases; 40% of these patients had nuclear and cytoplasmic inclusions typical of cytomegalovirus, two cases had necrotizing adrenalitis with multiple cytomegalovirus inclusions, and 17% had metastatic Kaposi sarcoma. Cytomegalovirus is the most frequent agent causing a variable degree of damage, ranging from focal adrenalitis to extensive necrosis. Mycobacterium avium-intracellulare, Cyptococcus neoformans, Pneumocystis carinii, and Histoplasma capsulatum have also been reported.2O.~ 5 66, Many HIV-infected patients hospitalized for acute opportunistic infections have clinical features suggestive of adrenal insufficiency, such as hyponatremia, hypotension, anemia, anorexia, and failure to thrive; however, despite the high frequency of pathologic involvement of the adrenal gland at autopsy, verifiable adrenal insufficiency is infrequent in patients infected with HIV. Raffi and c o - w ~ r k e r performed s~~ corticotropin (ACTH) stimulation tests in 98 HIV-infected patients at various stages of illness. Adrenal function was within normal values in most cases, with no significant differences in cortisol responses between patient groups. Mineralocorticosteroid response was also normal in all
758
BHASIN et a1
patients,5O and only 9 of 98 patients had either a low baseline or poststimulation serum cortisol. In another study, Dobs and co-~orkers'~ tested 39 patients with AIDS for adrenocortical reserve by using the ACTH stimulation test. Thirty-six of the 39 patients (92%) had a peak value greater than 20 pg/dL, consistent with normal adrenal function. The mean cortisol concentrations increased from a baseline of 14 k 1 pg/dL to 30 ? 2 pg/dL at 60 minutes. Only 3 of 39 patients showed a blunted response. Taken together, these studies demonstrate that primary adrenal insufficiency is an uncommon complication of HIV infection but can occur owing to involvement of the adrenal gland by infectious agents and metastatic neoplasms. Baldwin and Allo4 have proposed that some patients with critical nonadrenal illness might have glucocorticoid resistance and might need glucocorticoid administration despite apparently normal cortisol response to ACTH. These researchers reported on the case records of four patients in the surgical intensive care unit who had critical multisystem disease, refractory high cardiac output, and low vascular resistance shock. After the institution of hydrocortisone infusion in doses typical of stress response (100 to 300 mg of hydrocortisone over 24 hours), the patients demonstrated improvements in blood pressure or decreased requirements for vasopressor drugs. In each case, cosyntropin testing revealed serum cortisol levels higher than the threshold classically used to define adrenal insufficiency. It was hypothesized that patients with multisystem critical illness might have glucocorticoid resistance and might benefit from stress doses of glucocorticoids despite cosyntropin stimulation test results that would rule out hypoadrenalism in a normal person. In vitro, chronically HIV-infected cells of the lymphoid line have indeed been shown to have resistance to glucocorticoid-induced a p o p t ~ s i s therefore, ~~; it is possible that there may be attenuation of the glucocorticoid response in HIV-infected cells, probably owing to altered interactions between the glucocorticoid receptor and its hormone. This provocative hypothesis remains to be tested in prospective, placebocontrolled, randomized clinical trials. Changes in the cortisol to dehydroepiandrosterone (DHEA) ratio in HIV-infected men have been implicated in immunologic and metabolic perturbations leading to malnutrition and lipodystrophy." The cortisolto-DHEA ratio is increased in HAART-treated men with lipodystrophy but normal in HAART-treated patients without lipodystrophy. Changes in the cortisol-to-DHEA ratio are negatively correlated with CD4 T-cell counts, body cell mass and fat mass, and increased circulating lipids associated with the lipodystrophy syndrome; however, the therapeutic implications of an altered cortisol-to-DHEA ratio in HIV-infected men, particularly during the syndromes of malnutrition and lipodystrophy, are not clear. The fat redistribution associated with the use of HIV-1 protease inhibitors is a syndrome of increased intra-abdominal adiposity with concomitant dyslipidemia and insulin resistance that has many clinical similarities with Cushing's syndrome; however, plasma cortisol levels
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
759
and urinary free cortisol excretion rates are not increased in patients affected by the fat redistribution syndrome.", 53, 67 Urinary 17-hydroxycorticosteroid excretion is slightly increased but is insufficient to explain the observed lip~dystrophy.~~ Corticotropin-releasing hormone (CRH)stimulated morning plasma cortisol levels are similar in HIV-infected patients with fat redistribution syndrome and Glucocorticoid receptor number and affinity are normal in patients with the fat redistribution syndrome. It is not known whether postreceptor alterations in HIV-infected individuals make them more sensitive to glucocorticoid effects. Recommendations
HIV-infected individuals who are hospitalized because of secondary illnesses and who present with hyponatremia and hypotension often have other causes to explain their hyponatremia and hypotension; however, because of the high prevalence of adrenal involvement at autopsy, these patients should undergo a rapid ACTH test to exclude adrenal insufficiency. Any cortisol value, including a baseline value, greater than 18 p,g/dL during the ACTH stimulation test makes adrenal insufficiency unlikely. The available data do not support glucocorticoid replacement in HIV-infected patients with cortisol values greater than 18 p,g/dL or the premise that these patients have resistance to glucocorticoids. Similarly, glucocorticoid excess has not been demonstrated in HIV-infected patients with the fat redistribution syndrome, although the existing data do not exclude the possibility of increased sensitivity to glucocorticoids. ABNORMALITIES OF THE SOMATOTROPIC AXIS IN HIV-INFECTED INDIVIDUALS
Despite considerable variability in growth hormone secretion in HIV-infected 40, 52, 56 there is agreement that growth hormone action is impaired in these patients as indicated by decreased circulating concentrations of insulin-like growth factor 1 (IGF-1). Gelato and coworkers" found that AIDS patients who met the Centers for Disease Control (CDC) definition of AIDS wasting syndrome demonstrated a marked reduction in serum IGF-1 and IGF-2 concentrations when compared with healthy HIV-negative subjects. IGF-1 levels were depressed, even in patients who had high serum levels of growth hormone. AIDS patients who had lost more than 10% of their ideal body mass had low levels of IGF binding protein 3 (IGFBP-3) and a reduced ability to form the IGFBP-3 ternary complex, consistent with diminished growth hormone action. These data led to the suggestion that AIDS wasting is associated with a growth hormone-resistant Further support for the hypothesis that patients with the AIDS wasting syndrome have a growth hormone-resistant state is provided
760
BHASIN et a1
by studies examining changes in the rates of skeletal muscle protein synthesis in response to recombinant human growth hormone (rhGH) administration. In one such study, McNurlan and c o - ~ o r k e r sfound ~~ that, although the fractional rates of muscle protein synthesis were similar in controls and in all stages of disease, after growth hormone administration, the rates of protein synthesis were stimulated in controls, with a smaller increase in HIV-positive persons and a significant depression in patients with the AIDS wasting syndrome despite a fourfold elevation in IGF-1 in all groups. Rates of muscle protein degradation were higher in patients with AIDS and AIDS wasting than in HIVpositive or healthy i n d i v i d ~ a l sThese . ~ ~ data suggest that increased muscle protein breakdown and decreased responsiveness of muscle protein synthesis to growth hormone in the later stages of disease might contribute to muscle wasting in HIV-infected ~atients.4~ Administration of supraphysiologic doses of rhGH can induce increased nitrogen retention, weight gain, and accretion of fat-free mass in HIV-infected patients. In two recently published clinical trials, treatment of HIV-infected men with human growth hormone was associated with a 1.5-kg increase in lean body mass.60,65 Although greater gains in weight were recorded after 6 weeks of human growth hormone treatment, these gains were not sustained with continued treatment for 12 weeks.65The reasons for the failure to sustain weight gains during human growth hormone treatment are not clear; it is conceivable that weight gain early in the course of treatment is caused by water retention. It is not known whether rhGH administration can improve muscle strength or measures of physical function. Growth hormone administration in HIV-infected men is associated with a high frequency of side effects, including edema, arthralgias, myalgias, and jaw pain. Not surprisingly, the treatment discontinuation rates were high (21% to 40%) in the two human growth hormone studies. The doses of rhGH used in both clinical trials in HIVinfected patients were high. It is not known whether clinically meaningful gains in lean body mass, physical function, and health-related outcomes can be achieved with doses of rhGH lower than those used in initial studies of rhGH in AIDS wasting. Abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected, hemophilic adolescent^.^^ The growth impairment in HIV infection seems to be the result of a multifactorial process that includes diminished growth hormone production or release, decreased androgen secretion, inadequate caloric intake in some, but not all, patients, and superadded infections. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response is positively correlated with CD4 + count. Alterations of the circadian pattern of growth hormone secretion have been demonstrated in HIV-infected The 24-hour secretory profile of growth hormone is flattened with loss of diurnal rhythm. These alterations of the circadian temporal profiles of growth hormone
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
761
secretion precede the development of wasting and infectious complications in HIV-infected individuals. Patients with HIV-associated lipodystrophy have reduced mean growth hormone concentrations, basal growth hormone concentrations, and growth hormone pulse amplitude; however, growth hormone pulse frequency is normal in these patients.55Increased visceral adiposity is associated with reduced growth hormone concentrations in HIV lipodysSeveral case reports have reported improvements in visceral fat following administration of rhGH. Placebo-controlled, randomized trials of rhGH in patients with HIV-associated fat redistribution syndromes are in progress.
OTHER ENDOCRINE DYSFUNCTIONS ASSOCIATED WITH HIV/AIDS
Panhypopituitarism in AIDS owing to Toxoplusmu gondii infection47 has been reported in an HIV-infected patient with brain toxoplasmosis. Hypopituitarism was confirmed with standard endocrinologic evaluation. At autopsy, the pituitary was necrotic, and Toxoplusmu abscesses were found in the neighboring brain structures. Nephrogenic diabetes insipidus associated with foscarnet treatment of cytomegalovirus retinitis has also been reported.22
References 1. Angulo JC, Lopez JI: Lethal cytomegalovirus adrenalitis in a case of AIDS. Scand J Urol Nephrol28:105, 1994 2. Arabi Y, Fairfax MR Adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by Nocardia asteroids in a patient with acquired immunodeficiency syndrome. Diagn Microbiol Infect Dis 24:47-51, 1996 3. Arver SA, Sinha-Hikim I, Beall G, et al: Serum dihydrotestosterone and testosterone levels in human immunodeficiency virus-infected men with and without weight loss. J Androl20:611, 1999 4. Baldwin WA, A110 M: Occult hypoadrenalism in critically ill patients. Arch Surg 128:673, 1993 5. Battan R, Mauriuz P, Raviglione MC, et al: Pneumocyctis curinii infection of thyroid in a hypothyroid patient with AIDS: Diagnosis by fine needle aspiration biopsy. J Clin Endocrinol Metab 72724, 1991 6. Behre HM, Bohmeyer J, Nieschlag E: Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxfl40341. 1994 7. Berger JR, Pall 'L, H a i CD, et al: Oxandrolone in AIDS-wasting myopathy. AIDS 10:1657, 1996 8. Bhasin S, Buckwalter GX Testosterone supplementation of older men: A rational idea whose time has not yet come. J Androl, in press 9. Bhasin S, Storer TW, Asbel-Sethi N, et al: Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virusinfected men with low testosterone levels. J Clin Endocrinol Metab 833155,1998 10. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone-replacement and resistance
762
BHASIN et a1
exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 283:763, 2000 11. Christeff N, Nunez EA, Gougeon M L Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy. Ann N Y Acad Sci 917962, 2000 12. Coodley GO, Coodley MK: A trial of testosterone therapy _ .for HIV-associated weight loss. AiDS 11:1347, 1997 13. Coodlev GO. Loveless MO. Nelson HD, et a1 Endocrine function in HIV wasting syndrome. J Acquir Immune Defic Syndr Hum Retrovirol746,1994 14. Croxon TC, Chapman WE, Miller LK, et a1 Changes in the hypothalamic pituitarygonadal axis in human immunodeficiency virus-infected hypogonadal men. J Clin Endocrinol Metab 68:317, 1989 15. DePaepe ME, Vuletin JC, Lee MH, et al: Testicular atrophy in homosexual AIDS patients. Hum Pathol20572,1989 16. Dobs A, Cofrancesco J, Nolten WE, et al: The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Am J Med 107126,1999 17. Dobs AS, Few WL, Blackman MR, et al: Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab 81:4108, 1996 18. Dobs AS, Dempsey MA, Ladenson PW, et al: Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 84611,1988 19. Drucker DJ, Baily D, Rotstein L: Thyroiditis as a presenting manifestation of disseminated extrapulmonary: Pneurnocyctis carinii infection. J Clin Endocrinol Metab 71:1663, 1990 20. Duch FM, Repele CA: Adrenal gland morphological alterations in acquired immunodeficiency syndrome. Rev SOCBras Med Trop 31957,1998 21. Engelson ES, Rabkin JG, Rabkin R, et al: Effects of testosterone upon body composition. J Acquir Immune Defic Syndr 11:510,1996 22. Ferese RV, Schamblan M, Holander H, et a1 Nephrogenic diabetes insipidus associated with foscamet treatment. Ann Intern Med 112955,1990 23. The First Andropause Consensus Statement. Endocrine Society, 2000 24. Frost RA, Fuhrer J, Steigbigel R, et a1 Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin-like growth factor system. Clin Endocrinol(0xf) 44:501,1996 25. Giampalmo A, Ardoino S: Anatomo-pathologic findings in 25 autopsy cases of AIDS. Pathologica 81(1071):146, 1989 26. Goggin K, Engelson ES, Rabkin JG, et al: The relationship of mood, endocrine, and sexual disorders in human immunodeficiency virus positive (HIV+) women: An exploratory study. Psychosom Med 6011, 1998 27. Gold J, High HA, Li Y, et al: Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS 10:745, 1996 28. Grinspoon S, Corcoran C, Askari H, et al: Effects of androgen administration in men with the AIDS wasting syndrome: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 129:18, 1998 29. Grinspoon S, Corcoran C, Lee K, et al: Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab 81:4051, 1996 30. Grinspoon S, Corcoran C, Miller K, et al: Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 821332, 1997 31. Grunfeld C, Pang M, Doerrler W, et al: Indices of thyroid function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Metabolism 421270, 1993 32. Guenthner EE, Robinowe SL, Neil AV, et a1 Primary Addison’s disease in a patient with acquired immunodeficiency syndrome. Ann Intern Med 100847,1984 33. Guttler R, Singer PA: Pneumocyctis carznii thyroiditis. Arch Intern Med 153:393, 1993 34. Hengge UR, Baumann M, Maleba R, et al: Oxymetholone promotes weight gain in
-
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
45. 46. 47. 48. 49. 50. 51. 52.
53. 54. 55. 56.
763
patients with advanced human immunodeficiency virus (HIV-1) infection. Br J Nutr 75:129, 1996 Hofbauer LC. Heufelder AE: Endocrine implications of human immunodeficiencv virus. Medicine 75262, 1996 Hommes MJT, Romjin JA, Endert E, et a1 Hypothyroid-like regulation of the pituitarythyroid axis in stable human immunodeficiency virus infection. Metabolism 42556, 1993 Kawa SK, Thompson EB: Lymphoid cell resistance to glucocorticoids in HIV infection. J Steroid Biochem Mol Biol57259, 1996 Kotler DP, Tierney AR, Wang J, et al: Magnitude of body cell mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50444,1989 Linden CP, Allen S, Serufilira A, et al: Predictors of mortality among HIV-infected women in Kigali, Rwanda. Ann Intern Med 116:320, 1992 Lo JC, Mulligan K, Tai VW, et a1 "Buffalo hump" in men with HIV-1 infection. Lancet 3512367, 1998 LoPresti JS, Fried JC, Spencer CA, et a1 Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110970,1989 McKarty M, Cocker R, Claydon E: Disseminated Pneurnocyctis carinii infection in a patient with acquired immune deficiency syndrome causing thyroid gland calcification and hypothyroidism. Clin Radio1 45209, 1992 McNurlan MA, Garlick PJ, Steigbigel RT, et a1 Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severitv of disease. 1 Clin Invest 100:2125, 1997 MeikldAW, Arver S, Dobs AS, et al: Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 49:191,1997 Meremich JA, McDermott MT, Asp AA, et a1 Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. J Clin Endocrinol Metab 70566,1990 Meyer-Bahlburg FH, et al: HIV positive gay men: Sexual dysfunction. In Proceedings of the VI International Conference on AIDS, San Francisco, June, 1989, p 701 Milligan SA, Katz MS, Craven PC, et al: Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome. Am J Med 77760, 1984 Paepe ME, Waxman M: Testicular atrophy in AIDS: A study of 57 autopsy cases. Hum Pathol20210,1989 Rabkin JG, Rabkin R, Wagner GJ: Testosterone treatment of clinical hypogonadism in patients with HIV/AIDS. Int J STD AIDS 8:537,1997 Raffi F, Brisseau J-M, Planchon B, et al: Endocrine function in 98 HIV-infected patients: A prospective study. AIDS 5:729,1991 Ragni MV, Decker A, DeRuberts FR, et al: Pneurnocyctis curinii infection presenting as a necrotizing thyroiditis and hypothyroidism. Am J Clin Pathol 95:489, 1991 Ratner Kaufman F, Gertner JM, Sleeper LA, et al: Growth hormone secretion in HIVpositive versus HIV-negative hemophilic males with abnormal growth and pubertal development: The Hemophilia Growth and Development Study. J Acquir Immune Defic Syndr Hum Retrovirol 15:137,1997 Renard E, Fabre J, Paris F, et al: Syndrome of body fat redistribution in HIV-1-infected patients: Relationships to cortisol and catecholamines. Clin Endocrinol (0x0. 51:223, 1999 Rietschel P, Corcoran C, Stanley T, et a1 Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 31:1240, 2001 Rietschel P, Hadigan C, Corcoran C, et al: Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab 86:504, 2001 Rondanelli M, Solerte SB, Fiovanti M, et al: Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection. AIDS Res Hum Retroviruses 13:1243, 1997
764
BHASIN et a1
57. Roubenoff R, McDermott A, Weiss L, et al: Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus. AIDS 13:231, 1999 58. Salehian 8, Jacobson D, Grafe M, et a1 Pituitary-testicular axis during HIV infection: A prospective study [abstract]. Presented at the 18th Annual Meeting of the American Society of Andrology, Tampa, FL, April 15-19, 1993 59. Sattler FR, Jaque SV, Schroeder ET, et al: Effect of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with the human immunodeficiency virus. J Clin Endocrinol Metab M1268, 1999 60. Schambelan M, Mulligan K, Grunfeld C, et al: Recombinant growth hormone in patients with HN-associated wasting. Ann Intern Med 125:873, 1996 61. Sellmeyer DE, Grunfeld C: Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 17518, 1996 62. Sinha-Hikim I, Arver S, Beall G, et a1 The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 83:1312, 1998 63. Spitzer RD, Chan JC, Marks JB, et al: Hypothyroidism due to Pneurnocyctis curinii thyroiditis in a patient with acquired immunodeficiency syndrome. Am J Med Sci 30298, 1991 64. Strawford A, Barbieri T, Neese R, et al: Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss. J Acquir Immune Defic Syndr Hum Retrovirol20137,1999 65. Waters D, Danska J, Hardy K, et a1 Recombinant human growth hormone, insulin-like growth factor-1, and combination therapy in AIDS-associated wasting: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 125:8665, 1996 66. Welch K, Finkbeiner W, Alpers CE, et al: Autopsy findings in acquired immunedeficiency syndrome. JAMA 252:1152, 1984 67. Yanovski JA, Miller KD, Kin0 T, et al: Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitorassociated lipodystrophy. J Clin Endocrinol Metab 84:1925, 1999
Address reprint requests to Shalender Bhasin, MD Division of Endocrinology, Metabolism, and Molecular Medicine Charles R. Drew University of Medicine and Science 1731 East 120th Street Los Angeles, CA 90059
0889-8529/01 $15.00
+ .OO
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION Shalender Bhasin, MD, Atam B. Singh, MD, and Majan Javanbakht, MPH
Functional derangement of every endocrine organ system has been reported in association with HIV infection. The changes in endocrine function may be related to the viral infection of the gland, to systemic effects of HIV or an opportunistic infection, to infiltration by a neoplasm such as Kaposi's sarcoma, to a complication of treatment, or to generation of cytokines. A wide spectrum of endocrine abnormalities is observed in HIV-infected patients. Some of these abnormalities are similar to those seen in other systemic illness, whereas others are unique to HIV infection. The clinical significance of many of these endocrine abnormalities is not well understood. The paucity of data makes it difficult to make general recommendations about hormone replacement therapy in all HIV-infected patients with diminished circulating levels of a particular hormone; however, in some circumstances, hormonal deficiencies can have significant clinical impact, affecting growth and development in HIV-infected children, and affecting sexual function, preservation of muscle mass and function, fat distribution, and quality of life in HIVinfected men and women. The evaluation and management of HIVinfected patients with endocrine abnormalities should be individualized and guided by the patient's clinical presentation.
From the Department of Medicine, University of California Los Angeles School of Medicine (SB); and the Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science (SB, ABS, MJ), Los Angeles, California
ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 30 NUMBER 3 SEI'TEMBER 2001
749
750
BHASIN et a1
ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-GONADAL AXIS IN HIV-INFECTED INDIVIDUALS
Androgen deficiency defined solely in terms of low testosterone levels is a common complication of HIV infection in men and women.* In a survey of 148 HIV-infected men who attended the authors’ clinic, approximately one third had serum total and free testosterone levels in the hypogonadal range.3 Other investigators have reported a similar prevalence of hypogonadism in HIV-infected men.* With the advent of highly active antiretroviral therapy (HAART), the prevalence of hypogonadism has decreased; however, recent surveys of HIV-infected men indicate that androgen deficiency continues to be a frequent metabolic complication that affects approximately 20% of patients on antiretroviral therapy.54 It has been difficult to determine the prevalence of androgen deficiency in HIV-infected women because sensitive assays for the measurement of total and free testosterone levels with precision and accuracy in the low range prevalent in women are not readily available. In addition, because of the paucity of normative data, there is no agreement on what thresholds of testosterone levels define androgen deficiency in women. Using sensitive assays for the measurement of total and free testosterone the authors found that 90% of HIV-infected women had serum total and free testosterone levels below the median for healthy menstruating women (<31 ng/dL); in fact, 80% of HIV-infected women had serum testosterone levels below the tenth percentile for healthy controls. GogginZ6and G r i n ~ p o o nand ~ ~ their co-workers have reported similar high prevalence rates of androgen deficiency in HIV-infected women. The pathophysiology of hypogonadism in HIV infection is complex and involves abnormalities at all levels of the hypothalamic-pituitarygonadal axis. In the authors’ survey of HIV-infected men, 20% of the patients with low testosterone levels had elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and hypergonadotropic hypogonadi~m.~ These patients presumably had primary testicular dysfunction. The remaining 80% of HIV-infected men with low testosterone levels had either normal or low LH and FSH levels; these men with hypogonadotropic hypogonadism had either a central defect at the hypothalamic or pituitary site or a dual defect involving the testis and the hypothalamic-pituitary centers. Testicular involvement is common in HIV infection (Table 1).In a study of 57 autopsy the pathologic findings included tubular scarring, thickening of the basement membrane, interstitial fibrosis, interstitial inflammation, a thickened vessel wall, alteration in Leydig cell number, and decreased spermatogenesis. These data indicate that the pathophysiology of hypogonadism in HIV infection is most likely multifactorial and involves defects at multiple levels of the hypothalamic-pituitary testicular axis. Malnutrition, media*References 3, 14, 15, 17, 18, 29, 30, 45, 50, 54, and 61.
NEUROENDOCFUNE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
751
Table 1. HISTOLOGIC FEATURES OF THE TESTIS IN HIV-INFECTED PATIENTS
Histologic Features
Tubular scarring Thickening of basement membrane Interstitial fibrosis Interstitital inflammation Thickened vessel wall Specific infection Leydig cells Increased Decreased Sperm score Mean Range
AIDS (n = 57)
Control (n = 55)
97 29 16 8 18
90 3 13 5 6 0
8 3
6 1
3.94 1.22-8.99
6.22 1.55-8.96
4
Adapted from Paepe ME, Waxman M Testicular atrophy in AIDS A study of 57 autopsy cases. Hum Pathol 20210, 1989; with permission. Note: The pertinent clinical data and histologic features of the testis in 57 autopsies of patients with acquired immunodeficiency syndrome (AIDS) were analyzed and compared with those of 55 aged-matched controls. The testis of AIDS patients showed a lower degree of spermatogenesis (determined by testicular score count), as well as more prominent thickening of basement membrane and interstitial fibrosis when compared with controls. Infection was found more often in AIDS patients than controls. Microorganisms were Mycobacterium aviurn-intracellulare in six cases and Toxoplasma in five cases.
tors and products of the systemic inflammatory response, drugs such as ketoconazole, weight loss, infectious agents, and metabolic derangement produced by the systemic illness all contribute to a decline in testosterone production. Is Androgen Deficiency an Adaptive or a Maladaptive Response in HIV-Infected Individuals?
It is not known whether the androgen deficiency observed in association with HIV infection is an adaptive response that is beneficial or a maladaptive response that needs to be corrected. Two approaches have been used to address this issue. First, in cross-sectional studies, serum testosterone levels have been correlated with disease outcomes. Second, in intervention studies, the effects of testosterone replacement on disease outcomes have been studied in a number of clinical trials. Low Testosterone Levels Correlate with Poor Disease Outcome in HIV-Infected Men
Low testosterone levels correlate with adverse disease outcome in HIV-infected men. Serum testosterone levels are lower in HIV-infected men who have lost weight when compared with men who have not.13 The authors’ survey revealed that serum testosterone levels correlate
752
BHASIN et a1
inversely with weight loss and Karnofsky performance score^.^ Longitudinal follow-up of HIV-infected homosexual men reveals a progressive decrease in serum testosterone levels.58This decrease is much greater in HIV-infected men who progress to acquired immunodeficiency syndrome (AIDS) than in men who do not. It is not known whether the decrease in testosterone levels is a consequence of weight loss or is a contributory factor that precedes muscle wasting. In a longitudinal study, Dobs and co-~orkers'~ reported that serum testosterone levels declined early in the course of events that culminated in wasting. Testosterone levels correlate with muscle mass and exercise capacity in HIVinfected leading to speculation that hypogonadism may contribute to muscle wasting and debility. Although patients with HIV infection may lose fat and lean tissue, the loss of lean body mass is an important aspect of the weight loss associated with wasting. The magnitude of the depletion of nonfat tissues is an important determinant of the time of death in AIDS.38,39 There is a high prevalence of sexual dysfunction in HIV-infected men46;decreased testosterone levels are only one component of the multifactorial pathophysiology of sexual dysfunction in these patients. With the increasing life expectancy of HIV-infected men, frailty and sexual dysfunction have emerged as important quality of life issues. Effects of Testosterone Replacement in HIV-Infected Men
Several studies of the effects of androgen supplementation in HIVinfected men have been reported*; however, many of these studies were not controlled clinical trials. Most of the studies were of short duration, ranging from 12 to 24 weeks. Several androgenic steroids have been studied in a limited fashion, including nandrolone decanoate, oxandrolone, oxymetholone, stanozolol, testosterone cypionate, and testosterone enanthate. Of the five placebo-controlled studies of testosterone replacement in HIV-infected men with weight loss, three9,lo,28 demonstrated an increase in fat-free mass and two'2,16did not. The three ~ t u d i e s ~ that ,'~,~~ showed gains in fat-free mass selected patients with low testosterone levels. Coodley and Coodley12examined the effects of 200 mg of testosterone cypionate given every 2 weeks for 3 months to 40 HIV-seropositive patients with weight loss of greater than 5% of usual body weight and CD4 cell counts less than 2 x lo5 /L in a double-blind, placebocontrolled study. Among the 35 patients who completed the first 3 months of treatment, there was no significant difference between the effects of testosterone and placebo treatment on weight gain; however, testosterone supplementation improved the overall sense of well-being ( P = 0.03). Body composition was not assessed. In a placebo-controlled, double-blind, clinical trial, the authors examined the effects of physiologic testosterone replacement by means of *References 7, 9, 10, 12, 16, 21, 27, 28, 34, 49, 57, 59, and 64
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
753
the nongenital patch.9 A total of 41 HIV-positive men with serum testosterone levels less than 400 ng/dL were randomly assigned to receive either two placebo patches nightly or two testosterone patches, designed to release 5 mg of testosterone over a 24-hour period. Testosterone replacement was associated with a 1.34-kg increase in lean body mass (P = 0.02) and a significantly greater reduction in fat mass than that achieved with placebo treatment alone. There were no significant changes in liver enzymes, plasma HIV RNA copy number, and CD4 and CD8 + T-cell counts. Placebo and testosterone treatment were associated with a significant increase in muscle strength. Because most of the participants in this study had no prior weight-lifting experience, it was hypothesized that the apparent increase in muscle strength in the placebo group reflected learning effect. Most other studies of testosterone replacement in HIV-infected men have also failed to demonstrate significant increases in muscle strength.12,16,28 In a subsequent studylo the authors had the subjects come back to the exercise laboratory on two or more occasions until they were familiar with the equipment and technique, achieving stability of measurement. This study determined the effects of testosterone replacement, with or without a program of resistance exercise, on muscle strength and body composition in androgen-deficient, HIV-infected men with weight loss and low testosterone levels. In this placebo-controlled, double-blind, randomized clinical trial, HIV-infected men with serum testosterone less than 350 ng/dL and weight loss of 5% or more in the previous 6 months were randomly assigned to one of four groups: (1)placebo, no exercise; (2) testosterone, no exercise; (3) placebo plus exercise; or (4) testosterone plus exercise. Placebo or 100 mg of testosterone enanthate were given intramuscularly weekly for 16 weeks. The exercise program was a thriceweekly, progressive, supervised strength-training program. Effort-dependent muscle strength in five different exercises was measured by the one-repetition maximum method. In the placebo alone group, muscle strength did not change in any of the five exercises (-0.3% to -4.O%), indicating that this strategy was effective in minimizing the influence of the learning effect. Men treated with testosterone alone, exercise alone, or combined testosterone and exercise experienced significant increases in maximum voluntary muscle strength in the leg press ( + 22%to So%), leg curls (+18% to 36%), bench press (+19% to 33%), and latissimus pulls (+17% to 33%) exercises. The gains in strength in all of the exercises were greater in men receiving testosterone or performing exercise alone when compared with men receiving placebo alone. The change in leg press strength was correlated with the change in muscle volume (R = 0.44, P = 0.003) and the change in fat-free mass (R = 0.55, P
754
BHASIN et a1
strength.l0f57 Supraphysiologicdoses of androgens augment the anabolic effects of resistance exercise on lean body mass and maximal voluntary strength.59, The previous data suggest that testosterone can promote weight gain and increase lean body mass and muscle strength in HIV-infected men with low testosterone levels. Nevertheless, it is not known whether physiologic androgen replacement can produce meaningful changes in the quality of life, the use of health care resources, or physical function in HIV-infected men. Testosterone replacement does not affect HIV copy number, but its effects on virus shedding in the genital tract are not known. Potential Adverse Effects of Androgen Therapy
The long-term risks of testosterone administration are poorly understood. Short-term testosterone administration is relatively safe in young androgen-deficient men. Common side effects associated with testosterone replacement in young men are acne, oiliness of skin, and breast tenderness. Testosterone administration can induce breast enlargement owing to testosterone conversion to estradiol, although this effect is an uncommon complication. Additional potential adverse effects of testosterone supplementation include erythrocytosis, the induction or exacerbation of sleep apnea, and breast tenderness or enlargement.s,23 The two major areas of concern are the effects of long-term testosterone administration on prostate cancer and the progression of atherosclerotic heart disease.8,23 Although it is generally agreed that testosterone does not cause prostate cancer, this cancer is a common androgen-dependent tumor, and androgen administration may promote tumor growth. Testosterone administration is absolutely contraindicated in men with history of prostate cancer. Many older men have microscopic foci of cancer in their prostates. It is not known whether testosterone administration will make these subclinical foci of cancer grow and become clinically overt. Serum prostate-specific antigen (PSA) levels are lower in testosterone-deficient men and are restored to normal following testosterone replacemen@@; however, serum PSA levels do not increase progressively in healthy hypogonadal men with replacement doses of testosterone. The increase in PSA levels during testosterone replacement might trigger evaluation and biopsy in some patients. More intensive PSA screening and followup of men receiving testosterone replacement might lead to an increased number of prostate biopsies and the detection of subclinical prostate cancers that would have otherwise remained undetected.s*23 Senim PSA levels tend to fluctuate when measured repeatedly in the same individual over time; therefore, when serum PSA levels in androgen-deficient men on testosterone replacement therapy show a change from a previously measured value, the clinician must decide whether the change warrants detailed evaluation of the patient for prostate cancer, or whether it is simply the result of test-to-test variability.
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
755
Recommendations
Because the beneficial effects of testosterone supplementation on health-related outcomes in HIV-infected men have not been clearly demonstrated and the long-term risks remain unknown, therapeutic decisions about testosterone replacement in HIV-infected men must be individualized and should follow an explicit discussion of the uncertainties about potential risks and benefits. ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-THYROIDAXIS
Clinically significant infections of the thyroid are uncommon in patients infected with HIV. Nevertheless, HIV-infected individuals, especially those with AIDS or opportunistic infections, often have abnormalities of thyroid function tests that are distinct from those associated with nonthyroidal illness in patients without HIV infection. Infections of the Thyroid Gland
Numerous case reports describe thyroid gland infection with Pneumocystis carinii, presenting as a neck mass with hypothyroidism5,19, 51, 63 and hyperthyroidism in the initial phase of infection.33,42 Pneumocystis carinii thyroiditis currently represents the most common HIV-associated thyroid infection. Patients may present with a neck mass, neck pain, diffuse goiter, hypothyroidism, and suppressed radioiodine uptake. These patients may go through an initial transient phase of hyperthyroidism, presumably owing to release of thyroid hormone. In a review of autopsy findings in 36 cases of AIDS, Welch and co-workers'j6found cytomegalovirus inclusions in 14%; however, the clinical significance of this finding remains unclear. Mycobacterium avium, Mycobacterium tuberculosis, Cryptococcus neoformans, and Pneumocystis carinii, as well as Kaposi's sarcoma, have been described.35,66 Abnormalities of Thyroid Function
In asymptomatic HIV-infected individuals who are free of concomitant infections or hepatic dysfunction, serum total thyroxine and triiodothyronine (T3)concentrations are typically normal when compared with the values in healthy age- and weight-matched controls (Table 2), whereas thyroid-binding globulin (TBG) concentrations are on average higher in HIV-infected patients than in age-matched healthy controls.17, 50, Consequently, HIV-infected patients have a lower thyroid hormonebinding index (THBI),free thyroxine index, and free thyroxine concentrations. In contrast to patients with nonthyroidal illness without HIV
756
BHASIN et a1
Table 2. ABNORMALITIES OF THYROID HORMONE LEVELS IN HIV-INFECTED INDIVIDUALS IN COMPARISON WITH SERONEGATIVE PATIENTS WITH NONTHYROIDAL ILLNESS
Hormone T3
rT3 TBG T4 TSH
Seronegative, Severe Nonthyroidal Illness
Markedly decreased Increased Increased Normal or decreased Normal, may be increased in recovery
HIVInfected, Stable
HIV-Infected, 111
Normal Decreased Increased Normal Normal
Decreased Decreased or normal Increased Normal Normal
T3 = triiodothyronine; rT, = reverse T3; TBG = thyroxine-binding globulin; T, = thyroxine; TSH thyroid-stimulating hormone. Adaptedfrom Sellmayer DE, Grunfield C: Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 17518,1996. =
infection who have higher reverse T, levels, HIV-infected patients typically have lower serum reverse T, levels.17,50* Although serum T3 concentrations are either normal or slightly reduced in patients with AIDS who are weight stable, the occurrence of secondary infection in these patients is characterized by a significant fall in T, levels in association with weight loss and anorexia.,l In a prospective study of serum thyroid hormone indices in patients with HIV infection, LoPresti and co-workers41 found that the T, level remained normal despite progression of HIV disease. In HIV-infected patients hospitalized with Pneumocystis carinii pneumonia, serum T, values generally remained normal until hospitalization and declined during hospitalization. A low serum T3on admission correlated with mortality. Serum TBG values rose and reverse T, levels declined with progression of HIV infection. It was speculated that the persistence of a normal T3 level despite progression of HIV infection might contribute to weight loss in HIV-infected i n d i v i d ~ a l s . ~ ~ Although serum thyroid-stimulating hormone (TSH) concentrations in HIV-infected patients are within the normal range, studies using intensive 24-hour sampling have reported higher mean 24-hour TSH concentrations in HIV-infected patients when compared with healthy controls.36Mean TSH pulse amplitude is also increased in HIV-infected patients, whereas the mean number of TSH pulses over the 24-hour period is not altered.36The peak TSH response to thyrotropin-releasing hormone (TRH) is higher in HIV-infected patients than in healthy cont r o l ~ . TSH , ~ sialylation is not altered.31 Recommendations
Thyroid hormone replacement in patients with low T3 or T4 related solely to nonthyroidal illness is not currently justified. Beneficial effects
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
757
of thyroid hormone replacement in HIV-infected patients in nonthyroidal illness have not been demonstrated, and there are concerns about inducing a catabolic response with thyroid hormone administration in patients who are already in negative nitrogen balance. ABNORMALITIES OF THE HYPOTHALAMICPITUITARY-ADRENAL GLAND
Although pathologic involvement of the adrenal gland is commonly observed at autopsy in HIV-infected individuals,2°, 66 clinically significant adrenal insufficiency is uncommon. Abnormalities of the adrenal gland found at autopsy in HIV-infected individuals are as follows:35 257
Necrotizing adrenalitis in association with an infectious agent Cytomegalovirus
Mycobacteriurn tuberculosis Cyptococcus neoformans Toxoplasma gondii Mycobacterium avium-intracellulare Pneumocystis carinii Histoplasma capsulatum Lymphoma Hemorrhage Cortical lipid depletion It is not known whether altered sensitivity to glucocorticoids contributes to the pathophysiology of fat redistribution syndrome. Pathologic involvement of the adrenal gland by opportunistic infection or by neoplastic infiltration is often observed at autopsy. Welch and co-workers66reported adrenal gland involvement in 35 of 36 autopsy cases; 40% of these patients had nuclear and cytoplasmic inclusions typical of cytomegalovirus, two cases had necrotizing adrenalitis with multiple cytomegalovirus inclusions, and 17% had metastatic Kaposi sarcoma. Cytomegalovirus is the most frequent agent causing a variable degree of damage, ranging from focal adrenalitis to extensive necrosis. Mycobacterium avium-intracellulare, Cyptococcus neoformans, Pneumocystis carinii, and Histoplasma capsulatum have also been reported.2O.~ 5 66, Many HIV-infected patients hospitalized for acute opportunistic infections have clinical features suggestive of adrenal insufficiency, such as hyponatremia, hypotension, anemia, anorexia, and failure to thrive; however, despite the high frequency of pathologic involvement of the adrenal gland at autopsy, verifiable adrenal insufficiency is infrequent in patients infected with HIV. Raffi and c o - w ~ r k e r performed s~~ corticotropin (ACTH) stimulation tests in 98 HIV-infected patients at various stages of illness. Adrenal function was within normal values in most cases, with no significant differences in cortisol responses between patient groups. Mineralocorticosteroid response was also normal in all
758
BHASIN et a1
patients,5O and only 9 of 98 patients had either a low baseline or poststimulation serum cortisol. In another study, Dobs and co-~orkers'~ tested 39 patients with AIDS for adrenocortical reserve by using the ACTH stimulation test. Thirty-six of the 39 patients (92%) had a peak value greater than 20 pg/dL, consistent with normal adrenal function. The mean cortisol concentrations increased from a baseline of 14 k 1 pg/dL to 30 ? 2 pg/dL at 60 minutes. Only 3 of 39 patients showed a blunted response. Taken together, these studies demonstrate that primary adrenal insufficiency is an uncommon complication of HIV infection but can occur owing to involvement of the adrenal gland by infectious agents and metastatic neoplasms. Baldwin and Allo4 have proposed that some patients with critical nonadrenal illness might have glucocorticoid resistance and might need glucocorticoid administration despite apparently normal cortisol response to ACTH. These researchers reported on the case records of four patients in the surgical intensive care unit who had critical multisystem disease, refractory high cardiac output, and low vascular resistance shock. After the institution of hydrocortisone infusion in doses typical of stress response (100 to 300 mg of hydrocortisone over 24 hours), the patients demonstrated improvements in blood pressure or decreased requirements for vasopressor drugs. In each case, cosyntropin testing revealed serum cortisol levels higher than the threshold classically used to define adrenal insufficiency. It was hypothesized that patients with multisystem critical illness might have glucocorticoid resistance and might benefit from stress doses of glucocorticoids despite cosyntropin stimulation test results that would rule out hypoadrenalism in a normal person. In vitro, chronically HIV-infected cells of the lymphoid line have indeed been shown to have resistance to glucocorticoid-induced a p o p t ~ s i s therefore, ~~; it is possible that there may be attenuation of the glucocorticoid response in HIV-infected cells, probably owing to altered interactions between the glucocorticoid receptor and its hormone. This provocative hypothesis remains to be tested in prospective, placebocontrolled, randomized clinical trials. Changes in the cortisol to dehydroepiandrosterone (DHEA) ratio in HIV-infected men have been implicated in immunologic and metabolic perturbations leading to malnutrition and lipodystrophy." The cortisolto-DHEA ratio is increased in HAART-treated men with lipodystrophy but normal in HAART-treated patients without lipodystrophy. Changes in the cortisol-to-DHEA ratio are negatively correlated with CD4 T-cell counts, body cell mass and fat mass, and increased circulating lipids associated with the lipodystrophy syndrome; however, the therapeutic implications of an altered cortisol-to-DHEA ratio in HIV-infected men, particularly during the syndromes of malnutrition and lipodystrophy, are not clear. The fat redistribution associated with the use of HIV-1 protease inhibitors is a syndrome of increased intra-abdominal adiposity with concomitant dyslipidemia and insulin resistance that has many clinical similarities with Cushing's syndrome; however, plasma cortisol levels
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
759
and urinary free cortisol excretion rates are not increased in patients affected by the fat redistribution syndrome.", 53, 67 Urinary 17-hydroxycorticosteroid excretion is slightly increased but is insufficient to explain the observed lip~dystrophy.~~ Corticotropin-releasing hormone (CRH)stimulated morning plasma cortisol levels are similar in HIV-infected patients with fat redistribution syndrome and Glucocorticoid receptor number and affinity are normal in patients with the fat redistribution syndrome. It is not known whether postreceptor alterations in HIV-infected individuals make them more sensitive to glucocorticoid effects. Recommendations
HIV-infected individuals who are hospitalized because of secondary illnesses and who present with hyponatremia and hypotension often have other causes to explain their hyponatremia and hypotension; however, because of the high prevalence of adrenal involvement at autopsy, these patients should undergo a rapid ACTH test to exclude adrenal insufficiency. Any cortisol value, including a baseline value, greater than 18 p,g/dL during the ACTH stimulation test makes adrenal insufficiency unlikely. The available data do not support glucocorticoid replacement in HIV-infected patients with cortisol values greater than 18 p,g/dL or the premise that these patients have resistance to glucocorticoids. Similarly, glucocorticoid excess has not been demonstrated in HIV-infected patients with the fat redistribution syndrome, although the existing data do not exclude the possibility of increased sensitivity to glucocorticoids. ABNORMALITIES OF THE SOMATOTROPIC AXIS IN HIV-INFECTED INDIVIDUALS
Despite considerable variability in growth hormone secretion in HIV-infected 40, 52, 56 there is agreement that growth hormone action is impaired in these patients as indicated by decreased circulating concentrations of insulin-like growth factor 1 (IGF-1). Gelato and coworkers" found that AIDS patients who met the Centers for Disease Control (CDC) definition of AIDS wasting syndrome demonstrated a marked reduction in serum IGF-1 and IGF-2 concentrations when compared with healthy HIV-negative subjects. IGF-1 levels were depressed, even in patients who had high serum levels of growth hormone. AIDS patients who had lost more than 10% of their ideal body mass had low levels of IGF binding protein 3 (IGFBP-3) and a reduced ability to form the IGFBP-3 ternary complex, consistent with diminished growth hormone action. These data led to the suggestion that AIDS wasting is associated with a growth hormone-resistant Further support for the hypothesis that patients with the AIDS wasting syndrome have a growth hormone-resistant state is provided
760
BHASIN et a1
by studies examining changes in the rates of skeletal muscle protein synthesis in response to recombinant human growth hormone (rhGH) administration. In one such study, McNurlan and c o - ~ o r k e r sfound ~~ that, although the fractional rates of muscle protein synthesis were similar in controls and in all stages of disease, after growth hormone administration, the rates of protein synthesis were stimulated in controls, with a smaller increase in HIV-positive persons and a significant depression in patients with the AIDS wasting syndrome despite a fourfold elevation in IGF-1 in all groups. Rates of muscle protein degradation were higher in patients with AIDS and AIDS wasting than in HIVpositive or healthy i n d i v i d ~ a l sThese . ~ ~ data suggest that increased muscle protein breakdown and decreased responsiveness of muscle protein synthesis to growth hormone in the later stages of disease might contribute to muscle wasting in HIV-infected ~atients.4~ Administration of supraphysiologic doses of rhGH can induce increased nitrogen retention, weight gain, and accretion of fat-free mass in HIV-infected patients. In two recently published clinical trials, treatment of HIV-infected men with human growth hormone was associated with a 1.5-kg increase in lean body mass.60,65 Although greater gains in weight were recorded after 6 weeks of human growth hormone treatment, these gains were not sustained with continued treatment for 12 weeks.65The reasons for the failure to sustain weight gains during human growth hormone treatment are not clear; it is conceivable that weight gain early in the course of treatment is caused by water retention. It is not known whether rhGH administration can improve muscle strength or measures of physical function. Growth hormone administration in HIV-infected men is associated with a high frequency of side effects, including edema, arthralgias, myalgias, and jaw pain. Not surprisingly, the treatment discontinuation rates were high (21% to 40%) in the two human growth hormone studies. The doses of rhGH used in both clinical trials in HIVinfected patients were high. It is not known whether clinically meaningful gains in lean body mass, physical function, and health-related outcomes can be achieved with doses of rhGH lower than those used in initial studies of rhGH in AIDS wasting. Abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected, hemophilic adolescent^.^^ The growth impairment in HIV infection seems to be the result of a multifactorial process that includes diminished growth hormone production or release, decreased androgen secretion, inadequate caloric intake in some, but not all, patients, and superadded infections. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response is positively correlated with CD4 + count. Alterations of the circadian pattern of growth hormone secretion have been demonstrated in HIV-infected The 24-hour secretory profile of growth hormone is flattened with loss of diurnal rhythm. These alterations of the circadian temporal profiles of growth hormone
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
761
secretion precede the development of wasting and infectious complications in HIV-infected individuals. Patients with HIV-associated lipodystrophy have reduced mean growth hormone concentrations, basal growth hormone concentrations, and growth hormone pulse amplitude; however, growth hormone pulse frequency is normal in these patients.55Increased visceral adiposity is associated with reduced growth hormone concentrations in HIV lipodysSeveral case reports have reported improvements in visceral fat following administration of rhGH. Placebo-controlled, randomized trials of rhGH in patients with HIV-associated fat redistribution syndromes are in progress.
OTHER ENDOCRINE DYSFUNCTIONS ASSOCIATED WITH HIV/AIDS
Panhypopituitarism in AIDS owing to Toxoplusmu gondii infection47 has been reported in an HIV-infected patient with brain toxoplasmosis. Hypopituitarism was confirmed with standard endocrinologic evaluation. At autopsy, the pituitary was necrotic, and Toxoplusmu abscesses were found in the neighboring brain structures. Nephrogenic diabetes insipidus associated with foscarnet treatment of cytomegalovirus retinitis has also been reported.22
References 1. Angulo JC, Lopez JI: Lethal cytomegalovirus adrenalitis in a case of AIDS. Scand J Urol Nephrol28:105, 1994 2. Arabi Y, Fairfax MR Adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by Nocardia asteroids in a patient with acquired immunodeficiency syndrome. Diagn Microbiol Infect Dis 24:47-51, 1996 3. Arver SA, Sinha-Hikim I, Beall G, et al: Serum dihydrotestosterone and testosterone levels in human immunodeficiency virus-infected men with and without weight loss. J Androl20:611, 1999 4. Baldwin WA, A110 M: Occult hypoadrenalism in critically ill patients. Arch Surg 128:673, 1993 5. Battan R, Mauriuz P, Raviglione MC, et al: Pneumocyctis curinii infection of thyroid in a hypothyroid patient with AIDS: Diagnosis by fine needle aspiration biopsy. J Clin Endocrinol Metab 72724, 1991 6. Behre HM, Bohmeyer J, Nieschlag E: Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxfl40341. 1994 7. Berger JR, Pall 'L, H a i CD, et al: Oxandrolone in AIDS-wasting myopathy. AIDS 10:1657, 1996 8. Bhasin S, Buckwalter GX Testosterone supplementation of older men: A rational idea whose time has not yet come. J Androl, in press 9. Bhasin S, Storer TW, Asbel-Sethi N, et al: Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virusinfected men with low testosterone levels. J Clin Endocrinol Metab 833155,1998 10. Bhasin S, Storer TW, Javanbakht M, et al: Testosterone-replacement and resistance
762
BHASIN et a1
exercise in HIV-infected men with weight loss and low testosterone levels. JAMA 283:763, 2000 11. Christeff N, Nunez EA, Gougeon M L Changes in cortisol/DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy. Ann N Y Acad Sci 917962, 2000 12. Coodley GO, Coodley MK: A trial of testosterone therapy _ .for HIV-associated weight loss. AiDS 11:1347, 1997 13. Coodlev GO. Loveless MO. Nelson HD, et a1 Endocrine function in HIV wasting syndrome. J Acquir Immune Defic Syndr Hum Retrovirol746,1994 14. Croxon TC, Chapman WE, Miller LK, et a1 Changes in the hypothalamic pituitarygonadal axis in human immunodeficiency virus-infected hypogonadal men. J Clin Endocrinol Metab 68:317, 1989 15. DePaepe ME, Vuletin JC, Lee MH, et al: Testicular atrophy in homosexual AIDS patients. Hum Pathol20572,1989 16. Dobs A, Cofrancesco J, Nolten WE, et al: The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Am J Med 107126,1999 17. Dobs AS, Few WL, Blackman MR, et al: Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab 81:4108, 1996 18. Dobs AS, Dempsey MA, Ladenson PW, et al: Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 84611,1988 19. Drucker DJ, Baily D, Rotstein L: Thyroiditis as a presenting manifestation of disseminated extrapulmonary: Pneurnocyctis carinii infection. J Clin Endocrinol Metab 71:1663, 1990 20. Duch FM, Repele CA: Adrenal gland morphological alterations in acquired immunodeficiency syndrome. Rev SOCBras Med Trop 31957,1998 21. Engelson ES, Rabkin JG, Rabkin R, et al: Effects of testosterone upon body composition. J Acquir Immune Defic Syndr 11:510,1996 22. Ferese RV, Schamblan M, Holander H, et a1 Nephrogenic diabetes insipidus associated with foscamet treatment. Ann Intern Med 112955,1990 23. The First Andropause Consensus Statement. Endocrine Society, 2000 24. Frost RA, Fuhrer J, Steigbigel R, et a1 Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin-like growth factor system. Clin Endocrinol(0xf) 44:501,1996 25. Giampalmo A, Ardoino S: Anatomo-pathologic findings in 25 autopsy cases of AIDS. Pathologica 81(1071):146, 1989 26. Goggin K, Engelson ES, Rabkin JG, et al: The relationship of mood, endocrine, and sexual disorders in human immunodeficiency virus positive (HIV+) women: An exploratory study. Psychosom Med 6011, 1998 27. Gold J, High HA, Li Y, et al: Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS 10:745, 1996 28. Grinspoon S, Corcoran C, Askari H, et al: Effects of androgen administration in men with the AIDS wasting syndrome: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 129:18, 1998 29. Grinspoon S, Corcoran C, Lee K, et al: Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab 81:4051, 1996 30. Grinspoon S, Corcoran C, Miller K, et al: Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 821332, 1997 31. Grunfeld C, Pang M, Doerrler W, et al: Indices of thyroid function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Metabolism 421270, 1993 32. Guenthner EE, Robinowe SL, Neil AV, et a1 Primary Addison’s disease in a patient with acquired immunodeficiency syndrome. Ann Intern Med 100847,1984 33. Guttler R, Singer PA: Pneumocyctis carznii thyroiditis. Arch Intern Med 153:393, 1993 34. Hengge UR, Baumann M, Maleba R, et al: Oxymetholone promotes weight gain in
-
NEUROENDOCRINE ABNORMALITIES ASSOCIATED WITH HIV INFECTION
35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
45. 46. 47. 48. 49. 50. 51. 52.
53. 54. 55. 56.
763
patients with advanced human immunodeficiency virus (HIV-1) infection. Br J Nutr 75:129, 1996 Hofbauer LC. Heufelder AE: Endocrine implications of human immunodeficiencv virus. Medicine 75262, 1996 Hommes MJT, Romjin JA, Endert E, et a1 Hypothyroid-like regulation of the pituitarythyroid axis in stable human immunodeficiency virus infection. Metabolism 42556, 1993 Kawa SK, Thompson EB: Lymphoid cell resistance to glucocorticoids in HIV infection. J Steroid Biochem Mol Biol57259, 1996 Kotler DP, Tierney AR, Wang J, et al: Magnitude of body cell mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50444,1989 Linden CP, Allen S, Serufilira A, et al: Predictors of mortality among HIV-infected women in Kigali, Rwanda. Ann Intern Med 116:320, 1992 Lo JC, Mulligan K, Tai VW, et a1 "Buffalo hump" in men with HIV-1 infection. Lancet 3512367, 1998 LoPresti JS, Fried JC, Spencer CA, et a1 Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 110970,1989 McKarty M, Cocker R, Claydon E: Disseminated Pneurnocyctis carinii infection in a patient with acquired immune deficiency syndrome causing thyroid gland calcification and hypothyroidism. Clin Radio1 45209, 1992 McNurlan MA, Garlick PJ, Steigbigel RT, et a1 Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severitv of disease. 1 Clin Invest 100:2125, 1997 MeikldAW, Arver S, Dobs AS, et al: Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 49:191,1997 Meremich JA, McDermott MT, Asp AA, et a1 Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. J Clin Endocrinol Metab 70566,1990 Meyer-Bahlburg FH, et al: HIV positive gay men: Sexual dysfunction. In Proceedings of the VI International Conference on AIDS, San Francisco, June, 1989, p 701 Milligan SA, Katz MS, Craven PC, et al: Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome. Am J Med 77760, 1984 Paepe ME, Waxman M: Testicular atrophy in AIDS: A study of 57 autopsy cases. Hum Pathol20210,1989 Rabkin JG, Rabkin R, Wagner GJ: Testosterone treatment of clinical hypogonadism in patients with HIV/AIDS. Int J STD AIDS 8:537,1997 Raffi F, Brisseau J-M, Planchon B, et al: Endocrine function in 98 HIV-infected patients: A prospective study. AIDS 5:729,1991 Ragni MV, Decker A, DeRuberts FR, et al: Pneurnocyctis curinii infection presenting as a necrotizing thyroiditis and hypothyroidism. Am J Clin Pathol 95:489, 1991 Ratner Kaufman F, Gertner JM, Sleeper LA, et al: Growth hormone secretion in HIVpositive versus HIV-negative hemophilic males with abnormal growth and pubertal development: The Hemophilia Growth and Development Study. J Acquir Immune Defic Syndr Hum Retrovirol 15:137,1997 Renard E, Fabre J, Paris F, et al: Syndrome of body fat redistribution in HIV-1-infected patients: Relationships to cortisol and catecholamines. Clin Endocrinol (0x0. 51:223, 1999 Rietschel P, Corcoran C, Stanley T, et a1 Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis 31:1240, 2001 Rietschel P, Hadigan C, Corcoran C, et al: Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab 86:504, 2001 Rondanelli M, Solerte SB, Fiovanti M, et al: Circadian secretory pattern of growth hormone, insulin-like growth factor type I, cortisol, adrenocorticotropic hormone, thyroid-stimulating hormone, and prolactin during HIV infection. AIDS Res Hum Retroviruses 13:1243, 1997
764
BHASIN et a1
57. Roubenoff R, McDermott A, Weiss L, et al: Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus. AIDS 13:231, 1999 58. Salehian 8, Jacobson D, Grafe M, et a1 Pituitary-testicular axis during HIV infection: A prospective study [abstract]. Presented at the 18th Annual Meeting of the American Society of Andrology, Tampa, FL, April 15-19, 1993 59. Sattler FR, Jaque SV, Schroeder ET, et al: Effect of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with the human immunodeficiency virus. J Clin Endocrinol Metab M1268, 1999 60. Schambelan M, Mulligan K, Grunfeld C, et al: Recombinant growth hormone in patients with HN-associated wasting. Ann Intern Med 125:873, 1996 61. Sellmeyer DE, Grunfeld C: Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 17518, 1996 62. Sinha-Hikim I, Arver S, Beall G, et a1 The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 83:1312, 1998 63. Spitzer RD, Chan JC, Marks JB, et al: Hypothyroidism due to Pneurnocyctis curinii thyroiditis in a patient with acquired immunodeficiency syndrome. Am J Med Sci 30298, 1991 64. Strawford A, Barbieri T, Neese R, et al: Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss. J Acquir Immune Defic Syndr Hum Retrovirol20137,1999 65. Waters D, Danska J, Hardy K, et a1 Recombinant human growth hormone, insulin-like growth factor-1, and combination therapy in AIDS-associated wasting: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 125:8665, 1996 66. Welch K, Finkbeiner W, Alpers CE, et al: Autopsy findings in acquired immunedeficiency syndrome. JAMA 252:1152, 1984 67. Yanovski JA, Miller KD, Kin0 T, et al: Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitorassociated lipodystrophy. J Clin Endocrinol Metab 84:1925, 1999
Address reprint requests to Shalender Bhasin, MD Division of Endocrinology, Metabolism, and Molecular Medicine Charles R. Drew University of Medicine and Science 1731 East 120th Street Los Angeles, CA 90059