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Context Hypogonadism is a well-established consequence of opioid use. It has been reported in both men and women, although more widely studied in men. Evidence Acquisition PubMed was searched for articles in English until December 2019 for opioids and hypogonadism. Bibliography of retrieved articles was searched for relevant articles. Evidence Synthesis The prevalence of opioid-induced hypogonadism (OIH) varies between studies but was reported to be 69% in a recent systematic review. There is large heterogeneity in the studies, with different factors shown to have stronger association with hypogonadism such as specific types of opioids, higher doses, and longer durations of use. The consequences of OIH include sexual dysfunction, depression, decreased quality of life, and low bone density. There is paucity of randomized controlled trials assessing the efficacy of testosterone replacement therapy (TRT) for OIH in men, and even less studies on treating OIH in women. TRT studies in men reported varying outcomes with some studies favoring and others showing no clear benefit of TRT on different measures. Conclusions Despite the high prevalence of OIH, it remains underrecognized and undertreated with multiple endocrine and metabolic consequences. A reasonable approach in patients using opioids includes informing them of this complication and its potential consequences, screening for signs and symptoms of hypogonadism then sex hormone levels if prolonged opioid use > 3 months, and treating patients diagnosed with hypogonadism, if and when clinically indicated, with sex hormones if chronic opioids are planned to be continued for ≥ 6 months.

Adult women with polycystic ovarian syndrome (PCOS) have an increased risk for cardiovascular disease, but the evidence for this is controversial in adolescents and young women with PCOS. Measurement of low-density lipoprotein (LDL) particle number, measured by nuclear magnetic resonance spectroscopy is a novel technology to assess cardiovascular risk.The objective of the study was to evaluate lipoprotein particle number and size in young women with PCOS and its relationship with insulin resistance and hyperandrogenism.This was a cross-sectional case control study.The study was conducted at a clinical research center.Women with PCOS (n = 35) and normal controls (n = 20) participated in the study.Blood samples and anthropometric measures were obtained.LDL particle size and number were measured using nuclear magnetic resonance spectroscopy. A secondary outcome was to investigate the correlation of LDL particle number with high-sensitivity C-reactive protein, waist to hip ratio, hyperandrogenism, insulin resistance, and adiponectin.Women with PCOS had higher LDL particle number when compared with healthy controls (935 ± 412 vs 735 ± 264, P = .032); LDL particle number correlated strongly with high-sensitivity C-reactive protein (r = 0.37, P = .006) and waist-to-hip (r = 0.57, P = .0003). The higher LDL particle number was driven mainly due to differences in the small LDL particle number (sLDLp), with PCOS patients having more sLDLp (348 ± 305 vs 178 ± 195, P = .015). The sLDLp correlated with the Matsuda index (r = -0.51, P = .0001), homeostasis model assessment index of insulin resistance (r = 0.41, P = .002), and adiponectin (r = -0.46, P = .0004) but not with T.Adolescent and young women with PCOS have an atherogenic lipoprotein profile suggestive of increased cardiovascular risk that appears to be driven by the degree of visceral adiposity and insulin resistance.

Context: Epidemiologic studies suggest that endogenous testosterone (T) levels in males may be implicated in cardiovascular disease (CVD), however further clarification is needed. Objective: We assessed the cross-sectional relationship between endogenous plasma T and mean carotid intima media thickness (cIMT), and the longitudinal relationship with incident clinical CVD events, cardiac mortality, and all-cause mortality using male participants in the Atherosclerosis Risk in Communities (ARIC) study. Design: This study involved a subset of men from visit 4 of the ARIC study. Setting: The study was conducted in a community based cohort. Participants: Males who provided a morning blood sample excluding those taking androgen therapy, with prevalent coronary heart disease (CHD), stroke, or heart failure (HF) (n = 1558). Intervention: None. Main Outcome Measures: Plasma T by liquid chromatography mass spectrometry and carotid IMT using high resolution B-mode ultrasound were obtained at visit 4. Incident CHD, HF, cardiac mortality, and all-cause mortality were identified by surveillance through 2010 (median 12.8 years). Results: Lower T was significantly associated with higher body mass index, greater waist circumference, diabetes, hypertension, lower HDL, and never smoking (P = 0.01). T was not associated with mean cIMT in unadjusted or adjusted analyses. Following multivariable adjustment, there was no association of quartile (Q) of T with incident CHD [hazard ratio (HR) = 0.87 (95% CI = 0.60–1.26) for Q1; 0.97 (95% CI = 0.69–1.38) for Q2; 0.97 (95% CI = 0.69–1.36) for Q3 compared to reference of Q4] or for incident HF [HR = 0.77 (95% CI = 0.46–1.29) for Q1; 0.72 (95% CI = 0.43–1.21) for Q2; 0.87 (95% CI = 0.53–1.42) for Q3 compared to reference of Q4]. Similarly there was no association of Q of T with mortality or cardiac-associated mortality. Conclusions: Low male plasma T is cross-sectionally associated with key CVD risk factors, but after adjustment there was no association with mean cIMT, incident cardiac events, or mortality. Our results are reassuring that neither high nor low T levels directly predict atherosclerosis, but are a marker for other cardiovascular risk factors.

In the absence of panhypopituitarism and low serum IGF-I levels, the diagnosis of adult GH deficiency (AGHD) requires confirmation with a GH stimulation test. Macimorelin is a novel, orally active ghrelin mimetic that stimulates GH secretion.The objective of the study was to determine the diagnostic efficacy and safety of macimorelin in AGHD.This was a multicenter open-label study comparing the diagnostic accuracy of oral macimorelin with that of arginine+GHRH in AGHD patients and healthy, matched controls. After 43 AGHD patients and 10 controls were tested, the GHRH analog Geref Diagnostic [GHRH(1-29)NH2] became unavailable in the United States. The study was completed by testing 10 additional AGHD patients and 38 controls with macimorelin alone.Peak GH area under the receiver operating characteristic curve after macimorelin was measured.Fifty AGHD subjects and 48 controls were evaluated. Peak GH levels in AGHD patients and controls after macimorelin were 2.36 ± 5.69 and 17.71 ± 19.11 ng/mL, respectively (P.0001). With macimorelin, the receiver operating characteristic analysis yielded an optimal GH cut point of 2.7 ng/mL, with 82% sensitivity, 92% specificity, and 13% misclassification rate. For subjects receiving both tests, macimorelin showed discrimination comparable with arginine+GHRH (area under the receiver operating characteristic curve 0.99 vs 0.94, respectively, P = .29). Obesity (body mass index30 kg/m(2)) was present in 58% of subjects, and peak GH levels were inversely associated with body mass index in controls (r = -0.37, P = .01). Using the separate cut points of 6.8 ng/mL for nonobese and 2.7 for obese subjects reduced the misclassification rate to 11%. Only 1 drug-related serious adverse event, an asymptomatic QT interval prolongation on the electrocardiogram, was reported.Oral macimorelin is safe, convenient, and effective in diagnosing AGHD with accuracy comparable with the arginine+GHRH test.

Context: Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population. Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men. Participants, Design, and Setting: A total of 1413 men aged 20+ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988–1991 were included in this cross-sectional study. Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays. Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n = 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n = 674; 5.11 ng/ml; P > 0.05) but were higher in Mexican-Americans (n = 376; 5.48 ng/ml; P < 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P < 0.01) and Mexican-Americans (34.11 pg/ml; P < 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than non-Hispanic whites (34.91 nmol/liter; P < 0.05) and Mexican-Americans (35.04 nmol/liter; P < 0.05). Conclusions: Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity.

Context: Recently, the field of androgen therapy in postmenopausal women has received much attention and press. Although the ovary ceases to produce follicles and estrogen at menopause, it continues to produce androgens. Hence, many oophorectomized women complain of sexual dysfunction (despite adequate estrogenization). Previous studies of nontransdermal testosterone replacement have shown an improvement in libido and sexual frequency, although at the cost of supraphysiological testosterone levels. Transdermal testosterone patch (Intrinsa) was developed to deliver a physiological amount of testosterone. In 2004, the Food and Drug Administration voted not to approve Intrinsa until long-term safety data are available. Evidence Acquisition: Recent trials of Intrinsa in postmenopausal women were included. A MEDLINE search was conducted for articles published over the last 40 yr based on the key words androgen therapy/replacement and postmenopausal women. Relevant placebo-controlled trials of nontransdermal an...

Previous studies have revealed that exogenous estrogen has a beneficial effect on the lipid profile; however, studies examining the relation between endogenous hormones and lipid profiles in postmenopausal women have yielded conflicting results. We sought to characterize the cross-sectional relationship between endogenous hormones and lipid parameters in postmenopausal women with significant (cases, n = 156) and minimal (controls, n = 172) carotid atherosclerosis not taking hormone therapy in the Atherosclerosis Risk in Communities Study. Endogenous hormone status was assessed by measuring levels of estrone, total testosterone, androstenedione, dehydroepiandrosterone sulfate, and SHBG. Free testosterone was estimated using the free androgen index (total testosterone/SHBG). Lipid parameters assessed included total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. We found that SHBG was significantly associated with a more favorable lipid profile, including lower total and LDL cholesterol and triglycerides and higher HDL cholesterol among controls. This association was less prominent among cases where SHBG was only associated with higher triglycerides and lower HDL cholesterol. The free androgen index was associated with a more atherogenic lipid profile, including increased LDL cholesterol among controls and increased total and LDL cholesterol and triglycerides among cases. These relations were independent of demographic and metabolic factors and health behaviors. In contrast to controls, estrone was associated with higher total cholesterol and triglycerides among cases in multivariate analyses. Our data suggest that endogenous sex hormones may play a role in regulating lipid metabolism in postmenopausal women.

Reduced bone mineral density (BMD) and abnormalities in fat redistribution, glucose homeostasis, and lipid metabolism are prevalent among HIV-infected patients on highly active antiretroviral therapy (HAART). The relationship between the metabolic and skeletal complications of HIV is unclear. Fifty-one HIV patients on HAART (aged 30-54 yr, 86% male) and 21 HIV-negative control subjects (aged 31-51 yr, 82% male) were examined with oral glucose tolerance testing, a fasting lipid profile, and dual x-ray absorptiometry, and markers of bone formation (serum osteocalcin) and resorption (urinary deoxypyridinoline). HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis (World Health Organization criteria) at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P = 0.02) and evidence of increased bone resorption (urine deoxypyridinoline, 14.7 +/- 6.5 vs. 10.9 +/- 2.5 nmol/mmol creatinine, P = 0.012). Among the HIV-infected patients, those with reduced bone mineral density (n = 32) were similar to the group with normal BMD (n = 19) in the use of protease inhibitors, duration of HAART therapy, or other demographic variables. Plasma glucose 2 h after a glucose load (odds ratio 1.02 per 1 mg/dl increase, 95% confidence interval 1.01-1.05, P = 0.009) and central adiposity (trunk fat/total fat) (odds ratio 1.09 per 1% ratio increase, 95% confidence interval 1.00-1.18, P = 0.012) were associated with reduced BMD. These associations remained significant in a multivariate model including age and body mass index. Bone resorption was associated with female gender (P < 0.001) and non-high-density lipoprotein cholesterol (P = 0.034) in a multivariate linear regression model controlling for age, body mass index, protease inhibitor use, duration of HAART, and extremity fat. Reduced BMD is prevalent in HIV-infected patients on HAART and is related to central adiposity and postload hyperglycemia. Bone resorption is independently associated with female gender and dyslipidemia. HIV-infected patients with metabolic abnormalities may represent a population that would benefit from bone density screening.

Cross-sex hormone treatment is an important component in medical treatment of transsexual people. Endocrinologists are often faced with designing treatment recommendations. Although guidelines from organizations, such as the Harry Benjamin International Gender Dysphoria Association, have been helpful, management remains complex and experience guided. We discuss the range of treatment used by transsexual people, the rationale behind these, and the expectation from such treatment. Recommendations from seven clinical research centers treating transsexual people are discussed. In addition, self-reported hormonal regimens from 25 male-to-female transsexual people and five female-to-male transsexual people are reported. Finally, the potential adverse effects of cross-sex hormone treatment of transsexual people are reviewed. In light of the complexity of managing treatment goals and adverse effects, the active involvement of a medical doctor experienced in cross-sex hormonal therapy is vital to ensure the safety of transsexual people.

The purpose of this study was to review the preclinical and clinical literature relevant to the efficacy and safety of anabolic androgen steroid therapy for palliative treatment of severe weight loss associated with chronic diseases. Data sources were published literature identified from the Medline database from January 1966 to December 2000, bibliographic references, and textbooks. Reports from preclinical and clinical trials were selected. Study designs and results were extracted from trial reports. Statistical evaluation or meta-analysis of combined results was not attempted. Androgenic anabolic steroids (AAS) are widely prescribed for the treatment of male hypogonadism; however, they may play a significant role in the treatment of other conditions as well, such as cachexia associated with human immunodeficiency virus, cancer, burns, renal and hepatic failure, and anemia associated with leukemia or kidney failure. A review of the anabolic effects of androgens and their efficacy in the treatment of these conditions is provided. In addition, the numerous and sometimes serious side effects that have been known to occur with androgen use are reviewed. Although the threat of various side effects is present, AAS therapy appears to have a favorable anabolic effect on patients with chronic diseases and muscle catabolism. We recommend that AAS can be used for the treatment of patients with acquired immunodeficiency syndrome wasting and in severely catabolic patients with severe burns. Preliminary data in renal failure-associated wasting are also positive. Advantages and disadvantages should be weighed carefully when comparing AAS therapy to other weight-gaining measures. Although a conservative approach to the use of AAS in patients with chronic diseases is still recommended, the utility of AAS therapy in the attenuation of severe weight loss associated with disease states such as cancer, postoperative recovery, and wasting due to pulmonary and hepatic disease should be more thoroughly investigated.

Serum lipoproteins and cardiovascular risk are affected by endogenous and exogenous sex hormones. As part of a multicenter evaluation of a permeation-enhanced testosterone transdermal system (TTD), the interrelationships among serum lipoproteins, hormone levels, anthropometric parameters, and age were investigated in 29 hypogonadal men. Subjects (aged 21-65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 +/- 1.6% (+/-SEM); P

Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.

Testosterone (T) therapy for hypogonadal men should correct the clinical abnormalities of T deficiency, including improvement of sexual function, increase in muscle mass and strength, and decrease in fat mass, with minimal adverse effects. We have shown that administration of a new transdermal T gel formulation to hypogonadal men provided dose proportional increases in serum T levels to the normal adult male range. We now report the effects of 180 days of treatment with this 1% T gel preparation (50 or 100 mg/day, contained in 5 or 10 g gel, respectively) compared to those of a permeation-enhanced T patch (5 mg/day) on defined efficacy parameters in 227 hypogonadal men. In the T gel groups, the T dose was adjusted up or down to 75 mg/day (contained in 7.5 g gel) on day 90 if serum T concentrations were below or above the normal male range. No dose adjustment was made with the T patch group. Sexual function and mood changes were monitored by questionnaire, body composition was determined by dual energy x-ray absorptiometry, and muscle strength was measured by the one repetitive maximum technique on bench and leg press exercises. Sexual function and mood improved maximally on day 30 of treatment, without differences across groups, and showed no further improvement with continuation of treatment. Mean muscle strength in the leg press exercise increased by 11 to 13 kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/chest muscle strength. At 90 days of treatment, lean body mass increased more in the 100 mg/day T gel group (2.74 6 0.28 kg; P 5 0.0002) than in the 50 mg/day T gel (1.28 6 0.32 kg) and T patch groups (1.20 6 0.26 kg). Fat mass and percent fat were not significantly decreased in the T patch group, but showed decreases in the T gel groups (50 mg/day, 20.90 6 0.32 kg; 100 mg/day, 21.05 6 0.22 kg). The increase in lean mass and the decrease in fat mass were correlated with the changes in average serum T levels attained after transdermal T replacement. These beneficial effects of T replacement were accompanied by the anticipated increases in hematocrit and hemoglobin but without significant changes in the lipid profile. The increase in mean serum prostate-specific antigen levels (within the normal range) was correlated with serum levels of T. The greatest increases were noted in the 100 mg/day T gel group. Skin irritation was reported in 5.5% of subjects treated with T gel and in 66% of subjects in the permeationenhanced T patch group. We conclude that T gel replacement improved sexual function and mood, increased lean mass and muscle strength (principally in the legs), and decreased fat mass in hypogonadal men with less skin irritation and discontinuation compared with the recommended dose of the permeation-enhanced T patch. (J Clin Endocrinol Metab 85: 2839 ‐2853, 2000)

The pharmacokinetics, efficacy, and safety of the Androderm testosterone (T) transdermal system (TTD) and intramuscular T enanthate injections (IM) for the treatment of male hypogonadism were compared in a 24-week multicenter, randomized, parallel-group study. Sixty-six adult hypogonadal men (22–65 years of age) were withdrawn from prior IM treatment for 4–6 weeks and then randomly assigned to treatment with TTD (two 2.5-mg systems applied nightly) or IM (200 mg injected every 2 weeks); there were 33 patients per group. Twenty-six patients in the TTD group and 32 in the IM group completed the study. TTD treatment produced circadian variations in the levels of total T, bioavailable T, dihydrotestosterone, and estradiol within the normal physiological ranges. IM treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients (range, 77–100%) than IM patients (range, 19–84%). Both treatments normalized LH levels in approximately 50% of patients with primary hypogonadism; however, LH levels were suppressed to the subnormal range in 31% of IM patients vs. 0% of TTD patients. Both treatments maintained sexual function (assessed by questionnaire and Rigiscan) and mood (Beck Depression Inventory) at the prior treatment levels. Prostate-specific antigen levels, prostate volumes, and lipid and serum chemistry parameters were comparable in both treatment groups. Transient skin irritation from the patches was reported by 60% of the TTD patients, but caused only three patients (9%) to discontinue treatment. IM treatment produced local reactions in 33% of patients and was associated with significantly more abnormal hematocrit elevations (43.8% of patients) compared with TTD treatment (15.4% of patients). Gynecomastia resolved more frequently during TTD treatment (4 of 10 patients) than with IM treatment (1 of 9 patients). Although both treatments seem to be efficacious for replacing T in hypogonadal men, the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over IM in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.

Transbuccal administration of drugs provides an easy route of administration. To test the safety and efficacy of a novel testosterone (T) product, we performed a randomized, double blind, placebo-controlled study in a parallel design. Men with serum T levels below 250 ng/dL were administered either an active buccal tablet containing 10 mg T (n = 7) or a buccal placebo tablet (n = 6) containing 3 mg pseudoephedrine HCl for taste matching. Men were studied while taking a standard T enanthate dose, after 6 weeks of a wash-out period, and after 8 weeks of therapy. The men were matched for age (mean ± sd, 41 ± 16 vs. 47 ± 16) and type of hypogonadism (three primary testicular failures in each group, with the remainder having a central etiology). Acute pharmacokinetic testing showed peak serum hormone levels at 30 min, with a mean serum T concentration of 2688 ± 147 ng/dL (range, 1820–3770 ng/dL). Levels returned to baseline in 4–6 h, resulting in a total T area under the curve level of 3865 ng/hn·dL, less than that using other available forms of T administration. Similar pharmacokinetics were observed for the hormone’s metabolites, bioavailable T, free T, and estradiol. After 8 weeks of treatment, the results of nocturnal penile tumescence studies evaluating rigidity and circumference were significantly different from those in the placebo group (P < 0.05) and comparable to those during T enanthate therapy. In conclusion, transbuccal T therapy was sufficient to maintain normal sexual function while minimizing the total time of exposure to elevated circulating serum T levels.

Weight loss is commonly associated with increased morbidity and mortality in individuals with human immunodeficiency virus (HIV) infection. We performed a nested case-control study of 26 HIV-infected subjects recruited from a cohort of gay men enrolled in the Multicenter Acquired Immunodeficiency Syndrome Cohort Study. To test the hypothesis that hormonal changes precede and may induce the wasting syndrome, we performed a nested case-control study and analyzed serum gonadal steroids and GH in samples of HIV-infected men with or without weight loss, uncomplicated by diarrhea or ever having an opportunistic infection. We studied 13 cases (mean age +/- SD, 45 +/- 7.2 yr) with a mean weight loss of 13 +/- 3.6%, considered to have the wasting syndrome by Centers for Disease Control criteria (weight loss of10%) and 13 controls matched for age and duration of follow-up. Serum bioavailable testosterone (T) levels decreased in the case group (P0.05) before the definition of wasting was attained, although weight loss had already begun. More impressive declines occurred in serum T (P = 0.012), free T (P = 0.0025), and bioavailable T (P0.0001) during the 6 months immediately before documentation of wasting. These changes were concurrent with an increase in serum FSH (P = 0.0135) without a change in serum LH. We conclude that a decline in bioavailable T occurs early in the course of events leading to wasting, suggesting that changes in gonadal hormones may contribute to the multifactorial etiology of the wasting syndrome.