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The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection∗

      Abstract

      PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients.
      SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification.
      RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone—placebo) in mean weight change (−0.3 kg [95% confidence interval (CI): −1.4 to 0.8]) or body cell mass (−0.2 kg [95% CI: −1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group.
      CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.
      Weight loss and wasting in persons with advanced human immunodeficiency virus (HIV) infection are strong predictors of morbidity and mortality (
      • Palenicek J.P
      • Graham N.M
      • He Y.D
      • et al.
      Weight loss prior to clinical AIDS as predictor of survival. Mulitcenter AIDS Cohort Study Investigators.
      ,
      • Suttmann U
      • Ockenga J
      • Selberg O
      • et al.
      Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients.
      ). Kotler and colleagues (
      • Kotler D.P
      • Tierney A.R
      • Wang J
      • Pierson Jr, R.N
      Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.
      ) have suggested that the time of death from wasting is related to the magnitude of body cell mass depletion: There is a critical body cell mass for survival, and maintaining this mass could prolong survival. Men with acquired immunodeficiency syndrome (AIDS) lose muscle with little loss of fat (
      • Kotler D.P
      • Wang J
      • Pierson Jr, R.N
      Body composition studies in patients with the acquired immunodeficiency syndrome.
      ). Moreover, the development of malnutrition may contribute to immune dysfunction, the development of opportunistic infections, and the progression of AIDS (
      • Kotler D.P
      • Tierney A.R
      • Wang J
      • Pierson Jr, R.N
      Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.
      ,
      • Sluys T.E.M.S
      • van der Ende M.E
      • Swart G.R
      • et al.
      Body composition in patients with acquired immunodeficiency syndrome a validation study of bioelectric impedance analysis.
      ).
      Wasting is a multifactorial problem (
      • Graham N.H.M
      • Rubb S
      • Hoover D.R
      • et al.
      Beta2-microglobulin and other early predictors of human immunodeficiency virus Type 1-related wasting.
      ,
      • Grunfeld C
      • Kotler D.P
      The wasting syndrome and nutritional support in AIDS.
      ,
      • Grunfeld C
      What causes wasting in AIDS?.
      ,
      • Grunfeld C
      • Feingold K.R
      Metabolic disturbances and wasting in the acquired immunodeficiency syndrome.
      ,
      • Melchior J.C
      • Salmon D
      • Rigaud D
      • et al.
      Resting energy expenditure is increased in stable, malnourished HIV-infected patients.
      ). However, hypogonadism in men who are HIV-infected is common (
      • Croxson T.S
      • William E.C
      • Miller L.K
      • et al.
      Changes in the hypothalamic-pituitary-gonadal axis in human immunodeficiency virus-infected homosexual men.
      ,
      • Martin M.E
      • Benassayag C
      • Amiel C
      • et al.
      Alterations in the concentrations and binding properties of sex steroid binding protein and corticosteroid-binding globulin in HIV+ patients.
      ), and it correlates with lymphocyte depletion (
      • Blackman M.R
      • Weintraub B.D
      • Rosen S.W
      • Harman S.M
      Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary-gonadal function in men.
      ,
      • Dobs A.S
      • Dempsey M.A
      • Ladenson P.W
      • Polk B.F
      Endocrine disorders in men infected with human immunodeficiency virus.
      ) and the degree of wasting (
      • Laudat A
      • Blum L
      • Guechot J
      • et al.
      Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men relationship with CD4 counts.
      ,
      • Coodley G
      • Loveless M
      HIV-associated wasting.
      ,
      • Christeff N
      • Lortholary O
      • Cassassus P
      • et al.
      Relationship between sex steroid hormones levels and CD4 lymphocytes in HIV infected men.
      ). Chronic illness (
      • DeKrester D.M
      The effects of systemic disease on the function of the testis.
      ), opportunistic infections (
      • Davidson J.M
      • Kwan M
      • Greenleaf W.J
      Hormonal replacement and sexuality in men.
      ,
      • Rodgers C
      • Klatt E.C
      Pathology of the testis in acquired immunodeficiency syndrome.
      ,
      • Ferreiro J
      • Vinters H.V
      Pathology of the pituitary gland in patients with the acquired immune deficiency syndrome.
      ,
      • Dalton A.D
      • Harcourt-Webster J.N
      The histopathology of the testis and epididymis in AIDS—a post-mortem study.
      ), and commonly used medicines, including megestrol acetate (

      Engleson ES, Pi-Sunyer FX, Kotler DP. Effects of megestrol acetate therapy on body composition and circulating testosterone concentrations in patients with AIDS. AIDS 1995;9:1107–1108. Letter.

      ) and ketoconazole (
      • Sonino N
      The use of ketokonazole as an inhibitor of steroid production.
      ), may also contribute to hypogonadism.
      Testosterone, an anabolic agent, may reverse weight loss. Skeletal muscle contains androgen receptors (
      • Kochakian C.D
      Definition of androgens and protein anabolic steroids.
      ) and testosterone administration in rats increases skeletal muscle protein synthesis and RNA polymerase activity (
      • Krieg M
      Characterization of the androgen receptor in the skeletal muscle of the rat.
      ). Chronic treatment increases muscle mass and decreases adipose tissue mass in castrated rats (
      • Rogozkin V
      Metabolic effects of anabolic steroids on skeletal muscle.
      ). Injections of testosterone in healthy men increases muscle mass and stimulates muscle protein synthesis (
      • Griggs R.C
      • Kingston W
      • Jozefowica R.F
      • et al.
      Effects of testosterone on muscle mass and muscle protein synthesis.
      ). Testosterone replacement in HIV-negative, hypogonadal men leads to increases in weight, fat-free mass, and muscle strength (
      • Bhasin S
      • Storer T.W
      • Berman N
      • et al.
      Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.
      ). Recently, Grinspoon and colleagues (
      • Grinspoon S
      • Corcoran C
      • Askari H
      • et al.
      Effects of androgen administration in men with AIDS wasting syndrome.
      ) demonstrated that intramuscular testosterone replacement led to significant increases in fat-free, lean body, and muscle mass, as well as improved quality of life.
      In this study we evaluated the effects of testosterone replacement using a transscrotal testosterone patch (6 mg/day) in men with hypogonadism and HIV-related wasting.

      Methods

      This multicenter, randomized, double-blinded, placebo-controlled trial compared the effects of transdermal scrotal testosterone patches (Testoderm, ALZA Corporation, Palo Alto, California) with identical placebo patches. Each testosterone patch system contained 15 mg of testosterone and was designed to release controlled amounts of testosterone continuously upon application to the scrotal skin. In hypogonadal men without HIV infection, this system provides delivery of 6 mg testosterone per day. The patch has two layers: a soft flexible backing of polyethylene terephthalate and a drug-containing film of ethylene-vinyl acetate copolymer impregnated with testosterone (
      • Cunningham G.R
      • Cordero R.N
      • Thornby J.I
      Testosterone replacement with transdermal therapeutic systems.
      ,

      Testoderm Testosterone Transdermal System. Product monograph [data on file]; ALZA Corporation, Palo Alto, California.

      ).
      After we explained the protocol and obtained signed consent, each subject underwent a baseline evaluation to determine eligibility, including HIV testing, verification of weight loss, and measurement of morning serum testosterone level. Enrolled participants were seen at weeks 2, 4, 8, and 12 after randomization. Weight was measured at all visits using the same instrument at each site. Serum hormone levels, bioelectrical impedance assessment of body composition, and quality of life questionnaires were measured at baseline and weeks 4, 8, and 12. There was no structured exercise program.
      The testosterone and placebo patch systems were identically packaged in foil-lined pouches. Patches were to be applied each morning and worn for 22 to 24 hours each day. Men were instructed to dry shave their scrotum weekly and use a hair dryer to warm the patch before application for better adherence.
      A private nutritionist provided nutritional evaluations based on 24-hour dietary recall at weeks 0, 4, 8, and 12. Each site faxed intake information to the study nutritionist after the patient visit. Total caloric and protein intake were estimated, and an assessment of their adequacy was faxed back to the site. If intake was not adequate, the site was instructed to counsel the patient on proper nutrition. The protocol was reviewed and approved by the human subjects committee at each participating institution.

      Study sample

      Men, 18 years of age and older, with a diagnosis of AIDS (based on 1993 Center for Disease Control criteria) were eligible for enrollment. Subjects were required to have lost between 5% and 20% of their baseline weight, as noted in their primary provider’s written records. Additional enrollment criteria included either a morning serum total testosterone level ≤400 ng/dL or a morning serum free testosterone level ≤16 pg/mL. Subjects could not have received testosterone or anabolic steroids within 6 months before entry into the study. Laboratory enrollment criteria included a prostate specific antigen (PSA) level <4 ng/mL, serum aminotransferase levels <5 times the upper limit of reference range, hemoglobin level >8.5 g/dL, and a hematocrit <54%. There were no restrictions on antiretroviral regimen or therapy or prophylaxis for pneumocystis carinii or Mycobacterium avium complex infections. Subjects were excluded if they had an active or recent opportunistic infection requiring systemic anti-infective agents, any predisposing condition affecting oral ingestion or food absorption, or concurrent therapy with medications known to affect testosterone metabolism or alter its serum levels (ie, spironlactone, megestrol acetate, dronabinol, or ketoconazole).
      Subjects were randomly assigned in equal proportions to either the active treatment or placebo group.

      Hormonal assays

      Morning serum was collected at weeks 0, 2, 4, 8, and 12 for measurement of total and free testosterone levels. All hormones were measured using standard radioimmunoassay techniques at one laboratory (Scicor). Corning Hazleton Laboratories assayed dihydrotestosterone levels after the study’s completion, using serum from day 0 and week 12 of the study.

      Outcome measures

      Body cell mass was measured by single frequency bioelectrical impedance analysis using the BIA 101Q instrument (RJL Systems, Inc., Clinton Township, Michigan) and the “Fluid and Nutrition Analysis Version 3.1” software, provided by the manufacturer. Bioelectrical impedance analysis is a validated, noninvasive method to determine body cell mass in a three-compartment model (
      • McDougall D
      • Shizgal H.M
      Body composition measurements from whole body resistance and reactance.
      ,
      • Kushner R.F
      • Schoeller D.A
      Estimation of total body water by bioelectrical impedance analysis.
      ,
      • Jodoin R.R
      • Trott S.G
      • Shizgal H.M
      Determination of whole body composition from whole body electrical impedance.
      ,
      • Shizgal H.M
      Validation of the measurement of body composition from whole body bioelectric impedance analysis.
      ). Measured resistance, reactance plus standard anthropometric measurements, and the patient’s age were used to determine body cell mass using prediction equations (Operations and Instructions Manual, RJL Systems, Inc.).
      To measure the effect of the intervention on HIV disease progression, serum specimens were collected at weeks 0 and 12 for measurement of lymphocyte subsets and plasma HIV-1 quantification. Plasma HIV-1 quantification was assayed by the Chiron Reference Testing Laboratory (Emeryville, California) using signal amplification technology for performing ultrasensitive branched-chain DNA assays, with a limit of detection of 500 equivalents/mL.
      Several self-assessment quality of life scales were administered at baseline and at weeks 4, 8, and 12 to evaluate overall mental health, pain, health perceptions, energy/fatigue, health distress, quality of life, health transitions, and cognitive/physical/social/sexual functioning. The validated instruments employed included the Rand HIV-Medical Outcomes Study short form instrument (

      RAND: Scoring Manual. Adult health status and patient satisfaction measures used in RAND’s health insurance experiment. 1988: Santa Monica, California: RAND Corp.

      ), the EUROQOL Feeling Thermometer scale (
      EUROQOL Group
      EUROQOL—a new facility for the measurement of health-related quality of life.
      ,
      • Jacobs D.O
      Bioelectrical impedance analysis a way to assess changes in body cell mass in patients with acquired immunodeficiency syndrome?.
      ), and the Sexual Functioning Questionnaire for males adapted from the Reynolds’s Sexual Assessment Scale and the Watts Sexual Functioning Questionnaire for Males (
      • Watts R.J
      Sexual function, health beliefs, and compliance with high blood pressure medications.
      ).

      Statistical analysis

      Sample size calculations were done to provide 90% power to detect a difference of 2.0 kg in the change in body cell mass from baseline to 12 weeks after treatment between the two groups, assuming a standard deviation of 3.0 kg and a two-sided alpha of 0.05. To allow for 20% attrition, the anticipated sample size was 124 subjects. The primary outcome variable was mean change in body cell mass evaluated by bioelectrical impedance analysis from baseline to week 12. Secondary efficacy parameters were mean change in body weight from baseline to week 12 and quality of life parameters. Two-sample t tests, chi-square tests, or two-way analysis of variance (ANOVA) were used as appropriate. All analyses were performed in SAS. For subjects who terminated the study before 12 weeks, the last “on-treatment” value was carried forward for analysis. This value had to be obtained within 5 days of termination of study treatment. Statistical significance was set at P <0.05 (two-sided). Continuous data are reported as mean ± SD.

      Results

      Of the 133 patients enrolled in the study, 67 received testosterone and 66 received placebo. A total of 110 men had at least one follow-up evaluation and were included in the analysis. Fifteen (23%) of the testosterone-treated subjects and 20 (30%) of the placebo-treated subjects did not complete the study. Reasons for premature termination were not significantly different between the treatment groups.
      Characteristics of the subjects were similar in the active treatment and control groups (Table 1). About half had a history of prior opportunistic infections. There were no significant between-group differences in weight, body cell mass, total and free testosterone levels (Figure 1, Figure 2 ) , and CD4 cell counts.
      Table 1Baseline Characteristics of All Enrolled Subjects
      Number (Percent) or Mean ± SDP Value
      Testosterone Patch (n = 67)Placebo Patch (n = 66)
      Age (years)0.09
      18–2905 (8%)
      30–4960 (90%)53 (80%)
      50–647 (10%)7 (11%)
      65+01 (1.5%)
      Mean39 ± 741 ± 80.23
      Race0.34
      Native American1 (1%)2 (3%)
      Asian2 (3%)0
      Black6 (9%)11 (17%)
      Caucasian51 (76%)44 (67%)
      Hispanic7 (10%)9 (41%)
      Current weight (kg)67.5 ± 12.369.3 ± 11.00.36
      Usual weight (kg)72.9 ± 13.574.1 ± 11.20.58
      Weight loss (%)
      From usual to current weight.
      7.3 ± 4.36.5 ± 3.10.19
      Height (cm)173.9 ± 7.0176.3 ± 7.90.06
      Body mass index (kg/m2)22.3 ± 3.722.3 ± 3.00.99
      History of opportunistic infection30 (45%)30 (46%)0.94
      CD4 lymphocyte count156 ± 143177 ± 1710.46
      From usual to current weight.
      Table 2Mean Changes (95% Confidence Interval) in Selected Parameters during the Study, and Between-Group Differences in Changes in Parameters
      ParameterChange in Testosterone-treated Subjects (n = 67)Change in Placebo-treated Subjects (n = 66)Difference (testosterone—Placebo)P value
      Body cell mass (kg)0.3 (−0.2, 0.9)0.6 (0, 1.1)−0.2 (−1.0, 0.6)0.55
      Weight (kg)0.8 (0, 1.5)1.1 (0.3, 1.8)−0.3 (−1.4, 0.8)0.60
      HIV-1 log (mEq/mL)−0.3 (−0.5, 0)−0.1 (0.3, 0.1)−0.1 (−0.4, 0.1)0.33
      CD4 lymphocyte count18 (−2, 38)24 (−10, 58)−7 (−45, 32)0.74
      Total testosterone level (ng/dL)277 (193, 361)30 (−27, 87)247 (142, 352)0.0001
      Free testosterone level (pg/mL)11 (8, 14)1 (−2, 3)10 (6, 14)0.0001
      Figure thumbnail GR1
      Figure 1Morning serum total testosterone levels (mean with 95% confidence intervals) at baseline and weeks 4, 8, and 12. Testosterone-treated subjects are shown in diamonds, placebo in squares. The change in serum testosterone level from baseline to week 12 was significant for testosterone-treated subjects (P <0.01); there was no significant change for the placebo-treated subjects (P = 0.3).
      Figure thumbnail GR2
      Figure 2Morning serum free testosterone levels (mean with 95% confidence intervals) at baseline and weeks 4, 8, and 12. Testosterone-treated subjects are shown in diamonds, placebo in squares. The change in serum testosterone level from baseline to week 12 was significant for testosterone-treated subjects (P <0.01); there was no significant change for the placebo-treated subjects (P = 0.6).

      Hormone changes

      At baseline, 44% of subjects had serum total testosterone levels ≤400 mg/dL, and 75% had free testosterone levels ≤16 pg/mL. Testosterone patches were effective in increasing serum testosterone levels (Figure 1, Figure 2). The mean total testosterone level in the subjects treated with testosterone patches at week 12 was 697 ± 327 ng/dL, a mean increase of 277 ± 43 ng/dL. Subjects treated with placebo had no significant change in total testosterone levels at week 12. Similarly, changes in free testosterone levels were apparent in testosterone-treated subjects by week 4 and maintained through the study, with a mean level of 24 ± 11 pg/dL at week 12 (a mean change of 11 ± 2 pg/mL). No changes were observed in the placebo-treated subjects.
      Serum dihydrotestosterone levels were similar in the two groups at baseline and increased only in the treatment group (to 183 ng/dL; 95% confidence interval [CI]: 197 to 220 ng/dL). No significant changes were seen in the placebo group.

      Body composition (table 2)

      Use of testosterone or placebo patches did not significantly affect body cell mass or weight. After up to 12 weeks, the difference in weight change between groups (testosterone—placebo) was −0.3 kg (95% CI: −1.4 to 0.8 kg, P = 0.6). The difference in change in body cell mass, −0.2 kg (CI: −0.3 to 0.6 kg, P = 0.6), was not statistically significant. Subgroup analysis by baseline total testosterone levels (<400, ≥400 ng/dL), free testosterone levels (<16 pg/mL, ≥16 pg/mL), and CD4 counts (<200, ≥200 cells/mm3) showed no significant testosterone-induced changes. Testosterone replacement failed to correct the pretreatment weight loss.
      The majority of patients in both groups consumed adequate calories and protein as determined by 24-hour recall: at week 12, 76% of testosterone-treated and 80% of placebo-treated subjects consumed adequate calories, and 64% of testosterone-treated and 61% of placebo-treated subjects had adequate protein intake. There were no statistically significant differences in caloric or protein consumption between the two groups.

      Immunologic parameters

      There were no significant differences between the testosterone and placebo groups in the changes in either CD lymphocyte subset (as absolute numbers or percentages), or plasma quantification of HIV-1. CD4 lymphocyte counts increased by 18 to a mean of 166 ± 171 cells/mm3 in the testosterone group, and by 24 to a mean of 193 ± 180 cells/mm3 in the placebo group (P = 0.74). The mean difference between treatment groups in change in HIV serum quantification during the course of the study was −0.1 log mEq/mL (95% CI: −0.4 to 0.1 log mEq/mL).

      Quality of life measures

      No statistically significant differences were observed between the testosterone and placebo groups in changes in overall health, pain, functioning, role or social functioning, mental health, energy/fatigue, health distress, cognitive functioning, quality of life, or health transition at baseline using the Rand HIV-Medical Outcomes Study short form instrument. A trend toward improvement with testosterone was noted in two areas: “overall health” (P = 0.05) and “cognitive functioning” (P = 0.08).
      Using the EUROQOL Feeling Thermometer, the testosterone and placebo groups were comparable at baseline, and neither group had statistically significant changes in mood at any time points measured. The testosterone group had a mean score of 73 ± 24 at week 12; the placebo group had a mean score of 74 ± 21. No differences were noted between the testosterone and placebo groups in sexual function and satisfaction at baseline, nor were any changes noted at 4, 8, or 12 weeks in either group. The patches were well-tolerated. Adverse event rates, including any local reaction to the patch, were comparable in the testosterone (1.4%) and placebo (1.5%) groups.

      Discussion

      This multicenter, placebo-controlled study demonstrated that hypogonadal men with AIDS and documented 5% to 20% weight loss could achieve adequate morning serum testosterone levels using a transscrotal testosterone delivery system applied in the morning. However, there was no effect on weight, body cell mass, measured quality of life parameters, or sexual function. There were no differences in adverse events between subjects treated with testosterone or placebo, and there were no differences in changes in CD4 lymphocyte counts and percentages, or plasma HIV-1 RNA quantification. Serum dihydrotestosterone levels were greater than normal in testosterone-treated subjects, likely due to the high level of 5 alpha-reductase activity in scrotal skin. The clinical significance of this increase is unknown.
      There are several possible explanations for why replacement with testosterone failed to reverse weight loss. Progressive malnutrition and body cell mass depletion in AIDS patients can be resistant to therapy, even during periods of clinical stability, and this may include resistance to the anabolic effects of testosterone replacement (
      • Kotler D.P
      • Wang J
      • Pierson Jr, R.N
      Body composition studies in patients with the acquired immunodeficiency syndrome.
      ,
      • Hellerstein M.K
      • Kahn J
      • Mudie H
      • Viteri F
      Current approach to the treatment of human immunodeficiency virus-associated weight loss pathophysiologic considerations and emerging management strategies.
      ). Furthermore, the AIDS wasting syndrome may be caused by a combination of hormonal abnormalities. Ng and colleagues (
      • Ng T.T.C
      • O’Connell I.P.M
      • Wilkins E.G.L
      Growth hormone deficiency coupled with hypogonadism in AIDS.
      ) reported growth hormone deficiency along with hypogonadism in patients with AIDS and suggested that the hypogonadism was a result of the pituitary dysfunction associated with growth hormone deficiency. In that case, testosterone replacement alone would not be expected to be sufficient. The role of cytokines in HIV-related weight loss also needs further consideration (
      • Hellerstein M.K
      • Wu K
      • McGrath M
      • et al.
      Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the acquired immune deficiency syndrome relation to indices of cytokine production.
      ,
      • Maury C.P.J
      • Lahdevirta J
      Correlation of serum cytokine levels with hematological abnormalities in human immunodeficiency virus infection.
      ).
      Physical exercise, nutritional status, and degree of exercise training (
      • Swerdloff R.S
      • Wang C
      Androgen and aging in men.
      ) influence the effects of exogenous androgens. There was no systematic exercise component to the intervention, and lack of exercise may have limited the efficacy of testosterone.
      Bioelectrical impedance analysis may have been unable to detect changes in body cell mass, although this is unlikely. Body composition measurements by bioelectrical impedance analysis in AIDS patients are strongly correlated with the results of deuterium and sodium chloride (22NaCl) dilution (
      • Sluys T.E.M.S
      • van der Ende M.E
      • Swart G.R
      • et al.
      Body composition in patients with acquired immunodeficiency syndrome a validation study of bioelectric impedance analysis.
      ). Among HIV-infected men, there are no significant differences between mean lean-body mass estimates obtained by total body electrical conductivity using a prediction equation based on body mass index, or by bioelectrical impedance analyses (
      • Risser J.M.H
      • Rabeneck L
      • Foote L.W
      • Klish W.J
      A comparison of fat-free mass estimates in men infected with the human immunodeficiency virus.
      ). Bioelectrical impedance is less accurate in estimating body cell mass if there has been a change in the normally constant relation between body fluid and lean body mass, as may occur in patients with AIDS who have changes in total body water and its distribution, opportunistic infections, and abnormal hydration states (
      • Sluys T.E.M.S
      • van der Ende M.E
      • Swart G.R
      • et al.
      Body composition in patients with acquired immunodeficiency syndrome a validation study of bioelectric impedance analysis.
      ,
      • Jacobs D.O
      Bioelectrical impedance analysis a way to assess changes in body cell mass in patients with acquired immunodeficiency syndrome?.
      ). Subjects in this study did not have any opportunistic infections that required systemic therapy, nor did they have intractable diarrhea or marked dehydration. Moreover, although testosterone may increase sodium absorption, body weight did not change significantly during the study. Consequently, there are no reasons to suspect any major changes in the relation between lean body mass and body fluid content during the study.
      The lack of improvement in several measures of quality of life with testosterone replacement therapy is somewhat surprising. This suggests that adequate levels of hormone were not maintained throughout the day, or that the subjects were not truly hypogonadal at baseline. A recent study demonstrated that intramuscular testosterone replacement increased fat-free, lean body, and muscle mass in HIV-infected hypogonadal men (
      • Grinspoon S
      • Corcoran C
      • Askari H
      • et al.
      Effects of androgen administration in men with AIDS wasting syndrome.
      ). Perhaps the transscrotal delivery of testosterone was ineffective at maintaining hormone levels or did not achieve peak serum levels necessary for an anabolic effect. Given the lack of effect on quality of life and sexual function, we believe the transscrotal patch did not maintain adequate serum testosterone levels throughout the day.
      Our sample may have been too small to detect small changes in quality of life. Baseline quality of life was relatively high and offered limited opportunity for improvement. Our instruments may have been inadequate, or the 12-week duration of study may have been too short, to detect relatively small changes. Finally, there are conflicting reports of the prevalence of hyperprolactinemia in HIV-infected men (
      • Graef A.S
      • Gonzalez S.S
      • Baca V.R
      • et al.
      High serum prolactin levels in asymptomatic HIV-infected patients and patients with acquired immunodeficiency syndrome.
      ,
      • Gorman J.M
      • Warne P.A
      • Begg M.D
      • et al.
      Serum prolactin levels in homosexual and bisexual men with HIV infection.
      ,
      • Chernow B
      • Schooley R.T
      • Dracup K
      • et al.
      Serum prolactin concentrations in patients with the acquired immunodeficiency syndrome.
      ). Correction of hyperprolactinemia, if present, may be required before testosterone hormone replacement is effective in correcting sexual dysfunction.
      Because AIDS-related weight loss is a complex problem, patients require evaluation of their nutritional needs, gastrointestinal absorptive and digestive capabilities, metabolic demands, exercise capabilities, psychosocial concerns, cytokine levels, and serum hormone levels. Treatment of HIV-associated weight loss will likely require a multifaceted approach. The role of anabolic steroids requires further investigation. Although it is reassuring that testosterone replacement did not adversely affect immune status, this study suggests that testosterone replacement administered via a scrotal patch does not reverse the loss of body cell mass or improve quality of life.

      References

        • Palenicek J.P
        • Graham N.M
        • He Y.D
        • et al.
        Weight loss prior to clinical AIDS as predictor of survival. Mulitcenter AIDS Cohort Study Investigators.
        J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10: 336-373
        • Suttmann U
        • Ockenga J
        • Selberg O
        • et al.
        Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients.
        J AIDS Hum Retrovirol. 1995; 8: 239-246
        • Kotler D.P
        • Tierney A.R
        • Wang J
        • Pierson Jr, R.N
        Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.
        Am J Clin Nutr. 1989; 50: 444-447
        • Kotler D.P
        • Wang J
        • Pierson Jr, R.N
        Body composition studies in patients with the acquired immunodeficiency syndrome.
        Am J Clin Nutr. 1985; 42: 1255-1265
        • Sluys T.E.M.S
        • van der Ende M.E
        • Swart G.R
        • et al.
        Body composition in patients with acquired immunodeficiency syndrome.
        J Parenter Enteral Nutr. 1993; 17: 404-406
        • Graham N.H.M
        • Rubb S
        • Hoover D.R
        • et al.
        Beta2-microglobulin and other early predictors of human immunodeficiency virus Type 1-related wasting.
        AEP. 1994; 4: 32-39
        • Grunfeld C
        • Kotler D.P
        The wasting syndrome and nutritional support in AIDS.
        Semin Gastrointest Dis. 1991; 2: 25-36
        • Grunfeld C
        What causes wasting in AIDS?.
        NEJM. 1995; 333: 123-124
        • Grunfeld C
        • Feingold K.R
        Metabolic disturbances and wasting in the acquired immunodeficiency syndrome.
        NEJM. 1992; 327: 329-337
        • Melchior J.C
        • Salmon D
        • Rigaud D
        • et al.
        Resting energy expenditure is increased in stable, malnourished HIV-infected patients.
        Am J Clin Nutr. 1991; 53: 437-441
        • Croxson T.S
        • William E.C
        • Miller L.K
        • et al.
        Changes in the hypothalamic-pituitary-gonadal axis in human immunodeficiency virus-infected homosexual men.
        J Clin Endocrinol Metab. 1989; 68: 317-321
        • Martin M.E
        • Benassayag C
        • Amiel C
        • et al.
        Alterations in the concentrations and binding properties of sex steroid binding protein and corticosteroid-binding globulin in HIV+ patients.
        J Endocrinol Inves. 1992; 15: 597-603
        • Blackman M.R
        • Weintraub B.D
        • Rosen S.W
        • Harman S.M
        Comparison of the effects of lung cancer, benign lung disease, and normal aging on pituitary-gonadal function in men.
        J Clin Endocrinol Metab. 1988; 66: 88-95
        • Dobs A.S
        • Dempsey M.A
        • Ladenson P.W
        • Polk B.F
        Endocrine disorders in men infected with human immunodeficiency virus.
        Am J Med. 1988; 84: 611-616
        • Laudat A
        • Blum L
        • Guechot J
        • et al.
        Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men.
        Eur J Endocrinol. 1995; 133: 418-424
        • Coodley G
        • Loveless M
        HIV-associated wasting.
        J Acquir Immune Defic Syndr Hum Retrovirol. 1991; 4: 826
        • Christeff N
        • Lortholary O
        • Cassassus P
        • et al.
        Relationship between sex steroid hormones levels and CD4 lymphocytes in HIV infected men.
        Exper Clin Endocrinol Diabet. 1996; 104: 130-136
        • DeKrester D.M
        The effects of systemic disease on the function of the testis.
        Clin Endocrinol Metab. 1979; 8: 487-498
        • Davidson J.M
        • Kwan M
        • Greenleaf W.J
        Hormonal replacement and sexuality in men.
        Clin Endocrinol Metab. 1982; 11: 599-623
        • Rodgers C
        • Klatt E.C
        Pathology of the testis in acquired immunodeficiency syndrome.
        Histopathology. 1988; 12: 659-665
        • Ferreiro J
        • Vinters H.V
        Pathology of the pituitary gland in patients with the acquired immune deficiency syndrome.
        Pathology. 1988; 20: 211-215
        • Dalton A.D
        • Harcourt-Webster J.N
        The histopathology of the testis and epididymis in AIDS—a post-mortem study.
        J Pathology. 1991; 163: 47-52
      1. Engleson ES, Pi-Sunyer FX, Kotler DP. Effects of megestrol acetate therapy on body composition and circulating testosterone concentrations in patients with AIDS. AIDS 1995;9:1107–1108. Letter.

        • Sonino N
        The use of ketokonazole as an inhibitor of steroid production.
        NEJM. 1987; 317: 812-818
        • Kochakian C.D
        Definition of androgens and protein anabolic steroids.
        Pharmacol Ther. 1975; 1: 49-177
        • Krieg M
        Characterization of the androgen receptor in the skeletal muscle of the rat.
        Steroids. 1976; 28: 261-274
        • Rogozkin V
        Metabolic effects of anabolic steroids on skeletal muscle.
        Med Sci Sports Exer. 1979; 11: 160-166
        • Griggs R.C
        • Kingston W
        • Jozefowica R.F
        • et al.
        Effects of testosterone on muscle mass and muscle protein synthesis.
        J Appl Physiol. 1989; 66: 498-503
        • Bhasin S
        • Storer T.W
        • Berman N
        • et al.
        Testosterone replacement increases fat-free mass and muscle size in hypogonadal men.
        J Clin Endocrinol Metab. 1997; 82: 407-413
        • Grinspoon S
        • Corcoran C
        • Askari H
        • et al.
        Effects of androgen administration in men with AIDS wasting syndrome.
        Ann Intern Med. 1998; 129: 18-26
        • Cunningham G.R
        • Cordero R.N
        • Thornby J.I
        Testosterone replacement with transdermal therapeutic systems.
        JAMA. 1989; 261: 2525-2530
      2. Testoderm Testosterone Transdermal System. Product monograph [data on file]; ALZA Corporation, Palo Alto, California.

        • McDougall D
        • Shizgal H.M
        Body composition measurements from whole body resistance and reactance.
        Surg Forum. 1986; 37: 42-54
        • Kushner R.F
        • Schoeller D.A
        Estimation of total body water by bioelectrical impedance analysis.
        Am J Clin Nutr. 1986; 44: 417-424
        • Jodoin R.R
        • Trott S.G
        • Shizgal H.M
        Determination of whole body composition from whole body electrical impedance.
        Surg Forum. 1988; 39: 50-52
        • Shizgal H.M
        Validation of the measurement of body composition from whole body bioelectric impedance analysis.
        Infusions Therapie. 1990; 17: 64-74
      3. RAND: Scoring Manual. Adult health status and patient satisfaction measures used in RAND’s health insurance experiment. 1988: Santa Monica, California: RAND Corp.

        • EUROQOL Group
        EUROQOL—a new facility for the measurement of health-related quality of life.
        Health Policy. 1990; 16: 199-200
        • Jacobs D.O
        Bioelectrical impedance analysis.
        J Parenter Enteral Nutr. 1993; 17: 401-402
        • Watts R.J
        Sexual function, health beliefs, and compliance with high blood pressure medications.
        Nurs Res. 1982; 31: 278-283
        • Hellerstein M.K
        • Kahn J
        • Mudie H
        • Viteri F
        Current approach to the treatment of human immunodeficiency virus-associated weight loss.
        Semin Oncol. 1990; 17: 17-33
        • Ng T.T.C
        • O’Connell I.P.M
        • Wilkins E.G.L
        Growth hormone deficiency coupled with hypogonadism in AIDS.
        Clin Endocrinol. 1994; 41: 689-694
        • Hellerstein M.K
        • Wu K
        • McGrath M
        • et al.
        Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the acquired immune deficiency syndrome.
        J Acquir Immune Defic Syndr Hum Retrovirol. 1996; 11: 258-270
        • Maury C.P.J
        • Lahdevirta J
        Correlation of serum cytokine levels with hematological abnormalities in human immunodeficiency virus infection.
        J Intern Med. 1990; 227: 253-257
        • Swerdloff R.S
        • Wang C
        Androgen and aging in men.
        Exper Gerontol. 1993; 28: 435-446
        • Risser J.M.H
        • Rabeneck L
        • Foote L.W
        • Klish W.J
        A comparison of fat-free mass estimates in men infected with the human immunodeficiency virus.
        J Parenter Enteral Nutr. 1995; 19: 28-32
        • Jacobs D.O
        Bioelectrical impedance analysis.
        J Parenter Enteral Nutr. 1993; 17: 401-402
        • Graef A.S
        • Gonzalez S.S
        • Baca V.R
        • et al.
        High serum prolactin levels in asymptomatic HIV-infected patients and patients with acquired immunodeficiency syndrome.
        Clin Immunol Immunopathol. 1994; 72: 390-393
        • Gorman J.M
        • Warne P.A
        • Begg M.D
        • et al.
        Serum prolactin levels in homosexual and bisexual men with HIV infection.
        Am J Psych. 1992; 149: 367-370
        • Chernow B
        • Schooley R.T
        • Dracup K
        • et al.
        Serum prolactin concentrations in patients with the acquired immunodeficiency syndrome.
        Crit Care Med. 1990; 18: 440-441