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Prevalence of Hypogonadism among Men with Weight Loss Related to Human Immunodeficiency Virus Infection Who Were Receiving Highly Active Antiretroviral Therapy

  1. Petra Rietschel1,
  2. Colleen Corcoran1,
  3. Takara Stanley1,
  4. Nesli Basgoz2,
  5. Anne Klibanski1, and
  6. Steven Grinspoon1
  1. 1 Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
  2. 2 Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
  1. Reprints or correspondence: Dr. Steven Grinspoon, Neuroendoctrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, MA 02114 (sgrinspoon{at}partners.org).
 
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Abstract

Previous studies have indicated that there is a significant prevalence (50%) of hypogonadism among men with acquired immunodeficiency syndrome (AIDS)–associated wasting, and for these patients testosterone administration has been shown to increase lean body mass and improve quality of life. However, the prevalence of hypogonadism is not known among men with weight loss related to human immunodeficiency virus (HIV) infection who are receiving highly active antiretroviral therapy (HAART). From 1997 through 1999, we investigated total and free testosterone levels in 90 men who were <90% of ideal body weight or had weight loss of >10% from preillness weight; 71% of these subjects were receiving HAART. Twenty-one percent of the subjects receiving HAART had low free testosterone levels. No correlation was seen between weight, CD4 cell count, medication status, and other clinical factors. These data suggest that hypogonadism remains relatively common in men with AIDS wasting, despite treatment with HAART. HIV-infected men with wasting syndrome should be screened for hypogonadism and receive physiological androgen replacement therapy if they are hypogonadal.

Hypogonadism is common in HIV-infected men. In a study of endocrine disorders in men with AIDS in 1988, Dobs et al. [1] found that 50% of the men had hypogonadism, as assessed by total testosterone levels. In another study by Rafi et al. [2] in 1991, a smaller but significant prevalence of hypogonadism (29%) was found among men with AIDS, also as assessed by total testosterone levels. In a study by Laudat et al. [3], unbound testosterone levels were significantly lower in asymptomatic HIV-infected men than in age-matched, non-HIV–infected control subjects. In a study conducted in 1995 and 1996, we [4] described a reduction in free testosterone levels in 49% of HIV-infected men with AIDS wasting, but testosterone levels did not correlate with weight or CD4 cell count. Similarly, Dobs et al. [5] demonstrated that bioavailable testosterone levels were reduced before weight loss in a nested case-control study of HIV-seropositive men enrolled in the Multicenter AIDS Cohort Study initiated in 1984. Screening for androgen deficiency has become common practice in AIDS clinics. Most studies now demonstrate that testosterone replacement therapy increases lean body mass and improves quality of life in hypogonadal men with AIDS wasting [6–8], although the effects of testosterone may be less, depending on initial testosterone levels and the type of testosterone preparation used [9, 10].

However, the prevalence of hypogonadism and its relationship to wasting among HIV-infected men receiving highly active antiretroviral therapy (HAART) is unknown. Given the enormous impact of such therapy on the long-term health and management of HIV-infected patients, it is important to determine whether hypogonadism remains a significant problem in this population. Berger et al. [11] reported that 25% of men with wasting who were identified in 1996 and 1997 were hypogonadal, as assessed by either total or free testosterone levels. However, testosterone levels in patients identified by chart review were assessed retrospectively. Therefore, from 1997 through 1999, we prospectively screened 90 consecutive men with weight loss related to HIV infection for gonadal function, most (71%) of whom were receiving HAART. Our data demonstrate that hypogonadism is less prevalent in the era of potent antiviral therapy (even among men with significant weight loss related to HIV infection) but nonetheless occurs in a significant minority of such men.

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Patients and Methods

Experimental subjects and study design. From November 1997 through April 1999, 90 HIV-infected men were screened for hypogonadism. Subjects were recruited for a treatment study of AIDS-related weight loss through newspaper advertising, community referrals, and the multidisciplinary HIV clinic of the Massachusetts General Hospital (Boston). HIV-infected subjects were asked during a telephone screening about their history of weight loss, opportunistic infections, and medications. Subjects with a history of recent opportunistic infection (within 6 weeks of screening) or those using testosterone, megestrol acetate, or other anabolic agents within the previous 3 months were excluded from further study. Subjects deemed eligible by telephone screening who identified low weight or a significant history of weight loss were investigated at the General Clinical Research Center, Massachusetts General Hospital.

History of weight loss, medication use, and opportunistic infection and recent CD4 cell count were confirmed. Height and weight were assessed, and percentage of ideal body weight (IBW) was determined by using standardized height and weight tables [12]. Symptoms of hypogonadism were assessed, and blood samples were obtained for determination of total and free testosterone levels in subjects with confirmed weight of <90% of IBW or weight loss of >10% (AIDS wasting group). In a subset of 54 patients with free testosterone levels of >12.0 pg/mL, further blood samples were obtained at a subsequent visit for determination of sex hormone–binding globulin (SHBG) levels. Antiviral medication was classified according to current use of protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), or nonnucleoside reverse transcriptase inhibitors (NNRTIs) use. HAART was defined as treatment with 2 NRTIs and either a PI or an NNRTI.

Two control groups were also investigated: 19 age-matched HIV-infected men with weight loss of <10% of IBW who did not have complaints of wasting, and 22 age-matched healthy men without prior illness or use of any medication known to affect gonadal status.

Laboratory assessment and methodology. Serum levels of total and free testosterone were measured by use of RIA kits (Diagnostics Products, Los Angeles) with intra-assay coefficients of variation of 5%–12% for total testosterone and 3.2%–4.3% for free testosterone. SHBG levels were measured according to previously reported methods [13].

Statistical analysis. The HIV-infected subjects with wasting and without wasting were each compared with the healthy control group by using Dunnett's test. Pearson correlation coefficients were determined for clinical variables for the HIV-infected group with wasting. Clinical variables for men with AIDS wasting were also compared by medication status (HAART and use of PI, NRTI, and NNRTI) by use of Student's t test, and these variables were compared with those for the healthy control group by use of Dunnett's test.

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Results

The clinical characteristics of the study subjects are shown in table 1. The subjects with wasting weighed significantly less than did healthy control subjects, whereas the mean weight ± SEM of patients without wasting was not significantly different from that of healthy control subjects. As expected, weight loss was significantly greater in the wasting group. The mean total duration of weight loss (time from maximum weight to current weight) ± SEM was 5 ± 1 years. The mean percentage of weight loss ± SEM over the year before the study and over the month before the study was 5.2% ± 1.0% and 1.9% ± 0.5%, respectively, among subjects in the wasting group. Total and free testosterone levels were not significantly different for subjects with wasting and subjects without wasting.

Table 1
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Table 1

Comparison of clinical characteristics of human immunodeficiency virus (HIV)–infected patients with wasting, HIV-infected patients without wasting, and healthy control subjects in a study of hypogonadism in men with weight loss related to HIV infection.

Free testosterone levels were low in 19% of patients with AIDS wasting, and total testosterone levels were low in 5%. Eighty-one percent of patients with decreased levels of free testosterone complained of decreased libido, compared with 47% of HIV-infected patients with normal levels of free testosterone (P = .01). In a comparison of HIV-infected patients with age-matched healthy control subjects, the mean free testosterone level ± SEM was not significantly different (16.5 ± 0.8 vs. 18.8 ± 1.0 pg/mL, respectively; P = .17), but the mean total testosterone level ± SEM was increased (600 ± 23 vs. 482 ± 22 ng/dL, respectively; P = .02). The mean SHBG level ± SEM was 38 ± 2 nmol/L, and these levels were increased above the normal range (4–44 nmol/L) in 25% of subjects. For 60% of subjects whose SHBG levels were available, SHBG level correlated highly with total testosterone level (r = .62; P < .0001) but not with free testosterone level (r = −.27; P = .08) or weight (r = −.11; P = .45). For the subjects with AIDS wasting, neither free testosterone levels nor total testosterone levels correlated with weight, history of weight loss, reported CD4 cell count, antiviral medications, history of opportunistic infection, total duration of weight loss, or weight trend in the year before the study (table 2). There was a trend toward increasing total testosterone levels with increasing duration of HIV infection (r = .20; P = .06). Total and free testosterone levels were not different between patients with CD4 cell counts of ⩾500 cells/mm3 or <500 cells/mm3 or between patients with weight of ⩾90% or <90% of IBW (data not shown).

Table 2
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Table 2

Results of univariate correlation analyses for 90 human immunodeficiency virus (HIV)–infected patients with wasting in a study of hypogonadism in men with weight loss related to HIV infection.

Of the patients with wasting, 70% were receiving HAART, and 30% were not receiving HAART. The average duration of current antiretroviral treatment ± SEM was 9.0 ± 1.0 months. No difference in testosterone or free testosterone levels was observed between groups of patients classified by whether they were receiving HAART (table 3) or individual classes of antiviral medication (i.e., PIs, nucleoside analogues, or nonnucleoside analogues; table 4). Twenty-one percent of HIV-infected men with wasting who were receiving HAART were hypogonadal, as assessed by free testosterone levels. Similarly, 20% of PI-treated subjects with wasting, 22% of NRTI-treated subjects with wasting, and 18% of NNRTI-treated subjects with wasting were hypogonadal. In a comparison of patients receiving and patients not receiving antiretroviral treatment, a trend toward lower free testosterone levels was seen for the 80% of the patients receiving antiretroviral therapy (mean level ± SEM, 15.8 ± 0.8 vs. 19.3 ± 2.2 pg/mL, respectively; P = .07) despite a higher mean body mass index ± SEM (22.8 ± 0.3 vs. 21.4 ± 0.6, respectively; P < .05; table 4). Total testosterone levels were higher both in patients receiving therapy with antivirals, PIs, NRTIs, and/or NNRTIs and in patients not receiving them than in healthy control subjects.

Table 3
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Table 3

Comparison of clinical characteristics of human immunodeficiency virus (HIV)–infected patients with wasting who were receiving highly active antiretroviral therapy (HAART), HIV-infected patients with wasting who were not receiving HAART, and healthy control subjects in a study of hypogonadism in men with weight loss related to HIV infection.

Table 4
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Table 4

Comparison of testosterone levels and clinical variables for human immunodeficiency virus (HIV)–infected patients with wasting according to type of drug therapy received and for healthy control subjects in a study of hypogonadism in men with weight loss related to HIV infection.

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Discussion

It is important to diagnose hypogonadism in HIV-infected men because physiological testosterone replacement therapy has been shown to result in sustained increases in lean body mass and weight and improved quality of life in this population [6–8]. Additional important benefits of testosterone treatment in this population include improvement of insulin resistance [14] and depression indices [15]. As such, therapy for hypogonadism is routine in the management of AIDS wasting. Of men with AIDS wasting in this study, 19% had hypogonadism, as assessed by free testosterone levels. In comparison, previous studies conducted in 1995 and 1996 that used the same testosterone assay found a prevalence of hypogonadism of nearly 50% among men with AIDS wasting [4]. Furthermore, the mean free testosterone level ± SEM was not significantly lower for the subjects with AIDS wasting than for HIV-infected subjects without wasting or healthy control subjects. In contrast, total testosterone levels were higher in HIV-infected patients with wasting than in healthy control subjects. Gonadal status was not related to HAART or PI, NRTI, or NNRTI use.

In previous studies, hypogonadism was most often secondary in nature, related to pituitary or hypothalamic dysfunction [1, 4]. In contrast, primary hypogonadism has been suggested by increased gonadotropin levels in some studies [16]. Potential mechanisms of hypogonadotropic hypogonadism in HIV-infected men include undernutrition [17, 18], severe illness [19, 20], medications [21], or an HIV-specific effect on the pituitary or hypothalamus [22]. Although gonadotropin levels were not available for hypogonadal subjects in this study, no correlation between degree of illness and testosterone levels was observed for our HIV-infected patients when reported CD4 cell count was used as a surrogate marker of generalized disease severity. These data are in contrast to those reported by Wagner et al. [23], who demonstrated a correlation between CD4 cell count and testosterone level. However, in this study the mean reported CD4 cell count ± SEM was 384 ± 29 cells/mm3 for the HIV-infected patients with wasting, which is significantly higher than the counts of the patients described by Wagner et al. This finding indicates that our patients were less immunocompromised, despite weight loss, than HIV-infected patients described in previous studies. It is unclear if the mechanisms leading to weight loss are similar in patients with relatively preserved immune function in the current era of potent antiretroviral therapy. Furthermore, CD4 cell count may be a less accurate marker of clinical status in HAART recipients.

We did not observe an effect of HAART or any specific class of antiretroviral therapy on testosterone levels. The prevalence of hypogonadism was ∼20% in all medication groups and was not significantly different between the patients receiving HAART (21%) and those not receiving HAART (15%). No differences in testosterone or free testosterone levels were seen among patients categorized by PI, NRTI, or NNRTI treatment status. Similarly, no significant differences in testosterone levels could be detected by antiviral treatment status among patients described in our earlier studies [4]. Taken together, these data suggest that gonadal function is not related directly to antiviral treatment status in men with AIDS wasting.

Neither free nor total testosterone levels correlated with weight or weight trend. In addition, testosterone levels were not different between patients weighing ⩾90% or <90% of IBW. Body mass index, but not body composition, was measured in our subjects. In this regard, we used a standardized criterion of weight of <90% of ibw or weight loss of >10% to define wasting in the study population. We have previously shown that weight per se does not predict gonadal function in men with AIDS wasting [4], and this observation was again confirmed in the current study. In contrast, indices of lean body mass may better define muscle wasting and predict morbidity associated with it. As such, lean body mass may better predict testosterone levels in HIV-infected men with wasting.

Increased SHBG levels were seen in previous studies of HIV-infected men, which suggests the importance of the measurement of bioavailable testosterone levels in this population [3, 24]. Although SHBG levels were on average within normal limits in our patients, 25% of HIV-infected men had increased levels. SHBG levels were highly correlated with total but not with free testosterone levels. One hypothesis to explain the relative discordance between free testosterone levels (which were low in 19% of HIV-infected men with wasting) and total testosterone levels (which were elevated in our study population) is therefore an effect of increased SHBG levels. For this reason, it is recommended that HIV-infected patients are screened for hypogonadism by bioavailable or free testosterone levels. We used a linear analogue method to determine free testosterone levels, which differs from more direct methods of determination of free testosterone levels by dialysis [25]. Although an effect of SHBG levels on the determination of free testosterone levels by the analogue assay has been postulated, we found no correlation between SHBG levels and free testosterone levels in our study.

In patients with hypogonadotropic hypogonadism, consideration should be given to diagnostic imaging of the pituitary if there is headache, visual changes, or increased prolactin levels. In the absence of these findings or in the setting of medication known to cause hypogonadism, such as megestrol acetate [21], empirical physiological testosterone replacement therapy can be started for hypogonadal HIV-infected men; there should be yearly monitoring of levels of prostate-specific antigen during long-term use in patients older than 50 years of age and periodic reassessment of testosterone levels.

Our data demonstrate that almost 20% of men with HIV-related wasting are hypogonadal based on low free testosterone levels. These data suggest that HIV-infected men with wasting syndrome should be screened for hypogonadism, even if such patients are receiving HAART and have relatively preserved immune function. For hypogonadal patients with wasting syndrome, physiological testosterone replacement therapy is indicated and may increase weight and lean body mass and improve quality of life. Further studies are necessary to determine if testosterone treatment is effective for hypogonadal HIV-infected patients with normal weight but decreased lean body mass and eugonadal patients with AIDS wasting.

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Note Added in Proof

Treatment data on a subset of the patients were published after the submission of this article [26].

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Acknowledgments

We thank Gregory Neubauer for his help in the performance of the RIAs and the nursing and nutrition staffs of the General Clinical Research Center, Massachusetts General Hospital (Boston), for their dedicated patient care.

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Footnotes

  • Informed consent was obtained from the patients, and the guidelines for human experimentation of the US Department of Health and Human Services and the Massachusetts General Hospital Subcommittee on Human Studies were followed in the conduct of this research.

  • Financial support: This work was supported by the National Institutes of Health (grants R01-DK49302, MO1-RR01066, and F32-DK09218).

  • Received October 14, 1999.
  • Revision received March 1, 2000.
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  1. Clin Infect Dis. (2000) 31 (5): 1240-1244. doi: 10.1086/317457
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