The effect of ARV therapy on testosterone levels is unclear. Studies looking at the effect of ARV on androgen levels have shown conflicting results.

A study performed in 2007, Crum-Cianflone et al. aimed to establish the prevalence and risk factors for hypogonadism amongst a modern cohort of HIV-infected men [9]. Three hundred HIV positive men were enrolled in this study, 60% of which were on ARV with generally good immune function (mean CD4 cell count of 522 cells/mm³). All had mean age of 39 and included a mixture of ethnicities. Seventeen percent (50/296) of the men were hypogonadal (as defined by a morning total testosterone level <300 ng/dL), and a further 16% had a borderline testosterone level (300–400 ng/dL) [9]. In multivariate analysis, increasing age and a higher body mass index (BMI) were positively associated with hypogonadism, while smoking was negatively associated (OR 0.44, p  =  0.02). A subset of participants with low testosterone had luteinizing hormone (LH) and FSH measured, all of which were found to be low, suggesting secondary hypogonadism. There was no association observed between hypogonadism and current, past, or cumulative use of HIV medications.

Wunder et al. demonstrated a high prevalence of low free testosterone levels amongst an untreated HIV positive cohort and studied the effect of ARV therapy on androgen levels over time [10]. Data were derived from stored serum samples from the Swiss HIV Cohort Study (SHCS), which is an ongoing multicenter research project. Ninety-seven participants had serum levels of LH, FSH, and FT measured at baseline, and again, after 2 years of successful HAART. At baseline, 68 patients (70%) had subnormal FT levels based on an age-adjusted normal range. Of these, LH levels were low in 44%, normal in 47%, and high in 9%, indicating a mainly secondary hypogonadism in this group. There was a trend for association between lower CD4+ T-cell counts and hypogonadism, but no other associations were found for age, BMI, sexuality, duration of HIV disease, or plasma HIV viral load. No significant changes in free testosterone, LH, or FSH were observed after 2 years of successful ARV therapy. Overall, >60% remained hypogonadal at this point. Twenty-four percent of those who were originally hypogonadal returned to normal levels, and 32% of those originally within normal levels became hypogonadal after 2 years of therapy. All participants on the ARV regime were on the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine. Sixty-three percent were also on a boosted protease inhibitor (bPI) as the third agent, and the remaining 37% were on a non-nucleoside reverse transcriptase inhibitor (NNRTI). The authors acknowledged that the use of stored serum samples was a limiting factor in the interpretation of these findings, as the samples were not consistently morning levels; therefore, this may have led to higher rates of reported hypogonadism.

Effective treatment with ARV has been shown to increase lean body mass (LBM), particularly in individuals with low CD4 counts at initiation of treatment [11]. In a study looking at the effect of some older ARVs on LBM and testosterone levels, Dube et al. noted increases in free testosterone after initiation of ARV, along with an increase in fat-free mass [12]. The rise appeared to be more marked with certain types and classes of ARV, with greater increases at 64 weeks among zidovudine–lamivudine recipients than among stavudine–didanosine recipients, and among efavirenz (an NNRTI) recipients than among nelfinavir (a bPI) recipients [12]. It is worth noting that in recent years, usage of stavudine, nelfinavir, and to a lesser degree didanosine has declined in parts of the world with access to newer ARV agents, due to the high levels of toxicities observed, including lipodystrophy.

In the Massachusetts Male Aging Study, rates of hypogonadism amongst HIV negative men were reported as between 6 and 12% amongst 40–69-year-old American males [13]. Reported prevalence of hypogonadism in HIV positive men varies widely, and rates reported depend on the type of testosterone measurement used; however, it seems clear that prevalence of hypogonadism is higher in HIV positive compared to HIV negative males.

While studies show there are high levels of biochemical hypogonadism in clinical practice, a diagnosis of testosterone deficiency is usually made in conjunction with consistent clinical symptoms and signs [14]. Testosterone deficiency can cause nonspecific symptoms such as fatigue, depressed mood, weakness, and sexual dysfunction, all of which are also frequently associated with many chronic illnesses, HIV virus, ARV therapy, and opportunistic infections. Careful history, examination, and appropriate investigation are essential when trying to ascertain whether biochemical hypogonadism is clinically relevant in an individual.

The US Centers for Disease Control and Prevention (CDC) classification system for HIV disease staging and classification defines HIV wasting syndrome as involuntary weight loss >10% of baseline body weight, in association with either chronic diarrhea or chronic weakness and documented fever for ≥1 month. Wasting is further identified as an indicator for the AIDS condition [15]. In the developed world, wasting amongst HIV positive persons taking ARV is now less common and frequently reverses quickly with appropriate HIV viral control and nutritional supplementation. However, even in the era of HAART, HIV-associated weight loss remains prevalent. A large retrospective observational study of a contemporary managed care population in the United States observed that even amongst a modern cohort of HIV, almost one in ten had evidence of HIV-associated weight loss [16].

In a study presented in 2000, by Desyatnik et al., the association between clinical wasting and hypogonadism was investigated [17]. A retrospective review of 88 male patients with HIV infection who had been on HAART for at least 6 months was performed. Hypogonadism was defined as serum-free testosterone <15 pg/mL and was observed in 20% of participants. Wasting was defined as weight loss >5% of ideal body weight and was observed in 42% of the subjects. The investigators observed that testosterone deficiency in these males did not correlate with wasting.

The same year a paper was published by Rietschel et al. looking specifically at androgen levels in a group of HIV positive men with wasting [18]. Seventy percent of participants were receiving ARV therapy. The authors found that in this population with wasting, 21% of patients receiving HAART had hypogonadism compared with 15% of those not on HAART. The prevalence of hypogonadism was not related to any particular class of ARV. Comparison was also made with a control group of HIV positive men without wasting, and total and free testosterone levels were not significantly different for subjects with wasting and subjects without wasting.

In the context of the developing world, wasting syndromes are commonly encountered and may have multiple etiologies including lack of appropriate ARV, concomitant infections, such as parasitic infection and tuberculosis, and lack of nutritional intake and food security. In this instance, the appropriate remedy of the any exacerbating underlying cause of wasting would be indicated in the first place before consideration of testosterone replacement.

The contributions of catabolic cytokines to HIV-associated wasting and weight loss, in a group of HIV positive men, were investigated by Roubenoff et al. [19]. The authors studied a group of 172 men, 43% of which were on HAART. They found that both TNF-α and IL-1β production by peripheral blood mononuclear cells predicted loss of LBM, and that serum-free testosterone was inversely associated with TNF-α production. However, serum-free testosterone alone was not an independent predictor of either LBM or resting energy expenditure after adjustment for cytokine production. The authors suggested that the inverse relationship between testosterone and cytokine production might be due to testosterone acting as a modulator of the effect of TNF-alpha and IL-1beta and not as a direct determinant of body composition or metabolic rate.

Hypogonadism has been observed in the presence of many common acute and chronic illnesses in men such as chronic liver and renal disease, cancer, and sepsis. In the case of depressed testosterone in HIV disease, the symptoms and signs observed are often nonspecific and may be attributed to the underlying disease or treatment. Low levels of testosterone may cause loss of LBM, bone mass density, and produce symptoms such as depressed mood, loss of energy, and sexual dysfunction. The mechanisms explaining hypogonadism and various systemic diseases are incompletely understood, but these conditions are likely caused by a combination of stress, nonspecific weight loss, inflammation, and medication [20].

There are various treatments available for hypogonadism and wasting syndrome in HIV positive men. The literature is wide ranging on the multitude of therapy options and benefits seen in HIV men. Treatment of hypogonadism and wasting syndrome in HIV positive men has been shown to help with LBM, weight loss, depression, fatigue, libido, and BMD.

Therapy ranges from testosterone replacement to synthetic analogues such as anabolic steroids as well as growth hormone, dronabinol, megestrol acetate, and insulin-like growth factor I. In this section, treatment for hypogonadism and wasting syndrome in HIV positive men will be reviewed. The review will include various types of treatments, methods of delivery, benefits, and side effects.