Androgen Deficiency and HIV Infection

Hypogonadism is known to be prevalent among HIV-infected men with low weight and wasting. Initial estimates demonstrated that hypogonadism occurs in 50% of men with AIDS-related wasting [1]. More recently, hypogonadism has been shown to be present in ∼20% of men who receive HAART [2]. Similarly, among women with HIV disease, testosterone levels are reduced, compared with levels in age- and sex-matched control subjects [3]. What are the mechanisms and consequences of hypogonadism in HIV-infected patients? Hypogonadism among men is usually the result of inadequate stimulation from the gonadotrophs and is termed “hypogonadotropic hypogonadism.” It is important to consider that even normal levels of gondotropins in the context of low testosterone levels may be inappropriate. Causes of hypogonadotropic hypogonadism in the HIV-infected population include undernutrition, severe illness, use of drugs (use of opiates, megestrol acetate, or steroids or prior use of testosterone itself), or pituitary dysfunction due to a tumor, hyperprolactinemia, or (very rarely) an AIDS-related lesion. In addition, use of anabolic steroids, which is common among HIV-infected patients, is associated with hypogonadotropic hypogonadism. Less commonly, hypogonadism is due to a primary testicular etiology, which can be infectious or due to receipt of medications. Among women, inadequate adrenal androgen secretion in association with severe illness may contribute to reduced overall androgen levels [4]. In assessing androgen levels among HIV-infected patients, consideration should be given to measuring levels of free (bioavailable) testosterone, unbound to sex hormone—binding globulin (SHBG). Increased SHBG levels among HIV-infected patients may result in relative increases in total testosterone levels that do not reflect bioavailable or free testosterone. What are the clinical consequences of androgen deficiency in HIV-infected patients? Among both HIV-infected men and women, hypogonadism is associated with reduced muscle mass, decreased strength, and decreased functional status [5, 6]. Among HIV-infected men, reduced androgen levels are associated with bone loss and depression [7, 8]. Fewer data are available regarding the consequences of androgen deficiency in HIV-infected women. Treatment of hypogonadal HIV-infected men has been shown to increase muscle mass, strength, and quality of life and to improve depression indices and bone mass [7, 9, 10]. Among HIV-infected women with low weight, physiologic androgen replacement results in improved strength [6]. Most prior studies of androgen status in HIV-infected men have been performed among younger men in the third and fourth decade of life. Among non—HIV-infected men, androgen levels decrease gradually with aging, although considerable debate continues as to whether this is a physiologic or pathologic process, and there is also debate about the appropriate thresholds for the diagnosis and treatment of androgen deficiency in the elderly population, for whom the risks of androgen replacement are considerably greater [11]. These risks include prostrate growth, polycythemia, and sleep apnea, although such risks are relatively low among patients with clear hypogonadism receiving physiologic replacement with natural testosterone derivatives. In this issue of Clinical Infectious Diseases, Klein et al. [12] report the results of a large study that provides new information on the relative risk of hypogonadism among men aged 49–81 years who had HIV infection or who were at risk of acquiring HIV infection. Among the 275 HIV-infected patients, 54% were demonstrated to have hypogonadism on the basis of a total testosterone level of <300 mg/dL, and 28% had a total testosterone level of <200 mg/dL. As anticipated, a higher prevalence of hypogonadism was seen using the free androgen index, correcting for SHBG level. Among the whole group (n = 502), HIV infection was not associated with androgen deficiency, whereas other factors, including injection drug use, seropositivity for antibody to hepatitis C virus (HCV), and use of psychotropic medicines were associated with reduced free androgen index. Among the whole group, reduced testosterone levels were associated with depressive symptoms and with reduced subjective overall health. As is commonly seen, erectile dysfunction is not always associated with mild hypogonadism. In the HIV-infected group, higher viral load was associated with reduced androgen levels, whereas use of HAART was not. What are we to learn from the study of Klein et al. [12]? This study suggests that hypogonadism is common among older HIV-infected men, although the anticipated age-associated reductions were not seen. Furthermore, HCV infection and other factors, such as injection drug use, were associated with reduced testosterone levels, whereas HIV status was not associated with hypogonadism. Therefore, these data suggest that hypogonadism may be common among older HIV-infected men but is more often associated with comorbid conditions than with HIV infection itself. Among people with such comorbidities (e.g., hepatitis C and injection drug use), screening for hypogonadism may be useful. These data also suggest that a screening strategy based on the presence of erectile dysfunction and other factors may not yield a high percentage of cases of hypogonadism. Conversely, the data of Klein and colleagues suggest that treatment of older, hypogonadal, HIV-infected patients may have less effect on erectile dysfunction and more effect on depressive symptoms and overall well being. Although important, the study by Klein et al. [12] has a number of limitations. Free testosterone level was not measured, which may affect the results. Furthermore, the cutoffs to define hypogonadism are not clearly defined in the literature, and some may argue that a single total testosterone level of <300 mg/dL is not sufficient for a diagnosis of hypogonadism. Furthermore, levels were not obtained in the morning for 42% of the patients, and this affected the results. Higher levels are seen in morning specimens because of the diurnal rhythm of testosterone secretion. It is common practice to measure levels in the morning and to confirm hypogonadism with an additional sample before making the diagnosis. The authors controlled for timing of testosterone level determination in the regression analysis, but the percentage of subjects with hypogonadism may nonetheless have been overestimated in the current study. The study by Klein et al. [12] is an important addition to the literature that investigates the issue of androgen deficiency among older HIV-infected men. Clinicians should be vigilant and screen patients with symptoms and associated risk factors for hypogonadism, including hepatitis C and injection drug use, but testing should be performed by determining the free testosterone level, using dialysis methodology, when available, and it should be done in the morning, when possible. Confirmation of low levels should be standard practice, because treatment of older HIV-infected men with testosterone may be associated with greater risk than treatment of younger patients. Potential conflicts of interest. S.G.: no conflicts.