Longitudinal Changes Over 10 Years in Free Testosterone Among HIV-Infected and HIV-Uninfected Men

Abstract

Background Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus is not known. Methods HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age ≥ 45 years at highly active antiretroviral therapy initiation, who had ≥ 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus. Results 182 HIV-infected and 267 HIV-uninfected men were included: median age 48.8 years (Interquartile range (IQR); 45.8, 53.4), median numbers of FT measurements per participant 4 (IQR; 3, 5), 65% were drawn in the AM. Mean adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples (−6.1 ng/dL (95% CI: −9.8, −2.4), p=0.001), but not in PM samples (−1.7 ng/dL (−6.0, 2.6), p=0.441). The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: −13.4, −5.0) per 10 years for HIV- infected vs. 7.9 ng/dL (95% CI: −10.2, −5.5) for HIV-uninfected men, p = 0.578. Conclusion FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not PM, FT levels among HIV-infected men compared to HIV-uninfected men suggests a loss of diurnal variation in FT among HIV-infected men.

Longitudinal Changes in Sex Hormone–Binding Globulin in Men With HIV

“…We conducted a nested cohort study with the data from the MACS, and samples from participants were selected on the basis of the following criteria: MWH aged 45 years or older and not taking exogenous testosterone of any kind. This was performed because of the potential effects of exogenous testosterone on circulating SHBG concentrations 16 to ensure the inclusion of an older population and to examine the natural history of sex hormone and SHBG concentrations over time in men with and without HIV. We identified HIV-infected men at highly active antiretroviral therapy (HAART) initiation, with at least 2 samples available from the 10 years after HAART initiation.…”

“…Eighty-nine MWH and 4 HIV-seronegative men were excluded from the analysis because they had excessively high levels of calculated FT (>150 ng/dL) at ≥1 visit, suggesting unreported exogenous testosterone use. 16 Thus, the study included 449 men (182 MWH and 267 HIV-seronegative men) who contributed to a total of 1737 person-visits to the analyses.…”

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

“…While, endocrine disorders have declined in the post-cART era, secondary hypogonadism is still prevalent among HIV + patients (16–25%) [ 18 , 21 , 67 , 68 ]. Testosterone insufficiency is associated with depression/apathy, cognitive impairment, sexual dysfunction, fatigue, reduced muscle strength, and increased risk for HIV-associated lipodystrophy [ 19 , 20 ]. Herein, we find that older age and/or Tat expression increase anxiety-like behavior in an open field and in an elevated plus-maze.…”

“…Actions of HIV in the CNS may contribute to premature aging partly by promoting secondary hypogonadism (i.e., hypothalamic and/or pituitary hormonal dysregulation) which is observed in 16% to 25% of young adult or middle-aged HIV-infected men [ 15 – 19 ]. In support, HIV + men transition sooner to andropause [ 18 , 19 ], characterized by lower total and/or free testosterone (T) seen in patients aged 20–39 years old [ 16 – 18 , 20 ], greater circulating sex hormone-binding globulin [ 16 , 17 ], and greater estradiol (E 2 )-to-T ratios [ 18 ] versus healthy age-matched men [ 21 – 23 ]. In the post-cART era, neurotoxic viral proteins persist within the CNS and contribute to mild and moderate forms of neuroHIV [ 24 , 25 ], yet their contributions to neuroendocrine dysfunction and/or age-related neuroHIV remain unclear and understudied.…”

Allopregnanolone and neuroHIV: Potential benefits of neuroendocrine modulation in the era of antiretroviral therapy

“…127,130,[148][149][150] The incidence of hypogonadism increases with age, HIV duration and lower CD4 + T-cell counts. [150][151][152][153] Men living with HIV experience a premature transition to andropause associated with a lower level of circulating testosterone, 127,131,[154][155][156][157][158] normal or low levels of luteinizing hormone, 127,131,159 a greater level of sex hormone binding globulin 150,155,160 and a greater estradiol-to-testosterone ratio. 159 Androgen deficiency increases the risk for central fat accumulation, cardiovascular diseases and frailty among HIV-infected men.…”