Research Article: Morning free and total testosterone in HIV-infected men: implications for the assessment of hypogonadism

Date Published: January 22, 2014

Publisher: BioMed Central

Author(s): Anne K Monroe, Adrian S Dobs, Frank J Palella, Lawrence A Kingsley, Mallory D Witt, Todd T Brown.


Hypogonadism is common among HIV-infected men, even among men receiving antiretroviral therapy (ART). Our objective in this study was to determine the prevalence of biochemical hypogonadism among HIV-infected men compared with HIV-uninfected controls. We also examined the use of free testosterone (FT) and total testosterone (TT) measurements in the assessment of biochemical hypogonadism in HIV-infected and –uninfected men.

This was a cross-sectional analysis from the Multicenter AIDS Cohort Study (MACS). TT levels were measured from archived serum using liquid chromatography-tandem mass spectrometry. FT was calculated from TT and sex hormone-binding globulin (SHBG) (measured by radioimmunoassay) using the Vermeulen equation. Biochemical hypogonadism was defined as having low TT, low FT, or both.

Of 945 men in the MACS Cardiovascular Substudy, T assays were not performed in 89 because of insufficient/no stored serum (n = 18) or use of T replacement therapy (TRT) (n = 71). 530 men had morning (AM) T measurements; 364 (68.7%) were HIV-infected. The prevalence of biochemical hypogonadism was similar in HIV-infected (34/364 = 9.3%) and HIV-uninfected (12/166 = 7.2%) men. Prevalence of hypogonadism, when men on TRT (n = 71) were included in the group of hypogonadal men, was higher in HIV-infected (104/434 = 24.0%) compared with HIV-uninfected (13/167 = 7.8%) men (p < 0.0001). Of 34 HIV-infected men with biochemical hypogonadism not on TRT, 11 (32.4%) had normal TT, but low FT. Of 12 HIV-uninfected men with biochemical hypogonadism not on TRT, none were in this category (p = 0.04) – all had low TT. The prevalence of biochemical hypogonadism in our sample of HIV-infected men was approximately 10%, with a substantial proportion of these men having a normal TT, but low FT. The measurement of AM FT, rather than TT, in the assessment of hypogonadism in HIV-infected men will likely increase diagnostic sensitivity and should be recommended.

Partial Text

Hypogonadism is common among HIV-infected men, even among men receiving antiretroviral therapy (ART), with prevalence estimates ranging from approximately 20% to 70% [1-3]. The cause of low testosterone (T) in HIV infection is multifactorial, and has been associated with poor clinical or nutritional status, use of certain prescription/illicit drugs (including opiates and methadone), pituitary dysfunction, HCV co-infection, advancing age, and changes in body composition [3-5]. Men with clinical symptoms of hypogonadism, including fatigue, weight loss, loss of libido or erectile dysfunction, depressive symptoms, or evidence of reduced bone mineral density, should undergo a laboratory evaluation for low T.

This analysis used data collected in the MACS Cardiovascular Disease (CVD) substudy, which has been described previously [14]. Briefly, the substudy enrolled men older than 40 years who weighed less than 300 pounds and who had no history of coronary heart disease. Blood draws were performed at regularly scheduled MACS follow-up visits between April 2004 and January 2006. For this analysis, we included men who had undergone AM blood sampling for T measurement. Testosterone and SHBG were measured from archived sera using liquid chromatography-tandem mass spectrometry and radioimmunoassay, respectively, and assays were performed in Dr. Shalender Bhasin’s lab at Boston University. The testosterone assay had a sensitivity of 2 ng/dL, with an interassay co-efficient of variation ranging from 3.3% to 7.7% with three pooled samples analyzed in nine different assays. SHBG levels were measured using a two-site immunofluorometric assay (DELFIA-Wallac, Inc., Turku, Finland) [15,16]. The inter-assay CVs were 8.3%, 7.9%, and 10.9%, and intra-assay CVs 7.3%, 7.1% and 8.7%, respectively, in the low, medium, and high pools. The analytical sensitivity of the assays was 0.5 nmol/L. The assay has negligible crossreactivity with beta-microglobulin, thyroxine binding globulin (TBG), or corticosteroid binding globulin (CBG). Free testosterone was calculated using the Vermeulen equation [17].

Among men participating in the MACS CVD substudy for whom an AM blood sample was available for T assay, the overall prevalence of biochemical hypogonadism was 8.7% (9.3% among HIV-infected men and 7.2% among HIV-uninfected men). Prevalence of hypogonadism, when men on TRT (n = 71) were included in the group of hypogonadal men, was significantly higher in HIV-infected compared with HIV-uninfected men (24.0% v. 7.8%). In the men not on TRT, the diagnosis of hypogonadism would have been missed among one-third of HIV infected men if TT only had been measured, while no HIV-uninfected men would have gone undiagnosed. Our results underscore the importance of using free T for hypogonadism diagnosis among HIV-infected men.

The prevalence of biochemical hypogonadism in our overall sample was approximately 10%, and prevalence of hypogonadism in HIV-infected men, when men on testosterone therapy were included in the estimate, was 24%. Use of morning TT levels to diagnose hypogonadism in HIV-infected men results in approximately 30% missed cases. Morning free T levels are more sensitive diagnostically and should be measured in HIV-infected men in whom hypogonadism is suspected.

F.J.P. has received honoraria from Gilead Sciences, Tibotec Pharmaceuticals, and Bristol Myers Squibb. T.T.B. has received honoraria from Bristol Myers Squibb, Gilead Sciences, Tibotec Pharmaceuticals, ViiV, and serves as a consultant to EMD-Serono and Theratechnologies.

TTB conceived of the study; TTB and AKM helped design the study. AKM and TTB acquired, analysed and interpreted the data. AKM drafted the manuscript, ASD, FJP, LAK, MDW and TTB have revised it critically for important intellectual content. All authors have given final approval of the version to be published.




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