Premature Decline of Serum Total Testosterone in HIV- Infected Men in the HAART-Era Vincenzo Rochira 1 *, Lucia Zirilli 1 , Gabriella Orlando 2 , Daniele Santi 1 , Giulia Brigante 1 , Chiara Diazzi 1 , Federica Carli 2 , Cesare Carani 1 , Giovanni Guaraldi 2 1 Chair and Unit of Endocrinology & Metabolism, Department of Medicine, Endocrinology & Metabolism, Geriatrics, University of Modena & Reggio Emilia, Azienda AUSL- NOCSAE of Baggiovara, Modena, Italy, 2 Metabolic Clinic, Infectious and Tropical Disease Unit, Department of Medicine and Medical Specialties, University of Modena & Reggio Emilia, Modena, Italy Abstract Background: Testosterone (T) deficiency remains a poorly understood issue in men with Human Immunodeficiency Virus (HIV). We investigated the gonadal status in HIV-infected men in order to characterize T deficiency and to identify predictive factors for low serum T. Methodology/Principal Findings: We performed a cross-sectional, observational study on 1325 consecutive HIV male outpatients, most of them having lipodystrophy. Serum total T,300 ng/dL was used as the threshold for biochemical T deficiency. Morning serum total T, luteinizing hormone (LH), estradiol, HIV parameters, and body composition parameters by CT-scan and Dual-Energy-X-ray-Absorptiometry were measured in each case. Sexual behavior was evaluated in a subset of 247 patients. T deficiency was found in 212 subjects, especially in the age range 40–59, but was frequent even in younger patients. T deficiency occurred mainly in association with low/normal serum LH. Adiposity was higher in subjects with T deficiency (p,0.0001) and both visceral adipose tissue and body mass index were the main negative predictors of serum total T. Osteoporosis and erectile dysfunction were present in a similar percentage in men with or without T deficiency. Conclusions/Significance: Premature decline of serum T is common (16%) among young/middle-aged HIV-infected men and is associated with inappropriately low/normal LH and increased visceral fat. T deficiency occurs at a young age and may be considered an element of the process of premature or accelerated aging known to be associated with HIV infection. The role of HIV and/or HIV infection treatments, as well as the role of the general health state on the gonadal axis, remains, in fact, to be elucidated. Due to the low specificity of signs and symptoms of hypogonadism in the context of HIV, caution is needed in the diagnosis of hypogonadism in HIV-infected men with biochemical low serum T levels. Citation: Rochira V, Zirilli L, Orlando G, Santi D, Brigante G, et al. (2011) Premature Decline of Serum Total Testosterone in HIV-Infected Men in the HAART- Era. PLoS ONE 6(12): e28512. doi:10.1371/journal.pone.0028512 Editor: Sunil K. Ahuja, South Texas Veterans Health Care System, United States of America Received June 7, 2011; Accepted November 9, 2011; Published December 9, 2011 Copyright: ß 2011 Rochira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: vincenzo.rochira@unimore.it Introduction Circulating testosterone (T) declines with advancing age [1] especially after the age of 65 years [1–3]. The prevalence of T deficiency in different studies varies from 13.8% [4] to 20%–25% [5,6] and 38.7% [3], depending on different cut-off values of serum T and different age ranges. Androgen deficiency is common among men with human immunodeficiency virus (HIV) infection treated with highly active antiretroviral therapy (HAART), ranging from 20 to 30% according to different studies [7,8]. In the past, men with acquired immunodeficiency syndrome (AIDS) showed a high prevalence of hypogonadism (29%–50%), mainly caused by impaired testicular function due to both wasting syndrome and opportunistic infections [9–12]. The introduction of HAART changed the spectrum and modified the prevalence of several co-morbidities, including androgen deficiency [11], which seems to occur less frequently than in the past [9,10]. Despite its frequent occurrence, the actual prevalence of T deficiency remains not well defined in HIV-infected patients, ranging from 3–7% [7,12,13,14,17] to 54– 64% [15,16] in the different reports. An impairment of the hypothalamic-pituitary axis plays a possible major role in determining T deficiency, as suggested by the common occurrence of low T in concomitance with inappropriately low or normal serum luteinizing hormone (LH) in HIV-infected patients [12,17,18]. However, the underlying causes and mechanisms remain unknown. Previous studies on T deficiency in HIV- infected men suffer from several limitations: i) the lack of of information on gonadotropins in most studies [7,12,13], ii) the small number of subjects enrolled [7,12–17], iii) the possibility of inappropriate blood sampling [7,13–16] e.g. not considering serum T diurnal variations [19], iv) the measurement of free T alone [7,16] by inaccurate assays [20], v) the retrospective design only from record charts [14], and, finally, vi) the lack of studies with an endocrinological rather than infectivological focus. These limitations weaken the evidence regarding T deficiency in HIV- infected men. As a result, clinical evidence resulting in the form of guidelines [21] or expert-based opinions [8,22] is scarce. PLoS ONE | www.plosone.org 1 December 2011 | Volume 6 | Issue 12 | e28512