Introduction: Obesity is a worldwide pandemic, and in men can often be associated with hypogonadotropic hypogonadism (HH), a finding consistent with a clear link between sex steroids and reproduction. In this study, we aimed to characterize the phenotypic spectrum of male obesity, focusing on the metabolic and reproductive effect of weight loss after bariatric surgery, as well as to explore the role of central inflammation.
Methods: We conducted an observational study on 32 morbidly obese men (BMI > 35 kg/m2) scheduled to undergo Roux-en-Y Gastric Bypass (RYGB) and prospectively followed for 12 months thereafter. Nine lean men with strictly normal metabolic and reproductive status were also recruited. Obese men were categorized as either HH (ObHH, n=15; testosterone < 10.4 nmol/l) or non-HH (ObnHH, n=17; testosterone ≥ 10.4 nmol/l). In addition to standard metabolic and reproductive profiles, a deep phenotyping consisted of Dual X-ray absorptiometry, metabolomics and blood transcriptomics. We also performed brain MRI Diffuse Tensor Imaging (DTI) in a subset of patients before and after RYGB.
Results: Despite comparable BMI, ObHH exhibited more severe insulin resistance (HOMA-IR, P=0.01), a trend for expanded visceral fat (P=0.08) and higher systemic (serum hs-CRP, P=0.09) and hypothalamic inflammation (lower fractional anisotropy and higher diffusivity at DTI, P<0.05) as compared to ObnHH. Blood transcriptomics revealed a distinct expression profile in ObHH related to overexpression of genes implicated in inflammation and mitochondrial function, especially oxidative phosphorylation. In addition to lower testosterone levels, higher FGF21 and lower morning cortisol in the cohort of obese men strongly correlated with the transcriptomic changes. Following RYGB, all men lost substantial weight (21-39% at month 12) independent of the baseline gonadal status. Longitudinal assessment in nine men revealed a rise in plasma FGF21 at day 28 post RYGB (P=0.04), concomitant to the early decrease in HOMA-IR. FGF21 subsequently returned to baseline levels and decreased by month 12 (P=0.02). A significant reduction in plasma isoleucine levels (day 2, P=0.01) preceded the FGF21 peak. The extent of the FGF21 peak at day 28 significantly correlated with the degree of HH reversal at month 12 (P=0.04).
Conclusions: HH is a marker of metabolic syndrome in obese men, accompanied by MRI signs of altered hypothalamic structure. Serum levels of cortisol and FGF21 are additional predictors of metabolic defects. Post RYGB, FGF21 showed a unique bimodal change, tightly associated with the metabolic improvement and the recovery of obesity-induced HH.
21 May 2022 - 24 May 2022