madman
Super Moderator
Background
Male obesity-related secondary hypogonadism (MOSH) affects two-thirds of men with BMI ≥40 kg/m2 and is associated with increased mortality. Animal models suggest decreased hypothalamic function in obesity-related hypogonadism. Existing data in men suggests reduced LH pulse-amplitude but no change in LH pulse-frequency with obesity. Herein, we use kisspeptin to directly examine hypothalamic function in men with obesity, both with and without hypogonadism.
Methods
Men with MOSH (n =21) (BMI ≥30 kg/m2) were identified by fasting total testosterone <10.50nmol/l and free testosterone <0.22nmol/l. We also enrolled eugonadal controls with normal BMI (<30 kg/m2, n =80) and with obesity (BMI ≥30 kg/m2, n =20). Detailed endocrine profiling included assessment of LH-pulsatility (10-minutely sampling for 8hrs), endocrine responses to intravenous bolus administration of kisspeptin-54 to interrogate hypothalamic function, and to gonadotrophin-releasing hormone to interrogate pituitary function, during three study-visits. Hormone concentrations were compared between groups using the Kruskal Wallis test, and endocrine profiles over time using mixed effects models.
Results
Serum total testosterone (β = -0.47), free testosterone (β = -0.01), and dihydrotestosterone (β = -0.04) were inversely associated with BMI (all P <0.0001). LH pulse frequency (median, IQR) was increased with obesity (BMI 20–30 kg/m2: 3.00 [3.00, 4.75] vs >40 kg/m2: median 5.00 [IQR 4.00, 6.00]) pulses per 8h; P =0.007 but LH pulse-amplitude did not differ. Pituitary response to GnRH did not differ between groups. The early-phase LH response to kisspeptin-54 was blunted in men with MOSH compared to eugonadal men (median area under the curve (AUC) at 60 minutes: MOSH 38.78 [23.85, 78.26] vs lean controls 108.7 [78.56, 190.40]P <0.0001, vs eugonadal men with obesity 124.1 [81.58, 163.90] IU·h/l, P =0.0011). The FSH response to kisspeptin-54 was higher in eugonadal men with obesity than lean controls (median AUC of FSH rise after kisspeptin-54: obese eugonadal 893.80 [596.10, 1104.00] vs lean eugonadal 434.80 [292.70, 692.10] IU·h/l; P =0.003).
Conclusion
Our data revealed increased LH pulse-frequency but not pulse-amplitude in men with obesity. Eugonadal men with obesity had increased response to kisspeptin, but the early phase response to kisspeptin was reduced in men with obesity-related hypogonadism. Our data reveal novel insights into the neuroendocrine interplay that regulates obesity-related hypogonadism.
