Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients

Background: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. Aim: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naive and leptin-treated subjects with lipodystrophy. Methods: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naive subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. Results: Mean (on vs. off: 5.0 +/- 3.1 vs. 3.2 +/- 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 +/- 1,495 vs. 1,534 +/- 642 IU x l(-1) x min(-1), p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7 +/- 15.4 vs. 7.0 +/- 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 +/- 0.26 vs.0.67 +/- 0.24 h(-1), p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 +/- 101 vs. 57 +/- 73 IU x l(-1) x 8 h(-1), p = 0.01). On leptin, testosterone (507 +/- 286 vs. 360 +/- 174 ng/dl, p = 0.09) and estradiol levels (74 +/- 36 vs. 29 +/- 24 pg/ml, p = 0.01) were higher in males and females, respectively. Conclusions: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy. (C) 2015 S. Karger AG, Basel