Leptin is an effective treatment for hypothalamic amenorrhea

Abstract

Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.

Fig. 1.

Body composition. Anthropometric changes over the 36 wk of treatment and at the follow-up visit at week 52 as assessed by body weight (A), body mass index (B), total body fat (C), and percentage total body fat (D). Solid black lines represent the metreleptin-treated group; gray dashed lines represent the placebo-treated group. Metreleptin treatment had a significant effect over time on total body fat (P = 0.02) and percentage total body fat (P = 0.01).

Fig. 2.

Total and free leptin levels and restoration of menses. (A) Total leptin levels during the 36 wk of treatment and at the week 52 follow-up visit. The solid black line represents mean total leptin levels in the metreleptin-treated group; the gray dashed line represents mean total leptin levels in the placebo-treated group. The serum total leptin level increased significantly in the metreleptin-treated group, compared with the placebo-treated group (P < 0.0001). The leptin level decreased quickly with discontinuation of metreleptin and was not significantly different from that in the placebo-treated group at the week 52 follow-up visit (P = 0.0536). The control group, as expected, did not have any significant changes in leptin levels throughout the study duration (P = 0.5395). (B) Free leptin levels during the 36 wk of treatment and at the week 52 follow-up visit. The solid black line represents the mean free leptin levels in the metreleptin-treated group; the black dashed line represents the mean free leptin levels in the placebo-treated group. Similar to total leptin levels, free leptin levels increased significantly over the study duration in the metreleptin-treated group but remained stable in the placebo-treated group (P < 0.0001). (C) The cumulative percentage of women in which menstruation occurred. The black solid line represents the metreleptin-treated group; the gray dashed line represents the placebo-treated group. Over time, significantly more participants in the metreleptin group than in the placebo group regained menses (P = 0.0046). The table reports P values at every time point using Fisher's exact test.