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.H ypothalamic amenorrhea (HA) is characterized by cessation of menstrual cycles because of dysfunction of the hypothalamicpituitary-gonadal axis, abnormalities in gonadotropin pulsatility, and subsequent estrogen deficiency. This disorder is associated with chronic energy deficiency, usually caused by strenuous exercise, stress, and/or reduced food intake, and accounts for more than 30% of cases of amenorrhea in women of reproductive age (1). In addition to infertility, HA is associated with other neuroendocrine abnormalities, including dysfunction of the thyroid, growth hormone, and adrenal axes (2-7) as well as bone loss (8, 9) and propensity for fractures.Circulating leptin levels reflect the amount of energy stores in fat as well as acute changes in energy intake (10). Hypoleptinemia, signaling a state of energy deficiency, may mediate the changes in the neuroendocrine axes observed in HA. We first showed that acutely depriving mice and then healthy men of energy by caloric restriction resulted in relative leptin deficiency and neuroendocrine abnormalities affecting the gonadal and thyroid axes, and these abnormalities were prevented with recombinant methionyl human leptin (metreleptin) replacement (11,12). Women with HA are chronically energy deficient and, in observational studies, have low leptin levels and loss of diurnal leptin variation (13-16). In our proof-of-concept, open-label pilot study, we administered metreleptin s.c. for 3 mo to normalize leptin levels in women with HA and found that metreleptin treatment resulted in ovulatory menses and significant increases in levels of luteinizing hormone (LH), estradiol, insulin-like growth factor-1 (IGF1), thyroid hormones, and bone formation markers (17). O...

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