Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6585-90. doi: 10.1073/pnas.1015674108. Epub 2011 Apr 4.
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.
下丘脑性闭经（HA）与下丘脑-垂体-外周内分泌轴的功能障碍有关，导致不孕和骨丢失，通常是由剧烈运动和/或减少食物摄入引起的慢性能量缺乏引起的。能量缺乏还导致瘦素水平降低，基于观察性研究以及一项开放标签研究，瘦素被提出介导与这种情况相关的神经内分泌异常。为了明确证明瘦素在 HA 发病机制中的因果作用，我们进行了一项随机、双盲、安慰剂对照试验，用人重组瘦素（metreleptin）在 36 周内以替代剂量治疗 HA 女性。我们评估了它对生殖结局、神经内分泌功能和骨代谢的影响。瘦素替代治疗导致月经恢复，纠正了性腺、甲状腺、生长激素和肾上腺轴的异常。我们还证明了骨代谢标志物的变化提示骨形成，但在这项研究的短时间内未检测到骨密度的变化。如果这些数据得到证实，以替代剂量给予 metreleptin 以使循环瘦素水平正常化可能被证明是 HA 女性的一种安全有效的治疗方法。
