Endocrine Abstracts

Hypothalamic amenorrhea, characterized by suppressed GnRH secretion, occurs when energy output is greater than energy intake. Leptin concentrations, which reflect adipose stores and energy availability, are low in hypothalamic amenorrhea. Our study and others provide evidence that leptin is the critical link between energy stores and normal reproductive function.

Evidence that leptin is critical for reproduction comes from the onset of pubertal development in patients with leptin mutations who are treated with recombinant leptin. Leptin treatment reverses fasting induced decreases in LH pulse frequency in men and women and testosterone levels in men. Finally, leptin replacement improves menstrual function in women with lipodystrophy and low leptin levels.

In our study, women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied before and during treatment with recombinant human leptin for up to 3 months. The study was approved by the Partners Human Research Committee and all subjects gave written informed consent. Mean LH levels (2.8±1.6 to 4.8±1.5 IU/L, P=0.005) and LH pulse frequency (2.4±1.2 to 5.0±0.9 pulses/12-hr, P=0.049) increased after 2 weeks of recombinant human leptin. During leptin treatment, maximum follicle diameter, dominant follicle number, ovarian volume, estradiol and inhibin B levels increased (all P<0.01), despite a decrease in weight and % body fat. 43% of subjects had an ovulatory menstrual cycle and an additional 29% had preovulatory follicle development (both P=0.004) during treatment. Thus, physiologic leptin replacement in women with hypothalamic amenorrhea improves gonadotropins and reproductive function. These findings suggest that leptin is the peripheral signal of adequate energy stores required for normal hypothalamic-pituitary-gonadal function in women. They further suggest that leptin could serve as a treatment for hypothalamic amenorrhea.