Hypothalamic amenorrhea, characterized by absent menstrual cycles and low estrogen levels, reportedly accounts for more than 30% of all cases of amenorrhea in women of reproductive age. Infertility and bone loss are possible consequences. Functional hypothalamic amenorrhea occurs when, for any reason, there is a relative energy deficit. Leptin levels are low in these patients, and the normal diurnal variation in leptin levels is absent. To determine whether low leptin levels cause neuroendocrine and reproductive dysfunction, 8 women with hypothalamic amenorrhea resulting from low body weight or strenuous exercise prospectively received recombinant human leptin for 2 to 3 months. Six control women received no treatment. Participants self-administered 0.08 mg/kg of recombinant human leptin subcutaneously each day, 40% of it in the morning and 60% in the evening.Serum leptin levels increased during treatment and body weight decreased slightly. Food intake and resting metabolic rate did not change appreciably. Three of 8 women had an ovulatory menstrual cycle while receiving leptin. Two others had a preovulatory follicle but did not ovulate. Leptin treatment significantly increased maximum follicle diameter, the number of dominant follicles, ovarian volume, and endometrial thickness. Mean levels of luteinizing hormone (LH) increased during treatment, and LH pulse patterns improved or became normal in 6 of 8 women. Thyroid hormone levels increased but remained within the normal range. Markers of bone formation, including bone alkaline phosphatase and osteocalcin, rose significantly during leptin treatment. There was no significant change in urinary N-telopeptides, a marker of bone resorption. Total bone density did not change significantly. No adverse effects were noted. Patients reported decreased appetite but felt well.In this prospective study, leptin treatment of women with hypothalamic amenorrhea normalized reproductive hormone levels, follicle development, and menstrual cyclicity. The findings suggest that leptin, which reflects the adequacy of stored energy, is necessary for normal neuroendocrine and reproductive functioning. EDITORIAL COMMENT(During the past few years, I have been reviewing studies dealing with the role of hormones regulating satiety and weight. Most recently, I have discussed the recently described adiponectin, which is produced by the adipocyte. The most extensively studied of the adipocyte-producing hormones regulating satiety and weight is leptin. When first characterized, several pharmaceutical companies competed for the patent rights to leptin, believing that it would be the holy grail for the management of obesity, and they would tap into a huge consumer market of overweight individuals seeking an easy way to manage their weight. Although that did not appear to be the case, investigators continued to explore the functions and actions of leptin in energy balance, other aspects of metabolism, and its effects on reproductive function.Some years ago, an investigator at our medical center, D...

Up to 28% of female fragile X premutation carriers develop premature ovarian failure. To test the hypothesis that fragile X premutation carriers with ovulatory menstrual cycles exhibit hormone changes characteristic of early ovarian aging, 11 regularly cycling fragile X premutation carriers, 24-41 yr old (34.5 +/- 5.7 yr, mean +/- sd), drew daily blood samples across one menstrual cycle. LH, FSH, estradiol, progesterone (P4), inhibin A, and inhibin B levels were compared with levels in 22 age-matched, regularly cycling women, 23-41 yr old (34.6 +/- 5.8 yr), at each cycle stage. Total cycle (26.1 +/- 1.0 vs. 28.2 +/- 0.4 d; P < 0.05) and follicular phase length (12.9 +/- 0.8 vs. 14.5 +/- 0.4 d; P < 0.05) were decreased in fragile X premutation carriers compared with age-matched controls, whereas luteal phase length was similar (13.2 +/- 0.5 vs. 13.7 +/- 0.3 d; P = not significant). FSH was elevated across the follicular (21.9 +/- 3.5 vs. 11.2 +/- 0.5 IU/liter; P < 0.001) and luteal phases (14.6 +/- 3.9 vs. 7.9 +/- 0.5 IU/liter; P < 0.05) in fragile X premutation carriers compared with age-matched controls. Inhibin B in the follicular phase (77 +/- 11 vs. 104 +/- 6 pg/ml; P < 0.05) and inhibin A (3.4 +/- 0.7 vs. 5.8 +/- 0.5 IU/ml; P < 0.01) and P4 [7.3 +/- 1.0 vs. 10.1 +/- 0.7 ng/ml (23.2 +/- 3.0 vs. 32.1 +/- 2.3 nmol/liter); P < 0.05] in the luteal phase were decreased in fragile X premutation carriers compared with age-matched controls, whereas there was no difference in estradiol or LH. In summary, despite regular ovulatory cycles, FSH was increased in fragile X premutation carriers compared with age-matched controls. The increased FSH was accompanied by decreased inhibin B in the follicular phase and inhibin A and P4 in the luteal phase. These hormonal changes suggest that fragile X premutation carriers exhibit early ovarian aging despite regular menstrual cycles. Early ovarian aging in fragile X premutation carriers likely results from decreased follicle number and function, as reflected by lower inhibin B, inhibin A, and P4 levels.