BACKGROUND:Disruptions in hypothalamic -gonadal and other endocrine axes due to energ y deficits are associ-ated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalami c amenorrhea.We hypothesized that exogenous recomb inant leptin replace-ment would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea.METHODS:Eight women with hypothala mic amenorrhea due to strenuous exercise or low weig ht were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to t hree months.Six con-trol subjects with hypothalamic ame norrhea received no treatment and were studied for a mean(±SD)of 8.5±8.1months.RESULTS:Luteinizing hormone(LH)-pulsatility,body weight,ovarian v ariables,and hormone levels did not change significantly over time in the controls and during a one -month control perio d before recombinant leptin therapy in the treated subjec ts.In contrast,recom-binant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and i ncreased maximal follicular diameter,the number of d ominant follicles,ovarian volume,and estradiol levels over a period of three months.Three patients had an ovulatory menstrual cycle(P<0.05for the comparison with an expec ted rate of spontaneous ovulation of 10percent );two others had pre-ovulatory follicular development a nd withdrawal bleeding during treatment (P<0.05).Recombinant leptin signifi-cantly increased levels offree trii odothyronine,free thyrox-ine,insulin -like growth factor 1,i nsulin -like growth factor -binding protein 3,bone alkaline phosphatase,and osteocalcin but not cortisol,corti cotropin,or urinary Ntelopeptide.CONCLUSIONS:Leptin administration for the relative leptin deficiency in wo men with hypothalamic amenorrhea appears to improve repro ductive,thyroid,and growth hormone axes and markers of bone formation,sug-gesting that leptin,a peripheral signal reflecting the ade-quacy of energy stores,is required f or normal reproductive and neuroendocrine function. BACKGROUND: Disruptions in hypothalamic-gonadal and other endocrine axes due to energ y deficits are associ-ated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalami c amenorrhea. We hypothesized that exogenous recomb inant leptin replace-ment would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea. METHODS: Eight women with hypothala mic amenorrhea due to strenuous exercise or low weig ht were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to t hree months. Six con -trol subjects with hypothalamic ame norrhea received no treatment and were studied for a mean (± SD) of 8.5 ± 8.1 months.RESULTS: Luteinizing hormone (LH) -pulsatility, body weight, ovarian v ariables, and hormone levels did not change significantly over time in the controls and during a one-month control perio d before recombinant leptin therapy in the treated subjec ts.In contrast, recombination leptin treatm ent increasing mean LH levels and LH pulse frequency after two weeks and i ncreased maximal follicular diameter, the number of d dominant follicles, ovarian volume, and estradiol levels over a period of three months. Thhree patients had an ovulatory menstrual cycle (P <0.05 for the comparison with an expec ted rate of spontaneous ovulation of 10percent); two others had pre-ovulatory follicular development a nd withdrawal bleeding during treatment (P <0.05) .Recombinant leptin signifi-cantly increased levels off trii odothyronine, free thyrox-ine , insulin-like growth factor 1, i nsulin-like growth factor-binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corti cotropin, or urinary Ntelopeptide. CONCLUSIONS: Leptin administration for the relative leptin deficiency in wo men with hypothalamic amenorrhea appears to improve repro ductive, thyroid, and growth hormone axes and markers of bone formation, sug-gesting that leptin, a peripheral signal reflecting the ade-quacy of energy stores, is required f or normal reproductive and neuroendocrine function.