Endocrine responses to caloric restriction in the non-human primate: Effect of leptin administration and re-alimentation

To test the hypothesis that hypoleptinemia is critical to the maintenance of nutritional amenorrhea, we developed a model of nutritional amenorrhea in rhesus monkeys and investigated the effect of intracerebroventricular (i.c.v) leptin administration on anovulation induced by chronic caloric restriction. Beginning at a body mass index (BMI) of 23--24kg/m2, caloric intake was gradually reduced up to 40%. Body weight measurements were taken weekly to verify a gradual weight loss that did not exceed 20%. Amenorrheic animals were initiated on 16 weeks of continuous recombinant human leptin infusion (25ug/kg/day). Following treatment, food intake was increased to restore normal BMI. Caloric restriction decreased weight and inhibited ovulation in all monkeys. Inhibition of ovulation occurred at a BMI of 21.7 +/- 0.6kg/m2. Caloric restriction stimulated cortisol release but cortisol was not significantly increased prior to the onset of anovulation. FSH and T3 secretion was suppressed in caloric-restricted animals. Leptin normalized cortisol secretion but did not restore levels of FSH, T 3 or ovulation. An immune response to human leptin was detected in all animals. Re-alimentation resulted in weight gain and reversed all endocrine responses to caloric restriction. The BMI at which ovulation was restored (21.5 +/- 0.5kg/m2) mirrored that at which anovulation occurred. Having identified a BMI threshold for reproductive function in rhesus monkeys, we investigated the effect of chronic caloric restriction on the positive gonadotropin feedback response to ovarian steroids in ovariectomized animals. Caloric restriction inhibited gonadotropin surges in the majority of monkeys indicating that the effects of caloric restriction extend beyond inhibition of tonic gonadotropin secretion to include a disturbance of phasic gonadotropin secretion. In conclusion, this is the first demonstration that caloric restriction can inhibit ovulation in the non-human primate. Caloric restriction may affect the reproductive axis at several levels. If leptin abrogates some, but not all the effects of caloric restriction on the reproductive axis, leptin-induced ovulation is unlikely to occur. Given the immunogenic response demonstrated by this species to human leptin, cautious interpretation of these results is warranted until the efficacy of chronic administration of human leptin in rhesus monkeys can be established.