A chronic negative energy balance due to low nutritional intake or increased energy expenditure alters several neuroendocrine axes. The reproductive and thyroid axes are inhibited while the adrenal axis is stimulated. In primates, anovulation resulting from a chronic negative energy balance is a condition often referred to as nutritional amenorrhea. The objective of the current study was to determine if hypoleptinemia induced by dietary restriction is responsible for these neuroendocrine changes, particularly anovulation. Five rhesus monkeys had their dietary intake gradually reduced to inhibit ovulation. Dietary restriction inhibited follicle-stimulating hormone (FSH) and triiodothyronine (T(3)) secretion and stimulated cortisol release. Recombinant human leptin (rhleptin) administered by continuous infusion into the lateral ventricle for 16 weeks inhibited cortisol secretion but failed to stimulate FSH, T(3) or ovulation. An immune response to rhleptin was noted after 3 weeks of leptin administration. Realimentation resulted in weight gain and reversed all endocrine responses to dietary restriction, including ovulation. These results do not support a role for reduced leptin secretion in anovulation induced by dietary restriction. The inability of rhleptin to reverse anovulation induced by a negative energy balance in monkeys is in contrast to its stimulatory effect on ovulation in women with functional hypothalamic amenorrhea. Different outcomes may be attributed to the degree of negative energy balance, the immune response generated by interspecies leptin administration, and/or other experimental variables such as dose or route of administration. Attributing opposing outcomes to species differences is unwarranted until these variables can be further examined.