Leptin and Reproduction

[*]Early studies investigating the regulation of adiposity and satiety indicated that some humoral factor was involved in the control of appetite and had profound effects on obesity. The recognition of genetic animal models indicated that at least one gene was involved in the regulation of these factors. In 1994, Friedman's laboratory identified and isolated leptin. The availability of this hormone produced from adipose tissue was quickly used to validate studies that inferred the nature of this substance. We now know that leptin is indeed a hormone made by adipose tissue and that it feeds back to the hypothalamus to regulate satiety and has a genuine effect on energy metabolism and appetite.

Surprisingly, when these first studies were done, other information very quickly became available to demonstrate that leptin not only had effects on metabolism, energy expenditure, and satiety but also had profound effects on several areas of reproductive function. Perhaps the first was the recognition that fertility was restored in the genetically obese mouse by regulating leptin levels, whereas food restriction would not elicit the same effect. Very rapidly, other studies demonstrated a relationship with puberty. In short order, expression of the leptin mRNA was noted in the placenta, and it was recognized that leptin levels in the maternal circulation were elevated throughout pregnancy. These have now become important areas for research, and, indeed, a very controversial topic is the role that leptin plays in pubertal development.

More importantly, in the human, several high-risk pregnancy situations have been identified with alterations in leptin production. Perhaps the one under closest scrutiny at the present is preeclampsia, which is typified by elevated levels of maternal serum leptin, as well as enhanced placental production of the polypeptide. In addition, ovarian function seems to be involved with leptin regulation and may be affected by estrogen, especially at high levels, to increase leptin abundance. Changes during the menstrual cycle seem to occur with changes in either estradiol and/or progesterone. Leptin receptors have been identified in the ovarian follicle, and more recently the expression of the leptin message has been reported, so that the ovarian follicle appears to be both a target and a source of leptin, and a paracrine role might be indicated. Studies in infertility patients undergoing ovulation induction indicate that the efficiency of ovulation induction in subsequent pregnancy is related to leptin levels, in particular the leptin-body mass index ratio, with higher levels resulting in poorer outcomes.

A gender difference has been reported, and it was observed early in the human that leptin levels were always higher in the females, especially when adjusted to some index of adiposity. Leptin receptors have been identified in many reproductive tissues but the role of leptin has not found a clinical home. Leptin impinges on many aspects of reproductive function, and in the next few years studies should define multiple roles for leptin with regard to reproductive function.

In the present issue of Seminars in Reproductive Medicine, we have attempted to review some of the more important aspects of reproductive function, extending from basic physiology to the clinical situation. It appears clear that the future should hold many surprises and new developments in the area of leptin physiology.