The Importance of Leptin to Reproduction.

A healthy nutritional state is required for all aspects of reproduction and signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range; too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary (PMV) neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone neurons (GnRH). Suppression of Kiss1 neurons occurs when AgRP neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHR) and follicle-stimulating hormone (FSH) at midcycle, by activating pathways that de-repress actions of the mRNA translational regulatory protein Musashi. In females, rising estrogen stimulate a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal Luteinizing hormone (LH) pulses. The normal range of serum leptin levels (10-20 ng/ml) along with gonadotropins and growth factors, promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10-50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.