Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin

Excess or loss of body fat can be associated with infertility, suggesting t hat adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedl y increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-defic ient ob/ob mice. These findings suggest a role for leptin as an endocrine s ignal between fat depots and the reproductive axis, but the effect of hyper leptinemia on the initiation and maintenance of reproductive function has n ot been elucidated. To address this issue, we examined the reproductive phe notypes of female transgenic skinny mice with elevated plasma leptin concen trations comparable to those in obese subjects. With no apparent adipose ti ssue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterize d by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonad otropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are assoc iated with chronic hyperleptinemia, thereby leading to a better understandi ng of the pathophysiological and therapeutic implication of leptin.