Leptin modulates fertility under the influence of elevated growth hormone as modeled in oMt1a-oGH transgenic mice.

Abstract

Elevated growth hormone (GH) concentrations suppress reproductive function in a variety of species, although it is unclear whether GH directly suppresses reproductive performance, or whether GH activates other pathways to achieve these effects. The ovine metallothionein 1a-ovine GH (oMt1a-oGH) transgenic mouse has been used to model the effects of GH on both body composition and reproductive function. A recent report has documented increased leptin levels in obese oMt1a-oGH mice. Given the importance of leptin in modulation of the reproductive endocrine axis, as well as the reports documenting reduced leptin signal transduction in animals with elevated leptin levels, we hypothesized that high leptin concentrations in response to elevated GH would reduce fertility. To determine the effects of high circulating leptin levels on the reproductive endocrine axis, we assessed hypothalamic neuropeptide Y (NPY) and GnRH expression. At weaning, oMt1a-oGH transgenic (TG) and wild-type (WT) female mice were allocated to one of four treatment groups: oMt1a-oGH females chronically expressing the transgene (TG ON); oMt1a-oGH females expressing the transgene from 3 to 8 weeks of age (TG ON/OFF); WT females receiving the transgene stimulus from 3 to 8 weeks of age (WT ON/OFF); and WT females never receiving the transgene stimulus (WT OFF). Eight-week-old females were housed with males for a 2-week period, after which females were isolated from males and allowed to carry pregnancies to term. Body and gonadal fat pad (GFP) weights, along with plasma leptin concentrations, estrous cyclicity, pregnancy rate and litter characteristics, were recorded for each female. Chronic expression of the oMt1a-oGH transgene resulted in larger leaner mice, and inactivation of the transgene produced obese females. Pregnancy rate was reduced in TG ON females when compared with all other groups, and infertility was associated with elevated leptin levels. In addition, high leptin levels were associated with increased NPY expression, suggesting reduced leptin-signaling capacity, which may contribute to suppression of the reproductive axis in oGH animals.