Normalization of hormonal imbalances, ovarian follicular dynamics and metabolic effects in follitrophin receptor knockout mice

Abstract

Genetically modified follitrophin receptor knockout female mice with total FSH-receptor (FSH-R) deletion are sterile and their combined estrogen deficiency-hyperandrogenemic status provides an experimental paradigm to study the effect of hormonal imbalances on ovarian function and metabolic alterations. Elevated LH levels causing hyperandrogenemia perturb normal folliculogenesis. To control diverse pathophysiology associated with hormonal imbalances, we investigated the effects of transplanting a single normal mouse ovary in young mutants. An intact FSH-R signalling system in the graft responded promptly to the up-regulated pituitary gonadotrophins circulating in the host mutant. Resumption of regular estrous cycles validated stimulation of uterine functions. Secretions from the viable functioning grafts partially corrected follicular abnormalities originally present in host ovaries. Stromal hyperplasia responsible for high ovarian LH-receptor and key enzymes in host thecal/interstitial complex and hyperandrogenemia was reduced in host ovaries. Increases in plasma estradiol and reduced LH and free testosterone re-established the negative-feedback system. Reduced android obesity and activation of mammary glands indicated the combined beneficial effects of normalized steroid hormones on target organs. These data provide evidence that ovarian transplantation in mutants corrects estrogen loss and hyperandrogenemia. However, correction of hormonal imbalances is not sufficient to fully restore effects of FSH-R loss in host granulosa cells.