The long-term goals of this research are to understand the reproductive consequences of expression of constitutively active luteinizing hormone receptors (LHR). The critical role of LHR in male and female reproduction is underscored by the developmental and reproductive defects resulting from activating and inactivating mutations in the receptor. For example, activating mutations in human LHR are associated with familial male-limited precocious puberty (FMPP) and Leydig cell hyperplasia. Transgenic and knockout mouse models have facilitated our understanding of normal and pathophysiological functions of hormones and receptors. To examine the consequences of chronic ligand-mediated LHR activity, we have generated transgenic mice expressing a yoked hormone-receptor fusion protein (YHR) with constitutive activity. Male transgenic mice produce increased prepubertal levels of testosterone, accompanied by decreased testicular size and diameter of the seminiferous tubules. Female transgenic mice exhibit increased folliculogenesis at early ages, and at three months there is increased follicular atresia and the presence of follicular cysts suggesting that constitutive LHR activity may result in premature ovarian failure. The goals of this proposal are to elucidate the endocrine and molecular basis for altered testicular development and early reproductive senescence observed in the ovary. In the first aim we will examine the developmental changes in testicular and ovarian morphology and histology and determine the effect of chronic LHR activation on testicular somatic cell development and oocyte depletion. In the second aim we will analyze the temporal changes in hormone levels and expression of key molecules in the LHR signaling pathways to determine the endocrine and molecular basis of the testicular and ovarian phenotype. These studies will contribute new information on testicular and ovarian physiology and pathophysiology and provide insight into the molecular mechanisms of FMPP, female infertility and premature ovarian failure. ? ?
