TARGETED OVEREXPRESSION OF LUTEINIZING-HORMONE IN TRANSGENIC MICE LEADS TO INFERTILITY, POLYCYSTIC OVARIES, AND OVARIAN-TUMORS

Hypersecretion of luteinizing hormone (LH) is implicated in infertilit y and miscarriages in women, A lack of animal models has limited progr ess in determining the mechanisms of LH toxicity, We have recently gen erated transgenic mice expressing a chimeric LH beta subunit (LH beta) in gonadotropes. The LH beta chimera contains the C-terminal peptide of the human chorionic gonadotropin beta subunit, Addition of this pep tide to bovine LH beta resulted in a hormone with a longer half-life. Furthermore, targeted expression of the LH beta chimera led to elevate d LH levels and infertility in female transgenics. These mice ovulated infrequently, maintained a prolonged luteal phase, and developed path ologic ovarian changes such as cyst formation, marked enlargement of o varies, and granulosa cell tumors, Testosterone and estradiol levels w ere increased compared to nontransgenic littermates. An unusual extrag onadal phenotype was also observed: transgenic females developed hydro nephropathy and pyelonephritis. The pathology observed demonstrates a direct association between abnormal secretion of LH and infertility an d underscores the utility of the transgenic model for studying how exc ess LH leads to cyst formation, ovarian tumorigenesis, and infertility .