ELEVATED LUTEINIZING-HORMONE IN PREPUBERTAL TRANSGENIC MICE CAUSES HYPERANDROGENEMIA, PRECOCIOUS PUBERTY, AND SUBSTANTIAL OVARIAN PATHOLOGY

In women, chronically elevated androgens have been associated with pol ycystic ovarian syndrome and infertility. Recently, we described trans genic mice with elevated serum LH secondary to targeted expression of a transgene encoding a chimeric LH P-subunit. Mature transgenic female s exhibit elevated androgens, anovulation, and a range of ovarian phen otypes including cysts, widespread luteinization, and tumors. In the p resent study we have examined serum levels of LH and testosterone and the concurrent development of the reproductive system in prepubertal m ice. Serum LH in prepubertal females was elevated despite increased se rum testosterone and estradiol, indicating a relative insensitivity to steroid negative feedback. Elevated serum LH and hyperandrogenemia re sulted in accelerated vaginal opening and ovarian follicular developme nt in transgenic females. Precocious antral follicle formation and con spicuous hypertrophy of the theca-interstitium preceded the developmen t of large cysts with marked hemorrhage. Based on these studies we con clude that chronic prepubertal elevation of serum LH results in gonado tropin-dependent hyperandrogenemia, leading to abnormal sexual develop ment and significant ovarian pathology.