{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:29:20Z","timestamp":1783517360888,"version":"3.55.0"},"reference-count":46,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2013,10,1]]},"abstract":"<jats:p> Transgenic female mice overexpressing the hCG\u03b2 subunit (hCG\u03b2<jats:sup>+<\/jats:sup>) and producing elevated levels of luteinizing hormone (LH)\/hCG bioactivity present as young adults with enhanced ovarian steroidogenesis, precocious puberty, and infertility. They subsequently develop pituitary prolactinomas, high circulating prolactin (PRL) levels, and marked mammary gland lobuloalveolar development followed by adenocarcinomas. None of these phenotypes appear in gonadectomized mice, indicating that the hCG-induced aberrations of ovarian function are responsible for the extragonadal phenotypes. PRL receptor-deficient (PRLR<jats:sup>\u2212\/\u2212<\/jats:sup>) female mice are sterile, despite ovulating, due to a failure of embryo implantation, as a consequence of decreased ovarian LH receptor (Lhcgr) expression and inadequate corpus luteum formation and progesterone production. To study further the presumed permissive role of PRL in the maintenance of gonadal responsiveness to LH\/hCG stimulation, we crossed the hCG\u03b2<jats:sup>+<\/jats:sup> and PRLR<jats:sup>\u2212\/\u2212<\/jats:sup> mice. The double-mutant hCG\u03b2<jats:sup>+<\/jats:sup>\/PRLR<jats:sup>\u2212\/\u2212<\/jats:sup> females remained sterile with an ovarian phenotype similar to PRLR<jats:sup>\u2212\/\u2212<\/jats:sup> mice, indicating that LH action, Lhcgr expression, and consequent luteinization are not possible without simultaneous PRL signaling. The high frequency of pituitary prolactinomas in PRLR<jats:sup>\u2212\/\u2212<\/jats:sup> mice was not affected by transgenic hCG\u03b2 expression. In contrast, none of the hCG\u03b2<jats:sup>+<\/jats:sup>\/PRLR<jats:sup>\u2212\/\u2212<\/jats:sup> females showed either mammary gland lobuloalveolar development or tumors, and the increased mammary gland Wnt-5b expression, possibly responsible for the tumorigenesis in hCG\u03b2<jats:sup>+<\/jats:sup> mice, was absent in double-mutant mice. Hence, high LH\/hCG stimulation is unable to compensate for missing PRL signaling in the maintenance of luteal function. 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