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Expression of a Gonadotropin-Releasing Hormone Receptor-Simian Virus 40 T-Antigen Transgene Has Sex-Specific Effects on the Reproductive Axis

Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine (K.-H.J., J.C.G., R.S.C., U.B.K.) and Department of Pathology (V.N.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and National Hormone and Peptide Program (A.F.P.), Harbor-University of California Los Angeles Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Ursula B. Kaiser, M.D., Brigham and Women’s Hospital, Division of Endocrinology, Diabetes and Hypertension, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: UKAISER{at}PARTNERS.ORG.

The GnRH receptor (GnRHR) responds to pulsatile GnRH signals to coordinate pituitary gonadotropin synthesis and secretion. Previously, a 1.2-kb fragment of the 5'-flanking region isolated from the mouse GnRHR gene was shown to target expression to pituitary gonadotropes in vivo. The 1.2-kb gene promoter fused to the simian virus 40 large T antigen (TAg) was used to generate transgenic mice that form gonadotrope-derived pituitary tumors at 4–5 months of age. Transgenic female mice have hypogonadotropic hypogonadism, infantile gonads, and are infertile throughout their life span, whereas males remain reproductively intact until their tumors become large. We hypothesized that the targeted TAg expression causes a sex-specific disruption of the reproductive axis at the level of the pituitary gland. To test this hypothesis, we characterized the pituitary gonadotropin β-subunit and TAg expression patterns, and measured plasma gonadotropin and gonadal steroid levels in female and male mice before and after pituitary tumor development. TAg expression was observed in transgenic females and males 15 d of age, before tumor development. Interestingly, and in contrast to the transgenic males, pituitary LHβ and FSHβ subunit protein levels, and plasma LH and FSH levels, were reduced in transgenic females. Reproductive organs in transgenic female mice remained underdeveloped but were normal in transgenic males. We conclude that the expression of the TAg transgene driven by the GnRHR gene promoter results in female-specific infertility due to disruption of gonadotropin production and secretion even before tumor development.