Elevated hypothalamic aromatization at the onset of precocious puberty in transgenic female mice hypersecreting human chorionic gonadotropin: effect of androgens

GONZALEZ, B.; RATNER, L.D.; SCERBO, M.J.; DI GIORGIO, N.P.; POUTANEN, M.; HUHTANIEMI, I.T.; CALANDRA, R.S.; LUX LANTOS, V.A.R.; CAMBIASSO, M.J.; RULLI, S.B.

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2014 vol. 390 p. 102 - 111

0303-7207

Transgenic female mice overexpressing the alpha and beta subunits of human chorionic gonadotropin (hCG+), an agonist of LH acting through the same receptor, presented with chronically elevated hCG levels and precocious puberty (PP) at 20±1 days of age, evidenced by the vaginal opening about 6 days before wild-type animals. In the present study we investigated the etiology of hCG-dependent PP and the role of gonadal signals by characterizing the hypothalamic-pituitary-gonadal axis of 21-day-old hCG+ females. Chronically elevated hCG stimulated gonadal androgen production, which exerted negative feedback over the gonadotropin synthesis, and activated the hypothalamic GnRH pulsatility and gene expression. Transgenic females also exhibited elevated Cyp19a1expression and aromatase protein levels in the preoptic area-anterior hypothalamus (POA-AH). The gonadal input removal by Ovx at 14 days of age was not able to rescue this phenotype. However, the blockade of androgen action by the antiandrogen flutamide from postnatal day 6 was able to reduce the aromatase levels in the POA-AH of hCG+ females, indicating that this was an androgen receptor mediated event. However, advanced vaginal opening was not dependent on androgen excess, since it occurred prematurely with flutamide treatment. Our results suggest that early exposure of females to androgen action during a critical period between postnatal days 6 to 14 would induce sex-specific organizational changes of the brain, which affect the aromatase expression in the POA-AH in females at the onset of precocious puberty.