Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice

BETINA GONZALEZ; LAURA D. RATNER; NOELIA P. DI GIORGIO; MATTI POUTANEN; ILPO HUHTANIEMI; RICARDO S. CALANDRA; VICTORIA A.R. LUX-LANTOS; SUSANA B. RULLI

MOLECULAR AND CELLULAR ENDOCRINOLOGY.

ELSEVIER IRELAND LTD

Año: 2011 vol. 332 p. 78 - 87

0303-7207

Transgenic male mice that express human chorionic gonadotropin (hCG) a and b subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGab+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGab males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGab+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGab+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.