The regulation of the hypothalamic-pituitary axis is altered in transgenic male mice overexpressing human chorionic gonadotrophin (hCG)

GONZALEZ B, DI GIORGIO NP, RATNER LD, POUTANEN M, HUHTANIEMI I, CALANDRA RS, LUX LANTOS VAR, RULLI SB

Praga, Republica Checa

Congreso; 12nd European Congress of Endocrinology; 2010

European Society of Endocrinology

Male transgenic (TG) mice overexpressing both the hCGa- and hCGb- subunits present with elevated levels of circulating hCG, Leydig cell hyperplasia/hypertrophy, elevated androgen levels and infertility. In addition, serum FSH is significantly reduced in prepuberal and adult TG males compared with wild type (wt), and does not change after treatment with the antiandrogen flutamide. The aim of this study was to evaluate the regulation of the hypothalamic-pituitary axis in 4 week- old TG and wt males, by analyzing the effect of castration (Cx) for 2 weeks. We evaluated: a) serum FSH levels by radioimmunoassay (RIA); b) pituitary mRNA expression of FSHb (Fshb), GnRH receptor (Gnrhr), estrogen receptor a (Esr1) and the common a-subunit (Cga) by qRT-PCR; c) the hypothalamic GnRH concentration and GnRH pulsatility ex-vivo (by RIA). FSH serum levels were: wt: 48.5±1.4, wt Cx: 77.5±2.0*, TG: 5.4±0.4*, TG Cx: 7.4±0.4* ng/ml (* p<0.001 vs wt). Fshb expression was lower in TG compared with wt (p<0.001), and Cx increased the expression in wt (p<0.001), without changes in TG. The expression of both Gnrhr and Esr1 were reduced in TG compared with wt, and Cx showed no effects. The GnRH hypothalamic concentration (µg/mg proteins) was higher in TG compared with wt (p<0.05), and no changes were observed post-Cx. GnRH pulsatility showed a higher pulse frequency in TG compared with wt, and Cx increased the pulse frequency in wt and decreased in TG (p<0.05). These results indicate that the hypersecretion of hCG in male mice produced a persistent inhibition of FSH synthesis and secretion, through alterations at both the pituitary and hypothalamic level, and was not modified after Cx. Because hCG overexpression occurs from the fetal stage in this model, this effect could be related to a higher exposure of the neuroendocrine system to steroids during the early stages of sexual differentiation.