The regulation of the hypothalamic-pituitary axis is altered in transgenic male mice overexpressing human chorionic gonadotrophin (hCG)
Betina Gonzalez1, Noelia Di Giorgio1, Laura Ratner1, Matti Poutanen2, Ilpo Huhtaniemi3, Ricardo Calandra1, Victoria Lux-Lantos1 & Susana Rulli1
Male transgenic (TG) mice overexpressing both the hCGα- and hCGβ- subunits present elevated levels of circulating hCG, Leydig cell hyperplasia/hypertrophy, elevated androgen levels and infertility (Rulli et al. 2003). In addition, serum FSH is significantly reduced in prepuberal and adult TG males compared with wild-types (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: i) serum FSH levels by RIA; ii) pituitary mRNA expression of FSHβ (Fshb), GnRH receptor (Gnrhr), estrogen receptor α (Esr1) and the common α-subunit (Cga) by qRT-PCR; iii) 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 versus 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 Gnrhr and Esr1 were reduced in TG compared with WT, and Cx showed no effects. The GnRH hypothalamic concentration (μg/mg protein) 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 it in TG (P<0.05). These results indicate that the chronic 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.