Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model

To address whether gonadotropin-releasing hormone (GnRH) regulates its own expression and the expression of its receptor in the hypothalamus and ovary , we treated five groups of prepubertal/peripubertal female rats from postn atal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 mug/day, or a placebo. We comp ared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ov ary and uterus. Onset of puberty was determined by vaginal opening, and exp ression levels of GnRH and GnRH-receptor were determined using either quant itative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 mug/day) inhibited while TRIP (10 and 100 mug/ day) stimulated serum gonadotropins (P <0.05). The expression of GnRH in th e preoptic area did not show significant differences among the treatment gr oups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 mug/day). GnRH mRNA could not be detected in the uterus by either real-rim e PCR or competetive RT-PCR. The GnRH-receptor expression ill the hypothala mus (preoptic area and medio-basal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimula ted by TRIP (10 mug/day) but inhibited by CET (100 mug/day). In contrast, i n the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 mug/ day) and CET (100 mug/day). Interestingly, the GnRH-receptor was even expre ssed in the uterus where it was strongly stimulated by both CET and TRIP in a dose-related manner. This shows that in addition to their different pitu itary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also dem onstrates an organ-specific regulation of GnRH and GnRH-receptor gene expre ssion which is likely part of a local autoregulatory system. We conclude th at the ovarian and uterine effects of GnRH analogs must be considered in ad dition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.