Comparative analysis of different puberty inhibiting mechanisms of two GnRH agonists and the GnRH antagonist cetrorelix using a female rat model

GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by dese nsitization of pituitary GnRH receptors. Little has been published about th e use of GnRH antagonists such as cetrorelix to control the onset of pubert y and whether they are potentially advantageous compared with GnRH agonists . We conducted two multigroup experiments (12 and 10 d, respectively) treat ing prepubertal/peripubertal female rats with either the GnRH agonist tript orelin or buserelin and compared them with rats treated with the GnRH antag onist cetrorelix and controls to assess the effects on pubertal progress an d serum hormones. In the second experiment, the effects of buserelin and ce trorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and th e alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by d elayed vaginal opening, lower ovarian weights, and lower serum estradiol le vels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin expe riment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subun it were stimulated by buserelin but not by cetrorelix. Even though all thre e of these GnRH analogues inhibited gonadal development and delayed the ons et of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effec ts. We conclude from this female rat model that cetrorelix may offer advant ages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.