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

• Published in: Journal of endocrinology Vol. 169; no. 2; pp. 361 - 371
• Main Authors: Roth, C, Schricker, M, Lakomek, M, Strege, A, Heiden, I, Luft, H, Munzel, U, Wuttke, W, Jarry, H
• Format: Journal Article
• Language: English
• Published: Colchester BioScientifica 01.05.2001; Portland Press
• Subjects: Analysis of Variance; Animals; Autocrine Communication; Biological and medical sciences; Dose-Response Relationship, Drug; Estradiol - blood; Female; Follicle Stimulating Hormone - blood; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Gonadotropin-Releasing Hormone - agonists; Gonadotropin-Releasing Hormone - analogs & derivatives; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - pharmacology; Homeostasis; Hormone metabolism and regulation; Humans; Hypothalamus - metabolism; Luteinizing Hormone - blood; Mammalian female genital system; Models, Animal; Ovary - metabolism; Pituitary Gland - metabolism; Puberty, Precocious - drug therapy; Rats; Rats, Sprague-Dawley; Receptors, LHRH - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Sexual Maturation - physiology; Stimulation, Chemical; Triptorelin Pamoate - pharmacology; Uterus - metabolism; Vertebrates: reproduction; Puberty; Rat; Rodentia; Central nervous system; Gonadotropin RH; Hypothalamus; Gene expression; Hypothalamic hormone; Ovary; Vertebrata; Mammalia; Female genital system; Self regulation; Hormone releasing factor; Brain (vertebrata); Hormonal receptor
• DOI: 10.1677/joe.0.1690361
• ISSN: 0022-0795

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 postnatal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 microgram/day, or a placebo. We compared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ovary and uterus. Onset of puberty was determined by vaginal opening, and expression levels of GnRH and GnRH-receptor were determined using either quantitative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 microgram/day) inhibited while TRIP (10 and 100 microgram/day) stimulated serum gonadotropins (P<0.05). The expression of GnRH in the preoptic area did not show significant differences among the treatment groups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 microgram/day). GnRH mRNA could not be detected in the uterus by either real-time PCR or competetive RT-PCR. The GnRH-receptor expression in the hypothalamus (preoptic area and mediobasal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimulated by TRIP (10 microgram/day) but inhibited by CET (100 microgram/day). In contrast, in the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 microgram/day) and CET (100 microgram/day). Interestingly, the GnRH-receptor was even expressed 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 pituitary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also demonstrates an organ-specific regulation of GnRH and GnRH-receptor gene expression which is likely part of a local autoregulatory system. We conclude that the ovarian and uterine effects of GnRH analogs must be considered in addition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.