Pituitary and gonadal effects of GnRH (gonadotropin releasing hormone) analogues in two peripubertal female rat models.
Central precocious puberty is commonly treated by gonadotropin releasing hormone (GnRH) agonists. To compare modes of action and effectiveness of GnRH analogues and assess treatment combinations of agonistic (triptorelin) and antagonistic (cetrorelix acetate) GnRH analogues with established treatment, we used prepubertal 31-d-old ovariectomized female rats. Strongest inhibition of LH and FSH occurred after 2-d treatment with antagonist alone (LH 0.08 +/- 0.02 versus 3.2 +/- 0.56 ng/mL in controls; FSH 10.8 +/- 2.8 versus 44.2 +/- 5.0 ng/mL in controls, p < 0.001). Combined agonist/antagonist was second most effective of the treatments (after 5 d treatment, LH 0.52 +/- 0.15 versus 4.9 +/- 1.1 ng/mL in controls; p < 0.01). Pituitary gonadotropin subunit LHbeta mRNA levels were inhibited in all groups except controls, but pituitary GnRH receptor mRNA was stimulated by agonist yet unaffected by combined analogues. Explanted ovaries were incubated with either analogue, both 10-6 M. After 4 h, GnRH receptor mRNA levels were significantly reduced by antagonist but not agonist. To verify puberty-inhibiting effects of GnRH analogues, we used 26-d-old female rats with androgen-induced precocious puberty after injecting subcutaneously single 300 microg danazol on postnatal d 5. Single application of cetrorelix depot (cetrorelix embonate) reduced serum estradiol levels and pituitary LHbeta expression; GnRH receptor mRNA levels were down-regulated in the pituitary and ovary (p < 0.05). In androgen-induced precocious puberty model, single injection of antagonist effectively arrests premature hormonal activation and down-regulates pituitary and ovarian GnRH receptors. We conclude that GnRH analogue combination and especially antagonist alone treatment most directly suppress gonadotropin levels. This implies that early treatment gonadotropin flare-up associated with agonist treatment is avoidable.
Roth
Christian
C
Children's Hospital Medical Center, University of Bonn, Bonn, Germany. croth@ohsu.edu
Hegemann
Frank
F
Hildebrandt
Judith
J
Balzer
Ivonne
I
Witt
Annette
A
Wuttke
Wolfgang
W
Jarry
Hubertus
H
D000728:Androgens; D000818:Animals; D003613:Danazol / Q000494:pharmacology; D004195:Disease Models, Animal; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D008186:Luteolytic Agents / Q000494:pharmacology*; D010052:Ovariectomy; D010053:Ovary / Q000187:drug effects* / Q000502:physiology; D010902:Pituitary Gland / Q000187:drug effects* / Q000502:physiology; D011629:Puberty, Precocious / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D017329:Triptorelin Pamoate / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D000728:Androgens; D004965:Estrogen Antagonists; D006727:Hormone Antagonists; D008186:Luteolytic Agents; D011960:Receptors, Estrogen; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D003613:Danazol; C062876:cetrorelix