Medical hypophysectomy: I. Dose-response using a gonadotropin-releasing hormone antagonist.
The hypothalamic-pituitary-ovarian axis can be "dissected" in a nonsurgical and reversible fashion by the administration of a potent gonadotropin-releasing hormone (GnRH) antagonist. We created a transient, functional lesion at the level of the pituitary gonadotrope by using a potent GnRH antagonist ([ Ac- pClPhe1 , pClDPhe2 , DTrp3 , DArg6 , DAla10 ]-GnRH). In long-term castrate cynomolgus monkeys, doses of 0.05 to 2.0 mg/kg/day intramuscularly were administered for a total of 32 days. At doses up to 0.2 mg/kg/day, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in circulation were only moderately suppressed; these subjects responded to an estradiol challenge by manifesting an LH elevation or surge within 48 hours. At doses of 0.5 to 1.0 mg/kg/day, FSH and LH secretion was suppressed to or below the limits of assay detection within 7 days, remaining in a severely hypogonadotropic state for the remainder of the treatment interval. Using 2 mg/kg/day, estradiol-positive feedback for midcycle-like LH/FSH surges was fully inhibited. This suppression of gonadotropin secretion was rapidly reversible, in that circulating gonadotropin levels had returned to pretreatment castrate levels within 60 days after termination of GnRH antagonist treatments. These findings suggest that potent GnRH antagonists can effectively create a hypogonadotropic milieu without the initial enhancement of gonadotropin secretion that occurs during initiation of GnRH agonist therapy. "Medical hypophysectomy" through GnRH antagonist administration may permit a more direct and controlled approach to gonadal therapies such as ovulation induction.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007016:Hypophysectomy / Q000379:methods*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism*; D008252:Macaca fascicularis
D007987:Gonadotropin-Releasing Hormone; C035819:LHRH, N-Ac-(4-Cl-Phe)(1,2)-Trp(3)-Arg(6)-AlaNH2(10)-; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone