A novel regimen of gonadotropin-releasing hormone (GnRH) antagonist plus pulsatile GnRH: controlled restoration of gonadotropin secretion and ovulation induction.

Using a primate model, we have tested a novel regimen of gonadotropin-releasing hormone (GnRH) antagonist plus pulsatile GnRH for the achievement of controlled restoration of gonadotropin secretion and ovulation induction. As a prelude, ovariectomized cynomolgus monkeys (n = 3) were treated with Antide ([N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Pal(3)3, Lys(Nic)5, D-Lys(Nic)6, Lys(iPr)8, D-Ala10]-GnRH) (3 mg/kg per day) for 6 consecutive days. On the 7th day, pulsatile GnRH therapy was initiated in a 7 day-on: 7 day-off regimen for a total of four exposures. Next, four intact monkeys were given Antide to suppress ovarian function (estradiol less than 10 pg/mL) followed by pulsatile GnRH. In the ovariectomized monkeys, Antide-induced suppression of gonadotropin concentrations was reversed by the pulsatile GnRH so that follicle-stimulating hormone concentrations were completely normalized and luteinizing hormone concentrations were returned to within the lower range (+/- 2 SD) of the pretreatment mean. The abruptness of the onset or loss of gonadotropin secretion was precisely synchronized with the weekly on and off phases of the GnRH pulse regimen. In intact monkeys, ovarian steroid secretions were abruptly subdued and then successfully re-established by pulsatile GnRH in the face of sustained circulating levels of Antide. Thus, we conclude that our primate model of combination therapy, GnRH antagonist plus pulsatile GnRH, establishes the possibility of a new clinical treatment regimen for patients desiring relief from the sequelae of hyperandrogenemia (polycystic ovarian disease) and ovulatory dysfunction.