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.