Pharmacodynamics of a single low dose of long-acting recombinant follicle-stimulating hormone (FSH-carboxy terminal peptide, corifollitropin alfa) in women with World Health Organization group II anovulatory infertility.

In a double-blind, placebo-controlled, randomized study, 55 anovulatory subjects received a single s.c. injection of placebo (n = 10) or recombinant long-acting FSH [FSH-carboxy terminal peptide (CTP), ORG 36286, corifollitropin alfa; NV Organon, The Netherlands] in doses of 7.5 (n = 13), 15 (n = 10), 30 (n = 11), or 60 microg (n = 11). The injection was given 2 or 3 d after the onset of a spontaneous or progestagen-induced withdrawal bleed. After drug administration, the induced follicular response varied widely among subjects in each dose group. The percentage of subjects with a follicular response (at least one follicle > or = 10.0 mm) increased with the dose (P < 0.01) and was 10, 31, 70, 73, and 82% in the placebo and 7.5-, 15-, 30-, and 60-microg treatment groups, respectively. In responding subjects, the average maximum number of follicles was 4.0, 7.6, 13.4, and 20.0, respectively, which was reached at 6.5, 6.9, 6.6, and 8.2 d after a single dose of 7.5, 15, 30, and 60 microg FSH-CTP, respectively. The dose-response for the number of follicles was statistically significant within the dose range tested (P < 0.01). Peak serum inhibin-B levels were significantly correlated with serum estradiol (E2) levels (r = 0.84, P < 0.01), and peak concentrations of inhibin-B and E2 correlated with the number of follicles observed at the same time point (for both hormones; r = 0.47, P < 0.01). Overall per treatment group, serum E2 and inhibin B concentrations significantly increased only in the two highest FSH-CTP dose groups, reaching peak concentrations at d 3 in the 30-microg group and at d 5 in the 60-microg group. Thereafter these hormone values declined rapidly, returning to baseline within 1 wk after FSH-CTP administration. In total, nine of the 55 treated subjects (16.4%) ovulated after drug administration: one subject in the placebo group, two subjects in the 7.5-microg group, three subjects in the 15-microg group, two in the 30-microg group, and one in the 60-microg group. Three subjects had monofollicular ovulation after placebo (n = 1) and a single dose of 15 microg FSH-CTP (n = 2). In two subjects with too many preovulatory follicles, (multiple) ovulation was prevented by GnRH antagonist administration. Thus, a single low dose of long-acting FSH-CTP was able to induce one or more follicles to grow up to ovulatory sizes, but the anovulatory status was not reversed because the incidence of subsequent (mono)ovulations was low.

Ovarian function during and after treatment with the new progestagen Org 30659.

OBJECTIVE: To evaluate ovarian function during 21 days of oral administration of different doses of Org 30659, a novel selective progestagenic steroid. DESIGN: Randomized, double-blind, dose-finding study. SETTINGS: Three centers in Austria, Sweden, and the United Kingdom. PARTICIPANTS: Eighty-one healthy women 19-40 years of age with regular ovulatory cycles. INTERVENTION: Daily oral administration of 0.060, 0.120, 0.180, or 0.240 mg of Org 30659, or 0.075 mg desogestrel (reference group), for 21 days. MAIN OUTCOME MEASURE(S): Once-daily measurements of follicular diameter and 17-beta estradiol, progesterone, FSH, and LH levels. RESULT(S): Daily treatment with Org 30659 for 21 days caused dose-dependent suppression of ovarian activity. No ovulation was observed in any study group. On average, ovulation returned 16.5 to 22.1 days after treatment. The effects of desogestrel, 0.075 mg, were similar to those of 0.060 and 0.120 mg of Org 30659. All doses were well tolerated, as shown by the type of side effects that occurred, the absence of an effect on physical and laboratory findings, and the low rate of study discontinuation. CONCLUSION(S): Daily oral administration of 0.060-0.240 mg of Org 30659 suppresses ovarian function to a level sufficient to inhibit ovulation. This effect is dose-dependent, and the suppressive effect is readily reversible at all doses tested. Org 30659 can thus be safely administered orally for 21 days to healthy female volunteers in a dosage of 0.060 mg/d to 0.240 mg/d.