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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

Department of Reproductive Medicine (A.H.B.), Leeds General Infirmary, Leeds, LS2 9NS United Kingdom; Erasmus Medical Center (A.G.M., B.C.F.), 3000 CA Rotterdam, The Netherlands; Catharina Ziekenhuis (B.C.S.), 5602 ZA Eindhoven, The Netherlands; University Hospital of Antwerp (M.A.R.), B-2650 Edegem, Belgium; Center for Reproductive Medicine (P.D.), Dutch-Speaking Brussels Free University, 1090 Brussels, Belgium; and NV Organon (M.J.S., B.M.M.), 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Bernadette Mannaerts, M.Sc., Clinical Development Department, P.O. Box 20, 5340 BH Oss, The Netherlands. E-mail: b.mannaerts{at}organon.com.

In a double-blind, placebo-controlled, randomized study, 55 anovulatory subjects received a single sc 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 µg (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 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-µg 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 µg 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-µg group and at d 5 in the 60-µg 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-µg group, three subjects in the 15-µg group, two in the 30-µg group, and one in the 60-µg group. Three subjects had monofollicular ovulation after placebo (n = 1) and a single dose of 15 µg 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.

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