Gonadotropin-Releasing Hormone-Antagonist in Human In Vitro Fertilization doc

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Gonadotropin-Releasing

Hormone-Antagonist in Human

In Vitro Fertilization

F. Olivennes

Department of Obstetrics and Gynecology, Hospital Cochin, Paris, France

INTRODUCTION

Gonadotropin-releasing hormone antagonists (GnRH-nt) available for clini￾cal use are GnRH molecules with amino acid modifications in positions 1, 2,

3, 6, and 10. They are not associated with the histaminic-release effects of

previous compounds (1). These compounds immediately block GnRH recep￾tor in a competitive fashion (2). They decrease the luteinizing hormone (LH)

and follicle-stimulating hormone (FSH) secretion within a period of eight

hours. Inhibition of LH secretion is more important than FSH. This is prob￾ably due to the different forms of gonadotropin regulation, the prolonged

FSH half-life, or the immunoactive and bioactive forms of FSH (3,4).

Administered during the follicular phase, GnRH-nt can prevent or

interrupt LH surges (5). In addition, their use has been proposed in in vitro

fertilization (IVF)–embryo transfer (ET) cycles to obtain results similar to

those obtained with GnRH-a, however with the simplest protocol and fewer

side effects (6).

Two different compounds are available: the Cetrorelix (Cetrotide1,

formerly ASTA Medica, now Serono) and the Ganirelix (Antagon1 or

Orgalutran1, Organon). Two different protocols of administration (Fig. 1)

have been proposed in the literature for using GnRH-nt in controlled

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ovarian stimulation (COH). In the multiple-dose protocol, small doses

(0.25 mg) of the GnRH-nt are injected in the middle of the follicular phase

(7–9). In the single-dose protocol, a higher dose (3 mg) is injected during the

late follicular phase, when the LH surge is most feared (10,11).

PHASE II DOSE-FINDING STUDIES

Single-Dose Protocol

In the first investigation with Cetrorelix, we simply reproduced the pre￾viously published Nal–Glu protocol consisting of two 5 mg injection 48 hr

apart in the late follicular phase (12,13). We therefore proposed two

administrations of 5 mg Cetrorelix 48 hour apart, the first injection being

administered on stimulation day 7. We observed that the second injection

was often unnecessary as hCG was given on the same day. We concluded

also that the 5 mg dose induced a deep suppression of LH and that a lower

dose should be tried (10). A single-dose protocol was designed where a single

injection of 3 mg of the GnRH-nt is performed on stimulation day 7 (11).

To determine the minimal effective dose, we conducted a dose-finding

study. We compared the use of 2 and 3 mg to investigate the ‘‘protection

period,’’ the time during which an LH surge is prevented after the antagonist

administration. The IVF-ET results were strictly comparable between the

Figure 1 Gonadotropin-releasing hormone antagonist multiple- and single-dose

protocols. Fixed day regimens. Abbreviations: FSH, follicle-stimulating hormone;

hMG, human menopausal gonadotropin; hCG, human chorionic gonadotropin.

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