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Inhibition of Follicular Development by a Potent Antagonistic Analog of Gonadotropin-Releasing Hormone (Detirelix)^*

LORNA A. MARSHALL, MARGO R. FLUKER, ROBERT B. JAFFE and SCOTT E. MONROE

Reproductive Endocrinology Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Scott E. Monroe, Institute of Clinical Medicine, Syntex Research, Palo Alto, California 94303.

Present address: Virginia Mason Clinic, 1100 Ninth Avenue, Seattle, Washington 98111.

Postdoctoral fellow. Supported by the Alberta Heritage Foundation for Medical Research.

The ability of a potent long-acting antagonistic analog of GnRH to suppress gonadotropin secretion, disrupt follicular development, and inhibit ovulation was studied in six women with normal menstrual cycles. The GnRH antagonist detirelix ([N-Ac-D-Nal(2)¹ D-pCl-Phe², D-Trp³, D-hArg(Et₂)⁶, D-Ala¹⁰]GnRH; Syntex Research) was administered to six women by sc injection on alternate days during a 27-day period. Six additional women underwent blood sampling only, without receiving detirelix. Within 8 h after the initial injection of detirelix, mean (±SEM) serum LH and FSH concentrations decreased by 74 ± 2% and 26 ± 3%, respectively. Mean immunoreactive FSH levels, however, returned to baseline after the first 72 h despite continued administration of detirelix. Mean estradiol (E₂) concentrations decreased from 165 ± 15 to 70 ± 11 pmol/L in the first 24 h. During the treatment period follicular development was inhibited, and none of the six volunteers showed evidence of ovulation, as assessed by serum progesterone (P) levels. Maximal suppression of serum LH and E₂ was observed approximately 24 h after each injection of detirelix. Compared to the control volunteers, those receiving detirelix had significantly lower mean serum LH (P < 0.001), E₂ (P < 0.001), and P (P < 0.001) levels during treatment; mean FSH concentrations, however, were not statistically different in the treatment and control groups. Rapid recovery of pituitary-ovarian function occurred after completion of treatment. In all six volunteers receiving detirelix, a LH surge occurred 10–16 days after the final injection, followed by increased P levels (>32 nmol/L), indicating ovulation and a luteal phase of normal duration (12–14 days). Detirelix injections elicited local skin reactions (erythema and pruritus), but no systemic side-effects were observed. Thus, this long-acting GnRH antagonist can rapidly suppress gonadotropin secretion, inhibit follicular development, and prevent ovulation. (J Clin Endocrinol Metab 72: 927–933, 1991)

^* This work was supported by NIH Contract 1-HD-4-2801 and Radioimmunoassay Core Grant 1-P30-HD-11979-08.

Received June 15, 1990.

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