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

Abstract

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 less than 0.001), E2 (P less than 0.001), and P (P less than 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 (greater than 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.

Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women

“…As shown in our study, (17) and 74% (18) decreases in immunoreactive LH after a single-dose injection administered during the follicular phase, and decreases in immunoreactive FSH levels of 29% (17), 26% (18) and 22% (15). The late maximal suppression after the first injection of Cetrorelix and the high suppressive power could be explained perhaps by the pharmacokinetic profile of Cetrorelix, i.e.…”

“…However, in contrast to other studies (15)(16)(17)(18) (17) observed the lowest values of the gonadotropins 8 h after sc injection of 10 mg of Detirelix administered in the midfollicular phase; the lowest serum concentrations of LH and FSH were found 8 h (18) after 5 mg of Detirelix was administered, and the greatest decline of FSH was described 9 h (15) after 80/ig/kg of 4F antagonist. As shown in our study, (17) and 74% (18) decreases in immunoreactive LH after a single-dose injection administered during the follicular phase, and decreases in immunoreactive FSH levels of 29% (17), 26% (18) and 22% (15).…”

“…LH and FSH were determined by IRMA (Serono, Freiburg, Germany) and estradiol and progesterone by RIA (estradiol: Serono, Freiburg, Germany; progesterone: RSL, ICN Biomedicals Inc., Costa Mesa, CA, USA). The lower limits of detection were 0.1 IU/1 for LH, 0.25 IU/1 for FSH, 18.35 pmol/l for estradiol and 0.73 nmol/1 for progesterone. The withinassay variations for LH, FSH, estradiol and progesterone were 2.2%, 4.0%, 5 Repeated sc administration of Cetrorelix resulted in a constant and significant decrease of LH, FSH and estradiol (Fig.…”

“…17,18), Nal-Glu(14) and, in four of five women, with the 4F antagonist(23), but great differences concerning the duration of suppression were revealed. While Marshall et al(18) observed, after an initial suppressive effect, a constant tendency towards increasing LH and estradiol concentrations during the period of application of 5 mg of Detirelix on alternate days over a 2 7-day period, Fluker et al found(17) lowest values of gonadotropins and estradiol at the end of a 10-mg Detirelix administration for 3 consecutive days.…”

Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells.

“…Progesterone was measured directly from the medium by radioimmunoassay as described previously from these laboratories (20). For the assessment of aromatase activity, 10-6 M androstenedione was added as precursor to the culture medium and the spent medium was assayed for 17-f3 estradiol by RIA as described previously (21,22).…”