CONCORDANT SUPPRESSION OF SERUM IMMUNOREACTIVE LUTEINIZING-HORMONE (LH), FOLLICLE-STIMULATING-HORMONE, ALPHA-SUBUNIT, BIOACTIVE LH, AND TESTOSTERONE IN POSTMENOPAUSAL WOMEN BY A POTENT GONADOTROPIN-RELEASING-HORMONE ANTAGONIST (DITIRELIX)

The purposes of the current study were 2-fold: 1) to assess the effects of a new antagonistic analog of GnRH [N-Ac-D-Nal(2)1, D-pC1-phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] GnRH, or detirelix (Syntex Research) on gonadotrope function as reflected by serum levels of immuno- and bioassayable LH, and immunoactive FSH and alpha-subunit concentrations in postmenopausal, hypergonadotropic women; and 2) to determine if androgen production in the postmenopausal ovary is gonadotropin dependent. Six normal postmenopausal women were studied. Each volunteer received doses of 1, 5, and 20 mg detirelix sc in a random order separated by at least a 1-week interval. Serum LH, FSH, and alpha-subunit were measured by RIA at frequent intervals for 72 h after each injection. Bioactive LH levels were measured at 0, 24, 48, and 72 h after injection by a mouse Leydig cell bioassay, to permit comparison of biological with immunological LH activity. The steroids testosterone (T) and dehydroepiandrosterone sulfate were measured before injection and 12 (T only), 24 and 48 h after injection of the 20 mg dose. Immunoactive levels of serum LH and FSH were both suppressed in a dose-dependent manner, but LH suppression was greater than that of FSH. Maximum LH suppression (mean +/- SEM) after the 1, 5, and 20 mg doses was 40.2 +/- 7.0%, 63.2 +/- 3.4%, and 75.8 +/- 2.2%, respectively. For the same doses, maximum FSH suppression was 18.0 +/- 6.0%, 25.6 +/- 4.6%, and 39.6 +/- 2.7%. LH levels remained suppressed below baseline for up to 72 h after the 20 mg dose. Bioactive LH changes closely paralleled those of immunoactive LH. Mean LH suppression (area under the serum concentration curve) during the first 24 h after injection was 23.5 +/- 6.2% for the 1-mg dose, 47.2 +/- 4.7% for the 5-mg dose, and 61.0 +/- 2.1% for the 20-mg dose. Mean percent FSH suppression during the first 24 h, calculated in the same manner, was 6.8 +/- 3.9% (1 mg), 14.5 +/- 2.9% (5 mg), and 18.2 +/- 2.6% (20 mg). Serum alpha-subunit concentrations were significantly suppressed by 1 h after dosing with the 5- and 20-mg doses (P < 0.05), and remained suppressed throughout the 72-h sampling period. Gonadotropin dependence of steroidogenesis in the postmenopausal ovary was suggested by a significant suppression of serum T concentrations after the 20-mg dose of detirelix. Baseline T levels of 0.90 +/- 0.17 nmol/L decreased to 0.59 +/- 0.10 nmol/L at 12 h (P < 0.01) and were still suppressed to 0.62 +/- 0.14 nmol/L (P < 0.01) 24 h after drug administration. There were no significant changes in mean serum concentrations of dehydroepiandrosterone sulfate, suggesting that the changes in serum T levels were secondary to decreased ovarian androgen secretion. Thus, this study demonstrates that: 1) detirelix is a potent GnRH antagonist which suppresses gonadotropins, particularly LH, in a dose-dependent manner; 2) free alpha-subunit secretion is GnRH dependent and can be suppressed by a GnRH antagonist without alteration in estrogen milieu; and 3) postmenopausal ovarian androgen secretion is, in part, gonadotropin dependent.