Human Reproduction, Vol. 18, No. 9, 1820-1827,
September 2003
© 2003 European Society of Human Reproduction and Embryology
Luteal phase dose–response relationships of the antiprogestin CDB-2914 in normally cycling women*
1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, 2 Department of Nursing, Warren Grant Magnuson Clinical Center, 3 Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892 and 4 Contraception & Reproductive Health Branch, National Institute of Child Health and Human Development, Executive Bldg, Rm 8B07, 6100 Executive Blvd MSC 7510, Bethesda, MD 20892-7510, USA
5 Present address: 650 Pennsylvania Ave SE, Suite 50, Washington, DC 20003, USA.
6 Current address: 12 Wexford Glenn, Pittsford, NY 14534, USA.
7 Present address: 3 Chevy Chase Circle, Chevy Chase, MD 20815, USA
8 To whom correspondence should be addressed. e-mail: NiemanL{at}nih.gov
BACKGROUND: Progesterone receptor modulators have potential therapeutic use in progesterone-dependent conditions such as endometriosis, fibroids and induction of labour. The synthetic steroid CDB-2914 binds to the progesterone and glucocorticoid receptors. In animals it has antiprogestational activity at doses 50-fold less than those required for antiglucocorticoid effects. METHODS AND RESULTS: We evaluated the biological activity, blood levels and safety of CDB-2914 at escalating single doses, in 36 normally cycling women at mid-luteal phase. CDB-2914 at doses of 1–100 mg did not change luteal phase length, but after 200 mg, all women had early endometrial bleeding. Four women with early menses had concurrent functional luteolysis (one at 10, 50, 100 and 200 mg). There were no biochemical or clinical signs of toxicity, and no effect on urinary cortisol or circulating thyroxine, prolactin, adrenocorticotrophic hormone or renin levels. Higher serum equivalents of CDB-2914 were observed by radioimmunoassay than by high performance liquid chromatography detection, indicating a considerable contribution of metabolites. CONCLUSIONS: Mid-luteal administration of CDB-2914 antagonizes progesterone action on the endometrium, in a dose-dependent fashion, without apparent antiglucocorticoid effects. Further study of CDB-2914 is needed to determine its clinical role.
Key words: CDB-2914/menses/normally cycling women/progesterone receptor modulator
* Part of this work was previously presented and published as an abstract: Passaro, M., Piquion, J., Mullen, N., Sutherland, D., Alexander, N.J. and Nieman, L., ‘Safety and luteal phase effects of the antiprogestin CDB2914 in normally cycling women.’ Proceedings of the 79th meeting of the Endocrine Society, Minneapolis, MN, 1997, p. 227.
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