TY - JOUR
T1 - Luteal phase dose-response relationships of the antiprogestin CDB-2914 in normally cycling women
AU - Passaro, Maureen D.
AU - Piquion, Johann
AU - Mullen, Nancy
AU - Sutherland, Dorette
AU - Zhai, Suoping
AU - Figg, William D.
AU - Blye, Richard
AU - Nieman, Lynnette K.
N1 - Funding Information:
1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, 2Department of Nursing, Warren Grant Magnuson Clinical Center, 3Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892 and 4Contraception & 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, 5Present address: 650 Pennsylvania Ave SE, Suite 50, Washington, DC 20003, USA. 6Current address: 12 Wexford Glenn, Pittsford, NY 14534, USA. 7Present address: 3 Chevy Chase Circle, Chevy Chase, MD 20815, USA
Funding Information:
Pure crystalline CDB-2914 and its putative metabolites, and the 3-carboxymethyloxime–bovine serum albumin (BSA) and 3-carboxymethyloxime–histamine conjugates of CDB-2914 were synthesized by the Southwest Foundation for Biomedical Research (USA) under contract N01-HD-1-3137 to the Contraception and Reproductive Health Branch, NICHD, and were a gift from that branch (Rao et al., 1999). The Clinical Center Pharmaceutical Development Service sieved the powder with a 125 mm mesh sieve and formulated gelatin capsules containing either 1, 10, 50, 100 or 200 mg of CDB-2914, or inert powder (Avicel™ microcrystalline cellulose; FMC Corp., USA). Mifepristone was purchased from Sigma–Aldrich Company (USA).
PY - 2003/9/1
Y1 - 2003/9/1
N2 - 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.
AB - 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.
KW - CDB-2914
KW - Menses
KW - Normally cycling women
KW - Progesterone receptor modulator
UR - http://www.scopus.com/inward/record.url?scp=0041761970&partnerID=8YFLogxK
U2 - 10.1093/humrep/deg342
DO - 10.1093/humrep/deg342
M3 - Article
C2 - 12923133
AN - SCOPUS:0041761970
SN - 0268-1161
VL - 18
SP - 1820
EP - 1827
JO - Human Reproduction
JF - Human Reproduction
IS - 9
ER -