Luteal phase dose-response relationships of the antiprogestin CDB-2914 in normally cycling women.
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.


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.
Passaro
Maureen D
MD
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Piquion
Johann
J
Mullen
Nancy
N
Sutherland
Dorette
D
Zhai
Suoping
S
Figg
William D
WD
Blye
Richard
R
Nieman
Lynnette K
LK
D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003338:Corpus Luteum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008183:Luteal Phase / Q000187:drug effects; D003341:Luteolysis; D008597:Menstrual Cycle / Q000187:drug effects; D008598:Menstruation / Q000187:drug effects; D009649:Norpregnadienes / Q000008:administration & dosage* / Q000097:blood; D011372:Progestins / Q000037:antagonists & inhibitors*; D011863:Radioimmunoassay; D012016:Reference Values; D013997:Time Factors
D009649:Norpregnadienes; D011372:Progestins; C094854:ulipristal