Human Reproduction Update Advance Access originally published online on March 24, 2005
Human Reproduction Update 2005 11(3):293-307; doi:10.1093/humupd/dmi002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications
1 Vascular Medicine Unit, Tenon Hospital APHP, 4 rue de la Chine, F 75020 Paris, 2 Hormonal Biochemistry Unit, Molecular Pharmacology of Progesterone Group, Bicêtre Hospital, APHP, 74 rue du Général Leclerc, F 94 000 Bicêtre, 3 Endocrinology Unit and EA 1533, University Pierre et Marie Curie, Genetics of Human Reproduction, St Antoine Hospital APHP, 184 rue du Fg St Antoine, F 75012 Paris, France and 4 Institute of Hormone Research, P.O.Box 3235, Jerusalem 91031, Israel
5 To whom correspondence should be addressed at: Vascular Medicine Unit, Tenon Hospital APHP, 4 rue de la Chine, F 75020 Paris, France. Email: nathalie.chabbert-buffet{at}tnn.ap-hop-paris.fr
Since the discovery of the antiprogestin mifepristone, hundreds of similar compounds have been synthesized, which can be grouped in a large family of progesterone receptor ligands. This family includes pure agonists such as progesterone itself or progestins and, at the other end of the biological spectrum, pure progesterone receptor antagonists (PA). Selective progesterone receptor modulators (SPRM) have mixed agonist–antagonist properties, and occupy an intermediate position of the spectrum. These compounds have numerous applications in female health care. Mifepristone is used to terminate pregnancy, and as such is commercially available in many countries. The negative abortion-related image of mifepristone has clearly limited the involvement of the major pharmaceutical companies in the development of PA and SPRM. Many PA and SPRM display direct antiproliferative effects in the endometrium, although with variable actions which seem product- and dose-dependent. This property justifies their use in the treatment of myomas and endometriosis. PA also suppress late follicular development, block the LH surge and retard endometrial maturation, which renders them potential estrogen-free contraceptive drugs. SPRM such as asoprisnil are not as effective in blocking the LH surge and appear to target the endometrium directly and produce amenorrhoea. Interestingly, clinical data show that treatment with these compounds is not associated with hypo-estrogenism and bone loss. The potential clinical applications of these compounds cover a broad field and are very promising in major public health areas. These include emergency contraception, long-term estrogen-free contraception (administered alone, or in association with a progestin-only pill to improve bleeding patterns), myomas (where they induce a marked reduction in tumour volume and produce amenorrhoea) and endometriosis. Further developments might also include hormone replacement therapy in post-menopausal women, as well as the treatment of hormone-dependent tumours.
Key words: contraception / mifepristone / myomas / progesterone receptor antagonists / selective progesterone receptor modulators
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. A. Friberg, D.G. J. Larsson, and H. Billig Dominant Role of Nuclear Progesterone Receptor in the Control of Rat Periovulatory Granulosa Cell Apoptosis Biol Reprod, June 1, 2009; 80(6): 1160 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gellersen, M.S. Fernandes, and J.J. Brosens Non-genomic progesterone actions in female reproduction Hum. Reprod. Update, January 1, 2009; 15(1): 119 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ravet, C. Munaut, S. Blacher, G. Brichant, S. Labied, A. Beliard, N. Chabbert-Buffet, P. Bouchard, J.-M. Foidart, and A. Pintiaux Persistence of an Intact Endometrial Matrix and Vessels Structure in Women Exposed to VA-2914, a Selective Progesterone Receptor Modulator J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4525 - 4531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. de Giorgio-Miller, P. Bungay, M. Tutt, J. Owen, D. Goodwin, and N. Pullen The Translational Pharmacology of a Novel, Potent, and Selective Nonsteroidal Progesterone Receptor Antagonist, 2-[4-(4-Cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 78 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan and B. W. O'Malley Selective Estrogen-Receptor Modulators and Antihormonal Resistance in Breast Cancer J. Clin. Oncol., December 20, 2007; 25(36): 5815 - 5824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Johanssen and B. Allolio Mifepristone (RU 486) in Cushing's syndrome Eur. J. Endocrinol., November 1, 2007; 157(5): 561 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Horne and D. L. Blithe Progesterone receptor modulators and the endometrium: changes and consequences Hum. Reprod. Update, November 1, 2007; 13(6): 567 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Girling, F. L. Lederman, L. M. Walter, and P. A. W. Rogers Progesterone, But Not Estrogen, Stimulates Vessel Maturation in the Mouse Endometrium Endocrinology, November 1, 2007; 148(11): 5433 - 5441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Pan, X. Luo, T. Toloubeydokhti, and N. Chegini The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression Mol. Hum. Reprod., November 1, 2007; 13(11): 797 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Chabbert-Buffet, A. Pintiaux-Kairis, P. Bouchard, and on behalf of the VA2914 Study Group Effects of the Progesterone Receptor Modulator VA2914 in a Continuous Low Dose on the Hypothalamic-Pituitary-Ovarian Axis and Endometrium in Normal Women: A Prospective, Randomized, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3582 - 3589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Birrell, L. M. Butler, J. M. Harris, G. Buchanan, and W. D. Tilley Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer FASEB J, August 1, 2007; 21(10): 2285 - 2293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System Endocr. Rev., June 1, 2007; 28(4): 387 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. P. Madauss, E. T. Grygielko, S.-J. Deng, A. C. Sulpizio, T. B. Stanley, C. Wu, S. A. Short, S. K. Thompson, E. L. Stewart, N. J. Laping, et al. A Structural and in Vitro Characterization of Asoprisnil: A Selective Progesterone Receptor Modulator Mol. Endocrinol., May 1, 2007; 21(5): 1066 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Han, S. Y. Tsai, M.-J. Tsai, and B. W. O'Malley Distinct Temporal and Spatial Activities of RU486 on Progesterone Receptor Function in Reproductive Organs of Ovariectomized Mice Endocrinology, May 1, 2007; 148(5): 2471 - 2486. [Abstract] [Full Text] [PDF]
|
|