Pharmacology and mechanism of action of progesterone receptor modulators (PRMs)
- Irving M Spitz, MD, DSc, FRCP
Irving M Spitz, MD, DSc, FRCP
- Adjunct Professor of Medicine
- Weill Cornell Medical College
- Emeritus Professor of Endocrinology
- Ben Gurion University of the Negev, Jerusalem, Israel
Progesterone is essential for the initiation and maintenance of pregnancy. After the discovery of the progesterone receptor (PR) in 1970, it was realized that a progesterone receptor antagonist (PA) would have a major impact on female reproductive health. In 1981, a glucocorticoid receptor antagonist now known as RU 486 (mifepristone) was synthesized. It soon became evident that this antiglucocorticoid also displayed marked antiprogestin activity. Since the discovery of mifepristone, several hundred similar compounds have been synthesized. These compounds may display progesterone agonist, antagonist, or mixed agonist/antagonist activity.
The chemical structure, mechanism of actions, and biological effects of progesterone receptor modulators (PRMs) will be discussed in this topic review. Their clinical applications and adverse effects, and their use for medical termination of pregnancy and emergency contraception are discussed separately. (See "Therapeutic use and adverse effects of progesterone receptor antagonists and selective progesterone receptor modulators" and "First trimester medication abortion (termination of pregnancy)" and "Emergency contraception", section on 'Antiprogestins'.)
In this topic, progesterone receptor antagonists are referred to as PAs and compounds with mixed agonist/antagonist activity are referred to as selective progesterone receptor modulators (SPRMs). Collectively, these compounds are known as progesterone receptor modulators (PRMs) (figure 1).
The term SPRM is in keeping with the terminology adapted for selective estrogen receptor modulators (SERMs) and selective androgen receptive modulators (SARMs). (See "Mechanisms of action of selective estrogen receptor modulators" and "Use of androgens and other hormones by athletes", section on 'SARMs'.)
From a pharmacologic, biochemical, and clinical perspective, a SPRM represents a class of progesterone receptor (PR) ligands that exerts clinically relevant, tissue selective, mixed progesterone agonist and antagonist effects, which may be full or partial, on various progesterone target tissues in an in vivo situation depending on the biological action studied (figure 1) .
- Chwalisz K, Perez MC, Demanno D, et al. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005; 26:423.
- Baulieu EE. Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor. Science 1989; 245:1351.
- Spitz IM, Bardin CW. Mifepristone (RU 486)--a modulator of progestin and glucocorticoid action. N Engl J Med 1993; 329:404.
- Spitz IM, Croxatto HB, Robbins A. Antiprogestins: mechanism of action and contraceptive potential. Annu Rev Pharmacol Toxicol 1996; 36:47.
- Wiechert R, Neef G. Synthesis of antiprogestational steroids. J Steroid Biochem 1987; 27:851.
- Fuhrmann U, Hess-Stumpp H, Cleve A, et al. Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist. J Med Chem 2000; 43:5010.
- Slayden OD, Chwalisz K, Brenner RM. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques. Hum Reprod 2001; 16:1562.
- Heikinheimo O, Vani S, Carpén O, et al. Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study. Hum Reprod 2007; 22:2515.
- DeManno D, Elger W, Garg R, et al. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids 2003; 68:1019.
- Elger W, Bartley J, Schneider B, et al. Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids 2000; 65:713.
- Chwalisz K, Larsen L, Mattia-Goldberg C, et al. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil Steril 2007; 87:1399.
- Jang GR, Benet LZ. Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use. J Pharmacokinet Biopharm 1997; 25:647.
- Lähteenmäki P, Heikinheimo O, Croxatto H, et al. Pharmacokinetics and metabolism of RU 486. J Steroid Biochem 1987; 27:859.
- Robbins A, Spitz IM. Mifepristone: clinical pharmacology. Clin Obstet Gynecol 1996; 39:436.
- Kekkonen R, Heikinheimo O, Mandelin E, Lähteenmäki P. Pharmacokinetics of mifepristone after low oral doses. Contraception 1996; 54:229.
- Blithe DL, Nieman LK, Blye RP, et al. Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids 2003; 68:1013.
- Gainer EE, Ulmann A. Pharmacologic properties of CDB(VA)-2914. Steroids 2003; 68:1005.
- Giangrande PH, McDonnell DP. The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. Recent Prog Horm Res 1999; 54:291.
- Leonhardt SA, Edwards DP. Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 2002; 227:969.
- Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004; 25:45.
- Bray, JD, Grygielko, et al. Asoprisnil, a selective progesterone receptor modulator, displays a distinct profile in PR-mediated assays, and the ability to recruit both coactivators and corepressors may explain its failure to demonstrate antiestrogenic activity on eutopic and ectopic rat uterine tissue. Endocrine Society Meeting, 2006.
- McPhail MK. The assay of progestin. J Physiol 1934; 83:145.
- Garfield RE, Blennerhassett MG, Miller SM. Control of myometrial contractility: role and regulation of gap junctions. Oxf Rev Reprod Biol 1988; 10:436.
- Bygdeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 1985; 32:45.
- Cheng L, Kelly RW, Thong KJ, et al. The effect of mifepristone (RU486) on the immunohistochemical distribution of prostaglandin E and its metabolite in decidual and chorionic tissue in early pregnancy. J Clin Endocrinol Metab 1993; 77:873.
- Cheng L, Kelly RW, Thong KJ, et al. The effects of mifepristone (RU486) on prostaglandin dehydrogenase in decidual and chorionic tissue in early pregnancy. Hum Reprod 1993; 8:705.
- Väisänen-Tommiska M, Butzow R, Ylikorkala O, Mikkola TS. Mifepristone-induced nitric oxide release and expression of nitric oxide synthases in the human cervix during early pregnancy. Hum Reprod 2006; 21:2180.
- Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P, 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 2007; 92:3582.
- Spitz IM. Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century. Contraception 2010; 82:442.
- Spitz IM. Progesterone receptor antagonists and selective progesterone receptor modulators; proven and potential clinical indications. Expert Rev Obstet Gynecol 2007; 2:227. http://www.expert-reviews.com/doi/abs/10.1586/1747418.104.22.168 (Accessed on September 06, 2013).
- Chwalisz K, Elger W, Stickler T, et al. The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women. Hum Reprod 2005; 20:1090.
- Hodgen GD, van Uem JF, Chillik CF, et al. Non-competitive anti-oestrogenic activity of progesterone antagonists in primate models. Hum Reprod 1994; 9 Suppl 1:77.
- Slayden OD, Zelinski-Wooten MB, Chwalisz K, et al. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct. Hum Reprod 1998; 13:269.
- Slayden OD, Brenner RM. RU 486 action after estrogen priming in the endometrium and oviducts of rhesus monkeys (Macaca mulatta). J Clin Endocrinol Metab 1994; 78:440.
- Baird DT, Brown A, Critchley HO, et al. Effect of long-term treatment with low-dose mifepristone on the endometrium. Hum Reprod 2003; 18:61.
- Grow DR, Williams RF, Hsiu JG, Hodgen GD. Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study. J Clin Endocrinol Metab 1996; 81:1933.
- Narvekar N, Critchley HO, Cheng L, Baird DT. Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor. Hum Reprod 2006; 21:2312.
- Zelinski-Wooten MB, Slayden OD, Chwalisz K, et al. Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity. Hum Reprod 1998; 13:259.
- Chwalisz K, Brenner RM, Fuhrmann UU, et al. Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium. Steroids 2000; 65:741.
- Mutter GL, Bergeron C, Deligdisch L, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol 2008; 21:591.
- Ioffe OB, Zaino RJ, Mutter GL. Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator. Mod Pathol 2009; 22:450.