Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications

Abstract

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.

The spectrum of endometrial pathology induced by progesterone receptor modulators

“…Those with progesterone antagonist activity have potential application in contraception and treatment of uterine leiomyomata and endometriosis. 1 Some agents, such as mifepristone (RU486), are already approved in the United States for single use application. New clinical applications of mifepristone, and other PRMs such as asoprisnil (J867), CDB-2914, and onapristone, are under development.…”

Gynaecological uses of a new class of steroids: the selective progesterone receptor modulators

“…PAs and SPRMs do have contraceptive potential possibly, by several mechanisms [5,43]. They inhibit ovulation by blocking the LH surge and can induce endometrial desynchronisation, thereby interfering with implantation.…”

“…Two-hundred milligrams of mifepristone, administered 48 hours after the LH surge, shows contraceptive efficacy. However, this option is not clinically relevant because the detection of an LH surge routinely is an expensive and an unreliable method [5,47].…”

“…It transforms the endometrium from a proliferative to a secretory state and, together with estradiol, maintains endometrial integrity [5] preparing the endometrium for implantation. It inhibits uterine contractility [6].…”

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

“…It is generally accepted that progesterone receptor (PR) is an estrogen-regulated gene and its synthesis in normal and tumor cells requires estrogen and estrogen receptor (ER; refs. 4,5). As a result of endocrine therapy with tamoxifen, ER and PR in breast cancer cells may decrease, but complete loss of receptor does not occur (6)(7)(8).…”