Selective progesterone receptor modulators 1: use during pregnancy

Background: A large number of synthetic compounds known as selective progesterone receptor modulators can bind to progesterone receptors: the ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. Objectives: Only a dozen or so selective progesterone receptor modulators have been tested to any significant extent: among them are mifepristone (RU 486), asoprisnil (J867), onapristone (ZK 98 299), ulipristal (CDB 2914), Proellex^? (CDB 4124), ORG 33628 and ORG 31710. Their clinical applications during pregnancy are discussed. Methods: A careful evaluation of existing major review papers and recently published articles was carried out focusing on mifepristone, the most widely studied selective progesterone receptor modulator, which was first used for the voluntary interruption of an early gestation. Other selective progesterone receptor modulators, especially those with partial agonist action, have shown little activity during pregnancy in animal models. Results/conclusions: Besides early and late voluntary interruption of gestation, selective progesterone receptor modulators have been tested in a variety of obstetrical situations: to obtain a ripening of the cervix, for the medical management of early embryonic loss and foetal death, for the induction of labour at term and for the medical treatment of extra-uterine pregnancies. The only applications that seem worthy of large-scale utilisation during pregnancy are voluntary interruption of early and late gestation, medical management of early delayed miscarriage and late foetal demise.     

Effect of antiprogestins and tamoxifen on growh inhibition of MCF-7 human breast cancer cells in nude mice

This is the first report demonstrating an in vivo antitumor activity of antiprogestins (mifepristone, onapristone) alone and in combination with tamoxifen in the MCF-7 human breast cancer model. The MCF-7 cells produced progressive growing tumors in female nude mice supplemented with 17-estradiol. Tumor regression was observed following either estrogen ablation alone or estrogen ablation in combination with tamoxifen. Monotherapy with tamoxifen or antiprogestins caused a retardation of estrogen-induced tumor progression. Complete inhibition or prevention of tumor growth occurred as a result of simultaneous administration of mifepristone and tamoxifen. The addition of mifepristone in this combination treatment was also effective in delaying or preventing tumor escape (relapse) from the antiestrogenic (antitumor) effect of tamoxifen. These results suggest a potential clinical benefit of adding an antiprogestin to antiestrogen therapy of breast cancer patients.     

The effects of mifepristone (RU486) on prostaglandin dehydrogenase in decidual and chorionic tissue in early pregnancy

Prostaglandin dehydrogenase is the main inactivating enzymefor prostaglandins and therefore controls local levels of prostaglandins.Since there is some evidence that the expression of this enzymeis under progesterone control it is reasonable that one of theeffects of antiprogestin is to reduce the concentration of thisenzyme and thus increase the effective concentration of prostaglandinwithin tissue. We have investigated the amount of enzyme activitywithin decidua and chorionic villi from women receiving theantigestagen mifepristone (RU486) 12, 24 and 36 h prior to surgicalabortion, and examined the effect on tissue concentrations ofprostaglandin dehydrogenase. Women receiving mifepristone inall groups had a significant reduction in concentration of prostaglandindehydrogenase enzyme in decidual tissue. There was also a markedreduction in prostaglandin dehydrogenase in decidual cells followingRU486, as demonstrated by immunochemical methods. At this stageof pregnancy, prostaglandin dehydrogenase was present in abundancein cytotrophoblast cells of chorionic villi but virtually absentfrom syncytiotrophoblast. In chorionic villi after RU486 administrationin vivo, there were no obvious differences in prostaglandindehydrogenase distribution or reactivity in the majority ofcases.     

Expression of 67 kDa laminin receptor in human breast cancer cells: regulation by progestins

The level of 67 kDa laminin receptor (67LR) expression on breast and colon tumor cell surfaces was previously shown to be correlated with the capacity of tumor cells to metastasize. In the present work we investigate the effects of progestins and estrogen on the expression of 67LR in two sublines of the T47D human breast cancer cells: weakly tumorigenic, poorly invasive parental T47D cells and a highly tumorigenic, more invasive T47Dco subclone. Inmmunoblotting with an affinity purified antibody directed against a synthetic peptide recognizes the 67LR in these cells. 67LR expression in the T47Dco subclone is 5,5-fold higher than in their parental T47D cells. Treatment of T47D cells with 1 nM of the synthetic progestin R5020 results in a 4-fold increase in 67LR protein expression. Estrogen also induced 67LR expression, but only by 1.5-fold. The progestin-stimulated expression of the 67LR correlates with a 4.3-fold increase in attachment of T47D cells to laminin. A monoclonal antibody, mAb 13, directed against ₁ integrin, completely blocks the attachment of T47D cells to fibronectin, only partially inhibits the attachment of T47D cells to laminin, and appears not to affect the progestin-stimulated laminin attachment of T47D cells. A new antiprogestin, ZK 112.993, significantly inhibits both progestin-stimulated 67LR expression and the increased attachment to laminin. These results suggest a possible role for progestin in mediating one of the multiple events thought to be important in metastasis of steroid receptor positive human breast cancer cells.     

Is ICI 182,780 an antiprogestin in addition to being an antiestrogen?

The pure antiestrogen ICI 182,780 has been shown to have antiprogestin activity in reporter gene constructs. Cell lines, naturally devoid of progesterone receptors (PR) were transfected with either the A or B forms of the human PR and a luciferase construct driven by a progesterone-response element (PRE). Because this system is an artificial one, our purpose was to determine whether these observations could be made in a human breast cancer cell line, naturally containing PR. We further evaluated the dose-response of ICI 182,780 and RU-486 (mifepristone) on PR and estrogen receptors (ER) in the presence of either progesterone, norgestrel or estradiol. These effects were measured using immunoassays for prostate-specific antigen (PSA) and human glandular kallikrein (hK2) and pS2. We found that ICI 182,780 blocked progesterone-stimulated PSA and hK2 production 100% at 10^–5 M, which decreased significantly by 10^–6 M. This inhibition did not occur when norgestrel was the progestin used. RU-486 showed 100% blockade for both progestins at all concentrations used. We concluded that the antiprogestin activity of ICI 182,780 exists for progesterone only. This weak antiprogestin activity may be unlikely to have significant clinical implications.     

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)‐resistant murine carcinomas antiprogestin responsiveness was restored by re‐expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH‐6 cells), and the other expressing only PRA (T47D‐YA) or PRB (T47D‐YB), MFP selectively inhibited the growth of PRA‐overexpressing tumors and stimulated IBH‐6‐PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB‐dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA‐overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.     

A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel)

BACKGROUND: The acceptability and continuation rate of oral contraceptive steroids are limited by unpredictable bleeding and the fear of long-term risks such as breast cancer. By inhibiting ovulation and by altering the receptivity of the endometrium, antagonists of progesterone, such as mifepristone, could be developed as estrogen-free novel contraceptives. METHODS: Multicentre, double-blind, randomized controlled trial comparing frequency of amenorrhoea (primary outcome), bleeding patterns, side effects and efficacy in women taking daily 5 mg mifepristone (n = 73) or 0.03 mg levonorgestrel (progestogen-only pill; POP, n = 23) for 24 weeks. RESULTS: More women were amenorrhoeic while taking mifepristone than POP (49 versus 0% P < 0.001), and fewer women bled or spotted for >5 days per month (4 versus 39% P < 0.001). Forty-eight percent of women who took mifepristone for 6 months had cystic glandular dilatation of the endometrium but none showed hyperplasia or atypia. There were no pregnancies in 356 months of exposure in women who used only mifepristone for contraception. Two pregnancies occurred in women taking mifepristone who were also using condoms for dual protection. CONCLUSIONS: Daily mifepristone (5 mg) is an effective oral contraceptive pill which has a better pattern of menstrual bleeding than an existing POP (levonorgestrel).     

Selective progesterone receptor modulators 3: use in oncology,endocrinology and psychiatry

Background: A number of synthetic steroids are capable of modulating progesterone receptors with a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. The best known of these are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex^? (CDB 4124), ORG 33628 and ORG 31710. Objective: Outside reproduction selective modulators of progesterone receptors have been under investigation for a large variety of indications, for example in oncology as adjuvants in breast, cervical, endometrial, ovarian and prostate cancer, as well as inoperable meningioma and leiomyosarcoma. In addition, they have been used as antiglucocorticoids. It is therefore useful to review the results obtained in these conditions. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone but also on those other selective modulators of progesterone receptors for which data are available. Results/conclusions: In preliminary studies selective modulators of progesterone receptors had some activity on a number of neoplasias. Their antiglucocorticoid activity has been tested with some success in Cushing's syndrome, several psychiatric conditions (e.g., mood disorders and Alzheimer's disease) and acute renal failure. Finally they are being used in a gene regulator system.