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Raloxifene, a selective estrogen receptor modulator (SERM), was designed to have the expected benefits of long-term estrogen replacement therapy without the risks. This paper reviews the clinical trial evidence for raloxifene benefits and risks, and how they compare with those of hormone replacement therapy (HRT) and relate to the choices of postmenopausal women.
Lasofoxifene [CP 336156] is a potent, nonsteroidal, tissue-selective estrogen receptor modulator (SERM). It has the bone-sparing and cardioprotective effects of estrogen, but lacks estrogen's uterine cancer risk. Lasofoxifene is under development with Ligand Pharmaceuticals and Pfizer (formerly Parke-Davis) for the prevention of postmenopausal osteoporosis and breast cancer. In June 2000, Parke-Davis' parent company, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development. The discovery of lasofoxifene resulted from a research collaboration between Pfizer and Ligand Pharmaceuticals. There was a contract dispute between the two companies relating to their research agreement. Under a settlement of litigation, Ligand is entitled to milestone and royalty payments. If Pfizer is successful in developing the drug through to regulatory approval in the US, Ligand could receive royalty revenues from lasofoxifene as early as 2003-2004. The royalties will be equal to 6% of net sales and will be in addition to milestone payments for continuing development of the drug. However, on 6 March 2002, Ligand Pharmaceutical announced an agreement with Royalty Pharma in which the latter purchased the rights to a share of these future payments. Under the agreement, Ligand received US dollars 6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Royalty Pharma retains the option to purchase, at escalating prices, additional rights (subject to timing restrictions) to extend this stake up to 1.0%, for a total of US dollars 56 million. In April 2002, Royalty Pharma exercised its first option to purchase an additional 0.125% of potential future sales of the three SERMS in exchange for US dollars 3 million. Subsequently, in December 2002, Royalty Pharma exercised an expanded option and agreed to pay Ligand US dollars 6.775 million for 0.1875% of potential future sales of SERM products. Royalty Pharma and Ligand Pharmaceutical amended their royalty agreement in October 2003 for the three SERM products. Under the amended agreement, Royalty Pharma exercised an option to pay Ligand US dollars 12.5 million, plus cumulative milestones of up to US dollars 2.5 million upon the launches of the three SERMs (provided they are approved by 30 September 2005), in exchange for 0.7% of potential future sales of the products for 10 years. In November 2004, Ligand Pharmaceuticals and Royalty Pharma further amended their existing royalty agreement for the three SERM products. Under the terms of the revised agreement, Royalty Pharma will purchase an additional 1.625% of the SERM products' net sales for US dollars 32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following the first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets will be paid to Ligand as earned and are not included in this amended agreement. In September 2004, Ligand Pharmaceuticals earned a milestone payment of approximately US dollars 2 million from Pfizer, payable in 181,818 shares of Ligand stock held by Pfizer. The payment was triggered by Pfizer's NDA submission for lasofoxifene in August 2004. Under the terms of the agreement between Ligand and Pfizer, Ligand is entitled to receive an additional milestone upon successful approval of lasofoxifene. On 19 August 2004, Pfizer filed an NDA with the US FDA for lasofoxifene for the prevention of osteoporosis in postmenopausal women. Product launch is forecasted to occur in 2006-2007. Ligand reported in January 2004 at the 22nd Annual JP Morgan Healthcare Conference that it anticipated the availability of phase III data and NDA filing sometime in 2004. Lasofoxifene has undergone two phase III studies with Pfizer in the US as an orally administered therapy for postmenopausal osteoporosis. In June 2003, Pfizer reported that enrolment was completed in a trial evaluating lasofoxifene in the prevention of bone loss. The trial also evaluated lasofoxifene's effect on lipid levels. The trial enrolled approximately 2000 postmenopausal women. Another trial was conducted among 8500 patients to investigate lasofoxifene in the treatment of fractures. In addition, Pfizer began a third worldwide phase III trial to evaluate whether lasofoxifene reduced the risk of vertebral fractures, breast cancer and cardiovascular disease. At the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003), Ligand also confirmed that lasofoxifene was in phase III development for breast cancer. Lasofoxifene is under clinical evaluation as a treatment for vaginal atrophy. According to Pfizer's pipeline in November 2004, the company anticipates regulatory submission for vaginal atrophy by the end of 2004. In June 2002, Ligand estimated that lasofoxifene has the potential to reach sales of US dollars 1-2 billion, pending approval.
Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.
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From the perspective of endometrial safety, there has been great controversy about what special management, if any, tamoxifen-treated patients should undergo. Periodic blind endometrial sampling or transvaginal ultrasound has been advocated by some. Because of the problems associated with either of these techniques alone, we recommended an approach that used transvaginal ultrasound and then proceeded to sonohysterography when the endometrial echo on transvaginal ultrasound was not reliably thin and distinct. The American College of Obstetricians and Gynecologists (ACOG), in its committee opinion, stated that patients receiving tamoxifen therapy should only have an annual pelvic exam with pap smear if they remain asymptomatic. Newer data suggest, however, that there are high- and low-risk groups that can be identified by pretreatment screening. Before tamoxifen therapy, 17% of patients have polyps. These patients have 17 times the incidence of atypical hyperplasia than those whose uterus was negative before tamoxifen therapy. Such findings call into question the validity of the only study of raloxifene where uterine safety was the primary endpoint. In that study, any woman with baseline endometrial findings other than pristinely negative (i.e., low risk) was excluded. However, other raloxifene studies without pretreatment screening show relative risk (RR) = 0.8 (95% CI = 0.2, 2.7) for endometrial carcinoma. This compares with the women over 50 years of age in the Breast Cancer Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-1) with tamoxifen when the RR = 4.01 (95% CI= 1.70, 10.90). The existence of potentially high- and low-risk groups should be taken into account in any future clinical trials looking at the endometrial safety of selective estrogen receptor modulators (SERMs).
BACKGROUND: Selective estrogen receptor modulators (SERMs) have been defined as compounds that display tissue specificity with regard to estrogenic effects. They appear to share the beneficial effects of estrogen on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. Estrogen relaxes coronary arteries and has long-term protective effects on the vascular system. The effect of SERMs on the coronary vasculature is unknown. We therefore investigated the effects of the SERM raloxifene on isolated rabbit coronary arteries. METHODS AND RESULTS: Rings of coronary artery from adult male and nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension was then measured. Raloxifene induced coronary arterial relaxation in male and female coronary arteries by an endothelium-dependent and estrogen receptor-dependent mechanism involving nitric oxide. Raloxifene also had a direct calcium antagonistic effect on the coronary myocyte. Estrogen, however, induced only endothelium-independent coronary arterial relaxation. The endothelium-dependent component of relaxation induced by raloxifene 10(-6) mol/L resulted in almost 100% (79+/-7% versus 43+/-3%, P<0.001) more relaxation than that induced by estrogen 10(-6) mol/L. CONCLUSIONS: These data demonstrate that raloxifene has vascular relaxing properties. The surprising finding is that the receptor-dependent effects via the endothelium are observed in coronary arteries from both male and female animals.
Estrogens are represented by a diverse group of compounds. Within this large family of molecules are tissue-selective estrogens that have been classified as selective estrogen receptor modulators (SERMs). These compounds are characterized by the fact that they exhibit both estrogen agonist and antagonist activity dependent upon the gene promoter and target tissue being examined. SERMs have been intensively studied over the past decade, especially since one, raloxifene, has been approved for the prevention and treatment of postmenopausal osteoporosis. While not a replacement for hormone replacement therapy (HRT), raloxifene can be an alternative to it and other treatments for osteoporosis. The ideal SERM would provide the positive benefits associated with HRT without the uterine and breast stimulation. Raloxifene does achieve some of the benefits of HRT, specifically on the skeleton and lipid metabolism with no apparent uterine effects, and a potential decreased risk of developing breast cancer associated with raloxifene therapy. However, there are a number of parameters that can be improved. A number of SERMs have been evaluated only to fail in development due to, for the most part, uterine safety issues. In order to develop an improved SERM, a stringent screening process was designed to select compounds that did not stimulate the uterus or breast. At the same time, these new compounds would have a positive impact on the skeleton and lipid metabolism with the additional improvement (over raloxifene) of a neutral effect on hot flashes. Under these strict conditions, WAY-140424 was developed and, to date, the preclinical pharmacology data have accurately predicted the clinical response demonstrated in phase I and II trials.
Approximately 10% of women of reproductive age suffer from endometriosis, a potentially painful disease process and important cause of female infertility. Raloxifene, a commercially available SERM (selective estrogen receptor modulator) compound, used for the treatment of postmenopausal osteoporosis, has preclinically demonstrated its estrogen antagonist effect on uterine tissue in rats. There is potential that SERM compounds may become a viable treatment option for human endometriosis, although more investigation is needed. In this study, raloxifene was administered at various doses to determine the efficacy and an appropriate dose level for use as a positive control in a rat model of endometriosis. Prior to dose administration, all rats underwent a bilateral ovariectomy, autologous transplantation of uterine tissue onto the peritoneal surface of the abdominal wall, and implantation of a subcutaneous estrogen pellet (E2). Two separate postsurgical experiments were performed. In experiment 1, following a 4-wk recovery, the rats bearing implants were assigned to three groups: (1) removal of the E2 pellet and dosing vehicle only (n = 7); (2) E2 and vehicle (n = 6); and (3) E2 and raloxifene at 10.0 mg/kg (n = 6). In experiment 2, also following a 4-week recovery, the rats bearing implants were assigned to five groups (n = 8/group): (1) E2 and vehicle only; (2) E2 and raloxifene, 0.3 mg/kg/d; (3) E2 and raloxifene, 1.0 mg/kg/d; (4) E2 and raloxifene, 3.0 mg/kg/d; (5) E2 and raloxifene, 10.0 mg/kg/d. All rats were dosed orally BID for 14 d. At the end of the study, the implanted endometrium was remeasured and compared to the pretreatment measurement. The results from both studies demonstrated that Raloxifene at only one dose (10.0 mg/kg) displayed significant implant regression (p < .05). Subsequently, our rat endometriosis experimental model consistently uses the exogenous E2 pellet and raloxifene at 10 mg/kg, BID, as a positive control to help screen and compare novel SERM compounds.
Experimental and epidemiological studies have pointed to a major role of estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis (1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as adjuvant therapy. We need to know whether the new non-steroid antiestrogens (idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator (raloxifen), whith preclinical characteristics better than those of tamoxifen will be more efficient clinically. Large-scale trials to compare the new drugs with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is looking as a better choice than ovariectomy or irradiation of the pelvis for ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are more efficient than progestins and much safer than aminoglutethimide. It has been shown recently that these inhibitors keep metastatic breast cancer at bay longer, and with longer survival. The non-steroid inhibitors (anastrozole and letrozole) and the steroid oral drug exemestane are undergoing clinical trials as means of adjuvant treatment of breast cancer. The trial of arimidex and tamoxifen administered alone or in combination (ATAC) is unique since it is using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New methods of endocrine therapy have resulted in less toxic and more convenient procedures. Also, longer therapeutic effects and survival are becoming more apparent.
Recent studies have provided strong evidence that the biological activity of selective estrogen-receptor modulators (SERMs) depends on the conformation of the SERM-receptor complex, the estrogen-receptor-signaling mechanism, and the tissue co-regulator composition. In addition to these new observations, other studies convincingly demonstrate that estrogen has cardioprotective properties, favorably regulating genes that are crucial to vascular physiology. These novel findings could thus be key to generating SERMs that solve the risks currently associated with hormone replacement therapy. In addition, further development could result in SERMs that possess not only anti-estrogenic actions in the breast and uterus, but also estrogenic protective actions in bone and the cardiovascular system.
Caveolin-1 is regulated by estrogen in vascular smooth muscle cells. Raloxifene, a selective estrogen receptor modulator that possibly has cardioprotective properties without an increased risk of cancer or other side effects of estrogen, may be used in women with risk of coronary artery disease. However, the relationship between raloxifene and caveolin-1 is still unknown. Therefore, this study was designed to see whether raloxifene regulates caveolin-1 expression and if so, whether such regulation is mediated by estrogen receptor. Rat aortic smooth muscle cells were cultured in the absence or presence of raloxifene (10(8-) to 10(6-) M) for 12 or 24 h. Both mRNA and protein levels of caveolin-1 were increased significantly after 24 h treatment with raloxifene. These increases were inhibited by estrogen receptor antagonist ICI 182780 (10(5-) M). Results of this study suggest that raloxifene stimulates caveolin-1 transcription and translation through estrogen receptor mediated mechanisms.
Introduction: Raloxifene, a selective estrogen receptor modulator (SERM), acts as an estrogen agonist in the bone and on serum lipids and an estrogen antagonist in breast tissue. The effect of raloxifene on the endometrium of postmenopausal women is a key factor in determining its clinical application.Objectives: The objectives are to determine and compare the histologic outcomes of endometrial samples from healthy postmenopausal women receiving either a high dose of raloxifene or hormone replacement therapy (HRT).Design: The current study is a 24-month, multicenter, double-blind, randomized study of 136 healthy postmenopausal women randomized to receive either raloxifene 150 mg/day (RLX) or continuous combined HRT (Premarin(R) 0.625 mg/day and Provera(R) 2.5 mg/day).Materials and Methods: Endometrial samples obtained by Pipelle biopsy at baseline and endpoint were evaluated using Blaustein's criteria (Kurman RJ, editor Blaustein's pathology of the female genital tract. 1994), which is composed of descriptive diagnostic categories and a newly developed estrogenicity scoring system to quantify subtle morphologic changes in the postmenopausal endometrium (Boss et al. Am J Obstet Gynecol, in press). All subjects with adequate baseline and post-baseline endometrial samples were included in the analyses. The results from the 12-month interim analyses are reported and the Blaustein's criteria and the estrogenicity scoring system are compared.Results: Overall, 95.2% of the baseline biopsies were normal. At endpoint 30.6% of the subjects in the HRT group with normal baseline biopsies developed proliferative endometrium and 2.8% developed a polyp, while none in the RLX group developed either. Histological evaluation of stromal and glandular features revealed substantially lower estrogenicity scores in the RLX group. As shown in the table, a high degree of agreement was observed between the estrogen effect grades and the Blaustein's descriptive diagnostic categories at endpoint as shown by a Spearman correlation coefficient of 0.75 and a Kappa coefficient of 0.91.Conclusion: Results from the 12-month interim analyses reveal that, in contrast to HRT, raloxifene does not have stimulatory effects on the endometrium. Also, there is high degree of agreement between Blaustein's criteria and the estrogenicity scoring system used to evaluate endometrial histology.
Despite biologically plausible mechanisms whereby estrogen may confer cardioprotection as well as observational data suggesting cardiovascular benefit, data from the sole randomized controlled clinical outcomes trial reported on the benefit of hormone use. A trend was observed in the Heart and Estrogen/progestin Replacement Study (HERS) of an early increase in coronary events with possible late benefit, and in a recent angiographic trial, the Estrogen Replacement and Atherosclerosis trial (ERA) where no benefit was seen. Furthermore, selective estrogen receptor modulators may enable dissociation of estrogen risks and benefits; the selective estrogen replacement modulator raloxifene is under study in a large randomized clinical outcomes trial entitled the Raloxifene Use for the Heart trial (RUTH). (c) 2000 by CVRR, Inc.
Endometriosis is an important clinical problem in routine practice. Besides the problems of dysmenorrhea, dyspareunia and chronic abdominal pain, women with endometriosis are often infertile. We performed a systematic literature review on two issues: firstly, we clarified which medical treatment options have been investigated in prospective, randomized studies. Secondly, potential future treatments, still being preclinically investigated, were examined. A meta-analysis was not possible as the studies varied too much in their protocols and inclusion and exclusion criteria, as well as in the drugs and doses administered. Gonadotropin-releasing hormone (GnRH) agonists, progestins and oral contraceptives all appear to offer certain advantages for endometriosis patients. GnRH agonists appear to be the most effective but they are expensive and long-term treatment is not possible because of loss of bone mineral density. Estrogen add-back may offer some benefit for the clinical complaints of patients, but it may reduce the efficacy of GnRH agonists. Progestins have the best clinical profile and a good cost-effectiveness balance; however, most studies found that they were not as effective as GnRH agonists. Oral contraceptives are only effective during treatment and have a high relapse rate after therapy is completed. Future options may include the use of GnRH agonists, selective estrogen receptor modulators (SERMs) and anti-estrogens, as well as immunomodulators.
The new anti-estrogens, including the selective estrogen receptor modulators (e.g., toremifene, droloxifene, idoxifene, raloxifene and arzoxifene), the selective estrogen receptor downregulators (e.g., fulvestrant), and the new steroidal (e.g., exemestane) and non-steroidal (anastrozole and letrozole) aromatase inhibitors have been investigated in the treatment of breast cancer and hormonally sensitive tumors of the uterine body. In postmenopausal women, anastrozole, letrozole and exemestane appear to have superior efficacy and an improved toxicity profile than tamoxifen, and fulvestrant seems to be at least as effective as anastrozole in patients in whom tumors have progressed after prior endocrine treatment. Preliminary data showed a high response rate and a favorable toxicity profile for arzoxifene in endometrial cancer, whereas letrozole could represent a new interesting therapeutic tool for endometrial cancer as well as for low-grade endometrial stromal sarcoma.
Heart disease, breast cancer, and hormone therapy were top clinical concerns in women's health in 1997. One of the major reports on heart disease confirmed that women are no different from men in terms of early infarct-related artery patency rates, reocclusion after thrombolytic therapy, and ventricular functional response to injury/reperfusion; nevertheless, women have 3 times the mortality of men in the first 30 days after an acute myocardial infarction. Research brought only modest gains in the understanding of breast cancer etiology in 1997, but engendered major debate on whether women younger than 50 years should have mammograms every 1 to 2 years. A National Institutes of Health consensus conference said no, but the National Cancer Institute's National Cancer Advisory Board said yes. Evidence of estrogen benefits and risks mounted: One report added to the data suggesting that estrogen may retard age-related memory loss, while another study reported that the risk of breast cancer significantly increased with long-term use of estrogens. The interest in selective estrogen receptor modulators (SERMs), also called "designer estrogens," grew. Efforts to develop pharmacologic treatment for obesity suffered a setback in 1997 when a team reported that 1 in 3 patients who used d-fenfluramine developed abnormal valvular thickening, with the most severe cases needing valve replacement. One of the most promising events in colorectal cancer, the third most common cancer in women, was the set of screening guidelines issued by the Agency for Health Care Policy and Research. The year ended with major ethical debates about multiple gestation and cloning.
BACKGROUND: Resistance to tamoxifen, a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis and enhance cell proliferation and survival. Paradoxically, estrogen treatment inhibits the growth of long-term tamoxifen-treated breast tumors. Because of the increasing use of raloxifene, another SERM, to prevent osteoporosis and potentially reduce breast cancer risk, some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol. METHODS: Raloxifene resistance and hormone responsiveness were assessed by proliferation assays and cell cycle analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor kappaB (NF-kappaB) activity was investigated with a transient transfection assay. Apoptosis was investigated by annexin V staining, mRNA was measured by real-time polymerase chain reaction, and protein was measured by western blotting. Tumorigenesis was studied by injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. RESULTS: Basal NF-kappaB activity was higher in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to 2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P =.004). When cultured with 1 microM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol treatment of MCF-7/Ral cells arrested cells in G(2)/M phase of the cell cycle, decreased NF-kappaB activity (0.2 U, 95% CI = 0.2 to 0.3 U; P<.001), increased expression of Fas protein and mRNA (4.5-fold, 95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold for control treatment; P<.001), and induced apoptosis. Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs. When a 9-week raloxifene or tamoxifen treatment was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors stimulated by raloxifene or tamoxifen (at week 14, P =.004 for raloxifene and P<.001 for tamoxifen). CONCLUSIONS: Growth of raloxifene-resistant MCF-7/Ral cells in vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2/M-phase arrest, decreased NF-kappaB activity, and increased Fas expression to induce apoptosis.
The discussion on the risks of hormone therapy supports the search for alternative drugs such as selective estrogen receptor modulators (SERMs). These compounds are suitable for special preventive goals, but cannot be expected to replace the use of estrogens in patients with estrogen deficiency. The development of selective progesterone receptor modulators (SPRMs) which has to resolve various problems, might be a promising approach. Hormone replacement therapy (HRT) with natural estrogens remains the measure of choice for treatment of symptoms caused by estrogen deficiency. Recent findings suggest that the additional progestogen which is used for the protection of the endometrium, plays a crucial role with regard to the risk of breast cancer and cardiovascular disease. As surrogate parameters cannot predict the extent of risks, suitable tools for the selection of progestogens with the least potential for causing adverse effects, are urgently needed. Experimental, clinical and epidemiological data suggest that the elevation in breast cancer risk is due to the proliferative effect of estrogens on breast tissue which is largely enhanced by progestogens. A short-term in vivo-test might be helpful for the evaluation of proliferative effects of estrogen-progestogen preparations. Similarly, a strictly standardized in vivo-test for the assessment of the atherogenic potential of estrogen-progestogen preparations might help to select the preparations with the lowest risk for ischemic diseases. The available data suggest that it is probably not the androgenic but the glucocorticoid activity of a progestogen which plays a role in the development of cardiovascular disease. Progestogens with glucocorticoid effects may up-regulate the thrombin receptor in the vessel wall which is involved in the development of atherosclerosis and stimulation of extrinsic coagulation.