Selective oestrogen receptor modulators

The relevance of hormone-replacement therapy (HRT) in the treatment of the short- and long-term complications of the menopause has become clearly evident. This treatment, however, has been associated with the emergence of complications, namely breast cancer and endometrial neoplasia.These side effects have led to research in the direction of tissue-specific effects leading to the evolution of selective oestrogen receptor modulators (SERMs). Tamoxifen was the first SERM employed in the prevention of breast cancer recurrence. Although anti-oestrogenic to the breast tissue, tamoxifen was found to maintain bone mass and preserve a favourable lipoprotein profile. Tamoxifen, however, led to endometrial stimulation with consequent polyp formation and hyperplasia.Raloxifene, a more recent SERM appears to have similar effects as tamoxifen on breast tissue, bone density and the lipoprotein profile. However, unlike tamoxifen, raloxifene does not appear to stimulate the endometrium – on the contrary it appears to be anti-oestrogenic to the endometrial epithelium. A more recent SERM, droloxifene appears to have a more anti-oestrogenic effect to the endometrium with bone sparing effects.Raloxifene has not been shown to improve on the short-term effects of the menopause, such as hot flushes and sweats. Similar to HRT, there appears to be a slight risk for deep vein thrombosis with raloxifene treatment.Tibolone is a SERM-like compound with beneficial effects on both the short- and the long-term complications of the menopause. Tibolone appears to have a beneficial influence of hot flushes, bone density and the lipoprotein profile. Conversely, tibolone does not appear to stimulate significantly either breast or endometrial tissue.SERMS and SERM-like compounds appear to have a promising future for the treatment and prevention of menopausal complications. Clinical proof for the affectiveness is still required. Possibly with further pharmacological manipulation more modern SERMS may be able to reduce both the short- and long-term complications of the menopause and simultaneously reduce the incidence of neoplasia such as breast and uterine carcinoma.     

Tamoxifen in gynaecology

Tamoxifen, a nonsteroidal synthetic anti-oestrogen is the most widely used selective estrogen receptor modulator (SERM). Designed as a contraceptive it is most frequently used in prevention and treatment of breast cancer. Its role in gynaecology is limited to ovulation induction. Although it has a favourable effect on lipid profiles and increases bone density in postmenopausal women its use for these indications is not warranted. The practising gynaecologist will most likely be faced with the risks associated with long-term tamoxifen use: endometrial polyps, endometrial hyperplasia and endometrial cancer; venous thromboembolism, ovarian cysts and endometrioid ovarian cancers. Further insight into the oestrogen receptor (ER) tamoxifen induced changes could potentially identify new therapeutic opportunities.     

Drugs for the gynecologist to prescribe in the prevention of breast cancer: current status and future trends

Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.     

Risk-reducing strategies for breast cancer--a review of recent literature

The incidence of newly diagnosed breast cancer cases world-wide is expected to double by 2020. Risk-reducing strategies for breast cancer include lifestyle modifications, chemoprevention and surgery (bilateral mastectomy and/or oophorectomy). Lifestyle modifications include avoidance of postmenopausal obesity and hormone replacement therapy (HRT), regular physical activity, and restriction of alcohol and animal fat intake. Tamoxifen is a selective estrogen receptor modulator (SERM) shown in randomized controlled trials to reduce the incidence of estrogen receptor (ER)-positive breast cancer in high-risk healthy women. However, its routine use cannot be recommended for breast cancer prevention in healthy women due to its significant adverse effects, specifically in terms of endometrial carcinoma and thromboembolism. On the other hand, tamoxifen may be used for chemoprevention in women at high risk of developing ER-positive breast cancer and at low risk of developing complications. Raloxifene, another SERM, also appears to be effective in reducing breast cancer risk, and lacks the unwanted stimulatory effect on the uterus. Other promising chemopreventive agents currently under investigation include cyclo-oxygenase 2 (COX-2) inhibitors, fenretinide, aromatase inhibitors, and goserelin. Prophylactic mastectomy can reduce breast cancer risk by 90% in high-risk women. Bilateral oophorectomy has the potential of reducing the risk of both breast and gynecologic cancer in women carrying BRCA-1 or BRCA-2 mutations. Further research is required to identify novel strategies to prevent ER-negative breast cancer, minimize the adverse effects of tamoxifen and other SERMs, and evaluate the role of mammary ductal lavage and ductoscopy in guiding risk-reducing strategies.     

Selective estrogen receptor modulators: a new category of compounds to extend postmenopausal women's health

Selective estrogen receptor modulators (SERMs) are a new category of therapeutic agents, which bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as estrogen antagonists in others. Tamoxifen, a triphenylethylene derivative, was the first clinically available SERM. It is a potent anti-estrogen in the breast, and its use in breast cancer patients has made it the most widely prescribed antineoplastic drug worldwide. It has estrogen-like activity on bone metabolism, as well as cholesterol reduction. However, its ability to produce proliferation, and polyp formation, and even carcinomas, in the endometrium is well known. A new SERM, raloxifene, a benzothiopene derivative, has a clinical profile similar to tamoxifen's. However, preclinical as well as clinical studies reveal that unlike tamoxifen it is a pure anti-estrogen in the uterus. It has recently been FDA approved for prevention of osteoporosis in postmenopausal women. This report reviews pertinent preclinical and currently available clinical studies about this new SERM and discusses clinical applicability.     

Large endometrial polyp with sarcomatous stromal components following long-term tamoxifen treatment for breast cancer: a case report and review of the literature

Tamoxifen is commonly used in the management of patients with breast cancer because of its anti-oestrogenic effects to the breasts. However, tamoxifen acts as an oestrogen agonist on the endometrium increasing the incidence of endometrial polyps, hyperplasia and cancer. In addition, it may be possible that tamoxifen increases the occurrence of uterine body tumours. We describe a rare case of a large endometrial polyp with sarcomatous stromal components in a 73-year-old breast cancer patient treated daily with 20 mg of tamoxifen for four years. The glands of the polyp were lined by benign appearing epithelium. The polyp was twisted and protruded from a dilated cervix at the entrance of the vagina. The patient was treated by removal of the polyp and dilatation and curretage. A postoperative computed tomography scan showed many focal hypodense lesions in the hepatic lobes with a well-defined profile suggestive of metastatic disease and the patient was referred for combined chemotherapy. In conclusion, a case of a mesenchymal malignant neoplasm arising in the uterus of a breast cancer patient treated with tamoxifen is reported and its clinical, histological and immunohistochemical features are discussed. Also, the international literature is reviewed.     

Effect of selective estrogen receptor modulators on estrogen-sensitive tissues

Selective estrogen receptor modulators (SERMs) act exclusively through estrogen receptors and possess tissue-specific agonistic or antagonistic properties. The effects of all referred SERMs in bone and cardiovascular system are estrogenic, namely they inhibit postmenopausal bone loss and favorably influence plasma lipoproteins and some coagulation factors. The aim of this paper is to review the effects of SERMs on estrogen-dependent breast tissues and on the endometrium. There are two types of SERMs in clinical use, based on their chemical structure: the triphenylethylenes and the benzothiophenes. The prototype of the SERMs with triphenylethylene structure is tamoxifen. Tamoxifen, like all other SERMs, is an estrogen antagonist in the breast and is widely used for adjuvant treatment of breast cancer. A recent study suggests that tamoxifen also may prevent breast cancer in patients at risk. Because of the partial estrogenic activity of tamoxifen in the endometrium, its clinical use is associated with uterine hypertrophy and an increased risk of endometrial cancer. Other triphenylethylene SERMs, droloxifene, toremifene, and idoxifene, also show efficacy in the treatment of breast cancer, in a manner similar to tamoxifen. A better toxicology profile and a decreased endometrial estrogen agonism may be advantages of the new triphenylethylene SERMs. Raloxifene is a SERM with a chemical structure different from triphenylethylenes. Raloxifene, a benzothiophene, possesses an estrogen-antagonistic effect in the breast similar to triphenylethylenes. Clinical studies on postmenopausal osteoporotic women on raloxifene as compared with placebo show a significant decrease in the rate of newly diagnosed breast cancers. In clinical studies, in contrast to tamoxifen, no stimulatory effect in the endometrium could be observed with raloxifene.     

Endometrial adenocarcinoma appearing during tamoxifen therapy. Report of a clinical case

Tamoxifen is a non-steroid estrogenic antagonist, used in post-surgical therapy of breast cancer. It interferes with endocrinous promotion of breast cancer. Tamoxifen could determine endometrial, even carcinomatous, alterations. The case of a postmenopausal patient surgically treated for breast cancer and successively treated with tamoxifen (20 mg/die), is reported. She underwent ultrasonographic and hysterosonographic endometrial evaluation and finally a hysterectomy with bilateral annessiectomy. This case seems to confirm tamoxifen possible carcinogenical effects on the endometrium.     

Cancer of the endometrium caused by antiestrogens]

Tamoxifen is the most widely used non-steroidal antiestrogen compound for adjuvant treatment of postmenopausal breast cancer. Tamoxifen has both antiestrogen and estrogen-agonistic activity, which depends on the target tissue involved owing its systemic distribution. Upon the endometrium the agonistic estrogenic effect, so-called "paradoxical" effect, is suggested to induce proliferative changes such as hyperplasia or carcinoma. The authors report four cases of endometrial cancer developed in postmenopausal patients with breast cancer receiving tamoxifen. According to the literature data, the relationship of the tamoxifen to the endometrial remains uncertain: women with breast cancer are at increased risk for this neoplasm sharing common aetiologic hormonal factors and, in most published case reports, the uterine cavity has not been checked up before starting tamoxifen administration.     

Expression and clinical significance of pepsinogen C in epithelial ovarian carcinomas

OBJECTIVES: To describe the endometrial appearance in postmenopausal breast cancer patients on tamoxifen and to assess a routine surveillance scheme for endometrial lesions. STUDY DESIGN: Three hundred and seventeen postmenopausal breast cancer women already on tamoxifen at the start of the study (group I) and 89 breast cancer women assessed before any tamoxifen intake (group II) underwent an initial and then yearly scans with transvaginal ultrasonography, followed by an hysteroscopy and biopsy for women with an endometrium thickened above 8mm. Endometrial thickness was also measured in 823 women with no breast cancer nor tamoxifen intake (group III). RESULTS: Initial mean endometrial thickness was 8.2mm in group I, 4.4mm in group II and 3.4mm in group III (P<0.001). Eighteen percent endometrial lesions were found in group I and 3.3% in group II. We observed a significant association between endometrial pathology and both cumulated dose and total duration. Polyps were the most frequent and first to appear pathology. Five cancers were detected in group I, and all of them had taken tamoxifen for more than 3 years. CONCLUSION: Our surveillance scheme could be lightened; an acceptable screening scheme might include a baseline assessment before the start of tamoxifen and, if normal, yearly screening after 3 years of tamoxifen therapy, yearly surveillance for women with an abnormal baseline assessment and immediate investigation for symptomatic women.     

Tamoxifen and endometrial cancer. Is screening necessary? A review of the literature

Tamoxifen is a selective oestrogen receptor modulator (SERM) with anti-oestrogenic activity in the breast and oestrogenic effects in various tissues such as the endometrium, bone and cardiovascular territory. As adjuvant hormone therapy, it has a clear beneficial effect in patients with breast cancer, reducing relapses, contralateral breast cancer and mortality. Its most important secondary effect is a greater rate of occurrence of endometrial cancer. Although the risk/benefit ratio is clearly positive, the follow-up on these patients is still an issue. In women with metrorrhagia, it is clear that an endometrial sample must be obtained for histological examination and the best procedure today is hysteroscopic-directed biopsy. Nevertheless, the need to screen asymptomatic patients is not universally accepted. The vaginal ultrasound scan gives a great number of false positives. This entails more aggressive and more expensive procedures such as hysteroscopic-directed biopsy, meaning greater expense and more complications. As a result, the cost/benefit ratio is not very favourable. The rate of occurrence of endometrial cancer in 1026 tamoxifen-treated patients with breast cancer in our hospital between 1999 and 2001 was 1.25%. Two cases were diagnosed in asymptomatic patients. In this article, we analyse the literature on the need to screen patients on tamoxifen and about the most appropriate diagnostic protocol.     

Tamoxifen for breast cancer prevention: a framework for clinical decisions

OBJECTIVE: Given the potential side effects and an uncertain survival benefit, decisions about tamoxifen treatment for the primary prevention of breast cancer remain complex. Primary care providers, including gynecologists, will need to counsel patients regarding this form of preventive care. In this report, we update cost-effectiveness calculations for tamoxifen chemoprevention and establish reasonable parameters for clinicians' use. METHODS: We performed a cost-effectiveness analysis that compared women aged 50 years who were treated with tamoxifen for 5 years with an untreated cohort. In the base model, we assumed a 3.4% 5-year breast cancer risk. Quality-of-life estimates for important outcomes (breast cancer, endometrial cancer, deep venous thrombosis, pulmonary embolism, stroke, metastatic cancer, and hot flushes) were obtained from 106 women. Probabilities and costs of outcomes were derived from the Breast Cancer Chemoprevention Trial and other published estimates. Broad sensitivity analyses were performed. Cost per quality-adjusted life-year gained as a result of tamoxifen breast cancer prevention was the main outcome measure. RESULTS: The use of tamoxifen led to a remaining life expectancy of 26.07 quality-adjusted life-years compared with 25.97 without treatment. The cost per quality-adjusted life-year gained was $43,300. Sensitivity analysis revealed that younger age, the absence of the uterus, higher initial risk of breast cancer, increased fear of curable breast cancer, and reduced tamoxifen cost further favored treatment. CONCLUSION: Tamoxifen chemoprevention is cost-effective for women aged 40-50 years who are at significant breast cancer risk. Whether this holds true for older women depends on the initial breast cancer risk, fear of breast cancer, and presence of the uterus.     

Prädiktion und endokrine Prävention des Mammakarzinoms

A variety of parameters may be used to assess an individual woman’s risk of developing breast cancer, among them personal history in a standardized form, e.g. the Claus and Gail models, postmenopausal serum estradiol levels, bone mineral density, and mammographic breast density. The endocrine prevention of breast cancer using the antiestrogen tamoxifen and the selective estrogen receptor modulator (SERM) raloxifene has been assessed in a number of prospective randomized trials. Based on these trials, it is reasonable to recommend raloxifene to women with osteoporosis and an elevated risk of breast cancer. Tamoxifen as a breast cancer preventive agent should be limited to women who are at a significantly elevated risk according to standard models as well as to women affected by BRCA-2 mutations and those affected by either BRCA-1 or BRCA-2 mutations who have developed unilateral breast cancer. The results of ongoing clinical trials on the preventive potential of aromatase inhibitors will be available in the near future.     

Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients

Tamoxifen citrate, a nonsteroidal antiestrogen with agonistic properties, is prescribed as an adjuvant to surgery in the treatment of breast cancer. Recent reports have suggested that tamoxifen has an estrogenic property and may be implicated in the development of endometrial carcinomas. Seven new cases are reported to the existing literature in which endometrial carcinomas developed in postmenopausal women on tamoxifen therapy for breast carcinomas.     

Chemoprävention des Mammakarzinoms durch Tamoxifen und Raloxifen

Chemoprevention with tamoxifen or raloxifene is a promising strategy to decrease the incidence of breast cancer. The MORE-trial reported a 76% decrease in the incidence of breast cancer in women who took raloxifene. The results for tamoxifen are contradictory. The BCPT-trial found a 69% and the latest IBIS-trial a 32% decrease in breast cancer incidence, but the Royal Marsden and the first Italian trials showed no benefit for tamoxifen. The recent Italian update found a reduction in the incidence of estrogen-positive breast cancer among a subgroup of women. All investigators found adverse effects of tamoxifen, such as an increased rate of thromboembolic events, endometrial cancer, cataract and hot flushes. Tamoxifen is effective for the chemoprevention of breast cancer. Whether mortality due to breast cancer can be reduced has yet to be examined. Since the selective estrogen receptor modulators are used in healthy women for preventive strategies, their adverse effects should be small. New drugs are to be developed for this purpose.     

Uterine side effects of treatment with tamoxifen

OBJECTIVE: To assess a causal the relationship between endometrial lesions and tamoxifen therapy in patients with breast cancer. DESIGN: Prospective longitudinal study and cross-sectional study. SETTING: Cancer prevention unit at Basurto Hospital, Bilbao. POPULATION AND METHODS: Three populations of breast cancer were studied: 43 before the beginning of tamoxifen; 78 after 5-72 months of tamoxifen, and 34 before tamoxifen and after 12-24 months of tamoxifen treatment (PAIRED GROUP). All of them were systematically studied with CO(2) diagnostic hysteroscopy and endometrial biopsy by the same clinician. RESULTS: Before tamoxifen, the following endometrial lesions were detected: endometrial polyps 9.3%; endometrial cysts 16.3%; synechiae 11.6%. In the paired group the ingestion of tamoxifen shows a direct causal effect with a significant increase in endometrial polyps (11.8% vs. 29.4%; OR=13; CI=7.9-18.1), in endometrial cysts (17.7% vs. 55.9%; OR=7.5; CI=5. 9-9.1) and in synechiae (14.7% vs. 35.5%; OR=8; CI=4.7-11.3). In the group under tamoxifen for 5-72 months, one endometrial carcinoma was detected. CONCLUSIONS: Breast cancer patients have a number of endometrial lesions before undergoing any hormonal therapy. Tamoxifen significantly increased benign endometrial lesions, usually after less than one year of treatment. No cases of endometrial carcinoma was found in our series of 34 patients with 1-2 years of tamoxifen treatment, and 1/78 in patients with 5-72 months of tamoxifen.     

The gynaecological management of women on tamoxifen: a national questionnaire survey.

Tamoxifen is the standard adjuvant treatment for women with breast carcinoma, decreasing the incidence of contralateral disease. However, the risk of endometrial cancer is increased. To establish current gynaecological management of women receiving tamoxifen in the United Kingdom we conducted a postal questionnaire of consultant gynaecologists, enquiring about frequency of, and methods used to investigate women on tamoxifen. Ninety-five per cent investigate women on tamoxifen only if they are symptomatic. Pelvic ultrasound and endometrial sampling are used for first-line investigation by 68.7%. Interpreting ultrasound findings, endometrial thickness is the parameter regarded as most important. An endometrial thickness of greater than 5 mm is regarded abnormal by 47.8% of respondents and of 4 mm by 23.6%. As there is no consensus of opinion regarding normal values for endometrial thickness, further data are required to ensure consistency when interpreting ultrasound reports of women on tamoxifen.     

Hysteroscopic evaluation of the endometrium in postmenopausal women taking tamoxifen

STUDY OBJECTIVE: To evaluate hysteroscopic endometrial changes due to tamoxifen therapy in postmenopausal women with breast cancer. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. Patients. Eighty-eight postmenopausal women (or with iatrogenic amenorrhea) receiving tamoxifen 20 mg/day for at least 1 year for breast cancer. INTERVENTION: Record review of patients undergoing transvaginal sonography (TVS) and office hysteroscopy with eye-directed biopsy specimens obtained with a 5-mm, continuous-flow, operative hysteroscope. MEASUREMENTS AND MAIN RESULTS: Patients with thickened endometrium and pathologic findings at hysteroscopy had taken tamoxifen for significantly longer times than those without such findings (p < 0.05). CONCLUSION: Our findings confirm the estrogenic effect of tamoxifen on endometrium. Endometrial evaluation by TVS suggests further diagnostic procedures, but only hysteroscopy allows the surgeon to visualize endometrial lesions and obtain eye-directed biopsy tissue.     

Evaluation of endometrium during tamoxifen therapy of breast cancer

Tamoxifen is one of most common drugs for breast cancer therapy. But its weak estrogenic activity in endometrium can be the source of different abnormalities including even endometrial cancer. OBJECTIVES: The aim of this clinical trial was to compare ultrasound scan results, hysteroscopy and pathomorphological findings of tamoxifen treated patients with breast cancer who complained of bleeding. MATERIALS AND METHODS: Analyzed group consisted of 10 patients treated for abnormal endometrium during breast cancer tamoxifen therapy. RESULTS: Among 10 examined women 7 presented no pathological changes, there was 1 case of simple benign hypertrophy and 2 cases of endometrial polyps. CONCLUSIONS: There is no exact correlation between ultrasound scan results and pathomorphological findings in patients treated with tamoxifen for of breast cancer. Transvaginal ultrasound examination is not efficient screening test for endometrial abnormalities during tamoxifen therapy.     

Uterine pleomorphic rhabdomyosarcoma in a patient receiving tamoxifen therapy

INTRODUCTION: Tamoxifen has been used as adjuvant therapy for the treatment of breast cancer. Its use has been associated with the development of proliferative endometrial lesions such as polyps, hyperplasia, and carcinoma. Mesenchymal tumors including malignant mixed mullerian tumors, endometrial stromal sarcomas, adenosarcomas, and leiomyosarcomas have been more recently described with tamoxifen use. CASE REPORT: This report describes the first case of a pure uterine rhabdomyosarcoma in a patient receiving tamoxifen therapy. DISCUSSION: Although uterine rhabdomyosarcomas are rare tumors and may arise de novo, we discuss the possible role of tamoxifen in the development of these mesenchymal tumors.