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Tamoxifen and the female genital tract

UGWUMAGU, A. H. N.*; CARMICHAELS, P. L.§; NEVEN, P.

International Journal of Gynecological Cancer: January-February 1998 - Volume 8 - Issue 1 - p 6-15
Review

Tamoxifen was originally developed by Imperial Chemical Industries(England) (ICI) in 1966 as an anti-estrogenic contraceptive. Ironically, it found a role in the treatment of anovulatory infertility, but its most important application to date is in adjuvant hormonotherapy for breast cancer. Tamoxifen has a complex and poorly understood mix of estrogenic and anti-estrogenic properties with variable and contrasting effects on hormone-sensitive target tissues, such as the endometrium. This article reviews the gynecologic lesions associated with tamoxifen therapy and discusses the merits and acceptability of endometrial surveillance tests and the role of progestogens.

*Department of Obstetrics & Gynecology, St. George's Hospital Medical School; §Department of Pharmacology & Toxicology, Imperial College School of Medicine, St. Mary's Hospital, London, England, UK; and ¶Kliniek St.-Jan, Brussels, Belgium

Address for correspondence: Dr. A. H. N. Ugwumadu, Department of Obstetrics & Gynaecology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, England, UK.

Accepted for publication November 4, 1997

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Introduction

Tamoxifen is a non-steroidal anti-estrogen with a partial estrogen agonist activity, widely used as first choice endocrine therapy for breast cancer. It decreases the incidence of contralateral breast cancer and prolongs disease-free survival, especially in post-menopausal women with estrogen receptor (ER) positive breast cancer(1,2). Tamoxifen also exerts a beneficial effect on bone(3) and on cholesterol, preventing fatal myocardial infarction and osteoporosis in breast cancer patients on adjuvant hormonotherapy(4,5). On the basis of these favorable effects and its perceived low toxicity profile, clinical trials are underway in the USA, Canada, Italy and a growing list of countries participating in the International Breast Intervention Study (IBIS), including the UK, Australia, Germany, the Netherlands, Belgium, and Switzerland; all aimed at testing the efficacy of tamoxifen as a chemoprophylactic agent in healthy women at increased risk of breast cancer. However, there are growing fears of its long-term effects, particularly in the female genital tract where chronic exposure to the relatively weak estrogen agonist activity may cause proliferative and neoplastic effects. Within the uterus, the glandular, stromal and myometrial components respond differently to the actions of tamoxifen, resulting in complex clinico-pathological manifestations. The endometrial effect was demonstrated in a prospective, longitudinal follow-up study evaluating the uterine cavity with hysteroscopy and guided endometrial biopsy before and during tamoxifen therapy(6). A considerable body of evidence no suggests an increased incidence of neoplastic lesions such as endometrial carcinoma and, although controversial, uterine sarcomas, especially malignant mixed mullerian tumors (MMMT) and gastrointestinal cancers in women on tamoxifen therapy(7-21).

Approximately 40% of postmenopausal women receiving tamoxifen have some sort of endometrial abnormality(22) but only 2-3/1000 per year are estimated to develop symptomatic endometrial cancer. Most lesions, therefore, rarely evolve into invasive malignancies. Endometrial screening to identify women at risk and target them for earlier intervention would seem desirable; however, uncertainties surround the test characteristics and cost effectiveness of available methods of endometrial monitoring. There is no question that the benefits of tamoxifen far outweigh the risks of endometrial cancer in patients with breast cancer, but for healthy subjects in the chemoprevention trials that argument is untenable and indeed raises serious ethical questions(23).

In the future, these concerns may be overcome with the introduction of the new class of non-hormonal anti-estrogens, which are termed Selective Eestrogen Receptor Modulators (SERM) and exemplified by raloxifen. These compounds interact with the ER and exert estrogen agonist effect in desired target tissues, such as bone or the cardiovascular system together with estrogen antagonism in reproductive tissues, such as the uterus and breast.

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Mechanisms of action of tamoxifen

Modulation of the estrogen receptor

Tamoxifen is lipid soluble and diffuses freely across the cell and nuclear membranes. It binds to the ER in the nuclei of responsive cells mainly in the form of its hydroxylated metabolites. The receptor undergoes conformational changes (activation) and the resultant ER-tamoxifen complex then binds to a specific nuclear DNA sequence called the Estrogen Receptor Element (ERE), which is present in the promotor regions of those genes whose transcription is regulated by estrogen(24,25), such as genes encoding endometrial proteins like growth factors, their binding proteins, and receptors including progesterone receptor. A cascade of biologic actions such as mRNA and protein synthesis is elicited which may lead to growth and proliferation. The ER protein itself can be divided into domains with specific functions (ligand binding, dimerization and DNA-binding domains) and in addition contains two transcriptional activity functions (TAF-1 and TAF-2)(26). TAF-1 is constitutively active and may be activated by estrogen-like compounds such as tamoxifen, whereas TAF-2 is specific and inducible only by estrogen(26). The gene response to estrogen/anti-estrogen binding depends on a number of factors:

  1. The nature of the ER which could be wild-type or a variant;
  2. The nature of the gene promotor, that is the relative contributions of TAF-1 and TAF-2 to promotor activity;
  3. The ligand, for example tamoxifen, regulates the transcription of estrogen responsive genes while pure anti-estrogens inhibit receptor dimerization, DNA binding, and promote receptor degradation.

Furthermore, cell-specific Receptor Interacting Proteins (RIPs) or other adapter proteins may also be involved. By altering the signal generated by the binding of tamoxifen to the ER, such adapter proteins could suppress or activate receptor function in a cell/tissue-specific manner(27). Tamoxifen, for example, may have stronger estrogen agonist properties in the bone and uterus because these tissues may possess other proteins that augment transcriptional activation via the TAF-1 site. It is also conceivable that cellular levels of RIPs or other transcriptional factors may change over time and could augment the agonist properties of tamoxifen. Estrogenic action can also be exerted by activation of genes that do not necessarily contain the ERE sequence. The Raloxifen Response Element (RRE) and AP-1 transcription complex are examples of such gene sequences(28).

The tissue specific effects of tamoxifen may suggest the existence of native ER subtypes in responsive tissues, but such bifunctional ER subtypes have not been described in humans. However, a second ER [termed estrogen receptor beta (ERβ)] has recently been described in the ovarian granulosa cells and prostate gland of rats(29), while the gene for the human ERβ has also very recently been cloned(30). The discovery of ER-β may help to explain the different sensitivities of tissues to estrogen antagonists(31). Tamoxifen may alter the structure and function of ERs(32) or exert agonist effect through its metabolites cis-tamoxifen and transmetabolite E which are well-known estrogen agonists(33). Overall, it would seem that both estradiol and tamoxifen modulate more molecular targets than just the ER. Tamoxifen is reported to inhibit protein kinase C(34) which plays an important role in the control of cellular proliferation and angiogenesis. It lowers prolactin levels(35) but elevates estradiol and SHBG(36) in premenopausal and postmenopausal females, respectively. It also induces alterations in the circulating levels of insulin-like growth factor-1(37).

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Modulation of endometrial proteins

Peptide growth factors are important mediators of estrogenic promotion of tumor cell growth. Anti-estrogens also modulate endometrial cancer growth by influencing the production of stimulatory growth factors such as TGF-α, IGF-I/II and EGF, and inhibitory growth factors such as TGF-β. The response of human endometrial adenocarcinoma cells to estrogen and anti-estrogens varied between cell lines, and this response was dependent upon the culture conditions used(38,39). Both 4(OH)-tamoxifen and estradiol had growth stimulatory effects on the well-differentiated ER-positive endometrial cancer Ishikawa cell line through suppression of TGF-β, stimulation of IGF-I, and decreased production of its binding protein IGFBP-3(39-42). Tamoxifen exhibited contrasting and tissue-specific effects on the breast and the uterus with respect to TGF-β, IGF-I, and binding proteins. Both tamoxifen and estradiol reduce TGF-β in cultured human endometrial cancer cells under estrogen-depleted conditions(40), whereas tamoxifen stimulates production of TGF-β1 in breast cancer cells(43,44). Whether tamoxifen down-regulates TGF-β in the human endometrium resulting in a negative apoptotic influence and positive signal for the proliferation of endometrial cells is currently under investigation. Although 4-(OH)tamoxifen increased the tumor size of Ishikawa xenografts in nude mice, TGF-α was lowered(38) while TGF-β was unaltered, suggesting a discordance between the hormonal effects of tamoxifen on TGF expression and cellular proliferation. These findings argue against a major role for TGF in the regulation of human endometrial adenocarcinoma cell proliferationin vivo. In the ovariectomized rat, both tamoxifen and estradiol increased the gene expression for uterine IGF-I and decreased the gene expression for IGF receptor, IGFBP-3, and TGF-β3, leading to an increased mitogenic activity of IGF-I and subsequent growth(45,46). Through early growth genes such as c-fos (47), tamoxifen stimulated growth and progesterone receptor expression in the steroid-responsive endometrial cancer grown in ovariectomized nude mice(48,49). It also augmented c-fos and c-jun proto-oncogene expression in the immature rat uterus(50-52).

In animal models specific mitogens with potent angiogenic activity, such as vascular endothelial growth factor (VEGF), are also regulated by estradiol and progesterone receptor ligands(53,54). Following exposure to estradiol and tamoxifen VEGF mRNA is heavily expressed in the periluminal region of the endometrial stroma with a decreasing intensity of expression going from the periluminal region towards the stroma(53). This cellular pattern of expression is consistent with the uterine response to estrogenic stimulation. The stroma has the highest blood vessel density and exhibits massive edema after treatment with tamoxifen, especially within the functional layer of the endometrium. The demonstration of direct transcriptional regulation of VEGF expression by tamoxifen(53) suggests that human endometrial changes may involve increases in tissue VEGF production.

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DNA-adduct formation (genotoxicity)

DNA-adducts are covalent modifications of DNA by metabolically-activated chemical carcinogens. They are generally considered to be an initiating event in chemical carcinogenesis. Animal studies show that tamoxifen is metabolized within hepatocytes to derivatives capable of forming DNA-adducts in vitro and in vivo (55). In the rat species, these adducts are hepatocarcinogenic(56,57). Furthermore, tamoxifen induced chromosomal changes in the rat hepatocytes, including mutations in the tumor suppressor gene p53(58). A similar alteration in tumor suppression function of p53 gene in endometrial cells and indeed other tissues exposed to tamoxifen has been suggested, but data from epidemiological studies do not support an increased incidence of malignancies in extrauterine sites at present. Although tamoxifen is hepatotoxic in the rat, extensive studies in the liver and other organ tissues in other species have not reproduced these findings. In humans postmortem analysis of DNA extracted from the liver of females treated with tamoxifen did not show any evidence of DNA adducts(59). Even in the rat, the levels of DNA-adducts produced in the liver were forty times higher than the uterine levels(60). Two recent studies, including ours, addressed the question of the genotoxic potential of tamoxifen in the human endometrium, but conflicting conclusions were reached.

We examined endometrial DNA from 18 patients on daily tamoxifen 10-40 mg over a three month to nine year period for DNA-adducts using the highly sensitive 32P postlabelling(61). No evidence of DNA-adducts was demonstrated, suggesting that the genotoxic events in the rat may not apply to humans. However, Hemminki et al.(62), using an alternative 32P post-labelling procedure, detected a very weak signal for a putative DNA-adduct in the endometrium of five out of seven patients treated with tamoxifen. The adduct levels detected in this study are exceedingly low-at the very lowest limits of detection-even using this highly sensitive technique. It has also been speculated that tamoxifen may act selectively at exceptional DNA sequences such as oncogenes or tumor suppressor genes, but this is not supported by data from experiments in rats where tamoxifen appears to bind non-selectively to guanine bases, regardless of the DNA sequence. On the weight of current evidence we may conclude that the levels of tamoxifen DNA adducts seen in the human endometrium are far too low to pose a significant genotoxic risk comparable to that seen in the rat.

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Effects of tamoxifen on the female genital tract

Uterine corpus

Tamoxifen may cause myometrial hypertrophy and increase in the size of leiomyomata in postmenopausal females on long-term therapy(22,63,64). It is as yet unclear whether tamoxifen exerts these effects by directly binding to the ER or acting through some secondary peptide hormone mediators, such as epidermal growth factors (EGF), or by both mechanisms. Growth factors control the growth of leiomyomas in rodents(65) and in association with estrogen regulate their growth in humans(66). Although myomatas may shrink in size during the postmenopausal years (and if treated with GnRH-analog), they paradoxically increase their ER numbers as estrogen levels fall(67,68). This up-regulation of the ER probably makes myomas sensitive to the weak oestrogenic actions of tamoxifen and it may be for the same reasons that fibroids resume growth rapidly in premenopausal females once GnRH-analog is withdrawn and spontaneous steroidogenesis is restored(69). Tamoxifen also increases myometrial volume and uterine size(22) probably associated with de novo induction or reactivation of pre-existing adenomyosis in treated postmenopausal women(70,71). Cohen et al. found adenomyosis in approximately 60% of 14 postmenopausal female on chronic tamoxifen treatment who had total hysterectomy for unrelated indications(71). Although atypical hyperplasia occurs commonly in deep foci of ectopic endometrium without a concomittantly higher incidence of primary adenocarcinoma, such chronic and persistent estrogenic effect of tamoxifen may in the long-term elicit neoplastic changes. Growth of myomas and adenomyosis sustained by tamoxifen may not run the usually benign courses associated with these conditions(63).

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Endometrium

Tamoxifen probably exerts its variable and inconsistent effects on the endometrium because of differential responses of the epithelial elements of the endometrium. Endometrial atrophy is the most common histological finding in postmenopausal females on tamoxifen, but proliferation, hyperplasia, polyposis, adenocarcinoma and endometrial decidualization have all been reported(6,7,22,63,72-74). It is unclear why some women do not develop proliferative and hyperplastic lesions on tamoxifen therapy. Indeed, different parts of the same endometrium in an individual patient may display contrasting features(70,74). The endometrium probably progresses through different histological stages in response to tamoxifen, as biopsies in a 77 year-old patient showed proliferation, decidualization and atrophy at different times during investigations for recurrent postmenopausal bleeding while on tamoxifen therapy(74,75). The relative risk of endometrial carcinoma in females on tamoxifen varies between 2.0-7.5, depending on the series(6,10,76); however, the size of this risk is difficult to quantify given that breast and uterine cancers share common genetic and hyperestrogenic risk factors. In the general population the age-dependent endometrial cancer rate is approximately 0.7/1000 women and 1.0/1000 in females with breast cancer not treated with tamoxifen. Evidence from some retrospective studies suggests that endometrial carcinomas occurring in patients on tamoxifen are of unfavorable histological subtypes (mucinous and clear cell types) with poorer prognosis(72,77,78). However, these observations have not been confirmed by data from randomized comparisons(76,79). Moreover, evidence from meta-analysis of randomized trials does not show an excess mortality from cancers other than that of the breast in patients treated with long-term tamoxifen(7). Ectopic endometrium, even when dormant, seems to respond to tamoxifen. There are reports of reactivation of endometriosis in postmenopausal females on tamoxifen(80). Recently, transformation of an ovarian focus of endometriosis into an endometroid type ovarian cancer has also been reported(81).

Endometrial polyps occur with varying frequency in patients on tamoxifen. These polyps are reported to be histologically different from the usual polyps by their combination of proliferative activity, aberrant epithelial differentiation, metaplasia, and focal periglandular stromal condensation and are more likely to harbor polyp cancers compared to controls(82,83). The background hyperplasia and multiple polyps showing variable degrees of atypical epithelial hyperplasia may suggest that these polyps are intermediate lesions between simple endometrial hyperplasia and endometrial carcinoma(82).

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Cervical and vulvovaginal tissues

The cervico-vaginal squamous epithelium shows estrogenic changes following treatment with tamoxifen in postmenopausal breast cancer patients(84). However, vaginal discharge, irritation, and dryness may also occur in up to 20% of patients on tamoxifen therapy(85), presumably from its antiestrogenic effect.

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The ovaries

Tamoxifen causes increased steroidogenesis and ovarian cyst formation in premenopausal females. Amenorrhea occurs in 25% and irregular cycles are common(86). Some females experience no change in their menstrual cycles and should continue to use appropriate contraception because of the perceived teratogenic risk of tamoxifen(87), although no laboratory evidence exists to substantiate this risk. There is an increased risk of hot flushes, especially in perimenopausal females. No proven association with ovarian carcinoma has been reported. In postmenopausal women, the epithelial elements of the ovaries may show a wide range of metaplasias, including mucinous and papillary oxyphil cell metaplasias(88). The ovary may also be involved in reactivation of endometriosis.

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Gynecologic surveillance and prevention of endometrial lesions

Transvaginal ultrasound scan (TVS) vs saline infusion sonography(SIS)

Endovaginal pelvic ultrasound scan as a tool for endometrial assessment in asymptomatic patients on tamoxifen is of limited value and could be frankly misleading. Tamoxifen causes blurring and irregularity of the endometrial/myometrial junction making accurate measurement of the endometrial thickness (ET) impossible(89). Furthermore, up to 75% of tamoxifen users on ultrasonography have an irregularly pseudothickened endometrium sometimes associated with a Swiss cheese appearance or an overt glandulocystic polyp(22,89,90). This bizzare sonographic appearance, commonly interpreted as endometrial thickening, generates undue anxiety and unnecessary biopsies which frequently yield scanty or no material and inactive/atrophic endometrium on histological examination. The changes are now recognized to be localized in the subendometrium and in the substance of the myometrium where possibly foci of reactivated adenomyosis appear as irregularly distributed microcysts(89,90). Ultrasound studies on asymptomatic postmenopausal females on tamoxifen reflect this poor correlation between endometrial thickness and histological findings(91), and as such previously established ET cut off values should not be applied to patients on tamoxifen. Saline infusion sonography first described by Randolph and his colleagues(92) delineates the contours of the uterine cavity with the saline acting both as a contrast medium and a distending agent(93). The technique when applied to the investigation of patients on tamoxifen(94) facilitates a more precise ET measurement and improves detection of endometrial polyps.

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Transvaginal Doppler studies

Tamoxifen induces significant reductions in impedance to blood flow in the uterine arteries of treated subjects compared to controls on placobo(22). It exerts similar effects in the endometrial and subendometrial vasculature probably through dilatation of the preexisting vascular bed(95). Nevertheless, the size of the reduction in impedance to blood flow [mean resistance index (RI) 0.39± 0.10 range 0.32-0.54] in tamoxifen-treated patients with ET > 5 mm and benign endometrial polyps(95) was similar to values seen in endometrial malignancies (RI of < 0.4)(96). Restoration of the RIs to normal followed hysteroscopic resection of the benign polyps(95). These reductions in RI in the uterine artery, subendometrial and myometrial blood flow in patients on tamoxifen therapy do not necessarily suggest pathology, and indeed similar changes occur in females on hormone replacement therapy(97). The clinical significance of the thickened/cystic endometrium with altered uterine vascularity is unclear. Bourne obtained full thickness endometrial resection biopsy from 73 tamoxifen-treated patients with ET > 8 mm on TVS(98) and found atypical hyperplasia and endometrial carcinoma in 16% of cases, none of which was detected by prior outpatient endometrial biopsy(98).

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Pipelle aspiration biopsy and dilatation and curettage (D&C)

Aspiration biopsy and D&C are blind and may fail to sample endometrial polyps. In one study D&C performed prior to hysterectomy failed to sample even 50% of the cavity in 60% of cases examined(99), while in a similarly designed study 5.7% of endometrial hyperplasia and carcinoma were missed by D&C(100). Pipelle frequently yields inadequate tissue for histology from tamoxifen-treated patients and these limitations weaken their value as reliable methods of evaluating the endometrial cavity exposed to tamoxifen.

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Hysteroscopy and biopsy

Hysteroscopy and directed biopsy may offer a more reliable means of endometrial evaluation(73) by reducing sampling error. It is of particular value in detecting endometrial polyps which frequently complicate tamoxifen therapy. Hysteroscopy is user friendly and permits direct inspection of the cavity and biopsy, all in an outpatient setting. In the UK, however, some gynecologists are still reluctant to use it routinely. Although the typical hysteroscopic appearance of the tamoxifen-treated endometrium-pale, smooth but hypervascularized with scattered protuberances-has been described(101), there is at present no consensus on the optimal frequency of such examinations. A policy of mass hysteroscopic screening of all volunteers in the Breast Cancer Prevention Trial and indeed patients on adjuvant therapy will have considerable resource implications. Perhaps all perimenopausal and postmenopausal females should have a baseline hysteroscopy prior to tamoxifen therapy to exclude pre-existing endometrial disease which may potentially become accelerated by tamoxifen.

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Dose effect

Some studies suggest that the cumulative dose of tamoxifen may be crucial in the development of endometrial hyperplasia, polyps(102) and carcinoma(82,103). All the malignancies observed in one such study occurred in patients who consumed over 35 g of tamoxifen, irrespective of daily dose(82). However, in three patients who received well over 35 g of tamoxifen, two had simple hyperplasia and the third polyps, suggesting that other factors may modify the dosage effect(82). Endometrial cancers have also been reported well before 35 g of tamoxifen intake and within a few months of therapy(6). These reports emphasize the case for screening prior to treatment. The dose-disease relationship is also consistent with the discrepancy in the reported incidence of endometrial carcinoma between the high-dose Swedish trial(5) and the lower-dose Scottish trial(104) since subjects on the lower dose may develop endometrial carcinoma after a longer period of treatment. The current recommended dose of tamoxifen is 20 mg daily for a maximum of five years. This is equivalent to 36.5 g of tamoxifen, assuming full compliance. However, there are still adjuvant treatment programs using 30-40 mg daily for life, averaging 70 g of tamoxifen in five years. Tamoxifen may be omitted entirely in patients with small volume breast disease, negative nodes, and favorable histology, since surgery alone has been shown to produce equivalent results as surgery followed by adjuvant hormonotherapy(105). Such a policy will eliminate any further increase in endometrial cancer risk attributable to tamoxifen.

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The role of progestogens

The exact mechanism of tamoxifen's endometrial effect is unknown, but since progestogens are effective in preventing endometrial hyperplasia and carcinoma in females on estrogens, they have been proposed and in some cases used to treat/prevent endometrial lesions in patients on tamoxifen therapy(6,78). There are at present no scientific data to support this approach. Moreover, endometrial malignancy in patients on tamoxifen has been reported to be morphologically different from that arising from unopposed estrogen therapy, but similar to that occurring after synthetic progestogen therapy(77). Tamoxifen and progestogens have been reported to induce proliferation in the endocervical mucosa together with mucinous and clear cell metaplasia on a background of atrophic and resting endometrium(77). Mucinous type endometrial carcinoma could theoretically arise from such foci of metaplasia.

Progestogens may blunt the anti-tumor action of tamoxifen on breast tissue(106,107) and when administered to breast cancer patients on tamoxifen therapy did not decrease the frequency of endometrial hyperplasia(102). Its adverse effects on lipid profile may also lower overall life expectancy. The addition of progestogen to adjuvant tamoxifen may therefore sacrifice its efficacy for breast cancer treatment in pursuit of an unproven endometrial protection. It is unknown which progestogen, what route of administration, dosage, duration of treatment, and whether continuous or intermittent therapy is best. Although Levonorgestrel bearing intrauterine device is effective in treating all types of endometrial hyperplasia(108), there is no evidence that it is equally efficacious against similar lesions mediated by tamoxifen. Unless the results of studies evaluating the role of progestogens in controlling the proliferative effects of tamoxifen on the endometrium show a beneficial effect, they should not be routinely applied to patients on tamoxifen. Even so, the intrinsic progestogenic action of tamoxifen observed on the human endometrium(74,77,109) muddies the water and further complicates our limited understanding of this compound and the potential value of these studies.

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Conclusions

Tamoxifen remains the most effective agent for hormonotherapy following breast cancer diagnosis. Its exact mechanism of action on the human endometrium is under investigation. Endometrial changes are detectable using TVS although their clinical significance is still in doubt. Pre-existing pathology should be treated and annual follow-up evaluations may be advisable for the asymptomatic tamoxifen user. Hysteroscopy or contrast sonography are at present the only reliable tools to exclude endometrial changes in cases of thickening. We recommend removal of asymptomatic polyps since they may harbor polyp cancers. The future may bring newer and potentially safer anti-estrogens with effective anti breast/uterine action and beneficial cardioprotective and osteoblastic effects.

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Keywords:

progestogens; surveillance; tamoxifen; uterus

© 1998 Blackwell Science Ltd.