Postmenopausal testosterone therapy and breast cancer risk

Background: Testosterone therapy is being increasingly used in the management of postmenopausal women. However, as clinical trials have demonstrated a significantly increased risk of breast cancer with oral combined estrogen–progestin therapy, there is a need to ascertain the risk of including testosterone in such regimens. Objective: Evaluation of experimental and epidemiological studies pertaining to the role of testosterone in breast cancer. Design: Literature review. Setting: The Jean Hailes Foundation, Research Unit. Main Outcome Measures: Mammary epithelial proliferation, apoptosis and breast cancer. Results: In experimental studies, testosterone action is anti-proliferative and pro-apoptotic, and mediated via the AR, despite the potential for testosterone to be aromatized to estrogen. Animal studies suggest that testosterone may serve as a natural, endogenous protector of the breast and limit mitogenic and cancer promoting effects of estrogen on mammary epithelium. In premenopausal women, elevated testosterone is not associated with greater breast cancer risk. The risk of breast cancer is also not increased in women with polycystic ovary syndrome who have chronic estrogen exposure and androgen excess. However, in postmenopausal women, who are oestrogen deplete and have increased adipose aromatase activity, higher testosterone has been associated with greater breast cancer risk. Conclusion: Available data indicate the inclusion of testosterone in estrogen–progestin regimens has the potential to ameliorate the stimulating effects of hormones on the breast. However, testosterone therapy alone cannot be recommended for estrogen deplete women because of the potential risk of enhanced aromatisation to estrogen in this setting.     

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy

OBJECTIVE: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. DESIGN: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. RESULTS: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. CONCLUSIONS: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.     

Breast cancer risk in postmenopausal women using testosterone in combination with hormone replacement therapy

OBJECTIVES: Testosterone supplementation can be considered as a treatment option for surgically postmenopausal women with a distressful low sexual desire disorder, while on oestrogen therapy with or without progestagens. The purpose of this study is to review the available clinical data on the impact of exogenous testosterone containing postmenopausal hormone therapy on breast cancer risk. METHODS: A literature search was done in MEDLINE (1969-July 2007) and in addition in EMBASE and Biosis (1990-July 2007) for original reports in English and French. Case reports and studies without a control group were excluded. RESULTS: No prospective randomized clinical trials were found. The five studies found (two case-control studies, two cohort studies and one retrospective observational study) showed inconsistent results. All studies had severe methodological limitations. Formulations and dosages used could be considered suboptimal. CONCLUSION: At present, there are no valid randomized or observational clinical studies that provide evidence that the addition of testosterone to conventional postmenopausal hormone therapy influences breast cancer risk.     

Androgens and the breast

There is increasing interest in the role of androgens in the treatment of women but little is known about their long-term safety. There are also very few studies on testosterone therapy and breast cancer risk. However, some observations support the concept that androgens may counteract the stimulatory effects of estrogen and progestogen in the mammary gland. Mammographic breast density and breast cell proliferation could be regarded as surrogate markers for the risk of breast cancer. Recently the addition of testosterone to a common estrogen/progestogen regimen was found to inhibit the stimulatory effects of hormones on breast cell proliferation. The effects of testosterone alone on the postmenopausal breast remain to be investigated.     

Hormone replacement therapy and breast cancer

Numerous studies on oestrogen replacement therapy have failed to incriminate the use of exogenous oestrogen as a cause of breast cancer in post-menopausal women. Since so many variables influence breast cancer risk, it has not been possible for any single study to evaluate every potential risk factor included in the epidemiological and clinical reports on hormone use and carcinoma of the breast. The relative risk (RR) for breast cancer in oestrogen users has been found to vary from 0.4 to 3.4, with the vast majority of investigators reporting an RR very close to 1.0, or no increased risk at all. There is growing evidence that progesterone deficiency may increase the risk for breast cancer in some women. At least three studies have indicated that the addition of progestogen to oestrogen replacement therapy may significantly decrease the risk for carcinoma of the breast. It was observed that the RR of breast cancer varied from 0.47 to 0.89 in these studies when oestrogen-progestogen users were compared with unopposed oestrogen users. However, it is pointed out that progestogens are not added to oestrogen replacement therapy to negate an increased risk of breast cancer from unopposed oestrogens, since oestrogen therapy does not increase the risk. Combination oestrogen-progestogen therapy is recommended for hormone replacement treatment, even in women who have had a hysterectomy, because it will reduce the risk for breast cancer in some women.     

Postmenopausal hormone replacement in the woman with a reproductive risk factor for breast cancer

Objective: to assess the interaction between postmenopausal hormone replacement therapy (HRT) and various reproductive risk factors for breast cancer such as early menarche, late menopause, late first delivery and nulliparity. Design: three cohort studies and fourteen case control studies, published between 1975 and 1997, provided relative risks (RRs) of HRT use in women with, as well as in those without, a reproductive risk factor for breast cancer. Methods: using an additive RR model reported before, we investigated whether the RR for breast cancer in women with a combination of HRT and a given reproductive risk factor result from a simple addition of RRs of HRT on the one hand, and of the pre-existing reproductive risk factor on the other hand, or that synergism between both risk factors occurs. Results: simple addition of RRs was shown in the case of early menarche and late menopause. Less increase of risk, suggesting antagonism, was found for both late first delivery and nulliparity in combination with HRT use. Conclusion: we could not observe any synergistic effect of the combined risks of any of the following reproductive risk factors for breast cancer: early menarche, late menopause, late first delivery or nulliparity on the one hand, with the risk resulting from HRT use on the other hand. Therefore, as far as the risk of breast cancer is concerned, the use of HRT appears not to be highly detrimental in women with a reproductive breast cancer risk factor, as it results in not more than a simple addition of risks at the most.     

Study of adverse outcomes in women using testosterone therapy

Objectives

There are concerns that exogenous testosterone therapy may be associated with adverse cardiovascular effects, increases in risk of breast or uterus cancer and alterations in insulin sensitivity. Objective of this study was to explore the safety of testosterone therapy in actual clinical practice.

Methods

Data from the General Practice Research Database and the Health Improvement Network was used, including computerised medical records of UK general practitioners. The study population included women aged 18+ years prescribed testosterone, administered through implants (72.2%), tablets (18.4%) or injections (7.9%). Each testosterone user was matched by age and practice to three control patients. Cox proportional hazards models were used to compare the rates of several outcomes.

Results

The study population included 8412 women, 2103 testosterone users and 6309 controls. There were no statistically significant differences between the cohorts in the rates of cerebrovascular disease, ischemic heart disease, breast cancer, deep venous thrombosis/pulmonary embolism, diabetes mellitus or acute hepatitis. The rate of breast cancer was comparable between testosterone users and control patients. The rate of androgenic events was increased in the testosterone cohort (relative rate of 1.55 [95% CI 1.21–1.97]). Differences in outcomes between the cohorts were generally comparable across subgroups based on age and use of hormone therapy.

Conclusions

This study found no major increase in the risk of cardiovascular diseases or breast cancer in women using testosterone (implants, tablets, or injections), while the risk of androgenic events was increased. It would be useful to conduct similar studies at lower doses with transdermal testosterone.     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

Objectives

There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design

This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results

Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion

T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.     

性激素替代治疗与乳腺癌

目前世界范围内乳腺癌发病率呈上升趋势Ｍａｒｉａｎｎｅ指出１９８５年时医学家估计全世界每年出现７２万新病例，预计至２０００年每年将出现１００万新病例［１］之所以出现乳癌发病率增长，其原因是与妇女平均寿命的提高有关，因为４０岁以上妇女乳腺癌的发生率升高...     

The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women

At least 16 million women over the age of 50 currently experience low sexual desire, with approximately 4 million women exhibiting hypoactive sexual desire disorder (HSDD). Although early research established that testosterone therapy improves sexual desire in postmenopausal women, safer and more efficacious administration routes were explored. Large randomized, double-blinded placebo-controlled studies demonstrate that transdermal testosterone improves sexual function and activity in postmenopausal women with HSDD. Large multi-center Phase III trials further confirm the positive effects of the testosterone patch in the treatment of HSDD. More recent studies are exploring the utility of testosterone gels. Based upon data from two recent clinical relevance studies, physicians can be reassured that postmenopausal women with HSDD report a meaningful benefit with testosterone therapy, and further, women will only continue therapy if they experience a meaningful benefit. Although most trials combined testosterone with estrogen/progesterone therapy, the recent APHRODITE trial examined testosterone alone, showing increased sexual desire with mild adverse events. Concerns regarding the long-term safety profile of transdermal testosterone must be addressed before the FDA will approve a testosterone product for women. Although some fear an increased risk of breast cancer with exogenous testosterone administration, recent studies support the idea that androgens can play a role in suppressing the proliferative effects of estrogen and progesterone. Long-term safety data is now being collected and analyzed and Phase III trials focusing on long-term risks are underway. In the meantime, transdermal testosterone appears to be a safe and effective therapy for postmenopausal women with HSDD [Swanson S, DeRogatis L, Snabes M, Simes S, Zborowski J. Treatment of HSDD in surgically menopausal women: a newly initiated Phase III, randomized, double-blind, placebo-controlled, multi-center study of the safety and efficacy of LibiGel. Presented at the Annual Meeting of the International Society for the Study of Women's Sexual Health, February 22–25, Orlando, FL; 2007].     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

ObjectivesThere is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.Study designThis is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.ResultsSince March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).ConclusionT and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.     

Postmenopausal hormone therapy before and after breast cancer: clinical experiences

Conventional oestrogen-based hormone therapy (HT) increases the incidence of breast pain and tenderness, mammographic density and the risk of breast cancer. Combined oestrogen plus progestogen therapy (EPT) increases the risk of breast cancer to a greater degree than oestrogen alone (ET). Attention must therefore be focused on identifying women at risk of breast cancer or on producing a HT that has fewer breast side effects. Randomised controlled trials have shown that while EPT induces breast tenderness or pain in up to 50% of women and increases mammographic density in up to 70% during the first year of treatment, only about as many as one-tenth women report breast tenderness or pain with tibolone and increases in mammographic density are rare, occurring with a similar incidence as seen in untreated controls. Many women with breast cancer suffer vasomotor symptoms rather than risk recurrence with conventional HT. However, in a small randomised controlled trial in women with early breast cancer undergoing adjuvant tamoxifen treatment, tibolone reduced hot flushes, night sweats and improved quality of life compared with placebo.     

Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention

Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.     

A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk

The increased risk of breast cancer recently observed with some specific estro-progestin associations has raised concerns about the harmful effects of menopausal hormone replacement therapy (HRT). It has been proposed that phytoestrogens (PEs), which have a similar chemical structure to estrogens, could be used as HRT. The main selling points of these preparations concern the management of hot flashes and their potential beneficial effects on breast tissue. In this review, we will address the effects of PE on hot flashes and breast cancer risk as well as the questions raised on a chemical point of view. We conclude that the efficacy of a PE rich diet or nutritional supplements is not clearly established. The use of PE as an alternative for HRT cannot be advocated for now, due to insufficient and conflicting data on efficacy and safety. Moreover, due to the hormone dependence of breast cancer, PE use must be contraindicated in breast cancer survivors.     

HRT, breast and endometrial cancers: strategies and intervention options

The demand for hormone replacement therapy (HRT) by women who enter the menopause is rapidly increasing in all developed countries. The concern that HRT may enhance morbidity and mortality from malignant diseases still limits the widespread adoption of hormonal treatments. Overall, epidemiological data on cancer incidence and HRT are reassuring, although long-term or inappropriate therapies may slightly increase the risk of developing malignant diseases. Many commercial hormonal compounds are currently available and the safest HRT regimen with regard to cancer risk must be identified. It is equally important that the best strategies for breast and endometrial surveillance in women commencing HRT be outlined, bearing in mind that the diffusion of hormonal therapies may be halted by unnecessary medical interventions.     

Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health

Objective: To briefly summarize the therapeutic choices for osteoporosis prevention which are currently available to post-menopausal women. Methods: Results of randomized clinical trials and epidemiological studies in post-menopausal women, and pre-clinical studies in ovariectomized rats were summarized. Results: Estrogen combined with progestogen in hormone replacement therapy (HRT) is effective in relieving perimenopausal symptoms and maintaining bone mineral density. However, the increased breast cancer risk associated with long-term HRT use makes it a less desirable option for many women. Selective estrogen receptor modulators (SERMs), such as raloxifene, are also effective in maintaining bone density, without stimulating the breast or uterus. However, SERMs do not relieve perimenopausal hot flashes. Conclusion: HRT is effective for acute relief of perimenopausal symptoms, but for women who are unwilling or unable to take HRT long-term, SERMs such as raloxifene are a useful therapy for the prevention of osteoporosis.     

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.     

Memory impairments with adjuvant anastrozole versus tamoxifen in women with early-stage breast cancer

OBJECTIVE: Hormones have been implicated as modulators of cognitive functioning. For instance, results of our previous work in women with breast cancer showed that cognitive impairment was more severe and involved more memory domains in those who received adjuvant tamoxifen therapy compared with women who received chemotherapy alone or no adjuvant therapy. Recently aromatase inhibitors such as anastrozole have been used in lieu of tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor-positive, early-stage breast cancer. Plasma estrogen levels are significantly lower in women who receive anastrozole compared with those who receive tamoxifen. We hypothesized, therefore, that anastrozole would have a more profound effect on cognitive function than tamoxifen, a mixed estrogen agonist/antagonist. DESIGN: To test this hypothesis we compared cognitive function in women with early-stage breast cancer who received tamoxifen with those who received anastrozole therapy in a cross-sectional study. We evaluated cognitive function, depression, anxiety, and fatigue in 31 postmenopausal women with early-stage breast cancer who were between the ages of 21 and 65 years and treated with tamoxifen or anastrozole for a minimum of 3 months. RESULTS: The results showed that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen. CONCLUSIONS: Additional, prospective studies are needed to validate and confirm the changes in cognitive function associated with hormone therapy for breast cancer.     

Estrogen replacement therapy in women with a history of breast cancer.

Estrogens are known as potent mammary mitogen substances and are the major stimulus for the growth of hormone-dependent tumors and clearly implicated in the pathogenesis of breast cancer. Therefore it is a general belief that hormone replacement therapy (HRT) after breast cancer will increase the risk of developing recurrences, though there are no clear data available to support this suggestion. No prospective study with a large number of patients and a long treatment period was performed concerning this issue. On the other hand it may not be justifiable to withhold hormone replacement therapy from low-risk patients after menopause, knowing the benefits of this therapy concerning osteoporosis and cardiovascular advantages. Nevertheless, until appropriate clinical trials help to resolve this problem, non hormonal alternatives constitute the standard of care. One possible approach is to treat menopausal women who have had breast cancer symptomatically and avoid ERT unless absolutely necessary. The risk of cardiovascular diseases can be reduced with lifestyle. Tamoxifen has a beneficial effect on serum lipids and the intake for 5 years leads to a 50% reduction in the incidence of fatal myocardial infarction and a decrease in morbidity associated with ischaemic heart disease. Low doses of progestogen is effective for menopausal hot flushes. Tibolone reduces vasomotoric symptoms such as hot flushes and offers benefit on osteoporosis and has shown a significant reduction in high-density lipoprotein cholesterol. Whether replacing of estrogens is safe for patients after breast cancer remains uncertain. There is a need for a large controlled clinical trial to evaluate the safety and advantages of long time estrogen replacement in women treated for breast cancer.     

Postmenopausal hormone therapy and the risk of breast cancer: the view of an epidemiologist

OBJECTIVES: Postmenopausal hormone therapy (PMH) has been widely used by menopausal women living in western countries for the past several decades. Numerous studies have evaluated the relationship between PMH and breast cancer risk because steroid hormones have been implicated in breast cancer etiology. METHODS: A review of selected studies was performed to evaluate the history of investigations of the association between PMH and breast cancer, with a focus on studies evaluating different PMH regimens and different histologic types of breast cancer. RESULTS: Though studies conducted before the early 1990s suggest that both combined estrogen and progestin (E + P) PMH and unopposed estrogen (E) PMH are associated with an increased risk of breast cancer, more recent observational studies suggest that E + P, particularly current use for 5 years or longer, is more strongly associated with breast cancer risk than is unopposed E. Results from the Women's Health Initiative (WHI) randomized trials have confirmed these findings as they indicate that E + P is causally related to breast cancer (relative risk (RR) = 1.24; 95% confidence interval (CI): 1.01-1.54), while E alone is not (RR = 0.77; 95% CI: 0.59-1.01). CONCLUSIONS: There is clear and consistent evidence that use of E + P increases a woman's risk of breast cancer. Alternatively, current evidence suggests that use of unopposed E is not as strongly associated with breast cancer risk. Further studies are needed though to examine how different PMH regimens, doses, and methods of delivery are related to breast cancer risk, and how PMH impacts the risks of different types of breast cancer.