Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer

Objective

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

October 2001.Hormone replacement therapy (HRT) connotes treatment with either estrogen alone or estrogen with progesterone in postmenopausal women. Menopausal symptoms, such as hot flashes and vaginal dryness, and the potential long-term effects of estrogen deprivation are a concern to women with breast cancer, particularly those in whom menopause develops early as a result of adjuvant chemotherapy.Traditionally, the use of HRT has been contraindicated in women with breast cancer because of the notion that the development and growth of breast cancer is estrogen dependent and that the introduction of HRT may increase the risk of breast cancer recurrence. The focus of this guideline is on whether it is safe to give HRT to women with breast cancer.     

Antiestrogenic activities of Ginkgo biloba extracts

Most climacteric and postmenopausal women appear to have vasomotor symptoms as well as a high risk of osteoporosis and cardiovascular disease. Although exogenous estrogens can reduce these symptoms, women are reluctant to use hormone replacement therapy (HRT) due to its undesirable side effects, such as irregular bleeding and an increased risk of breast cancer. A previous study suggested that Ginkgo biloba extracts (GBE) have estrogenic activity and might be suitable as an alternative to HRT. However, there are no reports of the preventive effect of GBE on breast cancer, which is the side effect of classical HRT. In this study, it was confirmed that GBE exhibits estrogenic and antiestrogenic activity depending on the E₂ and GBE concentration, via estrogen receptor (ER)-dependent and ER-independent pathways. In addition, GBE reduced the E₂ levels by stimulating the E₂ metabolism and inhibiting E₂ synthesis, which indicates that GBE can induce antiestrogenic activity via the depletion of E₂. Furthermore, GBE might have similar action to selective arylhydrocarbon receptor modulators (SAhRMs), which induce antiestrogenic activity through cross-talk between the arylhydrocarbon receptor (AhR) and ER. In conclusion, GBE has a biphasic effect on estrogen, and can be considered as a potential alternative to HRT with chemopreventive effects on breast cancer. However, further studies on animals and humans will be required.     

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.     

Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer

Estrogen replacement therapy (ERT) increases a woman's risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman's risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) or with each dose of ERT (continuous-combined EPRT; CEPRT). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT was not associated with any increased risk of endometrial cancer. SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of 'terminal' differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an 'adequate' progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 212-fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than ERT. Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.     

The menopause,hormone replacement therapy and breast cancer

Concern exists that the reduction in breast cancer risk associated with the onset of the menopause will be negated with exposure to hormone replacement therapy (HRT). Evidence from large-scale randomised HRT trials support observational data that have shown a modest increase in breast cancer risk with long-term use (i.e. >15 years) of combined therapy, although this falls following HRT cessation suggesting a growth-promoting effect. Randomised evidence demonstrates that the efficacy of anti-estrogens, aromatase inhibitors and raloxifene in the treatment and chemoprevention of breast cancer are restricted to women with oestrogen receptor positive (ER +ve) disease; however, HRT has not been associated conclusively with a predominance of hormone sensitive breast cancer. Despite stimulating the breast cancer cell growth, HRT has not been shown to increase breast cancer recurrence or mortality when prescribed to breast cancer survivors experiencing oestrogen deficiency symptoms and randomised trials have been recommended and commenced. In conjunction with controlled breast cancer trials demonstrating a therapeutic benefit of high dose estrogens and interest in the use of additive oestrogen therapy in patients developing resistance to oestrogen deprivation, the dogma that HRT is an absolute contra-indication following diagnosis is challenged.     

Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women

OBJECTIVE: To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. STUDY DESIGN: From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. RESULTS: Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. CONCLUSION: Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.     

Vascular effects of aromatase inhibitors: data from clinical trials

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.     

Hormonal Therapy and Risk of Breast Cancer in Mexican Women

The use of hormonal therapies, including hormonal contraceptives (HC) and postmenopausal hormone replacement therapy (HRT) have been shown to influence breast cancer (BC) risk. However, the variations of these effects among populations and ethnic groups are not completely documented, especially among Hispanic women. We evaluated the association between HC and premenopausal BC risk, and between HRT and postmenopausal BC risk in Mexican women. Data from a Mexican multi-center population-based case–control study ofwomen aged 35 to 69 years were analysed. A total of 1000 cases and 1074 matched controls were recruited between 2004 and 2007. Information on hormonal therapy was collected through a structured questionnaire. Results were analysed using conditional logistic regression models. Overall, HC were used by 422/891 (47.3%) premenopausal women and HRT was used by 220/1117 (19.7%) postmenopausal women. For HC, odds ratios (ORs) for BC were 1.11 (95% confidence interval (CI): 0.82, 1.49) for current users and 1.68 (95% CI: 0.67, 4.21) for ever-users. No clear effect of duration of use was observed. For HRT, the OR for BC was significantly increased in ever users (OR: 1.45; 95% CI: 1.01, 2.08). A non-significant increased risk was observed for combined estrogen/progestin, (OR =  1.85; 95% CI: 0.84, 4.07) whereas no effect was observed for the use of estrogen alone (OR = 1.14; 95% CI: 0.68, 1.91). Our results indicate that, HC had a non-significant effect on the risk of pre-menopausal BC, but suggested that injected contraceptives may slightly increase the risk, whereas HRT had a significant effect on post-menopausal BC in this population. This study provides new information about the effects of HC and HRT on BC risk in a Mexican population, which may be of relevance for the population of Latin America as a whole.     

Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study

Objective To examine the relation between body mass index (kg/m²) and cancer incidence and mortality.Design Prospective cohort study.Participants 1.2 million UK women recruited into the Million Women Study, aged 50-64 during 1996-2001, and followed up, on average, for 5.4 years for cancer incidence and 7.0 years for cancer mortality.Main outcome measures Relative risks of incidence and mortality for all cancers, and for 17 specific types of cancer, according to body mass index, adjusted for age, geographical region, socioeconomic status, age at first birth, parity, smoking status, alcohol intake, physical activity, years since menopause, and use of hormone replacement therapy.Results 45 037 incident cancers and 17 203 deaths from cancer occurred over the follow-up period. Increasing body mass index was associated with an increased incidence of endometrial cancer (trend in relative risk per 10 units=2.89, 95% confidence interval 2.62 to 3.18), adenocarcinoma of the oesophagus (2.38, 1.59 to 3.56), kidney cancer (1.53, 1.27 to 1.84), leukaemia (1.50, 1.23 to 1.83), multiple myeloma (1.31, 1.04 to 1.65), pancreatic cancer (1.24, 1.03 to 1.48), non-Hodgkin''s lymphoma (1.17, 1.03 to 1.34), ovarian cancer (1.14, 1.03 to 1.27), all cancers combined (1.12, 1.09 to 1.14), breast cancer in postmenopausal women (1.40, 1.31 to 1.49) and colorectal cancer in premenopausal women (1.61, 1.05 to 2.48). In general, the relation between body mass index and mortality was similar to that for incidence. For colorectal cancer, malignant melanoma, breast cancer, and endometrial cancer, the effect of body mass index on risk differed significantly according to menopausal status.Conclusions Increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined. Among postmenopausal women in the UK, 5% of all cancers (about 6000 annually) are attributable to being overweight or obese. For endometrial cancer and adenocarcinoma of the oesophagus, body mass index represents a major modifiable risk factor; about half of all cases in postmenopausal women are attributable to overweight or obesity.     

The Relationship between Body Weight and Health Care among German Women

Objective: To investigate the relationship between body weight and the use of health care services among women from southern Germany. Research Methods and Procedures: Data were drawn from the 1994 to 1995 Monitoring of Trends and Determinants in Cardiovascular Disease Augsburg survey, covering a population‐representative sample of women 25 to 74 years old (n = 2301). Logistic regression models were used to calculate odds ratios (ORs) for the use of medical services by women with overweight (BMI 25.0 to 29.9 kg/m²) or obesity (BMI ≥ 30 kg/m²) in comparison with normal‐weight women (BMI < 25.0 kg/m²). Results: In multivariable analysis, obese women 50 to 74 years old were more likely than normal‐weight women to delay cancer screening procedures, such as manual breast examination and Papanicolaou smear (OR 0.52, 95% confidence interval 0.37 to 0.74) in the previous 12 months. However, the relationship between obesity and cancer screening was not found to be significant in 25‐ to 49‐year‐old women (OR 0.92, 95% confidence interval 0.62 to 1.36). Neither in the 25‐ to 49‐year‐old age group nor in the 50‐ to 74‐year‐old age group were independent relationships between higher body weight and total physician visits, hospitalizations, or medication use observed. Discussion: Obese women tended to use medical services with greater frequency due to obesity‐related diseases. However, postmenopausal women with a BMI ≥ 30 kg/m² were more likely to delay routine cancer screening, putting them at a greater risk for death from breast, cervical, and endometrial cancer. Thus, obese postmenopausal women should be targeted for increased screening.     

Targeted anti-estrogens to treat and prevent diseases in women

The estrogen receptor has been successfully targeted with the anti-estrogen tamoxifen to treat all stages of breast cancer. Because tamoxifen is a partial agonist, it exhibits target-site specificity: it acts as an anti-estrogen in the breast to inhibit tumor growth, while exhibiting estrogenic effects on bones and lipid metabolism. Therefore, tamoxifen has the added benefit of maintaining bone density and reducing the risk of myocardial infarction in postmenopausal women.However, undesirable side effects of tamoxifen preclude its use as a hormone replacement therapy for otherwise healthy women. New anti-estrogens are currently being developed that may prevent osteoporosis, breast and endometrial cancer, and reduce the risk of myocardial infarction.     

How to evaluate the risk-benefit ratio of the low-dose hormone replacement therapy?

Since the results of the women health initiative study showing an overall negative risk-benefit ratio with 0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate, the use of the lowest effective dose of steroids in hormone replacement therapy (HRT) is recommended.

A low-dose regimen appears to induce less side effects such as breast tenderness or leg pain than do higher dose preparations.

The decrease in hot flashes with low-dose estrogens, range 60–70%, is less than the 80–90% reduction with standard dosing. But this mean that 60–70% of menopausal women do not need higher doses.

The same applies to bone preservation which is dose dependent: the number of non-respondant women will be higher than with standard doses. However, randomized double-blind, placebo controls trials have defined positive effects on bone of low doses of HRT with adequate calcium and Vitamin D in elderly women. The use of bone densitometry and of biochemical markers of bone turnover is mandatory in women using low or ultra-low-dose preparations.

In spite of the lack of trials conducted with low-dose HRT, this treatment seems to be safer:

• the plasma levels of estradiol are lower; as far as breast cancer risk is concerned, the decrease of this subrogate marker is considered as favourable;

• the increase in breast density is less pronounced;

• the nurses's health study found a dose relationship for stroke, with no increase in risk with low-dose of estrogens;

• the effects on subrogate markers of cardiovascular risk seem to be more favourable.

Beside the low-dose HRT, one must consider some other facts:

• the “critical window” theory: it is biologically plausible that HRT, if started early after the menopause can slow the progression of coronary atherosclerosis;

• the way of administration of HRT: some observational studies have shown no increase in the risk of venous thromboembolism risk among women treated with transdermal estrogens;

• the progestogen used: a French cohort study recently performed found no increase in breast cancer risk with the use of micronized progesterone meanwhile the increase in risk observed with other progestogens was similar to the findings of the WHI study.

In the future, it is conceivable that more comprehensive pharmacogenomic studies will lead to effective algorithms for individualizing the right dose of steroids to be used in HRT.     

Hormone replacement therapy--is there a place for its use in neurology?

Stroke remains the third leading cause of mortality in developed countries despite declining tendency over the past decades. As the leading cause of disability and second cause of dementia, primary prevention should be the main way to fight the disease, since therapy is not efficient enough. Several observations pointed to estrogen as a protective agent that may reduce stroke risk, however, studies have shown conflicting data. There is no strong evidence that hormone replacement therapy (HRT) increases stroke risk. Several studies have shown that HRT may reduce the risk of fatal stroke. Conflicting results have been found for Alzheimer's disease and HRT as well. An association between higher serum concentration of estradiol and decreased risk of cognitive decline has been found in some studies, supporting the hypothesis that estrogen concentration may play a significant role in brain protection. Having in mind results of recent randomized trials, it is suggested that HRT should not be recommended on general basis for the primary or secondary prevention of cardiovascular/cerebrovascular diseases or for primary prevention of degenerative diseases such as Alzheimer's disease. Osteoporosis, cognitive decline and climacteric symptoms that are likely to impact on quality of life, speak in favor for recommendation of HRT use. On the other side, family history of breast carcinoma, mastopathy, thromboembolism, in certain cases gallbladder disease, will discourage the commencement of HRT. Respecting the patient's preferences and having benefits and risks in mind as well as science advisory statements, individual counseling regarding HRT should be the leading concept in the healthcare of postmenopausal women.     

Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk

Multiple lines of evidence support a central role of hormones in the etiology of breast cancer. In epidemiologic studies, considerable effort has focused on delineating the role of endogenous hormones in risk of breast cancer among postmenopausal women. Recently, substantial additional data has accrued from prospective studies where endogenous hormones are measured in study subjects prior to disease diagnosis. In this review, the epidemiologic evidence linking sex steroids—estrogens, testosterone, and progesterone, specifically—with subsequent risk of breast cancer in both premenopausal and postmenopausal women is summarized. Overall, a strong positive association between breast cancer risk and circulating levels of both estrogens and testosterone has now been well confirmed among postmenopausal women; women with hormone levels in the top 20% of the distribution (versus bottom 20%) have a two- to three-fold higher risk of breast cancer. Evidence among premenopausal women is more limited, though increased risk associated with higher levels of testosterone is consistent. However, both positive and null associations have been observed with estrogens and progesterone and clearly more evaluation is needed.     

脂联素及其受体抗肿瘤的研究进展

目前大量的研究已表明循环系统的脂联素浓度与恶性肿瘤的发病风险呈负相关。这些恶性肿瘤包括绝经后乳腺癌、子宫内膜癌、大肠癌、前列腺癌等。脂联素是在其受体(AdipoR1和AdipoR2)的介导下发挥其生物学作用。相关实验发现,AdipoR1/R2在乳腺癌、子宫内膜癌、结直肠癌等肿瘤组织中有表达。因此针对脂联素的研究可能揭示其与恶性肿瘤的发生、发展的相关性。     

Progestins in the menopause

While the benefits of progestin use in hormone replacement therapy (HRT) are well recognised as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. The data related to the progestin effect on breast tissue has been interpreted differently from country to country. However it has been admitted that, according to the type of progestin used, the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any difference between the estrogens given alone or combined to progestins in HRT. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others, attenuate the beneficial effects of estrogens on the lipid profile and the vasomotion as well. On the other hand, other progestins devoid of androgenic properties do not exert these deleterious effects. The epidemiological data does not suggest any negative effect of the progestins administered together with estrogens on cardiovascular morbidity or mortality.

However, recent results suggest that in women with established coronary heart disease (CHD), HRT may not protect against further heart attacks, when the progestin selected possesses androgenic properties.

Complying with the classic contra indications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.     

Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Menopausal hormone therapy and cancer: Changing clinical observations of target site specificity

Menopausal hormone therapy with estrogen plus progestin or estrogen alone (for women with prior hysterectomy) is still used by millions of women for climacteric symptom management throughout the world. Until 2002, hormone therapy influence on cancer risk and other chronic diseases was determined through observational study reports. Since then, results from the Women’s Health Initiative randomized, placebo-controlled hormone therapy trials have substantially changed concepts regarding estrogen plus progestin and estrogen alone influence on the most common cancers in postmenopausal women. In these trials, estrogen plus progestin significantly increased breast cancer incidence and deaths from breast cancer, significantly increased deaths from lung cancer, significantly decreased endometrial cancer, and did not have a clinically significant influence on colorectal cancer. In contrast, estrogen alone use in women with prior hysterectomy significantly reduced breast cancer incidence and deaths from breast cancer without significant influence on colorectal cancer or lung cancer. These complex results are discussed in the context of known potential mediating mechanisms of action involved in interaction with steroid hormone receptors.