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.     

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.     

Postmenopausal estrogen and progestogen therapy and the risk of uterine leiomyomas

OBJECTIVE: Leiomyomas are common benign neoplasms. Although hormone therapy is the most common and effective treatment for menopausal symptoms, little is known about its effect on leiomyomas. We examined the risk of a first diagnosis of leiomyomas in peri- and postmenopausal women associated with prior use of estrogen and progestogen therapy (EPT). DESIGN: A case-control study was conducted among enrollees from a nonprofit health plan. Cases had a first diagnosis of leiomyomas confirmed by surgery or ultrasound. Controls were women of the same age range without a diagnosis of leiomyomas selected at random from membership and outpatient files. Participants were interviewed regarding prior use of exogenous hormones, medical history, and reproductive history. This analysis was restricted to cases (n = 256) and controls (n = 276) who were peri- or postmenopausal and more than 40 years of age. Adjusted odds ratios (OR) and 95% CIs were estimated using logistic regression models. RESULTS: EPT use for more than 5 years was associated with a 1.7-fold increased risk of leiomyomas (95% CI, 0.9-3.3). Associations with EPT use were only present among women with a body mass index less than 24 kg/m; OR (ever-use), 2.3 (95% CI, 1.2-4.3); and OR (>or= 5 years use), 4.0 (95% CI, 1.6-10.3). CONCLUSION: Among peri- and postmenopausal women, prior EPT use was associated with an increased risk of a subsequent leiomyomas. This association seemed limited to the subset of women with low body mass index. Exogenous sources of estrogen and progestin in the setting of low adiposity may contribute to the development of leiomyomas.     

Use of hormones in the menopausal transition period in the Netherlands between 1993 and 1997

OBJECTIVES: To describe the patterns and to assess the indicators of hormone use during the menopausal transition period in a Dutch population. METHODS: Between 1993 and 1997, 17,357 women aged 49-70 years participated in the Prospect-EPIC (European Prospective Investigation into Cancer and Nutrition) cohort and filled out an extensive questionnaire, which included information about hormone use during menopausal transition and other medical and lifestyle characteristics. Patterns of hormone use were described and various characteristics were evaluated as indicators of current hormone use by logistic regression. RESULTS: Overall, 13% of women were current hormone users, which was highest in the 49-54 age group (19%). Hysterectomized women and older non-hysterectomized women mainly used unopposed estrogen therapy (ET), whereas younger non-hysterectomized women mainly used oral contraceptives or combined estrogen+progestogen therapy. Of all ever users, 61% used hormones for more than 1 year and 28% for more than 5 years. The most important indicators of hormone use for women without a surgical menopause were age, alcohol use, smoking, parity, ever use of oral contraceptives and family history of breast cancer. For women with a surgical menopause age, parity, ever use of oral contraceptives, diastolic blood pressure and the number of removed ovaries were the most relevant indicators. CONCLUSIONS: The frequency of hormone use during menopausal transition in the Netherlands is low compared to other western countries, but the duration of use is quite long. Hormone use seems to be largely determined by factors that are known to affect endogenous estrogen levels.     

Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women

Background: C-reactive protein (CRP) represents an independent risk factor for coronary disease and stroke. Because oral estrogens increase CRP levels, with inflammatory and thrombotic consequences, we determined whether the co-administration of a progestin might modify the estrogenic effect on CRP. Methods: In a non-randomized, non-blinded study, we measured C-reactive protein serum concentrations with high-sensitivity technique (hs-CRP) in 163 healthy postmenopausal women divided into groups as follow: 52 not taking hormones (referent group), and 111 taking hormone replacement therapy (HRT) (42 of whom treated with unopposed estrogen, and 69 with an estrogen/progestin combination). Results: Compared with non-users of hormones, median CRP levels were 66% (95% confidence interval: from 44 to 89%) higher and 112% (95% confidence interval: from 89 to 168%) higher among women using a combined estrogen/progestin regimen and, respectively, among women taking unopposed estrogen [1.54 mg/L in the referent group; 2.56 mg/L in the estrogen/progestin group (P=0.032), and 3.27 mg/L in the unopposed estrogen group (P=0.004)]. Furthermore, there was no difference in CRP distributions between women taking different types of progestins. Conclusion: concurrent progestin administration may attenuate estrogen’s pro-inflammatory effects, independently on the type of used progestin.     

Coronary heart disease in menopausal women: implications of primary and secondary prevention trials of hormones

In direct contrast to the observational studies, both primary and secondary prevention trials of female reproductive hormones have found no benefit for coronary heart disease (CHD). Basic science studies have elucidated several mechanisms by which estrogen may improve coronary arterial physiology and prevent pathology, but have also found mechanisms by which estrogen might increase coagulation or inflammation, or might trigger coronary events in advanced lesions. Animal studies suggest that hormones may retard early atherosclerosis, while both animal studies and human angiographic trials are conclusive that hormones do not retard progression of raised lesions. Hormone use in the primary prevention observational studies would mostly have started at the age of menopause, in women whose arteries on average would be closer to normal than those of women in the clinical trials. One hypothesis worthy of further study is that estrogen may have a beneficial effect in normal or near-normal arteries, but the opposite effect in the presence of established atherosclerosis. However, at the average age of menopause, a substantial proportion of women has raised lesions, and a smaller proportion already has advanced lesions. Also, the apparent benefit of hormone use was found in secondary prevention observational studies, i.e., in women with compromised arteries. It is likely that uncorrected biases in the observational studies lead to an overestimation of any benefit of hormone use. On the other hand, endogenous estradiol may be responsible for the later onset of coronary disease in women compared to men; if so, then the appropriate test of the estrogen hypothesis would employ transdermal estradiol in a young population of menopausal women. Hormones are not indicated for the prevention of CHD, particularly in the light of the increased risk for stroke and venous thrombosis. Their use for other indications (menopausal symptoms, osteoporosis) needs to be tempered by the risk for cardiovascular disease (CVD).     

Postmenopausal hormone replacement therapy: endometrial and breast effects

The history of hormone replacement therapy (HRT) dates back to the late 1800s, when animal extracts of ovaries were first used. With the development of synthetic hormones, widespread use in postmenopausal women extended throughout the industrialized world, so that by the late 1900s roughly one-third to one-half of all postmenopausal women in the United States and Europe were taking HRT. Two events changed the course of use of HRT: the association of an increased rate of endometrial carcinoma with estrogen-only HRT and the association of an increased breast cancer rate with combined estrogen and progestin HRT. This review explores the evidence of the effects of HRT on the endometrium and the breast, with emphasis on the pathologic changes.     

Hormone therapy initiation after the Women's Health Initiative

OBJECTIVES: To describe hormone therapy (HT) initiation after the 2002 publication of the Women's Health Initiative. DESIGN: Observational cohort (1999-2003) of women ages 40 to 79 years, five health plans, used HT in July 2002 and subsequently discontinued or never used before August 2002. RESULTS: Of discontinuers, 15.8% (3,203 of 20,205) reinitiated HT. Reinitiation was higher among estrogen users (23.8%) versus estrogen with progestin users (11.3%), and lower among those with diabetes (relative risk [RR]=0.68, 95% CI: 0.61-0.76), cardiovascular disease (RR=0.87, 95% CI: 0.83-0.92), and hyperlipidemia (RR=0.83, 95% CI: 0.79-0.88). Only 2.3% (2,072 of 90,261) of never users initiated (August 2002 to December 2003). First-time initiation was associated with cardiovascular disease (RR=1.17, 95% CI: 1.10-1.25) and hyperlipidemia (RR=1.24, 95% CI: 1.17-1.33) and was less common among those with diabetes (RR=0.70, 95% CI: 0.63-0.79). CONCLUSIONS: After the Women's Health Initiative, a minority of women reinitiated or became first-time initiators of HT. Women with cardiovascular disease, diabetes, and hyperlipidemia were less likely to reinitiate; women with cardiovascular disease and hyperlipidemia were more likely to be first-time initiators.     

Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin

OBJECTIVES: To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial. METHODS: Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up. RESULTS: Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors. CONCLUSION: A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

Menopausal hormone therapy (HT) in patients with breast cancer

OBJECTIVES: To assess the effect of menopausal hormone therapy (HT) on reoccurrence, cancer-related mortality, and overall mortality after a diagnosis of breast cancer. METHODS: We performed a quantitative review of all studies reporting experience with menopausal HT for symptomatic use after a diagnosis of breast cancer. Rates of reoccurrence, cancer-related mortality, and overall mortality were calculated in this entire group. A subgroup analysis was performed in studies using a control population to assess the odds ratio of cancer reoccurrence and mortality in hormone users versus non-users. RESULTS: Fifteen studies encompassing 1416 breast cancer survivors using HT were identified. Seven studies included a control group comprised of 1998 patients. Among the 1416 HT users, reoccurrence was noted in 10.0% (95% CI: 8.4-11.6%). Cancer-related mortality occurred at a rate of 2.6% (95% CI: 1.8-3.7%), while overall mortality was 4.5% (95% CI: 3.4-5.8%). Compared to non-users, patients using HT had a decreased chance of reoccurrence and cancer-related mortality with combined odds ratio of 0.5 (95% CI: 0.2-0.7) and 0.3 (95% CI: 0.0-0.6), respectively. CONCLUSIONS: In our review, menopausal HT use in breast cancer survivors was not associated with increased cancer reoccurrence, cancer-related mortality or total mortality. Despite conflicting opinions on this issue, it is important for primary care physicians to feel comfortable medically managing the increasing number of breast cancer survivors. In the subset of women with severe menopausal symptoms, HT options should be reviewed if non-hormonal methods are ineffective. Future trials should focus on better ways to identify breast cancer survivors who may safely benefit from HT versus those who have a substantial risk of reoccurrence with HT use.     

Breast cancer: hormones and other risk factors

In North America and Northern Europe, breast cancer incidence rates begin increasing in the early reproductive years and continue climbing into the late seventies, whereas rates plateau after menopause in japan and less developed countries. Female gender, age and country of birth are the strongest determinants of disease risk. Family history and mutations in the BRCA1 and BRCA2 genes are important correlates of lifetime risk. Genetic polymorphisms associated with estrogen synthesis and metabolism are currently under study. Atypical hyperplasia and molecular alterations in benign breast lesions appear to be involved in the pathogenesis of invasive carcinoma. In postmenopausal women, increased breast density on mammograms increases risk. Bone density and breast cancer are associated, presumably through the mechanism of endogenous estrogen levels. Serum estrogen levels are higher in breast cancer cases than controls. Many established risk factors for breast cancer may function through and endocrine mechanism. Current use of oral contraceptives and prolonged, current or recent use of hormone replacement therapy moderately increase risk. Tamoxifen and possibly other selective estrogen receptor modulators reduce breast cancer risk in high risk women. Relationships between various dietary micro and macronutrients and breast cancer have been suggested but require evaluation in clinical trials. Whereas alcohol consumption is associated with increased risk, most environmental factors, including polychlorinated compounds and electromagnetic fields, are not. Conclusion: Breast cancer etiology is becoming clearer through the study of molecular alterations in germline and somatic cell genes, and the interaction of these genes with steroid hormones and relevant growth factors. This knowledge should be useful for breast cancer prevention.     

Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research

Estrogen has the potential to influence brain processes implicated in Alzheimer's disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer's disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women's Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. Mechanisms of harm in this setting are unknown. Bias and unrecognized confounding in observational research are leading candidates for discrepant results between observational studies and the Women's Health Initiative Memory Study trial. Studies are also distinguished by differences in outcome measures, hormone therapy formulations, prevalence of menopausal symptoms among study participants, and participant age. Finally, Women's Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women's Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer's disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.     

Menopausal hormone therapy and risk of lung cancer—Systematic review and meta-analysis

Objectives

Lung cancer rates increase among women in many regions of the world. To explore whether menopausal hormone therapy (MHT) plays a role.

Methods

We conducted a systematic search of the literature and performed meta-analyses of cohort studies (C), case–control studies (CC), randomized controlled trials (RCTs), and cancer registry studies (CR) to analyse the impact of estrogen therapy (ET), estrogen/progestin therapy (EPT) and any hormone therapy (HT) on lung cancer risks. We explored associations between ever-use of therapies and risks, analysed annual changes of risk, and the impact of therapies on histological subtypes. We calculated summary odds ratios, relative risks, 95% confidence intervals (CI; fixed-effects model), and assessed heterogeneity across studies. Eighteen studies were eligible (9 CC, 4 C, 3 RCT, 2 CR).

Results

We found a significant increase of risk – 76.2% – in non-smoking women with adenocarcinoma (CI 1.072–2.898) reporting ever-use of HT. Estrogen plus progestin therapy does not change the risk; however, the pooled analysis of 2 RCTs points at an increased risk (RR 1.359; CI 1.031–1.791). Our further results should be interpreted with caution as significances were found in analyses only when smoking and non-smoking women, various hormone regimens, or histological subtypes, respectively, were pooled.

Conclusions

Dedicated studies designed to more adequately delineate the role of MHT are necessary to substantiate whether use of MHT is a risk factor for this or other types of lung cancer.     

Comparison of patient recall of hormone therapy with physician records

OBJECTIVE: The objective of this study was to compare patient recall of menopausal hormone therapy, obtained by personal interview, with that recorded in physicians' records. DESIGN: Data were from a case-control study of women aged 55 to 64 years at diagnosis of breast cancer in Los Angeles County, CA, between 1987 and 1989. Medical record information on 1,115 women reporting hormone therapy use (652 case patients and 463 control participants) was sought from 2,734 physicians and obtained from 1,350. Physician records for an additional 126 case patients and 90 control participants not reporting hormone therapy but reporting oral contraceptive use or benign breast disease were also obtained. RESULTS: Agreement between interview and physician records was 85% (kappa=0.59) for ever/never use of estrogen and 84% (kappa=0.59) for progestogen. The correlations for months of use were 0.43 and 0.34, respectively. For both drugs participants tended to report longer use, primarily because they reported earlier starting ages. Older and unmarried women recalled more unconfirmed estrogen use, whereas naturally menopausal women were more likely to report no estrogen use when the medical record was positive. We found no evidence of preferential recall bias by case patients. CONCLUSIONS: Interviews provide a moderately reliable measure for ever use of postmenopausal estrogen and progestogen. Recalled details are less reliable and may be affected by age, type of menopause, and recall interval.     

Physicians' views and practices concerning menopausal hormone therapy

OBJECTIVE: To examine physicians' views and practices concerning estrogen+progestogen therapy (EPT). DESIGN: Questionnaires were mailed to a random sample of physicians in the United States (US) in 2003. A total of 1614 (53.8%) surveys were returned (633 obstetricians and gynecologists (Ob/Gyns), 571 family practitioners, and 410 internists). RESULTS: Only a minority of the physicians (16%) would offer EPT to menopausal women in the absence of menopausal symptoms (26% Ob/Gyn, 11% family practitioners, 6% internists, p<0.0001). However, many physicians (62%) believed that EPT could be offered "short term" to menopausal women with menopausal symptoms assuming no contraindications (82% Ob/Gyn, 54% family practitioners, 42% internists; p<0.0001). Irrespective of specialty, the strongest contraindications to EPT use reported by these physicians were personal history of breast cancer (93%), thrombosis (92%), cerebrovascular disease (84%), ischemic heart disease (74%), uterine cancer (73%), as well as women's subjective "concern" about breast cancer (57%). Procedures reported as always required by physicians for continuing women on EPT were breast examination (97%), mammogram (96%), blood pressure measurement (94%), and pelvic examination (91%). CONCLUSIONS: Internists and family practitioners address more contraindications to EPT use than Ob-Gyns. Although many physicians appear to be accepting of short-term use of EPT for menopausal indications in the absence of contraindications, the majority would not prescribe it for prophylactic purposes.