Estrogen-only Hormone Replacement Therapy Research Articles

#370 : Hormone Replacement Therapy and Risk of Cardiovascular Diseases in Postmenopausal Women Aged 50-59 Years: A Systematic Review of Randomized Controlled Trials

Background and Aims: Cardiovascular diseases are the leading cause of mortality worldwide. Due to declining estrogen levels, women are at higher risk of contracting cardiovascular diseases. Although hormone replacement therapy (HRT) has the potential to prevent cardiovascular diseases, its safety and efficacy are still controversial. The window of opportunity theory suggests that initiating HRT during the early stages of menopause could have the most significant benefits. This review aims to assess available evidence on the effects of HRT in preventing cardiovascular disease in early postmenopausal women aged 50-59 years old. Method: Systematic literature searching was conducted on four databases: Pubmed, EMBASE, EBSCOhost, and ProQuest. Using previously designed keywords, we searched for randomized controlled trials assessing the association between HRT and various cardiovascular outcomes. Critical appraisal was conducted using the Cochrane Risk of Bias 2.0. Results: Six post-interventional analyses from 2 randomized controlled trials with a total of 9,838 subjects were included. The review only assessed the data from subjects aged 50-59 years old without any known comorbidities. Despite varying statistical significance among studies, we observed a relatively consistent trend that estrogen-only HRT lowers the risk of cardiovascular events, thus supporting the window of opportunity theory. However, there was also an increase in the risk of cardiovascular events in estrogen-progesterone combination compared to placebo or estrogen-only HRT. Conclusion: By taking into account aspects of patient characteristics, age during first administration, regimens, and therapy duration, hormone replacement therapy has the potential to prevent cardiovascular diseases in early postmenopausal women aged 50-59 years old.

THU477 Drivers Of Estrogen Induced Invasive Lobular Carcinoma

Abstract Disclosure: C. Ufondu: None. L. Clem: None. M. Musick: None. M.J. Sikora: None. J.H. Ostrander: None. Invasive lobular carcinoma (ILC) is an estrogen-receptor (ER)-positive histologic subtype of breast cancer typically treated with anti-estrogens (i.e., tamoxifen and aromatase inhibitors). Anti-estrogen resistance and disease progression occur in about 34% of patients with ILC, but mechanisms of resistance have been underexplored. Additionally, estrogen-only hormone replacement therapy increases the risk of ILC, but not the more common invasive ductal carcinoma (IDC), highlighting a potentially unique role for estrogen in ILC initiation and progression. To identify mediators of estrogen-induced ILC progression we are using the the mouse mammary intraductal (MIND) model, which better recapitulates the progression of ILC and response to estrogen in vivo. MM134, MM330, and SUM44PE ILC cell lines were injected intraductally into the #4 mammary glands of NSG mice. Mice were monitored for up to 20 weeks with or without estrogen supplemented in the drinking water. Our results show that MIND supports an in situ-like to invasive disease progression for ILC cell lines, and that estrogen accelerated tumor growth and invasion in vivo. Current studies are aimed at identifying mediators that drive estrogen-induced tumor growth and invasion in vivo, focusing on E-cadherin (CDH1) loss as the genetic hallmark of ILC occurring in ∼95% of cases. We aim to identify how loss of E-cadherin in normal human mammary epithelial cells (HMECs) may lead to reprogramming of ER and promote the development of ILC. We are developing a CRISPR/Cas9 approach for knocking out CDH1 in HMECs. We will study estrogen response in the CDH1-knockout versus control HMECs in vitro to examine whether loss contributes to ILC-specific estrogen activity. Using the MIND model, we will engraft the control and knockout cells into the ducts of adult female NSG mice and monitor tumor growth through bioluminescence imaging. ER reprogramming will be assessed in the engrafted cells using RNAseq and CUT&RUN (Cleavage Under Target & Release Using Nuclease). We predict that E-cadherin loss will reprogram ER DNA binding, dysregulate transcription factors linked to E-cadherin, such as TCF/LEF, and confirm critical downstream regulators that mediate estrogen-driven tumorigenesis. Understanding the unique contributions of ER in ILC could lead to new therapeutic strategies for the prevention and treatment of ILC. Presentation: Thursday, June 15, 2023

The Correlation Between Progesterone and Mammographic Density in Postmenopausal Women: A Systematic Review of the Literature and Meta-Analysis.

Higher mammographic breast density in premenopausal and postmenopausal women is related to a higher breast cancer risk. In this review, we analyze the correlation between estrogen, progesterone, and mammographic density in postmenopausal women and clarify whether these findings are consistent across different types of mammographic breast density. We extracted data concerning mammographic density increases in the populations treated with estrogen-only hormone replacement therapy and those treated with estrogen and progestin hormone replacement therapy. Postmenopausal women treated with estrogen and progesterone regimens had a statistically significant lesser mammographic density increase than estrogen-only hormone replacement therapy regimens.

What is the association between estrogen and breast cancer?

Aim: There is a historical acceptance about the causal relationship between Estrogens and Breast cancer which has either affected the incidence rate or mortality rate of breast cancer, or could have influenced the uptake or continuation of Estrogen in Hormone Replacement Therapy (HRT). Estrogens are useful either as Estrogen-only HRT (ERT) or as combined Estrogen and Progestogen HRT. There is now a need to clearly differentiate between ERT and HRT in their consequences with regard to breast cancer. This review documents the basis of the historical causal connection and the current situation Methodology: The literature was searched with the following key words: Estrogen, Breast cancer, Estrogen receptors and Menopause;. Incidence and mortality rates of breast cancer associated with Estrogen. Randomized controlled Trials, Observational studies. Cell proliferation, cell differentiation and cell development. Results: The relationship between Estrogen & Breast Cancer with regard to incidence and mortality requires a rigorous scrutiny because: There are prenatal influences which have an impact on exposure to Xenoestrogens across the life course, starting with conception – if not before, giving possible effects on germ cells and gametes. The evidence from observational studies should be interpreted with caution because of procedural inadequacies. The evidence that should be used for care of women is that from Randomised controlled trials because they are geared to infer on cause and effect relationships. The relationship between Estrogen alone for peri-menopause and menopause shows that it does not increase the risk of breast cancer or the mortality from breast cancer. Conclusion: Estrogen alone does not increase the risk and the mortality of breast cancer. The combination of ERT with a progestogen can increase the risk of breast cancer.

Could Perimenopausal Estrogen Prevent Breast Cancer? Exploring the Differential Effects of Estrogen-Only Versus Combined Hormone Replacement Therapy.

Breast cancer is the commonest cancer among women in the western world, accounting for up to 30% of all cancers in women. There is a long-standing controversy about the potential link to hormone replacement therapy (HRT), with large observational studies suggesting that HRT increases the risk, while the Women’s Health Initiative (WHI), a prospective, randomized placebo-controlled trial, has reported several times over a period of 20 years that combined (estrogen and progestogen) HRT increases the risk, while estrogen-only HRT given to women who have had a prior hysterectomy, is associated with a significantly reduced risk of developing breast cancer. Evidence from the randomized trial shows a significant reduction in both incidence of and mortality from breast cancer in women who took estrogen replacement therapy; this message needs to be presented clearly and robustly so that it can help women with decision making when considering HRT for menopause.

DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

Hormone Replacement Therapy and Risk of Severe Asthma Exacerbation in Perimenopausal and Postmenopausal Women: 17-Year National Cohort Study

The impact of hormone replacement therapy (HRT) on clinical outcomes in menopausal women is uncertain. To investigate the association between use of HRT and severe asthma exacerbation in perimenopausal and postmenopausal women with asthma. We used the Optimum Patient Care Research Database, a population-based longitudinal primary care database in the United Kingdom, to construct a 17-year (January 1, 2000, to December 31, 2016) cohort of perimenopausal and postmenopausal (46-70 years, N= 31,656) women. We defined use of HRT, its subtypes, and duration of HRT use. Severe asthma exacerbation was defined as an asthma-related hospitalization, emergency department visits due to asthma, and/or prescription of oral corticosteroids. Analyses were undertaken using multilevel mixed-effects Poisson regression. At baseline, 22% of women were using any HRT, 11% combined HRT, and 11% estrogen-only HRT. Previous, but not current, use of any (incidence rate ratio [IRR]: 1.24, 95% confidence interval [CI]: 1.22-1.26), combined (IRR: 1.28, 95% CI: 1.25-1.31), and estrogen-only HRT (IRR: 1.18, 95% CI: 1.14-1.21), and longer duration (1-2 years: IRR: 1.16, 95% CI: 1.13-1.19; 3-4 years: IRR: 1.43, 95% CI: 1.38-1.48; 5+ years: IRR: 1.32, 95% CI: 1.28-1.36) of HRT use were associated with increased risk of severe asthma exacerbation compared with nonuse. The risk estimates were greater among lean women (body mass index [BMI] <25 kg/m2) than among heavier women (BMI 25-29.9 kg/m2 and ≥30 kg/m2) and higher among smokers than nonsmokers. Use of HRT and subtypes, particularly previous, but not current, use and use for more than 2 years, is associated with an increased risk of severe asthma exacerbation in perimenopausal/postmenopausal women with established asthma. Lean women and smokers are at greater risk than heavier women and nonsmokers, respectively.

Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database.

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35–55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.

MP43-11 PROTECTIVE EFFECT OF POSTMENOPAUSAL HORMONE REPLACEMENT AGAINST UROLITHIASIS

INTRODUCTION AND OBJECTIVE: Menopause is reported to be associated with increased urinary calcium excretion, which may enhance the risk for the development of urolithiasis. However, it remains controversial about whether postmenopausal hormone replacement is a risk factor for formation of urolithiasis. Therefore, we conducted a population-based retrospective cohort study to evaluate the effect of hormone replacement therapy (HRT) on the formation of urolithiasis. METHODS: We used data sourced from Longitudinal Health Insurance Database, which consists of one million randomly selected subjects from the National Health Insurance Research Database of Taiwan. Health Insurance System of Taiwan covers approximately 23 million people (98% of population). Women who were prescribed HRT continually for longer than 3 months during 1997 to 2009 were classified as HRT users; the others were classified as non-users. A total of 13724 HRT users aged ≥ 45 years in 1997 without previous diagnosis of urolithiasis were enrolled. A cohort of 13724 age and metabolic syndrome matched non-HRT users were enrolled as the control group. HRT users were followed from the date of commencing HRT until six months after discontinuation of HRT. Non-users were followed from 1 January 1997 to 31 December 2009. Stratified cox regression model was used to examine the risk of subsequent urolithiasis between HRT users and non-users. RESULTS: Of the sampled patients, HRT users had a significantly lower cumulative incidence of urolithiasis than non-users (4.66% vs 5.94%, p < 0.001). The log-rank test revealed that HRT users had significantly higher urolithiasis-free survival rates than non-users (p < 0.001). HRT users were found to be at 0.78 times the risk of urolithiasis than non-users (95% confidence interval 0.70–0.87, p < 0.001). We further divided the HRT users into two groups according to HRT regimens: estrogen-only vs estrogen combined with progestin. The hazard ratio for urolithiasis in the estrogen-only HRT users compared with non-users was 0.78 (95% confidence interval 0.61–0.99, p = 0.04) and 0.78 (95% confidence interval 0.70–0.88, p < 0.001) in the patients with combined regimen. CONCLUSIONS: HRT use was associated with a lower risk of urolithiasis independent of the regimen difference. Source of Funding: None

Abstract 866: The proportion of breast and gynecological cancers in Australian women that can be attributed to the use of oral contraceptives and hormone replacement therapy

Abstract Introduction: In 2008 The International Agency for Research on Cancer concluded that combined oral contraceptives (OCs) are a cause of cancer of the breast and cervix but decrease the risk of ovarian and endometrial cancer. They also concluded that estrogen-only hormone replacement therapy (HRT) increases the risk of both endometrial and ovarian cancer, while use of estrogen plus progestogen (combined) HRT increases the risks of breast cancer. The level of risk associated with each cancer type varies by duration and recency of use of hormones. Our aim was to calculate the proportion of breast and gynecological cancers arising in Australian women (population attributable fractions - PAF) that could be attributed to these commonly used hormonal medications. Methods: We calculated PAFs using the standard formula, which requires an estimate of the relative risk for each exposure-cancer association and the prevalence of the causal factor in the population. Relative risks were obtained from published pooled or meta-analyses of the associations and prevalence estimates were derived from Australian National Health Survey estimates or other large national studies. For factors inversely associated with cancer we calculated the “prevented fraction” and estimated the number of cancers that were prevented due to exposure to the factor. Results: The estimated PAFs suggested that fewer than 5% of breast and gynecological cancers in Australia in 2010 could be attributed to oral contraceptive use and estimates were similar for HRT use. However, the calculated preventive fractions for oral contraceptives suggested that the numbers of endometrial and ovarian cancers may have been 46% and 24% higher respectively if no Australian women had used OCs. Given combined HRT increases breast cancer risk and breast cancer is much more common than endometrial or ovarian cancer we also assessed the likely effect if all women taking combined HRT instead took estrogen-only HRT. Under this scenario, we estimate the absolute numbers of ovarian and endometrial cancers would increase slightly but the number of breast cancers attributable to HRT use would decrease substantially. Conclusions: Our analyses suggest that the use of combined OCs confers more benefit than harm with respect to cancer incidence, with a small increase in breast/cervical cancer diagnoses weighed against a much larger decrease in numbers of endometrial and ovarian cancers. In contrast, our results indicate that there would be fewer cancers overall if women did not use HRT. When HRT is required, most guidelines recommend that women with a uterus take combined HRT to prevent endometrial cancer. However, our findings suggest that, in terms of total cancer burden, it might be safer for women to avoid progestogens and use estrogen-only HRT for symptom relief. Future studies should examine this possibility. Citation Format: Susan J. Jordan, Louise Wilson, David Whiteman, Penelope Webb, PAF Project Group. The proportion of breast and gynecological cancers in Australian women that can be attributed to the use of oral contraceptives and hormone replacement therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 866. doi:10.1158/1538-7445.AM2015-866

Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study.

BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study.

Association of progesterone receptor gene (PGR) variants and breast cancer risk in African American women

Prolonged exposure to combined hormone replacement therapy (estrogen plus progestin) increases a woman's risk of breast cancer, whereas estrogen-only hormone replacement therapy does not. This suggests that progesterone may play a role in breast carcinogenesis. Association studies have reported inconsistent relationships between progesterone receptor gene variants and breast cancer. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated 8 PGR candidate SNPs and 18 PGR tagging SNPS in 487 breast cancer cases and 843 controls using multivariable logistic regression with adjustment for combined hormone replacement therapy use. Separate analyses were conducted for European Americans (EA: 399 cases, 490 controls) and African Americans (AA: 88 cases, 353 controls). In EAs, no significant associations were observed with the investigated PGR variants. In AAs, two tagging SNPs (rs590688 and rs10895054) were statistically significantly associated with breast cancer. For rs590688, each addition of the C allele was protective compared to the G allele (OR=0.56, 95% CI 0.39-0.82, p value 0.003, corrected p value 0.03). For rs10895054, each addition of the T allele increased the risk of breast cancer compared to the A allele nearly threefold (OR=2.9, 95% CI 1.47-6.02, p value 0.002, corrected p value 0.04). Three haplotype blocks, all containing rs590688, were found to be significantly associated with breast cancer risk. Environmental exposures, namely parity and obesity modified the effect of both SNPs on breast cancer risk in EA. This is the first study to find an association between two PGR variants and breast cancer in AA women. These results suggest that studies of PGR variants in other non-White populations may reveal additional cancer associations of interest.

An Estrogen Model: The Relationship between Body Mass Index, Menopausal Status, Estrogen Replacement Therapy, and Breast Cancer Risk

We present a mathematical model that lends support to the hypothesis that estrogen levels mediate the complex relationship between body mass index (BMI), menopausal status, estrogen-only hormone replacement therapy (HRT), and breast cancer risk. The model predicts a decrease in the relative risk of breast cancer of 3% per unit increase in BMI (kg/m2) for premenopausal women and an increase in the relative risk of 4% per unit increase in BMI for postmenopausal women who are not HRT users. When comparing postmenopausal women who use estrogen-only HRT to postmenopausal women who do not use HRT, the model predicts an increased risk of breast cancer associated with use of estrogen that diminishes with increasing BMI, with a relative risk of 1.6 for women with BMI of 18, 1.2 for women with BMI of 25, and 1.0 for women with BMI ≥ 30. Model predictions agree with data from five major epidemiological studies.

Risk factors for HR- and HER2-defined breast cancer in Slovenian postmenopausal women

Objective The study aimed to investigate the influence of some generally recognized risk factors for hormone receptor (HR)- and human epidermal growth factor receptor 2 (HER2)-defined breast cancer among Slovenian postmenopausal women.Method Eligible women diagnosed with breast cancer were compared with 709 controls of the same age and ethnicity. Immunohistochemistry and FISH analyses were used to classify cases into molecular subtypes: 454 HR+, 106 HR−, 81 HER2+ and 603 HER2−. Adjusted odds ratios and 95% confidence intervals were estimated using multivariate logistic regression analysis.Results Overweight and obese women were at increased risk of HR+, HER2− and of HR+, HR−, HER2− tumors, respectively. Women who started menstruating at the age of 11 years or earlier were at decreased risk of ER−PR− tumors. Users of hormone replacement therapy (HRT) were negatively associated with HR+ and HER2− tumors. The inverse effect was most pronounced with the use of estrogen-only HRT, and longer duration of HRT use did not result in a significant change in risk. In contrast, combined HRT decreased the risk of HER2+ tumors. Having a first-degree relative with breast and/or ovarian cancer increased the risk of HR+ and HER2− tumors.Conclusion We conclude that certain breast cancer risk factors may vary by molecular subtypes. According to our results, HRT use may have a greater influence on HR + and HER2− breast cancers and the risk of HER2-defined breast cancer may differ with respect to the regimen of HRT.

Compliance with estrogen hormone replacement therapy after oophorectomy: a prospective study

To quantify compliance with using estrogen-only hormone replacement therapy (HRT) up until the time of mean age of natural menopause in women undergoing either bilateral oophorectomy or removal of one remaining ovary at the time of hysterectomy for benign disease. Prospective study. Annual questionnaire follow-up for ten years of women undergoing hysterectomy and bilateral oophorectomy for benign disease aged 46 or less at the time of surgery. Gloucestershire Royal Hospital. Five hundred and twenty-one women recruited over a four-year period from 1994 to 1997. Compliance with HRT use, changes in HRT preparations and reasons for discontinuation. The median age of women at the time of hysterectomy was 42 (range 22-46) years; 4.9% (n = 24) stopped HRT within the first two years and 16.5% (n = 86) by the end of the study. The majority of women were prescribed HRT tablets (253, 48%) and the next most common being patches. In total, there were 1271 episodes of changing HRT, with the range between 0 and 18 changes per woman over the ten-year period. In all, 32% of changes were to a different route of HRT, 19% were to a different preparation of the same route, 18% were to an increased dose of the same preparation and 7% were to a decreased dose of the same preparation. Compliance with HRT use was high throughout the study, although responses decreased after five years. Change to HRT preparations was consistently high across all preparations. Women requiring HRT after surgical menopause need to be supported in finding the right preparation for them.

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 replacement therapy and risk for venous thromboembolism: what??s new and how do these findings influence clinical practice?

Although an association between hormone replacement therapy and venous thromboembolism has been established, several unanswered questions remain. This review will address additional questions relating to hormone replacement therapy and venous thromboembolism. Does the risk for venous thromboembolism differ according to the type of hormone replacement therapy? Does the presence of thrombophilia influence the risk for venous thromboembolism in hormone replacement therapy users? Should hormone replacement therapy be temporarily interrupted around the time of surgery? The risk for venous thromboembolism seems to be less in users of estrogen-only hormone replacement therapy (odds ratio = 1.2; 95% confidence interval: 0.6-2.6) than in users of estrogen-progestin hormone replacement therapy (odds ratio = 2.7; 95% confidence interval: 1.4-5.1), and there may be no increased risk for venous thromboembolism with transdermal hormone replacement therapy (odds ratio = 1.0; 95% confidence interval: 0.3-3.3). The presence of a prothrombotic blood abnormality, such as the factor V Leiden mutation, seems to further increase the risk for venous thromboembolism in hormone replacement therapy users (odds ratio = 17.1; 95% confidence interval: 3.7-78). Continued use of hormone replacement therapy in the perioperative period does not seem to have an impact on the overall risk for postoperative venous thromboembolism (odds ratio = 0.66; 95% confidence interval: 0.35-1.18). Recent studies have extended our understanding regarding the association between hormone replacement therapy and venous thromboembolism. The implications of these findings on clinical practice are discussed.

Hormone Replacement Therapy and Breast Cancer Risk in California

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT. This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.

Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case–control study

Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

No Association between the Progesterone Receptor Gene +331G/A Polymorphism and Breast Cancer

No Association between the Progesterone Receptor Gene <i>+331G/A</i> Polymorphism and Breast Cancer