Postmenopausal Estrogen Replacement Therapy Research Articles

Abstract P3119: Identifying The Windows Of Cardiac Risk And Opportunity In Menopause

Post-acute myocardial infarction (AMI) mortality has significant sex differences with a bias towards higher rates in women. While treatment inequities and access to care profoundly impact outcomes, biological factors also contribute to survival discrepancies. One complicating factor that drives worse outcomes in women is menopause. Understanding the biological basis for AMI mortality risk and the exacerbating role of menopause has been hampered by the lack of an animal model that recapitulates the dynamic changes associated with the perimenopausal transition. We used a mouse model of menopause in which ovarian failure is gradually induced following treatment with 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg, 15d), allowing for examination of cardiac alterations established during perimenopause. Echocardiography revealed no contractile changes during perimenopause, but cardiac myofilament activation was significantly affected. Calcium re-uptake by SERCA was impaired by the end of perimenopause. Changes in calcium handling were associated with alterations in calcium handling protein expression and phosphorylation. Activation of RISK and SAFE signaling molecules that protect against ischemia-reperfusion (IR) injury was altered throughout perimenopause, and the RISK-SAFE response to IR differed at points during perimenopause. The myocardial response to cardioprotective estrogen receptor activation also varied throughout perimenopause. Together these data reveal significant, nonlinear alterations in myocardial physiology and endogenous protective signing pathways during perimenopause. Disruptions in endogenous protection and calcium handling are established prior to menopause, providing possible mechanisms for worse post-menopausal AMI outcomes. The altered response to estrogen receptor activation preceding menopause may explain the inconsistent effectiveness of post-menopausal estrogen replacement therapy.

Estrogen-regulated miRs in bone enhance osteoblast differentiation and matrix mineralization

Estrogen signaling is critical for the development and maintenance of healthy bone, and age-related decline in estrogen levels contributes to the development of post-menopausal osteoporosis. Most bones consist of a dense cortical shell and an internalmesh-like network of trabecular bone that respond differently to internal and external cues such as hormonal signaling. To date, no study has assessed the transcriptomic differences that occur specifically in cortical and trabecular bone compartments in response to hormonal changes. To investigate this, we employed a mouse model of post-menopausal osteoporosis (ovariectomy, OVX) and estrogen replacement therapy (ERT). mRNA and miR sequencing revealed distinct transcriptomic profiles between cortical and trabecular bone in the setting of OVX and ERT. Seven miRs were identified as likely contributors to the observed estrogen-mediated mRNA expression changes. Of these, four miRs were prioritized for further study and decreased predicted target gene expression in bone cells, enhanced the expression of osteoblast differentiation markers, and altered the mineralization capacity of primary osteoblasts. As such, candidate miRs and miR mimics may have therapeutic relevance for bone loss resulting from estrogen depletion without the unwanted side effects of hormone replacement therapy and therefore represent novel therapeutic approaches to combat diseases of bone loss.

LATE and potential estrogen-related risk factors collected 30 years earlier:The 90+ Study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

The risk of Parkinson's disease in women who underwent hysterectomy before the age of menopause.

IntroductionParkinson’s disease (PD) is the second most common neurodegenerative aging disorder. Oestrogen has been shown to have a neuroprotective effect against PD in animal models.This study aimed to detect the risk of PD in women who underwent hysterectomy before the age of menopause.Material and methodsSeventy-six women with PD (study group) were recruited for this retrospective study and compared to 80 controls. Collected data included the education level, smoking, age of menopause, type of menopause (natural or surgical), past surgical history of hysterectomy, type of hysterectomy (hysterectomy only or hysterectomy with oophorectomy [unilateral, bilateral]), and use of postmenopausal oestrogen replacement therapy. The collected data were analysed to detect the risk of PD in women who underwent hysterectomy before the age of menopause.ResultsThe odds ratio (OR) and relative risk (RR) of PD was significantly higher after surgical menopause in the study group (30 [39.5%]) compared to controls (17 [21.25%]), (OR 2.4 [95% CI: 1.19–4.8]; p = 0.01, RR 1.9 [95% CI: 1.12–3.1]; p = 0.016). In addition, the OR and RR of PD was significantly higher after bilateral oophorectomy in the study group (19 [25%]) compared to controls (8 [10%]), (OR 3.0 [95% CI: 1.22–7.4]; p = 0.016, RR 2.5 [95% CI: 1.16–5.4]; p = 0.01).ConclusionsThe risk of PD increased in women who underwent hysterectomy and bilateral oophorectomy before the age of menopause, and the risk of PD did not increase whether the menopause, either natural or surgical, occurred before 48 years of age.

Tamoxifen protective role in ovariectomy related- metabolic disorders in rats

Background: postmenopausal women are more susceptible to insulin resistance. Many studies reported that estrogen (E2) contributes in insulin sensitivity improvement. As a result of postmenopausal estrogen replacement therapy (ERT) hazards, tamoxifen (TAM) as an alternative to estrogen are now applicable. There are no published data distinguishing the effects of TAM on insulin sensitivity in non-diabetic post menopause women. Objectives: Test whether TAM acts as E2 in improving insulin sensitivity in post- menopausal period and to what extent the effect would be similar for both, together with exploring the underlying mechanism. Material & method: Forty female albino rats were divided into 4 groups (10 rats each): sham (SH), ovariectomized (OV), ovariectomized E2 (OVE) treated and ovariectomized TAM (OVT) treated groups. At the end of experiment, blood samples were taken for estimation of fasting blood glucose (FBG), serum concentration of insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid parameters and tumour necrosis factor α (TNFα), then adipose tissues were removed for measurement of MDA and SOD. Also, histopathological and immunohistochemical examination of adipose tissue were done. Results: Ovariectomy worsened glycemic state, insulin resistance and lipid profile. TAM was like E2 induced glucose metabolic improvement, decreased insulin resistance alongside with lipid profile improvement. These metabolic changes might assert to oxidative state and inflammatory response improvement accompanying apparent histopathological and immunohistochemical changes on adipose tissue. Conclusion: TAM can counterbalance the metabolic disorders in postmenopausal period and this may improve metabolic disorders as E2 with avoiding the undesired effects of ERT.

Antiosteoporotic activities of isoquercitrin in ovariectomized rats: Role of inhibiting hypoxia inducible factor-1 alpha

Postmenopausal osteoporosis is a common and disabling disorder that increases the risk of bone fractures due to estrogen deprivation; this can be simulated in rats by ovariectomy. Hypoxia inducible factor-1 alpha (HIF-1α) expression in osteoclasts predominantly leads to its activation increasing bone resorption. Premenopausal, estrogen prevents HIF-1α expression maintaining bone density. Unfortunately postmenopausal estrogen replacement therapy is not recommended due to its potential tumor development risk. Isoquercitrin, a common edible plants phytoestrogen, is known to inhibit HIF-1α. This study was conducted to investigate the potential antiosteoporotic activity of isoquercitrin (15, 30 and 60 mg/kg/day) in ovariectomized rats with reference to 17β-estradiol (25 mcg/kg/day). Animals were bilaterally ovariectomized to induce osteoporosis and one month later they were assigned into groups and administered isoquercitrin and 17β-estradiol for 8 weeks. Ovariectomy reduced lumbar compression strength, distorted bone microscopic architecture, inducing cartilage and trabecular dystrophy, and increased the markers of bone turnover (serum alkaline phosphatase and osteocalcin and urinary calcium, phosphorus and creatinine). It also increased the gene expression of HIF-1α and the levels of nuclear factor-kappa B (NF-κB) and decreased the expression of vascular endothelial growth factor (VEGF) and β-catenin in the femurs. Isoquercitrin was found to improve bone histological features, increase lumbar strength and improve most of the biochemical markers of bone turnover in a manner comparable to 17β-estradiol. Isoquercitrin also attenuated the increased HIF-1α expression while increased that of the VEGF and β-catenin. It also decreased the levels of NF-κB. Therefore isoquercitrin may be considered a safer alternative for managing osteoporosis.

Long-term postmenopausal estrogen therapy may be associated with increased risk of breast cancer: a cohort study.

Reports of a role of postmenopausal estrogen replacement therapy in the development of breast cancer have been inconsistent. Although many epidemiologic studies have failed to show an association between short-term use of estrogen and breast cancer, there are indications that long-term use may present an increased risk. We undertook a long-term, retrospective cohort study of the incidence of breast cancer in women who had taken long-term estrogen (average 17.2 years), compared to women who had not taken estrogen. Subjects were 454 women born between 1900 and 1915, who were members of a large health maintenance organization in northern California. By the end of 1995, 26 (11.2%) of estrogen users developed breast cancer, as did 9 (4.1%) of the nonusers; the relative risk (RR) for estrogen use was 2.8 [95% confidence interval (95% CI) 1.3-5.9]. Adjustment for age and multiple breast cancer risk factors, including breast cancer surveillance, reduced the RR for estrogen to 2.0 (95% CI 0.9-4.5). We conclude that long-term estrogen use is associated with a substantially increased risk of breast cancer.

Factors Associated With an Abnormal Mammogram Finding in Women Undergoing Screening in Kuala Lumpur, Malaysia

Background: Breast cancer is the most common cancer among Malaysian women, with a rising incidence from 16.5% in 2006%–17.7% in 2011. One of the key strategies in breast cancer control is early screening; of which mammography is a highly accurate tool, having been shown to reduce the number of mortality rates due to breast cancer up to 30%. However, mammography is often not as widely available in Malaysia; and in many local settings, healthcare providers have to limit screenings to only particular groups such as those with abnormal clinical breast examinations due to limited resources. Knowledge of other predictive factors may assist in further decision-making to prioritize patients for screening mammography in a low-resource setting. Aim: This study aimed to determine such predictive factors for abnormal mammogram findings among women who underwent mammography examination at a center in Kuala Lumpur, Malaysia. Methods: This was a cross-sectional study of women (n = 5491) who underwent a three-dimensional tomosynthesis mammography procedure at the Cancer and Health Screening Clinic, National Cancer Society of Malaysia (NCSM) in Kuala Lumpur, from Jan 2016 until Dec 2017 (2 years). Patients were surveyed on: i) age, ii) ethnicity, iii) family history of breast or any cancers, if any, iv) reproductive history (age of menarche, age of first delivery, age of menopause); and v) history of postmenopausal estrogen and hormone replacement therapy (HRT). Bivariate analysis was conducted by using χ2 tests in determining associations between variables and a multiple logistic regression model built to identify factors which were predictive of an abnormal mammogram finding (BI-RADS 4 & 5). Results: From the bivariate analysis; nulliparous status ( P = 0.02), a family history of breast cancer ( P = 0.04), and a history of postmenopausal hormone replacement therapy (HRT) ( P = 0.01) were determined to significantly associated with an abnormal mammogram finding. There were also significant ethnic differences between women who had abnormal mammogram findings; with Chinese women having highest odds of this (OR:3.22; 95% CI 1.86-5.74). Women within the age group of 45-54 (OR:1.84, 95% CI 1.19-3.12), a family history of breast cancer (OR 2.03, 95% CI 1.31-3.27) or any cancer (OR 1.56, 95% CI 1.06-2.94), age of menopause (OR 2.86; 95% CI 1.43-4.02) and age of first delivery above 30 (OR 1.73, 95% CI 1.26-3.45) were significantly associated with abnormal mammogram findings. Conclusion: Factors which predict abnormal mammogram findings in a Malaysian setting can be used as baseline evidence to formulate criteria which can be used to carry out targeted screening programs or even as cutoff criteria for focusing screening resources in resource-limited settings. This data may be of benefit in aiding healthcare providers in provisioning of services at a macro level as well as for frontline healthcare personnel in helping them profile women who should be focused on to be screened for the disease.

A heartfelt message, estrogen replacement therapy: use it or lose it.

The issue of cardiovascular and cognitive health in women is complex. During the premenopausal phase of life, women have healthy blood pressure levels that are lower than those of age-matched men, and they have less cardiovascular disease. However, in the postmenopausal stage of life, blood pressure in women increases, and they are increasingly susceptible to cardiovascular disease, cognitive impairments, and dementia, exceeding the incidence in men. The major difference between pre- and postmenopausal women is the loss of estrogen. Thus, it seemed logical that postmenopausal estrogen replacement therapy, with or without progestin, generally referred to as menopausal hormone treatment (MHT), would prevent these adverse sequelae. However, despite initially promising results, a major randomized clinical trial refuted the benefits of MHT, leading to its falling from favor. However, reappraisal of this study in the framework of a "critical window," or "timing hypothesis," has changed our perspective on the benefit-to-risk ratio of MHT, and this review discusses the historical, current, and future approaches to MHT.

난소절제 마우스에서 잔대 추출물의 인지능 개선 효과

Adenophora triphylla var. japonica extract has been reported to have estrogenic activity and beneficial effects in postmenopausal women requiring estrogen replacement therapy. This study investigated the effects of A. triphylla extract on cognitive function in ovariectomized mice. Water extracts fro...

Safety, efficacy and patient acceptability of the contraceptive and non-contraceptive uses of the LNG-IUS.

Intrauterine devices (IUDs) provide highly effective, long-term, safe, reversible contraception, and are the most widely used reversible contraceptive method worldwide. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a T-shaped IUD with a steroid reservoir containing 52 mg of levonorgestrel that is released at an initial rate of 20 μg daily. It is highly effective, with a typical-use first year pregnancy rate of 0.1% - similar to surgical tubal occlusion. It is approved for 5 years of contraceptive use, and there is evidence that it can be effective for up to 7 years of continuous use. After removal, there is rapid return to fertility, with 1-year life-table pregnancy rates of 89 per 100 for women less than 30 years of age. Most users experience a dramatic reduction in menstrual bleeding, and about 15% to 20% of women become amenorrheic 1 year after insertion. The device's strong local effects on the endometrium benefit women with various benign gynecological conditions such as menorrhagia, dysmenorrhea, leiomyomata, adenomyosis, and endometriosis. There is also evidence to support its role in endometrial protection during postmenopausal estrogen replacement therapy, and in the treatment of endometrial hyperplasia.

Hormone replacement therapy and cardiovascular disease: the case for a randomized controlled trial.

The menopause is associated with an increased risk of developing cardiovascular disease. Oestrogen may influence various metabolic pathways which contribute to the pathogenesis of cardiovascular disease, and observational studies suggest that in postmenopausal women oral oestrogen replacement therapy confers some protection against coronary heart disease and to a lesser extent against stroke. What is not clear is the magnitude of the cardioprotective effect and the overall balance of long-term benefits and hazards. Research is also required to establish the relative effects of oestrogen replacement therapy and combined or opposed hormone replacement therapy (HRT) where progestogen is added to counter the proliferative action of oestrogen on the endometrium. A large randomized controlled trial is the only way to provide accurate estimates of the cardioprotective effect of HRT and of other long-term benefits and hazards. Feasibility studies undertaken through the UK Medical Research Council (MRC) General Practice Research Framework show that such a trial is acceptable to patients and their doctors. Recruitment and withdrawal rates indicate that a trial of sufficient size to show a 25% reduction in cardiovascular disease with 90% power at the 1% level would be feasible. The full trial is costly and it is proposed that the UK collaborates with other countries in a major international trial to complement the Women's Health Initiative trial in the USA. Feasibility studies in Europe are underway, the design and scientific rationale for the trial have been approved by the UK MRC and it is hoped that recruitment to the full-scale trial can begin soon.

Hormone Replacement Therapy and Atherosclerosis in Postmenopausal Women

Despite the clear-cut epidemiological evidence of protective effects of endogenous estrogens in premenopausal women,1,2 the results of randomized clinical trials using conjugated equine estrogens and medroxyprogesterone acetate instead of natural hormones have led to a paradigm shift in the usefulness of hormone treatment in postmenopausal women.3,4 One of the main criticisms in addition to the types of drugs chosen for treatment was the age of the patients. Indeed, in both WHI trial and HERS study, treatment of patients was initiated in women many years beyond menopause.5 In fact, the number of years since menopause was an independent indicator for nonfatal myocardial infarction or coronary related death.5 In this context, it appears of interest that heart disease may contribute to menopausal age and that menopausal age actually may be an indicator of cardiovascular risk.6,7 See page 1782 It was noted as early as 1952 that the natural endogenous estrogen 17β-estradiol inhibits experimental atherosclerosis,8 and oral estrogens were even unsuccessfully evaluated to treat coronary artery disease in male patients.9–11 However, at the time little was known about the mechanisms by which sex steroid hormones affect vascular homeostasis and thrombogenesis. During the past 2 decades, considerable advances were made in the understanding of how natural estrogens act on the vasculature. 17β-estradiol causes rapid and endothelium-independent dilation of coronary arteries of men and women,12 and chronic treatment with 17β-estradiol inhibits experimental atherosclerosis in males and females.13,14 On the other hand, treatment with conjugated equine estrogens, which contain more than 30 different steroid compounds including testosterone and substances of still undefined vascular activity (Table), have shown less favorable effects,2–4 as has been reported for the synthetic progestin medroxyprogesterone acetate.15 With the identification of molecular targets of 17β-estradiol and other estrogens it now appears that …

Long-term use of progestogens: Colon adenoma and colon carcinoma

Colon cancer is the second most common cancer in women in the Western world and there is a trend towards an increasing risk. Colon adenoma is a potential precursor for colon cancer. Adenoma and carcinoma of the colon seem to be influenced by estrogens and progesterone/progestins. This is related to the presence of estrogen and progesterone receptors, with apparently higher concentrations in colon cancers than in adenomas. Epidemiological data and the finding of a significant reduction in colon cancer risk related to hormone replacement therapy (HRT), and in particular the length of HRT intake, indicate that progesterone/progestins have a preventive effect. This has not been shown with postmenopausal estrogen replacement therapy (ERT) alone. Furthermore, the recurrence rate of adenoma appears to be reduced, and the survival of colon cancer patients improved, with HRT; such effects have not been documented with ERT.

Implications for Estrogens in Parkinson's Disease

Evidence from experimental and epidemiological studies suggests a role of sex hormones in the pathogenic process leading to neurodegenerative diseases, (i.e., Alzheimer's and Parkinson's disease). The effects of sexual steroid hormones are complex and vary with the events of women's fertile life. Estrogens are supposed to influence dopamine synthesis, metabolism, and transport; however, there is no consensus regarding the direction, locus, and mechanism of the effect of estrogens on the dopaminergic system. A neuroprotective effect of estrogens has been demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal models of Parkinson's disease (PD). Epidemiological studies indicate gender differences regarding the onset and the prognosis of PD. Most of the analytical studies explored the relationship between PD and exogenous estrogens. Only three studies investigated the role of endogenous estrogens in the risk of developing PD. These studies reported an increased risk of PD in conditions causing an early reduction in endogenous estrogens (early menopause, reduced fertile life length). Longer cumulative length of pregnancies has also been associated with an increased PD risk. A lack of consensus still exists on the effect of the type of menopause (surgical vs. natural) on PD risk. Finally, the effect of postmenopausal estrogen replacement therapy is still debated. Inconsistencies across studies are in part explained by the complexity of the mechanisms of action of sexual hormones and by the paucity of analytical studies.

Case-Control Study of Postmenopausal Hormone Replacement Therapy and Endometrial Cancer

This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50-79 years in the Philadelphia, Pennsylvania, region during 1999-2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.

Enhanced Growth of Hepatic Hemangiomatosis in Two Adults after Postmenopausal Estrogen Replacement Therapy

Liver hemangiomatosis is defined as extensive hemangioma in the liver. Although hemangioma is the most common hepatic tumor, diffuse hepatic hemangiomatosis is very rare. Most cases of hepatic hemangiomatosis are seen in infancy, but it is extremely rare in adults. This is the first report, showing the enhanced growth of diffuse hepatic hemangiomatosis after hormone replacement therapy. We report herein two unrelated women, 47 and 42 year-old, from different regions of Turkey, who admitted to hospital because of right abdominal pain with diffuse hepatic hemangiomatosis, developed after hormone replacement therapy for menopause. The patients were healthy, except for hemangiomatosis, and their physical examination, routine laboratory tests, and tumor marker levels were within normal limits. It should be noted that their abdominal ultrasonography was normal before hormone therapy, but ultrasonography on admission revealed numerous, ill defined, diffusely located liver nodules in both patients. Dynamic magnetic resonance imaging and scintigraphy have revealed that these lesions are compatible with hemangiomatosis. These results suggest that hepatic hemangiomatosis was induced by estrogen therapy. Consequently, hormone replacement therapy was discontinued, and the patients were followed up for 3 years. Their physical examination and blood chemistry, including liver enzymes, remained within normal range, and the follow-up examination with ultrasonography showed no changes in size of lesions. Because of the possible association of hemangioma with estrogen administration, decisions should be made carefully about estrogen therapy for patients who already have hemangioma, and the periodic ultrasonograpy examination should be planned to detect possible new growth of liver hemangiomatosis.

The Importance of Phytoestrogens in Food Supplements and Phytopharmaceuticals

Different natural products from the plant kingdom including isoflavones, prenylflavones, coumestans, stilbenes, and lignans can cause endocrine perturbations, especially on the estrogenic hormonal pathway because of their structural analogies to estradiol. Several studies report the presence of such compounds in food, the richest source being soy and soy products. These substances, commonly called phytoestrogens, are known to influence the human hormonal profile and soy preparations are being considered for use as post-menopausal estrogen replacement therapy. Numerous clinical and epidemiological reports have studied the influence of phytoestrogens on the development of hormone-dependent cancers. The effect on genital development of postnatal phytoestrogen exposure is still under debate. Consumption of phytoestrogens may also influence the incidence of bone diseases, atherosclerosis, or Alzheimer's disease. This article summarizes the classification of phytoestrogens, their pharmacological evaluation and properties, and the methods used for their identification.

Oestrogen plus progestin hormone replacement therapy increases venous thrombosis in postmenopausal women

QuestionDoes oestrogen plus progestin hormone replacement therapy increase the risk of venous thrombosis in postmenopausal women?Study designDouble-blind, randomised controlled trial.Main resultsIn postmenopausal women, oestrogen plus progestin hormone replacement therapy increased the risk of venous thrombosis, deep vein thrombosis and pulmonary embolism compared with placebo (see results table). Older, obese or overweight women taking hormone replacement therapy had an increased risk of venous thrombosis (see results table). The homozygous variant of Factor V Leiden was associated with an increased risk of venous thrombosis (OR 7.5, 95% CI 0.6 to 87.8).Authors’ conclusionsOestrogen plus progestin hormone replacement therapy significantly increased the risk of venous thrombosis in postmenopausal women. Increasing age, excess weight and obesity, and the Factor V Leiden genetic variant significantly increased the risk of venous thrombosis associated with this hormone replacement therapy.

Postmenopausal hormone therapy and breast cancer: What is the problem?

Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one! The problems are as follows: • There are many observational studies, but these are not consistent in their results. • Relative risk increases, if any, are small and thus often statistically non-significant. • Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized clinical trials (RCTs). • There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population. • In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints, and therefore lacking any indication for postmenopausal hormone therapy (HT). • The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone, a valuable alternative to classical HT in Europe. • And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does the Women's Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis? In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial data to our daily practical work. So, we have a problem and not a firm basis for undisputable statements.