Menopausal hormone therapy and the risk of cataracts in postmenopausal women in South Korea.

PURPOSE: Postmenopausal women have a higher prevalence of cataracts than men of a similar age. This study aimed to evaluate the effects of menopausal hormone therapy (MHT) on lens opacities in postmenopausal women. METHODS: This retrospective cohort study analysed population-based health insurance data in South Korea collected from 2002 to 2019. To determine the risk factors associated with cataract, postmenopausal women (N = 2,506,271) were grouped according to post-MHT use. The treatment group was further divided into the following subgroups: tibolone, combined oestrogen plus progestin by manufacturer, oral oestrogen, combined oestrogen plus progestin by physician and topical oestrogen groups. The main outcome measure was the prevalence of cataracts. RESULTS: The control group comprised 463,151 postmenopausal women who had never used MHT after menopause, while the treatment group included 228,033 postmenopausal women who had used MHT continuously for at least 6 months. The treatment group had a higher incidence of cataracts than the control group based on Cox proportional hazards ratio analysis. Low socioeconomic status and high parity were identified as risk factors for cataracts, and reduced risk of cataracts was associated with living in rural areas and drinking alcohol. CONCLUSIONS: Women undergoing post-MHT, including tibolone, had a higher incidence of cataracts. Cataract development should be a concern when examining postmenopausal patients using MHT.

BRCA mutation carriers' perceptions on postmenopausal hormone therapy: An Italian study.

OBJECTIVE: To evaluate the actual perceptions of postmenopausal hormone therapy (HT) in BRCA mutation carriers (BRCAmc) in comparison with women from the general population. METHODS: Questionnaire-based study of 83 BRCAmc and a control group of 89 women without a genetic mutation. Perceptions were evaluated by specific questions and Likert scales (-5-+5). RESULTS: Present and past users of HT were more frequent in the control group (p = 0.01), with a longer time of use (p = 0.03). The preferred route of administration of HT was 'oral' (54.6%). The most frequently reported adverse effect of HT was venous thrombosis (0.8), while a protective effect on bone health was reported. No noticeable beneficial effects of HT have been recognised for hot flushes (0.2) and vaginal dryness (0.1). The most frequently perceived beneficial and adverse effects of HT were not significantly different between BRCA mutation carriers and controls. The greatest oncological fear was breast cancer (1.0). The protective role of HT on colorectal cancer was not known (0.1). These oncological impacts were mostly overestimated in BRCAmc, however this was not significant. Few BRCAmc would think of taking HT after risk-reducing surgeries. CONCLUSIONS: Knowledge of the effects of HT on BRCAmc is relatively poor and they are likely to overstate its negative effects and underestimate its health benefits; however, this is not significant in comparison to the general population. More and better information should be given to BRCAmc to allow them to make informed decisions about the use of HT, especially before undergoing risk-reducing surgeries.

Menopausal Hormone Therapy and Risks of First Hospitalized Heart Failure and its Subtypes During the Intervention and Extended Postintervention Follow-up of the Women's Health Initiative Randomized Trials.

BACKGROUND: We assessed whether postmenopausal hormone therapy (HT) was associated with incident heart failure (HF) and its subtypes and examined whether there was a modifying effect of age on the associations. METHODS AND RESULTS: Postmenopausal women aged 50-79 enrolled in the Women's Health Initiative HT trials were analyzed. The 16,486 women with a uterus were randomized to receive conjugated equine estrogens (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo, and 10,739 women with prior hysterectomy were randomized to receive CEE (0.625 mg/day) alone or placebo. Incident HF was defined as the first HF hospitalization. HF with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) was defined as EF < 50% or ≥ 50%. During the intervention phase, median follow-up was 5.6 years in the CEE-plus-MPA trial and 7.2 years in the CEE-alone trial. During the cumulative follow-up of 18.9 years, women randomized to HT vs placebo in the 2 combined trials had incidence rates of 3.90 vs 3.89 per 1000 person-years for total HF; 1.25 vs 1.40 per 1000 person-years for HFrEF, and 1.88 vs 1.79 per 1000 person-years for HFpEF, respectively. There were no significant effects of HT on the risk of total incident HF or its subtypes in either trial, and age at randomization did not significantly modify the results. CONCLUSIONS: Postmenopausal HT did not alter the risk of hospitalization for HF or its subtypes during the intervention or cumulative 18.9 years of follow-up, and results did not vary significantly by age at randomization. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT0000611 https://clinicaltrials.gov/ct2/show/NCT00000611?cond=women%27s±health±initiative&rank=5.

The gendered impact of coronavirus disease (COVID-19): do estrogens play a role?

Objective: Although sex-disaggregated data for COVID-19 show equal numbers of cases between men and women, there seem to be sex differences in mortality rate and vulnerability to the disease: more men than women are dying. Methods: We have explored the potential role of estrogens in this COVID-19 gendered impact. Results: Estrogens stimulate the humoral response to viral infections, while testosterone and progesterone give an immune suppression of both innate and cell-mediated immune responses. We hypothesise that estrogens, in particular estradiol but also synthetic estrogen such as ethinylestradiol, could protect women from the most serious complications of COVID-19. The use of medications that keep hormonal levels high and stable, such as combined hormonal contraceptive, could therefore play a protective role. These potential benefits overtake the thrombotic risk in healthy women. As stated by the World Health Organization, all modern methods of contraception were safe to use during the COVID-19 pandemic.

Female sex hormones and risk of incident abdominal aortic aneurysm in Norwegian women in the HUNT study.

OBJECTIVE: The delayed development of abdominal aortic aneurysm (AAA) in women compared with men might be secondary to a protective effect from endogenous estrogens. The role of postmenopausal hormone therapy remains unclear. The aim of the present study was to evaluate the effect of female sex hormones compared with other risk factors associated with AAA through a long-term study of a large female cohort. METHODS: The present prospective cohort study included 20,024 postmenopausal women from the Norwegian Nord-Trøndelag Health Study. A total of 201 cases of AAA were identified during a median follow-up period of 18 years (295,554 person-years; 1995-2014). The data were recorded from questionnaires, physical measurements, medical records, blood sample test results, and the Norwegian Cause of Death Registry. The effect of risk factors was evaluated in a multiple Cox regression analysis. Multiple imputation was performed for missing data (n = 50 data sets). The serum estradiol concentrations in women with and without incidental AAAs were compared. The median interval from blood sample collection to the AAA diagnosis was 7 years. RESULTS: Current smokers had >10-fold increased risk of incident AAA during the follow-up period (hazard ratio [HR], 10.9; 95% confidence interval [CI], 7.4-16.1). Positive associations were found for hypertension (HR, 2.0; 95% CI, 1.4-3.0) and coronary heart disease (HR, 2.2; 95% CI, 1.6-3.2). The HR associated with the current use of postmenopausal hormone therapy was 0.58 (95% CI, 0.6-1.5). No substantial difference in estradiol concentrations was found between women with and without AAA (P = .075). CONCLUSIONS: The effect of female sex hormones on the risk of incident AAAs in women, as evaluated by the serum concentrations of estradiol and the use of postmenopausal hormone therapy, is clinically less important than the strong associations found with smoking, hypertension, and coronary heart disease.

Associations of coffee consumption and caffeine intake with mammographic breast density.

PURPOSE: Previous studies suggest that coffee and caffeine intake may be associated with reduced breast cancer risk. We investigated the association of coffee and caffeine intake with mammographic breast density by woman's menopausal status and, in postmenopausal women, by hormone therapy (HT). METHODS: This study included 4130 cancer-free women within the Nurses' Health Study and Nurses' Health Study II cohorts. Percent breast density (PD) was measured from digitized film mammograms using a computer-assisted thresholding technique and square root-transformed for the analysis. Average cumulative coffee/caffeine consumption was calculated using data from all food frequency questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations of regular, decaffeinated, and total coffee, and energy-adjusted caffeine intake with percent density. RESULTS: In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: ß = 0.23, p trend = 0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated 2+ cups/day: ß = - 0.24, p trend = 0.04; total 4+ cups/day: ß = - 0.16, p trend = 0.02). Interaction of decaffeinated coffee with menopausal status was significant (p-interaction < 0.001). Among current HT users, regular coffee and caffeine were inversely associated with PD (regular coffee 4+ cups/day: ß = - 0.29, p trend = 0.01; caffeine 4th vs. 1st quartile: ß = - 0.32, p trend = 0.01). Among past users, decaffeinated coffee was inversely associated with PD (2+ cups/day ß = - 0.70, p trend = 0.02). CONCLUSIONS: Associations of decaffeinated coffee with percent density differ by woman's menopausal status. Associations of regular coffee and caffeine with percent density may differ by HT status.

Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis.

Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE risk, there is also increasing evidence that progestogens may modulate the estrogen-related VTE risk. This review updates previous meta-analyses of VTE risk in HT users, focusing on the route of estrogen administration, hormonal regimen and progestogen type. Among women using estrogen-only preparations, oral but not transdermal preparations increased VTE risk (relative risk (RR) 1.48, 95% confidence interval (CI) 1.39-1.58; RR 0.97, 95% CI 0.87-1.09, respectively). In women using opposed estrogen, results were highly heterogeneous due to important differences between the molecules of progestogen. In transdermal estrogen users, there was no change in VTE risk in women using micronized progesterone (RR 0.93, 95% CI 0.65-1.33), whereas norpregnane derivatives were associated with increased VTE risk (RR 2.42, 95% CI 1.84-3.18). Among women using opposed oral estrogen, there was higher VTE risk in women using medroxyprogesterone acetate (RR 2.77, 95% CI 2.33-3.30) than in those using other progestins. These clinical findings, together with consistent biological data, emphasize the safety advantage of transdermal estrogen combined with progesterone and support the current evidence-based recommendations on HT, especially in women at high VTE risk.

Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes.

PURPOSE: We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. METHODS: This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. RESULTS: Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant. CONCLUSION: Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

Hormone therapy and large bowel cancer revisited.

Many studies have investigated potential links between postmenopausal hormone therapy (HT) and the risk for colorectal cancer. Most of these studies showed some reduction in risk, but association with the exact grade of the tumor or with cancer mortality is less consistent. Activation of estrogen receptor beta (ERß) related cellular pathways is probably the pathophysiological basis for this HT effect, since ERßs exert antiproliferative and pro-apoptotic signaling, inhibit inflammatory signaling and modulate the tumor microenvironment. To note, the impact on health may not be substantial as the absolute numbers point at the order of only a few saved cases per 10 000 women per year of hormone use.

Alzheimer's disease, menopause and the impact of the estrogenic environment.

Decades ago, postmenopausal hormone replacement was considered the panacea for midlife women. Prevention of the age-related cognitive decline was among the top alleged benefits of this therapy. However, the data from the Women's Health Initiative Memory Study (WHI-WHIMS) study showed the opposite, indicating worsening of several cognitive domains in hormone users. Since WHIMS recruited women who were 65 years or older, it became crucial to investigate the effects of hormone therapy in the early menopause as well. Recent studies, such as WHIMS-Young, the Kronos Early Estrogen Prevention Study and the Early versus Late Intervention Trial with Estradiol targeted the younger women, and indeed showed that hormone therapy may have positive cognitive outcomes in this age group. Whether or not hormone therapy has an effect on already demented women remains to be further explored, as data are scarce.

A practitioner's toolkit for managing the menopause.

OBJECTIVE: A number of learned societies, including the International Menopause Society, have produced position statements pertaining to the use of postmenopausal hormone therapy. These documents are highly informative but are not designed for use by primary-care physicians and nurse practitioners during routine consultations. Our aim was to produce a toolkit for practitioners that could be used during office consultations to assist them in the assessment and management of the menopause. METHODS: We used clinical experience in primary care, combined with published diagnostic algorithms, positions statements from learned medical societies and relevant peer-reviewed literature to develop assessment and management algorithms relevant to the primary care of women age 40 years and older. RESULTS: The resultant 'Practitioner's Toolkit for Managing the Menopause' comprises algorithms for the reasons why a woman might present, determination of menopausal status, key information that should be ascertained, issues that may influence treatment decision-making, hormonal and non-hormonal treatment options, symptom management and patient review, and a brief supporting document. CONCLUSIONS: We believe these algorithms and supporting document provide an accessible desktop tool for health-care practitioners caring for women at midlife. The toolkit has been endorsed by the International Menopause Society for global use.

Hormones and venous thromboembolism among postmenopausal women.

Abstract Venous thromboembolism (VTE) is a common and potentially fatal disease in postmenopausal women. VTE has emerged as the most prevalent adverse effect of oral estrogens in 50-60-year-old women. Obesity and VTE history can be easily used to identify women at high risk but genetic screening is not cost-effective. Based on consistent biological and epidemiological findings, transdermal estrogen is the safest option with respect to VTE, especially in women at high risk. There is strong evidence that VTE risk is greater in women using medroxyprogesterone acetate compared with those receiving other progestins. Based on observational data, progesterone appears safe with respect to VTE. More research and action are needed to avert the hepatic first-pass effect of oral estrogens and to increase awareness of hormone-related VTE. Improving individual risk stratification and a personalized approach to hormone therapy are major challenges for future work.

Treatment of menopausal skin - A narrative review of existing treatments, controversies, and future perspectives.

Menopause is a state of estrogen deficiency that affects numerous estrogen-dependent tissues in the female body. Skin is one of the most affected organs. Many consider menopausal skin changes to be merely an aesthetic problem; however, they can significantly affect women's quality of life. Currently, there are no approved effective treatments to prevent or alleviate skin changes associated with estrogen deficiency. Standard systemic hormone replacement therapy used to treat menopausal symptoms may be effective to some degree for skin treatment. In addition, compounded bioidentical hormone replacement therapy, selective estrogen receptor modulators, and phytoestrogens could also be used for skin treatment, although this is only hypothetical due to lack of data. Many questions therefore remain unanswered. On the other hand, topical, low-dose estrogen that would act only on the skin without systemic effects could be a possible option, as could be skin-only acting topical phytoestrogens. Such topical products without systemic effects could play a role in the treatment of menopausal skin. However, they are not currently approved because there is insufficient data on their safety and efficacy. A healthy lifestyle could have a positive effect on the menopausal skin. In this review, we provide an overview of the characteristics of menopausal skin, an outlook on the future treatment of menopausal skin with estrogens and other approaches, and the associated controversies and speculations. Overall, the importance of menopausal skin changes should not be neglected, and high-quality research is needed to gain new insights into the treatment of menopausal skin.

Coffee consumption was associated with a lower prevalence of airflow limitation in postmenopausal women.

BACKGROUND: Several studies have suggested a potential correlation between menopause and airflow limitation. However, the presence of protective factors in postmenopausal women remains uncertain. Therefore, our study seeks to examine potential protective factors associated with a reduced prevalence of airflow limitation among postmenopausal women. METHODS: Postmenopausal women were recruited from the Taiwan Biobank for this cross-sectional study. Airflow limitation was defined by a forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio <0.7. The participants were categorized into two groups: non-coffee drinkers and coffee drinkers, and the association between coffee consumption and airflow limitation was examined using binary logistic regression models. RESULTS: A total of 8149 women with available information were enrolled. Compared to the non-coffee drinkers, the coffee drinkers had a significantly lower prevalence of airflow limitation (7% vs. 5%). The odds ratio (OR) for airflow limitation was lower in the coffee drinkers than in the non-coffee drinkers (OR = 0.77; 95% confidence interval [CI] = 0.63 to 0.94) after adjusting for confounding factors. We also examined the association between daily coffee consumption in cups and airflow limitation. The women who consumed ≥2 cups of coffee per day had an OR of 0.74 (95% CI = 0.59 to 0.94) compared to those who did not consume coffee. CONCLUSIONS: Our results suggest that habitual coffee consumption is associated with a reduction in the prevalence of airflow limitation in postmenopausal women, warranting further prospective studies to explore possible causal effects and mechanisms.

Association between Menopause, Postmenopausal Hormone Therapy and Metabolic Syndrome.

(1) Background: We aimed to explore the associations between menopause, postmenopausal hormone therapy, and metabolic syndrome in a large community-based group of Asian women. (2) Methods: This is a cross-sectional study in which we enrolled women aged 30 to 70 years with sufficient information about menopausal status from the Taiwan Biobank. The definition for metabolic syndrome used in this study aligns with the Bureau of Health Promotion's (Taiwan) proposed definition. (3) Results: A total of 17,460 women were recruited. The postmenopausal group had a higher metabolic syndrome prevalence (30% vs. 14%) and 1.17 times higher odds ratio (OR) than the premenopausal group (95% confidence interval [CI] = 1.02 to 1.33). Regarding the types of menopause, surgical menopause was associated with metabolic syndrome (OR = 1.40; 95% CI = 1.20 to 1.63); however, natural menopause was not associated with metabolic syndrome. Interestingly, postmenopausal hormone therapy was associated with a lower risk of metabolic syndrome in the women with natural menopause (OR = 0.79; 95% CI = 0.70 to 0.89), but not in those with surgical menopause. (4) Conclusions: Our results suggest that menopause is associated with an increased prevalence of metabolic syndrome, while postmenopausal hormone therapy is associated with a lower prevalence of metabolic syndrome in women with natural menopause.

Systemic hormone therapy and dementia: A nested case-control and co-twin control study.

OBJECTIVE: The effect of systemic hormone therapy (HT) on dementia risk is unclear. Our aim was to investigate the association between HT and dementia. STUDY DESIGN: This register-based study consists of a nested case-control study and a co-twin control design, which controls for familial confounding, including shared genetics. MAIN OUTCOME MEASURES: Through Danish national registries from 1995 to 2011, we identified: a) 2700 female singletons with incident dementia and 13,492 matched controls; b) 288 female twins with incident dementia and co-twins without dementia. Data on HT and education were retrieved, and analyses were performed using conditional logistic regression and McNemar's χ2-test. HT use decreased dramatically after the Women's Health Initiative study results were published in 2002, and the analyses were stratified accordingly to account for potentially different HT user characteristics. RESULTS: The odds ratio (OR) for the association between systemic HT and dementia was 1.05, 95% CI = [0.93-1.19] in singletons and 2.10, 95% CI = [0.99-4.46] in twins. A statistically significant association was found for systemic HT before 2003 in both populations, with an OR of 1.14, 95% CI = [1.01-1.28] in singletons and an OR of 2.20, 95% CI = [1.04-4.65] in twins. CONCLUSION: Using Danish nationwide registries and controlling for education and for familial factors in a subsample, systemic HT was found to be associated with increased dementia risk if used before 2003, when HT was more commonly prescribed.

Attitudes of women towards products containing hormones (hormonal contraceptives or hormone therapy): what changes from pre to postmenopause?

INTRODUCTION: To evaluate the actual perceptions of hormonal contraceptives (HC) in women of reproductive age in comparison with similar concerns of postmenopausal women in relation to hormone therapy (HT). MATERIALS AND METHODS: A questionnaire-based study was conducted in a population of 370 women, 198 (53.5%) premenopausal and 172 (46.5%) postmenopausal. Perceptions were evaluated using specific questions and Likert scales (-5 to +5).Multivariate regression analyses were adjusted for categories of HC/HT use (never, past and current). RESULTS: The most reported adverse effect associated with hormonal treatments was venous thrombosis (1.4 ± 0.1), especially for HC use in premenopausal women (p < .0001). According to responses, hormonal treatments can increase the risk of developing venous thrombosis (OR 0.79; 95% CI 0.67-0.96, p = .004) and depression (OR 0.80; 95% CI 0.69-0.92, p = .002) more in pre-menopause, while they can increase the risk of weight gain more in post-menopause (OR 1.24: 95% CI 1.07-1.42, p = .003).The greatest oncological concern throughout life was about breast cancer (0.9 ± 0.1). There was the perception that hormonal treatments can increase the risk of developing ovarian cancer more in post-menopause (OR 1.44; 95% CI 1.19-1.75, p = .0002), while they can increase the risk of uterine cervix cancer more in pre-menopause (OR 0.74; 95% CI 0.52-0.97, p = .03). CONCLUSIONS: Our data suggest that our patients are primarily concerned about the effects of hormonal treatments on venous thrombosis, mood, breast cancer and cervical cancer risk, and, later in life, about their impact on weight gain, breast and ovarian cancer risk.KEY MESSAGESYoung patients are primarily concerned about the effects of hormonal treatments on venous thrombosis, mood, breast cancer and cervical cancer risk.Older patients are primarily concerned about the effects of hormonal treatments on weight gain, breast and ovarian cancer risk.The greatest oncological concern throughout life was about breast cancer.

Postmenopausal hormone therapy in BRCA gene mutation carriers: to whom and which?

INTRODUCTION: Risk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause. AREAS COVERED: To evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC. EXPERT OPINION: All BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to 'progestin-free' HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these 'progestin-free' preparations and BC safety.

The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease.

The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause.