Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses.

OBJECTIVES: The study aims to assess the use of menopausal hormone therapy beyond age 65 years and its health implications by types of estrogen/progestogen, routes of administration, and dose strengths. METHODS: Using prescription drug and encounter records of 10 million senior Medicare women from 2007-2020 and Cox regression analyses adjusted for time-varying characteristics of the women, we examined the effects of different preparations of menopausal hormone therapy on all-cause mortality, five cancers, six cardiovascular diseases, and dementia. RESULTS: Compared with never use or discontinuation of menopausal hormone therapy after age 65 years, the use of estrogen monotherapy beyond age 65 years was associated with significant risk reductions in mortality (19% or adjusted hazards ratio, 0.81; 95% CI, 0.79-0.82), breast cancer (16%), lung cancer (13%), colorectal cancer (12%), congestive heart failure (CHF) (5%), venous thromboembolism (3%), atrial fibrillation (4%), acute myocardial infarction (11%), and dementia (2%). For the use of estrogen and progestogen combo-therapy, both E+ progestin and E+ progesterone were associated with increased risk of breast cancer by 10%-19%, but such risk can be mitigated using low dose of transdermal or vaginal E+ progestin. Moreover, E+ progestin exhibited significant risk reductions in endometrial cancer (45% or adjusted hazards ratio, 0.55; 95% CI, 0.50-0.60), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%), whereas E+ progesterone exhibited risk reduction only in CHF (4%). CONCLUSIONS: Among senior Medicare women, the implications of menopausal hormone therapy use beyond age 65 years vary by types, routes, and strengths. In general, risk reductions appear to be greater with low rather than medium or high doses, vaginal or transdermal rather than oral preparations, and with E2 rather than conjugated estrogen.

Nonhormone therapies for vasomotor symptom management.

Vasomotor symptoms (VMS) are associated with adverse health consequences and can cause significant morbidity for postmenopausal women. Although hormone therapy remains the gold standard of VMS treatment in menopausal women, some women have contraindications to or may choose not to take hormone therapy. This article provides an up-to-date overview of the current evidence-based nonhormone therapies available for managing VMS. Evidence supporting various treatment options is reviewed, including lifestyle interventions, mind-body therapies, procedures, pharmacologic agents, and emerging therapies, such as neurokinin-receptor antagonists. The efficacy, safety, and clinical use of these treatments are detailed, offering insights for clinicians to make informed decisions in menopausal VMS management.

Risks and benefits of hormone therapy after menopause for cognitive decline and dementia: A conceptual review.

OBJECTIVE: The effects on the brain of hormone therapy after the onset of menopause remain uncertain. The effects may be beneficial, neutral, or harmful. We provide a conceptual review of the evidence. METHODS: We 1) provide a brief history of the evidence, 2) discuss some of the interpretations of the evidence, 3) discuss the importance of age at menopause, type of menopause, and presence of vasomotor symptoms, and 4) provide some clinical recommendations. RESULTS: The evidence and the beliefs about hormone therapy and dementia have changed over the last 30 years or more. Five recent observation studies suggested that hormone therapy is associated with an increased risk of dementia, and the association appears not to change with the timing of initiation of therapy. These harmful associations may be explained by a causal effect of hormone therapy on the brain or by several confounding mechanisms. We suggest that the use of hormone therapy should be customized for different subgroups of women. It may be important to subgroup women based on age at onset of menopause, type of menopause, and presence or absence of vasomotor symptoms. In addition, the effects may vary by type, dose, route, and duration of administration of estrogens and by the concurrent use of progestogens. DISCUSSION: The relation of hormone therapy with the risk of dementia is complex. Hormone therapy may have beneficial, neutral, or harmful effects on the brain. Hormone therapy should be guided by the clinical characteristics of the women being treated.

Prediagnostic use of menopausal hormone therapy and long-term survival of localized epithelial ovarian cancer: The Extreme study.

Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.

Changes in menopausal symptoms comparing oral estradiol versus transdermal estradiol.

OBJECTIVE: This study aimed to compare the efficacy and safety of oral and transdermal estradiol in alleviating menopausal symptoms. METHOD: A total of 257 recently menopausal women were randomized into two groups. The t-E2 group received transdermal estradiol (2.5 g per day) (n = 128) and the o-E2V group received oral estradiol valerate (2 mg per day) (n = 129) for 24 weeks; both groups received micronized progesterone (200 mg per day). The primary outcome measure is the change in the modified Kupperman Menopausal Index (KMI) after 24 weeks of treatment. Menopausal symptoms were recorded at screening and at 4, 12 and 24 weeks using both the KMI and the Menopause Rating Scale (MRS). RESULTS: Significant amelioration was observed by KMI and MRS scores for both groups after treatment (p < 0.001). The mean KMI scores showed no difference between the two groups. The mean MRS scores were similar between the two groups at baseline and after 4 weeks of treatment. The results showed statistical differences after 12 weeks and 24 weeks of treatment (p = 0.005 and p = 0.011). Both the after-treatment scores minus the baseline scores of KMI and MRS and the incidence of adverse effects showed no difference between the two groups. CONCLUSIONS: This study shows that both transdermal and oral estradiol are effective in relieving menopausal symptoms, with little difference in treatment efficacy and safety. CLINICAL TRIAL NUMBER: ChiCTR2300073146.

Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer.

Importance: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer. Objective: To determine whether the risk of breast cancer-specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT). Design, Setting, and Participants: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer-specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023. Exposure: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort. Main Outcomes and Measures: The primary outcome was time to breast cancer-specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer-specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade. Results: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer-specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer-specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94). Conclusions and Relevance: Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

Use of MHT in women with cardiovascular disease: a systematic review and meta-analysis.

This systematic review assesses the effect of menopausal hormone therapy (MHT) on cardiovascular outcomes and risk factors in postmenopausal women with cardiovascular disease (CVD). The Medline, Embase and Cochrane databases were searched from inception to December 2022 for randomized controlled trials (RCTs) and observational studies using methodology from a previous Cochrane review. Quality assessment used the Cochrane risk of bias tool and Newcastle-Ottawa scale, respectively. From 5647 studies identified, 29 (23 RCTs and six observational studies) were included. Most studies were conducted in North America or Europe and investigated oral estrogens. Participants were older with varying frequency of cardiac risk factors and underlying CVD. No significant difference was observed between MHT users and controls regarding primary outcomes of non-fatal myocardial infarction, cardiovascular death or stroke. No difference in frequency of angina, heart failure and transient ischemic attacks was observed. Inconsistent effects of MHT on angiographic progression were seen and varied with glycemic status. Estradiol had a positive effect on flow-mediated dilatation. Limited studies identified differing effects of MHT on cardiac risk factors, varying with estrogen preparation. This study confirms no benefit of MHT for secondary CVD prevention, highlighting evidence limitations and the importance of shared decision-making when managing menopausal symptoms in women with CVD.

'Tis but a scratch: a critical review of the Women's Health Initiative evidence associating menopausal hormone therapy with the risk of breast cancer.

ABSTRACT: Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased breast cancer risk and did not improve quality of life. More recently, Women's Health Initiative (WHI) publications acknowledge HT as the most effective treatment for managing menopausal vasomotor symptoms and report that CEE alone reduces the risk of breast cancer by 23% while reducing breast cancer death by 40%. Their sole remaining concern is a small increase in breast cancer incidence with CEE and medroxyprogesterone acetate (1 per 1,000 women per year) but with no increased risk of breast cancer mortality. This article closely examines evidence that calls even this claim of breast cancer risk into serious question, including the WHI's reporting of nonsignificant results as if they were meaningful, a misinterpretation of its own data, and the misleading assertion that the WHI's findings have reduced the incidence of breast cancer in the United States. A generation of women has been deprived of HT largely as a result of this widely publicized misinterpretation of the data. This article attempts to rectify this misunderstanding, with the goal of helping patients and physicians make informed joint decisions about the use of HT.

Oestradiol implants for gender-affirming hormone therapy: an observational study of serum oestradiol levels and consumer survey.

BACKGROUND: Custom-compounded subcutaneous implants are being used widely in Australia for gender-affirming hormone therapy. However, there is no published literature regarding their use for this purpose. METHODS: Electronic medical records were audited for consecutive clients who received oestradiol implants April 2019-November 2022 in gender clinics held within Hunter New England Health District in New South Wales, Australia. Serum oestradiol levels were analysed for implant doses 50-200mg, and predicted oestradiol level was modelled following 100mg implant insertion. An electronic consumer survey was sent to a convenience sample of implant recipients. RESULTS: A total of 38 clients received 88 implants, with 100mg oestradiol implants being the most frequently used (68%). The median interval between insertion procedures was 270 (IQR 186-399) days. The median serum oestradiol levels following implant insertion, for all implants combined, were within the target range of 250-600pmol/L at 1-, 3-, 6-, 9- and 12-month time points. Following insertion of a 100mg implant, the estimated time to reach a predicted serum oestradiol of ≤250pmol/L was 4months after an initial implant, and 13months after subsequent implants. Seventeen consumer surveys were received from 28 invitations. All respondents had previous experience of oral and/or transdermal oestradiol use. Oestradiol implants were preferred due to ease of use, perceived effectiveness, and the belief that other methods were less safe or associated with intolerance and side effects. CONCLUSIONS: Oestradiol implants are effective in achieving target serum oestradiol levels over a sustained period. Further research with larger cohorts could identify the optimal dosage regimen.

Pharmacological interactions and menopausal hormone therapy: a review.

IMPORTANCE AND OBJECTIVE: Menopausal hormone therapy (HT) is widely used, and there are several statements of international scientific societies to guide prescribers; however, a summary of existing literature about possible drug interactions with HT does not exist, although many midlife women take medications for other conditions. Therefore, our objective was to create a document that presents and synthesizes the most relevant interactions. The impact of the interaction itself and the number of candidates for HT who are likely to use other treatments are considered based on the best available evidence. METHODS: A systematic review was performed to determine the best evidence of interaction effects on relevant outcomes of interest for decision making. A working framework was developed to formulate explicit and reasoned recommendations according to four predefined categories for coadministration: (1) can be used without expected risks, (2) acceptable use (no evidence of negative interaction), (3) alternative treatment should be considered, and (4) nonuse without express justification. The project protocol was registered in the Open Science Framework platform (doi: 10.17605/OSF.IO/J6WBC ) and in PROSPERO (registration number CRD42020166658). RESULTS: Studies targeting our objective are scarce, but 23 pharmacological groups were assigned to one of the predefined categories of recommendation for concomitant use of HT. Vaginal HT was assigned to category 1 for 21 of the analyzed pharmacological groups. For oral and transdermal HT (estrogen-only or combined) and tibolone, there were 12 pharmacological groups assigned to category 1, 12 to category 2, 5 to category 3, and 4 to category 4. Results are shown in crossed-tables that are useful for counseling and prescription. DISCUSSION AND CONCLUSIONS: Available evidence of HT interactions with other drugs is scarce and mainly indirect. It comes from biological plausibility, knowledge of extensive concomitant use without reported incidents, and/or extrapolation from hormonal contraception, but there are pharmacological groups in all categories showing that information is useful. These eligibility criteria summarize it and can help in the decision process of HT coadministration with other drugs. Decisions should be taken based on these recommendations but also individualized risk/benefit evaluation, according to underlying pathology, patient's clinical requirements, and the existence or nonexistence of alternatives.

Hormone replacement therapy did not increase risk of melanoma in Chinese female with menopausal and postmenopausal disorders: A population-based retrospective cohort study in Taiwan.

Hormone replacement therapy (HRT) is widely used to relieve symptoms of menopause with proven efficacy. However, there has been significant controversy surrounding the use of HRT because of its potential link with an increased risk of cancer, particularly female reproductive organ cancers. That HRT increases the risk of melanoma is also disputed, and several cohort studies have produced variable results. To delineate the association between HRT and melanoma in Taiwan, we conducted a population-based retrospective cohort study on 14 291 patients who had received HRT and 57 164 population controls in Taiwan between 2000 and 2013. Multivariate odds ratios (ORs) were calculated utilizing conditional logistic regression. Overall, the use of HRT was not significantly correlated with a higher risk of developing melanoma in Taiwan (95% confidence interval 0.386-1.099; p = 0.341). The hazard ratio analysis of melanoma and different HRTs showed there was no significant association between melanoma and the use of oral or external estrogens alone, including conjugated estrogens, estradiol, and estriol. Estrogen plus progesterone combined therapy was associated with a lower risk of melanoma. Only one case of melanoma was observed among the 2880 patients in this subgroup.

The 2023 nonhormone therapy position statement of The North American Menopause Society.

OBJECTIVE: To update the evidence-based Nonhormonal Management of Menopause-Associated Vasomotor Symptoms: 2015 Position Statement of The North American Menopause Society. METHODS: An advisory panel of clinicians and research experts in women's health were selected to review and evaluate the literature published since the Nonhormonal Management of Menopause-Associated Vasomotor Symptoms: 2015 Position Statement of The North American Menopause Society. Topics were divided into five sections for ease of review: lifestyle; mind-body techniques; prescription therapies; dietary supplements; and acupuncture, other treatments, and technologies. The panel assessed the most current and available literature to determine whether to recommend or not recommend use based on these levels of evidence: Level I, good and consistent scientific evidence; Level II, limited or inconsistent scientific evidence, and Level III, consensus and expert opinion. RESULTS: Evidence-based review of the literature resulted in several nonhormone options for the treatment of vasomotor symptoms. Recommended: Cognitive-behavioral therapy, clinical hypnosis, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors, gabapentin, fezolinetant (Level I); oxybutynin (Levels I-II); weight loss, stellate ganglion block (Levels II-III). Not recommended: Paced respiration (Level I); supplements/herbal remedies (Levels I-II); cooling techniques, avoiding triggers, exercise, yoga, mindfulness-based intervention, relaxation, suvorexant, soy foods and soy extracts, soy metabolite equol, cannabinoids, acupuncture, calibration of neural oscillations (Level II); chiropractic interventions, clonidine; (Levels I-III); dietary modification and pregabalin (Level III). CONCLUSION: Hormone therapy remains the most effective treatment for vasomotor symptoms and should be considered in menopausal women within 10 years of their final menstrual periods. For women who are not good candidates for hormone therapy because of contraindications (eg, estrogen-dependent cancers or cardiovascular disease) or personal preference, it is important for healthcare professionals to be well informed about nonhormone treatment options for reducing vasomotor symptoms that are supported by the evidence.

Hormone replacement therapy and cancer risks in perimenopausal women: A retrospective cohort study using a Japanese claims database.

AIM: Hormone replacement therapy (HRT) relieves menopausal syndromes but concerns regarding certain cancer risks remain. This study aimed to investigate cancer risks in perimenopausal women using HRT. METHODS: Using a health care database in Japan, we compared breast cancer and other cancer risks in perimenopausal women who started HRT between January 2011 and October 2021 at age 45-54 years with that of women who did not use HRT. Women in the control group were selected by 1:4 exact matching on birth year, and followed from the same index time as their counterparts. RESULTS: Data from 12 207 women in the exposure group and 48 828 age-matched women in the control group were analyzed. The median HRT duration was 16.1 (interquartile range, 9.9-28.0) months. Breast cancer risk was lower in the HRT group (adjusted hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.54-0.82). When stratified by age, breast cancer risk was lower in the HRT group who started HRT at age 45-49 years (adjusted HR, 0.54; 95% CI, 0.40-0.72). Estrogen-major HRT accounted for approximately one-third of HRT and uterine corpus cancer risk was increased in estrogen-major HRT (adjusted HR, 2.44; 95% CI, 1.56-3.81). CONCLUSIONS: Breast cancer risk in women starting HRT between 45 and 49 years is lower than that in the average population; this finding might be susceptible to unmeasured factors such as early menopause among HRT recipients. Unopposed estrogen therapy accounts for considerable proportion of HRT in Japan and it increases uterine corpus cancer.

Assessment of knowledge, understanding and awareness of Chinese women clinical staff towards menopause hormone therapy: a survey study.

Menopausal Hormone Therapy (MHT) is recommended for climacteric peri- and postmenopausal symptoms. The rate of use of MHT in China is much lower than the western regions. Therefore, a survey was conducted for the understanding and utilization of MHT among clinical staff in various hospitals of China. A total of 3216 eligible questionnaires were included for the evaluation. According to 19.2% participant opinion, MHT could relieve menopausal symptoms, whereas the majority had no knowledge of the benefits and risks of MHT. The most common concern about MHT was the risk of cancer and about 430 (13.4%) and 176 (5.5%) participants were apprehensive that MHT could increase the risk of breast and endometrial cancer, respectively. This survey demonstrated that the knowledge of clinical staff was not comprehensive and they should be educated more about the use of MHT so that this knowledge can be imbibed into the general population.Impact StatementWhat is already known on this subject? Menopausal Hormone Therapy (MHT) is recommended for climacteric peri- and postmenopausal symptoms. The rate of use of MHT in China is much lower than the western regions.What do the results of this study add? Only 19.2% of the respondents were of the opinion that MHT could relieve menopausal symptoms. The most common concern about MHT was the risk of cancer and about 430 (13.4%) and 176 (5.5%) participants were apprehensive that MHT could increase the risk of breast and endometrial cancer.What are the implications of these findings for clinical practice and/or further research? The survey demonstrated that Chinese medical professionals had some understanding about MHT, but their knowledge was not comprehensive. Thus, it is necessary to educate these medical professionals which in turn will help them to imbibe this knowledge among the general population.