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.

Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition.

Introduction: Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial. Methods: We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants. Results: Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT. Discussion: These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

Hormone replacement therapy and breast cancer incidence in Korean women.

OBJECTIVES: After the 2002 Women's Health Initiative (WHI) study, the global use of menopausal hormone therapy (MHT) declined, and despite subsequent studies indicating a low risk of breast cancer, concerns about MHT usage persist. We examined the relationship between changes in MHT use and changes in the incidence of breast cancer from 2002 to 2020 in South Korea. STUDY DESIGN: This study used tumor registry information from 2002 to 2020 from the Korean Statistical Information Service and analyzed the incidence rate of invasive breast cancer in women, who were divided into two age groups: <50 and >50 years. The numbers of MHT prescriptions in Korea between 2002 and 2020 was determined from pharmacy data. RESULTS: The incidence of breast cancer per 100,000 women in South Korea increased from 34.3 in 2002 to 96.4 in 2020. Breast cancer incidence rates increased annually in both groups of women (those aged under and over 50 years), with no significant difference between the two (p = 0.614). Prescriptions for estrogen therapy (ET) in 2020 were 52.7 % lower than those in 2002. Prescriptions for estrogen-progesterone therapy (EPT) decreased by 27.9 % over the same period. Conversely, tibolone prescriptions, which had initially decreased by 25.4 % in 2004, subsequently showed a steady increase and were 93.6 % higher in 2020 than in 2002. CONCLUSION: The incidence of breast cancer increased annually in Korean women of all ages; however, the use of ET and EPT for MHT has declined since 2002, particularly the use of EPT after 2010. MHT, especially EPT, did not significantly increase the incidence of breast cancer in Korean women.

Obesity and menopause.

Obesity is not a choice or a result of lack of willpower, but a multifactorial, chronic, progressive, and relapsing disease. During menopause, hormonal and body composition changes lead to greater visceral adiposity, that aggravates women's health at a cardiometabolic, mechanic and mental level. Adiposity has been identified as an important modifier of reproductive hormones. During female midlife, obesity has been associated with menstrual cycle alterations (anovulatory cycles ending with abnormal bleedings), menopausal symptoms including hot flashes, poor quality of sleep, aches and joint pain, genitourinary symptoms, and reduced quality of life. However, the relationships between weight, the menopausal process, aging, and hormone levels remain poorly understood. Women with obesity have an increased risk of thromboembolic disease when using menopause hormone therapy (MHT), and it is probably the main medical condition to prescribe or not MHT. However, this risk depends on the route and type of MHT. The use of estrogen-only or combined transdermal MHT does not increase the risk of a thrombotic event in women with obesity.

Establishing a Rationale for Compounding Hormone Replacement Therapy.

Why compound bioidentical hormones? Are there no similar commercial products? What is unique about the options compounding pharmacists offer compared with what is out in the marketplace? These are questions that physicians and other practitioners are asking, and it is very important that we have intelligent, well-thought answers when we respond. Times have changed, and the challenges we face today in marketing our compounded therapies are not the same as those of twenty years ago. Premarin is no longer at the top of the heap, and there are topical, commercial products that contain bioidentical estradiol, and capsules that contain the same progesterone that we use. Our compounding advantage comes from our abilities to prepare unique patient-specific products, and, very importantly, from our growing understanding of hormone receptors; we now know there are two main estrogen receptors, 1) estrogen receptor alpha and 2) estrogen receptor beta, and the growing knowledge base associated with the discovery of estrogen receptor beta is quite significant.

The Physiologic Role and Use of Estriol.

Obtaining estrogen balance with a physiologic estriol and estradiol ratio is an important aspect of physiologic bioidentical hormone restoration therapy. Risks, including that of breast cancer, should be minimized while attempting to obtain the protective benefits and symptom management with therapy. Estriol plays a central role in protecting against breast cancer and should be considered an integral part of therapy for any patient with lower than normal physiologic levels.

Correlating estrogen replacement therapy and temporomandibular disorders: a comprehensive review following PRISMA principles and cochrane handbook for systematic reviews of interventions.

BACKGROUND: Estrogen replacement therapy (ERT) is a common hormonal treatment for postmenopausal women, aimed at alleviating menopausal symptoms and reducing the health risks associated with estrogen deficiency. However, the impact of ERT on temporomandibular disorders (TMDs) remains unclear. This systematic review aims to evaluate the relationship between ERT and TMDs, including TMD occurence, pain, and associated symptoms. METHODS: A comprehensive search of seven electronic databases was conducted using predefined search terms and Boolean operators. Inclusion criteria encompassed studies examining the association between ERT and TMDs. Two independent reviewers screened the identified articles, extracted data, and assessed the risk of bias using the RoB -2 tool. RESULTS: Search strategy identified a total of 3 articles which met the inclusion criteria. The included studies investigated the impact of ERT on TMD occurrence and its related symptoms. The analysis revealed no significant association between ERT and TMD occurrence. A significant dose relationship was noted in one of the studies while another mentioned the possible relationship of TMD with educational status. Risk of bias among the studies was low, and the overall quality of evidence was deemed to be high. CONCLUSION: This systematic review suggests that there is no conclusive evidence supporting an increased risk of TMDs among women receiving ERT. The findings indicate that ERT is unlikely to have a noticeable impact on TMDs. However, due to the limited number of studies available, further research is warranted to strengthen these conclusions and explore potential factors that may influence the relationship between ERT and TMDs.

Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case-control study in Sweden.

Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case-control study (2007-2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13-1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23-1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11-1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96-1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

Ovarian Insufficiency: Clinical Spectrum and Management Challenges.

The term "ovarian insufficiency" describes the decline of ovarian function resulting in fertility loss and the marked decrease of ovarian steroid hormone production. From a clinical standpoint, ovarian insufficiency presents in three different settings. The first is natural menopause at midlife occurring at the average age of 51 years. The second arises after surgical oophorectomy owing to disease or elective cancer prophylaxis. Finally, primary or premature ovarian insufficiency is characterized by menopause occurring before age 40, often of undetermined etiology, but at times linked with genetic mutations, autoimmune syndromes, metabolic conditions, iatrogenic etiologies, and toxic exposures. Each clinical situation presents unique concerns and management challenges. The majority of women with intact ovaries who live to age 51 experience natural menopause, with early menopause <45 years. In the United States, surgical menopause with bilateral oophorectomy occurs in ∼600,000 women per year. The timing and specific clinical indication for oophorectomy alters management. Primary ovarian insufficiency occurs in 1% of women, although recent estimates suggest the prevalence may be increasing. Symptoms of ovarian insufficiency include hot flashes or vasomotor symptoms, mood disorders, sleep disruption, and vaginal/urinary symptoms. Health concerns include bone, cardiovascular, and cognitive health. Management of symptoms and preventive strategies varies depending upon the age, clinical situation, and specific health concerns of each individual. Treatment options for symptom relief include cognitive behavior therapy and hypnosis, nonhormonal prescription therapies, and hormone therapy. Tailoring the therapeutic approach over time in response to age, emerging medical issues, and patient desires constitutes individualized care.

Counseling in menopausal women: How to address the benefits and risks of menopause hormone therapy. A FIGO position paper.

Menopause marks the end of menstrual cyclicity and, depending on individual vulnerability, has several consequences related to gonadal steroid deprivation, especially if it is premature. Menopause may be more burdensome for some women than for others. Individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, affect symptomatology and, thereby, the menopausal experience. In addition, some menopausal symptoms, such as severe hot flashes, sleep disorders, and depression, are markers of future health risks. Counseling is a fundamental part of health care in the peri- and postmenopause periods. It must include an assessment of the patient's symptoms, needs, desires, and risk profile to address the benefits and risks of menopausal hormone therapy (MHT) on an individual basis and promote a healthy lifestyle. Indeed, healthcare practitioners can and must protect the health and lives of mid-life women by increasing awareness of menopausal symptoms and ensuring healthcare options, especially MHT. The type and duration of MHT should be tailored based on the patient's history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks. This FIGO position paper focuses on the benefits and risks of MHT on health domains, target organs, and systems, and on systemic and vaginal MHT regimens, to provide indications that can be used in the clinical practice for menopausal counseling. Moreover, it offers insights into what FIGO considers the mainstay for the healthcare management of women in peri- and postmenopause, worldwide.

Association with menopausal hormone therapy and asymptomatic gallstones in US women in the third National Health and Nutrition Examination Study.

15% of US adults have gallstones, most of which are clinically "silent". Several studies show that menopausal hormone therapy (MHT) increases symptomatic gallstones and cholecystectomy risk. MHT use may be contraindicated in women with gallstones and population studies may be biased by "confounding by contraindication" while the true association between MHT and gallstones remains underestimated. We sought to examine whether MHT use was associated with asymptomatic gallstones using instrumental variable (IV) analysis to account for confounding by contraindication. We used 2018 postmenopausal women from the Third National Health and Nutrition Examination Survey to estimate associations of MHT use with asymptomatic gallstones. A traditional logistic regression analysis was compared to instrumental variable (IV) analysis to account for confounding by contraindication. 12% of women with asymptomatic gallstones and 25% of women without gallstones were current MHT users (P < 0.001). The traditional analysis suggested a decreased odds of asymptomatic gallstones in current versus never users (OR 0.58, 95% CI 0.37, 0.89), but increased odds (OR 1.51, 95% CI 0.44, 5.16) in the IV analysis. The traditional analysis consistently underestimated the odds of asymptomatic gallstones with MHT use compared to the IV analysis. Accounting for confounding by contraindication, we found a suggestive, though imprecise, positive association between MHT use and asymptomatic gallstones among postmenopausal women. Failure to consider contraindication can produce incorrect results.

Early Estrogen Replacement Therapy Attenuates Cardiac Dysfunction Caused by Aging and Ovariectomy in Female Wistar Rats.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of women's mortality, linked to aging and reduced estrogen during menopause. Estrogen replacement therapy (ERT) is suggested for CVDs prevention. Yet, its timing initiation remains contentious. Thus, we aimed to evaluate the effect of early and late estrogen therapy on cardiac function and lipid metabolism in ovariectomized old female Wistar rats. METHODS: Fifty randomized female Wistar rats were included in 5 groups (n = 10, 18 months old): (1) Sham, (2) 10 weeks post ovariectomy (Ovx-10 w), (3) 10 weeks post Ovx + early estrogen replacement therapy (Ovx 10 w-early ERT), (4) 20 weeks post Ovx (Ovx-20 w) and (5) Ovx 20 w-late ERT. Three days (early ERT) or 10 weeks (late ERT) after surgery 17-ß estradiol was given (5 µg/kg/day), and 10 weeks after the start of ERT, we assessed cardiac function by echocardiography, electrocardiography, and cardiac catheterization. Estradiol, cholesterol, triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels were determined. Cardiac histology was performed with Masson's staining. RESULTS: Ovariectomy (Ovx) increases left ventricle internal systolic diameter (0.4 vs 0.3 cm, *p = 0.020) and decreases shortening fraction (40 vs 54 %, *p = 0.030) regardless of therapy. ERT prevents the increase in left ventricle mass after 10 weeks post-Ovx and the ejection fractionreduction after 20 weeks. Lower P wave amplitudes (18.8 vs 24.2 ms, *p = 0.013) were found in the Ovx-20 w group. A longer duration of the QRS complex after 20 weeks post-Ovx with and without ERT was found (32.5 and 32.1 vs 28.3 ms, *p = 0.003; *p = 0.007). Diastolic blood pressure was higher 20 weeks post-Ovx (86 vs 76 mmHg, *p = 0.047), regardless of ERT. The left ventricle (LV) -dP/dt was decreased in Ovx groups without ERT (-750 vs -1320 mmHg, *p = 0.034). An increase in LV collagen deposition was found in the Ovx 10 w group vs Sham (9.58 vs 4.54 %, *p = 0.028). Early ERT avoids the increase in body weight, cholesterol and LDL caused by Ovx. CONCLUSIONS: Ovariectomy causes time-dependent alterations in lipid metabolism, morphology, electrical activity, and heart contractile function. Early but not late ERT prevents some of these effects.

Cardiovascular health and the menopause, metabolic health.

Estrogen depletion following menopause predisposes to increased risk of cardiovascular disease (CVD), mainly due to ischemic heart disease. This is mostly evident in cases with premature menopause. The pathophysiological basis for this atherosclerotic process is the accumulation of several risk factors, such as abdominal obesity, atherogenic dyslipidemia, insulin resistance and arterial hypertension. The presence of vasomotor symptoms may further augment this risk, especially in women younger than 60 years. Menopausal hormone therapy (MHT) exerts many beneficial effects on lipid profile and glucose homeostasis as well as direct arterial effects, and may reduce CVD risk if initiated promptly (i.e.,<60 years or within ten years of the final menstrual period). Transdermal estradiol and micronized progesterone or dydrogesterone are the safest regimens in terms of venous thromboembolic events (VTE) and breast cancer risk. In any case, an individualized approach, taking into account the patient's total CVD, VTE and breast cancer risk, is recommended.

Menopausal symptoms and attitudes toward hormone replacement therapy among Israeli women.

Menopause occurs around midlife and is an inevitable component of women's aging. The study aimed to investigate the associations between the lifetime prevalence of menopausal symptoms and health-related characteristics among Israeli postmenopausal women aged 55-75 years. Additionally, this study aimed to estimate the use of hormone replacement therapy (HRT) and women's attitudes toward this treatment. Data for this study were extracted from a cross-sectional national telephone survey conducted in Israel between 2018 and 2020. For the current study, only postmenopausal women aged 55-75 years were included. Multivariate analyses were used to identify demographic and health-related characteristics associated with menopausal symptoms. The study included 688 participants. Most (68.8%) reported one or more menopausal symptoms, specifically vasomotor symptoms (50.4%). According to the multivariate logistic regression analysis, menopausal symptoms were associated with moderate-high anxiety and/or depression symptoms (OR = 2.01, 95% CI 1.12-3.58) and with osteoporosis (OR = 1.78, 95% CI 1.08-2.92). Although most (78.3%) symptomatic women were bothered by their symptoms, 29.1% received any treatment for symptom relief and only 12.6% reported current or past use of HRT. The findings show that menopausal symptoms were associated with a higher prevalence of anxiety and/or depression symptoms and osteoporosis in the years following menopause. Most symptomatic women did not receive any treatment and the majority were against HRT. Knowledge and awareness about menopause and treatment options should be increased among Israeli women. Additionally, the promotion of positive attitudes toward menopause and HRT use among women and healthcare providers is strongly recommended.

Effect of tibolone vs hormone replacement therapy on climacteric symptoms and psychological distress.

BACKGROUND: The objective was to elucidate the effect of tibolone vs hormone replacement therapy (HRT) on climacteric symptoms and psychological distress. METHODS: All consecutive women with climacteric symptoms were allocated to receive tibolone (2.5 mg) or estradiol valerate (1 mg) plus medroxyprogesterone acetate (2.5 mg). RESULTS: The improvement in "feeling dizzy or faint" after tibolone treatment was more prominent than that after HRT (-0.7 ± 0.8 vs -0.0 ± 0.9, p = 0.004). In addition, other climacteric symptoms, including anxiety, depression, somatic symptoms, and vasomotor symptoms, and sexual function improved after tibolone and HRT, but there were no between-group differences. Psychological distress assessment demonstrated that somatic complaints, obsessive-compulsive symptoms, depressive symptoms, hostility, additional symptoms, and the General Symptom Index improved after tibolone treatment and HRT, but there were no between-group differences. Personality traits assessment revealed that neuroticism improved after tibolone treatment. CONCLUSION: Tibolone seems more beneficial than HRT in treating symptoms of dizziness and faintness. Both tibolone and HRT could improve psychological distress.

Menopausal hormone therapy and coronary heart disease: the roller-coaster history.

In the USA it is estimated that more than one million women become menopausal each year. Coronary heart disease (CHD) is the leading cause of mortality in menopausal woman globally. The majority of perimenopausal to postmenopausal women experience bothersome symptoms including hot flashes, night sweats, mood liability, sleep disturbances, irregular bleeding and sexual dysfunction. While menopausal hormone therapy (HT) effectively treats most of these symptoms, use of HT has become confusing, especially related to CHD risk. Despite years of observational and retrospective studies supporting a CHD benefit and improved survival among HT users, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) raised doubts about this long-held premise. The timing hypothesis has since emerged and states that when HT is initiated in younger women, soon after menopause onset, there may be cardiovascular benefit. The following review discusses the roller-coaster history of HT use as it pertains to CHD in postmenopausal women. Studies that highlight HT's CHD benefit are reviewed and provide reassurance that HT utilized in appropriately selected younger postmenopausal women close to the onset of menopause is safe from a cardiovascular perspective, in line with consensus recommendations.