From discovery to debate: The history of menopausal hormone therapy and its impact on cardiovascular health

Cardiovascular disease (CVD) continues to persist as the primary cause of mortality for women in the United States (US), contributing to over 300,000 deaths annually ( Tsao et al., 2022 ). Although CVD poses a problem for both sexes, the prevalence, progression, and mechanisms of CVD differ greatly between men and women. In fact, CVD has long been thought of as a condition primarily affecting men, but as medicine has evolved to include more sex-specific research, evidence has shown that women experience a greater prevalence and mortality from CVD compared to men ( Virani et al., 2020 ). Women also tend to show obstruction and disease in their microvasculature, leading to atypical myocardial infarction (MI) symptoms, while men tend to present with macrovascular disease and “typical” MI symptoms ( Safdar et al., 2016 ). While traditional risk factors are used clinically to assess CVD risk, sex differences exist in the association of various risk factors and outcomes ( Humphries et al., 2017 ; Huxley et al., 2006 ; Prescott et al., 1998 ; Ogunniyi et al., 2022 ). In addition to sex differences, racial disparities in CVD development and progression are also evident. Moreover, a unique set of risk factors specific to women have been identified, such as pregnancy, gestational diabetes, preeclampsia, and menopause, which can impact future development of CVD ( Humphries et al., 2017 ). These female-specific risk factors may be just as strong in predicting / contributing to future CVD but have been largely understudied until recently, leading to poor understanding of pathology and treatment of CVD in women. For clarity throughout this review, we refer to women as cis-gender women (i.e., women whose gender is consistent with their sex assigned at birth) to focus on biological women who experience menopause ( Usselman et al., 2024 ). Despite making up half of the US population, inequality in healthcare has been a long-standing issue for women. Women of childbearing potential were not allowed to participate in clinical trials until mandated by the National Institutes of Health (NIH) Revitalization Act in 1993. As women of childbearing potential (i.e. 15–44 years) make up more than 39 % of the female population and nearly 20 % of the entire US population ( Osterman et al., 2024 ), this demonstrates lack of representation and research on a substantial portion of the population for all but the last 30 years ( Blakeslee et al., 2023 ). Although the Revitalization Act was considered a victory for women's health and sex disparities, women continue to experience trivialization of physical conditions and underrepresentation in trials ( Mirin, 2021 ). A recent 2022 study found that women are still under-represented in early phase biomedical clinical trials, accounting for just 29–34 % of participants ( Cottingham and Fisher, 2022 ). This may be in part due to the continued underrepresentation of women in science and engineering careers ( Colwell et al., 2021 ), leading to lack of advocacy for inclusion of women in biomedical trials. Additionally, the inclusion of women has been met with study design issues around controlling for menstrual cycles to deal with hormonal variations, adding to the resistance to include women in biomedical research trials. Together, this historical and continued low recruitment of women has translated into understudied diseases and burdens (i.e. migraines, anxiety and depression, hypertensive pregnancy, endometriosis, menopause) that are either more prevalent in women compared to in men or are sex-specific to women ( Mirin, 2021 ; Steinberg et al., 2021 ). Women have been subjected to neglect in sex-specific care across the field of cardiology, however most notably facing controversy involving treatment and care of menopause. Nearly 2 million women in the US reach menopause each year and women will collectively spend greater than a third of their life postmenopausal ( El Khoudary et al., 2020 ; Tsao et al., 2023 ). Defined by the cessation of ovarian function and menstrual cycles for one full year, menopause signals the change to a non-reproductive stage of life, as production of estrogens and progesterone significantly decline ( El Khoudary et al., 2020 ). Natural menopause typically occurs around the age of 51 years ( El Khoudary et al., 2020 ). Greater than 80 % of women will experience hallmark vasomotor symptoms, such as hot flashes and night sweats, in the years leading up to menopause, as well as subsequent years following full transition ( Avis et al., 2015 ). Data from The Study of women's Health Across the Nation found that on average, vasomotor symptoms persist for a total of 7.4 years, and continue for 4.5 years after the final menstrual period, indicating a substantial duration of time for women to experience and manage menopause symptoms ( Avis et al., 2015 ). Aside from vasomotor symptoms, menopause can negatively affect many aspects of cardiovascular health including, but not limited to, body fat distribution, lipid profile, vascular function and health, and overall risk of disease development ( El Khoudary et al., 2020 ). Although symptoms of menopause are well documented, there is still a lack of research exploring the consequences of menopause and treatment options. In fact, less than 1 % of current clinical trials are focused on or related to menopause ( NIH, 2024 ), supporting continued issues with research inclusion of women and diseases specific to women. Women have struggled with not only the lack of options for menopausal symptoms management, but also drastic increases in CVD risk and complications following menopause with little to no understanding of underlying mechanisms or mitigating strategies. The profound changes in cardiovascular health are thought to be driven by the decline in endogenous sex hormones, specifically estradiol, in postmenopausal women. Evidence suggests that premenopausal women are protected from CVD because of the beneficial effects of endogenous estradiol, and this cardioprotective effect is quickly lost after menopause. Indeed, the rates of CVD in women and the rapid rise that is seen in CVD risk during the 4th and 5th decades of life, coinciding with the menopausal transition ( Tsao et al., 2023 ). Further support for this claim comes from the Framingham Study, where it was found that the age-specific CVD incidence is two- to six-fold greater for postmenopausal than premenopausal women between the ages of 40–54 ( Kannel et al., 1976 ). This problem of declining cardiovascular health in postmenopausal women is not of new knowledge, however very few strategies and treatment options have been developed and researched to try to address this growing issue. The most notable menopausal treatment option is hormone therapy (HT). The concept behind HT is the idea that replacing or supplementing estrogen to manage vasomotor symptoms and possibly prevent disease associated with menopause, including CVD. Once thought to be an effective prevention and treatment method against not only menopausal symptoms, but also prevention of chronic diseases like CVD, HT has been viewed with caution and conflicting opinions due to the unfavorable findings from the Women's Health Initiative (WHI) that was published in 2002. The unfavorable findings regarding CVD with the use of HT has translated to more than 20 years of menopausal women struggling to find therapy options to help them. However, there have been multiple trials since the WHI that have shown that HT is indeed safe and effective in treating menopausal symptoms, but may also improve various cardiovascular health metrics and attenuate CVD ( Langer et al., 2021 ; Hodis and Mack, 2022 ). Additionally, it has been reported that the WHI publication was further complicated by study design flaws, as principal investigators did not have an opportunity to review the data, and the publication was rushed to the media ( Langer et al., 2021 ; Lobo, 2013 ). Despite multiple trials disputing the unfavorable findings from the WHI and many organizations recognizing the positive benefits of HT, women are still hesitant to use HT. Treatment prescriptions of menopausal HT remain low and are used in less than 5 % of postmenopausal women today ( Yang and Toriola, 2024 ) despite the current research on HT, leaving women still in the dark when it comes to managing menopause. Therefore, the purpose of this review is to provide a clear timeline of HT usage and trials in overall support of HT as a safe and beneficial strategy for menopausal women. A summary of trials highlighted in this review can be found in Table 1 . This review aims to bring light to continued disparities in CVD treatment specific to menopause, with overall hope to continue advocating for better treatment options for women's health across the lifespan.

The timing hypothesis was developed by Hodis and Mack and proposed that the timing of HT administration following menopause determines the likelihood of benefit vs. risk ( Hodis and Mack, 2013 ). The two articulated the phenomenon of the “timing hypothesis” after cumulating data from multiple clinical trials in women and seeing a clearly different response to HT according to the timing of HT initiation relative to age and time since menopause ( Hodis and Mack, 2013 ). The timing hypothesis was supported through prior meta-analysis ( Salpeter et al., 2006 ; Boardman et al., 2015 ). In women who initiated HT within 10 years since menopause or a age 60 years or younger, the risk of CHD is 32 % less than with placebo ( Salpeter et al., 2006 ; Hodis and Mack, 2013 ). Hodis and Mack even provided evidence that the data from the WHI supports the timing hypothesis. In the combination treatment group of CEE plus MPA, women given HT less than 10 years since menopause had a 12 % lower risk of CHD than the placebo group, whereas women who initiated HT greater than 10 years since menopause showed no benefit or a possible increased CHD risk ( Rossouw et al., 2007 ; Hodis and Mack, 2013 ). In the CEE-only treatment group, women given HT less than 10 years since menopause had a 52 % reduced risk for CHD compared to placebo ( Rossouw et al., 2007 ; Hodis and Mack, 2013 ). With both treatment groups combined, women given HT within 10 years of menopause onset had an overall 24 % lower risk of CHD and a 30 % lower total mortality rate than the placebo group. The 11-year WHI trial follow up showed that women aged 50–59 who were given CEE-only had a significantly lower risk of CVD, MI, and total mortality than those given the placebo ( Hodis and Mack, 2013 ). Therefore, this evidence provided clear findings that the timing of initiating HT appears to have significant clinical implications to the effectiveness of HT preventing CVD. The timing hypothesis was prospectively tested by two large RCTs, the Kronos Early Estrogen Prevention Study (KEEPS) and the Early versus Late Intervention Trial with Estrogen (ELITE). Both studies enrolled over 600 healthy, postmenopausal women and used a double-blind, controlled placebo design to test the timing hypothesis. The primary CVD measures were carotid intima media thickness (CIMT), blood pressure, and lipid panels ( Harman et al., 2014 ). The KEEPS trial enrolled healthy menopausal women (aged 42–58 years, average age 52.7 years) between 6 months and 3 years from last menses and looked to investigate a HT formulation of an oral CEE, 0.45 mg/d plus 200 mg of oral MP for 12 days per month or a transdermal 17β-estradiol 50μg/d plus 200 mg of oral MP for 12 days per month ( Harman et al., 2014 ). At the four-year follow up, the rate of increase in CIMT progression was not different between treatment groups (mean rate of increase: 0.0076 mm/y). Blood pressure did not change in either oral CEE or transdermal 17β-estradiol groups, while both LDL-C and HDL-C levels improved with oral CEE. Importantly, no adverse events or increased risk for CVDs were observed, indicating no acceleration of disease due to HT use ( Harman et al., 2014 ). Transdermal 17β-estradiol significantly improved insulin and homeostasis model assessment insulin resistance scores ( Harman et al., 2014 ). Although the KEEPS trial found no attenuation in CIMT progression or reduction in blood pressure between either groups, the data did not show acceleration of either measure or increase in disease risk in the HT groups ( Harman et al., 2014 ). Accordingly, the KEEPS trial provided data that supported the value and safety of HT use in early postmenopausal women for menopausal symptoms, while not imposing additional risk ( Harman et al., 2014 ). The ELITE trial enrolled 643 healthy postmenopausal women and stratified participant groups according to the number of years past menopause: less than 6 years (early group) or 10 or more years (late group) ( Hodis et al., 2016 ). Based on these groups, women were then randomized into treatment groups to receive either oral 17β-estradiol, 1 mg/d, or placebo. Women with an intact uterus also received MP, 45 mg, as a 4 % vaginal gel or a matched placebo gel that was to be applied once daily for 10 days during each 30-day cycle ( Hodis et al., 2016 ). The early group averaged 3.5 years since menopause (average age 55.4 years), while the late group averaged 14.3 years since menopause (average age 63.6 years). After a median of five years, the ELITE trail found significantly lowered CIMT progression in the early estradiol group (mean rate of increase: 0.0044 mm/y), compared to both the early placebo (mean rate of increase: 0.0078 mm/y) and the late estradiol group (mean rate of increase: 0.0088 mm/y) ( Hodis et al., 2016 ). LDL-C and HDL-C levels were significantly improved in the estradiol group than the placebo group ( Hodis et al., 2016 ). Blood pressure during the trial did not differ significantly between all groups, as well as no difference in adverse event rates ( Hodis et al., 2016 ). The ELITE trials concluded that oral estradiol therapy was associated with less progression of atherosclerosis when initiated early (within 6 years of menopause) and is a safe and effective therapy in the prevention of CVD ( Hodis et al., 2016 ).

It is important to distinguish the different types and forms of hormones to fully understand the results and implications of HT. There are many different types, forms, and routes of HT. The two most common forms of therapy are estrogen only therapy and combined estrogen and progesterone therapy ( Mehta et al., 2021 ). Estrogen alone therapy is used in women who have undergone a hysterectomy and do not have a uterus, while estrogen and progesterone therapy is used for women who have an intact uterus ( Mehta et al., 2021 ). The use of progesterone is needed in women with a uterus to prevent against endometrial wall thickening and endometrial cancer ( Mehta et al., 2021 ). Hormonal intrauterine devices (i.e. levonorgestrel releasing intrauterine device) are also used in conjunction with estrogen therapy for prevention of endometrial hyperplasia, most commonly in perimenopausal women who may still be cycling ( Clark and Westberg, 2019 ). Various forms of estrogens and progestins/progesterone have been developed for HT uses. Estrogen forms include human estrogens (17β-estradiol, estrone, and estriol) and animal-derived estrogens ( Mehta et al., 2021 ). Human estrogens are made molecularly identical to the structure of endogenous hormones, while animal-derived estrogens are synthetic, conjugated forms ( Mehta et al., 2021 ). The most common animal-derived estrogen is conjugated equine estrogen (CEE), which is derived from the urine of pregnant mares ( Mehta et al., 2021 ). CEEs were an original form of HT that was most commonly used up to the late 1990s and early 2000s. Routes of administration for estrogens come in many forms, most commonly as oral, transdermal patches, and vaginal or topical creams ( Mehta et al., 2021 ). Dosage of estrogen will depend on treatment goals for each individual woman, and typically range from 0.3 to 2.5 (mg/d) for oral forms and 0.025–0.1 (mg) weekly or bi-weekly for transdermal forms ( Mehta et al., 2021 ). Currently, transdermal estradiol is considered the first line of treatment for administration of HT ( Palacios et al., 2019 ). Progesterone forms include micronized progesterone (MP) and synthetic progestins (medroxyprogesterone acetate (MPA) or norenthindrone) ( Mehta et al., 2021 ). MP is made to mimic the endogenous form of progesterone in the body, while MPA and norenthindrone are synthetically made ( Mehta et al., 2021 ). Progestins come in oral and transdermal forms and dosages will vary depending on the estrogen form used, as well as treatment goals of the individual woman ( Mehta et al., 2021 ).

The “timing hypothesis” and KEEPS and ELITE trials were key milestones in the menopausal therapy field, providing excellent knowledge for safe and effective use of HT. Following the focus on the “timing hypothesis”, many other questions were formulated and investigated regarding effectiveness and safety of HT, including route of administration (i.e. oral, transdermal, vaginal). Oral administration is the most common and widely accepted form of estrogen therapy ( Mehta et al., 2021 ). However, previous data suggested potential harm in oral based HT and increased cardiovascular risk with prolonged use ( Kalenga et al., 2023 ; Bassuk and Manson, 2014 ), compared to non-oral HT forms such as transdermal HT that may be associated with a lower cardiovascular risk ( Bezwada et al., 2017 ). Indeed, recent data from a large prospective study of 112,240 women observed that oral estrogen-only HT use was associated with an increased risk of hypertension, whereas transdermal (HR, 1.00 [95 % CI, 1.08–1.20]) and vaginal (HR, 1.19 [95 %, CI 1.13–1.25]) estrogen-only HT were not ( Kalenga et al., 2023 ). Additional data has shown that oral estrogen therapies may exert a more prothrombotic effect through the hepatic “first-pass”, compared to transdermal estrogens that do not have this suppressive hepatic and prothrombotic effect ( Lowe et al., 2001 ). In addition to the route of administration, recent studies have focused on the importance of formulation of HT. The formulation of HT has been a large issue since the WHI, as sub-analyses found that the progesterone form MPA that was used in the study had negative implications to cardiovascular risk ( Rossouw et al., 2002 ; Hsia et al., 2006 ; Manson et al., 2003 ). Additionally, the form of estrogen therapy has been a topic of interest since the WHI publication. There has been a variety of estrogen forms used in the large RCTs, most notably the CEE form used in the WHI. The data from the WHI in CEE-only therapy showed a beneficial cardiovascular effect when stratified for age ( Salpeter et al., 2006 ; Salpeter et al., 2004 ), however others have shown CEE to be not as effective. 17β-estradiol is the other common form of estrogen used, most notably in the KEEPs and ELITE trial, and has become the most popular formulation used in RCTs in both transdermal and oral forms. The KEEPS and ELITE trials that found beneficial cardiovascular effects of 17β-estradiol use (alone and in combination with micronized progesterone), and recent prospective data showed 17β-estradiol-only therapy to be associated with a reduced risk of hypertension compared to CEE ( Kalenga et al., 2023 ). Although this prospective study provided valuable knowledge of HT usage, limitations persist, as large, randomized trials are still needed to fully account for the complexities of estrogen and progesterone HT formulations. Due to research in this area showing no detrimental effects of HT, The Menopause Society has supported the safety and benefits of HT when used appropriately. In their latest 2022 position statement, The Menopause Society supports the use of HT in postmenopausal women <60 years old and/or within 10 years of menopause onset ( The North American Menopause Society Advisory Panel, 2022 ). Although the support of The Menopause Society is a step in the right direction for advocating therapies for postmenopausal women, HT is not recommended as a primary or secondary prevention strategy for CVD. Indeed, HT is only approved for four indications: moderate to severe vasomotor symptoms, prevention of osteoporosis, treatment of hypoestrogenism (i. e caused by hypogonadism, bilateral oophorectomy, or primary ovarian insufficiency), and treatment of moderate to severe vulvovaginal symptoms ( The North American Menopause Society Advisory Panel, 2022 ). Although there is some robust evidence of HT attenuating CVD when used in appropriate timing, there is still resistance to prescribe HT as a primary or secondary prevention strategy for CVD due to inconsistencies in trial data. More research is needed to solidify the effects of HT on the cardiovascular system, specific to route of administration, formulation of hormones, and length of use. Although most of these HT-related studies that have been discussed above are large RCTs, few investigated or speculated on actual mechanisms connecting HT to the cardiovascular related benefits. Since the conclusion of the WHI study, smaller studies have conducted acute estrogen administration supplementation in postmenopausal women to understand mechanistically how HT effects cardiovascular health. Aside from main end points that have been typically examined in large RCTs (CHD and CVD risk, all-cause mortality, hypertension, CIMT), additional independent cardiovascular variables have been examined in these studies. The effects of acute estrogen therapy in postmenopausal women on measures of macrovascular function, blood pressure, and oxidative stress have been assessed in various studies. Various studies have found that endothelial function, an established non-traditional risk factor for CVD and a biomarker of the development of atherosclerosis ( Hadi et al., 2005 ; Bonetti et al., 2003 ; Modena et al., 2002 ), improved after short term (i.e. 9–12 weeks) oral or transdermal estrogen treatment in postmenopausal women compared to placebo ( Moreau et al., 2013 ; Lieberman et al., 1994 ). Additionally, it has also been shown that increases in endothelial function from aerobic exercise are only evident in postmenopausal women using estrogen ( Moreau et al., 2013 ). Similarly, carotid compliance increased by 25–30 % after 12 weeks of aerobic exercise only among postmenopausal women who were treated with estrogen compared to estrogen-deficient postmenopausal women ( Moreau et al., 2003 ). Although less consistent in the literature, there is some evidence that use of HT reduced 24-h systolic and diastolic pressure, as well as restored nighttime blood pressure dipping ( Mercuro et al., 1997 ; Mercuro et al., 1998 ). In rodent models, estradiol suppressed oxidative stress levels in wild type mice following ovariectomy ( Almeida et al., 2010 ). Similar findings were seen in cell culture models, where administration of 17β-estradiol markedly reduced the reactive oxygen species levels induced by homocysteine in Raw 264.7 cells ( Zhang et al., 2015 ). Improved endothelial function, carotid compliance, and oxidative stress levels could be potential mechanisms behind HT positively benefiting CVD risk. Variables of autonomic function and the effects of acute estrogen supplementation in postmenopausal women have also been assessed in previous work. Manhem et al. found that 24-h of transdermal estradiol and micronized progesterone significantly reduced resting ambulatory systolic and diastolic blood pressure, as well as attenuated diastolic pressure reactivity during a mental stressor ( Manhem et al., 2003 ). Wenner et al. found that one month of transdermal estradiol (100 μg/ day) attenuated muscle sympathetic nervous activity and blood pressure responses to exercise in postmenopausal women ( Wenner et al., 2022 ). Hunt et al. observed an improvement in baroreflex function of vascular sympathetic outflow in 11 postmenopausal women after six months of oral estrogen ( Hunt et al., 2001 ). Multiple studies have assessed the effects of HT on indices of heart rate variability and have reported inconsistent findings. Based on current evidence, estrogen-only therapy significantly improved heart rate variability measures ( Rosano et al., 1997 ; Yang et al., 2013 ), however combination therapy of estrogen plus progesterone diminished these positive effects in postmenopausal women ( Yang et al., 2013 ; Christ et al., 1999 ; Lantto et al., 2012 ). These findings indicate a potential mechanism of estradiol improving neural control of heart rate and blood pressure, leading to improved autonomic regulation and a lower overall CVD risk. Although these studies investigated acute effects of estradiol in small sample sizes, these data together provide insight that HT can benefit cardiovascular health and contribute to a lower risk of CVD development and complications in menopausal women ( Fig. 2 ). However, the translation of these mechanistic data on HT to large RCT findings have been inconsistent and require additional investigation. Together, these data provide a strong rationale for continued research and new large RCTs that investigate both acute and chronic effects of a variety of HT formulations and route of administration to get a full picture of the mechanistic effects of HT. Despite the advancement in knowledge of the safety and efficacy of HT, prescriptions of HT remain extremely low, with less than 5 % of postmenopausal women using HT today ( Yang and Toriola, 2024 ). Prior to the WHI, it is reported that 27–38 % of menopausal women were using HT. ( Lobo, 2013 ; Yang and Toriola, 2024 ) After its publication, usage quickly plummeted more than 80 %, with further declines persisting today. A recent study analyzing physician-reported data of 5959 health care visits, representing approximately 24.3 million visits in multistage probability sampling, found that only 4 % of women aged 50 and older received a prescription for menopausal HT ( Sobel et al., 2024 ). Within that sample, only 30 % of women were aged 50–60, the primary age group to receive the most effective and safe benefits from HT. Although menopausal women still fear the risks of HT due to the WHI, another reason for decreased usage is practitioners lack of knowledge and education on HT at the clinical level ( Spangler et al., 2009 ). Medical students and program directors report concerns with lack of menopause training in their education, as only 31 % report having a menopause curriculum in their programs and only 29 % had dedicated time assigned to a menopause clinic ( Allen et al., 2023 ). Survey data suggested that only 35 % of obstetrics/gynecology physicians and 15 % of primary care physicians feel very well prepared to counsel women on HT ( Spangler et al., 2009 ). Additionally, variation in prescribing practices were associated with provider characteristics (i.e. type of practitioner, female sex of practitioner, age of practitioner), indicating it is likely that clinicians need additional training regarding menopause and HT to ensure unbiased, evidence-based advice ( Langer et al., 2021 ; Spangler et al., 2009 ). There is an observable gap between the evidence-based research and clinical application of HT. Moving forward, it is critical for better collaboration between researchers and clinicians to ensure menopausal women are receiving proper care to manage menopause. With continued low prescriptions and usage, new therapies have emerged for menopausal women, such as compounded bioidentical hormone therapy (cBHT). Bioidentical hormones are derived from plant sources (i.e. soy, yams) and are claimed to be chemically similar or structurally identical to endogenous hormones ( Conaway, 2011 ; Donnelly and Balneaves, 2022 ). cBHT is produced by a compounding pharmacy by using a saliva or blood test to create customized hormone therapy to meet each individual's needs ( Conaway, 2011 ). Estrogens (estriol, estradiol, and estrone), progesterone, and testosterone can all be compounded into cBHT, consisting of more options than FDA-approved bioidentical hormones ( Bhavnani and Stanc-zyk, 2012 ; Stuenkel, 2021 ). Combinations of one or multiple hormones can be administered in different routes such as subdermal implants, pellets, creams, and troches ( Bhavnani and Stanczyk, 2012 ; Stuenkel, 2021 ). cBHT has become quite popular among menopausal women, with an estimated 1 to 2.5 million users and 26 to 33 million prescriptions filled annually ( Stuenkel, 2021 ; Liu et al., 2022 ). Although not approved by the FDA largely due to the lack of regulation in the individualized nature of cBHT, smaller cohort studies have shown benefit of cBHT on vasomotor symptoms ( Conaway, 2011 ; Liu et al., 2022 ), as well as some improvement to cardiovascular risk factors such as clotting factors ( Stephenson et al., 2013 ; Gómez-Santos et al., 2012 ), lipid profiles ( Stephenson et al., 2013 ), and blood pressure ( Seely et al., 1999 ). An excellent review by Liu et al. (2022) discusses the safety and effectiveness of cBHT. Many women are opting to use cBHT due to its marketing as a safer, more “natural” hormone option ( Liu et al., 2022 ), however similar to traditional HT, more conclusive research on the systemic effects of cBHT are needed to gain support for the use of cBHT to manage menopause symptoms. Genistein is an additional menopausal management alternative to traditional HT. Genistein is one of three soybean estrogenic isoflavones ( Lee et al., 2022 ). The chemical structure of genistein is similar to 17β-estradiol, allowing it to act on various molecular pathways to mimic the effects of estrogens ( Johnson et al., 2019 ). Of the two estrogen receptors (ER) β and α, the binding of estradiol to ER-β is thought to create beneficial effects, while limiting adverse side effects that are associated with binding of estrogens to ER-α. Genistein is more highly selective in binding to ER-β than α, creating potential beneficial properties of this phytoestrogen ( Johnson et al., 2019 ). The use of genistein as a menopausal therapy has been tested in various trials and results show benefits to vasomotor symptoms ( Guo et al., 2019 ), cardiovascular and inflammatory markers ( Si and Liu, 2007 ; Braxas et al., 2019 ), cancer incidences ( Mareti et al., 2019 ; Pons et al., 2019 ), and stress responses ( Kageyama et al., 2010 ). Although genistein shows great potential as a menopausal therapy option, much more research is needed in this area to gain further insight into mechanisms and molecular pathways by which genistein can treat menopausal symptoms and reduce disease risk and occurrence. Veozah (Fezolinetant) is a recent FDA approved non-hormonal drug shown to be effective in treating moderate to severe vasomotor symptoms ( Johnson et al., 2023 ). Veozah is a daily oral medication approved at 30 and 45 mg doses. The drug works by targeting the thermoregulatory center in the brain hypothalamus that triggers hot flashes and vasomotor symptoms. The thermoregulatory center is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons that are stimulated by the neuropeptide neurokinin B (NKB) on the neurokinin-3 receptors, and is inhibited by estrogen ( Johnson et al., 2023 ). As estrogen declines across the menopausal transition, the neurokinin-3 receptors are left unopposed, triggering vasodilation and heat dissipation from the thermoregulatory center ( Johnson et al., 2023 ). Veozah is a selective neurokinin-3 receptor antagonist that blocks the binding of NKB on the KNDy neuron, restoring balance in the thermoregulatory center ( Johnson et al., 2023 ). Veozah has been tested in a double blinded, placebo-controlled 12-week phase 3 clinical trial. 500 menopausal women ages 40–65 were randomized to either 30 mg of Veozah, 45 mg of Veozah, or placebo for 52 weeks, with vasomotor symptoms assessed at 12 and 52 weeks. Results showed that both 30 mg and 45 mg of Veozah significantly reduced the frequency and severity of vasomotor symptoms by more than 50 %, without adverse events or unopposed risk development ( Johnson et al., 2023 ). Veozah has not been associated with any significant increase in cardiovascular events and diseases, however changes in blood pressure and heart rate are noted as potential side effects, indicating importance for future research to investigate cardiovascular related effects ( Crespo and Erlich, 2024 ). Veozah shows great promise as a non-hormonal menopause management alternative to traditional HT, however more research is needed to assess any systemic or cardiovascular related impacts with use. Additionally, selective serotonin/norepinephrine reuptake inhibitors (SSRIs/SNRIs) and supplements such as Ginseng, Black Cohosh, and Vitamin E are all alternative therapies to traditional HT that have shown some promise in benefiting menopausal symptoms. Although historically prescribed for anxiety and depressive symptoms, SSRIs and SNRIs have recently been prescribed to menopausal women dealing with severe vasomotor symptoms. SSRIs and SNRIs have been tested in multiple RCTs and have been found to be well tolerated and effective in reducing vasomotor symptoms by up to 65 % within one week of use ( Handley and Williams, 2015 ; Azizi et al., 2022 ). SSRIs and SNRIs have a known influence on cardiovascular function ( Nezafati et al., 2016 ), however no studies have investigated the effects of SSRIs/SNRIs on cardiovascular health in the context of menopausal symptom management. Ginseng, a root plant characterized by the presence of ginseno-sides and gintonin, promotes resistance to external and internal stresses and improves mental and physical performance ( Lee et al., 2022 ). Improvement in quality of life and reductions in hot flashes with supplementation of ginseng have been shown in a small trial ( Ghorbani et al., 2019 ), however this finding has not been supported in additional trials ( Lee et al., 2022 ; Wiklund et al., 1999 ). Ginseng has also shown beneficial effects on cardiovascular measures, including improved control of vasomotor function, improvement to lipid profile, reduction in platelet adhesion, improvement to blood pressure, and improvements to cardiac function ( Kim, 2018 ). However, most of these studies were not in menopausal women. More rigorous, unbiased RCTs are needed to elicit the full effects of ginseng on menopausal management and cardiovascular health in menopausal women. Black Cohosh is a widely studied phytopharmaceutical plant that has been used historically as an indigenous treatment for menopause symptoms ( Johnson et al., 2019 ). Multiple RCTs have been conducted to examine the effects of Black Cohost on menopause symptoms, however inconclusive and insufficient evidence has been found to fully support Black Cohost reducing vasomotor symptoms and improving quality of life, in addition to minimal investigation into influences on cardiovascular health with use ( Leach and Moore, 2012 ). Vitamin E has been tested on anecdotal accounts of antioxidant related benefits for menopausal symptoms ( Johnson et al., 2019 ). One trial of 120 women receiving 800 IU of vitamin E for four weeks reported a reduction of 1 hot flash per day ( Barton et al., 1998 ), while another trial of 50 women taking 400 IU of vitamin E for four weeks showed a reduction of 2 hot flashes per day ( Ziaei et al., 2007 ), however both deemed not clinically significant. Due to its antioxidant properties, Vitamin E has been shown to be beneficial in improvements to vascular modulation and lipid profiling in postmenopausal women, providing some evidence suggesting benefits to menopausal symptoms and cardiovascular health. More research is needed on vitamin E benefits for clinically significant improvements to menopausal symptoms. Eloquent reviews have been published on alternative therapies for menopausal symptoms ( Lee et al., 2022 ; Johnson et al., 2019 ; Guo et al., 2019 ; Azizi et al., 2022 ; Feduniw et al., 2023 ). Collectively, abundant research is greatly needed in the field of alternative menopausal therapeutics.

Women experience unique changes in cardiovascular function and disease pathology related to menopause, as evidence demonstrates a substantial increase in CVD risk factors and events that occur in postmenopausal women compared to age-matched premenopausal women and men. HT is a well-researched therapy that has proven effective for reducing vasomotor symptoms, with potential benefit to women's heart health. Due to inconsistencies between trial and observational data, prescription of HT for primary or secondary prevention of CVD is not recommended by The Menopause Society and other organizations. Additionally, overall use of HT for its approved indications remains low today due to lingering repercussions from the WHI and lack of recent trial knowledge and advocacy by clinicians. Although more research is needed, there are still robust clinical evidence that when used with appropriate timing and in the appropriate population, HT is safe and effective in reducing CVD and all-cause mortality in healthy menopausal women. Follow-up data from the WHI trials indicate that among women using CEE plus MPA or CEE-only, there was no associated risk of all-cause or cardiovascular mortality during an 18-year follow up ( Manson et al., 2017 ). The ELITE trial provided evidence that early initiation of HT reduced the progression of subclinical atherosclerosis ( Hodis et al., 2016 ). Systematic reviews and meta-analyses of cumulative data on HT use indicate that women less than 60 years and/or within 10 years of menopause onset have a significant reduction in all-cause mortality, CHD, and CVD events with HT use ( Hodis and Mack, 2022 ; Salpeter et al., 2006 ; Boardman et al., 2015 ; Salpeter et al., 2004 ). This data is in conjunction with significant reduction in frequency and severity of vasomotor symptoms, improvement to genitourinary symptoms, and improvements to quality of life. Despite these data, clinical prescriptions of HT continue to be very low among menopausal women. Clear gaps in the literature revolving HT persist, including a dearth of research on the impacts of HT in minority groups, which is incredibly important to investigate as nearly 60 % of Black women ages ≥20 years are living with some form of CVD, marking the highest disease burden among all sex and racial groups in the US ( Ogunniyi et al., 2022 ). Black women are also at a higher risk for early menopause ( Gold et al., 2001 ; Lister, 2019 ), experience more severe menopause symptoms ( Harlow et al., 2022 ), and have the longest median total duration of menopausal symptom (median of 10.1 years) ( Avis et al., 2015 ; Harlow et al., 2022 ), making future research on whether HT can benefit the cardiovascular health of Black women imperative. A full summary of gaps in knowledge and future directions in this field can be found in Table 2 . Together, a better effort and connection needs to be established between researchers and clinicians to utilize HT and allow menopausal women to manage menopause effectively and safely. However, this should not be the only option. As clinical trials regarding menopause make up less than 1 % of research ( NIH, 2024 ), women are in dire need of more therapeutic options and answers regarding menopause and its effects on heart health and overall wellbeing. Non-hormonal treatment options need significant more research, to guarantee safe and effective menopause therapies for all women. We hope the takeaway from this review is for more advocacy for the use of HT in menopausal women, with continued need for more trials involving traditional HT and alternative therapies specific for menopause-related issues.