One size does not fit all: how type of menopause and hormone therapy matters for brain health.

There is not one type of perimenopause, menopause or postmenopause. Similarly, there is not one type of MHT. Given this, it is unrealistic to expect that one type of MHT will equally benefit all females, who have different genetics and varied life experiences. Females and healthcare practitioners alike must appreciate these nuances to ensure all females receive informed, individualised menopausal care to support their healthy brain ageing. This starts with improved menopausal education. Approximately 65% of females do not feel prepared for menopause, 152 and most general practitioners acknowledge that they are lacking menopause education, especially education surrounding menopause management and various forms of MHT. 153 One survey found that only 6.8% of USA medical practitioners felt sufficiently prepared to support females through the menopause transition. 154 In fact, only 31.3% of USA obstetrics and gynaecology residency programmes reported having a menopause curriculum. 155 This is concerning, knowing that 38% of females feel that their menopausal symptoms are undertreated, 51 and in Canada alone, 540 000 days of work are lost each year because of ineffective menopausal symptom management. 51 Unmanaged menopausal symptoms negatively influence quality of life and have negative economic consequences. This lack of menopause education increases the possibility that menopausal symptoms, especially if they deviate from the commonly reported VMS, may be left unrecognised or mistakenly attributed to other causes. In current medical practice, the onus falls on the patients to determine when their menopause transition is commencing and to advocate for treatments to help ease this transition. There are significant delays in diagnosis across disorders in females compared with males, and females feel their symptoms are dismissed in healthcare practitioner offices. 156 Coupled with the findings that healthcare practitioners are not equipped with knowledge on menopause, it is imperative that more research and education of healthcare practitioners takes place. Given that 50% of the population will go through menopause and that just less than half of the female lifespan will be spent in a perimenopausal or postmenopausal state, it is shocking so little attention has been paid to menopause care. Compounded bioidentical hormone therapy (cBHT) has exploded in popularity, partly because of the lack of appropriate care by healthcare practitioners and physician prescriptions are not needed to obtain it. cBHT is taken by up to 40% of females in the USA. 157 cBHT is marketed as a more ‘natural’ option; however, it undergoes chemical extraction and stabilisation processes. 158 It is overlooked is that many prescribed MHTs also use natural hormones of oestradiol, E1 or even oestriol and P4. Moreover, cBHT is not approved by Health Canada, meaning that their safety and efficacy have not been evaluated with the same standards as prescribed MHT. In fact, there is no procedure to ensure cBHT contains the listed amount of active ingredient, and many cBHT formulations use E1. 158 The safety and efficacy of prescribed MHT is influenced by the type, route of administration and dose of oestrogens and progestogens. These same factors influence the safety and efficacy of cBHT, but they have not been formally regulated. Current guidelines suggest that more research is needed on the efficacy of cBHT, and it is recommended that their use be restricted to patients with a known allergy to an active pharmaceutical agent. 158 Most guidelines recommend the cessation of MHT at 60 years of age or 10 years after menopause, guidelines that are still informed by the WHIS findings. 159 Additionally, because of the WHIS findings, many physicians believe that MHT duration should be limited to 5 years or less, 160 despite the average duration of VMS being approximately 7 years. 108 Notably, a significant proportion of females – nearly 40% 161 – experience the resurgence of menopausal symptoms following the discontinuation of MHT, even if the MHT dose is gradually tapered. In light of research linking more severe menopausal symptoms to MCI, 118 research associating VMS with brain and sleep disturbances and research indicating minimal or decreased cancer risk with MHT (especially with non-oral routes of administration), whether there should be a push to stop MHT after a certain age or time of use is debatable. This is especially true for those with persistent menopausal symptoms (e.g. females who continue to experience hot flashes into their 70s) and in the case of surgically induced menopause caused by bilateral oophorectomy, where there is a complete absence of postmenopausal ovarian hormone production. In transgender and gender-diverse populations, gender-affirming hormone therapy continues into older ages. Risks of continuing care are balanced with the need to reduce gender dysphoria and feminisation/masculinisation effects. 162 The risks for continuing MHT care in cisgender females beyond age 60 years or beyond 10 years after menopause should be balanced with the need to reduce menopausal symptoms and improve quality of life. Other MHT options should be considered rather than strict adherence to an age or duration cut-off; lower, effective MHT doses with transdermal or vaginal routes of administration should be offered. 105 , 106 The potential of brain-selective oestrogens for maintaining brain health should also be explored. The prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) can be systemically administered, but converts to E2 only in the brain. DHED has shown promise in preserving working and recognition memory in ovariectomised mice, and providing neuroprotection in rat stroke models and improving sleep in disturbances in ovariectomised marmosets. 163 – 165 The risk and benefits of MHT need to be updated and appropriately balanced with the emergence of new scientific evidence. In addition to considering genetic risk factors for Alzheimer’s disease, like APOE4 status, in evaluating MHT’s influence on cognition and the brain, other reproductive and lifestyle factors need to be considered. The menopausal period is often studied in isolation, but there are several other reproductive health transition periods that may also interact with MHT status. Pregnancy complications (e.g. preeclampsia) may set a trajectory for poorer brain health. 166 Parity (number of children) history influences APOE4 ’s effects on the brain and cognition, 167 and use of hormonal contraception has been associated with reduced cognitive impairment and reduced dementia risk. 28 Although pregnancy and hormonal contraception use may occur decades before menopause, the substantial ovarian hormone changes during these periods may result in lasting brain changes that influence an individual’s response to MHT (see Box 1 below). Additionally, several other modifiable dementia risk factors, including obesity, hypertension, diabetes, physical activity, smoking, cognitive engagement and social interaction, 168 should be addressed to optimise brain health. Importantly, MHT can interact with these risk factors, which likely works to influence dementia and Alzheimer’s disease risk. 169 Moreover, stress and trauma influence menopausal symptoms, 170 further suggesting that life experience could have important implications for reproductive senescence and MHT response. In addition to taking a ‘lifespan approach’ to studying menopause, there is a pressing need to further our understanding of the connection of menopausal symptoms to brain health, given their associations with MCI and dementia brain pathology. 112 , 117 Menopausal symptoms are often studied in isolation (e.g. only investigating VMS), but females experience an average of seven symptoms at a given time. 51 Moreover, the nature and severity of menopausal symptoms depends on culture and menopause type; 56 , 57 , 118 however, Western populations with spontaneous menopause are largely studied. Considering the collective impact of menopausal symptoms on brain health, within the context of cultural diversity and differing menopause types, should be a priority in developing targeted menopause treatments. Embracing these complexities in research is a necessary path forward to develop tailored MHT treatments with the greatest brain benefits for females. Box 1 Key research questions Do other menopausal symptoms, aside from VMS, drive cognitive and brain changes in females? How does this differ by intersectional factors such as ethnicity and economic status? Do other female-specific experiences, including hormonal contraception, menstrual cycle characteristics, parity and length of the perimenopausal period, influence MHT’s effects on the brain and cognition? Does MHT route of administration influence the brain and cognition? What combination of treatments for menopausal symptoms (e.g. MHT, cognitive–behavioural therapy, exercise, diet change) is most effective for symptom alleviation and does this differ for different symptom constellations? What brain and cognitive benefits, if any, does MHT provide for older females with persistent menopausal symptoms (i.e. symptoms that continue beyond age 60 years and beyond 10 years since menopause)? Key research questions Do other menopausal symptoms, aside from VMS, drive cognitive and brain changes in females? How does this differ by intersectional factors such as ethnicity and economic status? Do other female-specific experiences, including hormonal contraception, menstrual cycle characteristics, parity and length of the perimenopausal period, influence MHT’s effects on the brain and cognition? Does MHT route of administration influence the brain and cognition? What combination of treatments for menopausal symptoms (e.g. MHT, cognitive–behavioural therapy, exercise, diet change) is most effective for symptom alleviation and does this differ for different symptom constellations? What brain and cognitive benefits, if any, does MHT provide for older females with persistent menopausal symptoms (i.e. symptoms that continue beyond age 60 years and beyond 10 years since menopause)? Menopause is a pivotal inflection point in the ageing trajectory. Early identification of the menopausal transition and furthering our MHT knowledge is key for initiating appropriate care to preserve brain health in females. This starts with better-quality female health research that considers the many varieties of MHT and menopause. Several lines of research point to transdermal oestradiol as an effective form of MHT with brain and cognitive benefits. However, its effectiveness may depend on individual factors, such as APOE genotype, reproductive history and life experiences. Embracing this complexity in research is necessary to identify effective, individualised MHT. Rodent models present an attractive option to further our knowledge of the biological and environmental factors that affect an individual’s MHT response; they provide mechanistic insights into the actions of MHT on the brain and cognition. Importantly, the appropriate model of rodent menopause must be carefully selected to most accurately model the type of human menopause and MHT in question. In addition to dedicated research, more menopause education is needed. Healthcare practitioners need to proactively initiate conversations about menopause with their female patients. The undertreatment of menopausal symptoms suggests that more menopause specialists are needed. Specialists must be well-versed and kept up to date with the many types of menopause, the many symptoms of menopause and the many varieties of MHT including their risks and benefits. To support healthy brain ageing, menopause care beyond 60 years of age or 10 years postmenopause is needed. Half of the human population will go through menopause, yet our knowledge about menopause and brain health is considerably lacking. We must prioritise research that embraces the many menopause types, symptoms and therapies, and support all females in receiving informed and continued menopause care into later life.