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. 2023 Dec 10;33(4):113–119. doi: 10.1093/ppar/prad023

Menopause Is More Than Just Loss of Fertility

Clayton Baker 1,2, Bérénice A Benayoun 3,4,✉
Editor: Brian Kaskie
PMCID: PMC10751372  PMID: 38155935

Menopause is described as the point in time 12 months after a woman’s last menstrual cycle. Menopause typically begins between the ages of 45 and 55, with a mean age of ~51 years, but for a small percentage of the population (around 0.1%), it can occur as early as the second decade of life (Davis and Baber, 2022). Early menopause and the transition to menopause are accompanied by a myriad of systemic symptoms (e.g., irregular periods, hot flashes, sleep problems, and more) (Santoro et al., 2015). The three main stages of menopause include perimenopause, menopause, and postmenopause (Sherman, 2005). Perimenopause generally starts 3 to 5 years prior to the onset of menopause and is a period where most women begin to exhibit symptoms of menopause but still have menstrual cycles and can become pregnant (Barth et al., 2015). Menopause is the point where menstrual cycles have concluded, resulting in ovaries ceasing egg release and significantly reducing the amount of estrogen produced (Davis et al., 2015). Finally, postmenopause is categorized as the rest of a woman’s life after menopause has occurred. During this stage, acute symptoms may continue for several years (Peacock and Ketvertis, 2023).

Notably, although historically the focal point of menopause has primarily been the resulting loss of fertility (for good reason, as it is the most obvious and immediate consequence of the cessation of ovarian function), there are also significant consequences regarding aging and aging-related diseases caused by menopause (Cui et al., 2013). Beyond the continuation of systemic symptoms mentioned above, the reduction in circulating levels of estrogen and other ovarian hormones with menopause has been linked to increased risk for numerous age-related phenotypes and diseases, including Alzheimer’s disease, osteoporosis, and cardiovascular disease (Cheng et al., 2022; Davezac et al., 2021; Paganini-Hill and Henderson, 1994). Of note, estrogen primarily exerts its protective effects on age-related diseases through the binding and activation of one of three main estrogen receptors (ERα, ERβ, and GPER1). Because the expression pattern of these receptors is very tissue and system specific, the effects of menopause-induced reduced estrogen levels on each tissue or system are expected to be unique (resulting in varying degrees of effects between disparate tissues or systems) (Chen et al., 2022; Eyster, 2016). Importantly, menopause has been proposed to accelerate the biological aging of women (Levine et al., 2016). Consistently, age-at-menopause remains one of the best predictors of overall lifespan in women, with later menopause associating to decreased all-cause mortality and increased life expectancy (Ossewaarde et al., 2005).

Here, we provide an overview of the consequences of menopause (mainly through reduced estrogen levels) on cognitive function, bone mass and strength, and cardiovascular disease, with the purpose of painting a more complete picture of the consequences of menopause on health and lifespan (Figure 1). We also highlight concerning shortcomings regarding women’s health, including lack of equal representation in Food and Drug Administration (FDA) Phase 1/2 clinical dosing trials, dearth of reporting on women-specific adverse effects to drug treatments, limited consideration of menopause as a biological variable, and inadequate access to reliable diagnostic tests for menopause, all of which could be easily addressed by policy makers moving forward.

Figure 1.

Figure 1.

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The many health risks of menopause. Menopause leads to increased risk of diseases in the central nervous system, skeletal bone, and cardiovascular system, mainly due to decreasing estrogen levels, which can be prevented or treated with hormone replacement therapy. Premenopausal women (left) have high levels of circulating estrogens, which provide protective and homeostatic effects on the central nervous system, skeletal bone, and cardiovascular system. During the menopausal transition circulating estrogen levels decrease drastically. Postmenopausal women (right) have low circulating estrogen levels resulting in increased risks for Alzheimer’s disease, osteoporosis, and cardiovascular diseases. Hormone replacement therapy increases circulating estrogen levels and is effective in decreasing disease risk and severity (of previously described diseases), especially if initiated within 10 years of menopause. AD, Alzheimer’s disease; BMD, bone mass density. Figure created with BioRender.com.

Menopause and Cognitive Function

The central nervous system (CNS) comprises the brain and spinal cord, with the main functions of this system involving body homeostasis, voluntary movement, memory, learning, and much more (Thau et al., 2023). Estrogen has many key effects on the brain, including neural development, neuroprotective actions, modulating neurotransmitter function, and protective effects against the development of Alzheimer’s disease (AD) and other forms of dementia (Barth et al., 2015; Brann et al., 2007; Fu et al., 2022; McCarthy, 2008). Estrogen mainly functions through the binding and activation of its cognate receptors, enabling their downstream effects in the CNS through regulation of transcriptional landscapes (for nuclear receptor forms) or kinase activity (for membrane-associated receptor forms) (Arevalo et al., 2015). Specifically, estrogen’s role in modulating neurotransmitter function is enacted through effects on neurotransmitter release and regulation of cognate neurotransmitter receptors (Barth et al., 2015).

Because menopause is associated with a significant decrease in circulating estrogen levels, postmenopausal women lose the vast majority of positive or protective effects that estrogen exerts on the brain (Russell et al., 2019). The consequences of decreasing estrogen levels postmenopause can be directly linked to a substantial increase in AD risk, compared with both premenopausal females and age-matched males, based on the loss of neuroprotection, neurotransmitter function, and control of proteins involved in AD, all of which estrogen played a critical role in premenopause (Hara et al., 2015). Along with the increased risk of AD for postmenopausal females, cognitive issues also occur during the menopausal transition. Cognitive decline (impaired verbal learning, decreased verbal processing speed, and forgetfulness) is common during menopause and may be explained by decreases in both gray and white matter in the brain during this period (Kim et al., 2018). Although gray matter reduction in specific brain regions and cognitive decline generally revert back to healthy levels postmenopause, it is important to note that all brain regions with reduction in white matter persist at reduced levels for the rest of a woman’s life after menopause (Mosconi et al., 2021). Thus, menopause has strong and long-lasting consequences on women’s cognitive function during aging.

Vasomotor symptoms (more commonly known as “hot flashes” and “night sweats”) are one of the most common and recognized consequences of menopause (Thurston and Joffe, 2011). Vasomotor symptoms have previously been associated with significant increases in risks for diabetes and high blood pressure (Gray et al., 2018; Szmuilowicz et al., 2011). In accordance with these reports, it has also been suggested that females with severe vasomotor symptoms are at higher risk for stroke (Zhu et al., 2020). Vasomotor symptoms have also been linked to menopausal women being more susceptible to stress and having stronger responses to stressful events (as measured by increased cortisol levels shortly after the event) compared with premenopausal women (Nedstrand et al., 1998). Importantly, increased cortisol levels have been linked to memory impairment and decreasing blood flow rate (Thurston and Joffe, 2011). Together, these results suggest that vasomotor symptoms (and the severity) could be a risk factor for cardiovascular disease and cognitive impairment during the menopausal transition (cardiovascular disease will be discussed in more details below). Overall, menopause has significant effects on CNS function and disease.

Menopause and Bone Mass

Bone strength, which is determined by cortical thickness and porosity, bone geometry, intrinsic properties of bony tissue, and trabecular bone morphology, is currently the best proxy for bone health (Ott, 2016). Bone strength can be indirectly estimated by bone mineral density (Ammann and Rizzoli, 2003). Estrogen plays a crucial role in bone mass doubling during puberty, as well as bone turnover and formation homeostasis during adulthood by keeping resorption and formation in a balance (Khosla et al., 2012). In adulthood, estrogens suppress bone turnover and maintain a specific rate of bone formation, thus promoting bone health (Vaananen and Harkonen, 1996). During menopause, with the reduction in circulating estrogen, bone mineral density decreases roughly ~2.5% per year (from 1.5 years before menopause to 1.5 years after menopause), which is significantly higher than the premenopausal rate of 0.13% (Riggs et al., 1986; Slemenda et al., 1987). Reduced bone mineral density can eventually lead to a diagnosis of osteoporosis, with increased risk for debilitating fractures and injuries (Sozen et al., 2017). Importantly, ~35% of White postmenopausal females are estimated to have osteoporosis based on bone mineral density, compared with only ~19% of age-matched White males (Cauley, 2011; Melton et al., 1992). This sexual dimorphism in osteoporosis rates can mainly be attributed to menopause and the accompanying loss of estrogen-promoted bone homeostasis. Osteoporosis is extremely concerning in terms of public health because women with an osteoporosis diagnosis have a 40% lifetime fracture risk (Cooper et al., 1992). Indeed, another study showed that postmenopausal White women have a tenfold higher hip fracture rate compared with perimenopausal White women (Gourlay and Brown, 2004). This immense increase in osteoporosis and hip fracture incidence postmenopause is not exclusive to White women (although multiple studies suggest the increase is most dramatic in White women), with similar trends being observed in African American, Asian, Hispanic, and Indigenous American women (Burge et al., 2007; Cauley, 2011). However, despite these observations, there are still substantial ethnic and racial disparities that exist in screening, diagnosis, and treatment of osteoporosis, which could be addressed by policy makers moving forward (Calikyan et al., 2023). Because hip fractures are a leading cause of mortality and morbidity in aging women, increased rates of osteoporosis in the postmenopausal window represent a particularly concerning health risk for women’s health and life expectancy (Lo et al., 2015).

Menopause and Cardiovascular Disease Risk

The cardiovascular system consists of the heart and a closed network of veins, arteries, and capillaries. The main function of the cardiovascular system is to distribute oxygen, hormones, nutrients, and other important materials to all cells and organs in the body (Chaudhry et al., 2023). Importantly, estrogens play a crucial role in the health of the cardiovascular system (Knowlton and Lee, 2012). Estrogens are involved in vasodilation (expanding blood vessels and decreasing blood pressure), reducing inflammatory activation, and lessening atherosclerotic plaque lesion progression (Gilligan et al., 1994; Mendelsohn and Karas, 1999).

Broadly speaking, cardiovascular disease can be defined as a disease of the blood vessels or heart. Some examples of cardiovascular diseases include peripheral arterial disease, coronary heart disease, and aortic atherosclerosis (Olvera Lopez et al., 2023). In premenopausal females, the incidence rate of cardiovascular disease is approximately 0.31% per year, which is three times lower than that of age-matched males. However, this incidence rate dramatically and significantly increases to around 5.0% per year in postmenopausal women, representing a greater than sixteenfold risk increase compared with premenopausal women, closely matching the incidence rate of approximately 5.3% per year in age-matched men (Bleumink et al., 2004; Kannel et al., 1976; Zhu et al., 2019). These numbers clearly indicate that menopause greatly increases the risk of cardiovascular disease in women to the point where woman-biased protection observed at earlier ages is completely eliminated. As further evidence linking menopause to increased cardiovascular disease risk (as opposed to just natural aging), prior studies have shown that women who exhibit premature menopause (occurring before the age of 35) show a twofold to threefold increase on the risk of myocardial infarction, also known as a “heart attack” (Shin et al., 2022). Additionally, ovariectomy (surgical removal of one or both ovaries) of women before the age of 35 increases the risk of myocardial infarction sevenfold (Rosenberg et al., 1981). Cardiovascular disease risk can also be linked to the treatment of breast cancer in postmenopausal women through the prescription of aromatase inhibitors. Aromatase inhibitors function by preventing the conversion of androgens to estrogens, which can result in a 95% decrease of circulating estrogen levels, resulting in a higher risk of cardiovascular disease for breast cancer patients (Peters and Tadi, 2023). This drastic reduction in circulating estrogen (which mimics exaggerated and accelerated menopause phenotypes) is key in preventing breast cancer recurrence because many types of breast cancer are stimulated and activated by circulating estrogen (Yue et al., 2010). Unfortunately, this therapy also presents patients with drastic side effects and health consequences, as postmenopausal women treated with aromatase inhibitors for more than 4 years have been shown to present with increased risk for ischemic heart disease and arrhythmia (Sund et al., 2021). Another issue with aromatase inhibitor treatment is the low adherence rate observed, notably due to a multitude of factors including socioeconomic status and adverse or side effects (Brier et al., 2018; Sawesi et al., 2014). Despite the significant shortcomings of aromatase inhibitors, there has been little effort to research possible alternative treatments for breast cancer patients. Thus, there is an urgent need for research into alternatives to aromatase inhibitors moving forward, which could be recognized by policy makers to shift funding priorities.

Cardiovascular disease risk is of upmost important to women’s health because coronary artery disease is currently the leading cause of mortality and morbidity in postmenopausal women (El Khoudary et al., 2020). For postmenopausal women, there is a 31% lifetime death risk of cardiovascular disease, whereas breast cancer only has a 3% lifetime death risk (Cummings et al., 1989). Although previous studies have demonstrated that postmenopausal women have an accelerated rise in total cholesterol in the blood compared with age-matched males that potentially leads to increased cardiovascular disease rates in postmenopausal women, the current view in the field is that estrogen’s effects on blood vessels are as important, if not more, than the changes in lipids and lipoproteins postmenopause (Matthews et al., 1989). Taken together, these results indicate that menopause directly increases cardiovascular disease rates, with estrogen reduction at least partially responsible for the rise of these rates.

Postmenopausal Hormonal Replacement Therapy

Because loss of ovarian estrogen production during menopause is believed to exacerbate the risk of many age-related diseases, multiple studies have attempted to look at the benefit or detriment of hormone replacement therapy (HRT) in postmenopausal women, where women are provided treatment with exogenous estrogen or other ovarian hormones (Harper-Harrison and Shanahan, 2023). Due to trial design and premature termination of the Women’s Health Initiative HRT trial, there is still much resistance from the public to using HRT to alleviate and mitigate menopausal symptoms (Lobo, 2013). However, the new consensus is that HRT has overall beneficial effects in menopausal women, especially when initiated early in the menopausal transition and in the absence of specific risk factors (i.e., familial or personal history of breast cancer, a known mutation in BRCA1 or BRCA2 genes, or history of clotting disorders) (Lobo, 2013). Specifically, HRT for postmenopausal women with osteoporosis has been shown to improve bone mineral density and reduce fracture risk (Gambacciani and Levancini, 2014). Additionally, HRT (administration of estrogen alone or in combination with progesterone) has a promising impact on cardiovascular disease risk as a preventative treatment. Multiple studies conclude that both the administration of estrogen alone or an estrogen/progesterone combination have positive effects on cardiovascular disease if treatment is started within ~10 years of menopause (Grodstein et al., 1997, 2000; Schierbeck et al., 2012). For women who start HRT within 10 years of menopause, there was a significant reduction in mortality and cardiovascular events in a 16-year follow-up study (Schierbeck et al., 2012). On the other hand, when initiated > 10 years after menopause, studies suggest that HRT may then have negative outcomes on cardiovascular disease and health. Hormone replacement therapy as a therapy for cardiovascular disease prevention is vital for aging women because other preventative strategies, which have been more successful in male patients (aspirin and statins), have shown minimal efficacy in women (Petretta et al., 2010; Ridker et al., 2005).

In addition to cardiovascular disease, many studies have also looked at the effect of HRT on Alzheimer’s disease (Compton et al., 2001). Multiple studies have shown that HRT significantly decreases the risk of Alzheimer’s disease for postmenopausal women. In fact, one study concluded that long-term use of estrogen treatment decreased the risk of developing Alzheimer’s disease by ~5% annually (Compton et al., 2001). One important caveat regarding these studies is that each study only included women that had not been subjected to long periods of estrogen deprivation (i.e., women either going through perimenopause or previous long-term estrogen treatment). Although encouraging results suggest HRT may reduce Alzheimer’s disease risk, studies are less optimistic for HRT as a treatment for diagnosed Alzheimer’s disease patients. Three studies concluded there were no beneficial effects on Alzheimer’s disease symptoms after disease onset (Compton et al., 2001). Taken together, these results suggest that HRT may have therapeutic value in postmenopausal women for reducing Alzheimer’s disease risk, although potential risk factors would need to be accounted for in individualized plans to take into account health history and genetic risk.

In contrast, the benefits of HRT on stroke risk have not been established. Although an initial report suggested that HRT recipients had significantly higher rates of stroke, subsequent studies suggested a more moderate effect (Henderson and Lobo, 2012). However, no study to date has shown positive effects on stroke incidence. Thus, additional studies are needed for HRT to be considered or ruled out as a viable option to reduce stroke risk (Lobo, 2007).

In summary, these results suggest that HRT can be beneficial to aging postmenopausal women, especially if initiated early and in the absence of specific counterindication (e.g., family history of breast cancer), to reduce postmenopausal risks of osteoporosis, cardiovascular disease, and dementia. However, additional well-controlled long-term studies must be completed to determine the best long-term dosing scheme, and to better understand the mechanistic effect—and the appropriate therapeutic window—of HRT on postmenopausal disease risk. These future steps are vital to improve both women’s life expectancy and health span.

Conclusions

Menopause is an inevitable event for aging women. Along with this inevitability comes a substantial increased risk for almost all known age-related diseases (including many not described above such as diabetes, gastroenteritis, and cancer) (Fu et al., 2016; McCarthy and Raval, 2020). Although loss of fertility is a major hallmark of menopause, it is important to understand and recognize that this is just one of many consequences that arise from menopause. To date there have been numerous clinical studies on humans showing connections between menopause and many age-related diseases. In fact, there have been many clinical trials attempting to reverse the effects of menopause (through administration of exogenous estrogen) for different age-related diseases (like those mentioned above).

Interestingly, there are currently only three known species that undergo menopause (humans, killer whales, and short-finned pilot whales). Because traditional animal models used for preclinical studies (rodents, fruit flies, round worms, etc.) do not undergo natural menopause, it has been difficult to model the effect of menopause on age-related diseases and develop tailored, personalized therapies to help alleviate the consequences of menopause in women. Animal studies are vital to disease treatment and prevention because it allows for the biological mechanism of disease formation and progression to be deciphered. This vital information can then be used to create human therapies. Although work is underway in the field to create reliable, age-relevant preclinical mouse models for menopause, the work is still ongoing (Diaz Brinton, 2012).

Unfortunately, inclusion of women in early phase interventional clinical trials is still lagging even after the reversal of the 1977 FDA ban. This is especially concerning for Phase 1/2 dosing trials, due to large differences in drug pharmacokinetics in men versus women, which has led to the risk of adverse events in women occurring twice as often as in men (Zucker and Prendergast, 2020). Because of the lack of sufficient representation of women in clinical trials (and the lack of awareness on the nonfertility impacts of menopause), there is a large dearth of data on how most drugs and treatments for age-related conditions may interact (positively or adversely) with menopausal status. Indeed, age-at-menopause is rarely taken into account as a potential modifying factor, although epidemiological data (some of it discussed here) suggests that it is a crucial life event with long term consequences on women’s health that needs to be considered as a critical interacting variable. Additionally, because women experience adverse effects twice as often as men in dosing trials, there should be a requirement for all dosing trials to publicly release a list of potential women-specific adverse or side effects reported during the trial to prepare providers and female patients with a more accurate picture of treatment risks, benefits, and potential interactions.

Because of the lack of sufficient representation of women in clinical trials (and the lack of awareness on the non-fertility impacts of menopause), there is a large dearth of data on how most drugs/treatments for age-related conditions may interact (positively or adversely) with menopausal status.

Another current limitation in women’s health is the lack of access to an accurate and timely test to diagnose or predict age-at-menopause. Currently, the standard practice for menopause diagnosis is through self-reported systemic symptoms (hot flashes, sleep problems, and more) and only after 12 months of amenorrhea (absence of menstruation) (National Institute for Health and Care Excellence, 2019). These diagnosis methods have no predictive power about when menopause will occur, because in fact, it is only after the transition has concluded that a patient can even be diagnosed with menopause. Because the positive effects of HRT are more pronounced with earlier treatment initiation (as described above), a timelier diagnosis method may allow HRT to begin early and improve women’s health and lifespan. One alternative to the traditional diagnosis method could be to test for ovarian reserve (number of eggs remaining in the ovaries) through biomarkers such as serum anti-Müllerian hormone levels (Nelson et al., 2023). Because menopause is experienced by all aging women and due to all the implications it has on age-related diseases, one potential solution to the diagnosis problem is to mandate private and federal insurance policies to provide coverage for yearly ovarian reserve testing starting at age 45. A similar mandate was issued for the coverage of mammograms (in an attempt to lower breast cancer mortality) in the late 1900s in many states (Bitler and Carpenter, 2016). This mandate was extremely successful in increasing mammogram frequency and decreasing breast cancer mortality (by up to 40% compared with no screening) (Grimm et al., 2022). Using this framework, mandates on regular ovarian reserve testing coverage could result in higher HRT uptake at earlier timepoints relative to the menopausal transition, which would help blunt the effects of (peri-)menopause on many age-related diseases and increase women’s life expectancy and health span.

Altogether, policy efforts should go beyond recommending representation of women in clinical trials by not only mandating equal representation of genders in the recruited population but also sampling across the lifespan and with sufficient power to disentangle potential interactions with menopausal age. In terms of public health, women represent half the aging population, which makes taking into account female biological specificities (such as menopause) of the upmost importance to implement therapies to control age-related disease rates and improve the health of the aging human population. Because at the end of the day, menopause is more than just loss of fertility.

At the end of the day, menopause is more than just loss of fertility.

Acknowledgments

The authors thank Dr. Jennifer Garrison for feedback on the manuscript.

Contributor Information

Clayton Baker, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA; Molecular and Computational Biology Department, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA.

Bérénice A Benayoun, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA; Molecular and Computational Biology Department, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA.

Funding

B. A. Benayoun is supported by National Institute of General Medical Sciences R35 GM142395, NIA R01 AG076433, Simons Foundation award SF811217, and Pew Biomedical Scholar award #00034120.

Conflict of Interest

None.

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