Reproductive Fitness and the Links to Chronic Disease and Systemic Aging.

Women are born with a fixed number of eggs, called the ‘ovarian reserve’, which is established during fetal development ( 20 ). From about 7 million eggs created during mid-fetal stages, this number declines to 1–2 million at birth and further drops to 300,000–500,000 by the time puberty is achieved. Subsequently, this population undergoes monthly attrition during menstruation, wherein one egg matures while innumerable others die by apoptotic ‘atresia’, ultimately leaving fewer than 500 eggs by the time menopause is reached marking the cessation of the ovarian cycle and menstruation and the definitive end of fertility ( Fig. 2 ) ( 21 ). Menstrual cycles and reproductive health are governed by the functional units of the ovary, the ovarian follicles, and the inter-organ signaling system, the hypothalamic-pituitary-ovarian (HPO) axis. Gonadotrophin-releasing hormone (GnRH) secreted from the hypothalamus stimulates the pituitary gland to release follicle stimulating hormone (FSH) and Luteinizing Hormone (LH). Upon reaching the ovaries, FSH and LH signal the development of ovarian follicles that in turn support maturation of one oocyte ( 20 , 21 ). Somatic cells of the ovarian follicle called granulosa and theca cells produce the key reproductive hormones, estrogen and progesterone. These hormones not only provide endocrine support for different steps of the menstrual cycle, and pregnancy if fertilization and implantation occur, they have widespread systemic effects, especially estrogen, for maintenance of cardiovascular, cognitive, metabolic and bone health ( 22 – 24 ). With age, the follicle pool is significantly depleted resulting in reduced estrogen production, widespread fibrosis and ovarian shrinkage ( 21 , 25 , 26 ). Age-related fertility decline is a result of diminishing ovarian reserve compounded by a deterioration in egg quality and increased rates of aneuploidy due to meiotic errors ( 27 ). Female fertility peaks in the late teens to early twenties, begins to decline in the early thirties, and sharply drops in the mid-to-late thirties such that by age 35, ~10% of women are infertile, and those in their forties have <5% monthly chance of achieving natural conception ( Fig. 1 ) ( 28 ). By age 40, an estimated 80–90% of ovulated eggs are also aneuploid (compared to < 25% before age 35), decreasing the likelihood of pregnancy and increasing the risk of fetal chromosomal abnormalities ( 27 , 28 ). Reproductive span (RS) in women is measured as the age at first menstruation, or menarche (AAM) subtracted from the age at natural menopause (ANM) which is defined as one year after the final menstrual period (FMP). Currently, the median AAM is ~12–13 years (with a global trend towards decline) and median ANM is ~49–50 years ( 29 , 30 ). Both AAM and ANM are highly heritable, with estimates suggesting up to 60% genetic contributions ( 31 ), and both have been found to have significant impacts on a variety of late-life health measures and susceptibilities ( 3 , 32 ). However, there is tremendous variation in the size of ovarian reserves women are born with as well as their rate of attrition with few reliable, diagnostic measures ( 27 , 31 , 33 ). Anti-mullerian hormone (AMH) produced by the follicles, together with measurement of FSH and Estradiol, are used to estimate ovarian reserve but have limited efficacy in predicting the fitness of the remaining reserve ( 33 , 34 ). However, the exact mechanisms that determine establishment of the ovarian reserve or govern its depletion during adult life remain poorly understood.

Despite strengthening empirical support that reproductive dysfunction reflects broader health vulnerability, clinical care continues to focus narrowly on fertility outcomes. There is an urgent imperative to clinically reframe reproductive transitions, including menarche, cycle regularity, and menopause, as predictive health indicators that warrant integrated risk assessment and ongoing clinical monitoring. Currently, clinical management predominantly follows gynecological diagnoses emerging from fertility issues and relies on symptom management by medications and/or lifestyle changes such as diet and exercise. These interventions however are much less effective when started after systemic-disease progression has commenced. In healthcare settings, screenings for reproductive risk factors that start early and regularly, as part of routine medical monitoring such as lipid profiling, will be beneficial for early identification of susceptibilities and prevention of long-term systemic dysfunctions. These screening need to be part of annual pediatric and general health exams, similar to metabolic profiling for example, and not necessarily dependent upon gynecological and obstetric interventions. Initiatives by professional societies like American Council of Obstetricians and Gynecologists and the American Association of Pediatrics to recognize the menstrual cycle as a fifth vital sign represent a promising step toward embedding reproductive health into routine care ( 29 ). With over a million women estimated to be transitioning into menopause annually in the U.S.A ( 18 , 65 ), integrating reproductive history into preventive health frameworks that enables early identification of chronic disease risks has the potential for transforming biomedical and economic outlooks. Looking ahead, transdisciplinary research that bridges reproductive and aging biology is essential to develop interventions that simultaneously promote reproductive and systemic health. Priorities include the development of new model systems, longitudinal studies, investigations into upstream shared mechanisms, effective interventions and precision medicine approaches to women’s health informed by reproductive history. Combining the rapid advances in continuous health monitoring devices with artificial intelligence (AI)-driven analytics is a promising approach to accelerate the pace of research and practice in this space. Wearables and monitoring devices can help generate consistent, real-time data on reproductive and metabolic parameters, while AI analytics can help to identify previously unrecognized patterns that traditional clinical assessments might miss ( 162 ). Existing AI-based methods for fertility tracking and improving success of artificial reproductive technologies (ARTs) can be harnessed towards reproductive-aging assessments. Encouragingly, AI-based non-invasive tests for measuring reproductive aging through retinal age gap detection have been devised along with AI-based wearable sensors and digital platforms to track perimenopause and PCOS ( 163 , 164 ). Ultimately, a life course, holistic perspective that recognizes reproductive health as a window into somatic aging will be key to improving healthspan and reducing chronic disease burden in aging populations.

Strong associations have been established between early puberty, especially AAM of <12 years of age, and higher body mass index (BMI), increased adiposity, non-alcoholic fatty liver disease (NAFLD) and heightened vulnerabilities to Type 2 Diabetes (T2DM), metabolic syndrome, hypercholesteremia, cardiovascular disease (CVD) and PCOS in adult life ( 30 , 32 , 40 – 43 ). Recent meta-analyses have reported 22% higher risks for T2DM and 15–20% higher risk of breast cancer in women with AAM <12 years ( 44 , 45 ). These susceptibilities are attributed, in part, to increased adiposity, along with earlier, higher levels of circulating estrogen and a transient, growth-associated insulin resistance seen in adolescence ( 40 , 46 , 47 ). Paradoxically, late AAM may also be linked to increased disease susceptibilities, and early and late AAM are both linked to early onset of menopause ( 30 , 41 ). In some studies- but not others- later AAM has been found to be linked with increased risk of neurodegenerative diseases such as Alzheimer’s Disease (AD), the most common form of dementia, suggesting a complex relationship shaped by duration of lifelong exposure to estrogen ( 48 , 49 ). The link between puberty and breast cancer in adulthood is also related to lifetime estrogen exposure but more clearly established, with 5% higher risk for every 1 year reduction in AAM ( 50 , 51 ). Genome-wide association studies (GWAS) have identified hundreds of loci predicted to influence pubertal timing ( 41 , 42 , 52 – 54 ) and experimental dissections of some single genes implicated in precocious or delayed AAM have been conducted ( 55 , 56 ). Unsurprisingly, many of these loci encode elements of the HPO axis such as ones encoding subunits of FSH ( FSHB ), or FSH Receptor ( FSHR ) or ones involved in metabolic signaling pathways also implicated in BMI and energy homeostasis such as the Leptin Receptor ( LEPR ) ( 42 , 52 , 57 – 59 ). While the basic functions of these genes are known, what is needed are studies that help understand their roles in specific tissues and different ages. Detailed mechanistic investigations on how their regulation changes across time and biological contexts will help unravel how variations in these patterns shape systemic outcomes.

The influence of reproductive status on long-term health reaches beyond the roles of normal fertility transitions described above. The link between early ANM and increased risk of chronic diseases is now well recognized ( 15 , 104 ). There is also growing evidence that a broad range of reproductive dysfunctions, from severe infertility to moderate menstrual irregularities, are also associated with higher risks of morbidity and mortality ( 15 , 17 ). Crucially, as with normal reproductive transitions, it is not only the occurrence of reproductive dysfunction but also the age at which it arises that shapes the severity of systemic consequences. These insights underscore the recognition that reproductive fitness at any age is both a marker and a driver of long-term physiological well-being.

Collectively, the evidences enumerated above illustrate the strong associations between normal reproductive milestones, reproductive aging, and fertility disorders, with overall health, chronic disease risk and late-life health outcomes ( 15 , 17 ). Nevertheless, the biology underpinning these relationships remains largely unresolved. A key challenge is determining whether these patterns represent direct causal connections or instead arise from shared genetic, hormonal, and environmental determinants. Reproductive hallmarks may serve multiple roles: as early markers of underlying vulnerability, as active contributors to disease pathways, or as modulators that amplify or buffer other risks. Importantly, since the etiology of many metabolic diseases often begins years before clinical diagnosis, these factors may influence health even before the reproductive years. The complexity arises, in part, from the challenge of disentangling overlapping contributions of endocrine function, genetic predisposition, body weight, and nutrition in human populations ( 17 , 103 ). Moreover, limitations in longitudinal data and mechanistic tools hinder our ability to trace reproductive-somatic interactions in humans over time, underscoring the need for integrative, longitudinal approaches and in-depth investigations. Animal models have proven extremely valuable in bridging this gap. Invertebrates model organisms such as Caenorhabditis elegans and Drosophila melanogaster have provided key insights into evolutionary trade-offs between reproduction, longevity and immunity ( 134 – 137 ) and have helped identify conserved pathways that link reproductive signaling to somatic aging processes, including stress resistance, protein homeostasis, and lipid metabolism ( 138 – 141 ). In Drosophila , maternal diet and specific amino acid restriction have been shown to affect reproductive span, providing models for unraveling the impact of nutritional interventions on the reproduction-longevity relationship ( 142 ). Interestingly, studies in C. elegans have shown that disrupting meiosis, a germline-specific process, accelerates somatic aging and shortens lifespan, suggesting germline-soma crosstalk in aging regulation and directly testing the causal relationships between germline fitness and somatic aging ( 143 ) that are severely limited in human studies ( 144 ). Mice have been valuable for advancing this field as the primary mammalian model recapitulating aspects of ovarian aging not accessible in invertebrate systems ( 25 ). Mouse ovarian transplantation studies have shown that young ovarian tissue can extend lifespan and improve cardiovascular health in older females, effects that appear relatively independent of estrogen production ( 145 – 148 ). Together, studies from worms, flies and mice are yielding unprecedented insights into sex-specific neurobiology and immunology as well as the role of microbiota in the linking reproduction and aging across the lifespan ( 149 – 151 ). Mice have also served as critical platforms for elaborating the molecular and cellular biology of reproductive aging from novel oocyte quality control mechanisms to broad tissue-level fibrotic deterioration and its quantification ( 152 – 154 ). Indeed, over a decade after the molecular hallmarks of organismal aging were described (and recently updated) ( 155 , 156 ), the molecular hallmarks of reproductive aging have now been elaborated, many of which parallel the established hallmarks of somatic aging ( 25 , 26 ). Moreover, interventions known to delay somatic aging across species such as calorie restriction and mTOR inhibition have been tested for their potential in extending reproductive lifespan in mice and have accelerated identification of candidate drugs for extending reproductive span in human trials ( 39 , 157 – 161 ). For example, a recent clinical trial testing rapamycin, an mTOR inhibitor known to extend lifespan and healthspan, has provided highly promising results for delaying menopause (VIBRANT, NCT05836025 ). While encouraging, these findings also underscore the gaps in knowledge in this area and the need for interdisciplinary research at the interface of reproductive and aging biology to identify interventions that simultaneously enhance reproductive and overall health.

It was originally thought that menopause was rare in mammals, affecting mainly humans and a few species of whales. However, given how uncommon menstruation is in the animal kingdom, recent findings suggest that this presumed rarity may in fact reflect how menopause has been defined rather than a biological reality. When menopause is defined as a cessation of ovarian function, with the end of menstruation serving only as a detectable marker of this transition, a larger fraction of mammalian species appear to undergo menopause and spend a considerable time in a post-reproductive state ( 60 , 61 ). While widespread in nature, the evolutionary origins of menopause remain debated. Menopause has been proposed to be either a vestigial byproduct of increased lifespan or, as outlined by the ‘grandmother hypothesis’, a beneficial adaptation by which post-reproductive females enhance survival of future generations ( 62 , 63 ). When the term ‘menopause’ was coined in the 1820s ( 64 ) average female lifespan (~40–50 years) was nearly aligned with the average ANM of around 50 years ( 30 ). However, since then lifespan has increased by two to three decades, while ANM has remained unchanged, underscoring its biological constancy amid extended longevity. The typical ANM ranges between ages 45–55 years based on genetics, race, geography and lifestyle. Clinically ANM between 40–45 years is classified as early menopause and before 40 years of age as premature menopause ( 30 , 65 ). Menopause is preceded by perimenopause, a transitional phase characterized by hormonal fluctuations and a constellation of vasomotor, metabolic, genitourinary, cognitive, and psychological symptoms ( 65 , 66 ). The vasomotor symptoms (VMS)- notably hot flashes and night sweats- are hallmark features and have been independently linked to increased cardiometabolic risk ( 66 , 67 ). Over 70% women reportedly experience some menopausal symptoms, especially VMSs, but there is tremendous variability in their incidence, intensity and length, ranging from transient discomfort to debilitations spanning 7–10 years ( 65 , 68 ). Importantly, the menopausal transition is associated with dyslipidemia, insulin resistance, weight gain, body fat redistribution, and increased visceral adiposity ( 66 , 67 ), all of which elevate the risk for major, chronic diseases especially CVD, the leading cause of death in aging women, and T2DM, named the ‘defining disease of the 21 st century ( 69 – 71 ). The risk of developing both metabolic syndrome and CVD is most pronounced during perimenopause, independent of age ( 66 , 67 ). Additionally, the effects of adiposity on VMS symptoms shift during the transition itself, with higher body weight worsening symptoms during perimenopause but reducing them after menopause ( 66 ) further suggesting this transitional period may be particularly critical for cardiovascular and metabolic health. Several epidemiological studies, particularly the longitudinal Study of Women’s Health Across the Nation (SWAN), have indicated that menopause itself, rather than aging per se , is a critical determinant of midlife and late-life health ( 66 , 67 ). There are also compelling findings that VMS severity is positively correlated with dyslipidemia and CVD risk, independent of the levels of sex hormones or lifestyle factors such as diet and physical activity. Moreover, shorter menstrual cycles (<25 days) are predictive of earlier menopause and more intense VMS ( 69 ). Surprisingly, obesity is associated with later ANM but exacerbated VMS severity ( 72 ). The timing of menopause is a critical determinant of long-term health, as later menopause is strongly associated with enhanced lifespan. Historical epidemiological studies have found reproductive longevity to be a hallmark of exceptional longevity, with > 20% female centenarians having borne children after age 40, compared to less than 5% in the general population ( 73 ). More recently, molecular analyses have shown that women who undergo later menopause (>55 years), exhibit a younger biological age based on epigenetic aging clocks, whereas, those with early menopause display accelerated epigenetic aging signatures ( 4 ). These findings support the notion that extended reproductive span is not only a reflection of slower aging but may also be mechanistically linked to the biological pathways that promote healthy lifespan. Conversely, multiple studies have demonstrated that menopause before age 45 is associated with significantly increased all-cause mortality, especially due to CVD ( 74 – 76 ). This risk decreases progressively with each additional year of age at menopause ( 74 , 77 ). This pattern is observed regardless of whether early menopause results from surgical removal of the ovaries or due to spontaneous early menopause ( 77 ). The consistency of these findings across different etiologies suggests that the timing of menopause, rather than the specific cause, drives the increased health risks associated with early menopause. Post-menopausal women are at a greater risk of developing osteoporosis, cognitive dysfunction and neurodegenerative diseases such as AD ( 78 , 79 ). AD prevalence is twice as high in women 65 years and older as compared to men. Women not only comprise two thirds of dementia cases, their symptoms of cognitive decline are also more severe and progress more rapidly into advanced disease ( 80 , 81 ). Some of this increased prevalence can be attributed to greater longevity in females, but increasingly the menopause transition is being recognized as a contributor to female AD vulnerability ( 78 , 82 , 83 ). Menopause is recognized as the greatest risk factor for osteoporosis but bone loss, in fact, begins during perimenopause ( 84 ). Amongst the spectrum of menopause-associated disease vulnerabilities, osteoporosis especially demonstrates the importance of timing of menopause and the menopausal transition. The SWAN study has provided compelling evidence that bone mineral density (BMD) begins to decline in women about one year before the final menstrual period, accelerates during the menopausal transition, and then slows down in post-menopause ( 84 , 85 ). This critical phase, sometimes termed ‘transmenopause’, closely parallels changes in estradiol and FSH. It also incurs deficits in bone microarchitecture that may be irreversible establishing long-term susceptibility to osteoporosis and fracture ( 86 ). Hence, while both men and women lose on an average 1% of BMD each year after age 50, women comprise two-thirds of fragility-related fractures observed in the elderly because of the striking bone loss that occurs within 10 years of menopause ( 1 ). The menopausal transition represents a critical window for osteoporosis risk determination but preventive strategies are hampered because FMP determination is currently retrospective by at least a year. Altogether, while women live longer than men they experience a greater burden of diseases and disability in later years. The pronounced effects of menopause are largely attributable to changes in estrogen. Declining estrogen levels are a key factor influencing diverse features of menopausal pathophysiology. Before menopause, circulating estrogen helps maintain oxidative balance, reduce arterial stiffness and fibrosis and confers a cardioprotective advantage on pre-menopausal women, as compared to age-matched men ( 23 ). With menopause, the diminished estrogen production, hormonal variations and cycle irregularities lead to a systemic milieu of chronic inflammation ( 1 , 3 ). Disruptions in reproductive hormone-regulated lipid and glucose metabolism substantially increase the risk of CVD and T2DM ( 87 ). Menopausal disruption of neuromodulatory functions of estrogen are believed to result in the aberrant neuronal bioenergetics, inflammation, and lipid homeostasis that underlie the vulnerability to neuronal decline and neurodegenerative diseases ( 24 , 83 ). Estrogen’s role in regulating bone remodeling is also well established. Serum estrogen levels are directly correlated to BMD and anti-correlated with bone-fracture susceptibilities ( 1 , 22 ). Hormone therapy has been shown to reduce bone loss and fracture risk, underscoring the importance of estrogen in the health outcomes associated with menopause. Supplemental estrogen therapy (SET) has been found to be a potent mitigator of VMSs as well as some medium-term disease risks of menopause. Epidemiological data from a 20 year longitudinal Nurses Health Study revealed that hormone replacement therapy (HRT) reduced CVD risk amongst menopausal women ( 88 ). Since then, several successive studies across the globe such as the Early vs. Late Intervention Trial with Estradiol (ELITE), the Kronos Early Estrogen Prevention Study (KEEPS) and the Danish Osteoporosis Prevention Study (DOPS) have all supported the value of estrogen supplementation during perimenopause and early menopausal years for mitigating VMS symptoms and, in several cases, protection against T2DM, CVD and atherosclerosis ( 89 – 91 ). Importantly, these early treatments have been found to show no significant increase in cancer risks ( 91 ). However, clarity on the optimal timing and length of SET usage in ameliorating long-term cardiometabolic risk is mixed and confounded by the tarnished perception of early HRT trials that were erroneously reported to be linked with increased risk of stroke and heart disease ( 92 ). The data on HRT benefits against neurodegenerative diseases is also more equivocal. While at least two epidemiological studies have demonstrated neuroprotection with early usage of vaginal or transdermal estrogen supplements ( 93 , 94 ), studies in menopausal women >65 have found increased dementia risk suggesting that estrogen’s neuroprotective effects vary based on menopause stage and the age at treatment initiation ( 95 , 96 ). Data from animal and human studies strongly suggest a role for estrogen in influencing dementia risk, and there is promising evidence for its supplementation as an early, time-sensitive approach for AD risk reduction ( 96 ). However, this area remains in dire need of rigorous clinical trials and mechanistic studies, as do many unexplained features of menopausal symptoms and susceptibilities. For instance, menopausal symptom severity does not consistently track with circulating estrogen levels. Higher FSH and lower estradiol levels, rather than absolute estrogen levels, have been found to be more predictive of VMS occurrence, duration and severity ( 97 ). The reasons for this are unclear. Altogether, our limited knowledge about the mechanisms underlying the timing and variability of menopause and its associated systemic consequences severely limit the scope of existing preventive and therapeutic interventions. Recent large-scale GWAS have uncovered nearly 300 genetic loci associated with ANM ( 52 , 57 , 98 , 99 ). These studies have repeatedly identified common polymorphisms distributed across these loci, including those containing DNA damage response (DDR) genes such as CHEK2 , BRCA1 , BRCA2 , and MCM8 , highlighting the critical role of DDR pathways in preserving the ovarian reserve ( 99 – 101 ). Follow-up sequencing analysis of GWAS loci have identified rare protein coding variants in DDR genes. Notably, BRCA1 and BRCA2 variants are linked to earlier menopause, likely due to defective DNA repair during meiosis, whereas, rare loss-of-function variants in CHEK2 are linked with delayed menopause ( 52 , 99 , 100 ). Other rare protein-coding variants in DDR genes such as ZNF518A , PALB2 , and SAMHD1 have been found to exert large effects on menopause timing, with some variants advancing menopause by up to six years ( 52 , 102 ). Beyond DDR, GWAS have identified common variants in loci that encode hormonal regulators ( FSHB , ESR1) and folliculogenesis-related genes ( WNT4 , CYP19A1) some of which are, expectedly, also implicated in reproductive disorders such as POI and endometriosis ( 52 , 103 ). Additionally, metabolic regulators such as FTO , known for their association with BMI and insulin sensitivity, appear to impact reproductive lifespan, possibly through effects on the HPO axis. Several loci that influence both AAM and ANM have also been identified ( 42 , 52 , 103 ). These gene identifications are promising as they open avenues for unraveling the complex biology that determines reproductive span in normal women as well as its short- and long-term systemic consequences.

PCOS is the most common endocrine disorder in reproductive-age women, affecting 8–13% depending on diagnostic criteria including hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology ( 111 ). Although classified as a reproductive disease due to its association with menstrual abnormalities and infertility, PCOS is increasingly recognized as a lifelong condition with major health risks ( 112 ). In fact, beyond reproductive symptoms, PCOS itself is characterized by metabolic dysregulation, including disrupted insulin signaling, chronic inflammation, oxidative stress, and excess androgen production- all of which contribute to elevated cardiometabolic risk. Hyperandrogenia is a characteristic feature of PCOS that is linked to metabolic disorders ( 13 ). Central to its pathophysiology are insulin resistance, present in up to 70% of obese and 30% of lean women with PCOS. Women with PCOS are significantly more likely to develop impaired glucose tolerance (23–35%) and T2DM (4–10%), even when matched for BMI. The prevalence of metabolic syndrome is expectedly markedly higher in PCOS patients, reaching over 50% in those aged 30–39 ( 113 ). Notably, about one third of PCOS patients are not obese and have normal BMI. So, while reproductive dysfunction may be exacerbated by metabolic disturbance in high-BMI PCOS, both are manifestations of shared upstream pathology ( 114 ). Gestational diabetes is also a frequent complication, affecting up to 40% of pregnancies in women with PCOS, who are also more likely to experience hypertensive pregnancy disorders and have 7 times greater lifetime risk of developing T2DM ( 113 , 115 ). Cardiovascular risk factors such as central adiposity, dyslipidemia, and hypertension emerge early in women with PCOS and persist with age. Although direct evidence of increased cardiovascular events is limited, surrogate markers suggest elevated CVD risk and subclinical atherosclerosis ( 116 ). Some studies indicate that PCOS during reproductive ages also confers a higher risk for developing hypertension after menopause. PCOS is also linked to NAFLD, with greater severity and higher rates of fibrosis than in non-PCOS counterparts ( 117 ). Women with PCOS have a 2.7-fold higher risk for developing endometrial cancer, attributed to the prolonged exposure of the endometrium to elevated estrogen levels ( 118 ). Recently, PCOS was positively associated with elevated risk of pancreatic cancer after adjusting for age, race and ethnicity, BMI, and estrogen use ( 119 ). While no additional risk for breast or ovarian cancers has been reported, there have been few large-scale cohort studies addressing this ( 119 , 120 ). The constellation of cardiometabolic aberrations triggered by PCOS are also implicated in the etiology of neurodegenerative disorders such as AD. But, since PCOS is studied in young women and AD manifests in late life, there have been no reports examining neurodegenerative disease incidence in late life following PCOS diagnoses, although one report showed elevated amyloid precursor protein (APP) in blood of PCOS women ( 121 ). A recent, preliminary report indicates increased mortality in PCOS patients ( 122 ). The genetic underpinnings of PCOS remain relatively elusive, despite several genome-wide association studies implicating genes related to the HPO axis, insulin signaling, and inflammatory cytokines ( 123 , 124 ). Predictably, several of these loci are also implicated in other reproductive disorders and traits such as POI and AAM, respectively ( 52 , 58 , 123 ). Lastly, clinical care remains focused primarily on symptom relief, with insufficient emphasis on the lifelong cardiometabolic risks ( 111 ), and there remains a pressing need for more comprehensive, evidence-based approaches that address the full spectrum of PCOS related long-term morbidities.

Infertility, whether due to idiopathic factors or clearly defined conditions such as POI, has emerged as a vital marker of long-term health vulnerabilities in women, with implications that extend far beyond the inability to conceive ( 16 ). Traditionally defined as the failure to achieve pregnancy after 12 months of regular, unprotected intercourse, infertility affects a substantial proportion of the population and can arise from a range of etiologies besides POI. This includes diminished ovarian reserve (DOR), a condition defined by high FSH, low AMH, reduced antral follicle count, and poor ovarian response to stimulation. DOR, in fact, afflicts a much larger proportion than POI with prevalence rates of ~14% and ~1%, respectively ( 15 ). Infertility itself, regardless of etiology, is associated with elevated mortality and morbidity, and in both sexes ( 16 , 19 ). Multiple large-scale, population studies have revealed that infertile women face a 26–32% higher risk of all-cause mortality compared to their fertile counterparts ( 15 ). This elevated risk is particularly pronounced in women who become infertile before age 40. Whether through surgically induced early menopause or spontaneous POI, they have an increased risk of all-cause mortality, particularly due to cardiovascular disease ( 75 ). For example, a U.S. claims-based analysis spanning over 15 years found a 32% increase in mortality risk among infertile women across ages, races, and socioeconomic strata ( 105 ). Cancer-related mortality is also significantly elevated in this population, with one cohort study showing a 23% increase in overall death risk, and a twofold higher risk of breast cancer–specific death among infertile women ( 106 ). Similarly, data from the Nurses’ Health Study II reported a 26% elevation in premature mortality (defined as death before age 70) which was primarily driven by cancer diagnoses and was especially pronounced in younger infertile women ( 107 ). The burden of chronic diseases is also disproportionately high amongst infertile women. A history of infertility has been linked with 80% greater likelihood of developing metabolic syndrome and a 71% increased risk of CVD ( 108 ). Large cohort studies analyzing U.S. health-insurance claims data have identified increased incidences of T2D, liver disease, and cerebrovascular events in this group. Importantly, these studies have examined found these associations independent of confounders such as obesity, BMI, age and race ( 109 , 110 ). These findings suggest infertility may directly contribute to metabolic dysfunction rather than simply correlating with it. The persistence of associations after excluding PCOS and POI ( 108 ) and the absence of typical racial health disparities among infertile women ( 109 ) both also point toward infertility related mechanisms as primary drivers of increased disease risk.

Reproductive status and overall health are intimately and reciprocally linked. Historically, reproductive fitness has been viewed narrowly through the lens of fertility and procreation. However, a large and emerging body of evidence is leading to the recognition that the reproductive system profoundly impacts every aspect of lifelong health. Female reproductive decline represents one of the earliest signs of aging, often occurring decades before the onset of other systemic, age-related changes ( Fig. 1 ) ( 1 ). In the last three decades, remarkable advances have been made in our knowledge of the basic biology of organismal aging, including discoveries of pathways regulating longevity, healthspan and resilience ( 2 ). But, the understanding of reproductive aging, and its systemic consequences has been comparatively limited. This is a critical gap because menopause is emerging as a powerful driver of systemic aging, characterized by unfavorable shifts in lipid profiles, accelerated vascular aging, and heightened vulnerability to metabolic and neurological diseases ( 3 , 4 ). Notably, while human lifespan has increased dramatically over the past century, the timing of menopause has remained relatively constant, resulting in women spending an increasing fraction of their lives in a post-reproductive state ( 5 ). This mismatch is leading to a scenario wherein although women live longer than men, they experience higher burdens of chronic illness and disability across their later years, with far-reaching implications for biomedical, public health and social systems as well as economic outlooks ( 5 – 7 ). The long-term impact of reproductive events is not limited to menopause. Pregnancy, traditionally viewed as a transient physiological state, is now understood to have lasting effects on multiple aspects of maternal health ( 8 – 12 ). Indeed, other major normal life-course reproductive events such as puberty and childbearing also appear to be critical inflection points that influence women’s long-term risk for chronic diseases and late-life health ( Fig. 2 ). Moreover, besides normal physiological transitions, reproductive dysfunction is emerging as a predictor of adverse long-term health outcomes. Reproductive disorders ranging from infertility and primary ovarian insufficiency (POI) to widely prevalent diseases such as polycystic ovary syndrome (PCOS) and endometriosis are found to be linked with increased risk of late-life morbidities ( Fig. 2 ) ( 13 – 16 ). Altogether, clinical and epidemiological evidence increasingly points towards a strong connection between normal reproductive milestones, reproductive senescence and fertility disorders, with the risk of chronic diseases and late-life health outcomes ( 15 , 17 ). underscoring the need for examining reproductive health from a broader perspective. However, the mechanistic basis for these associations remains largely elusive with a major challenge being the determination whether they arise from direct causal relationships or from shared genetic, hormonal, and environmental influences. Global demographic changes, including delayed childbearing and reduced fertility rates, are altering the landscape of reproductive health and modifying women’s long-term risk profiles ( 6 , 18 ). These shifts highlight the need for a deeper understanding of the prevalence and mechanistic underpinnings of such health modifiers. There are numerous evidences suggesting that the impacts of reproductive status on systemic health and aging likely extend to males too ( 19 ). Yet, the discrete onset and conclusion of female reproductive capacity provide a unique window into unraveling these relationships, with the ensuing knowledge likely to benefit health outcomes in both sexes. In this review, we focus specifically on the relationships between reproduction, systemic health and aging in women, referring to individuals with ovaries and assigned female at birth. We provide an overview of current knowledge on how normal reproductive transitions and reproductive dysfunctions appear to shape long-term health trajectories, particularly in relation to cardiometabolic diseases, neurological disorders and cancer. We briefly describe discoveries on the genetic bases of these links and key mechanistic insights from experimental studies. By elaborating these interconnections, we aim to highlight opportunities for early interventions and policy changes to improve health of women and men across the lifespan.

Endometriosis is a common gynecologic condition that is estimated to afflict ~10% of reproductive-age women. It is characterized by chronic pelvic pain, menstrual abnormalities, intestinal distress, and in a significant number of cases, infertility ( 125 ). The disease is generally defined by the presence of ectopic endometrial-like tissue implants outside the uterine cavity, which can also spread to extra-pelvic sites. Endometriosis diagnosis is frequently delayed, by up to 7–10 years, due to nonspecific symptoms and the need for surgical confirmation ( 125 ). Endometriosis is being recognized as a disease of chronic inflammation and immune dysregulation, triggered by extra-uterine gynecologic lesions that incite persistent immune responses. Hence, while pain, infertility and gynecological features dominate the clinical outlook, evidence increasingly points to its associations with long-term disease risks that extend well beyond the reproductive years ( 14 , 125 , 126 ). The most consistently observed long-term risk is for cancer susceptibility, especially a near twofold increased likelihood of developing epithelial ovarian cancer of the endometrioid and clear cell subtypes ( 14 , 127 , 128 ). This risk is most pronounced in women with ovarian endometriomas or deep infiltrating lesions, as shown in population-based cohorts such as the Utah Population Database ( 127 ). Beyond malignancy, endometriosis may also influence long-term health as multiple metabolic dysregulations has been reported in patients, likely stemming from the chronic inflammatory milieu that characterizes the disease ( 125 , 126 ). It has also been linked to elevated cardiovascular risk, including hypertension and hypercholesterolemia. Though data on this link is limited, the pro-inflammatory state and aberrant angiogenesis observed in endometriosis provide a plausible mechanistic link to cardiovascular pathology ( 14 , 125 , 126 ). Additional risks include an increased incidence of autoimmune disorders such as systemic lupus erythematosus, as well as a modest elevation in breast cancer and melanoma risk in some studies, although these findings are inconsistent ( 14 ). Wang et al.’s study of over 100,000 participants reported over twofold higher risk of mental disorders in endometriosis patients compared to the comparison ( 129 ). A similar magnitude of risk has been observed for dementia, alongside lower cognitive performance, and more frequent cognitive complaints ( 130 ). These associations remain even after adjustment for menopausal status, comorbidities, and lifestyle factors. Despite these persuasive findings, the literature linking endometriosis and dementia remains sparse and needs further investigation. The mechanisms underlying the systemic, long-term comorbidities of endometriosis remain poorly defined as with other reproductive ailments. Shared mechanisms such as chronic inflammation, oxidative stress, estrogen excess have been proposed to explain the overlapping pathophysiology between endometriosis and cancers ( 127 , 128 ). Further, somatic mutations in genes such as ARID1A, PTEN , and KRAS have are posited to underlie the susceptibilities to neurological disorders ( 131 ). GWAS have identified loci associated with endometriosis risk, implicating genes involved in hormone regulation, inflammation, and cell adhesion ( 132 , 133 ). However, these findings are not yet sufficient to guide diagnostic approaches, personalized care or long-term prevention strategies. While hormonal therapies, NSAIDs, and surgical interventions remain the mainstay of treatment, none offer a durable cure or fully alleviate long-term systemic risks ( 125 ). As our understanding of endometriosis evolves, there is a pressing necessity for integrated approaches that address both the gynecologic and chronic disease dimensions of this complex condition.