Hormone therapy (HT) in women with premature ovarian insufficiency or early menopause: Time to think of a new paradigm for healthy aging. A joint FIGO and IMS position paper

Abstract

Premature ovarian insufficiency (POI) and early menopause (EM) affect millions of women worldwide. Compared with normal menopause, they confer a longer duration of estrogen deficiency and are associated not only with a shorter lifespan, but with a reduced healthspan, owing to an increased risk of cardiovascular, skeletal, cognitive and psychological morbidity, and sexual health concerns. Therefore, interventions in POI/EM represent some of the most actionable opportunities to reduce long‐term disability and promote healthy longevity. However, current approaches to hormone therapy (HT) in POI/EM remain fragmented, delayed, and overly influenced by paradigms derived from older postmenopausal populations. We propose a shift toward a life‐course model of care. POI and EM should no longer be managed as variants of menopause at normal age but recognized as chronic endocrine conditions and sentinel events for accelerated aging in women. HT should be reframed as a hormonal replacement aimed at preventing long‐term disability. Timely initiation, adequate dosing, and long‐term continuation of HT should be considered foundational to POI/EM care, alongside integrated preventive strategies. FIGO and IMS, therefore, call for a globally coordinated effort to strengthen awareness, professional education, and research on POI/EM, and to ensure equitable access to multidisciplinary care, with the goal of improving women's health and supporting the long‐term sustainability of healthcare systems.

Key points.

• Why greater awareness of POI and EM is needed. POI and EM are not solely reproductive disorders: They are associated with early estrogen deprivation, shortened life expectancy, and increased chronic disease burden, highlighting their substantial implications for both individual and public health (Section 1).

• Why prompt diagnosis of POI and EM is essential. Delayed recognition may prolong untreated hypoestrogenism and postpone preventive care, increasing the risk of long‐term adverse health outcomes (Section 2).

• Hormone therapy (HT) as a cornerstone of POI and EM care. In the absence of contraindications, HT alleviates symptoms and mitigates the long‐term health consequences of prolonged estrogen deficiency. Prompt initiation and ongoing individualized treatment are essential, and should be accompanied by lifestyle‐based prevention and risk‐factor optimization as integral components of care for all women with POI/EM. Evidence supporting HT use, dosing principles, and duration of treatment are summarized (Section 3).

• Management when systemic HT is contraindicated. Contraindications to systemic HT do not remove the need for active long‐term care. Management should focus on lifestyle optimizations, cardiovascular risk reduction, bone protection, and individualized treatment of vasomotor and genitourinary symptoms (Section 4).

• Education and research to improve outcomes. FIGO and IMS call for improved professional education, public awareness, and multidisciplinary collaboration to reduce diagnostic delay and undertreatment. Research priorities include better etiological characterization, development of global registries and studies assessing treatment adherence, optimal HT/MHT regimens, and long‐term health outcomes in women with POI/EM (Section 5).

• A new paradigm for healthy aging. POI and EM should no longer be managed as earlier variants of natural menopause, but as chronic conditions and sentinel events for accelerated aging. Optimizing healthspan requires a life‐course approach integrating timely diagnosis, personalized treatment, lifestyle‐based prevention, and long‐term multidisciplinary care (Section 6).

1. BACKGROUND

Premature ovarian insufficiency (POI) and early menopause (EM) represent a spectrum of ovarian impaired function occurring well before the expected age of normal menopause, exposing women to prolonged estrogen deficiency. POI is defined as the loss of ovarian function occurring before the age of 40 years, whereas EM refers to the type of menopause that occurs in women between the ages of 40 and under 45 years. ¹

Importantly, the timing of natural menopause exhibits substantial geographical variation worldwide. ² , ³ , ⁴ , ⁵ A systematic review and meta‐analysis estimated a global mean age at natural menopause of 48.8 years, while documenting pronounced interregional differences, with mean ages ranging from 47.2 years in Latin America and 47.4 years in the Middle East to 48.4 years in Africa, 48.7 years in Asia, 49.1 years in the USA, 50.5 years in Europe, and 51.2 years in Australia. ³ Notably, country‐specific studies have reported some of the earliest ages at natural menopause among Indian (46.3–46.7 years), Mexican (46.5–46.7 years), Pakistani (46.4–47.2 years), and Turkish (46.2–47.3 years) women. ³ , ⁶ , ⁷ This geographical heterogeneity may affect the interpretation and comparability of global prevalence estimates, as the use of uniform age thresholds may not adequately reflect population‐specific patterns of menopausal timing.

1.1. The global picture

Global prevalence estimates for non‐iatrogenic POI vary substantially, from the historically cited estimate of approximately 1% ¹ to 3.7% in more recent systematic reviews and meta‐analyses, whereas the reported global prevalence of EM is 12.2%. ⁸

Applying these estimates to 2024 world female population age‐structure data from the UN World Population Prospects/World Bank indicators (approximately 1.49 billion women aged 15–39 years and approximately 262.5 million aged 40–44 years) suggests that approximately 55 million women may be affected by non‐iatrogenic POI and 32 million by EM, corresponding to a combined global burden of roughly 87 million women. ⁹ , ¹⁰

A growing additional burden is attributable to iatrogenic POI, due to chemotherapy, radiotherapy, and/or surgical treatments. Although its global prevalence is still poorly characterized, it may be increasing because of improved survival among cancer patients. ¹¹ More than 9 million women are diagnosed with cancer each year and a recent meta‐analysis reported a median age at menopause of 44 years in patients who had survived cancer. ¹² Moreover, a further relevant contributor to iatrogenic POI/EM is cancer risk‐reducing bilateral salpingo‐oophorectomy performed before the natural age of menopause in women at increased hereditary risk of ovarian cancer, particularly carriers of BRCA1 or BRCA2 pathogenic variants, or in selected women with a strong family history of ovarian cancer. ¹³

Ethnic, socioeconomic, environmental, and geographic factors, along with healthcare access, may influence the reported prevalence of both POI and EM. ⁸ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ In addition, cultural perceptions of menopause may further affect health‐seeking behavior and diagnostic recognition, particularly in non‐Western settings, contributing to substantial regional differences in reported prevalence and clinical impact. ¹⁹ , ²⁰ In some cultural contexts, the impact of POI extends beyond health, encompassing infertility‐related stigma and broader social consequences, thereby highlighting the need for culturally sensitive education among both healthcare professionals and the public. ²¹

1.2. Impact of POI and EM on lifespan and healthspan

Without adequate hormone therapy (HT), women with POI or EM have a reduced lifespan. ²² , ²³ , ²⁴ In a cohort study of 3650 European postmenopausal women, life expectancy was estimated to be 3.1 years shorter than in women with menopause at normal age (45–54 years) and 3.5 years shorter than in those with late menopause (≥55 years). ²⁵

Moreover, compared to menopause occurring within the typical age range, both POI and EM carry a significantly greater long‐term health burden. ²⁶ , ²⁷ Women with POI consistently report a lower health‐related quality of life (QoL), affecting physical, emotional, and sexual functioning, as well as higher levels of psychological distress. ²⁸ , ²⁹ , ³⁰ POI is described as a disruptive event, characterized by grief over the loss of fertility, premature aging, and altered body image. ³¹ Likewise, EM has been associated with poorer health status and QoL. ³²

Beyond subjective health perceptions, earlier loss of ovarian function is associated with objective indicators of functional decline. Population‐based cohort studies show that women who enter menopause at an earlier age, particularly those with POI, have poorer physical functioning ³³ , ³⁴ and steeper frailty trajectories in midlife and later life (Figure 1). ³⁵ This suggests an increased burden of disability across their lifespan ²⁸ , ³⁰ and, consequently, a shorter healthspan.

FIGURE 1.

Frailty trajectories in midlife and later life. Modified from Verschoor and Tamin, 2019. ³⁵ Frailty, defined as a reduction in physical strength and bodily function that increases susceptibility to illness, diminishes independence and ultimately raises the risk of death, is higher for women with POI and EM than for those who reached menopause after 45 years of age (NM). Men show lower levels of frailty index throughout the age period considered. The frailty index in this cross‐sectional analysis represents the non‐weighted sum of 93 accumulated health‐related deficits, including variables related to chronic diseases, functional status, activities of daily living, depression, satisfaction with life, nutritional risk, physical activity, and perceived health. EM, early menopause; NM, menopause at normal age; POI, premature ovarian insufficiency.

Cardiovascular disease (CVD), particularly ischemic heart disease and stroke, appears to account for much of the excess mortality and disability associated with POI/EM. ²² , ²³ , ³⁶ , ³⁷ , ³⁸ This association has been consistently demonstrated in retrospective and longitudinal cohort studies, which show a stepwise increase in cardiovascular risk and mortality with decreasing age at menopause. ³⁷ Surgical menopause confers an even greater burden of cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes, as well as a higher risk of cardiovascular events than natural ovarian aging. Importantly, this excess risk extends beyond ischemic heart disease and stroke to include heart failure, aortic stenosis (AS), mitral regurgitation, atrial fibrillation, peripheral artery disease, and venous thromboembolism. ³⁹

Accelerated bone loss and increased fracture risk are other major contributors to reduced healthspan in women with POI/EM. Compared with women undergoing menopause at the usual age, those with POI/EM experience more rapid bone loss and are at increased risk of osteoporosis and fractures. ⁴⁰ Osteoporosis appears to be particularly common among women affected by iatrogenic POI relative to those diagnosed with spontaneous POI (40.9% vs. 20.0%); delayed diagnosis and treatment are important modifiable contributors. ⁴¹ Consistent with these findings, longitudinal cohort studies have demonstrated a significantly increased fracture risk in women with POI/EM. ⁴² Beyond bone health, a meta‐analysis found that EM is associated with reduced muscle mass, whereas POI is associated with reduced muscle strength and physical performance, suggesting that sarcopenia may further contribute to frailty and impaired physical function in these women. ⁴³

POI/EM are also associated with adverse neurocognitive outcomes, including an increased risk of cognitive impairment, dementia, Parkinson's disease, and depression. ²⁴ Although mood disorders are multifactorial, the psychological and sociocultural consequences of a POI diagnosis may contribute to depressive and anxiety symptoms. ⁴⁴

Taken together, the increased burden of cardiovascular, metabolic, musculoskeletal, and neurocognitive impairments observed in women with POI/EM, supports the concept that these conditions may represent sentinel events for accelerated biological aging. ⁴⁵ This hypothesis is reinforced by recent population‐based studies showing accelerated biological aging and shorter leukocyte telomere length in women with POI, irrespective of whether ovarian insufficiency is natural or surgical. ⁴⁶ Notably, biological age acceleration appears to be attenuated by HT use. ⁴⁵ Consistent with these findings, studies using the epigenetic clock, which estimates biological age from DNA methylation patterns, have demonstrated epigenetic age acceleration in women with EM and after bilateral oophorectomy. ⁴⁷

Furthermore, genetic variants associated with earlier menopausal age have also been linked to epigenetic age acceleration, suggesting that reproductive and biological aging are closely interconnected and may share common underlying pathways. Collectively, these observations suggest that women with POI/EM may reach the age of natural menopause biologically older than their peers, with potential implications for both lifespan and healthspan. ⁴⁵ , ⁴⁶ , ⁴⁷

1.3. Disparities and barriers affecting outcomes in POI/EM

Compared with men, women experience a greater burden of disability and age‐related functional decline, including frailty, cognitive impairment, and reduced QoL. Although women live longer than men globally, they spend a greater proportion of their lifespan in poor health and with functional limitations, resulting in a gender gap in healthy life expectancy of approximately 2 years in most regions worldwide. ⁴⁸ , ⁴⁹ , ⁵⁰

Accelerated reproductive aging and prolonged estrogen deficiency further exacerbate this gap, by increasing the risk of long‐term morbidity. This suggests that POI and EM are key adverse modifiers of women's healthspan trajectories (Table 1). ³² , ⁵¹

TABLE 1.

Comparative biological profile and healthspan trajectories of women with POI, EM, or menopause at normal age.

Condition	Age at ovarian loss of function (years)	Biological profile	Expected healthspan trajectory
POI	<40	Abrupt or intermittent ovarian insufficiency Longest exposure to hypoestrogenism Occurs during key periods for bone and cardiometabolic health	Early onset of long‐term morbidity Increased lifetime risk of osteoporosis/fractures, diabetes mellitus, arterial hypertension, cardiovascular disease, neurocognitive/psychological disorders, frailty, and disability
EM	40–44	Earlier‐than‐expected cessation of ovarian function Intermediate duration of hypoestrogenism relative to POI and menopause at normal age Often under‐recognized and under‐treated with potential downstream biological consequences	Increased risk of osteoporosis/fractures, diabetes mellitus, arterial hypertension, cardiovascular disease, dementia, and frailty compared with menopause at normal age Greater later‐life disability burden
Menopause at normal age	45–55	Gradual ovarian senescence Shorter duration of hypoestrogenism compared with POI/EM	Morbidity and disability are usually concentrated in later life More favorable balance between lifespan and healthspan, compared with POI/EM

Abbreviations: EM, early menopause; POI, premature ovarian insufficiency.

However, awareness gaps remain substantial, and POI is still frequently overlooked despite being a significant health concern. The reported median 48‐month interval between symptom onset and diagnosis may increase morbidity, ¹⁸ , ⁵² further emphasizing the need for education to promote earlier recognition and timely engagement with care. ⁵³ , ⁵⁴

Beyond achieving timely recognition, the way in which a diagnosis of POI is communicated may profoundly influence subsequent experiences of the condition and attitudes toward treatment. Although 64% of women with POI reported satisfaction with diagnosis disclosure, nearly 70% sought additional information, approximately one‐third did not initiate HT at diagnosis and only 20% were offered psychological support despite guideline recommendations. ²⁴ , ⁵⁵ These findings suggest that important opportunities to optimize treatment initiation and supportive care may be missed at the time of diagnosis.

The consequences of missed opportunities at diagnosis may be further amplified by persistent gaps and inequities in care. Compared with men, women with disabilities are less likely to have access to specialist assessment, rehabilitation services, and assistive technologies, particularly in resource‐limited settings. ⁵⁶ , ⁵⁷

Access to HT is also uneven across geographic regions and healthcare systems. Even among women undergoing natural menopause, menopause hormone therapy (MHT) use varies according to affordability, prescribing practices and access to specialist care. ⁵⁸ In women with POI/EM, these challenges may be compounded by the need for prolonged treatment, the higher cost or limited availability of some formulations, particularly transdermal estrogen, and the failure to recognize asymptomatic young women as candidates for preventive hormone replacement. These barriers are likely to be greatest in low‐ and middle‐income countries (LMICs). ⁵⁹ , ⁶⁰

Such gaps in care may contribute not only to poorer health outcomes but also to broader occupational and socioeconomic consequences. Symptoms, comorbidities, and the challenges of managing a chronic condition at a young age can impair work performance and work ability, influence career trajectories, and increase the risk of disability‐related absences and premature exit from the workforce. ⁶¹ , ⁶² , ⁶³ , ⁶⁴

1.4. Public health and policy implications of POI and EM

Disability‐adjusted life years (DALYs) provide a useful framework for understanding the potential population burden of POI and EM. Although DALYs attributable to these conditions have not been directly quantified, many of their major long‐term consequences—including ischemic heart disease, stroke, diabetes, depression, dementia, and osteoporosis—are among the leading contributors to disability and premature mortality worldwide. ⁶⁵ , ⁶⁶

From a health‐system perspective, the excess burden of chronic disease, disability, frailty, and long‐term care needs associated with POI and EM may translate into substantial healthcare and societal costs. These considerations support greater recognition of POI and EM as public health priorities with implications for healthcare planning, social welfare systems, and healthy aging strategies. ⁶⁷ , ⁶⁸ , ⁶⁹

Given the central role of HT in mitigating many of the adverse consequences of premature estrogen deficiency, equitable and affordable access to treatment should be considered a policy priority. Full reimbursement, or regulated pricing, of clinically appropriate formulations may help prevent cost‐related undertreatment and premature discontinuation, particularly in settings where access remains limited.

More broadly, the growing emphasis on healthspan, the years lived in good health and free from major chronic disease and disability, ⁷⁰ , ⁷¹ has important implications for public health policy. As populations age worldwide, preserving healthspan, rather than extending lifespan alone, should become a key objective. In this context, POI and EM warrant greater recognition within public health and welfare strategies because their consequences extend far beyond reproductive health and may substantially reduce healthy life expectancy.

1.5. Lack of data, rationale for a personalized treatment approach

Current international guidelines recommend continuation of HT at least until the average age of natural menopause for women with POI or EM, ²⁴ given the lack of randomized controlled trials (RCTs) evaluating the long‐term effects of extending treatment beyond this threshold in these populations. Evidence from studies in women undergoing menopause at normal age suggests that prolonged MHT use may extend not only lifespan, ⁷² , ⁷³ but also healthspan through reductions in musculoskeletal, ⁷⁴ cardiovascular, ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ and/or cognitive morbidity. ⁷⁹ , ⁸⁰ , ⁸¹ Accordingly, fixed limits on MHT duration are increasingly being abandoned in favor of an individualized approach, whereby therapy is maintained as long as the benefits continue to outweigh the risks. ⁸² This principle may be even more pertinent in women with POI or EM, conditions that confer a higher lifetime risk of morbidity and functional disability, in whom HT should be considered a cornerstone intervention and incorporated into a structured life‐course care pathway.

Importantly, treatment personalization should also take into account that iatrogenic POI or EM may differ biologically from non‐iatrogenic forms, which may, in some cases, represent the consequence of accelerated vascular aging consistent with the “reverse causality hypothesis,” whereby antecedent cardiovascular risk factors may drive early natural menopause. ⁸³ Therefore, the choice of hormonal regimen, including dose, route of administration, and hormonal formulation, should ideally be aligned with the underlying biological phenotype of the condition.

1.6. Aim of this paper

This joint International Federation of Gynecology and Obstetrics (FIGO)‐International Menopause Society (IMS) paper is a call to action, based on available evidence and clinical experience, advocating for a paradigm shift in the management of POI and EM. The goal is to raise awareness on both conditions and their impacts and to promote strategies that will hopefully extend women's healthspan and better address the individual and socioeconomic needs related to these conditions. Meeting these multiple and evolving needs represents a major challenge for contemporary and future medicine, not only to improve women's health and well‐being, but also to ensure the long‐term sustainability of healthcare systems.

2. POI AND EM: ETIOPATHOGENESIS AND DIAGNOSIS

The timing of menopause depends on the complex interaction between genetic background and the exposome, including both voluntary and involuntary environmental exposures, which influence the establishment of the primordial follicular pool during intrauterine life and/or the rate of follicular depletion throughout the reproductive lifespan. ⁸⁴ EM and POI are distinct clinical entities defined by the age at diagnosis of ovarian exhaustion. ²⁴ , ⁸⁵ , ⁸⁶ However, because POI and EM share common risk factors and clinical consequences, they can be conceptualized as different stages along a continuum of early reproductive senescence. Importantly, the misperception of EM as a gray area between POI and menopause at normal age might lead to a suboptimal management of its long‐term consequences. ⁸⁷

2.1. Etiopathogenesis

POI and EM may occur spontaneously or secondarily to pelvic surgery (not only oophorectomy, but also hysterectomy that has been associated with increased risk of EM), irradiation and/or chemotherapy. ⁸⁸ Establishing the etiology of non‐iatrogenic POI/EM remains challenging for both clinicians and patients. A definitive diagnosis may benefit patients by facilitating psychological acceptance and providing valuable information for their own health and that of their relatives. ⁸⁹

Although the exact cause of POI is often unknown, epidemiological studies have identified several personal and familial risk factors associated with the condition (Table 2). Recognizing these risk factors can help healthcare providers (HCPs) offer appropriate counseling to asymptomatic women and facilitate earlier diagnosis in symptomatic ones. This is especially important in resource‐limited countries, where laboratory tests needed to diagnose POI may not be readily available due to limited healthcare resources; in this setting, identifying women who have risk factors can help HCPs decide who should be prioritized for testing, especially for etiological definition.

TABLE 2.

Risk factors associated with POI/EM according to epidemiological studies. ¹

Genetic factors	Family or personal history of genetic disease (Turner syndrome, X‐fragile, monogenic syndromes associated with POI) Family history of POI/maternal age at menopause Ethnicity
Medical comorbidities	Autoimmune disease History of chemotherapy/radiotherapy/pelvic surgery Galactosemia
Lifestyle factors	BMI <18.5 Cigarette smoking Chemical exposure (endocrine disruptors)
Early life factors	Being part of multiple pregnancy Preterm birth In utero smoke exposure Reduced duration of breastfeeding
Reproductive factors	Early menarche (<11 years) Menstrual cycle length < 25 days
Infectious diseases	Mumps Tuberculosis HIV

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); EM, early menopause; HIV, human immunodeficiency virus; POI, premature ovarian insufficiency.

It is believed that most POI cases defined as idiopathic are genetic in origin, as supported by the fact that a family history of POI is common in affected patients and represents a major risk factor for the condition (estimated to be 18‐fold if a first‐degree relative is affected). ⁹⁰ However, there is still no comprehensive understanding of genotype/phenotype relationship, as genetic transmission in POI is complex and likely polygenic, so that menopausal age can be modulated by a sum of variants common in the general population, especially when ovarian exhaustion occurs after the age of 34 years. ⁵¹ Among chromosomal causes of POI, Turner syndrome (TS) is the most common abnormality and should always be considered in the diagnostic work‐up, particularly in women presenting with primary amenorrhea or suggestive phenotypic features. ⁹¹ More than 100 genes implicated in POI pathogenesis have been identified as participating in primordial germ cell development, meiosis, folliculogenesis, and mitochondrial function. ⁹² , ⁹³

Mitochondrial dysfunction may mediate the harmful effects of environmental exposures through increased oxidative stress, thereby compromising oocyte homeostasis. ⁹³ Moreover, increasing evidence supports the role of epigenetic mechanisms in the etiology of POI, with non‐coding RNAs, DNA methylation, and histone modifications representing the intersection mechanisms between genetic and environmental factors. ⁹⁴ , ⁹⁵ , ⁹⁶ Advances in this field will improve our understanding of how modifiable lifestyle and environmental factors might influence the development of POI and whether addressing these factors might modify the trajectory of ovarian aging.

Immune dysregulation represents an additional mechanism of follicular depletion. Although an epidemiological association between autoimmune conditions, particularly autoimmune thyroid disorders and Addison's disease, has been described, early ovarian dysfunction occurs only in a minority of women with autoimmune disorders, and the pathophysiological mechanisms mediating gonadotoxicity in this setting remain to be fully elucidated. ⁹⁷ For instance, a recent small case–control study reported significantly higher interferon‐gamma (IFN‐γ) and interleukin‐22 (IL‐22) levels in women with POI than in controls; within the POI group, these cytokine levels were positively correlated with FSH and negatively correlated with anti‐Müllerian hormone (AMH). ⁹⁸

In clinical practice, adrenal steroidogenesis autoantibodies, particularly 21‐hydroxylase antibodies, have been identified as being the most specific marker of autoimmune oophoritis and have been proposed in the diagnostic work‐up of spontaneous POI in guidelines. ²⁴ According to this criterion, the prevalence of autoimmune POI was reported to be 4.5% in a recent cohort study. ⁹⁹

Additional recognized causes of POI are even rarer, including metabolic disease (such as galactosemia) and infectious conditions (mumps, tuberculosis, and HIV). ¹⁰⁰

2.2. Diagnostic criteria

The diagnostic criteria for POI were recently revised in the 2024 guidelines. ²⁴ To reduce potential diagnostic delays, a single elevated follicle‐stimulating hormone (FSH) level (>25 mIU/mL) in women younger than 40 years, presenting with menstrual irregularities or amenorrhea lasting at least 4 months, is sufficient for diagnosis. Repeat measurement of FSH and assessment of AMH levels to evaluate ovarian reserve may be useful in selected cases when diagnostic uncertainty exists. ²⁴ Although these diagnostic criteria do not formally apply to EM, recent IMS recommendations suggest prompt evaluation of women over 40 years of age presenting with menopausal symptoms and, whenever feasible, FSH assessment to support diagnosis and differential diagnosis. ¹⁰¹

Figure 2 summarizes the diagnostic work‐up for women with suspected POI, including investigations aimed at identifying the underlying etiology once the diagnosis has been confirmed. It should be emphasized that the diagnostic approach needs to be adapted to the local healthcare setting, as the availability and affordability of diagnostic tests vary considerably worldwide. Therefore, although a limited number of investigations are recommended as mandatory according to current guidelines, more advanced diagnostic testing should be tailored to the individual clinical context and specific risk factors. For instance, a strong family history would warrant second‐level exams including next‐generation sequencing (NGS), if chromosomal abnormalities and FMR1 premutation are excluded.

FIGURE 2.

Flowchart summarizing the diagnostic work‐up, including investigations aimed at identifying the etiology of POI. Investigations are categorized as mandatory, shown on the left, or optional, shown on the right, acknowledging that technologies and resources may vary in availability and allocation worldwide. 21OH, 21‐hydroxylase; AMH, anti‐Müllerian hormone; CHT, chemotherapy; FMR1, fragile X messenger ribonucleoprotein 1; FSH, follicle‐stimulating hormone; RT, radiotherapy; TSH, thyroid‐stimulating hormone.

Previous POI guidelines recommended only karyotype analysis and Fragile X Messenger Ribonucleoprotein 1 (FMR1) premutation testing, detecting chromosomal abnormalities in up to 30% of women with primary amenorrhea and 11.6% of those with secondary amenorrhea, as well as FMR1 gene premutations in 5%–10% of women with POI. ²⁴ , ¹⁰² , ¹⁰³

Conversely, updated guidelines additionally endorse NGS approaches, including whole‐exome sequencing (WES). ²⁴ , ¹⁰² , ¹⁰³ However, these techniques are not universally available and a relatively low diagnostic yield has been reported. Indeed, several WES studies on large‐scale cohorts identified biallelic pathogenic variants in only a minority of sporadic POI cases. ¹⁰² This implies the need for careful evaluation of cost‐effectiveness on an individual basis.

3. HORMONE THERAPY IN WOMEN AFFECTED BY POI OR EM

HT is the cornerstone of treatment for women with POI or EM. In the absence of contraindications, scientific society guidelines have conventionally recommended that HT is used at least until the usual age of menopause (50–51 years in high‐income countries [HICs]), with the objective of restoring physiological estrogen concentrations. ²⁴ In this clinical context, the primary indication of HT is not just the alleviation of vasomotor symptomatology (VMS), but also the mitigation of long‐term health risks associated with chronic hypoestrogenism, including CVD, osteoporosis, fractures, and cognitive impairment. ⁸⁷ Failure to initiate or maintain HT in women with POI or EM is associated with reduced life expectancy, mainly driven by an elevated risk of CVD. ²⁴ , ¹⁰⁴ , ¹⁰⁵ Given all of this, the previous paradigm to continue HT at least until the usual age of menopause warrants review, as previously discussed in this position paper. If we are to optimize both lifespan and healthspan in this population of women, a more individualized approach is called for, where the usual age of menopause, which varies globally and is lower in LMICs, is not necessarily considered a stopping point for HT.

3.1. Evidence supporting beneficial effects of HT on long‐term health outcomes in women with POI or EM

In general, the extent to which HT reduces CVD morbidity and mortality in women with POI or EM remains uncertain. According to a recent prospective cohort study from South Korea (n = 1 159 405 postmenopausal women), both POI and EM were independent risk factors for CVD, especially for myocardial infarction, after adjustment for HT. Specifically, the HR for myocardial infarction was 1.40 (95% confidence interval [CI] 1.31–1.50) for POI and 1.18 (95% CI 1.13–1.24) for EM, compared with women experiencing menopause at 50 years of age or above. ¹⁰⁶ In contrast, the risk of ischemic stroke was increased only among women with POI or EM who had not received HT (hazard ratio [HR] 1.23 [95% CI 1.16–1.31] and 1.18 [95% CI 1.14–1.22], respectively). A similar pattern was reported for all‐cause mortality, but only for women with POI (in those with EM, HT had no effect on all‐cause mortality). Of note, the reported HT use within the cohort was low (only 18% of participants), with only approximately 6% of women with POI having received MHT for 5 years or more. ¹⁰⁶ It can therefore be hypothesized that the absence of a positive effect on myocardial infarction in women with POI, compared with women with physiological menopause, is due to the likelihood that they did not continue HT for long enough, which may have even been required beyond the usual age of menopause. Furthermore, a USA‐based retrospective cohort study of 1091 women who had undergone bilateral oophorectomy and 2383 age‐matched controls without oophorectomy showed that bilateral oophorectomy before the age of 45 years was associated with increased CVD mortality in untreated women compared with controls (HR 1.84 [95% CI 1.27–2.68]). In contrast, this excess risk was not observed among women who received HT through age 45 years or longer (HR 0.65 [95% CI 0.30–1.41]). ¹⁰⁴ This was also the case in another cohort study from the USA, according to which, increased all‐cause mortality was observed in women who had undergone prophylactic oophorectomy before the age of 45 years (HR 1.67 [95% CI 1.16–2.40]). This risk remained significant in those who had not received HT (HR 1.93 [95% CI 1.25–2.96]), whereas it was attenuated and no longer significant among those treated with estrogen (HR 1.27 [95% CI 0.67–2.39]). ¹⁰⁵

Conversely, data from the UK Biobank study did not demonstrate a significant association between HT use and either CVD or all‐cause mortality among women with natural or surgical menopause before the age of 45 years. Nevertheless, HT was associated with lower breast cancer mortality in women with both spontaneous (HR 0.59 [95% CI 0.36–0.95]) and surgical menopause before the age of 45 years (HR 0.17 [95% CI 0.08–0.36]), compared with no HT use. Notably, the association between HT use and reduced breast cancer mortality did not vary according to HT duration (<6 or 6–20 years). ¹⁰⁷ Whether the type of menopause (spontaneous vs. surgical) differentially affects the long‐term health consequences of POI or EM, or alters the benefits associated with HT, remains uncertain. ⁸⁷

In light of the potential adverse sequelae associated with premature surgical menopause, the decision to perform prophylactic oophorectomy should be guided by a thorough evaluation of the individual risk–benefit profile. ¹⁰⁸

Another underestimated aspect of POI/EM and HT is AS and aortic valve calcification (AVC). It has been shown that untreated menopause that occurs before the age of 45 years is independently associated with accelerated AVC progression, as well as with anatomical and hemodynamic progression of AS compared with those women who received HT or had normal age at menopause. ¹⁰⁹

Regarding skeletal health, sparse data from observational studies have shown that HT reduces the risk of osteoporosis and fractures. In particular, a cross‐sectional analysis from the Canadian Longitudinal Study on Aging, including 12 339 postmenopausal women, of whom 374 had POI and 1396 had EM, found that HT use was associated with a lower risk of osteoporosis among both current (OR 0.65 [95% CI 0.46–0.91]) and former users (OR 0.76 [95% CI 0.63–0.90]), after adjustment for age and education. ¹¹⁰

Furthermore, the Australian Longitudinal Study on Women's Health, a prospective cohort study including 8603 postmenopausal women, 610 of whom had POI/EM, found that estrogen use before or at study entry (ages 45–50 years) was associated with a lower risk of fractures (OR 0.88 [95% CI 0.82–0.95]) compared with non‐use. ⁴²

Therefore, despite lack of evidence from RCTs, observational data demonstrate a likely cardio‐protective and bone‐protective effect of HT in women with POI, with more limited evidence in EM. However, no definitive conclusions can be drawn regarding the exact HT regimen used, including dose and route of administration.

The lack of data from RCTs is mainly due to feasibility and economic reasons, although ethical issues of randomizing women to placebo or potentially suboptimal regimens must also be considered. However, the absence of regimens specifically designed and licensed for women with POI/EM is an issue that warrants urgent attention.

3.2. Optimal HT regimen for women with POI or EM

In general, dose–response data for HT in women with POI remain limited. ¹¹¹ However, the estrogen dose that is recommended for women with POI/EM is typically two‐fold higher than the conventional doses used in postmenopausal women in order to alleviate VMS. ⁸⁵ In women with POI/EM with few or no menopause associated symptoms, HT should still be used for primary prevention of CVD and bone fragility (osteoporosis, fractures) or for achievement of peak bone mass, if used at an earlier stage. ¹¹¹ The typical dose of estrogen recommended for POI is 100 μg/day or 2–4 mg/day for transdermal and oral estradiol, respectively. ²⁴ , ⁸⁵ In women with an intact uterus, concomitant progestogen is required, with doses adjusted proportionally to the estrogen regimen, applied sequentially for 12–14 days per month (e.g., micronized progesterone 200–300 mg/day, dydrogesterone 20 mg/day, norethisterone 5–10 mg/day). ²⁴ , ⁸⁵ Another possible option for endometrial protection up to 5 years is the levonorgestrel intrauterine system, which also provides effective contraception in those wishing to minimize the chance of natural contraception. ²⁴ , ⁸⁵ So far, no clear recommendations exist for women with EM, but in the absence of good quality data, the pragmatic consensus is to follow the same principles as in POI.

In practice, the choice of HT type, route, and formulation should be guided by what is locally available, since access to specific HT formulations varies widely across different healthcare settings, particularly in LMICs. Table 3 reports HT regimens and doses suggested for POI/EM management.

TABLE 3.

Summary of suggested HT regimens and doses in women with POI/EM (modified from Panay et al. and European Society of Human Reproduction and Embryology ESHRE ¹ , ⁸⁵ ). ^a

Component	Dose	Clinical practice tips
17‐β‐estradiol (E2)
• Transdermal: patch	75–100 μg/day	• Prefer transdermal estradiol in women with cardiovascular risk factors, including obesity
• Transdermal: gel sachet	2–3 mg/day
• Transdermal: gel pump (1 metered dose = 0.75 mg)	3–4 mg/day
• Transdermal: spray (1.53 mg/spray)	3–4 spray/day
• Oral	2.0–4.0 mg/day (continuous regimen); 2.5–4 mg/day (sequential regimen)	• Avoid hormone‐free intervals in sequential regimens
Progestogen
• Micronized progesterone (oral or vaginal)	≥200 mg/day (continuous regimen); 300–400 mg/day for 12–14 days/month (sequential regimen)	• Prefer sequential regimen in women who wish to conceive
• Dydrogesterone (oral)	10 mg/day (continuous regimen); 20 mg/day for 12–14 days/month (sequential regimen)	• Prefer progesterone‐like progestogens in women with cardio‐metabolic risk factors
• Medroxyprogesterone acetate (oral) b	5 mg/day (continuous regimen); 10–20 mg/day for 12–14 days/month (sequential regimen)	• Consider LNG IUS in women requiring contraception for whom COC is not indicated/accepted
• Norethisterone acetate (oral) b	2.5–5 mg/day (continuous regimen); 2.5–10 mg/day for 12–14 days/month (sequential regimen)
• LNG IUS	20 μg/day for 5 years (52 mg, LNG IUS)
E2/progestogen fixed dose combined preparations c
• E2/micronized progesterone (oral)	3.0–4.0 mg/300–400 mg (continuous regimen); ≥2.0 mg/≥200 mg (sequential regimen)
• E2/dydrogesterone (oral)	3.0–4.0 mg/7.5–10 mg (continuous regimen); 3.0–4.0 mg/20 mg (sequential regimen)
• E2/norethisterone acetate (transdermal patch)	75–100 μg/255–340 μg/day (continuous and sequential regimen)
• E2/norethisterone acetate (oral)	3.0–4.0 mg/1.5–2.0 mg (continuous regimen); 3.0–4.0 mg/2.0–4.0 mg (sequential regimen)

Abbreviations: COC, combined oral contraception; EM, early menopause; HT, hormone therapy; LNG IUS, levonorgestrel intrauterine system; POI, premature ovarian insufficiency; TSEC, tissue‐selective estrogen complex.

^a Estrogens other than estradiol (including conjugated equine estrogens and ethinyl estradiol) are not mentioned in the table because the doses required to achieve adequate estrogen replacement in women with POI may be associated with an increased risk of estrogen‐related adverse effects and long‐term complications. Current POI guidelines do not recommend the routine use of TSECs, consisting of conjugated equine estrogens (0.45 mg) combined with bazedoxifene (20 mg). Nevertheless, TSECs may represent a therapeutic option for selected women with POI/EM who are intolerant to progestogens or are particularly concerned about breast cancer risk, while acknowledging the lack of studies in this specific population. Similarly, tibolone, which is available in some countries for the treatment of vasomotor symptoms, is not included as a first‐line option for women with POI/EM because its relatively weak estrogenic activity may be insufficient to achieve adequate estrogen replacement, but its use may be considered in selected clinical settings.

^b Although medroxyprogesterone acetate and norethisterone acetate remain established options for endometrial protection in women receiving estrogen therapy, clinical practice has increasingly favored micronized progesterone and other progestogens with a more physiological profile, owing to their potentially more favorable cardiometabolic and breast safety profile. ¹⁰¹

^c Estradiol/progestogen fixed doses formulations are mostly available as standard doses and may require dose adjustment for off‐label prescription in women with POI/EM.

The formulations listed in Table 3 may not be available globally. Conversely, some formulations available in specific countries may not be included. Therefore, treatment choices should be adapted to local availability and prescribing practices.

The priority is to use doses higher than standard postmenopausal doses. In determining the optimal dose for each patient, measurement of serum estradiol concentrations can reasonably serve as a useful, additional tool to guide dose titration, although there is still debate about the value of measuring it, given the marked variability in absorption both between and within women. In any case, clinical response, tolerability, and individual risk profile must all be considered. Moreover, a multidisciplinary approach involving primary care physicians, oncologists, endocrinologists, and fertility specialists should be implemented. In countries where access even to a general practitioner is limited, trained nurses and other allied healthcare professionals, such as pharmacists, may also contribute in this regard.

3.3. Rationale for higher estrogen doses in women with POI or EM

In general, therapeutic strategies aim to restore physiological estradiol concentrations comparable to those found in women with normal menstruation, with mean levels of approximately 50–100 pg/mL (180–370 pmol/L). ²⁴ , ⁸⁵ It has been shown that these levels can be achieved with transdermal 17β‐estradiol 100 μg/day ¹¹² , ¹¹³ or with oral 17β‐estradiol 2–4 mg/day. ¹¹⁴ This recommendation has been endorsed by international guidelines, such as those recently released by the European Society of Human Reproduction ²⁴ and the European Society of Endocrinology. ⁸⁶ It should be noted that physiological replacement of estradiol in women with POI/EM has not been associated with an increased risk of breast cancer compared to women of similar age with normal ovarian function. ²⁴

The evidence for a beneficial effect of higher‐than‐conventional estradiol doses derives predominantly from skeletal outcomes. Conventional HT regimen (i.e., oral conjugated equine estrogen 0.625 mg/day or 17β‐estradiol 1 mg/day) is usually effective for VMS relief but may be inadequate to prevent POI‐associated bone loss. ¹¹⁵ In contrast, transdermal 17β‐estradiol 100 μg/day can restore bone mineral density (BMD) to normal levels, at both the lumbar spine (LS) and femoral neck (FN) in women with POI. ¹¹² In the general postmenopausal population, serum estradiol concentrations have been consistently associated with higher BMD ¹¹⁶ and a lower risk of vertebral and hip fracture, ¹¹⁷ , ¹¹⁸ although comparable data are lacking for women with POI/EM.

However, evidence supporting a benefit of higher estradiol doses on skeletal outcomes is not entirely consistent. In a 5‐year RCT in women with TS, no dose‐dependent effect of oral estradiol on BMD or markers of bone turnover was observed, although a high estrogen dose (4 mg/day) was associated with greater gains in lean body mass. ¹¹⁹

In contrast, a dose‐dependent effect of HT may exist regarding cardiovascular health. In women with TS, higher 17β‐estradiol doses (i.e., 4 mg/day) resulted in more pronounced reduction in carotid intima media thickness, a surrogate marker of atherosclerotic disease, compared with conventional doses (1–2 mg/day). ¹¹⁴ However, whether these observations extend beyond TS to women with POI or EM, arising from other etiologies, remains uncertain.

3.4. Differences between HT and combined oral or other contraceptives

Combined oral contraceptives (COCs) may also be used as HT in women with POI, particularly in those who prefer this option and/or require contraception. ²⁴ Evidence from RCTs suggests that estradiol‐based HT is superior to COCs containing 30 μg ethinyl estradiol in preserving LS BMD. This was demonstrated both with oral estradiol 2 mg/day in women with spontaneous POI ¹²⁰ and with transdermal estradiol 100–150 μg/day in women with TS. ¹²¹ No differences were observed in FN or total hip BMD. Markers of bone turnover were comparably reduced in both groups, although a trend toward a greater reduction was observed with HT. ¹²⁰

However, it should be noted that the studies discussed above used non‐continuous COC regimens (i.e., those including hormone‐free intervals/inactive tablets), resulting in up to 12 weeks per year without estrogen exposure. This may have contributed to the inferior effects of COCs compared with HT on BMD. Notably, a retrospective study found that COCs containing 30 μg ethinyl estradiol achieved BMD outcomes comparable to those observed with higher‐dose continuous HT regimens (conjugated equine estrogens [CEE] 1.25 mg/day or 17β‐estradiol 2 mg/day) and superior to those achieved with lower‐dose HT regimens (CEE 0.625 mg/day or 17β‐estradiol 1 mg/day) at both the LS and total hip. ¹²²

Furthermore, no studies have evaluated the comparative effects of HT and COCs on major cardiovascular outcomes. ¹²³ Nevertheless, in a small open‐label, crossover RCT involving 34 women with POI, transdermal 17β‐estradiol (100 μg/day for 1 week followed by 150 μg/day for 3 weeks) was associated with lower 24‐h systolic and diastolic blood pressure (BP), lower serum creatinine levels, and reduced activation of the renin‐angiotensin system compared with a COC containing 30 μg ethinyl estradiol administered for 21 days. ¹²⁴ The ongoing “Premature Ovarian Insufficiency Study of Effectiveness of HT (POISE)” may shed light on these issues. This trial has been designed to determine whether HT is superior to COC on important clinical outcomes (i.e., BMD, CVD markers), as well as on VMS relief and acceptability of treatment. ¹²⁵

Specific data are lacking on the use of other contraceptive options in the POI/EM population, including COC regimens containing body‐identical estrogens, such as estradiol or estetrol, rather than ethinyl estradiol. Although the principle of replacing estrogen with body identical contraceptive varieties might seem a good one, in the absence of data on cardiometabolic and bone health, it is not possible to make firm recommendations. This is an area where further POI specific research would be valuable, including other contraceptive hormonal options such as the transdermal and vaginal varieties.

3.5. Optimal duration of HT in women with POI or EM

Although no evidence on cardiovascular and bone outcomes exists for a longer duration of HT in women with POI or EM, continuation after the usual age of menopause (i.e. 50–51 years in HICs) should be individualized, considering current evidence on the risks and benefits, as well as patient‐specific issues such as persistent VMS, pre‐existing low BMD, and high risk of CVD. ²⁴

Notably, long‐term adherence appears suboptimal, with only a minority of women maintaining therapy beyond 5 years from the last menstrual period (22% for <1 year, 39% for 1–4 years, 28% for 5–10 years, and 6% for >10 years, according to the Australian Longitudinal Study on Women's Health). ⁴² Continuation of HT at low or ultra‐low doses (e.g. transdermal 17β‐estradiol 25 or 12.5 μg/day) may be considered even for women aged over 60 years, in the absence of contraindications. ¹²⁶

There should be at least an annual review of the route, regimen, and dosage of HT to optimize the benefit–risk profile, with consideration of dose reduction from the usual higher POI doses as time progresses, especially in women in their 50s and beyond (Table 4). ¹²⁷ This assessment should take into account bone, cardiometabolic, cognitive, and oncologic risks, bearing in mind that women with persistent osteopenia/osteoporosis or distressing menopausal symptoms might still require higher doses beyond the usual age of menopause.

TABLE 4.

Main MHT regimens and low standard doses to which POI/EM can be shifted upon reaching usual menopausal age (data from Panay et al. and Davis et al.—Society of Human Reproduction and Embryology ESHRE ¹ , ⁸⁵ , ¹²⁷ ). ^a

Component	Dose
Estradiol
• Transdermal: patch	25–50 μg/day
• Transdermal: gel sachet	0.5–1.5 mg/day
• Transdermal: gel pump (1 metered dose = 0.75 mg)	0.75–1.5 mg/day (1–2 metered doses/day)
• Transdermal: spray (1.53 mg/spray)	1.53–3.06 mg/day (1–2 sprays/day)
• Oral	1.0–2.0 mg/day
Progestogen
• Micronized progesterone (oral or vaginal)	100 mg/day (continuous regimen); 100–200 mg/day for 12–14 days/month (sequential regimen)
• Dydrogesterone (oral)	2.5–5 mg/day (continuous regimen); 5–10 mg/day for 12–14 days/month (sequential regimen)
• Medroxyprogesterone acetate (oral) b	2.5 mg/day (continuous regimen); 5–10 mg/day for 12–14 days/month (sequential regimen)
• Norethisterone acetate (oral) b	0.1–1.0 mg/day (continuous regimen); 1.25–2.5 mg/day for 12–14 days/month (sequential regimen)
• LNG IUS	20 μg/day for 5 years (52 mg, LNG IUS)
Estrogen/progestogen fixed dose combined preparations
• E2/micronized progesterone (oral)	1.0–2.0 mg/100–200 mg (continuous regimen)
• E2/dydrogesterone (oral)	0.5–1.0 mg/2.5–5.0 mg (continuous regimen); 1.0–2.0 mg/10 mg (sequential regimen)
• E2/norethisterone acetate b (transdermal patch)	25–50 μg/85–170 μg (continuous and sequential regimen)
• E2/norethisterone acetate b (oral)	0.1–2.0 mg/0.5–1.0 mg (continuous regimen); 1.0–2.0 mg/1.0 mg (sequential regimen)
• E2/levonorgestrel (patch)	50 μg/7 μg/day (continuous regimen)
• E2/drospirenone	1.0 mg/2.0 mg/day (continuous regimen)
• E2/nomegestrol acetate	1.5 mg/3.75 mg/day (sequential regimen)
• Estradiol valerate/dienogest	1.0 mg/2.0 mg (continuous regimen)
Tibolone (oral)	1.25–2.5 mg/day
Conjugated equine estrogens/bazedoxifene (oral)	0.45 mg/20 mg/day

Abbreviations: EM, early menopause; LNG IUS, levonorgestrel intrauterine system; MHT, menopause hormone therapy; POI, premature ovarian insufficiency; RCT, randomized controlled trial.

^a Although low‐ or standard‐dose estrogen therapy is often prescribed at the time of natural menopause, this approach is largely based on clinical practice, as RCT evidence is lacking. Therefore, no definitive recommendation can be made and treatment should be individualized, with dose adjustments guided by the indication and patient tolerability. Moreover, prescribing practices may also vary according to the global availability of specific products.

^b Medroxyprogesterone acetate and norethisterone acetate remain approved options. However, current MHT recommendations acknowledge the increasing use of micronized progesterone and other progestogens with a more physiological profile as alternatives. ¹⁰¹

It may be that some progestogens could confer a cardiovascular advantage. In a retrospective cohort study, the combination of oral 1 mg estradiol with drospirenone 2 mg/day reduced BP, daytime and nighttime heart rate, body mass index, apolipoprotein B, and total cholesterol concentrations. ¹²⁸

The formulations listed in Table 4 may not be available globally. Conversely, some formulations available in specific countries may not be included. Therefore, treatment choices should be adapted to local availability and prescribing practices.

3.6. Key takeaways

A growing body of evidence shows that women with a history of EM share a similar long‐term profile to those with POI, including increased risk of CVD, fractures, osteoporosis, dementia, and mortality. ⁸⁷ Therefore, POI and EM should be considered as a risk continuum and managed accordingly, as an integrated condition, avoiding arbitrary limits to treatment duration. Including women with menopause aged between 40 and 45 years will provide a more comprehensive approach to their management. Although direct evidence demonstrating reductions in CVD and/or osteoporosis/fractures remains limited in this population, early initiation of HT at higher than conventional doses to achieve estradiol levels in physiological mid‐follicular range appears justified in women with EM as well as those with POI.

However, some issues still remain unresolved and should be further addressed in future studies. First, the optimal estrogen doses beyond usual ages of menopause should be clearly defined. Second, how should bone health be managed if HT is discontinued? According to a recent systematic review, there are only two studies that have attempted to answer this question, showing that either alendronate (only a 12‐month follow‐up) or raloxifene could be used to maintain or further increase BMD both at LS and FN. ¹²⁹ However, given the lack of efficacy and safety data on non‐hormonal bone‐sparing medications in women with POI/EM, together with the well‐documented benefits of HT beyond bone protection in this age group, it seems reasonable to favor HT over alternative therapies unless clear contraindications exist.

4. MANAGEMENT OPTIONS FOR POI/EM IN WOMEN WITH CONTRAINDICATIONS TO HT

In women with POI/EM for whom systemic HT is contraindicated, such as a history of hormone‐sensitive malignancy, lifestyle and pharmacologic interventions should be optimized toward reducing the risk of CVD and fractures. Lifestyle interventions include weight loss of at least 5%–10% (in cases with overweight or obesity), adoption of a dietary pattern with low intake of saturated fat and high intake of vegetables, fruits, legumes, nuts, whole grains, olive oil, and fish (e.g., the Mediterranean diet), regular exercise (≥150 min of moderate‐intensity exercise per week) and avoidance of smoking. ¹⁰¹ These “interventions” should underpin whatever hormonal and non‐hormonal pharmacological and other approaches are considered.

Notably, POI has been recognized as a CVD risk enhancing factor by international guidelines. ¹³⁰ Therefore, despite lack of interventional data, it is prudent to consider intensifying lipid‐lowering therapy to achieve lower targets for low‐density lipoprotein cholesterol than those set by 10‐year or lifetime CVD risk assessment. ¹³¹ Traditional cardiovascular risk factors, including hypertension, diabetes, and smoking, should also be managed accordingly in women with POI or EM, consistent with strategies implemented in populations at high CVD risk.

Regarding skeletal health, traditional recommendations to maintain skeletal integrity, such as weight‐bearing exercise, optimal calcium/vitamin D supplementation and avoidance of smoking, are strongly recommended. ¹³² , ¹³³ , ¹³⁴

Ten‐year fracture risk assessment using the FRAX model should guide consideration of bone‐specific therapies in women at high or very high risk of fracture. However, the FRAX model is currently validated only for individuals older than 40 years. ¹³² , ¹³³ , ¹³⁴ It should be emphasized that fracture outcome data are lacking in women with POI/EM treated with bone‐specific agents such as bisphosphonates, denosumab, teriparatide, or romosozumab, although these therapies may improve BMD. ¹³² , ¹³³ Therefore, any potential benefits should be carefully weighed against long‐term safety considerations, particularly in women of childbearing potential, including the prolonged skeletal retention of bisphosphonates and the limited pregnancy safety data available for bone‐specific agents.

For the management of VMS, non‐hormonal therapies may be considered where available. Traditionally, these have included selective serotonin reuptake inhibitors (SSRIs) and serotonin‐norepinephrine reuptake inhibitors (SNRIs), although they are less effective than HT. ⁸⁶ Both SSRIs and SNRIs can reduce the frequency and severity of VMS, by up to 65%, with paroxetine, escitalopram, and citalopram being the most efficacious among SSRIs, and venlafaxine and desvenlafaxine among SNRIs. ¹³⁵ Gabapentin and oxybutynin may also be considered for VMS relief, although their potency is low and they are associated with an increased risk of side effects, such as drowsiness. Clonidine is no longer recommended as a first‐line treatment for the same reasons. ¹⁰¹ It must be underscored that representation of women with EM in clinical trials has been limited. Similarly, little to no data exist in women with POI. Nevertheless, available data suggest comparable efficacy to that observed in the general postmenopausal population. ¹³⁶ , ¹³⁷ Their benefit should always be weighed against potential side effects, such as nausea, dry mouth, constipation, increase in BP (particularly with SNRIs), and decrease in libido. ¹³⁵

A new class of non‐hormonal therapies has recently emerged for the treatment of VMS, targeting the hypothalamic thermoregulatory pathway. This effect is achieved by inhibiting the binding of neurokinin B to neurokinin 3 receptors (NK3R) on kisspeptin–neurokinin B–dynorphin (KNDy) neurons, a pathway normally regulated by estrogen and believed to play a central role in the pathophysiology of VMS. ¹³⁸ Two NK3R antagonists are currently available: fezolinetant and elinzanetant, the latter also exhibiting antagonistic activity at the neurokinin 1 receptor. Large phase III trials conducted in postmenopausal women aged 40–65 years have demonstrated their efficacy in reducing both the frequency and severity of VMS, while also improving sleep disturbances and QoL. ¹³⁹ , ¹⁴⁰ , ¹⁴¹ , ¹⁴² , ¹⁴³ To date, however, no studies specifically evaluating these agents in women with POI/EM have been published. A reversible increase in transaminase levels (>3 times the upper limit of normal) remains a safety concern with fezolinetant, although it occurs in only a small proportion of users (1%–3%), thereby necessitating periodic monitoring of liver function during the early stages of treatment. ¹³⁹ , ¹⁴⁰ A recent indirect comparison suggested that fezolinetant and elinzanetant have similar efficacy in the treatment of VMS, with elinzanetant providing additional benefits for sleep disturbances. ¹⁴⁴

Additional non‐hormonal options for the management of VMS in postmenopausal women include interventions with potential psychological benefits, such as cognitive behavioral therapy, hypnosis, relaxation techniques, mindfulness‐based stress reduction, yoga, aromatherapy, and physical activity, as well as plant‐based products (e.g., phytoestrogens, maca, pollen extract, and dong quai). However, evidence supporting their efficacy for VMS remains inconclusive. ⁸⁶ In women with POI, a recent systematic review suggests that Chinese herbal medicine and acupuncture may reduce VMS and may represent alternatives to HT, although the available evidence is limited. Chinese herbal medicine may also be used as an adjunct to HT. ¹⁴⁵

Finally, in women with symptoms of genitourinary syndrome of menopause (GSM), low‐dose vaginal estrogen (either 17β‐estradiol or estriol) may be considered, even in those with a history of breast cancer when non‐hormonal therapies have proven ineffective. ⁸⁶ Vaginal dehydroepiandrosterone and ospemifene have demonstrated efficacy and safety profiles comparable to those of local vaginal estrogen therapy. Ospemifene is an oral selective estrogen receptor modulator with mild estrogenic activity in the vaginal epithelium and anti‐estrogenic effects on the endometrium and breast tissue. ¹⁴⁶ , ¹⁴⁷

In conclusion, for women with POI/EM in whom systemic HT is contraindicated, a whole‐toolkit approach should be applied, recognizing that available options vary by healthcare setting. Where HT cannot be used, management should prioritize lifestyle and pharmacologic interventions to reduce cardiovascular and fracture risk. Regarding bone health, optimization of calcium plus vitamin D supplementation, as well as regular (mostly weightbearing) exercise, are essential for preventing bone loss. In patients at high or very high risk of fractures, bone‐specific agents may be considered, after excluding secondary causes of osteoporosis. Non‐hormonal VMS treatments (NK3R antagonists, SSRIs, SNRIs) may be employed after careful assessment of risks and benefits, where available. Low‐dose vaginal estrogen can be considered for genitourinary symptoms if other non‐hormonal therapies are ineffective, with further safety data needed particularly for breast cancer patients on aromatase inhibitors. In the absence of long‐term RCTs, special interest groups and ongoing collection of registry data, which should include EM as well as POI data, would be helpful to optimize the diagnosis and management of this distressing scenario. ⁸⁹

5. IMPROVING POI/EM MANAGEMENT THROUGH EDUCATION AND RESEARCH

Optimizing the management of POI/EM requires a concerted effort across medical field, academia, and society as a whole, to promote evidence‐based education that reaches all segments of the population. Figure 3 presents a proposed multi‐level call to action aimed at prioritizing POI/EM management and research and enhancing women's physical, psychological, and social well‐being.

FIGURE 3.

A multi‐level framework to optimize the management of women with POI/EM through education and research. HT, hormone therapy; MHT, menopausal hormone therapy.

5.1. Education in POI/EM management: Critical areas

Gaps in medical education regarding the diagnosis and management of POI/EM have been mainly documented through patient surveys or interviews rather than direct assessment of clinicians. Nevertheless, the limited menopause‐specific training in many obstetrics and gynecology curricula ¹⁴⁸ may contribute to suboptimal management of this population of early menopausal women. The publication of jointly endorsed guidelines for fertility and menopause has been pivotal in disseminating evidence‐based recommendations for the diagnosis and management of POI. ²⁴ However, broader dissemination is essential, not only among obstetricians and gynecologists, but also among physicians who may encounter women with POI/EM due to risk factors, symptoms, or long‐term complications, including general practitioners, hematologists, oncologists, rheumatologists, cardiologists, neurologists, and endocrinologists. In this context, IMS and FIGO's collaboration may enhance the global dissemination of evidence‐based education and facilitate dialogue with scientific societies across other medical disciplines.

Critical emerging gaps in the clinical management of POI/EM include delayed diagnosis and suboptimal HT in terms of both dosage and duration, with potential adverse effects on short‐ and long‐term health outcomes and quality of life. From this point of view, the present position paper provides a framework to start rethinking the paradigm of menopause at normal age as a time limit for POI/EM treatment. This approach may represent the minimum requirement but not the optimal management strategy.

Education for the general population is also needed to raise awareness and reduce social stigmatization. A recent survey among women of childbearing age showed poor general knowledge of POI, confusion between natural menopause and EM and limited awareness of symptoms requiring specialist evaluation. ⁵³ Disseminating high‐quality evidence is therefore essential, particularly in the era of social media, where women with POI/EM may encounter unreliable information. ¹⁴⁹ Patient associations and support groups can bridge patients, clinicians, academics, and institutions, while providing valuable support at diagnosis. Since these initiatives are not uniformly available worldwide, scientific societies may help support and expand them globally.

5.2. Research agenda

Critical research gaps encompass:

• The development of predictive tools for POI/EM. Longitudinal studies in women at risk of POI/EM (e.g., those with a positive family history or exposure to gonadotoxic treatment) may facilitate the prospective collection of data required to develop predictive tools integrating clinical, genetic, environmental, hormonal, and/or biochemical markers. This approach could improve personalized risk counseling and empower women to make informed decisions, including those related to fertility preservation.

• The etiological characterization of POI/EM and possible implications on clinical characteristics and long‐term consequences. As studies report results from relatively small cohorts of patients, expansion of global POI registry collecting high‐quality prospective data represents a priority. ¹⁵⁰

• The definition of optimal type, dose, and duration of HT/MHT in women with POI/EM and their impact on long‐term outcomes. Although RCTs provide the most robust evidence to evaluate the effects of a given treatment, they are more difficult to conduct in POI/EM populations as they require long‐term therapy and extended follow‐ups to obtain data on clinically relevant outcomes, such as cardiovascular events, hip fractures, and/or dementia. To better assess the impact of specific treatment regimens, real‐world clinical data should be collected through global registries of women with POI/EM. Such registries may represent a more reliable source of information than large population datasets, which often lack detailed data on HT or report it without details about type, dose, and/or duration. In line with the aims of this position paper, follow‐up should extend beyond the normal age of menopause, to better define the long‐term impact of sustained MHT on future health outcomes and healthspan.

6. NEW PERSPECTIVES AND FUTURE CHALLENGES TO INCREASE THE HEALTHSPAN OF WOMEN WITH POI OR EM: A NEW PARADIGM FOR HEALTHY AGING

In women, healthspan is strongly influenced by the timing of reproductive aging and by the duration of estrogen deficiency. ⁵¹ , ¹⁵¹

Both POI and EM are associated with a shorter healthspan, characterized by an earlier onset of osteoporosis and fractures, cardiovascular disease, metabolic dysfunction, cognitive decline, and frailty, compared with menopause at the typical age. ²⁴ , ⁸⁵

All of this gives rise to challenges and unmet needs, both for affected women and for the wider community, that warrant a response. Tables 5 and 6 outline strategies with the potential to help address these needs.

TABLE 5.

Strategies to address the unmet needs of women with POI/EM.

Current problems	Strategies to address women's needs
POI/EM are frequently overlooked, resulting in delayed diagnosis 18 , 54	Increasing health literacy and empowerment Implementing standardized diagnostic pathways for early recognition and timely diagnosis, to avoid prolonged hypoestrogenism and delayed preventive care 1
Gaps in awareness of the short‐ and long‐term health impact of POI/EM 53 , 54	Implementing longitudinal follow‐up to capture fluctuating ovarian function and evolving comorbidities 1 Providing clear, culturally appropriate information on the long‐term health implications of POI and EM, enabling informed decision‐making and adherence to recommended care 24
Inappropriate use of HT: 152 Common underdosing Focus on vasomotor symptoms rather than long‐term prevention Delayed initiation, early discontinuation and poor adherence due to misperceptions about HT‐related risks	Appropriate use of HT: 24 , 153 Using estrogen therapy as a physiological hormone replacement aimed at achieving premenopausal estradiol levels, rather than applying symptom‐based minimal dosing Reframing HT as a long‐term replacement therapy to reduce long‐term morbidity while managing menopause‐related symptoms Reframing the benefit–risk balance as not treating estrogen deficiency carries well documented harm Tailoring treatment at every stage of care over time
Fragmented care, characterized by hormone‐focused gynecologic management, delayed multispecialty involvement and lack of systematic long‐term follow‐up	Positioning POI/EM care within a healthy aging framework, with HT as foundational therapy but not the only intervention Implementing structured, evidence‐based multidisciplinary strategies for preventing long‐term morbidity and for early assessment of cardiovascular, musculoskeletal, metabolic, and mental health risks 85 Implementing a value‐based, patient‐centered model of care, with standardized assessment of outcomes that matter to women, including quality of life, emotional well‐being, sexual function, fertility concerns, symptom burden, and functional health 154

Abbreviations: EM, early menopause; HT, hormone therapy; POI, premature ovarian insufficiency.

TABLE 6.

Strategies to address health science gaps in POI/EM management.

Current problems	Strategies to address health science gaps
Limited scientific data 1 , 153 on: HT specifically targeted to POI or EM The long‐term effects of extending HT treatment beyond the average age of physiological menopause The long‐term effects of lifestyle approaches in POI/EM management	Developing large‐scale, multinational prospective studies and data registries to inform optimal management 155
Major public health burden: Poorly managed POI/EM is associated with substantial morbidity, disability, and increased healthcare and long‐term care expenditures 71 Inequity in access to specialized care 57	Integrating POI/EM care into chronic disease prevention frameworks, rather than episodic or symptom‐driven models Including age at menopause and POI/EM status as routine variables in population health surveillance and non‐communicable disease prevention programs Implementing policies acknowledging POI and EM as contributors to earlier onset of disability and dependence, with implications for workforce participation, productivity, and long‐term care needs Aligning reproductive health, aging, and social care policies to promote healthy longevity rather than survival alone Reducing disparities in access to diagnosis, HT, and long‐term preventive care, particularly in LMICs, where POI/EM are frequently under‐diagnosed and under‐treated Ensuring access to fertility counseling, psychosocial support, and sexual health care to mitigate the substantial emotional and social impact of early loss of ovarian function

Abbreviations: EM, early menopause; HT, hormone therapy; LMIC, low‐ and middle‐income country; POI, premature ovarian insufficiency.

6.1. POI and early menopause: An integrated resource‐aware management framework

Healthspan‐oriented interventions in POI and EM represent some of the most actionable opportunities to reduce long‐term disability and improve healthy longevity. Because menopause‐related estrogen deficiency is modifiable, unlike many other determinants of aging, its prompt recognition and treatment may help preserve healthspan. ²⁴

Therefore, POI and EM should no longer be managed as variants of physiological menopause but recognized as chronic endocrine conditions and sentinel events for accelerated aging. ⁴⁵ Current approaches to HT in POI/EM remain overly conservative, symptom‐driven, and influenced by risk paradigms derived from older postmenopausal populations. ²⁶ A paradigm shift is required, reframing estrogen therapy as a hormonal replacement aimed at preserving cardiovascular, bone, psychological, sexual, cognitive, and functional health across the life course.

Timely initiation, adequate dosing and long‐term continuation of HT should be considered foundational to POI/EM care, alongside integrated preventive strategies. Such strategies align reproductive endocrinology with healthy aging medicine, enabling a shift from reactive disease management to proactive healthspan optimization.

The proposed flowchart (Figure 4) reflects a reframed approach to POI/EM management, shifting from symptom‐based menopause care to a structured life‐course strategy in which HT serves as a physiological replacement to preserve healthspan and prevent long‐term disability.

FIGURE 4.

Flowchart summarizing a new paradigm for healthy aging in women with POI or EM integrating diagnosis, hormone therapy, and lifelong preventive care. ¹ , ²⁴ , ²⁶ , ¹⁵⁶ BMI, body mass index; CV, cardiovascular; DXA, dual‐energy X‐ray absorptiometry; EM, early menopause; HT, hormone therapy; MHT, menopausal hormone therapy; POI, premature ovarian insufficiency.

Framing POI/EM management within healthy aging medicine offers a unique opportunity to reduce long‐term disability, improve quality of life, and narrow the gap between lifespan and healthspan in affected women.

Before the age of 50 years in particular, HT should be considered as a replacement treatment targeting physiological premenopausal estrogen levels, analogous to insulin in type 1 diabetes or thyroxine in hypothyroidism. After that age, the dose may be tapered to conventional MHT. ¹⁵⁷

Unfortunately, extension of HT beyond the natural age of menopause in POI or EM has not been adequately studied as a distinct exposure. As a result, international guidelines tend to be directive only up to a minimum threshold, recommending HT until at least the average age of natural menopause. ²⁴ , ¹⁵³ , ¹⁵⁸

However, in menopause at the usual age, MHT is commonly started around the time of the menopausal transition, with a favorable benefit–risk ratio for those who started the therapy before the age of 60 years or within 10 years of the final menstrual period and can be continued after proper individual risk reassessment as long as the potential benefits outweigh the risks. ⁸² , ¹⁵⁹

Therefore, for women with POI/EM, discontinuing HT once they reach the usual age of menopause may create a clinical paradox. At this stage, an individualized transition to standard MHT regimens may be appropriate, not only for symptom control but also for long‐term preventive benefits. ²⁴ , ¹⁵³ , ¹⁵⁸

For these reasons, until robust data on prolonged MHT use beyond the age of natural menopause become available, women with POI or EM should not be denied a potentially valuable treatment to enhance healthspan.

In summary, achieving the goal of improving healthy life expectancy, at both the individual and societal levels, while containing long‐term healthcare costs, will require an important cultural shift in how both POI and EM are recognized, managed, and prioritized within healthcare systems. As authors of this joint FIGO‐IMS paper, we call for the urgent adoption of such a shift.

AUTHOR CONTRIBUTIONS

All authors assisted in the conceptualization, draft and review of the manuscript. All authors take responsibility for the contents of this article.

CONFLICT OF INTEREST STATEMENT

C.B. has acted in an advisory capacity for Gedeon Richter. R.E.N. is current President of the International Menopause Society (IMS). She has lectured and acted in an advisory capacity for Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Biocodex, Exeltis, Fidia, Gedeon Richter, Ibsa, Merck & Co, Novo Nordisk, Organon & Co, Shionogi Limited, Theramex, Viatris. She declares that none of these could be perceived as prejudicing the impartiality of the content reported. A.R.G. is immediate Past President of the International Society of Gynecological Endocrinology (ISGE) and European Society of Gynecology (ESG), President of the International Academy of Human Reproduction (IAHR), and Executive Director of ISGE. He has lectured and acted in an advisory capacity for Abbott, Astellas, Bayer, Besins, Bionorica, Elea, Gedeon Richter, Secure Pharma, Serelis, and Theramex. P.A. has lectured and acted in an advisory capacity for Astellas, Astrazeneca, Elpen, and UCB. L.C. is a current member of IMS Innovations Committee. She has lectured or acted in advisory capacity for Bayer, Eli Lilly, Exeltis, Fidia, Gedeon Richter, Named, and Pharmextracta. N.P. is immediate Past President of IMS and a current IMS Board Member. He has lectured and acted in an advisory capacity for Abbott, Astellas, Bayer, Besins, Gedeon Richter, Mithra, Novo Nordisk, SeCur, Theramex, and Viatris. S.S.K. and F.F. have no conflicts of interest.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.