Endometriosis beyond menopause: a call for greater clinical awareness

Endometriosis is an estrogen-dependent gynecological disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity. Although it has been traditionally regarded as a disease confined to the reproductive years, where cyclical ovarian estrogen production drives its proliferation and symptomatology, it is now increasingly recognized that endometriosis can persist into, or even first manifest during, the postmenopausal period, albeit at a considerably lower rate [Citation1]. The actual incidence of endometriosis in postmenopausal women is not well established. Available data mainly focus on the proportion of women with endometriosis who are postmenopausal, which is at most 3–5% of all endometriosis cases [Citation1–4]. One paper reported finding endometriosis in about 5% of postmenopausal women undergoing major gynecologic operations [Citation2]; however, this figure comes from a selected surgical population and should not be taken as representative of the general postmenopausal population. The pathophysiology of endometriosis remains incompletely understood, and this uncertainty is even greater when considering postmenopausal cases [Citation5]. While the majority of lesions regress after the cessation of ovarian function and the accompanying decline in circulating estrogen with menopause, a subset of women continue to exhibit persistent disease, and others are diagnosed for the first time after menopause. Whether such cases represent truly de novo endometriosis resulting from coelomic metaplasia or long-standing, previously silent disease that only becomes clinically apparent later in life remains unclear. Although the central role of estrogen in the development and maintenance of endometriotic implants is consistent, accumulating evidence also suggests the existence of a more aggressive subset that is comparatively less estrogen-dependent, potentially accounting for some postmenopausal cases [Citation6]. These lesions appear biologically distinct from typical endometriotic foci, characterized by reduced progesterone receptor expression, aggressive growth and resistance to progesterone. Furthermore, resistance to gonadotropin-releasing hormone antagonist therapy has also been observed, suggesting that these lesions may exhibit a more estrogen-independent phenotype [Citation6]. In the postmenopausal state, possible sources of estrogen include peripheral conversion of androgens in adipose tissue, exogenous hormone replacement therapy or, more rarely, local estrogen production by the lesions themselves through aromatase activity [Citation7]. These mechanisms may provide sufficient hormonal stimulation to maintain or reactivate endometriotic foci despite the absence of ovarian function. The likelihood of underdiagnosis is higher in postmenopausal women, as the cessation of menstruation removes some of the most characteristic manifestations of endometriosis (cyclical pelvic pain and dysmenorrhea), leaving non-cyclical pelvic pain as a predominant symptom [Citation8]. Moreover, infertility, which is a prominent complaint in patients of reproductive age and a common reason why they undergo extensive evaluation leading to a diagnosis of endometriosis, is inherently absent in this group [Citation9]. Consequently, the clinical picture in postmenopausal women may differ significantly. The most commonly reported features are persistent pelvic pain, adnexal masses detected on imaging and gastrointestinal or urinary disturbances related to deep pelvic or extra-pelvic involvement [Citation10]. These symptoms reflect a more atypical and insidious disease course compared to the classical reproductive-age presentation. Such deviations from the expected pattern complicate recognition, and clinicians may be less inclined to include endometriosis in the differential diagnosis of pelvic pain in this population. Accurate diagnosis in the postmenopausal population is further complicated by the broad and clinically relevant differential for pelvic pain and adnexal masses in later life, which includes malignancies, pelvic cysts and gastrointestinal or urinary tract disease. As in premenopausal women, imaging alone cannot establish the diagnosis of endometriosis, yet it remains central to evaluation and is frequently employed to guide clinical decision-making, even though findings may differ from those typically seen in patients of reproductive age [Citation11]. Transvaginal ultrasonography is most often used as the first-line modality due to its wide availability, affordability and utility in detecting adnexal pathology. However, its sensitivity is lower for detecting pelvic endometriotic lesions located outside the adnexa or uterus, and its specificity is reduced when endometriotic foci lack classic sonographic features [Citation12]. Magnetic resonance imaging offers superior sensitivity for identifying endometriotic nodules and deep pelvic involvement, particularly when using T1-weighted, T2-weighted and fat-suppressed sequences, which help characterize hemorrhagic lesions and fibrotic disease [Citation13]. Computed tomography has more restricted utility but may occasionally aid in detecting extra-pelvic involvement when gastrointestinal or urinary tract pathology is suspected. Nevertheless, none of these imaging approaches can establish a definitive diagnosis of endometriosis, and histopathological confirmation remains the gold standard for diagnosis [Citation14]. Consequently, a lower threshold for surgical evaluation is often necessary to exclude malignancy and to establish definitive diagnosis in this patient population. Similar to premenopausal endometriosis, one of the main concerns in postmenopausal women is the potential for malignant transformation of endometriotic lesions. The overall risk remains poorly defined, as the body of evidence is limited to case reports and small series, making it difficult to establish accurate incidence rates in this age group. Suspicion of malignancy is typically based on a combination of clinical features, such as new-onset or rapidly progressive pain, vaginal bleeding or dyspareunia, and imaging findings on transvaginal ultrasonography and magnetic resonance imaging suggestive of atypical or solid components [Citation13,Citation15]. Nevertheless, available data suggest that, as in premenopausal endometriosis, the majority of malignancies arising in association with endometriosis are endometrioid and clear cell carcinomas, with ovarian endometriosis representing the most frequent site of transformation, most commonly observed around the perimenopausal period in both age groups [Citation16]. Extra-ovarian malignant transformation, although rare, appears to be more common in postmenopausal women [Citation17]. Given this potential risk, any new or enlarging pelvic mass in a woman with a history of endometriosis should prompt careful evaluation, as early recognition of malignant change is crucial for prognosis and management. Management of endometriosis in postmenopausal women presents unique challenges, as therapeutic decisions must balance symptom relief and quality-of-life improvement, goals that are equally important in patients of reproductive age, against the potentially heightened risks of treatment-related adverse effects, including potential malignant transformation, in this age group. Surgical excision is generally regarded as the preferred approach, particularly in women with symptomatic disease or when malignant transformation is suspected, as it provides both definitive diagnosis and treatment. However, surgery can be technically more challenging in postmenopausal women due to the presence of comorbidities and surgical difficulties, particularly in cases of recurrence after prior operations [Citation18]. Medical management plays a more limited role due to concerns about exogenous unopposed estrogen exposure and its potential to reactivate disease [Citation19]. Nevertheless, aromatase inhibitors and progestins have been employed for symptomatic relief in selected cases, although supporting evidence remains sparse and is primarily extrapolated from studies in premenopausal populations [Citation20]. These agents may represent a viable alternative for women who are poor surgical candidates or who decline operative management. When menopausal hormone therapy is indicated, options may include combined estrogen–progestin therapy, tissue-selective estrogen complexes or tibolone [Citation15]. Such therapy requires particularly cautious consideration, as unopposed estrogen may increase the risk of disease persistence or recurrence, in contrast to the premenopausal population, where the benefits of hormone therapy often outweigh the risks [Citation19,Citation21]. Thus, individualized management within a multidisciplinary framework – integrating lifestyle measures such as regular physical activity, weight management and nutritional modifications such as limiting processed or red meat intake and emphasizing fiber-rich foods [Citation15,Citation21] – is essential to achieve symptom control while minimizing treatment-related risks. Despite growing recognition of endometriosis in postmenopausal women, substantial gaps remain in understanding its true epidemiology, natural history and optimal management. Much of the available evidence is limited to case reports, small case series and observational studies, which restricts generalizability and limits the development of evidence-based clinical guidelines. Future research should focus on elucidating the mechanisms underlying de novo postmenopausal disease. Additionally, prospective studies are needed to evaluate the efficacy and safety of medical therapies such as aromatase inhibitors in this population, as current treatment strategies are largely extrapolated from premenopausal cohorts. Also, there is a pressing need for further investigation of the potential for malignant transformation in postmenopausal endometriosis, as this will be essential for the development of evidence-based, tailored management recommendations for this understudied patient group. Acknowledgment The first draft of the manuscript was written by S. Apelian. P. Chedraui and H. S. Taylor provided senior intellectual input to the original draft. 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