From prevalence to precision: Integrating phenotype, symptoms, reproductive goals, and treatment in leiomyoma care

Management of uterine fibroids has evolved substantially over recent decades, moving from a predominantly surgical paradigm to a broader spectrum of medical, image‐guided, and minimally invasive surgical options. This expansion reflects both advances in technology and a growing emphasis on individualized, uterus‐preserving care. This targeted approach means that, to be effective, management requires determining whether identified fibroids are responsible for the patient's presenting symptoms or reproductive concerns in the context of their specific goals. A critically important concept occurs when the clinician is faced with a leiomyoma phenotype that is not thought to be related to abnormal uterine bleeding or infertility in a cause‐and‐effect fashion. For example, a singular 2.5‐cm Type 4 myoma almost certainly does not cause the symptom of heavy menstrual bleeding in the context of regular, predictable timing of periods with a cycle length of 24–38 days; instead, the clinician should consider AUB‐A (adenomyosis), AUB‐C (coagulopathy), or, especially if there is no evidence of adenomyosis, AUB‐E (a primary endometrial disorder). Appropriate therapies exist for each of these options. When infertility exists in conjunction with a 3‐cm Type 6 myoma, the clinician can be relatively confident that myomectomy will not improve outcomes. Another important consideration in therapeutic decision‐making is the natural history of fibroid‐related symptoms. For many individuals, symptoms such as abnormal uterine bleeding diminish or resolve following the menopausal transition. As a result, medical management that provides a bridge to menopause represents a rational and often effective strategy, particularly for those in the later reproductive years, especially if the leiomyoma phenotype is not amenable to a simple procedure such as hysteroscopic myomectomy. The availability of medical therapies that can be used for heavy and/prolonged periods—often incorporating estrogen and progestin components to mitigate hypoestrogenic effects and the risk of endometrial neoplasia—has enhanced the feasibility of this approach and may allow many patients to avoid procedural intervention altogether. However, for patients whose primary concern is infertility, medical therapy alone is generally ineffective at improving reproductive outcomes and does not replace procedural intervention when fibroids are thought to cause or contribute to the problem. When surgical management is indicated, the choice of approach should be guided by fibroid phenotype, including size, FIGO type, and the number of lesions. Wherever feasible, hysteroscopic removal of submucosal fibroids should be performed in preference to abdominal approaches, whether laparoscopic or laparotomic. For intramural and other nonhysteroscopically accessible lesions, myomectomy remains appropriate, with increasing use of minimally invasive hysteroscopic and laparoscopic techniques. An understanding of fibroid pathogenesis—including the noninvasive growth pattern of leiomyomas and the presence of a well‐defined pseudocapsule—supports dissection within this natural plane, facilitating removal while allowing the surrounding myometrium to re‐expand and preserve uterine structure and function. 30 In this context, it is important to recognize that the symptom of heavy menstrual bleeding is not only disruptive at the time of an episode, but the condition is frequently associated with iron deficiency, with or without anemia. Iron deficiency itself contributes substantially to an impaired quality of life, including diminished cognitive and physical function. 34 Effective medical management may therefore improve patient well‐being not only by reducing bleeding but also by allowing the restoration of normal iron balance with appropriate oral or intravenous preparations. For those who ultimately require procedural or surgical intervention, preoperative medical management that reduces bleeding and allows repletion of iron stores is also important, as anemia at the time of surgery is associated with increased morbidity and mortality. 18 , 19 Despite the advances of the hysteroscopic and laparoscopic surgical approaches, significant challenges remain in the management of patients with markedly enlarged uteri or with fibroids that distort pelvic anatomy and potentially impact adjacent structures such as the ureters, bladder, or bowel. In such cases, surgical management—whether myomectomy or hysterectomy—requires advanced technical expertise to minimize surgical morbidity. These patients should ideally be managed in centers with the appropriate resources and experience, including surgeons skilled in minimally invasive techniques for large uteri. Equally important is a comprehensive approach to patient blood management, including preoperative optimization of iron stores and hemoglobin levels, meticulous intraoperative surgical technique to minimize blood loss, and the availability of adjunctive measures, such as intraoperative cell salvage, to reduce the need for allogeneic transfusion. 20 , 35 These considerations are particularly relevant for individuals who decline blood transfusion, 36 underscoring the importance of both surgical expertise and institutional preparedness. Taken together, the expanding range of therapeutic options underscores the importance of aligning treatment with fibroid phenotype, symptom attribution, reproductive goals, and the anticipated natural history of disease. Rather than a binary choice between observation and surgery, contemporary management involves selecting from a continuum of options that differ in mechanism, durability, invasiveness, and impact on reproductive outcomes.

MGM conceptualized, drafted, and reviewed the manuscript.

Despite the substantial progress reflected in this series, the limitations outlined above highlight an important opportunity to move beyond the current paradigm of reactive management toward a more anticipatory or preventive approach. At present, clinical care is largely initiated after the development of symptoms or the recognition of reproductive impairment. However, given the high prevalence of fibroids and the observation that only a subset becomes clinically meaningful, there is increasing interest in identifying those individuals at risk for progression to symptomatic or functionally significant disease at an earlier stage. The concept of screening for fibroids requires careful consideration. Given that most women will develop fibroids that never become clinically relevant, population‐based screening for the presence of leiomyomas with current or future clinical relevance is a challenging proposition. However, this does not preclude the development of strategies aimed at risk stratification and the identification of such tumors in selected populations. Such approaches may be particularly relevant for individuals known to be at higher risk for earlier onset or more severe disease, such as those of African or other ancestry, who are at increased risk, potentially employing genetic screening. 37 The concept of early clinically meaningful tumors refers not simply to the presence of fibroids but to fibroids with characteristics associated with future symptom development or reproductive impairment. These may include specific phenotypic features, proximity to the endometrium, effects on uterine peristalsis, or molecular and metabolomic signatures that might reflect or predict altered endometrial or myometrial function. The identification and validation of such markers would represent an important step toward more precise clinical management. The potential implications of earlier identification are significant but must be approached with caution. While advances in medical, image‐guided, and minimally invasive therapies raise the possibility that earlier intervention could alter disease trajectories, the risks of overtreatment remain substantial. Any strategy that seeks to intervene before clear clinical indications develop must therefore be supported by robust evidence demonstrating that such interventions improve meaningful outcomes without introducing unacceptable risk. Such evidence may well require the development of research networks acquiring and appropriately storing carefully phenotyped specimens of endometrium, myometrium, and/or leiomyoma tissue with adjacent hormonal and imaging data sufficient to provide a characterization that represents the structural and metabolomic features that change dramatically in response to the cyclical production of estradiol and progesterone from the ovary. Future research should also focus on longitudinal studies that link fibroid phenotype, biological characteristics, and patient outcomes over time. In parallel, comparative effectiveness studies are needed to define the role of existing and emerging therapies across the spectrum of leiomyoma phenotypes, including their impact when applied earlier in the course of disease. Advances in imaging, molecular characterization, and data science may facilitate the development of predictive models that better identify individuals at risk for clinically significant disease and guide individualized management. Taken together, these considerations suggest that the next phase of progress in fibroid care will not be driven solely by the development of new treatments, but by the ability to apply existing and emerging therapies more precisely. Achieving this goal will require a shift from a focus on the presence of fibroids to a more nuanced understanding of which fibroids matter, for whom, and at what point, as well as which interventions improve outcomes.

No external or internal funds were obtained or used for this work.

Despite substantial advances in understanding and management, important uncertainties remain. A central limitation is the inability to reliably predict which fibroids will become clinically meaningful. Although phenotype, defined by size, number, and location, provides a useful framework, it does not consistently predict symptom development, reproductive impairment, or progression. Growth rates also vary substantially, even among leiomyomas in a single individual, and potentially modifiable factors such as vitamin D deficiency remain incompletely understood. As a result, clinical decision‐making continues to rely heavily on individualized assessment rather than predictive models. A related challenge is the attribution of symptoms to fibroids. While associations between fibroids and abnormal uterine bleeding, infertility, and pregnancy complications are well described, causality is often difficult to establish with certainty. This is particularly relevant in individuals with multiple potential contributors to their symptoms, in whom interventions directed at fibroids may not fully address the underlying clinical problem. Improved methods for distinguishing fibroid‐related symptoms from coexisting conditions would enhance both patient selection and treatment outcomes. In the context of reproductive outcomes, gaps in the evidence are especially apparent. Although submucosal fibroids are consistently associated with impaired fertility and adverse outcomes, the impact of intramural fibroids remains less clearly defined. 25 , 26 Furthermore, while myomectomy is widely accepted as the standard of care for selected patients with infertility, there are limited high‐quality data to guide the management of less clearly defined phenotypes. Similarly, although image‐guided and ablative therapies have expanded treatment options, their effects on fertility and pregnancy outcomes across the spectrum of leiomyoma phenotypes remain incompletely characterized, particularly with respect to potential myometrial injury and its consequences in a subsequent pregnancy. Uncertainty also exists regarding the optimal integration of emerging therapies into clinical practice. While medical, image‐guided, and minimally invasive surgical options provide a broad range of choices, comparative effectiveness data are limited, and long‐term outcomes are not well established for many interventions. As a result, treatment selection is often guided by a combination of available evidence, clinical experience, and patient preferences, rather than by high‐quality, definitive data. Finally, disparities in disease burden and access to care represent an additional area of uncertainty and unmet need. The earlier onset and greater severity of fibroid disease in some populations highlight the importance of understanding both biological and social determinants of health. At the same time, access to advanced imaging, medical therapies, and minimally invasive or image‐guided procedures varies across regions and healthcare systems, limiting the generalizability of the available evidence and the implementation of optimal care. Taken together, these gaps underscore the need for continued investigation into the natural history of fibroids, mechanisms of symptom development, and comparative effectiveness of available treatments. Addressing these uncertainties will be essential to advancing a more precise, evidence‐based approach and may enable a transition toward earlier identification and more targeted intervention.

Uterine fibroids are highly prevalent, with population‐based studies demonstrating that more than two‐thirds of women will develop one or more leiomyomas during their lifetime. 1 , 4 , 9 However, only a minority of these individuals will experience symptoms severe enough to warrant clinical intervention. 1 This disparity between prevalence and clinical impact underscores the importance of distinguishing between the mere presence of fibroids and the subset that is clinically relevant. A central challenge in clinical practice is the attribution of symptoms to fibroids. Abnormal uterine bleeding, pelvic pain, pressure symptoms, and infertility are all commonly associated with fibroids, yet each may arise from a variety of alternative or coexisting conditions. Consequently, the identification of fibroids on imaging does not, in isolation, establish causality. Failure to recognize this distinction may lead to interventions, especially procedures, when fibroids are not responsible for the presenting complaint, exposing patients to unnecessary risk without clear benefit. The likelihood that a fibroid is clinically relevant is influenced by several factors, including its size, number, and anatomical location, as well as patient‐specific factors such as age, reproductive status, and symptom profile. The FIGO classification system provides a structured framework for describing fibroid location; 10 however, predicting clinical impact remains imperfect, and assumptions about the relationship between fibroid characteristics and symptoms continue to evolve. Individual tumors vary in genetic composition, cellular content, and relevant molecular expressions—a fact that has been demonstrated scientifically but not yet incorporated into clinical care. 4 , 11 , 12 , 13 Epidemiologic data further demonstrate that the burden of fibroid‐related disease is not evenly distributed. Women of African ancestry tend to develop fibroids at an earlier age and are more likely to experience a higher number and larger volume of tumors, contributing to a disproportionate impact on quality of life and reproductive health. 1 , 9 , 14 These disparities highlight the importance of considering population‐specific risk factors when evaluating both the clinical significance of fibroids and potential strategies for earlier identification or intervention. An additional consideration influencing both patient and clinician decision‐making is the perceived risk of occult malignancy, particularly leiomyosarcoma. Although this risk is widely acknowledged, it is rare, and its magnitude has frequently been overestimated in certain contexts due to reliance on data from selected surgical populations. 15 Overstatement of this risk may contribute to heightened concern and a preference for more aggressive surgical management, even when expectant, medical, or minimally invasive approaches would otherwise be appropriate. A balanced understanding of this risk is therefore essential to support rational, patient‐centered care. Despite these advances, significant challenges remain in the management of patients with markedly enlarged uteri, including those with fibroids that affect pelvic anatomy by distorting relationships of adjacent structures such as the ureters, bladder, bowel, and relevant vasculature. In such cases, surgical management—whether myomectomy or hysterectomy—requires advanced technical expertise to minimize surgical morbidity. These patients should ideally be managed in centers with the appropriate resources and experience, including surgeons skilled in minimally invasive techniques for large uteri. 16 , 17 Available evidence from studies of anemic women undergoing major surgery, typically hysterectomy, shows a substantially increased risk of global morbidity and mortality. 18 , 19 Consequently, it is critically important to have a comprehensive approach to patient blood management in place, including preoperative optimization of iron stores and hemoglobin levels, meticulous intraoperative surgical technique to minimize blood loss, and the availability of adjunctive measures, such as intraoperative cell salvage, to reduce the need for allogeneic transfusion. 20 These considerations are particularly relevant for individuals who decline blood transfusion, underscoring the importance of both surgical expertise and institutional preparedness. Taken together, these considerations reinforce the need to move beyond a binary view of fibroids as either present or absent, and toward a more nuanced approach that identifies which lesions are clinically meaningful within a given patient context. This perspective provides the foundation for phenotype‐informed, goal‐directed management strategies that are developed in subsequent sections of this series.

Uterine fibroids exemplify a condition in which high prevalence coexists with highly variable clinical impact. The work presented in this FIGO series underscores that effective management depends not simply on the detection of fibroids but on the careful integration of phenotype, symptom attribution, and patient‐specific goals. Central to this framework is the recognition that the presence of leiomyomas does not necessarily confer clinical significance and that inappropriate attribution of symptoms may lead to both overtreatment and undertreatment. The FIGO classification system provides a common language that facilitates research, education, and clinical care by linking anatomical findings to symptoms. However, clinical decision‐making also requires an understanding of the underlying pathophysiology of leiomyoma‐related symptoms—including effects on endometrial function and myometrial peristalsis—to assess the potential clinical relevance of individual lesions. These elements must then be interpreted in the context of patient priorities, including symptom burden, reproductive goals, and tolerance for intervention. The expanding range of medical, image‐guided, and surgical therapies offers substantial opportunities for individualized care but also introduces complexity to decision‐making. Selection of therapy should therefore be guided not only by fibroid characteristics but by a balanced assessment of anticipated benefit, potential risk, and the natural history of a given tumor or set of tumors, including the likelihood of symptom resolution with the menopausal transition. In this context, strategies that optimize overall health—such as management of iron deficiency and application of patient blood management principles when surgery is required—are integral to improving outcomes. Important uncertainties remain, particularly regarding the prediction of clinically meaningful disease, the attribution of symptoms, and the optimal role of emerging therapies. Addressing these gaps will require longitudinal, phenotype‐informed research as well as improved methods for integrating clinical, imaging, and biological data. Ultimately, the next phase of progress in fibroid care will depend, in part, on identifying those with lesions and, perhaps more importantly, on determining which fibroids matter, for whom, and at what point intervention improves outcomes. Achieving this goal will require continued refinement of diagnostic approaches, better characterization of disease biology, and a sustained commitment to individualized, patient‐centered care.

Uterine fibroids (leiomyomas) are commonly encountered in gynecologic practice, ultimately affecting most women by the end of their reproductive years. 1 , 2 Despite this high prevalence, their clinical significance varies widely. Many fibroids remain asymptomatic and are detected incidentally, and even in individuals who present with symptoms such as abnormal uterine bleeding, pelvic pain, or infertility, their presence does not necessarily imply causality. This distinction between the presence of fibroids and clinically meaningful tumors represents a fundamental challenge in both clinical care and research. The consequences of this distinction are substantial. Overattribution of symptoms to fibroids may result in unnecessary or inappropriate intervention, while failure to recognize clinically relevant tumors may delay effective treatment and contribute to avoidable morbidity, including anemia, impaired fertility, and adverse pregnancy outcomes. These challenges are further compounded by risk perceptions—particularly regarding the possibility of occult malignancy—which, when overstated, may influence both patient and clinician preferences toward more aggressive intervention. At the same time, emerging therapeutic options—including medical, image‐guided, and minimally invasive surgical approaches—suggest that, in selected cases, earlier or more targeted intervention could alter disease trajectories. However, such considerations must be balanced against the risks of overtreatment, particularly given the high prevalence of asymptomatic lesions. In this context, FIGO has developed a series of evidence‐based papers addressing the epidemiology and pathogenesis of fibroids, their diagnosis and classification, their impact on fertility and pregnancy, and the full spectrum of available treatments. 2 , 3 , 4 , 5 , 6 , 7 , 8 This body of work provides a comprehensive foundation for understanding fibroids across clinical domains. The purpose of the present paper is to integrate these perspectives and to outline a conceptual framework that links fibroid phenotype, symptom attribution, and patient‐centered goals to rational, individualized management. The central challenge is not simply detecting fibroids but determining when they are clinically relevant and how their characteristics and context should guide care.

MGM is a Speaker/Consultant for Pharmacosmos and CSL‐Vifor.

Accurate determination of fibroid phenotype is central to the framework described in this series, as it underpins assessment of clinical relevance, informs symptom attribution, and guides therapeutic decision‐making. In most clinical scenarios, manual examination alone is insufficient to establish the presence, number, size, and location of leiomyomas—a circumstance of relevance in patients with abnormal uterine bleeding or infertility. Submucosal fibroids, often the most clinically relevant in these settings, are frequently not palpable, whereas palpable subserosal lesions are commonly unrelated to bleeding or reproductive dysfunction. Beyond identifying leiomyomas, imaging is essential for distinguishing fibroids from other uterine disorders that may present with similar symptoms or coexist in the same patient, including congenital uterine anomalies, adenomyosis, and adnexal masses. Failure to recognize these conditions may lead to inappropriate symptom attribution and result in suboptimal management. Transvaginal ultrasonography remains the first‐line imaging modality in most settings. However, conventional ultrasound has limitations in defining the relationship between fibroids and the endometrium and in assigning FIGO classification categories with the precision required to determine causality and guide therapy, particularly for procedural or surgical interventions. Adjunctive techniques, including sonographic evaluation with infusion of contrast media such as saline or gel (sonohysterography), substantially enhance the characterization of fibroid phenotype. 31 , 32 These approaches improve delineation of the endometrial cavity and facilitate more accurate categorization of submucosal and intramural lesions. Importantly, they are widely available, relatively inexpensive, and applicable across diverse clinical settings, including low‐ and middle‐income countries. Magnetic resonance imaging may provide additional detail in selected cases, particularly when anatomy is complex or alternative diagnoses are suspected, but it is not required for most patients. The goal is to employ imaging strategies sufficient to confirm diagnosis and define phenotype in a manner that supports clinical decision‐making while maintaining accessibility and cost‐effectiveness. There has been considerable effort to use magnetic resonance imaging to identify lesions at risk of leiomyosarcoma, often in combination with serum biomarkers. Both sensitivity and specificity for this rare tumor remain inconsistent, and their role in management is yet to be clearly determined. 33 Taken together, these considerations highlight that imaging is not simply a tool for detecting fibroids but a critical component of phenotype determination. The ability to accurately define the relationship between fibroids and the endometrium and surrounding structures is essential for linking anatomical findings to symptoms, predicting potential clinical impact, and selecting the most appropriate therapeutic approach.