This study was designed as a structured narrative (evidence-informed) clinical review, supported by a structured literature search, rather than a systematic review, meta-analysis, or a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant evidence synthesis. To inform this evidence-informed review of AUB, we searched PubMed/MEDLINE, Scopus, and Web of Science, with supplementary screening in Google Scholar and citation chaining from key articles and guideline documents. The search was guided by the PICOs framework (Population, Intervention, Comparator, Outcomes, Study design) to capture evidence relevant to AUB classification, diagnostic evaluation, medical and surgical management, and transfusion/PBM) considerations.

Operational definitions were as follows: Population: women with AUB (including adolescents and women of reproductive age when applicable); Interventions: diagnostic evaluation, medical therapy, surgical/procedural management, and PBM strategies; Comparators: when applicable (e.g., alternative diagnostic or therapeutic approaches); Outcomes: bleeding control, anemia/iron deficiency, transfusion utilization, and safety outcomes; Study designs: guidelines/consensus statements, randomized controlled trials, observational studies, and relevant reviews. The PICOs framework used for this review is summarized in Supplementary Table 1. In PubMed, we applied a MeSH-based Boolean strategy to improve precision, including the following core string:

(“Uterine Hemorrhage”[MeSH] OR “Abnormal Uterine Bleeding”[All Fields]) AND (“Therapeutics”[MeSH] OR “Hormone Replacement Therapy”[MeSH] OR “Blood Coagulation Factors”[MeSH] OR “Surgical Procedures, Operative”[MeSH]) AND (“Hormone Imbalance”[All Fields] OR “Uterine Diseases”[MeSH] OR “Endometrial Hyperplasia”[MeSH] OR “Leiomyoma”[MeSH]).

Search terms were expanded iteratively using relevant keywords, index terms, and citation chaining from key articles and guidelines. Searches were last performed on September 30, 2025. No lower date limit was applied. Publications in English were included; non-English articles were screened when an English abstract allowed clinically interpretable assessment. No age filter was applied, but the synthesis focused on clinically relevant evidence for adolescents and women of reproductive age with AUB. Where database filters were available, we prioritized human clinical research, relevant reviews (including systematic reviews), and society guidelines/consensus statements, and excluded non-human studies.

We considered primary clinical research (randomized controlled trials and observational studies), systematic reviews, and significant clinical guidelines/consensus statements that addressed AUB diagnosis, treatment, and transfusion/PBM-related decision-making. Eligibility was determined using predefined criteria aligned with the PICOs scope: studies were prioritized if they (i) involved women with AUB (including reproductive-aged and perimenopausal populations), (ii) evaluated diagnostic modalities (e.g., imaging, hysteroscopy, endometrial sampling), (iii) assessed medical and/or surgical therapies, and/or (iv) informed anemia correction and transfusion practice in AUB. Studies focusing exclusively on non-uterine sources of bleeding, non-human data, or without clinically interpretable outcomes were excluded.

Records were deduplicated and screened in two stages (title/abstract screening followed by full-text review). Title/abstract and full-text screening were performed independently by two reviewers; disagreements were resolved by consensus, with arbitration by a third reviewer when needed. For transparency, a PRISMA-style flow diagram summarizing study identification, deduplication, screening, full-text assessment, and inclusion—along with database-specific record counts—is provided in Supplementary Fig. 1.

Evidence was synthesized using a thematic narrative approach, structured around a clinically integrated pathway linking diagnostic evaluation (PALM-COEIN-informed classification and differential diagnosis), medical and surgical management strategies, and PBM/transfusion decision points, with emphasis on clinical relevance, feasibility, and applicability to routine AUB care.

To enhance clinical interpretability, we appraised included evidence with attention to study design and methodological rigor (e.g., risk of selection and measurement bias, consistency of findings, and applicability to AUB practice settings), prioritizing higher-level evidence and society guidelines when available. Given the narrative design, we did not perform a formal tool-based risk-of-bias assessment for each included study; instead, we assessed methodological limitations and applicability qualitatively and considered them in the synthesis. Key areas of uncertainty or heterogeneity (including differences in patient populations, diagnostic thresholds, intervention protocols, and outcome definitions) are explicitly highlighted in the Results and Discussion to contextualize practice recommendations.

A structured initial assessment is essential in AUB, with the objectives to (i) classify bleeding using the FIGO PALM-COEIN framework, (ii) estimate severity and patient impact (including HRQoL and anemia/iron deficiency risk), and (iii) exclude pregnancy and other time-sensitive etiologies (e.g., malignancy and infection) when clinically indicated. History-taking should document bleeding pattern and severity (frequency, regularity, duration, volume), intermenstrual and postcoital bleeding, associated pain, medication use (e.g., anticoagulants), pregnancy risk when applicable, comorbidities and risk factors for endometrial pathology, and red-flag symptoms.

Initial laboratory testing should be targeted rather than exhaustive. At minimum, testing should include beta-human chorionic gonadotropin ($\beta$-hCG) when pregnancy is possible, and a complete blood count with ferritin/iron studies to assess anemia and iron deficiency. Additional tests should be ordered selectively according to history and examination, such as thyroid-stimulating hormone (TSH) when thyroid dysfunction is suspected, and coagulation studies (including evaluation for von Willebrand disease when appropriate) in adolescents/young women with heavy menstrual bleeding or a suggestive bleeding history. A structured history and focused workup support efficient triage within PALM-COEIN and help determine when escalation (e.g., imaging and/or endometrial assessment) is warranted [11, 13]. Identifying cases of postcoital bleeding is crucial, as it may be linked to cervical cancer or Chlamydia trachomatis infection. Postcoital bleeding should trigger targeted evaluation for cervical pathology and sexually transmitted infections, given its association with cervical neoplasia and Chlamydia trachomatis infection [9, 10, 14].

Given the potential association between heavy menstrual bleeding and bleeding disorders, the American College of Obstetricians and Gynecologists (ACOG) recommends screening for bleeding disorders in adolescents and young adult women presenting with heavy menstrual bleeding [15]. Accordingly, early consideration of an underlying bleeding disorder can guide safer selection of hemostatic and hormonal therapies and avoid delays in definitive management [9, 10, 14].

Clinical implication: A risk-stratified, PALM-COEIN-informed approach—combining focused history, severity/impact assessment, and targeted initial laboratory testing—supports timely exclusion of pregnancy and other urgent etiologies and directs appropriate escalation to imaging and/or endometrial evaluation when indicated [8, 9, 10, 12, 14, 16, 17].

Imaging in AUB should be used to answer a clinical question: to support PALM-COEIN etiologic classification, localize structural pathology, and determine whether additional anatomic detail will change management. Transvaginal ultrasound (TVUS) is generally used as the first-line modality, particularly when conservative management fails, physical examination findings are abnormal, dysmenorrhea is severe, bleeding persists, or malignancy risk is increased. In practice, TVUS is appropriate for most patients with suspected structural disease or when symptoms are persistent/recurrent, and it provides a baseline assessment of the uterus and endometrium to guide downstream testing and treatment selection. When TVUS is inconclusive—especially for suspected submucosal fibroids, polyps, or focal endometrial pathology—hysteroscopy or sonohysterography can be used as an adjunct; magnetic resonance imaging (MRI) is typically reserved for cases in which prior methods are inconclusive or impractical, considering cost and availability.

TVUS is favored as first-line imaging due to accessibility and its utility for identifying structural etiologies and assessing endometrial characteristics [18, 19, 20, 21, 22, 23, 24]. Doppler and endometrial measurements may provide supportive information, but they should be interpreted within the overall clinical and malignancy-risk context rather than used as stand-alone discriminators [24].

When TVUS diagnoses remain uncertain, especially in cases where submucosal fibroids, polyps, or endometrial abnormalities are suspected, hysteroscopy can be an alternative option. When focal intracavitary pathology is suspected, or TVUS findings are inconclusive/discordant with symptoms, saline infusion sonohysterography and/or hysteroscopy provide improved cavity assessment and enable targeted evaluation (and, when indicated, directed biopsy or polypectomy) [25, 26]. To better align imaging with downstream decisions. Magnetic resonance imaging (MRI) is best reserved for selected situations in which prior approaches are inconclusive or impractical, or when detailed mapping is required for management planning. Escalation should be anchored to the clinical question: (i) “Is there a focal intracavitary lesion?” $\to$ prioritize sonohysterography or hysteroscopy; (ii) “Is endometrial assessment inadequate/discordant with symptoms?” $\to$ proceed to cavity assessment with targeted evaluation; (iii) “Will additional anatomic detail change management planning?” $\to$ reserve MRI for selected cases [8, 22, 24].

Clinical implication: Use a stepwise, question-driven strategy—TVUS first for most patients; escalate to sonohysterography/hysteroscopy for suspected focal intracavitary disease or discordant findings; reserve MRI for unresolved cases or complex mapping when it will change management [18, 19, 20, 21, 22, 23, 24, 25, 26].

Endometrial sampling is a key component of evaluation in AUB patients at increased risk of endometrial cancer or atypical hyperplasia. Office-based endometrial biopsy and hysteroscopy-guided biopsy are commonly prioritized, and hysteroscopy-guided targeted sampling should be considered when TVUS suggests localized lesions to improve diagnostic yield and procedural safety.

Endometrial sampling should be risk-stratified and performed according to standard indications. Sampling is indicated in women aged $\ge$45 years; in women 45 years with risk factors (e.g., obesity, polycystic ovary syndrome [PCOS]/chronic anovulation, tamoxifen exposure, or Lynch syndrome/hereditary nonpolyposis colorectal cancer [HNPCC]); and in any age group with persistent or recurrent abnormal bleeding, or failure of medical therapy. These criteria support a lower sampling threshold for higher-risk presentations and help avoid false reassurance from delayed evaluation. Observational and pooled evidence support these risk associations, including age $\ge$45 years, obesity/weight-related factors, infertility/nulliparity, and relevant family history, as well as diabetes, which collectively justify a lower sampling threshold for higher-risk AUB presentations [27, 28]. The Society of Obstetricians and Gynaecologists of Canada (SOGC) also recommends considering an endometrial biopsy for irregular bleeding that may reflect anovulatory cycles. Technique selection (synthesis): office biopsy vs hysteroscopy-guided biopsy. Office endometrial biopsy is an efficient first-line approach for malignancy-risk triage when diffuse endometrial pathology is the primary concern, especially in outpatient care. However, because blind sampling can miss focal intracavitary lesions, hysteroscopy-guided biopsy is preferred when imaging suggests focal pathology (e.g., polyp/submucosal fibroid), when office biopsy is insufficient/nondiagnostic, or when bleeding persists despite a negative blind biopsy and clinical concern remains [26]. This “office-first, targeted-escalation” strategy aligns diagnostic intensity with pretest probability and reduces false reassurance from nondiagnostic blind sampling.

Clinical implication: Integrate sampling with age/risk profile and imaging. Perform early sampling in higher-risk AUB ($\ge$45 years or 45 years with risk factors/persistent bleeding/treatment failure); use office biopsy for diffuse-disease triage when focal pathology is not suspected; and escalate to hysteroscopy-guided biopsy for focal lesions or persistent bleeding with negative/insufficient office sampling [26, 27, 28]. This approach optimizes diagnostic yield while limiting unnecessary procedural burden in low-risk presentations.

In hospitalized AUB patients who are clinically stable and whose bleeding is controllable with other medical treatments, transfusion therapy is generally not required when hemoglobin (Hb) concentration is $>$10 g/dL. However, transfusion decisions should be individualized based on hemodynamic stability, ongoing bleeding, anemia symptoms, comorbidities (e.g., cardiovascular disease), and the timing/urgency of procedures. For patients with Hb $\le$7 g/dL, a restrictive transfusion strategy is typically favored [30]. Transfusion may be considered for AUB patients who exhibit anemia and meet surgical criteria when Hb $\le$8 g/dL. When transfusion is given to stable patients, a single-unit strategy with clinical reassessment (symptoms/vitals and repeat Hb as appropriate) is preferred over an automatic multi-unit transfusion. In addition, establishing a PBM program for AUB patients can support individualized transfusion thresholds by incorporating clinical risk factors, symptom burden, and tolerance to anemia.

The Association for the Advancement of Blood & Biotherapies (AABB) 2023 guidelines recommend a restrictive transfusion strategy for stable hospitalized patients with Hb $\le$7 g/dL [30]. Guidelines updated in 2021 by the Society of Cardiovascular Anesthesiologists (SCA), the American Society of ExtraCorporeal Technology (AmSECT), and the Society for the Advancement of Blood Management (SABM) indicate that transfusions are not indicated when Hb concentrations are $>$10 g/dL, but may be considered when Hb concentrations are 6 g/dL [31]. In perioperative patients and those with symptomatic anemia, a threshold of Hb $\le$8 g/dL is commonly used, with clinical judgment driving decision [27, 28, 32, 33, 34].

Within AUB care, PBM is intended to align transfusion practice with patient-centered outcomes by reducing avoidable exposure to allogeneic blood products while ensuring timely support for patients who are symptomatic or at higher risk. In AUB patients, a PBM program can be operationalized around four elements: perioperative anemia management, coagulation function management, blood conservation strategies, and patient outcome indicators.

First, perioperative anemia management emphasizes early identification of anemia (often iron deficiency) and appropriate correction alongside timely planning around procedures. Second, coagulation function management highlights the need to evaluate and address coagulopathy when suspected (particularly in adolescents or young women with heavy menstrual bleeding), and to integrate hemostatic strategies with definitive bleeding control. Third, blood conservation strategies focus on reducing preventable blood loss and minimizing iatrogenic anemia, including rational phlebotomy, careful procedural technique, and judicious perioperative planning. Fourth, patient outcome indicators support continuous improvement by tracking outcomes linked to transfusion practice (e.g., appropriateness of transfusion triggers, complication rates, length of stay, recurrent bleeding, and patient-reported measures).

To improve guideline-calibrated practice, PBM implementation should prioritize (i) appropriate triggers (restrictive thresholds with symptom-based exceptions), (ii) avoidance of preventable transfusion-related harm (e.g., TACO/TRALI and other reactions), and (iii) auditable outcomes (units per admission/procedure, appropriateness by trigger, readmissions for recurrent bleeding, and length of stay) [35, 36, 37].

Anemia in AUB is frequently related to blood loss and iron depletion; therefore, strategies that address both bleeding control and anemia correction are central to reducing transfusion requirements. In routine AUB, iron replacement (oral or intravenous, depending on severity, tolerance, and urgency) is the cornerstone of anemia correction. It should be coordinated with definitive bleeding control to prevent recurrent anemia. Erythropoiesis-stimulating agents (ESAs) are not routinely indicated for typical AUB-related iron-deficiency anemia; when discussed, the evidence base is primarily extrapolated from oncology or other settings and should be applied cautiously with careful patient selection. If ESAs are considered (e.g., selected patients with concurrent chemotherapy-related anemia or specific comorbid indications), they should be used under guideline-based indications and with thrombosis-risk mitigation.

ESAs have been approved for the treatment of chemotherapy-induced anemia. Numerous studies have shown that ESAs reduce the need for transfusions and improve patients’ quality of life [38, 39]. The American Society of Clinical Oncology (ASCO) and the American Society of Hematology recommend ESAs for chemotherapy-related anemia in patients with Hb 10 g/dL, with a treatment goal of increasing Hb concentration to or near 12 g/dL [40]. Significant Hb increases are typically observed 4–6 weeks after initiating treatment, with even greater increases when combined with intravenous iron supplementation [41, 42, 43]. Taken together, much of the ESA evidence base derives from oncology and perioperative settings, and its applicability to AUB should be interpreted in light of patient selection, anemia etiology, and competing thrombotic risk.

Despite ESA efficacy in reducing transfusion needs, some studies have indicated an increased risk of death and thromboembolic events in patients treated with these agents, potentially shortening overall survival [44]. It is unclear whether the thrombosis risk is directly related to ESA’s biological action or mediated through increased red blood cells. Current data suggest that standard doses of ESAs can impact primary and secondary hemostasis by promoting blood coagulation and moderately increasing platelet count and activity [45]. There are also warnings that ESA treatment may increase the risk of death among cancer patients and reduce overall survival [46]. These risks underline that ESA use should be restricted to guideline-supported indications with close monitoring, rather than applied broadly to AUB-associated anemia [47]. The National Comprehensive Cancer Network (NCCN) guidelines suggest that ESAs should be used after careful evaluation due to the potential increase in mortality and thrombosis risks, especially in patients with chronic kidney disease, receiving palliative care, undergoing myelosuppressive chemotherapy, and those refusing blood transfusions. Close monitoring of patient conditions is recommended when using ESAs [48].

For Rhesus D antigen (RhD)-negative women of childbearing age, the risk of RhD alloimmunization is clinically meaningful. However, in life-threatening bleeding, the risk of delaying transfusion generally outweighs potential future pregnancy-related risks. In life-threatening bleeding, the clinical risk of delaying transfusion generally outweighs the potential future risk of alloimmunization and its adverse effects on subsequent pregnancies. Accordingly, for RhD-negative women of childbearing age experiencing significant bleeding, the life-threatening risks of waiting for matched RhD-negative red blood cells may far exceed the potential risks associated with alloimmunization and hemolytic disease of the fetus and newborn (HDFN) following emergency RhD-positive red blood cell exposure.

RhD-negative patients receiving RhD-positive red blood cells may generate RhD antibodies, leading to delayed hemolysis and crossmatching challenges. Furthermore, RhD-negative women of childbearing age receiving RhD-positive red blood cells face a risk of HDFN if the fetus is RhD-positive. For these reasons, multiple transfusion guidelines and consensus documents recommend RhD-negative blood transfusions for RhD-negative patients, particularly women of childbearing age [49, 50, 51, 52]. However, because RhD-negative blood resources are scarce, meeting demand during emergencies with significant bleeding can be challenging [53]. Clinical consensus, based on high-quality clinical research, also supports considering RhD-positive blood for transfusion in life-threatening situations where RhD-negative blood is unavailable [54]. In such scenarios, transfusion should follow institutional protocols for massive hemorrhage/emergency release, and anti-D immunoglobulin should be administered promptly after RhD-incompatible exposure when indicated, with follow-up for alloimmunization.

Thus, emergency transfusion decisions in RhD-negative women of childbearing potential should explicitly balance immediate survival against future alloimmunization risk, aligning practice with local blood availability and guideline-based mitigation strategies [55].

After structural causes have been excluded, medical therapy is generally prioritized over transfusion and surgical interventions for women with AUB. Treatment should be individualized according to bleeding acuity, patient history, and overall risk assessment. In acute AUB with a structurally normal uterus, commonly used options include intravenous estrogen, multi-dose oral contraceptives, progestin regimens, and tranexamic acid. For severe menorrhagia, practical medical approaches include the levonorgestrel-releasing intrauterine system, oral contraceptives, progestins, and tranexamic acid. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used as adjuncts to hormonal therapies to reduce bleeding. These therapeutic principles are also applicable to patients with uterine fibroids and to women with hereditary bleeding disorders; in anticoagulated women, progestins and gonadotropin-releasing hormone (GnRH) agonists may be convenient options. Overall, multiple medical pathways can help many patients avoid surgery.

For cyclic or predictable heavy bleeding, non-hormonal agents such as NSAIDs and tranexamic acid are commonly considered, particularly for women who prefer to avoid hormonal adverse effects.

When hormonal therapy is appropriate, combined oral contraceptives, progestin-releasing intrauterine systems (e.g., levonorgestrel intrauterine contraceptive device, LNG-IUCD), and progestin medications are commonly used options. These therapies can substantially reduce menstrual blood loss and also provide contraception. Medication choice should be tailored to the patient’s fertility intentions, underlying health status, and individual response to therapy. A pragmatic selection approach is: LNG-IUS for long-term control of heavy bleeding when uterine cavity anatomy allows; combined hormonal contraception for cycle regulation and contraception when no contraindications exist; and oral/intramuscular (IM) progestins for patients in whom estrogen is contraindicated, for anovulatory bleeding, or as transitional therapy while arranging definitive evaluation/treatment. For acute AUB, short-course high-intensity hormonal regimens may be used to rapidly suppress bleeding, followed by maintenance therapy aligned with patient goals.

Obesity is a recognized risk factor for AUB [63, 64], and obese women have higher rates of menstrual irregularities and PCOS [65]. Several mechanisms may contribute, including persistently high estrogen levels driven by increased aromatization of peripheral androgens, reduced sex hormone-binding globulin leading to higher free estradiol and testosterone, and insulin resistance with hyperinsulinemia that stimulates ovarian androgen production and disrupts follicular development. Body weight may also exert a direct suppressive effect on gonadotropin and estradiol production [66]. Consequently, weight reduction is widely regarded as an essential component of AUB management in obese women. Lifestyle interventions—including increased physical activity and dietary optimization—should be integrated into care, as such changes promote weight loss and improve insulin sensitivity, potentially supporting more regular menstrual cycles. Evidence indicates that weight loss can improve hyperandrogenemia and anovulation, facilitating normalization of menstrual cycles and improvement of AUB symptoms [67]. For patients without comorbidities such as diabetes, when body mass index (BMI) $>$32.5 kg/m² and lifestyle interventions (including pharmacotherapy) are ineffective or weight regain occurs, surgical treatment should be actively considered.

In selected circumstances—such as failure of other medical therapies or contraindications to hormonal therapy—GnRH agonists may be considered. When GnRH agonists are used continuously beyond 6 months, it is advisable to evaluate the need for hormone replacement therapy (add-back therapy) to reduce low-estrogen adverse effects, notably decreased bone density.

Mechanistically, GnRH agonists inhibit gonadotropin secretion, induce endometrial atrophy, and create a hypogonadal state. They are handy for heavy bleeding driven by a hormonal imbalance related to uterine fibroids. However, menopausal-type adverse effects—including vasomotor symptoms, vaginal atrophy/dryness, depression, and osteoporosis—limit long-term use [68, 69, 70]. If treatment is anticipated to exceed 6 months, low-dose estrogen plus norethindrone add-back therapy may be considered to mitigate adverse effects. Short- versus long-term use should be balanced against clinical necessity, especially when other medical or surgical options are strongly contraindicated.

Evidence remains limited: only a small number of randomized controlled trials have evaluated GnRH agonists for AUB [71, 72], and methodological constraints underscore the need for further research. The FDA has approved leuprolide acetate for short-term preoperative treatment of uterine fibroids to delay surgery and potentially reduce intraoperative bleeding [73]; leuprolide can reduce uterine volume by 30% to 60% and improve anemia symptoms in women with AUB and uterine fibroids [71]. Goserelin acetate (subcutaneous) has also received FDA approval for inducing endometrial atrophy before treating AUB, with endometrial atrophy and amenorrhea typically occurring within 3 to 4 weeks in premenopausal women [74].

This narrative review has limitations. The underlying evidence base is heterogeneous in design and outcome definitions, and topic-specific publication bias cannot be excluded. Moreover, AUB-specific transfusion and PBM thresholds remain incompletely defined, necessitating careful clinical judgment and contextualization. Despite these constraints, the totality of available evidence supports an integrated pathway that combines risk-stratified evaluation, timely correction of anemia, and individualized medical or procedural therapy with PBM-informed transfusion stewardship.