Abnormal Uterine Bleeding

• Estrogen-Progesterone Imbalance and Endometrial Thickening: In anovulatory cycles (most common mechanism in adolescents and perimenopausal women), the hypothalamic-pituitary-ovarian (HPO) axis fails to produce a coordinated LH surge, preventing ovulation. Without ovulation, the corpus luteum fails to form, resulting in absent or severely reduced progesterone secretion. Unopposed estrogen continuously stimulates the endometrial basalis layer through estrogen receptor activation, causing uncontrolled endometrial proliferation. This unregulated growth produces thick, friable endometrium lacking the structural support of progesterone-induced stroma. The endometrium becomes histologically disorganized, containing variable-sized glands without the organized architecture normally produced by the secretory transformation. When the estrogen stimulus wanes, the unstimulated endometrium sheds unpredictably and incompletely, resulting in prolonged, heavy menstrual bleeding. The molecular basis involves sustained activation of mitogen-activated protein kinase (MAPK) pathways and cyclooxygenase-2 (COX-2) upregulation without the progesterone-mediated suppression via the progesterone receptor (PR).

• Coagulopathy and Platelet Dysfunction: Von Willebrand disease (vWD) and factor deficiencies impair primary hemostasis by reducing platelet adhesion and thrombin generation. In vWD, reduced von Willebrand factor (vWF) levels or dysfunction decrease platelet binding to subendothelial collagen through the glycoprotein Ib-IX-V complex. Additionally, vWF serves as the carrier protein for factor VIII, so vWF deficiency secondarily reduces factor VIII activity, impairing the intrinsic coagulation cascade. This dual mechanism—affecting both primary and secondary hemostasis—produces particularly heavy menstrual bleeding. Other coagulopathies, including factor XI deficiency, factor XIII deficiency, and thrombocytopenia, similarly impair hemostasis at the endometrial-myometrial interface where microvasculature rupture occurs during menstruation. Platelet dysfunction in inherited disorders of platelet secretion (e.g., delta storage pool disease) reduces platelet aggregation and thrombin generation, exacerbating bleeding.

• Prostaglandin Dysregulation and Myometrial Dysfunction: The endometrium produces prostaglandins (particularly PGE₂ and PGF₂α) that regulate myometrial contractility, vasoconstriction, and hemostasis. In heavy menstrual bleeding, endometrial tissue produces elevated levels of prostaglandin E₂ and reduced levels of prostacyclin (PGI₂), disrupting the normal balance. Elevated PGE₂ causes sustained myometrial relaxation and vasodilation, reducing the vasoconstriction necessary to compress bleeding vessels. Additionally, PGE₂ increases endometrial fibrinolysis by upregulating tissue plasminogen activator (tPA) and downregulating plasminogen activator inhibitor-1 (PAI-1), creating a hyperfibrinalytic state. The result is increased endometrial bleeding and impaired hemostasis within the endometrium. This mechanism explains why NSAIDs (which inhibit prostaglandin synthesis) reduce menstrual bleeding by approximately 25-30%.

• Angiogenic Dysregulation and Abnormal Vasculature Formation: Structural lesions such as adenomyosis and fibroids induce abnormal angiogenesis through increased vascular endothelial growth factor (VEGF) and angiopoietin dysregulation. These lesions create abnormal vascular architecture with increased vessel density, larger vessel caliber, and tortuous, fragile blood vessels. In adenomyosis specifically, ectopic endometrial glands invade the myometrium, inducing pathologic neoangiogenesis and lymphangiogenesis. The increased vascular surface area and abnormal hemostatic properties of these vessels lead to excessive menstrual bleeding. Additionally, hypoxia inducible factor (HIF-1α) is upregulated in adenomyotic lesions, driving VEGF expression. Fibroids similarly promote abnormal angiogenesis, particularly submucosal fibroids that distort the endometrial-myometrial interface and increase vascular permeability.

• Impaired Myometrial Contractility and Molecular Remodeling: Adenomyosis and fibroids disrupt normal myometrial contractions that are essential for hemostasis. Normal menstruation requires coordinated junctional zone contractions that promote endometrial shedding and compress bleeding vessels. In adenomyosis, the junctional zone becomes thickened and disorganized, with impaired contractility patterns. Abnormal expression of gap junction proteins (connexins), reduced oxytocin receptor expression, and altered β-adrenergic signaling all contribute to dysfunctional myometrial contractions. Transforming growth factor-β (TGF-β) dysregulation and altered muscle ion channel function further impair contractile physiology. Fibroids distort the myometrial architecture, preventing normal coordinated contractions and promoting abnormal vascular bleeding patterns.

• Endometrial Hemostatic Defects: Beyond systemic coagulopathies, local endometrial hemostatic mechanisms are disrupted in AUB. The endometrium normally expresses tissue factor (TF), factor VII, and other hemostatic factors concentrated near the basal layer. In heavy menstrual bleeding, the spatial organization of hemostatic factors is disrupted. Additionally, tissue factor pathway inhibitor (TFPI) expression is increased, providing local anticoagulation that paradoxically worsens bleeding. Altered expression of thrombin activatable fibrinolysis inhibitor (TAFI) and other fibrinolytic regulators creates a net hyperfibrinalytic state in the endometrium.

Structural Causes (PALM)

• Polyps (Endometrial/Cervical): Benign proliferations of endometrial basalis layer that project into the endometrial cavity. Prevalence increases with age, obesity, and tamoxifen use. Typically present as focal areas of abnormal bleeding or prolonged bleeding. The mechanism involves increased vascular density within polyps, local prostaglandin dysregulation, and distortion of normal hemostasis.

• Adenomyosis: Ectopic endometrial glands and stroma within the myometrium, typically extending >2.5 mm into the myometrial layer (junctional zone). Prevalence increases with age and parity, affecting 10-15% of women in reproductive years and up to 30% of women seeking hysterectomy. Risk factors include multiparity, intrauterine procedures (dilation and curettage, curettage for miscarriage), miscarriage, uterine artery embolization, and cesarean delivery. Adenomyosis causes heavy or prolonged menstrual bleeding through multiple mechanisms: abnormal neoangiogenesis, impaired myometrial contractility, increased endometrial fibrinolysis, and disrupted hemostatic factors.

• Leiomyomas (Fibroids): Benign smooth muscle tumors arising from myometrial cells. Prevalence is 70-80% by age 50, though only 20-25% cause AUB. Risk factors include African-American ancestry (3-fold increased incidence and earlier onset), age (peak incidence 35-50 years), obesity, nulliparity, and estrogen exposure. Submucosal fibroids (protruding into the endometrial cavity) most commonly cause AUB through increased vascular permeability, distortion of endometrial architecture, and impaired hemostasis. Intramural fibroids may cause AUB if they distort the junctional zone.

• Malignancy (Endometrial Cancer, Cervical Cancer, Uterine Sarcoma): Malignant transformation of endometrial, cervical, or myometrial tissue. AUB is the presenting symptom in 90% of endometrial cancer cases. Risk factors for endometrial cancer include obesity (BMI >30 associated with 2-5 fold increased risk), diabetes, hypertension, tamoxifen use, and unopposed estrogen exposure. Endometrial sarcomas are rare but particularly aggressive, presenting with abnormal bleeding. Postmenopausal AUB is malignancy until proven otherwise, warranting urgent evaluation.

Non-Structural Causes (COEIN)

• Coagulopathy: Inherited or acquired bleeding disorders affecting hemostasis. Von Willebrand disease is the most common inherited coagulopathy, present in 5-20% of women with heavy menstrual bleeding (HMB) compared to 1-2% in the general population. Other inherited coagulopathies include factor XI deficiency, factor XIII deficiency, platelet function disorders, and thrombocytopenia. Acquired coagulopathies include anticoagulation therapy (warfarin, direct oral anticoagulants), antiplatelet agents, and liver disease. A family history of bleeding disorder should raise suspicion; approximately 25% of women with HMB and inherited bleeding disorders have a family history of excessive bleeding.

• Ovulatory Dysfunction: Failure to regularly ovulate results in anovulatory cycles with unopposed estrogen stimulation and absent progesterone. Most common in adolescents (45% of AUB in teen girls) due to immaturity of the HPO axis and in perimenopausal women (40%) due to declining ovarian reserve. Polycystic ovary syndrome (PCOS) affects 6-20% of reproductive-age women and causes AUB through chronic anovulation. Thyroid disorders, hyperprolactinemia, and functional hypothalamic amenorrhea also impair ovulation. Obesity exacerbates ovulatory dysfunction through insulin resistance, altered adipokine signaling, and increased aromatase activity in peripheral fat.

• Endometrial Disorder (Not otherwise specified): Includes endometritis (infection), endometrial hyperplasia, and atrophy. Endometritis from infection (bacterial, viral, fungal) causes bleeding through inflammatory destruction of the endometrium. Chronic endometritis is increasingly recognized and characterized by abnormal uterine bleeding, pelvic pain, and plasma cells in endometrial biopsy. Endometrial hyperplasia results from prolonged unopposed estrogen exposure and represents a spectrum from simple hyperplasia (1-3% malignant potential) to complex atypical hyperplasia (8-29% malignant potential). Atrophic endometrium in postmenopausal women is fragile and prone to bleeding.

• Iatrogenic Causes: Related to medical interventions. Hormonal contraceptives (estrogen-progestin, progestin-only pills, depot medroxyprogesterone acetate, implants) commonly cause breakthrough bleeding or, paradoxically, amenorrhea. Copper intrauterine devices increase menstrual bleeding by 30-50%. Anticoagulation therapy (warfarin, direct oral anticoagulants, heparin) impairs hemostasis. Chemotherapy agents and immunosuppressants may cause AUB. Medications affecting coagulation or platelet function warrant careful history.

• Not Yet Classified: Conditions not fitting above categories, including recurrent pregnancy-related bleeding, uncharacterized endometrial conditions, and uterine artery abnormalities.

• Heavy Menstrual Bleeding (HMB): Defined as menstrual bleeding exceeding 80 mL per cycle or lasting >7 days. Patients typically describe soaking through pads or tampons hourly, passage of blood clots >1 inch in diameter, and need for double protection (pad plus tampon). HMB results from endometrial or systemic hemostatic dysfunction and carries the highest risk of iron deficiency anemia. The physiologic mechanism depends on etiology: in structural causes, increased endometrial vascular permeability and distorted vascular architecture promote prolonged bleeding; in ovulatory dysfunction, unopposed estrogen produces uncontrolled endometrial growth with friable architecture.

• Prolonged Menstrual Bleeding (Menorrhagia): Bleeding lasting >7 days within normal volume range (≤80 mL). Suggests ongoing endometrial shedding without normal hemostatic control. In ovulatory dysfunction, incomplete endometrial shedding from thin, disorganized endometrium leads to prolonged oozing. In adenomyosis, impaired myometrial contractility fails to compress bleeding vessels, extending the menstrual period.

• Frequent Menstrual Bleeding (Polymenorrhea): Menstrual cycles occurring at intervals <21 days. Indicates shortened follicular phase or anovulatory cycles with erratic hormone fluctuations. In ovulatory dysfunction (particularly PCOS), erratic FSH and LH secretion produces unpredictable cycle lengths. Short cycle length in reproductive-age women suggests anovulatory bleeding.

• Irregular Menstrual Bleeding (Metrorrhagia): Unpredictable bleeding patterns with variable cycle lengths and flow. Strongly suggestive of anovulatory cycles where hormone fluctuations are erratic. Also occurs with structural lesions or coagulopathies causing breakthrough bleeding. The unpredictability reflects lack of coordinated HPO axis regulation.

• Intermenstrual Bleeding (Intermenorrhagia): Bleeding between regular menstrual periods. Suggests anovulation with estrogen fluctuations triggering breakthrough bleeding, or structural lesions causing irregular bleeding. Cervical lesions (polyps, cervicitis, cervical cancer) commonly present with intermenstrual or postcoital bleeding.

• Postcoital Bleeding: Bleeding following vaginal intercourse. Localizes the bleeding source to the lower genital tract (cervix, vagina, vulva), raising concern for cervical pathology including cervicitis, polyps, or malignancy. Physical examination is essential in this population.

• Anemia Symptoms: Iron deficiency anemia from chronic blood loss produces fatigue, dyspnea on exertion, lightheadedness, syncope, and tachycardia. Severe acute bleeding may present with orthostatic hypotension or hemodynamic instability. The hemoglobin level correlates with symptom severity; hemoglobin <7 g/dL typically produces significant constitutional symptoms.

• Physical Examination Findings:
• Vital Signs Abnormalities: Tachycardia and orthostatic vital sign changes indicate acute or severe bleeding with hemodynamic compromise
• Pallor and Conjunctival Pallor: Reflects anemia from chronic blood loss
• Abdominal/Pelvic Examination: May reveal uterine enlargement (fibroids, adenomyosis), cervical lesions (polyps, cervicitis, malignancy), or adnexal masses
• Speculum Examination Findings: Cervical polyps, cervicitis, cervical lesions, or cervical malignancy causing postcoital or intermenstrual bleeding

• Menstrual History and Bleeding Characterization: The history should precisely describe the bleeding pattern using standardized terminology. Key questions include: When did abnormal bleeding begin? What is the cycle length (interval between menstrual onsets)? How many days does bleeding last per cycle? How heavy is the flow (pads/tampons per day, passage of clots)? Has the pattern changed? Does the patient have dysmenorrhea, dyspareunia, or pelvic pain (suggesting adenomyosis)? The Pictorial Blood Loss Assessment Chart (PBAC) is a validated tool assigning points for pad

Immediate stabilization (acute AUB with hemodynamic compromise — an emergency)

• Exclude pregnancy first: hCG before any therapy; ectopic pregnancy and miscarriage are managed differently and are life-threatening distractors.
• Resuscitation: two large-bore IVs, isotonic crystalloid, type and cross, transfusion guided by hemodynamics rather than a single hemoglobin number.
• High-dose IV conjugated equine estrogen: promotes rapid re-epithelialization of denuded endometrium and stimulates clotting factor/fibrinogen synthesis; ACOG's guidance on acute AUB in nonpregnant reproductive-aged women lists this as first-line for severe bleeding (typically 25 mg IV every 4–6 hours). Alternatives are high-dose monophasic combined oral contraceptive or oral medroxyprogesterone acetate tapers.
• Mechanical/surgical rescue: intrauterine Foley balloon tamponade, then dilation and curettage or hysteroscopic intervention if medical therapy fails; uterine artery embolization or hysterectomy for refractory hemorrhage.

First-line therapy for chronic heavy menstrual bleeding (ACOG)

• Levonorgestrel-releasing IUD: the most effective medical option; local progestin causes endometrial decidualization then atrophy. Preferred when contraception is also desired.
• Antifibrinolytics — tranexamic acid: blocks plasminogen binding to fibrin, countering the endometrial hyperfibrinolytic state; taken only during menses.
• NSAIDs — naproxen: COX inhibition lowers PGE₂, restoring vasoconstriction; also treats dysmenorrhea.
• Combined hormonal contraceptives or cyclic/continuous progestins (e.g., norethindrone) for ovulatory dysfunction, providing the missing progestin opposition.

Escalation

• GnRH agonists/antagonists: leuprolide or elagolix combination therapy shrinks leiomyomas and induces amenorrhea; add-back estrogen/progestin limits hypoestrogenic bone loss. Bridge to surgery, not long-term monotherapy.

Definitive/surgical

• Lesion-directed: hysteroscopic polypectomy or myomectomy for polyps and submucosal fibroids; uterine artery embolization for fibroids with preserved uterus.
• Endometrial ablation: for completed childbearing only.
• Hysterectomy: definitive cure; required for malignancy.

Contraindicated

• Estrogen with prior VTE, migraine with aura, or smoking at age ≥35 (CDC US MEC category 3/4).
• Ablation with desire for fertility, atypical hyperplasia, or carcinoma.
• Tranexamic acid with active thromboembolic disease.

Complications of the disease

• Iron deficiency anemia: chronic loss exceeding absorptive capacity; microcytic, hypochromic indices with low ferritin and high RDW. The most common complication of AUB and the reason a CBC and ferritin are checked in every patient.
• Hemorrhagic shock: acute high-volume loss; tachycardia, orthostatic hypotension, narrowed pulse pressure. An emergency requiring resuscitation before diagnostic workup beyond hCG.
• Endometrial hyperplasia and carcinoma: sustained unopposed estrogen in chronic anovulation (PCOS, obesity, perimenopause) drives proliferation without progestin-mediated differentiation; signaled by atypia on biopsy or a thickened endometrial stripe. Atypical hyperplasia carries substantial concurrent carcinoma risk — treat, do not observe.
• Infertility and pregnancy loss: anovulation, submucosal fibroids, and polyps distort implantation.
• Missed malignancy: any postmenopausal bleeding attributed to "atrophy" without tissue sampling or adequate imaging. Functionally an emergency in terms of workup urgency.

Complications of treatment

• Venous thromboembolism: estrogen-containing therapy increases hepatic procoagulant synthesis; unilateral leg swelling or pleuritic dyspnea. Risk is compounded when combined with tranexamic acid.
• Hypoestrogenism from GnRH analogues: vasomotor symptoms and accelerated bone mineral density loss; mitigated with add-back therapy and limited duration.
• Asherman syndrome: intrauterine adhesions after repeated or aggressive curettage, especially postpartum; presents as secondary amenorrhea or hypomenorrhea with cyclic pain and infertility.
• Uterine perforation and infection: instrumentation during hysteroscopy, D&C, or ablation; fever, peritonitis, or hemodynamic change intraoperatively — an emergency.
• Post-ablation complications: postablation tubal sterilization syndrome (trapped bleeding in cornual endometrium causing cyclic pain), obscured future endometrial sampling, and abnormal placentation if pregnancy occurs — hence mandatory reliable contraception.
• Uterine artery embolization: post-embolization syndrome with fever and pain; rare ovarian failure.
• Surgical/hysterectomy risks: hemorrhage, ureteral or bladder injury, VTE.

• The single best first step in any reproductive-aged woman with AUB is a pregnancy test. Hormones, imaging, and biopsy all come after hCG. This is the most commonly missed "next step" on Step 2 CK.
• Postmenopausal bleeding is endometrial cancer until proven otherwise. ACOG accepts either transvaginal ultrasound or endometrial biopsy as the initial test; an endometrial stripe ≤4 mm has a high negative predictive value, but persistent or recurrent bleeding mandates tissue sampling regardless of stripe thickness.
• Endometrial biopsy is indicated in AUB at age ≥45, and earlier with unopposed estrogen exposure (obesity, PCOS, chronic anovulation), Lynch syndrome, or failed medical therapy (ACOG).
• **Heavy menstrual bleeding since menarche, plus epistaxis, gum bleeding, or postpartum hemorrhage, equals von Willebrand disease.** Order vWF antigen, ristocetin cofactor activity, and factor VIII. Desmopressin and tranexamic acid are the therapeutic buzzwords.
• The levonorgestrel IUD is the most effective medical therapy for heavy menstrual bleeding — the right answer over cyclic progestins or OCPs when the stem mentions a patient who also wants contraception.
• Tranexamic acid is menses-only therapy, exploiting the hyperfibrinolytic endometrium; avoid with active thromboembolic disease.
• A normal transvaginal ultrasound does not exclude a focal lesion. Saline infusion sonohysterography or hysteroscopy is the next step when bleeding persists and a polyp or submucosal fibroid is suspected.
• Common distractor — endometrial ablation. Never the answer in a patient who may want future pregnancy, and never before excluding hyperplasia with atypia or carcinoma.
• Association examiners love: chronic anovulation (PCOS, obesity, perimenopause) → unopposed estrogen → endometrial hyperplasia → carcinoma. Progestin therapy interrupts this chain even when contraception is not needed.
• Adolescent with irregular heavy cycles in the first 1–2 years after menarche is usually immature HPO-axis anovulation — but still screen for coagulopathy before calling it physiologic.