Uterine Fibroids and Adenomyosis

Mechanistic groupings — fibroids

• Somatic mutation/clonal expansion: each fibroid is a monoclonal tumor; MED12 mutations predominate, with HMGA2 rearrangements in a subset. This explains why multiple fibroids in one uterus are genetically independent rather than metastases.
• Cumulative estrogen/progesterone exposure: anything lengthening the reproductive window or raising unopposed steroid tone favors growth; menopause removes the drive and fibroids typically regress.
• Germline predisposition: hereditary leiomyomatosis and renal cell cancer (autosomal dominant fumarate hydratase deficiency) — cutaneous leiomyomas plus early, numerous, symptomatic uterine fibroids and papillary type 2 RCC. This is the syndrome examiners plant when fibroids appear in a woman in her twenties with skin nodules.

Non-modifiable risk factors

• Age: incidence rises through the reproductive years and peaks in the 40s.
• Black race: earlier onset, greater number and size, more severe symptoms, and earlier surgery — the single most heavily tested demographic association.
• Family history: first-degree relative with fibroids substantially raises risk.
• Early menarche and late menopause: longer lifetime steroid exposure.

Modifiable/acquired risk factors

• Obesity: peripheral aromatization of androgens in adipose tissue raises circulating estrogen.
• Nulliparity: parity is protective (postpartum myometrial remodeling and involution).
• Diet and vitamin D deficiency: associated in observational data; causality is not established.
• Distractor to avoid: cigarette smoking is epidemiologically associated with lower fibroid risk — never a recommendation.

Adenomyosis

• Junctional-zone injury: prior cesarean delivery, curettage, myomectomy, or any instrumentation disrupts the endometrial–myometrial interface and permits basalis invagination.
• Multiparity (opposite of the fibroid pattern) and age in the 40s.
• Hyperestrogenic states, including tamoxifen use, and frequent coexistence with fibroids and endometriosis.

Uterine Fibroids

• Clonal proliferation of smooth muscle cells driven by somatic mutations (70% harbor mutations in MED12, a transcriptional regulator); benign but growth is hormone-dependent
• Estrogen and progesterone sensitivity: fibroids contain higher concentrations of estrogen and progesterone receptors than normal myometrium; growth accelerates during reproductive years and regresses postmenopausally
• Growth factors and angiogenesis: increased expression of VEGF, TGF-β, and FGF promote vascularization and proliferation; altered vascular permeability contributes to abnormal bleeding
• Altered myometrial contractility: disruption of normal smooth muscle architecture and junctional zone function impairs uterine peristalsis, affecting embryo transport and hemostasis
• Classification by location: submucosal (project into endometrial cavity), intramural (within myometrium), subserosal (project outward), or cervical

Adenomyosis

• Invagination hypothesis: repetitive uterine contractions and junctional zone disruption allow basalis layer endometrium to progressively invade deeper into myometrium; exaggerated myometrial contractions (especially during menses) facilitate this process
• Estrogen-progesterone resistance: adenomyotic lesions exhibit progesterone receptor (PR) dysfunction and altered signaling; increased local estrogen synthesis (elevated aromatase) and impaired inactivation create a hyperestrogenic environment
• Defective decidualization and implantation: abnormal endometrial-myometrial interface with increased nerve fiber density (neuroangiogenesis) and inflammatory cytokines (IL-6, IL-8, TNF-α) impair uterine receptivity
• Altered myometrial phenotype: transition of smooth muscle cells toward a more contractile phenotype with disrupted calcium handling; junctional zone hypercontractility and reduced relaxation during luteal phase
• Stem cell dysfunction: impaired bone marrow-derived progenitor cells unable to properly regenerate damaged endometrium, perpetuating the adenomyotic lesion

Uterine Fibroids

• Menorrhagia (heavy menstrual bleeding): most common symptom; mechanism involves submucosal fibroid-induced disruption of endometrial hemostasis, increased endometrial surface area, and altered vascularity; occurs in 30% of women with fibroids
• Dysmenorrhea (painful periods): caused by increased myometrial contractions attempting to expel fibroids (particularly submucosal); distinct from adenomyosis dysmenorrhea by onset (typically secondary in fibroids with onset after fibroid development)
• Pelvic pressure and mass effect symptoms: sensation of heaviness, pelvic pain, urinary frequency (bladder compression), urinary retention, constipation or rectal pain (bowel compression), and rarely dyspareunia if distorting vaginal anatomy
• Asymptomatic presentation: 50% of women with sonographically detected fibroids are asymptomatic; incidental finding on imaging for other indications
• Reproductive complications: infertility (submucosal fibroids distorting cavity), recurrent pregnancy loss, preterm birth, and abnormal fetal presentation (intramural fibroids distorting uterine shape)
• Red degeneration (carneous degeneration): acute necrosis of fibroid typically during pregnancy; presents with acute pain, fever, elevated WBC; self-limited and managed conservatively

Adenomyosis

• Dysmenorrhea: severe, progressive secondary dysmenorrhea typically beginning days before menses and continuing throughout; caused by increased prostaglandin production and myometrial hypercontractility; often refractory to NSAIDs
• Menorrhagia: abnormal heavy or prolonged menstrual bleeding occurring in 50-60% of adenomyosis patients; mechanism involves increased endometrial vascularity, impaired hemostasis, and fibrinolytic abnormalities
• Dyspareunia (deep): pain with deep penetration due to myometrial tenderness and reduced uterine compliance; more characteristic of adenomyosis than fibroids
• Chronic pelvic pain: dull, aching lower abdominal and pelvic pain; may worsen during menses but often persistent throughout cycle (distinguishing feature from fibroids)
• Palpable uterine enlargement: symmetric, tender, boggy, enlarged uterus (typically 2-3x normal size); described as "adenomyotic uterus" on exam
• Reproductive dysfunction: impaired fertility (30-50% infertility rate), increased miscarriage risk, and reduced implantation rates; mechanism involves impaired endometrial receptivity and abnormal decidualization
• Clinical pearl: adenomyosis typically affects older women (mean age 40s) compared to fibroids (mean age 30s-40s), though overlap is common

Uterine Fibroids

• Transvaginal ultrasound (TVUS): first-line imaging modality; highly sensitive for detection; provides location, size, number, and impact on endometrial cavity; characterized by discrete, hypoechoic or isoechoic masses with acoustic shadowing
• Transabdominal ultrasound: useful for large fibroids or those in upper uterine segments; less sensitive for small intramural lesions
• Magnetic resonance imaging (MRI): gold standard for fibroid mapping, especially pre-operatively; superior for detecting adenomyosis coexistence, assessing junctional zone involvement, and planning hysteroscopic procedures; T2-weighted images show hypointense fibroids against bright myometrium
• Sonohysterography (SHG): infusion of saline into endometrial cavity during TVUS; superior to standard ultrasound for evaluating submucosal fibroid extent, degree of cavity distortion (FIGO classification), and impact on implantation cavity
• Hysteroscopy: direct visualization allows assessment of submucosal fibroid size, location, and relationship to ostia (important for hysteroscopic resection planning); gold standard for evaluating cavity-distorting lesions
• Diagnostic criteria: imaging showing discrete myometrial masses distinct from surrounding myometrium; submucosal fibroids classified by FIGO system (Type 0: pedunculated, Type 1: <50% intramural, Type 2: ≥50% intramural)

Adenomyosis

• Transvaginal ultrasound (TVUS): first-line imaging; features include asymmetric junctional zone thickening (>12 mm), heterogeneous echotexture, increased vascularity on Doppler, and subendometrial lucencies (linear hypoechoic areas); less specific than MRI but widely available
• Magnetic resonance imaging (MRI): gold standard diagnostic test; T2-weighted sequences show junctional zone thickening with disrupted definition (ill-defined junction between endometrium and myometrium), diffuse low-signal intensity lesions, and stripe sign (abnormal high-signal endometrial stripe); T1-weighted imaging detects hemorrhage within adenomyotic lesions
• Three-dimensional ultrasound (3D-US): emerging technology allowing volumetric assessment of junctional zone and adenomyotic lesions; improves diagnostic accuracy
• Diagnostic criteria: no single pathognomonic finding; diagnosis based on constellation of imaging findings; morphologic criteria for diagnosis include junctional zone thickening ≥12 mm, junctional zone asymmetry >5 mm, or presence of myometrial cysts
• Hysteroscopy and endometrial sampling: not standard diagnostic tools (diagnosis is imaging-based); hysteroscopic findings may show irregular endometrial surface

Immediate stabilization (acute heavy bleeding)

• Hemodynamic assessment first: IV access, CBC, type and screen, transfusion for symptomatic anemia; always exclude pregnancy with a hCG before anything else.
• High-dose hormonal control: IV conjugated estrogens or high-dose combined oral contraceptives stabilize the endometrium; tranexamic acid (antifibrinolytic) reduces bleeding volume. ACOG addresses acute abnormal uterine bleeding in nonpregnant reproductive-age women along these lines. Intracavitary tamponade or urgent D&C is a temporizing measure.

First-line medical therapy (ACOG, symptomatic fibroids and AUB)

• Levonorgestrel-releasing IUD: best-evidenced medical option for heavy menstrual bleeding; local progestin causes endometrial atrophy. Cavity distortion by submucosal fibroids limits placement and increases expulsion.
• NSAIDs (e.g., naproxen): prostaglandin synthase inhibition reduces both flow and dysmenorrhea — particularly useful in adenomyosis.
• Combined hormonal contraceptives or oral/depot progestins: cycle control and endometrial suppression.
• Tranexamic acid: nonhormonal, taken only on bleeding days.

Escalation/second line

• GnRH antagonist combination therapy (elagolix or relugolix with estradiol/norethindrone add-back): FDA-approved for heavy menstrual bleeding from fibroids; rapid hypoestrogenism without the initial flare seen with agonists.
• GnRH agonists (leuprolide): shrink fibroids and correct anemia preoperatively; limited to short-term use unless add-back is given, because of bone mineral density loss.

Procedural and definitive management

• Hysteroscopic myomectomy: for FIGO type 0/1 submucosal fibroids causing bleeding or infertility.
• Abdominal/laparoscopic myomectomy: uterus-sparing option when future fertility is desired.
• Uterine artery embolization: infarcts fibroids while sparing myometrium; effective for bleeding and bulk, but ACOG considers fertility outcomes inadequately studied — myomectomy is preferred if pregnancy is planned. UAE is also used for adenomyosis.
• Endometrial ablation: bleeding only, and only if childbearing is complete.
• Hysterectomy: definitive cure for both conditions, and the only definitive treatment for adenomyosis.

Contraindicated/avoid

• Uncontained power morcellation — FDA safety communication warns of disseminating occult leiomyosarcoma.
• Ablation or UAE in a woman desiring pregnancy; endometrial ablation before excluding malignancy.

Complications of the disease

• Iron-deficiency anemia: chronic menorrhagia depletes iron stores; microcytic, hypochromic indices with low ferritin. The most common complication and a frequent indication for surgery.
• Hydronephrosis / obstructive uropathy: a large or broad-ligament fibroid compresses the ureter at the pelvic brim; rising creatinine or flank pain with ureteral dilation on imaging. Acute urinary retention from cervical/lower-segment fibroid compression is an emergency requiring catheterization.
• Torsion of a pedunculated subserosal fibroid: acute-onset severe pain, peritoneal signs, nausea — a surgical emergency mimicking adnexal torsion.
• Red (carneous) degeneration: outgrowth of blood supply, classically in pregnancy; pain, low-grade fever, leukocytosis — managed conservatively with analgesia, not surgery.
• Obstetric morbidity: malpresentation, obstructed labor, preterm birth, and postpartum hemorrhage from impaired myometrial contraction; adenomyosis is additionally associated with implantation failure and miscarriage.
• Leiomyosarcoma: rare and arises de novo; a rapidly enlarging uterus or new fibroid growth after menopause demands evaluation for malignancy.

Complications of treatment

• GnRH agonist/antagonist therapy: hypoestrogenic bone mineral density loss and vasomotor symptoms — the reason add-back estrogen/progestin is used and duration is capped.
• Uterine artery embolization: post-embolization syndrome (pain, fever, malaise from ischemic tumor necrosis) is self-limited; non-target embolization causing ovarian failure, fibroid sloughing/expulsion, and infected necrotic fibroid with sepsis — persistent fever and purulent discharge after UAE is an emergency.
• Hysteroscopic resection: fluid absorption from hypotonic distension media causing dilutional hyponatremia and cerebral edema (emergency), uterine perforation, and later Asherman syndrome presenting as amenorrhea/infertility.
• Myomectomy: adhesion formation, recurrence, and myometrial scar with risk of uterine rupture in a subsequent labor.
• Hysterectomy: hemorrhage, ureteral or bladder injury, VTE, and — with uncontained morcellation — intraperitoneal dissemination of occult sarcoma.

• Exam-shape distinction: an irregular, firm, mobile, nontender enlarged uterus is fibroids; a symmetrically enlarged, globular, boggy, tender uterus is adenomyosis. This physical-exam pair is the highest-yield discriminator in the stem.
• Single best next step for either presentation: urine or serum hCG, then transvaginal ultrasound. MRI is reserved for surgical mapping or when adenomyosis versus fibroid cannot be resolved.
• Do not skip endometrial sampling: ACOG recommends endometrial biopsy for abnormal uterine bleeding in women 45 or older, and younger if risk factors for hyperplasia exist (obesity, chronic anovulation, unopposed estrogen, failed medical therapy). Attributing all bleeding to a visible fibroid without excluding hyperplasia/carcinoma is the classic trap.
• The one association examiners test: cutaneous and uterine leiomyomas plus papillary type 2 renal cell carcinoma = hereditary leiomyomatosis and renal cell cancer, from germline fumarate hydratase mutation.
• Postmenopausal red flag: fibroids should shrink after menopause. A growing uterine mass in a postmenopausal woman — or one growing while on hypoestrogenic therapy — raises concern for leiomyosarcoma.
• Common distractor: leiomyosarcoma does not arise from malignant transformation of a benign leiomyoma; it arises de novo. Likewise, "rapid growth" in a premenopausal woman is a poor predictor of sarcoma.
• Pregnancy pearl: acute focal pain with low-grade fever and leukocytosis over a known fibroid in the second trimester is red (carneous) degeneration — treat with analgesia and observation, not laparotomy.
• Fertility-preserving choice: if the patient wants future pregnancy, choose myomectomy over uterine artery embolization or endometrial ablation; ACOG regards fertility data after UAE as insufficient, and ablation destroys the endometrium.
• Definitive therapy for adenomyosis is hysterectomy; everything else (levonorgestrel IUD, GnRH analogs, NSAIDs) is symptom control.