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Uterine Fibroids

Basics

Description

- Family and twin studies suggest a genetic predisposition. - Associated with 3 hereditary syndromes: - Reed 's syndrome: Uterine and subcutaneous myomas - Bannayan-Zonana syndrome: Uterine myomas, lipomas, and hemangiomas - Hereditary leiomyomatosis and renal cell carcinoma syndrome

- Compression of pelvic structures - Acute pelvic pain - Torsion of pedunculated myoma - Protrusion of myoma through cervix - Infarction as myoma outgrows blood supply

- May be found incidentally on bimanual examination or pelvic imaging - Pelvic/reproductive - Heavy, prolonged menses, may be associated with fatigue, dyspnea, palpitations - Pelvic pressure or fullness - Acute pelvic pain

- Gastrointestinal - Increased abdominal girth - Constipation, tenesmus (posterior myomas)

- Abnormal uterine bleeding - Anovulation - Thyroid dysfunction - Endometrial hyperplasia or malignancy

- Pelvic mass - Pregnancy - Adenomyosis, uterine polyp - Ovarian malignancy - Leiomyosarcoma

- Iron supplementation to correct anemia - Trial of oral contraceptives reasonable to attempt control of bleeding; use of levonorgestrel intrauterine device has also been reported - Tranexamic acid (1,300 mg t.i.d. for up to 5 days during menses) exerts antifibrinolytic effects to reduce bleeding by approximately 30% (1)[A]. - Studied only in smaller fibroids - Contraindicated if risk for thrombosis - Fibroid infarction reported

- Gonadotropin-releasing hormone (GnRH) agonists (2)[B] - Cause hypoestrogenic state and decrease uterine artery blood flow - Leuprolide: 3.75 mg IM monthly or 11.25 mg IM depot every 3 months, only FDA-approved agent - Nafarelin: 400 ¼g intranasally b.i.d. (alternate nostrils) - Goserelin: 3.6 mg implant SC every 28 days

- Ulipristal acetate (5 or 10 mg daily), a selective progesterone-receptor modulator, controls bleeding in approximately 90% of women (NNT 1.4) and decreases fibroid volume by approximately 20% (3,4)[B] - Studied in 13-week trial of symptomatic women planning hysterectomy - Induced amenorrhea in majority of subjects - Headache and breast discomfort most common side effects, but comparable to placebo - Benign endometrial changes more common with ulipristal - Both doses found to be noninferior to leuprolide for control of bleeding, with a lower incidence of hot flashes, in a separate study

- Indications for surgery - Contraindication to, intolerance of, or failure of drug therapy - Concern for malignancy - Mass effect causing pain, pressure, or urinary or GI tract symptoms - Distortion of uterine cavity causing infertility or repeated pregnancy loss

- Hysterectomy - Definitive treatment as it eliminates symptoms and the development of new myomas - Indicated for extensive disease, uncontrolled acute hemorrhage, suspected malignancy, and myomas in association with other pelvic abnormalities - Associated with significant improvement in symptoms and quality of life - Precludes future pregnancy

- Myolysis - Thermo- or cryoablation of myoma via laparoscopy with decrease in size over 3 " 6 months; may carry increased risk of adhesions and uterine rupture - Indicated for ≤3 myomas, largest <10 cm - More effective combined with endometrial ablation, but precludes pregnancy - Magnetic resonance guided focused ultrasound thermoablation available, but few long-term outcome data

- Uterine artery embolization (6)[B] - Procedure under fluoroscopy in which gel, beads, or coils are introduced through a catheter to the uterine artery - Disrupts blood supply, causing degeneration - Rapid recovery compared with surgery - Usually requires brief hospitalization for pain control - Resolution of bleeding symptoms in up to 75% reported at 5 years, up to 20% require second procedure to treat symptoms - May be less effective for large, pedunculated, or submucosal tumors - Associated with significant pain, fever, nausea, vomiting, and myalgias in first 48 hours; sepsis and death have been reported - Early menopause reported in up to 3% of women under 45 - Long-term effect on fertility and pregnancy outcomes not known

- Asymptomatic myomas may be followed by exam or ultrasound every 3 months to determine growth pattern, then every 6 months if stable - Examine at same time in cycle to limit effects of hormonal stimulation on tumor size

  • Uterine myomas are benign smooth muscle cell tumors, also called fibroids and leiomyomas.
  • Described by location, although most myomas involve more than one layer of the uterusSubserosal: Projects into the pelvis, may be pedunculatedIntramural: Within uterine wallSubmucosal: Projects into the uterine cavityMay arise from cervix or broad ligament
  • Range from microscopic to easily palpable, size described in gestational weeks
  • May be single or multiple
  • Most common solid pelvic tumor in women, most common indication for hysterectomy

Epidemiology

  • True incidence and prevalence are unknown because myomas are usually asymptomatic
  • Typically become symptomatic in women between the ages of 30 and 40
  • Black women are 2 " 3 times more likely to develop myomas, are younger at time of diagnosis and hysterectomy, have higher uterine weights, and are more likely to be anemic.

Incidence

Estimated at 12.8/1,000 women aged 25 " 44

Prevalence

  • Clinically apparent in approximately 25% of reproductive-age women
  • May exceed 75% in surgical pathology series

Risk Factors

  • Early menarche
  • Nulliparity
  • Oral contraceptive use before age 16
  • Black race
  • Hypertension
  • Increased alcohol or red meat consumption

Genetics

  • Family and twin studies suggest a genetic predisposition.
  • Associated with 3 hereditary syndromes:Reed 's syndrome: Uterine and subcutaneous myomasBannayan-Zonana syndrome: Uterine myomas, lipomas, and hemangiomasHereditary leiomyomatosis and renal cell carcinoma syndrome

General Prevention

  • Depot medroxyprogesterone acetate may prevent by suppressing cyclic variation of hormones
  • No evidence that diet prevents myomas

Pathophysiology

  • Heavy/prolonged mensesIncreased vascularity and venous congestionIncreased surface area of uterine cavity
  • Compression of pelvic structures
  • Acute pelvic painTorsion of pedunculated myomaProtrusion of myoma through cervixInfarction as myoma outgrows blood supply
  • Impaired fertilityDistortion of uterine cavity may interfere with sperm transport or implantation.

Etiology

  • Transformation of normal smooth muscle cell to cell responsive to cyclic hormone variation, followed by clonal proliferation
  • Likely involves multiple growth factors
  • Perimenopausal growth related to high estrogen levels during anovulatory cycles

Associated Conditions

  • Iron-deficiency anemia
  • Endometritis
  • Adenomyosis
  • Impaired fertility (with significant distortion of uterine cavity or postoperative adhesions)

Diagnosis

  • May be found incidentally on bimanual examination or pelvic imaging
  • Pelvic/reproductiveHeavy, prolonged menses, may be associated with fatigue, dyspnea, palpitationsPelvic pressure or fullnessAcute pelvic pain
  • GastrointestinalIncreased abdominal girthConstipation, tenesmus (posterior myomas)
  • UrinaryFrequency, urgency (anterior myomas)

History

  • Menstrual, sexual, obstetrical histories
  • Quantify blood loss during menses

Physical Exam

  • Enlarged, firm, irregular uterus
  • Peritoneal signs (infarcted myoma)
  • Conjunctival pallor, tachycardia

Tests

Lab

  • ²- hCG
  • Thyroid-stimulating hormone
  • CBC
  • Iron, total iron-binding capacity, ferritin
  • Type and crossmatch before surgery

Imaging

  • Transvaginal ultrasound to confirm diagnosis, evaluate for ovarian neoplasm
  • Renal ultrasound to evaluate for obstruction
  • MRI to visualize individual myomas, identify malignant sarcomas, detect adenomyosis, plan complex surgeries and uterine artery embolization
  • Hysterosalpingography to define submucosal myomas or to evaluate uterus and fallopian tubes

Surgery

Endometrial biopsy to evaluate abnormal bleeding

Pathological Findings

  • Multinodular uterine tumor
  • Smooth muscle fibers organized in bundles, surrounded by fibrous tissue

Differential Diagnosis

  • Abnormal uterine bleedingAnovulationThyroid dysfunctionEndometrial hyperplasia or malignancy
  • Pelvic painEndometriosisAdenomyosisEctopic pregnancyTorsion or rupture of ovarian cystPelvic inflammatory disease
  • Pelvic massPregnancyAdenomyosis, uterine polypOvarian malignancyLeiomyosarcoma

Treatment

  • Insufficient data to compare treatments or recommend treatment to asymptomatic women
  • Drug therapy may be sufficient for women nearing menopause; none improve fertility.

Medication

  • Iron supplementation to correct anemia
  • Trial of oral contraceptives reasonable to attempt control of bleeding; use of levonorgestrel intrauterine device has also been reported
  • Tranexamic acid (1,300 mg t.i.d. for up to 5 days during menses) exerts antifibrinolytic effects to reduce bleeding by approximately 30% (1)[A].Studied only in smaller fibroidsContraindicated if risk for thrombosisFibroid infarction reported
  • Gonadotropin-releasing hormone (GnRH) agonists (2)[B]Cause hypoestrogenic state and decrease uterine artery blood flowLeuprolide: 3.75 mg IM monthly or 11.25 mg IM depot every 3 months, only FDA-approved agentNafarelin: 400 ¼g intranasally b.i.d. (alternate nostrils)Goserelin: 3.6 mg implant SC every 28 daysReduce uterine size by up to 65% and induce amenorrhea within 3 months in most womenPreoperative use can correct anemia and allow less invasive approach, but may complicate dissection or embolization.Side effects and expense limit long-term use.Associated with hot flushes, vaginal dryness, mood swings, and accelerated bone loss, although addition of hormone replacement therapy may reduce side effectsMyomas regain pretreatment size within months after drug is stopped.Not well studied beyond 6 months of use
  • Ulipristal acetate (5 or 10 mg daily), a selective progesterone-receptor modulator, controls bleeding in approximately 90% of women (NNT 1.4) and decreases fibroid volume by approximately 20% (3,4)[B]Studied in 13-week trial of symptomatic women planning hysterectomyInduced amenorrhea in majority of subjectsHeadache and breast discomfort most common side effects, but comparable to placeboBenign endometrial changes more common with ulipristalBoth doses found to be noninferior to leuprolide for control of bleeding, with a lower incidence of hot flashes, in a separate study
  • Danazol or progestins can induce amenorrhea, but true benefit unknown
  • Mifepristone, selective estrogen receptor modifiers, and aromatase inhibitors may have benefit, but their use is largely investigational.

Additional Treatment

Issues for Referral

  • Refer to fertility specialist to evaluate for other causes of infertility
  • Refer to urology for ureteral obstruction

Surgery

  • Indications for surgeryContraindication to, intolerance of, or failure of drug therapyConcern for malignancyMass effect causing pain, pressure, or urinary or GI tract symptomsDistortion of uterine cavity causing infertility or repeated pregnancy loss
  • Carries risk of infection, bleeding, damage to adjacent organs, adhesion formation
  • Consider autologous blood donation

Rapid growth (increase in uterine size by 6 weeks in 1 year) in a nonpregnant woman or growth in a menopausal woman suggests malignancy and should prompt surgical removal.

  • HysterectomyDefinitive treatment as it eliminates symptoms and the development of new myomasIndicated for extensive disease, uncontrolled acute hemorrhage, suspected malignancy, and myomas in association with other pelvic abnormalitiesAssociated with significant improvement in symptoms and quality of lifePrecludes future pregnancy
  • Abdominal myomectomyRemoval of myomas via laparotomy while preserving uterusIndicated for multiple or deep intramural myomas, >3 larger than 5 cm, or uterus >18 weeks in sizePreferred in women desiring future pregnancy as risk of uterine rupture is extremely lowMay involve more time and greater blood loss than hysterectomy
  • Laparoscopic myomectomy (5)[B]Removal of myomas via laparoscope while preserving uterusIndicated for ≤3 intramural or subserosal myomas ≤5 cm in diameter or uterine size <18 weeksLonger surgery but reduced bleeding and recovery compared with abdominal approachRisk of uterine rupture is controversial.
  • Hysteroscopic myomectomyRemoval of intracavitary submucosal myomas via endoscope introduced through the cervixMore effective combined with endometrial ablation, but precludes pregnancyMay be performed as outpatient procedure
  • MyolysisThermo- or cryoablation of myoma via laparoscopy with decrease in size over 3 " 6 months; may carry increased risk of adhesions and uterine ruptureIndicated for ≤3 myomas, largest <10 cmMore effective combined with endometrial ablation, but precludes pregnancyMagnetic resonance guided focused ultrasound thermoablation available, but few long-term outcome data
  • Uterine artery embolization (6)[B]Procedure under fluoroscopy in which gel, beads, or coils are introduced through a catheter to the uterine arteryDisrupts blood supply, causing degenerationRapid recovery compared with surgeryUsually requires brief hospitalization for pain controlResolution of bleeding symptoms in up to 75% reported at 5 years, up to 20% require second procedure to treat symptomsMay be less effective for large, pedunculated, or submucosal tumorsAssociated with significant pain, fever, nausea, vomiting, and myalgias in first 48 hours; sepsis and death have been reportedEarly menopause reported in up to 3% of women under 45Long-term effect on fertility and pregnancy outcomes not known

In-Patient Considerations

Initial-Stabilization

  • Control severe bleeding and pain
  • Treat iron-deficiency anemia

Ongoing Care

Follow-Up Recommendations

  • No high-quality trials support preconception myomectomy in asymptomatic women
  • Large myomas may be associated with pain, bleeding, breech presentation, premature labor, or increased risk of cesarean section.
  • Rapid growth may occur in first trimester in response to estrogen, increased blood flow, or edema, but most enlarge by <10%.
  • Risk of abruption increases if the placenta overlies a myoma.
  • Considerations after myomectomyAdhesions may impair fertility.Postpone pregnancy at least 6 monthsCesarean delivery may be preferable after laparoscopic myomectomy.

Patient Monitoring

  • Asymptomatic myomas may be followed by exam or ultrasound every 3 months to determine growth pattern, then every 6 months if stableExamine at same time in cycle to limit effects of hormonal stimulation on tumor size
  • Watchful waiting may be appropriate for large, asymptomatic myomas in women approaching menopause if malignancy has been excluded.
  • Annual bone mineral density studies if GnRH agonist is continued >6 months; consider calcium and bisphosphonate therapy

Prognosis

  • Most symptomatic women require surgery
  • May recur after myomectomyRisk increases with number of myomasUp to 60% recurrence at 5 yearsUp to 25% require second surgery
  • Regress during menopause

Complications

  • Secondary infection of degenerating myoma
  • Osteoporosis secondary to GnRH agonist
  • Malignant transformation (rare)

References

1Lukes A, Moore K, Muse K. Tranexamic acid treatment for heavy menstrual bleeding. Obstet Gynecol. 2010;116:865 " 875. [View Abstract]2Lethaby A, Vollenhove B, Sowter MC. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fiboids. Cochrane Database Syst Rev. 2011;1:CD000547. [View Abstract]3Donnez J, Tatarchuk T, Bouchard P Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366:409 " 420. [View Abstract]4Donnez J, Tomaszewski J, Vazquez F Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012;366:421 " 432. [View Abstract]5Jin C, Hu Y, Chen X. Laparoscopic versus open myomectomy " a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2009;145(1):14 " 21. [View Abstract]6Gupta JK, Sinha A, Lumsden MA. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2009;1:CD005073.

Additional Reading

1 Alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol. 2008;112:387 " 400.

Codes

ICD9

  • 218.0 Submucous leiomyoma of uterus
  • 218.1 Intramural leiomyoma of uterus
  • 218.9 Leiomyoma of uterus, unspecified
  • 218.2 Subserous leiomyoma of uterus

ICD10

  • D25.0 Submucous leiomyoma of uterus
  • D25.1 Intramural leiomyoma of uterus
  • D25.9 Leiomyoma of uterus, unspecified
  • D25.2 Subserosal leiomyoma of uterus

SNOMED

  • 95315005 uterine leiomyoma (disorder)
  • 95279007 submucous leiomyoma of uterus (disorder)
  • 93616000 intramural leiomyoma of uterus (disorder)
  • 95280005 subserous leiomyoma of uterus (disorder)

Clinical Pearls

  • Common in reproductive-age women
  • Most are asymptomatic, but can cause significant morbidity
  • Base treatment on woman 's age, proximity to menopause, symptoms, myoma burden, other conditions, preferences, and desire for pregnancy, as well as availability of physicians experienced with the selected treatment