ABNORMAL (DYSFUNCTIONAL) UTERINE BLEEDING

Stephen D. Cagle Jr., MD • Matthew J. Snyder, DO

 BASICS

DESCRIPTION

•  Abnormal uterine bleeding (AUB) is irregular menstrual bleeding (usually heavy, prolonged, or frequent); it is a diagnosis of exclusion after establishment of normal anatomy and the absence of other medical illnesses.

•  The International Federation of Gynecology and Obstetrics (FIGO) revised the terminology system and now uses AUB rather than dysfunctional uterine bleeding (DUB).

•  Commonly associated with anovulation

EPIDEMIOLOGY

Adolescent and perimenopausal women are affected most often.

Incidence

5% of reproductive age women will see a doctor in any given year for AUB.

Prevalence

10–30% of reproductive age women have AUB.

ETIOLOGY AND PATHOPHYSIOLOGY

•  Anovulation accounts for 90% of AUB.

–  Loss of cyclic endometrial stimulation

–  Elevated estrogen levels stimulate endometrial growth.

–  No organized progesterone withdrawal bleeding

–  Endometrium eventually outgrows blood supply, breaks down, and sloughs from uterus.

–  6–10% will have polycystic ovarian syndrome (PCOS).

•  Adolescent AUB is usually due to an immature hypothalamic-pituitary-ovarian (HPO) axis that leads to anovulatory cycles.

•  The mnemonic PALM-COEIN was developed as the new nomenclature to describe AUB in reproductive-aged women.

•  PALM describes structural causes of abnormal uterine bleeding, and COEIN describes nonstructural causes of AUB.

–  PALM: polyp, adenomyosis, leiomyoma, and malignancy and/or hyperplasia

–  COEIN: coagulopathy, ovulatory disorders, endometrial, iatrogenic, and not yet classified.

–  Reproductive pathology and structural disorders

  Uterus: leiomyomas, endometritis, hyperplasia, polyps, trauma

  Adnexa: salpingitis, functional ovarian cysts

  Cervix: cervicitis, polyps, STIs, trauma

  Vagina: trauma, foreign body

  Vulva: lichen sclerosus, STIs

•  Malignancy of the vagina, cervix, uterus, and ovaries

•  Systemic diseases

–  Hematologic disorders (e.g., von Willebrand disease, thrombocytopenia)

•  Diseases causing anovulation

–  Hyperthyroidism/hypothyroidism

–  Adrenal disorders

–  Pituitary disease (prolactinoma)

–  PCOS

–  Eating disorders

•  Medications (iatrogenic causes)

–  Anticoagulants

–  Steroids

–  Tamoxifen

–  Hormonal medications: intrauterine devices (IUDs)

–  Selective serotonin reuptake inhibitors (SSRIs)

–  Antipsychotic medications

•  Other causes of AUB not defined in PALM-COEIN

–  Pregnancy: ectopic pregnancy, threatened or incomplete abortion, or hydatidiform mole

–  Advanced or fulminant liver disease

–  Chronic renal disease

–  Inflammatory bowel disease

–  Excessive weight gain

–  Increased exercise

Genetics

Unclear but can include inherited disorders of hemostasis

RISK FACTORS

Risk factors for endometrial cancer (which can cause AUB)

•  Age >40 years

•  Obesity

•  PCOS

•  Diabetes mellitus

•  Nulliparity

•  Early menarche or late menopause (>55 years of age)

•  Hypertension

•  Chronic anovulation or infertility

•  Unopposed estrogen therapy

•  History of breast cancer or endometrial hyperplasia

•  Tamoxifen use

•  Family history: gynecologic, breast, or colon cancer

 DIAGNOSIS

HISTORY

•  Menstrual history

–  Onset, severity (quantified by pad/tampon use, presence and size of clots), timing of bleeding (unpredictable or episodic)

–  Menorrhagia with onset of menarche is suggestive of a coagulation disorder.

–  Menopausal status

–  Association with other factors (e.g., coitus, contraception, weight loss/gain)

•  Gynecologic history: gravidity and parity, STI history, previous Pap smear results

•  Review of systems (exclude symptoms of pregnancy and of bleeding disorders, bleeding from other orifices, stress, exercise, recent weight change, visual changes, headaches, galactorrhea)

•  Medication history: Evaluate for use of aspirin, anticoagulants, hormones, and herbal supplements (1,2).

ALERT

Postmenopausal bleeding is any bleeding that occurs >1 year after the last menstrual period; cancer must always be ruled out (2)[C].

PHYSICAL EXAM

Discover anatomic or organic causes of AUB.

•  Evaluate for

–  Body mass index (obesity)

–  Pallor, vital signs (anemia)

–  Visual field defects (pituitary lesion)

–  Hirsutism or acne (hyperandrogenism)

–  Goiter (thyroid dysfunction)

–  Galactorrhea (hyperprolactinemia)

–  Purpura, ecchymosis (bleeding disorders)

•  Pelvic exam

–  Evaluate for uterine irregularities and Tanner stage.

–  Check for foreign bodies.

–  Rule out rectal or urinary tract bleeding.

–  Include Pap smear and tests for STIs (2)[C].

Pediatric Considerations

Premenarchal children with vaginal bleeding should be evaluated for foreign bodies, physical/sexual abuse, possible infections, and signs of precocious puberty.

DIFFERENTIAL DIAGNOSIS

See “Etiology.”

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

•  Everyone: urine human chorionic gonadotropin (hCG; rule out pregnancy and/or hydatidiform mole) and complete blood count (CBC) (1)

–  For acute bleeding, a type and cross should be obtained (3)[C].

•  If disorder of hemostasis is suspected, a partial thromboplastin time (PTT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level is appropriate (3)[C].

•  If anovulation is suspected: thyroid-stimulating hormone (TSH) level, prolactin level (1)

•  Consider other tests based on differential diagnosis.

–  Follicle-stimulating hormone (FSH) level to evaluate for hypo- or hypergonadotropism

–  Coagulation studies and factors if coagulopathy is suspected (1)

–  17-Hydroxyprogestrone if congenital adrenal hyperplasia is suspected

–  Testosterone and/or dehydroepiandrosterone sulfate (DHEA-S) if PCOS

–  Screening for STI

•  Endometrial biopsy (EMB) should be performed as part of the initial evaluation for postmenopausal uterine bleeding and in premenopausal women with risk factors for endometrial carcinoma. Medical management can be initiated in premenopausal women with normal TVUS and low risk for malignancy (1)[A].

•  TVUS, sonohysterography, and hysteroscopy may be similarly effective in detection of intrauterine pathology in premenopausal women with AUB (1)[A].

•  If normal findings following imaging in patients without known risk factors for endometrial carcinoma, a biopsy should be performed if not done so previously (2)[C].

Diagnostic Procedures/Other

•  Pap smear to screen for cervical cancer if age >21 years (2)[C]

•  EMB should be performed in

–  Women age >35 years with AUB to rule out cancer or premalignancy

–  Postmenopausal women with endometrial thickness >5 mm

–  Women aged 18 to 35 years with AUB and risk factors for endometrial cancer (see “Risk Factors”)

–  Perform on or after day 18 of cycle, if known; secretory endometrium confirms ovulation occurred.

•  Dilation and curettage (D&C)

–  Perform if bleeding is heavy, uncontrolled, or if emergent medical management has failed.

–  Perform if unable to perform EMB in office (2)[C].

•  Hysteroscopy if another intrauterine lesion is suspected

Test Interpretation

Pap smear could reveal carcinoma or inflammation indicative of cervicitis. Most EMBs show proliferative or dyssynchronous endometrium (suggesting anovulation) but can show simple or complex hyperplasia without atypia, hyperplasia with atypia, or endometrial adenocarcinoma.

 TREATMENT

Attempt to rule out other causes of bleeding prior to instituting therapy.

GENERAL MEASURES

NSAIDs (naproxen sodium 500 mg BID, mefenamic acid 500 mg TID, ibuprofen 600 to 1,200 mg/day) (1)[B]

•  Decreases amount of blood loss and pain compared with placebo, with no one NSAID clearly superior

MEDICATION

First Line

•  Acute, emergent, nonovulatory bleeding

–  Conjugated equine estrogen (Premarin): 25 mg IV q4h (max 6 doses) or 2.5 mg PO q6h should control bleeding in 12 to 24 hours (4)[A].

–  D&C if no response after two to four doses of Premarin or sooner if bleeding >1 pad/hr (2)[C]

–  Then change to oral contraceptive pill (OCP) or progestin for cycle regulation, that is, IUD (5)[A]

•  Acute, nonemergent, nonovulatory bleeding

–  Combination OCP with ≥30 μg estrogen given as a taper. An example of a tapered dose: 4 pills/day for 4 days; 3 pills/day for 3 days; 2 pills/day for 2 days, daily for 3 weeks then 1 week off, then cycle on OCP for at least 3 months.

•  Nonacute, nonovulatory bleeding (ranked in order based on decision analysis as best option based on efficacy, cost, side effects, and consumer acceptability) (5)[A]

–  Levonorgestrel IUD (Mirena) is the most effective form of progesterone delivery and is not inferior to surgical management.

–  Progestins: medroxyprogesterone acetate (Provera) 10 mg/day for 5 to 10 days each month. Daily progesterone for 21 days per cycle results in significantly less blood loss.

–  OCPs: 20 to 35 μg estrogen plus progesterone

•  Do not use estrogen if contraindications, such as suspicion for endometrial hyperplasia or carcinoma, history of deep vein thrombosis (DVT), or the presence of smoking in women >35 years of age (relative contraindication), are present.

•  Precautions

–  Failed medical treatment requires further workup.

–  Consider DVT prophylaxis when treating with high-dose estrogens (2)[C].

Second Line

•  Leuprolide (varying doses and duration of action); gonadotropin-releasing hormone (GnRH) agonist

•  Danazol (200 to 400 mg/day for a maximum of 9 months) is more effective than NSAIDs but is limited by androgenic side effects and cost. It has been essentially replaced by GnRH agonists.

•  Antifibrinolytics such as tranexamic acid (Lysteda) 650 mg, 2 tablets TID (max 5 days during menstruation) (1)[A]

•  Metformin or Clomid alone or in combination in women with PCOS who desire ovulation and pregnancy

ISSUES FOR REFERRAL

•  If an obvious cause for vaginal bleeding is not found in a pediatric patient, refer to a pediatric endocrinologist or gynecologist.

•  Patients with persistent bleeding despite medical treatment require reevaluation and possible referral.

ADDITIONAL THERAPIES

•  Antiemetics if treating with high-dose estrogen or progesterone (2)[C]

•  Iron supplementation if anemia (usually iron deficiency) is identified

SURGERY/OTHER PROCEDURES

•  Hysterectomy in cases of endometrial cancer or if medical therapy fails or if other uterine pathology is found

•  Endometrial ablation is less expensive than hysterectomy and is associated with high patient satisfaction; failure of primary medical treatment is not necessary (1,4)[A].

–  This is a permanent procedure and should be avoided in patients who desire continued fertility.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

•  Significant hemorrhage causing acute anemia with signs of hemodynamic instability; with acute bleeding, replace volume with crystalloid and blood, as necessary (1)[A].

•  Pad counts and clot size can be helpful to determine and monitor amount of bleeding.

•  Discharge criteria

–  Hemodynamic stability

–  Control of vaginal bleeding (2)[C]

 ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

•  Once stable from acute management, recommend follow-up evaluation in 4 to 6 months for further evaluation (5).

•  Routine follow-up with a primary care or OB/GYN provider

Patient Monitoring

Women treated with estrogen or OCPs should keep a menstrual diary to document bleeding patterns and their relation to therapy.

DIET

No restrictions, although a 5% reduction in weight can induce ovulation in anovulation caused by PCOS.

PATIENT EDUCATION

Explain possible/likely etiologies.

•  Answer all questions, especially those related to cancer and fertility.

•  http://www.acog.org/Patients

PROGNOSIS

•  Varies with pathophysiologic process

•  Most anovulatory cycles can be treated with medical therapy and do not require surgical intervention.

COMPLICATIONS

•  Iron deficiency anemia

•  Uterine cancer in cases of prolonged unopposed estrogen stimulation

REFERENCES

1.  Sweet MG, Schmidt-Dalton TA, Weiss PM, et al. Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012;85(1):35–43.

2.  Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged woman. Obstet Gynecol. 2012;120(1):197–206.

3.  American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 557: management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013;121(4):891–896.

4.  DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding—a double-blind randomized control study. Obstet Gynecol. 1982;59(3):285–291.

5.  Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2006;(2):CD003855.

ADDITIONAL READING

•  Farquhar C, Ekeroma A, Furness S, et al. A systematic review of transvaginal ultrasonography, sonohysterography and hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal women. Acta Obstet Gynecol Scand. 2003;82(6):493–504.

•  Kouides PA, Conard J, Peyvandi F, et al. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005;84(5):1345–1351.

•  Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;(4):CD002126.

•  Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;(4):CD000249.

•  Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev. 2008;(1):CD001016.

 SEE ALSO

•  Dysmenorrhea; Menorrhagia (Heavy Menstrual Bleeding)

•  Algorithm: Menorrhagia

 CODES

ICD10

•  N93.9 Abnormal uterine and vaginal bleeding, unspecified

•  N93.8 Other specified abnormal uterine and vaginal bleeding

•  N91.2 Amenorrhea, unspecified

CLINICAL PEARLS

•  AUB is irregular bleeding that occurs in the absence of pathology, making it a diagnosis of exclusion.

•  Anovulation accounts for 90% of AUB.

•  An EMB should be performed in all women >35 years of age with AUB to rule out cancer or premalignancy, and it should be considered in women aged 18 to 35 years with AUB and risk factors for endometrial cancer.

•  It is appropriate to initiate medical therapy in females <35 years of age with no apparent risk of endometrial cancer prior to performing an EMB.