Abnormal Uterine Bleeding

Epidemiology and Definitions

Epidemiology

Abnormal uterine bleeding (AUB):

• Lifetime incidence: affects 10%–35% of women of reproductive age
• Accounts for ⅓ of gynecological outpatient visits
• 21%–67% of cases develop iron-deficiency anemia.

Normal menstrual bleeding

• Normal frequency (cycle length): ≥ 24 days to ≤ 38 days
• Normal duration: ≤ 8 days
• Normal flow volume: no physical, social, or emotional distress caused by flow
  • Determined by patient
  • Average flow is approximately 30 mL
• Normal regularity: variation between shortest and longest cycles is ≤ 7–9 days (or average cycle length ± 4 days)
  • 18–25 and 42–45 years of age: ≤ 9 days
  • 26–41 years of age: ≤ 7 days

Abnormal uterine bleeding

• Symptomatic abnormalities in the regularity, duration, frequency, and volume of menses
• Also includes intermenstrual bleeding (IMB) (bleeding between normal menses)
• Variation may be:
  • Acute AUB: bleeding in sufficient quantity that warrants immediate intervention to prevent further blood loss
  • Chronic AUB: abnormalities in uterine bleeding present for most of the last 6 months

Updated nomenclature

Owing to the previous lack of consistency in terminologies surrounding AUB, a new system was developed in 2011 to describe and classify AUB.

• Abnormalities in frequency:
  • Infrequent uterine bleeding: 
    • Menstrual interval > 38 days
    • Previously called oligomenorrhea
  • Frequent uterine bleeding: 
    • Menstrual interval < 24 days
    • Previously called polymenorrhea
• Abnormalities in volume:
  • AUB/heavy menstrual bleeding (HMB):
    • Excessive menstrual blood loss (objectively defined as > 80 mL blood loss/cycle)
    • Can be based on heavy flow, as determined by the patient
    • Interferes with physical, social, emotional, and/or material quality of life
    • Independent of cycle duration, frequency, or regularity (although abnormalities may coexist)
    • Previously called menorrhagia
  • Light menstrual bleeding:
    • < 5 mL blood loss/cycle
    • Infrequent
    • While rare, may result from cervical stenosis or intrauterine synechiae
• Abnormalities in regularity:
  • Irregular uterine bleeding: variation between shortest and longest cycles is ≥ 8‒10 days 
  • In some young women, long cycles evolve and eventually fit the usual variation.
• Abnormalities in duration:
  • Prolonged uterine bleeding: menses lasting > 8 days
  • No consensus on lower limit: ↓ duration is not specifically related to a clinical condition, except for amenorrhea.
• IMB: 
  • Bleeding between the cyclic, regular onset of menses that can be:
    • Random
    • Cyclic (early, mid, or late cycle)
  • Previously called metrorrhagia
  • Includes breakthrough bleeding (from hormone administration) and postcoital bleeding
• Absence of menstruation:
  • Primary amenorrhea: 
    • No menses by 13 years of age in the absence of secondary sex characteristics 
    • No menses by 15 years of age regardless of secondary sex characteristics
    • Secondary sex characteristics include the development of breasts, axillary hair, and pubic hair.
  • Secondary amenorrhea:
    • Absence of menses for 3 months after previously regular menstrual cycles
    • Absence of menses for 6 months after previously irregular menstrual cycles
    • Absence of menses for 3 cycle lengths (in women with infrequent menstrual bleeding)

Etiologies

The causes of AUB are classified according to the PALM-COEIN system, which is an acronym.

PALM (structural causes)

• Polyp (AUB-P):
  • Overgrowth of epithelial cells arising from the endometrium
  • Risk factors: obesity, tamoxifen use, ↑ age
• Adenomyosis (AUB-A):
  • Presence of endometrium (stroma and glandular tissue) within the uterine myometrium
  • Often associated with endometriosis
• Leiomyoma (AUB-L):
  • Leiomyoma-submucosal (AUB/HMB-L_SM)
  • Leiomyoma-other (AUB/HMB-L_O)
• Malignancy and hyperplasia (AUB-M):
  • Endometrial 
  • Uterine sarcomas

COEIN (non-structural causes)

• Coagulopathy (AUB-C):
  • Seen in 20% of adolescents with AUB
  • Common AUB-Cs: platelet-function disorders, von Willebrand’s disease
  • Deficient coagulation factors (V, VII, VIII, IX, XI, XII) 
• Ovulatory dysfunction (AUB-O):
  • Polycystic ovarian syndrome (PCOS): most common cause of ovarian dysfunction
  • Functional hypothalamic amenorrhea (stress, overexercising, eating disorders)
  • Primary ovarian insufficiency (POI)
  • Other endocrine disorders
  • Age-related anovulation near menarche or menopause
• Endometrial (AUB-E):
  • Endometritis or pelvic inflammatory disease (PID): commonly chlamydia
  • Endometrial atrophy (thin, fragile endometrial tissue) in post-menopausal women
• Iatrogenic (AUB-I):
  • Contraceptives (including intrauterine devices (IUDs))
  • Anticoagulants
  • Chemotherapy
  • Selective estrogen receptor modulators
  • Drugs related to dopamine metabolism: antidepressants, antipsychotics
• Not yet classified (AUB-N)

Clinical Presentation

Presentation of PALM (structural causes)

Presentation of COEIN (non-structural causes)

Diagnosis

History and exam

• Menstrual history to classify AUB
• Screen for AUB-C based on history (any 1 of the following requires lab evaluation):
  • HMB since menarche
  • 1 of the following: 
    • Postpartum hemorrhage
    • Surgery-related bleeding
    • Severe bleeding with dental work
  • 2 or more of the following:
    • Bruising 1–2 times every month
    • Epistaxis (nose bleeds) 1–2 times every month
    • Frequent gum bleeds
    • Family history of bleeding symptoms
• Uterine abnormalities on exam:
  • Symmetrical enlargement → suspect:
    • AUB-A
    • AUB-M
    • Pregnancy
  • Asymmetrical enlargement → suspect AUB-L
  • Severe tenderness → consider PID (AUB-E)

Laboratory tests

• Pregnancy test: if positive → obstetric complications (e.g., ectopic)
• CBC: 
  • ↓ Hemoglobin or hematocrit → anemia related to AUB/HMB
  • ↓ Platelets → further workup for AUB-C
  • ↑ WBCs → present in PID → consider AUB-E (especially with pelvic tenderness)
• Coagulation tests (if patient screens positive during history taking):
  • PT, PTT, INR
  • Screening for von Willebrand’s disease:
    • von Willebrand factor antigen test
    • von Willebrand functional assay
    • Factor VIII activity
• Endocrine tests for AUB-O:
  • Order for patients with infrequent bleeding or amenorrhea:
    • Thyroid-stimulating hormone (TSH)
    • Prolactin
    • Follicle-stimulating hormone (FSH)
    • Estradiol
    • Androgen levels
  • Interpretation:
    • ↑/↓ TSH: thyroid disease 
    • ↑ Prolactin: hyperprolactinemia
    • ↑ FSH with ↓ estradiol: POI
    • ↓ FSH with ↓ estradiol: functional hypothalamic amenorrhea
    • ↑ Androgens: PCOS
• Chlamydia screen: 
  • Endometritis/PID → AUB-E
  • Cervicitis → vaginal bleeding without AUB

Cytology and biopsy

• Endometrial biopsy:
  • To rule out AUB-M
  • 45 years of age to menopause with any AUB
  • < 45 years of age with AUB and other risk factors: 
    • Unopposed estrogen exposure (obesity, ≥ 6 months of ovarian dysfunction)
    • Tamoxifen use
    • Lynch or Cowden syndromes 
• Pap smear: 
  • Ensure that cervical cancer screening is updated.
  • Consistent post-coital bleeding suggests cervical pathology.

Imaging

• Transvaginal ultrasound (TVUS):
  • 1st-line imaging modality for AUB
  • AUB-P: thickened endometrial lining
  • AUB-L: hypoechoic, well-circumscribed, round mass 
  • AUB-A: enlarged uterus with heterogenous echotexture
  • AUB-M: thickened endometrial lining in postmenopausal women
• Saline infusion sonogram (SIS):
  • Injection of saline into the uterine cavity for distension during sonography 
  • Ideal test for the diagnosis of: 
    • AUB-P
    • Submucosal AUB-L
    • Other uterine pathologies that contribute to infertility: septa, synechiae
• Pelvic MRI:
  • 2nd-line modality if TVUS is unable to provide sufficient information
  • Rarely required
• Hysteroscopy:
  • Surgical alternative to SIS
  • Allows for simultaneous diagnosis (visualization with biopsy) and treatment of AUB-P and submucosal AUB-L

Management

Management approach

• Dependent on hemodynamic stability:
  • General supportive measures in bleeding:
    • Stabilization (fluid resuscitation)
    • Transfusion, if needed
  • Acute heavy uterine bleeding:
    • IV estrogen
    • Dilation and curettage
• Dependent on the underlying etiology:
  • Structural causes (PALM) → surgical resection (often, but not always)
  • AUB-O → medical management
  • Infections → antibiotics
  • AUB-C → medical management

Medical management

• Minimize HMB with progestin therapy:
  • Oral contraceptive pills (OCPs)
  • Levonorgestrel-containing IUDs
  • High-dose oral progestins: norethindrone, medroxyprogesterone acetate
• Minimize HMB with anti-fibrinolytics: tranexamic acid (alternative to hormone therapy)
• Treat underlying endocrine disorders:
  • Bromocriptine or cabergoline (hyperprolactinemia)
  • Levothyroxine (hypothyroidism)
  • Spironolactone (hyperandrogenism seen in PCOS)
• Iron supplementation in anemia
• Pain management for dysmenorrhea or pelvic pain (NSAIDs)

Surgical management

• Women desiring future fertility:
  • Surgical resection of polyps (polypectomy)
  • Surgical resection of leiomyomas (myomectomy)
• After childbirth:
  • Endometrial ablation
  • Uterine-artery embolization (for large leiomyomas only)
  • Hysterectomy (definitive treatment of AUB)

Differential Diagnosis

• Non-uterine lower genital-tract bleeding: vaginal bleeding that may arise from the cervix due to either cervicitis or vaginitis, which irritates the cervix. Cervical, vaginal, or vulvar bleeding due to lacerations secondary to trauma may also occur. Diagnosis is made based on a pelvic exam, screening for gonorrhea and chlamydia infections, and using a wet mount and potassium hydroxide smear of vaginal fluid to confirm vaginitis. The patient should also have an up-to-date Pap smear and biopsy of any suspicious vulvovaginal lesions.
• Urinary tract infection (UTI): a condition that may present with vaginal bleeding and can sometimes be mistaken for uterine bleeding. If the patient only notes AUB while urinating, and/or has any bladder symptoms, urinalysis and culture should be ordered. Treatment is with antibiotics.