Description

• Menopausal transition (MT)
  • Commonly referred to as “perimenopause”
  • Begins with onset of cycle irregularity
  • Ends at 1 year from last menstruation
• Menopause
  • Absence of menstruation for 1 year
  • Due to physiologic decline in ovulatory function
• Abnormal uterine bleeding (AUB) during MT
  • May be defined by increase in volume or frequency of bleeding, midcycle bleeding, postcoital bleeding
• Postmenopausal AUB
  • Uterine bleeding that occurs >1 year after last menstruation or unscheduled bleeding for women taking hormone replacement therapy (HRT) (1,2)
    • Women taking HRT may have irregular bleeding for several months after initiation of therapy. Bleeding that recurs after a long bleed-free period should be considered abnormal and prompt further investigation.

Epidemiology

• Average length of MT is 4 years (3).
• Mean age of menopause in developed countries is 51.4 years of age (3).
  • Premature ovarian failure is defined as onset of menopause <40 years of age.
• Incidence of postmenopausal AUB is as high as 10%, with majority of cases occurring shortly after menopause (1).
• AUB is most commonly caused by endometrial polyps or atrophy (1).
• Prevalence of endometrial cancer among postmenopausal women is 0.7% but increases with additional risk factors (2). Among with postmenopausal AUB, risk of endometrial cancer is significantly higher, approximately 9% (4).
• Peak incidence of endometrial cancer is between 65 and 75 years of age.

Etiology and Pathophysiology

• Pregnancy, ectopic pregnancy, or miscarriage
• Endometrial polyps
• Leiomyomas/adenomyosis
• Endometrial hyperplasia/cancer
• Premature ovarian failure
• Ovarian cancer
• Infections: pelvic inflammatory disease (PID), endometritis
• Thyroid dysfunction
• Pituitary dysfunction
• Coagulopathy

Risk Factors

For endometrial cancer:

• Age
• Time since menopause
• Obesity (body mass index [BMI] >25)
• Type 2 diabetes
• Hypertension
• Smoking
• Early menarche and/or late menopause
• Nulliparity/infertility
• Polycystic ovarian syndrome
• Estrogen therapy
• Tamoxifen therapy
• Previous endometrial hyperplasia or polyps
• Hereditary nonpolyposis colorectal cancer

General Prevention

• There are no recommended screening tests for endometrial cancer (4,5)[A].
• Women undergoing HRT with estrogen should also be treated with progesterone to reduce risk of endometrial hyperplasia (4,5)[A]. Progesterone is generally considered not to be necessary for women using vaginal cream to treat local vaginal symptoms.
• Use of combined oral contraceptives, depot medroxyprogesterone acetate, or the levonorgestrel intrauterine device (IUD) are protective factors against developing endometrial cancer (5).

History

• Date of last menstruation
• Bleeding patterns
  • Menses length/frequency
  • Volume of menstrual bleeding
  • Presence of midcycle bleeding
  • Postcoital bleeding
• History of abnormal cervical lesions
• Sexual activity and contraception use
• Parity
• Medication history—particularly anticoagulants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, corticosteroids, hormone replacement, tamoxifen, and herbal supplement (especially Ginkgo biloba, ginseng, soy)
• Smoking history
• History of colon cancer/last colon cancer screening
• Family history—age of menopause onset; bleeding disorders; colon, cervical, endometrial, or ovarian cancers

Physical Exam

• BMI
• Pelvic speculum exam—assess for cervical and vaginal lesions.
• Bimanual exam—assess for uterine enlargement, adnexal masses, and cervical motion tenderness.
• Abdominal exam—assess for masses.

Differential Diagnosis

• Uterine source bleeding
  • See list of possible etiologies.
• Cervical source bleeding
  • Cervical polyps
  • Cervicitis
  • Cervical dysplasia or neoplasia
• Vaginal source bleeding
  • Vaginitis
  • Atrophy
  • Trauma
  • Vaginal cancer

Diagnostic Tests & Interpretation

• Initial tests:
  • Urine or serum hCG
    • Must exclude pregnancy, especially during MT as intermittent ovulation may occur
  • Thyroid function tests
  • Follicle-stimulating hormone (FSH)
  • Serum prolactin level
  • Complete blood count (CBC)
  • Consider coagulopathy.
  • Pap smear, if indicated
  • Test for infection if clinically indicated: gonorrhea, chlamydia, Trichomonas, yeast, bacterial vaginosis.
• Imaging
  • TVUS
    • Postmenopausal endometrial thickness (ET) <4 mm does not require endometrial sampling unless bleeding is persistent or recurrent, whereas ET >4 mm in should prompt further evaluation (5)[B].
    • ET <3 mm provides 98% sensitivity for ruling out endometrial cancer, with 35% specificity.
    • ET <5 mm provides 90% sensitivity for ruling out endometrial cancer, with 54% specificity.
    • ET is not useful in premenopausal women (5)[C].
  • Saline infusion sonohysterography
    • Advantages
      • Better able to define intrauterine pathology compared to TVUS alone
      • Less invasive than hysteroscopy
    • Disadvantages
      • More invasive than TVUS
      • Lacks ability to perform targeted biopsy or removal of suspected lesions as with hysteroscopy
      • May risk dissemination of neoplastic cell, therefore should not be performed if abnormal cytology present on endometrial biopsy (2)

• Endometrial sampling
  • Indicated for all women >45 years of age with AUB if not using TVUS triage strategy
  • Indicated for MT women <45 years of age with AUB with risk factors for endometrial cancer
  • Advantages: simple in-office procedure
  • Disadvantages: can miss up to 18% focal lesions (2)
• Hysteroscopy
  • Advantages: allows targeted biopsy at the time of procedure; greater sensitivity and specificity over TVUS for diagnosis of uterine polyps; greater sensitivity over TVUS for diagnosis of submural fibroids
  • Disadvantages: more invasive procedure; increased pain of procedure; possible anesthesia risk if unavailable in outpatient setting
• Dilation and curettage
  • Less commonly performed due to increased availability and tolerance of endometrial sampling biopsy and hysteroscopy for targeted biopsy (1)

General Measures

• Endometrial cancer, atypia, and hyperplasia must be ruled out prior to proceeding with treatment. Recommendations vary for reasonable exclusion of possible endometrial cancer; most using a cut point between 3 and 5 mm on TVUS if the endometrium is thin and homogeneous. Some are more conservative, recommending at least:
  • Negative cytology on endometrial biopsy
  • <3 mm endometrial stripe on TVUS or sonohysterography
• If above criteria are met, may proceed with:
  • Watchful waiting
  • Combined contraceptive hormone therapy
  • Progestin-only therapy
  • Other treatments as indicated for specific diagnoses if identified on workup such as atrophic vaginitis or genital infection
• If above criteria cannot be met or patient has persistent AUB:
  • Further investigation is indicated for additional workup and treatment.
• Referral to gynecology for surgical procedures as indicated, such as removal of endometrial polyps or fibroids, endometrial ablation, or hysterectomy

Medication

• For patients in MT, not indicated in postmenopausal (see surgical options)
  • Bleeding at this time is likely anovulatory due to paucity of progesterone in the second half of the cycle, leading to unopposed estrogen; raises the concern for endometrial hyperplasia, which must be ruled out prior to hormonal therapy
  • Goal of therapy is to stabilize the endometrium with progesterone. This can also help regulate the cycle and minimize other associated menopausal symptoms if present.
  • No real consensus in the literature on best therapy out of choices listed below or length of therapy (6 to 12 months prior to discontinuing is reasonable) (6)[C]
• Progestin-only oral therapy (for symptom control only, no contraceptive coverage)
  • Medroxyprogesterone acetate 10 mg PO daily for 14 days each month
    • Start on cycle day 14, taken for 14 days to cover second half of theoretical cycle (then 14 days off, 14 days on, etc.).
  • Megestrol acetate 40 mg PO daily
  • Norethindrone acetate 2.5 to 10.0 mg PO daily times 5 to 10 days each cycle
    • Start on cycle day 14 to 21 taken during second half of theoretical cycle.
• Depot medroxyprogesterone acetate 150 mg every 1 to 3 months
• Levonorgestrel IUD
• Combined hormonal contraceptives
  • ≤35 μg ethinyl estradiol plus progesterone agent
  • If no contraindications to estrogen use
  • Oral, transdermal, and vaginal ring preparations available (6)[C]
• Nonhormonal options to reduce heavy AUB
  • Tranexamic acid 1,300 mg PO taken 3 times daily for first 5 days of cycle, beginning with bleeding onset
    • Caution in patients with risk factors for thromboembolic disease
    • May be more effective than nonsteroidal anti-inflammatory drugs (NSAIDs) or luteal phase progestins
  • NSAIDs (6)
    • Ibuprofen 600 to 1,200 mg PO daily, taken for first 5 days after bleeding onset
    • Naproxen 550 to 1,100 mg PO daily, taken for first 5 days after bleeding onset
  • Comparable to hormonal therapies

ALERT
Consider patient’s individual risk for thromboembolic disease, breast cancer, and gastrointestinal bleeding.

Issues For Referral

Gynecology referral

• Abnormal endometrial sampling results
• Indication for hysteroscopy or dilation and curettage, to further evaluate and biopsy suspected focal lesions
• Removal of endometrial polyps/fibroids
• Uncertain diagnosis
• Patient preference or indication for hysterectomy

Surgery/Other Procedures

• Polypectomy or myomectomy
  • Can reduce 75–100% of symptomatic bleeding
  • Endometrial polyps more likely to represent premalignant or malignant lesions in women >60 years of age with postmenopausal AUB
• Uterine artery embolization
• Endometrial ablation
• Hysterectomy
  • Indicated if premalignant or malignant lesions are identified during workup of AUB
  • May be preferred by patient for severe anemia-associated heavy menstrual losses in MT or postmenopausal bleeding, multiple or large fibroids, recurrent abdominal pain, uterine prolapse, or recurring bleeding after other procedures attempted

Follow-up Recommendations

• Routine well woman care
• Should be followed by gynecologic oncology if indicated for premalignant or malignant diagnosis and treatment
• Consider referral to reproductive endocrinology for complicated menopausal symptom management.

Prognosis

• AUB in MT typically improves on its own with onset of menopause.
• If endometrial cancer is found, prognosis depends on the extent of the disease at the time of diagnosis. Most cases when diagnosed early have a 5-year survival rate of >95% (2,4). 5-year survival estimates of later stage endometrial cancers ranges from 16% to 45% (4).

ICD-10

• N92.4 Excessive bleeding in the premenopausal period
• N93.9 Abnormal uterine and vaginal bleeding, unspecified
• N95.0 Postmenopausal bleeding

ICD-9

• 626.8 Other disorders of menstruation and other abnormal bleeding from female genital tract
• 626.9 Unspecified disorders of menstruation and other abnormal bleeding from female genital tract
• 627.0 Premenopausal menorrhagia
• 627.1 Postmenopausal bleeding

SNOMED

• 19155002 Dysfunctional uterine bleeding (finding)
• 312984006 Abnormal uterine bleeding unrelated to menstrual cycle (disorder)
• 76742009 Postmenopausal bleeding (finding)
• 88424000 Premenopausal menorrhagia (finding)