Abnormal Uterine Bleeding: Postmenopausal and Menopausal Transition

Basics

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).
  • Postmenopausal AUB is caused by endometrial cancer in 10–15% cases. AUB is more commonly caused by endometrial polyps or atrophy (1).
  • Incidence of endometrial cancer among postmenopausal women is 0.7% but increases with additional risk factors (2).
  • 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)[A].
  • Women undergoing HRT with estrogen should also be treated with progesterone to reduce risk of endometrial hyperplasia (4)[A].
  • Use of combined oral contraceptives, depot medroxyprogesterone acetate or the levonorgestrel intrauterine device (IUD) is a protective factor against developing endometrial cancer (4).

Diagnosis

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 gingko, 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 (lab, imaging)
  • 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 (4)[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 (4).
    • 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)

Surgery/Other Procedures

  • 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)

Treatment

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 cutpoint 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) (5)
  • 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 (5)[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 (5)
      • 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 biopsy
  • 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

Ongoing Care

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 >96% (2).

Codes

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)

Clinical Pearls

  • Endometrial cancer must be reasonably ruled out in patients with AUB in MT or menopause.
  • Medical management should be first line for patients in MT, once endometrial cancer and hyperplasia are ruled out. Surgical options should be reserved for persistent symptoms or postmenopausal patients.
  • AUB in MT is likely anovulatory and would benefit from progesterone in the luteal phase of theoretical menstrual cycle.

Authors


Catherine A. Gill, MD

Bibliography

  1. Breijer MC, Timmermans A, van Doorn HC, et al. Diagnostic strategies for postmenopausal bleeding. Obstet Gynecol Int. 2010;2010:850812. [PMID:20169169]
  2. Null DB, Weiland CM, Camlibel AR. Postmenopausal bleeding-first steps in the workup. J Fam Pract. 2012;61(10):597–604. [PMID:23106061]
  3. Committee on Practice Bulletins—Gynecology. Practice Bulletin No. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122(1):176–185. [PMID:23787936]
  4. Committee on Practice Bulletins—Gynecology. Practice Bulletin No. 149: endometrial cancer. Obstet Gynecol. 2015;125(4):1006–1026. [PMID:25798986]
  5. 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. [PMID:22230306]


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