Bleeding, Abnormal Uterine: Postmenopausal and Menopausal Transition

Menopause

• Absence of menstruation for 1 year

• Due to physiologic decline in ovulatory function (1)

Menopausal transition (MT)

• Commonly referred to as "perimenopause"

• Begins with onset of cycle irregularity

• Ends at 1 year from last menstruation (1)

Postmenopausal abnormal uterine bleeding (AUB)

• Uterine bleeding that occurs >1 year after last menstruation or unscheduled bleeding for women taking hormone replacement therapy (HRT) (2,3).

• Women taking HRT may have abnormal bleeding for several months after initiation of therapy (4). Bleeding that recurs after long bleeding-free period should be considered abnormal and prompt further investigation (5).

AUB during MT

• May be defined by increase in volume or frequency of bleeding, midcycle bleeding, postcoital bleeding

Average length MT is 4 years (1).

Mean age of menopause in developed countries is 51.4 years of age (1).

• 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 (2).

AUB accounts for nearly 20% of outpatient office visits for gynecologic reasons (6).

Postmenopausal AUB is caused by endometrial cancer in 10–15% cases. More commonly caused by endometrial polyps or atrophy (2).

Incidence of endometrial cancer among women, aged 40–50 years, ranges from 13.6 to 24 cases per 100,000 women-years (1).

Peak incidence of endometrial cancer is between 65 and 75 years of age.

Endometrial polyps

Leiomyomas/adenomyosis

Endometrial hyperplasia/cancer

Thyroid dysfunction

Premature ovarian failure

Pituitary dysfunction

Coagulopathy

Ovarian cancer

Infections: pelvic inflammatory disease (PID), endometritis

Pregnancy, ectopic pregnancy, or miscarriage

Age

Time since menopause

Obesity/diabetes/hypertension

Smoking

Early menarche and/or late menopause

Nulliparity

Estrogen therapy

Previous endometrial hyperplasia or polyps

Hereditary nonpolyposis colorectal cancer

Screening for endometrial cancer by transvaginal ultrasound (TVUS) is not recommended for asymptomatic women (7)[A].

Women undergoing HRT with estrogen should also be treated with progesterone to reduce risk of endometrial hyperplasia (8)[A].

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) (6)

Family history—age of menopause onset; bleeding disorders; and cervical, endometrial, or ovarian cancers

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.

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

Initial tests:

• Urine or serum hCG

  • Must exclude pregnancy, especially during MT as intermittent ovulation may occur (1)

• Thyroid function tests (1,6)

• Serum prolactin level

• Complete blood count (CBC)

• Consider coagulopathy.

• Pap smear, if indicated

• Testing for infection if clinically indicated: gonorrhea, chlamydia, Trichomonas, yeast, bacterial vaginosis

Imaging

• TVUS

  • Endometrial thickness <3 mm provides 98% sensitivity for ruling out endometrial cancer, although some recommend a cutoff of <4–5 mm (9)[B].

  • Stripe >4 mm in postmenopause should prompt further evaluation.

• 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 (EMB) (3).

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 if additional risk factors for endometrial cancer. Uterine stripe measurement generally not useful.

• Advantages: simple in-office procedure

• Disadvantages: can miss up to 18% focal lesions (3)

Hysteroscopy

• Advantages: allows targeted biopsy at time of procedure has greater sensitivity and specificity over TVUS for diagnosis of uterine polyps and greater sensitivity for diagnosis of submural fibroids

• Disadvantages: more invasive procedure, increased pain of procedure, and possible anesthesia risk if unavailable in outpatient setting (10,11)

Dilation and curettage

• Less commonly performed with increased availability and tolerance of endometrial sampling biopsy and hysteroscopy for targeted biopsy (2)

Endometrial cancer, atypia, and hyperplasia must be ruled out prior to proceeding with treatment. Recommendations for reasonable exclusion of likelihood of endometrial cancer vary, with some using a cutpoint of <3–4 mm on TVUS if the endometrium is thin and homogeneous and most conservative recommending at least TVUS and endometrial sampling. Following this strategy, if

• Negative cytology on endometrial biopsy

• <3 mm endometrial stripe on TVUS or sonohysterography

And if above criteria are met, may proceed with

• Watchful waiting

• 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, such as removal of endometrial polyps or fibroids, endometrial ablation, or hysterectomy

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 also regulates the cycle and minimizes other associated menopausal symptoms if present. No real consensus in the literature on best therapy out of choices listed below or length of therapy (6–12 months prior to discontinuing is reasonable) (6).

Progestin-only oral therapy (for cycle 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 2.5–10 mg PO daily times 5–10 days each cycle

  • Start on cycle day 14–21 taken during second half of theoretical cycle

Depot medroxyprogesterone acetate 150

Levonorgestrel intrauterine device (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

• NSAIDs (6)

  • Ibuprofen 600–1,200 mg PO daily, taken for first 5 days after bleeding onset

  • Naproxen 550–1,100 mg PO daily, taken for first 5 days after bleeding onset

• Comparable to hormonal therapies

• Caution in patients with gastrointestinal (GI) disease

• Tranexamic acid, 1,300 mg PO taken three 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 NSAIDs or luteal phase progestins (6,12)

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

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

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.

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% (3).

626.9 Unspecified disorders of menstruation and other abnormal bleeding from female genital tract

627.1 Postmenopausal bleeding

627.0 Premenopausal menorrhagia

626.8 Other disorders of menstruation and other abnormal bleeding from female genital tract

N93.9 Abnormal uterine and vaginal bleeding, unspecified

N95.0 Postmenopausal bleeding

N92.4 Excessive bleeding in the premenopausal period

N93.8 Other specified abnormal uterine and vaginal bleeding

312984006 Abnormal uterine bleeding unrelated to menstrual cycle (disorder)

76742009 Postmenopausal bleeding (finding)

88424000 Premenopausal menorrhagia (finding)

19155002 Dysfunctional uterine bleeding (finding)

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 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.