Best Dx/Best Rx: Menopause

Menopause

Susan D. Reed, M.D., M.P.H.
Eliza L. Sutton, M.D., F.A.C.P.
University of Washington School of Medicine

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

Permanent cessation of menses (≥ 12 mo of amenorrhea)
Menopausal transition: period of physiologic change around cessation of ovarian function

Average duration 4 yr before menopause (range 0–10 yr)
Early: variable menstrual cycle length (> 7 days different from normal)
Late: ≥ 2 skipped cycles and an interval of amenorrhea (≥ 60 days)

Natural menopause: menopause at or after age 40, with no underlying pathologic cause

Mean age 51 yr in developed countries
95% of women experience menopause by age 55

Induced menopause: menopause caused by chemotherapy, pelvic radiation, or bilateral oophorectomy
Premature ovarian failure (POF): menopause before age 40, without iatrogenic cause
- Fragile X premutation in 3%–5%
- Immune-mediated in 30%–50%
- Associated autoimmune conditions common
Menstrual changes
- Irregular cycle length, progressing to missed menses
- Heavier or lighter flow, or both
- Eventual progression to amenorrhea
Vasomotor instability (hot flushes and/or night sweats)
- Common, though unpredictable; prevalence 80% in developed countries
- Episodes are self-limited, typically of several minutes' duration
- Maximum frequency and intensity 2 yr before and after final menstrual period; gradually resolves
Changes in libido, sleep, mood, and cognition
Genitourinary atrophy
- Typically mild and asymptomatic during menopausal transition
- Progressive during postmenopausal years; may become severe
- Atrophic vulvovaginitis
  - Vaginal dryness
  - Vulvovaginal pruritus
  - Vaginal dyspareunia
  - Postcoital spotting
- Atrophic urethritis; recurrent cystitis
  - Dysuria
  - Urinary frequency
  - Incontinence

Differential Diagnosis

Menstrual changes

Oligomenorrhea or amenorrhea
Pregnancy
Prolactinoma
Thyroid dysfunction
Medication or supplement use

Menorrhagia or intermenstrual bleeding (interval < 21 days)

Thyroid dysfunction
Pregnancy
Blood dyscrasias
Leiomyoma
Adenomyosis
Endometrial/endocervical polyps
Endometriosis
Endometrial or cervical neoplasia
Hormone-secreting neoplasms (e.g., granulosa cell ovarian cancer)
Medication or supplement use

Genitourinary atrophy
- Vulvovaginal symptoms
  - Trichomonas vaginitis
  - Yeast vulvovaginitis
  - Desquamative inflammatory vaginitis
  - Vestibulitis
  - Allergic vulvovaginitis
  - Vulvar dysplasia or cancer
- Urinary symptoms
  - Dietary bladder irritants
  - Detrusor instability
  - Urinary tract infection
  - Interstitial cystitis
- Hot flushes and night sweats
  - Hyperthyroidism
  - Pheochromocytoma
  - Carcinoid
  - Occult infection (e.g., tuberculosis, HIV)
  - Occult neoplasm, including lymphoma with B symptoms
- Changes in libido, sleep, mood, and cognition
  - Mood or anxiety disorders
  - Thyroid dysfunction
  - Stress
  - Medications or other substances
  - Unrecognized sleep disorder (e.g., obstructive sleep apnea, restless legs syndrome)
  - Early dementia

Best Tests

History and physical examination
- Age 45 or older, with progressive menstrual changes and vasomotor symptoms consistent with natural menopause
Laboratory tests

Follicle-stimulating hormone (FSH)

Most useful in diagnosis of POF
Widely variable during menopausal transition
Typically 15–25 IU/L in incipient ovarian failure; can fluctuate
FSH > 25 IU/L on repeated measurements: complete ovarian failure
Suppressed by oral contraceptives; check during off-week of pill pack

Urine or serum ß-human chorionic gonadotropin (ß-hCG)

If potential for pregnancy with missed period, oligomenorrhea, or irregular vaginal bleeding with or without pain

Thyroid-stimulating hormone (TSH)

If menorrhagia, menstrual irregularities, amenorrhea, excessive diaphoresis, or neurocognitive changes

Prolactin

If suspected prolactinoma, including oligomenorrhea or amenorrhea pattern atypical of natural menopause, and in any patient with galactorrhea and/or bitemporal hemianopsia

Coagulation studies

In patients with menorrhagia that could be secondary to hemorrhagic diathesis

Platelet count
Prothrombin time
Partial thromboplastin time
von Willebrand factor if indicated

Evaluation of POF

Test for premutation allele of fragile X if results useful to the patient (or to other family members) and patient agrees
Test for manifestations of other autoimmune diseases

Complete blood count
Erythrocyte sedimentation rate
Rheumatoid factor
Antinuclear antibody
Serum glucose
Serum calcium
Serum phosphorus
TSH

Vaginal fluid pH and microscopic examination (saline and 10% KOH preparations)

In patients with vaginal dyspareunia or vulvovaginal pruritus, to evaluate for Candida, trichomoniasis, or bacterial vaginosis

Pelvic ultrasound

During menopausal transition, to evaluate endometrial cavity and myometrium in women with menorrhagia or menometrorrhagia

Leiomyoma
Endometrial polyps
Adenomyosis
Test cannot rule out endometrial neoplasia

After menopause, to evaluate the endometrium and myometrium of women with spotting or bleeding occurring spontaneously or with hormone therapy

Homogeneous endometrial thickness ≤ 4 mm rules out endometrial hyperplasia or cancer in 96% of cases

Endometrial biopsy

During menopausal transition, to evaluate women at risk for endometrial hyperplasia or carcinoma who have either of the following:

Intermenstrual bleeding
Menometrorrhagia and risk factors for endometrial hyperplasia (e.g., obesity, diabetes)

After menopause, to evaluate women at risk for endometrial hyperplasia or carcinoma who have either of the following:

Vaginal bleeding after 12 mo of amenorrhea
Endometrium ≥ 4 mm on ultrasound

Best Therapy

General Considerations

Routine use of hormone therapy (HT) in menopausal transition and menopause is no longer standard care
- HT increases risk for the following:
- In women 50–79 years of age, HT reduces risk for the following:
- HT and placebo do not differ in overall or disease-specific mortality for use up to 5–6 years in women 50–79 years of age
Screen for conditions common in postmenopausal women and use approaches other than HT for prevention of the following:

Breast cancer
Colon cancer
Coronary artery disease (CAD)
Diabetes mellitus
Osteoporosis
Dementia

POF is treated with estrogen/progestin until age 50, based on expert opinion

HT or low-dose combination estrogen/progestin contraceptive to prevent bone loss and premature CAD
If pregnancy is desired, in vitro fertilization using donor eggs

Uterine bleeding in the menopause transition, after appropriate evaluation

Low-dose oral contraceptive with 20 µg ethinyl estradiol (also treats vasomotor symptoms)

Discontinue and reassess symptoms at age 50

Progestin intrauterine device (will not treat vasomotor symptoms)

Vasomotor symptoms

Treatment recommended only for symptoms significantly impacting quality of life

Individualize treatment
Use lowest effective dose
Consider transdermal therapy
Annual evaluation recommended; discontinue HT 1 wk before assessment to allow evaluation of current severity of symptoms
Treat for shortest duration that will ease menopausal transition

Recommended limit of use is 5 years
May require taper over 3–6 months at discontinuance

Low-dose oral contraceptives (off-label use)

Best method for women in the menopause transition who are at risk for pregnancy and have heavy or frequent menses

Combination estrogen/progestin, preferably cyclic HT, in women in the menopausal transition who are predominantly anovulatory and do not need contraception
Unopposed estrogen in women who have had hysterectomy
Types of estrogen, with lowest effective doses for vasomotor symptoms:

Oral conjugated estrogen, 0.3 mg/day
Oral estradiol, 0.5 mg/day
Transdermal estradiol patch, 0.025 mg/day
Vaginal estradiol ring 0.05 mg/day

Venlafaxine (off-label use), 37.5–150 mg/day
Selective serotonin reuptake inhibitors (SSRIs) (off-label use)

Fluoxetine, 20 mg/day
Paroxetine CR, 12.5–25 mg/day, or paroxetine, 10–20 mg/day

Gabapentin (off-label use), 300–900 mg/day

Changes in libido, sleep, mood

Libido: estrogen combined with methyltestosterone (MT) may be useful (off-label use)

Esterified estrogen, 0.625 mg/day, and MT, 1.25 mg/day
Transdermal testosterone patch (not available for clinical use)

Insomnia

HT for vasomotor instability that disrupts sleep
Hypnotic agents (e.g., zolpidem, trazodone)

Mood

Antidepressants, with or without adjunctive HT

Genitourinary atrophy

Vaginal estrogen creams

Little or no systemic absorption at low doses
Conjugated equine estrogen cream, 0.625 mg/g (2 g per applicator)

Dose: 1/4–1/8 applicator nightly for 2–6 wk, then 1–3 times/wk

Estradiol cream, 0.01% (0.1 mg/g, 4 g per applicator)

Dose: 1/8–1/16 applicator nightly for 2–6 wk, then 1–3 times/wk

Vaginal estradiol ring: 2 mg (0.0075 mg/day), changed every 90 days
Vaginal estradiol tablet: 0.025 mg, one tablet 2 times/wk
Lubricants for sexual intercourse
Vaginal moisturizers

Best References

Rossouw JE, et al: JAMA 288:321, 2002 [PMID 12117397]

Anderson GL, et al: JAMA 291:1701, 2004 [PMID 15082697]

September 2006