Menopause

Jill Patton, DO Reviewed 06/2017
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Subject: Menopause

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BASICS

DESCRIPTION

  • Natural menopause: defined retrospectively after 12 consecutive months of amenorrhea in a nonpregnant woman ≥40 years of age:

    • ▪ Results from loss of ovarian activity
    • ▪ Not associated with a pathologic etiology
  • Perimenopause/menopausal transition (MT): defined as the period from the onset of irregular menses to the final menstrual cycle. Begins on average 4 years before menopause. Starts at mean age of 47 years.

  • Postmenopause: usually >1/3 of a woman's life

  • Primary ovarian insufficiency: irregular or cessation of menses before age 40 years

EPIDEMIOLOGY

  • The median age of menopause is 51 years.

  • 5% of women undergo menopause after age 55 years; another 5% between ages 40 and 45 years.

  • Occurs earlier in Hispanic women and later in Japanese American women as compared with Caucasians

Incidence

In the United States, 1.3 million women reach menopause annually. 

ETIOLOGY AND PATHOPHYSIOLOGY

Normal physiologic process: 
  • As women age, the number of ovarian follicles decreases: Ovarian production of estrogen varies and then decreases. Follicle-stimulating hormone (FSH) production varies and then increases.

  • Inadequate estradiol production leads to absence of the luteinizing hormone (LH) surge and failure to ovulate. These cycles result in anovulation and lack of progesterone production.

  • Eventual failure to produce estradiol leads to thinning of endometrial lining and eventual menses cessation.

  • Surgical menopause: Removal of functioning ovaries leads to immediate menopause.

RISK FACTORS

  • Aging

  • Oophorectomy

  • Hysterectomy

  • Sex chromosome abnormalities (e.g., Turner syndrome and fragile X syndrome)

  • Family history of early menopause

  • Smoking (earlier age of onset by 2 years)

  • Chemotherapy and/or pelvic radiation (permanent or reversible)

GENERAL PREVENTION

Menopause is physiologic event. Increased risk of long-term medical issues include cardiovascular disease (CVD) and osteoporotic fractures: 
  • Decrease risk of CVD by:

    • ▪ Increased exercise
    • ▪ Avoiding smoking
    • ▪ Maintaining healthy diet and lose weight
    • ▪ Treating hyperlipidemia, diabetes, and hypertension
    • ▪ Taking daily low-dose aspirin
  • Decrease risk of osteoporotic fractures by:

    • ▪ Weight-bearing exercise
    • ▪ Avoiding smoking
    • ▪ Avoiding excessive alcohol intake
    • ▪ Dietary calcium of 1,200 mg/day
    • ▪ Adequate vitamin D (800 to 1,200 IU daily)
    • ▪ Fall prevention

DIAGNOSIS

HISTORY

  • Cessation of menses:

    • ▪ Generally preceded by a period of irregular cycles with heavy vaginal bleeding followed by diminished vaginal bleeding
  • Vasomotor symptoms: sudden feeling of warmth, most commonly over face, neck, and chest, with average duration of ∽3 minutes; intervals unpredictable

    • ▪ Most commonly reported symptom; reported by over 80% of women
    • ▪ Frequency and duration varies. 87% of women who report flushes experience them daily; ∽33% have >10 per day. Mean duration of symptoms lasts 4 to 10.2 years and may begin during MT and extend well past menopause 1[A].
    • ▪ Varies with ethnicity; greatest in African and Hispanic women and least in Asian women
    • ▪ More common in obese women
  • Urogenital atrophy in up to 50% 2[B]:

    • ▪ Vaginal/vulvar dryness discharge, itch, dyspareunia, and possible sexual dysfunction
    • ▪ Alkaline vaginal pH and atrophy increases risk of vaginal infections and UTIs.
    • ▪ Persists or worsens with aging
    • ▪ Urologic symptoms (urgency, frequency, dysuria, incontinence) not clearly correlated with MT
  • Anxiety, depression: Some studies show a new diagnosis of depression is 2.5 times more likely to occur during the MT as compared to premenopause.

  • Sleep disturbance: Arousal from sleep and chronic insomnia may be linked with vasomotor symptoms.

  • Joint pain with unclear link to loss of estrogen

  • Change in intensity and severity of migraines

  • Skin thinning, mild hirsutism, brittle nails

Geriatric Considerations

Vaginal bleeding in postmenopausal women is abnormal; endometrial cancer/endometrioid adenocarcinoma (EAC) must be ruled out. 

PHYSICAL EXAM

  • Decrease in breast size and change in breast texture

  • External, speculum, and bimanual pelvic exams: atrophic vulva and vaginal mucosa; increased risk for uterine prolapse

DIFFERENTIAL DIAGNOSIS

Pregnancy, hyperthyroidism and other thyroid disease, pituitary adenoma, Sheehan syndrome, hypothalamic dysfunction, anorexia nervosa, Asherman syndrome, obstruction of uterine outflow tract 

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

  • U.S. Preventive Service Task Force (USPSTF) recommends mammogram every 2 years from ages 50 to 74 years.

  • Lab testing for menopause is not required; the patient's age and symptoms establish the diagnosis.

  • If laboratory confirmation is desired:

    • ▪ Elevated serum FSH level >30 mIU/mL indicates ovarian failure.
    • ▪ Symptoms may precede lab changes.
    • ▪ Infertility evaluation: may use elevated day 3 FSH, decreased anti-müllerian hormone levels, and decreased antral follicle count to predict decreased ovarian reserve
  • Estrogens, androgens, and oral contraceptive pills (OCPs) may alter lab results.

Follow-Up Tests & Special Considerations
  • Pregnancy test

  • TSH and prolactin level if pituitary disease is suspected

  • Vaginal bleeding in a postmenopausal patient should be evaluated by transvaginal ultrasound (TVUS) and/or endometrial biopsy (EMB). If endometrial stripe is ≪5 mm on TVUS, EAC is unlikely.

  • USPSTF recommends bone mineral density (BMD) screening with dual energy x-ray absorptiometry (DEXA) scan in postmenopausal women >65 years, or ≪65 years if the risk for fracture is equivalent to that of a 65-year-old woman (using the FRAX tool to assess, http://www.shef.ac.uk/FRAX/). Risk factors include a previous history of fractures, low body weight, cigarette smoking, and family history of osteoporotic fracture.

Test Interpretation

  • Abnormal BMD and DEXA scan results:

    • ▪ T-score on DEXA of -1 to -2.5 = osteopenia
    • ▪ T-score ≪ -2.5 = osteoporosis
    • ▪ Defer to femoral neck T-score over spine T-score.
  • Z-score measures age-matched mean bone density (not clinically useful).

TREATMENT

MEDICATION

First Line

Hormone therapy (HT): developing an individual risk-benefit profile is essential. Treatment goal is to minimize menopausal symptoms to improve quality of life. 
  • The primary indication for HT is the treatment of moderate to severe vasomotor symptoms.

    • ▪ Oral estrogen or estrogen-progestin mix can reduce weekly hot flush frequency ∽75% 1[A].
  • HT also helpful with sleep disorders, urogenital atrophy, and lowers risk of osteoporotic fractures and colorectal cancer; may help with mood symptoms.

  • In women with an intact uterus, give estrogen with progestin as unopposed estrogen carries an increased risk of EAC.

  • Treatment regimens include, but are not limited to:

    • ▪ Standard dose: conjugated equine estrogen (CEE) 0.625 mg/day OR micronized estradiol 17β 1.0 mg/day OR transdermal estradiol 17β 0.0375 to 0.05 mg/day
    • ▪ Low dose: CEE 0.3 to 0.45 mg/day OR micronized estradiol 17β 0.5 mg/day OR transdermal estradiol 17β 0.025 mg/day
    • ▪ Ultra-low dose: micronized estradiol 17β 0.025 mg/day OR transdermal estradiol 17β 0.014 mg/day
    • ▪ Micronized progesterone 100 mg/day can be used as progestin. Alternative: medroxyprogesterone acetate (MPA) 2.5 mg/day. Combination estradiol/progestin transdermal treatments have either levonorgestrel or norethindrone as progestin source. Although NOT approved for postmenopausal women, the levonorgestrel intrauterine system (IUS) has been used.
    • ▪ Bazedoxifene + conjugated estrogens for relief of vasomotor symptoms and bone loss prevention
  • MenoPro app is free for iPhones and iPad from The North American Menopause Society (NAMS). It has two modes: one for clinicians and one for patients to aid in shared decision making. It allows users to progress through questions to evaluate cardiovascular and reproductive organ cancer risk 3.

  • American Congress of Obstetricians and Gynecologists (ACOG) recommends HT should be individualized with lowest effect dose given for the shortest duration of time needed to relieve vasomotor symptoms. Lower doses have similar symptom reduction profiles for many patients. Results of ultra-low-dose regimens are mixed 4[A].

  • Although generally well tolerated, side effects of HT include breast tenderness, vaginal bleeding, bloating, and headaches.

  • Precautions:

    • ▪ Women's Health Initiative (WHI) study demonstrate of every 10,000 women who take CEE with MPA, each year, there were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers independent of mammography screening frequency. Absolute risk reductions revealed 6 fewer colorectal cancers and 5 fewer hip fractures 5[A].
    • ▪ Breast cancer risk not seen until 5 years of use.
    • ▪ Cardiovascular risks not seen until after age 60 years or 10 years from menopause.
    • ▪ Women on estrogen alone had no increased risk of breast cancer in the 8 years of the study and showed later cardiovascular risk compared to estrogen + progestin.
    • ▪ HT should NOT be used for cardioprotective benefit as risk outweighs benefit 6[A].
    • ▪ Higher doses of estrogen can cause hypercoagulability, breast tenderness, gallbladder disease, and hypertension (HTN).
    • ▪ Contraindications to HT:
      • * Estrogen-dependent malignancies
      • * Unexplained uterine bleeding
      • * History of thromboembolism or stroke
      • * CAD
      • * Active liver disease
  • For osteoporosis: women with a history of hip or vertebral fracture or personal history of osteoporosis should be treated with one of the following:

    • ▪ Bisphosphonates to inhibit osteoclast action and resorption of bone:
    • ▪ Selective estrogen receptor modulators (SERMs) selectively inhibit or stimulate estrogen-like action with stimulation of osteoblasts:
      • * Raloxifene: 60 mg/day
        • ▪ Decreases the risk of vertebral fracture but failed to demonstrate a decrease in the risk of extravertebral fractures.
      • * Bazedoxifene + conjugated estrogens (0.45 mg/20 mg)
        • ▪ FDA approved for moderate to severe vasomotor symptoms and osteoporosis.
    • Denosumab (60 mg SC every 6 months) is a monoclonal antibody that prevents RANKL (receptor activator of nuclear factor kappa-B ligand) from accelerating osteoclast generation. Reduces incidence of vertebral and hip fractures in postmenopausal women
    • ▪ Parathyroid hormone—rarely used due to the adverse effect on bone but shown to reduce fracture risk in menopausal women with osteoporosis
  • For vulvar/vaginal atrophy:

    • ▪ Topical estrogen therapy (ET) reverses vaginal atrophy, enhances blood flow, and reduces UTI. Continue for as long as distressing symptoms remain. Initiate treatment daily for 1 to 2 weeks, then decreased to 2 times weekly. Comes as estradiol cream, tablet, or ring. Apply vaginally:
      • * Estradiol cream 0.01% (1 g), conjugated estrogen 0.625 mg/g (0.5 g), vaginal tablet (10 μg) used twice weekly, or vaginal ring (7.5 μg daily lasting for 3 months)
      • * Ospemifene: 60 mg PO daily. SERM for moderate to severe dyspareunia associated with vaginal atrophy
  • Although there is no increased risk of endometrial hyperplasia or EAC, women with bleeding on these treatments should be evaluated with TVUS or EMB. Patients with h/o hormone-dependent cancer should meet with a gynecologist before using medication.

Second Line

Nonhormonal treatments may be helpful to treat vasomotor symptoms in women who wish to or need to avoid HT (e.g., breast cancer): 
  • Paroxetine (7.5 mg/day) is approved for treatment of vasomotor symptoms. This SSRI demonstrated modest decrease in hot flushes.

  • Other SSRI/SSNIs: venlafaxine (37.5 to 75 mg/day) or fluoxetine (20 mg/day) and citalopram (20 mg/day) shown to reduce hot flushes as compared to placebo

  • Gabapentin (300 to 900 mg/day) shown to have an effect on lowering hot flushes compared to placebo

  • Clonidine (.05 mg BID) may be used to treat mild hot flashes, less effective than SSRI/SRNIs.

  • Note that most trials of second-line therapies have been brief (i.e., a few months).

COMPLEMENTARY & ALTERNATIVE MEDICINE

Trials of nonprescribed therapies are difficult to interpret due to variability of components and doses: 
  • Soy isoflavone in placebo-controlled trials showed a mixed effect in reducing hot flashes.

  • Red clover, black cohosh, reflexology, aerobics, and magnet therapy showed no impact on hot flashes when compared with placebo.

  • Small clinical trials of evening primrose, dong quai, ginseng, and wild yam do not support use for relief of hot flashes.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

A DEXA scan is indicated at age 65 years for all women and for younger women with risk equivalent to age 65 years. 

DIET

Calcium-rich diet and vitamin D supplementation (800 to 1,200 IU/day). Calcium supplements may have adverse effects including increased risk of kidney stone and increased risk of cardiac events. 

PATIENT EDUCATION

Encourage lifestyle modifications: 
  • Smoking cessation

  • Weight-bearing exercise >30 minutes, 3 times weekly

  • Healthy diet to maintain appropriate weight

  • Avoid excess alcohol.

  • Address cardiovascular risk factor modification.

PROGNOSIS

If untreated: 
  • Ultimate disappearance of vasomotor symptoms

  • Worsening of vaginal/vulvar atrophy

  • Osteoporosis: possible fractures of the hip, vertebrae, and wrists

COMPLICATIONS

  • Osteoporosis: At menopause, women have accelerated bone loss up to 3-5% per year for 5 to 7 years.

  • Increased risk of CVD following menopause

REFERENCES

MacLennan  AH, Broadbent  JL, Lester  S, et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev.  2004;(4):CD002978.  [View Abstract]
Dennerstein  L, Dudley  EC, Hopper  JL, et al. A prospective population-based study of menopausal symptoms. Obstet Gynecol.  2000;96(3):351–358.  [View Abstract]
Manson  JE, Ames  JM, Gass  MLS, et al. MenoPro: A mobile app for women bothered by menopause symptoms [published online ahead of print October 15, 2014]. Menopause.
Diem  S, Grady  D, Quan  J, et al. Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years. Menopause.  2006;13(1):130–138.  [View Abstract]
Rossouw  JE, Anderson  GL, Prentice  RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA.  2002;288(3):321–333.  [View Abstract]
Marjoribanks  J, Farquhar  C, Roberts  H, et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev.  2012;(7):CD004143.  [View Abstract]

ADDITIONAL READING

  • ACOG Practice bulletin no. 141: management of menopausal symptoms. Obstet Gynecol.  2014;123(1):202–216.

  • Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med.  2006;355(22):2338–2347.

  • Mørch LS, Løkkegaard E, Andreasen AH, et al. Hormone therapy and ovarian cancer. JAMA.  2009;302(3):298–305.

  • National Guideline Clearinghouse. Menopause. http://www.guideline.gov

  • Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA.  2004;291(13):1610–1620.

  • North American Menopause Society. The 2012 hormone therapy position statement of the North American Menopause Society. Menopause.  2012;19(3):257–271.

  • U.S. Preventive Services Task Force. Screening for breast cancer, topic page. http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm. Accessed December 7, 2016.

CODES

ICD10

  • E28.310 Symptomatic premature menopause

  • N95.1 Menopausal and female climacteric states

  • Z78.0 Asymptomatic menopausal state

  • E89.40 Asymptomatic postprocedural ovarian failure

  • E28.319 Asymptomatic premature menopause

  • E89.41 Symptomatic postprocedural ovarian failure

ICD9

  • 627.2 Symptomatic menopausal or female climacteric states

  • 256.31 Premature menopause

  • 627.4 Symptomatic states associated with artificial menopause

  • 256.2 Postablative ovarian failure

SNOMED

  • 289903006 Menopause present (finding)

  • 237123000 Normal menopause (finding)

  • 373717006 Premature menopause (finding)

  • 21801002 menopausal symptom (finding)

  • 278063007 Post-hysterectomy menopause (disorder)

  • 278064001 Post-radiation menopause (disorder)

  • 371036001 Postsurgical menopause (disorder)

  • 123756000 Menopausal syndrome (disorder)

CLINICAL PEARLS

  • Menopause is usually diagnosed by history alone.

  • HT can be used short term for relief of moderate to severe vasomotor symptoms but should not be used for long-term prevention of CVD.

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