Menopause

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Chapter 171 Menopause

INTRODUCTION

Description: Menopause is an endocrinopathy caused by the loss of normal ovarian steroidogenesis because of age, chemotherapy, radiation, or surgical therapy. (An endocrinopathy is the loss of an endocrine function with adverse health consequences.)
Prevalence: Of postmenopausal women who do not receive estrogen replacement, 100%.
Predominant Age: Median 51.5, 95% between 44 and 55 (or after surgical menopause).
Genetics: Loss of genetic material from the long arm of the X chromosome is associated with premature menopause.

ETIOLOGY AND PATHOGENESIS

Causes: Loss of estrogen production because of surgery, chemotherapy (alkylating agents), radiation, or natural cessation of ovarian function (menopause).
Risk Factors: Menopause may occur at a younger age in smokers, those with poor nutrition or chronic illness, or those who have a loss of genetic material from the long arm of the X chromosome.

CLINICAL CHARACTERISTICS

Signs and Symptoms

• Absence of menstruation (with a normal uterus and outflow tract)
• Hot flashes, flushes, and night sweats
• Vaginal atrophy
• Dysuria, urgency, and urgency incontinence; urinary frequency; nocturia; and an increased incidence of stress urinary incontinence
• Decrease in libido
• Irregular bleeding common during the climacteric (perimenopausal) period

DIAGNOSTIC APPROACH

Differential Diagnosis

• Pregnancy
• Hypothyroidism
• Polycystic ovary syndrome
• Prolactin-secreting tumor
• Hypothalamic dysfunction
• Hypothyroidism

Associated Conditions: Dyspareunia, vulvodynia, atrophic vulvitis, osteoporosis, increased risk of cardiovascular disease, hot flashes and flushes, sleep disturbances, stress urinary incontinence, and others.

WORKUP AND EVALUATION

Laboratory: Usually not necessary. When the diagnosis of ovarian failure must be confirmed, measurement of serum follicle-stimulating hormone (FSH) is sufficient. Levels of greater than 100 mIU/mL are diagnostic, although lower levels (40 to 50 mIU/mL) may be sufficient to establish a diagnosis when symptoms are also present. Serum estradiol levels may be determined (generally less than 15 pg/mL) but are less reliable as a marker of ovarian failure. A pregnancy test is always indicated in women who are perimenopausal and sexually active and not using contraception.
Imaging: No imaging indicated. Standard imaging does not document bone loss of less than 30%.
Special Tests: A vaginal maturation index may be obtained but is generally not required for diagnosis. Bone densitometry may be indicated for those at special risk. When noncyclic bleeding occurs in these patients, endometrial biopsy should be strongly considered. Women younger than age 30 years who have ovarian failure should have a karyotype performed.

Pathologic Findings

Vaginal, vulvar, and endometrial atrophy. Thinned ovarian stroma with few, inactive oocytes. Accelerated calcium loss from bone.

MANAGEMENT AND THERAPY

Nonpharmacologic

General Measures: Health maintenance, annual mammogram, annual pelvic and rectal examinations, thyroid and cholesterol screening every 5 years or as indicated, tetanus booster shot every 10 years, pneumococcus vaccine as indicated.
Specific Measures: For symptom relief: systemic estrogen (estrogen/progestin) therapy. (Less than 1% of women do not benefit from therapy.) Topical estrogen supplements.
Diet: Adequate dietary calcium (1000 to 1500 mg/day).
Activity: No restriction, weightbearing activity to promote bone health, cardiovascular fitness training/maintenance.
Patient Education: Reassurance; American College of Obstetricians and Gynecologists Patient Education Pamphlet AP047 (The Menopause Years), AP066 (Hormone Replacement Therapy), AP158 (Herbal Products for Menopause), AP048 (Preventing Osteoporosis), AP028 (Vaginitis: Causes and Treatments).

Drug(s) of Choice

(Most common drug doses shown.)
Oral estrogens—conjugated equine estrogens (0.625 to 1.25 mg/day), diethylstilbestrol, esterified estrogens (0.625 to 1.25 mg/day), ethinyl estradiol (0.05 mg/day), micronized estradiol (0.5 to 1 mg/day), piperazine estrone sulfate, estropipate, quinestrol.
Injectable estrogens—conjugated equine estrogens, estradiol benzoate, estradiol cypionate, estradiol valerate (oil), estrone (aqueous), ethinyl estradiol, polyestradiol phosphate.
Topical estrogens—17β-estradiol (transdermal) (0.05 to 0.10 mg/day), conjugated equine estrogens (0.625 mg/g), estradiol (0.1 mg/g), estropipate (1.5 mg/g).

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Contraindications: Systemic therapy: active liver disease, carcinoma of the breast (current), chronic liver damage (impaired function), endometrial carcinoma (current), recent thrombosis (with or without emboli), unexplained vaginal bleeding. Relative contraindications/special considerations—endometriosis, familial hyperlipidemia, gallbladder disease, hypertension (uncontrolled), migraine headaches, seizure disorders, thrombophlebitis (unknown risk), uterine leiomyomas. Topical use—known sensitivity to vehicle.
Precautions: Continuous estrogen exposure without periodic or concomitant progestins increases the risk of endometrial carcinoma 6-fold to 8-fold. Continuous estrogen/progestin therapy frequently results in random vaginal bleeding, but biopsy or other investigation is still warranted. Patients receiving cyclic estrogen/progestin therapy should experience vaginal bleeding only after withdrawal of the progestin; biopsy or other investigation is warranted for other bleeding.
Interactions: Raloxifene should not be used with cholestyramine. Most therapies alter the effects of warfarin therapy.

Alternative Drugs

Raloxifene (Evista) 60 mg PO daily—no relief for hot flashes or vaginal dryness, but does reduce breast cancer risk.
Progestin therapy (oral, vaginal, or injectable)—effective for hot flashes, may reduce bone loss, but has no effect on coronary artery disease or urogenital atrophy.
Clonidine (oral or transdermal).
Bellergal-S (phenobarbital, ergotamine tartrate, belladonna).
Alendronate (Fosamax)—for osteoporosis.
Topical moisturizers for atrophic vaginitis.
(Botanical agents have not been shown to be efficacious for most menopausal symptoms or for osteoporosis prevention.)

FOLLOW-UP

Patient Monitoring: Normal health maintenance. Serious consideration should be given to a trial of therapy discontinuation after 2 or more years.
Prevention/Avoidance: Estrogen replacement therapy at menopause. The use of progestins is required if the patient retains her uterus to reduce the risk of iatrogenic endometrial hyperplasia or cancer. Therapy may be oral (such as medroxyprogesterone acetate [Provera] 5 to 10 mg PO daily for 12 to 14 days per month or 2.5 mg PO daily) or vaginal (progesterone bioadhesive gel [Crinone] 4% to 8%, 45 mg [1.125 g] intravaginally every other day for six doses per month).
Possible Complications: Endometrial hyperplasia if the uterus is present and progestins not used, vaginal bleeding (predictable or otherwise).
Expected Outcome: Reversal of symptoms, reestablishment of normal physiology with treatment. Selective estrogen receptor modulators (also called SERMS or tissue-specific estrogens) may provide protection against cardiac, bone, and colon cancer and Alzheimer’s disease with reduced rates of risk for both breast and endometrial cancer.

MISCELLANEOUS

Pregnancy Considerations: Menopause is associated with the loss of fertility.
ICD-9-CM Codes: 627.2 (Menopause or female climacteric states), 256.3 (Premature), 256.2 (Premature: post irradiation or surgical), 627.4 (Surgical).

REFERENCES

Level I

Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006;145:869.

Rapp SR, Espeland MA, Shumaker SA, et alWHIMS Investigators. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2663.

Reddy SY, Warner H, Guttuso TJr, et al. Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial. Obstet Gynecol. 2006;108:41.

Shumaker SA, Legault C, Rapp SR, et alWHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289:2651.

Simon JA, Bouchard C, Waldbaum A, et al. Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007;109:588.

Steiner AZ, Xiang M, Mack WJ, et al. Unopposed estradiol therapy in postmenopausal women: results from two randomized trials. Obstet Gynecol. 2007;109:581.

Level II

Anderson GL, Limacher M, Assaf AR, et alWomen’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701.

Bath PM, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ. 2005;330:342. Epub 2005 Jan 7

Cauley JA, Robbins J, Chen Z, et alWomen’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women’s Health Initiative randomized trial. JAMA. 2003;290:1729.

Cheong JM, Martin BR, Jackson GS, et al. Soy isoflavones do not affect bone resorption in postmenopausal women: a dose-response study using a novel approach with 41Ca. J Clin Endocrinol Metab. 2007;92:577. Epub 2006 Dec 5

Cushman M, Kuller LH, Prentice R, et alWomen’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573.

Hendrix SL, Wassertheil-Smoller S, Johnson KC, et alWHI Investigators. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113:2425. Epub 2006 May 15

Hsia J, Langer RD, Manson JE, et alWomen’s Health Initiative Investigators. Conjugated equine estrogens and coronary heart disease: The Women’s Health Initiative. Arch Intern Med. 2006;166:357.

Magliano DJ, Rogers SL, Abramson MJ, Tonkin AM. Hormone therapy and cardiovascular disease: a systematic review and meta-analysis. BJOG. 2006;113:5.

Manson JE, Allison MA, Rossouw JE, et alWHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591.

Nedrow A, Miller J, Walker M, et al. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med. 2006;166:1453.

Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. JAMA. 2004;291:1610.

Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057.

Rossouw JE, Anderson GL, Prentice RL, et alWriting Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321.

Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465.

Wassertheil-Smoller S, Hendrix SL, Limacher M, et alWHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women’s Health Initiative: a randomized trial. JAMA. 2003;289:2673.

Level III

American College of Obstetricians and Gynecologists. Use of botanicals for management of menopausal symptoms. ACOG Practice Bulletin 28. Washington, DC: ACOG, 2001.

American College of Obstetricians and Gynecologists. Selective estrogen receptor modulators. ACOG Practice Bulletin 39. Obstet Gynecol. 2002;100:835.

American College of Obstetricians and Gynecologists. Osteo-porosis. ACOG Practice Bulletin 50. Obstet Gynecol. 2004;103:203.

American College of Obstetricians and Gynecologists. Compounded bioidentical hormones. ACOG Committee Opinion 322. Obstet Gynecol. 2005;106:1139.

Cheung AM, Feig DS, Kapral M, et alCanadian Task Force on Preventive Health Care. Prevention of osteoporosis and osteoporotic fractures in postmenopausal women: recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ. 2004;170:1665.

Creasman WT, Hoel D, Disaia PJ. WHI: Now that the dust has settled: a commentary. Am J Obstet Gynecol. 2003;189:621.

Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355:2338.

Grimes DA, Lobo RA. Perspectives on the Women’s Health Initiative trial of hormone replacement therapy. Obstet Gynecol. 2002;100:1344.

Hickey M, Davis SR, Sturdee DW. Treatment of menopausal symptoms: what shall we do now? Lancet. 2005;366:409.

National Institutes of Health. National Institutes of Health State-of-the-Science Conference statement: Management of menopause-related symptoms. Ann Intern Med. 2005;142:1003. Epub 2005 May 27

Roberts H. Managing the menopause. BMJ. 2007;334:736.

Sahdev A. Imaging the endometrium in postmenopausal bleeding. BMJ. 2007;334:635.

Santoro N. The menopausal transition. Am J Med. 2005;118:8.

Warren MP. Historical perspectives in postmenopausal hormone therapy: defining the right dose and duration. Mayo Clin Proc. 2007;82:219.

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