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Menopause

by Margery Gass, MD

Menopause is physiologic or iatrogenic cessation of menses (amenorrhea) due to decreased ovarian function. Manifestations may include hot flushes and vulvovaginal atrophy. Diagnosis is clinical: absence of menses for 1 yr. Manifestations may be treated (eg, with lifestyle modification, complementary and alternative medicine, and/or hormone therapy).

In the US, average age of physiologic menopause is 51. Other factors such as smoking, living at high altitude, and undernutrition may lower the age. Perimenopause refers to the several years (duration varies greatly) before and the 1 yr after the last menses. It is typically the most symptomatic phase. Perimenopause is characterized by changes in the menstrual pattern.

Physiology

As ovaries age, their response to the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) decreases, initially causing a shorter follicular phase (with shorter and less regular menstrual cycles), fewer ovulations, and decreased progesterone production (see Figure: The idealized cyclic changes in pituitary gonadotropins, estradiol (E 2 ), progesterone (P), and uterine endometrium during the normal menstrual cycle.). Double ovulation and luteal out-of-phase (LOOP) events (ie, premature formation of a follicle due to the major surge in FSH during the luteal phase) occur and occasionally cause estradiol levels to be above normal. The number of viable follicles decreases; eventually, the few remaining follicles do not respond, and the ovaries produce very little estradiol. Estrogens are also produced by peripheral tissues (eg, fat, skin) from androgens (eg, androstenedione, testosterone ). However, the total estrogen level is much lower, and estrone replaces estradiol as the most common estrogen.

Around menopause, androstenedione levels decrease by half. The decrease in testosterone , which begins in young adulthood, does not accelerate during menopause because the stroma of the postmenopausal ovary and adrenal gland continue to secrete substantial amounts. Decreased levels of ovarian inhibin and estrogen , which inhibit pituitary release of LH and FSH, result in a substantial increase in circulating LH and FSH levels.

Rapid bone loss occurs during the first 2 yr after estrogen begins to decrease. After this period of rapid bone loss, the age-related rate of bone loss in women is similar to that in men.

Primary ovarian insufficiency (premature ovarian failure—see Premature Ovarian Insufficiency or Failure) is cessation of menses due to noniatrogenic ovarian failure before age 40. Contributory factors are thought to be primarily genetic.

Symptoms and Signs

Changes in the menstrual cycle usually begin during a woman’s 40s, with variation in cycle length. Persistent changes of ≥ 7 days defines early perimenopause. Skipping an entire month (ie, cycle length of 60 days) defines late perimenopause.

The marked fluctuations in estrogen levels may contribute to other perimenopausal symptoms and signs (eg, breast tenderness, changes in menstrual flow, moodiness, exacerbation of menstrual migraines). Symptoms can last from 6 mo to > 10 yr and range from nonexistent to severe.

Vasomotor

Hot flushes (hot flashes, night sweats) due to vasomotor instability affect 75 to 85% of women and usually begin before menses stop. Hot flushes continue for > 1 yr in most women, for > 4 yr in 50%, and for > 12 yr in 10%. Women feel warm or hot and may perspire, sometimes profusely; core temperature increases. The skin, especially of the face, head, and neck, may become red and warm. The episodic flush, which may last from 30 sec to 5 min, may be followed by chills. Flushes may manifest during the night as night sweats. The mechanism of hot flushes is unknown, but they are thought to result from changes in the thermoregulatory center located in the hypothalamus. The range of core body temperatures that is comfortable to the woman decreases; as a result, a very small increase in core body temperature can trigger heat release as a hot flush.

Vaginal

These symptoms include dryness, dyspareunia, and occasionally irritation and itching. As estrogen production decreases, vulvar and vaginal mucosae become thinner, drier, more friable, and less elastic, and vaginal rugae are lost. This vulvovaginal atrophy may also result in dysuria.

Neuropsychiatric

Neuropsychiatric changes (eg, poor concentration, memory loss, depressive symptoms, anxiety) may transiently accompany menopause. Recurrent night sweats can contribute to insomnia, fatigue, irritability, and poor concentration by disrupting sleep.

Other

Menopause is a normal, healthy phase in a woman's life, but each woman has a unique experience. Quality of life may decrease if symptoms are severe or if less common symptoms of menopause, such as joint aches and pains, develop. For some women (eg, those with a history of endometriosis, dysmenorrhea, menorrhagia, premenstrual syndrome, or menstrual migraine), quality of life improves after menopause.

Diagnosis

  • Clinical evaluation

  • Rarely FSH levels

Diagnosis is clinical. Perimenopause is likely if the woman is in the appropriate age range and has some of the symptoms and signs of perimenopause. However, pregnancy should be considered. Menopause is confirmed when a woman has had no menses for 12 mo. Pelvic examination is done; the presence of vulvovaginal atrophy supports the diagnosis. Any abnormal findings are evaluated (see Pelvic Mass : Evaluation).

FSH levels may be measured, but this test is rarely necessary except perhaps in women who have had a hysterectomy and in women who are younger than the usual age of menopause. Consistently elevated levels confirm menopause.

Postmenopausal women who have a high risk of fracture (eg, based on the Fracture Risk Assessment Tool—FRAX FRAX ) and all women > 65 should be screened for osteoporosis (see Osteoporosis : Diagnosis).

Treatment

  • Lifestyle modification

  • Complementary and alternative medicine

  • Hormone therapy

  • Other neuroactive drugs

Treatment is symptomatic (eg, to relieve hot flushes and symptoms due to vulvovaginal atrophy).

Discussing the physiologic causes of menopause and possible symptoms and signs with women helps them manage the changes that occur.

Lifestyle modification

For hot flushes, avoiding triggers (eg, bright lights, comforters, predictable emotional reactions), cooling the environment (eg, lowering the thermostat, using fans) and wearing clothing in layers that can be removed as needed may help.

OTC vaginal lubricants and moisturizers help relieve vaginal dryness. Women should be told that regular sexual intercourse or other vaginal stimulation helps preserve vaginal function.

Complementary and alternative medicine

Black cohosh, other herbal preparations, and OTC products do not appear helpful. Soy protein has been studied with mixed results; however, one soy product, S-equol, has been reported to relieve hot flushes.

Use of regular exercise, paced respirations (a type of slow, deep breathing), or relaxation techniques to reduce hot flushes has had mixed results, although exercise and relaxation techniques may improve sleep. Acupuncture has also had mixed results. In one study, hypnosis appeared to relieve hot flushes and may be recommended to women who want to try it.

Hormone therapy

Hormone therapy (estrogen, a progestin, or both) is the most effective treatment for menopausal symptoms. It is used to relieve moderate to severe hot flushes and, when an estrogen is included, to relieve symptoms due to vulvovaginal atrophy. Hormone therapy improves quality of life for many women by relieving their symptoms but does not improve quality of life for asymptomatic women and is thus not routinely given to postmenopausal women. If hormone therapy is needed to control menopausal symptoms, the lowest dose should be used for the shortest time period. Also, hormone therapy is not recommended for prevention or treatment of chronic disorders (eg, coronary artery disease, dementia, osteoporosis).

For women who have had a hysterectomy , estrogen is used alone. Oral, transdermal (patch, lotion, spray, or gel), or vaginal forms may be used. Treatment should start with the lowest dose; the dose is increased every 2 to 4 wk as needed. Doses vary by preparation. Low doses include 0.3 mg po once/day (conjugated equine or synthetic estrogens), 0.5 mg po once/day (oral estradiol), and 0.025 mg once/day (estradiol patch).

Women who have a uterus should be given a progestin in addition to estrogen because unopposed estrogen increases risk of endometrial cancer. The progestin is taken with estrogen continuously (ie, daily) or sequentially (12 to 14 consecutive days of every 4 wk). The dose of medroxyprogesterone acetate is 2.5 mg for daily use and 5 mg for sequential use. The dose of micronized progesterone (a natural rather than synthetic progesterone) is 100 mg for daily use and 200 mg for sequential use. Bleeding due to progestin withdrawal is less likely with continuous therapy. Combination products of estrogen and a progestin are available as pills (eg, 0.3 mg of conjugated equine estrogens plus 1.5 mg of medroxyprogesterone acetate once/day) or patches (eg, 0.045 mg of estradiol plus 0.015 mg of levonorgestrel once/day).

When the only symptoms are vaginal , low-dose vaginal estrogen therapy is preferred. Topical forms (eg, creams, vaginal tablets or rings) may be more effective for vaginal symptoms than oral forms. Vaginal tablets and rings that contain estradiol in low doses (eg, 10 mcg for tablets, 7.5 mcg for rings) deliver less estrogen to the systemic circulation. Vaginal estrogen should be used at the lowest recommended doses because higher doses can deliver as much estrogen as oral or transdermal therapy and, if given to women who still have a uterus, require the addition of a progestin.

Progestins (eg, medroxyprogesterone acetate 10 mg po once/day or depot 150 mg IM once/mo, megestrol acetate 10 to 20 mg po once/day) are sometimes used alone to relieve hot flushes when estrogen is contraindicated, but they are not as effective as estrogen for hot flushes and do not relieve vaginal dryness. Micronized progesterone can be taken in doses of 100 to 200 mg at bedtime. Drowsiness may occur. Micronized progesterone is contraindicated in women who are allergic to peanuts.

Risks with estrogen therapy and combined estrogen /progestin therapy include

  • Endometrial cancer, mainly if women who have a uterus take estrogen without a progestin

  • Deep vein thrombosis

  • Pulmonary embolism

  • Stroke

  • Breast cancer

  • Gallbladder disease

  • Stress urinary incontinence

Deep vein thrombosis, pulmonary embolism, and stroke are risks with combination therapy or with estrogen alone. The risk of breast cancer begins to increase after 3 to 5 yr of combination therapy. When estrogen is used alone, risk of breast cancer may not increase until after 10 to 15 yr of use. Incidence of gallbladder disease and urinary incontinence may be increased. Risk of all these disorders is low in healthy women who take hormone therapy temporarily, during or shortly after perimenopause. Older postmenopausal women (> 10 yr past menopause) are at higher risk of most of these disorders and may be at risk of coronary artery disease when given combination therapy. The risk of venous thromboembolism may be lower when transdermal estrogen is used.

Estrogen therapy may be contraindicated in women who are at high risk of breast cancer, stroke, coronary artery disease, or thrombosis.

Estrogen therapy has beneficial effects on bone density and reduces the incidence of fractures in postmenopausal women (not particularly those with osteoporosis). Nonetheless, estrogen therapy (with or without a progestin) is not recommended as first-line treatment or as prophylaxis for osteoporosis. When osteoporosis is the only concern, clinicians should consider hormone therapy only if women who are at significant risk of osteoporosis cannot take first-line drugs for osteoporosis (see Osteoporosis : Treatment).

Progestins may have adverse effects (eg, abdominal bloating, breast tenderness, increased breast density, headache, increased low-density lipoprotein, decreased high-density lipoprotein); micronized progesterone appears to have fewer adverse effects. Progestins may increase the risk of thrombosis. There are no long-term safety data for progestins.

Before prescribing hormone therapy, clinicians should discuss its risks and benefits with women

The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene have been used primarily for their antiestrogenic properties and not to relieve menopausal symptoms. However, ospemifene, a SERM, can be used to treat dyspareunia due to vaginal atrophy if women cannot use estrogen or a vaginal drug (eg, if they have severe arthritis) or if they prefer to use an oral drug other than estrogen ; dose is 60 mg po once/day.

Bazedoxifene given with conjugated estrogens can relieve hot flushes and vaginal atrophy. Risk of venous thromboembolism is similar to that of estrogen , but the drug appears to protect the endometrium and potentially the breast. Bazedoxifene is not yet available in the US.

Neuroactive drugs

In well-designed, randomized, controlled trials, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentin have been shown to be moderately effective in reducing hot flushes. However, they are less effective than hormone therapy.

Key Points

  • In the US, menopause occurs at an average age of 51.

  • Symptoms of menopause tend to be maximal during the few years before and the year after menopause (during perimenopause).

  • Consider menopause confirmed if a woman who is an appropriate age and who is not pregnant has not had menses for 12 mo.

  • For vaginal dryness, recommend vaginal stimulation and OTC vaginal lubricants and moisturizers, and if they are ineffective, prescribe low-dose vaginal estrogen creams, tablets, or rings.

  • Before prescribing hormone therapy, talk to women about the risks (eg, deep vein thrombosis, pulmonary embolism, stroke, breast cancer; low risk of gallbladder disease and stress urinary incontinence).

  • If women choose hormone therapy to relieve hot flushes, prescribe estrogen plus, for women with a uterus, a progestin.

  • Consider SSRIs, SNRIs, and gabapentin as less effective alternatives to hormone therapy for relieving hot flushes.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CRINONE
  • DELATESTRYL
  • ESTRADERM, ESTROGEL, VIVELLE
  • MEGACE
  • NOLVADEX
  • MIRENA, PLAN B
  • PROVERA
  • EVISTA
  • NEURONTIN
  • LEVOPHED

* This is a professional Version *