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Menopause

By

JoAnn V. Pinkerton

, MD, University of Virginia Health System

Last full review/revision Dec 2019| Content last modified Dec 2019
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Menopause is physiologic or iatrogenic cessation of menses (amenorrhea) due to decreased ovarian function. Manifestations may include hot flushes, night sweats, sleep disruption, and genitourinary syndrome of menopause (symptoms and signs due to estrogen deficiency, such as vulvovaginal atrophy). Diagnosis is clinical: absence of menses for 1 year. 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 52. 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 year after the last menses. It is typically the most symptomatic phase because hormones are fluctuating.

The menopausal transition refers to the years in perimenopause that lead up to the last menses; it is characterized by changes in the menstrual pattern and is divided into early and late stages (see table Stages of Menopause). The menopausal transition lasts 4 to 8 years; it lasts longer in women who smoke and in women who were younger at onset of menopausal transition (1).

Postmenopause refers to the time after the last menstrual period; it is also divided into early and late stages.

Table
icon

Stages of Menopause

Feature

Early Menopausal Transition

Late Menopausal Transition

Early Postmenopause

Late Postmenopause

Duration

Variable

1–3 years

2 years

3–6 years

Until death

Menstrual cycle

Variable length (a persistent difference of ≥ 7 days in the length of consecutive cycles)

Interval of amenorrhea that lasts ≥ 60 days

FSH level on cycle days 2–5

High but variable

High (> 25 IU/L)

High but variable

Stabilizes*

Symptoms

Vasomotor symptoms likely to occur

Vasomotor symptoms most likely to occur

Symptoms of genitourinary syndrome of menopause

* FSH levels increase until about 2 years after the last menstrual period, then stabilize.

FSH = follicle-stimulating hormone.

Adapted from Harlow SD, Gass M, Hall JE, et al: For the STRAW 10 Collaborative Group: Executive summary of the Stages of Reproductive Aging Workshop + 10: Addressing the unfinished agenda of staging reproductive aging. Menopause 19 (4):387–395, 2012.

General reference

  • 1. Paramsothy P, Harlow SD, Nan B, et al: Duration of the menopausal transition is longer in women with young age at onset: The multi-ethnic Study of Women's Health Across the Nation. Menopause 24 (2):142–149, 2017. doi: 10.1097/GME.0000000000000736.

Physiology

As ovaries age, their response to the pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) decreases, initially causing the following:

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 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 gradually decreases during the 5 years after menopause, 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.

Premature ovarian failure (primary ovarian insufficiency) is cessation of menses due to noniatrogenic ovarian failure before age 40. Contributory factors are thought to be primarily genetic or autoimmune.

Symptoms and Signs

Changes in the menstrual cycle usually begin during a woman’s 40s, with variation in cycle length. A persistent difference in consecutive menstrual cycle length of ≥ 7 days defines early menopausal transition. Skipping ≥ 2 cycles defines late menopausal transition.

The marked fluctuations in estrogen levels may contribute to other perimenopausal symptoms and signs such as

  • Breast tenderness

  • Changes in menstrual flow

  • Moodiness

  • Exacerbation of menstrual migraines

Symptoms can last from 6 months to > 10 years 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. Vasomotor symptoms last an average of 7.4 years and can persist for > 10 years in some groups of women (1).

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 seconds to 5 minutes, 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

Vaginal 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.

Genitourinary syndrome of menopause includes symptoms and signs due to estrogen and androgen deficiency such as

  • Vulvovaginal atrophy

  • Urinary urgency

  • Dysuria

  • Frequent urinary tract infections

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.

Cardiovascular

After menopause, levels of low-density lipoprotein (LDL) cholesterol increase in women. Levels of high-density lipoprotein (HDL) cholesterol remain about the same as before menopause. The change in LDL levels may partly explain why atherosclerosis and thus coronary artery disease become more common among women after menopause. However, whether these changes result from aging or from the decrease in estrogen levels after menopause is unclear. Until menopause, the high estrogen levels may protect against coronary artery disease.

Musculoskeletal

Up to 20% of bone density loss occurs during the first 5 years after menopause. After this period of rapid bone loss, the age-related rate of bone loss in women is similar to that in men.

Other symptoms

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.

Symptoms and signs reference

  • 1. Avis NE, Crawford SL, Greendale G, et al: Duration of menopausal vasomotor symptoms over the menopause transition (Study of Women's Health Across the Nation). JAMA Intern Med 175 (4):531–539, 2015. doi: 10.1001/jamainternmed.2014.8063.

Diagnosis

  • Clinical evaluation

  • Rarely FSH levels

Diagnosis of menopause 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 months.

Pelvic examination is done; the presence of vulvovaginal atrophy supports the diagnosis. Any abnormal findings (eg, pelvic masses) are evaluated.

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.

The following postmenopausal women should be screened for osteoporosis:

Treatment

  • Lifestyle modification

  • Complementary and alternative medicine

  • Hormone therapy

  • Neuroactive drugs

Treatment of menopause is symptomatic (eg, to relieve hot flushes and symptoms due to vulvovaginal atrophy). Treatment may also include prevention of bone loss.

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

Hormone therapy (eg, estrogen, a progestogen, or both) is the most effective treatment for menopausal symptoms.

Nonpharmacologic options shown to be effective in randomized trials for the treatment of vasomotor symptoms include cognitive-behavioral therapy and hypnosis (1)

Lifestyle modification

For hot flushes, the following may help:

  • Avoiding triggers (eg, spicy food, bright lights, comforters, predictable emotional reactions)

  • Cooling the environment (eg, lowering the thermostat, using fans)

  • Wearing clothing in layers that can be removed as needed may help

  • Exercise and weight loss (2, 3)

Over-the-counter vaginal lubricants and moisturizers help relieve vaginal dryness. Regular sexual intercourse or other vaginal stimulation helps preserve vaginal function.

Complementary and alternative medicine

Black cohosh, other herbal preparations, and over-the-counter 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), mindfulness, or relaxation techniques to reduce hot flushes have had mixed results, although exercise, yoga, and relaxation techniques may improve sleep. Acupuncture has also had mixed results.

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. A low dose (7.5 mg once a day) of paroxetine (a selective serotonin-reuptake inhibitor) is the only approved nonhormone therapy used specifically for hot flushes. However, all of these drugs are less effective than hormone therapy.

Emerging therapies

Other therapies that may be useful include the anticholinergic drug oxybutynin, stellate ganglion blockade, and neurokinin B antagonists (4, 5).

Treatment references

  • 1. Nonhormonal management of menopause-associated vasomotor symptoms: Nonhormonal 2015 position statement of The North American Menopause Society. Menopause 22 (11):1155–1172; quiz 1173–1174, 2015. doi: 10.1097/GME.0000000000000546.

  • 2. Thurston RC, Ewing LJ, Low CA, et al: Behavioral weight loss for the management of menopausal hot flashes: A pilot study. Menopause 22 (1):59–65, 2015. doi: 10.1097/GME.0000000000000274.

  • 3. Bailey TG, Cable NT, Aziz N, et al: Exercise training reduces the frequency of menopausal hot flushes by improving thermoregulatory control. Menopause 23 (7):708–718, 2016. doi: 10.1097/GME.0000000000000625.

  • 4. Rahimzadeh P, Imani F, Nafissi N, et al: Comparison of the effects of stellate ganglion block and paroxetine on hot flashes and sleep disturbance in breast cancer survivors. Cancer Manag Res 10:4831–4837, 2018. doi: 10.2147/CMAR.S173511. eCollection 2018.

  • 5. Prague JK, Roberts RE, Comninos AN, et al: Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet 389 (10081):1809–1820, 2017. doi: 10.1016/S0140-6736(17)30823-1. Epub 2017 Apr 3.

Hormone Therapy

Hormone therapy ( estrogen, a progestogen, or both) is the most effective treatment for menopausal symptoms (1). 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, clinicians should determine the most appropriate type, dose, route of administration, and duration, based on goals of treatment and individual health risks. Potential benefits and harms due to hormone therapy should be periodically reevaluated.

For women who are < 60 years old or < 10 years past menopause onset, potential benefits of hormone therapy are most likely to exceed potential harms. If such women are at risk of bone loss or fracture, hormone therapy reduces bone loss and incidence of fractures and can be used in women who are not candidates for first-line drugs for osteoporosis.

Starting hormone therapy in women who are > 60 years old or > 10 to 20 years past menopause onset is not recommended. In these women, potential harms of hormone therapy (eg, coronary artery disease, stroke, venous thromboembolism, dementia) are likely to exceed potential benefits.

Unless the clinical recommendation is clear, shared decision is recommended because of the following:

  • Potential benefits and harms of hormone therapy can be complicated.

  • The net benefit and harm can be marginal.

  • Health risks may change over time.

Choice of hormone therapy

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 weeks as needed. Doses vary by preparation. Low doses include

  • 0.3 mg orally once a day (conjugated equine or synthetic estrogens)

  • 0.5 mg orally once a day (oral estradiol)

  • 0.025 to 0.375 mg a day released by a patch applied to the skin once or twice a week (estradiol patch)

Women who have a uterus should be given a progestogen in addition to estrogen because unopposed estrogen increases risk of endometrial cancer. The progestogen is taken with estrogen continuously (ie, daily) or sequentially (12 to 14 consecutive days of every 4 week). The dose is

  • Medroxyprogesterone acetate: 2.5 mg for daily use and 5 mg for sequential use

  • Micronized progesterone (a natural rather than synthetic progesterone): 100 mg for daily use and 200 mg for sequential use

Bleeding due to progestogen withdrawal is less likely with continuous therapy, although irregular bleeding can occur during the first 6 months of therapy.

Combination products of estrogen and a progestogen are available as

  • Pills (eg, 0.3 mg of conjugated equine estrogens plus medroxyprogesterone acetate 1.5 mg once a day; norethindrone acetate 0.1 mg plus estradiol 0.5 mg or 1 mg once a day; estradiol 1 mg plus progesterone 100 mg once a day; estradiol 1 mg plus drospirenone 0.5 mg once a day; estradiol 0.5 mg plus drospirenone 0.25 mg once a day)

  • Patches (eg, estradiol 0.045 mg plus levonorgestrel 0.015 mg a day released by a patch applied to the skin once a week, estradiol 0.05 mg plus norethindrone acetate 0.14 mg or 0.25 mg a day released by a patch applied twice a week.).

An alternative is combination conjugated estrogen/bazedoxifene (a selective estrogen receptor modulator [SERM] that protects the uterus without the need for a progestogen). Benefits of conjugated estrogen/bazedoxifene include a lower incidence of breast tenderness and bleeding than with other forms of hormone therapy; incidence is similar to that with placebo. Breast density and incidence of breast cancer did not increase in women who were followed for 2 years (2). Conjugated estrogen/bazedoxifene can relieve hot flushes, improve sleep, prevent bone loss, and lessen symptoms of vaginal atrophy. Risk of venous thromboembolism is similar to that with estrogen, but conjugated estrogen/bazedoxifene appears to protect the endometrium and potentially the breast. Bazedoxifene as a single drug is not available in the US.

When the only symptoms are vaginal, low-dose vaginal estrogen therapy is preferred. Topical forms (eg, creams; vaginal tablets, suppositories, or rings) may be more effective for vaginal symptoms than oral forms. Vaginal tablets, suppositories, or rings that contain estradiol in low doses (eg, 10 mcg for tablets, 7.5 mcg for rings, 4 mcg and 10 mcg for vaginal suppositories) deliver less estrogen to the systemic circulation. When vaginal estrogen is used at the lowest recommended doses, a progestogen is not needed. Higher doses of vaginal estrogen 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 progestogen. Any vaginal bleeding in women taking hormonal therapy should be immediately evaluated to rule out endometrial cancer.

Newer therapies for dyspareunia include

  • A SERM (eg, oral ospemifene)

  • Intravaginal dehydroepiandrosterone (DHEA)

DHEA may relieve vaginal dryness and other symptoms of vaginal atrophy; it is available and effective for relief of dyspareunia due to menopause and is under study as treatment for sexual dysfunction in women (3).

Progestogens (eg, medroxyprogesterone acetate 10 mg orally once a day or depot 150 mg IM once a month, megestrol acetate 10 to 20 mg orally once a day, progesterone 300 mg nightly) 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 300 mg at bedtime. Drowsiness may occur. Micronized progesterone in peanut oil is contraindicated in women who are allergic to peanuts. Newer combination products do not contain peanut oil.

Estrogen therapy has beneficial effects on bone density and reduces the incidence of fractures in postmenopausal women (not particularly those with osteoporosis). In one large study, hormone therapy reduced the incidence of fractures by 24%.(4). Nonetheless, estrogen therapy (with or without a progestogen) is usually not recommended as first-line treatment or as prophylaxis for osteoporosis. When osteoporosis or prevention of osteoporosis is the only concern, clinicians should consider starting hormone therapy if the following apply:

Risks and adverse effects

Risks with estrogen therapy or combined estrogen/progestogen therapy include

The risk of endometrial cancer is higher in women who have a uterus and are given unopposed estrogen therapy. Nevertheless, any vaginal bleeding in a woman on hormonal therapy should immediately be evaluated to rule out endometrial cancer.

The risk of breast cancer begins to increase after 3 to 5 years of combination therapy when the standard dose (eg, conjugated estrogen 0.625 mg and medroxyprogesterone acetate at 2.5 mg once/day) is used. When estrogen is used alone, risk of breast cancer was slightly lower at 7 years in the Women's Health Initiative study, but this benefit appears to disappear after 10 to 15 years of use. The risk of venous thromboembolism and stroke may be lower when low-dose transdermal estrogen is used. Older postmenopausal women (> 10 years past menopause or > 60 years old when they start hormone therapy) are at higher risk of coronary artery disease and dementia when they are given combination therapy. Incidence of gallbladder disease and urinary incontinence may be increased. Risk of all these disorders is very low in healthy women who take hormone therapy for a short time after menopause.

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

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

Before prescribing hormone therapy and periodically as therapy continues, clinicians should discuss its risks and benefits with women.

Selective estrogen receptor modulators (SERMS)

The 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 orally once a day (5). In women who have recently been taking hormone therapy, hot flushes may temporarily increase, but in most women, hot flushes resolve after about 6 weeks.

Bazedoxifene is given with conjugated estrogens; it can relieve hot flushes, improve sleep, prevent bone loss, and lessen symptoms of vaginal atrophy. Risk of venous thromboembolism is similar to that of estrogen, but conjugated estrogen/bazedoxifene appears to protect the endometrium and potentially the breast. Bazedoxifene as a single drug is not available in the US.

Hormone therapy references

  • 1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel: The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 24 (7):728–753, 2017. doi: 10.1097/GME.0000000000000921.

  • 2. Pinkerton JV, Pickar JH, Racketa J, et al: Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric 15 (5):411–418, 2012. doi: 10.3109/13697137.2012.696289.

  • 3. Labrie F, Archer DF, Koltun W, et al: Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause 23 (3):243–256, 2016. doi: 10.1097/GME.0000000000000571.

  • 4. 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 288 (3):321–333, 2002.

  • 5. Constantine G, Graham S, Portman DJ, et al: Female sexual function improved with ospemifene in postmenopausal women with vulvar and vaginal atrophy: Results of a randomized, placebo-controlled trial. Climacteric 18 (2): 226–232, 2015.

Key Points

  • In the US, menopause occurs at an average age of 52.

  • Symptoms of menopause tend to be maximal during the few years before and the year after menopause (during perimenopause), except for symptomatic vulvovaginal atrophy, which may worsen over time.

  • Up to 20% of bone density loss occurs during the first 5 years after menopause, followed by age-related rate of bone loss similar to that in men.

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

  • For vaginal dryness or dyspareunia due to menopause, recommend vaginal stimulation and OTC vaginal lubricants and moisturizers, and if they are ineffective, consider low-dose vaginal estrogen creams, tablets, suppositories, or rings; other options include oral ospemifene or intravaginal DHEA suppositories.

  • Before prescribing hormone therapy and periodically as therapy continues, talk to women about the potential benefits and harms (eg, deep venous thrombosis, pulmonary embolism, stroke, breast cancer; low risk of gallbladder disease, stress urinary incontinence); potential harms are greater for women who start hormone therapy after age 60 or who are > 10 to 20 years past menopause onset.

  • If women choose hormone therapy to relieve hot flushes, prescribe estrogen plus, for women with a uterus, a progestogen or prescribe conjugated estrogen/bazedoxifene.

  • Individualize treatment with hormone therapy to maximize benefits and minimize harms, and periodically reevaluate benefits and harms; low-dose transdermal hormone therapy may have less risk of deep venous thrombosis and stroke.

  • Consider SSRIs, SNRIs, and gabapentin as less effective alternatives to hormone therapy for relieving hot flushes; paroxetine 7.5 mg is the only nonhormone drug approved in the US for relief of hot flushes.

  • Effective nonpharmacologic options include cognitive-behavioral therapy and hypnosis.

Drugs Mentioned In This Article

Drug Name Select Trade
PROVERA
MIRENA, PLAN B
LEVOPHED
AYGESTIN, CAMILA
CRINONE
EVISTA
PAXIL
DITROPAN XL
NEURONTIN
ESTRADERM, ESTROGEL, VIVELLE
Estrogens
NOLVADEX
MEGACE
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