Menopause

Menopause is the permanent cessation of menstruation (diagnosed after 12 months of amenorrhea) and is a normal part of the aging process. Perimenopause, sometimes called the menopausal transition, is characterized by gradually decreasing ovarian function resulting in less frequent menstruation and decreased production of female sex hormones until menstruation ceases altogether (usually between 45 and 56 years of age). Induced menopause (due to surgery and chemotherapy) leads to a swift decline in hormones, with menopause occurring earlier and more rapidly compared to physiological menopause. While menopause is defined as an absence of menstruation, it also leads to multiple other physiological changes because of the decline in sex hormones, leading to significant vasomotor symptoms, changes to the genitourinary tract, and neuropsychiatric symptoms (e.g., mood swings, sleep disturbance). In individuals with a characteristic history (e.g., the typical age of menopause with vasomotor symptoms and amenorrhea), a diagnosis of perimenopause or menopause can be made clinically. Diagnostic tests are reserved for individuals with premature menopause (i.e., before the age of 40 years) or if the clinical history requires the exclusion of alternative diagnoses. Nonpharmacological interventions are recommended for mild symptoms. Pharmacological therapy is used for moderate to severe symptoms that impair quality of life and for patients with premature, early, or induced menopause who are at increased risk for complications of menopause.

The female reproductive period comprises the following phases: ^[1][2][3]

• Premenopause: begins with menarche and ends with the onset of perimenopause
• Perimenopause (also called the menopausal transition): the length of time from the first occurrence of irregular menstruation cycles ; to 12 months after the final menstrual period (FMP) ^[1][2]
  • Fluctuating hormonal levels lead to increasingly infrequent, lighter menstruation and vasomotor symptoms. ^[4][5]
  • Duration: variable; median length 4 years ^[4]
• Menopause: the date of an individual's FMP
  • Retroactively determined after 12 months of complete amenorrhea ^[1][6]
  • Onset: usually from 45–56 years of age (average is 51 years of age); earlier average age in smokers ^[5][6][7][8]
  • Physiological menopause is the normal age-related loss of ovarian function with no other identified cause ^[2]
• Postmenopause: the time after the FMP; the first 12 months are called early postmenopause. ^[1]

Perimenopause begins with the onset of irregular menstrual cycles, includes the date of the FMP (i.e., menopause), and ends after the first year of postmenopause (i.e., early postmenopause). ^[4][5]

The onset and intensity of symptoms depend on the phase of menopause and vary greatly between individuals. Symptoms begin during perimenopause and typically peak during the first 1–2 years of postmenopause. ^[4]

In the US, more intense and longer-lasting vasomotor symptoms are reported for Black individuals than individuals of other racial or ethnic groups. ^[4][5]

In menopausal individuals, estrogen production mainly results from the conversion of adrenal androgens by peripheral aromatase in adipose tissue. The onset of menopause may occur later in individuals with obesity, who have additional estrogen from adipose stores. ^[4][11][16] ; Menopausal HAVOCS: Hot flashes/Heat intolerance, Atrophy of Vagina, Osteoporosis, Coronary artery disease, Sleep impairment.

Induced menopause ^[2][6]

Induced menopause is the permanent loss of ovarian function as a result of medical interventions.

Etiology

• Iatrogenic ovarian ablation (e.g., due to chemotherapy, radiation)
• Surgical menopause: menopause resulting from the removal of both ovaries (i.e., bilateral oophorectomy)

Clinical features ^[14]

• Clinical features of menopause may be more pronounced because of the rapid drop in hormone levels.
• Vasomotor menopause symptoms are more severe and frequent in surgical menopause.

Treatment

• Hormone therapy if patients are below the average age of physiological menopause (∼ 51 years of age). ^[14]
• See also “Treatment of menopause.”

Premature menopause ^[7][14]

Premature menopause is the permanent cessation of ovarian function and menses before the age of 40 years.

Etiology

• Induced menopause
• Primary ovarian insufficiency; (POI): occurs in 1% of women; may be idiopathic ^[6][17]

Clinical features

• Clinical features of menopause
• Patients may also present with infertility, or menstrual cycles that do not resume after stopping hormonal contraception. ^[18]

Diagnostics

• May not be required if the underlying cause is known (e.g., induced menopause)
• If the cause is unknown, diagnostic studies for menopause are recommended.
• Additional workup for POI (e.g., karyotyping) may be required.

Treatment

• Hormonal therapy is recommended to reduce:
  • Symptoms of menopause
  • Risks of early menopause, e.g., increased risk of heart disease, dementia, and increased risk of overall mortality ^[14]
• Consider oral contraceptive use in patients with no contraindications to combined hormonal contraception. ^[14]
• Continue systemic HRT (unless contraindicated) until at least the average age of physiological menopause (∼ 51 years of age). ^[6][7][14]
• See also “Treatment of menopause.”

Early menopause ^[11][14]

• The occurrence of physiological menopause between 40 and 45 years of age with no other identified cause ^[11]
• Affects 5% of women ^[6]
• Clinical features and diagnostics are the same as for older patients.
• Systemic HRT is usually recommended to reduce risks associated with early menopause, e.g.: ^[14]
  • Increased risk of heart disease
  • Dementia
  • Increased risk of overall mortality

Smoking is associated with earlier onset of menopause. ^[4][7][19]

General principles ^[7][11]

• In individuals ≥ 40 years of age, perimenopause and menopause are diagnosed clinically.
• A pelvic examination is usually performed to confirm GSM or evaluate for other causes. ^[9]
• Diagnostic testing is reserved for:
  • Premature menopause
  • Patients with an unreliable menstrual cycle history ^[7]
  • Suspected differential diagnoses of menopause and perimenopause ^[7][11][20]

The effects of oral contraceptives can mask the signs and symptoms of menopause. ^[21]

Supportive studies to confirm menopause ^[1][7][11]

These studies are typically determined by a specialist; there is significant controversy regarding which tests are appropriate. ^[7][11][17]

• FSH: ↑↑; ; however, levels widely fluctuate during perimenopause ^[1][11]
• Estradiol: ↓ ^[1][17]
• Rarely tested for as not routinely recommended: ↓ progesterone; , ↓ inhibin B, and ↓ antimüllerian hormone ^[4][6][22]

If FSH levels are needed to verify menopause in individuals using oral contraceptives, discontinue oral contraceptives at least 2 weeks prior to testing. ^[6][21]

Studies to exclude differential diagnoses of menopause ^[23]

• Pregnancy test: to rule out pregnancy as a cause of amenorrhea ^[7]
• Prolactin: elevated in hyperprolactinemia
• LH: elevated in POI
• TSH: Both hypothyroidism and hyperthyroidism can cause menstrual irregularities.
• Tests for hyperandrogenism: testosterone, dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP)
• Transvaginal ultrasound +/- endometrial sampling if endometrial cancer is suspected ^[24]

Individuals with hyperthyroidism and menopause have similar symptoms. Maintain a low threshold for checking serum TSH in individuals with heat intolerance, irregular menstruation, and disturbed sleep. ^[23]

Studies for complications of menopause

These studies are not routinely part of the menopause workup but if performed, findings may show characteristic changes.

• Lipid panel: ↑ total cholesterol and ↓ HDL are common during menopause
• DXA scan: recommended for all women aged ≥ 65 years and younger women with additional risk factors (see “Screening for osteoporosis”) ^[25][26]
  • May show osteopenia or osteoporosis
  • Significant bone mineral density is lost over a 3-year period around the FMP. ^[27]

The differential diagnoses listed here are not exhaustive.

The information in this section is on the management of physiological menopause in individuals aged > 45 years. For the management of premature menopause, early menopause, and induced menopause, see “Subtypes and variants.”

Approach ^[5][11][14]

• Determine the severity of symptoms and their impact on the patient's quality of life.
• All symptomatic patients: Initiate symptom-specific nonpharmacological interventions for menopause.
• For patients with moderate to severe symptoms, consider adding pharmacological therapy for menopause. ^[7][30]
• For perimenopausal individuals, discuss contraception during perimenopause.
• Screen for and treat associated conditions and/or complications and provide appropriate preventive care.
  • Screen for depression.
  • Educate patients on the increased risk of osteoporosis and heart disease and initiate:
    • Primary prevention of ASCVD
    • Prevention of osteoporosis

Questionnaires, e.g., the menopause-specific quality of life scale, may help to determine the severity of symptoms and guide treatment.

Hormone replacement therapy is not indicated for all patients but should be prescribed for premature menopause, early menopause, and patients with moderate to severe symptoms of menopause. ^[11]

For further information on indications, contraindications, and dosages, see “Pharmacological therapy for menopause.”

Evidence does not support the use of alternative medical therapies for menopause, e.g., soy, black cohosh, omega-3 supplementation, and acupuncture. ^[5][7]

Systemic hormone replacement therapy (HRT) ^[7][11][14]

General principles

• HRT should be titrated to the lowest effective dose. ^{[5][7][11][14]}
• Reevaluate patients on HRT yearly. ^[4]
• Short-term use (< 5 years) may be preferred to reduce the risk of adverse effects (e.g., breast cancer). ^[5][14][34]

Indications ^[7][14]

• Premature menopause, induced menopause, or early menopause
• Moderate to severe vasomotor symptoms affecting quality of life if both criteria are met : ^[11]
  • < 60 years of age
  • Menopausal for < 10 years
• Moderate to severe genitourinary symptoms of menopause ^[14]
• Prevention of osteoporosis in postmenopausal individuals (controversial) ^{[7][11][30][35]}

Multiple medical societies do not recommend systemic HRT solely for the prevention of chronic diseases (e.g., osteoporosis and cardiovascular diseases) in menopausal individuals. ^[7][30]

Options for HRT ^[4][7][14]

• Systemic estrogen hormonal options include oral and transdermal preparations.
• Transdermal preparations may have a lower risk of VTE and cardiovascular disease. ^[7][14]
• Patients without a uterus: estrogen-only HRT
  • Micronized 17β-estradiol ^[5][11]
  • Conjugated estrogen ^[5][11]
  • Transdermal 17β-estradiol gel OR patch ^[5][11]
• Patients with a uterus: estrogen-containing HRT combined with an endometrial protection agent
  • Combined estrogen-progestin HRT preparations, e.g.:
    • Conjugated estrogen/medroxyprogesterone acetate ^[5][11]
    • 17β-estradiol/norethindrone acetate patch or pill ^[7][11]
  • Estrogen PLUS an SERM, e.g., conjugated estrogen PLUS bazedoxifene ^[5][11]
  • Estrogen-only HRT plus a levonorgestrel-releasing IUD (off-label) ^[14]

Unopposed systemic estrogen can increase the risk of endometrial hyperplasia and endometrial cancer. In individuals with a uterus, add an agent that protects the endometrium (e.g., progestins, bazedoxifene). ^[5][14]

Some clinicians prescribe compounded bioidentical hormones; however, these are not FDA-approved and are not recommended by any major societies as there is no evidence they are superior to standard HRT. ^[5][7][14]

Contraindications to HRT ^[7][14]

• Unexplained vaginal bleeding
• Estrogen-sensitive cancer (e.g., endometrial or breast cancer)
• Chronic liver disease
• Current or prior DVT, stroke, thromboembolic disease, or thrombophilia
• Coronary artery disease or myocardial infarction

Adverse effects ^[14]

• Serious: thromboembolic events, estrogen-sensitive cancer (e.g., endometrial cancer, breast cancer) ^[14][34]
• Common: mood swings, headache, gastrointestinal upset (e.g., nausea, bloating), weight gain, retained fluid, breast pain, breakthrough bleeding
• Other: stress urinary incontinence, gallbladder disease

Vaginal hormone therapy ^[7][9][14]

Vaginal hormone therapy is indicated for moderate to severe genitourinary symptoms of menopause.

Options

• Estrogen-based intravaginal treatments ; ^[5][9][11]
  • Creams, e.g., conjugated estrogen OR estradiol ^[7][9]
  • Gel capsules, e.g., estradiol ^[7][9]
  • Rings, e.g., estradiol ^[7][9]
• Intravaginal DHEA, i.e., vaginal prasterone ^[7][9][14]

Contraindications ^[9]

• Undiagnosed vaginal bleeding
• Estrogen-sensitive cancers (e.g., endometrial or breast cancer) ^[9]
• History of a prior thromboembolic event ^[7]
• Liver disease ^[7]

In consultation with oncology, low-dose vaginal estrogen may be considered in individuals with a history of breast cancer. ^[9][14][31]

Adverse effects ^[9]

• Risk of estrogen-sensitive cancers and thromboembolic events; however, risk is lower than for systemic HRT ^[9]
• Vaginal discharge, candidiasis, or bleeding

As low-dose vaginal estrogen is generally not associated with endometrial hyperplasia, additional progestin is typically not added for endometrial protection. However, patients should be advised to immediately report any vaginal bleeding. ^[5][7][14]

Nonhormonal therapy ^[5][9][31]

Indications

• Alternative treatment for patients who decline, or have contraindications to, HRT
• Second-line treatment for moderate to severe menopausal symptoms

Options

• Vasomotor symptoms
  • Fezolinetant
  • Paroxetine ^[5][7][21]
  • Gabapentin (off-label) ^[5]
  • Clonidine (off-label) ^[5]
• Genitourinary symptoms: a SERM, e.g., ospemifene ^{[5][7][9][21]}
• Benign hirsutism: antiandrogen therapy ^[6][36]

• Ovulation can still occur until the FMP. ^[4][37]
• Discuss the risks and benefits of continuing hormonal contraception until menopause is confirmed. ^[38]
  • Benefits
    • Pregnancy prevention
    • Oral contraceptives can also alleviate symptoms of perimenopause.
    • Patients using a hormonal IUD can use estrogen-only HRT to manage perimenopausal symptoms. ^[14]
  • Risks
    • Some adverse effects of combined hormonal contraception are more common in older individuals (e.g., VTE, cardiovascular events).
    • Contraceptive use may mask menopause.
• Options: any form of contraception, unless contraindicated ^[6][7][14]
• Continue contraception until pregnancy is unlikely, e.g.: ^[21]
  • Once individuals are older than the average age of menopause (i.e., 51 years of age) ^[7][21][37]
  • Patients using nonhormonal contraception: no occurrence of menstrual cycles for 12 months ^[6]
  • Patients using hormonal contraception: if FSH levels taken ≥ 2 weeks after discontinuing oral contraceptives indicate menopause (unreliable) ^[21]

• Coronary artery disease
  • Estrogen exerts protective effects on the cardiovascular system. ^[39]
  • Menopause is associated with increased triglycerides, LDL, weight gain, and hypertension. ^[8]
• Osteoporosis: Decreased circulating estrogen impairs bone formation. ^[4]

Associated conditions

• Postmenopausal bleeding
  • Vaginal bleeding after menopause requires evaluation to rule out malignancy. ^[40]
  • See “Approach to postmenopausal bleeding” for details.
• Unplanned pregnancy: Ovulation, though infrequent, still occurs during perimenopause (see also “Contraception during perimenopause”. ^[4]

We list the most important complications. The selection is not exhaustive.

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