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    Perimenopause and Menopause

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    Sep.06.2023

    Perimenopause and Menopause

    Synopsis

    Key Points

    • Perimenopause is the interval preceding menopause until 12 months after last menstrual period which is characterized by irregular menstrual cycles; menopause is permanent cessation of menses (determined retrospectively)
    • Most common symptoms of perimenopause and menopause include menstrual cycle irregularity (perimenopause) or cessation (menopause) and vasomotor symptoms
    • Diagnosis of perimenopause and menopause is based on history of menstrual cycles and symptoms of hypoestrogenism; laboratory studies are usually unnecessary
    • Menopausal hormone therapy has complex profile of risks and benefits, which varies by component and route
    • Focus treatment of perimenopause on alleviating symptoms and provision of contraception, if needed; long-term use of hormone therapy for chronic disease prevention is not warranted
    • Complications of menopause include bone loss and cardiovascular disease
    • Treatment of symptoms secondary to hypoestrogenism does not alter prognosis. Rather, preventing and treating age-related medical conditions improve quality of life in postmenopausal patients

    Pitfalls

    • Perimenopausal patients who are sexually active, fertile, and do not want to become pregnant require reliable contraception
    • Unlike vasomotor symptoms, vulvovaginal atrophy does not improve over time without treatment
    • Menopausal hormone therapy is effective for reversing changes and symptoms of the genitourinary syndrome of menopause
    • Patients with an intact uterus require progestogen therapy in addition to estrogen therapy to prevent endometrial hyperplasia and cancer
    • OTC herbal formulations (eg, soy, phytoestrogens, black cohosh) are ineffective for treating vasomotor symptoms r1r2
    • Avoid paroxetine in females who are taking tamoxifen, because it interferes with metabolism of tamoxifen to its metabolite, endoxifen

    Terminology

    Clinical Clarification

    • Perimenopause (menopausal transition) is the variable period during which females undergo physiologic and endocrinologic changes as they traverse the reproductive years through the postmenopausal years r3r4
      • Begins with the onset of menstrual irregularities and ends at menopause, after 1 year of amenorrhea has occurred
      • There are two stages: early transition, where cycles are still mostly regular; and late transition, where amenorrhea becomes prolonged for at least 60 days r5
      • Duration is variable; on average lasts 4 to 5 years r4r6
    • Menopause is the permanent cessation of menses due to loss of ovarian follicular activity
      • Determined retrospectively after cessation of menses for 12 months in a previously cycling patient with no other obvious pathologic or physiologic cause
    • Primary ovarian insufficiency is loss of ovarian function before age 40 years r7
      • Typically has waxing and waning course
      • Usually treated as synonymous with premature or early menopause, although potential still exists for menses to resume, conception to happen, and pregnancy to occur. During the first 12 months, it is not definitively known whether amenorrhea represents menopause; therefore, in most patients, distinction between primary ovarian insufficiency and premature/early menopause is made in retrospect r8

    Classification

    • Stages of Reproductive Aging Workshop + 10 staging system r5
      • Late reproductive stage (stage −3)
        • Stage −3b: menstrual cycles remain regular without change in length or early follicular phase follicle-stimulating hormone levels. Antimüllerian hormone and antral follicle counts are low
        • Stage −3a: menstrual cycles are shortening
        • Symptoms typical of the menopause transition are common during this time, even before significant variation in cycle length r9
      • Early menopausal transition (stage −2)
        • Increased variability in menstrual cycle length, defined as persistent difference of 7 days or more in length of consecutive cycles
        • Variable early follicular phase follicle-stimulating hormone levels and low antimüllerian hormone levels and antral follicle counts
      • Late menopausal transition (stage −1)
        • Amenorrhea for 60 days or more
        • Follicle-stimulating hormone level greater than 25 units/L in random blood draw is characteristic
        • Stage is estimated to last, on average, 1 to 3 years
      • Menopause
        • Anchor point of 12 months of amenorrhea after last menstrual period
      • Early postmenopause (stages +1a, +1b, +1c)
        • Stage +1a: marks end of 12 months of amenorrhea required to confirm final menstrual period has occurred; marks end of perimenopause
        • Stage +1b: includes remainder of period of rapid changes in both mean follicle-stimulating hormone and estradiol levels
        • Stage +1c: period of stabilization of both high follicle-stimulating hormone and low estradiol levels; estimated to last 3 to 6 years
      • Late postmenopause (stage +2)
        • Further changes in reproductive endocrine function are more limited and processes of somatic aging take precedence

    Diagnosis

    Clinical Presentation

    History

    • Most common symptoms r10
      • Vasomotor symptoms (including hot flashes and night sweats) c1c2
        • Hot flashes manifest as sudden sensation of heat centered on upper chest and face
        • Occur in up to 85% of postmenopausal patients and up to 55% of perimenopausal patients; typically occur daily r10
        • Most bothersome symptoms begin about 1 year before final menstrual period r11
        • Average duration is approximately 4 to 5 years but for nearly a quarter of females will last up to 10 years r6r12
      • Changes in length of and intervals between menstrual cycles r13c3
      • Sleep disorders (eg, insomnia, nighttime waking, early waking) r14c4c5
      • Genitourinary syndrome of menopause combines vulvovaginal atrophy and urinary tract dysfunction r15r16c6c7c8
        • Occurs in at least 25% of patients and includes:
          • Vaginal dryness r17c9
          • Dyspareunia c10
          • Spotting or bleeding after intercourse c11
          • Bladder symptoms
            • Dysuria c12
            • Urinary frequency or urgency c13c14
            • Incontinence c15
          • Predisposition to urinary tract infection r15r16
      • Mood changes r18
        • Depressive symptoms (45%-68% of perimenopausal females report elevated depressive symptoms) r19c16
        • Anxiety c17
    • Menstrual history r20
      • Menstrual cycle changes in a patient in their 30s through 50s suggest perimenopause c18
      • Amenorrhea for 12 months or more in a patient in their 40s through 50s suggests postmenopause c19
    • Other symptoms reported by perimenopausal patients for which there is an uncertain relationship with hormonal changes of menopause include: r10
      • Decline in cognitive function c20
      • Arthralgias and myalgias c21c22
      • Changes in body composition and shape c23
      • Increased skin wrinkling c24
      • Frailty c25

    Physical examination

    • Perimenopause r10r21c26
      • Physical and pelvic examination results are normal
    • Postmenopause r10
      • Most notable changes on general physical examination are cutaneous thinning and weight gain c27c28
      • Characteristic findings on pelvic examination include:
        • Thinning of vaginal epithelial lining c29
        • Erythema of vaginal mucosa c30
        • Loss of vaginal mucosa rugation c31
        • Decrease in ovary size (nonpalpable ovaries on abdominopelvic examination) c32
        • Decrease in uterine size c33

    Causes and Risk Factors

    Causes

    • Naturally occurring perimenopause and menopause are caused by ovarian follicular depletion and, ultimately, gametogenic failure r22c34
    • Pharmacologically and surgically induced menopause
      • Pharmacologically induced menopause, through gonadotropin suppression, is transient c35
      • Surgical menopause, through bilateral oophorectomy, is permanent c36

    Risk factors and/or associations

    Age
    • Median age at natural menopause is 52 years r23c37
    • Median age at onset of perimenopause is 47 years r4c38
    Genetics
    • Genetic factors strongly influence age at which natural menopause occurs c39
    • Strong correlation in age at natural menopause is observed between mothers and daughters, with heritability rates around 50% r24
    • Genome-wide association studies have identified 17 genetic loci influencing age at natural menopause; however, alterations at these loci account for only a small fraction of heritability r25
      • Most significant study findings include single nucleotide polymorphisms at loci of 4 genes: MCM8, BRSK1, UIMC1, and SYPC2L
    • Large-scale genomic analyses have identified genetic variants involved in hypothalamic signaling, breast cancer susceptibility via BRCA1, and DNA damage response, with biologically plausible roles that could affect timing of menopause r26
    • FMR1-related primary ovarian insufficiency can result in premature menopause r27
    Ethnicity/race
    • Black and Hispanic females reach menopause at younger age than females of other ethnicities
    Other risk factors/associations
    • Menopause begins approximately 1.5 to 2 years earlier in cigarette smokers r28r29
    • Higher BMI is associated with later onset of menopausal transition r30

    Diagnostic Procedures

    Primary diagnostic tools

    • Perimenopause and menopause are diagnosed by assessing menstrual cycle patterns and longitudinal symptoms of hypoestrogenism (eg, vasomotor symptoms, genitourinary changes, sleep disturbance, mood changes) r18c40
      • Menopause itself is a clinical diagnosis retrospectively assigned based on menses stopping for at least 12 months
      • Recent disruption in menstrual pattern and symptoms of hypoestrogenemia in a female older than 45 years suggest start of menopausal transition
      • Evaluate patients younger than 40 years who have signs and symptoms of menopause or menopausal transition for primary ovarian insufficiency
    • Laboratory studies can support diagnosis of menopause, but they are seldom useful and are not typically ordered r31
      • Sex steroids, gonadotropins, inhibin B, and antimüllerian hormone measurements do not further inform diagnosis and do not indicate precisely when final menstrual period will occur
      • Patients older than 45 years who have experienced 12 months of amenorrhea can be considered to be menopausal without requiring laboratory studies
        • Although epidemiologic trend toward elevated follicle-stimulating hormone and decreased estradiol levels as people progress through menopausal transition exists, measurements of follicle-stimulating hormone, inhibin B, and estradiol levels are unreliable markers of menopausal status on an individual level r32
      • For patients aged 40 to 45 years with signs and symptoms of menopause or menopausal transition, basic laboratory testing to exclude nonmenopausal causes of oligomenorrhea include serum β-hCG, TSH, and prolactin

    Laboratory

    • The following laboratory findings may support—but are not considered diagnostic of—perimenopause or menopause. In most situations, these tests are not ordered because diagnosis is clinical, but they could be obtained to help clarify an uncertain clinical diagnosis:
      • Estradiol (decreased) c41
      • Inhibin B (decreased) c42
      • Follicle-stimulating hormone (increased) c43

    Differential Diagnosis

    Most common

    • Pregnancy c44
      • Rule out pregnancy by measuring β-hCG in amenorrheic patients of reproductive age who are not using reliable form of contraception
    • Thyrotoxicosis c45
      • Clinical state induced by excess circulating thyroid hormones
      • Symptoms similar to vasomotor symptoms of menopause include hyperhidrosis and heat intolerance. Other symptoms common to both thyrotoxicosis and perimenopause are menstrual cycle irregularity and anxiety
      • Hyperthyroidism due to Graves disease most often has physical examination findings of diffusely enlarged thyroid gland and occasional signs of ophthalmopathy (eg, proptosis, conjunctival injection, lid lag) d1
      • Distinguish from menopausal transition or menopause with thyroid function tests, beginning with TSH level
        • TSH level falls below lower reference limit in hyperthyroid states but is within reference range in perimenopausal and postmenopausal patients
    • Hyperprolactinemia r33c46
      • State of excess circulating prolactin; common cause of amenorrhea
      • Occurs in several pathologic pituitary conditions or can be induced by drugs in several classes, including antipsychotics, antidepressants, and H₂ receptor antagonists r34
      • Presenting symptoms can include galactorrhea or headache; the latter is observed in presence of mass caused by pituitary adenoma
      • Differentiate with prolactin level, which is within reference range in perimenopausal and postmenopausal patients
    • Primary ovarian insufficiency (premature ovarian failure, premature menopause) r7c47
      • Irregular menstrual cycles in patients younger than 40 years (loss of menstrual regularity for 3 or more consecutive months)
      • May be accompanied by hypoestrogenic symptoms (eg, hot flashes, night sweats, sleep disruption, mood disorders, vaginal dryness) but are often unrecognized leading to a delay in diagnosis and treatment
      • Increases risk of cognitive impairment or dementia, parkinsonism, mood disorders, osteoporosis, coronary heart disease, and early mortality r35
      • Negative β-hCG level is mandatory to exclude pregnancy
      • Elevated levels of follicle-stimulating hormone (greater than 20 units/L) with low estradiol levels (less than 30 pg/mL) on 2 occasions (at least 4-6 weeks apart) are consistent with diagnosis of primary ovarian insufficiency
      • Hormone therapy is recommended in absence of contraindications to manage symptoms, protect against bone loss and fracture, and possibly for reduction of risk of cognitive impairment and for cardiovascular benefit r7r35

    Differential diagnosis for hot flashes

    • Pheochromocytoma r36c48
      • Rare adrenal medullary tumor secreting catecholamine or catecholamine metabolites, causing spells of palpitations, diaphoresis, and headache
      • Sustained or paroxysmal hypertension is an essential feature of pheochromocytoma
      • Biochemical diagnosis of pheochromocytoma is made with demonstration of elevated levels of plasma-free metanephrines or urinary fractionated metanephrines. In straightforward menopause, these levels are within reference range
    • Carcinoid syndrome r37c49d2
      • Carcinoids are well-differentiated neuroendocrine tumors arising in gastrointestinal tract. Carcinoid syndrome is caused by release of vasoactive amines into systemic circulation and occurs in about 20% of patients with carcinoid tumors
      • Symptomatic carcinoids have some features similar to those of menopause, including facial flushing and warmth; diarrhea, abdominal pain, and rash are other distinctive symptoms
      • Differentiated by elevated levels of 24-hour urinary 5-hydroxyindoleacetic acid and plasma chromogranin A
    • Systemic mastocytosis r38c50
      • Mast cell accumulation and infiltration in 1 or more internal organs, leading to highly variable symptoms of flushing, hives, urticaria, angioedema, itching, nasal congestion, shortness of breath, chest tightness, nausea, vomiting, diarrhea, migraine headache, difficulty concentrating, or loss of memory
      • Hypotension, tachypnea, and tachycardia are common signs
      • Differentiated by elevated serum tryptase level initially; screening for KIT variant in peripheral blood, followed by bone marrow biopsy, is ultimately required to establish diagnosis

    Treatment

    Goals

    • Relieve menopausal symptoms

    Disposition

    Recommendations for specialist referral

    • Peri- and postmenopausal care can be managed by primary care physicians or gynecologists
    • Refer patients with symptoms recalcitrant to standard therapy to either a gynecologist, a general or reproductive endocrinologist, or a female's health specialist

    Treatment Options

    Short-term therapy for treatment of menopausal symptoms

    • Risk-benefit assessment is the most important consideration when deciding whether to prescribe pharmacotherapy and whether to use menopausal hormone therapy or nonhormone therapy r39r40
    • Menopausal symptoms that can be managed or improved with pharmacotherapy
      • Vasomotor symptoms
        • Hormone therapy improves menopausal symptoms in both perimenopausal and postmenopausal patients
          • Dose-response efficacy observed, such that higher doses are associated with greater reductions in hot flashes r41
            • Overall frequency reduced by approximately 75%
          • Menopausal hormone therapy doses are not adequate to prevent ovulation and pregnancy; hormonal contraceptives may be a better option for symptom management in perimenopause
        • A number of nonhormonal therapies are effective against vasomotor symptoms and can be considered in patients who are averse to using exogenous hormones or who have contraindications r42
      • Vulvovaginal atrophy and dyspareunia r17
        • OTC lubricants and moisturizers may effectively treat mild symptoms, but hormone therapy is the mainstay for more severe symptoms
        • For those with no history of estrogen-dependent cancers who are seeking relief from symptoms of genitourinary syndrome of menopause, low-dose vaginal hormone therapies are recommended
          • For those with history of estrogen-dependent cancers who are seeking relief from symptoms of genitourinary syndrome of menopause, nonhormone therapies are first line choices; reserve vaginal estrogen or prasterone (dehydroepiandrosterone) for patients unresponsive to nonhormone therapy r43
        • Intravaginal estrogens relieve symptoms of vaginal atrophy and dryness in perimenopausal or menopausal patients (eg, cream, vaginal ring, intravaginal tablet, or insert)
          • Low- and ultralow-dose vaginal estrogen preparations are usually ideal for patients with isolated genitourinary symptoms and can be continued for as long as required r44
          • No requirement to combine with systemic progestogens for endometrial protection, because they do not result in significant systemic absorption or endometrial hyperplasia r44
        • Prasterone (dehydroepiandrosterone) reduces symptoms of dyspareunia in patients with vulvovaginal atrophy due to menopause r45
          • Not approved for use in patients with breast cancers
          • Improvements last up to 1 year r46
        • Ospemifene reduces symptoms of dyspareunia associated with vaginal atrophy in postmenopausal patients
          • Suitable for those with estrogen-sensitive cancers (eg, breast cancer) for whom exogenous estrogen use is contraindicated
          • Improvements occur within 1 month and endure for up to 1 year;r47hot flashes may temporarily worsenr48
        • Systemic hormone therapy given for vasomotor symptoms may be adequate, but addition of low-dose vaginal hormone therapies may be needed for persistent genitourinary symptoms
      • Affective disorders associated with perimenopause and menopause
        • Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is useful both to reduce hot flashes and to improve mood r49
        • Other selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitors found to be beneficial for management of vasomotor symptoms include paroxetine, escitalopram, citalopram, and desvenlafaxine, and may also be useful for females with affective symptoms r42
      • Cognitive symptoms associated with perimenopause and menopause
        • Menopausal hormone therapy may help relieve some short-term cognitive symptoms related to the menopause r44
      • Low sexual desire
        • Testosterone replacement may provide benefit to patients with low sexual desire r44
        • Can be considered if systemic menopausal hormone therapy resulting in adequate levels of estrogen has not been effective
    • Nonhormone therapies
      • Consider nonhormonal options for symptom relief for patients with conditions precluding hormone therapy or for whom substantial risk of breast cancer or cardiovascular disease exists r39r50
      • Usually act quickly; if no improvement occurs within 2 to 4 weeks, consider another therapy
      • Nonpharmacologic measures include clinical hypnosis, cognitive behavioral therapy, and weight loss r42
      • A variety of pharmacologic options are available r42
        • Gabapentin has been found to reduce vasomotor symptoms in multiple studies. Bedtime dosing may be helpful for females with sleep issues
        • Oxybutynin reduces vasomotor symptoms in low doses. Can also be used to treat urinary tract symptoms
        • Selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors found to be beneficial for management of vasomotor symptoms include paroxetine, escitalopram, citalopram, venlafaxine, and desvenlafaxine; may be ideal for females with coexisting mood or anxiety symptoms
        • Fezolinetant, a neurokinin B antagonist that targets the neural mechanism underlying vasomotor symptoms, is FDA approved for management of vasomotor symptoms
        • Stellate ganglion block can be considered in select females but is associated with potential risks
    • Oral contraceptives
      • Oral contraceptives with low-dose estrogen (20 mcg) are a therapeutic option for perimenopausal patients who desire contraception or have abnormal uterine bleeding
      • At average age of menopause, patient may discontinue oral contraceptives or change to standard postmenopausal hormone therapy regimen, if needed
    • Menopausal hormone therapy
      • Appropriate for postmenopausal patients who are younger than 60 years, are less than 10 years from menopause onset, and have moderate to severe menopausal symptoms r39r50
        • Risk-benefit profile is more favorable for patients aged 50 to 59 years than for those who are older r51
        • Women's Health Initiative trial results provide most useful available data on risks and benefits of menopausal hormone therapy in patients aged 50 to 59 years r51
      • Contraindications to hormone therapy r39
        • Unexplained vaginal bleeding
        • Thrombophilia
        • Known, suspected, or history of breast or endometrial cancer r44
        • Active arterial thromboembolic disease (eg, stroke, transient ischemic attack, myocardial infarction) or history of these conditions
        • Active pulmonary embolus or deep vein thrombosis, or history of these conditions
        • Liver disease
      • Caution should be exercised when considering oral estrogen therapy in the following conditions: r52
        • Hypertriglyceridemia (greater than 400 mg/dL)
        • Active gallbladder disease
        • Migraine with aura
      • Risks of hormone therapy r51
        • Estrogen plus progestogen (oral conjugated equine estrogen plus medroxyprogesterone acetate)
          • Ischemic stroke (hazard ratio, 1.37; 95% CI, 1.07-1.76)
          • Thromboembolism
            • Pulmonary embolism (hazard ratio, 1.98; 95% CI, 1.36-2.87)
            • Deep vein thrombosis (hazard ratio, 1.87; 95% Cl, 1.37-2.54)
          • Invasive breast cancer (hazard ratio, 1.24; 95% CI, 1.01-1.53)
          • Cardiovascular events (hazard ratio, 1.13; 95% CI, 1.02-1.25)
        • Estrogen alone (oral conjugated equine estrogen) r51
          • Ischemic stroke (hazard ratio, 1.35; 95% CI, 1.07-1.70)
          • Deep vein thrombosis (hazard ratio, 1.48; 95% CI, 1.06-2.07)
          • Cardiovascular events (hazard ratio, 1.11; 95% CI, 1.01-1.22)
      • Other benefits of hormone therapy, beyond relief of vasomotor symptoms r51
        • Estrogen plus progestogen
          • Reduced risk of hip fracture (hazard ratio, 0.67; 95% CI, 0.47-0.95)
          • Reduced risk of colorectal cancer (hazard ratio, 0.62; 95% Cl, 0.43-0.89)
          • Reduced risk of diabetes (hazard ratio, 0.81; 95% CI, 0.70-0.94)
        • Estrogen alone r51
          • Reduced risk of hip fracture (hazard ratio, 0.67; 95% CI, 0.46-0.96)
          • Reduced risk of diabetes (hazard ratio, 0.86; 95% CI, 0.76-0.98)
      • Practical factors to consider when choosing specific hormone therapy include whether to use a progestogen in conjunction with estrogen, type of estrogen/progestogen, route, and dose
      • Menopausal hormone therapy consists of estrogen plus progestogen for patients with an intact uterus or estrogen alone for those who have undergone hysterectomy
        • Estrogen types include estradiol-17β, synthetic conjugated estrogen, or conjugated equine estrogens. Progestogen types include medroxyprogesterone acetate, micronized progesterone, levonorgestrel (patch), or norethindrone acetate (patch)
        • Systemic menopausal hormone therapy with estrogen alone, or in combination with progestogen, is the most effective therapy for vasomotor symptoms
      • Available in oral, transdermal, and intravaginal formulations, and prescribed based on cardiovascular risk, thromboembolic risk, or patient preference. Efficacy is similar among different formulations r53
        • For those with moderate risk of cardiovascular disease, transdermal (nonoral) estradiol is recommended as first line treatment because of fewer adverse effects on blood pressure, triglycerides, and carbohydrate metabolism r50
        • For those at increased risk of venous thromboembolism who request hormone therapy, transdermal (nonoral) route of estrogen is recommended r50
        • For those at intermediate or high risk of breast cancer, nonhormone therapies are recommended over hormone therapy to alleviate vasomotor symptoms r44r50
        • Compounded bioidentical hormone therapy preparations are not recommended because of concerns about safety and efficacy as well as incomplete adverse event reporting and lack of oversight (not FDA regulated) r44r54
      • Use an adequate dose of hormone therapy to manage symptoms; start with a low dose and increase if symptoms persist
        • Among lower estrogen doses typically used in initiating systemic menopausal hormone therapy are 0.3 to 0.45 mg oral conjugated estrogen, 0.5-mg oral micronized estradiol-17β, and 0.025- to 0.0375-mg transdermal estradiol-17β patch r55
          • Studies using ultralow dosing (eg, oral micronized estradiol 0.25 mg, transdermal estradiol 0.014 mg/day) have had mixed results and have not supported FDA approval of ultralow estrogen dosing r55
      • Limit hormone therapy to the duration needed to achieve treatment goals while balancing risks for each patient; periodically reassess the ongoing need for hormone therapy as clinically appropriate
      • Can prescribe the combination of conjugated estrogens/bazedoxifene as an alternative to progestogen for patients with an intact uterus
        • Bazedoxifene is a selective estrogen receptor modulator with antagonistic action in breast and uterus and is available in combination with conjugated estrogens in a single pill
        • Potential users include females who are unable to tolerate any progestogen due to adverse effects
        • Improves vasomotor symptoms and vulvovaginal atrophy and has protective effect on vertebral skeleton r56
        • Associated with increased risk of venous thromboembolism
      • Effects of discontinuing menopausal hormone therapy r51
        • Estrogen plus progestogen
          • Risk of cardiovascular disease remains nonsignificantly elevated, endometrial cancer risk is reduced, risk of hip fractures remains reduced, and risk of invasive breast cancer remains elevated
        • Estrogen alone
          • Risk of invasive breast cancer remains significantly reduced

    Long-term therapy r40

    • Menopausal hormone therapy
      • Not recommended for primary or secondary prevention of cardiovascular disease, stroke, or for prevention of dementia r44r57r58
      • May be considered as an additional, alternative option to prevent and treat osteoporosis, particularly in younger postmenopausal females with menopausal symptoms who are also at increased risk of fractures r44
      • Can be considered in healthy patients with persistent vasomotor symptoms with shared decision-making and regular assessment of risks/benefits r39
    • Nonhormone therapies (bisphosphonates) are recommended as first line to prevent and treat osteoporosis in postmenopausal patients r44
    • Testosterone supplementation is not recommended for prevention or treatment of osteoporosis or fracture prevention r44

    Drug therapy

    • Menopausal hormone therapy is FDA approved for treatment of vasomotor symptoms, moderate to severe symptoms of vulvovaginal atrophy (with a preference for low-dose vaginal therapy if solely prescribed for vulvar or vaginal symptoms), and for prevention of osteoporosis r39
    • Menopausal hormone therapy for patients with hysterectomy consists of estrogen alone, starting with a low dose and titrating to symptoms as needed
    • Menopausal hormone therapy for patients with intact uterus includes both estrogen plus a progestogen given continuously or cyclically 10 to 14 days per month to protect against endometrial hyperplasia and cancer
      • Oral contraceptives with low-dose estrogen (20 mcg) are a therapeutic option for perimenopausal patients who desire contraception or have abnormal uterine bleeding
        • At average age of menopause, patients may discontinue oral contraceptives or change to standard postmenopausal hormone therapy regimen, if needed
    • Reevaluate ongoing need for hormone therapy periodically along with assessment of risk to benefit balance and individual preferences
    • Estrogen
      • Oral
        • Estradiol Oral tablet; Adult menopausal and postmenopausal females: 0.5 mg to 2 mg PO once daily. Usual initial dose: 1 or 2 mg PO once daily. Less than 1 mg/day PO may suffice for vaginal/vulvar symptoms only. Administration should be cyclic (e.g., 3 weeks on and 1 week off). In women with an intact uterus, estrogen may be given cyclically or combined with a progestin for at least 10 to 14 days per month.
        • Conjugated Estrogens Oral tablet; Adult menopausal and postmenopausal females: Initially, 0.3 mg PO once daily. May titrate if needed. Use lowest effective dose. Few patients need up to 1.25 mg/day PO. Doses of less than 0.45 mg/day may be adequate for vaginal/vulvar symptoms only. Continuous, unopposed estrogen is acceptable in women without a uterus. In women with an intact uterus, estrogen may be given cyclically (e.g., 25 days of month then 5 days off) or combined with a progestin for at least 10 to 14 days per month to reduce risk of endometrial hyperplasia. Reassess hormone therapy every 3 to 6-months.
      • Transdermal
        • Topical estrogen gel or emulsion
          • Divigel
            • Estradiol Topical gel; Adult menopausal and postmenopausal females: Initially, one 0.25 gram/day packet once daily; apply contents of 1 unit-dose packet topically to upper thigh once daily; alternate the right and left upper thigh each day. Adjust dose to individual response; use lowest effective dose. Unit-dose packets are available as 0.25 gram/day, 0.5 gram/day, 0.75 gram/day, 1 gram/day, and 1.25 grams/day. Max: 1.25 grams/day.
          • Elestrin
            • Estradiol Topical gel; Adult menopausal and postmenopausal females: Initially, apply 1 actuation of the pump (0.87 grams estradiol gel containing 0.52 mg of estradiol and delivering 12.5 mcg/day of estradiol systemically) once daily to the upper arm. Adjust based upon the individual patient response. Usual dose range is 1 to 2 pump actuations per day. Use the lowest effective dose.
          • EstroGel metered dose pump
            • Estradiol Topical gel; Adult menopausal and postmenopausal females: Apply 1 complete actuation of the pump (1.25 grams of 0.06% estradiol gel that contains 0.75 mg of estradiol) topically to 1 arm once daily; applied in a thin layer over the entire arm on the inside and outside from wrist to shoulder.
        • Topical estrogen spray
          • Evamist
            • Estradiol Topical solution, spray; Adult menopausal and postmenopausal females: Initially, apply 1 spray (pump actuation, which supplies 1.53 mg estradiol) to the inner surface of the forearm once daily in the morning; if needed and based on clinical response, the dose may be increased to 2 to 3 sprays once daily in the morning. Each spray should be administered to adjacent, but non-overlapping sections of the inner surface of the forearm, starting near the elbow. Use lowest effective dose.
        • Topical patch
          • Estradiol (estradiol-17β) transdermal patch (Alora, Climara, Esclim, Menostar, Vivelle, Estraderm) c51
            • Estradiol Transdermal patch - weekly; Adult menopausal and postmenopausal females: 1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.06 mg, 0.075 mg, or 0.1 mg per day) applied and replaced every 7 days. Usual initial dose is 0.0375 mg/day or 0.05 mg/day. Use lowest effective dose.
            • Estradiol Transdermal patch - biweekly; Adult menopausal and postmenopausal females: 1 patch (delivering 0.025 mg, 0.0375 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day); replace twice weekly (every 3 to 4 days). Usual initial dose is 0.0375 mg/day or 0.05 mg/day; see individual patch recommendations.
            • An ultralow-dose patch is available (delivering 0.014 mg of estradiol daily)
      • Vaginal
        • Estradiol vaginal ring
          • Femring c52
            • Estradiol Acetate Vaginal insert; Adult menopausal and postmenopausal females: Insert 1 vaginal ring (delivering either 50 or 100 mcg per 24 hours) vaginally into the upper third of the vaginal vault; keep in place continuously for 3 months, then remove. If appropriate, insert a new ring. Use lowest effective dose. While Femring may be used to treat isolated genitourinary symptoms, consider other vaginal products of lower estradiol dosage first.
    • Progestogen c53
      • Progestogens initially can be administered cyclically to limit irregular bleeding, but for females who are 3 or more years beyond the start of menopause, a continuous regimen is usually preferred r59
      • Give females with an intact uterus who are receiving estrogen therapy a progestogen to prevent endometrial hyperplasia and cancer r50
      • Oral
        • Progesterone Oral capsule; Adult females with an intact uterus: 200 mg PO in the evening for 12 sequential days of every 28-day cycle of daily estrogen.
        • Medroxyprogesterone Acetate Oral tablet; Adult females with an intact uterus: 5 to 10 mg PO once daily for 10 to 14 or more days each month in those whom estrogen is given in a sequential manner (e.g., withdrawal bleeding is expected). Alternatively, 2.5 to 5 mg PO once daily if estrogens are administered continuously each day (when withdrawal bleeding not desirable).
    • Continuous combined estrogen plus progestogen formulations
      • Oral
        • Conjugated equine estrogens plus medroxyprogesterone
          • Conjugated Estrogens, Medroxyprogesterone Acetate Oral tablet; Adult menopausal and postmenopausal females: 1 tablet PO once daily. Dosage titration options include: A) 0.3 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, B) 0.45 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, C) 0.625 mg conjugated estrogen/2.5 mg medroxyprogesterone acetate tablet, or D) 0.625 mg conjugated estrogen/5 mg medroxyprogesterone acetate tablet. Titrate as needed, using the lowest effective dose. Cycles are repeated continuously, using a new blister card every 28 days. Reevaluate at 3 to 6 month intervals to determine appropriate dose and need for continued treatment.
        • Estradiol plus norethindrone acetate
          • Estradiol, Norethindrone Acetate Oral tablet; Adult menopausal and postmenopausal females: 1 tablet (0.5 mg estradiol and 0.1 mg of norethindrone acetate) OR 1 tablet (1 mg estradiol and 0.5 mg norethindrone acetate) PO once daily for vasomotor symptoms; initiate at the lowest dose. For vulvar/vaginal atrophy, use 1 tablet (1 mg estradiol/0.5 mg norethindrone acetate) PO once daily. Re-evaluate at 3 to 6-month intervals to determine if the dose and/or if continued hormone therapy is appropriate.
        • Ethinyl estradiol plus norethindrone acetate
          • Norethindrone Acetate, Ethinyl Estradiol Oral tablet [Estrogen Replacement/Osteoporosis]; Adult menopausal and postmenopausal females: 1 tablet (containing norethindrone acetate 0.5 mg with ethinyl estradiol 2.5 mcg OR containing norethindrone acetate 1 mg with ethinyl estradiol 5 mcg) PO once daily. Use lowest effective dose. Reevaluate the appropriateness of HRT at 3 to 6-month intervals
      • Transdermal patch
        • CombiPatch (estradiol-17β plus norethindrone acetate) c54
          • Estradiol, Norethindrone Acetate Transdermal patch - biweekly; Adult menopausal and postmenopausal females: Initiate with 1 transdermal patch system (delivering 0.05 mg estradiol/0.14 mg norethindrone acetate per day) topically to the lower abdomen; remove and replace the patch twice weekly (every 3 to 4 days). If a greater progestin dose is desired, use the 0.05 mg estradiol with 0.25 mg norethindrone acetate per day patch. Re-evaluate at 3 to 6-month intervals to determine if the dose and/or if continued hormone therapy is appropriate.
        • ClimaraPro (estradiol-17β plus levonorgestrel) c55
          • Estradiol, Levonorgestrel Transdermal patch - weekly; Adult menopausal and postmenopausal females: Apply 1 transdermal system (delivering 0.045 mg estradiol/0.015 mg levonorgestrel per day) topically to the lower abdomen to be worn continuously for 1 week, then remove and replace. Reevaluate hormone replacement therapy at 3 to 6-month intervals.
    • Cyclic combined estrogen plus progestogen formulation
      • Oral
        • Premphase (conjugated equine estrogens plus medroxyprogesterone) c56
          • Conjugated Estrogens, Medroxyprogesterone Acetate Oral tablet; Adult menopausal and postmenopausal females: 1 tablet PO once daily. Dosage titration options include: A) 0.3 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, B) 0.45 mg conjugated estrogen/1.5 mg medroxyprogesterone acetate tablet, C) 0.625 mg conjugated estrogen/2.5 mg medroxyprogesterone acetate tablet, or D) 0.625 mg conjugated estrogen/5 mg medroxyprogesterone acetate tablet. Titrate as needed, using the lowest effective dose. Cycles are repeated continuously, using a new blister card every 28 days. Reevaluate at 3 to 6 month intervals to determine appropriate dose and need for continued treatment.
    • Combined conjugated estrogen plus bazedoxifene c57
      • A single tablet contains a low dose (0.45 mg) of conjugated estrogens
      • Reductions in the frequency and severity of hot flashes are comparable to those achieved with menopausal hormone therapy r60
      • Reduces objective findings of vulvovaginal atrophy and severity of the most bothersome symptoms r61
      • Ancillary benefit of reducing the risk of vertebral fractures by approximately 30% to 37% in postmenopausal patients with osteoporosis r62
      • Conjugated Estrogens, Bazedoxifene Oral tablet; Adult menopausal and postmenopausal females: 1 tablet PO once daily (conjugated estrogens 0.45 mg and bazedoxifene 20 mg per tablet). Reevaluate every 3 to 6 months to determine if the dose and continued hormone replacement are appropriate.
    • Vaginal hormone therapy (nonsystemic, local) for patients with genitourinary syndrome of menopause c58
      • Nonsystemic (local) doses of estrogen are intended to treat local symptoms only, not vasomotor symptoms. Systemic absorption is minimal r39
      • Estradiol vaginal insert (Vagifem, Yuvafem, Imvexxy) c59
        • Estradiol Vaginal insert; Adult menopausal and postmenopausal females: Place 1 insert vaginally once daily at approximately the same time of day for 2 weeks, followed by 1 insert twice weekly (e.g., Monday and Thursday). Generally, initiate with the 4 mcg insert. Max: 10 mcg/dose vaginally. Use the lowest effective dose.
      • Estradiol cream (Estrace) c60
        • Estradiol Vaginal cream; Adult menopausal and postmenopausal females: Initially, 0.5 to 1 grams vaginally once daily for 2 weeks; then reduce to 0.5 to 1 grams vaginally 1 to 3 times weekly r15
      • Conjugated equine estrogens cream (Premarin) c61
        • Conjugated Estrogens Vaginal cream; Adult menopausal and postmenopausal females: Initially, 0.5 to 1 grams vaginally once daily for 2 weeks; then reduce to 0.5 to 1 grams vaginally 1 to 3 times weekly r15
      • Vaginal ring (Estring) c62
        • Estradiol Vaginal insert; Adult menopausal and postmenopausal females: Insert 1 vaginal system ring (delivering estradiol 7.5 mcg/24 hours) deep into the upper third of the vaginal vault. Keep in place continuously for 3 months, then remove. If appropriate, insert a new system. Estring vaginal system ring is not effective at treating vasomotor symptoms.
    • Other pharmacotherapy for patients with genitourinary syndrome of menopause
      • Ospemifene r63c63
        • Selective estrogen receptor modulator that reduces the severity of dyspareunia and vaginal dryness; not associated with endometrial or breast-related safety concerns when used up to 1 year r64
        • Ospemifene Oral tablet; Adult menopausal and postmenopausal females: 60 mg PO once daily with food. Consider the addition of a progestin in postmenopausal women with an intact uterus to reduce risk for endometrial hyperplasia. Assess the need for continued treatment periodically.
      • Prasterone (dehydroepiandrosterone) c64
        • Prasterone reduces the severity of dyspareunia and vaginal dryness; contraindicated for use in females with known or suspected estrogen-dependent neoplasias r65
        • Prasterone Vaginal insert; Adult menopausal and post-menopausal females: 1 insert (6.5 mg) administered vaginally once daily at bedtime, using the provided applicator.
    • Nonhormone medical therapy for vasomotor symptoms r66
      • For females seeking relief from moderate to severe vasomotor symptoms when menopausal hormone therapy is contraindicated r50
      • Paroxetine (selective serotonin reuptake inhibitor) c65
        • Reduces moderate to severe hot flashes in patients both with and without a history of breast cancer
        • 40% to 67% of patients with history of breast cancer experienced reduced hot flash frequency with 4 to 6 weeks of treatment, compared with 14% to 27% of patients taking a placebo r67
        • 33% to 65% of patients without history of breast cancer experienced reduced hot flash frequency with 6 to 12 weeks of treatment, compared with 17% to 38% of patients taking a placebo r67
        • Paroxetine Oral capsule; Postmenopausal Adults: 7.5 mg PO once daily at bedtime, with or without food.
      • Venlafaxine (serotonin-norepinephrine reuptake inhibitor)
        • For the treatment of hot flashes, either as a symptom of natural or chemotherapy-induced menopause; efficacy in reducing frequency of hot flashes is similar to that of low-dose systemic estradiol r49
        • Particularly useful for females who also experience affective disorders
        • Venlafaxine Hydrochloride Oral tablet, extended-release; Adult females: 37.5 mg PO once daily for 1 week, followed by titration to 75 mg PO once daily has been effective in decreasing hot flash frequency and severity in clinical trials. Venlafaxine is considered a first line, effective alternative for females who cannot or do not wish to use hormone replacement therapy
      • Gabapentin (anticonvulsant) c66
        • Reduces frequency and severity of hot flashes; particularly useful for females whose hot flashes occur at night r50
        • Reductions in composite hot flash frequency and severity scores are approximately 20% to 30% r68
        • Gabapentin Oral tablet; Adult females: Initially, 300 mg/day PO is recommended, with titration to 300 mg 3 times daily PO if the patient still has hot flashes at lower doses
      • Pregabalin c67
        • Limited data show that pregabalin is effective for reducing hot flashes with short-term use (6 weeks) r69
        • However, because pregabalin is a controlled substance and causes significant weight gain, gabapentin is preferred
        • Pregabalin Oral tablet; Adult females: 75 mg PO twice daily; may increase to 150 mg PO twice daily within 1 week based on tolerability and response
      • Oxybutynin (antimuscarinic, anticholinergic therapy) c68
        • Reduces moderate to severe hot flashes in females with and without breast cancer r70
        • Particularly useful for females who also experience overactive bladder symptoms
        • Most common adverse effects (dose dependent) include dry mouth and difficulty urinating
        • Long-term use associated with cognitive decline, particularly in older persons
        • Oxybutynin Chloride Oral tablet; Adult females: 2.5 to 5 mg PO twice daily r70
      • Fezolinetant
        • Fezolinetant Oral tablet; Adult menopausal and postmenopausal females: 45 mg PO once daily at about the same time each day.
        • Check ALT, AST, total and direct serum bilirubin levels before initiation of therapy, and then after initiation of therapy at 3, 6, and 9 months.
    • Oral contraceptives c69
      • Indicated for
        • Perimenopausal symptoms and birth control for patients aged 40 to 50 years r71
        • Hormone replacement therapy in patients with primary ovarian insufficiency
      • Ethinyl estradiol plus desogestrel c70c71
        • Ethinyl Estradiol, Desogestrel Oral tablet, Inert Oral tablet; Adult and Adolescent females: 1 tablet (containing 0.15 mg desogestrel and 30 mcg of ethinyl estradiol) PO daily for 21 days, followed by 7 days without drug.
    • Hormone therapy for menopause.CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate.Data from Stuenkel CA et al: Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 100(11):3975-4011, 2015; Santoro N et al: Menopausal symptoms and their management. Endocrinol Metab Clin North Am. 44(3):497-515, 2015; and The NAMS 2020 GSM Position Statement Editorial Panel: The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 27(9):976-92, 2020.
      Route of administrationProductDosagesCommentsTrade name examples
      Estrogen
      OralCEE0.3, 0.45, or 0.625 mg/dayPremarin
      OralSynthetic conjugated estrogens0.3, 0.45, or 0.625 mg/dayCenestin
      OralEstradiol-17β0.5, 1, or 2 mg/dayEstrace
      OralEsterified estrogens0.3, 0.45, or 0.625 mg/dayMenest
      Transdermal estrogen—patchEstradiol-17β0.025-0.1 mg once or twice weekly (1 patch weekly or twice weekly)An ultralow dose (0.14 mg/week) is also available, which preserves bone in females older than 60 yearsClimara, Vivelle, Estraderm
      Transdermal estrogen—gelEstradiol-17β0.25-1.5 g dailyPotential transfer to other people or petsDivigel, Elestrin
      Transdermal estrogen—emulsionEstradiol-17β0.05 mg/dayComes in foil packetsEstrasorb
      Transdermal estrogen—spray mistEstradiol-17β1.5 mg daily (1 spray daily)Potential transfer to other people or petsEvamist
      Intravaginal—insertsEstradiol hemihydrate vaginal tablet10 mcg once daily for 2 weeks, then twice weeklyVagifem,
      Yuvafem
      Intravaginal—insertsEstradiol-17β4 or 10 mcg once daily for 2 weeks, then twice weeklyInvexxy
      Intravaginal—creamEstradiol-17β0.5-1 g daily for 2 weeks, then 1-3 times weeklyEstrace
      Intravaginal—creamCEE0.5-1 g daily for 2 weeks, then 1-3 times weeklyPremarin
      Intravaginal—ringEstradiol acetateSystemic dosing at 0.05-0.10 mg/dayFor systemic (vasomotor) and local symptoms; 90-day
      duration of ring      		Femring
      Intravaginal—ringEstradiol-17βLocal dosing, delivering estradiol 7.5 mcg/24
      hours      		For genitourinary symptoms only; 90-day duration
      of ring      		Estring
      Progestogens
      OralMPA2.5-10 mg PO daily for continuous use, or 2.5-10 mg PO daily 12-14 consecutive days per month for cyclic use
      OralMicronized progesterone100 mg PO daily for continuous use, or 200 mg PO daily for 12 days each month for cyclic use
      Combined estrogen plus progestogen
      OralCEE plus
      medroxyprogesterone      		CEE 0.625 mg/MPA 2.5 mg, then CEE 0.625 mg/MPA 5 mg (1 tablet daily)Prempro
      OralCEE plus
      medroxyprogesterone, used cyclically      		CEE 0.625-mg tablet days 1-14, then CEE 0.625-mg/MPA 5-mg tablet days 15-28Premphase
      OralEstradiol-17β plus norethindrone acetateEstradiol-17β 1 mg/norethindrone 0.5 mg (1 tablet daily)Activella
      OralEthinyl estradiol plus norethindrone acetateEthinyl estradiol 0.005 mg/norethindrone 0.5 mg (1 tablet daily)Femhrt
      TransdermalEstradiol-17β plus norethindrone acetateEstradiol-17β 0.05-/0.14-mg norethindrone acetate (delivered per day)1 patch applied every 3-4 daysCombiPatch
      TransdermalEstradiol-17β plus levonorgestrelEstradiol-17β 0.045-/0.015-mg levonorgestrel (delivered per day)1 patch applied per weekClimaraPro
      Combined estrogen plus selective estrogen receptor modulator
      OralCEE plus bazedoxifeneCEE 0.45 mg/bazedoxifene 20 mg (1 tablet daily)

    Nondrug and supportive care

    • Recommendations for managing mild or less bothersome hot flashes
      • Lower thermostat r50c72
      • Dress in removable layers r50c73
      • Avoid alcohol and spicy foods r50c74c75
      • Cognitive behavioral therapy r72c76
        • Includes education about vasomotor symptoms and how thoughts and emotions can affect physical sensations, training in relaxation and paced breathing, identifying and challenging negative beliefs, monitoring and modifying triggers, and relaxation exercises
        • Reduces effect of vasomotor symptoms by average of 50% after 8 hours of group therapy; similar results are observed with self-guided therapy (using booklet, audio, and up to 1.5 hours of telephone support) r73
        • Reduces frequency of night sweats by 39% r73
      • Hypnosis r72
        • Involves deep relaxation and individualized mental imagery (eg, for coolness) and suggestion
        • Recommended by the North American Menopause Society after randomized controlled trials demonstrated reduction in vasomotor symptoms (subjective and objective) after 5 weekly sessions r72
      • Weight loss
        • North American Menopause Society recommends females who are overweight lose weight r72
    • Nutritional/herbal supplements
      • Not recommended to treat perimenopausal and postmenopausal symptoms
      • Safety and efficacy of nutritional/herbal supplements (including bioidentical hormones and phytoestrogens) to treat peri- and postmenopausal symptoms have not been established r74

    Special populations

    • Females with primary ovarian insufficiency
      • Follow diagnosis of primary ovarian insufficiency with evaluation of potential underlying causes or associated conditions
      • Several hormone replacement options exist for young patients with primary ovarian insufficiency, including oral, transdermal, and vaginal formulations
      • Symptomatic control in younger patients often requires use of higher doses of estrogen to achieve relief compared with doses that are effective in patients in natural menopause.r7r39 Options include:
        • Transdermal (gel, spray, or patch) estradiol at dose of 100 mcg daily r75
        • Oral estradiol at dose of 1 to 2 mg daily r75
        • Conjugated estrogen at dose of 0.625 to 1.25 mg daily r75
      • Add a progestogen to estrogen therapy for all females with an intact uterus to minimize risk of endometrial hyperplasia and cancer. Options include:
        • Oral or vaginal micronized progesterone at dose of 100 mg daily, or 200 mg daily for 10 to 12 days each month r75
        • Medroxyprogesterone acetate at dose of 10 mg daily for 10 days each month r75
        • Cyclic administration of progesterone, which usually induces regular withdrawal bleeding, is not required but is preferred by some younger patients r75
      • Hormone therapy is the first line prevention and treatment of osteoporosis in females with premature ovarian insufficiency and early menopause r44
      • Combined hormonal contraceptives (eg, pills, vaginal ring, patch) are an option and may be used until patient reaches approximately age 50 years
    • Females with history of estrogen-dependent breast cancer
      • Systemic hormone therapy is contraindicated in females with history of, or current, breast cancer
      • Nonhormone approaches are first line choices for managing urogenital symptoms during or after breast cancer treatment
      • Use of vaginal hormone therapies (estrogens or prasterone) for genitourinary syndrome of menopause in females with history of, or current, breast cancer is controversial r43r76
        • Most available data do not show association between vaginal estrogen and risk of breast cancer recurrence r77
        • Professional society guidelines recommend use be reserved for those patients who are unresponsive to nonhormonal remedies and in coordination with an oncologist r43
        • Low rates of systemic absorption are found in vaginal ring and vaginal tablet r43
      • Avoid paroxetine to females with breast cancer who are taking tamoxifen, because paroxetine interferes with metabolism of tamoxifen to its metabolite, endoxifen
    • Females at risk for breast cancer
      • Estimate breast cancer risk as first step
        • National Cancer Institute has an online interactive tool to estimate 5-year and lifetime risk of breast cancer based on personal characteristics r78
      • General suggestions from professional societies r50
        • Avoid prescribing menopausal hormone therapy to females whose risk meets criteria for breast cancer prevention with selective estrogen receptor modulators or aromatase inhibitors
          • US Preventive Services Task Force recommends that females at increased risk be considered for preventive therapy with tamoxifen, raloxifene, or aromatase inhibitors as long as they do not have contraindications and are at low risk of adverse medication effects r79
          • American Society of Clinical Oncology recommends anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day) to reduce estrogen receptor–positive breast cancers in postmenopausal females at increased risk of developing breast cancer r80
          • American Society of Clinical Oncology guideline suggests discussing such therapy with females who have risk of 1.67% or more r80
      • Potential algorithm for counseling about menopausal hormone therapy, based on 5-year estimate of breast cancer risk as assessed by National Cancer Institute's tool, is as follows: r50
        • Low 5-year breast cancer risk (less than 1.67%): menopausal hormone therapy is acceptable
        • Intermediate 5-year breast cancer risk (1.67%-5%): use caution when prescribing menopausal hormone therapy
        • High 5-year breast cancer risk (more than 5%): avoid menopausal hormone therapy
    • Females with hypertriglyceridemia
      • Transdermal estrogen is preferred for postmenopausal patients with baseline triglyceride level higher than 200 mg/dL r50
    • Females with thrombophilia
      • Transdermal estrogen or nonhormone therapies are preferred for postmenopausal patients with inherited thrombophilia or family history of venous thromboembolism r81
      • For females with a uterus, prescribe a progestogen (eg, progesterone and dydrogesterone) that has neutral effects on coagulation r50
      • Observational studies suggest that risk of thromboembolism is lower with transdermal preparations r82
    • Females with hypothyroidism
      • Monitor TSH level 6 to 12 weeks after starting menopausal oral estrogen therapy in patients taking levothyroxine, as dose of thyroid hormone may need to be increased r50
    • Females at risk for endometrial cancer r83
      • Continuous combined hormone therapy with synthetic progestogens reduces risk of endometrial cancer r83
      • Estrogen-only hormone therapy in females with a uterus increases risk of endometrial cancer r83
      • Sequential combined hormone therapy with synthetic progestogens used less than 10 days per month is associated with increased risk of endometrial cancer r83
      • Sequential combined hormone therapy with synthetic progestogens used more than 10 days per month is not associated with increased risk of endometrial cancer r83

    Monitoring

    • Inform females about possible increased risk of breast cancer during and after discontinuing estrogen-progestogen therapy, and emphasize importance of adhering to age-appropriate breast cancer screening
    • Annually reassess benefits and risks individualized to each patient r84
      • In annual assessment, include breast examination, mammogram, symptom review, and intervening health issue updates c77c78c79c80
      • At least annually, reassess ongoing need for hormone therapy in the context of the patient's personal and family history, treatment goals, and personal preferences
    • Routine monitoring of estradiol levels is not indicated unless symptoms are inadequately relieved despite escalating doses of estrogen r59
      • Serum estradiol levels fluctuate widely when oral estrogen preparations are used
      • Appropriate target serum estradiol range for females using transdermal estradiol preparations is 40 to 100 pg/mL
    • Management of nonresponders r85
      • Monitor response 6 to 8 weeks after initiating menopausal hormone therapy and increase estrogen dose if symptom relief is inadequate
      • If symptoms persist on higher doses, consider changing administration route (oral to transdermal and vice versa)
    • Management of adverse effects r59
      • Breast tenderness usually responds to reduced estrogen dose or changed progestogen preparation
        • Alternatively, changing to conjugated estrogen/bazedoxifene also may improve these symptoms
      • Alleviate mood symptoms from progestogen use by changing to different preparation (micronized progesterone is preferred), lowering progestogen dose, or initiating antidepressant therapy
      • Refer females who have persistent (longer than 6 months) unscheduled bleeding while taking hormone therapy to a gynecologist to assess for endometrial hyperplasia and cancer
    • Menopausal hormone therapy can be tapered or stopped abruptly, in accordance with individual patient's preferences r50
      • Symptoms recur in approximately one-third to one-half of females who abruptly discontinue menopausal hormone therapy r86
      • Tapering has not been shown to be more effective, but it can be tried to prevent recurrent vasomotor symptoms r87
      • Tapering strategies include:
        • Gradually reduce dose of oral or transdermal estrogen until taper is complete
        • Continue with progestogen in females with a uterus until estrogen taper is complete
    • Young patients with primary ovarian insufficiency and/or early menopause who do not have contraindications are advised to take hormone therapy at least until the age of natural menopause (age 52 years), at which time the need for ongoing hormone therapy can be reassessed r7

    Complications and Prognosis

    Complications

    • Postmenopausal osteopenia and osteoporosis r88c81c82d3
      • Rapid trabecular bone loss occurs at menopause in association with decline in estrogen and continues for 5 to 8 years after menses stops r89
      • About a decade after menopause, second phase of bone loss occurs in which both trabecular and cortical bone are lost at equal rates r89
      • Approximately 50% of postmenopausal patients experience an osteoporosis-related fracture during their lifetime
      • Screening for osteoporosis is recommended for postmenopausal patients r90
        • Screen all females aged 65 years or older, regardless of risk factors, for osteoporosis with bone mineral density testing using DXA of hip and lumbar spine
        • For females aged 50 to 64 years, no consensus exists regarding when to begin bone mineral density screening
          • US Preventative Services Task Force recommends using a validated prediction tool to identify higher-risk asymptomatic younger postmenopausal patients r91
            • Task Force also recommends screening younger females whose 10-year risk of any major osteoporotic fracture is greater than that of a 65-year-old White female who has no additional risk factors (more than 8.4%) r91
          • National Osteoporosis Foundation recommends screening additional subgroups of younger perimenopausal or postmenopausal patients using DXA of hip and lumbar spine r92
            • Younger postmenopausal patients with clinical risk factors for fracture
            • Postmenopausal patients who have a fracture after age 50 years
            • Patients in perimenopausal transition with clinical risk factors for fracture
            • Risk factor assessment tools that have been validated to identify asymptomatic younger patients who are at greater risk may be used and include FRAX (Fracture Risk Assessment Tool)r93 and Osteoporosis Self-Assessment Toolr94r95
        • Screen females who have a fracture after age 50 years for osteoporosis with bone mineral density testing using DXA
      • Consider rescreening females who do not initially meet criteria for osteoporosis
        • No consensus exists regarding ideal interval for rescreening
        • One strategy is to rescreen people based on severity of osteopenia on baseline DXA r90
          • Normal or mild osteopenia (T-score more than −1.5): 7 to 15 years
          • Moderate osteopenia (T-score between −1.5 and −2): 5 years
          • Advanced osteopenia (T-score between −2 and −2.49): 1 year
      • Management of postmenopausal osteoporosis is directed toward prevention of future fractures
        • Adequate intake of calcium (1200 mg daily) and vitamin D (600-1000 units daily) r92r96
        • Pharmacotherapy is available for osteoporosis prevention and treatment
        • Endocrine Society has published guidelines on pharmacologic management of osteoporosis in postmenopausal patients r97r98
    • Cardiovascular disease r99c83
      • Incidence of cardiovascular disease in patients increases sharply at time of menopause and continues to increase with advancing age r100
      • No screening tests are recommended to evaluate for cardiovascular disease specifically related to onset of menopause
      • Cardiovascular effects of menopausal hormone therapy r101
        • Menopausal hormone therapy with combined estrogen and progestogen does not confer cardioprotective benefits in postmenopausal patients who have established cardiovascular disease
        • Safety and efficacy of menopausal hormone therapy for primary prevention of cardiovascular disease in postmenopausal patients as a whole is presently uncertain; however, limited evidence suggests that hormone therapy has favorable effects on risk of heart disease in patients who start menopausal hormone therapy before the age of 60 years or within 10 years of menopause r44r51
          • May result in reduction in atherosclerosis progression, coronary heart disease, and may lower cardiovascular and all-cause mortality
        • There are conflicting results regarding stroke risk and hormone therapy during menopause r57
          • European Stroke Organization recommends against use of hormone therapy to reduce risk of ischemic or hemorrhagic stroke in postmenopausal females or to reduce mortality in postmenopausal females with acute stroke

    Prognosis

    • Treatment of symptoms secondary to hypoestrogenism has no prognostic significance
      • Use of menopausal hormone therapy—with either combined estrogen-progestogen or estrogen alone—does not affect all-cause mortality rates r51
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