Reproductive · PANCE / PANRE

Menopause

Permanent cessation of menses after 12 months of amenorrhea due to loss of ovarian follicular activity.

Also known as: menopause, perimenopause, climacteric, vasomotor symptoms, hot flashes

Overview

Permanent cessation of menstruation diagnosed retrospectively after 12 consecutive months of amenorrhea in the absence of other pathology. Average age 51 in the US. Perimenopause is the menopausal transition characterized by cycle irregularity and vasomotor symptoms preceding the final menstrual period.

Epidemiology

Universal in women who reach reproductive senescence. Vasomotor symptoms affect ~75-80% of women; ~25% have severe symptoms lasting >5 years (median duration ~7-10 years).

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Risk factors

Earlier menopause: smoking (~2 years earlier), nulliparity, family history, certain ethnicities, autoimmune conditions
Surgical menopause: bilateral oophorectomy
Iatrogenic menopause: chemotherapy, pelvic radiation

Pathophysiology

Progressive depletion of ovarian follicles → decreased inhibin B and AMH → loss of negative feedback → elevated FSH (and LH). Reduced estradiol production produces vasomotor symptoms (hypothalamic thermoregulatory instability), genitourinary atrophy, bone loss, and adverse lipid/metabolic changes.

Clinical presentation

Symptoms

Vasomotor symptoms: hot flashes, night sweats
Menstrual irregularity (perimenopause): variable cycle length, skipped periods, heavier/lighter flow
Genitourinary syndrome of menopause: vaginal dryness, dyspareunia, urinary urgency/frequency, recurrent UTIs
Sleep disturbance, mood changes, brain fog
Loss of libido

Signs / physical exam

Vaginal/vulvar atrophy: pale, thin mucosa; loss of rugae; petechiae
Decreased breast fullness
BP, weight, BMI changes
Skin and hair changes

Differential diagnosis

Premature ovarian insufficiency — Same physiology but onset <40 yo; warrants karyotype, autoimmune workup, fragile X testing
Hyperthyroidism — Heat intolerance and palpitations can mimic vasomotor symptoms; check TSH
Pheochromocytoma — Episodic palpitations, headache, hypertension; plasma/urine metanephrines
Carcinoid syndrome — Flushing with diarrhea; urinary 5-HIAA
Medication effects (SSRIs, opioids, vasodilators) — Temporal relation; review meds
Anxiety/panic disorder — Hot flushes with anxiety; psychiatric history

Diagnostic workup

Labs

Diagnosis is clinical for women >45 with typical symptoms — labs not required
FSH (≥25-30 IU/L, repeated) — useful in younger women or atypical presentations
TSH, prolactin, hCG to exclude alternatives
Estradiol typically low but variable in perimenopause
Lipid panel, bone density (DEXA) — baseline screening per USPSTF (age ≥65, earlier if risk factors)

Imaging

Endometrial evaluation (TVUS, biopsy) for any postmenopausal bleeding
DEXA for osteoporosis screening

Diagnostic algorithm

Symptom Domain	First-Line	Alternatives
Vasomotor (mod-severe)	Systemic estrogen ± progestin	SSRI/SNRI (paroxetine, venlafaxine), gabapentin, fezolinetant, CBT
Genitourinary (GSM)	Topical vaginal estrogen	Moisturizers, lubricants, vaginal DHEA (prasterone), ospemifene
Bone loss	Calcium + vitamin D, exercise, HT if indicated	Bisphosphonates, denosumab, raloxifene
Sleep / mood	Sleep hygiene, exercise, HT	SSRI/SNRI, CBT-I
Contraindications to HT	—	Breast/estrogen-sensitive cancer, VTE, stroke/MI, active liver disease, unexplained bleeding

Menopausal symptom domains and evidence-based therapies.

Treatment

First-line

Lifestyle: cooling strategies, exercise, weight management, smoking cessation, limit alcohol/caffeine
Vaginal moisturizers and lubricants for genitourinary symptoms
Topical vaginal estrogen — estradiol cream, ring, or tablets — first-line for isolated GSM, minimal systemic absorption
Systemic hormone therapy for moderate-to-severe vasomotor symptoms (see by_subtype)

Systemic hormone therapy (HT)

Estrogen alone (transdermal estradiol patch, oral conjugated equine estrogen, oral estradiol) — for women without a uterus
Estrogen + progestin (combined oral, sequential or continuous; or estrogen + levonorgestrel IUD) — for women with a uterus to protect endometrium
Lowest effective dose for shortest duration consistent with goals; reassess annually
Initiate ideally <60 yo and within 10 years of menopause ('timing hypothesis')
Contraindications: history of breast cancer, estrogen-sensitive cancer, unexplained vaginal bleeding, active VTE/stroke/MI, active liver disease

Nonhormonal options for vasomotor symptoms

SSRIs/SNRIs — paroxetine (FDA-approved for VMS, avoid with tamoxifen), venlafaxine, escitalopram
Gabapentin (especially night sweats)
Clonidine
Fezolinetant — neurokinin-3 receptor antagonist (novel nonhormonal)
Cognitive behavioral therapy, clinical hypnosis (evidence-based)

Bone health

Calcium 1200 mg/day and vitamin D 800-1000 IU/day
Weight-bearing exercise
Bisphosphonates, denosumab, or other osteoporosis therapy as indicated

Complications

Osteoporosis and fragility fractures
Cardiovascular disease (risk equalizes with men post-menopause)
Genitourinary syndrome of menopause: recurrent UTIs, dyspareunia, pelvic floor dysfunction
Sleep disturbance, mood disorders, cognitive symptoms
Weight gain and metabolic changes

PANCE pearls

Any postmenopausal bleeding requires evaluation for endometrial cancer (endometrial biopsy or TVUS, with biopsy if thickness >4 mm).
Women with an intact uterus on systemic estrogen MUST also receive progestin to prevent endometrial hyperplasia/cancer.
Vaginal estrogen is safe even in women with prior estrogen-receptor-positive breast cancer in many cases (with oncology consultation); minimal systemic absorption.
Hormone therapy initiated <60 yo and within 10 years of menopause has the most favorable risk-benefit profile (WHI re-analyses).
Paroxetine inhibits CYP2D6 and decreases tamoxifen efficacy — avoid in patients taking tamoxifen; use venlafaxine instead.

References

NAMS 2022 — The 2022 Hormone Therapy Position Statement of the North American Menopause Society (Menopause 2022)
ACOG PB 141 — ACOG Practice Bulletin No. 141: Management of Menopausal Symptoms
USPSTF 2022 — Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons: USPSTF Recommendation Statement (JAMA 2022)

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