menopause

Introduction

Cessation of menstruation with age.

Definitive when amenorrhea has lasted for 12 months.

Etiology

• failure of ovarian follicular development in the presence of sufficient gonadotropin levels
• gradual decline in ovarian function & estrogen production
• age at natural menopause unaffected by tubal ligation
• pregnancy & breast-feeding may lower risk for early menopause

Epidemiology

• average age of menopause is 51-52 years
• range is 40-60 years
• smokers may have accelerated menopause
• 75-80% of women experience discomfort associated with menopause
• 10-15% experience symptoms that interfere with activities of daily living
• 25% complain of symptoms lasting more than 5 years

Pathology

• declining estrogen levels result in onset of accelerated bone loss
• skin thickness & collagen content are reduced, resulting in wrinkles
• urogenital atrophy
  • mucosa of vagina becomes extremely sensitive to estrogen
  • vaginal atrophy
  • increased susceptibility to bacterial vaginitis
  • vulvar & labial atrophy
  • atrophy of urethra & bladder trigone
  • atrophy of pelvic support increasing risk of uterine prolapse, cystocele & rectocele
  • change in vaginal endogenous flora from Lactobacillus to Streptococcus & Prevotella
• androgen deficiency may contribute to:
  • sarcopenia
  • osteoporosis
  • fatigue & psychological symptoms
• progressive increase in risk of coronary artery disease
  • estrogen acts directly on coronary arteries inducing vasodilation
  • estrogen inhibits development of atheromatous plaques by favorable effects on lipoprotein profile
  • higher serum testosterone in postmenopausal women increases risk of cardiovascular disease
    • in contrast, higher serum estradiol in postmenopausal women associated with lower cardiovascular risk
• carotid intima-media thickness & adventitial diameter increase in the perimenopausal period
• cardiovascular disease may influence onset of menopause

Genetics

• common gene variants affecting timing of menopause:
  • ETAA1, ZNF518A, PNPLA8, PALB2, SAMHD1
    • SAMHD1 variants are associated with extended reproductive lifespan in women & increased all-cause cancer risk in both men & women
• UK Biobank identified gene-based associations :
  • CHEK2, DCLRE1A, HELB, TOP3A, BRCA2, CLPB
• 5 genes harbouring variants with large effects
  • protein-truncating variants in ZNF518A are associated with earlier age at menopause (by 5.61 years) & later age at menarche (by 0.56 years)
  • CHEK2 1.6 years later menopause
  • HELB 1.8 years later menopause
  • HROB 2.9 years earlier menopause
  • BRCA2 1.2 years earlier menopause
• 4 genes associated with timing of menopause increase risk of cancer
  • BRCA2 (breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, other)
  • CHEK2 (breast cancer, myeloid leukemia, prostate cancer)
  • PALB (breast cancer, pancreatic cancer, other)
  • SAMHD1 (prostate cancer, mesothelioma, breast cancer)
• women homozygous for stop-gain variant rs117316434(A) in CCDC201 (p.(Arg162Ter) reached menopause 9 years earlier than other women
  • minor allele frequency ~1%
  • present in one in 10,000 northern European women

Clinical manifestations

• hypermenorrhea, oligomenorrhea & finally amenorrhea
  • MKSAP19 would disagree (see below)#
• hot flashes* (16%)
  • mean duration 5.2 years
  • hot flashes often recurr after cessation of hormone replacement therapy (HRT)
• night sweats
• vaginal dryness (26%)
  • dysparunia
  • atrophic vaginitis*
  • vaginal bleeding
• genital irritation (10%)
• urinary stress incontinence
• symptoms of cystitis
• insomnia, early awakening, irritability &/or anxiety (46-53%)
• depression generally resolves within 1 year
• arthralgias ?
• weight gain NOT associated with menopause
• low estrogen levels of menopause associated with nighttime hot flashes, sleep disturbance, & depression

* the 2 manifestations that may be definitively attributed to menopause

# irregular menses with period lasting 15 days is anovulatory bleeding or abnormal vaginal bleeding warranting endometrial biopsy without transvaginal ultrasound in perimenopausal women according to MKSAP19

Laboratory

• in general, diagnosis is clinical & no specific laboratory testing is required
• for premature menopause (<40): serum FSH, serum TSH & serum prolactin
• serum gonadotropins
  • serum follicle-stimulating hormone (serum FSH) is increased generally > 40 mIU/mL
  • serum luteinizing hormone (serum LH)
    • during the perimenopausal period, LH levels remain in the high normal range
    • serum LH levels reach a peak 1-3 years after the menopause followed by a gradual decline
  • serum FSH/serum LH ratio > 1 suggestive of menopause
• Mullerian inhibiting substance in serum/plasma (PicoAMH Elisa)
• serum estradiol levels tend to be diminished
• women on oral contraceptives
  • check hormone levels on 7th day of pill-free interval
  • serum estradiol < 25 pg/mL & FSH/LH ratio of > 1 indicates menopause
• home menopause test NOT recommended

Diagnostic procedures

• endometrial biopsy if breakthrough bleeding

Complications

• osteoporosis
  • early menopause leads to more osteoporotic fractures & earlier death
  • unintentional weight loss associated with highest risk of bone fracture in postmenopausal women
• atherosclerosis
  • natural menopause before age 45
    • 50% increased risk for coronary heart disease
    • 19% increased risk for cardiovascular mortality
    • 12% increased risk for overall mortality
  • premature & early menopause are risk factors for cardiovascular disease whether natural or surgical (RR = 1.6 to 1.8)
  • age of menopause not a cardiovascular risk factor
• sleep disturbance
• depression generally resolves within 1 year
• sleep disturbance & depression increase cardiovascular risk
• hot flashes may persist in older menopausal women in a minority of cases
• vasomotor symptoms of menopause are linked to dyslipidemia, insulin resistance, & hypertension
• memory loss ?
  • verbal memory scores may be somewhat better with later menopause
• increased risk of new-onset asthma (RR=3.4)
• pregnancy is possible in the perimenopausal period even if menstrual cycles are irregular

Management

• topical agents
  • vaginal moisturizers or lubricants
  • vaginal estrogen for atrophic vaginitis
  • transdermal estradiol(Climara) 50 micrograms/day
    • use in combination with progesterone if woman still has uterus
• oral agents
  • hormone replacement therapy short term < 3 years
    • estrogen is most effective therapy for vasomotor symptoms
    • indications:
      • women < 60 years with 10 years of menopause
      • intolerable vasomotor symptoms
      • low-dose estrogen may improve mood
      • urinary incontinence, decreased libido are NOT indications
      • may reduce cardiovascular risk when initiated during menopausal transition, but may be harmful when initiated > 10 years since menopause
    • contraindications:
      • pregnancy, vaginal bleeding, liver disease, coronary artery disease, stroke venous thromboembolism, breast cancer, endometrial cancer
      • chest wall radiation
      • chemotherapy is not a contraindication
    • unopposed estrogen: Premarin 0.625 mg QD if woman has had hysterectomy
    • cyclic therapy results in resumption of menses
      • Premarin 0.625 mg QD days continuously
      • Provera 5-10 mg QD days 1-14
    • continuous therapy
      • Premarin 0.625 mg plus Provera 2.5 mg PO QD
      • Prempro is combination of Premarin plus Provera
  • hot-flashes in estrogen-intolerant women
    • chest wall radiation but not chemotherapy increases risk for breast cancer
    • Provera only
    • megace 20 mg PO BID
    • venlafaxine (Effexor): start 12.5 mg PO BID
    • serotonin re-uptake inhibitors (SSRI)
      • paroxetine (Paxil) 10-20 mg PO QD
        • only nonhormonal medication approved in U.S.for treatment of vasomotor symptoms of menopause
        • start 7.5 mg QHS, increase PRN to 25 mg QHS
      • fluoxetine (Prozac) 20 mg PO QD
      • sertraline (Zoloft) 25-50 mg PO QD
      • escitalopram (Lexapro) 10-20 mg PO QD
    • gabapentin (Neurontin): start 100 mg PO QHS (modest efficacy)
    • pregabalin
  • clonidine 0.05-0.2 mg BID - little or no benefit
  • evaluate annually for continued need of therapy
• diet & lifestyle
  • lifestyle interventions may reduce cardiovascular risk
  • no evidence to support routine supplementation with calcium &/or vitamin D
  • soy protein enriched in isoflavones of limited benefit
  • oily fish & fresh legumes associated with a delay in menopause; refined pasta & rice associated with earlier menopause
• medicinal herbs
  • black cohosh is questionable recommendation
    • no effect on vasomotor activity
  • phytoestrogens
    • modest benefit for hot flashes & vaginal dryness
    • no effect on night sweats
    • soy isoflavones
      • modest benefit for hot flashes & vaginal dryness
      • no value in preventing hot flashes or loss of bone mineral density
  • pine bark extract appears of benefit for hot flashes
  • chinese herbal remedies (dong quai) of no benefit
  • MKSAP 19 concludes herbal therapies of unproven benefit
• exercise - regular aerobic weight-bearing exercise
  • may reduce risk of hip fractures & total fracture risk
  • may increase risk of knee fracture & arm or forearm fracture
• cognitive behavioral therapy for insomnia due to hot flashes
  • mindfulness training, cognitive behavioral therapy, & behavior-based therapy helpful in relieving hot-flashes
• acupuncture may help treat some symptoms (hot flashes, sleep, emotions)
• patient education
  • monthly self breast exam
  • regular mammograms
  • a mobile app from the North American Menopause Society
• dysfunctional uterine bleeding in perimenopausal women
  • pelvic exam
  • Pap smear
  • endometrial biopsy

Clinical trials

• KEEPS trial reports that estrogen-progesterone treatment started soon after menopause
  • relieves menopausal symptoms of hot flashes & night sweats
  • improves mood
  • improves bone mineral density
  • improves sexual function

More general terms

• age-related endocrinopathy

More specific terms

• menopausal disorder

Additional terms

• amenorrhea (oligomenorrhea)
• home menopause test
• hormone replacement therapy (HRT); estrogen replacement therapy; postmenopausal hormone replacement therapy
• hot flash; menopausal vasomotor symptom

Patient information

menopause patient information