hormone replacement therapy (HRT); estrogen replacement therapy; postmenopausal hormone replacement therapy

Introduction

Replacement of estrogen in postmenopausal women. (also see estrogen)

Indications

• menopause (see Women's Health Initiative)
  • vasomotor symptoms, hot flashes
    • most effective treatment for vasomotor symptoms
  • 2-3 years duration
  • menopausal hormone replacement therapy lowers risk of psychosis relapse in midlife women with schizophrenia or schizoaffective disorder 16%
• osteoporosis*
  • for women who cannot tolerate bisphosphonate or raloxifene
    • USPSTF recommends against estrogen or raloxifene for osteoporosis
  • increases bone mineral density
  • reduces risk of fracture
  • cessation of HRT associated with
    • decreased bone mineral density
    • increased risk of hip fracture (HR=1.5 after 2 years)
  • may prevent age-related hyperkyphosis
• atrophic vaginitis
  • low-dose vaginal estrogen
  • oral therapy for failure of topical estrogen
• hypogonadism & primary ovarian failure
  • premature menopause
  • chemotherapy-induced premature ovarian failure
• depression#
  • HRT may lower risk for depression in perimenopausal women
• may reduce risk of colon cancer$
  • but cancers more advanced at presentation
  • no effect on mortality from colon cancer
• may reduce risk of diabetes mellitus {HERS}
• may reduce risk of knee osteoarthritis
• diminished mortality (estrogen alone)
  • among women with BSO at hysterectomy, estrogen-only HRT appears to diminish all-cause mortality with long-term follow-up
• hormone replacement therapy treatment with estrogen alone probably slightly improves the sexual function, uncertain whether estrogen combined with progestogens improves sexual function

* estrogen-progestin therapy reduces risks for diabetes mellitus & fractures (hip fracture & vertebral fractures)

* estrogen alone lowers risks for fractures, invasive breast cancer, & mortality mortality

* has NOT been demonstrated to reduce risk of fractures in women > 60 years of age

# effect of different estrogens & of progestins is not clear

$ relative risk 0.63; see Women's Health Initiative Prempro doubles risk of dementia in women > 65 (see Womens Health Initiative (WHI) memory study)

May diminish physical function & feeling of well-being in elderly.

Contraindications

• pregnancy, vaginal bleeding, liver disease, coronary artery disease, stroke history of venous thromboembolism, breast cancer, endometrial cancer
  • chemotherapy-induced premature menopause is not a contraindication
• estrogen receptor-positive breast cancer*
  • HRT after successful treatment for breast cancer is controversial see HABITS trial;
  • in women treated for breast cancer, menopausal hormone replacement therapy is not associated with increased risk for either breast cancer recurrence or mortality
• treatment with tamoxifen or aromatase inhibitor
  • tamoxifen may not be contraindication
• concurrent vaginal estrogen for atrophic vaginitis
• USPSTF recommends against HRT to prevent chronic disease
• NOT currently indicated for prevention or treatment of Alzheimer's disease or other dementias
  • may lower risk of Alzheimer's disease if started within 5 years of menopause
  • reduces risk for Alzheimer's disease only after 10 years of self-reported use
• NOT beneficial for cardiovascular disease
  • may actually increase risk of myocardial infarction#
  • does not attenuate progression of coronary artery disease
  • 4 years of HRT do not affect carotid intima-media thickness or coronary calcium scores
  • HRT slows atherosclerosis (assesed by carotid intima- media thickness) in recently menopausal women but not in those > 10 years past menopause onset
  • if 10 year cardiovascular risk is > 10% do NOT prescribe HRT
• women > 60 years of age, unless previous HRT & menopause at median age - may increase cardiovascular risk
  • HRT past age 65 is acceptable provided the woman has been advised of increased risks after age 60, she continues to have bothersome symptoms or is unable to use any other appropriate medication, & her clinician has determined that benefits outweigh risks
• does NOT reduce frequency of urinary tract infection
• does NOT help & may worsen urinary incontinence
• any reduced risk for endometrial cancer outweighed by increased risk of breast cancer (see Million Women Study)
• BRAC1 mutation apparently not contraindication
• concurrent statin use not a contraindication
• not recommended for prevention of diabetes mellitus
• not beneficial for prevention of sarcopenia
• not recommended for treatment of osteopenia or osteoporosis

* obtain mammogram prior to initiation of therapy

# may diminish risk of acute coronary syndrome in women who begin HRT within a few years of menopause apparent] after 6 years;

• risk of adverse coronary events increases with age of starting HRT

Benefit/risk

• no benefit for primary or secondary prevention of cardiovascular events
• number need to harm
  • 100 for deep vein thrombosis or pulmonary embolism
  • 200 for stroke
  • 250 for MI
• symptomatic benefits most likely to outweigh risks when begun <= 60 years of age, or within 10 years of menopause onset
• longer duration of estrogen exposure (endoenous or exogenous) associated with prevention of cognitive impairment
  • HRT begun within 5 years of menopause onset associated with better late-life cognitive function vs delayed initiation of HRT

Dosage

• unopposed low-dose oral estrogen if woman has had hysterectomy*
  • otherwise estrogen + progestin
  • transdermal estradiol is probably treatment of choice
  • Premarin 0.625 mg PO QD
  • transdermal estradiol modestly improves sexual function in early menopause
    • conjugated estrogens do not
• cyclic therapy results in resumption of menses
  • Premarin 0.625 mg QD days continuously
  • Provera 5-10 mg QD days 1-12 or 1-14
• continuous therapy
  • Premarin 0.625 mg plus Provera 2.5 mg PO QD
  • Prempro is combination of Premarin plus Provera
• Provera only in women unable to tolerate estrogens
• larger & smaller doses of estrogen & progesterone are used in special circumstances
• lower dosages may become the standard of treatment
  • Premarin 0.3 mg plus Provera 1.5 mg PO QD
  • Provera may potentiate benefits of Premarin
  • unopposed transdermal estrogen 0.014 mg QD increases bone mineral density 2.1% at lumbar spine after 2 years
• transdermal estrogen with vaginal progesterone may have better safety profile than oral HRT
• transdermal estradiol* plus a levonorgestrel-releasing IUD may improve hot flashes, sleep quality, daytime fatigue, & depression
• daily oral conjugated estrogens (0.45 mg) or transdermal estradiol (50 ug) with micronized oral progesterone (200 mg for 12 days each month) effective for hot flashes & night sweats
• disontinuation:
  • duration of HTR > 5 years associated with increased risk of breast cancer
    • individualized risk assessment for HRT > 5 years
  • tapering upon discontinuation
    • of no benefit
      • does NOT affect recurrence of menopausal symptoms
    • may lessen recurrence of menopausal symptoms
  • 25% of women report difficulty discontinuing HRT due to withdrawal symptoms
  • paraxetine, pregabalin, venlafaxine or clonidine may diminish hot flashes during tapering of HRT

* transdermal estradiol 75 mg daily

* estradiol alone in women with prior hysterectomy doubles risk of ovarian cancer & increases mortality in postmenopausal women

Adverse effects

• estrogen-progestin therapy increases risk for
  • breast cancer
    • invasive breast cancer (> 5 years of HRT)
    • all types of HRT except vaginal estrogen associated with increased risk for breast cancer
  • stroke
  • venous thromboembolism (VTE)
    • statins may reduce risk; no plausible mechanism
    • oral HRT but not transdermal estrogen increases risk of VTE
  • lung cancer mortality
  • gallbladder disease
  • dementia
  • urinary incontinence
  • risk of fatal & nonfatal malignancies persists 3 years after cessation of HRT
  • conjugated equine estrogens plus medroxyprogesterone does not increase ovarian cancer or endometrial cancer mortality at 20 years
• increased growth of estrogen-dependent breast cancer*
  • 3-fold increased risk of lobular breast cancer
  • NO increased risk of breast cancer if < 5 years of HRT
  • risk increases with duration of HRT
  • increased risk of breast cancer if > 4 years of HRT
  • relative risk of breast cancer 1.66, women age 50-64
  • all types of estrogens & progestins increase risk of breast cancer identified
  • risk greatest with estrogen-progestin combinations
  • increased mortality associated with combined use of estrogen plus progestin (HR = 2.0)
  • estrogen-progestin hormone therapy close to the time of menopause is associated with highest breast cancer risk
  • relative risk of breast cancer = 1.42 after 20 years of unapposed estrogen in women s/p hysterectomy, relative risk 0.8 in another study, although node+ cancers were increased & need for mammography increased
  • a window of time after menopause during which HRT can confidently be considered to be free of risk has not been
  • risk declines after cessation of HRT; returns to baseline in 3 years
  • black women, obese women, & women with less dense breast may be at less risk of developing breast cancer associated with HRT
• estrogen alone increases risks for
  • stroke
  • deep vein thrombosis
  • gallbladder disease
  • urinary incontinence
  • endometrial cancer
  • ovarian cancer in women with prior hysterectomy (2-fold risk)
  • mortality in postmenopausal women with prior hysterectomy
• breast tenderness (40% 1st year, 13% 4th year of HRT)
• interference with mammograms
  • continuous Progestin increases breast tissue radiographic density interfering with sensitivity of mammography for detecting breast cancer
  • increased false positive mammograms regardless of estrogen alone or estrogen + progestin
• increased risk of ovarian cancer
  • excess risk 0.1%
  • increased risk for serous or endometrioid ovarian carcinoma
  • does not decrease survival among women receiving treatment for nonserous ovarian carcinoma
• vaginal bleeding
• increased risk of thromboembolism
  • transdermal estrogen not associated with increased risk
• increased mortality in non-small cell lung cancer
• increased cardiovascular risk seems linked to progestin
  • increased risk of thrombosis, myocardial infarction* & stroke* within 1st 2 years of use, even in women without heart disease
  • platelet polymorphisms in platelet glycoproteins may predict risk
  • conjugated equine estrogens associated with a higher risk of venous thrombosis & possibly MI than estradiol
  • increased risk of stroke (relative risk: 1.41)
  • neither benefit or harm of HRT after myocardial infarction
  • in early menopause, 10 years of hormone therapy might lower risk for cardiac events without raising risk for cancer, thrombosis, or stroke
  • transdermal estrogen lower risks for cardiovascular disease
  • low-dose conjugated equine estrogens lowers risk of cardiovascular disease & cardiovascular mortality
  • oral estradiol lowers risk for stroke
  • stopping HRT increases cardiovascular risk
    • NNH = 2500 for MI, 2000 for stroke
    • editorialist notes conclusion is not consistent with randomized trial data (NEJM JWatch Oct 27 2015)
• no increase in overall mortality (+/- hysterectomy)
• increased risk of gall bladder disease (cholecystitis)
• increased risk or urinary incontinence
• lupus flares ?
• increased risk of GERD
• increased risk of acute pancreatitis (RR=1.9)
• cognitive impairment
  • cognitive decline may be associated with HRT-related decreases in hippocampal & frontal lobe volumes
  • HRT in midlife may decrease risk for dementia, but HRT in later life increases risk of dementia
  • HRT at age 50-55 years is not associated with increased risk of cognitive impairment
  • whether initiated early or late after menopause, hormone replacement therapy does not affect cognition
  • HRT may be associated with a slight increase in risk for Alzheimer disease (18.6% vs 17.0%)
  • HRT increases risk of dementia 20 vs 16 cases per 1000 womeen within 12 years

* absolute risks are small; 7 more MI, 8 more strokes & 8 more <A13981>breast cancers</A13981> per 10,000 women per year;only continuous, combined (estrogen + progestin) found associated with breast cancer

* from the Women's Health Initiative

• women taking Prempro have a high risk of heart disease, breast cancer, stroke & dementia
• premarin alone does NOT increase the risk of heart disease or breast cancer, but does increase the risk of stroke

Drug interactions

• check thyroid function studies in patients receiving synthroid (T4) 12 weeks after initiating HRT#
• estrogen may be synergistic with bisphosphonates in increasing bone density
• statins may diminish risk of venous thromboembolism

# estrogen increases serum thyroxine-binding globulin (TBG)

Laboratory

• serum estradiol not routine
  • higher among obese women & those consuming alcohol
  • lower among those who smoked cigarettes

Mechanism of action

• benefits on bone density
  • still observed if started in women > 60 years of age
  • 6% gain after 3 years at spine
  • 4% gain after 3 years at femoral neck (hip)
  • 2/3 of gain at spine & femoral neck lost after 2 years off HRT
  • diminished risk of hip fracture (estrogen only)
• estrogen therapy improves insulin-stimulated glucose uptake among women in early menopause but impairs this in women > 10 years past menopause
• diminished mortality
  • 56.4 per 1000 person-years among nonusers, 52.8 among all users, 50.4 among those who used estrogen for 15 years or longer
• HRT slows atherosclerotic plaque progression in recently menopausal women but has neutral or adverse effects in women >= 10 years post menopause
• favorable vascular effects of estradiol appear limited to women without atherosclerosis at menopause

Notes

• cessation of HRT
  • 2-3 years after stopping HRT, relative risks compared with women who did not use HRT
  • mortality same
  • breast cancer same
  • cardiovascular risk same
  • fractures same
  • deep vein thrombosis same
• use of HRT in Norway declined abruptly following publication of the WHI results in 2002, & rates have remained low
  • HRT use in France in higher than Norway
• only markedly supraphysiologic testosterone levels enhance sexuality, lean body mass, & muscle strength in women receiving HRT

More general terms

• long-term pharmacologic therapy
• hormonal therapy

More specific terms

• Estring

Additional terms

• Heart & Estrogen/Progestin Replacement Study (HERS)
• menopause
• Million Women Study
• Study of Osteoporotic Fractures (SOF)