HORMONE REPLACEMENT THERAPY












  • Reference [3]
North American Menopause Society 2017 HRT recommendations
Menopause symptoms and diagnosis
Indications for HRT
  • Bothersome menopause vasomotor symptoms - hot flashes and night sweats. HRT is the most effective treatment.
  • Vulvovaginal atrophy - vaginal dryness, burning, and irritation; sexual symptoms of diminished lubrication and pain
  • Urinary symptoms of menopause - urgency, dysuria, and recurrent urinary tract infections
  • Premature hypoestrogenism - caused by premature ovarian failure or surgery
  • Osteoporosis prevention - in postmenopausal women at increased risk for osteoporosis
Risks / Benefits of HRT
  • The benefits of HRT likely outweigh the risks when it is initiated at less than 60 years of age or within 10 years of menopause onset
  • Initiating HRT at less than 60 years of age and < 10 years from menopause onset may reduce the risk of coronary heart disease and have a favorable effect on all-cause mortality
  • Initiating HRT at greater than 60 years old and/or > 10 years from menopause onset may increase the risk of coronary heart disease, pulmonary embolism, and stroke
  • Women with premature hypoestrogenism should initiate HRT at the onset of their condition
Duration of HRT
  • General
    • The duration of HRT should be based on the patient's individual needs and risk factors
    • Estrogen therapy alone may reduce the risk of breast cancer. Women who only require estrogen may be more appropriate for longer durations of use.
    • Estrogen + progesterone therapy may increase the risk of breast cancer
    • Prevention of bone loss and fracture may be an indication for longer therapy in susceptible women
  • Early hypoestrogenism
    • HRT should continue until at least the median age of menopause which is 52 years
Choice of therapy
  • Women with a uterus
    • Women with a uterus using systemic estrogen therapy require endometrial protection with a progesterone or bazedoxifene (Duavee®)
    • Progesterone therapy is not recommended with low-dose vaginal estrogen therapy
  • Sexual symptoms (vulvovaginal atrophy)
    • Vaginal estrogen preparations are preferred
    • For women choosing systemic therapy, transdermal HRT may be preferred over oral therapy in women with sexual function or libido issues, because it has less of an effect on sex hormone-binding globulin and free testosterone levels
    • Nonestrogen products (ospemifene and prasterone) are also effective
  • Urinary tract symptoms
    • If the primary indication is for urinary tract symptoms, vaginal estrogen therapy should be used. Systemic therapy does not improve urinary incontinence and may increase the incidence of stress urinary incontinence.
  • Vasomotor symptoms
    • Estrogen therapy is preferred
    • Progesterone therapy alone has been shown to be effective in treating vasomotor symptoms, but there is no long-term data on its risks and benefits
      • Treatments used in clinical trials include the following:
Special populations
  • Family history of breast cancer
    • Evidence from observational studies suggests that HRT does not further increase the risk of breast cancer in women with a family history of breast cancer
  • BRCA-positive women without breast cancer
    • BRCA-positive women are at higher risk for breast cancer, primarily estrogen receptor-negative cancer
    • For women who undergo bilateral oophorectomy, consider offering HRT until the median age of menopause (52 years old)
  • Breast and endometrial cancer survivors
    • In general, systemic therapy is not recommended. Any decision to use systemic therapy should be made with an oncologist.
    • For urinary and sexual symptoms, low-dose vaginal therapy has minimal systemic absorption and may be safer in this population. Decisions to use vaginal estrogen therapy should be made with an oncologist.

  • Reference [4]
USPSTF 2017 HRT Recommendations
  • The USPSTF recommends against the use of combined estrogen and progestin therapy for the primary prevention of chronic conditions in postmenopausal women
  • The USPSTF recommends against the use of estrogen only therapy for the primary prevention of chronic conditions in postmenopausal women who have had a hysterectomy




  • Data for hip fractures only
  • HR - hazard ratio (treatment/placebo); S - statistically significant; NS - statistically nonsignificant; CI - 95% confidence interval; NA - not available
  • Case diff - # of cases (treatment - placebo) per 10,000 patients taking treatment for a year
  • Active phase results - results that occurred while the study was ongoing
  • Cumulative results - Results at the end of active phase + post-study follow-up
  • Reference [1,2]
Premarin® 0.625 daily vs Placebo
Outcome Active phase results (median 7.2 years) Cumulative results (median 13 years) Cumulative results (median 18 years)
All-cause mortality HR 1.03 (CI 0.88 - 1.21)
NS
Case diff = +3
HR 0.99 (CI 0.90 - 1.10)
NS
Case diff = -1
HR 0.94 (CI 0.88 - 1.01)
NS
Coronary heart disease HR 0.94 (CI 0.78 - 1.14)
NS
Case diff = -3
HR 0.94 (CI 0.82 - 1.09)
NS
Case diff = -4
CHD mortality
HR 0.89 (CI 0.75 - 1.05)
NS
Invasive breast cancer HR 0.79 (CI 0.61 - 1.02)
NS
Case diff = -7
HR 0.79 (CI 0.65 - 97)
S
Case diff = -7
Breast cancer mortality
HR 0.55 (CI 0.33 - 0.92)
S
Stroke HR 1.35 (CI 1.07 - 1.70)
S
Case diff = +11
HR 1.15 (CI 0.97 - 1.37)
NS
Case diff = +5
NA
Pulmonary embolism HR 1.35 (CI 0.89 - 2.05)
NS
Case diff = +4
HR 1.15 (CI 0.87 - 1.51)
NS
Case diff = +2
NA
Colorectal cancer HR 1.15 (CI 0.81 - 1.64)
NS
Case diff = +2
HR 1.13 (CI 0.85 - 1.51)
NS
Case diff = +2
Colorectal cancer mortality
HR 1.21 (CI 0.79 - 1.84)
NS
All fractures HR 0.72 (CI 0.64 - 0.80)
S
Case diff = -61
HR 0.91 (CI 0.72 - 1.15)
NS
Case diff = -2
NA
Deep vein thrombosis HR 1.48 (CI 1.06 - 2.07)
S
Case diff = +7
HR 1.05 (CI 0.82 - 1.33)
NS
Case diff = +1
NA
Probable dementia
(in women ≥ 65 years old only)
HR 1.47 (CI 0.85 - 2.52)
NS
Case diff = +15
NA NA


  • Data for hip fractures only
  • HR - hazard ratio (treatment/placebo); S - statistically significant; NS - statistically nonsignificant; CI - confidence interval; NA - not available
  • Case diff - # of cases (treatment - placebo) per 10,000 patients taking treatment for a year
  • Active phase results - results that occurred while the study was ongoing
  • Cumulative results - Results at the end of active phase + post-study follow-up
  • Reference [1,2]
Prempro® 0.625/2.5 mg daily vs Placebo
Outcome Active phase results (median 5.6 years) Cumulative results (median 13 years) Cumulative results (median 18 years)
All-cause mortality HR 0.97 (CI 0.81 - 1.16)
NS
Case diff = -1
HR 0.99 (CI 0.91 - 1.08)
NS
Case diff = -1
HR 1.02 (CI 0.96 - 1.08)
NS
Coronary heart disease HR 1.18 (CI 0.95 - 1.45)
NS
Case diff = +6
HR 1.09 (CI 0.96 - 1.24)
NS
Case diff = +3
CHD mortality
HR 1.05 (CI 0.89 - 1.23)
NS
Invasive breast cancer HR 1.24 (CI 1.01 - 1.53)
 S
Case diff = +9
HR 1.28 (CI 1.11 - 1.48)
 S
Case diff = +9
Breast cancer mortality
HR 1.44 (CI 0.97 - 2.15)
NS
Stroke HR 1.37 (CI 1.07 - 1.76)
S
Case diff = +9
HR 1.16 (CI 1.00 - 1.35)
NS
Case diff = +5
NA
Pulmonary embolism HR 1.98 (CI 1.36 - 2.87)
S
Case diff = +9
HR 1.26 (CI 1.00 - 1.59)
NS
Case diff = +4
NA
Colorectal cancer HR 0.62 (CI 0.43 - 0.89)
S
Case diff = -6
HR 0.80 (CI 0.63 - 1.01)
NS
Case diff = -3
Colorectal cancer mortality
HR 1.01 (CI 0.69 - 1.49)
NS
Endometrial cancer HR 0.83 (CI 0.49 - 1.40)
NS
Case diff = -1
HR 0.67 (CI 0.49 - 0.91)
S
Case diff = -3
NA
All fractures HR 0.76 (CI 0.69 - 0.83)
S
Case diff = -51
HR 0.81 (CI 0.68 - 0.97)
S
Case diff = -5
NA
Deep vein thrombosis HR 1.87 (CI 1.37 - 2.54)
S
Case diff = +12
HR 1.24 (CI 1.01 - 1.53)
S
Case diff = +4
NA
Probable dementia
(in women ≥ 65 years old only)
HR 2.01 (CI 1.19 - 3.42)
S
Case diff = +23
NA NA




ELITE trial - HRT vs Placebo in Early vs Late Menopause for Carotid Artery Intima-Media Thickness, NEJM (2016) [PubMed abstract]
  • The Elite trial enrolled 643 postmenopausal women without a history of coronary artery disease
  • Patients were stratified by duration of time since menopause with early postmenopause being < 6 years since menopause, and late postmenopause being ≥ 10 years since menopause
Main inclusion criteria
  • Postmenopausal
  • No history of CAD
  • No regular menses for at least 6 months or surgically-induced menopause
  • Estradiol level < 25 pg/ml
Main exclusion criteria
  • Diabetes
  • Serum triglycerides > 500 mg/dl
  • SBP > 160 | DBP > 110
  • History of DVT or PE
  • Hormone therapy within 1 month of screening
Baseline characteristics
  • Median age: 55 years (early) | 64 years (late)
  • Median time since menopause: 3.5 years (early) | 14.3 years (late)
  • Median LDL: 136 mg/dl (early) | 132 mg/dl (late)
  • Median BP: 116/76 (early) | 118/74 (late)
Randomized treatment groups
  • Group 1 (297 patients): Estradiol 1mg once daily. Women with a uterus also received progesterone vaginal gel (45 mg) for 10 days during each 30-day cycle.
  • Group 2 (299 patients): Placebo once daily. Women with a uterus also received placebo vaginal gel for 10 days during each 30-day cycle.
  • Randomization was stratified based on duration of time since menopause: early postmenopause (< 6 years since menopause), late postmenopause (≥ 10 years since menopause)
Primary outcome: The rate of change in intima–media thickness of the far wall of the right distal common carotid artery, assessed by means of computer image processing of B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up
Results

Duration: Median of 5 years
Outcome HRT Placebo Comparisons
Primary outcome (early postmenopause) 0.0044 mm/yr 0.0078 mm/yr p=0.008
Primary outcome (late menopause) 0.0100 mm/yr 0.0088 mm/yr p=0.29
  • At the end of treatment, some patients underwent coronary artery calcium scoring (n=380) and CT-angiography measurements of coronary artery stenosis and plaque burden (n=375). No significant differences between the HRT group and placebo group were found in either strata. No interaction was observed between strata.
  • There was no significant difference between groups in adverse events

Findings: Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum.