Hormone replacement therapy

ACRONYMS AND DEFINITIONS

Active phase results - Results that occurred while the study was ongoing

Case diff - # of cases (treatment - placebo) per 10,000 patients taking treatment for a year

CI - Confidence interval

CIMT - Carotid artery intima–media thickness

Cumulative results - Results at the end of active phase + post-study follow-up

HR - Hazard ratio (Treatment/placebo)

HRT - Hormone replacement therapy

NAMS - North American Menopause Society

NS - Nonsignificant

S - Statistically significant

USPSTF - U.S. Preventive Services Task Force

WHI - Women's Health Initiative trials

OVERVIEW OF HRT

When women go through menopause, they experience a wide range of symptoms, most of which are bothersome and uncomfortable. For years, hormone replacement therapy was prescribed freely to women to treat and prevent menopause-related conditions. Then in 2002, results from the Women's Health Initiative (WHI) Study were published. The WHI found that postmenopausal women taking combination (estrogen and progestin) hormone therapy for menopause symptoms had an increased risk for breast cancer, heart disease, stroke, blood clots, and urinary incontinence. These findings drastically changed the perception and prescribing of HRT. Since 2002, more information has become available that has helped to further define the risks and benefits of HRT
Current recommendations from the NAMS and USPSTF for HRT are presented below along with results from the WHI trial and more recent ELITE trial which looked at the effects of HRT on CIMT thickness, a surrogate measure for atherosclerosis

GUIDELINES

Reference [3]
North American Menopause Society 2017 HRT recommendations
Menopause symptoms and diagnosis See female hormone physiology
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: Medroxyprogesterone acetate 10 mg once daily [PMID 17419685] Micronized progesterone 300 mg once daily at bedtime [PMID 22453200] Megestrol acetate 20 mg once daily [PMID 18375894]
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. STUDY: an observational study (N=8461) published in 2022 found that women with early-stage invasive estrogen receptor-positive nonmetastatic breast cancer who used vaginal or oral estrogen therapy after their diagnosis did not have an increased risk of recurrence or mortality. [PMID 35854422]

Reference [4]
USPSTF 2022 HRT Recommendations
The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy

WOMEN'S HEALTH INITIATIVE TRIALS

Overview

The Women's Health Initiative trials (WHI) were two large studies that examined the effects of female hormone replacement therapy in postmenopausal women aged 50 - 79 years. Over the years, a number of analyses have been performed on the trial data. The information in the charts below is from a comprehensive review published in 2013 and a long-term mortality study published in 2017.

Estrogen study (Premarin®)

In the estrogen study, women without a uterus (s/p hysterectomy) were randomized to conjugated estrogens 0.625 mg/d (Premarin®) (5310 patients) or placebo (5429 patients)
The active phase of the study lasted a median of 7.2 years, after which participants were followed for an additional 6 years, providing a cumulative follow-up of 13 years
After the active phase of the study, less than 4% of participants reported using hormone replacement therapy on their own
The primary outcome of the study was the incidence of coronary heart disease and invasive breast cancer

^✝ 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

Estrogen + progesterone study (Prempro®)

In the estrogen + progesterone study, women who still had their uterus were randomized to conjugated estrogens 0.625 mg/d + medroxyprogesterone 2.5 mg/d (Prempro®) (8506 patients) or placebo (8102 patients)
The active phase of the study lasted a median of 5.6 years, after which participants were followed for an additional 7 years, providing a cumulative follow-up of 13 years
After the active phase of the study, less than 4% of participants reported using hormone replacement therapy on their own
The primary outcome of the study was the incidence of coronary heart disease and invasive breast cancer

^✝ 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

Overview

Observational studies have found a beneficial effect of hormone replacement therapy (HRT) on coronary heart disease while large, randomized controlled trials have not. One proposed reason for the discrepancy is that the timing of HRT in relation to menopause plays a role. It has been theorized that the beneficial effect occurs if HRT is prescribed closer to menopause (typically within 2 years), but does not occur if prescribed later (typically > 10 years after menopause).
The ELITE trial was a randomized controlled trial designed to evaluate the timing of HRT in relation to menopause and its effects on carotid artery intima–media thickness (CIMT), a surrogate measure for atherosclerosis

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

Outcome	HRT	Placebo	Comparisons
Duration: Median of 5 years
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.

Summary

In the ELITE trial, HRT in early menopause had a beneficial effect on carotid intima-media thickness (CIMT). HRT in late menopause had no significant effect on CIMT.
It's important to note that CIMT is a surrogate marker for atherosclerosis, and it is unknown what effect HRT has on meaningful outcomes like heart attack and stroke. Niacin has also been shown to have a favorable effect on CIMT, but in large, randomized controlled trials, it did not improve cardiovascular outcomes. The fact that CAC scoring and CT-angiography findings at the end of the study were not different between the groups also casts doubt on any cardioprotective effects from HRT.
The main takeaway from this trial is that HRT for up to 5 years in early menopause (< 6 years) does not appear to have a negative effect on cardiovascular health

BIBLIOGRAPHY

1 - PMID 24084921 - Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials, JAMA (2013)
2 - PMID 28898378 - Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality, JAMA (2017)
3 - PMID 28650869 - The 2017 hormone therapy position statement of The North American Menopause Society, Menopause (2017)
4 - USPSTF website

HORMONE REPLACEMENT THERAPY