Major Studies Involving HRT, Summary

It is important to give patients the best information possible in regards to your risks and benefits when considering HRT.  Most of the studies done on HRT have been done on synthetic drugs that mimic your own natural hormones so it is NOT accurate to translate these studies to the use of bioidentical hormones.  However, we want you to have as much information as possible.  Following are summaries of some major studies on HRT.

1976-present Nurses’ Health Study (NHS)

The single largest cohort study of women, the ongoing NHS was established in 1976 to study the relationship between oral contraceptive use and cigarette smoking and risk of major illnesses. The scope and range has since broadened to include implications of various lifestyle factors (i.e. exercise and diet) on women’s health. Initially comprised of 127,000 nurses, 30 to 55, participants receive detailed questionnaires every 2 years in which they report medical histories, daily diet habits and major life events that have occurred in the previous 24 months.

Response rate averages 90 percent. Major findings include:

• Birth control pills do not increase non-smoking women’s risk of heart disease
• Women who take oral contraceptives for more than 5 years have less than half the risk of ovarian cancer than women who have never used birth control pills
• The use of estrogen alone or a combination of estrogen and progestin is associated with an increased risk of breast cancer. Specifically, the use of combined estrogen-progestin therapy has been linked to a higher risk compared to estrogen alone.  NOTE that much of the estrogen used was equine based (Premarin) and the progestin was synthetic analogue to progesterone (Provera).

1987-1990 Post-menopausal Estogen/Progestin Interventions (PEPI) Trial

This three-year study involved 875 postmenopausal women aged 45 to 64 years.  32% previously had a hysterectomy.  The study’s purpose was to test the effects of estrogen therapy on four factors that affect a woman’s risk of heart disease: HDL (good) cholesterol, systolic blood pressure, fibrinogen and insulin.

Women were randomly assigned to five treatment groups:

1. A placebo (no hormone)
2. Estrogen (0.625 mg Premarin)
3. Estrogen (0.625 mg Premarin) and progestin (2.5 mg Provera) taken daily
4. Estrogen (0.625 mg Premarin) taken daily and progestin (10 mg) taken 12 days each month
5. Estrogen (0.625 mg Premarin) and micronized progesterone (200 mg progesterone USP) taken daily.

In the study, all of the estrogen/progestin combinations produced significantly greater increases in HDL (good) cholesterol levels than the placebo.  Estrogen combined with bioidentical, micronized progesterone provided the best cardiovascular protection of all the combined regimens, nearly equal to taking estrogen alone.  Combining estrogen with progesterone or progestin was shown to help protect women against endometrial cancer.  The study also discovered postmenopausal women taking hormones gained less weight than if not taking hormones.

1995-1998 Heart and Estrogen/Progestin Replacement Study (HERS)

This three year study of 2,300 postmenopausal women with coronary heart disease (CHD) studied the role of hormone therapy on heart disease risk.  After 6.8 years, those randomly assigned to take supplemental estrogen (Premarin) and progestin (Provera) showed no cardiovascular benefit or harm.  The study recommended women not start estrogen/progestin to prevent future heart attacks, but if already using estrogen therapy, to continue as there may be a long-term benefit.

1998-2002 Heart and Estrogen/Progestin Replacement Study (HERS II)

Follow-up study concluded that postmenopausal women with CHD should not use combination hormone therapy to reduce the risk of CHD events, such as heart attacks.

1991-2005 Women’s Health Initiative Study (WHI)

Involving over 161,000 women ages 50-79, the WHI had two components. The primary component, a randomized controlled trial on hormone therapy in postmenopausal women with breast cancer as a primary endpoint, had three arms.

1. Administration of oral, single dose Prempro synthetic estrogen and progestin
2. Administration of oral, single dose Premarin synthetic estrogen
3. Administration of calcium/vitamin D to evaluated the effect on prevention of osteoporosis related fractures and colorectal cancer.  The second component examined the relationship between lifestyle, health and risk factors and specific disease outcomes.  This 15-year project ended March 2005.

Summaries of the findings are given below.  However, be aware that the findings for the two studies should not be compared directly because of differences in the women’s characteristics at the time of their enrollment in the studies.  For example, those in the estrogen-alone study had a higher risk of cardiovascular disease than those in the estrogen-plus-progestin study.  Women in the estrogen-alone study were more likely to have such heart disease risk factors as high blood pressure, high blood cholesterol, diabetes, and obesity.

Compared with the placebo, estrogen (Premarin) plus progestin (Provera) resulted in:

• Increased risk of heart attack
• Increased risk of stroke
• Increased risk of blood clots
• Increased risk of breast cancer (1.4x relative risk)
• Reduced risk of colorectal cancer
• Fewer fractures
• No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)

Compared with the placebo, estrogen alone resulted in:

• No difference in risk for heart attack
• Increased risk of stroke
• Increased risk of blood clots
• Uncertain effect for breast cancer (1.1x relative risk)
• No difference in risk for colorectal cancer
• Reduced risk of fracture

2005 Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort.

Most epidemiological studies have shown an increase in breast cancer risk related to hormone replacement therapy (HRT) use.  A recent large cohort study showed effects of similar magnitude for different types of progestogens and for different routes of administration of estrogens evaluated.  Further investigation of these issues is of importance. We assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women who had never taken any HRT 1 year before entering the E3N-EPIC cohort study.

Results agree with WHI showing increased risk of breast cancer with estrogen alone (1.1x) and with addition of medroxy-progesterone (1.4x). Most importantly it showed a reduction in breast cancer risk with addition of Bioidentical progesterone (0.9x relative risk).

2012 Effect of hormone replacement therapy on cardiovascular events in recently postmenopausalwomen: randomised trial.

1006 healthy women aged 45-58 who were recently postmenopausal, with 502 women randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control).  In the treatment group, women were treated with triphasic estradiol and norethisterone acetate while women who had undergone hysterectomy received 2 mg estradiol a day.  Participants were followed for 16 years.

Conclusions:  After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.

2012 The Kronos Early Estrogen Prevention Study (KEEPS)

KEEPS is a 5-year clinical trial that evaluated the effectiveness of 0.45 mg of conjugated equine estrogens, 50 mcg weekly transdermal estradiol (both in combination with cyclic oral, micronized progesterone, 200 mg for 12 days each month), and placebo in preventing progression of carotid intimal medial thickness and the accrual of coronary calcium in women aged 42-58 years who are within 36 months of their final menstrual period.

Conclusions:  Estrogen/progesterone treatment started soon after menopause appears safe and relieves many of the symptoms menopausal women face as well as improving mood and markers of cardiovascular risk, according to a multicenter randomized study presented at the North American Menopause Society (NAMS) Annual Meeting in Orlando, Florida.

2017 Estradiol therapy and breast cancer risk in perimenopausal and postmenopausal women: a systematic review and meta-analysis