Estradiol is the estrogen the body makes most during the reproductive years. As a medicine it has been studied for more than two decades, in very different groups of women, and the results differ by age, by time since menopause and by route. This article covers the trials behind estradiol itself, not the broader hormone-therapy question covered elsewhere.
Hot flashes: the best-established benefit
A Cochrane review pooled placebo-controlled trials of oral estrogen lasting at least three months. Hot flushes and night sweats became less frequent and less severe than with placebo. The trials were short and mostly tested tablets, so the review says little about years of use.
The large trial that changed the field
The Women's Health Initiative estrogen-alone trial enrolled 10,739 women aged 50 to 79 who had had a hysterectomy. They took conjugated equine estrogen 0.625 mg a day or placebo for about 6.8 years. Stroke was higher on estrogen (hazard ratio 1.39, 95% CI 1.10 to 1.77), hip fracture was lower (0.61, 0.41 to 0.91), and coronary heart disease did not differ. The trial used conjugated equine estrogen, not estradiol, so its numbers do not transfer directly to estradiol products.
Timing: why age and years since menopause matter
ELITE randomized 643 healthy women, grouped by years since menopause, to oral estradiol 1 mg daily or placebo. Carotid artery wall thickening rose 0.0078 mm a year on placebo and 0.0044 mm a year on estradiol in women under 6 years past menopause. In women 10 or more years past menopause the rates were 0.0088 and 0.0100 mm a year, with no difference. The interaction between treatment and timing was significant (P=0.007). Artery thickness is a surrogate measure, not a heart attack or stroke count.
Route: clots depend on how estrogen is taken
A 2008 BMJ meta-analysis of observational studies and randomized trials found that oral estrogen raised venous thromboembolism risk, while transdermal estrogen did not show the same signal (observational odds ratio 2.5 for oral and 1.2 for transdermal among current users). The risk for oral users was highest in the first year. Transdermal forms are generally preferred when clot risk is a concern.
Current guidance
The 2022 North American Menopause Society statement judges the balance of benefit and risk to favor treatment for women under 60 or within 10 years of menopause without contraindications. It finds the balance less favorable when treatment starts more than 10 years after menopause or after age 60, because absolute risks of heart disease, stroke, clots and dementia are higher. It advises against compounded bioidentical hormone products.
What this does not say
- The trials tested conjugated equine estrogen (WHI), oral estradiol 1 mg (ELITE) and oral estrogen (Cochrane). They do not test compounded creams, capsules or injections.
- Results are averages for groups of women, not predictions for one person; the risks and benefits shift with age, history and time since menopause.
- A surrogate such as artery thickness does not show that a heart event is prevented.
How we use this
Our physicians decide on estrogen by age, time since menopause, medical history and clot risk, and they choose the route with that in mind. The trials above set the boundaries of what we can say; they do not promise an outcome.
Compounded estradiol products are not the trial products. We say so when we prescribe them, and we follow the society's advice on when a compounded product is not needed.
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- 1.Anderson GL et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. JAMA
- 2.Hodis HN et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231. NEJM
- 3.MacLennan AH et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004 (CD002978). Cochrane Library
- 4.Canonico M et al. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336:1227-1231. BMJ
- 5.Faubion SS et al. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29(7):767-794. Menopause (NAMS)