Menopausal Estrogen-Alone Therapy

Estrogen products and the 1975 endometrial reports

A historical review reports that the US Food and Drug Administration approved marketing of diethylstilbestrol in 1941 and conjugated equine estrogens in 1942 for menopausal symptoms. It states that estrogen sales doubled and tripled from the mid-1960s to the mid-1970s, and it names Premarin as the brand of conjugated estrogen tablets from Wyeth Pharmaceuticals. These dates describe the United States only.

In December 1975 the New England Journal of Medicine published two reports on endometrial carcinoma. In the Ziel and Finkle case-control study of 94 patients, 57 percent used conjugated estrogens against 15 percent of controls, giving a risk ratio of 7.6 that rose with duration of use. Smith and colleagues compared 317 patients with matched controls who had other gynecologic cancers and found a 4.5-fold higher risk of endometrial cancer among women exposed to estrogen therapy.

The historical review states that these reports led to a dramatic decline in estrogen use. Use then rose again, which the review links to evidence that progestins protected against estrogen-induced endometrial changes. The review adds that a 1982 report of retained bone mass and a 1984 NIH consensus statement on osteoporosis also supported renewed use.

The Women's Health Initiative and stopping early

The same review reports that about 15 million US women used estrogen, with or without progestins, by 2001, and that the 2002 Women's Health Initiative (WHI) report on combined estrogen plus progestin led to a precipitous fall in use. The WHI estrogen-alone trial enrolled 10,739 women aged 50 to 79 with prior hysterectomy at 40 US centers from 1993. In February 2004 the National Institutes of Health ended its intervention phase early, after an average follow-up of 6.8 years.

The Million Women Study

The Million Women Study recruited 716,738 UK postmenopausal women without a hysterectomy between 1996 and 2001. Only 4 percent of those reporting hormone therapy had last used estrogen alone, which fits the shift toward adding a progestogen in women with a uterus. Compared with never users, last use of estrogen alone was associated with a relative risk of endometrial cancer of 1.45 (95% CI 1.02 to 2.06).

Names used in the sources

Sources use several terms for the same family of treatments. NICE writes oestrogen-only HRT for people who have had a total hysterectomy and combined HRT for estrogen plus a progestogen. The Endocrine Society uses menopausal hormone therapy, and the 2022 position statement of the North American Menopause Society uses hormone therapy and distinguishes regimens by whether a progestogen is used. In this article estrogen-alone therapy means estrogen given without a progestogen.

Unopposed describes estrogen given without a progestogen to oppose its effect on the uterine lining, and it appears in the title of a 1995 study of endometrial cancer after conjugated estrogens were stopped. The term is mainly used for women who still have a uterus. A named product such as conjugated equine estrogen is one estrogen preparation, so results for it are not automatically results for every estrogen.

Related Machipedia pages

This page belongs to the Machipedia family page Hormone Replacement Therapy and covers only estrogen without a progestogen. Menopausal Estrogen-Progestogen Therapy covers combined regimens, and Low-Dose Vaginal Estrogen covers locally applied estrogen. Bioidentical Hormone Replacement covers a separate marketing and prescribing category. The historical review notes that interest in bioidentical hormones grew after the 2002 WHI report.

What the therapy is

Estrogen-alone therapy is a prescription medical treatment that gives estrogen without a progestogen. NICE guideline NG23 recommends offering oestrogen-only HRT to people who have had a total hysterectomy and combined HRT to people with a uterus. It states that endometrial cancer risk increases with oestrogen-only HRT in people with a uterus, with both oral and transdermal forms.

The Million Women Study authors state that progestagens counteract the adverse effect of estrogens on the endometrium. A Cochrane review defined hormone therapy in its trials as estrogens, with or without progestogens, by oral, transdermal, subcutaneous or intranasal routes. This page names these categories only and gives no doses, products or instructions.

A standard medical treatment

Estrogen-alone therapy is a standard medical treatment prescribed within conventional care, not an alternative or traditional practice. It appears on Machipedia because people often compare it with other approaches. The Endocrine Society guideline states that other options exist for those who prefer not to use menopausal hormone therapy or who have contraindications. Machipedia has separate pages for Acupuncture and Herbal Medicine, and this page does not assess them.

Who delivers it and how it is overseen

The sources describe delivery by prescribing clinicians within health systems. The Endocrine Society guideline says health care professionals should individualize therapy and screen for cardiovascular and breast cancer risk before starting. The 2022 position statement calls for periodic reevaluation of benefits and risks. NICE refers complex cases to a healthcare professional with expertise in menopause, whose training should be recognized by a body such as the British Menopause Society, the Faculty of Sexual and Reproductive Healthcare or the Royal College of Obstetricians and Gynaecologists. The sources reviewed do not describe a US register.

Hot flashes and other menopausal symptoms

The 2022 North American Menopause Society position statement says hormone therapy remains the most effective treatment for vasomotor symptoms and the genitourinary syndrome of menopause. The Endocrine Society guideline likewise calls menopausal hormone therapy the most effective treatment for vasomotor symptoms. A Cochrane review of 24 trials with 3,329 participants found a 75 percent reduction in weekly hot flush frequency relative to placebo (95% CI 64.3 to 82.3), with a 57.7 percent reduction in placebo groups. That review pooled estrogen-alone and combined oral regimens.

Bone and fracture

The position statement says hormone therapy has been shown to prevent bone loss and fracture. In the WHI estrogen-alone trial, hip fracture had a hazard ratio of 0.61 (95% CI 0.41 to 0.91), an absolute reduction of 6 hip fractures per 10,000 person-years. The Cochrane review calls fracture the only outcome with strong evidence of clinical benefit and says therapy is generally an option only for women at significant risk for whom non-estrogen therapies are unsuitable.

Uses the guidelines do not support

The historical review notes that observational reports of lower heart disease risk in estrogen users promoted wider use through the 1990s. The Endocrine Society states that current evidence does not justify hormone therapy to prevent coronary heart disease, breast cancer or dementia. NICE says not to offer estrogen-alone or combined therapy for primary or secondary prevention of cardiovascular disease.

The Women's Health Initiative estrogen-alone trial

This randomized, double-blind trial compared one conjugated equine estrogen preparation with placebo in 10,739 women with prior hysterectomy. After an average of 6.8 years, hazard ratios were 0.91 (95% CI 0.75 to 1.12) for coronary heart disease, 0.77 (0.59 to 1.01) for breast cancer, 1.39 (1.10 to 1.77) for stroke and 1.34 (0.87 to 2.06) for pulmonary embolism. Absolute differences were 12 additional strokes and 6 fewer hip fractures per 10,000 person-years. The authors found no overall benefit in the global index and advised against use for chronic disease prevention.

Extended follow-up

With 13 years of cumulative follow-up, invasive breast cancer was diagnosed in 168 women on estrogen alone and 216 on placebo (hazard ratio 0.79, 95% CI 0.65 to 0.97). Absolute global-index risk per 10,000 women each year ranged from 19 fewer cases at ages 50 to 59 to 51 excess cases at ages 70 to 79. After a median of more than 20 years, annualized breast cancer incidence was 0.30 percent against 0.37 percent (hazard ratio 0.78), and breast cancer deaths numbered 30 against 46 (hazard ratio 0.60, 95% CI 0.37 to 0.97).

For all-cause mortality over 18 years, the hazard ratio for estrogen alone was 0.94 (95% CI 0.88 to 1.01), so the trial did not show a mortality difference. The breast cancer result in women with a hysterectomy contrasts with a higher incidence (hazard ratio 1.28) in the estrogen plus progestin trial, and the findings should not be transferred between the two groups.

Pooled trial evidence

A 2017 Cochrane review of 22 trials with 43,637 women reported that estrogen-only therapy increased venous thromboembolism, stroke and gallbladder disease, and reduced breast cancer and clinical fracture, without raising coronary events. After 7 years, stroke rose from 24 to between 25 and 40 per 1,000 and clinical fracture fell from 141 to between 92 and 113 per 1,000. Quality was moderate, nearly 70 percent of data came from two trials, and only about 30 percent of women were aged 50 to 59.

Professional-body and guideline statements

The 2022 position statement says risks differ by type, dose, duration, route, timing of initiation and whether a progestogen is used. It finds the benefit-risk ratio favorable for bothersome vasomotor symptoms and bone loss in women under 60 or within 10 years of menopause onset without contraindications. The US Preventive Services Task Force concluded with moderate certainty that estrogen alone has no net benefit for primary prevention of chronic conditions after hysterectomy and recommended against it (grade D) for that purpose.

NICE states that oestrogen-only HRT is unlikely to affect life expectancy, with very little or no increase in breast cancer risk and no increase in coronary heart disease risk. It reports decreased fragility fracture risk while taking therapy, and stroke risk that rises with oral but is unlikely to rise with transdermal oestrogen-only HRT.

Cognition and dementia

In the WHI Memory Study, 2,808 women aged 65 to 79 with prior hysterectomy were followed for a mean 5.4 years. Cognitive scores were slightly lower with estrogen than placebo (0.26 points, P = .04), and the relative risk of a large score decline was 1.47 (95% CI 1.04 to 2.07). NICE states that dementia risk is unlikely to increase with oestrogen-only HRT, and the Cochrane review says therapy is not indicated to prevent dementia.

Limits of the evidence

The main randomized evidence tests a single conjugated equine estrogen preparation in women who had a hysterectomy, most of them over 60. NICE reports similar breast cancer risk with oestradiol and conjugated equine oestrogen. The sources reviewed do not report head-to-head randomized trials of every preparation and route, and they do not test whether results in older trial participants apply to younger women at menopause.

Uterine lining changes in women with a uterus

Estrogen without a progestogen is associated with endometrial cancer in women who still have a uterus. The Million Women Study found a relative risk of 1.45 for last use of estrogen alone, with the effect greatest in non-obese women. A California study found the excess risk fell as the estrogen-free interval grew, from 5.0 within 24 months to values near one after 48 months. NICE advises that people with a uterus on systemic therapy who have unscheduled vaginal bleeding beyond the expected early period seek medical help promptly.

Stroke, blood clots and gallbladder disease

The WHI estrogen-alone trial found 12 additional strokes per 10,000 person-years. The Cochrane review reported increased venous thromboembolism, stroke and gallbladder disease with estrogen-only therapy. After 7 years, gallbladder disease rose from 27 to between 38 and 60 per 1,000. NICE states that venous thromboembolism risk is greater with oral than transdermal therapy and that very slight increases in ovarian cancer risk occur after 5 years of estrogen-only use.

Contraindications and care boundaries

The Endocrine Society guideline says women with contraindications should not use menopausal hormone therapy. The Cochrane review lists those at increased cardiovascular, thromboembolic or some cancer risk as possibly unsuitable. The 2022 position statement finds the benefit-risk ratio less favorable when therapy starts more than 10 years after menopause onset or after age 60, because of greater absolute risks of coronary heart disease, stroke, venous thromboembolism and dementia. This page is information only and does not replace advice from a prescribing clinician.