Menopausal Estrogen-Progestogen Therapy

Estrogen products and the endometrial cancer findings

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. Estrogen sales doubled and tripled between the mid-1960s and the mid-1970s. In 1975, reports of increased endometrial cancer in estrogen users led to a dramatic decline in use.

One of those 1975 reports compared 94 women with endometrial carcinoma with age-matched controls. Conjugated estrogen use was recorded for 57 percent of the patients and 15 percent of the controls, giving a risk ratio estimate of 7.6 that rose with duration of use. The authors concluded that conjugated estrogens appeared to have an etiologic role in endometrial carcinoma. This is a case-control finding in women taking estrogen without a progestogen.

Adding a progestogen and the rise of use

According to the same historical review, estrogen use increased again after evidence of protective effects of progestins on estrogen-induced changes in the uterine lining, a 1982 report that conjugated estrogen tablets retained bone mass, and a 1984 National Institutes of Health consensus statement that estrogens were the most effective means of preventing bone loss. Observational reports of lower coronary heart disease among users encouraged further use through the 1990s, and by 2001 about 15 million US women were using estrogen with or without a progestin.

The Women's Health Initiative and later trials

The Women's Health Initiative estrogen-plus-progestin trial was stopped in May 2002 after a mean 5.2 years of follow-up, when the data and safety monitoring board judged that the invasive breast cancer boundary had been exceeded and that risks outweighed benefits. The historical review states that the report produced a precipitous decrease in use and a serious reevaluation of menopausal hormone therapy. The 2003 Million Women Study, a UK cohort of 1,084,110 women aged 50 to 64, reported higher breast cancer incidence among current users, especially with estrogen-progestagen combinations.

Later work examined whether starting close to menopause changes the picture. The Danish Osteoporosis Prevention Study (DOPS), the Kronos Early Estrogen Prevention Study (KEEPS) and the Early versus Late Intervention Trial with Estradiol (ELITE) each enrolled recently postmenopausal women or compared early with late starters. Their findings are described under Research and Evidence.

Names used in the sources

The sources reviewed use several overlapping names, including menopausal hormone therapy, hormone replacement therapy, combined hormone therapy and combined HRT. They spell the progesterone-like component as progestin, progestagen or progestogen, and the main hormone as estrogen or oestrogen. This page uses Menopausal Estrogen-Progestogen Therapy for treatment that combines the two in women with a uterus.

Relationship to other Machipedia pages

This page is one member of the family described on the Machipedia page Hormone Replacement Therapy and does not repeat it. The Menopause Society states that the risks of hormone therapy differ by type, dose, duration of use, route of administration, timing of initiation and whether a progestogen is used. Results for the combined form therefore are not carried to estrogen alone, which has its own page, Menopausal Estrogen-Alone Therapy, or to Low-Dose Vaginal Estrogen, Bioidentical Hormone Replacement or Hormone Pellet Therapy.

What the therapy is

Menopausal estrogen-progestogen therapy is a prescription medical treatment in which estrogen is given together with a progestogen to women who still have a uterus and who have menopausal symptoms. It is a standard medical treatment delivered within conventional healthcare, not a complementary or alternative practice, and Machipedia lists it for context alongside practices that people use next to medical care. The Women's Health Initiative randomized women with a uterus to a combination of conjugated equine estrogens and medroxyprogesterone acetate or placebo.

Why a progestogen is added

The reason for adding a progestogen is protection of the uterine lining. A historical review describes evidence that progestins protect against estrogen-induced endometrial changes, and a 1975 case-control study linked conjugated estrogen use without a progestogen to endometrial carcinoma. A Cochrane review notes that the risk of endometrial cancer among women with a uterus taking estrogen-only therapy is well documented. NICE guideline NG23 advises offering combined therapy to people with a uterus and estrogen-only therapy to people who have had a total hysterectomy.

NICE also states that endometrial cancer risk decreases with continuous combined therapy, and may slightly increase with sequential combined therapy, with a larger increase possible with longer use, fewer progestogen days per cycle and higher estrogen exposure. It advises that people with a uterus are told that vaginal bleeding is common in certain periods after starting or changing therapy and that unscheduled bleeding beyond those periods needs prompt medical review.

Who delivers it and how guidelines frame it

The therapy is prescribed by licensed clinicians. The Endocrine Society guideline, co-sponsored by several menopause and endocrine societies, advises clinicians to individualize therapy and to screen women before starting for cardiovascular and breast cancer risk. The Menopause Society calls for individualized treatment with periodic reevaluation and shared decision-making. NICE advises that people with a history of coronary heart disease or stroke have the option discussed with a healthcare professional with expertise in menopause. The sources reviewed do not describe training or registration standards for prescribers.

Menopausal symptoms and bone loss

The Menopause Society describes hormone therapy as the most effective treatment for vasomotor symptoms (hot flushes and night sweats) and for the genitourinary syndrome of menopause, and states that it has been shown to prevent bone loss and fracture. The Endocrine Society likewise calls it the most effective treatment for vasomotor symptoms. NICE advises offering hormone replacement therapy to people with vasomotor symptoms associated with menopause. A Cochrane review reported that fracture was the only outcome for which strong evidence showed clinical benefit, while advising that it is generally an option for bone protection only for women at significant risk for whom non-estrogen therapies are unsuitable.

Prevention of chronic disease

Use for the prevention of heart disease, cancer and dementia was once common, helped by observational reports. Later trials and guidelines do not support it. The 2022 US Preventive Services Task Force recommendation concluded with moderate certainty that combined estrogen and progestin for primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit, and recommended against it (grade D). The Women's Health Initiative follow-up and the Endocrine Society reach the same view on prevention while keeping symptom management as an appropriate use. The task force statement concerns asymptomatic people and is not a statement about treating menopausal symptoms.

Women's Health Initiative combined trial

The trial randomized 16,608 US women aged 50 to 79 with an intact uterus to conjugated equine estrogens plus medroxyprogesterone acetate or placebo. Hazard ratios after a mean 5.2 years were 1.29 for coronary heart disease, 1.26 for invasive breast cancer (confidence interval 1.00 to 1.59), 1.41 for stroke, 2.13 for pulmonary embolism, 0.63 for colorectal cancer and 0.66 for hip fracture; total mortality was 0.98. Absolute excess risks per 10,000 person-years were 7 coronary events, 8 strokes, 8 pulmonary emboli and 8 invasive breast cancers, with 6 fewer colorectal cancers and 5 fewer hip fractures.

The integrated 2013 report followed 27,347 women across both Women's Health Initiative hormone trials for 13 years. In the combined arm, the intervention-phase hazard ratio was 1.18 for coronary heart disease (not statistically significant) and 1.24 for invasive breast cancer, with cumulative breast cancer 1.28 (confidence interval 1.11 to 1.48). Other risks included stroke, pulmonary embolism, dementia in women aged 65 and over and gallbladder disease; benefits included fewer hip fractures and fewer vasomotor symptoms. A pooled 18-year analysis found no association of combined therapy with all-cause mortality (hazard ratio 1.02).

Systematic reviews

The 2017 Cochrane review included 22 randomized trials with 43,637 women. In relatively healthy postmenopausal women, combined continuous therapy increased the risk of venous thromboembolism (from 2 per 1000 to between 4 and 11 per 1000 after 1 year), stroke (from 6 per 1000 to between 6 and 12 per 1000 after 3 years), breast cancer (from 19 per 1000 to between 20 and 30 per 1000 after 5.6 years) and gallbladder disease (from 27 per 1000 to between 38 and 60 per 1000). Fracture risk fell from 111 per 1000 to between 79 and 96 per 1000.

The 2025 update included 24 studies with 45,660 participants and drew its combined-therapy results from the Women's Health Initiative: little-to-no difference in coronary events (risk ratio 1.17), possible increases in stroke (1.39) and venous thromboembolism (2.03), a probable increase in breast cancer (1.27) and a probable reduction in clinical fractures (0.78). Its authors caution that these rest on one study of oral therapy. A 2015 Cochrane review of 19 trials found no protective effect on mortality or cardiovascular death.

Timing of initiation and the younger-woman trials

The Menopause Society judges the benefit-risk balance favorable for bothersome vasomotor symptoms and prevention of bone loss in women younger than 60 or within 10 years of menopause onset with no contraindications, and less favorable later because absolute risks of coronary heart disease, stroke, venous thromboembolism and dementia are greater. The Endocrine Society also states that benefits may exceed risks for most symptomatic women under 60 or within 10 years of menopause. In the Cochrane cardiovascular review, women who started within 10 years of menopause had lower mortality (risk ratio 0.70) in subgroup analyses.

DOPS randomized 1,006 recently postmenopausal Danish women, mean age 50, to hormone therapy (estradiol with norethisterone acetate in women with a uterus) or no treatment in an open-label design. After 10 years, the composite of death, heart failure admission or myocardial infarction occurred in 16 women versus 33 (hazard ratio 0.48). KEEPS (727 women) found no effect of either treatment on carotid intima-media thickness over 4 years, and ELITE found less progression with estradiol within 6 years of menopause but not 10 or more years after. Both used surrogate measures, and DOPS was open label.

Breast cancer in observational data

The Collaborative Group on Hormonal Factors in Breast Cancer pooled prospective studies including 108,647 women with breast cancer. Estrogen-progestagen risk ratios for current users were 1.60 in years 1 to 4 and 2.08 in years 5 to 14, higher than for estrogen alone (1.17 and 1.33). If the associations are causal, the authors estimate that 5 years of use starting at age 50 would add about one breast cancer in every 50 users of estrogen with daily progestagen, with about twice that excess after 10 years. Some excess persisted for more than 10 years after stopping. The Million Women Study estimated 19 additional cancers per 1000 users of estrogen-progestagen over 10 years of use. Observational data cannot show causation.

Reported harms

Across the sources reviewed, combined therapy is associated with higher breast cancer incidence, venous thromboembolism including pulmonary embolism, stroke and gallbladder disease. NICE states that breast cancer risk increases with combined therapy, rises with duration of use, is higher in current than past users and persists at least 10 years after stopping, with a very small increase in risk of death from breast cancer. It adds that venous thromboembolism risk is increased with oral therapy but not with transdermal therapy, and that stroke risk rises with oral estrogen and is unlikely to rise with transdermal estrogen.

NICE states that coronary heart disease risk does not increase with combined therapy, a point on which the Women's Health Initiative and later syntheses differ in their estimates, as described above. NICE also reports a very slight increase in ovarian cancer risk. The Women's Health Initiative Memory Study enrolled 4,532 women aged 65 or older and found probable dementia in 45 versus 22 per 10,000 person-years (hazard ratio 2.05), an additional 23 cases per 10,000 women per year, with no difference in mild cognitive impairment. NICE says dementia risk might increase if combined therapy is started at 65 or over.

Who may not be suited to it

The Endocrine Society states that people with contraindications should not use menopausal hormone therapy and advises screening for cardiovascular and breast cancer risk before starting. A Cochrane review lists groups for whom it may be unsuitable: those at increased cardiovascular risk, at increased thromboembolic risk (such as with obesity or a history of venous thrombosis) and at increased risk of some cancers, such as breast cancer in women with a uterus. NICE advises that people with a history of coronary heart disease or stroke have the option discussed with a clinician with menopause expertise. The sources reviewed give no complete contraindication list.

Absolute risk and shared decision-making

NICE directs clinicians to share its table of combined therapy versus no therapy and a numerical discussion aid, tailored to age, circumstances and risk factors. The 2017 Cochrane review concluded that women with intolerable menopausal symptoms may wish to weigh symptom relief against the small absolute risk of harm from short-term low-dose therapy if they have no specific contraindications. In its subgroup of women aged 50 to 59 on combined therapy, the only significantly increased risk was venous thromboembolism, below 1 in 500, though the trial was not powered for subgroups.

Care boundaries and gaps in the sources

This page does not replace care from a licensed clinician and should not be used to start, stop or change a prescribed treatment. Unscheduled vaginal bleeding, symptoms of a blood clot or stroke, or a breast change need prompt medical assessment. The sources reviewed do not address prescriber training or registration, and no legal or regulatory material was reviewed. Machipedia pages on Acupuncture, Herbal Medicine and Nutritional Therapy cover other approaches.