Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Estrogen alone increases endometrial hyperplasia in postmenopausal women

ACP J Club. 1999 Nov-Dec;131:59. doi:10.7326/ACPJC-1999-131-3-059

Source Citation

Lethaby A, Farquhar C, Sarkis A, et al. The association of oestrogen, oestrogen-progestogen and placebo with endometrial hyperplasia and irregular bleeding in the menopause. Cochrane Review, latest version 24 Feb 1999. In: The Cochrane Library. Oxford: Update Software.



Which hormone-replacement therapy (HRT) regimens protect against endometrial hyperplasia or cancer with a low rate of irregular bleeding?

Data sources

Studies were identified from the Cochrane Menstrual Disorders and Subfertility Group Register of Trials, MEDLINE, EMBASE/Excerpta Medica, PsycLIT, Current Contents, Biological Abstracts, Social Sciences Index, CINAHL, bibliographies of relevant papers, and contact with experts.

Study selection

Studies were selected if they were randomized controlled trials; included postmenopausal women who had an intact uterus; compared unopposed estrogen, estrogen plus continuous or sequential progestogen, and placebo; continued treatment for ≥ 6 months; assessed endometrial hyperplasia, carcinoma, or both; and assessed rate of irregular bleeding. Studies of women who had concurrent disease, were receiving HRT ≤ 1 month before study entry, or had contraindications to HRT were excluded.

Data extraction

Data were extracted on study and participant characteristics, clinical outcomes, and adherence to therapy.

Main results

23 studies were identified, and 18 trials (5247 women; treatment range 6 mo to 3 y) met the selection criteria. Results are shown in the Table. Endometrial hyperplasia, irregular bleeding, and nonadherence to therapy correlated with the dose of unopposed estrogen. Compared with unopposed estrogen, estrogen plus continuous or sequential progestogen was associated with a lower risk for endometrial hyperplasia and improved adherence to treatment. No increase in endometrial cancer was seen in any group, but follow-up was a maximum of only 3 years.


Compared with placebo or regimens of estrogen plus progestogen, unopposed estrogen at moderate or high doses produces adverse outcomes in postmenopausal women who have an intact uterus.

Source of funding: Health Research Council, New Zealand.

For correspondence: Ms. Anne Lethaby, Department of Obstetrics and Gynaecology, 2nd Floor, National Women's Hospital, Claude Road, Epsom, Auckland, New Zealand. FAX 64-9-630-9858.

Table. Comparison of hormone replacement therapy regimens for endometrial hyperplasia (EH) and irregular bleeding (IB) in women who have an intact uterus

Outcomes Comparisons Weighted event rates RRI (95% CI) NNH (CI)
EH Est-mod vs placebo 21% vs 0.6% 1890% (290 to 104) 5 (4 to 8)
Est vs con-EP 9% vs 0.2% 3770% (1285 to 104) 11 (9 to 15)
Est vs seq-EP 22% vs 1% 1820% (893 to 3630) 5 (5 to 6)
IB Est-mod vs placebo 37% vs 24% 54% (1 to 133) 8 (4 to 77)

*con-EP = continuous estrogen plus progestogen; est-mod = moderate-dose estrogen; seq-EP = sequential estrogen plus progestogen. Other abbreviations defined in Glossary; RRI, NNH, and CI calculated from data in article.


Since the 1970s, estrogen has been linked to endometrial cancer and clinicians have used combined regimens for women who have not had a hysterectomy. This review shows that the addition of progestins reduces the rates of endometrial hyperplasia and irregular bleeding, and improves compliance.

However, neither this review nor individual studies (1) show that continuous regimens are superior to sequential regimens. Continuous progestin regimens produce less endometrial hyperplasia after 36 months but cause more irregular bleeding during the first year. Adding progestins to HRT may have therapeutic disadvantages in addition to extra costs. Combination estrogen and progestin therapy causes more breast symptoms (2) and reduces the favorable effects of estrogen on high-density lipoprotein cholesterol levels (3).

The most critical question, however, remains unanswered: Which regimens are most protective or least harmful with respect to cardiovascular disease and breast cancer? In women with heart disease, continuous estrogen and progestin therapy did not improve coronary events compared with placebo and caused a 3-fold increase in venous thrombosis (4). A favorable trend in coronary events after 4 and 5 years was offset by a 50% increase in first-year events. Until the Women's Health Initiative reports results, it will remain unclear whether these data represent the adverse effects of daily progestin, whether the results apply to women without heart disease, and whether estrogen or progestin increases the risk for breast cancer. Meanwhile, clinicians should pay attention to the cost, side effects, and convenience of and adherence to the various HRT options now available.

David Atkins, MD, MPH
Agency for Health Care Policy and ResearchRockville, Maryland, USA


1. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370-5.

2. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92:982-8.

3. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199-208.

4. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-13.