Oestrogen-only HRT raises womb-lining risk, adding progestogen offsets it

Falling oestrogen levels around menopause can cause symptoms severe enough to affect a woman's health and wellbeing, and hormone therapy, whether oestrogen alone or oestrogen combined with a progestogen, is an effective treatment for them. But hormone therapy carries risks, and guidelines recommend using the lowest effective dose with regular review. One central safety question is what happens to the endometrium, the lining of the womb: oestrogen stimulates it, and unchecked stimulation can lead to hyperplasia, an overgrowth that can precede cancer. This review set out to identify which regimens, and what minimum progestogen dose, protect against that risk.

The reviewers searched an extensive set of databases, including the Cochrane Library, MEDLINE, EMBASE and others, through to 2008, and also chased citation lists and contacted drug companies for unpublished data. They included randomised comparisons of unopposed oestrogen, continuous combined oestrogen-progestogen and sequential oestrogen-progestogen regimens against each other or placebo, given for at least twelve months. A required outcome was endometrial hyperplasia or carcinoma assessed by biopsy at the end of treatment. Forty-five studies met the criteria, with odds ratios calculated for dichotomous outcomes; small study numbers and clinical heterogeneity prevented pooling for many comparisons.

Unopposed oestrogen was associated with an increased risk of endometrial hyperplasia at all doses, across treatment durations of one to three years. By contrast, for women with a uterus, hormone therapy combining low-dose oestrogen continuously with a minimum of 1 mg norethisterone acetate or 1.5 mg medroxyprogesterone acetate showed a hyperplasia risk not significantly different from placebo, with the 1 mg norethisterone acetate comparison yielding an odds ratio of 0.04, and no hyperplasia events at all recorded on 1.5 mg medroxyprogesterone acetate. The authors concluded that hormone therapy for postmenopausal women with an intact uterus should include both oestrogen and a progestogen.

This review provides the trial-level evidence behind a cornerstone of menopause care: that oestrogen given alone to a woman with a uterus stimulates the endometrium in a dose-independent way, and that adding an adequate continuous progestogen neutralises that risk. It quantified the minimum protective progestogen doses rather than simply asserting the principle. Limitations remain, heterogeneity blocked meta-analysis for many outcomes, and the review has since been updated, but the direction of the finding is consistent and has shaped prescribing guidance. Questions about the finer trade-offs between regimens and doses continued into subsequent updates.

For anyone navigating menopause and weighing hormone therapy, this is the evidence base for why the presence or absence of a uterus changes the regimen: oestrogen alone raised womb-lining overgrowth risk at every dose studied, while properly combined therapy did not. It is a reason to understand that 'HRT' is not one thing: the composition of the regimen is what governs this particular risk. This is informational context for a conversation with a clinician, who tailors regimen and dose to the individual; it is not a prescription in itself.