Estrogen beat progestin alone in perimenopause, with three times more side effects

Progestin-only therapy is sometimes used for perimenopausal symptom relief, particularly for women who want to avoid estrogen or manage irregular bleeding, but how it actually compares against combined estrogen-progestin therapy in routine practice has had limited real-world data. A study published this month in Frontiers in Endocrinology directly compares the two in a real-world clinical cohort [s1].

The design

This retrospective cohort study included 150 women with perimenopausal symptoms treated at a tertiary gynecological outpatient clinic between July 2022 and January 2025 — 60 on dydrogesterone monotherapy (a synthetic progestin) and 90 on combined estradiol-dydrogesterone (E2/DYD) therapy [s1]. The primary endpoint was change in the Kupperman Menopause Index (KMI), a standard symptom-severity scale, from baseline to 12 weeks [s1]. Secondary outcomes included clinical response (defined as a 50% or greater KMI reduction), change in endometrial thickness, and adverse events [s1].

What it found

At 12 weeks, the Kupperman Index fell by 8.0 points in the dydrogesterone group and by 12.5 points in the combination group — an adjusted mean difference of −4.51 points favoring combination therapy (95% CI −6.90 to −2.12, p < 0.001) [s1]. Clinical response — at least a 50% symptom reduction — occurred in 31.5% of the dydrogesterone group versus 51.2% of the combination group (adjusted odds ratio 2.08, 95% CI 1.02–4.45, p = 0.042) [s1]. Improvements in vasomotor symptoms (hot flashes and related symptoms) and mood-related symptoms were more pronounced with combination therapy specifically [s1].

On safety, endometrial thickness increased modestly in the combination group, by 0.60 mm, though week-12 measurements remained within normal physiological ranges [s1]. Adverse events of any kind were reported in 11.1% of the dydrogesterone group versus 31.7% of the combination group — nearly three times as frequent (adjusted odds ratio 3.55, 95% CI 1.29–9.77, p = 0.014) — though the study describes these events as predominantly mild and self-limited [s1].

The trade-off at the center of this study

This comparison lays out a fairly clean efficacy-versus-tolerability trade-off: combination therapy produced meaningfully better symptom control (a larger KMI reduction and roughly 1.6 times the clinical response rate) but at the cost of roughly three times the rate of reported adverse events [s1]. Neither option comes free of downsides, and the study frames its data as useful for informing that specific discussion between a patient and her clinician, rather than establishing one regimen as categorically superior.

Why the endometrial thickness finding matters

Adding estrogen to progestin therapy in a woman with an intact uterus carries a specific safety consideration: unopposed estrogen exposure is a known driver of endometrial overgrowth and, over time, elevated endometrial cancer risk, which is precisely why a progestin (dydrogesterone, in this case) is paired with estrogen rather than using estrogen alone. The modest 0.60 mm increase in endometrial thickness observed in the combination group, while measured, stayed within physiologic ranges over this 12-week window [s1] — a reassuring, if short-term, signal that the progestin component was doing its intended job, though the study explicitly notes it cannot speak to longer-term endometrial safety.

What this doesn't establish

This is a retrospective, real-world observational cohort, not a randomized trial — the study's own authors state this directly, noting that "causal conclusions cannot be drawn" and that the findings "should be regarded as hypothesis-generating" [s1]. Which women received which regimen reflected routine clinical decision-making rather than randomization, meaning differences between the groups in baseline symptom severity, other health factors, or clinician preference could influence the comparison independent of the drugs themselves. The 12-week follow-up window is short relative to how long perimenopausal symptom management often continues.

What to watch

Whether a prospective randomized trial confirms this efficacy-tolerability trade-off, and longer-term endometrial safety data for the combination regimen beyond 12 weeks. This article is not medical advice.

Sources

1. Efficacy and safety of dydrogesterone monotherapy versus estradiol-dydrogesterone combination therapy in perimenopausal women: a real-world cohort study — Frontiers in Endocrinology, 8 May 2026