Early medical menopause raised heart risk — but the mortality excess stopped at age 45

Iatrogenic menopause — menopause brought on early by surgery, radiation or drug treatment rather than by age — is common, and it removes the body's own oestrogen years ahead of schedule. Its long-term consequences for the heart have been assumed more than measured, and in particular it has been unclear whether the age at which it happens changes the risk. A systematic review and meta-analysis published in JAMA Network Open on October 2 tried to pin both questions down, and the answer it gives on age is the more useful half [s1].

What was pooled

The authors searched seven databases — Scopus, MEDLINE, PubMed, Embase, the Cochrane Central Register, CINAHL and PsycINFO — from January 2004 to March 2026, for observational studies and randomised trials reporting cardiovascular outcomes in women with iatrogenic menopause before the natural menopausal age, compared with naturally menopausal or age-matched women [s1].

From 14,409 records they included 36 studies covering 2,617,942 women [s1]. The iatrogenic-menopause group had a mean age of 55.52 years and the comparators 45.58 years; median follow-up was 16.0 years, ranging from 4.8 to 36.0 years across studies [s1]. Results were combined as random-effects pooled hazard ratios, with age at menopause carried through as a moderator [s1].

The overall associations

Against comparators, iatrogenic menopause was associated with higher risks across the board: all-cause mortality (pooled hazard ratio 1.08, 95% CI 1.01-1.16), cardiovascular events (1.25, 1.12-1.39), coronary heart disease (1.48, 1.07-2.03) and stroke (1.22, 1.15-1.28) [s1]. Stroke was the most consistent signal [s1].

Taken alone, those numbers read as a uniform hazard. The age analysis shows they are not.

Where the age cut-off bites

The excess in mortality was not spread evenly. It was confined to women whose iatrogenic menopause occurred before age 45 — cardiovascular mortality pooled hazard ratio 1.20 (95% CI 1.04-1.37) and all-cause mortality 1.15 (1.06-1.25) in that group [s1]. For women whose iatrogenic menopause came at or after 45, the estimates were null: cardiovascular mortality 0.95 (0.81-1.11) and all-cause mortality 0.99 (0.89-1.09) [s1].

A post-hoc meta-regression put a slope on that pattern. Each additional five years of age at iatrogenic menopause was associated with a lower risk on the composite cardiovascular outcome (hazard ratio 0.89, 95% CI 0.83-0.97), drawn from 37 estimates across 11 independent populations [s1]. The authors read this as a period of elevated risk before age 45, rather than a single cliff-edge threshold [s1].

That distinction is the practical point. The headline "iatrogenic menopause raises cardiovascular risk" is true but incomplete; the risk that matters for mortality is loaded onto the women who lose ovarian function earliest, and thins out as the age at menopause rises toward the natural range.

The limits

This is a meta-analysis of mostly observational studies, and it inherits their weaknesses [s1]. Women who undergo early oophorectomy or cancer-related treatment differ from comparators in ways beyond menopausal age — the underlying disease, the treatment itself, and whether they received hormone therapy afterward, which the pooled estimates cannot fully separate. The comparators were on average nearly a decade younger than the iatrogenic group, a mismatch the age-stratified analysis mitigates but does not erase [s1].

Heterogeneity across 36 studies spanning more than two decades of follow-up is also substantial, and pooled hazard ratios smooth over real differences in how menopause was defined and how outcomes were captured [s1]. These are associations, not proof that early menopause itself causes the excess.

The direction, though, is consistent with earlier cohort work. A UK Biobank study of 144,260 postmenopausal women reported higher incident cardiovascular disease in those with natural or surgical menopause before age 40 [s2], the youngest and highest-risk end of the same gradient this meta-analysis describes.

What to watch

Whether trials of hormone therapy after early iatrogenic menopause show the mortality excess is modifiable; whether the under-45 threshold holds in individual-patient-data analyses; and whether guideline bodies fold an age gradient, rather than a single cut-off, into how they counsel women facing early surgical or medical menopause.

This article describes a meta-analysis of observational studies and is informational only. It is not medical advice.

Sources

• [s1] Age at Iatrogenic Menopause and Cardiovascular Morbidity and Mortality, JAMA Network Open, 2026;9:e2637545, published online 2026-10-02. PMID 42826016.
• [s2] Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease, JAMA, 2019;322(24):2411-2421, published 2019-12-24. PMID 31738818.