Hormone replacement therapy shows no rise in overall mortality

Menopausal hormone therapy (commonly known as hormone replacement therapy or HRT) is not associated with an increased risk of death, finds a Danish study of over 800,000 women published by The BMJ today.

The findings support current guidelines that recommend hormone therapy for women who have recently begun menopause who have moderate to severe symptoms and no contraindications, say the researchers.

Menopausal hormone therapy can help relieve menopausal symptoms such as hot flashes, sleep disturbance, mood swings, and depression. But its use has steadily declined during the last two decades, mainly due to safety concerns, and real world evidence regarding the effect of menopausal hormone therapy on death is lacking.

To address this, researchers used nationwide Danish registers to track women born between 1950 and 1977 and alive at age 45. Women were excluded if they had a history of blood clots, liver disease, breast, womb, or ovarian cancer, had previously used menopausal hormone therapy or undergone surgery to remove both ovaries (bilateral oophorectomy).

Follow-up began on each woman's 45th birthday and ended on 31 July 2023 (a median of just over 14 years).

Potentially influential factors including age, number of children (parity), education, income, country of birth, and underlying conditions such as diabetes, high blood pressure and heart disease, were also taken into account.

Of the 876,805 women included in the main analysis, 104,086 (11.9%) redeemed a prescription for menopausal hormone therapy, and 47,594 (5.4%) died. By the end of the follow-up period, the median duration of menopausal hormone therapy use was 1.7 years, with 41,433 (4.7%) women using it for less than one year, and only 7,337 (0.8%) women reporting ten or more years of use.

When not considering influential factors, the risk of all-cause death for women with past or present use of menopausal hormone therapy was 54.9 deaths per 10,000 person years compared with 35.5 deaths per 10,000 for women who had never used it. However, when influential factors were taken into account, no meaningful difference in risk of death was found.

Investigating the duration of use revealed no increased risk of death, even after 10 or more years of use. And no unequivocal differences were found between the groups for specific causes of death, such as heart disease, stroke or cancer.

What's more, women who had undergone bilateral oophorectomy aged 45 to 54 for non-cancerous reasons experienced a significant survival benefit when using menopausal hormone therapy, corresponding to a 27-34% lower risk of death than women in the same group who did not use hormone therapy.

The study also found some evidence suggesting that menopausal hormone therapy in a transdermal form (such as skin patches or gels) had a slightly lower risk of death compared to no treatment although the authors stress that this finding should await scrutiny in future studies.

This is an observational study so no firm conclusions can be drawn about cause and effect, and the authors acknowledge several limitations that may have affected their results.

However, they point out that this was a large study based on a near complete record and follow-up of almost a generation of women, and results were materially unchanged after further sensitivity analyses, suggesting they are robust.

As such, they conclude: "In this large nationwide cohort study, menopausal hormone therapy was not associated with increased mortality. No unequivocal differences in cardiovascular specific or cancer specific mortality were found between groups."

The significant increase in survival found among women using menopausal hormone therapy after bilateral oophorectomy for non-cancerous reasons should also prompt further discussion as to whether more women should be offered hormone therapy after undergoing this type of surgery, they add.