Global experts welcome reassurance but caution healthy-user bias and missing smoking and BMI data may cloud the full picture.
Menopausal hormone therapy does not increase women’s risk of death, according to a large Danish registry study of more than 800,000 women published in The BMJ this week.
The findings are attracting mixed expert comment around the world, including Australia. While they have welcomed the findings, some cautioned the study did not include data on high-risk patients.
Researchers followed 876,805 Danish women from age 45 for a median of 14.3 years, tracking prescriptions for systemic menopausal hormone therapy and deaths recorded in national registers.
Women with major contraindications, such as prior thrombosis, liver disease, or breast, endometrial, or ovarian cancer, were excluded, as were women who had used hormone therapy before age 45, to focus on new users without clear high-risk conditions.
Of the cohort, 104,086 women (11.9%) filled at least one prescription for systemic menopausal hormone therapy during follow-up.
Overall, 47,594 women (5.4%) died. Crude mortality rates were higher among women who had ever used hormone therapy compared with non-users (54.9 versus 35.5 deaths per 10,000 person-years).
However, after adjustment for age, calendar period, parity, education, income, country of birth, and comorbidities including diabetes, hypercholesterolaemia, hypertension, atrial fibrillation, valvular disease and heart failure, the association was neutral, with an adjusted hazard ratio for all-cause mortality of 0.96.
Duration analyses did not demonstrate an excess mortality risk even with prolonged exposure. Adjusted hazard ratios were 1.01 for less than one year of use, 0.94 for 1–2.9 years, 0.90 for 3–4.9 years, 0.89 for 5–9.9 years, and 0.98 for 10 years or more.
Cause-specific analyses showed no unequivocal differences in cardiovascular or cancer mortality between users and non-users. Cardiovascular deaths accounted for 11.6% of deaths, cancer for 48.3%, and other causes for 40.0%.
Short-term use under five years was associated with a slight reduction in cardiovascular mortality and a small increase in cancer mortality, but these patterns were not sustained or statistically robust with longer-term use.
A notable finding was observed in women who underwent bilateral oophorectomy between ages 45 and 54 for non-malignant indications, the researchers said.
In this subgroup, menopausal hormone therapy use was associated with a 27–34% lower mortality hazard compared with non-use.
Among women in this group who died during follow-up, the median age at death was 60.9 years in users versus 56.6 years in non-users.
The researchers said these findings aligned with prior evidence suggesting adverse long-term outcomes when premenopausal oophorectomy was not followed by oestrogen therapy.
The said this may warrant renewed discussion regarding systematic offering of hormone therapy in surgically menopausal women without contraindications.
Stratified analyses suggested lower mortality among women predominantly using transdermal formulations compared with never-users (adjusted hazard ratio 0.85, 95% CI 0.80 to 0.90), and marginal reductions among those using oestrogen monotherapy or cyclic progestogen regimens.
Initiation at age 52 years or older was also associated with lower mortality relative to non-use. The authors cautioned that these subgroup findings should be interpreted carefully and confirmed in future studies.
Hormone therapy use declined markedly over the study period. Among women aged 55 years, current or past use fell from 27.0% in 2004–2006 to 9.7% in 2021–2023, reflecting the sustained impact of safety concerns following earlier trial data.
The current findings were broadly consistent with long-term follow-up from the Women’s Health Initiative, which reported a pooled hazard ratio for all-cause mortality of 0.99 (95% CI 0.94 to 1.03) after 18 years of follow-up, although the Danish cohort included younger women initiating therapy closer to menopause.
The authors emphasised that this was an observational study and residual confounding could not be excluded despite extensive adjustment and sensitivity analyses.
However strengths included near-complete national prescription and outcome data, minimal loss to follow-up, and robust sensitivity analyses with materially unchanged results.
The researchers said their data provided additional reassurance that systemic menopausal hormone therapy, when used in appropriately selected women, was not associated with excess long-term mortality.
The findings reinforced that treatment decisions should continue to be individualised, weighing symptom burden, cardiovascular and cancer risk profile, age at initiation, time since menopause, and patient preferences.
In women undergoing bilateral oophorectomy before the average age of natural menopause, the observed survival benefit associated with hormone therapy supports careful consideration of postoperative oestrogen replacement in the absence of contraindications.
“The magnitude of survival difference found in our study should prompt further discussion as to whether more women should be offered systemic menopausal hormone therapy after undergoing bilateral oophorectomy,” the researchers wrote.
“Future studies should assess the optimal timing, duration, and type of menopausal hormone therapy for these women.”
Associate Professor of Obstetrics and Gynaecology at the University of Queensland and President of the National Association of Specialist Obstetricians and Gynaecologists, Associate Professor Gino Pecoraro OAM, said the study added to the body of evidence that already exists around the safety profile of using MHT.
“It should be seen as reassuring for women who choose MHT for symptom control,” he said.
Menopausal symptoms could be disabling and disruptive, leading to difficulty maintaining employment and significant economic impact to the national workforce, Professor Pecoraro said.
University of the Sunshine Coast Associate Professor Mia Schaumberg said the study provided good population evidence that using HRT during menopause was not linked to increased risk of death, however she noted some limitations.
“Given the large number of women followed up (>800,000) for around 14 years, and the careful consideration of potential influences (such as age, number of children and heart health), these findings are relevant globally,” she said.
“Given some safety concerns in recent years, HRT use has been declining, even though it can help with a wide array of menopause symptoms that can significantly impact women at mid-life. Indeed, recent data from Australia suggest that less than one quarter of women experiencing menopause symptoms use HRT.
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“This study provides new evidence to mitigate these concerns, which is good news for the large number of women who suffer often debilitating symptoms for a number of years during the menopause transition.
“It is important to note that this study excluded women that had significant medical history such as blood clots or some cancers, so the results may not be applicable to people with this medical history.”
Endocrinologist Professor Susan Davis AO, head of the Monash University Women’s Health Research Program, said that while the Danish databases were some of the best in the world for studies of this nature, “observational studies of this kind have an intrinsic ‘healthy user bias’ – i.e. women who choose to use MHT are different from other women across an array of characteristics that we cannot measure – e.g. health knowledge, health behaviours etc.”.
“Notably in this study there is no data for smoking or weight/overweight/obesity (BMI) – women would be less likely to be prescribed MHT [especially oral MHT] if they are smokers or overweight/have obesity,” she said.
“So while the authors adjusted their analyses for a large number of characteristics, these critical factors that influence life expectancy were not included. This really matters as in 2010 ~20% (or possibly more) of Danish women were smokers.
“But when I searched the paper for anything to do with tobacco/smoking/ BMI – none of these factors were mentioned, which is a major limitation for the outcome of mortality.”
Professor Davis also noted that while the data suggested that starting MHT from the age of 57 years was not unsafe, “we do not know what proportion of women who started MHT at this age or older used oral or transdermal therapy, or their average duration of use”.
“This is important as the data also suggests transdermal estrogen potentially was associated with lower mortality,” she said.
“Why does transdermal estrogen appear safer? Were women who used transdermal instead of oral estrogen more health care literate, i.e. was there a healthy user bias in the access/choice of using transdermal estrogen when most women were prescribed oral estrogen?”
The finding Professor Davis felt most cautious about was that MHT users who had both ovaries removed between the ages of 45-54 years had a greater life expectancy (60.9 years) than non-users (56.6).
“What I cannot reconcile with these data is that the average life expectancy for women born in Denmark in 1950 was ~71 years [and longer for each later year of birth],” she said.
“I really would not expect women who had their ovaries out for reasons other than cancer to have a life expectancy that is 10-13 years younger than the general population. So why were the women in the study who had ovaries removed (cancer excluded) dying so young?
“So while this is a nice paper, the limitations are those of all observational studies, especially amplified in the post-WHI [Women’s health initiative] years when people thought MHT caused breast cancer and heart disease – this makes users different to non-users plus major factors that impact life expectancy, namely smoking and overweight obesity, were not even considered or even mentioned as a study limitation.”
