"This large, nationwide Danish cohort study of more than 800,000 women reports that menopausal hormone therapy (MHT) was not associated with increased all-cause mortality over a median 14 years of follow-up . After adjustment for key confounders, the hazard ratio for death among MHT users was 0.96 (95% CI 0.93–0.98), with no clear increase in cardiovascular or cancer-specific mortality.

Notably, women who underwent bilateral oophorectomy between ages 45–54 experienced a 27–34% reduction in mortality if they used MHT . These findings are consistent with current guideline recommendations for symptomatic women without contraindications.

This study provides reassuring real-world evidence that appropriately prescribed hormone therapy does not increase a woman’s overall risk of death. For women with significant menopausal symptoms, especially those who lose ovarian function early through surgery, the balance of evidence suggests that hormone therapy can be both safe and beneficial.

Importantly, mortality is a broad endpoint. Our work has focused on how specific synthetic progestins interact with estrogen receptor signalling in the breast, building on mechanistic evidence that progesterone receptor activation can reprogram estrogen-driven transcription in ER-positive breast cancer . Emerging data suggest that not all progestins are biologically equivalent, and breast cancer risk may vary by formulation rather than by hormone therapy per se.

Population-level studies like this are essential, but we also need mechanistic insight to understand which formulations are safest for the breast. The key message is nuance: hormone therapy is not one uniform entity, and individual risk depends on timing, indication, and the specific hormones used."

"Menopause is the natural physiological decrease and ultimate cessation of ovarian function that every woman can expect to experience during her lifetime. The average age in Australian women is around 50-52.

80% of women can expect to experience symptoms during this time and although the median length of time these symptoms last is seven years, some women will have them for much longer.

Menopausal symptoms can be disabling and disruptive, leading to difficulty maintaining employment and significant economic impact to the national workforce.

Menopausal hormone therapy (MHT)  is a proven effective treatment for these symptoms and this study further adds to the safety data around its use. The safety scare following the 2002 women’s health initiative study published in the States resulted in up to 80% decrease in the use of MHT at the time with many women denied effective therapy for their symptoms.

This new study was a large register-based cohort study of nearly 900,000 Danish women followed for a median of 14.3 years, specifically designed to see whether the use of MHT had an effect on mortality rates.

It looked at women aged 45 or older who used MHT and excluded those with contraindications to treatment or women who had undergone an early menopause (before age 45)  for whatever reason. The results are adjusted for age, number of children, education, income, birth country, diabetes, cardiac risk factors and more than three hospital contacts during age 44.

All available forms of combined (oestrogen and progesterone) or oestrogen-only preparations were included in the study. Tibolone, a synthetic molecule which acts as oestrogen, progesterone and androgen receptors, and other nonhormonal treatments were not studied.

The authors reported no overall increased mortality associated with the use of hormone treatment. 
Less than one year of treatment had a 1.01 hazard ratio, meaning a 1% increase in the number of deaths was reported, but this figure decreased, year-on-year, to a trough of 11% decrease between 5 and 9.9 years and a 10% decrease over 10 years of treatment.

For the group of women who had undergone surgical removal of ovaries, causing menopause, the use of hormone treatment was associated with a 27-34% decrease in mortality.

It also found no unequivocal differences in cardiovascular or cancer-specific mortality between those who used MHT and those who didn’t.

This study adds 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."

"This study, published out of Denmark, provides good population level evidence that using hormone replacement therapy (HRT) during menopause, is not linked to increased risk of death. 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. 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.

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."

"Menopausal Hormone Therapy (MHT) is an effective treatment for hot flushes and night sweats. This evidence is largely based on those with 7-10 moderate to severe hot flushes/day, more frequent and severe than most women experience. Treating hot flushes may improve sleep and mood. However, contrary to the BMJ press release, NICE guidelines do not advise MHT for depression.

Scandinavian registries have substantially advanced our understanding of health outcomes with MHT. This new study of >800,000 women concurs with 2024 NICE menopause guidelines that MHT does not increase overall mortality. However, participants were only followed until age 59 years (14 years from age 45), likely too early to determine mortality effects. Similarly, the median duration of MHT use was only 1.7 years.

In the UK, average duration of use is around six years so these findings may not reflect health outcomes for many women. Similarly, rates of MHT use were modest at 11.9% which is less than half that in White UK women (PMID: 40628417). The study reported higher mortality rates in MHT users (54.9 vs 35.5 per 10,000), but this difference disappeared when findings were adjusted.

There was a suggestion that MHT may reduce mortality after surgical menopause, but this was based on only 703 women and those younger than 45 were excluded. Ovarian cancer risk reduction is now a common indication for surgical menopause. However, this study is unable to comment on benefits of MHT in high-risk women."

"The paper of Mikkelsen and colleagues in The BMJ used national registry data for women born between 1950 and 1977 alive in Denmark when they turned 45 years old and looked at menopausal hormone therapy [MHT] use and mortality.

The Danish databases are some of the best in the world for studies of this nature. However, 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.

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.

Other key points:

Over two thirds used oral estrogen +/- a synthetic progestin. The general duration of use was brief, i.e. 1.7 years, with 75% using for less than 4.5 years. So would we expect MHT use for an average of less than two years to cause harm?

The data does suggest that starting MHT from the age of 57 years is not unsafe, but 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.

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 that I feel 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). 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."