Systemic MHT ups risk of depression: study

However, locally administered treatment appeared to have a protective effect for patients in their fifties
Sarah Simpkins
Anxious middle-age woman

Women initiated on systemic hormone therapy before or during menopause are at greater risk of depression than non-users, a large cohort study shows. 

In contrast, locally administered treatment appeared to be protective against depression risk, but only among women aged 54 and older, according to the population-based study.

Previous research suggested a link between menopausal hormone therapy (MHT) use and risk of depressive symptoms and suicide, but the type of therapy was often not indicated, said the team led by Clinical Professor Dr Merete Osler at the University of Copenhagen.

To determine whether first-time MHT use was associated with subsequent depression, they analysed data from 825,000 Danish women who reached age 45 between 1995 and 2017.

During an average 11 years’ follow-up, 23% of the cohort initiated systemic (oral or transdermal) and local (intravaginal or intrauterine) MHT, and about 2% were subsequently diagnosed with depression. 

The overall risk of developing depression was highest in the first year of treatment, with the likelihood of diagnosis 72% higher than it was for non-users, the study authors said.

The risk declined gradually with time since initiation, they added.

But the association was only significant for systemically administered MHT.

Among patients aged 45-47 who started oral or transdermal therapy, the likelihood of depression was 74% higher compared with controls, while the risk was 50% higher for patients aged 48-50. 

At the same time, locally administered MHT was associated with a 20% reduced risk of depression in women aged 54-56, compared with non-users.

“These findings suggest that women undergoing menopause who initiate systemically administered [MHT] should be aware of depression as a potential adverse effect, and locally administered [MHT] should be recommended when needed,” the researchers wrote in JAMA Network Open


Read more: No overall increase in dementia risk with MHT: study


The route of administration varied with age, with the study noting that women often started systemic MHT before and during menopause, while those older than 56 tended to start with locally administered treatments. 

Fewer than one-fifth of participants shifted between different types of MHT. 

The study excluded women who had already begun MHT before age 45, had ongoing depression or previously had an oophorectomy, breast cancer or cancer in their reproductive organs. 


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More information: JAMA Network Open 2022; 1 Nov.