Is hormone replacement therapy during menopause associated with a risk of depression?

Menopausal HRT and Depression Risk

Discussion and Context

Hormone replacement therapy is prescribed to women throughout the menopause transition to blunt the many symptoms — including mood disorders — that 60% to 70% of women experience due to declining levels of estrogen and progesterone. But some studies have suggested that hormone replacement therapy might be associated with resulting incidence of depression.

Study Design

Wium-Anderson et al conducted a nationwide register-based cohort, self-controlled case series study of 825,238 women in Denmark who reached the age of 45 between January 1, 1995, and December 31, 2017, whose ovaries were intact and who had not had cancer of the breast or reproductive organs. Follow-up ended on December, 31, 2018, and statistical analysis took place from September 1, 2021, to May 31, 2022.¹

Exposures were defined as prescriptions of hormone therapy defined by the Anatomical Therapeutic Chemical classification system codes (G03C [estrogen] and G03F [estrogen combined with progestin]) in the Danish National Prescription Registry during the study period. Delivery of therapy was divided into two categories, systemic (oral or transdermal) and local (intravaginal or intrauterine).

The main outcome was depression based on a hospital diagnosis of depression (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F32-F33 and International Classification of Diseases, Eighth Revision, codes 296.09, 296.29, 298.0, and 300.49). Associations in the cohort and self-controlled case studies were analyzed by using Cox proportional hazards and fixed-effects Poisson regression models.

Results

From age 45 to a mean of 56 years old nearly a quarter of the women (23%) began either systemically or locally administered hormone therapy. Of these 13,069 (1.6%) were diagnosed with depression. Systemically administered hormone therapy largely began before age 50 and was associated with a higher risk of subsequent depression, with the risk greatest within a year of beginning treatment. Locally administered hormone therapy began across the age span and was not associated with depression risk. Rather, it was associated with a lower risk of depression when the treatment began after age 54.

Practical Takeaways and Insights

Systemic hormone replacement therapy administered before and during menopause is associated with a higher risk of depression, particularly in the initial year of treatment. The authors note that women undergoing menopause who initiate systemically administered hormone therapy should be aware of depression as a possible side effect, and that locally administered hormone therapy might be a better recommendation. The study was published in JAMA Network Open¹

Expert Reactions

Professor of clinical trials and methodology at University College London Matt Sydes questioned the findings. He was among those who spoke to the United Kingdom-based Science Media Centre.² “This is not a randomised controlled trial. It isn’t possible to tell whether the factors that drive the decision to start hormone therapy are connected to the outcomes of interest here,” Dr. Sydes told the Centre. “What drives the choice to visit the family doctor and the joint decision to start HRT? Could mood disturbance be part of this? The rate of prior depression appears much lower in the non-hormone therapy group than the hormone therapy group.”

Women’s health specialist Professor Alex Polyakov of the University of Melbourne in Australia agreed with the findings and told COSMOS magazine that the results were no surprise. “Depression is one of the side effects, but for some women it’s a risk worth taking because they are significant symptoms which can affect their quality of life for a long time, maybe even years,” he said.³

Related Research and Perspectives

• Use of hormone replacement therapy after menopause was associated with a decreased risk of Alzheimer’s disease and vascular dementia in women with depression, according to a population cohort-based study in Korea. Alzheimer’s Research & Therapy

• Researchers suspect that fluctuating hormone levels are behind a high prevalence of depression and anxiety and heightened risk of suicide in women leading up to and during the menopause transition. Knowable Magazine

• Depression during menopause can be more severe than at other times in a woman’s life, bringing a high risk of suicide. Greater awareness among clinicians and more funding are needed to better treat women’s mental health issues in midlife and beyond. Nature