Study Links Hormone Therapy With Depression in Women Undergoing Menopause

Systemically administered hormonal therapy may be associated with a greater risk of depression before and during menopause.

Women undergoing systemically administered hormonal therapy (HT) before and during menopause were found to have a greater risk of depression, specifically in the years immediately after initiation, according to a recent study published by JAMA Open Network.

During menopause, estrogen and progesterone levels drop and 60% to 70% of women experience menopausal symptoms, such as mood disturbances. Although this may be prevented by HT, some studies have suggested that use of HT may be associated with a greater risk of depression.

“No prior study seems to have assessed the association of different types of HT (locally vs systemically administered) with subsequent risk of clinically verified depression in a prospective cohort design, taking temporality between the use of HT and development of depression into account and including censoring due to mortality or loss to follow-up,” the investigators wrote.

The objective of the study was to analyze whether use of HT during menopause was associated with a subsequent diagnosis of depression. The nationwide, register-based, cohort and self-controlled case series study included all women in Denmark who were 45 years of age between January 1, 1995, through December 31, 2017, without prior oophorectomy, breast cancer, or cancer of the reproductive organs. Follow-up was completed on December 31, 2018, and the statistical analysis was performed from September 1, 2021, through May 31, 2022.

The researchers used redeemed prescriptions of different types of HT identified by the Anatomical Therapeutic Chemical classification system codes in the Danish National Prescription Registry between 1995 and 2017. The type of administration was then divided into systemic (oral or transdermal) and local (intravaginal or intrauterine).

The results showed that during follow-up, from 45 years of age to a mean of 56.0 years, 189,821 women initiated systemically or locally administered HT and 13,069 were diagnosed with depression. Systemically administered HT was mainly initiated prior to women turning 50 years of age and was associated with a higher risk of a subsequent depression diagnosis.

Additionally, the risk was especially elevated the year after initiation of both treatment with estrogen alone and estrogen combined with progestin. Locally administered HT, which was initiated across all ages, was not found to be associated with depression risk. However, it was associated with a reduced risk of depression if initiated after 54 years of age.

“Our findings suggest that around menopause, women may be more sensitive to the influence of HT on mood than at later ages,” the study authors wrote. “This finding could be influenced by attrition of susceptibility to HT, but we could not calculate precise risk estimates for use of systemic HT in menopausal women older than 54 years because less than 1% initiated treatment with systemic HT after 54 years of age.”

In the self-controlled analysis, which accounted for time-invariant confounding, patients using systemically administered HT had increased rates of depression in the years following initiation of HT vs the years prior to treatment.

The study authors found that locally administered HT was associated with a lower risk of depression for women 54 years of age or older.

“In this nationwide cohort study, initiation of systemically administered HT was associated with a subsequent diagnosis of depression,” the authors wrote. “The risk was highest in women aged 45 to 50 years and during the first years after starting HT. Locally administered HT was not associated with risk of depression in women younger than 54 years and was associated with a lower risk for those 54 years or older.”


Wium-Andersen MK, Jørgensen TSH, Halvorsen AH, Hartsteen BH, Jørgensen MB, Osler M. Association of Hormone Therapy With Depression During Menopause in a Cohort of Danish Women. JAMA Netw Open. 2022;5(11):e2239491. doi:10.1001/jamanetworkopen.2022.39491