Systemic Hormone Therapy Before Menopause is Associated With Depression

Women who receive systemic estrogen and progestin hormone therapy (HT) either prior to or during the transition to menopause may have increased risk for depression, according to study results published in JAMA Network Open.

Researchers sourced data for this study from the Danish Civil Registration System. Women (N=825,238) who were born in Denmark between 1950 and 1972 were evaluated for a diagnosis of depression at a hospital on the basis of filling 1 or more estrogen with or without progestin HT prescription between 1995 and 2017.

The study cohort comprised women who obtained a middle level of education (44.7%), had not had a live or still birth in their lifetime (16.5%), had a history of using hormonal contraceptives (50.0%), had a history of receiving fertility hormones (5.4%), had a history of depression (2.4%), and had a history of postpartum depression (0.6%).

A total of 23.0% of participants initiated HT during the study period. More of the HT recipients had multiple childbirths, fewer had a history of using hormonal contraceptives or fertility hormones, and fewer had comorbidities compared with nonrecipients.

The incidence rate (IR) of depression was 17.3 per 10,000 person-years overall, or 19.6 per 10,000 person-years among the HT users and 16.8 per 10,000 person-years among the nonrecipients. Stratified by HT exposure time, risk for depression increased from 0.51 per 10,000 person-years in the year before HT exposure to 1.44 per 10,000 person-years during the first year and 1.60 per 10,000 person-years during the second year after HT exposure.

Stratified by time since initiation, risk for depression was highest during the first year (hazard ratio [HR], 1.72; 95% CI, 1.09-3.59; P =.02) and lowest at 5 or more years (HR, 1.07; 95% CI, 1.01-1.14; P =.02). In general, risk for depression was highest for systemic HT (HR range, 1.30-2.03; all P ≤.007) and systemic HT with progestin (HR range, 1.20-2.01; P ≤.003) regardless of time since HT initiation.

Stratified by age at HT initiation, risk for depression was elevated among women who started systemic HT at ages 45 to 47 (HR, 1.74; 95% CI, 1.44-2.10) and 48 to 50 (HR, 1.50; 95% CI, 1.24-1.81) years. Conversely, women who started receiving local HT at ages 54 to 56 years (HR, 0.80; 95% CI, 0.70-0.91), 57 to 59 years (HR, 0.68; 95% CI, 0.59-0.79), 60 to 62 years (HR, 0.73; 95% CI, 0.61-0.88), and 63 (HR, 0.74; 95% CI, 0.54-0.95) years of age and older were at decreased risk for depression.

In the analysis that stratified by depression history, the relationship between HT and depression appeared to be stronger among the women who had a history of depression. However, these results were likely not robust (P =.05).

The major limitation of this study is the lack of access to data about symptoms of menopause and menopausal status.

Study authors conclude, “The findings of this cohort study suggest that during menopause, use of systemically administered HT is associated with risk of a subsequent diagnosis of depression among women living in Denmark. Locally administered HT is not associated with depression risk and is even associated with a possible lower risk for women older than 54 years, and may therefore be recommended when appropriate.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.