Association of estrogen-containing menopause hormonal therapy with COVID-19 mortality

In a recent study published in BMC Medicine, researchers evaluated coronavirus disease 2019 (COVID-19)-related mortality among perimenopausal women prescribed estrogen-containing menopause hormonal therapies (MHT).

Study: Estrogen-modulating treatment among mid-life women and COVID-19 morbidity and mortality: a multiregister nationwide matched cohort study in Sweden. Image Credit: Andrey_Popov/Shutterstock.com

Background

The severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) pandemic has shown biological inequalities in clinical outcomes, with males having a greater chance of mortality, hospitalization, or intensive care unit (ICU) admission than women.

The causes of these changes are unknown, although speculations imply that sex hormones, such as estrogens, have a role in female immunological responses.

Despite this, few studies have investigated the possible involvement of estrogen-containing medications in COVID-19 mortality, and further information is required to inform therapeutic recommendations.

About the study

The present national register-based matched cohort study researchers assessed COVID-19-associated mortality among perimenopausal women concerning MHT.

The study was conducted in Sweden from 1 January to 31 December 2020 and included women aged >53 years. They acquired data by linking multiple national socioeconomic and healthcare registers using participants’ personal identification numbers (PINs).

The registries consisted of the National Patient Registry (NPR), the Prescribed Drug Registry (PDR), the Cause of Death Registry (CDR), the Total Population Registry (TPR), the Longitudinal Integration Database for Health Insurance and Labor Market Studies (LISA), and the Sminet monitoring system.

The study exposure consisted of prescriptions for estrogen-modulating medications such as local estrogen, systemic estrogen including or excluding progestogen, progestogen-only, or tibolone, with supply beginning January 1, 2020, and potentially continuing later.

The team used Anatomical Therapeutic Codes (ATC) to gather data on estrogen-modulating treatments. They characterized MHT usage as filled prescriptions for hormone-modifying treatments whose expected duration coincided with the study’s start date (January 1, 2020).

The primary study outcome was COVID-19 death, whereas secondary outcomes comprised outpatient visits, inpatient hospitalizations, and reverse transcription-polymerase chain reaction (RT-PCR)-confirmed COVID-19.

The researchers compared MHT users to matched non-users. They followed the subjects until they completed the study, emigrated, or died, whichever occurred first.

The researchers performed multivariate Cox regression modeling to calculate the adjusted hazard ratios (aHRs), including covariates such as age, educational attainment, income, civil status, comorbidities, alcohol use, and obesity.

They conducted sensitivity analyses to assess the influence of age and ongoing therapy on SARS-CoV-2 infection outcomes and the impact of current treatment on any-cause mortality by excluding exposed women who ceased therapy or reached supply end before study termination.

They excluded individuals diagnosed with gender dysphoria using the International Classification of Diseases, tenth revision, Swedish Edition (ICD-10-SE) codes during the study period.

Results

The study included 9,981 women who used various amounts of estrogen, such as local estrogens, systemic estrogens with progestogens, estrogens without progestogens, progestogens alone, and tibolone alone.

A higher percentage of females with systemic estrogens and progestogen exposure had educational attainment of >13 years. Obesity diagnoses occurred in fewer women receiving only systemic estrogen or tibolone therapy.

During the follow-up period, the team recorded 114 COVID-19 fatalities among unexposed females and 50 cases among those receiving local estrogen treatment (incidence rate of 5.3 cases among every 1,000 individual years), resulting in a significant aHR of 2.0 for SARS-CoV-2 infection-related mortality.

Women receiving systemic estrogen treatment without progestogens had a significantly higher COVID-19-associated mortality risk than those who were not exposed (aHR, 6.4).

Women who used just local estrogens were more likely to have outpatient visits and hospitalizations (aHR, 1.2), as well as COVID-19-related mortality (aHR, 2.0).

Systemic estrogens alone were associated with an increase in COVID-19-related deaths among older females (aHR, 4.7), but the link turned non-significant, accounting for estrogen cessation. Systemic estrogen and progestogen use (aHR, 1.1) or tibolone only (aHR, 1.2) enhanced COVID-19 probability.

The aHR for COVID-19 mortality was considerably higher for women aged >63 years who received local estrogens only, with the highest risk for those aged 63 to 72 years (4.2). Older women receiving systemic estrogen treatment but no progestogens also had a higher risk of COVID-19-associated mortality (aHR, 4.7).

The positive correlation with SARS-CoV-2 infection-associated mortality lost statistical significance for systemic estrogen treatment but remained statistically significant for local estrogen therapy solely (aHR, 1.7). The relationships between COVID-19 morbidity and death were statistically significant, particularly during the initial wave.

Conclusion

The study findings showed that MHT did not significantly lower COVID-19-related mortality compared to premenopausal levels. Instead, women taking local estrogens had a greater risk of death, outpatient visits, and COVID-19, particularly older females and those quitting medication.

Defining exposure as continuing systemic estrogen therapy rather than ever-treatment, the link between systemic estrogen therapy and COVID-19 mortality became insignificant.