A recent study published in Family Practice assessed the association of hormone replacement therapy (HRT) or the use of the combined oral contraceptive pill (COCP) with mortality among women with a previous history of coronavirus disease 2019 (COVID-19).
The causal pathogen of COVID-19, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to spread. Females and males are equally vulnerable, albeit males show a higher rate of severe outcomes like hospitalization and death. According to one study, COVID-19-related mortality among males was 1.7-fold higher than in females.
Similar higher mortality was recorded in previous outbreaks caused by SARS-CoV and middle east respiratory syndrome (MERS)-CoV. Although the reason for observed sex differences remains unknown, various theories have been hypothesized, including sex-based immunologic variations, smoking patterns, and comorbidities. The role of estrogen is being debated and has garnered much attention. For instance, younger women or those with high estrogen levels have lower odds of developing severe COVID-19 outcomes.
Further, estrogen has been reported to modulate immune responses by decreasing T cell exhaustion and suppressing the production of interleukin (IL)-6 and IL-1β, thereby limiting cytokine storm. This might explain the lower frequency of COVID-19-related hospitalizations and intensive care admissions among females relative to males. Recent evidence suggests that COCP users are at lower risk of COVID-19 and associated hospitalization; nevertheless, data on HRT has not been consistent.
The study and findings
In the current retrospective study, researchers investigated the associations between HRT/COCP use and the odds of COVID-19-related mortality among women in the early phase of the pandemic. They utilized computerized medical records from the Oxford Royal College of General Practitioners, Research and Surveillance Centre database. This database included 465 general practices in England, encompassing 1.8 million women. Females with a confirmed or probable diagnosis of COVID-19 were identified.
A confirmed case was defined as having a positive SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) result, and probable or suspected cases were those diagnosed clinically or radiologically according to the recommendations from Public Health England. The authors defined exposure as one or more prescriptions of COCP or HRT within six months of probable or confirmed diagnosis. The main outcome was all-cause mortality between January 1, 2020, and June 21, 2020.
Univariate logistic regression models quantified the association between HRT/COCP and all-cause mortality. Subsequently, a multivariable model adjusted for covariables was run, and a mixed-effects model was performed, accounting for practice clustering. The statistical tests were two-tailed and set at a 5% significance level.
The authors identified 5451 females with COVID-19 with a mean age of 59 years. The mean follow-up time was 164.9 days; more than 64% of subjects were White, and 80.6% lived in urban areas. There were 171 females with prescriptions for COCP use and 231 with HRT prescriptions. The mortality rate was 12.2% during the follow-up time. The researchers found that HRT had lower odds of all-cause mortality in unadjusted (Odds ratio, OR: 0.15) and adjusted (OR 0.22) models.
All-cause mortality was higher in those who were older, underweight, with immunosuppressants or hypertension, and from larger households. Those who had asthma were at a significantly lower risk of mortality. The team could not estimate the association between COCP use and all-cause mortality as no deaths were reported among those prescribed COCPs.
To summarize, the findings revealed that HRT use was associated with lower odds of mortality in women followed up for six months following COVID-19. Some of the study’s strengths were the population-based cohort across 465 general practices in England that ensured heterogeneity in clinical and sociodemographic variables. Notably, the authors did not analyze the type of dose or preparation for HRT due to the lack of data in the database.
Moreover, the duration of medication use was not examined, and the follow-up period was less than six months. The inclusion of age as only a categorical variable might have limited adjustment. Given that all-cause mortality was investigated, some deaths might not be associated with SARS-CoV-2 infection.
In conclusion, the authors observed that HRT prescription within six months after COVID-19 diagnosis was associated with a decrease in all-cause mortality. This meant that women should not discontinue using HRT because of the pandemic. Importantly, future work should evaluate variations in the preparation and dose of HRT and examine the association of COCP use with mortality.