Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study

Abstract

Background: Men and older women have been shown to be at higher risk of adverse COVID-19 outcomes. Animal model studies of SARS-CoV and MERS suggest that the age and sex difference in COVID-19 symptom severity may be due to a protective effect of the female sex hormone estrogen. Females have shown an ability to mount a stronger immune response to a variety of viral infections because of more robust humoral and cellular immune responses. Objectives: We sought to determine whether COVID-19 positivity increases in women entering menopause. We also aimed to identify whether premenopausal women taking exogenous hormones in the form of the combined oral contraceptive pill (COCP) and post-menopausal women taking hormone replacement therapy (HRT) have lower predicted rates of COVID-19, using our published symptom-based model. Design: The COVID Symptom Study developed by Kings College London and Zoe Global Limited was launched in the UK on 24th March 2020. It captured self-reported information related to COVID-19 symptoms. Data used for this study included records collected between 7th May - 15th June 2020. Main outcome measures: We investigated links between COVID-19 rates and 1) menopausal status, 2) COCP use and 3) HRT use, using symptom-based predicted COVID-19, tested COVID-19, and disease severity based on requirement for hospital attendance or respiratory support. Participants: Female users of the COVID Symptom Tracker Application in the UK, including 152,637 women for menopause status, 295,689 for COCP use, and 151,193 for HRT use. Analyses were adjusted for age, smoking and BMI. Results: Post-menopausal women aged 40-60 years had a higher rate of predicted COVID (P=0.003) and a corresponding range of symptoms, with consistent, but not significant trends observed for tested COVID-19 and disease severity. Women aged 18-45 years taking COCP had a significantly lower predicted COVID-19 (P=8.03E-05), with a reduction in hospital attendance (P=0.023). Post-menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P=2.22E-05) for HRT users alone. Conclusions: Our findings support a protective effect of estrogen on COVID-19, based on positive association between predicted COVID-19 and menopausal status, and a negative association with COCP use. HRT use was positively associated with COVID-19 symptoms; however, the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential comorbidities. Trial registration: The App Ethics has been approved by KCL ethics Committee REMAS ID 18210, review reference LRS-19/20-18210

The Physiological Mechanisms of the Sex-Based Difference in Outcomes of COVID19 Infection

“…Large-scale self-reported data obtained from the UK COVID19 symptom tracker application (C-19) showed a positive association between COVID19 and menopausal status, and a negative association with combined oral contraceptive pill use ( Costeira et al, 2020 ), supporting the hypothesis that E2 offers protection against disease severity. Hormone replacement therapy (HRT) use, however, was positively associated with COVID19 symptoms.…”

Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study

“…Recent observational data suggests that women aged 18-45 years taking the COCP have a lower risk of COVID-19 infection (P=<0.001) and a lower rate of hospital attendance (P=0.023). [7,8] Evidence on Hormone Replacement Therapy (HRT) has been more inconsistent. [7] To our knowledge, no studies have investigated the role of oestrogen containing products on mortality in COVID-19.…”

Sex, Hormones, Immune Functions, and Susceptibility to Coronavirus Disease 2019 (COVID-19)–Related Morbidity

“…One study assessed COVID-19 disease with respect to the use of combined hormonal oral contraceptives, which demonstrated a protective effect for symptomatic COVID-19 disease. 14 The primary study population were premenopausal women. However, the study did not include a subset analysis of postpartum patients.…”