Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study

Abstract

ObjectiveDetermine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19.DesignNationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death).ParticipantsPostmenopausal women between 50 and 80 years of age with verified COVID-19.InterventionsPharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI).Primary outcome measureDeath following COVID-19.ResultsFrom a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16).ConclusionsOestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.

Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19

“…The global data of COVID-19 showed that men have a higher mortality rate than women. In the recent retrospective cohort studies 59 , 60 , estrogens supplement or replacement therapy were associated with reduced mortality in COVID-19. For example, using a nationwide cohort of Sweden 59 , estrogen supplement/treatment in postmenopausal women is associated with a decreased risk of dying from COVID-19.…”

“…In the recent retrospective cohort studies 59 , 60 , estrogens supplement or replacement therapy were associated with reduced mortality in COVID-19. For example, using a nationwide cohort of Sweden 59 , estrogen supplement/treatment in postmenopausal women is associated with a decreased risk of dying from COVID-19. In another recent study 60 , it reported the protective effect of estrogen replacement therapy (hormone replacement therapy, HRT) within 6 months before the diagnosis of COVID-19.…”

Hormone Therapy in the Era of the COVID-19 Pandemic: A Review

“…On this pathophysiological basis summarized above, researchers and clinicians have been trying to verify whether female hormones, of which serum concentration can be a modifiable factor, could have a place in the therapeutic role against COVID-19. A large scale cohort study performed in Sweden revealed that estrogen supplementation in postmenopausal women is associated with decreased mortality [ 25 ]. In this study, an adjusted odds ratio of death following COVID-19 was 0.47 (95% confidence interval, 0.34 to 0.63) for women receiving estrogen replacement therapy.…”

Functional associations between polymorphic regions of the human 3′IgH locus and COVID-19 disease

“…The pattern of immune response in women has been hypothetically linked to estrogens ( Styrt and Sugarman, 1991 , Hirokawa et al, 2013 , Sund et al, 2022 ). DNA binding sites of the Estrogen Receptor alpha (ERα) have been reported in the Emu and hs1.2 enhancers, which are important regulatory DNA domains in the immunoglobulin (Ig) heavy (H) chain 3’Regulatory Region (3’RR) ( Jones et al, 2016 ).…”