In a previous blog post Fear of Covid Reigns over Fear of Estrogen, the protective effects of estrogen against Covid were discussed. At the time, these protective effects never made the headlines. Now, these very effects are coming to light.
A recently published study titled, “Association between pharmaceutical modulation of estrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study,” brings attention to estrogen’s protective effect against death from Covid.
Proposed mechanisms of estrogen’s role in combating respiratory viral infections include estrogen receptor sites. Estrogen receptor sites are present on all immune cells. These sites are crucial to immune signaling, tissue repair, and dampening of inflammatory reactions.
Estrogen has been shown to decrease expression of proteins ACE2 and TMPRSS2 which are necessary for Covid to enter host cells and replicate. In vitro studies have shown a decrease in SARS-CoV-2 viral load when treated with estrogen. Other experimental studies in female mice showed protection against SARS-CoV-2 was lost following oophorectomy, suggesting estrogen’s protective role.
Women are less susceptible to getting Covid and appear to be protected from poor outcomes compared to men. but postmenopausal women not on hormone replacement are not. Similar findings have been demonstrated for other viral infections such as MERS-CoV and SARS-CoV.
Is estrogen a critical link to this gender discrepancy? How might this compare to postmenopausal women who are receiving hormone replacement therapy (HRT)? The following study aims to shed light on this with the objective of determining whether augmentation of estrogen decreases the risk of death from Covid in postmenopausal women.
This is a retrospective, nationwide, registry-based study in Sweden of 14,685 women between 50 and 80 years old with verified Covid infection between February and September of 2020. Data was obtained from the Swedish Public Health Agency, Statistics Sweden Registry and the Swedish National Board of Health and Welfare.
The participants fell into 3 groups:
Decreased estrogen group: 227 patients with history of breast cancer receiving tamoxifen, fulvestrant, or an aromatase inhibitor. These medications decrease estrogen levels to avoid cancer recurrence
Augmented estrogen group: 2,535 patients treated with any of the following classified as postmenopausal HRT (estradiol, estriol, conjugated estrogen with bazedoxifene, tibolone, synthetic progesterone and estrogen combination)
Control group: 11,923 patients with no breast cancer diagnosis and no prescription of hormone pharmaceuticals
Groups were adjusted for confounders using a comorbidity index, age of Covid diagnosis, income, and education as previous studies identified these risk factors as affecting Covid outcomes.
The primary outcome measurement was death following Covid, identified as the main or contributing cause of death from the Cause of Death Register.
The use of estrogen significantly protected women against death due to Covid by 53% lower odds of dying from Covid compared to those not receiving estrogen.
The absolute risk of dying from Covid was 2.1% for the estrogen treated group, 10.1% for the decreased estrogen group, and 4.6% for the control group.
While the sample of women with breast cancer on anti-estrogen modulation therapy was too small to prove significance, it did demonstrate a trend of increased mortality.
This study demonstrates the protective role of estrogen against Covid as estrogen hormone replacement decreased the odds of death in postmenopausal women.
This study demonstrated several strengths. The results are based on all Covid diagnosed patients in Sweden nationwide between February and September of 2020. The registry data used are well validated and cross-linked allowing comorbidities and confounding factors to be adjusted for within the groups. This study was conducted prior to the availability of vaccines.
The limitations of this study were: exact duration and estrogen levels among women in this study were not tested or followed, difference in outcomes between synthetic and natural hormones were not made available, compliance to estrogen therapy was not available. BMI, smoking habits and nutrition were not included as they were not available on the national registry.
The trend towards worsened outcomes among women on anti-estrogen therapy for breast cancer was prevalent, however, larger population studies are necessary to determine non-estrogenic effect versus immunological stress effect from having cancer.
All said, the postmenopausal group receiving HRT was large enough to prove the protective effect of estrogen against Covid.
This observational study strengthens previous study findings demonstrating the beneficial effects of estrogen. Optimizing estrogen levels is important for all women but especially among postmenopausal women as it has persistently shown to be a crucial weapon against Covid.