JMIR Publications

ABSTRACT

Background:

Early epidemiological studies suggested that pre-menopausal women and post-menopausal women receiving estrogen therapy were less likely to develop severe disease or die from COVID-19 infection. Potential mechanisms include estrogen-mediated immunomodulation and 17β estradiol-induced downregulation of ACE2, the cellular receptor for SARS-COV-2.

Objective:

To evaluate the feasibility, safety, and preliminary efficacy of transdermal 17β estradiol as an adjunctive treatment for COVID-19 in men and post-menopausal women.

Methods:

We designed a randomized controlled trial comparing 17β-estradiol transdermal gel plus standard care vs standard care alone in adults with confirmed COVID-19. Initial ethics and funding approval were obtained in March 2021. Owing to changes in the epidemiology of COVID-19 in Qatar and revisions to national quarantine policies, protocol amendments were required before recruitment commenced in February 2022: treatment duration was reduced from 10 to 7 days due to changes in national quarantine guidelines. Recruitment and follow up were conducted between February and June 2022.

Results:

Recruitment was substantially lower than anticipated because widespread of COVID-19 vaccination, declining disease severity, and revised national quarantine policies markedly reducing the number of eligible hospitalized patients. Consequently, the planned sample size was not achieved. A total of 29 men with mild COVID-19 were enrolled, with 13 randomized to standard care and 16 to transdermal 17β estradiol plus standard of care. The intervention was well tolerated, with no adverse safety signals or thromboembolic events reported.

Conclusions:

While underpowered to assess efficacy because recruitment targets were not achieved, the study showed that transdermal 17β estradiol was well tolerated with no major safety concerns among enrolled participants. The experience also provides important operational lessons for conducting clinical trials during rapidly evolving pandemics. Adequately powered studies are required to determine whether transdermal estrogen has therapeutic potential against COVID-19, other ACE2-mediated coronavirus infections, or potentially to other severe viral illnesses. Clinical Trial: ClinicalTrials.gov identifier: NCT04853069. Registered on 21 March 2021