Female sex hormone, progesterone, ameliorates the severity of SARS-CoV-2-caused pneumonia in the Syrian hamster model

Abstract

<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 260 million people worldwide and causes coronavirus disease 2019 (COVID-19) with clinical spectrum ranging from mild to severe pneumonia. Recent clinical trials and experimental animal studies demonstrated that the severity of COVID-19 is lower in the females than in males.^{<a title="Clark, A. et al. Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study. Lancet Glob. health 8, e1003–e1017 (2020)." href="https://www.nature.com/articles/s41392-021-00860-5#ref-CR1">1</a>} However, it is unclear whether sex hormones are associated with disease severity in COVID-19 patients. Previously, the anti-inflammatory effects of progesterone, a major female sex hormone, were observed in patients who suffered from the influenza virus-infected diseases.^{<a title="Hall, O. J. et al. Progesterone-based therapy protects against influenza by promoting lung repair and recovery in females. PLoS Pathog. 12, e1005840 (2016)." href="https://www.nature.com/articles/s41392-021-00860-5#ref-CR2">2</a>,<a title="Ghandehari, S. et al. Progesterone in addition to standard of care vs standard of care alone in the treatment of men hospitalized with moderate to severe COVID-19: a randomized, controlled pilot trial. Chest 160, 74–84 (2021)." href="https://www.nature.com/articles/s41392-021-00860-5#ref-CR3">3</a>} In this study, we aimed to investigate the role of progesterone in the Syrian hamster model of SARS-CoV-2 infection-caused lung pathogenesis. In order to model the male COVID-19 patients with severe pneumonia, male hamsters were intranasally infected with 1 × 10⁴ plaque-forming unit (PFU) of SARS-CoV-2 (Fig. <a href="https://www.nature.com/articles/s41392-021-00860-5#Fig1">1a</a>). The SARS-CoV-2-infected hamsters were untreated or treated with 1-, 3- or 5-dose of progesterone (1 mg/kg per dose) via intraperitoneal injection (Fig. <a href="https://www.nature.com/articles/s41392-021-00860-5#Fig1">1a</a>). All of the hamsters with or without progesterone therapy survived throughout the infection course. The SARS-CoV-2-infected hamsters without progesterone treatment exhibited progressive body weight loss of up to 12.6 ± 1.1% from 1 to 7 days post infection (dpi) (Fig. <a href="https://www.nature.com/articles/s41392-021-00860-5#Fig1">1b</a>). However, the SARS-CoV-2-infected hamsters treated with 1-, 3- or 5-dose of progesterone exhibited body weight loss of 9.6 ± 0.9%, 6.7 ± 1.1% or 5.1 ± 1.2% at 7 dpi, respectively (Fig. <a href="https://www.nature.com/articles/s41392-021-00860-5#Fig1">1b</a>). The uninfected hamsters with or without 5-dose of progesterone treatment showed a body weight increase from 0 to 7 dpi (Fig. <a href="https://www.nature.com/articles/s41392-021-00860-5#Fig1">1b</a>). These data suggested that progesterone rescued the body weight loss of the SARS-CoV-2-infected hamsters in a dose-dependent manner.<br></p>