Progesterone in Addition to Standard of Care vs Standard of Care Alone in the Treatment of Men Hospitalized With Moderate to Severe COVID-19

Abstract

Background Severity of illness in COVID-19 is consistently lower in women. Focus on sex as a biologic factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. Research Question Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19? Study Design and Methods We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive standard of care (SOC) plus progesterone (100 mg subcutaneously twice daily for up to five days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status at day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes. Results Forty-two patients were enrolled from April - August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study prior to receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to Day 7 in patients in the progesterone group as compared to controls (95%CI:0.0-2.0; P=0.024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required 3 fewer days of supplemental oxygen (median of 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median of 7.0 vs 9.5 days) as compared to controls. Interpretation Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19.

Progesterone Dampens Immune Responses in In Vitro Activated CD4+ T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy

“…Interestingly, promising results were noted in a recent pilot clinical trial where progesterone was used in male patients with COVID-19 with the aim to mitigate the overactive immune system and sometimes fatal cytokine storm. Notably, no severe side effects associated with progesterone were reported, even at progesterone levels similar to those found during pregnancy (85). Although further investigations are needed, the study highlights the potential of use of progesterone as treatment in males as well.…”

Sex differences in immunological responses to COVID-19: a cross-sectional analysis of a single-centre cohort

“…7 Therapies aimed at modulating sex hormones show promise and warrant further attention. 8 A higher correlation between most cytokines was seen in female but not male patients, in particular IL-6, IL-10, and IP-10; cytokines associated with increased mortality risk in patients with COVID-19. 9 The clinical implications of this are unclear, but may represent a dysregulated host response to COVID-19 among male patients.…”

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity

“…In the USA, a pilot trial testing whether symptoms severity can be reduced with oral PG in men (NCT04365127) has been completed and showed very encouraging data. Indeed, results suggested that administration of PG at a dose of 100 mg twice daily by subcutaneous injection represents a safe and effective approach to treat COVID-19 by improving clinical status among men with moderate to severe illness [15] .…”