Can progesterone improve COVID-19 outcomes in men?

• Compared with women, men are more likely to develop severe COVID-19 and die.
• A small-scale pilot study tested whether injectable progesterone improved outcomes in men hospitalized with moderate-to-severe COVID-19.
• Participants receiving progesterone had better clinical outcomes after 7 days.
• The study concludes that further research is required to assess progesterone’s safety and efficacy for the treatment of COVID-19 in a larger, more diverse population.

Overall, men are 2.4 times more likely to die from COVID-19 than women. This disparity may result from a complex interplay of psychosocial, behavioral, and biological factors.

For instance, men tend to engage in higher-risk behaviors at a greater frequency than women, such as increased use of tobacco and alcohol. They also have lower rates of social distancing, hand-washing, and wearing masks.

Men also have a higher incidence of health conditions associated with poorer COVID-19 outcomes and are less likely to seek medical care proactively.

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Immune sex differences

Females tend to mount stronger immune responses than males, which may be due to differences in sex chromosome genes and sex hormones, such as progesterone.

Several immune cell types express progesterone receptors, which can inhibit inflammation in premenopausal females.

Progesterone is a hormone produced by the ovaries in females and the adrenal gland and testes in males. However, it is present in much lower concentrations in males and postmenopausal females.

Earlier research has shown that premenopausal females with COVID-19 tend to spend less time in hospital. They are also less likely to need respiratory support than postmenopausal females.

Progesterone may dampen the exaggerated immune response or “cytokine storm” that causes severe lung injury, which sometimes leads to fatalities in people with a SARS-CoV-2 infection.

Progesterone currently has approval in the United States to treat infertility, the absence of menses or amenorrhea, and abnormal uterine bleeding.

In one study, scientists infected mice with influenza A. When they treated the animals with progesterone, there was less lung inflammation, and they recovered more quickly.

This finding prompted researchers to conduct a randomized controlled pilot trial at Cedars-Sinai Medical Center to assess progesterone’s effectiveness and safety in men hospitalized for COVID-19. Their results appear in the journal Chest.

Testing progesterone

Dr. Sara Ghandehari, director of Pulmonary Rehabilitation in the Women’s Guild Lung Institute, assistant director of the Lung Transplant Program at Cedars-Sinai Medical Center, and principal investigator for the trial, states:

“As an [intensive care unit] doctor, I was struck by the [sex] disparity among COVID-19 patients who were very sick, remained in the hospital, and needed ventilators.”

Between April 27 and August 5, 2020, the study enrolled 42 men aged 18 or older hospitalized with moderate-to-severe COVID-19 with low oxygen levels.

The scientists split the participants into two groups — an experimental and a control group. They gave the experimental group a progesterone injection under the skin twice daily for 5 days with standard medical care, then gave the control group routine medical care alone.

The researchers assessed participants each day for 15 days or until discharge. For those discharged, the scientists followed them up with phone calls or video study visits on days 7 and 15.

For participants in the control group who were deteriorating or not improving by day 7, the study design allowed the researchers to give them progesterone.

Encouraging outcomes

The study analyzed the results from 18 participants in the progesterone group and 22 in the control group, with two participants in the progesterone group withdrawing from the trial. The researchers gave nine patients in the control group progesterone because they were not improving or their condition was worsening.

The study assessed clinical status based on a scale ranging from 1–7, with a higher score indicating a better clinical outcome. On average, participants in the progesterone group scored 1.5 points better than the control group on the clinical status scale after 7 days.

The participants receiving progesterone required 3 fewer days of supplemental oxygen and 2.5 fewer days of hospitalization than the control group, but the difference between the two groups was not statistically significant.

The study did not report any serious adverse events or increased risk for blood clots attributed to progesterone.

The primary limitation of the study was its small size. Also, patients, providers, and researchers all knew who was in the control group and who was in the experimental group, which may have biased the study results.

Additionally, most participants were primarily white and Hispanic and had existing conditions, such as diabetes, hypertension, and obesity, which are risk factors for severe COVID-19 disease.

The lack of diversity of study participants may limit the generalizability of the study to other populations.

Dr. Ghandehari comments on the need for additional investigation: “Further research is necessary in larger, more heterogeneous populations, including postmenopausal women and at other treatment centers, to establish the degree of clinical efficacy and to assess any other potential safety concerns of this treatment approach.”

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