By Regina Schaffer
As researchers continue to assess complications of COVID-19, one striking difference has become clear — men who contract the novel coronavirus are more likely to be intubated or die compared with women.
Animal model studies of the SARS virus suggest that the age and sex differences in COVID-19 symptom severity may be due to the protective and acute actions of estrogen, and researchers are initiating a trial designed to find out whether a transdermal estrogen patch placed on the skin of COVID-19-positive patients can reduce symptom severity compared with regular care.
Healio spoke with Sharon Nachman, MD, chief of the division of pediatric infectious diseases at Stony Brook Children’s Hospital and associate dean for research at the Renaissance School of Medicine at Stony Brook University, and Antonios Gasparis, MD, director of the Center for Vein Care at Stony Brook Medicine and a professor of surgery at the Renaissance School of Medicine at Stony Brook University about the role of estrogen in immune response, the sex-based differences in COVID-19 outcomes, and how “crosstalk” across specialties could drive new discoveries in the search for COVID-19 treatments.
What gave you and your colleagues the idea to study estrogen therapy in COVID-19?
Gasparis: It was borne about a month ago when this pandemic really took hold. We all observed significant clinical differences in the severity of COVID-19 between men and women. When you look at infection rates, they are similar in both groups; however, when you look at severity of disease, the risk for men requiring ventilator support or being admitted to the ICU or dying is much higher vs. women. Intubation rates and death in men hovers around 80% compared with 20% among women. This difference intrigued me. I’m a vascular surgeon, but I started looking more into this disparity, and I found that this sex-based difference was not unique to COVID-19. It was also observed during the SARS outbreak. We know that estrogen receptors exist in the vascular system and in the lungs. The thought is that, somehow, estrogen or the effects of estrogen may be protective in women — especially younger, premenopausal women — from progressing to severe respiratory infections and respiratory failure. Obviously, once a person with COVID-19 is intubated, mortality is very high. The idea was to treat these patients in the early phases, and see if giving estrogen to men could that boost immune response and help protect them.
What was your thinking as you designed this trial?
Nachman: With the COVID-19 pandemic, everyone across specialties was seeing the different parts. We were all able to talk together and ask what can we do about this observation between sexes? We see it, but what does it mean? The focus of the trial design was to ask, could estrogen therapy change disease outcomes? Could we use it in patients who are infected or presumed infected — symptomatic — and give them estrogen in a particular formulation, and will that change hospitalization rates and, ultimately, intubation rates? We decided the primary objective of the study would be to assess whether the application of estrogen, used in transdermal patch form for 7 days, would change the outcome of intubation in the population. We included men across ages, but also women. We are using the estrogen patch at the same dose as would be used for postmenopausal women, and we included postmenopausal women in the study.
Were there concerns about using estrogen therapy in men?
Nachman: We prefer not to call estrogen a “female” hormone. That tends to put a box around it. We prefer to call it a “molecule of interest.” People need to keep an open mind. When you look at the demographics of the people who are at risk for getting ill, it is not unreasonable to look at other molecules and ask, what is their role in pathogenesis? The dosing we are using is the same as used for postmenopausal women. The level of estrogen in a pregnant woman is approximately 20 times higher than the dose we are using here. We do not expect any feminization from this low-dose, brief exposure to estrogen, though, certainly, we will collect data on it. Typically, we start with animal models, understand the pathways, and then move to humans. Here, we are reverse engineering. We are starting with humans, trying a molecule, and saying, if we see a signal, let’s go back and try to understand it. In COVID-19, other researchers at other institutions are looking into this too. I am hopeful that, between our study and others, we will get a better sense of where this molecule fits in immune regulation.
Can you explain for our readers the study design and duration?
Nachman: This is a randomized study, which is critical because we don’t know the role estrogen plays in the big picture. This study has two study groups. One group will receive the study drug, a single-use transdermal estradiol patch [Climara 25cm2], for 7 days. The other group will receive standard of care. Participants will be asked questions about their symptoms up to six times in up to 45 days. This is not a phase I study, as estrogen patch safety has already been demonstrated. After the 7-day period, the patch is removed. What is good about a patch formulation is, if we see any reaction, the patch can be removed immediately.
What do you hope to learn from this trial?
Gasparis: We know that estrogen at low levels for a short period of time is safe. There is always a concern of thrombotic complications, especially since these patients are prothrombotic. However, given the dose and the duration early on before they get really sick, the risk for that is low. Unfortunately, since we are not starting in animals, the question is, what is the right dose? We are starting with a very low dose, and if we see some response, that would lead us to move forward with different doses. Estrogen receptors are everywhere, from the brain to the lungs to the endothelium. As women get older, we know their immune response goes down because of the drop in estrogen. We hope to see a response. This is not meant to be a silver bullet. That said, we know that once a person with COVID-19 gets transferred to the ICU and is intubated, mortality is high, regardless of sex. We hope to prevent that in the early phases and reduce risk for severe respiratory infection and respiratory failure.
Nachman: Any data we gain will advance the field, particularly with regard to COVID-19 in this population. We hope to understand the role this molecule plays in immune activation. We recognize that estrogen plays a role in T cells, lung tissue and many other areas for immune response. Also, as part of the biobanking agenda at our institution, we will have samples saved on all patients at our institution that will help further understand this phenomenon. The most important thing to talk about is how the team is working across divisions. In the past, in medicine, for the most part, you talked with your colleagues within your specialty. What COVID-19 has forced us to do — rightfully so — is talk across those silos. This is a great first attempt, and I am encouraged by it. It shows what a team pulling together can do together. We want teams that have not worked together to do this kind of crosstalk. This illness, this pandemic, requires us to do out-of-the-box thinking. We won’t always be right— and that is OK — but we are generating new science.
Disclosures: Gasparis and Nachman report no relevant financial disclosures.