Long COVID Rates Higher in Women: Evidence Grows

Medscape

02-07-2025

When Brazilian scientist Letícia Soares contracted COVID-19 in April 2020, she was in the final stretch of her postdoctoral studies in disease ecology at a Canadian University. By August, she was bedbound.
What began as piercing migraines quickly escalated into a cascade of long COVID symptoms — gastrointestinal distress, sleeplessness, joint and muscle pain, and crushing fatigue. For Soares and many other women with long COVID, it also included sudden menstrual changes that exacerbated her other symptoms.
'It just baffled me,' said Soares, now 40. 'It was debilitating.'
Before COVID, she had a stable, predictable cycle while using a hormonal IUD — light cramping, mild abdominal swelling, and consistent, manageable bleeding. Then, after her infection, her period disappeared entirely. A couple of years later, the pattern reversed: prolonged, heavy bleeding returned, compounding her long COVID symptoms and triggering severe crashes from post-exertional malaise — one of the hallmarks of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition linked to post-viral illness.
Cases like Soares's are leading scientists to spend more time trying to understand the biologic sex disparity in chronic illnesses such as long COVID that initially had all but been ignored. New research from the National Institutes of Health RECOVER initiative, the largest observational study to date, confirms what many have long suspected: Women face a significantly higher risk of developing long COVID than men. While men are more likely to experience severe acute illness and higher mortality, growing evidence suggests women are more vulnerable to chronic symptoms.
Published in JAMA Network Open , the study analyzed data from over 12,200 participants who had been infected by COVID between 2021 and 2024. Even after adjusting for clinical and demographic factors, women had a 31%-44% higher likelihood of developing long COVID than men. The risk was especially pronounced among nonpregnant, nonmenopausal participants.
This study is the first to examine risk across different groups assigned women at birth, revealing that age, pregnancy, and menopause all play a role in long COVID likelihood, said lead author Dimpy Shah, MD, PhD, assistant professor of population health sciences at The University of Texas Health Science Center at San Antonio. 'That is a very novel finding.'
Five years into the pandemic, with hundreds of millions of people worldwide affected by lingering symptoms, this emerging research on biologic sex disparities highlights the complexity of long COVID and how it intersects with hormonal cycles and life stages.
The study found that when adjusting for variables like age, race, and underlying health conditions, women had a 31% higher risk for long COVID. When only age and race were accounted for, the risk jumped to 44%, suggesting that other factors, including autoimmune conditions and post-viral illnesses, may influence the link between sex and long COVID.
The RECOVER study revealed notable patterns: Pregnant women aged 18-39 years had a lower long COVID risk than their nonpregnant counterparts compared with men in the same age group. Similarly, menopausal women aged 40-54 years had a lower risk than nonmenopausal women in that age group.
'This could be due to hormonal changes and variations in inflammatory responses, which shift with age,' Shah explained.
By identifying how biologic sex, pregnancy, and menopause affect long COVID risk, this study moves the field closer to understanding why some individuals experience prolonged illness — and how treatment strategies might be tailored accordingly.
While the latest RECOVER study wasn't designed to analyze hormone levels, senior author Nora G. Singer, MD, director of Rheumatology at MetroHealth Medical Center in Cleveland, emphasized the need for future research in this area. 'If we understood better the biologic mechanisms contributing to sex specificity, I think the question is, could we better stratify who we're worried about developing long COVID? Could we target drugs? Are there ways we could manipulate things to make people less likely to get long COVID, and are there different levels of immune response at these different ages?'
Emerging 'Menstrual Science' Could Be Key
Expanding this research is critical as long COVID and similar chronic conditions remain largely overlooked in medical funding and study. 'These illnesses are underfunded and understudied relative to their disease burdens,' said Beth Pollack, a research scientist at the Massachusetts Institute of Technology, Cambridge, Massachusetts, who studies complex chronic illnesses.
Addressing knowledge gaps, especially around sex differences, could significantly improve our understanding of complex chronic illnesses, said Pollack, who co-authored a 2023 literature review of female reproductive health impacts of long COVID.
For example, several previous studies and surveys of female patients with long COVID report an increase in symptoms related to menstruation, which further suggests a possible link between sex hormone fluctuations and immune dysfunction in the illness.
Sex Hormones and Immunity
The pathologies of long COVID currently focus on four hypotheses: persistent viral infection, reactivation of dormant viruses (such as common herpes viruses), inflammation-related damage to tissues and organs, and autoimmunity (the body attacking itself).
It's this last reason that holds some of the most interesting clues on biologic sex differences, said Akiko Iwasaki, PhD, a Yale University, New Haven, Connecticut, immunologist who has led numerous research breakthroughs on long COVID since the start of the pandemic. Women have two X chromosomes, for example, and although one is inactivated, the inactivation is incomplete.
Some cells still express genes from the 'inactivated genes' on the X chromosome, Iwasaki said. Those include key immune genes, which trigger a more robust response to infections and vaccinations but also predispose them to autoimmune reactions. 'It comes at the cost of triggering too much immune response,' Iwasaki said.
Sex hormones also factor in. Testosterone, which is higher in men, is immunosuppressive, so it can dampen immune responses, Iwasaki said. That may contribute to making men more likely to get severe acute infections of COVID but have fewer long-term effects.
Estrogen, on the other hand, is known to enhance the immune response. It can increase the production of antibodies and the activation of T cells, which are critical for fighting off infections. This heightened immune response, however, might also contribute to the persistent inflammation observed in long COVID, where the immune system continues to react even after the acute infection has resolved.
Sex-Specific Symptoms and Marginalized Communities
Of the more than 200 symptoms people with long COVID experience, Iwasaki said, several are also sex-specific. A draft study by Iwasaki and another leading COVID researcher, David Putrino, PhD, at Mount Sinai Health System in New York City, shows hair loss as one of the most women-dominant symptoms and sexual dysfunction among men.
In examining sex differences, another question is why long COVID rates in the trans community are disproportionately high. One of the reasons Iwasaki's lab is looking at testosterone closely is because anecdotal evidence from female-to-male trans individuals indicates that testosterone therapy improved their long COVID symptoms significantly. It also raises the possibility that hormone therapy could help.
However, patients and advocates say it's also important to consider socioeconomic factors in the trans community. 'We need to start at this population and social structure level to understand why trans people over and over are put in harm's way,' said J.D. Davids, a trans patient-researcher with long COVID and the co-founder and co-director of Strategies for High Impact and its Long COVID Justice project.
Where It All Leads
The possibility of diagnosing long COVID with a simple blood test could radically change some doctors' false perceptions that it is not a real condition, Iwasaki said, ensuring it is recognized and treated with the seriousness it deserves.
'I feel like we need to get there with long COVID. If we can order a blood test and say somebody has a long COVID because of these values, then suddenly the diseases become medically explainable,' Iwasaki added. This advancement is critical for propelling research forward, she said, refining treatment approaches — including those that target sex-specific hormone, immunity, and inflammation issues — and improving the well-being of those living with long COVID.
This hope resonates with scientists like Pollack, who led the first National Institutes of Health-sponsored research webinar on less studied pathologies in ME/CFS and long COVID, and with the experiences of individuals like Soares, who navigates through the unpredictable nature of both of these conditions with resilience.
'This illness never ceases to surprise me in how it changes my body. I feel like it's a constant adaptation,' said Soares. Now living in Salvador, Brazil, her daily life had dramatically shifted to the confines of her home. While her condition limits many aspects of her life, working remotely allows her to stay involved in disability advocacy as a co-lead and researcher at the international Patient-Led Research Collaborative.
Understanding sex differences in long COVID could also transform care for millions. From a public health perspective, new research could improve diagnosis in clinics, inform targeted therapies for high-risk groups, and encourage women to take their symptoms seriously.
'Because they are at potentially higher risk for long COVID, if they're not feeling well, they should definitely talk to their primary care or internal medicine physicians,' said Shah, reflecting on the latest RECOVER study's findings. 'It's a call to action.'