Hormones May Hold Key to Understanding Long COVID and Chronic Illness

In Canada, 44 percent of adults who are 20 years or older live with one or more chronic conditions, while in the US, 70 percent of all deaths are the result of chronic diseases, costing tax payers trillions of dollars in health care spending. Yet, people, primarily women and Black, Indigenous, and people of colour (BIPOC), living with chronic illnesses often face neglect by the medical community. But, if there were one positive thing to come out of the ongoing pandemic, it would be the reminder that millions of people worldwide live with chronic illnesses, which warrant far more research.

A gold mine for the study of the viral origins of chronic disease

"The literature shows a relationship between COVID-19 and metabolic dysfunction and inflammation."

Chronic illnesses have complex etiologies, but many begin with a viral infection. More than 90 percent of cervical cancers are caused by human papilloma viruses; 99 percent of patients with multiple sclerosis (MS) have been infected by Epstein-Barr virus (EBV), the leading cause of MS; and chronic respiratory infections and fatigue are strongly linked to viral infections. 

Significant similarities between post-acute sequelae of SARS-CoV-2, colloquially known as “long COVID,”  and myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) have prompted some experts to argue that the two syndromes could be one of the same, which is certainly intriguing—coronaviruses cause more than 20 percent of colds, and chronic fatigue is typically reported after Ebola, West Nile, Dengue, and coronavirus infections. The new-found interest in ME/CFS driven by long COVID has undoubtedly helped restore some hope for ME/CFS patients—the majority of which are women—who have long been ignored by the medical community.

"The literature shows a relationship between COVID-19 and metabolic dysfunction and inflammation."

Strong links between gender, metabolism, and long COVID

Similarly, women and BIPOC are also most likely to develop long COVID, which bears strikingly similar features to many chronic illnesses, including ME/CFS. But beyond gender, as is also the case for patients with ME/CFS, the main factors associated with COVID-19 and long COVID are age and high body mass index. Long COVID has been reported to detrimentally impact individuals with obesity. 

However, according to the Centers for Disease Control and Prevention (CDC), nearly one in three adults is overweight; previous research has also shown that obesity alone does not increase the risk of death. In general, there is a lack of consensus on which represents a greater risk factor for poor COVID-19 prognosis: obesity with or without insulin resistance and/or type 2 diabetes. Yet, the literature shows a relationship between COVID-19 and metabolic dysfunction and inflammation. 

In a clinical study published in Nature Metabolism, Montefusco and colleagues reported dysregulation of glucose metabolism in 46 percent (253) of patients hospitalized for COVID-19. But what was remarkable about their findings was that the results pointed to hormones as the culprits for metabolic dysregulation.

How hormones and viral entry receptors contribute to long COVID

A number of recent clinical studies in cells and tissues point to hormones as major players in the emergence of long COVID. A study published late last year in Cell Metabolism showed a strong link between increased insulin secretion and resistance, human adipocyte (fat cell) infection, and low expression of the adipokine (adipocyte-generated hormone) adiponectin. The team led by James C. Lo, MD, PhD, clinician-researcher at Weill Cornell Medicine Cardiovascular Research Institute, analyzed adiponectin and leptin—another adipokine—protein and mRNA levels in human blood plasma and adipocyte tissue samples from patients at Weill Cornell Medicine. 

Lo and colleagues found that in contrast to adiponectin, leptin is increased in patients with COVID-19; moreover, a low adiponectin to leptin ratio highly correlated to increased COVID-19 mortality and morbidities, and low to moderate ratios correlated with the onset of long COVID. Their study also demonstrated that human adipocytes can be infected by SARS-CoV-2. 

When it comes to acute COVID-19, men have a higher mortality risk than women, except in class III obese individuals, where visceral fat content and leptin levels are high. On average, women produce leptin hormone at higher levels than men; women in their 40s to 60s, when leptin hormone levels peak, happen to be the group with the highest risk for developing long COVID; and pregnant women are more susceptible to COVID-19 in the last two trimesters, when leptin levels are highest.

"Two and a half years since the first reported COVID-related death in the US, the sex-linked nature of long COVID remains convoluted."

The role of leptin and COVID onset in pregnant women should be studied further given that, as leptin levels rise, ACE2 expression decreases in the placenta. ACE2 or angiotensin-converting enzyme 2 is an important enzyme in blood pressure regulation, and the primary cell entry receptor exploited by SARS-CoV-2. But research on third trimester placentas has shown that only placenta tissue with higher ACE2 expression is susceptible to viral infection by SARS-CoV-2. The picture of how adipocyte hormones regulate infection remains incomplete, but understanding how they do may be critical to determine high risk populations to developing long COVID.

Similarly, studies analyzing the effect of sex hormones—estrogen and testosterone—on COVID-19 progression are confounding. Levels of testosterone have been used to explain observed health declines in men, as well as women with polycystic ovary syndrome and COVID-19. Early in the pandemic, Samuel et al. reported that high androgen receptor levels and signaling resulted in increased ACE2 expression and susceptibility to SARS-CoV-2 infection in human embryonic stem cells-derived cardiomyocytes and lung organoids. But additional studies show that testosterone levels prove fatal at both extremes: not enough is just as bad as too much. 

To complicate matters, social factors may impact prognosis to COVID-19 in men, and even suggest global reports may be skewed when it comes to women, resulting in underreporting of COVID-19 death rates in women. Organoids, precision cut tissue slices, and primary cells have been instrumental in recapitulating observed clinical findings, but nearly two and a half years since the first reported COVID-related death in the US, the sex-linked nature of long COVID remains convoluted. As is the case with ME/CFS, patients living with long COVID will likely have to contend with uncertainty and unfulfilling treatment options for the near future.