Read Part four of the series.
In May 2024, a scientific preprint showed that testosterone levels are lower in Long COVID patients than their sex-matched counterparts.
A preprint is a scientific article that has not yet been certified by peer review. It reports new medical research that has yet to be evaluated by experts.
Before formal publication in a scholarly journal, scientific and medical articles are traditionally validated through peer review. During peer review, the journal’s editors consult with various experts who evaluate the paper and may identify weaknesses in its assumptions, methods, and conclusions. A journal typically publishes an article only after the editors are satisfied that the data presented supports the conclusions. Because this process can be lengthy, authors sometimes make their manuscripts available as "preprints" before undergoing peer review, allowing other scientists to immediately see, discuss, and comment on the findings. For preprints, the confidence level mentioned in part one of this series is quite low.
Symptom differences between male and female Long COVID patients
As a first step, the study analyzed patient-reported symptom burden in 101 individuals with Long COVID (69 female, 32 male) in comparison to 82 controls (58 female, 24 male). Both sexes reported frequent symptoms like sleep disturbance and fatigue. Female participants, however, had higher overall frequencies of symptoms spanning multiple organ systems including changes in body temperature, coughs, and neurological and neurocognitive symptoms such as headaches and confusion. Moreover, hair loss was a symptom mostly reported by women, whereas men seemed to suffer from sexual dysfunction more often as short-term observations in part three of this series suggested. In general, females with Long COVID experienced a greater amount of symptom burden than males.
Additionally, females with Long COVID reported higher pain, higher impact on their overall health, and higher neurological impact, while males reported higher impacts on mood and higher rates of post-exertional malaise. The female and male healthy control groups showed no such differences.
Symptom burden in male vs female Long COVID patients (Source: Silva et al.)
Sex-specific immunological features in Long COVID
Next, the authors analyzed immune cells and immunological markers in blood samples of all four groups (male/female Long COVID vs male/female healthy control). Risk factors such as lack of vaccination are known predictors of higher Long COVID symptom burden. The study tried to identify additional predictive factors directly in the patients’ blood. They trained machine learning models to identify immunological and hormonal predictors. These key predictors were then used to predict female and male-specific immunological features in Long COVID patients.
Females with Long COVID showed, among others, an increase of T cell exhaustion, and other factors suggesting active immune processes such as inflammation and complement system activity. Compared to control females, levels of antibodies against SARS-CoV-2, as well as antibody activity against EBV were increased. Most notable hormone changes included a downregulation of testosterone and estradiol.
Males with Long COVID also showed higher levels of antibodies against SARS-CoV-2 but changes in different immune cell subpopulations then females. Compared to their healthy counterparts, estradiol and testosterone levels were decreased, while insulin and oxytocin levels appeared to be higher.
Irrespective of sex, levels of cortisol (a hormone that plays an important role in stress responses) were decreased in Long COVID patients.
When ranking all factors in their ability to predict sex specific Long COVID subtypes, testosterone was the most important predictor. This observation even held true when analyzing all patients together, meaning testosterone was able to predict symptom burden regardless of a patient’s sex designation.
This preprint suggests that sex hormones, especially testosterone, should be considered in the treatment and diagnosis of Long COVID. However, besides peer-review of this study, validation of this data is needed. The study identified predictors based on a machine learning model. Whether this predictive power holds true in clinical practice remains to be seen.
This post concludes the “Sex hormones and Long COVID” series for now. We will continue it once more research is available.
Did you observe any of the symptoms or hormonal changes mentioned in this series? Come discuss with other members of our community in the Altea Forum.
