The Covid-19 Sex Difference – why the overriding focus on the elderly is misguided

We urgently need to better protect the vulnerable from Covid-19 – but who are they? A disproportionate number of sportsmen have been diagnosed with Covid19. Former Scotland cricket captain Majid Haq contracted the virus and a host of elite footballers including teenager Callum Hudson-Odoi, Daniele Rugani and Paulo Dybala have tested positive, suffering pronounced symptoms and Lee Duffy was unable to breathe without intervention. Men in their prime are requiring intensive care to survive. As a researcher of biological sex differences, I’ve become increasingly alarmed the potential relevance of sex in the fight against Covid-19 has been side-lined. I put my concerns to physician Hugh Montgomery, UCL Professor of Intensive Care Medicine.

“In haste (front-line is frantic, I’m flat out). You are right. The sex difference in ICU [Intensive Care Unit] patients is large and, I think, will grow. It appears true that there are plenty of middle-aged men with only one a risk factor (e.g. high blood pressure) being admitted to ICU, and many are very fit and physically active. It’s possible this healthier population of males is created by ascertainment bias of treatment limitation, meaning the more frail who are considered more likely to have a poor outcome are not being admitted to ICU.”

The Covid-19 impact on the Italian population has seen a high number of otherwise fit male doctors dying from Covid-19. Frontline male medics are over-exposed to patients infected with a heavy viral load. But so are female doctors and nurses. I asked Prof Montgomery if elite athletes, frontline male medics and older adults are more vulnerable to this disease than other groups, is it possible testosterone is a common factor?

“Clearly Y-chromosome. But why? Is testosterone bad? Or is estrogen protective? We need big genetic, age specific data and I can’t get any from China, I’ve tried many routes. Studies here are starting. But we may be unable to collect data fast enough as research nurses are being pulled to front line duties.”

It’s been noted youngsters are not a Covid-19 vulnerable group, they are innately low in testosterone and so are fertile women. Medicine is well versed in testosterones’ many and varied immunosuppressive effects. Covid-19 is not the flu, but it is a respiratory disease. Estrogens help protect females against the flu by helping keep respiratory inflammatory responses within the optimal range. Estrogen’s protective factor has the potential to be lifesaving in defending against pneumonia, should Covid-19 spread to the lungs.

One of the latest NHS interventions to save lives involves the harvesting of blood plasma from those who are “hyperimmune” and the search for these people is on. Will it be the men who survive who have the largest immune response? Or, might young, fertile women, innately protected via higher than average estrogens be a likely candidate for the hyperimmune group? And could fertile women, sans noticeable symptoms, be unwitting Covid-19 ‘spreaders’? In Italy, at least one female nurse, who had not displayed symptoms, committed suicide after fearing she had spread the disease. (Whoever the spreaders are they need to be identified and protected from guilt and others need to be shielded from them.)

Conversely, post-menopausal women’s immunity is not bolstered by estrogens and we know older women are more vulnerable to Covid-19. Is it therefore possible that HRT (hormone replacement therapy) could help women with early menopause and older women to better survive this pandemic? When post-menopausal women take HRT for only three months, they experience a gray-matter increase in their hippocampus brain region, leading to improved learning and memory and thus HRT has the potential to protect against dementia.

I put my questions surrounding HRT and sex differences to Professor James Moon, Chief Investigator of the Barts/QMUL & UCLH/UCL COVID research strategy group,

“How timely. We are mobilising the COVID-19 consortium Health Care Workers study at UCL and Barts and getting the material needed to answer these questions. We have recruited 273 participants out of an initial 400, then probably 1000. We will capture athleticism, aspects of female biology (pregnancies/hormone status) and as an addition, micronutrients (vitamins A, B, C, D, E & zinc).”

If Covid-19 is a disease where estrogens protect and testosterone increases vulnerability could this mean trans women are better protected against Covid-19 due to transitioning? The increased vulnerability of the frail and those with underlying conditions notwithstanding, it’s possible people over exposed to androgens and taking steroids, such a body-builders, trans men and people transitioning to male, plus people with innately higher than average testosterone such as people with autism spectrum conditions, elite male and female athletes and otherwise fit men in their prime also belong to at-risk groups.

Professor Walter Malorni works closely with Italy’s trans community and established Rome’s National Institute of Health’s Center for Gender-Specific Medicine to research the role of XX chromosomes and estrogen in disease pathogenesis.

“Data on sport professionals, should be considered. I am fully convinced that testosterone and estrogen could affect the immune system’s integrity and function exerting opposite effects. However, this can only partially explain the observed gender disparity. We are researching the implication of X chromosomes and on receptors. One hypothesis could be that ACE2 molecules at the cell surface (receptors of COV-19) could be pivotal. The upregulation of these receptors, bolstered by estrogen could help women. However, what happens in aging subjects where estrogens are low? Gender differences between women and men in terms of incidence and mortality (more than double in men) could be associated with the activity of some genes encoded on the X chromosome and escaping inactivation in women (one of the two X chromosome is only partially inactivated). We have some thought and data on this. We have to consider that the mortality rate of 2/3rd of men could be underestimated. [Amongst the elderly] the population at that age is more than 80% female. I am afraid that, when epidemiological evaluation is carried out, we will realize that gender disparity could be really impressive. Finally, your idea that HRT could help is in my opinion, correct and your concern for the transgender population is appropriate”.

Sex hormones are not the only reason males and females have different predispositions to the same diseases. Genes are sexed and can have different effects on disease and cognition in males and females. One example is where the same gene protects young girls from contracting bronchitis while increasing the vulnerability of little boys. Dr Ted Morrow is an expert on sexually antagonistic effects where genetic variants produce different outcomes. “One major problem is the data that could help researchers investigate these questions are not publicly available. Basic data on infection rates and outcomes separated by sex is not being released (or even collected!). On the testosterone effect we need data stratified by age and sex simultaneously. I asked the authorities in Sweden where I work [for this information]. Each week they produce a plot with this precise data and delete the previous week’s reports and the underlying data is not in open access”.

Sex differences research was once a routine element of biomedicine. But for many years sex differences data collection (and research on the biological differences between distinct geographic populations) has received bad publicity. Activists have tended to promote sameness fearing a recognition of difference will lead to discrimination. (Recognising and protecting ‘difference’ is the raison d’ être of the Equality Act 2010.) Today, sex difference data is not routinely collected because accusations of sexism have thwarted research. The WHO have long been criticised for failing to include sex difference data in their vaccination campaigns and disease interventions. Professor David Geary is an expert on human evolution and vulnerabilities underscoring sex differences. I mentioned the difficulties the UK’s front-line physicians are facing in accessing analysis on the pandemic’s sex difference and asked Prof Geary if the politically correct push-back against sex differences research hadn’t happened might we now have greater insight to help us fight Covid19? “That’s a fair comment. The activists have set back research on sex differences, including Biomedical research, by decades” he said.

Boris Johnson’s fatalistic surrender advocating, “Say goodbye to your loved ones” was misguided in so many ways. The UK has seen a chilling, discriminatory over-focus on the frail and those with underlying conditions. These groups have been made to feel guilty for being a potential burden on the NHS and urged to sign DNRs (Do Not Resuscitate) certificates.

While those with learning disabilities and autism have also been discriminated against with NICE (National Institute for Health and Care Excellence) wrongly advising medics that patients with these disabilities would have inherent uncertainty around the benefits of critical care. Ageism and ableism are illegal and morally repugnant and this discrimination is a dangerous distraction from addressing the pandemic’s sex difference. Any delay in identifying who the vulnerable really are will cost lives.

Panama has just implemented a sex segregated social distancing regime, with men and women permitted out of their homes on alternate days for one hour and everyone ordered to stay home on a Sunday. Apparently, this method has not been established to use sex difference in vulnerability to comparatively measure the spread of Covid-19, but rather on the assumption that without the distraction of the opposite sex people are less likely to socialise. However, Panama’s social distancing measure has the serendipitous potential to deliver significant results.

Japan had its first Covid-19 case in January and managed the quarantine of the Diamond Princess cruise liner. Since then the disease has been comparatively slow to spread. It has been suggested this is because Japan has conscientiously tested for Covid-19 and they have a culture of not shaking hands which helps control infections. However, biology’s role may be more relevant. Japan has an aging population and many Japanese people live on past their one hundredth birthday. The Japanese male endocrine system is different to Western males and they have a lower baseline for testosterone and it been suggested they live longer because of it. Additionally, soya beans are naturally high in estrogen. Diets including high levels of soy-based foods causes feminisation and concerns have been raised that a low sperm count can result. Few want to breed during a pandemic. In the fight against Covid-19 a diet enriched with soya could provide both sexes with a life-saving estrogen boost.

In Australia there has been an attempt to isolate the First Nation people from Covid-19. Australia’s Aboriginals are descended from an ancient tribe that migrated from Africa around 70,000 years ago. The longevity of Aboriginal males and females is approximately 7 years lower than the wider Australian population. The First Nation people are known to be disproportionally susceptible to respiratory disease and females suffer higher incidences of polycystic ovary syndrome and diabetes and both of these conditions correlate with raised testosterone. In humans, in general, lower testosterone in males is linked to diabetes while in women raised testosterone correlates with diabetes and diabetics are a Covid-19 at-risk group.

The UK’s first frontline medics to give their lives fighting this pandemic were all BAME (Black, Asian, Minority Ethnic). It is possible BAME are genetically more vulnerable to this disease. If so, frontline BAME clinicians are facing increased risk and must be protected, or redeployed to less dangerous areas of clinical practice. Genetic data is urgently needed. The relationship of sex hormones to the pandemic’s natural selection of our species must not be underestimated. Differences between males and females and between historically and geographically distinct peoples must be researched and openly discussed and not stymied by accusations of sexism or racism. On this issue, Nicole Woitowich, Associate Director of the Women’s Health Research Institute at Northwestern University commented,

“It is paramount we consider the influences of both sex and gender when studying the prevalence, severity, and disease mechanisms of Covid-19. If we can gain a better understanding of how Covid-19 impacts men and women differently, we may be able to utilize this knowledge to develop novel therapeutics and design the most effective treatments for all people.”

The nations of the world will be better able to defend against this pandemic when they collaborate on biological sex differences data. Professor Montgomery concurs, “Testosterone inall areas should be included, example, in trial bloods, and in data on those who stay on ward with those needing CPAP [continuous positive airway pressure] or who go to ICU. Plus, a menstrual cycle study to ascertain a relationship of infection to phase of menstrual cycle and a genetic study is also needed.” This will help us know who is vulnerable to contracting Covid-19. Prof Montgomery emphasised, “If we could mobilise university researchers to come to hospital and provide samples and we could recruit them to genetic and drug trials, this would be a massive lifesaver. Feel free to lead this across the UK.”

Prof Montgomery added, There is an app out there now for tracking symptoms.

If participants can add menstrual cycle data that would be REALLY interesting and possibly important.”

This is a shout out to genetic epidemiologist Prof Tim Spector at Kings to please adapt the app to include menstrual phase data.

Prof Montgomery urged, “You could even approach the menstrual apps / fertility trackers that are in common use and ask them to add Covid-19 symptom questions to help us accrue life-saving data.”

The website Healthline lists 10 fertility apps. If these and other similar companies can take onboard Prof Montgomery’s suggestion and adapt apps so users can provide Covid-19 symptomatic data aligned to their menstrual cycle, the accumulation of this information could begin the revolution we need to fight this pandemic. If companies do make these changes please get in touch.

This is also a call out for meta data, researchers and the public, are wanted to provide genetic samples, to their local research hospitals, possibly to support the London Covid Consortium data collection.

It is possible Covid-19 is exacting a feminising effect upon us. The thing to appreciate about evolution’s natural selection – which is playing out right now as the Covid-19 pandemic sweeps around the globe, picking off victims, is that a species must have diversity to improve immunity and survive disease. Difference isn’t just a good thing it’s essential. If we were all the same and all equal and we all shared the same strengths and vulnerabilities a pandemic could wipe us out. The bigger, evolutionary perspective teaches protection of the vulnerable helps preserve human diversity, making us more resilient in the long term.

The Nipah virus emerged from Malaysian forests via bats that were disturbed when pig farmers encroached into pristine forest in the drive to produce more pork for the Chinese market. Nipah has a much higher death rate than Covid-19, killing up to 70% of those infected.

Now is the time, for once and for all to end the trade in wildlife whether for meat, or as exotic pets, or for body parts. For our own sake we must respect and understand nature and our place in it. Let’s celebrate our species’ diversity and protect our differences. We must unite to condemn discrimination, set censorious political correctness aside and work together to preserve what we have taken for granted for far too long.