In the last 8 months or so we have witnessed one of the most difficult and unprecedented times this earth has seen in the last century or so, the world had been brought to its proverbial ‘knees’ by the surfacing of SARS-CoV-2 virus, also known as Covid-19. A devastating virus which led to the loss of many lives.
The aetiology (the cause of the condition) and epidemiology (the methods/patterns of disease spread) of Covid-19 were unravelled over this time frame. However, treatment pathways remain in disarray, with arguments for and against therapies. A whole plethora of therapies have been used in attempts to treat the worst excesses of the virus from a whole host of antibiotics, antivirals and even in some cases antifungals…but until an effective, legitimate as well as safe vaccine has been developed we will continue to struggle to combat the virus with this eclectic mix of acute therapies.
What is evident is that Covid-19 sufferers on the whole (up to 80%) will have mild ‘flu-like’ symptoms (please be warned this illness is not the flu and should not be confused with the flu, only their presentations are in some cases alike) and recover remarkably well. However, there seems to be cohort (group) of patients who have a disastrous outcome with covid-19, who ominously progress to a severe type of respiratory distress, as a consequence of the infamous ‘cytokine storm’ (a great influx of cells which cause a lot of damage to your body’s compartments, that have been signalled by a over-exaggerated immune response). This cohort seems to be older men….
So why is this the case? In the beginning, there were a plethora of possible reasons, due to comorbidities (having other illness placing pressure on the body already overworked system), socioeconomic reasons, poor access to health care, and even some reported that this was due to a lack of oestrogen!??! However, no one wanted to raise the narrative of it being possibly due to testosterone deficiency. What we witnessed was nothing short of a ‘witch hunt’ against testosterone, one where postulation based on limited evidence suggested that men who were given powerful anti-androgen (blocking testosterone) drugs for prostate cancer were less likely to get coronavirus, and they suggested a link in regards to a specific receptor. However, it is important to remember that this data came from a limited population and was using a hypothesis with no real ‘hard’ endpoints.
OK, let’s talk about simple evidence-based medicine. If I walk into a cafe and see everyone wearing a pink tie, my hypothesis (proposed explanation) is that any person in that cafe can only have pink ties, which would be reasonable. However, when I check the local shops which sell clothing goods in that town then find out the only ties they sell are pink ties. Hence, the real reason for pink tie-wearing is that the shops only sell PINK TIES! We call this a confounder, aka a ‘red herring’. This is the same effect that was being postulated about the anti-androgen drug (testosterone blockers) and Covid-19.
This came from a small study done in Italy looking at prostate cancer patients given testosterone-blocking drugs found they were less likely to die from Covid-19 than those not given the same therapy.
However, commenting on the study in an article in the Daily Mail, Professor Nick James of London’s Institute for Cancer Research, said using the drugs as a large-scale method of preventing the virus was unthinkable. “Being on these drugs is the male equivalent of going through the menopause. You would almost certainly cause more harm than good”.
However, more and more studies have come about which have made it quite clear that normal levels of testosterone help rather than hinder the fight against Covid-19.
The first evidence was derived from a study of 31 male patients treated in a respiratory intensive care unit in Mantua in Lombardy in northern Italy. The study found that lower baseline levels of total testosterone and calculated free testosterone predicted higher mortality in men infected with the virus admitted to intensive care. Therefore, low testosterone could possibly be used as a screening tool for those who are admitted into the hospital. This would aid in the subsequent management with regards to those with low testosterone levels who are at greater risk of being admitted to intensive care.
This finding was echoed by another study of 45 patients, including 35 men, in Hamburg in Germany. Researchers at the University Medical Centre Hamburg-Eppendorf found that more than two-thirds of male Covid-19 patients admitted to intensive care showed low levels of testosterone, as did the majority of the Covid-19 patients who died.
Why is there much conflict in data? As explained earlier one reason is the presence of confounders. Another more sinister explanation could be the nefarious meddling of big pharma. However, conspiracy theories and confounders aside we need to review the aetiology of the disease process. What is evident is that Covid-19 seems to access your system via a protein expression of your lung tissue (TMPRSS2) which is thought to be upregulated by testosterone, however, newer evidence suggests that men’s testes may play a vital role in their vulnerability to covid-19. The virus uses Angiotensin-converting enzyme 2 (ACE2), an enzyme attached to the cell membrane, as its main route to enter cells. ACE2 is more highly expressed in men, particularly, among other organs, in the testis and the prostate. This raises the possibility that the testes may act as viral reservoirs, playing a role in the persistence of the virus, and also that the virus may adversely affect the testis and so reduce serum testosterone levels, with a resulting negative impact on recovery.
So what we can see is that older men are more susceptible than younger men, but why are men more susceptible than women? For this we need to look at the immune system and how the body manages inflammatory response (remembering its the ‘cytokine storm’ which causes all of the disastrous outcomes with Covid-19). Spoiler alert, plenty of exciting medical terms about to come up so please be warned…
How Testosterone works on the inflammatory system
Testosterone exerts its anti-inflammatory activity through different mechanisms. Firstly, Testosterone inhibits body fat expansion and reduces adipocytes size and metabolism. After its aromatization (conversion) into estradiol, Testosterone can activate AR (androgen receptor) and ER α (estrogen receptor alpha) and ERβ (estrogen receptor beta), which contribute to adipocytes regulation decreasing the release of adipokines (leptin, IL-6, TNF-α, OPG, MCP-1α) – these are the aggressive cytokines, specifically IL-6, which is one of the main orchestrators of the cytokine storm. Furthermore testosterone improves adiponectin and visfatin production, which possess an anti-inflammatory effect. Added to this is the effect testosterone has on insulin; Studies of testosterone in males suggest that physiological testosterone therapy improves insulin sensitivity, and in doing so reduced cRP from the liver (cRP = c-reactive protein, which is a marker of inflammation). Altogether, it results in a reduction of inflammation and development of both acute and chronic disease. Please see the below figure to understand this in more detail (Bianche et al 2018)
This narrative was echoed In a recent article in the Telegraph newspaper, by Professor Geoff Hackett, consultant in urology and professor in sexual medicine at Aston University, pointed to low testosterone as the culprit for the intensity of the inflammatory effects of the cytokine storm in destroying patients’ lungs and arteries. He concluded: “Of course we need a vaccine if we can get it. But it looks as though a man has a much greater chance of surviving this enemy and others if he goes into the battle with a normal testosterone level.”
In regards to covid-19, low testosterone has massive implications. Low testosterone appears to allow the body’s immune system to lose control, which leads to the horrible ‘cytokine storm’ which we mentioned earlier, inflaming the respiratory architecture and leading to acute respiratory distress. Unfortunately, this downward spiral left patients requiring intubation and mechanical ventilation (a machine which breaths for you) with the eventuality of death. Speaking to the Daily Mail, Professor Gülsah Gabriel from the Leibniz Institute for Experimental Virology in Hamburg, said: “Low testosterone levels in men seem to be a risk factor for severe and even fatal disease outcome in men upon infection with so-called ‘cytokine inducing’ respiratory viruses.”
Increasing numbers of experts in the field of testosterone and men’s health across the globe have expressed their views and made it clear that normal levels of the male hormone are vital in combating the coronavirus. The associate clinical professor of Urology at Harvard medical school and director of men’s health Boston clinic, Dr A Morgentaler, remarked on this and in summary, said;
“Those suggesting that testosterone must be dangerous because men are more at risk than women obviously know nothing about testosterone. It is particularly low in the elderly men, who are at greatest risk.”
Are you worried that you might be suffering from testosterone deficiency syndrome and worried about covid-19 in this respect? Please do feel FREE video call using the following link:
Bahmad HF, Abou-Kheir W. Crosstalk between COVID-19 and prostate cancer [published online ahead of print, 2020 Jul 24]. Prostate Cancer Prostatic Dis. 2020;1-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378980/
Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail. 2007 Jan;9(1):44-50. https://pubmed.ncbi.nlm.nih.gov/16828341/
Bianchi VE. The Anti-Inflammatory Effects of Testosterone. J Endocr Soc. 2018;3(1):91-107. Published 2018 Oct 22 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299269/
Ory J, Lima TFN, Towe M, et al. Understanding the Complex Relationship Between Androgens and SARS-CoV2. Urology. 2020;144:1-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346809/
Rastrelli G, Di Stasi V, Inglese F, Beccaria M, Garuti M, Di Costanzo D, Spreafico F, Greco GF, Cervi G, Pecoriello A, Magini A, Todisco T, Cipriani S, Maseroli E, Corona G, Salonia A, Lenzi A, Maggi M, De Donno G, Vignozzi L. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 https://pubmed.ncbi.nlm.nih.gov/32436355/
The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in Hamburg, Germany: a retrospective cohort study. Maria Schroeder, BerfinTuku, Dominik Jarczak, Axel Nierhaus, Tian Bai , Henning Jacobsen, Martin Zickler, Zacharias Müller, Stephanie Stanelle-Bertram, Andreas Meinhardt, Jens Aberle, Stefan Kluge, Gülsah Gabriel. https://www.researchgate.net/publication/341305549_The_majority_of_male_patients_with_COVID-19_present_low_testosterone_levels_on_admission_to_Intensive_Care_in_Hamburg_Germany_a_retrospective_cohort_study/citations