An example of environmental/lifestyle impacts on male reproduction that is not strongly correlated with sperm number per se but is a major determinant of sperm function – is oxidative stress. Spermatozoa are very vulnerable to oxidative stress largely because their intrinsic lack of cytoplasm places constraints on the antioxidant enzymes and free radical scavengers available to protect these cells.
They are also vulnerable to oxidative stress because they are professional generators of ROS from their mitochondria (Koppers et al., 2008), as well as a variety of dedicated enzyme systems including NADPH- and L-amino-acid-oxidases (Musset et al., 2021; Aitken et al., 2015; Houston et al., 2015; Vatannejad et al., 2019; Zhang et al., 2021). In addition, these cells contain many substrates that are vulnerable to free radical attack, including high levels of unsaturated fatty acid and DNA. In light of this inherent vulnerability, oxidative stress is now considered one of the major causes of male infertility (Aitken and Baker, 2020).
Oxidative damage to sperm DNA is therefore relatively common and may be one of the driving forces behind the high rates of spontaneous genetic and epigenetic mutations associated with the male germ line (Aitken, 2020). Such paternally medicated mutations have an important role to play in the aetiology of several disease states in the offspring, including neuropsychiatric conditions such as autism or spontaneous schizophrenia, as well as cancer.
Ironically, it is also possible that, amongst the range of pathologies generated in the offspring as a result of oxidative DNA damage in the paternal germ line, is infertility, due to a variety of causes including the spontaneous generation of Y-chromosome deletions (Aitken and Krausz, 2001). The factors responsible for the induction of oxidative stress in the male germ line have elaborated previously and include everything from smoking and obesity to varicocele and exposure to mobile phone radiation. How can we control this situation?
There are two fundamental ways in which we can address the oxidative stress issue, and they are not mutually exclusive. The first is to remove the source of the stress: repair the varicocele, stop smoking, lose weight, treat the infection, avoid heavily polluted environments, etc. The second is to counteract the excessive generation of ROS by using antioxidants to metabolise or scavenge these toxic oxygen metabolites before they have an opportunity to damage the host’s fertility.
This idea has been around since at least the 1940s (Mack, 1945; Blahak, 1947) and it is a matter of great frustration that the clinical validation of antioxidant therapy of male infertility has not been achieved more than 75 years later. Many trials have been conducted, including some recent studies that have involved large numbers of patients and have cost a great deal of time and money to conduct. Systematic reviews of randomised studies to evaluate the effects of oral antioxidants of sperm quality and fertility in infertile men have concluded that such treatment is beneficial (Ross et al., 2010). However, such positive outcomes are not consistently observed. Successive Cochrane reviews (a charitable organisation offering the best available assessments of evidence-based choices relating to health interventions) of the existing literature concluded that antioxidant therapy was generally beneficial in 2011, but by 2019 the evidence had weakened to the point of ‘inconclusive’. Some recent studies have even found no positive evidence at all to support a role for antioxidants in the treatment of male infertility (Joseph et al., 2020; Steiner et al., 2020). The problem is that most of these studies (positive and negative) have been a complete waste of time and resources. The reason for saying this is that none of these studies selected patients for treatment on the basis of oxidative stress. If patients are not suffering from infertility induced by oxidative stress, how can antioxidant therapy be expected to cure them?! I have previously suggested that this is like treating everyone who arrives in hospital in a coma, with insulin. Some patients will experience a miraculous cure, some will die, and any therapeutic benefit will be lost in the noise (Aitken, 2021). Another example of the same issue is the ancient practice of bloodletting.
Bloodletting, using either surgical incisions in various parts of the body or leeches to induce blood loss, has been practised since ancient times as a means of restoring health by purging the body of ‘bad humours’. The Greeks and Romans were enthusiastic practitioners, and it was endorsed by both Islam and Christianity in the Middle Ages; certain dates within the religious calendar were even regarded as propitious times for ritual exsanguination. However, during the nineteenth century, bloodletting gradually fell out of favour and was largely conducted by barbers, rather than surgeons, as an inexpensive might-do-some-good-will-not-do-any-harm form of treatment for a wide range of ailments – much like antioxidants in the twenty-first century.
With the progressive emergence of evidence-based medicine, barbers were finding it hard to justify their bloodletting services because the removal of blood from randomly selected patients generated no verifiable benefit. In fact, bloodletting, or venesection as it is now known, is an extremely effective treatment for a common genetic condition known as haemochromatosis. This genetic disease is characterised by an inability of patients to regulate their iron levels, ultimately leading to iron overload and the appearance of a wide range of symptoms including fatigue, joint pain, loss of body hair, liver disorders, diabetes, cardiomyopathy, osteoarthritis, mood swings, etc., etc. Treatment of such patients by venesection often generates miraculous recoveries from conditions that have plagued the victims of this disease for years. The rationale behind the treatment is very straightforward; following venesection, red blood cell generation (erythropoiesis) has to be accelerated to make up for the loss of blood and, in generating these replacement red blood cells, the body uses up its excess reserves of iron.
The condition is relatively common in Celtic people to the point that it has also been christened the ‘Celtic curse’. As the offspring of a Scottish father and a Cornish mother, it is a condition that I am intimately familiar with. My sister also suffers from the condition and once diagnosed, undertook a course of venesection that removed the joint pain from her hands that she had experienced for many years. In the context of this discussion, bloodletting would have been a much-lauded form of treatment earlier in its history, if we had known the condition for which it constituted a treatment. Now that we know how to diagnose iron overload effectively, venesection has become part of mainstream clinical practice. It was just another Joseph looking for a manger – a treatment in search of a condition. It presumably lasted as long as it did because it generated positive benefits in the large subpopulation of patients suffering from haemochromatosis (at 10%, it constitutes one of the most common genetic mutations in our species), possibly bolstered by the placebo effect and a mild impact in cases of hypertension.
Antioxidant therapy has suffered in the same way as bloodletting. It constitutes a perfectly rational form of treatment for patients diagnosed as suffering from infertility stemming from high levels of oxidative stress (Ross et al., 2010). However, if you just give antioxidants to everyone attending an infertility clinic, any therapeutic benefit will get lost in the overall chaos. We now urgently need randomised placebo-controlled trials of antioxidant therapy for patients, male and female, exhibiting infertility associated with oxidative stress. In order to achieve this important objective, we need to agree on a method for measuring oxidative stress so that we can identify those patients for whom this form of treatment is a rational option. This has to be a priority research aim for the future and one that I intend to pursue.
Source: Laureate Professor John Aitken, Scientific Director at Memphasy, Author of the The Infertility Trap
We are thrilled to have Professor Aitken as a key partner as we advance our focused business development efforts in the assisted reproduction and fertility market. Together, we aim to create a world-class portfolio of devices, diagnostics, and media products that address crucial issues in human and animal reproduction.
Our Felix™ device is the culmination of our ongoing collaboration with Professor John Aitken, a renowned figure in reproductive biology worldwide. The Felix™ utilises Memphasys’ innovative sperm separation technology, which is now in commercial production and available for purchase in early adopting countries like Japan, Canada, and New Zealand. We are currently conducting clinical studies and preparing regulatory certifications for markets in China and Australia.