- CellOxess LLC
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Recent Comments
We appreciate the comments raised by Dr. Coward and colleagues and in fact share much of the skepticism expressed over the efficacy of commercially available antioxidant therapies and questionable practices of the dietary supplement industry. Indeed, CellOxess biotechnology was founded to bring about the much needed clarity on the impact severity of oxidative stress in the etiology of many preventable diseases with our initial focus on male and female infertility and the roles antioxidants may play in alleviating the rapid decline of human fertility.
It is a fact that optimum gametogenesis is highly dependent on the redox homeostasis of the reproductive tissue. Therefore, the molecular interplay or the balance between oxidants (or toxic metabolites) generated by cells and antioxidants (the cellular guardians) become an important consideration when the gamete is evidenced to be unhealthy and fertility treatment is then sought. However, poor sperm motility, morphology, concentration, and even damage are not always indicators of chronic oxidative stress. Treating such patients with no evidence of oxidative stress with large doses of an untested combination of antioxidants, such as those used in MOXI or FAZST trials, will have virtually no chance of demonstrating the expected beneficial therapeutic effects and will in fact add more confusion to the benefits of the antioxidant therapy.
Fertilix was developed according to a stringent set of medicinal chemistry principles closely mirroring that of a pharmaceutical. Indeed, the detailed review of oxidative stress as a male infertility factor, the significance of oral antioxidant therapy1,2 (supported by Craig Niederberger3), the rationale for formulation design, as well as the preclinical evidence for Fertilix efficacy have all been covered by several publications.4 The preclinical evidence was also presented at ESHRE and ASRM.
Back in 2013, we also reached out to Dr. Eisenberg, a co-author on the MOXI publication, seeking her assistance to organize a human trial for Fertilix. Unfortunately, no progress was possible at that time. Following Dr. Eisenberg’s suggestion, we applied for NIH grants on two separate occasions in 2014 and 2016 but were turned down both times, without a clear explanation.
We ask Dr. Coward and colleagues to kindly note that, for a variety of reasons, such as market fragmentation, without the financial assistance from NIH or the cooperation of the fertility community in the trial, it is almost impossible to conduct a large, high-quality clinical study with pregnancy and live-birth outcomes as end-points. We point to the extant literature in the field of male infertility to support this statement.
There are also other misconceptions and inaccuracies in Dr. Coward’s et al recent comments, which we would like to address as bullet points below.
John Aitken (RJA), Parviz Gharagozloo (PG), Joel Drevet (JD), Jorge Hallak (JH), Alfonso Gutierrez-Adan (AGA). The following co-authors are not linked to the company but support the scientific statements and rationale pertaining to a large human clinical trial: Juan Alvarez, Gihan Bareh, Sheryl Homa, Sergey I. Moskovtsev, Mohammad Hossein Nasr-Esfahani, Cristian O'Flaherty, Suresh Sikka, Steven Somkuti, Armand Zini.
DECLARATION OF INTEREST
PG is CEO of a company, CellOxess biotechnology, involved in the design and manufacture of antioxidant formulations for male and female infertility. RJA, JD, JH and AGA are honorary advisors to this company.
* Correspondence: john.aitken@newcastle.edu.au and parviz.gharagozloo@celloxess.com
REFERENCES
Yet another flawed antioxidant trial; a plea for rigorous evaluation of antioxidant therapy for male infertility involving oxidative stress
The role of oxidative stress in the aetiology of male infertility has been appreciated since the 1920’s when it was demonstrated that depriving rats of natural vitamin E, the major antioxidant vitamin, generated testicular degeneration and infertility (1,2). Subsequently, a great deal of research has been conducted on the role of oxidative stress in male infertility and there is now a general consensus that reactive oxygen species play a significant role in the creation of defective sperm function and the induction of sperm DNA damage (3-6). Recent papers clearly reveal roles for oxidative stress in a variety of clinical situations including the aetiology of non-obstructive azoospermia (7), defective sperm quality in teratozoospermia (8), the origins of sperm DNA damage (9), the toxic impact of parabens (10) and the pathophysiology of varicocele (11). If oxidative stress is such an important cause of male infertility, then surely antioxidant therapy should be part of the cure (12).
In animal models, this is certainly the case. For example, the GPx5 (glutathione peroxidase 5) knockout mouse suffers from localized oxidative stress in the epididymis (13). As a consequence of this stress, the spermatozoa exhibit clear signs of oxidative damage including impaired DNA compaction and high levels of oxidative DNA damage. When Gpx5-deficient males were mated to normal females, the presence of oxidatively damaged spermatozoa was associated with higher incidences of miscarriage and developmental defects in the offspring. However, when such GPx5-/- males were treated with a carefully engineered antioxidant formulation, oxidative DNA damage in the spermatozoa was found to return to control levels (14). Similarly, treatment with the same antioxidant formulation almost completely restored the fertility of mice rendered infertile by a transient testicular hyperthermia (14). Indeed there is a wealth of animal literature demonstrating that antioxidants can restore fertility and testicular function in animals treated with a wide range of factors capable of causing oxidative stress in the male reproductive tract including cadmium (15), phthalate esters (16), lead, organophosphate pesticides (17), induced diabetes (18), acrylamide exposure (19), mental stress (20) and so on.
Against such a background of supportive data in animal models, it is perhaps surprising that extension of these studies into the clinical domain has not provided evidence of a clear therapeutic benefit of antioxidant administration in man. Several meta-analyses addressing this question have been performed. Recent systematic Cochrane analyses, for example, (21,22) concluded that there was low quality evidence for a positive effect on clinical pregnancy and live birth rates but emphasized the flaws in existing studies based on ‘on serious risk of bias due to poor reporting of methods of randomisation, failure to report on the clinical outcomes, live birth rate and clinical pregnancy, often unclear or even high attrition, and also imprecision due to often low event rates and small overall sample sizes’. Both Cochrane analyses called for large, well-designed, randomised placebo-controlled trials to clarify these results. It was, therefore, with interest that we encountered the paper in Fertility and Sterility by Steiner et al. (23) reporting the results of a large randomized placebo-controlled trial of antioxidant therapy in male infertility. While this study has many excellent features, disappointingly, it turned out to be as fundamentally flawed as its predecessors.
How is it possible to design a study determining the efficacy of antioxidant therapy when no attempt is made to determine levels of oxidative stress in the patients before or after the administration of treatment? This makes no sense. It is like giving insulin to everyone who comes into hospital in a coma. Some will improve, some will continue to deteriorate and, overall, any therapeutic benefit will be lost in the noise. The males selected in this study exhibited at least one abnormal semen parameter in the previous 6 months [sperm concentration <15 million/mL (oligospermia), total motility <40% (asthenospermia), normal morphology <4% (teratospermia), or DNA fragmentation >25%]. Naturally, there are many different reasons for males to exhibit such defects and only in a proportion will this be due to oxidative stress. The authors clearly recognise this fundamental defect in their study but justify the omission of oxidative stress measurements on the basis that the random allocation of antioxidant treatment to infertile patients, irrespective of need, represents the current standard of clinical practice. While this statement is clearly correct, surely we should be encouraging higher standards of clinical implementation, rather than just reinforcing the status quo.
Similar arguments could be directed towards the DNA damage component of the study which focused on the vulnerability of the chromatin to low pH (the sperm chromatin structure assay) rather than the formation of oxidative base adducts (8-Oxo-2'-deoxyguanosine) which has been recently shown to be rather a common trait of infertile male patients (24) and to concern specific paternal chromosomal regions that could be linked to developmental defects in the offspring (25).
The other major factor that needs to be considered is the choice of formulation used in the trial. There are numerous male fertility supplements available in the market worldwide, greatly varying by both the nature of antioxidants incorporated into the formulation and the doses used. So why this particular composition? The authors justify the ingredients and doses used because similar ones had been previously evaluated individually in clinical trials and demonstrated some benefit. However, other studies have demonstrated serious concerns with either the isoformic nature of the ingredients or high doses of the individual ingredients used (14). As an example, high doses of antioxidants such as vitamin C or Zinc, especially in the situation where oxidative stress is absent or minimal, can lead to reductive stress (12) causing sperm DNA decondensation (26-28). Reductive stress arising from over-supplementation can therefore be just as damaging to spermatozoa as oxidative stress and should be avoided. This is another reason why understanding a patient’s oxidative stress status is important to the success of a clinical trial, so patients with low or no oxidative stress can be excluded from the trial.
The field desperately needs to support large scale placebo-controlled studies of the type conducted by Steiner et al (23). However, we shall learn nothing if we do not select the patients on the basis of criteria reflecting levels of oxidative stress in the male reproductive tract, treat accordingly with an evidence-based formulation and measure the performance of the treatment against those oxidative stress markers. Whether such treatment will also increase pregnancy rates will depend on a variety of other factors that will not necessarily be impacted by antioxidant therapy. However, if antioxidant therapy can, as the animal models demonstrate, reverse levels of oxidative damage in both the male and female germ lines (29) then at least one component of the overall pregnancy equation will have been successfully addressed. Furthermore, reducing levels of oxidative DNA damage in the male germ line prior to conception is not just about establishing pregnancies per se, but making sure that the mutational load carried by the resultant offspring is kept as low as possible.
In conclusion, the paper by Steiner et al (23) clearly does indicate that the prevailing clinical practice of randomly prescribing antioxidant therapy to the subpopulation of males attending infertility clinics is unlikely to generate any overall benefit. However, this does not mean that carefully formulated antioxidant preparations are without significant therapeutic merit. They just have to be given to patients where there is evidence of oxidative stress as a causative factor in the patients’ infertility profile. This simple requirement has been met in previous small-scale studies and positive outcomes observed (30). The time has now arrived not for us to abandon this approach to therapy but to replicate such studies at scale, using a randomized, placebo-controlled, double-blinded study design, ensuring that the appropriate patients are selected for treatment and the appropriate assessment criteria are in place to measure the impact of antioxidant intervention.
John Aitken (RJA), Parviz Gharagozloo (PG), Joel Drevet (JD), Jorge Hallak (JH), Alfonso Gutierrez-Adan (AGA), Juan Alvarez, Rafael Ambar, Gihan Bareh, Sheryl Homa, Sergey I. Moskovtsev, Mohammad Hossein Nasr-Esfahani, Cristian O'Flaherty, Suresh Sikka, Steven Somkuti, Paul Turek, Armand Zini.
DECLARATION OF INTEREST
PG is CEO of a company, CellOxess biotechnology, involved in the design and manufacture of antioxidant formulations for male and female infertility. RJA, JD, JH and AGA are honorary advisors to this company.
* Correspondence: john.aitken@newcastle.edu.au and parviz.gharagozloo@celloxess.com
REFERENCES