A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility - Beyond the Abstract

Infertility impacts 15% of couples trying to conceive globally. Males are solely responsible for infertility 20-30% of the time and are a contributor to infertility approximately 50% of the time.1 There are many identified causes for infertility, however a large portion of cases remain unidentified (UMI) and/or idiopathic (IMI).2,3


Oxidative stress (OS) has been noted as an important etiology of male infertility, particularly due to the imbalance between antioxidants (AOX) and reactive oxygen species. An imbalance results in sperm DNA fragmentation (SDF) and semen abnormalities.4 Measuring OS is essential for a thorough male infertility evaluation considering its effects on various pathways producing and supporting semen. The utilization of AOX have become an attractive option for providers treating infertility due to their widespread availability, safety profile, and low cost.

While AOX treatment for infertility is becoming more common, there is no clear consensus on regimen, dosing, or length of treatment. Guidelines and usage of AOX and OS tests in clinical practice remains unclear, creating a need for identification of provider usage patterns. Therefore, using a cross sectional observational study through an internet survey, we investigated the use of OS testing, AOX treatment, and specific patterns of practice pertaining to the treatment of male infertility. The survey was composed of 29 questions aimed to determine participant demographics, participant profession, use of OS testing, and use of AOX therapy. The targeted participants of this survey included medical professionals involved in reproductive medicine, including those involved in the treatment of infertile couples.

A total of 1,327 participants from 88 countries completed the survey, making this the largest online survey performed to date on this topic. Geographical distribution of the participants included Asia (46.8%), South America (19.7%), Europe (15.7%), Africa (11.3%), North America (4.3%) and Australia (2.2%). Many of the participants were 35–64 years old (75.0%), and the remaining were 25–34 years old (15.1%) or more than 65 years old (9.9%). Nearly half of the participants (49.9%) reported themselves to be of the following professions: urology (20.2%), andrology (8.8%) and gynecology (6.7%).

Participant responses to OS testing survey questions revealed the following:

  • 34.3% of participants used OS when clinically evaluating male infertility. Specifically, SDF (53.4%) was most common, followed by ORP (31.3%)
  • Out of 416/448 (92.9%) respondents, 59% ordered OS testing after identifying abnormal semen parameters and 55.8% ordered OS testing for UMI.
  • Participants who received training specifically in male infertility were more likely to use OS testing (n=378 out of 448), however, the majority of participants chose not to use OS testing (n=628 out of 857)

Participant responses to AOX therapy survey questions revealed the following:

  • A total of 1,260 (94.9%) responded to the question on AOX treatment, revealing 85.6% of participants using AOX therapy as a treatment option for the management of male infertility, either routinely or for specific groups of people
  • Notably, 79.2% participants that did not seek OS testing reported prescribing AOX therapy
  • 43.7% of participants prescribed AOX therapy for 3 months, and 38.6% of participants prescribed for 6 months.
  • 177 participants did not recommend AOX treatment, while the remaining 1039 recommended based on evidence-based medicine or personal experience.
  • Out of all participants who recommend AOX treatment, there was a significant relationship between their age (p<.001), geographic origin (p<.004), experience or training in male infertility (p<.001)

In addition to the patterns of usage of AOX therapy to manage male infertility, the perception of AOX treatment in clinical practice was also assessed in the survey. 86.8% of participants responded to the strength of evidence for AOX use in male fertility. More than half of these participants described the clinical evidence as “modest” (52.3%), 22.2% described it as “no good evidence supporting its use,” and 19.7% described the evidence as “strong”. 88.3% of participants responded to the questions regarding what the appropriate outcomes of AOX treatment should be. 55.3% answered semen parameters, 54.9% answered live birth rate, 49.1% answered SDF, 47.3% answered clinical/ongoing pregnancy rate. Most importantly, 96.3% of respondents believe there is a need for the development of clinical guidelines for AOX usage.

AOX therapy has been an appealing option for male infertility for various reasons including accessibility, affordability, and safety. There is little information of the usage patterns of OS testing and AOX therapy, creating the need for exploration. The proportion of individuals surveyed using AOX therapy greatly outweighs those who prescribe OS testing, potentially due to OS testing variability in sensitivity and specificity, availability, cost, and time commitment. This poses a potential clinical concern when using AOX therapy without conformational OS testing can cause reductive stress, which is a cause of male infertility in itself.

The survey shows widespread usage of AOX therapy, despite the vast majority not testing for OS or SDF. Reasons for participant usage of AOX therapy is most likely due to no other correctable factors to male infertility currently available. In addition, they are familiar to patients and can be simply sold over the counter. Thirdly, AOX supplements are generally safe with appropriate dosing. The study also shows several inconsistencies in participant length of AOX treatment, varying from 3 months to 6 months and sometimes until pregnancy. Additionally, AOX treatment normally demonstrates an unpredictable outcome which can make patient compliance difficult as well as delay the initiation of other treatment options, such as ART. Significant diversity in outcome metrics creates a challenge for clinical exploration.

While prescribing patterns of AOX therapy are described in this study, the question remains whether the quality of evidence is sufficient to justify the usage of AOX therapy for male infertility. For many reasons high quality evidence is difficult to obtain, leaving clinical practice recommendations the best present approach. Recent evidence revealed improvement in semen quality when used in IMI or UMI.5 For these reasons, we advocate the use of AOX in clinical practice, provided that the following criteria are met:

  1. Laboratory evidence of seminal OS. Testing for OS is recommended to identify the appropriate candidates for AOX therapy.
  2. Consider treatment for a duration of 3–6 months, which is a sufficient intervention period to obtain a measurable impact on spermatogenesis.
  3. Avoid excessive use of AOX, in high doses or for a prolonged duration, to avoid iatrogenic infertility due to reductive stress.
  4. Finally, there is no consensus on the choice of AOX to be used. Based on physiological considerations, it would seem appropriate to use a combination of AOX that act on different physiological processes of the spermatozoa, such as preservation of energy metabolism, and improvement of sperm maturation and function, as well as providing protection from ROS.
  5. AOX therapy should not be used to replace any other kind of treatment but should instead be seen as a viable synergistic option.

Written by: Giovanna Leone, BS & Neel Parekh, MD

References:

  1. Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: a review of literature. J Hum Reprod Sci 2015;8:191-6.
  2. Leisegang K, Henkel R. Oxidative stress: relevance, evaluation, and management. In: Rizk B, Agarwal A, Sabanegh ES Jr, editors. Male infertility in reproductive medicine: diagnosis and management. Boca Raton (FL): CRC Press; 2019;119-28.
  3. Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): pro- posed terminology and clinical practice guidelines for management of idiopathic male infertility. World J Mens Health 2019;37:296-312.
  4. Kumar N, Singh AK. Reactive oxygen species in seminal plasma as a cause of male infertility. J Gynecol Obstet Hum Reprod 2018;47:565-72.
  5. Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Panner Selvam MK, et al. Utility of antioxidants in the treatment of male infertility: clinical guidelines based on a systematic review and analysis of evidence. World J Mens Health 2021. doi: 10.5534/wjmh.200196 [Epub].

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