GLOBAL ANDROLOGY FORUM
GLOBAL ANDROLOGY FORUM
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Male Infertility: New Developments, Current Challenges, and Future Directions
Article #45: “Male Infertility: New Developments, Current Challenges, and Future Directions”
Authors: Murat Gül, Giorgio Ivan Russo, Hussein Kandil, Florence Boitrelle, Ramadan Saleh, Eric Chung, Parviz Kavoussi, Taymour Mostafa, Rupin Shah, Ashok Agarwal
World J Men’s Health Published online Jan 2, 2024
CAPSULE
Contributors: Charalampos Konstantinidis, MD (Greece), and
Ryan Smith, MD (United States)
Commentary:
Introduction: This review addresses gaps in our knowledge, discusses new diagnostic methods/therapies/potential targets for new therapies, and provides insights for future research and therapy areas.
Towards a better understanding of the etiopathogenesis of male infertility: Factors to consider in spermatogenic aberration-male infertility, include anatomic etiologies such as varicoceles etc., environmental, genetic, inflammatory, infective, drug-induced/hormonal disorders. New diagnostic assessments that assess fertilization competent sperm are needed.
Male infertility diagnostics:
1. The 6th edition of the WHO manual for semen analysis
- Its novelty is the absence of recommended SA reference values.
- It does not detail all the new tests available for genetic and epigenetic diagnosis.
- In the research section (advanced SA) it lists some tests to assess seminal OS.
- It highlights the inherent limitations of semen analysis and the need for better adjunct tests.
2. Use of artificial intelligence in sperm analysis: While AI holds promise, it encounters challenges like patient care autonomy, cost, ethical concerns etc. There’s a concern of providing false reassurance without a complete formal SA.
3. Home testing of semen: The FDA has approved many at-home sperm testing products including SpermCheck®, YO®, and Trak®. These have improved access but have limitations compared to an andrology lab assessment.
4. Whole genome testing: It’s believed whole exome sequencing (WES) will be replaced by whole genome sequencing (WGS).
5. Epigenetic markers: Many epigenetic markers have been considered in assessing the presence of active spermatogenesis among NOA patients. For instance, ESX1 transcript. 396, 395, and 378 microRNAs.
6. Seminal proteomics: Studying the seminal plasma approach supports the management of male infertility, since this method’s rich in protein biomarkers.
7. Radiomics: The extraction of numerical values from radiological images offers a more comprehensive analysis beyond the simple visual capacity.
Relationship between a male’s fertility status and general health: Besides fertility therapies, general health issues must be considered and dealt with
Personalized medicine and male infertility: Personalized medicine (stem cell/gene therapy/nanoparticle drug delivery) is on the rise.
Male fertility preservation: Different techniques of sperm cryopreservation have been used for ICSI. However, a series of epigenetic modifications may occur secondary to cryopreservation, including changes in mRNA expression.
Future of stem cells in male infertility: Strategies to restore fertility for pre-pubertal boys include spermatogonial stem cell transplantation (SSCT), testicular tissue engraftment, and in vitro spermatogenesis.
The art of ART: ARTs have become the gold standard in medically assisted reproductive medicine.
AI for andrological surgeries: AI (through the use of ML models) can predict surgery outcomes.
The future of andrologists: The role of the andrologist is to expand with international initiatives already underway (Global Andrology Forum-GAF etc.).
Conclusions: The development of genetic testing, the use of epigenetic markers, seminal proteomes, radiomics, advancements in male fertility preservation tools, future application of AI, all, provide hope for various kinds of infertility cases and patients with cancer.
Key Takeaways: Contributor: Ashok Agarwal
The most important takeaways from this article for reproductive physicians are:
The field of male infertility is undergoing significant advancements through the integration of technology and innovative diagnostic methods. Advanced diagnostics, including genetic and epigenetic testing, seminal proteomics, and radiomics, are being increasingly used in trying to solve the complex etiology of male infertility, leading to personalized and more effective treatment options. Innovations in fertility preservation, such as cryopreservation of single or rare sperm and successful freezing of spermatozoa from testicular tissue, offer unimaginable hope to cancer patients at risk of treatment-induced infertility, ensuring their chance for future parenthood. Moreover, the application of AI in predicting treatment outcomes, sperm selection, and diagnosing infertility marks a move towards precision medicine. All these promising advances have the potential to enhance clinical decision-making and improve treatment success rates – however, the jury is out!
My Personal Viewpoint on New Developments in Male Infertility
Dr. Charalampos Konstantinidis responds to the questions by Ashok Agarwal
Q1: What are the latest advancements in the diagnostics and treatment of male infertility highlighted in recent decades?
A1: During the last decades advanced sperm manipulation techniques for improved assisted reproductive technologies, surgical procedures for sperm retrieval, and novel tests of sperm function have been developed offering more opportunities for parenthood in infertile couples.
Q2. How does seminal oxidative stress testing contribute to the management of male infertility?
A2: Although antioxidant supplements are used to improve sperm quality it is important to check the oxidation-reduction potential and in case of an imbalance, we can add or stop antioxidant factors.
Q3. What is the role of sperm DNA fragmentation testing in evaluating male infertility, and how does it impact treatment decisions?
A3: In case of unexplained inability of natural conception, varicocele, failure of ART and exposition to lifestyle/environmental risk factors, DNA fragmentation testing may suggest a contributing infertility factor suggesting treatment options such as varicocelectomy or anti-oxidation supplements.
Q4. In what ways do genetic and epigenetic tests advance our understanding and treatment of male infertility?
A4: In many cases of NOA, genetic and epigenetic tests may explain the condition and predict the presence of spermatogenesis in testicular biopsy.
Q5. How can artificial intelligence and personalized medicine be integrated into the management of male infertility?
A5: Artificial intelligence can analyze complex predictive models and provide treatment algorithms to improve sperm quality or for sperm retrieval. Personalized medicine is the future not only for infertility issues but for many conditions that genetic factors are contributing.
Q6. What are the ethical considerations in the use of advanced reproductive technologies for male infertility, including donor insemination and surrogacy?
A6: I believe that every person has the right to parenthood. Under that prism, ART can be helpful. Donor insemination and surrogacy can be an option in case the infertile couple makes this decision.
Charalampos Konstantinidis, MD, PhD, FEBU, FECSM: Short Biography
Charalampos Konstantinidis, MD
Head of Urology and Neuro-Urology Unit, National Rehabilitation Center
Ilion, Athens, Greece
Staff Member, Urology Department, General Hospital "Asklepieio Voulas"
Vasileos Paulou 1, 16673, Voula, Athens, Greece
E-mail: konstantinidischaralampos@yahoo.comORCID ID: 0000-0002-4689-6899
Dr. Charalampos Konstantinidis, a University of Patra medical graduate (1996), completed his Urology training in 2004 and became a Fellow of the European Board of Urology (FEBU) in 2005. His post-graduate journey included clinical fellowships in Germany, Serbia, and Austria, focusing on genito-urinary reconstructive surgery and neuro-urology. Since 2006, he has served as a Urology consultant at the National Rehabilitation Center of Athens. An active GAF member, Dr. Konstantinidis holds memberships in several national and international urological and scientific societies. He is a prolific speaker with over 260 lectures and has contributed to more than 300 presentations globally. His publications include 30 international and over 35 Greek articles, along with chapters in 8 books related to functional urology. Google Scholar cites him 422 times, with an h-index of 11 and an i10-index of 13.
My Personal Viewpoint on New Developments in Male Infertility
Dr. Ryan Smith responds to the questions by Ashok Agarwal
Q1. How does the introduction of novel sperm selection techniques for intracytoplasmic sperm injection (ICSI) improve outcomes?
A1. Over the past 30 years, the use of ICSI has rapidly increased and accounts for a preponderance of IVF cycles worldwide. This has included couples without severe male factor infertility in hopes that it might increase fertilization success. Studies now suggest that this is incorrect and therefore novel sperm selection techniques are an area seeing exponential growth in reproductive medicine.
Q2. Discuss the significance of telemedicine in the field of reproductive urology and male infertility.
A2. The COVID-19 pandemic resulted in the rapid adoption of telemedicine, including within reproductive urology. While challenges and limitations remain, telemedicine is here to stay in the assessment of male infertility. One may anticipate that we will likely see guiding principles surrounding telemedicine adopted into male infertility guidelines in the future.
Q3. How does the management and treatment of male infertility benefit from the development of andrology as an independent specialty?
A3. Advances in both the diagnostic assessment and treatment of male infertility have grown exponentially as the science has evolved. The role of the reproductive urologist has become more subspecialized as has the subspecialty training. Current guidelines reflect the complexity and prevalence of male infertility, recommending that couples undergo a concurrent evaluation and men with an abnormal semen analysis should be evaluated by a male reproductive expert.
Q4. What are the implications of recent research on environmental, genetic, and lifestyle factors affecting male fertility for clinical practice?
A4. The impacts of environmental and lifestyle factors on male infertility are likely underestimated. While difficult to quantify on an individual level, technology and diagnostic advancements may make this possible in the future. Environmental toxins and lifestyle factors have been implicated in the worldwide decline in semen parameters.
Q5. How is the understanding of microbiome's role in male infertility evolving, and what are the potential therapeutic interventions?
A5. While more research needs to be done, it is established that semen has its own microbiome. Several studies suggest that bacterial imbalances may impact sperm count and quality. The gut microbiome may similarly play a role in male fertility and research continues to elucidate these associations.
Q6. What are the current challenges and future directions in the surgical procedures for sperm retrieval?
A6. Promising technologies to assist in sperm identification at the time of sperm retrieval continue to evolve. One area is within the ability to identify sperm at the time of microTESE or ideally, to better assess the probability of sperm identification prior to the procedure. Unfortunately, access to care and costs for these procedures remain barriers to many couples receiving these necessary treatments.
Ryan Smith, MD: Short Biography
Ryan P. Smith, M.D.
Associate Professor of Urology
Male Reproductive Medicine and Surgery
Men's Health | UVA Health
University of Virginia
Email: margianaria@gmail.com
ORCID id: 0000-0002-3880-9740
Dr. Ryan P. Smith, Associate Professor of Urology at the University of Virginia, specializes in Male Reproductive Medicine and Surgery. A graduate and resident alumnus of the same university, he further honed his expertise with a fellowship at Baylor College of Medicine under Dr. Larry Lipshultz. Since joining the University of Virginia faculty in 2013, Ryan has held several leadership roles, including Co-Director of the Andrology Fellowship, Urology Residency Program Director, and Medical Student Clerkship Director. Recognized for his contributions, he has been a CREST Scholar with the American Society of Reproductive Medicine and a traveling scholar for key reproductive societies, besides serving on their boards. In practice, Ryan divides his time between UVA Health and Virginia Fertility & IVF, offering him extensive insight into fertility care. His research primarily focuses on male infertility and sperm-egg interactions. Ryan has over 50 PubMed indexed research articles to his credit with 1,437 citations and an h-index of 20 (source: Scopus, March’ 2024).