Recent advances in the management of male infertility

Abstract

Male factor infertility has been rising, which accounts for up to 30% of infertility cases and contributes to 50% of overall cases. The aim of this review is to explore the recent advances that have emerged in the field through a narrative review. A comprehensive literature search was conducted using multiple databases, including the Cochrane Library, PubMed, Scopus, and Web of Science. Gray literature was also reviewed through ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The findings were presented narratively to encompass the extensive range of published data on male infertility. Significant strides have been made in the field of male infertility, particularly with biomarkers, shear wave elastography, 3-dimensional (3D) bioprinting, artificial intelligence (AI), and robotic and microsurgical treatment, offering promising avenues for diagnosis and treatment. Continued research and technological innovation are essential to further improve outcomes for patients facing male factor infertility.

INTRODUCTION

Infertility is defined as the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.1,2 Infertility is a complex condition with multifactorial etiologies encompassing male, female, and combined factors. Male factor infertility is solely responsible for up to 30% of infertility cases but contributes to 50% of overall cases.2,3 The global prevalence of infertility is estimated to range between 12.6% and 17.5%, and this number is steadily increasing.4,5 An indicator of the rising infertility pandemic has been reflected in the increasing utilization of assisted reproductive technologies (ART).6

Male factor infertility can be attributed to a multitude of causes including congenital, acquired, and idiopathic.7 Congenital causes may include genetic abnormalities, such as Klinefelter syndrome, Y chromosome microdeletions, and other chromosomal anomalies that impair spermatogenesis. Acquired causes encompass lifestyle factors, environmental exposures, infections, and medical conditions such as varicocele and hormonal imbalances. Idiopathic infertility, in which no clear cause is identified despite thorough evaluation, remains a significant challenge in clinical practice.

Recent years have witnessed considerable advancements in the field of reproductive health, particularly in the management of male factor infertility. These advancements expanded from diagnostic to therapeutic with the utilization of the latest technological innovations. We aim to review these recent advancements and their application in the management of male infertility (summarized in Box 1).

Box 1.

Summary of contemporary advancements in male infertility. TEX101: testis-expressed sequence 101 protein; 3D: 3-dimensional; APHRODTIE: Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function; WKN3: with-no-lysine k 3; MEI1: meiotic double-stranded break formation protein 1; ADAD2: adenosine deaminase domain containing 2; FDA: Food and Drug Administration.

Our narrative review collected sources through a comprehensive database search that was performed using Cochrane library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials [CENTRAL], and Cochrane Methodology Register), PubMed, Scopus, and Web of Science for advances published over the past 14 years (from 2010 to 2024). Given the wide body of the literature, articles written in English were primarily selected and translations of non-English articles were considered as well when available. Gray literature was also used to search for ongoing studies using ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). The authors decided to present the review’s findings narratively in light of the volume of material that has been published on the topic as a whole and each of the active ingredients in particular. This article does not provide a systematic or meta-analytical comparison of varied outcomes in measures, population, and methods. The research strategy included the following keywords: “male factor infertility”, “advancement in infertility”, “assisted reproductive technologies”, “biomarkers”, “oxidative stress”, “sperm DNA fragmentation”, “artificial intelligence”, “machine learning”, “deep learning”, “shear wave elastography”, “3D bioprinting”, and “robotic surgery”.

ADVANCEMENTS IN THE DIAGNOSIS OF INFERTILITY

Biomarkers

An increasing number of studies explored the role of oxidative stress in the development of male factor infertility; 21 compounds were acting as biomarkers of male factor infertility in seminal plasma, including ascorbic acid, all-trans retinoic acid, all-trans retinol, α-tocopherol, γ-tocopherol, total carotenoids, malondialdehyde (MDA), 8-hydroxydeoxyguanesine (8-OHdG), nitrites, nitrates, creatinine, cytosine, cytidine, uracil, β-pseudouridine, hypoxanthine, xanthine, uridine, inosine, guanine, and guanosine.8,9,10,11 Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) and antioxidants, can damage sperm DNA, proteins, and lipids, leading to impaired sperm function. Those biomarkers have been correlated with reduced sperm quality and fertility potential.

Yuan et al.12 recently demonstrated in a systematic review and meta-analysis the benefit of sperm telomere length (STL) as a novel biomarker. In their review, they demonstrated a positive correlation between STL and clinical pregnancy rates, concluding that this new marker may have a clinical impact in predicting embryonic development.12

Seminal plasma proteomes have the potential to be explored in the context of male factor infertility, with testis-expressed sequence 101 protein (TEX101), a glycosylphosphatidylinositol-anchored (GPI) protein, being one of the most extensively studied. TEX101 undergoes cleavage from the sperm surface during the maturation of sperm cells in the epididymis, resulting in its release into seminal fluid. This cleavage is crucial to produce fertile spermatozoa. When TEX101 levels are measured, levels of ≥120 ng ml⁻¹ indicate normal spermatogenesis, levels of 5−120 ng ml⁻¹ suggest hypospermatogenesis or maturation arrest, and levels below 5 ng ml⁻¹ are indicative of Sertoli cell-only syndrome (SCOS). Therefore, TEX101 can be used as a diagnostic marker for idiopathic infertility.13

Sperm DNA fragmentation (S-DNA-F)

S-DNA-F is used to evaluate the breaks in the DNA of ejaculated sperm. S-DNA-F is seen more with infertile men than those with normal fertility. Factors that cause high levels of S-DNA-F include hormonal abnormalities, varicoceles, and smoking. The DNA fragmentation index (DFI) can be used to quantify DNA fragmentation. Studies have shown that a higher DFI is positively correlated with miscarriage rate and negatively correlated with birth weights.14 Thus, assessing oxidative stress biomarkers and sperm DNA integrity can guide clinicians in tailoring treatment strategies, such as antioxidant therapy or selecting appropriate ART methods, to improve fertility outcomes.15,16 As of today, the American Urological Association (AUA), the American Society for Reproductive Medicine (ASRM), and the European Association of Urology (EAU) do not recommend the utilization of DNA fragmentation in the initial evaluation of infertile couples.17,18

Artificial intelligence (AI)

AI has been applied to various aspects of infertility assessment, including sperm morphology evaluation, predicting seminal quality, semen analysis, and postvaricocelectomy sperm analysis.11 AI algorithms have shown remarkable accuracy in analyzing complex datasets and identifying subtle patterns that may not be discernible through traditional methods. For instance, AI-powered tools were shown to automate sperm morphology evaluation by analyzing digital images of sperm samples, thereby reducing human error and interobserver variability.11 These systems can classify sperm morphology with high precision, providing standardized and reproducible results. Additionally, AI models can predict seminal quality by integrating parameters such as sperm concentration, motility, and morphology, to generate comprehensive fertility profiles unique to each patient. Deep learning techniques, which involve multilayered neural networks, have been utilized to evaluate sperm motility and morphology, offering insights into sperm function and potential fertility.11,14 Artificial neural networks (ANNs) have demonstrated potential in predicting male fertility with up to 95% accuracy.15 ANNs can process large volumes of data and identify complex relationships between variables, enabling the prediction of fertility outcomes based on individual patient characteristics.

Shear wave elastography

Shear wave elastography is a technique to assess testicular stiffness in infertile patients, being able to predict parenchymal damage in testicular tissue that leads to abnormalities in sperm quantity.16 This noninvasive imaging modality measures the stiffness of tissues by analyzing the propagation of shear waves generated by an external mechanical stimulus. In the context of male factor infertility, shear wave elastography can provide insights into testicular architecture and detect subtle changes in tissue stiffness that may be indicative of underlying pathology. Increased testicular stiffness has been associated with conditions such as testicular atrophy, high grade varicoceles, and chronic orchitis, which are known to impair spermatogenesis and reduce sperm production. By quantifying testicular stiffness, shear wave elastography can aid in the diagnosis and monitoring of these conditions, facilitating early intervention and targeted treatment. Moreover, shear wave elastography can be used to assess the response to therapeutic interventions, such as varicocele repair or hormonal treatments. Changes in testicular stiffness over time can provide valuable feedback on the effectiveness of these interventions, allowing clinicians to make informed decisions regarding patient management.16

Whole-exome testing

The more cost- and time-efficient method of genome exome testing has been successful in flagging multiple genes relating to infertility in men with nonobstructive azoospermia. These include with-no-lysine k 3 (WKN3), meiotic double-stranded break formation protein 1 (MEI1), adenosine deaminase domain containing 2 (ADAD2), TEX101, polo kinase 4 (PLK4), and fanconi anemia complementation A (FANCA). Although the implications of those genes may not be understood currently, this sets the stage for further studies in the future.19

Radiomics

A recent study investigated the correlations between testicular ultrasound features and markers of testicular function.20 Ultrasound-derived textural characteristics showed significant associations with several semen parameters, including sperm concentration, count, motility, and morphology. These features also correlated with serum gonadotropin levels but not with total testosterone. The findings suggested that testicular ultrasonography may provide valuable, noninvasive insights into specific aspects of testicular function and sperm production. However, further research is needed to validate these results and determine their clinical utility in assessing male reproductive health.

Semen home testing

Many men are stressed when asked to provide a semen sample in a laboratory; thus, home semen collection kits have developed to help overcome this. Several products have been developed, and the U.S. Food and Drug Administration (FDA) has given approval to various at-home sperm testing kits because of their proven accuracy and user-friendly design, including SpermCheck® (Sperm Check, Fairfield, OH, USA) and YO® (Medical Electronic Systems, Encino, CA, USA). SpermCheck® employs sperm-specific monoclonal antibodies, achieving a high accuracy rate of 97% to 98% when compared with assessments made by laboratory professionals.21 The YO® system, which uses a smartphone camera connected to a sample testing station, measures motile sperm concentration, with accuracy rates ranging from 97.2% to 98.3%.22

TREATMENTS IN MALE FACTOR INFERTILITY

3-dimensionally bioprinted personalized testicular tubules

A 3-dimensional (3D) testis organoid derived from neonatal mouse primary testicular cells has demonstrated the ability to generate tubule-like structures and cellular organization resembling in vivo testis.13 This novel approach to tissue engineering involves the use of 3D bioprinting technology to create biomimetic structures that replicate the complex architecture of the testis. By precisely controlling the deposition of cells and biomaterials, researchers can fabricate functional testicular tubules that support spermatogenesis and hormonal regulation. This has also been reported in human experiment, in which a spermatogenic potential of a 3D bioprinted personalized human testicular cells was derived from a patient with nonobstructive azoospermia.16

Follicle-stimulating hormone (FSH)

Advancements in the understanding and application of FSH have influenced the management of male factor infertility, particularly in idiopathic cases. FSH therapy has been shown to improve sperm quality, concentration, motility, and DNA integrity, especially in normogonadotropic men.23 Evidence from studies, including the position statement by Barbonetti et al.,24 demonstrates that both recombinant (rhFSH) and purified (pFSH) forms are effective in enhancing spontaneous pregnancy rates and ART outcomes when appropriately tailored to the patient’s hormonal and seminal profiles. Meta-analyses have indicated a 4.5-fold increase in spontaneous pregnancy rates and a modest but significant improvement in ART-related pregnancy outcomes with FSH therapy.25 Complications associated with FSH therapy are generally mild but may include testicular discomfort, gynecomastia, and minor hormonal imbalances due to gonadotropin stimulation. FSH therapy, particularly when integrated into a precision medicine framework using advanced diagnostic criteria such as the Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function (APHRODITE) classification system,26 has the potential to optimize fertility outcomes when minimizing risks through targeted, individualized approaches.

Robotic surgery

The first utilization of robotic surgery in urology goes back to 1988, utilizing the PROBOT® (Surgical Supplies Limited, Dairy Flat, New Zealand) in performing transurethral surgery.27 Robotic-assisted surgical systems have since revolutionized the practice of urology, offering enhanced precision, dexterity, and visualization compared to traditional techniques. In 2004, the first robotic-assisted vasovasostomy was performed, marking the beginning of robotic surgery in male factor infertility. This innovation has led to numerous procedures, including robotic-assisted microscopic varicocelectomy, testicular sperm extraction, and targeted robotic-assisted microsurgical denervation of the spermatic cord for chronic orchialgia.28 These procedures leverage the advantages of robotic technology, such as 3D visualization, motion scaling, and tremor reduction, to enhance surgical outcomes and reduce complications.

Microsurgical advancements

Recent technological advancements have introduced novel approaches to microsurgical procedures in reproductive medicine. Video microscope surgery, employing 3D camera technology, offers enhanced visualization and improved ergonomics for surgeons.27 Additionally, multiphoton microscopy has emerged as a promising auxiliary tool, utilizing nonlinear excitation fluorescence to potentially improve tissue visualization during microdissection testicular sperm extraction (micro-TESE). This technique aims to enhance the precision of sperm retrieval procedures. However, the application of multiphoton microscopy in human subjects remains limited, with only a single pilot study conducted on ex vivo human testicular tissue.29

LIMITATIONS

This narrative review has several limitations. First, as a nonsystematic review, it may not capture all relevant studies in the field, leading to selection bias. Second, the rapid pace of technological advancements in male factor infertility diagnosis and treatment means that some information may become outdated quickly. Third, this review does not provide a quantitative analysis of the effectiveness of these new technologies compared to traditional methods. Fourth, the clinical applicability and cost-effectiveness of some advanced technologies (such as 3D bioprinting and AI) are not fully explored. Finally, the review primarily focuses on technological advancements and may not adequately address other important aspects of male factor infertility management, such as psychological support or lifestyle interventions.

CONCLUSION

Recent years have seen a revolution in male factor infertility treatment. Innovative diagnostic tools, therapies, and technologies have transformed our approach to this complex issue. Oxidative stress biomarkers, AI-assisted analysis, shear wave elastography, 3D bioprinting, and robotic surgery stand out as game changers. These advances promise to reshape how we diagnose, treat, and manage male factor infertility. As our understanding of underlying causes grows, these innovations offer hope for better outcomes and personalized care. The landscape of male fertility treatment is evolving rapidly, driven by scientific progress and the commitment of healthcare professionals worldwide.

AUTHOR CONTRIBUTIONS

OR contributed to conceptualization and overview of the study. OA contributed to data assimilation and referencing. RR contributed to manuscript drafting and referencing. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.