Male-factor infertility: addressing an unspoken matter

The inability to have a child is a distressing reality for a significant number of couples.¹ Male factors contribute by 60% to couples’ infertility problems.² Despite the high prevalence of 70 million people affected worldwide, the majority of new diagnostic and therapeutic approaches focus on women.³ Although there is progress in understanding male infertility, sperm abnormalities still account for about 30% of male infertility cases and hinder assisted reproductive technology (ART).³

Current therapy options are scarce, mainly because the aetiology of male infertility cannot be easily determined.¹ However, with scientific advances, we may be able to understand the causes of male infertility sooner and develop solutions to fill the gap and improve outcomes for patients undergoing ART.³

How can we improve infertility diagnosis and sperm selection?

Successful ART therapy relies on a successful diagnosis. Currently, assessing male infertility includes initial screening of reproductive history and semen analysis.² If any abnormalities are identified, a more thorough examination follows that may involve specialized laboratory tests on semen and sperm, such as quantification of white blood cells, sperm viability, DNA fragmentation tests and genetic screening.² Yet, these diagnostic tests fail to identify 50% of male infertility disorders.⁴

Assessment sperm DNA damage is recommended in certain cases, such as failure of in vitro fertilization or intracytoplasmic sperm injection and recurrent pregnancy loss.⁵ Sperm DNA fragmentation tests provide a reliable analysis of sperm DNA integrity that may help to identify men who are at risk of subfertility and decide on their clinical management.⁵

Despite their utility, current DNA damage tests have faced significant concerns due to the negative effect of sample preparation on sperm DNA integrity, the high cost and complexity of the assays and the high level of variability.^5,6 To overcome this issue, we need advanced standardized, affordable and low-impact diagnostic procedures.

Research in the field of molecular biology is advancing our understanding of proteomics, the protein patterns, giving hope that novel protein biomarkers for male infertility diagnostics will be available soon.⁷ Moreover, metabolomics, the booming study of metabolic profiles in modern medicine, could be leveraged for the development of more precise diagnostic tests using urine, plasma and sperm samples.⁴

Advanced digital technologies that enable people with infertility take control of their health and access care faster and more efficiently must also be considered. Developers have embraced mobile technology to create mobile device-based kits enabling sperm quality test at home, and the reproductive medical community wants to see more of these.⁸

How can we improve therapy?

The majority of approaches to improve male fertility focus on hormone therapy. Administration of clomiphene citrate, aromatase inhibitors or human chorionic gonadotropin (hCG) aims to stimulate spermatogenesis, the process of sperm production, by increasing the levels of testosterone.¹ Research findings from studies in mice indicate correction of prolactin hormone, growth or thyroid hormones levels may be promising solutions to improve spermatogenesis.¹  

Therapy with follicle stimulating hormone in combination with hCG is another strategy that can be followed for infertile men with hypogonadotropic hypogonadism.⁹ However, the duration of treatment and frequency of injections cause inconvenience in patients and further improvements are necessary. Without question, multicentre controlled-randomized trials are required in order to appropriately characterize the true potential of these interventions.

Scientists have also started looking for the causes of male infertility away from the genome on the epigenome.¹⁰ ‘The epigenome’ is the term used to describe collectively the changes on gene expression that are not due to sequence alterations, but other chemical modifications, such as methylation.¹⁰ Not only could these modifications serve as potential biomarkers of sperm function, but they could also be novel targets for therapeutic correction.

Besides the emerging clinical therapies, advances have also been observed in the laboratory setting. In particular the microfluidic technology can be used for quick and reliable sperm quantification, quality analysis, manipulation and purification to ensure optimal outcomes.¹¹ There are several existing microfluidic systems for sperm analysis, however their functionalities are limited to only a few parameters.¹¹ To take this technology one step further in ART, more funding, interdisciplinary collaborations and partnerships are needed.¹¹

Finally, precision medicine and personalized consultation should play a key role in tackling male infertility in order to maximize the potential of the right technologies for each individual, since “one size does not fit all”.¹² The evolution of proteomics and metabolomics can be invaluable in that direction.¹²

How can the MIP help?