The Genetics of Male Infertility

Imagine that you’ve met the love of your life and can finally picture yourself as a parent to a sweet, cooing baby. You’ve worked hard for years to feel stable and ready to provide a comfortable life for your family. You and your partner decide to have a baby! 

But after a year of trying, you still don’t have a positive pregnancy test. You begin to track your partner’s ovulation using apps and calendars, but another year slips by with no luck. She visits her gynecologist, but her doctor is unable to find a physiological reason that you two are unable to conceive. Finally, you both go in to see the doctor together. You get a full workup, including a semen analysis, blood hormone lab test, chromosome analysis, and genetic screening. A week later, the results hit you like a ton of bricks. Less than 2% of your sperm have normal morphology, and the doctor says it is due to a DNA abnormality. The problem is of genetic origin. 

You may feel alone, but 15% of US couples suffer from infertility at any given time, and male factors contribute to more than half of those cases [3]. Furthermore, 10-15% of severe cases of sperm impairment are genetic in origin [2]. As the genetics of male infertility are investigated in the years to come, researchers suspect that genetics will be identified as a major source of fertility impairment.

Sex Chromosome Aneuploidy

The genetic source of low sperm production is caused by numerical or structural abnormalities in either of the sex chromosomes[1]. The number of chromosomal abnormalities is inversely proportional to sperm production [3]. The way to determine whether you have a chromosomal abnormality is through a test called chromosomal analysis, also known as a karyotype.

The most common genetic cause of male infertility is Klinefelter Syndrome, which is a condition caused by the presence of one or more X chromosomes as part of the male sex chromosomes. Along with other symptoms, individuals with Klinefelter Syndrome have little or no sperm, and in the case that a pregnancy is achieved, there is a significant risk of producing offspring with chromosomal abnormalities. Therefore, tt is generally advised that people with this genetic problem use assisted reproductive therapy and get a preimplantation genetic diagnosis to ensure that the baby will have a normal set of chromosomes [4]. Other common sex chromosome-linked causes of male infertility include mixed gonadal dysgenesis and the 46,XX male syndrome [1].

Y Chromosome Microdeletions

The Y chromosome of males contains many of the genes required for making sperm and the testes, so abnormalities on this chromosome translate to functional challenges with sperm and reproduction. One notable cause of male infertility is Y chromosome microdeletions, which is the deletion of a small set of genes not detectable using traditional cytogenetic methods [4]. 

Microdeletions on the Y chromosome most often occur on the long arm, which is referred to as Yq, and the azoospermia factor region (AZF region) is of most interest on Yq because it contains genes for the growth and development of sperm [4]. AZF contains three subregions, and deletions result in a variety of abnormal phenotypes while maintaining normal karyotypes [4]. Ultimately, Y chromosome abnormalities are important to consider because they are always passed onto male offspring.

Nutritional Deficiencies

Nutritional deficiencies may also contribute to male infertility, and these nutritional deficiencies often have genetic origins. Folate is required for DNA and protein synthesis, so deficiencies in the metabolism of folate lead to problems in making functional sperm. The MTHFR gene codes for an enzyme essential for folate metabolism, and certain alleles are a risk factor for male infertility [5]. 

Zinc deficiencies have also been linked to reduced male sex hormone production, impaired spermatogenesis, and sperm death [6]. Genetic differences in genes related to zinc metabolism may lead to an increased risk in zinc deficiency, which is a problem that can be identified using genetic testing and remedied with simple supplementation. 

Recent studies have also implicated vitamin D in testicular hormone production and semen production [7]. Further studies are needed, but there is evidence that vitamin D supplementation could have positive effects on male fertility. Genetic testing for nutritional deficiencies would benefit all men struggling with fertility, since the solution could lie in supplementation.

Idiopathic Causes and Future Directions

There are over one thousand genes that are implicated in spermatogenesis, testicular development, and endocrine regulation of male reproduction [1]. Despite an abundance of research since the advent of genetic sequencing, 30-60% of cases of male infertility are diagnosed with idiopathic origin, often with a strong suspicion of genetic factors yet to be elucidated by basic research [1]. 

Genetic analysis in clinical practice is rare, and research is challenging because the etiology of male infertility is heterogeneous with genetic and environmental influences. Despite the current challenges, genetic testing plays a key role in a couples success on their journey to parenthood. It provides couples with a more precise diagnosis, lends a basis for appropriate genetic counseling, and guides assisted reproductive decisions to avoid passing chromosomal abnormalities on to offspring. 

Take Away Points

• 15% of couples struggle with infertility and half of those cases can be traced back to a problem with male infertility. 

• Genetic causes of male infertility include X chromosomes abnormalities, Y chromosome long arm microdeletions, autosomal abnormalities, and idiopathic causes which are still being investigated. 

• Chromosomal analysis can identify the genetic problem and help the couple make decisions on assisted reproductive therapy.

• Genetic testing is extremely important in complex reproduction cases because genetic problems can be passed onto offspring.

References

1. Alberto Ferlin, Savina Dipresa, Andrea Delbarba, Filippo Maffezzoni, Teresa Porcelli, Carlo Cappelli & Carlo Foresta (2019) Contemporary genetics-based diagnostics of male infertility, Expert Review of Molecular Diagnostics, DOI: 10.1080/14737159.2019.1633917

2. Ferlin, A., Raicu, F., Gatta, V., Zuccarello, D., Palka, G., & Foresta, C. (2007). Male infertility: role of genetic background. Reproductive biomedicine online, 14(6), 734-745. 

3. Flannigan, R., Schlegel, P. N. (2017). Genetic diagnostics of male infertility in clinical practice. Baillière's best practice & research. Clinical obstetrics & gynaecology, 44, 26-37. 

4. O'Flynn O'Brien, K. L., Varghese, A. C., Agarwal, A. (2010). The genetic causes of male factor infertility: a review. Fertility and sterility, 93(1), 1-12. 

5. Huang, W., Lu, X., Li, J., & Zhang, J. (2019). Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: a double-blind, randomized, placebo-controlled trial. Andrology.

6. Beigi Harchegani, A., Dahan, H., Tahmasbpour, E., Bakhtiari Kaboutaraki, H., & Shahriary, A. (2018). Effects of zinc deficiency on impaired spermatogenesis and male infertility: the role of oxidative stress, inflammation and apoptosis. Human fertility, , 1-12.  

7. Cito, G., Cocci, A., Micelli, E., Gabutti, A., Russo, G. I., Coccia, M. E., ... Natali, A. (2019). Vitamin D and Male Fertility: An Updated Review. The World Journal of Men's Health.