Martha Moysidou, B.Sc., M.Sc., PMI-RMP, Biologist, Sr. Clinical Embryologist, Deputy Head of the Laboratory in Embryolab Fertility Clinic
Genetic factors contributing to male infertility.
Infertility consists a major health concern nowadays, affecting about 15% of couples trying to conceive. Approximately 40 % of reproductively challenged couples face male infertility, while this can rise up to 80% in combination with female infertility (mixed aitiology).
Male infertility already affects about 5–7% of the general population of men and there are certain concerns that this will increase in the future. While factors like age, diet, lifestyle, environment and hormones may be common in men facing infertility, genetics is sometimes the sole cause of this condition.
Is male infertility genetic?
Despite the fact that increasing knowledge and understanding of human reproductive biology has shed light into the mechanisms that are involved in producing functional sperm, there is still a massive 50% of idiopathic infertility, for which we do not have clear answers yet! These genetic disorders can stop production of sperm (azoospermia), or result in very poor-quality sperm.
Diagnosing infertility in men caused by genetic abnormalities is a complex issue due to the wide range of genes involved in the production and transport of viable sperm. It has been estimated that over 2,000 genes are involved in spermatogenesis!
Genetic research has revealed a small number of genes, so far. Nevertheless, understanding the genetic mechanisms that are involved in spermatogenesis has created a new field of research
Known genetically based conditions that are involved in defective sperm production.
Abnormalities in Karyotype
- Sex chromosome aneuploidies. By this term we characterize all anomalies in the male karyotype that are connected with the sex chromosomes. A normal male should carry 23 sets of autosomal chromosomes, 1X and 1Y chromosome (46,XY). Any other deviations,such as 47,XXY (Klinefelter’s syndrome), 47,XYY (Super Male syndrome) is the source of primary testicular failure and will end up in severe oligo- astheno-teratospermia or complete azoospermia.
- Pathological male karyotype. While an abnormal karyotype can cause sperm problems, as described above, many men may experience other forms of karyotype abnormalities. Examples are balanced chromosome rearrangements and translocations (i.e. Robertsonian translocation). “Balanced” means that the person carrying it doesn’t have any phenotype or symptoms. Even more, these men are likely to have normal sperm counts! The difference is that each spermatozoon, may carry imbalanced DNA, which is highly associated with miscarriages and early abortions.
Alterations of genes
- Y chromosome microdeletion of genes. This is the condition that describes the deletion or duplication of a specific region within the Y-chromosome, which is responsible for sperm production (AZF region). Malfunction in this region will manifest from severe oligo-astheno-teratozoospermia to complete azoospermia. Y chromosome microdeletions is one of the causes of Sertoli only syndrome.
- Cystic fibrosis (CF) gene mutation. Male carriers of CF will experience absence of the vas deferens, which is the transportation tract from the testis to the ejaculatory canal. Therefore, in these men, the route to ejaculation is absent, whilst production of sperm takes place normally within the testis. This type of azoospermia is called “obstructive azoospermia”. It can be bypassed using the Testicular biopsy (TESE) or the FNA (fine needle aspiration) method, in order to retrieve spermatozoa from the site of production directly. Many men that are CF carriers, have fathered biological children, thanks to these methods.
- Defective AR androgen receptor (AR) gene. The AR gene provides instructions for making a protein called an androgen receptor. Androgens are hormones (such as testosterone) that are important for normal male sexual development before birth and during puberty. Androgen receptors allow the body to respond appropriately to these hormones. Mutations in this gene cause the androgen insensitivity syndrome, leading to spermatogenic arrest.
Syndromes
- Hypogonadotropic hypogonadism is a genetic disorder that originates from impaired function the hypothalamusor pituitary gland in brain. As a result, it prevents a person from starting or fully completing puberty. Diagnosis normally occurs during teenage years when puberty fails to start. Kallman’s syndrome is a member of this family of conditions. To date at least 25 different genes have been implicated in causing Kallmann syndrome or other forms of hypogonadotropic hypogonadism. Hormone replacement therapy (HRT) is suggested and is the major form of treatment.
- Noonan syndrome. Noonan syndrome is a genetic condition caused by an affected gene. More than 10 defective genes are involved in this condition. It is transmitted from one affected parent (dominant inheritance). Its major phenotype is that it stops the typical development in various parts of the body. More specific, in the human male, the affected gene can impair normal descent of the testis bilaterally, creating a risk of impaired fertility.
Sperm DNA associated conditions
- Increased aneuploidies in spermatozoa. This is a condition that is associated with the spermatozoa themselves, rather than the karyotype. Studies have revealed that some men may produce spz with imbalanced DNA. This is quite important since the defective DNA will contribute to the embryo’s half genetic information, leading it to either not implant or miscarry. This condition can originate from different sources; lifestyle, unhealthy habits or even be acquired after cytotoxic therapies for cancer. Patients that suffer from this type of infertility can be offered Preimplantation Genetic Testing (PGT) of embryos, through an IVF treatment.
- Increased DNA Fragmentation Index (DFI). A great deal of interest has been gathered around DFI, since it is being used as a diagnostic tool for male infertility the last few years. DNA Fragmentation measures the amount of damaged DNA (measured in broken chains or strands) in a sperm sample. Much controversy exists of whether it actually plays an important role in infertility. However, studies suggest that increased DFI may be associated with failed implantation and increased miscarriage rate. Men with increased DFI may benefit from the use of sperm separation devices that are available in the market.
Treatment options
When a man’s semen analysis reveals deficiencies in sperm production, further screening can be performed to determine whether this is due to a known genetic cause, as the ones described so far. These diagnostic results can help fertility specialists and genetic counselors to determine the best way to solve or overcome the issue. Depending on the source of the problem, these couples can be offered hormonal restoration, surgical intervention, preimplantation genetic screening of embryos or the use of donor sperm, in order to produce a viable pregnancy and a healthy child.
