Genetic Causes of Male Infertility

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Spermatogenesis - a complex process

Spermatogenesis is affected by the actions of thousands of genes. In theory, changes in any of these genes could cause spermatogenic failure, but so far only a small number of genetic alterations have been definitively shown to affect sperm production. At present there are few treatments for male infertility. The usual management is hyperstimulation of the unaffected female partner, which causes unpleasant symptoms and could have long-term side effects.

Abnormalities in Chromosome Number or Structure:

The most commonly seen abnormality of chromosome number is known as Klinefelters Syndrome (47, XXY) where patients have an extra X chromosome.

Structural chromosome abnormalities include translocations (e.g. Robertsonian translocations) and pericentric inversions.

Deletions in the Y-Chromosome

The Y-chromosome, the male sex chromosome (absent in women) contains many genes critical for spermatogenesis. Deletions are classified according to the area of the chromosome involved. A particular area of the Y-chromosome that appears to be involved in spermatogeneis is the AZF region (azoospermia factor region). Microdeletions in the AZF region are usually found in men with otherwise normal chromosomal make up.

Monogenic Disorders

  • These include Kallmann syndrome and Noonan syndrome, which are relatively rare conditions.
  • Autosomal Gene mutations: Cystic fibrosis is a monogenic disorder caused by a mutation in the CFTR genes and in males it may cause reduced fertility. Although spermatogenesis is unaffected, defects in the vas deferens (tubes that carry sperm out of the testes) results in the ejaculate containing no spermatozoa.
  • Other autosomal causes: mutations in the sex-hormone binding globulin gene (SHBG), involved in delivering sex hormones to target tissues and the ESR (estrogen receptor genes) can cause infertility.

Epigenetic Factors

Changes in the genetic material that do not alter the basic DNA sequence are called epigenetic factors. Epigenetic abnormalities include defects in :

  • Telomeres - these protect the genetic information, affect the location of chromosomes within the nucleus and are important in DNA replication and hence are important in spermatogenesis.
  • Mitochondrial DNA - abnormal mitochondria (involved in cellular energy production) can cause problems in sperm movement.

Research into the Genetic Causes of Male Infertility

The above genetic causes of male infertility are well established. In addition, there are a large number of studies on genetic variants and infertility. However, much of this literature is contradictory. One of the problems has been that different results occur due to the interaction of genetic factors and environmental factors. Studies looking at the same chromosome deletion have shown different results when conducted in different geographic regions.

There is a huge list of candidate genes and much work remains to be done. In order for this work to progress, large patient groups need to be studied. Studying the simultaneous expression of genes will allow geneticists to determine ‘molecular signatures’ associated with infertility. Furthermore, methods for studying live spermatozoa in the laboratory need improvement. This will aid research in the area and could lead to new treatments for male infertility.


Unravelling the Genetics of Spermatogenic Failure, L.Visser & S.Repping. Reproduction 2010, Vol 139 P303-307

The Genetic Causes of Male Factor Infertility: A review, K.L.O’Flynn, A.C.Varghese, A.Agarwal. Fertility and Sterility 2010, Vol 93, P1-12.