Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations

  title={Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations},
  author={Alberto Ferlin and Cinzia Vinanzi and Andrea Garolla and R. Selice and Daniela Zuccarello and Carla Cazzadore and Carlo Foresta},
  journal={Clinical Endocrinology},
Objective  Androgens and a functioning androgen receptor (AR) are essential for development and maintenance of the male phenotype and spermatogenesis. Consistent with this, mutations in the AR gene cause a variety of defects related to androgen insensitivity, ranging from complete feminization to phenotypic males with infertility. The aim of his study was to analyse the prevalence of AR gene mutations in male infertility and to clarify the genotype‐phenotype relation. 

Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility

Well‐characterized in vitro functional assays can be used for genotype–phenotype correlation; however, for mild forms of AIS, as associated with male infertility, experimental evidence is scarce or lacking and optimal in vitrofunctional tests informative about the genotype-phenotype relation have not been described.

Androgen insensitivity syndrome: clinical features and molecular defects

This review focuses on the clinical features and molecular pathophysiology of AIS and explores the relationship of the molecular defects in the AR gene to their clinical expression.

Androgen receptor gene mutations are associated with male infertility in Northeast China: Clinical features and identification of two novel mutations

In north‐east China, there was a higher androgen receptor gene mutation rate among these infertile men, and the mutation of p.S176R deserved more attention particularly, but hormone levels and clinical phenotypes did not help in screening patients at risk of mutations.

Genetic Aspects of Male Infertility

It is essential to appraise the current information on genetic basis of male reproductive system disorders to find the predicted genetic perturbations yet to find their place for clinical applications.

Healthy birth after testicular extraction of sperm and ICSI from an azoospermic man with mild androgen insensitivity syndrome caused by an androgen receptor partial loss‐of‐function mutation

The androgen receptor (AR) is essential for the development and maintenance of the male phenotype, and for spermatogenesis, and in a wide variety of androgen insensitivity syndromes.


Until further gene mutations are identified, standard genetic testing of infertile men is largely limited to chromosomal karyotyping, Y chromosome analysis, and cystic fibrosis gene mutation analysis.

Effects of androgen receptor mutation on testicular histopathology of patient having complete androgen insensitivity

It is suggested that the dysfunctioning of AR by mutation enhances AMH expression which ultimately leads to the failure in maturation of Sertoli cells.

Spermatogenesis disorder is associated with mutations in the ligand‐binding domain of an androgen receptor

The study suggests that mutations in the AR gene would change or disturb the receptor's normal activity and it is difficult to say that they lead to a lack of spermatogenesis.



Significance of mutations in the androgen receptor gene in males with idiopathic infertility.

A proportion of males with idiopathic infertility carry relevant variations within the AR-gene, which may be distinguished on the basis of hormone levels, calculating the androgen sensitivity index (ASI), although this index lacks specificity.

Androgen insensitivity and male infertility.

The molecular mechanisms that lead to inhibition of spermatogenesis because of a mutated androgen receptor are poorly understood and will need more focus in the future.

The contributions of deficient androgen action in spermatogenic disorders.

The role of mutations in the androgen receptor (AR) in idiopathic infertility and, in particular, the contribution of expanded cytosine-adenine-guanine (CAG) repeats in exon 1 of the AR gene to the occurrence of male idiopATHic infertility is highlighted.

Androgen receptor gene and male infertility.

Independent of missense mutations, studies involving Singaporean, Australian, North American and Japanese subjects indicate that increases in length of a trinucleotide repeat (CAG) tract, encoding a polyglutamine stretch in the transactivation domain of the AR, are associated with increased risk of defective spermatogenesis and undermasculinization.

Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation.

Genetic screening in subjects with defective spermatogenesis and in 110 fertile controls identified an azoospermic patient with an amino acid substitution (Gln-->Glu) in residue 798 of the AR gene, which caused a subtle, but significant, decrease in receptor trans-activation function in vitro that is consistent with the phenotype.

The androgen receptor gene mutations database (ARDB): 2004 update

The current version of the androgen receptor (AR) gene mutations database is described, and a 3D model of the AR ligand‐binding domain (AR LBD) has been added to give a better understanding of gene structure–function relationships.

Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions.

Coexpression of AR domain fragments in mammalian and yeast two-hybrid studies suggests that a functional element centered around M886 has a role, not for ligand binding, but for interdomain and coactivator interactions culminating in the formation of a normal transcription complex.

A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*

Resistance to androgens has been suggested as a possible cause of male infertility and binding studies in genital skin fibroblasts but the molecular evidence is sparse.

Androgen insensitivity as a cause of infertility in otherwise normal men.

The low amount of androgens receptor and the combination of high serum gonadotropins and plasma testosterone production rates suggest that the defective spermatogenesis in these infertile men was the consequence of androgen insensitivity.