Endocrine Abstracts

The gene NR5A1, which encodes steroidogenic factor 1 (SF-1), is a pivotal transcriptional regulator of genes involved in adrenal and gonadal function, including several steroidogenic enzymes and key genes necessary for male sex determination and differentiation, testicular descent and reproduction (such as SOX9, AMH, INSL3, and AR). The most severe phenotypes associated with NR5A1 mutations include gonadal dysgenesis, disorders of sex development (DSD) and adrenal insufficiency. However, recent studies are revealing that the spectrum of phenotypes caused by variations in this gene might be broader and include partial gonadal dysgenesis, hypospadias, microphallus with anorchia, and primary ovarian insufficiency. Preliminary studies also suggested that male infertility and cryptorchidism might be linked to mutations in NR5A1, but the data are not conclusive and replication studies in different populations have not been performed.

To clarify the role of NR5A1 variations in these conditions we sequenced the gene in 404 cryptorchid subjects (279 infants with cryptorchidism and 125 men with history of orchidopexy), 237 idiopathic infertile men with azoo-oligozoospermia, and 187 fertile normozoospermic men (controls).

No variations in NR5A1 gene was found in controls. A previously described polymorphism (P.G146A) was significantly associated with cryptorchidism (6.7% of the cryptorchid population, P=0.002) and to a lesser extent with spermatogenic impairment (2.1% of the azoo-oligozoospermic population, P=0.046). Furthermore, seven novel predicted damaging missense mutations were found in heterozygous condition in 5/404 (1.2%) cryptorchid subjects and 3/237 (1.3%) infertile subjects.

This study strongly suggests that variations in NR5A1 gene might be associated also with ‘mild’ phenotypes represented by spermatogenic impairment and especially cryptorchidism. Although none of our patients have evidence of adrenal insufficiency, long-term follow up of infants with cryptorchidism is needed to verify its possible development, particularly in cases with one of the 7 novel missense mutations identified in this study.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.