Follicle-Stimulating Hormone Ligand and Receptor Mutations, and Gonadal Dysfunction

In contrast to the general contention, infertility can be an inherited condition. Some of the genetic causes of male and female infertility have turned out to be due to inactivating mutations in the gonadotropin and gonadotropin receptor genes. The topic of the present text is to review current knowledge on mutations affecting the function of follicle-stimulating hormone (FSH). This gonadotropin, by binding to its specific G protein-coupled cell membrane receptor (FSHR), is important for normal gonadal function. Mutations affecting gonadotropin genes are extremely rare, but recent genetic studies have revealed that the pathogenesis of subfertility or infertility can be due to mutations in the FSH receptor (FSHR) gene. While mutations affecting FSHR are sporadic, polymorphism of the FSHR gene seems to be a common phenomenon. To date, six inactivating and only one activating mutation have been detected in the FSHR gene. In contrast to LHR gene, the majority of these mutations affect the extracellular domain of the receptor. Together with animal models using the transgenic and knock-out approaches, systematic analysis of alterations in the FSHR gene increases our knowledge on the structure and function of the FSHR and demonstrates that the integrity of each FSHR segment is required for proper expression of the fully active protein and for normal gonadal function. Mutations in the FSHR gene have different consequences in the reproductive function depending on the sex of the patient: while normal ovarian function is critically dependent on FSH, male fertility is possible with minimal or absent FSH action.