Mutations in gonadotropin-releasing hormone signaling pathway in two nIHH patients with successful pregnancy outcomes

Reprod Biol Endocrinol. 2016 Aug 20;14(1):48. doi: 10.1186/s12958-016-0183-8.


Background: Anomalous levels of gonadotropin-releasing hormone (GnRH) secretion result in a variety of reproductive phenotypes associated with infertility or subfertility. The normosmic isolated hypogonadotropic hypogonadism (nIHH) is due to a failure of either GnRH pulsatile secretion in hypothalamus or its reception in pituitary. The spectrum of nIHH-associated alterations continues to expand, especially when additional ethnic populations are investigated. The aim of this study was to uncover genetic causes for nIHH in patients of Russian origin.

Methods: For two nIHH patients referred to infertility clinic, both exons and promoter sequences of 6 GnRH signaling genes were sequenced.

Results: Patient 1 was a compound heterozygote for mutations in GnRH and its receptor encoding genes, while in Patient 2 GnRHR mutations were found in homozygous state. In both patients, the coding frame of GnRHR gene harbored missense-mutation Arg139His previously described as founder mutation in Polish and Brazilan patients. IVF/ET treatments were successful, with phenotypically healthy offsprings delivered.

Conclusion: Polish founder mutation Arg139His in GnRHR was found in two nIHH patients originating from Western region of Russia. Common variant of GnRH-encoding gene, Trp16Ser, could possibly contribute to reproductive phenotypes in patients with heterozygous mutations of other GnRH signaling pathway genes.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Female
  • Gonadotropin-Releasing Hormone / genetics*
  • Humans
  • Hypogonadism / diagnosis
  • Hypogonadism / genetics*
  • Hypogonadism / therapy
  • Infant, Newborn
  • Infertility, Female / diagnosis
  • Infertility, Female / genetics*
  • Infertility, Female / therapy
  • Male
  • Mutation, Missense / genetics*
  • Pregnancy
  • Pregnancy Outcome / genetics*
  • Signal Transduction / genetics*
  • Sperm Injections, Intracytoplasmic / methods


  • Gonadotropin-Releasing Hormone