Abstract
Introduction
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disorder caused by defective hypothalamic GnRH secretion or impared GnRH action on pituitary gonadotropins. It is classified into two groups: Kallmann syndrome (KS) and normosmic IHH (NIHH). However, this condition occurs in less than 30% of patients with IHH. The incidence of IHH is 1–10 per 100,000 live births, with nearly two-thirds of cases due to KS. Gene mutations have been identified in only 2-16% of patients with normosmic IHH. Mutations in the KISS1R (GPR54) gene occur in <5% of NIHH cases, while Kisspeptin (KISS1) gene mutations are even rarer. Kisspeptin binds to its receptor, the kisspeptin receptor (KISS1R), activating GnRH release and regulating the hypothalamic-pituitary-gonadal (HPG) axis. In males, it influences Leydig cell function, spermatogenesis, sperm activity and reproductive behavior. We present a case of NIHH with a homozygous KISS1R mutation and partial empty sella.
Clinical Case
A 21-year-old male presented in 2014 with incomplete development of secondary sexual characteristics, including sparse facial hair, reduced body hair and minimal pubic hair. Axillary hair was absent. He reported no headaches, visual disturbances, anosmia, smoking, alcohol use or family history of pubertal delay. His weight was 83 kg and height 180 cm. The laboratory tests revealed FSH: 1.76 mIU/mL, LH: 1.97 mIU/mL, and testosterone: 33.92 ng/dL. Results showed low testosterone levels combined with low gonadotropin levels, consistent with hypogonadotropic hypogonadism. On scrotal USG, the right testicle measured approximately 24x14x31 mm and the left testicle 23x15x34 mm. Parenchymal echogenicity of both testicles was homogeneous. In contrast-enhanced pituitary MRI, the pituitary thickness was 3 mm and had decreased, and the findings were consistent with partially empty sella. Genetic analysis revealed a homozygous likely pathogenic variant in the KISS1R gene (NM_032551.5):c.212dup. The patient was started on testosterone replacement therapy (testosterone propionate + testosterone phenylpropionate, 250 mg every 3 weeks) in 2014. He continues to be followed in our endocrinology outpatient clinic.
Conclusion
We report a rare case of NIHH associated with a homozygous KISS1R mutation and partial empty sella. The potential effects of kisspeptin on testicular germ cells and somatic cells have been investigated through tissue and cell culture experiments. But the exact nature of these effects in living organisms has not yet been clarified. In conclusion, a complete understanding of the expression, function and potential molecular mechanisms of kisspeptin/KISS1R in the HPG axis and conducting studies on this subject will provide new developments in the diagnosis, treatment and prevention of reproductive diseases.
Table 1:
Laboratory Findings
Hormonal profile of the patient diagnosed with IHH