Complete Kisspeptin Receptor Inactivation Does Not Impede Exogenous GnRH-Induced LH Surge in Humans.

Abstract

Context:

Mutations in the kisspeptin receptor (KISS1R) gene have been reported in a few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).

Objectives:

To describe a female patient with nCHH and a novel homozygous KISS1R mutation and to assess the role of kisspeptin pathway to induce an ovulation by GnRH pulse therapy.

Design, Setting, and Intervention:

Observational study of a patient including genetic and kisspeptin receptor functions and treatment efficiency using a GnRH pump.

Main Outcome Measure:

Response to pulsatile GnRH therapy.

Results:

A partial isolated gonadotropic deficiency was diagnosed in a 28-year-old woman with primary amenorrhea and no breast development. A novel homozygous c.953T>C variant was identified in KISS1R. This mutation led to substitution of leucine 318 for proline (p.Leu318Pro) in the seventh transmembrane domain of KISS1R. Signaling via the mutated receptor was profoundly impaired in HEK293-transfected cells. The mutated receptor was not detected on the membrane of HEK293-transfected cells. After several pulsatile GnRH therapy cycles, an LH surge with ovulation and pregnancy was obtained.

Conclusion:

GnRH pulsatile therapy can induce an LH surge in a woman with a mutated KISS1R, which was previously thought to be completely inactivated in vivo.

• Authors: Justine Hugon-Rodin, Keisuke Yoshii, Najiba Lahlou, Jennifer Flandrin, Anne Gompel, Nicolas de Roux
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 12 Pg. 4482-4490 (12 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 30124894 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KISS1 protein, human
• KISS1R protein, human
• Kisspeptins
• Receptors, Kisspeptin-1
• Gonadotropin-Releasing Hormone
• Luteinizing Hormone

Topics

• Adult
• Amenorrhea (drug therapy, genetics, metabolism)
• Female
• Gonadotropin-Releasing Hormone (administration & dosage)
• HEK293 Cells
• Homozygote
• Humans
• Hypogonadism (drug therapy, genetics, metabolism)
• Kisspeptins (metabolism)
• Loss of Function Mutation
• Luteinizing Hormone (metabolism)
• Ovulation (drug effects, metabolism)
• Pregnancy
• Pulse Therapy, Drug
• Receptors, Kisspeptin-1 (deficiency, genetics)
• Signal Transduction (genetics)
• Treatment Outcome