A new compound heterozygous mutation of the gonadotropin-releasing hormonereceptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: Chronic estrogen administration amplifies the gonadotropin defect

We describe a woman with complete hypogonadotropic hypogonadism and a new c ompound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mut ation L314X leading to a partial deletion of the seventh transmembrane doma in of the GnRHR is associated with a Q106R mutation previously described. L 314X mutant receptor shows neither measurable binding nor inositol phosphat e production when transfected in CHO-K1 cells compared to the wild-type rec eptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had norma l pubertal development and fertility. The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 mu g/pulse, sc, every 90 min). How-ever, GnRH triggered free cu-subunit (FAS) pulses of small amplitude, demonstrating partial res istance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations w ere evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced. This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evid ence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.