RESPONSE TO CHALLENGE WITH GONADOTROPIN-RELEASING-HORMONE AGONIST IN A MOTHER AND HER 2 SONS WITH A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING-HORMONE RECEPTOR - A CLINICAL RESEARCH-CENTER STUDY

The pituitary-gonadal axis was evaluated in a mother after two of her sons with familial mate-limited pseudoprecocious puberty were found to have a constitutively activating mutation of the LH receptor (LHR). G enotyping demonstrated that all showed a mutation in one of the two al leles, a substitution of Gly for Asp(578) in the sixth transmembrane s egment of the LHR. Ovarian function was normal in the 36-yr-old mother as assessed by LH dynamics and FSH and androgen levels throughout the menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone wer e also normal. Studies of the boys upon presentation at 2.4 and 3.5 yr of age revealed that acute LH responses to nafarelin were in the hypo gonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. Upon the incepti on of true puberty at 11 yr of age in the older brother, gonadotropin responses normalized for the state of development. The data show that this activating LHR mutation does not cause functional ovarian hyperan drogenism and causes only incomplete pubertal activation of Leydig cel ls. The results are compatible with relatively low constitutive activi ty associated with this structural abnormality of LHR.