Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor--a clinical research center study.

Abstract

The pituitary-gonadal axis was evaluated in a mother after two of her sons with familial male-limited pseudoprecocious puberty were found to have a constitutively activating mutation of the LH receptor (LHR). Genotyping demonstrated that all showed a mutation in one of the two alleles, a substitution of Gly for Asp578 in the sixth transmembrane segment 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 were 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 hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. Upon the inception 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 hyperandrogenism and causes only incomplete pubertal activation of Leydig cells. The results are compatible with relatively low constitutive activity associated with this structural abnormality of LHR.

An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

“…Thus, cAMP production was increased in the absence of added hCG, and at higher hCG concentrations the receptor responded with further increases in cAMP, never reaching the levels attained at maximal response in the non-mutant LH receptor. As noticed in other families (Rosenthal et al 1996), the mother of these two sons was also a carrier of the mutation, indicating that carriership of an activating mutation in the LH receptor gene has no adverse effects on female infertility (Latronico et al 2000).…”

Dynamics of Ovarian Function in an Adult Woman with McCune-Albright Syndrome

“…The only activating FSH receptor mutation was identified in a hypophysectomized male who remained fertile despite undetectable gonadotropin levels (28). Activating LH receptor mutations have been described in male-limited precocious puberty, whereas they do not seem to have any particular phenotype in females (29). Hence, in females with McCune-Albright syndrome symptoms might be due mainly to increased FSH signal transduction.…”

Receptores acoplados à proteína G: implicações para a fisiologia e doenças endócrinas

“…Desta forma, uma inativação inapropriada apenas do LH não deveria causar puberdade precoce em mulheres. De fato, nenhuma evidên-cia de hiperandrogenismo ovariano subclínico foi encontrada em uma mulher portadora da mutação D578G (68). O primeiro caso de tumor de células germinativas testiculares foi publicado em 1998 (69), referindo-se a um paciente com diagnóstico de puberdade precoce familiar masculina diagnosticada aos 27 meses de idade.…”