The effect of distinct activating mutations of the luteinizing hormone receptor gene on the pituitary-gonadal axis in both sexes

OBJECTIVE Familial or sporadic male-limited precocious puberty is a distinc t and unusual gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the luteinizing hormone receptor (LH R). In the present study, we evaluated the effect of known activating mutat ions at different sites of the LHR gene on the pituitary-gonadal axis in bo th sexes. PATIENTS Four unrelated Brazilian boys (I-IV) with gonadotrophin-independen t precocious puberty and two asymptomatic females (V-VI), a sister and moth er of two of the affected boys, were studied. Patients I, II and V carried the Ala568Val mutation located at the third intracellular loop of the LHR. Patient III carried the Leu457Arg mutation at the third transmembrane helix , and patients IV and VI carried the Thr577Ile mutation at the sixth transm embrane helix of the LHR. MEASUREMENTS Serum levels of LH, FSH, testosterone, and oestradiol under ba sal and GnRH-stimulated conditions were determined in all patients. Testost erone levels were also measured after a hCG stimulation test in patient III . RESULTS Basal LH and FSH levels were prepubertal in all boys studied. The G nRH-stimulated serum LH and FSH levels were prepubertal in three boys (I, I I and IV), whereas patient III showed totally suppressed LH and FSH levels at ages 2 and 7 years (bone ages 6 and 14 years, respectively). Serum testo sterone levels ranged from 3.8 to 69.5 nmol/l in the four boys. Patient III had the highest testosterone levels that did not respond to hCG stimulatio n. The 4 year-old girl (patient V) was phenotypically normal and the acute response to GnRH was indicative of prepubertal status. Patient VI had norma l menstrual cycles and fertility. CONCLUSIONSThese findings indicate variable effects of LHR activating mutat ions on the pituitary-gonadal axis in boys that can result in lack of norma l LH and FSH release. In contrast, prepubertal and adult females were asymp tomatic and had normal basal and GnRH-stimulated LH and FSH levels.