title: The effect of distinct activating mutations of the luteinizing hormone receptor gene on the pituitary-gonadal axis in both sexes.
abstract: OBJECTIVE
  Familial or sporadic male-limited precocious puberty is a distinct and unusual gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the luteinizing hormone receptor (LHR). In the present study, we evaluated the effect of known activating mutations at different sites of the LHR gene on the pituitary-gonadal axis in both sexes.
  
  
  METHODS
  Four unrelated Brazilian boys (I-IV) with gonadotrophin-independent precocious puberty and two asymptomatic females (V-VI), a sister and mother 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 transmembrane helix of the LHR.
  
  
  METHODS
  Serum levels of LH, FSH, testosterone, and oestradiol under basal and GnRH-stimulated conditions were determined in all patients. Testosterone 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 GnRH-stimulated serum LH and FSH levels were prepubertal in three boys (I, II 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 testosterone 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 stimulation. The 4 year-old girl (patient V) was phenotypically normal and the acute response to GnRH was indicative of prepubertal status. Patient VI had normal menstrual cycles and fertility.
  
  
  CONCLUSIONS
  These findings indicate variable effects of LHR activating mutations on the pituitary-gonadal axis in boys that can result in lack of normal LH and FSH release. In contrast, prepubertal and adult females were asymptomatic and had normal basal and GnRH-stimulated LH and FSH levels.
authors: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM/42, Hospital das Clínicas, Universidade de São Paulo, São Paulo, Brazil. anacl@usp.br
authors: A C
authors: AC
authors: Latronico
authors: T S
authors: TS
authors: Lins
authors: V N
authors: VN
authors: Brito
authors: I J
authors: IJ
authors: Arnhold
authors: B B
authors: BB
authors: Mendonca
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D006063:Chorionic Gonadotropin / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011629:Puberty, Precocious / Q000097:blood / Q000235:genetics*; D011974:Receptors, LH / Q000235:genetics*; D012737:Sex Factors; D013739:Testosterone / Q000097:blood
chemical_list: D006063:Chorionic Gonadotropin; D011974:Receptors, LH; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone