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Objective To test the hypothesis that lower sex hormone–binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism. Design Association study. Setting Academic research environment. Patient(s) Adolescent girls with a history of PP and healthy adolescent female control subjects. Intervention(s) Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)–binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Main outcome measure(s) Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes. Result(s) Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone–binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. Conclusion(s) The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

Objective: To ascertain the extent of phenotypic heterogeneity for premature pubarche and polycystic ovary syndrome between and within families. Design: Association study. Setting: Academic research environment. Patient(s): Three families in which the propositus had presented with either premature pubic hair or adolescent hyperandrogenism. Intervention(s): Detailed medical histories, hormone determinations, and genotype analyses. Main Outcome Measure(s): Clinical phenotype. Genotypes for CYP21, HSD3B2 , G972R variant of IRS-1 , N363S variant of GRL , W64R variant of ADRB3 , CAG repeat in exon 1 of AR , Msp AI polymorphism in CYP17 , and R264C variant of CYP19 . Result(s): Significant phenotypic and genetic heterogeneity was observed both within and between families. In one family, CYP21 and IRS-1 variants were observed to co-segregate with symptoms of androgen excess and obesity. No genetic markers were consistently noted to associate with clinical features of hyperandrogenism in the other two families. Conclusion(s): The difficulties in classifying female family members as clearly affected or unaffected and lack of definitive male phenotype complicate the use of linkage analysis to identify the polycystic ovary syndrome genes. Each family is best considered on an individual basis to identify genetic markers that segregate with the clinical features of androgen excess.

Objective: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. Design: Association study. Setting: Academic research environment. Patient(s): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. Intervention(s): None. Main Outcome Measure(s): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. Result(s): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1 , 2 of 30 (6.6%) for GRL , and 2 of 30 (6.6%) for ADRB3 . Conclusion(s): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.

Objective To determine whether frequencies of the mutations in the 21-hydroxylase ( CYP21 ) gene and the G972R variant of the insulin receptor substrate-1 ( IRS1 ) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess. Design Prospective case–control study. Setting University reproductive endocrinology laboratory and outpatient clinic. Patient(s) Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95). Intervention(s) Blood and DNA sampling before hormonal therapy. Main outcome measure(s) Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants. Result(s) Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3). Conclusion(s) The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

Objective: To ascertain whether variation in peroxisome proliferator-activated receptor-γ ( PPAR-γ ), a nuclear ligand-dependent transcription factor affecting both adipocyte differentiation and insulin sensitivity, influences body mass index (BMI). Design: Association study. Setting: Academic research environment. Patient(s): Children with premature pubic hair and adolescent girls with hyperandrogenism. Intervention(s): Assay for P12A and P115Q variants and measure BMI. Main Outcome Measure(s): BMI and PPAR-γ genotypes. Result(s): Fourteen subjects were heterozygous for P12A; two were homozygous. None carried the P115Q allele. No significant differences in BMI or basal androstenedione concentrations between P12 carriers and noncarriers were found. Thirty-nine subjects had BMI values at two time points; mean BMI was significantly greater in the P12A carriers at time point 2. Those P12A carriers obese at time point 1 became more obese; lean mutation carriers tended to remain lean. Annual rate of increase in BMI was significantly greater in the P12A carriers than the noncarriers. Conclusion(s): Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adolescence. Future studies are needed to determine whether the divergent effects of P12A persist into adulthood, to elucidate the mechanism of this effect, and to replicate our findings in other populations.