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Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Turner syndrome (TS), which affects approximately 1 in 2,500 live-born females, is characterized by loss or structural anomalies of an X chromosome. Clinical features vary among patients; multiple organ systems can be affected. Endocrinologists are involved in the management of short stature, delayed puberty, and infertility. Endocrine therapies can include growth hormone, estrogen, and progestogen to promote linear growth and pubertal development. The duration of estrogen and progestogen treatment hormone treatment (HT) is generally more than 40 years. No one standard HT is suitable for all women, so general guidelines are provided to induce pubertal development. Additional considerations regarding HT choice include thrombotic risk and disorders associated with thrombophilia. Involvement of cardiologists is important because approximately 50% of patients with TS have congenital structural cardiac anomalies linked to an increased risk for aortic dissection and rupture. Oocyte donation offers the chance to carry a pregnancy, but accumulating information has highlighted the potential dangers associated with pregnancy. Advances in the care of infants, girls, and women with TS have been achieved; management involves coordinated care from a multidisciplinary team including endocrinologists, cardiologists, geneticists, otolaryngologists, behavioral health experts, nurse educators, and social workers., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To test the a priori hypothesis that the frequency of a single-nucleotide polymorphism (SNP) located in the promoter region of the glutamate decarboxylase 2 (GAD2) gene (-243A-->G) would be overrepresented among children with higher body mass index (BMI) values., Design: Genotype-phenotype correlation study., Setting: University-based pediatric endocrinology practice., Patient(s): Eighty-seven girls with PP and 70 adolescent girls with hyperandrogenism., Intervention(s): Blood was obtained for genotype analysis, glucose measurement, and hormone (Delta(4)-A, insulin, 17-hydroxyprogesterone, and T) determinations., Main Outcome Measure(s): Frequency of this SNP in the GAD2 gene and correlation of this SNP with BMI and hormone concentrations., Result(s): Among the girls followed longitudinally, the presence of one or more G alleles was associated with increased BMI at both initial and recent visits and with greater BMI z score at the initial visit. No associations were found between androgen concentrations and the G-allele variant., Conclusion(s): Similar to the findings among French children, this SNP in the GAD2 gene was associated with increased BMI in late childhood and adolescence in this population of girls from western Pennsylvania. Additional prospective studies that replicate our findings are crucial. Verification of our findings will encourage the use of lifestyle interventions for young girls who carry the G allele.

Objective: To review all available data and recommend a definition for polycystic ovary syndrome (PCOS) based on published peer-reviewed data, whether already in use or not, to guide clinical diagnosis and future research., Design: Literature review and expert consensus., Setting: Professional society., Patients: None., Intervention(s): None., Main Outcome Measure(s): A systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, to identify studies evaluating the epidemiology or phenotypic aspects of PCOS., Result(s): The Task Force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the Androgen Excess and PCOS (AE-PCOS) Society AE-PCOS Board of Directors. No section was finalized until all members were satisfied with the contents, and minority opinions noted. Statements were not included that were not supported by peer-reviewed evidence., Conclusion(s): Based on the available data, it is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders. However, a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism, but recognized that more data are required before validating this supposition. Finally, the Task Force recognized and fully expects that the definition of this syndrome will evolve over time to incorporate new research findings.

Objective: A single-nucleotide polymorphism (SNP), the G variant in codon 1013 (GAA1013-->GAG) of the insulin-like growth factor-1 (IGF-1) receptor (IGFIR) gene, has been associated with higher IGF-1 concentrations in Caucasian subjects. Because elevated serum levels of IGF-1 have been described in children with premature pubarche (PP) and in adolescent girls with hyperandrogenism, we tested the a priori hypothesis that the frequency of the A-->G variant would be overrepresented among children with PP., Design: Case-control association study., Setting: University-based pediatric endocrinology practice., Patient(s): Sixty-nine children (63 girls and 6 boys) with PP, 52 adolescent girls with hyperandrogenism, and 92 healthy subjects., Intervention(s): Blood was obtained for genotype analysis, glucose measurement, and hormone (A, insulin, 17-hydroxyprogesterone, and T) determinations., Main Outcome Measure(s): Frequency of the SNP in the IGF1R gene and correlation of this SNP with hormone concentrations., Result(s): Distribution of the G allele was statistically significantly different between the children with PP and the healthy control subjects, independent of insulin sensitivity., Conclusion(s): This common SNP in the IGF1R gene may be associated with PP caused by premature adrenarche in children. Because PP has been associated with higher IGF-1 concentrations, these data suggest a potential molecular basis for prior clinical observations of elevated IGF-1 concentrations in children with PP.

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 <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the 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.

To determine if variants in the melanocortin-4 receptor (MC4R) gene are associated with premature pubarche (PP) in children and hyperandrogenism (HA) in adolescent girls, we performed single-strand conformational polymorphism (SSCP) in 75 children (69 girls/six boys) with PP, 53 adolescent girls with HA, and 95 healthy adult control subjects. DNA sequence analysis of the conformers identified by SSCP revealed variants in six patients (two silent and one missense) and in none of the control subjects.

Objective: Because the metabolic actions of insulin are more impaired than the mitogenic pathways in polycystic ovary syndrome (PCOS), genes coding for proteins involved in insulin-mediated glucose transport can be considered as candidate genes. The sorbin and SH3-domain-containing-1 (SORBS1) gene codes for c-Cbl-associated protein (CAP) involved in insulin-mediated glucose uptake. An association study showed that a missense variant of the SORBS1 gene is protective against obesity and diabetes. We tested the hypothesis that the frequency of the protective allele would be decreased in children with premature pubarche and adolescent girls with hyperandrogenism., Design: Association study., Setting: Academic research environment., Patient(s): Children referred for the evaluation of premature pubarche (n = 79), adolescent girls with hyperandrogenism (n = 56), and healthy nondiabetic controls (n = 50)., Intervention(s): None., Main Outcome Measure(s): Frequency of the T228A allele in our patients and the relationship of body mass index to presence or absence of the T228A variant in our patient population., Result(s): Using allele-specific restriction fragment length polymorphism, allele frequencies were found to be similar among the premature pubarche, hyperandrogenism, and control groups (6.0%, 4.6%, and 8.0%, respectively). No statistically significant relationships were found between the SORBS1 genotypes and body mass index or hormone status., Conclusion(s): This SORBS1 polymorphism does not play a major role in premature pubarche, hyperandrogenism, and/or polycystic ovary syndrome in our patient population.

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.Association study. Academic research environment. Adolescent girls with a history of PP and healthy adolescent female control subjects. 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. Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.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. 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, MspAI 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 ascertain whether variation in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma 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.

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 the frequency of the N363S variant of the glucocorticoid receptor (GRL) was increased in women with 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 = 92)., Intervention(s): Blood and DNA sampling before hormonal therapy., Main Outcome Measure(s): PCOS patient and healthy control genotypes, with the N363S allele representing a variant of GRL., Result(s): Fifty-four PCOS patients with (DHEAS > or = 3000 ng/mL) and 55 without (DHEAS < or = 2,500 ng/mL) AA excess, respectively, were studied. Six of 109 (5.5%) patients studied were found to be heterozygous carriers of the A-->G base pair substitution at cDNA position 1220, resulting in the missense mutation N363S. Of these six, four had excessive AA secretion (i.e., excess DHEAS levels). There was no significant difference in the allele frequency of the GRL variant between PCOS patients with and without AA excess and controls (3.7% [95% confidence interval: 1.0%-5.7%], 1.8% [0.2%-6. 0%], and 3.3% [2.3%-6.0%]). None of the subjects were found to be homozygous for the N363S allele., Conclusion(s): The N363S variant of GRL was an uncommon occurrence in our population of healthy women and PCOS patients and did not appear to play a major role in the genetic predisposition to PCOS or to AA excess in PCOS.

Objective: To determine if the Trp(64)Arg (W64R) variant of the beta(3)-adrenergic receptor (ADRB3) could be used as a genetic marker to define risk for polycystic ovary syndrom (PCOS) and/or obesity in children and adolescents., Design: Association study., Setting: Academic research environment., Patient(s): Children referred for evaluation of premature pubic hair (n = 63), adolescent girls referred for evaluation of hirsutism and/or oligomenorrhea (n = 33), and healthy adult controls (n = 67)., Intervention(s): None., Main Outcome Measure(s): Relationship of body mass index (BMI) to presence or absence of W64R variant and frequency of W64R variant in our patient population., Result(s): Body mass index (kg/m(2)) was determined for 63 children (55 girls and 8 boys) and 33 adolescent girls. Presence or absence of the W64R variant was assayed by polymerase chain reaction (PCR) amplification followed by allele-specific restriction fragment digest. Twelve subjects and 11 healthy controls were found to be heterozygous for the W64R variant. One subject was found to be homozygous for the W64R variant. Allele frequency for the W64R variant was comparable between patients and controls. Among the patients, mean BMI values were not different between carriers and noncarriers., Conclusion(s): Although other studies suggest that the W64R variant is associated with the development of obesity and insulin resistance, we cannot demonstrate that it has a major effect on BMI in children with premature pubarche or in adolescent girls with hyperandrogenism. Serial observations are necessary to determine if this variant predicts the development of obesity and/or PCOS in adulthood.

Objective: To determine the role of heterozygosity for mutations in the 21-hydroxylase gene (CYP21) in the pathogenesis of hyperandrogenism., Design: Controlled clinical study., Setting: Tertiary care institutional hospital., Patient(s): Forty hirsute women and 13 healthy control women., Intervention(s): The source of androgen excess was determined by the changes in serum testosterone levels in response to a single 3.75-mg i.m. dose of triptorelin., Main Outcome Measure(s): CYP21 molecular genetic analysis and serum 17-hydroxyprogesterone levels., Result(s): Eight patients and one control were heterozygous carriers of CYP21 mutations. Two patients with adrenal hyperandrogenism and one patient with ovarian hyperandrogenism, who carried the V281L mutation had an increased ACTH-stimulated 17-hydroxyprogesterone level (>4.1 ng/mL) that persisted during gonadal suppression. Another patient with adrenal hyperandrogenism carried the V281L mutation, and her ACTH-stimulated 17-hydroxyprogesterone level was elevated only during gonadal suppression. Four patients (three with idiopathic hirsutism, one with ovarian hyperandrogenism) and one control were carriers of CYP21 mutations typically associated with classic congenital adrenal hyperplasia but had normal basal and ACTH-stimulated 17-hydroxyprogesterone levels. Nine patients without CYP21 mutations had increased ACTH-stimulated 17-hydroxyprogesterone levels; these decreased to normal in six of the patients during gonadal suppression., Conclusion(s): The response of serum 17-hydroxyprogesterone to ACTH does not predict CYP21 carrier status. No clear concordance was found between the CYP21 genotype and the functional origin of androgen excess.

Objective: To determine if cryptorchidism is associated with microdeletions of interval 6 of the Y chromosome, we evaluated this locus in men with a history of cryptorchidism with and without azoospermia or oligospermia and in a control group., Design: Clinical study., Setting: Academic research environment., Patient(s): Men in whom surgical treatment of cryptorchidism had been performed in childhood and healthy control male subjects., Intervention(s): None., Main Outcome Measure(s): Genotyping of interval 6 of the Y chromosome., Result(s): Analysis of semen obtained from men treated for cryptorchidism in childhood showed azoospermia or oligospermia in 14 of 38 (37%) men. No microdeletions were identified with polymerase chain reaction amplification of 17 distinct sequence tagged sites located on the long arm of the Y chromosome and the sex determining region on Y (SRY) gene., Conclusion(s): Microdeletions of interval 6 of the Y chromosome were not detected in either the formerly cryptorchid or in the healthy subjects. Although we cannot exclude the possibility of point mutations, we conclude that cryptorchidism or cryptorchidism associated with azoospermia or oligospermia is not due to microdeletions involving interval 6 of the Y chromosome.