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• W2054921365 abstract "We studied the effects of the SHBG (TAAAA)n and androgen receptor gene [AR] (CAG)n allele length on endocrine-metabolic features and body composition (by dual-energy X-ray absorptiometry) before and after 1 year on metformin (850 mg/d) in 70 girls with polycystic ovary syndrome after precocious pubarche; allele lengths were assessed by polymerase chain reaction in both patients and in population control subjects (n = 107). Longer SHBG (TAAAA)n alleles (>8 repeats) were associated with more improvement of the lipid profile after 1 year on metformin, whereas longer AR (CAG)n alleles were related to more normalization of the androgen and lipid levels after therapy; longer alleles in both genes had an additive effect on the beneficial changes of SHBG, T, and lipids after metformin. We studied the effects of the SHBG (TAAAA)n and androgen receptor gene [AR] (CAG)n allele length on endocrine-metabolic features and body composition (by dual-energy X-ray absorptiometry) before and after 1 year on metformin (850 mg/d) in 70 girls with polycystic ovary syndrome after precocious pubarche; allele lengths were assessed by polymerase chain reaction in both patients and in population control subjects (n = 107). Longer SHBG (TAAAA)n alleles (>8 repeats) were associated with more improvement of the lipid profile after 1 year on metformin, whereas longer AR (CAG)n alleles were related to more normalization of the androgen and lipid levels after therapy; longer alleles in both genes had an additive effect on the beneficial changes of SHBG, T, and lipids after metformin. Girls with precocious pubarche (PP; pubic hair at <8 years old) are at increased risk of developing polycystic ovary syndrome (PCOS) after menarche, particularly if PP was preceded by a low birth weight (1Ibañez L. Potau N. Virdis R. Zampolli M. Terzi C. Gussinyé M. et al.Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism.J Clin Endocrinol Metab. 1993; 76: 1599-1603Crossref PubMed Scopus (256) Google Scholar, 2Ibáñez L. Potau N. Francois I. de Zegher F. Precocious pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth.J Clin Endocrinol Metab. 1998; 83: 3558-3662Crossref PubMed Scopus (462) Google Scholar). Hyperinsulinemia is thought to have a key role in this sequence; accordingly, metformin is an increasingly explored treatment (3Ibáñez L. Valls C. Potau N. Marcos M.V. de Zegher F. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia and hyperinsulinism after precocious pubarche.J Clin Endocrinol Metab. 2000; 85: 3526-3530Crossref PubMed Scopus (194) Google Scholar, 4Ibáñez L. Valls C. Ferrer A. Marcos M.V. Rodriguez-Hierro F. de Zegher F. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism.J Clin Endocrinol Metab. 2001; 86: 3595-3598Crossref PubMed Scopus (151) Google Scholar). Sex hormone–binding globulin regulates the access of androgens to target tissues; both hyperandrogenemia and hyperinsulinemia decrease circulating sex hormone-binding globulin (SHBG), but its production is also genetically determined (5Vanbillemont G. Bogaert V. De Bacquer D. Lapauw B. Goemaere S. Toye K. et al.Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men.Clin Endocrinol (Oxf). 2009; 70: 303-310Crossref PubMed Scopus (42) Google Scholar). The (TAAAA)n pentanucleotide repeat polymorphism in the SHBG gene has been associated with low SHBG levels and with risk for PCOS (6Hogeveen K.N. Talikka M. Hammond G.L. Human sex hormone–binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence.J Biol Chem. 2001; 276: 36383-36390Crossref PubMed Scopus (85) Google Scholar, 7Ferk P. Teran N. Gersak K. The (TAAAA)n microsatellite polymorphism in the SHBG gene influences serum SHBG levels in women with polycystic ovary syndrome.Hum Reprod. 2007; 22: 1031-1036Crossref PubMed Scopus (55) Google Scholar, 8Xita N. Tsatsoulis A. Chatzikyriakidou A. Georgiou I. Association of the (TAAAA)n repeat polymorphism in the sex hormone–binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels.J Clin Endocrinol Metab. 2003; 88: 5976-5980Crossref PubMed Scopus (110) Google Scholar). Variation in the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene influences the transcriptional activity of the receptor and is associated with clinical variations in androgen activity (9Ibáñez L. Ong K. Mongan N. Jäaskeläinen J. Marcos M.V. Hughes I. et al.Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.J Clin Endocrinol Metab. 2003; 88: 3333-3338Crossref PubMed Scopus (135) Google Scholar, 10Hickey T. Chandy A. Norman R.J. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian caucasian women with infertility related to polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 161-165Crossref PubMed Scopus (156) Google Scholar, 11Krithivas K. Yurgalevitch S.M. Mohr B.A. Wilcox C.J. Batter S.J. Brown M. et al.Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men.J Endocrinol. 1999; 162: 137-142Crossref PubMed Scopus (167) Google Scholar). In some populations, the combination of both long SHBG (TAAAA)n alleles and short AR (CAG)n alleles appears to influence the phenotype of PCOS, accounting for decreased circulating SHBG and higher androgen levels (12Xita N. Georgiou I. Lazaros L. Psofaki V. Kolios G. Tsatsoulis A. The role of sex hormone–binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome.Hum Reprod. 2008; 23: 693-698Crossref PubMed Scopus (47) Google Scholar). We hypothesized that the same genotype effects could be detectable in adolescents with PP who subsequently develop PCOS and that this genotype also influences the changes following metformin therapy. The study population consisted of 70 caucasian adolescents from northern Spain (age 17.0 ± 0.3 years, body mass index [BMI] 23.3 ± 0.4 kg/m2). All of the girls had a history of PP attributable to an exaggerated adrenarche (1Ibañez L. Potau N. Virdis R. Zampolli M. Terzi C. Gussinyé M. et al.Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism.J Clin Endocrinol Metab. 1993; 76: 1599-1603Crossref PubMed Scopus (256) Google Scholar) and had been followed since prepuberty in the outpatient clinic (1Ibañez L. Potau N. Virdis R. Zampolli M. Terzi C. Gussinyé M. et al.Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism.J Clin Endocrinol Metab. 1993; 76: 1599-1603Crossref PubMed Scopus (256) Google Scholar). The girls had been diagnosed with PCOS according to the following criteria: 1) hirsutism (13Ferriman D. Gallwey J.D. Clinical assessment of body hair growth in women.J Clin Endocrinol Metab. 1961; 21: 1440-1447Crossref PubMed Scopus (2102) Google Scholar); 2) amenorrhea or oligomenorrhea; 3) increased serum T and/or androstenedione and 17OH-P hyperresponse to GnRH-agonist (3Ibáñez L. Valls C. Potau N. Marcos M.V. de Zegher F. Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia and hyperinsulinism after precocious pubarche.J Clin Endocrinol Metab. 2000; 85: 3526-3530Crossref PubMed Scopus (194) Google Scholar); and 4) hyperinsulinemia during an oral glucose tolerance test (14Ibáñez L. López-Bermejo A. Díaz M. Enríquez G. del Rio L. de Zegher F. Low-dose pioglitazone and low-dose flutamide added to metformin and estro-progestagens for hyperinsulinemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months.Clin Endocrinol (Oxf). 2009; 71: 351-357Crossref PubMed Scopus (23) Google Scholar). All of the adolescents were ≥2 years beyond menarche at diagnosis of PCOS; a subgroup of 20 girls had been previously enrolled—when they were still prepubertal or early pubertal—in a clinical study that started before 2003, therefore before compulsory trial registration (15Ibáñez L. Ong K. de Zegher F. Marcos M.V. del Rio L. Dunger D. Fat distribution in nonobese girls with and without precocious pubarche: central adiposity related to insulinemia and androgenemia from pre-puberty to post-menarche.Clin Endocrinol. 2003; 58: 372-379Crossref PubMed Scopus (120) Google Scholar); none of the present results have been previously published. The girls were followed according to standard procedures, including yearly blood sampling in the fasting state and yearly assessment of body composition. The sampling for DNA extraction was performed at time of PP diagnosis. Baseline assessments were performed in the follicular phase (day 3–7) or after 2 months of amenorrhea; the girls were then started on metformin (850 mg, daily at dinner time); the medication was given for ≥1 year in monotherapy. None of the girls presented evidence for thyroid dysfunction, hyperprolactinemia, late-onset congenital adrenal hyperplasia, Cushing syndrome, or glucose intolerance. None had received oral contraceptives or medications affecting gonadal function or carbohydrate metabolism during the preceding 6 months. Healthy controls (n = 107; age 13.0 ± 0.3 y; BMI 19.0 ± 0.6 kg/m2) were either short-normal Spanish girls of the same region (heights 10th-25th percentile) attending the general pediatric clinic or subjects undergoing minor surgical procedures. None had a history of PP or PCOS or presented with androgen excess. The study protocol was approved by the Institutional Review Board of Barcelona University Hospital. Informed consent was obtained from parents and assent from study subjects, including for the collection and genotyping of DNA samples and for linking the phenotype to the genotype in an anonymized fashion. Birth weight and gestational age data were obtained from hospital records or from the girls' pediatricians and transformed into SD scores (2Ibáñez L. Potau N. Francois I. de Zegher F. Precocious pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth.J Clin Endocrinol Metab. 1998; 83: 3558-3662Crossref PubMed Scopus (462) Google Scholar). Fasting blood glucose, serum insulin, lipid profile, SHBG, androstenedione, DHEAS, and T were measured as described elsewhere (14Ibáñez L. López-Bermejo A. Díaz M. Enríquez G. del Rio L. de Zegher F. Low-dose pioglitazone and low-dose flutamide added to metformin and estro-progestagens for hyperinsulinemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months.Clin Endocrinol (Oxf). 2009; 71: 351-357Crossref PubMed Scopus (23) Google Scholar). Body composition was assessed by dual-energy X-ray absorptiometry (DXA) with Lunar Prodigy and software (version 3.4/3.5; Lunar Corp., Madison, WI) (14Ibáñez L. López-Bermejo A. Díaz M. Enríquez G. del Rio L. de Zegher F. Low-dose pioglitazone and low-dose flutamide added to metformin and estro-progestagens for hyperinsulinemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months.Clin Endocrinol (Oxf). 2009; 71: 351-357Crossref PubMed Scopus (23) Google Scholar). Genomic DNA was purified from whole blood samples using commercial reagents (Gentra Puragene cell kit; Qiagen Iberia, Madrid, Spain). Amplification of the TAAAA repeat region within the Alu sequence in the SHBG promoter and of the CAG region within AR was accomplished by polymerase chain reaction (PCR) using 1 IU high-fidelity TaqDNA polymerase (Roche Diagnostics, Indianapolis, IN) with a forward primer (5′-FAM-GCTTGAACTCGAGAGGCAG-3′) and a reverse primer (5′-CAGGGCCTAAACAGTCTAGCAGT-3′) for the SHBG (TAAAAA)n polymorphism and a forward primer (5′-FAM-TCCAGAATCTGTTCCAGAGCGTGC-3′) and a reverse primer (5′-ACGATGGGCTTGGGGAGAACCATCCT-3′) for the AR (CAG)n polymorphism. The PCR was carried out for 35 cycles using an initial denaturation at 94°C followed by denaturation at 94°C for 30 seconds, annealing at 61°C for 30 seconds, and primer extension at 72°C for 90 seconds for both polymorphisms. A final step of denaturation was performed at 72°C for 5 minutes. Both polymorphisms were assessed by a fluorescent-based PCR method using primers flanking the region of interest. DNA fragments amplified by PCR were 159–182 bp in size for SHBG (TAAAAA)n and 224–265 bp in size for AR (CAG)n. Amplified products were checked using 1% agarose gel electrophoresis. The fragment sizes were determined on an ABI Prism 3130 genetic analyzer using Genemapper software (V.4.0; Life technologies Corporation, Carlsbad, CA). Statistical analyses were performed using SPSS (Version 12.0; SPSS, Chicago, IL). Differences in genotype distribution between PCOS girls and control subjects were studied by chi-square test. Quantitative phenotypic data were compared across genotypes by repeated-measures general linear models (adjusted by age and BMI), in which the genotype was computed as the between-subjects effect, and both baseline and 1-year values as the within-subjects effect. Differences in 1-year changes across genotypes were tested by the interaction term among the between- and within-subjects effects. A P value of <.05 was considered to be statistically significant. In this study, there was 80% statistical power to be able to detect a difference of 1.0 SD in the dependent variables at baseline and of 0.5 SD in the response to metformin between genotypes defined by the absence or presence of longer alleles in either the SHBG or the AR gene. We classified the SHBG (TAAAA)n and AR (CAG)n alleles as short (≤8 repeats and ≤20 repeats, respectively), or long (>8 repeats and >20 repeats, respectively) according to published data (12Xita N. Georgiou I. Lazaros L. Psofaki V. Kolios G. Tsatsoulis A. The role of sex hormone–binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome.Hum Reprod. 2008; 23: 693-698Crossref PubMed Scopus (47) Google Scholar). Averages of repeats for both alleles were used in this classification. A similar distribution of the SHBG (TAAAA)n alleles was observed in PCOS girls and in control subjects (P=.62). In contrast, shorter AR (CAG)n alleles were significantly more frequent in PCOS girls than in control subjects (26% vs. 15%; P<.05) (Supplementary Figure 1, available online). At baseline, PCOS girls with longer SHBG (TAAAA)n alleles showed lower serum SHBG and higher levels of low-density lipoprotein cholesterol (LDL-C) (both P<.05). After 12 months on metformin, LDL-C decreased more in the girls with longer SHBG (TAAAA)n alleles compared with carriers of shorter alleles (P=.001). No associations were found between AR (CAG)n length and phenotype at baseline. However, PCOS girls with longer AR alleles showed a more pronounced decrease in androstenedione and a higher rise in high-density lipoprotein cholesterol (HDL-C) after 1 year on metformin (both P<.05). An additive effect on serum SHBG, T, and the LDL-to-HDL ratio, with more pronounced responses in carriers of longer alleles in both genes, was observed for these polymorphisms (P=.05 to P=.01; Table 1).Table 1Endocrine-metabolic variables by SHBG and androgen receptor (AR) gene repeat lengths in girls with PCOS (n = 70) before and after 1 year on metforminaThe study population was classified according to the presence of 0, 1, or 2 longer alleles to assess the additive effects after 1 year of therapy..BaselineΔ (0–1 y)SHBG, AR repeat lengths, respectivelySHBG, AR repeat lengths, respectively≤8 and ≤20(n = 12)>8 or >20(n = 46)>8 and >20(n = 12)P value≤8 and ≤20(n = 12)>8 or >20(n = 46)>8 and >20(n = 12)P valueAge (y)16.6 ± 0.517.2 ± 0.316.8 ± 0.8BMI (kg/m2)23.3 ± 0.523.7 ± 0.522.8 ± 0.80.1 ± 0.20.2 ± 0.20.0 ± 0.3SHBG (nmol/L)36 ± 533 ± 225 ± 2.075 ± 37 ± 215 ± 3.01T (ng/dL)66 ± 979 ± 577 ± 10.54−8 ± 7−22 ± 5−33 ± 9.05Androstenedione (ng/dL)327 ± 36375 ± 20334 ± 42.56−29 ± 41−100 ± 20−98 ± 33.35DHEAS (ng/dL)283 ± 49247 ± 17253 ± 28.59−62 ± 45−44 ± 12−40 ± 26.73LDL-/HDL-cholesterol1.8 ± 0.11.9 ± 0.12.1 ± 0.1.18−0.1 ± 0.2−0.3 ± 0.1−0.6 ± 0.1.02Note: Values are mean ± SEM; P values for endocrine-metabolic and body compositon variables are adjusted for age and BMI. BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein.a The study population was classified according to the presence of 0, 1, or 2 longer alleles to assess the additive effects after 1 year of therapy. Open table in a new tab Note: Values are mean ± SEM; P values for endocrine-metabolic and body compositon variables are adjusted for age and BMI. BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein. In agreement with earlier studies, we found an association between the SHBG (TAAAA)n length and circulating SHBG (12Xita N. Georgiou I. Lazaros L. Psofaki V. Kolios G. Tsatsoulis A. The role of sex hormone–binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome.Hum Reprod. 2008; 23: 693-698Crossref PubMed Scopus (47) Google Scholar, 16Huhtaniemi I.T. Pye S.R. Holliday K.L. Thomson W. O'Neill T.W. Platt H. et al.Effect of polymorphisms in selected genes involved in pituitary-testicular function on reproductive hormones and phenotype in aging men.J Clin Endocrinol Metab. 2010; 95: 1898-1908Crossref PubMed Scopus (30) Google Scholar). However, other reports have failed to replicate this association; this apparent controversy may be partly explained by the influence of other single nucleotide polymorphisms (SNPs) in the SHBG gene, such as the D327N variant in exon 8, which is directly implicated in the amount of circulating SHBG (17Cousin P. Calemard-Michel L. Lejeune H. Raverot G. Yesaad N. Emptoz-Bonneton A. et al.Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone–binding globulin concentration in hirsute women.J Clin Endocrinol Metab. 2004; 89: 917-924Crossref PubMed Scopus (108) Google Scholar) and by two additional SNPs influencing either the binding of SHBG to membrane receptors or its clearance from the circulation (18Ding E.L. Song Y. Manson J.E. Hunter D.J. Lee C.C. Rifai N. et al.Sex hormone–binding globulin and risk of type 2 diabetes in women and men.N Engl J Med. 2009; 361: 1152-1163Crossref PubMed Scopus (533) Google Scholar). To our knowledge, the association of SHBG (TAAAA)n repeat length with LDL-C levels has not been described previously. Circulating SHBG has been found to be an independent predictor of apolipoprotein A-I levels—the main structural protein of HDL-C particles—in lean PCOS women, accounting for a decreased HDL-C fraction and therefore increased LDL-C levels in this population (19Valkenburg O. Steegers-Theunissen R.P. Smedts H.P. Dallinga-Thie G.M. Fauser B.C. Westerveld E.H. et al.A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: a case-control study.J Clin Endocrinol Metab. 2008; 93: 470-476Crossref PubMed Scopus (147) Google Scholar). Shorter AR (CAG)n alleles were more frequent in PCOS girls, confirming our previous findings (9Ibáñez L. Ong K. Mongan N. Jäaskeläinen J. Marcos M.V. Hughes I. et al.Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.J Clin Endocrinol Metab. 2003; 88: 3333-3338Crossref PubMed Scopus (135) Google Scholar). However, we failed to replicate the association between the AR (CAG)n repeat length and phenotype. These discrepancies may be partly explained by differences in the studied populations, the present cohort being composed of older girls with clinical PCOS, whereas the previously reported group was composed of younger girls with only biochemical hyperandrogenism (9Ibáñez L. Ong K. Mongan N. Jäaskeläinen J. Marcos M.V. Hughes I. et al.Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism.J Clin Endocrinol Metab. 2003; 88: 3333-3338Crossref PubMed Scopus (135) Google Scholar). Alternatively, the AR (CAG)n genotype-phenotype correlations may be modified by other SNPs, such as the (GGN)n repeat, which affects the amount of AR protein translated, and thus functionally active, in target organs (20Rodríguez-González G. Ramírez-Moreno R. Pérez P. Bilbao C. López-Ríos L. Díaz-Chico J.C. et al.The GGN and CAG repeat polymorphisms in the exon-1 of the androgen receptor gene are, respectively, associated with insulin resistance in men and with dylslipidemia in women.J Steroid Biochem Mol Biol. 2009; 113: 202-208Crossref PubMed Scopus (18) Google Scholar). Recently, we reported that the rs8111699 SNP in serine-threonine-kinase (a key mediator of metformin's actions) influences metformin efficacy in girls with androgen excess (21Shaw R.J. Lamia K.A. Vasquez D. Koo S.H. Bardeesy N. Depinho R.A. et al.The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.Science. 2005; 310: 1642-1646Crossref PubMed Scopus (1584) Google Scholar, 22López-Bermejo A. Díaz M. Morán E. de Zegher F. Ibáñez L. A single nucleotide polymorphism in STK11 influences insulin sensitivity and metformin efficacy in hyperinsulinemic girls with androgen excess.Diabetes Care. 2010; 33 (1544–8)Crossref Scopus (29) Google Scholar). The present study is the first to report a similar association with the AR (CAG)n and SHBG (TAAAA)n repeat lengths and with the combination of longer alleles in both polymorphisms. Metformin decreases ovarian androgen synthesis and also improves insulin sensitivity (23Attia G.R. Rainey W.E. Carr Br Metformin directly inhibits androgen production in human techal cells.Fertil Steril. 2001; 76: 517-524Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 24Kumar N. Dey C.S. Metformin enhances insulin signalling in insulin-dependent and independent pathways in insulin resistant muscle cells.British J Pharmacol. 2002; 137: 329-336Crossref PubMed Scopus (112) Google Scholar). Shorter AR (CAG)n repeats are associated with a higher AR transcriptional activity, which in turn, might counteract metformin's action and explain the more modest improvement in the girls with a shorter repeat number. The changes in the lipid profile observed in the carriers of the longer SHBG (TAAAA)n alleles could reflect metformin's mediated changes in SHBG gene regulation in the access of androgens to target tissues. One of the limitations of the present study is the relatively small number of subjects, which did not allow adjusting our statistical results for multiple comparisons; however, the girls had a similar phenotype and ethnic background and were prospectively followed by the same clinician (L.I.), who used the same methods and the same metformin dose (850 mg/d) for the same timespan. In conclusion, both the SHBG (TAAAA)n and the AR (CAG)n repeat length predict the response to metformin in PCOS adolescents with a history of PP, so that girls with more repeats in both genes benefit more from metformin therapy. The authors thank Dr. Loreto Martorell and Jordi Genovès for technical assistance in the analysis of the polymorphisms." @default.
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• W2054921365 title "Efficacy of metformin therapy in adolescent girls with androgen excess: relation to sex hormone–binding globulin and androgen receptor polymorphisms" @default.
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