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Gonadal sex determination is a complex genetic process by which an embryonic primordium is driven to form an ovary or a testis, which requires a delicate dosage balance involving many genes. Disruption in this molecular pathway can lead to differences of sex development (DSD). Although some genetic mechanisms leading to 46,XY DSD have been elucidated, little is known about copy-number variation (CNV) causing testicular or ovotesticular 46,XX DSD. We describe a 20-year natural history of a man with SRY -negative 46,XX who was born with atypical male external genitalia, aortic coarctation, and bilateral blepharophimosis-ptosis. The molecular study identified a de novo heterozygous 3-Mb 15q26.2 deletion, a gene-poor locus containing NR2F2 , which encodes the nuclear receptor COUP-TFII that is highly expressed in ovary and cardiac arteries. Immunohistochemistry confirmed the low COUP-TFII expression on his ovotestis tissue. Monosomy of 15q26.2, encompassing the NR2F2 gene, may act as a Z-factor regulating the male sex determination negatively. This finding supports a novel type of CNV resulting in DSD in an individual who developed male puberty spontaneously. [ABSTRACT FROM AUTHOR]

Obese men may present hypogonadothrofic hypogonadism, mainly related to higher insulinemia and aromatase activity. Our objectives were to evaluate the relationship of sex-hormones profiles and frequency of depressive symptoms in 43 obese men, in a cross-sectional study. They had 19–60 years, and body mass index 30–50 kg/m2. LH, total and free testosterone (TT and FT), estradiol (E2), sex hormone binding globulin, estradiol/total testosterone ratio (E2/T) were analyzed. Depressive symptoms were evaluated by “beck depression inventory” (BDI), and significant depression was considered if BDI ≥ 16.Thirty-four (80%) presented low TT levels, but only 4 (14%) had low free testosterone and hypogonadism symptoms; 12 of 43 (28%) presented increased E2. Forty five (56%) presented depressive symptoms, but 16 (28% of the 45) had significant depression. BDI correlated positively with E2(r = 0.407;p = 0.001) and E2/T (r = 0.473;p = 0.001), but not TT or FT. Patients with significant depressive showed higher levels of estradiol (136 ± 48 versus 103 ± 48 pg/ml,p = 0.02) andE2/T(16.0 ± 9.9 versus 9.8 ± 4.6;p = 0.002) (mean ± SD).In conclusion, obese men may present relatively excess of estradiol and deficiency in testosterone, leading to an imbalance between these two hormones. The greater this imbalance, the more depressive symptoms had our patients. [ABSTRACT FROM PUBLISHER]

Individuals with Turner syndrome (TS) have increased risk for autoimmune diseases, especially thyroid abnormalities. The function of the vitamin D receptor ( VDR) gene is influenced by several genetic polymorphisms which are associated with a susceptibility to a range of autoimmune diseases. Thus, we have hypothesized a possible relationship between thyroid abnormalities and VDR polymorphisms ( ApaI/G1025-49T, TaqI/T1056C, FokI/T2C and BsmI G1024 ++ 283A) in TS patients. A case-control study was performed comprising 101 Brazilian women with TS and a control group consisting of 133 healthy fertile women without a history of autoimmune diseases. In TS group, 21.8% had Hashimoto's thyroiditis. Detection of VDR polymorphisms was performed using TaqMan system by real-time PCR. The χ2 was used to compare allele and genotype frequencies between groups. Combined genotypes of VDR gene polymorphisms were assessed by the haplotype analysis. A p value <0.05 was considered statistically significant. Relatively similar VDR polymorphisms genotype and allelic frequencies in cases and controls were found, even when only considering the patients with thyroid abnormalities. Haplotype analysis showed that none of the VDR haplotypes were associated to thyroid diseases in TS patients. In conclusion, the results showed no association between VDR gene polymorphisms and thyroid abnormalities in Brazilian TS patients tested. [ABSTRACT FROM AUTHOR]

Aims: To determine the frequency of C677T and A1298C polymorphisms of the MTHFR gene and correlate them with homocysteine serum levels in patients with Turner syndrome (TS) and controls., Methods: This case-control study included 78 women with TS and a control group of 372 healthy individuals without personal or family history of cardiovascular disease and cancer. C677T (rs1801133) and A1298C (rs1801131) polymorphisms were detected by polymerase chain reaction-restriction fragment-length polymorphism and the TaqMan system, respectively. Homocysteine serum levels were determined by high-performance liquid chromatography. The results were analyzed statistically, and p<0.05 was considered to represent a significant difference., Results: The homocysteine levels change was 13.9+3.3 nM in patients with TS and 8.8+3.2 nM in the control group. No significant difference between groups was found (p=0.348). Single-marker analysis revealed no association between MTHFR C677T polymorphism and TS when genotype (p=0.063) or allelic (p=0.277) distribution was considered. Regarding MTHFR A1298C polymorphism, a statistical difference was found between the TS group and the control group, for both genotype (p<0.0001) and allele (p<0.0001) distribution. Haplotype analysis of 2 MTHFR polymorphisms identified 2 haplotypes-CC and TC-associated with TS (p<0.001 and p=0.0165, respectively). However, homocysteine levels were not higher in patients with haplotype risk., Conclusion: The results suggest that the C677T and A1298C polymorphisms of the MTHFR gene are not related to homocysteine levels in Brazilian patients with TS, despite the differential distribution of the mutated allele C (A1298C) in these patients. Further studies are needed to investigate the possible genetic interaction with homocysteine levels in TS.

To show that in the dysgenetic gonads of 104 Turner syndrome patients no significant difference was found regarding the expression of the genes DAX1, FOG2, GATA4, OCT4, SF1, SRY, TSPY, WT1, and STRA8 compared with controls, except for genes OCT4, SRY, and TSPY in both gonads of a patient whose chromosomal constitution was 45,X/45,X,add(15)(p11). The expression analysis of genes OCT4, SRY, and TSPY in the dysgenetic gonads of Turner syndrome patients may allow introducing modifications in the microenvironment that could contributed to a malignant transformation process., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Cardiovascular disease is one of the main causes for Turner syndrome (TS) mortality and the evaluation of its risk factors such as excess body fat and its distribution is considered one of the major aspects of the adult patient care., Objective: To develop and validate a specific bioelectrical impedance analysis (BIA) equation to predict body composition in TS patients., Subjects and Methods: Clinical and anthropometric data, dual-energy X-ray absorptiometry (DXA) for total fat-free mass (FFM) and BIA for resistance and reactance were obtained from 50 adult TS patients. Linear regression analysis was performed with multiple clinical and BIA data to obtain a predicting equation., Results: The equation developed to estimate FFM in adult TS patients showed great consistency with DXA, elevated correlation (r = 0.974) and determination (r(2) = 0.948) coefficients and an adequate standard error estimate (SEE = 1.52 kg)., Conclusions: The specific equation developed here allowed making an adequate FFM estimate in adult TS patients.

Background: Paucity of data on childhood obesity and cardiovascular risk in Brazil., Objective: To determine the prevalence of hypertension, dyslipidemia, obesity and their correlations in a sample of school children in Itapetininga, State of Sao Paulo, Brazil., Methods: Cross-sectional study with systematic collection of anthropometric data (weight, height, waist circumference, BMI and blood pressure levels) and determination of glucose, total cholesterol, LDL, HDL, uric acid, and apolipoproteins A and B in a random sample representative of school children from the public education system in Itapetininga, State of Sao Paulo. For data analysis, we used population parameters from the NCHS curves (2000), blood pressure categories from NHBPEP (2004), and the serum cholesterol levels proposed by the AHA for children and adolescents (2003)., Results: A total of 494 children and adolescents participated in the study. Of these, 11.7% had HBP, 51% increased total cholesterol, 40.5% increased LDL-cholesterol, 8.5% increased triglycerides, and 6.1% low HDL-cholesterol levels. Mean (+/- standard deviation) TC, HDL-cholesterol, LDL-cholesterol and triglycerides were 172.1(27.9), 48.1(10.0), 105.7(23.1) and 90.9(43.8), respectively. Obesity and overweight were detected in 12.8% and 9.7% of the sample, respectively. Individuals of the obese group had a greater chance of presenting with dyslipidemia and hypertension in comparison with those of the other groups., Conclusion: This study supports the hypothesis of different prevalences of excess weight among school children from the public education system of the northeastern and southeastern regions of Brazil, with higher rates in the latter. Additionally, it demonstrates an association of obesity with dyslipidemia and hypertension in that group. In light of the paucity of Brazilian data on this issue, our study provides important data for further comparisons.

Background: Dysfunctions in the folate metabolism can result in DNA hypomethylation and abnormal chromosome segregation. Two common polymorphisms of this enzyme (C677T and A1298C) reduce its activity, but when associated with aneuploidy studies the results are conflicting. The objective of the present study is to analyze the MTHFR gene polymorphisms in women with Turner Syndrome and in a control group, correlating the findings to the chromosomal aneuploidy., Methods: The study comprised 140 patients with Turner Syndrome, of which 36 with chromosome mosaicism and 104 non-mosaics, and a control group of 209 fertile and healthy women without a history of any offspring with aneuploidy. Polymorphisms C677T and A1298C were studied by RFLP-PCR and the results were statistically analyzed., Results: The frequency of genotypes MTHFR 677CC, 677CT and 677TT in the patients with Turner Syndrome and chromosome mosaicism was, respectively, 58.3%, 38.9% and 2.8%. Among the patients with non-mosaic Turner Syndrome, 47.1% presented genotype 677CC, 45.2% genotype 677CT, and 7.7% genotype 677TT. Among the 209 individuals of the control group, genotypes 677CC, 677CT and 677TT were found at the following frequencies: 48.3%, 42.1% and 9.6%, respectively. As for polymorphism A1298C, the patients with Turner Syndrome and chromosome mosaicism presented genotypes 1298AA, 1298AC and 1298CC at the following frequencies: 58.3%, 27.8% and 13.9%, respectively. Among the non-mosaic Turner Syndrome patients, genotype 1298AA was found in 36.5%, genotype 1298AC in 39.4%, and genotype 1298CC in 22.1%. In the control group, genotypes 1298AA, 1298AC and 1298CC were present at the following frequencies: 52.6%, 40.7% and 6.7%, respectively., Conclusion: No correlation was observed between the MTHFR gene polymorphism 677 and chromosomal aneuploidy in the Turner Syndrome patients. However, the MTHFR gene polymorphism at position 1298, mainly genotype 1298CC that reduces the enzyme efficiency, was more frequent in the group of Turner Syndrome patients, suggesting its involvement in mechanisms related to chromosomal imbalances.

Objective: To determine the clinical implications of the presence of a Y chromosome in Turner's syndrome patients with karyotype abnormalities., Design: To investigate the presence of Y-chromosome sequences in different tissue samples., Setting: Endocrinology outpatient clinic of a federal university in Brazil., Patient(s): Five Turner's syndrome patients with karyotype abnormalities such as marker chromosomes, additional material, or ring chromosomes., Intervention(s): Peripheral blood, oral epithelial cells, and hair root samples were collected., Main Outcome Measure(s): The SRY gene and the DYZ3 repeat region were amplified by polymerase chain reaction followed by gel electrophoresis mobility of amplified genomic DNA, and ultraviolet visualization. Prophylactic gonadectomy was offered to the Y-positive patients., Result(s): The analysis of the different tissues revealed that three of the five patients studied presented Y-chromosome mosaicism. These three patients underwent prophylactic gonadectomy, and in one of them, the histopathologic study of the gonads disclosed hilus cell hyperplasia and stromal luteoma with contralateral nodular hyperthecosis., Conclusion(s): A systematic search for Y-chromosome mosaicism in Turner's syndrome patients is justified by the risk of developing gonadal tumors or androgen-producing lesions.

We report on a girl who, despite her 45,X/46,X,der(Y) karyotype, showed no signs of virilization or physical signs of the Ullrich-Turner syndrome (UTS), except for a reduced growth rate. After prophylactic gonadectomy due to the risk of developing gonadoblastoma, the gonads and peripheral blood samples were analyzed by fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) to detect Y-specific sequences. These analyses allowed us to characterize the Y-derived chromosome as being an isodicentric Yp chromosome (idic(Yp)) and showed a pronounced difference in the distribution of the 45,X/46,X,idic(Yp) mosaicism between the two analyzed tissues. It was shown that, although in peripheral blood almost all cells (97.5%) belonged to the idic(Yp) line with a duplicated SRY gene, this did not determine any degree of male sexual differentiation in the patient, as in the gonads the predominant cell line was 45,X (60%).

Introduction: 21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia, followed in frequency by 11beta-hydroxylase deficiency (11betaOHD). Although the relative frequency of 11betaOHD is reported as between 3 and 5% of the cases, these numbers may have been somewhat underestimated., Materials and Methods: In 133 patients (89 females/44 males; 10 d-20.9 yr) with alleged classic 21OHD and five (three females/two males; 7.3-21 yr) with documented 11betaOHD, we measured serum 21-deoxycortisol (21DF), 17-hydroxyprogesterone (17OHP), and 11-deoxycortisol (S), 48 h after glucocorticoid withdrawal. We also studied 20 sex- and age-matched control subjects. Serum steroid levels were determined by RIA after HPLC purification., Objectives: The objectives of this study were to: 1) quantify 21DF in patients with congenital adrenal hyperplasia, 2) correlate hormonal with clinical data, and 3) identify possible misdiagnosed patients with 11betaOHD among those with 21OHD., Results: In 21OHD, 17OHP (217-100,472 ng/dl) and 21DF (<39-14,105 ng/dl) were mostly elevated and positively correlated (r = 0.7202; P < 0.001). Except for higher 17OHP in pubertal patients, 17OHP and 21DF values were similar according to sex, disease severity, or prevailing glucocorticoid dose. One additional patient with 11betaOHD was detected (1%) and also one with apparent combined 11beta- and 21OHD. S levels were elevated in 11betaOHD and normal but significantly higher in 21OHD than in controls., Conclusion: To recognize patients with 21- and/or 11betaOHD, we recommend evaluation of 17OHP or 21DF and S. Also, 21DF may be useful to follow up pubertal patients with 21OHD. Because 1% of patients with alleged 21OHD may have 11betaOHD, its frequency seems underestimated, as per our experience in a Brazilian population.

Captive adult male jaguars (Panthera onca) from two locations in southeast Brazil were studied to evaluate the effects of season on endocrine and testicular function. For assessment of testicular steroidogenic activity, androgen metabolite concentrations were measured in fecal samples collected one to three times per week over 14 ( n=14 ), 9 ( n=1 ) or 7 months ( n=1 ). To assess seasonality, data were grouped by season (summer: December-February; autumn: March-May; winter: June-August; spring: September-November). Additionally, samples collected in the dry season (March-August) were compared with those collected in the wet season (September-February). There were no differences ( P>0.05 ) in fecal androgen concentrations in samples collected in spring, summer, autumn, and winter ( 480.8+/-50.4 ng/g, 486.4+/-42.0 ng/g, 335.4+/-37.7 ng/g, and 418.6+/-40.4 ng/g dry feces). However, there were differences ( P<0.05 ) in fecal androgen concentrations between the dry and wet seasons ( 380.5+/-28.0 ng/g versus 483.9+/-32.3 ng/g dry feces). Sperm samples, collected from all males twice (approximately 6 months apart) were similar; mean (+/-S.E.M.) motility, concentration and morphology were 57.0 %4.5%, 6.3+/-2.4 x 10(6) ml(-1), and 60.8+/-3.1 %, respectively. In conclusion, androgen metabolite concentrations in the captive male jaguar were not affected by season, but there was a difference between the wet and dry periods. Further research is needed to verify these results.

21-Hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH), followed by 11beta-hydroxylase deficiency (11beta-OHD). Diagnostic serum markers for these conditions are 17-hydroxyprogesterone (17-OHP) and 11-desoxycortisol (S), respectively. In 21-OHD, the large amounts of 17-OHP are further 11beta-hydroxylated to form 21-deoxycortisol (21-DF), making it also an excellent marker of this disease. These steroids can be measured in blood by radioimmunoassay (RIA). In this paper, we report the use of high-performance liquid chromatography (HPLC) for steroid purification, prior to RIA determinations of 21-DF, S, 17-OHP, and testosterone (T) in ether-extracted serum. The chromatographic separation is developed in a BDS-Hypersil column using water-methanol (53:47, v/v) as the mobile phase. The method is applied to 35 patients with the classic form of 21-OHD (18 females, 17 males, 5.1-14.2 years old) and 2 with 11beta-OHD (1 female, 1 male, 9.5 and 12.6 years old). Thirteen control children (5 females and 8 males, 5.2-15.2 years) are also studied. The results obtained for all measured steroids are compatible with those reported in the literature. The method is precise, and recovery is adequate. The HPLC technique proved to be of value for the purification of several steroids from single serum samples prior to RIA in patients with CAH.