Although thyroid dyshormonogenesis (TDH) accounts for 10-20% of congenital hypothyroidism (CH), the molecular etiology of TDH is unknown in Bangladesh. Thyroid peroxidase (TPO) is most frequently associated with TDH and the present study investigated the spectrum of TPO mutations in Bangladeshi patients and analyzed the effects of mutations on TPO protein structure through in silico approach. Sequencing-based analysis of TPO gene revealed four mutations in 36 diagnosed patients with TDH including three nonsynonymous mutations, namely, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, and one synonymous mutation p.Pro715Pro. Homology modelling-based analysis of predicted structures of MPO-like domain (TPO142-738) and the full-length TPO protein (TPO1-933) revealed differences between mutant and wild type structures. Molecular docking studies were performed between predicted structures and heme. TPO1-933 predicted structure showed more reliable results in terms of interactions with the heme prosthetic group as the binding energies were -11.5 kcal/mol, -3.2 kcal/mol, -11.5 kcal/mol, and -7.9 kcal/mol for WT, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, respectively, implying that p.Ala373Ser and p.Thr725Pro mutations were more damaging than p.Ser398Thr. However, for the TPO142-738 predicted structures, the binding energies were -11.9 kcal/mol, -10.8 kcal/mol, -2.5 kcal/mol, and -5.3 kcal/mol for the wild type protein, mutant proteins with p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro substitutions, respectively. However, when the interactions between the crucial residues including residues His239, Arg396, Glu399, and His494 of TPO protein and heme were taken into consideration using both TPO1-933 and TPO142-738 predicted structures, it appeared that p.Ala373Ser and p.Thr725Pro could affect the interactions more severely than the p.Ser398Thr. Validation of the molecular docking results was performed by computer simulation in terms of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulation. In conclusion, the substitutions mutations, namely, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, had been involved in Bangladeshi patients with TDH and molecular docking-based study revealed that these mutations had damaging effect on the TPO protein activity.

Background: Altered luteinizing hormone to follicle-stimulating hormone (LH-FSH) ratio and hyperandrogenism are two important pathophysiological characteristics of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate the relationship of LH-FSH ratio with androgen in women with PCOS. Methods: This cross-sectional study included 550 newly detected reproductive aged women with PCOS (mean ± standard deviation (SD): age 23.14 ± 4.80 years; body mass index (BMI) 27.64 ± 5.34 kg/m 2) according to revised Rotterdam criteria. Relevant clinical history, physical examination and ultrasonogram of ovaries were done for each participant. Fasting serum LH, FSH and total testosterone (TT) were measured by chemiluminescent microparticle immunoassay from blood collected during follicular phase of menstrual cycle. Results: More than two-thirds (n = 389, about 71%) had altered LH-FSH ratio (cut-off > 1.0) and about 43% (n = 234) had hyperandrogenemia (TT > 46 ng/dL). Frequency of none of the clinical variables or ovarian morphology differed statistically between the groups with or without altered LH-FSH ratio (NS for all). Serum TT and LH-FSH ratio were positively correlated (r = 0.139, P = 0.001). However, menstrual irregularity (P = 0.002), polycystic ovaries (P = 0.045), diabetes mellitus (P = 0.017), obesity (P = 0.009) and hirsutism (P < 0.001) were higher in frequency in the hyperandrogenic group. Serum TT had predictive association with altered LH-FSH ratio (odds ratio (OR) (95% confidence interval (CI)): 1.09 (1.02-1.16), P = 0.02) and LH-FSH had predictive association with hyperandrogenemia (OR (95% CI): 1.15 (1.03-1.28), P = 0.02) in women with PCOS. Conclusions: Serum LH-FSH ratio and androgenemia significantly correlate in women with PCOS. However, manifestations are more frequent with hyperandrogenemia rather than altered LH-FSH ratio.

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Polycystic ovarian syndrome (PCOS) is a common disorder