COMPARISON OF ANDROGEN AND ESTROGEN RECEPTORS’ EXPRESSION IN DARTOS TISSUE OF BOYS WITH AND WITHOUT HYPOSPADIAS
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Abstract
Objective: This study aims to investigate the characteristics of androgen receptors (AR), estrogen receptor 1 (ER1) and estrogen receptor 2 (ER2) expression in dartos tissue of patients with congenital hypospadias, compared to normal penis. Material & Methods: We harvested 63 dartos tissue consisting of 53 congenital hypospadias that underwent urethroplasty (20 distal and 33 proximal) and 10 normal penis that underwent circumcision as controls from September 2017 to September 2018. The expressions of AR, ER1, and ER2 were measured using Quantitative Real-Time PCR (qPCR). All data were analyzed by Prism 7, and one-way ANOVA tests were used to compare gene expressions between the groups. Results: The mean age was 68.99 (± 45.5) and 65.6 (± 25.8) months in boys with and without hypospadias, respectively. The expression of mRNA AR was decreased in proximal (6.26 ± 2.30) and distal hypospadias (6.43 ± 2.22) compared to controls (9.69 ± 1.10), which were statistically significant (p=0.0001 and p<0.0001, respectively). We found a statistically significant difference of ER1 expression compared to controls (p=0.0064). The expression of ER2 was significantly increased in distal (21.03 ± 5.00) and proximal hypospadias (25.21 ± 8.06) groups compared to controls (11.80 ± 2.49) (p<0.0001). There was no statistically significant mean difference in mRNA ER1 expression (p=0.65). Conclusion: The repressed AR and elevated ER mRNA as shown in our study may suggest that defects in those receptors’ interaction and/or balance may contribute to hypospadias and penile curvature condition. Further studies are needed to evaluate any gene-related problems in hypospadias. Keywords: Hypospadias, androgen receptor, estrogen receptor, dartos tissue.
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Hypospadias, androgen receptor, estrogen receptor, dartos tissue
Yuri P, Gunadi, Lestari RP, Fardilla FP, Setyaningsih WAW, Arfian N, Dachlan I. The impact of COL1A1 and COL6A1 expression on hypospadias and penile curvature severity. BMC Urol. 2020; 20: 1–5.
Yuri P, Heriyanto DS, Rodjani A, Hutasoit YI, Hutahaean AYA, Rahman MR, Amanda RR, Raksawardana YK, Lestar RP. Expression of mRNA Mastermind-like Domain-containing 1, Androgen Receptor, and Estrogen Receptor in Patients with Hypospadias.pdf. Open Access Maced J Med Sci. 2020; 8: 543–547.
Zanden LFM Van Der, Rooij IALM Van, Feitz WFJ, Franke B, Knoers NVAM, Roeleveld N. Aetiology of hypospadias : a systematic review of genes and environment. Hum Reprod Update. 2012; 18: 260–283.
Baskin L. What Is Hypospadias? Clin Pediatr (Phila). 2017; 1–10.
Hadidi A. Classification of hypospadias. In: Hadidi A, Azmy A (eds) Hypospadias Surg. Springer, Heidelberg. 2004. pp 79–83
Kalfa N, Philibert P, Baskin LS, Sultan C. Hypospadias: Interactions between environment and genetics. Mol Cell Endocrinol. 2011; 335: 89–95
Bouty A, Ayers KL, Pask A, Heloury Y, Sinclair AH. The genetic and environmental factors underlying hypospadias. Sex Dev. 2015; 9: 239–259.
Balaji DR, Reddy G, Babu R, Paramaswamy B, Ramasundaram M, Agarwal P, Joseph LD, D’Cruze L, Sundaram S. Androgen Receptor Expression in Hypospadias. J Indian Assoc Pediatr Surg. 2020; 25: 6–9.
Deng C, Dai R, Li X, Liu F. Association between SNP12 in estrogen receptor α gene and hypospadias: a systematic review and meta-analysis. Springerplus. 2016.
Atmoko W, Shalmont G, Situmorang GR, Wahyudi I, Tanurahardja B, Rodjani A. Abnormal dartos fascia in buried penis and hypospadias: Evidence from histopathology. J Pediatr Urol. 2018; 14: 536.e1-536.e7
Spinoit AF, Van Praet C, Groen LA, Van Laecke E, Praet M, Hoebeke P. Congenital penile pathology is associated with abnormal development of the dartos muscle: A prospective study of primary penile surgery at a tertiary referral center. J Urol. 2015; 193: 1620–1624
Spinoit AF, Buelens S, Van Praet C, Van Laecke E, Praet M, Hoebeke P. Influence of Dartos Tissue and the Androgen Receptor in Congenital Penile Malformations: Opening New Horizons in Research with Clinical Relevance [Figure presented]. Eur Urol Suppl. 2017; 16: 177–181.
Orkiszewski M. A standardized classification of hypospadias. J Pediatr Urol. 2012; 8: 410–414.
Aboutaleb H. Role of the urethral plate characters in the success of tubularized incised plate urethroplasty. Indian J Plast Surg. 2014; 47: 227–231.
Nathan GG, Varghese L, Kanmani J. Effectiveness of structured teaching programme on knowledge regarding preventive measures of uterine prolapse among mothers. J Clin Diagnostic Res. 2017; 11: QC05–QC08.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001; 25: 402–408.
Agras K, Willingham E, Liu B, Baskin LS. Ontogeny of Androgen Receptor and Disruption of Its mRNA Expression by Exogenous Estrogens During Morphogenesis of the Genital Tubercle. J Urol. 2006; 176: 1883–1888.
Kon M, Suzuki E, Dung VC, et al. Molecular basis of non-syndromic hypospadias: Systematic mutation screening and genome-wide copy-number analysis of 62 patients. Hum Reprod. 2015; 30: 499–506.
Qiao L, Tasian GE, Zhang H, Cao M, Ferretti M, Cunha GR, Baskin LS. Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells. Pediatr Res. 2012; 71: 393–398
Yuan S, Meng L, Zhang Y, Tu C, Du J, Li W, Liang P, Lu G, Tan YQ. Genotype-phenotype correlation and identification of two novel SRD5A2 mutations in 33 Chinese patients with hypospadias. Steroids. 2017; 125: 61–66.
Tack LJW, Praet M, Van Dorpe J, Haid B, Buelens S, Hoebeke P, Van Laecke E, Cools M, Spinoit AF. Androgen receptor expression in preputial dartos tissue correlates with physiological androgen exposure in congenital malformations of the penis and in controls. J Pediatr Urol. 2019.
Shiota M, Yokomizo A, Naito S. Increased androgen receptor transcription: A cause of castration-resistant prostate cancer and a possible therapeutic target. J Mol Endocrinol. 2011.
El Safoury O, Rashid L, Ibrahim M. A study of androgen and estrogen receptors α, β in skin tags. Indian J Dermatol. 2010; 55: 20–24.
Qiao L, Rodriguez E, Weiss DA, Ferretti M, Risbridger G, Cunha GR, Baskin LS. Expression of estrogen receptor alpha and beta is decreased in hypospadias. J Urol. 2012; 187: 1427–1433.
Cunha GR, Sinclair A, Cao M, Baskin LS. Development of the human prepuce and its innervation. Differentiation. 2020; 111: 22–40.
Lindström LS, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, Hatschek T, Skoog L, Bergh J. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012; 30: 2601–2608.
Liu G, Liu X, Shen J, Sinclair A, Baskin L, Cunha GR. Contrasting mechanisms of penile urethral formation in mouse and human. Differentiation. 2018; 101: 46–64.
Li Y, Sinclair A, Cao M, Shen J, Choudhry S, Botta S, Cunha G, Baskin L. Canalization of the urethral plate precedes fusion of the urethral folds during male penile urethral development: The double zipper hypothesis. J Urol. 2015; 193: 1353–1360.
Yiee JH, Baskin LS. Environmental Factors in Genitourinary Development. J Urol. 2010; 184: 34–41.
Botta S, Cunha GR, Baskin LS. Do endocrine disruptors cause hypospadias? Transl Androl Urol. 2014; 3: 330–339.
Baskin L, Cao M, Sinclair A, Li Y, Overland M, Isaacson D, Cunha GR. Androgen and estrogen receptor expression in the developing human penis and clitoris. Differentiation. 2020; 111: 41–59.