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J Pediatr Genet
DOI: 10.1055/s-0044-1787670
Original Article

Understanding the Endocrine and Molecular Signaling Cascade Regulation Pathways in Children with Hypospadias

Raghunath V Bangalore
1   Department of Pediatric Surgery, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India
,
Suramya Asthana
2   Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India
,
Reshma V. R.
2   Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India
,
Deepak Kumar Saini
3   Department of Molecular Reproduction, Development and Genetics, Associate Faculty, Center for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India
,
Anand Alladi
1   Department of Pediatric Surgery, Bangalore Medical College and Research Institute, Bengaluru, Karnataka, India
› Author Affiliations Funding This work was supported by Rajiv Gandhi University of Health Sciences (RGHUS grant no.: 17C006B), granted to Dr. Deepak K. Saini and Dr. BV Raghunath.
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Abstract

Hypospadias (HS) is a congenital defect that occurs due to defective androgenization. It is characterized by the aberrant location of the urinary meatus on the ventral aspect of the penis with various degrees of severity. The molecular mechanisms and genetic associations underlying the condition remain largely unknown. Existing literature revolves around surgical and medical management of the condition. Human chorionic gonadotropin pretreatment in HS is proposed to decrease the severity of the anomaly and improve the clinical outcome of surgery. The underlying mechanisms that drive these outcomes have not been explored. Few studies have explored the endocrine signaling and pathways which lead to the development of the condition. Hence, a prospective study was conducted to understand the same. Eighteen children with mid or proximal penile HS were included as cases, and nine children undergoing circumcision for phimosis (nonpathological) were included as controls. Serum samples from all these children and preputial skin samples taken during surgery were used in the analysis. The hormonal milieu was normal in all children in our cohort. A comparison of previously reported genes with our cohort sequencing revealed changes in several major pathways involved in cell proliferation and differentiation, cell signaling, angiogenesis, and immune response pathways. Compared with healthy controls, HS subjects had 152 differentially expressed genes. Of these, 93 genes were up-regulated, and 59 genes were found to be significantly down-regulated. The gene expression evaluation also showed changes in expression patterns in inflammatory genes and link RNAs, unlike previously reported genes.

Keywords

hypospadias - genetics - molecular signaling - testosterone - di-hydro testosterone

Data Availability

The sequencing data are available on request, please contact the corresponding authors.




Publication History

Received: 23 March 2023

Accepted: 13 May 2024

Article published online:
24 June 2024

© 2024. Thieme. All rights reserved.

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  • References

  • 1 Koff SA, Jayanthi VR. Preoperative treatment with human chorionic gonadotropin in infancy decreases the severity of proximal hypospadias and chordee. J Urol 1999; 162 (04) 1435-1439
    CrossrefPubMedGoogle Scholar
  • 2 Bhat A, Mandal AK. Acute postoperative complications of hypospadias repair. Indian J Urol 2008; 24 (02) 241-248
    CrossrefPubMedGoogle Scholar
  • 3 Yucel S, Guntekin E, Kukul E. et al. Comparison of hypospadiac and normal preputial vascular anatomy. J Urol 2004; 172 (5 Pt 1): 1973-1976 , discussion 1976
    CrossrefPubMedGoogle Scholar
  • 4 Kraft KH, Shukla AR, Canning DA. Hypospadias. Urol Clin North Am 2010; 37 (02) 167-181
    CrossrefPubMedGoogle Scholar
  • 5 Radojicic ZI, Perovic SV. Classification of prepuce in hypospadias according to morphological abnormalities and their impact on hypospadias repair. J Urol 2004; 172 (01) 301-304
    CrossrefPubMedGoogle Scholar
  • 6 Nazir Z, Masood R, Rehman R. Sensory innervation of normal and hypospadiac prepuce: possible implications in hypospadiology. Pediatr Surg Int 2004; 20 (08) 623-627
    CrossrefPubMedGoogle Scholar
  • 7 Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A. Androgen insensitivity syndrome: clinical features and molecular defects. Hormones (Athens) 2008; 7 (03) 217-229
    CrossrefPubMedGoogle Scholar
  • 8 Husmann DA. Microphallic hypospadias—the use of human chorionic gonadotropin and testosterone before surgical repair. J Urol 1999; 162 (04) 1440-1441
    CrossrefPubMedGoogle Scholar
  • 9 Chao M, Zhang Y, Liang C. Impact of preoperative hormonal stimulation on postoperative complication rates after hypospadias repair: a meta-analysis. Minerva Urol Nefrol 2017; 69 (03) 253-261
    PubMedGoogle Scholar
  • 10 Chen Y, Kuroki Y, Shaw G. et al. Androgen and oestrogen affect the expression of long non-coding RNAs during phallus development in a marsupial. Noncoding RNA 2018; 5 (01) 3
    PubMedGoogle Scholar
  • 11 Yang Q, Qu WY, Yang L, Wang K, Tu HY, Wang J. Literature on the aetiology of hypospadias in the last 5 years: molecular mechanism and environmental factors. Andrologia 2014; 46 (06) 583-591
    CrossrefPubMedGoogle Scholar
  • 12 Silver RI. Endocrine abnormalities in boys with hypospadias. Adv Exp Med Biol 2004; 545: 45-72
    CrossrefPubMedGoogle Scholar
  • 13 Utsch B, Albers N, Ludwig M. Genetic and molecular aspects of hypospadias. Eur J Pediatr Surg 2004; 14 (05) 297-302
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Walsh PC, Curry N, Mills RC, Siiteri PK. Plasma androgen response to hCG stimulation in prepubertal boys with hypospadias and cryptorchidism. J Clin Endocrinol Metab 1976; 42 (01) 52-59
    CrossrefPubMedGoogle Scholar
  • 15 Boehmer AL, Nijman RJ, Lammers BA. et al. Etiological studies of severe or familial hypospadias. J Urol 2001; 165 (04) 1246-1254
    CrossrefPubMedGoogle Scholar
  • 16 Feyaerts A, Forest MG, Morel Y. et al. Endocrine screening in 32 consecutive patients with hypospadias. J Urol 2002; 168 (02) 720-725 , discussion 725
    CrossrefPubMedGoogle Scholar
  • 17 Hiort O, Willenbring H, Albers N. et al. Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5 alpha-reductase deficiency. Eur J Pediatr 1996; 155 (06) 445-451
    CrossrefPubMedGoogle Scholar
  • 18 Silver RI, Russell DW. 5alpha-reductase type 2 mutations are present in some boys with isolated hypospadias. J Urol 1999; 162 (3 Pt 2): 1142-1145
    CrossrefPubMedGoogle Scholar
  • 19 Zhou L, Mei H, Liu T, Guang W. [Identification of mutations of SRD5A2 gene and SRY gene in patients with hypospadias]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 1999; 16 (05) 311-314
    PubMedGoogle Scholar
  • 20 Chen Z, Lin X, Wang Y, Xie H, Chen F. Dysregulated expression of androgen metabolism genes and genetic analysis in hypospadias. Mol Genet Genomic Med 2020; 8 (08) e1346
    CrossrefPubMedGoogle Scholar
  • 21 Balaji DR, Reddy G, Babu R. et al. Androgen receptor expression in hypospadias. J Indian Assoc Pediatr Surg 2020; 25 (01) 6-9
    CrossrefPubMedGoogle Scholar
  • 22 Gearhart JP, Linhard HR, Berkovitz GD, Jeffs RD, Brown TR. Androgen receptor levels and 5 alpha-reductase activities in preputial skin and chordee tissue of boys with isolated hypospadias. J Urol 1988; 140 (5 Pt 2): 1243-1246
    CrossrefPubMedGoogle Scholar
  • 23 Terakawa T, Shima H, Yabumoto H, Koyama K, Ikoma F. Androgen receptor levels in patients with isolated hypospadias. Acta Endocrinol (Copenh) 1990; 123 (01) 24-29
    PubMedGoogle Scholar
  • 24 Karabulut R, Turkyilmaz Z, Sonmez K. et al. Twenty-four genes are upregulated in patients with hypospadias. Balkan J Med Genet 2013; 16 (02) 39-44
    CrossrefPubMedGoogle Scholar
  • 25 Fernandez PM, Brunel F, Jimenez MA, Saez JM, Cereghini S, Zakin MM. Nuclear receptors Nor1 and NGFI-B/Nur77 play similar, albeit distinct, roles in the hypothalamo-pituitary-adrenal axis. Endocrinology 2000; 141 (07) 2392-2400
    CrossrefPubMedGoogle Scholar