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Department of Urology

Center for the Study & Treatment of Hypospadias

Mission Statement

Clinical excellence in the treatment of hypospadias

Research leaders in the study of hypospadias

The program is composed of an integrated team of pediatric urologists, endocrinologists, epidemiologists, geneticists, pathologists and basic scientists.

 

Clinical Overview

Introduction

Hypospadias is a congenital defect of the penis resulting in incomplete development of the penile urethra. The abnormal urethral opening may be any place along the shaft of the penis or may be on the scrotum or perineum. As the position of the urethral meatus becomes more proximal, ventral shortening and curvature during penile erection are more likely. In patients with severe hypospadias, the genitalia may look ambiguous at birth, resulting in emotional and psychological stress for parents in that the gender assignment of their baby immediately comes into question. Left uncorrected, patients with hypospadias may need to sit down to void and tend to shun intimate relationships because of fears related to normal sexuality.

Incidence

Hypospadias is one of the most common congenital anomalies, occurring in approximately one in 250 to one in 300 live births. In Europe, the prevalence of hypospadias in the 1970's and 1980's has been increasing with no obvious explanation. In the United States, data from two birth defects surveillance systems has shown an unexplained doubling in the incidence of hypospadias. (Paulozzi, Erickson et al. 1997) A U.S. study from the Centers for Disease Control is particularly intriguing because it shows that the incidence of severe hypospadias, not just mild forms, is increasing. This implies that the increase in hypospadias is not due to an increase in surveillance or reporting.

Treatment

The only treatment for hypospadias is surgical repair of the anatomical defect. (Baskin, Duckett et al. 1994; Baskin, Duckett et al. 1996; Duckett and Baskin 1996; Baskin and Duckett 1998) In experienced hands, the surgery is typically performed as an outpatient procedure, with 80-90% of children requiring one operation. Occasionally extensive surgery is necessary, and in some cases multiple operations leave the unfortunate child with a suboptimal result, the patient then being classified as a "hypospadias cripple." (Baskin and Duckett 1995) The health care dollars spent on hypospadias surgery are significant when you consider hospital cost, physician fees and time spent away from work caring for these young patients. The morbidity of surgery is also important in that patients with severe hypospadias will require a urethral stent or catheter in the postoperative period. In 1996, approximately 2 million males were born in the United States, which translates to approximately 7,000 new cases of hypospadias based on an incidence of one in 300.

 

Basic and Translational Research Center

Etiology

As the etiology, or cause, of hypospadias is unknown, the goal of the Hypospadias Research Center is to define the etiology of hypospadias and to translate basic science findings into prevention or new treatment options. Accomplishing this goal requires the expertise and collaboration of scientists from multiple disciplines. The center's research focuses on the hypothesis that genetic susceptibility along with environmental endocrine disruptors causes hypospadias. The hypothesis is being tested with animal models and the genetic analysis of patients and families with hypospadias.

Genetic Susceptibility

To examine this hypothesis, we first tested for evidence of genetic susceptibility in patients with hypospadias versus age-matched controls. Using gene microarrays we screened genes on a global scale and compared the expression of 22,000 genes from the two groups. A number of differences were found in the gene expression of each group. Gene differences were found in the CYR61, CTGF, ATF3, and GADD45β groups of genes, all of which are known either to respond to estrogen or to interact with an estrogen receptor. Further work revealed that ATF3, activating transcription factor 3, is unregulated in the skin of patients with hypospadias as compared to controls. ATF3 is localized at a protein level in the skin of patients with hypospadias, and was also expressed in the urethral plate of a fetus with hypospadias compared to normal fetal controls. This is consistent with ATF3 being an important gene in the regulation of normal penile and urethral development.

The estrogen responsive genes CYR61 and CTGF are upregulated, or increased in patents with hypospadias. These genes belong to the CCCN gene family, which increase with estrogen stimulation. CYR61 is known to function in matrix remodeling through the activation of metalloproteinases during wound healing. Upregulation of this gene in hypospadias may play a role in causing abnormal urethral seam development. CTGF is known to be part of the TGFβ singly pathway and is regulated by steroid hormones such as estrogen. Also, upregulation of CTGF during hypospadias may be a function of TGFβ and cellular remodeling. Interestingly, genes that might be expected to elevate hypospadias from previous research, such as P38 and EphrinB2 were not present in statistically significant numbers.

Endocrine Disruptors

The second part of the hypothesis is that patients with a genetic susceptibility for Hypospadias will develop Hypospadias only if an environmental exposure triggers the disease during urethral development. Exposure must occur prior to pregnancy or within the first sixteen weeks of fetal development, when the urethra develops. A number of epidemiologic studies throughout the world, and specifically in industrialized countries, suggest that environmental exposures increase the incidence of hypospadias and other birth defects. A retrospective study in the United Kingdom compared vegetarian mothers to mothers on regular diets. Vegetarian mothers have a higher chance of eating more vegetables, which may contain phytoestrogens from fertilizers. Thus some vegetarians may be exposed to an increase level of phytoestrogens in their diet. Hypospadias was twice as common in the progeny of the vegetarian mothers who were exposed to higher levels of estrogenic substances in their diet. This is consistent with the hypothesize that the affected progeny had a genetic susceptibility combined with a triggering environmental exposure, in this case estrogen during a critical time of urethral development.

Animal Models

Using mouse models we described normal urethra development by performing histological studies, and creating both a three dimensional reconstruction and a plastic anatomical cast of the male and female urethra. Using the normal as reference, hypospadias in the mouse was then defined as disruption of the urethral seam with clear anatomical differences between the male in comparison to the female, emphasizing that the hypospadiac mice had a different phenotype than the normal male or female. Using these animal models we studied endocrine disruptors that may cause hypospaidas. Our research demonstrated that exposure to various endocrine disruptor, including 17α estradiol, progesterone, the pesticide vinclozilin, and the antihistamine loratadine, in normally occurring levels cause hypospadias in our animal.

Conclusion

Based on epidemiologic human and experimental animal data we conclude that a number of genes are elevated in hypospadias. Genetic susceptibility combined with exposure to endocrine disruptors during the first trimester when genital development occurs may explain the cause of hypospadias for the majority of patients. We believe that the strategy to prevent hypospadias should focus on identifying genetic susceptibility prior to pregnancy, and to identify and eliminate exposure to endocrine disruptors that effect urethral development.

 

Clinical References

Baskin, L.S.: Hypospadias: a critical analysis of cosmetic outcomes using photography. British Journal of Urology, International 2001; 87 534-537.

Baskin, L.S., Editorial comment. Urology, 2002. 59(4): p. 586-7.

Mingin, G. and L.S. Baskin, Management of chordee in children and young adults. Urol Clin North Am, 2002. 29(2): p. 277-84, v.

Baskin, L.S., Anatomical studies of the female genitalia: surgical reconstructive implications. J Pediatr Endocrinol Metab, 2004. 17(4): p. 581-7.

Baskin, L.S. and M.B. Ebbers, Hypospadias: anatomy, etiology, and technique. J Pediatr Surg, 2006. 41(3): p. 463-72.

Snodgrass, W.T., M.A. Koyle, L.S. Baskin, and A.A. Caldamone, Foreskin preservation in penile surgery. J Urol, 2006. 176(2): p. 711-4.

Baskin, L.S., Can we prevent hypospadias? J Pediatr Urol, 2007. 3(6): p. 420-5.

Baskin, L.S., Can we prevent hypospadias? Fertil Steril, 2008. 89(2 Suppl): p. e39.

Hsieh, M.H., B.N. Breyer, M.L. Eisenberg, and L.S. Baskin, Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption. Curr Urol Rep, 2008. 9(2): p. 137-42.

Wang, M.H. and L.S. Baskin, Endocrine disruptors, genital development, and hypospadias. J Androl, 2008. 29(5): p. 499-505.

Yang, J.H., Baskin, L.S., and Disandro, M. (2009) Gender Identity in Disorders of Sex Development: Review Article. Urology 75:153-159. Epub 2009 Nov 14.

Yiee, J.H., Baskin, L.S. Environmental factors in genitourinary development. J Urol. 2010 Jul;184(1):34-41. Epub 2010 May 15. Review. PMID: 20478588 [PubMed - indexed for MEDLINE]

Kalfa, N., Sultan, C., Baskin, L.S. Hypospadias: etiology and current research.  Urol Clin North Am. 2010 May;37(2):159-66. Review.

Tasian, G.E., Zaid, H., Cabana, M.D., Baskin, L.S. Proximal hypospadias and risk of acquired cryptorchidism. J Urol. 2010 Aug;184(2):715-20.

Wilson, J.M., Arnhym, A., Champeau, A., Ebbers, M., Coakley, F., Baskin, L.S.  Complete androgen insensitivity syndrome: An anatomic evaluation and sexual function questionnaire pilot study.  J Pediatr Urol. 2010 Aug 16.

Speiser, P.W., Azziz, R., Baskin, L.S., Ghizzoni, L, Hensle, T.W., Merke, D.P., Meyer-Bahlburg, H.F., Miller, W.L., Montori, V.M., Oberfield, S.E., Ritzen, M., White, P.C. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline.  J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60.

van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, Renkema KY, Bongers EM, Vermeulen SH, Kiemeney LA, Veltman JA, Arias-Vásquez A, Zhang X, Markljung E, Qiao L, Baskin LS, Nordenskjöld A, Roeleveld N, Franke B, Knoers NV. Common variants in DGKK are strongly associated with risk of hypospadias.. Nat Genet. 2011 Jan;43(1):48-50. Epub 2010 Nov 28.  PMID: 21113153

Auchus RJ, Witchel SF, Leight KR, Aisenberg J, Azziz R, Bachega TA, Baker LA, Baratz AB, Baskin LS, Berenbaum SA, Breault DT, Cerame BI, Conway GS, Eugster EA, Fracassa S, Gearhart JP, Geffner ME, Harris KB, Hurwitz RS, Katz AL, Kalro BN, Lee PA, Alger Lin G, Loechner KJ, Marshall I, Merke DP, Migeon CJ, Miller WL, Nenadovich TL, Oberfield SE, Pass KA, Poppas DP, Lloyd-Puryear MA, Quigley CA, Riepe FG, Rink RC, Rivkees SA, Sandberg DE, Schaeffer TL, Schlussel RN, Schneck FX, Seely EW, Snyder D, Speiser PW, Therrell BL, Vanryzin C, Vogiatzi MG, Wajnrajch MP, White PC, Zuckerman AE.  Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative.  Int J Pediatr Endocrinol.  2010;2010:275213. Epub 2011 Jan 10. PMID: 21274448

Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hsieh MH, Eisenberg ML, Hittelman AB, Wilson JM, Tasian GE, Baskin LS. Hum Reprod. 2012 Mar 20. [Epub ahead of print] PMID: 22434852

Research References

Baskin, LS, Erol, A, Jegatheeson, P, Lee, Y-W, Liu W-H, Cunha, JR: Urethral seam formation in hypospadias. Cell Tissue and research, 305:379-387, 2001.

Kim, K.S., W. Liu, G.R. Cunha, D.W. Russell, H. Huang, E. Shapiro, and L.S. Baskin, Expression of the androgen receptor and 5 alpha-reductase type 2 in the developing human fetal penis and urethra. Cell Tissue Res, 2002. 307(2): p. 145-53.

Cunha, G.R., Y. Wang, N.J. Place, W. Liu, L. Baskin, and S.E. Glickman, Urogenital system of the spotted hyena (Crocuta crocuta Erxleben): A functional histological study. J Morphol, 2003. 256(2): p. 205-18.

Yucel, S. and L.S. Baskin, Neuroanatomy of the male urethra and perineum. BJU Int, 2003. 92(6): p. 624-30.

Yucel, S., A.G. Cavalcanti, Z. Wang, and L.S. Baskin, The impact of prenatal androgens on vaginal and urogenital sinus development in the female mouse. J Urol, 2003. 170(4 Pt 1): p. 1432-6.

Baskin, L.S., W. Liu, J. Bastacky, and S. Yucel, Anatomical studies of the mouse genital tubercle. Adv Exp Med Biol, 2004. 545: p. 103-21.

Cavalcanti, A.G., S. Yucel, D.Y. Deng, J.W. McAninch, and L.S. Baskin, The distribution of neuronal and inducible nitric oxide synthase in urethral stricture formation. J Urol, 2004. 171(5): p. 1943-7.

Cunha, G.R. and L. Baskin, Development of the penile urethra. Adv Exp Med Biol, 2004. 545: p. 87-102.

Holmes, N.M., W.L. Miller, and L.S. Baskin, Lack of defects in androgen production in children with hypospadias. J Clin Endocrinol Metab, 2004. 89(6): p. 2811-6.

Kim, K.S., C.R. Torres, Jr., S. Yucel, K. Raimondo, G.R. Cunha, and L.S. Baskin, Induction of hypospadias in a murine model by maternal exposure to synthetic estrogens. Environ Res, 2004. 94(3): p. 267-75.

Yucel, S. and L.S. Baskin, An anatomical description of the male and female urethral sphincter complex. J Urol, 2004. 171(5): p. 1890-7.

Yucel, S., A. De Souza, Jr., and L.S. Baskin, Neuroanatomy of the human female lower urogenital tract. J Urol, 2004. 172(1): p. 191-5.

Yucel, S., A. Desouza, and L.S. Baskin, In utero prednisone exposure affects genital development. J Urol, 2004. 172(4 Pt 2): p. 1725-30; discussion 1730.

Yucel, S., W. Liu, D. Cordero, A. Donjacour, G. Cunha, and L.S. Baskin, Anatomical studies of the fibroblast growth factor-10 mutant, Sonic Hedge Hog mutant and androgen receptor mutant mouse genital tubercle. Adv Exp Med Biol, 2004. 545: p. 123-48.

Cunha, G.R., N.J. Place, L. Baskin, A. Conley, M. Weldele, T.J. Cunha, Y.Z. Wang, M. Cao, and S.E. Glickman, The ontogeny of the urogenital system of the spotted hyena (Crocuta crocuta Erxleben). Biol Reprod, 2005. 73(3): p. 554-64.

Liu, B., Z. Wang, G. Lin, K. Agras, M. Ebbers, E. Willingham, and L.S. Baskin, Activating transcription factor 3 is up-regulated in patients with hypospadias. Pediatr Res, 2005. 58(6): p. 1280-3.

Agras, K., E. Willingham, B. Liu, and L.S. Baskin, Ontogeny of androgen receptor and disruption of its mRNA expression by exogenous estrogens during morphogenesis of the genital tubercle. J Urol, 2006. 176(4 Pt 2): p. 1883-8.

Baskin, L.S., S. Yucel, G.R. Cunha, S.E. Glickman, and N.J. Place, A neuroanatomical comparison of humans and spotted hyena, a natural animal model for common urogenital sinus: clinical reflections on feminizing genitoplasty. J Urol, 2006. 175(1): p. 276-83.

Blaschko, S.D., E.J. Willingham, and L.S. Baskin, Embryonic exposure to low-dose 17beta-estradiol decreases fetal mass sex specifically in male mice and does not cause hypospadias. J Investig Med, 2006. 54(8): p. 490-5.

Buckley, J., E. Willingham, K. Agras, and L.S. Baskin, Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice. Environ Health, 2006. 5: p. 4.

Li, J., E. Willingham, and L.S. Baskin, Gene expression profiles in mouse urethral development. BJU Int, 2006. 98(4): p. 880-5.

Liu, B., K. Agras, E. Willingham, M.L. Vilela, and L.S. Baskin, Activating transcription factor 3 is estrogen-responsive in utero and upregulated during sexual differentiation. Horm Res, 2006. 65(5): p. 217-22.

Willingham, E., K. Agras, A.E. de Souza, Jr., R. Konijeti, S. Yucel, W. Rickie, G.R. Cunha, and L.S. Baskin, Steroid receptors and mammalian penile development: an unexpected role for progesterone receptor? J Urol, 2006. 176(2): p. 728-33.

Willingham, E., K. Agras, M. Vilela, and L.S. Baskin, Loratadine exerts estrogen-like effects and disrupts penile development in the mouse. J Urol, 2006. 175(2): p. 723-6.

Agras, K., Y. Shiroyanagi, and L.S. Baskin, Progesterone receptors in the developing genital tubercle: implications for the endocrine disruptor hypothesis as the etiology of hypospadias. J Urol, 2007. 178(2): p. 722-7.

Agras, K., E. Willingham, Y. Shiroyanagi, P. Minasi, and L.S. Baskin, Estrogen Receptor-alpha and beta are Differentially Distributed, Expressed and Activated in the Fetal Genital Tubercle. J Urol, 2007. 177(6): p. 2386-2392.

Cavalcanti, A.G., W.S. Costa, L.S. Baskin, J.A. McAninch, and F.J. Sampaio, A morphometric analysis of bulbar urethral strictures. BJU Int, 2007. 100(2): p. 397-402.

Hsieh, M.H., E.C. Grantham, B. Liu, R. Macapagal, E. Willingham, and L.S. Baskin, In utero exposure to benzophenone-2 causes hypospadias through an estrogen receptor dependent mechanism. J Urol, 2007. 178(4 Pt 2): p. 1637-42.

Liu, B., G. Lin, E. Willingham, H. Ning, C.S. Lin, T.F. Lue, and L.S. Baskin, Estradiol upregulates activating transcription factor 3, a candidate gene in the etiology of hypospadias. Pediatr Dev Pathol, 2007. 10(6): p. 446-54.

Vilela, M.L., E. Willingham, J. Buckley, B.C. Liu, K. Agras, Y. Shiroyanagi, and L.S. Baskin, Endocrine disruptors and hypospadias: role of genistein and the fungicide vinclozolin. Urology, 2007. 70(3): p. 618-21.

Wang, Z., B.C. Liu, G.T. Lin, C.S. Lin, T.F. Lue, E. Willingham, and L.S. Baskin, Up-regulation of estrogen responsive genes in hypospadias: microarray analysis. J Urol, 2007. 177(5): p. 1939-46.

Willingham, E. and L.S. Baskin, Candidate genes and their response to environmental agents in the etiology of hypospadias. Nat Clin Pract Urol, 2007. 4(5): p. 270-9.

Yong, W., Z. Yang, S. Periyasamy, H. Chen, S. Yucel, W. Li, L.Y. Lin, I.M. Wolf, M.J. Cohn, L.S. Baskin, E.R. Sanchez, and W. Shou, Essential role for Co-chaperone Fkbp52 but not Fkbp51 in androgen receptor-mediated signaling and physiology. J Biol Chem, 2007. 282(7): p. 5026-36.

Kalfa, N., B. Liu, M. Cao, M. Vilella, M. Hsieh, and L.S. Baskin, 3-dimensional neuroanatomy of the human fetal pelvis: anatomical support for partial urogenital mobilization in the treatment of urogenital sinus. J Urol, 2008. 180(4 Suppl): p. 1709-14; discussion 1714-5.

Kalfa, N., B. Liu, O. Klein, M.H. Wang, M. Cao, and L.S. Baskin, Genomic variants of ATF3 in patients with hypospadias. J Urol, 2008. 180(5): p. 2183-8; discussion 2188.

Kalfa, N., B. Liu, K. Ophir, F. Audran, M.H. Wang, C. Mei, C. Sultan, and L.S. Baskin, Mutations of CXorf6 are associated with a range of severities of hypospadias. Eur J Endocrinol, 2008. 159(4): p. 453-8.

Ma, L.M., Wang, Z., Wang, H., Li, R.S., Zhou, J., Liu, B.C., and Baskin, L.S. (2009) Estrogen effects on fetal penile and urethral development in organotypic mouse genital tubercle culture. J Urol 182:2511-2517.

Yiee, J.H., Baskin, L.S. Penile embryology and anatomy.  ScientificWorldJournal. 2010 Jun 29;10:1174-9. Review.

Yang, J.H, Menshenina, J., Cunha, G.R., Place, N., Baskin, L.S. Morphology of Mouse External Genitalia: Implications for a Role of Estrogen in Sexual Dimorphism of the Mouse Genital Tubercle.
J Urol. 2010 Aug 19.

Rodriguez E Jr, Weiss DA, Yang JH, Menshenina J, Ferretti M, Cunha TJ, Barcellos D, Chan LY, Risbridger G, Cunha GR, Baskin LS.  New Insights on the Morphology of Adult Mouse Penis.  Biol Reprod. 2011 Sep 14. PMID:21918128

Weiss DA, Rodriguez E Jr, Cunha T, Barcellos D, Chan LY, Risbridger G, Baskin L, Cunha G. Morphology of the external genitalia of the adult male and female mice as an endpoint of sex differentiation.  Mol Cell Endocrinol. 2011 Aug 27. PMID: 21893161

Qiao L, Tasian GE, Zhang H, Cunha GR, Baskin L.  ZEB1 is estrogen responsive in vitro in human foreskin cells and is over expressed in penile skin in patients with severe hypospadias. J Urol. 2011 May;185(5):1888-93. Epub 2011 Mar 21. PMID: 21421232

Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells.
Qiao L, Tasian GE, Zhang H, Cao M, Ferretti M, Cunha GR, Baskin LS.
Pediatr Res. 2012 Apr;71(4-1):393-398. doi: 10.1038/pr.2011.49. Epub 2012 Jan 6. PMID: 22391641

Expression of Estrogen Receptor Alpha and Beta is Decreased in Hypospadias.
Qiao L, Rodriguez E Jr, Weiss DA, Ferretti M, Risbridger G, Cunha GR, Baskin LS.
J Urol. 2012 Apr;187(4):1427-33. Epub 2012 Feb 16. PMID: 22341273

Polymorphisms of MAMLD1 gene in hypospadias. Kalfa N, Cassorla F, Audran F, Oulad Abdennabi I, Philibert P, Béroud C, Guys JM, Reynaud R, Alessandrini P, Wagner K, Bréaud J, Valla JS, Morisson Lacombe G, Daures JP, Baskin L, Fukami M, Ogata T, Sultan C. J Pediatr Urol. 2011 Dec;7(6):585-91. Epub 2011 Oct 24.
PMID: 22030455

 

 

Faculty

Laurence Baskin, MD
Shweta Choudhry, PhD
Hillary Copp, MD, MS
Michael DiSandro, MD

Appointments & Location

UCSF Medical Center, Parnassus Campus
400 Parnassus Avenue, Suite A-610
San Francisco, CA 94143-0330

Contact Number

Clinical Program
Crede Ambulatory Care Center
400 Parnassus Avenue, Suite A-610
For appointments, please telephone 415/353-2200

Research Program
Health Sciences West, 1434

Patient Handouts

Visit our Patient Guides to Urological Treatments section to download Patient Handouts.

Laboratory

Baskin Lab