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Center for the Study & Treatment of
Hypospadias
Mission Statement
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Clinical excellence in the treatment of hypospadias |
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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.
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Images of the nerve supply to the normal female,
normal male, and hypospadias. |
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 |
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Baskin, L.S.: Hypospadias: a critical analysis of cosmetic
outcomes using photography. British Journal of Urology,
International 2001; 87 534-537. |
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Baskin, L.S., Editorial comment. Urology, 2002. 59(4):
p. 586-7.
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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.
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Baskin, L.S., Anatomical studies of the female genitalia:
surgical reconstructive implications. J Pediatr Endocrinol
Metab, 2004. 17(4): p. 581-7.
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Baskin, L.S. and M.B. Ebbers, Hypospadias: anatomy,
etiology, and technique. J Pediatr Surg, 2006. 41(3): p.
463-72.
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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.
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Baskin, L.S., Can we prevent hypospadias? J Pediatr
Urol, 2007. 3(6): p. 420-5.
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Baskin, L.S., Can we prevent hypospadias? Fertil
Steril, 2008. 89(2 Suppl): p. e39.
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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.
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Wang, M.H. and L.S. Baskin, Endocrine disruptors,
genital development, and hypospadias. J Androl, 2008. 29(5):
p. 499-505. |
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Research References |
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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. |
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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.
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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.
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Yucel, S. and L.S. Baskin, Neuroanatomy of the male
urethra and perineum. BJU Int, 2003. 92(6): p. 624-30. |
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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. |
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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. |
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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. |
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Cunha, G.R. and L. Baskin, Development of the penile
urethra. Adv Exp Med Biol, 2004. 545: p. 87-102. |
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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. |
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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. |
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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. |
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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. |
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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.
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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Li, J., E. Willingham, and L.S. Baskin, Gene expression
profiles in mouse urethral development. BJU Int, 2006.
98(4): p. 880-5. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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. |
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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
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