Expression of estrogen receptor alpha and beta is decreased in hypospadias, "Beyond the Abstract," by Laurence Baskin, MD

BERKELEY, CA (UroToday.com) - Hypospadias is the second most common urogenital anomaly in children. The etiology remains unknown with a general consensus that both genetic susceptibility and environmental exposure are at play as the cause of this anomaly.[1,2]

While Alford Jost’s theory of external genitalia development focuses exclusively on the presence or absence of androgen action is undoubtedly correct, it neglects that possibility of other endocrine mechanisms such as estrogen action relegating female development as a default pathway.[3] Recent murine work has emphasized that normal female sex differentiation of the external genitalia is a uniquely active process and not simply a default pathway associated with the absence of androgens.[4,5] The presence of estrogen receptor alpha (ERα), estrogen receptor beta (ERβ) and aromatase in the developing external genitalia in the mouse as well as estrogen ligands in serum when sex differentiation is occurring emphasizes the potential importance of estrogenic mechanisms during external genitalia development.[6] In addition, signalling via androgen receptor (AR) and ER can be antagonistic at the cellular, tissue, and systemic levels, and thus the balance between AR and ER signalling may be critical in normal male and female development of the external genitalia.

In this manuscript, we have extended our knowledge of the role of estrogen in patients with hypospadias by first documenting the presence of the ERα and ERβ receptor in the preputial tissue of patients with hypospadias and in the urethral, corporal cavernosal, and surrounding tissue of normal human fetal tissue. For estrogen to be an important ligand during normal and abnormal penile development it certainly has to be expressed in the affected tissue. i.e., the penis and foreskin. Indeed we found a difference in ERα and ERβ receptor expression and location in the foreskin of patients with hypospadias compared to controls. (See Figure 1) These findings are consistent with estrogenic effects having a role in normal penile development and the etiology of hypospadias.

Based on this work, we are now pursuing experiments to look at potential environmental agents whose mechanism of action is to disrupt and/or impede the estrogen receptor.

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Figure 1. (Click on thumbnail to enlarge)

 

References:

  1. Wang, M. H. and L. S. Baskin (2008). "Endocrine disruptors, genital development, and hypospadias." J Androl 29(5): 499-505.
  2. Kalfa, N., P. Philibert, et al. (2011). "Hypospadias: interactions between environment and genetics." Molecular and Cellular Endocrinology 335(2): 89-95.
  3. Jost, A. (1953). "Problems of fetal endocrinology: the gonadal and hypophyseal hormones." Recent Progress in Hormone Research 8: 379-418.
  4. Yang, J. H., J. Menshenina, et al. (2010). "Morphology of mouse external genitalia: implications for a role of estrogen in sexual dimorphism of the mouse genital tubercle." J Urol 184(4 Suppl): 1604-1609.
  5. Rodriguez, E., Jr., D. A. Weiss, et al. (2011). "New insights on the morphology of adult mouse penis." Biology of reproduction 85(6): 1216-1221.
  6. Agras, K., E. Willingham, et al. (2007). "Estrogen receptor-alpha and beta are differentially distributed, expressed and activated in the fetal genital tubercle." J Urol 177(6): 2386-2392.

Written by:
Laurence Baskin, MD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

*UCSF Children's Hospital
Chief Pediatric Urology
Professor of Urology and Pediatrics
400 Parnassus Ave.
San Francisco, CA 94143


 

Expression of estrogen receptor alpha and beta is decreased in hypospadias - Abstract

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