Androgen-independent events in penile development in humans and animals
Laurence Baskin, MD1, Mei Cao, MD1, Adriane Sinclair, PhD1, Steve Glickman, PhD2, Paul Cooke, PhD3, Gerald Cunha, PhD1.
1UCSF, San Francisco, CA, USA, 2UC Berkeley, Berkeley, CA, USA, 3University of Florida, Gainesville, FL, USA.
Background: The common view of penile development is that it is androgen-dependent, based first and foremost on the fact that the genital tubercle forms a penis in males and a clitoris in females. However, critical examination of the complex processes involved in human penile development reveals that many individual steps in development of the genital tubercle are common to both males and female, and thus can be interpreted as androgen-independent. For certain developmental events this conclusion is bolstered by observations in androgen-insensitive patients.
Methods: Gross and microscopic photography, scanning electron microscopy, optical projection tomography, light sheet microscopy and immunohistochemistry where used to characterize the ontogeny of the external genitalia of human, mouse, spotted hyena and mole. In total over 150 human fetal penises and clitori between 7 and 24 gestation were analyzed. Sex was verified by PCR. Normal and mutant mice, Talpidae moles (ovo-testicle) and the profoundly masculinized female external genitalia of spotted hyenas that have a penniform clitoris and urogenital sinus were examined for gross anatomy and histology.
Results: Events in genital tubercle development that are common to human males and females included: formation of (a) the genital tubercle, (b) the urethral plate, (c) the urethral groove, (d) the glans, (e) the prepuce and (f) the corporal body (Table). For humans 6 of 13 individual developmental steps in penile development were interpreted as androgen-independent. Androgen dependent events (7 of 13) in human penile formation included: (a) fusion of the urethral groove to form the penile urethra, (b) canalization of the glanular urethra, (c) phallic growth, (d) preputial growth, (e) erectile body growth (f) penile identity and (f) midline mesenchymal confluence.
For mice 5 of 11 individual developmental steps were found to be androgen-independent, which were verified through analysis of an androgen-insensitive mutant (Table). Observations from development of external genitalia of other species (moles and spotted hyena) provided further examples of androgen-independent events in penile development.
Conclusion: These observations support the counter-intuitive idea that penile development involves both androgen-independent and androgen-dependent processes.
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