Molecular mechanisms of external genitalia development

Abstract

External genitalia development occurs through a combination of hormone independent, hormone dependent, and endocrine pathways. Perturbation of these pathways can lead to abnormal external genitalia development. We review human and animal mechanisms of normal and abnormal external genitalia development, and we evaluate abnormal mechanisms that lead to hypospadias. We also discuss recent laboratory findings that further our understanding of animal models of hypospadias.

Figure 1. External Genitalia Development Processes

The development of external genitalia occurs through androgen dependent, androgen independent, and endocrine/environmental influences. These processes sometimes overlap and interact during development.

Figure 2

Genital tubercle differentiation from ambisexual stage to male and female external genitalia. The ambisexual stage is hormone independent. SRY and androgens are required for male development, while female development occurs in the absence of androgens.

Figure 3. Comparison of Day 1, 10, 21, and Adult Mouse Penises

Penile mes = penile mesenchyme, UGS = urogenital sinus, U = urethra, Ur = urethra, B = bone, Cart = cartilage, CCG or double- headed arrows = corpus cavernosum glandis, MUMPCC = MUMP corpus cavernosum, CCU = corpus cavernosum urethrae, PPL = preputial epithelial lamina At birth, the 1-day mouse genital tubercle (3A) contains undifferentiated mesenchyme, which will give rise to preputial stroma and the differentiated elements of adult penile stroma. The epithelial tube, “undifferentiated penile urethra”, (labeled urogenital sinus) is not a “differentiated penile urethra” because it is not located in mature penile stroma and is attached to other epithelial structures. Instead, the epithelial urine-transmitting tube observed prenatally and in the neonatal period should more appropriately be designated as “undifferentiated penile urethra”. At postnatal day 10 (3B) and day 21 (3C) a differentiated penile urethra can be identified in certain restricted proximal regions within the developing penis. In such areas the penile urethra is located within differentiated penile mesenchyme containing bone, cartilage, corpus cavernosum glandis, MUMP corpus cavernosum, and corpus cavernosum urethrae. Compare the 10- and 21-day images (3B & 3C) with the adult penile urethra (3D) versus the day 1 genital tubercle (3A), whose urogenital sinus falls far short of the definition of “differentiated penile urethra”. Likewise, in the 1-, 10- and 21-day specimens the preputial epithelial lamina has not yet canalized and thus a defined prepuce is still not present even out to 21 days postnatal. Defects in the penile urethra (if present) could be recognized and interpreted as hypospadias at 10 and 21 days postnatal only in areas where a “differentiated penile urethra” exists, but not at day 1 (3A), in which an “undifferentiated penile urethra” is present. The 21-day specimen is identical to adult penis except that the preputial lamina has not yet canalized to create the preputial space and to define the prepuce.