Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 261

Gonad

Paramesonephric duct (Müllerian)

Mesonephric duct (Wolffian)

Undifferentiated

Fallopian tube

Seminal vesicle

Uterus

Ovary

II

Mesonephric remnants

Vas deferens

Epididymis

Vagina

Appendix testis

Testis

Male

Female

FIGURE 8.5

Development of the External Genitalia In the bipotential state, which persists until 9 weeks of ges tation, the external genitalia consist of a genital tubercle, a urogenital sinus, and lateral labioscrotal folds or swellings. Unlike the internal genitalia where both duct systems ini tially coexist, the external genitalia are neutral primordia able to develop into either male or female structures, depending on gonadal steroid hormone signals. In the male, the Leydig cells of the fetal testis begin to secrete testosterone at 8–9 weeks of gestation, and masculin ization of the external genitalia begins 1 week later, at approx imately 10 weeks. The genital tubercle grows, forming the penis, the edges of the urogenital sinus fuse to form the penile urethra, and the labioscrotal folds fuse to form a scrotum . The process typically is completed by 12–14 weeks of gestation. Thereafter, the principal change is in the growth and length of the penis. Complete development of the male external genitalia and differentiation of the prostate requires the conversion of testosterone to DHT, via the action of the intracellular enzyme 5 α -reductase. The genital tubercle and

play key roles. AMH signaling induces coelomic epithelial cells expressing Wt1 , Amhr2 , and Alk3 to migrate and sur round the müllerian duct, transforming to mesenchymal cells in the process. 101,102 Wnt7a expression in the mülle rian duct mesoepithelium promotes secretion of a signaling molecule (WNT7a) that activates AMHR2 in the neighbor ing mesenchymal cells via WT1, which binds and activates the Amhr2 promoter. 91 At the same time, β -catenin gene expression increases in the mesenchymal cells surrounding the duct, and accumulation of β -catenin is accompanied by increased apoptosis in the müllerian ductal epithelium. 101,102 Whether WNT-dependent β -catenin activity is required to induce Amhr2 expression or functions downstream of AMH signaling, or both, is not yet clear. Regardless, the process of müllerian duct regression appears to involve both apoptosis and the transition of ductal epithelial cells to mesenchymal cells. 91 The matrix metalloproteinase MMP2 also plays a role, by mediating destruction of the extracellular matrix; avail able evidence indicates that MMP2 activity also is AMH dependent, although the mechanism involved has not been established 103 (Figure 8.6) .

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