Normal Development of the Genitalia

For the purpose of this book, only a few aspects of genital development will be highlighted to facilitate understanding of the various disorders. A crucial point is that the external genitalia develop ‘automatically’ in the female direction unless there is testosterone activity in a critical period between 4 and 12 weeks of gestation. Furthermore, the Müllerian ducts develop into the uterus and fallopian tubes unless Müllerian inhibiting factor (MIF) is produced and is effective. Both hormones are produced only by the testis. Therefore the testis and the two hormones it produces are essential for the development of the genitalia, while the ovary and estrogens do not appear essential in that period. The primitive gonads condense from the genital ridges and are populated by germ cells that have migrated in from the yolk sac. Factors transcribed from autosomal chromosomes (chromosome 11, WT1; chromosome 9, SF1; chromosome 17, SOX9; chromosome 2, LHR) help control the early process of gonadal development. A gene on the X (short arm) chromosome, DAX1, acts as an anti-testis factor if present in a ‘double dose’. Thereafter the presence of one gene, called testis determining gene (TDG or SRY), which usually resides on the Y chromosome, leads to the development of the undifferentiated gonad into a testis (Fig. 8.1). SRY is a 240 amino acid transcription factor active for only 36 hours of embryogenesis. A further gene, encoding spermatogenesis factor (SGF), is required for normal Sertoli cell function. Therefore, several disorders at the chromosomal level can prevent the testis from differentiating. These disorders include duplication of DAX1, camptomelic dwarfism (SOX9 mutation (Fig. 8.2), Leydig cell agenesis (LHR mutation), Drash syndrome (WT1 mutation) and mosaicisms of the sex chromosomes (e.g. 46XY/45X in mixed gonadal dysgenesis, and many others). Translocation of the TDG to another chromosome, for instance an X chromosome (XX males; Fig. 8.3), and deletion of the TDG (XY female). At a more subtle scale, abnormalities of TDG (deletions, mutations) also lead to insufficient differentiation of the testis (XY females with gonadal dysgenesis). These disorders (which may be generalized, chimeric or localized to the gonads) can lead to either an undifferentiated gonad or a dysgenetic testis. A combination of testicular and ovarian tissue, as seen in true hermaphroditism, may have many complex causes including tissue mosaicism and chimerism, causing XXand Y-containing tissue to be expressed simultaneously in the gonads. After differentiation the normal testis produces testosterone, inhibin and MIF. Inhibin B is a glycoprotein that feeds back to the pituitary to inhibit the secretion of follicle stimulating hormone (FSH). Its presence can serve as a useful marker of the presence of gonadal tissue. The presence of MIF leads to regression of the Müllerian ducts. If MIF production does not occur in the presence of a normal testosterone secretion, for example due to agenesis of Sertoli cells or a mutation in the MIF gene, the Müllerian duct develops into a uterus while the external genitalia are those of a normal male (Fig. 8.4). As would be expected, MIF receptor abnormalities lead to a similar persistent Müllerian duct syndrome as is seen in MIF gene mutations or deletions. The presence of testosterone normally leads to male differentiation of the external genitalia and development of the wolffian ducts. If testosterone production does not occur, the external genitalia do not develop in the male direction and the Wolffian duct does not develop into the internal male duct (vas deferens). Lack of testosterone production may be due to agenesis of the Leydig cells, luteinizing hormone (LH) receptor mutations, an inability of Leydig cells to produce testosterone (SF1 mutations and enzyme deficiencies of testosterone biosynthesis, which are common to the testis and adrenal gland) or a lack of stimulation of testosterone secretion as a result of insufficient production or action of placental human chorionic gonadotropin (hCG) and pituitary gonadotropins. Although directly active on embryonic Wolffian structures and muscle, testosterone can exert its effect on the external genitalia only if it is converted to dihydrotestosterone (DHT) within the target cells by 5α-reductase. DHT is subsequently bound to an