Summary
The development of internal and external genitalia starts from the same baseline embryological point. From the ninth week of gestation, it diverges to differentiate into either male or female, depending on chromosomes, genes and hormones. The development of internal female genitalia is closely linked to that of the urinary tract; hence relevant details of urinary tract embryology will be outlined in this chapter.
The development of internal and external genitalia starts from the same baseline embryological point. From the ninth week of gestation, it diverges to differentiate into either male or female, depending on chromosomes, genes and hormones. The development of internal female genitalia is closely linked to that of the urinary tract; hence relevant details of urinary tract embryology will be outlined in this chapter.
1.1 Control of Sex Differentiation and Genetics
In species with heteromorphic sex chromosomes, such as human beings, sex differences arise from the genetic differences found in the sex chromosomes. The numerous sex-specific and sex-biased factors that interact in the network of genes and molecules and result in sexual differentiation are called sexome [Reference Arnold and Lusis1]. Female-biasing factors include two X chromosomes, ovarian hormones; male-biasing factors include a single X chromosome, the Y chromosome, and testicular hormones. The primary sex-determining factors are encoded by the sex chromosomes and are the only factors that differ in the male and female zygote. The secondary factors involve genes that are coded in the autosomal chromosomes [Reference Arnold and Lusis1,Reference Arnold, Chen and Itoh2].
The key role in sex differentiation in male development is played by SRY (sex-determining region on Y chromosome), a transcription factor derived from the short arm of the Y chromosome (Yp11). SRY initiates a cascade of downstream genes that determine the male development. It acts directly on the gonadal ridge and indirectly on the mesonephric duct for the development of the testes. It also causes the activation of genes that inhibit ovarian differentiation, and it upregulates steroidogenesis factor 1 (SF1), which through the SOX9 gene causes the differentiation of Sertoli and Leydig cells [Reference Larsen3,Reference Catherine and Rien4].
Absence of SRY in conjunction with positive mediation by specific genes on X chromosome causes the zygote to develop into a female. The X-linked and autosomal genes initiate ovarian development and block testicular differentiation. The two main genes involved in female sexual differentiation are DAX1 and WNT4. DAX1 is a member of the nuclear hormone receptor family located on the short arm of the X chromosome and acts by downregulating SF1 activity. WNT4 is a growth factor early expressed in the genital ridge that is maintained only in females and contributes to ovarian differentiation [Reference Arnold, Chen and Itoh2,Reference Larsen3,Reference Blaschko, Cunha and Baskin5].
In addition to genes, sexual differentiation is affected by the hormonal milieu of the developing baby and end receptor sensitivity to hormones. Abnormal hormonal production by the placenta or adrenal cortex, or extraneous hormonal influence, or receptor insensitivity to hormones can affect sexual development, which may be contrary to that which would be expected from genetic sex.
1.2 Stages of Sex Differentiation
1.2.1 Early Development of the Zygote
Organogenesis occurs in the first 10 weeks of gestation and the remaining 28 weeks are spent in maturation, growth and development of function.
After fertilisation, the developing zygote divides and forms the blastocyst (Figure 1.1a). Later, two cavities – the amniotic cavity and the yolk sac – develop. The embryo arises from two layers of cells interposed between these two cavities, ectoderm and endoderm (Figure 1.1b). At approximately 15 days, an ingrowth of cells from the primitive streak forms a third layer between them, the mesoderm (Figure 1.1c). At the head and tail ends of the embryo, the mesoderm is deficient, resulting in the development of the buccopharyngeal and the cloacal membrane, respectively. The mesoderm is divided into three parts: lateral plate mesoderm, intermediate mesoderm and paraxial mesoderm (Figures 1.1d and 1.2a). Gonads, kidneys and genital ducts develop from the urogenital ridge on the intermediate mesoderm (Figure 1.2b). Definitive kidneys develop from the nephrogenic cord (Figure 1.2c), which is divided craniocaudally into pronephros (primitive kidney – disappears)/mesonephros (intermediate kidney – disappears)/metanephros (definitive kidney). Two symmetrical pairs of genital ducts – mesonephric (Wolffian) and paramesonephric (Müllerian) ducts – develop lateral to the nephric blastema (or nephrogenic cord) (Figure 1.2c) and give rise to internal male and female genitalia. Gonads develop anteromedial to the mesonephros, from the genital ridges (Figure 1.2c).
Figure 1.1 Early zygote development. (a) From fertilisation to implantation, first 5–6 days. (b) Development of two cavities – the amniotic cavity and the yolk sac – and bilaminar embryonic disc: endoderm and ectoderm. (c) Formation of third layer (mesoderm) from primitive streak. (d) Differentiation of mesoderm into paraxial, intermediate and lateral plate mesoderm. (e) Cephalocaudal folding of the embryo and development of early bladder (allantois), defining cloaca as part of hindgut distal to allantois. (f) Division of cloaca into urogenital sinus and anorectal canal by urorectal septum.
Figure 1.2 Gonadal development. (a, b) Cross section of the embryo showing intermediate mesoderm, which gives rise to the urogenital ridge. (c) Urogenital ridge differentiating into nephrogenic cord laterally and genital ridge medially. (d) Longitudinal section of the embryo showing migration of primordial germ cells into the genital ridge, from the yolk sac along the wall of the hindgut and the dorsal mesentery. (e) Cross section showing germ cell penetration into the genital ridges. (f) Early phase of ovarian development. (g) Advanced phase of ovarian development with degeneration of mesonephric duct.
Between the third and fourth weeks of gestation, head and tail ends of the embryo fold cephalocaudally. The endoderm of the yolk sac is included within the two folds and forms the gut. The allantois gains continuity with the developing gut and delimits the cloaca as the portion of hindgut distal to their confluence (Figure 1.1e). Between the fourth and sixth weeks of gestation, the cloaca is subdivided into the primitive urogenital sinus anteriorly and the anorectal canal posteriorly by the descent of the urorectal septum, from the point of confluence of allantois and hindgut, towards the cloacal membrane/perineum and laterally by the folds of Rathke (Figure 1.1f) [Reference Larsen3,Reference Gearhart, Rink and Mouriquand6,Reference Thomas, Duffy and Rickwood7].
1.2.2 Development of Gonads
Gonads appear as a pair of longitudinal ridges (genital or gonadal ridges) sited on the anteromedial aspect of the mesonephros, the intermediate kidney (Figure 1.2c). Derived from intermediate mesoderm and overlying epithelium, these ridges initially do not contain germ cells.
During the third week of gestation, primordial germ cells appear on the wall of the yolk sac close to the allantois. Subsequently, they migrate along the dorsal mesentery of the hindgut (Figures 1.2d and 1.2e) to the primitive gonads (fifth week). During the migration they proliferate through mitosis and in the sixth week they invade the genital ridges (Figures 1.2d and 1.2e). Throughout this period, the epithelial cells of the genital ridge proliferate and penetrate the underlying mesenchyme, forming the primitive sex cords. At this stage, the gonad is undifferentiated (Figure 1.2e). The primitive sex cords and the primordial germ cells are found in both the cortical and the medullary zone and it is not possible to distinguish between male and female gonads. The initial formation of the bipotential gonad requires two transcription factors: Wilms’ tumour 1 (WT1) and SF1. SRY is pivotal in further sexual determination and interplays mainly with two genes: SOX9 and DAX1, determining the differentiation into testis or ovary.
Due to their inductive influence on the development of gonad into ovary or testis, if the germ cells fail to reach the ridges, the gonads do not differentiate. From the sixth week, differentiation of gonads into testis or ovary occurs. In XX embryos the ovary will originate from the cortex and medulla will decline. In the XY embryo, medulla will develop into testis and cortex regresses [Reference Larsen3,Reference Gearhart, Rink and Mouriquand6–Reference Makiyan8].
1.2.2.1 Ovary
The ovary develops later than the testis and until the tenth to eleventh week, it does not have distinguishable histological features.
Once primordial germ cells have arrived in the gonad of a genetic female, they differentiate into oogonia and undergo several mitotic divisions (Figures 1.2e and 1.2f). In the meantime, in the presence of XX chromosomes and absence of SRY gene, the primitive sex cords degenerate. Instead, the epithelium of the gonad continues to proliferate producing secondary sex cords called cortical cords, that extend from the surface epithelium. As these cords increase in size, the primordial germ cells are incorporated into them. In females, the secondary sex cords retain their connection to surface epithelium and, therefore, the primordial germ cells are mainly found in the cortex (Figures 1.2e and 1.2f). Only a few of the sex cords reach the medulla, but those that go into depths and lose contact with the coelomic epithelium tend to undergo atrophy.
Oogonia proliferate by mitosis and then enter the first prophase of meiotic division to form primary oocytes. By the end of the third month of gestation, the oogonia are surrounded by a single layer of flattened epithelial cells which constitute the supporting cell lineage (granulosa or follicular cells) and are arranged in clusters (Figure 1.2g). By the fifth month of prenatal development, the total number of germ cells in the ovary reaches its maximum at about 7 million. However, many germ cells are lost during development. By the seventh month, all the surviving germ cells have entered meiosis and further germ cell development is arrested until puberty. A primary oocyte, together with its surrounding flat epithelial cells, is known as primordial follicle. The number of primordial follicles at birth amount to between 300,000 and 2 million, decreasing to 40,000 at puberty. Only about 300 primary oocytes develop further between puberty and menopause into fertilisable oocytes [Reference Larsen3,Reference Thomas, Duffy and Rickwood7,Reference Makiyan8].
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