Sexual Differentiation and Development: I Introduction
Miss JP was referred to the paediatric endocrine clinic at the age of 14 years because her periods had not started and she was noted to be of short stature. On examination in the clinic she was found to be below the 3rd centile of height for her age. She had a number of dysmorphic features including a ‘webbed’appearance to her neck, a wide carrying angle of the arms and widely spaced nipples with absent breast development (Fig. 23a). Turner syndrome was confirmed by the findings of raised gonadotrophin concentrations in the presence of an abnormal karyotype, 45XO. She was treated with low-dose ethinylestradiol and growth hormone to maximize growth, with subsequent increasing doses of estradiol to initiate pubertal development, followed by combined estrogen/ progestogens to maintain a menstrual cycle.
Sexual differentiation can be classified according to: (i) the genetic sex of the phenotype, that is whether it is XX or XY with respect to the sex chromosomes; and (ii) according to the sexual characteristics determined by the gonadal hormones (Fig. 23b). Every human normally has 46 chromosomes in each cell, consisting of 22 pairs of autosomal chromosomes, and a pair of sex chromosomes. Genetic sex is determined at the time of conception, when male and female gametes fuse to form a new individual. The possession of a Y chromosome determines that a male will develop, as the Y chromosome possesses the sex- determining gene, also called the Sry gene, which expresses the Sry antigen. The Sry antigen is a trigger that switches on genes on other chromosomes responsible for testicular development.
In the human fetus, at about 4 weeks, the gonads are indifferent, that is they cannot be distinguished as testis or ovary, and are capable of developing into either (Fig. 23c). The indifferent gonad before differentiation is composed of a coating of germinal epithelium, the genital ridge mesenchyme and the primordial germ cells. Thereafter, under the influence of the Sry antigen (Fig. 23d), the primordial germ cells will move to what is called the medullary region of the primitive gonad. Still under Sry influence, the indifferent gonad begins to develop into a testis. Primitive sex cords give rise to the seminiferous tubules, whose lining of epithelial cells will differentiate into the germinal epithelium, which will give rise to the spermatogonia and the Sertoli cells. Theseepithelialcellsalsodifferentiateintothe Leydigcells, which will produce the male sex hormone testosterone. Where the seminiferous tubule leaves the testis, it branches extensively to form the rete testis, which transports the sperm to the tubules. In the absence of the Sry antigen, the ovary develops. The ovary develops later than does the testis, although both gonadal forms develop steroidogenic competence at the same time.
Phenotypic sex: secondary sexual characteristics
Ductal differentiation. Before differentiation, the ductal systems are bipotential. If a testis develops, it produces a Müllerian inhibiting hormone, also known as anti-Müllerian hormone (AMH). AMH is a glycoprotein of molecular weight about 70 kDa, which causes atrophy of the Müllerian ducts. The
testis Leydig cells also start to secrete testosterone, which supports the development of the Wolffian ducts. This, in turn, leads to the development of the epididymis, seminal vesicles and the ductus deferens. In the absence of the ovaries and testis (i.e. if they are removed from the developing fetus or not functioning), the Müllerian ducts develop and the Wolffian ducts wither, which suggests that the gonads are not required for the develop- ment of a female ductal system.
External genitalia. In the absence of the Y chromosome, the female phenotypical external genitalia will develop. When the fetal testis starts producing androgen, the penis and scrotum form and the testes descend. In the female, the genital tubercle will become the clitoris and the labia will develop.
With the exception of Turner syndrome, syndromes of gonadal dysgenesis are rare. Girls with gonadal dysgenesis usually present with failure of pubertal development and primary amenorrhoea. Abnormalities of the X chromosome, such as partial deletions, multiplication and structural rearrangements, may present with primary or secondary amenorrhoea and absent or delayed puberty, possibly with some of the somatic abnormalities seen in Turner syndrome. Rarely, girls presenting with delayed puberty are found to have 46XX pure gonadal dysgenesis (associated with undetectable ovarian tissue) or to have the 46XY karyoptype. In the latter case, early failure of testicular development results in inactive gonads and feminization of the internal and external genitalia. Patients with gonadal dysgenesis in association with a Y chromosome have a high risk of developing gonadal tumours in testicular remnants and surgery is recommended to remove any intra-abdominal testicular tissue.
Klinefelter’s syndrome in males is characterized by a range of abnormal clinical features, from degrees of feminization to normal male habitus. Karyotypes vary from XXY, XXYY, XXXY to mosaic forms, usually XY/XXY. There is dysgenesis of the seminifero us tubules resulting in small, firmtestes and absent spermatogenesis (although rarely spermatogenesis and even fertility may be present in mosaic individuals). Most patients with Klinefelter’ssyndromearetall, infertile andhavegynaecomastia.
Classical Turner syndrome associated with a 45XO karyotype is the commonest form of gonadal dysgenesis. The ovaries are present only as fibrous ‘streaks’ resulting in pubertal failure and primary amenorrhoea. Short stature is always present and may respond to growth hormone (GH) therapy although higher doses of GH are required than needed in children with isolated GH deficiency and there is thought to be a degree of skeletal dysplasia causing end-organ resistance to treatment. There is a wide individual response to GH in girls with Turner syndrome, although most show some improvement with treatment. Anumber of clinical features may be present, as in Fig. 23a, as well as various other abnormalities, particularly of the renal tract and otolaryngeal system. Induction of puberty with low-dose ethinyl estradiol is associated with breast development and growth and maturation of the genital tract. Subsequent combined estrogen/ progestogen treatment results in maintenance of the menstrual cycle and prevention of osteoporosis. Other patients have mosaic karyotypes (usually 45XO/ 46XX) and may have few physical signs other than primary amenorrhoea. Rarely, such patients menstruate for some years and may present with secondary amenorrhoea.