Sexual Differentiation
and Development: I Introduction
Clinical scenario
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.
Genetic sex
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.
Gonadal sex
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.
