Secondary sexual characteristics absent normal height


In this condition the hypothalamus lacks the ability to produce GnRH and therefore there is a hypogo-nadotrophic state. The pituitary gland is normal and stimulation with exogenous GnRH leads to normal release of gonadotrophins. This condition arises due to a maldevelopment of neurones in the arcuate nucleus of the hypothalamus. These neurones are derived embryologi-cally from the olfactory bulb, and therefore some patients may also have failure of development of the ability to smell (anosmia). When this occurs it is known as Kallman syndrome. The genetic basis of Kallman syndrome is slowly being discovered and so far two possibilities exist which are either mutations of the X chromosome KAL1 gene (encoding anosmin) or the fibroblast growth factor receptor 1 gene (FGFR1), which both lead to agenesis of the olfactory and GnRH-secreting neurones [8]. There may well be other mutations and other genes involved which still need to be discovered.


Weight loss is more commonly associated with secondary amenorrhoea than primary amenorrhoea, but unfortunately it is increasingly apparent that young girls may suffer from anorexia nervosa in the prepubertal state. This leads to failure of the activation of the gene which initiates GnRH release in the hypothalamus, and therefore a persistent hypogonadotrophic state exists. The growth spurt is not usually influenced by this, but secondary sexual characteristics are absent.


Over recent years it has become increasingly recognized that excessive exercise in pubertal children leads to a decreased body fat content, without necessarily affecting body mass. Development of muscle contributes to overall weight, and therefore weight alone cannot be used as the parameter to discover whether or not there is an aetiology for their amenorrhoea through this mechanism. A number of examples of this exist including ballet dancers, athletes and gymnasts. These girls fail to menstruate and may actually develop frank anorexia nervosa.


This is an unusual cause of primary amenorrhoea and much more commonly seen as a cause of secondary amen-orrhoea. There may be a recognizable prolactinoma in the pituitary, but often no apparent reason is seen. Imaging may reveal an anomaly.


In this situation there is complete failure of development of the gonad. These girls may be either 46XX or 46XY. The 46XX pure gonadal dysgenesis is an autosomal recessive disorder and other genes other than those located on the X chromosome are involved. The location of these genes remains unclear and in all these patients their genotype does not affect their phenotype, all of them being female. In 46XY or 45X/46XY, when the absence of testic-ular determining factor or its receptor are postulated as the cause of the failure of differentiation of the gonad, there is absence of testicular development. They, therefore, fail to produce any androgen or Mullerian inhibitor. Therefore Wolffian structures regress and Mullerian structures persist and menstruation will occur when oestrogen is administered. The external genitalia reflect normal female phenotype. Height is normal as the growth spurt occurs at the normal time. However, in those girls who are 46XY the failure of production of androgen or oestrogen means that their long bones do not undergo epiphyseal closure at the normal time and therefore final height may be excessive.


These unfortunate girls have ovarian failure as a result of either chemotherapy or radiotherapy for childhood malignancy.


This inborn error of galactose metabolism is due to the deficiency of galactose-1-phosphate uridyl transferase.

The aetiology of the association between this and hypog-onadotrophic hypogonadism is still to be clarified but these patients have galactose-1-phosphate uridyltrans-ferase and this acute toxic syndrome causes ovarian cellular destruction which is thought to be due to the accumulation of galactose metabolites which may induce programmed cell death (apoptosis).


The gonad is described as dysgenetic if it is abnormal in its formation. This encompasses a spectrum of conditions which vary with the degree of differentiation. The commonest is Turner syndrome, which is a single X chromosome giving 45X as the karyotype. The missing chromosome may be either X or Y. There are other circumstances in which the gonadal dysgenesis may be associated with a mosaic. Here two cell lines exist within one individual, the most common being 45X/46XX. There are other structural chromosomal anomalies associated with gonadal dysgenesis known as deletions. If the deletion involves the part of the long arm of the X chromosome or the short arm then loss of this genetic material may affect gonadal development. In Turner's syndrome ovarian development is normal until 20 weeks' of gestation and at this stage oocytes are found in the ovaries. However, further maturation is impaired and a massive atresia occurs during the latter part of pregnancy. The ovaries in most individuals consist solely of stroma and are unable to produce oestrogen. There is a normal female phenotype and internal genital development is also normal. The loss of an X chromosome results in short stature as the genes for height are on the short arm of the X chromosome. In mosaicism the proportion of each cell line determines the manifestation of the condition. The higher the percentage of 45X cells the more likely are the features of Turner syndrome.

In XY individuals there may be a dysgenetic gonad associated with enzymatic failure. In this situation testosterone fails to be produced. This is usually associated with normal production of Mullerian inhibitor. Therefore internal development leads to Mullerian atrophy, but external development fails to masculinize due to the lack of testosterone. Wolffian structures also fail to develop. The external phenotype, therefore, is female with a short vagina.

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