The future gender of the individual coming into being is already fixed on a chromosomal level during the fertilization of the ovum. The determination and differentiation of the gender take place during the embryogenesis. Disturbances of the sexual differentiation can arise due to chromosome anomalies, gene mutations and exogenous or endogenous influences, which are remarkable at last in the puberty and cause patients to consult a doctor.
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Image: “Feminizing genital reconstruction in congenital adrenal hyperplasia.” by Leslie JA, Cain MP, Rink RC. License: CC BY 2.0

Definition, Epidemiology, and Etiology of Congenital Adrenal Hyperplasia

The congenital adrenal hyperplasia, or CAH, is the most frequent cause for a Pseudohermaphroditism femininus (chromosomal and gonadal female, habitus male). It includes a group of diseases which are based on a genetically conditioned defect of enzymes of the synthesis of steroid hormones in the adrenal cortex. The result of these enzyme defects is the increased formation of male sexual hormones (androgens) with virilisation of the outer female genital.

The autosomal recessive inherited disease occurs with a probability from 1 : 5000 to 1 : 15000.

Classification of Congenital Adrenal Hyperplasia

Generally, every enzyme in the chain of the synthesis of steroid hormones can be affected by a defect. Depending on the affected enzyme, the clinical appearance can vary. The following enzymes are most frequently affected by a defect:

  • 21-hydroxylase
  • 3β-hydroxysteroid-dehydrogenase
  • 11β-hydroxylase

The damage of an enzyme can be complete or incomplete which causes differently pronounced pathologies to occur (see below).

As the 21-hydroxylase defect is with 95 % the most frequent cause, the focus lies in the following section on this defect.

Pathophysiology of Congenital Adrenal Hyperplasia

Due to the defect of the 21-hydroxylase, cortisol is not or only to some extent produced what triggers due to a lack of negative feedback in the superior hormone centers an increased release of ACTH from the pituitary. This hormone stimulates the adrenal cortex, afterward, a hyperplasia of it occurs.

The result is an increased production of androgens and an accumulation of intermediate products which are in turn used for the androgenic synthesis.

Symptoms and Pathology of Congenital Adrenal Hyperplasia

In what follows, the impacts of the disease on the female patients are explained.

The patients have the karyotype 46, XX and female inner genitals which are normally formed. In the case of the outer genitals, however, it comes to a masculinization (virilisation), which can be pronounced to different extents depending on the dimension of the excess formation of androgens. The forms reach from sole hypertrophy of the clitoris to a merging of the labioscrotal folds and the formation of a male urethra.

The point of manifestation of the disease can vary as well and can take place during the fetal period, during childhood and during or after the puberty.

In the case of the classic 21-hydroxylase-defect, the virilization of female fetuses occurs already prenatally with masculinised outer genitals, pronounced to different extents, during birth.

If not treated, the growth of pubic and underarm hair already begins at the age of two. Additionally, the children are at first larger than other at the same age. This circumstance is nevertheless reversed when reaching adolescence or adulthood as it comes to an early closure of the epiphyseal plates. In addition to the male body hair (hirsutism), a change of voice can occur. The patients do not reach the female puberty and therefore suffer from amenorrhoea and infertility.

The non-classic 21-hydroxylase-defect (Late-Onset-CAH) manifests only in the course of time which means that the affected girls are still unobtrusive at birth. The onset of the disease during puberty is characterized by a mild course of the virilisation (acne, hirsutism, and seborrhoea are possible). Additionally, cycle disorders with prolonged cycles or amenorrhea can occur.

In the case of the cryptic form of the 21-hydroxylase-defect, the androgenization is just a little or not at all pronounced.

In some cases, the synthesis of aldosterone can also be restricted which results in a salt wasting syndrome with exsiccosis, hyponatremia, hypokalemia and acidosis. Affected babies are apathetic, throw up frequently and need an immediate therapy as they are vitally in danger.

Diagnostics and Differential Diagnostics of Congenital Adrenal Hyperplasia

The chromosomal gender can be determined by the chromosomal analysis. Different intermediate levels of the cortisol synthesis, which are noticeable depending on the defect enzyme, can be determined endocrinologically. Furthermore, the metabolites of the preliminary stages of the cortisol located in the urine can be verified (e.g. pregnanetriol).

To differentiate the 21-hydroxylase-defect, the ACTH-stimulation test can be performed. Hereby, 17-OH-progesterone and cortisol are determined at first in a fasting state. Afterward, ACTH (250 mg i.v.) is given. After one hour, 17-OH-progesterone and cortisol are again determined. If the difference between the first and the second value of 17-OH-progesteron does not exceed 2,5 ng/ml, it is a normal reaction. An increased level of cortisol shows an adrenal cortex hyperplasia.

Therapy of Congenital Adrenal Hyperplasia

A therapy of CAH should take place as soon as possible to prevent a virilisation of the patients and achieve a normalized ovarian function. Affected persons have to be substituted for their whole life with glucocortides (e.g. hydrocortisone or dexamethasone). Thus, the ACTH production and therefore the formation of androgens is reduced. The therapy should be adjusted individually as a Cushing syndrome and a growth inhibition can occur. By means of a sufficient therapy, a regular female development is achieved and the infertility of the patients can be left up, therefore a pregnancy is made possible. Healthy descendants are then the transmitters of CAH.

Note: Cushing syndrome in the case of overdosage of glucocortides!

If there is a salt wasting syndrome, additional mineralocorticoids (e.g. fludrocortisone) has to be given and electrolyte disorders have to be treated.

Prevention of Congenital Adrenal Hyperplasia

The disease is autosomal recessively inherited which means that if a mother has born a child with CAH, there is a probability of 25 % in another pregnancy that this child also has CAH. By means of taking dexamethasone (1—1,5 mg/d) during the pregnancy, the virilisation of an affected child can be avoided. The intake of dexamethasone can be stopped when there is proof for a male gender or an exclusion of CAHat a later point in the pregnancy by prenatal diagnostics.

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