Clinical background
Congenital adrenal hyperplasia (CAH)
describes a number of conditions arising from absence or impaired function of
enzymes in the adrenal steroidogenic pathway. Over 95% of cases represent
deficiencies in the 21-hydroxylase enzyme (21- OHD, ‘classical’ CAH), with
abnormalities of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase,
17α-hydroxylase and 20,22-desmolase deficiencies also being described (Fig.
19a).
The clinical features of CAH depend
upon the genetic basis of the disorder in individuals. Thus, complete deletion
of the 21-OH gene will produce the full-blown effects of CAH, whereas gene
mutations may be responsible for lesser clinical features corresponding to
impaired enzyme action. The clinical features of CAH can be surmised by
consideration of the steroidogenic pathway. In classical 21-OHD with severe
enzyme deficiency, androgen production is increased alongside decreased
synthesis of cortisol and aldosterone, leading to the typical clinical features
of a newborn with ambiguous genitalia. In females this is generally identified
at birth, so that early treatment prevents the onset of salt-losing crisis
secondary to mineralocorticoid deficiency. In male babies, this may present as
failure to thrive, and subsequent vomiting, diarrhoea and circulatory collapse
are the presenting clinical features. Milder variants of classical 21-OHD may
present in childhood with virilization and precocious puberty. Those with
‘non-classical’ forms of the disease may not present until early adulthood,
usually young women with irregular menses and hirsutism. Treatment of CAH is by
glucocorticoid replacement therapy, thereby restoring the negative feedback in
the pituitary–adrenal axis and lowering the ACTH drive to androgen production.
In young women with non-classical CAH this may be combined with antiandrogen
therapy.
The molecular genetics of CAH have
been the subject of much investigation. Prenatal diagnosis can be offered to
affected families, either by chorionic villous sampling in the early stages of
pregnancy or later amniocentesis. Prenatal treatment with glucocorticoids can
prevent the virilization of a female fetus.
Physiological actions of cortisol Physiologically, cortisol affects intermediary
metabolism, the nervous system and some processes related to reproduction. It
permits other chemical mediators to act and, overall, it enables the organism
to survive under stress (Fig. 19b; Table 19.1).
Intermediary metabolism. Cortisol increases the synthesis of a number of
enzymes which play key roles in hepatic gluconeogenesis. This is an anabolic
action of cortisol. In adipose tissue (fat) and skeletal muscle, however,
cortisol is catabolic, that is it causes a breakdown of body tissues in order
to mobilize energy. In these tissues, glucose uptake is inhibited and another
substrate for adenosine triphosphate (ATP) production is found through
proteolysis in muscle and lipolysis in fat. The free fatty acids released from
muscle and fat travel to the liver, where they are taken up and utilized as
substrates for gluconeogenesis. The net result is increased glucose or
hyperglycaemia.
Nervous system. Adrenocorticotrophic hormone (ACTH) and cortisol
are synthesized and released in a diurnal rhythm (Fig. 19c). The rhythm is
determined by the interaction with the external environment, particularly the
light–dark cycle and sleep patterns, and this implicates the brain. The brain
releases corticotrophin releasing hormone (CRH), which in turn releases ACTH,
which stimulates gluco corticoid release. Glucocorticoids feed back to the
anterior pituitary and hypothalamus to limit ACTH and CRH release,
respectively, through their intracellular receptors and possibly through
membrane gluco corticoid receptors. The application of the synthetic
glucocorticoid dex- amethasone abolishes the CRH stimulation of ACTH. The
diurnal rhythm of glucocorticoid secretion reflects a similar rhythm of ACTH
secretion. The rhythms are regulated by a ‘biological clock’, which may reside
in the suprachiasmatic area of the brain (Chapter 5). The mechanism that causes
the rhythm is thus inbuilt, but may be synchronized by exogenous (outside)
influences such as light. This is particularly important in the case of
seasonal breeding animals, where day length may determine the onset and offset
of reproductive activity.
Glucocorticoids influence neuronal
development in the fetal and neonatal brain. Administration of glucocorticoids
to neonatal rats results in a reduction in both the basal level and the diurnal
rhythm of ACTH and glucocorticoid release in the adult. This suggests that
endogenous glucocorticoids may play a part in the normal development of the
CRH–ACTH axis. In the adult rat, adrenalectomy (removal of the adrenal gland)
results in the loss of neurones in specific regions of the hippocampus, an area
of the brain concerned with memory, learning and the functioning of the
hypothalamic–pituitary systems. Concurrent administration of glucocorticoids
with adrenalectomy prevents neuronal loss, suggesting that glucocorticoids
help to maintain cellular and structural integrity in specific areas of the
brain.
Permissive actions and stress. Glucocorticoids allow other hormones to exert certain
effects. For example: they are required for catecholamine synthesis and
reuptake into nerve; they enable the process of catecholamine-stimulated fat
mobilization; and, through their effects on gluconeogenesis, they permit the
body to maintain its temperature and its response to stress. The body’s
response to stress has been termed the General Adaptation Syndrome (GAS). Three
main phases have been postulated: (i) alarm reaction; followed by (ii)
resistance; and then by (iii) exhaustion. The alarm reaction is the initial
release of epinephrine from the adrenal medulla and the release of
norepinephrine from sympathetic nerve terminals. At the same time,
glucocorticoids are released, and these permit the catecholamines to act. Their
onset of action is slower than that of the catecholamines, so they provide a
continued resistance to stress. If stress is prolonged, this leads to
exhaustion, characterized by muscle wasting, atrophy of tissues of the immune
system, gastric ulceration, hyperglycaemia and vascular damage.
