Steroid Physiology and
Biochemical 19
Assessment
Steroid synthesis
The adrenal cortex is fun into three zones which produce aldosterone (zona glomerulosa), cortisol
(zona fasciculata) and androgens (zona reticularis). Steroid synthesis proceeds
from cholesterol through a series of intermediary steps regulated by enzymes
(Figure 19.1).
Glucocorticoids
Cortisol is the major glucocorticoid and has a key
role in the regulation of metabolic, cardiovascular and immune responses. Its
synthesis is regulated by ACTH; cortisol exerts negative feedback on the
hypothalamus, to reduce vasopressin and corticotrophin releasing hormone (CRH)
production, and on the anterior pituitary to reduce ACTH (Figure 19.2).
Cortisol is secreted in a circadian rhythm, with
highest levels on waking at 08.00 falling gradually to very low levels at
midnight (Figure 19.3). This has diagnostic relevance with respect to timing of
cortisol measurement in the assessment of adrenal insufficiency and Cushing’s
syndrome (Chapter 20). Most cortisol circulates bound to CBG (80–90%) and
albumin (5–10%), with only a small proportion existing in the free biologically
active state. Current cortisol immunoassays measure total (bound and free)
cortisol, hence conditions that stimulate CBG levels (e.g. oestrogen therapy)
can increase measured cortisol levels without affecting biologically active
free levels.
Adrenal androgens
Adrenal androgens are principally controlled by ACTH.
They are of minor importance in adult men because testosterone secreted by
testicular Leydig cells is the main circulating androgen. They have a more
important physiological role in adult women and in both sexes pre-pubertally.
The main examples are dehydroepiandrosterone (DHEA and its sulfated form,
DHEA-S), and androstenedione. They are converted to the more potent androgens
testosterone and, via the enzyme 5α-reductase, dihydrotestosterone in peripheral
tissues. Androgens exert their effects on
sebaceous glands, hair follicles, the prostate gland and external genitalia.
Mineralocorticoids
Aldosterone is the major mineralocorticoid. In contrast to
cortisol and adrenal androgens, its synthesis is mainly regulated by the
renin-angiotensin system. In response to low circulating blood volume,
hyponatraemia or hyperkalaemia, renin is activated in the juxtaglomerular
apparatus of the kidney to catalyse the conversion of angiotensinogen to
angiotensin I, which is subsequently converted by angiotensin converting enzyme
(ACE) to angiotensin II (Figure 19.4). It stimulates aldosterone release upon
binding to the angiotensin receptor. Aldosterone acts mainly at the renal
distal convoluted tubule to cause sodium retention and potassium loss.
Biochemical assessment of the
adrenal axis
An early morning cortisol (08.00–09.00) of <100 nmol/L is
strongly suggestive of adrenal insufficiency, whereas a value of >500
nmol/L excludes the diagnosis in virtually all cases, with the caveat that
interpretation must take into account the clinical status of the patient
because a ‘normal’ level for a healthy individual can be entirely inappropriate
for someone who is critically ill. Random cortisol measurements rarely fall
into these diagnostic extremes, however, such that a stimulation test is needed
to confirm integrity or otherwise of the HPA axis.
A short ACTH stimulation test (Synacthen test) is the key
investigation. This involves IV (or IM) administration of Synacthen (250
µg), with measurement of cortisol at baseline and 30 minutes after injection. A
rise in serum cortisol to >500–550 nmol/L indicates a normal response
and excludes the diagnosis. However, interpretation must take into account the
local assay used and oestrogen therapy, which can raise total cortisol by CBG
stimulation. An additional practice point is that falsely reassuring normal
responses can be seen in recent onset secondary adrenal insufficiency (e.g.
after pituitary surgery), where adrenal atrophy has not yet ensued and the
cortex consequently retains its ACTH responsiveness. The test can be performed
at any time of day because it is the peak value that is relied upon for
interpretation.
