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Steroid Physiology and Biochemical 19 Assessment

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).

Steroid Physiology and Biochemical 19 Assessment

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.

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.