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Whilst primary adrenal failure is commonly isolated, secondary corticotrophin insufficiency is usually associated with hypopituitarism, with the main causes being as described in the above discussions. Isolated corticotrophin deficiency is rare, unless associated with suppression of the hypothalamo-pituitary –adrenal axis by exogenous corticosteroids, however may occur in chronic alcoholism and lymphocytic hypophysitis(191). Unlike primary hypoadrenalism corticotrophin deficiency is not associated with deficiencies of mineralocorticoids.

The symptoms of hypocortisolaemia can be vague and difficult to separate from other pituitary defects. Whist acute deficiencies may result in weakness, dizziness, nausea and vomiting, hypotension and hypoglycaemia, chronic cortisol deficiency produces tiredness, pallor, anorexia and weight loss(192). Replacement is easily given with oral hydrocortisone, however the aim of treatment – to mirror the normal diurnal variation in cortisol with highest concentrations on waking can be difficult to achieve, and modified release preparations are not yet available.

Cortisol is normally highly bound to albumin and other plasma proteins. Diagnosis of cortisol insufficiency based on total cortisol measurements should therefore be made with caution in otherwise sick patients in whom hypoalbuminaemia may also be a concern. (193).Measurement of free cortisol is more helpful, and is becoming more

The gold standard for diagnosis of cortisol insufficiency has always been the insulin tolerance test(194). Originally a cut off value of 580 nmol/L was proposed based on a comparison of the ITT against 20 patients undergoing major surgery(195). Hurel et al examined normal responses to ITT and synacthen in 57 volunteers (30 SST, 27 ITT)(196). They demonstrated a mean (SD) response to synacthen of 628(392-864) nmol/L and to ITT of 693(519 – 866) nmol/L with good correlation between cortisol responses to ITT and SST.

They went on to test these values in patients with pituitary disease, however and found that in patients who failed the ITT, 60% would have passed the SST at the lower end of the normal cut off found in healthy volunteers (390nmol/l). They found however that this figure reduced to 10% if a cut off of 600nmol/l were to be used in the SST, and therefore proposed this higher threshold for assessment of patients with hypothalamo-pituitary disease by SST, with a normal cut off for the ITT of 520nmol/l.

A lower cut off of 500nmol/ has since been recommended with the acknowledgement that normal individuals may peak lower than this(193), however the finding of a lower sensitivity for diagnosis of secondary AI by synacthen testing in a meta-analysis by Dorin et al led the authors to suggest that either the ITT or the metyrapone test should be used in patients with a high probability of secondary AI(197). Pavord et al looked at cortisol responses to ITT and concluded that a basal cortisol response >400nmol/l was predictive of satisfactory cortisol reserve thus making dynamic testing unnecessary(198). Karacca et al(199) demonstrated 100% of

acceptable response as attaining this level up to 2 hours post stimulus. Had the 30 min level been taken as is the case in other studies, 20% of healthy volunteers would have failed this test. The SST has far less risk than the ITT, however as this tests the adrenal glands directly, this mechanism relies on the presumed atrophy of adrenal glands as a result of lack of stimulation by ACTH. Therefore the SST can not be used in patients less than 1 month after the acute insult(193).

The synacthen test has historically been performed using a dose of 250 g, however this supra-physiological dose led to concerns about the sensitivity of this test in predicting adrenal insufficiency, and so the low dose test was introduced with the aim of improving the sensitivity of this method(200). Since this time however both standard and low dose tests have been demonstrated to have similar operating characteristics(194, 197). Despite these findings the Standard dose test remains the test of choice for secondary adrenal insufficiency in the united kingdom(201).

The GST has also been used to assess cortisol reserve in patients with hypothalamo- pituitary disease(104), however the precise cut off remains unclear. Littley et al compared cortisol responses to ITT and GST in 6 healthy men, finding a mean peak of 481nmol/L (range 289 – 717) in the GST compared to 602nmol/L (range 493-792) in the ITT(202). Whilst there was no significant difference between the means of the two tests, the range in the GST was considerably wider, with 4 subjects of the 6 failing to attain a level of >500nmol/L. The lack of a demonstrable difference in this study is likely to be due to insufficient statistical power. Of note the peak cortisol in two of the six subjects was greater than 3 hours post glucagon, demonstrating the

requirement for longer testing protocols when testing cortisol reserve. The GST has previously been shown to produce great variability in normal subjects(203-205).

Tanriverdi et al looked at cortisol responses to glucagon in 22 healthy volunteers, reporting a median value of 450nmol/L with the lowest normal value being 295nmol/L – this was recommended as the normal cut off value for subsequent studies, however a low dose SST was used to confirm deficiencies(206). The largest study of cortisol responses to glucagon in health was undertaken in 55 healthy volunteers by Karaca et al who compared the GST with standard and low dose synacthen tests(199). They reported a mean cortisol response to glucagon of 592nmol/l with the lowest response of 251nmol/L. When compared to synacthen tests, the LDSST returned similar results with a mean peak cortisol of 697nmol/l and lowest value of 345nmol/l. If the conventional cut off of 550nmol/l was applied to the GST, it demonstrated only 43.6% specificity, with 56% of healthy volunteers demonstrating a suboptimal response. Of these suboptimal responses 25% also failed the LDSST whereas all volunteers passed the SDSST however as previously mentioned, an acceptable response to SDSST in this study was any response up to 2 hours post stimulus.

In conclusion subtle corticotrophin deficiency, whilst less common than GHD, can be difficult to spot, with vague symptoms which overlap with other conditions. The ITT and metyrapone tests are acceptable methods of testing cortisol reserve, however their potential morbidity and side effect profile make them impractical. Both standard and low dose synacthen tests show good correlation with the ITT however

furthermore they do not test the complete HPA axis. The GST has been shown to act via an ACTH dependant mechanism(202) however produces wide variability in results leading to a much lower threshold for cortisol response of between 250 and 300nmol/l. It is likely that in the absence of an optimal response to a single test, multiple tests are more efficacious in reducing the false positivity in this field.