Education Resource from the Society for Endocrinology

What’s new in adrenal insufficiency and what’s stress?

W Arlt

Dept of Medicine, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK

Summer School 13-16 July 2004
St Anne's College, Oxford University, UK

Almost 150 years have passed since Thomas Addison first identified a syndrome characterized by wasting and hyperpigmentation as the result of adrenal gland destruction and more than 50 years have passed since the achievements of Kendall, Sarett and Reichstein led to widespread availability of life-saving glucocorticoid replacement. However, despite these achievements, the long-term management of patients with adrenal insufficiency remains a continuous challenge and while recent years have witnessed intense debate about diagnostic criteria, the heart of the matter lies beyond diagnosis. Some news are old in adrenal insufficiency: treatment is key.

Health-related quality of life in chronic adrenal insufficiency is more severely impaired than previously thought and the related socioeconomic impact is significant. Recently introduced dehydroepiandrosterone replacement may help to restore this to normal. Further optimization of glucocorticoid replacement is difficult considering the lack of objective assessment tools, with monitoring of glucocorticoid therapy largely based on clinical grounds. Mortality in patients with hypopituitarism including secondary adrenal insufficiency is increased, while data on mortality and prognosis in primary adrenal insufficiency are lacking.

Chronic replacement therapy in adrenal insufficiency

Glucocorticoid replacement is usually divided into 2 to 3 daily doses, with one half to two thirds of the daily dose administered in the morning to mimic the physiological cortisol secretion pattern. Recent studies report daily cortisol production rates between 5 and 10 mg/m². This is equivalent to the oral administration of 15 to 25 mg hydrocortisone (= cortisol) or 25 to 37.5 mg cortisone acetate. Cortisone acetate requires conversion to cortisol by 11b-hydroxysteroid dehydrogenase type 1. Hydrocortisone or cortisone acetate administration results in serum cortisol concentrations of high interindividual variability but generally within the supraphysiological range followed by a rapid decline to below 100 nmol/l five to seven hours after ingestion. Whether a thrice daily regimen of glucocorticoid administration should be preferred over a twice daily one is not clear as well-designed and appropriately powered studies are lacking. In general, if a twice daily regimen is applied, the second dose should be administered about six to eight hours after the first one. Long-acting glucocorticoids are also used for replacement with equipotency doses considered to be 1 mg hydrocortisone = 1.6 mg cortisone acetate = 0.2 mg prednisolone = 0.025 mg dexamethasone. Prednisolone and in particular dexamethasone have considerably longer biological half-lives, which may result in unfavourably high night-time glucocorticoid activity.

Treatment surveillance of chronic glucocorticoid replacemen (Table 1) is mainly based on clinical grounds as no objective assessment has proven to be a reliable tool for monitoring replacement quality. ACTH cannot be used as a criterion for glucocorticoid dose adjustment as in primary AI it is invariably high before the morning dose and rapidly declines with increasing cortisol levels after glucocorticoid ingestion. Aiming at ACTH levels continuously within the normal range would therefore lead to chronic over-replacement. However, in case of reappearance of skin hyperpigmentation in primary AI plasma ACTH should be measured.

Urinary 24-hour free cortisol excretion has been advocated for monitoring of replacement quality. However, after exogenous glucocorticoid administration, urinary cortisol excretion shows considerable interindividual variability. More importantly, following glucocorticoid absorption cortisol-binding globulin (CBG) will be rapidly saturated, resulting in transient but pronounced increases in renal cortisol excretion. Thus, one cannot refer to normal ranges for healthy subjects when judging urinary cortisol excretion during replacement therapy in AI. However, in cases of suspected under-replacement, e.g. due to non-compliance, urinary cortisol measurements may be helpful.

To measure a random serum cortisol without knowing the exact time of preceding glucocorticoid administration is not helpful in monitoring glucocorticoid replacement. Some authors have suggested regular measurements of serum cortisol day curves during replacement therapy aiming at serum cortisol concentrations within the normal range. However, due to their pharmacokinetic properties, none of the exogenous glucocorticoids currently used is suitable to mimic the diurnal cortisol pattern found in healthy subjects.

Thus, in the absence of objective parameters indicating replacement quality, the physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of glucocorticoid over- or under-replacement. Under-replacement bears the risk of incipient crisis and significant impairment of well-being. Conversely, chronic over-replacement may lead to substantial morbidity including impaired glucose tolerance, obesity and osteoporosis. With currently recommended doses of 15 to 25 mg hydrocortisone osteoporosis is not to be expected. Therefore, bone mineral density measurements are not required for regular monitoring in AI.

Mineralocorticoid replacement (only required in primary AI) consists of oral administration of 0.05 to 0.2mg fludrocortisone. Monitoring (Table 1) includes measurement of blood pressure, serum sodium and potassium and plasma renin activity (PRA) aiming at PRA levels within the middle or upper normal range. If primary hypertension develops during the long-term course of AI, mineralocorticoid replacement may be gradually reduced, accompanied by monitoring of serum sodium and potassium. Glucocorticoids also contribute to the mineralocorticoid pool as they bind to the mineralocorticoid receptor (MR). However, excessive MR binding is prevented by 11b-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone. With regard to mineralocorticoid potency, 20mg hydrocortisone are equivalent to 0.05 mg fludrocortisone.

Recently it has been demonstrated that DHEA replacement may have significant positive effects on well-being and mood in patients with primary and secondary AI. Treatment is hampered by the lack of pharmaceutically controlled preparations and phase II/III trials are currently underway. In the meanwhile, DHEA should be reserved for patients with AI suffering from significant impairment in well-being despite optimised glucocorticoid and mineralocorticoid replacement. Doses of 25 to 50 mg DHEA should be taken as a single dose in the morning. Treatment surveillance (Table 1) should include measurement of serum DHEA sulphate (DHEAS) aiming at the middle normal range for healthy young subjects. Dose recommendations for elderly patients with AI, who would physiologically experience an age-associated decline in serum DHEAS, remain to be established.

Table 1: Recommended management strategy in chronic adrenal insufficiency (AI)

Glucocorticoid replacement

Hydrocortisone 20-25 mg/d in primary (adrenal) AI and 15-20 mg/d in secondary (hypothalamic-pituitary) AI; should be administered in two to three doses with 1/2 to 2/3 of the daily dose given in the morning (immediately after rising)

Surveillance:

detailed history asking for clinical signs and symptoms suggestive of glucocorticoid over- or underreplacement and the ability to cope with daily stress
detailed account of stress-related gluococorticoid dose self-adjustments since last visit, potential adverse events including emergency treatment and/or hospitalization
verification of emergency bracelet/steroid car
re-instruction of stress-related glucocorticoid dose adjustment and emergency guidelines
body weight, blood pressure, serum sodium; optional: fasting glucose

Mineralocorticoid replacement (only in primary AI)

Fludrocortisone 0.05-0.1(0.2) mg/d taken as a single dose in the morning

Surveillance parameters:

blood pressure (supine/erect)
check for peripheral edema
serum sodium, serum potassium, plasma renin activity (aim at upper normal range)

DHEA replacement (optional)

DHEA 25-50 mg/d taken as a single dose in the morning

Surveillance:

serum DHEAS, in women also free testosterone (or total testosterone + SHBG)

Additional monitoring requirements

Primary AI due to autoimmune adrenalitis: serum TSH; in women: check for regularity of menstrual cycle
Secondary AI: monitoring of underlying hypothalamic-pituitary disease incl. replacement of other axes
Yearly out-patient visits in a specialized centre

Prevention and management of adrenal crisis

In a series of 53 patients with chronic AI representing 511 replacement years, we found an overall risk of adrenal crisis requiring hospital admission of 3.3/100 years. Risk of crisis was significantly higher in primary AI (3.8 vs. 2.5/100 years) and in women (4.4 vs. 1.6/100 years) with the highest overall risk in women with autoimmune adrenalitis (6.5/100 years). Most crises were due to glucocorticoid dose reduction or lack of stress-related dose adjustment by patients or general practitioners. Inappropriate stress-related glucocorticoid adjustment occurs more frequent in patients >60 years of age. All patients and their partners should receive regular crisis prevention training including verification of steroid emergency card/bracelet and instruction on stress-related glucocorticoid dose adjustment (Table 2). Patients should add 5-10 mg hydrocortisone to their usual regimen shortly before extraordinary activities, e.g. strenuous hiking. More severe physical stress like fever requires doubling of daily doses until recovery. In case of vomiting or diarrhoea glucocorticoids have to be administered parenterally. Some physicians advocate a hydrocortisone emergency supply for rectal or parenteral self-administration. For major surgery, trauma, and diseases requiring ICU monitoring, patients should receive 100-150 mg hydrocortisone/24h i.v. in 5% glucose. Some authors recently advocated even lower doses (25-75 mg/24h) for minor or moderate surgical stress.

Management of acute adrenal crisis consists of immediate intravenous administration of 100 mg hydrocortisone followed by 100-200 mg/24h and continuous infusion of larger volumes of physiological saline solution (initially 1 l/h) under continuous cardiac monitoring. With daily hydrocortisone doses of 50 mg or higher, mineralocorticoid replacement in primary AI can be reduced as this dose is equivalent to 0.1 mg fludrocortisone. In case of newly diagnosed (or suspected) AI, treatment must not be delayed by diagnostic work-up. Baseline blood samples for determination of cortisol and ACTH, (optional: PRA, aldosterone, DHEAS) should be drawn immediately before hydrocortisone administration.

Table 2: Recommendations for stress-related glucocorticoid dose adjustment

Exceptional activities (e.g. strenuous hike, stressful university exam)

5-10 mg hydrocortisone 1-2h before start (BUT the usual dentist visit or sports lessons at school do not routinely require glucocorticoid dose adjustment, neither does every perceived psychological stress)

Moderate stress (e.g. flu-like infection, surgical procedure with local anaesthesia)

double the usual oral daily dose until recovery (usually within 2-4 days) (in case of prolonged vomiting or diarrhoea seek emergency i.v./i.m. injection of hydrocortisone)

Severe stress (major surgery with general anesthesia, trauma, delivery)

100-150 mg continuously i.v./24 h (alternatively 3 x 50 mg i.m./24h) for 2-4 days, thereafter, dose tapering and switch to oral administration depending on clinical performance

Special therapeutic situations

Thyroid dysfunction

Hyperthyroidism increases cortisol clearance. In patients with AI and unresolved hyperthyroidism, glucocorticoid replacement should be doubled to tripled. To avoid adrenal crisis, thyroxine replacement for hypothyroidism should only be initiated after concomitant glucocorticoid deficiency has either been excluded or treated.

Pregnancy

Pregnancy is physiologically associated with a gradual increase in CBG and during the last term of pregnancy also with an increase in free cortisol. In addition, serum progesterone increases, exerting anti-mineralocorticoid action.

Therefore, during the third trimester, hydrocortisone replacement should be increased by 50%. Mineralocorticoids should be adjusted according to blood pressure and serum potassium. PRA cannot serve as a monitoring tool because it physiologically increases during pregnancy. Peripartal hydrocortisone replacement should follow the requirements for major surgery, i.e. 100 mg/24h starting with labor until 48 h after delivery, followed by rapid tapering.

Drug interactions

Treatment of tuberculosis with rifampicin increases cortisol clearance, but does not influence aldosterone clearance. Thus, glucocorticoid replacement should be doubled during rifampicin treatment.

Mitotane (o,p’DDD) decreases bioavailable glucocorticoid levels due to an increase in CBG and enhanced glucocorticoid metabolism. During chronic mitotane treatment, e.g. in adrenal carcinoma, usual glucocorticoid replacement doses should therefore be doubled to tripled.

Quality of Life, disablement and prognosis

Recent prospective data indicate excess mortality in hypopituitarism including secondary AI, mainly due to vascular and respiratory disease. However, deficiencies of other hormonal axes may contribute to this finding. Mortality in patients with primary AI has not been studied yet. Nevertheless, life expectancy may be reduced as a consequence of unrecognised adrenal crisis, underlying illness (e.g. adrenomyeloneuropathy), and other yet unknown causes.

Despite adequate glucocorticoid and mineralocorticoid replacement health-related quality of life is significantly impaired in patients with primary and secondary AI. Predominant complaints are fatigue, lack of energy, depression and anxiety and reduced ability to cope with daily demands. In addition, affected women frequently complain about impaired libido. In a recent survey from the Netherlands 50% of patients with primary AI (n=91) considered themselves unfit to work and 30% needed household help. In another survey from Norway (n=88) the number of patients receiving disablement pensions was 2 to 3 times higher than in the general population. The adverse impact of chronic AI on health-related quality of life is comparable to that of congestive heart failure. However, fine-tuning of glucocorticoid replacement leaves only a narrow margin for improvement and changes in timing or dosage did not result in improved well-being. By contrast, DHEA replacement in AI has been shown to significantly improve well-being and mood and thus may open up a perspective for substantial advance.