LABORATORY EVALUATION OF ADRENAL GLAND FUNCTION
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ACTH stimulates adrenal steroid synthesis. Circulating concentrations of cortisol are maintained within the normal range by the negative feedback effect of cortisol on pititary ACTH elaboration. Aldosterone synthesis is not stimulated by ACTH but by angiotensin II, although ACTH does stimulate synthesis of aldosterone precursors. Circulating Potassium exerts a permissive effect on angiotensin II stimulation; high potassium enhances and low potassium diminishes.
In pathologic conditions, adrenal synthesis of precursor steroids may be greatly stimulated by high ACTH concentrations so that circulating concentrations of cortisol precursors may be sufficiently high to exhibit glucocorticoid activity and/or the circulating concentration of 11-deoxycorticosterone may be sufficiently high to exhibit mineralcorticoid activity.
17-keto steroids are by-products of adrenal steroid synthesis and are also synthesized at increased rates by ACTH stimulation. High circulating concentrations of dehydroepiandrosterone exhibit androgenic activity.
The symptoms of adrenal disease result from abnormal circulating hormone concentrations because of altered function. The abnormal functional state associated with specific disease entities is summarized in the table to the right.
A. Pheochromocytoma/Neuroblastoma (increased catecholamines)
Determination of increased circulating concentration of catecholamines is technically difficult and is not commonly performed. Metanephrines and VMA are degradation products of the catecholamines and their determination in urine specimens is more commonly done.
catecholamines ---> metanephrines ---> VMA
Determination of VMA is simplest but suffers from false positives. Analysis of metanephrines is more specific and is done to confirm increased VMA.
B. Conn's disease (Increased aldosterone & decreased renin)
Serum concentrations of aldosterone and renin are not routine tests but are determined in reference laboratories by radioimmunoassay. In primary hyperaldosteronism, serum concentrations of renin are decreased in contrast to other causes of hypertension not involving adrenal dysfunction. Renin is also decreased in Cushing's syndrome and in some cases of congenital adrenal hyperplasia because of hypertension from increased plasma concentrations of the aldosterone precursor, 11-deoxycorticosterone, having only weak mineral corticoid activity at normal concentrations.
Test Normal Range serum cortisol 8 AM 7-25 ug/dl 4 PM ~ one-half the AM value urine free cortisol 30-100 µg/24 hrs. 17 hydroxy corticosteroids 3-12 mg/24 hrs. 17 ketosteroids male 10-25 mg/24 hrs. female 5-15 17 ketogenic steroids male 8-25 mg/24 hrs. female 5-18 *plasma ACTH - 8 AM 20-100 pg/ml ---------------------------------------------------------
The 17-Hydroxy Steroids assay measures reduced products of cortisol and its immediate precursor, 11-deoxycortisol, excreted in urine. The results provide an indication of the activity of the glucocorticoid pathway (amount of steroids catabolized and excreted = synthetic activity). Normally, the catabolic products of cortisol are the major steroids measured. In cases of 11-hyroxylase deficiency or when metyrapone is administered diagnostically to inhibit 11-hydroxylase activity, then 11-deoxycortisol and its catabolic products are substantially increased and contribute to the measurement.
The 17-ketosteroid assay measures the 17-ketosteroids. The major urine 17-ketosteroids are dehydroepiandrosterone and the reduced catabolic product of Δ-4-androstenedione, androsterone. The assay results indicate the activity of the androgen pathway.
The 17-ketogenic assay measures all steroids, and reduced catabolic products, with oxygen atoms on carbons 17 and 20; i.e., all of the steroids in the glucocorticoid pathway. (In contrast, the 17-hydroxycorticosteroid assay only measures cortisol and 11-deoxycortisol and reduced catabolic products.) The assay is useful in investigating enzyme deficiencies in congenital adrenal hyperplasia.
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Primary adrenal insufficiency - most common
Panhypopituitarism - less frequent
Iatrogenic - atrophic hypofunction of the adrenals and pituitary from long term, high dose steroid therapy.
Definite cases exhibit low serum cortisol concentrations with loss of diurnal variation. If serum results are equivocal, 24 hour urine free cortisol would be conducted and found to be low.
Because of the great functional reserve of the adrenal cortex, greater than 90% of tissue must be destroyed before clinically obvious symptoms develop and plasma and urine steroid levels are subnormal. Suspected borderline cases are confirmed by testing the reserve capacity of the adrenals by metyrapone inhibition, or hypoglycemic "stress" induced by insulin administration, or by directly stimulating with ACTH.
secondary to pituitary hypersecretion of ACTH (Cushing's disease) ~ 70%
secondary to ectopic ACTH secretion ~ 15%
primary adrenal tumor ~ 15%
Definite cases exhibit increased serum cortisol concentrations with loss of diurnal variation, increased free cortisol in 24 hour urine specimens, increased 24 hour urine 17-OH corticosteroids, as well as other characteristic laboratory findings such as hyperglycemia, hypertension, hypokalemia and mild alkalosis. Borderline cases and distinction between primary and secondary hyperfunction require further evaluation:
| Results in Hypercorticism|
Before the advent of reliable ACTH determination, the high dose dexamethasone supression test was most commonly used to evaluate etiology. Suppression occurs only in cases of pituitary Cushing's. Ectopic tumors are not turned off by dexamethasone; nor, of course, are primary adrenal turmors.
It should be clear why each condition responds as it does in each of the other tests.
3. Laboratory Evaluation of Enzyme Deficiencies in Congenital Adrenal Hyperplasia
In cases of congenital adrenal enzyme deficiency, increased, compensatory pituitary ACTH elaboration causes adrenal hyperplasia. In most cases, the enzyme deficiency is
partial and the compensatory hyperplasia results in near normal circulating cortisol concentrations. Symptoms (hypertension and/or virilism) are caused by accumulation of steroid precursors proximal to the deficient enzyme. Accumulation of 11-deoxycorticosterone accounts for hypertension and accumulation of dehydroepiandrosterone (DHEA) accounts for virilism.
The symptoms associated with the different enzyme deficiencies and the corresponding findings of urine steroid assays are summarized in the table below.
Most of the other 5% of cases of congenital adrenal hyperplasia are due to partial deficiency of the 11-β-hydroxylase. The ACTH stimulated compensatory hyperplasia permits near normal synthesis of cortisol and aldosterone, but the increased precursors, 11-deoxycorticosterone and DHEA, cause hypertension and virilism (or precocious puberty), respectively. Results from all three urine steroid assays are increased. Increased 11-deoxycortisol accounts for the increased 17-hydroxycorticosteroids.
Partial deficiency of the 17-hydroxylase occurs only rarely. ACTH stimulated hyperplasia allows near normal synthesis of glucocorticoids and androgens. The mineral corticoid pathway is hyperstimulated and increased concentration of 11-deoxycorticosterone causes hypertension. Results from all three urine steroid assays are near normal or slightly decreased.