This chapter will begin with adrenal cortex hormones and conclude with adrenal medulla hormones. The adrenal medulla produces epinephrine and norepinephrine. The relationships of the principal adrenal cortex hormones, their actions, and their metabolites are shown in Fig. 30-1. The adrenal cortex is divided into three areas. A narrow outer (subcapsular) region is known as the “zona glomerulosa”. It is thought to produce aldosterone. The cortex middle zone, called the “zona fasciculata”, mainly secretes 17-hydroxycortisone, also known as “hydrocortisone” or “cortisol”. This is the principal agent of the cortisone group. A thin inner zone, called the “zona reticularis”, manufactures compounds with androgenic or estrogenic effects. Pathways of synthesis for adrenal cortex hormones are outlined in Fig. 30-2. Production of cortisol is controlled by pituitary secretion of adrenal cortex-stimulating hormone, or adrenocorticotropic hormone (corticotropin; ACTH). The pituitary, in turn, is regulated by a feedback mechanism involving blood levels of cortisol. If the plasma cortisol level is too high, pituitary action is inhibited and ACTH production is decreased. If more cortisol is needed, the pituitary increases ACTH production.


Fig. 30-1 Derivation of principal urinary steroids.


Fig. 30-2 Adrenal cortex steroid synthesis. Important classic alternate pathways are depicted in parentheses, and certain alternate pathways are omitted. Dotted lines indicate pathway that normally continues in another organ, although adrenal capability exists.

Excess or deficiency of any one of adrenal cortex hormones leads to several well-recognized diseases which are diagnosed by assay of the hormone or its metabolites. In diseases of cortisol production, three assay techniques form the backbone of laboratory diagnosis: 17-hydroxycorti-costeroids (17-OHCS), 17-ketosteroids (17-KS), and direct measurement of cortisol. Before the use of these steroid tests in various syndromes is discussed, it is helpful to consider what actually is being measured.


These are C21 compounds that possess a dihydroxyacetone group on carbon number 17 of the steroid nucleus (Fig. 30-3). In the blood, the principal 17-OHCS is hydrocortisone. In urine, the predominating 17-OHCS are tetrahydro metabolites (breakdown products) of hydrocortisone and cortisone. Therefore, measurement of 17-OHCS levels can be used to estimate the level of cortisone and hydrocortisone production. Estrogen therapy (including oral contraceptives) will elevate plasma 17-OHCS values, although degradation of these compounds is delayed and urine 17-OHCS levels are decreased.

Adrenal cortex steroid nomenclature.

Fig. 30-3 Adrenal cortex steroid nomenclature. A, basic 17-OHCS nucleus with standard numerical nomenclature of the carbon atoms. B, configuration of hydrocortisone at the C-17 carbon atom. C, configuration of the 17-KS at the C-17 carbon atom.


These are C19 compounds with a ketone group on carbon number 17 of the steroid nucleus (see Fig. 30-3). They are measured in urine only. In males, about 25% of 17-KS are composed of metabolites of testosterone. The remainder of 17-KS in males and nearly all 17-KS in females is derived from androgens other than testosterone, although lesser amounts come from early steroid precursors and a small percentage from hydrocortisone breakdown products. Testosterone itself is not a 17-KS. The principal urinary 17-KS is a compound known as dehydroisoandrosterone (dehydroepiandrosterone; DHEA). This compound is formed in the adrenal gland and has a weak androgenic effect. It is not a metabolite of cortisone or hydrocortisone, and therefore 17-KS cannot be expected to mirror or predict levels of hydrocortisone production.

In adrenogenital or virilization syndromes, high levels of 17-KS usually mean congenital adrenal hyperplasia in infants and adrenal tumor in older children and adults. In both conditions, steroid synthesis is abnormally shifted away from cortisone formation toward androgen production. High 17-KS levels are occasionally found in testicular tumors if the tumor produces androgens greatly in excess of normal testicular output. In Cushing’s syndrome, 17-KS production is variable, but adrenal hyperplasia is often associated with mild to moderate elevation, whereas adrenal carcinoma frequently produces moderate or marked elevation in urinary values. In adrenal tumor, most of the increase is due to DHEA.

Low levels of 17-KS are not very important because of normal fluctuation and the degree of inaccuracy in assay. Low levels are usually due to a decrease in DHEA. This may be caused by many factors, but the most important is stress of any type (e.g., trauma, burns, or chronic disease). Therefore, normal 17-KS levels are indirectly a sign of health.

Plasma cortisol

Plasma cortisol, like thyroxine, exists in two forms, bound and unbound. About 75% is bound to an alpha-1 globulin called “transcortin,” about 15% is bound to albumin, and about 10% is unbound (“free”). The bound cortisol is not physiologically active. Increased estrogens (pregnancy or estrogenic oral contraceptives) or hyperthyroidism elevates transcortin (raising total serum cortisol values without affecting free cortisol), whereas increased androgens or hypothyroidism decreases transcortin. In addition, pregnancy increases free cortisol. A marked decrease in serum albumin level can also lower total serum cortisol levels. There is a diurnal variation in cortisol secretion, with values in the evening being about one half those in the morning. Lowest values are found about 11 P.M.

Cortisol test methods. All current widely used assays for serum cortisol measure total cortisol (bound plus free). There are three basic assay techniques: Porter-Silber colorimetric, Mattingly fluorescent, and immunoassay. The Porter-Silber was the most widely used of the older chemical methods. It measures cortisol, cortisone, and compound S (see Fig. 30-2), plus their metabolites. Ketosis and various drugs may interfere. The Mattingly fluorescent procedure is based on fluorescence of certain compounds in acid media at ultraviolet wavelengths. It is more sensitive than the Porter-Silber technique, faster, requires less blood, and measures cortisol and compound B but not compound S. Certain drugs that fluoresce may interfere. Immunoassay has two subgroups, competitive protein binding (CPB) and radioimmunoassay (RIA) or enzyme immunoassay (EIA). The CPB technique is the older of the two. It is based on competition of patient cortisol-like compounds with isotope-labeled cortisol for space on cortisol-binding protein. CPB measures cortisol, cortisone, compound S, and compound B. Advantages are small specimen requirement and less interference by drugs. RIA or EIA is based on competition of patient cortisol with labeled cortisol for anticortisol antibody. The method is nearly specific for cortisol, with less than 20% cross-reaction with compound S. In certain clinical situations, such as congenital adrenal hyperplasia or the metyrapone test, it is important to know what “cortisol” procedure is being performed to interpret the results correctly.

All techniques measure total blood cortisol, so that all will give falsely increased values if increases in cortisol-binding protein levels occur due to estrogens in pregnancy or from birth control pills. Stress, obesity, and severe hepatic or renal disease may falsely increase plasma levels. Androgens and phenytoin (Dilantin) may decrease cortisol-binding protein levels. In situations where cortisol-binding protein levels are increased, urine 17-OHCS or, better, urine free cortisol assay may be helpful, since urine reflects blood levels of active rather than total hormone.