The adrenal cortex produces three classes of corticosteroid hormones: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and adrenal androgen precursors (e.g., dehydroepiandrosterone, DHEA) (Fig. 342-1). Glucocorticoids and mineralocorticoids act through specific nuclear receptors, regulating aspects of the physiologic stress response as well as blood pressure and electrolyte homeostasis. Adrenal androgen precursors are converted in the gonads and peripheral target cells to sex steroids that act via nuclear androgen and estrogen receptors.
Adrenal steroidogenesis. CYP11A1, side chain cleavage enzyme; CYP17A1, 17α-hydroxylase/17,20 lyase; POR, P450 oxidoreductase; ADX, adrenodoxin; HSD3B2, 3β-hydroxysteroid dehydrogenase type 2; CYP21A2, 21-hydroxylase; CYP11B1, 11β-hydroxylase; CYP11B2, aldosterone synthase; HSD11B1, 11β-hydroxysteroid dehydrogenase type 1; HSD11B2, 11β-hydroxysteroid dehydrogenase type 2; H6PDH, hexose-6-phosphate dehydrogenase; HSD17B, 17β-hydroxysteroid dehydrogenase; SRD5A, 5α-reductase; SULT2A1, DHEA sulfotransferase; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; PAPSS2, PAPS synthase type 2.
Disorders of the adrenal cortex are characterized by deficiency or excess of one or several of the three major corticosteroid classes. Hormone deficiency can be caused by inherited glandular or enzymatic disorders or by destruction of the pituitary or adrenal gland by autoimmune disorders, infection, infarction, or by iatrogenic events such as surgery or hormonal suppression. Hormone excess is usually the result of neoplasia, leading to increased production of adrenocorticotropic hormone (ACTH) by the pituitary or neuroendocrine cells (ectopic ACTH), or increased production of glucocorticoids or mineralocorticoids by adrenal nodules. Adrenal nodules are increasingly identified incidentally during abdominal imaging performed for other reasons.
Adrenal Anatomy and Development
The normal adrenal glands weigh 6–11 g each. They are located above the kidneys and have their own blood supply. Arterial blood flows initially to the subcapsular region and then meanders from the outer cortical zona glomerulosa through the intermediate zona fasciculata to the inner zona reticularis and eventually to the adrenal medulla. The right suprarenal vein drains directly into the vena cava while the left suprarenal vein drains into the left renal vein.
During early embryonic development, the adrenals originate from the urogenital ridge and then separate from gonads and kidneys about the 6th week of gestation. Concordant with the time of sexual differentiation (seventh to ninth week of gestation, see Chap. 349), the adrenal cortex starts to produce cortisol and the adrenal sex steroid precursor DHEA. The orphan nuclear receptors SF1 (steroidogenic factor 1) and DAX1 (dosage-sensitive sex reversal gene 1), among others, play a crucial role during this period of development, as they regulate a multitude of adrenal genes involved in steroidogenesis.
Regulatory Control of Steroidogenesis
Production of glucocorticoids and adrenal androgens is under the control of the hypothalamic-pituitary-adrenal (HPA) axis, whereas mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system.
Glucocorticoid synthesis is under inhibitory feedback control by the hypothalamus and the pituitary (Fig. 342-2). Hypothalamic release of corticotropin-releasing hormone (CRH) occurs in response to endogenous or exogenous stress. CRH stimulates the cleavage of the 241–amino acid polypeptide pro opiomelanocortin (POMC) by pituitary-specific prohormone convertase, yielding adrenocorticotropic hormone (ACTH). ACTH is released by the corticotrope cells of the anterior pituitary and acts as the pivotal regulator of cortisol synthesis, with additional short-term effects on mineralocorticoid and adrenal androgen synthesis. The release of CRH, and subsequently ACTH, occurs in a pulsatile fashion that follows a circadian rhythm under the control of the hypothalamus, specifically its suprachiasmatic nucleus (SCN), with additional regulation by a complex network of cell-specific clock genes. Reflecting the pattern of ACTH secretion, adrenal cortisol secretion exhibits a distinct circadian rhythm, with peak levels in the morning and low levels in the evening (Fig. 342-3).
Physiologic cortisol circadian rhythm. Circulating cortisol concentrations drop under the rhythm-adjusted mean (MESOR) in the early evening hours, with nadir levels around midnight and a rise in the early morning hours; peak levels are observed ∼8:30 a.m. (acrophase). (Modified after Debono M et al: Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 94:1548, 2009.)
Diagnostic tests assessing the HPA axis make use of the fact that it is regulated by negative feedback. Glucocorticoid excess is diagnosed by employing a dexamethasone suppression test. Dexamethasone, a potent glucocorticoid, suppresses CRH/ACTH and, therefore, endogenous cortisol. Various versions of the dexamethasone suppression test are described in detail in Chap. 339. If cortisol production is autonomous (e.g., adrenal nodule), ACTH is already suppressed and dexamethasone has little additional effect. If cortisol production is driven by an ACTH-producing pituitary adenoma, dexamethasone suppression is ineffective at low doses but usually induces suppression at high doses. If cortisol production is driven by an ectopic source of ACTH, the tumors are usually resistant to dexamethasone suppression. Thus, the dexamethasone suppression test is useful to establish the diagnosis of Cushing's syndrome and to assist with the differential diagnosis of cortisol excess.
Conversely, to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used. The ACTH peptide contains 39 amino acids but the first 24 are sufficient to elicit a physiologic response. The standard ACTH stimulation test involves administration of cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and collection of blood samples at 0, 30, and 60 minutes for cortisol. A normal response is defined as a cortisol level >20 μg/dL or an increment of >10 μg/dL over baseline. A low-dose (1 μg cosyntropin IV) version of this test has been advocated to avoid overstimulation of the adrenal gland. Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal insufficiency. It involves ...