Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.

Figure 1

The hypothalamic-pituitary-adrenal axis. Inputs from the hypothalamic circadian rhythm generator in the suprachiasmatic nucleus (SCN) and neural stress pathways in the central nervous system (CNS) control the activity of the corticotrophin-releasing hormone (CRH) neuronal cell bodies in the paraventricular nucleus. These neurons are also capable of synthesizing arginine vasopressin (AVP), which can augment the pituitary response to CRH. CRH (and AVP) are released into the portal circulation in capillaries in the median eminence and drain onto the anterior pituitary where they stimulate the pituitary corticotrophs to release adrenocorticotropic hormone (ACTH). ACTH stimulates the zona fasciculata (ZF) and zona reticularis (ZR) via the MC2R (melanocortin 2 receptor, also known as the ACTH receptor). This G-protein coupled receptor increases intracellular cAMP release, which activates StAR-mediated cholesterol transport into the mitochondria (the rate-limiting step of steroidogenesis). Once cholesterol reaches the inner mitochondrial (Mito) membrane, it is acted on by the first steroidogenic enzyme, and then by subsequent sequential enzymes in the smooth endoplasmic reticulum (SER) and Mito with cortisol as an end product (see Fig. 12). Cortisol is released into the plasma compartment where it binds reversibly to corticosteroid-binding globulin (CBG; also known as cortisol-binding globulin). As CBG-bound plasma cortisol enters the capillaries in target tissue, it dissociates from CBG and diffuses into the target cell. In the pituitary and hypothalamus, negative feedback inhibition is exerted with the binding of cortisol to glucocorticoid (GR) and mineralocorticoid (MR) receptors.

Figure 2

The mechanisms of glucocorticoid (GC)-induced decreases in growth in children and suppression of growth hormone (GH) in adults. GHRH is growth-hormone release hormone, IGF1 is insulin-like growth factor 1; GnRH is gonadotropin-releasing hormone, LH is luteinizing hormone, and FSH is follicle-stimulating hormone. Adapted from (7) with kind permission from WB Saunders through the Copyright Clearance Center.

Figure 3

The use of late-night salivary cortisol (LNSC) for screening patients with suspected Cushing’s syndrome. Note that because Cushing’s syndrome is relatively rare and its phenotype very common, most patients screened will have normal LNSCs and Cushing’s syndrome will be ruled out. Conversely, most patients with true Cushing’s syndrome will have consistently increased LNSCs. Even so, the diagnosis is usually confirmed with urine free cortisol (UFC) measurements and/or the overnight low-dose dexamethasone suppression test (oDST). Occasionally, the LNSCs are discordant as shown or the samples are suspicious for contamination with over-the-counter hydrocortisone creams. In that case, measurement of cortisol and cortisone by liquid chromatography/tandem mass spectrometry (LC-MS/MS) will resolve the problem. Adapted from (211) with kind permission from Springer.

Figure 4

The physiological basis for the approach to the differential diagnosis of Cushing’s syndrome. CT is computed tomography radiography and MRI is magnetic resonance imaging. Once the diagnosis is established (see Fig. 3), measurement of a suppressed plasma level of adrenocorticotropic hormone (ACTH) identifies ACTH-independent (adrenal) Cushing’s syndrome. *Adrenal computed tomography (CT) is then performed, and a more detailed analysis is needed to differentiate among the subtypes of adrenal Cushing’s syndrome. The most challenging problem is the differential diagnosis of ACTH-dependent Cushing’s syndrome. The high-dose dexamethasone suppression test is no longer recommended. If the results of magnetic resonance imaging (MRI) of the pituitary show a mass > 6 mm, referral to a neurosurgeon is appropriate. If not, bilateral inferior petrosal sinus sampling with administration of corticotropin-releasing hormone (CRH) is performed. This method reliably distinguishes pituitary Cushing’s disease from occult ectopic ACTH syndrome. For a more thorough discussion, see text. From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.

Figure 5

Plasma ACTH concentrations in patients with established ACTH-dependent Cushing’s syndrome (Cushing’s disease [pituitary corticotroph adenomas] and ectopic ACTH) and ACTH-independent Cushing’s syndrome (Adrenal tumor). Note that plasma ACTH is often within the reference range (blue shading) in Cushing’s disease and that, on average, patients with ectopic ACTH have very high plasma ACTH. To convert to pmol/L, multiply pg/mL by 0.2202.

Figure 6

Summary of inferior petrosal sinus (IPS) sampling in the differential diagnosis of ACTH-dependent Cushing’s syndrome. IPS:P is the ratio of plasma ACTH concentration between an inferior petrosal sinus sample and a sample from a peripheral vein (usually the inferior vena cava) drawn simultaneously. Adapted from (77) with permission from John Wiley and Sons.

Figure 7

Adrenal insufficiency. In primary adrenal insufficiency, the adrenal cortex is typically destroyed (indicated by an X). This relieves the hypothalamus of cortisol negative feedback such that, presumably, corticotrophin-release hormone (CRH) is increased, although sampling portal vein blood is not possible in humans. The loss of negative feedback at the pituitary leads to a large increase in plasma ACTH. In secondary adrenal insufficiency, adequate ACTH secretion is lost (indicated by an X) resulting in suboptimal plasma ACTH and adrenal atrophy.

Figure 8

Typical plasma glucose, ACTH, and cortisol response to insulin-induced hypoglycemia in a healthy subject and a patient with secondary adrenal insufficiency (hypopituitarism). Notice there is a small increase in ACTH and cortisol in this patient with secondary adrenal insufficiency indicating there are still a few remaining functioning pituitary corticotrophs. To convert glucose to mmol/L, multiply mg/100 ml by 0.056; to convert ACTH to pmol/L, multiply pg/mL by 0.2202. To convert cortisol to nmol/L, multiply μg/dL by 27.59.

Figure 9

Plasma ACTH in patients with untreated primary and secondary adrenal insufficiency, and in patients on chronic pharmacological glucocorticoid therapy. Notice that plasma ACTH is often within the reference range (blue shading) in patients with secondary adrenal insufficiency. To convert to pmol/L, multiply pg/mL by 0.2202.

Figure 10

The large protein proopiomelanocortin (POMC) is produced by transcription and translation of the POMC gene. Adrenocorticotropic hormone is then produced by posttranslational processing. Note that other products of POMC can be produced (for example, beta and gamma-lipotropic hormone [LPH], N-terminal POMC fragment [N-POC], and melanocyte-stimulating hormone [M]). Also notice that ACTH contains the sequence of MSH within it. Ectopic ACTH-secreting tumors can perform the same processing but often produce large amounts of precursors (particularly pro-ACTH). From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.

Figure 11

Pattern of the recovery of ACTH from the pituitary and cortisol from the adrenal after discontinuation of chronic pharmacological glucocorticoid therapy. From (71) with kind permission of McGraw Hill.

Figure 12

The normal human steroidogenic pathway. Under normal conditions, the human adrenal cortex produces only small amounts of estrone, estradiol, testosterone, and adrenostenediol. The main adrenal secretory products are aldosterone (produced in the zona glomerulosa), and cortisol, dehydroepiandrosterone (DHEA), and androstenedione (produced in the zonae fasciculata and reticularis). StAR, steroidogenic acute regulatory protein; P450scc, side-chain cleavage, HSD, hydroxysteroid dehydrogenase; P450c17, 17-hydroxylase; POR, P450 oxoreductase; P450c21, 21-hydroxylase; P450c11, 11-hydroxylase; P450aro, aromatase; 5α-red, 5-alpha-reductase; DHT, dihydrotestosterone. Reproduced from (118) with kind permission from Elsevier.

Figure 13

Mechanism of virilization in female fetuses with congenital adrenal hyperplasia. An enzyme defect (usually partial; in this case to P450c21) in the steroidogenic pathway leads to decreased production of cortisol and a shift of precursors into the adrenal androgen pathway. Because cortisol negative feedback is decreased, ACTH release from the fetal pituitary gland increases. Although cortisol can eventually be normalized, it is at the expense of ACTH-stimulated adrenal hypertrophy and excess fetal adrenal androgen production. Adapted from (276) with kind permission from McGraw-Hill.