Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome

Abstract

Endogenous Cushing's syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed "Cushing's disease") and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

Graphical Abstract

Figure 1.

The hypothalamic-pituitary-adrenal axis of healthy people, those with pseudo-Cushing’s syndrome (CS), and those with the 3 main causes of CS. In healthy people, corticotropin-releasing hormone (CRH) is secreted from the hypothalamus, travels to the pituitary gland, and stimulates ACTH production and secretion. ACTH stimulates the adrenal gland to make cortisol. Cortisol negative feedback (shown by dashed red lines) reduces ACTH production by action on the hypothalamus (to decrease CRH) and the corticotrope (to directly inhibit proopiomelanocortin production). In addition, cortisol negative feedback inhibits corticotrope secretion of ACTH. Stress is thought to stimulate CRH production, which increases ACTH secretion, resulting in excess cortisol production. However, the excessive CRH and ACTH can be turned off by the excess cortisol, bringing the person back into balance. Unregulated, excessive cortisol production is the hallmark of CS, as shown by thicker lines. Another common feature is that the pathologic hypercortisolism of CS acts via negative feedback to suppress normal CRH and ACTH, so that these lines are now quite thin. Pituitary corticotrope tumors and nonpituitary (ectopic) tumors make excessive ACTH, which drives cortisol production. Primary adrenal tumors, which may be unilateral or bilateral, benign or malignant, make cortisol autonomously.

Figure 2.

Representational schema promoter regions 1 and 2 of the human proopiomenocortin gene. Shown are the response elements, (the DNA binding regions) that are important for transcription, and some of the co-factors for each, many of which recruit additional factors to the response element complex. The symbols and arrows denote transcription as follows: green, normal corticotopes and corticotrope tumors 2) pink, corticotrope tumor (not normal cells), 3) orange, unknown whether used by normal or tumoral corticotropes 4) blue, ectopic ACTH-secreting tumors. The estimated median percentage of methylation for the two promoter regions for corticotrope and ectopic ACTH-secreting tumors, and normal tissue is shown in the table below, for the DNA regions denoted by the dotted line (estimated from reference 58). Note that individual estimates for two patients with ectopic ACTH secretion are shown.

Figure 3.

Schematic representation of cortisol patterns over 24 h, showing ultradian pulses (green dashed line) and mean values (purple dashed line) in healthy individuals. The normal nadir is tightly entrained to the onset of sleep. The pink line represents the relatively invariant levels seen in Cushing’s syndrome, in which the bedtime nadir is lost.

Figure 4.

The fates of blood cortisol after secretion by the adrenal glands. Nearly all cortisol circulates in blood bound to a chaperone protein, either corticosteroid binding globulin (CBG) or albumin. The remaining unbound (free) fraction is biologically active and diffuses into target tissues, where it (1) exerts metabolic effects, (2) is metabolized (eg, renal inactivation into cortisone by 11βHSD2 or additional hepatic conversions), (3) is incorporated into growing hair, or (4) is excreted in sweat, urine, or feces. The pink arrows denote tissues in which free cortisol and/or its metabolites can be measured using commercially available assays; the blue arrows indicate research assays. Free cortisol in blood can be measured commercially or calculated using serum cortisol, albumin, and CBG values.

Figure 5.

Photographs of 3 patients with Cushing’s syndrome, illustrating the range of physical features. The man on the left demonstrates central obesity, striae, supraclavicular fullness, rounded face with filling of the temporal fossae, and poor skin healing (bandage). The woman in the middle has increased supraclavicular fullness, facial plethora, and a history of new hypertension and depression. The woman on the right appears normal except for some facial fullness in comparison to previous photographs. By history, she was gained weight, with increased abdominal girth, and a history of mild decreases in cognition and short-term recall (memory).