• DOI:10.7326/0003-4819-138-12-200306170-00010
• Corpus ID: 14930007

A Physiologic Approach to Diagnosis of the Cushing Syndrome

@article{Raff2003APA,
  title={A Physiologic Approach to Diagnosis of the Cushing Syndrome},
  author={Hershel Raff and James W. Findling},
  journal={Annals of Internal Medicine},
  year={2003},
  volume={138},
  pages={980-991}
}

• H. Raff, J. Findling
• Published 17 June 2003
• Biology, Medicine
• Annals of Internal Medicine

Clinical Principles* General Obesity Hypertension Metabolic Diabetes mellitus or impaired glucose tolerance Hyperlipidemia Nephrolithiasis Polyuria Skin Plethora Hirsutism Striae Acne Bruising Musculoskeletal Osteopenia or osteoporosis Proximal myopathy Neuropsychiatric Depression Cognitive impairment Emotional lability Euphoria Psychosis Gonadal dysfunction Oligomenorrhea or amenorrhea Impotence, decreased libido Immune suppression (susceptible to opportunistic infection) *Notice that many of the features of the Cushing syndrome resemble those of the metabolic syndrome (e.g., obesity, hypertension, impaired glucose tolerance, hyperlipidemia, hirsutism, acne, and gonadal dysfunction). Pathophysiologic Principles The hypothalamicpituitaryadrenal axis Control of adrenal function and growth Hypothalamic control of pituitary function Glucocortcoid-negative feedback Circadian rhythm The stress response Posttranslational processing of proopiomelanocortin to adrenocorticotropic hormone Cortisol plasma binding, metabolism, and excretion Glucocorticoid action 11-hydroxysteroid dehydrogenase type 1 and 11-hydroxysteroid dehydrogenase type 2 The relationship among obesity, impaired glucose tolerance or diabetes, hypertension, and gonadal dysfunction was initially recognized in two clinical syndromes described early in the 20th century. In 1932, Harvey Cushing reported these findings as well as other features of endogenous hypercortisolism in patients with small basophilic pituitary adenomas (1). A decade earlier, two French physicians, Drs. Archard and Thiers, described a similar phenotype in the syndrome that is now recognized as the syndrome of insulin resistance (the metabolic syndrome) and the polycystic ovary syndrome (2). Recently, increasing evidence has shown that the Cushing syndrome is a reversible cause of the metabolic syndrome (3) and that it may be more common than previously thought. Some patients with incidentally discovered adrenocortical tumors have subclinical hypercortisolism and experience clinical improvement in diabetes, hypertension, and obesity after adrenalectomy; this illustrates the importance of discovering even mild cases of the Cushing syndrome (4). In addition, two recent studies found that 2% to 3% of patients with poorly controlled type 2 diabetes mellitus may have unrecognized Cushing syndrome (5, 6). The clinical and biochemical discrimination of true Cushing syndrome from the Cushing phenotype and the metabolic syndrome may be very difficult, particularly when hypercortisolism is mild. Since obesity, hypertension, diabetes, and lipid disorders are common in the general population, it is important for internists and other primary care physicians to be able to identify patients with the Cushing syndrome. This review demonstrates that an understanding of the physiologic characteristics of the hypothalamicpituitaryadrenal axis is essential in formulating strategies to confirm the diagnosis of the Cushing syndrome as well as establish its cause. The Basic Organization of the HypothalamicPituitaryAdrenal Axis The general organization of the hypothalamicpituitaryadrenal axis (Figure 1) has been appreciated for almost half a century. However, many recently described new concepts have significant implications for the understanding of the pathophysiologic characteristics, diagnosis, and treatment of the Cushing syndrome. Figure 1. The hypothalamicpituitaryadrenal control system. CRH AVP ACTH Control of Adrenal Function The primary controller of the synthesis and release of cortisol from the adrenal zona fasciculata is adrenocorticotropic hormone (ACTH) (7). This hormone exerts acute control, causing the plasma cortisol level to increase within minutes of an elevation in ACTH level. The main mechanism of action of ACTH is to activate adenylate cyclase activity, increase cytosolic cyclic adenosine 3,5-monophosphate (cAMP), and activate protein kinase A. This leads to an increase in the rate-limiting step: cholesterol transport from the cytosol across the mitochondrial membrane to provide substrate for the first enzyme in the steroidogenic pathway (P450 side-chain cleavage). At least two proteins expressed within the steroidogenic cellsteroidogenic acute regulatory protein and the peripheral-type benzodiazepine receptormediate this mitochondrial transport step. The mechanisms of action and control of expression of these two proteins are currently an area of intense investigation that has implications for a variety of adrenocortical disorders. Adrenocorticotropic hormone also exerts long-term trophic effects on the adrenal cortex. Prolonged stimulation leads to adrenal hypertrophy (as in bilateral adrenal hyperplasia), and prolonged decreases in ACTH level lead to adrenal atrophy (as in so-called secondary adrenal insufficiency and as observed with long-term glucocorticoid therapy). It is also possible that the steroidogenic acute regulatory protein, the peripheral-type benzodiazepine receptor, or both are involved in the control of adrenocortical growth and atrophy. Synthesis of ACTH Adrenocorticotropic hormone is synthesized as part of a large precursor molecule called proopiomelanocortin (8). Along with other peptides such as lipotropin, ACTH is released from proopiomelanocortin by posttranslational processing within the pituitary corticotroph cells (Figure 2). Furthermore, nonpituitary tumors, which have undergone abnormal differentiation, can synthesize proopiomelanocortin and some or all of its posttranslational products; this explains the ectopic ACTH syndrome. Figure 2. Production of adrenocorticotropic hormone ( ACTH ) in the anterior pituitary corticotroph cell. LPH N N-POC M HypothalamicPituitary Function The release of ACTH from the normal anterior pituitary is controlled by stimulatory and inhibitory inputs (9-11). Most of our knowledge about this system comes from experimental studies in animals. The primary stimulatory input is corticotropin-releasing hormone (CRH), which is synthesized in the parvocellular nerves of the paraventricular nucleus of the hypothalamus and released from their nerve terminals into capillaries in the median eminence. Arginine vasopressin (AVP) synthesized in parvocellular nerves of the paraventricular nucleus is also involved in the control of ACTH (12). This is distinct from AVP released from magnocellular nerve terminals in the posterior pituitary, which controls free water clearance in the kidney (13). Corticotropin-releasing hormone and AVP, once released into capillaries in the median eminence, drain into the anterior pituitary through the long portal veins and increase ACTH release. The other main controller of ACTH release is inhibition through glucocorticoid-negative feedback, which causes cortisol released from the adrenal to ultimately restrain its own release (10, 11). Glucocorticoid-negative feedback is the physiologic basis of the dexamethasone suppression test described later in this review. The release of CRH (and AVP) from parvocellular neurons of the paraventricular nucleus of the hypothalamus into the portal veins is controlled by a variety of neural and hormonal inputs. The response to stress is mediated by neural inputs from several areas within the brain (9-11). For example, hypoglycemia is sensed by the hypothalamic glucose sensors, which have input into the paraventricular nucleus. In addition, the circadian rhythm of cortisol described later in this review is mediated by neural input from the suprachiasmatic nuclei of the hypothalamus. Glucocorticoid-negative feedback also suppresses CRH and AVP by direct action on parvocellular neurons. A newly appreciated mechanism of negative feedback is that glucocorticoids inhibit CRH release from the hypothalamus through input from the hippocampus, which expresses high levels of glucocorticoid receptor (10). In fact, many areas of the central nervous system with input into the hypothalamus can express high levels of the glucocorticoid receptor (14). Circadian Rhythm Cortisol is released episodically. The main rhythm is circadian, in which cortisol level is at its peak around the time of awakening (approximately 7:00 or 8:00 a.m.) and at its nadir at or soon after midnight (14, 15). Changes in this circadian rhythm, ranging from subtle alterations to complete disruption, are common in patients with the Cushing syndrome (15). Detection of these changes can be exploited as a diagnostic tool. Cortisol Metabolism and Mechanisms of Action Metabolism Cortisol circulates in the plasma both in the free (biologically active) form (approximately 5%) and while bound to corticosteroid-binding globulin and albumin (approximately 95%) (16). Cortisol is cleared from the circulation primarily after conjugation to glucuronide in the liver and excretion in the urine. In addition, plasma free cortisol is filtered in the renal glomerulus and appears in the urine as free cortisol. This is the basis for using urine free cortisol level to diagnose hypercortisolism. Mechanisms of Action Appreciation of the distribution of the glucocorticoid receptor and its mechanism of action helps to explain the very wide range of symptoms found in patients with the Cushing syndrome. Glucocorticoid receptors are located within the cell, primarily in the cytoplasm. Binding of cortisol to the glucocorticoid receptor ultimately increases the expression of specific genes (transcription) and synthesis of new proteins (translation). A current area of investigation is the nongenomic actions of cortisol, which may be transduced through the cell membrane. The notion that steroids can activate cellular phenomena through transduction at the cell membrane is a new and exciting area, but its clinical significance is not yet clear (17). Glucocorticoid receptors in the anterior pituitary, hypothalamus, and hippocampus account for glucocorticoid-negative feedback (10, 14, 18). Glucocorticoid receptor expression throughout the brain accounts for man