The body’s response to stress involves the release of cortisol, a glucocorticoid hormone, which is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. When this system is chronically overactive, the resulting condition of excess cortisol, known as hypercortisolism, can cause significant health problems. Clinicians face a challenge in distinguishing between Cushing’s Syndrome, a rare, disease-driven state of hypercortisolism, and the more common, functional state that mimics it. This mimicked condition, often termed Pseudo-Cushing’s Syndrome, presents with similar physical and biochemical features, but arises from a fundamentally different underlying cause.
Defining Functional Hypercortisolism
Pseudo-Cushing’s Syndrome (PCS) is accurately described as functional hypercortisolism. The condition is characterized by consistently elevated cortisol levels, resulting in many physical signs associated with prolonged cortisol exposure. Unlike true Cushing’s Syndrome, PCS does not stem from a tumor or primary endocrine gland dysfunction within the pituitary or adrenal glands.
Functional hypercortisolism represents a chronic overstimulation of the HPA axis due to persistent external or internal stressors. The system remains structurally intact, retaining its ability to respond to feedback mechanisms. This sustained activation leads to a mild-to-moderate elevation in cortisol that is secondary to another underlying health issue. The biochemical changes are often reversible once the primary trigger is successfully addressed.
Pathophysiological Differences from True Cushing’s
Distinguishing PCS from true Cushing’s Syndrome (CS) is necessary because the treatment approaches are entirely different. Standard screening tests, such as the overnight Dexamethasone Suppression Test (DST), often yield abnormal results in both conditions, indicating poor cortisol suppression. In both PCS and CS, the body’s feedback loop is temporarily resistant to the synthetic glucocorticoid dexamethasone, complicating the initial diagnosis.
Cortisol secretion normally follows a clear diurnal rhythm, peaking in the morning and reaching its lowest point late at night. In true CS, this rhythm is typically flattened or lost, meaning late-night cortisol levels remain abnormally high. Conversely, many patients with PCS retain some degree of this natural circadian rhythm, offering a differentiating clue.
The Dexamethasone-Corticotropin-Releasing Hormone (Dex-CRH) test combines suppression with stimulation. After dexamethasone administration, which suppresses cortisol in most PCS cases, a CRH injection is given. In true CS, the tumor-driven cells often show an exaggerated response, with cortisol levels rising significantly, sometimes exceeding 87 nmol/L (3.2 µg/dL) at 15 minutes post-injection.
Patients with PCS show a muted or absent cortisol response to the CRH stimulation after dexamethasone suppression, confirming the non-tumor-related nature of their hypercortisolism. Furthermore, some studies suggest that a midnight-to-morning cortisol ratio above 0.67 is highly suggestive of true CS. The underlying pathology in CS involves an adenoma or hyperplasia, whereas PCS is driven by a functional overdrive linked to hypothalamic-level dysregulation.
Primary Triggers and Causes
The “pseudo” state is caused by common conditions that place a chronic burden on the body’s stress system. Chronic alcohol abuse is a frequent cause of PCS, often leading to a temporary elevation in plasma cortisol. This alcohol-induced hypercortisolism results from the substance’s disruptive effect on the central nervous system, which drives the HPA axis.
Severe major depressive disorder, or other chronic neuropsychiatric conditions, cause sustained activation of the HPA axis through increased release of corticotropin-releasing hormone (CRH) from the hypothalamus. This constant neuroendocrine stress signal leads to a persistent state of functional hypercortisolism. The biochemical changes observed in these patients, including poor DST suppression, can be virtually indistinguishable from those seen in true Cushing’s disease.
Obesity, particularly the morbid and insulin-resistant type, commonly contributes to PCS. Visceral fat tissue is metabolically active and generates inflammatory signals that activate the HPA axis, altering the peripheral metabolism of cortisol. The enzyme 11β-hydroxysteroid dehydrogenase type 1, which regenerates active cortisol from inactive cortisone, shows increased activity in the adipose tissue, locally boosting glucocorticoid effects.
Other chronic metabolic and inflammatory states, such as poorly controlled Type 2 diabetes and obstructive sleep apnea, can similarly provide the persistent stress required to maintain PCS. The resulting hypercortisolemia is a physiological, albeit excessive, response to an ongoing systemic health issue or psychological distress. This functional activation is typically mediated by an upstream increase in CRH and arginine vasopressin secretion.
Resolution and Management
Because Pseudo-Cushing’s Syndrome is secondary to an underlying condition, the management strategy focuses on treating or removing the primary trigger. This contrasts sharply with the typical surgical or targeted pharmacological interventions required for true Cushing’s Syndrome. For patients whose PCS is linked to chronic alcohol use, complete abstinence from alcohol is the recommended course of action.
In cases related to severe depression, the initiation of appropriate psychiatric treatment, often involving antidepressant medication and psychotherapy, is necessary to calm the overactive HPA axis. For hypercortisolism driven by metabolic factors, such as obesity and uncontrolled diabetes, the therapeutic focus shifts to weight loss and rigorous glycemic control. Successful management of these underlying conditions typically leads to a progressive normalization of cortisol levels.
The positive prognosis of PCS is directly tied to the reversibility of the initial cause. Cortisol levels are usually reassessed three to six months after the treatment of the underlying disorder has begun. This period allows the HPA axis time to reset and restore its normal regulatory function. By addressing the root cause, patients with functional hypercortisolism can avoid unnecessary investigations or invasive treatments intended for neoplastic disease.