Endogenous hypercortisolism occurs when the body produces an abnormally high amount of cortisol from internal sources. Cortisol is a steroid hormone made in the adrenal glands that regulates metabolism, blood pressure, inflammation, and the stress response. Prolonged exposure to excessive cortisol leads to a constellation of symptoms known as Cushing’s syndrome. This form is distinct from exogenous hypercortisolism, which is caused by external glucocorticoid medications like prednisone. Understanding the underlying mechanisms is crucial for diagnosing and managing this complex endocrine disorder.
The Mechanisms Behind Excess Cortisol Production
Cortisol production is tightly regulated by the hypothalamic-pituitary-adrenal (HPA) axis, a complex feedback loop involving the brain and the adrenal glands. Endogenous hypercortisolism results from a breakdown in this system, categorized by the level of circulating adrenocorticotropic hormone (ACTH). ACTH is the pituitary hormone that signals the adrenal glands to synthesize and release cortisol.
One major category is ACTH-dependent hypercortisolism, where excess ACTH drives the adrenal glands to overproduce cortisol. The most frequent cause is Cushing’s disease, resulting from a benign pituitary tumor (adenoma) that autonomously secretes excessive ACTH. This tumor is unresponsive to the normal negative feedback mechanism where high cortisol levels signal the pituitary to stop ACTH production.
Another ACTH-dependent cause is ectopic ACTH production, a less common but often more severe form. Here, a tumor originating outside the pituitary gland—frequently a neuroendocrine tumor in the lungs, thymus, or pancreas—produces and secretes ACTH. The excess ACTH hyperstimulates the adrenal glands, leading to high cortisol levels that fail to suppress the abnormal ACTH secretion from the ectopic source.
The second main category is ACTH-independent hypercortisolism, where the problem originates directly in the adrenal glands. This is usually caused by a benign adrenal adenoma or, less commonly, a malignant adrenocortical carcinoma that autonomously secretes cortisol. Since the adrenal tumor acts independently, the resulting high cortisol suppresses the pituitary gland, leading to low or undetectable circulating ACTH levels.
Recognizing the Physical Manifestations
Chronic exposure to excess cortisol affects nearly every system, causing a diverse range of physical and psychological changes. A recognizable sign is central obesity, where fat accumulates predominantly in the trunk, face, and upper back. This redistribution creates a rounded face (“moon facies”) and a fatty pad between the shoulders (“buffalo hump”).
Cortisol increases glucose production, leading to insulin resistance and often resulting in type 2 diabetes. Musculoskeletal tissues are severely impacted, as excess cortisol promotes protein breakdown, causing muscle wasting and weakness, particularly in the proximal muscles. This catabolic state accelerates bone turnover, leading to osteopenia and osteoporosis, which increases the risk of fractures in the vertebrae and ribs.
Dermal changes are characteristic due to the breakdown of collagen and connective tissue. The skin becomes thin and fragile, prone to easy bruising, and patients develop wide, purplish-red stretch marks (striae) on the abdomen, thighs, and breasts. High cortisol levels also contribute to cardiovascular issues, including persistent hypertension and an increased risk for thromboembolic events. Many individuals experience psychological symptoms, such as depression, anxiety, irritability, and cognitive difficulties.
The Diagnostic Process
Diagnosing endogenous hypercortisolism is a multi-step process that first confirms cortisol excess before determining its specific source. The initial phase relies on screening tests that detect the loss of the normal circadian rhythm or an overall increase in cortisol production.
The primary screening tools include the 24-hour urinary free cortisol (UFC) test and the late-night salivary cortisol test, where an elevated result suggests disruption of the HPA axis. The low-dose dexamethasone suppression test (LDDST) is also used; failure to suppress cortisol production after administration of the synthetic steroid dexamethasone indicates hypercortisolism.
Once hypercortisolism is established, the next step is localization, starting with plasma ACTH levels. An undetectable ACTH level points to an ACTH-independent cause, such as an adrenal tumor, localized using a CT scan. Conversely, a normal or elevated ACTH level indicates an ACTH-dependent cause, requiring further dynamic testing to distinguish between a pituitary or ectopic source.
The high-dose dexamethasone suppression test (HDDST) or a corticotropin-releasing hormone (CRH) stimulation test helps differentiate between pituitary and ectopic ACTH production. If these tests are equivocal, the gold standard for definitive localization is Inferior Petrosal Sinus Sampling (IPSS). This invasive procedure compares ACTH concentration in the veins draining the pituitary gland to peripheral blood levels to confirm a pituitary source, especially when imaging is inconclusive.
Treatment Approaches and Management
The primary goal of treatment is to normalize cortisol levels to reverse health complications and restore quality of life. Treatment is tailored specifically to the identified source of excess cortisol. For a pituitary adenoma (Cushing’s disease), the preferred approach is surgical removal via transsphenoidal surgery.
For ACTH-independent hypercortisolism caused by a benign adrenal adenoma, the standard treatment is unilateral adrenalectomy. If hypercortisolism is due to an ectopic ACTH-producing tumor, surgical resection is attempted first, though this can be challenging. When surgery is unsuccessful or contraindicated, medical therapies are used to control cortisol overproduction.
Medical Management
Medical management involves several classes of drugs:
- Steroidogenesis inhibitors (e.g., ketoconazole or metyrapone), which block enzymes responsible for cortisol synthesis.
- Glucocorticoid receptor blockers (e.g., mifepristone), which prevent cortisol from binding to its receptors, neutralizing its adverse effects.
In cases of persistent or recurrent disease, a bilateral adrenalectomy may be considered as a last resort, providing permanent biochemical control.
Following successful surgery, the remaining HPA axis is often suppressed and unable to produce adequate cortisol immediately. This results in temporary adrenal insufficiency, requiring patients to receive temporary glucocorticoid replacement therapy, typically hydrocortisone. This replacement is gradually tapered over months as the remaining gland recovers function. Patients undergoing bilateral adrenalectomy require permanent, lifelong replacement of both glucocorticoid and mineralocorticoid hormones.