Endogenous hypercortisolism is a condition where the body overproduces cortisol. This hormone, produced by the adrenal glands, helps regulate metabolism, reduce inflammation, and manage stress. While cortisol is necessary for health, persistently high levels can lead to significant health problems. This condition differs from exogenous hypercortisolism, which is caused by external factors like corticosteroid medications, because the issue originates within the body’s systems.
Internal Causes of Excess Cortisol
The causes of hypercortisolism are categorized based on their dependence on adrenocorticotropic hormone (ACTH), which stimulates cortisol production. The most common cause is a benign pituitary gland tumor (pituitary adenoma), accounting for 70% to 80% of cases. These tumors secrete excess ACTH, overstimulating the adrenal glands to produce too much cortisol. This form of the condition is called Cushing’s disease.
Another cause involves tumors within the adrenal glands. These tumors, which can be benign or malignant, directly produce excess cortisol independent of ACTH. In this case, the high cortisol levels lead to suppressed ACTH production by the pituitary gland. This type of hypercortisolism is less common than Cushing’s disease.
A third cause is ectopic ACTH syndrome, where tumors outside the pituitary or adrenal glands produce ACTH. These tumors are often found in the lungs but can occur elsewhere. This ectopic ACTH production stimulates the adrenal glands to release high levels of cortisol, similar to a pituitary adenoma.
Recognizable Signs and Symptoms
One of the most noticeable changes is in physical appearance. Individuals may experience weight gain in the trunk while the arms and legs remain thin. A rounded “moon face” and an accumulation of fat between the shoulders, known as a “buffalo hump,” are also characteristic.
Skin may become thin, fragile, and heal poorly from cuts and bruises. Distinctive purple or reddish stretch marks, called striae, can appear on the abdomen, thighs, and breasts. Other signs include a round, red face (facial plethora) and the development of acne.
High blood pressure and elevated blood sugar are frequent complications, increasing the risk for cardiovascular disease and type 2 diabetes. The condition can also cause muscle weakness, especially in the hips and shoulders, making activities like climbing stairs or getting up from a chair difficult. Bone loss (osteoporosis) can also occur, leading to a higher risk of fractures.
Many people experience mood changes, including anxiety, depression, and irritability. Cognitive difficulties, such as problems with memory and attention, are also reported. In women, the condition can lead to menstrual irregularities and increased facial and body hair (hirsutism).
The Diagnostic Process
Diagnosing endogenous hypercortisolism is a multi-step process that begins with confirming excessive cortisol levels. Since cortisol levels fluctuate throughout the day, a single blood test is insufficient. Instead, several tests are used to measure cortisol production, including:
- A 24-hour urinary free cortisol test, which measures cortisol excreted over a full day.
- A late-night salivary cortisol test; in a healthy person, levels are lowest at night but remain elevated with this condition.
- A low-dose dexamethasone suppression test, where a synthetic steroid is given; if cortisol levels remain high, it suggests hypercortisolism.
Once high cortisol is confirmed, the next step is to determine the source by measuring blood ACTH levels. Suppressed ACTH points to an adrenal gland problem. Normal or high ACTH levels suggest the cause is a pituitary adenoma or an ectopic ACTH-producing tumor.
Imaging studies are then used to pinpoint the tumor’s location. An MRI of the pituitary gland is performed if Cushing’s disease is suspected. For a suspected adrenal tumor, a CT scan of the adrenal glands is ordered, while imaging of the chest and abdomen may be needed to locate an ectopic tumor.
Treatment Pathways
The primary treatment goal is to normalize cortisol levels by addressing the underlying cause. For Cushing’s disease, the most common treatment is the surgical removal of the pituitary adenoma. This procedure, called transsphenoidal surgery, is performed through the nose to access the pituitary gland.
If the cause is an adrenal tumor, an adrenalectomy is performed to remove the affected gland; chemotherapy may be required if the tumor is cancerous. For ectopic ACTH syndrome, treatment involves surgically removing the tumor producing the excess ACTH.
When surgery is not an option or is unsuccessful, other treatments are used. Radiation therapy can be directed at the pituitary gland to shrink a tumor and reduce ACTH production. Medications that inhibit cortisol production, such as ketoconazole or metyrapone, can also control levels before surgery or as a long-term treatment. After successful treatment, some patients may need temporary cortisol replacement therapy while their body’s hormone production recovers.