Cushing’s Syndrome is a condition characterized by prolonged exposure to high levels of cortisol, a hormone naturally produced by the adrenal glands. This excess cortisol can arise from various sources within the body or from external medications. While many cases involve consistently elevated cortisol, a distinct variant known as cyclical Cushing’s syndrome presents a unique challenge. In this form, cortisol levels fluctuate, making it a particularly complex condition to diagnose and manage.
Understanding Cyclical Cushing’s
Cyclical Cushing’s syndrome is defined by rhythmic fluctuations in cortisol production, where periods of high cortisol are interspersed with periods of normal or even low cortisol. These cycles can vary significantly in their duration and intensity, ranging from days to several months. This intermittent nature distinguishes it from the more common continuous form of Cushing’s syndrome, where cortisol levels remain consistently elevated.
The causes of cyclical Cushing’s syndrome mirror those of continuous Cushing’s, but involve episodic hormone release. Pituitary tumors, secreting adrenocorticotropic hormone (ACTH), are the most frequent cause, accounting for 67% to 80% of cases. Other causes include adrenal tumors that directly produce cortisol, or ectopic sources outside the pituitary or adrenal glands that produce ACTH. The exact mechanisms driving the cyclical pattern are not fully understood, but theories suggest possibilities such as spontaneous bleeding within a tumor, changes in central nervous system regulation, or the influence of inflammatory factors.
Recognizing the Fluctuating Signs
The signs and symptoms of cyclical Cushing’s syndrome are similar to those of continuous Cushing’s, but their waxing and waning nature can make them difficult to recognize. Patients may experience periods where symptoms are pronounced, followed by times when they seemingly improve or disappear, only to return later. This fluctuating presentation often delays diagnosis and can be confusing for both patients and healthcare providers.
Common manifestations include weight gain, particularly around the midsection, face, and neck, leading to a “moon face” or “buffalo hump” appearance. Fatigue and muscle weakness are also frequently reported. Skin changes like thinning, easy bruising, and purple stretch marks (striae) are also characteristic. Mood swings, irritability, anxiety, and depression are also common, reflecting the impact of cortisol on brain function.
Other symptoms that may come and go with the cycles of cortisol excess include high blood pressure, elevated blood glucose levels, and low potassium levels. The intermittent nature of these symptoms means that a patient might present with typical signs during one visit, but appear relatively normal during another, complicating the diagnostic process.
Navigating Diagnosis
Diagnosing cyclical Cushing’s syndrome presents a significant challenge due to the unpredictable fluctuations in cortisol levels. The intermittent nature of hypercortisolism means that a single test, or even a few tests, might miss the periods of elevated cortisol, leading to false-negative results. This often necessitates a prolonged period of observation and repeated testing to capture the characteristic cycles of excess cortisol.
Diagnostic protocols involve multiple 24-hour urine free cortisol (UFC) measurements collected over several days or weeks to detect periods of cortisol overproduction. Late-night salivary cortisol tests are also frequently used, as cortisol levels are lowest in the late evening, making elevated levels indicative of Cushing’s. Low-dose dexamethasone suppression tests, which assess the body’s ability to suppress cortisol production, can also be employed, though paradoxical responses may occur during fluctuating cortisol levels. For a formal diagnosis, at least three periods of confirmed hypercortisolemia interspersed by two periods of normal cortisol are required.
A comprehensive medical history is important to reveal fluctuating symptom patterns and guide test timing. After biochemical evidence of cyclical hypercortisolism, imaging studies pinpoint the source of excess cortisol. Magnetic resonance imaging (MRI) of the pituitary gland helps identify pituitary adenomas, which are the most common cause. Computed tomography (CT) scans of the adrenal glands are used to detect adrenal tumors. Specialized endocrine testing, such as bilateral inferior petrosal sinus sampling (BIPSS), can differentiate between pituitary and ectopic sources of ACTH, particularly when initial imaging is inconclusive.
Treatment Options
Treatment for cyclical Cushing’s syndrome is highly individualized and primarily depends on the underlying cause of the cortisol fluctuations. The aim is to normalize cortisol levels and alleviate symptoms, improving the patient’s quality of life. Surgical intervention is the primary treatment approach when a specific tumor is identified as the source of excess hormones.
For pituitary adenomas, transsphenoidal surgery, a procedure performed through the nose, is the most common surgical method to remove the tumor. If an adrenal tumor is the cause, an adrenalectomy, the surgical removal of the affected adrenal gland, is performed. In cases of ectopic ACTH-producing tumors, surgical removal of the tumor is also the preferred option. However, identifying and localizing these ectopic sources can be challenging.
Medical therapies are also used, either as a primary treatment when surgery is not feasible, or as an adjunct to surgery to control cortisol levels before or after the procedure. These medications work by either lowering cortisol production (e.g., ketoconazole, osilodrostat, metyrapone) or by blocking the effects of cortisol on tissues (e.g., mifepristone). Radiation therapy may be considered if surgery is unsuccessful or not an option, particularly for pituitary tumors, though its effects on cortisol levels can take months to years to become apparent. Ongoing management by an endocrinologist is necessary to monitor cortisol levels and adjust treatment as needed.