Cushing’s Syndrome is a complex endocrine disorder caused by prolonged exposure to excessive levels of the hormone cortisol (hypercortisolism). This condition typically presents as persistent, leading to a host of physical and metabolic changes. Cyclical Cushing’s Syndrome (CCS) is a rare and challenging variant defined by spontaneous, intermittent periods of cortisol overproduction that alternate with periods of normal or near-normal secretion. This unpredictable fluctuation makes the condition difficult to diagnose and manage.
Defining Cyclical Hypercortisolism
Cyclical hypercortisolism is characterized by a transient and recurring state of abnormally high cortisol secretion interspersed with phases where levels return to a physiological baseline. The “cycle” refers to the fluctuation between an active hypercortisolemic phase and a remission or quiescent phase. These cycles are highly variable and unpredictable, lasting anywhere from a few days to several months before a spontaneous return to normal hormone levels occurs.
The core distinction from classic Cushing’s Syndrome is this intermittent nature, which complicates both the clinical picture and biochemical testing. This fluctuation has led to the use of alternative terms such as intermittent hypercortisolism or periodic hormonogenesis. Even brief, repeated periods of cortisol excess can lead to the long-term health complications associated with the persistent form of the syndrome. Therefore, damage to the body’s tissues continues even during periods of normal cortisol, necessitating prompt diagnosis.
Etiology: Sources of Cortisol Overproduction
The excess cortisol production that drives cyclical hypercortisolism originates from the same sources as the classic form of Cushing’s Syndrome. These causes are categorized based on whether cortisol production is dependent on Adrenocorticotropic Hormone (ACTH) or independent of it. ACTH is the pituitary hormone that normally stimulates the adrenal glands to release cortisol.
The majority of cyclical cases are ACTH-dependent, meaning a tumor releases too much ACTH, which overstimulates the adrenal glands. A pituitary tumor (corticotroph adenoma) is the most frequently identified cause, accounting for over half of all reported CCS cases. Less commonly, an ectopic source, such as a neuroendocrine tumor elsewhere in the body (e.g., in the lung or pancreas), can secrete ACTH.
ACTH-independent causes involve a problem directly within the adrenal glands themselves, accounting for a smaller percentage of cases. This typically involves an adrenal adenoma or carcinoma producing cortisol autonomously, independent of ACTH stimulation. The exact biological mechanism causing these tumors to cycle their hormone release is not fully understood. Suggested explanations include intermittent blood flow changes within the tumor or periodic fluctuations in the tumor’s sensitivity to regulatory signals.
Identifying Fluctuating Symptoms and Diagnostic Hurdles
Identifying cyclical Cushing’s Syndrome is challenging because clinical signs and symptoms wax and wane, often mimicking less severe conditions. Patients exhibit classic signs of hypercortisolism, such as truncal weight gain, a round face, or purple stretch marks (striae). Unlike the classic syndrome, these manifestations may lessen or disappear entirely during periods of remission.
This fluctuating clinical picture often leads to a substantial delay or initial misdiagnosis. If a patient is seen during a quiescent phase, they may not display physical hallmarks, and initial biochemical tests may appear normal. The unpredictable nature of the cycles means that a single laboratory test is insufficient to capture the hypercortisolemic episode.
Diagnosis relies heavily on demonstrating periods of cortisol excess through repeated, serial testing over time. Clinicians often require at least three confirmed high-cortisol periods interspersed by two periods of normal cortisol to formally establish the cyclical nature of the disorder. Reliable screening tools include frequent late-night salivary cortisol measurements, which patients can collect at home over multiple nights, and serial 24-hour urinary free cortisol collections.
Specific diagnostic tests, such as dynamic suppression or stimulation tests, can yield ambiguous results if performed during the trough of a cycle. For instance, a patient in remission might show appropriate cortisol suppression after a low-dose dexamethasone test, falsely suggesting a normal response. Newer diagnostic approaches, such as measuring cortisol levels in hair samples, are being explored because hair growth provides a retrospective, long-term record of circulating cortisol levels, which can help detect a history of hormonal cycling.
Therapeutic Strategies
The primary objective for treating cyclical Cushing’s Syndrome is to eliminate the source of the excess cortisol production. The preferred first-line approach is surgical removal of the tumor, which offers the best chance for long-term remission. For pituitary adenomas, the standard procedure is transsphenoidal surgery.
If the source is an adrenal tumor, a unilateral adrenalectomy (removal of the affected adrenal gland) is the standard surgical treatment. For ectopic ACTH-secreting tumors, surgery to resect the non-pituitary tumor is attempted if it can be precisely located. Patients with cyclical Cushing’s disease have a higher rate of recurrence following pituitary surgery compared to those with the non-cyclical form.
Medical management is a secondary option when surgery is unsuccessful, not feasible, or while a patient awaits radiation therapy effects. Pharmacological agents block excessive cortisol production by the adrenal glands. Examples of these steroidogenesis inhibitors include ketoconazole and metyrapone, which interfere with cortisol synthesis enzymes. In severe cases where other treatments fail, a bilateral adrenalectomy (removal of both adrenal glands) may be considered, though this necessitates lifelong hormone replacement therapy.
Long-term follow-up and monitoring are essential due to the disorder’s cyclical nature. Post-treatment assessment is complicated because a patient may cycle into a remission phase, making it difficult to confirm a true cure. Regular monitoring of cortisol levels over an extended period is necessary to detect recurrence.