Cyclical Cushing's syndrome – what to know?

The condition known as cyclical Cushing's syndrome is an extremely rare disorder. In its course, cortisol is excessively secreted, but in an episodic manner. This makes it similar to Cushing's syndrome, yet it poses a greater challenge for endocrinologists. Its symptoms can be confused with other diseases, often leading to delays in diagnosis.

In Poland, only a few specialized centers are involved in diagnosing and treating this syndrome. This in turn makes its diagnosis difficult, and patients often remain without help. It therefore requires an experienced endocrinologist who knows how to diagnose this syndrome.

Proper diagnosis of cyclical Cushing's syndrome requires a multi-step approach that includes repeatedly performed laboratory tests and imaging studies, as single tests are not reliable. A key element is the measurement of cortisol at different times of the day. These can be tests of urine, saliva, or blood, but in many cases, this is not sufficient for a full diagnosis due to fluctuations in cortisol levels influenced by various factors.

Hospitals use suppression tests with dexamethasone, which are an important diagnostic method. These involve administering a synthetic glucocorticoid that should reduce cortisol secretion. In most patients with cyclical Cushing's syndrome, the response may be inadequate or contrary. A reliable method is the measurement of cortisol in hair, which can estimate its concentration over the past few months, helping to confirm the diagnosis.

Imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), are also essential. These allow for the localization of pituitary or adrenal tumors that may be causing excessive cortisol secretion. However, in some patients, these methods may not confirm the diagnosis. In such cases, scintigraphy, which uses labeled isotopes, is employed. This helps in the identification of structures that cause cyclical cortisol spikes.

Differentiating symptoms is also crucial, as those associated with cyclical Cushing's syndrome are similar to those seen in metabolic syndrome, depression, and other endocrine disorders. Making an accurate diagnosis requires the doctor to rule out these conditions.

Endocrinologists from the Military Medical Institute in Warsaw were the first in Poland to start routinely performing inferior petrosal sinus sampling in adults. Current guidelines state that this procedure should be performed in most patients with suspected Cushing's disease, including its cyclical form. Despite being a complex diagnostic method, specialists at the Military Medical Institute decided to implement it.

This has improved the quality of care for patients with cyclical Cushing's syndrome, a particularly challenging form of the disease. It poses diagnostic difficulties even for very experienced endocrinologists because the troublesome symptoms of hypercortisolemia can occur irregularly and be interspersed with periods of normocortisolemia lasting from a few days to even several years.

The most common cause of the disease is a pituitary adenoma that secretes ACTH, stimulating the adrenal glands to overproduce cortisol, causing symptoms. However, the disease can also be caused by tumors of the lungs, pancreas, adrenal cortex, or colon, and sometimes other areas. These are often ectopic tumors, meaning they are located outside the brain.

Literature shows that ectopic ACTH secretion can be associated with various tumors, such as carcinoid tumors of the thymus, lungs, pancreas, kidneys, or stomach. Much less frequently, cyclical Cushing's syndrome is ACTH-independent, which may result from even the smallest adrenal cortex tumors or nodular adrenal hyperplasia, posing a significant threat.

Before the implementation of the petrosal sinus sampling method, the search for a pituitary tumor occurred only during neurosurgical operations, which were sometimes unnecessary. If the tumor was located in another organ, this complex surgery did not solve the problem. Currently, thanks to this new diagnostic method, it is possible to locate the source of the disease earlier and more precisely.

In many countries, petrosal sinus sampling is a standard diagnostic procedure for Cushing's disease. This is especially important because half of pituitary adenomas are smaller than 5 millimeters, making them invisible in magnetic resonance imaging and therefore undetectable.

According to international recommendations, it should be performed in most patients with suspected Cushing's disease. In Poland, these standards were not previously met because no center was willing to undertake this complex procedure.

The cyclical nature of this form of Cushing's syndrome makes its diagnosis particularly challenging. Episodic symptoms can come and go, leading to misinterpretation of test results, especially during remission phases when cortisol levels are normal. This, in turn, hinders the diagnosis, leading to incorrect conclusions.

Another challenge is the lack of specific symptoms that indicate cyclical Cushing's syndrome. The symptoms are nonspecific and include fatigue, weight gain, and mood disturbances, but often also involve skin problems and hypertension. Such a variety of symptoms can cause doctors to suspect other diseases.

Another barrier is the low availability and high cost of tests conducted by specialized facilities. Diagnostic tests, such as cortisol measurement from hair, are quite expensive. Even a 24-hour cortisol measurement may not help in diagnosis if it does not coincide with a cortisol release cycle. Therefore, such tests are not performed in smaller medical centers. It requires a stay in a specialized facility, where waiting lists can exceed several years.

Diagnosis is complicated by the uncertainty of test results, as it is never certain if the patient's cortisol level is temporary. The nature of this disease means that high cortisol appears cyclically and in response to certain factors. These factors typically remain unknown until full diagnostics are performed. Cyclical changes in cortisol levels can cause even multiple tests to yield inconclusive results. This requires repeated testing over different periods.

In Poland, only a few specialized centers are involved in diagnosing and treating cyclical Cushing's syndrome. Such studies are primarily conducted by the Military Medical Institute in Warsaw, but some patients report that they are also conducted by other facilities, such as the University Clinical Center WUM in Warsaw and the University Hospital in Krakow.

The lack of access to specialized centers in smaller cities means that patients often have to travel long distances to receive proper medical care. This can be very burdensome for some patients.

Another problem is the shortage of endocrinologists, which is related to the declining number of doctors. Many regions lack specialist doctors with the appropriate knowledge and experience in diagnosing cyclical Cushing's syndrome, leading to significant delays in diagnosis and treatment. Patients often have to wait several months for an appointment with a specialist.

Financial constraints of the healthcare system also affect the diagnosis of cyclical Cushing's syndrome. Although diagnostic tests and therapies are fully covered by the National Health Fund, they are costly. As a result, not every facility is willing to perform them. This in turn limits access to essential services for many patients.

Education and awareness of the disease among primary care physicians are insufficient. Many doctors are not familiar with the cyclical nature of this form of Cushing's syndrome, leading to incorrect diagnoses and numerous unnecessary tests. Increasing awareness and training in recognizing rare endocrine diseases could significantly improve the situation.

Properly planned treatment of cyclical Cushing's syndrome may include pharmacotherapy, surgery, and lifestyle changes. In cases of pituitary or adrenal tumors, surgical removal of the tumor often yields the best results. Conversely, pharmacological treatment inhibits cortisol secretion or blocks its action.

A crucial aspect of managing the disease is a healthy lifestyle, which can help lower cortisol levels in the blood. Patients should avoid stress, which can trigger episodes of excessive cortisol secretion. Relaxation techniques such as yoga and meditation can be helpful as they effectively reduce stress, thereby lowering stress hormone levels.

A balanced diet is also significant, allowing the body to function better. It is recommended to consume healthy and balanced meals rich in protein, fiber, and healthy fats. It is also important to avoid excess simple sugars and salt to prevent weight gain and hypertension.

Sleep is vital in managing the disease. Patients with cyclical Cushing's syndrome should ensure regular and sufficient sleep as sleep disturbances can cyclically affect cortisol secretion. Establishing a bedtime routine, such as avoiding caffeine and electronics before sleep and creating an optimal sleep environment, can be significant.

We also encourage you to explore other articles on the best sleep and health blog, as well as the Encyclopedia of Healthy Sleep prepared by the ONSEN® team of specialists. For those who care about spine health, we recommend a set of spine exercises prepared by our physiotherapist.