What Causes Cushing’s Syndrome?

Cushing’s syndrome is a hormonal disorder that occurs as a result of having higher-than-normal levels of cortisol in the body for a prolonged period. Cortisol is one of the important hormones produced by the adrenal glands and regulates the body’s stress response. It also plays a role in blood sugar, blood pressure, the immune system, metabolism, and energy use. However, when cortisol levels remain high for a long time, they can cause adverse changes in many systems of the body.

The causes of Cushing’s syndrome may vary. In some people, the condition results from the long-term use of medications containing cortisone, while in others, it develops as a result of the body producing excessive amounts of cortisol. The Endocrine Society identifies corticosteroid use as one of the most common causes of Cushing’s syndrome and states that, in cases where the body’s own cortisol production increases, mechanisms such as excess ACTH or direct overproduction of cortisol by the adrenal glands may play a role.

Prof. Dr. Ömür Günaldı emphasizes the importance of investigating not only the symptoms of the condition but also its underlying cause in patients with suspected Cushing’s syndrome. This is because once the cause of Cushing’s syndrome is identified, the treatment approach is shaped accordingly.

What Is the Most Important Cause of Cushing’s Syndrome?

• Cushing’s syndrome caused by externally administered cortisol-like medications

• Cushing’s syndrome caused by excessive cortisol production within the body

In the medical literature, Cushing’s syndrome caused by externally administered corticosteroid medications is referred to as “exogenous” or “iatrogenic” Cushing’s syndrome. Increased production of the body’s own cortisol is referred to as “endogenous Cushing’s syndrome.”

The symptoms of these two conditions can be very similar. However, the treatment of the disease and the approach to its underlying cause are different.

Can Cortisone Medications Cause Cushing’s Syndrome?

Yes. Long-term or high-dose corticosteroid use is one of the most common causes of Cushing’s syndrome. Prednisone and similar medications with cortisol-like effects may be used for various purposes, including the treatment of asthma, rheumatic diseases, certain immune system disorders, inflammatory diseases, and suppression of the immune system following organ transplantation.

The dose, duration of use, and method of administration of these medications may affect the likelihood of developing Cushing-like symptoms. The Endocrine Society specifically recommends obtaining a detailed medication history before beginning hormone testing in patients with suspected Cushing’s syndrome.

There is an important point here: Medications containing cortisone should not be stopped suddenly without a doctor’s recommendation. Abrupt discontinuation of corticosteroids that have been used for a long period may cause the body’s own cortisol production to become insufficient. Reducing or discontinuing these medications must be carried out under medical supervision.

Are Cushing’s Disease and Cushing’s Syndrome the Same?

Cushing’s syndrome and Cushing’s disease are two related concepts, but they do not have the same meaning.

Cushing’s syndrome refers to the general clinical condition that occurs when the body is exposed to excessive cortisol for a prolonged period.

Cushing’s disease, on the other hand, is a specific type of Cushing’s syndrome and most commonly develops when a benign ACTH-secreting tumor in the pituitary gland produces excessive amounts of ACTH. The ACTH hormone stimulates the adrenal glands, increasing cortisol production.

Therefore, every case of Cushing’s disease is Cushing’s syndrome, but not every case of Cushing’s syndrome is Cushing’s disease.

How Does a Pituitary Tumor Cause Cushing’s Syndrome?

The pituitary gland is an important structure located at the base of the brain that regulates many hormonal systems in the body. When a small ACTH-producing adenoma develops in the pituitary gland, ACTH production may increase.

Excess ACTH continuously stimulates the adrenal glands to produce cortisol. As a result, the level of cortisol in the blood becomes higher than normal, and symptoms of Cushing’s disease may develop.

In pituitary-related Cushing’s disease, the tumors are usually benign and may sometimes be very small. Therefore, the diagnostic process may not always be easy. The Endocrine Society states that a pituitary adenoma is the most common cause of Cushing’s disease.

Prof. Dr. Ömür Günaldı emphasizes the importance of a comprehensive approach in pituitary-related hormonal disorders, in which changes in hormone production are carefully evaluated alongside the tumor itself.

Can the Adrenal Glands Cause Cushing’s Syndrome?

Yes. The adrenal glands are the organs that produce cortisol. If a cortisol-producing tumor or nodule develops in these glands, excessive cortisol may be produced independently of ACTH.

A significant proportion of cortisol-producing tumors in the adrenal glands may be benign. However, in some cases, malignant tumors may also produce hormones. Therefore, when a mass is detected in the adrenal gland during imaging, whether it produces hormones and its structural characteristics should be evaluated by a specialist physician.

The Endocrine Society states that, in endogenous Cushing’s syndrome, excess cortisol production may originate from the adrenal glands independently of ACTH.

What Is Ectopic ACTH Syndrome?

Another cause of Cushing’s syndrome is the production of ACTH by a tumor located outside the pituitary gland. This condition is called ectopic ACTH syndrome.

Under normal circumstances, the main source of ACTH is the pituitary gland. However, some tumors can also produce ACTH. These tumors may be located in different organs, such as the lungs. Excess ACTH may stimulate the adrenal glands and lead to excessive cortisol production.

The characteristics of tumors that cause ectopic ACTH production may differ from one another. Therefore, after diagnosis, it is important to identify the source of the hormone excess.

Can Stress Cause Cushing’s Syndrome?

Stress experienced in daily life is not, by itself, a direct cause of classic Cushing’s syndrome. During periods of stress, cortisol levels naturally increase in the body. This is a normal mechanism that helps the body adapt to stressful situations.

However, in Cushing’s syndrome, the problem is that cortisol remains higher than the body needs for a prolonged period. Therefore, experiencing intense stress and having Cushing’s syndrome in the medical sense are not the same thing.

In some situations, conditions such as depression, excessive alcohol consumption, or uncontrolled diabetes may also cause changes in cortisol regulation and produce a clinical picture resembling Cushing’s syndrome. Therefore, all of the patient’s clinical characteristics should be taken into consideration during the diagnostic process.

What Symptoms Are Seen in Cushing’s Syndrome?

Regardless of the cause of Cushing’s syndrome, prolonged excess cortisol may lead to similar symptoms.

• Weight gain in the trunk and abdominal area
• Rounding of the face
• Fat accumulation in the neck and upper back
• Muscle loss in the arms and legs
• Muscle weakness
• Purple or red stretch marks on the skin
• Easy bruising
• Thinning of the skin
• High blood pressure
• Elevated blood sugar
• Menstrual irregularities
• Excessive hair growth
• Decreased sexual desire
• Psychological changes
• Decreased bone density

may occur.

However, none of these symptoms alone is specific to Cushing’s syndrome. The Endocrine Society recommends investigating Cushing’s syndrome particularly in individuals who have multiple characteristic findings that progressively worsen.

Why Is Cushing’s Syndrome Diagnosed Late in Some People?

One of the important reasons Cushing’s syndrome may be recognized late is that its symptoms can develop gradually. A person may attribute weight gain to their diet, fatigue to a demanding work schedule, or high blood pressure to age.

However, the combination and progressive worsening of symptoms may be an important clue.

For example, the development of high blood pressure in someone whose blood pressure was previously normal, accompanied by significant abdominal weight gain and wide purple stretch marks, may require a more careful evaluation for Cushing’s syndrome.

Therefore, it is necessary to consider the symptoms as a whole rather than focusing on a single symptom.

How Is the Cause of Cushing’s Syndrome Determined?

First, it is investigated whether excess cortisol is actually present. For this purpose, methods such as 24-hour urinary free cortisol, late-night salivary cortisol, or the dexamethasone suppression test may be used when considered appropriate by the doctor.

Once excess cortisol has been confirmed, ACTH levels may be evaluated to determine whether the condition is ACTH-dependent. At a later stage, imaging methods targeting the pituitary gland, adrenal glands, or, when necessary, other areas of the body may be used.

An important point is that imaging tests do not replace hormone tests. Diagnosis and investigation of the underlying cause should be carried out in a step-by-step manner.

How Does the Cause of Cushing’s Syndrome Affect Treatment?

Treatment of Cushing’s syndrome is directed specifically at the underlying cause. If the condition is related to corticosteroid medication use, adjustment of the medications under medical supervision may be considered.

In pituitary-related Cushing’s disease, surgical removal of the tumor is one of the primary treatment options in appropriate patients. For cortisol-producing tumors in the adrenal glands, an appropriate surgical approach may be considered. In tumors producing ectopic ACTH, the goal is to locate and treat the tumor. When surgery is not possible or the disease persists, options such as medication and radiotherapy may be considered.

Therefore, accurately identifying the cause of Cushing’s syndrome is extremely important for the success of treatment.

Is Cushing’s Syndrome a Serious Disease?

Untreated, prolonged excess cortisol can lead to serious health problems. These may include hypertension, diabetes, osteoporosis, increased susceptibility to infections, and cardiovascular problems. The Endocrine Society recommends that these health conditions associated with Cushing’s syndrome also be addressed during treatment and follow-up.

There is no single answer to the question, “What causes Cushing’s syndrome?” The condition may develop due to externally administered corticosteroid medications or as a result of excessive cortisol production by the body. In endogenous Cushing’s syndrome, ACTH-producing tumors in the pituitary gland, independent overproduction of cortisol by the adrenal glands, and ACTH-producing tumors outside the pituitary gland are among the important causes.

It is also important to understand the difference between Cushing’s disease and Cushing’s syndrome. Cushing’s disease refers to pituitary-related Cushing’s syndrome. Because the symptoms of the condition often develop gradually, diagnosis may be delayed. Therefore, specialist evaluation should be considered particularly when multiple symptoms such as significant weight gain in the trunk, rounding of the face, purple stretch marks, muscle weakness, high blood pressure, and elevated blood sugar occur together.

Prof. Dr. Ömür Günaldı represents a comprehensive evaluation approach that emphasizes the importance of thoroughly investigating the cause of Cushing’s syndrome in order to reach an accurate diagnosis and developing a treatment plan according to the underlying cause.