Cushing’s syndrome arises when the body is exposed to an abnormally high level of cortisol for an extended period. This excess cortisol can be due to several factors. One common cause is the overproduction of adrenocorticotropic hormone (ACTH). This overproduction can stem from tumors in the pituitary gland or from non-cancerous growths (adenomas) or an abnormal increase in the size of the adrenal glands (nodular hyperplasia).

Alternatively, Cushing’s syndrome can be defined as a hormonal disorder resulting from an overproduction of corticosteroids by the adrenal glands themselves or by the pituitary gland’s influence on the adrenal glands. Furthermore, prolonged use of corticosteroid medications can also lead to this syndrome.

Causes of Cushing’s Syndrome

• Prolonged Use of Corticosteroid Medications: Taking corticosteroid medications, such as prednisone, for extended periods is a significant cause of Cushing’s syndrome. These medications are often prescribed to treat inflammatory conditions or suppress the immune system.

• Hyperplasia of the Adrenal Gland: This refers to the enlargement of the adrenal glands, which can lead to the production of excess cortisol.

• Tumor in the Pituitary Gland Enhancing Overproduction of ACTH: The pituitary gland, located at the base of the brain, produces ACTH, which signals the adrenal glands to release cortisol. A tumor in the pituitary can cause it to overproduce ACTH, leading to excessive cortisol production. This specific form of Cushing’s syndrome is often referred to as Cushing’s disease.

• Tumor in One of the Adrenal Glands Above the Kidneys: A tumor in one of the adrenal glands can directly cause the gland to produce too much cortisol, independent of ACTH levels.

Clinical Presentation of Cushing’s Syndrome

The signs and symptoms of Cushing’s syndrome can vary from person to person but often include:

• Hirsutism: Excessive hair growth in women in places where it typically doesn’t occur, such as the face, chest, and back.

• Amenorrhea: The absence of menstruation in women of reproductive age.

• Easy Bruising and Acne: The skin may become thinner and more fragile, leading to easy bruising. Acne is also a common skin manifestation.

• Osteoporosis: The bones can become weakened and brittle due to the effects of excess cortisol, increasing the risk of fractures.

• Cataracts and Glaucoma: Individuals with Cushing’s syndrome have an increased risk of developing these eye conditions.

• Hypertension and Heart Failure: High blood pressure (hypertension) is common, and over time, the strain on the heart can lead to heart failure.

• Truncal Obesity, Moon Face, Buffalo Hump: A characteristic pattern of weight gain occurs, with increased fat around the abdomen (truncal obesity), a rounded face (moon face), and a collection of fat on the upper back and base of the neck (buffalo hump).

• Sodium Retention, Hypokalemia, Hyperglycemia: The body may retain excess sodium, leading to fluid retention. Low potassium levels (hypokalemia) and high blood sugar levels (hyperglycemia) are also frequently observed.

• Negative Nitrogen Balance and Altered Calcium Metabolism: The body may break down more protein than it builds (negative nitrogen balance). Calcium metabolism is also affected, which contributes to bone weakening.

• Decreased Inflammatory Responses, Impaired Wound Healing, Increased Susceptibility to Infections: Cortisol can suppress the immune system, leading to a reduced ability to fight off infections and slower wound healing.

• Peptic Ulcers and Pancreatitis: There is an increased risk of developing ulcers in the stomach or duodenum (peptic ulcers) and inflammation of the pancreas (pancreatitis).

• Thinning of Skin, Striae, Acne: The skin can become thin and fragile, leading to the formation of purple or pink stretch marks (striae), particularly on the abdomen, thighs, and arms. Acne is also a common skin problem.

• Mood Alterations: Individuals with Cushing’s syndrome may experience a range of mood changes, including irritability, anxiety, and emotional lability.

• Depression: Depression is a significant psychological symptom associated with Cushing’s syndrome.

Diagnosis

Diagnosing Cushing’s syndrome involves several tests:

• Overnight Dexamethasone Suppression Test: This is a frequently used screening test. Dexamethasone, a synthetic corticosteroid, is administered, typically around 11 pm. The next morning, around 8 am, the level of cortisol in the blood is measured. In individuals with normal adrenal function, dexamethasone should suppress cortisol production.

• Suppression of Cortisol: If the cortisol level is suppressed to less than 5 micrograms per deciliter (mcg/dL), it generally indicates normal functioning of the adrenal glands.

• Measurement of Plasma ACTH (Radioimmunoassay) in Conjunction with Dexamethasone Suppression Test: Measuring ACTH levels alongside the dexamethasone suppression test helps to determine the underlying cause of Cushing’s syndrome. It can differentiate between a pituitary source (Cushing’s disease) where ACTH levels might be elevated or inappropriately normal, and other causes like adrenal tumors or ectopic ACTH production, where ACTH levels might be low or very high, respectively.

• MRI, CT, and CT Scans: Imaging techniques such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scans are used to visualize the pituitary and adrenal glands to detect the presence of tumors or other abnormalities.

Management

The treatment strategy for Cushing’s syndrome depends on the underlying cause:

1. If Pituitary Source: For Cushing’s disease caused by a pituitary tumor, the primary treatment is often transsphenoidal hypophysectomy. This is a surgical procedure performed to remove the pituitary tumor, typically through the nasal passages.

2. Radiation of Pituitary: Radiation therapy to the pituitary gland may be considered if surgery is not feasible or if the tumor recurs after surgery.

3. Adrenalectomy: In cases where Cushing’s syndrome is caused by a tumor or hyperplasia of one or both adrenal glands, adrenalectomy, the surgical removal of one or both adrenal glands, may be necessary.

4. Temporary Replacement Therapy with Hydrocortisone or Florinef: Following surgery, particularly after bilateral adrenalectomy or hypophysectomy, the body may not produce enough cortisol. Therefore, temporary hormone replacement therapy with medications like hydrocortisone (a synthetic cortisol) or Florinef (fludrocortisone, a synthetic mineralocorticoid) may be needed to replace the hormones the body is no longer producing.

5. Adrenal Enzyme Reducers: If the source of excess cortisol is ectopic (meaning it’s produced by a tumor outside of the pituitary or adrenal glands) and inoperable, medications that reduce the production of cortisol by the adrenal glands may be used. Examples of these adrenal enzyme inhibitors include ketoconazole, mitotane, and metyrapone.

6. If Cause is Related to Excessive Steroid Therapy: If Cushing’s syndrome is due to the long-term use of corticosteroid medications, the appropriate management involves gradually tapering the dosage of the steroid down to the minimum effective dose necessary to manage the underlying condition. Abruptly stopping steroid medication can be dangerous.