Cushing's Syndrome: Causes and Symptoms

Cushing's Syndrome

• Cushing's syndrome results from prolonged exposure to high levels of cortisol.
• Cortisol is a glucocorticoid hormone produced by the adrenal glands, vital for regulating metabolism, immune response, and stress response.
• Cushing's syndrome can result from either endogenous causes (within the body) or exogenous causes (outside the body).
• Exogenous Cushing's syndrome is more common and typically caused by long-term, high-dose glucocorticoid medications, such as prednisone, used to treat inflammatory conditions like arthritis, asthma, or autoimmune diseases.
• Endogenous Cushing's syndrome can be further divided into ACTH-dependent and ACTH-independent causes.
• ACTH-dependent Cushing's syndrome is caused by excessive production of adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol.
• The most common cause of ACTH-dependent Cushing's is a pituitary adenoma (Cushing's disease) that secretes excessive ACTH.
• Ectopic ACTH syndrome, where non-pituitary tumors (e.g., lung tumors, pancreatic tumors) secrete ACTH, is a less common cause of ACTH-dependent Cushing's.
• ACTH-independent Cushing's syndrome is caused by adrenal gland abnormalities that lead to excessive cortisol production, regardless of ACTH levels.
• Adrenal adenomas or carcinomas are common causes of ACTH-independent Cushing's syndrome.
• Nodular adrenal hyperplasia, where both adrenal glands are enlarged and produce excess cortisol, is a rarer cause.

Signs and Symptoms of Cushing's

• Weight gain, particularly in the trunk (central obesity) and face ("moon face").
• Changes to the skin, including acne, thin skin, easy bruising, and purplish stretch marks (striae) on the abdomen, thighs, and breasts.
• Muscle weakness, especially in the upper arms and thighs.
• Fatigue and depression or anxiety.
• High blood pressure and elevated blood sugar levels, potentially leading to diabetes.
• Osteoporosis and increased risk of fractures due to cortisol's effects on bone metabolism.
• In women, hirsutism (excessive hair growth) and menstrual irregularities.
• In men, decreased libido and erectile dysfunction.
• Other signs may include headaches, cognitive difficulties, and increased susceptibility to infections.

Diagnosis of Cushing's

• Initial screening tests include a 24-hour urinary free cortisol test, late-night salivary cortisol measurement, or a low-dose dexamethasone suppression test (LDDST).
• The 24-hour urinary free cortisol test measures the total amount of cortisol excreted in the urine over 24 hours, with elevated levels suggesting Cushing's syndrome.
• Late-night salivary cortisol measurement assesses cortisol levels in saliva collected late at night, as cortisol levels are normally low at this time.
• The LDDST involves administering a low dose of dexamethasone (a synthetic glucocorticoid) and measuring cortisol levels the next morning; failure to suppress cortisol indicates Cushing's syndrome.
• If screening tests are positive, further tests are needed to determine the cause of Cushing's syndrome.
• An ACTH measurement can differentiate between ACTH-dependent and ACTH-independent causes.
• High or normal ACTH levels suggest ACTH-dependent Cushing's, while low ACTH levels suggest ACTH-independent Cushing's.
• A high-dose dexamethasone suppression test (HDDST) may help differentiate between pituitary and ectopic sources of ACTH.
• Imaging studies, such as MRI of the pituitary and CT scans of the adrenal glands, can help locate tumors or abnormalities.
• Inferior petrosal sinus sampling (IPSS) is a specialized test used to confirm a pituitary source of ACTH by measuring ACTH levels in the petrosal sinuses, which drain the pituitary gland.

Treatment of Cushing's

• Treatment depends on the underlying cause of Cushing's syndrome.
• For exogenous Cushing's syndrome, gradually reducing the dose of glucocorticoid medication is recommended under medical supervision.
• For Cushing's disease (pituitary adenoma), surgical removal of the tumor via transsphenoidal surgery is the primary treatment.
• Radiation therapy may be used if surgery is not completely successful or if the tumor recurs.
• Medications, such as ketoconazole, metyrapone, or osilodrostat can be used to block cortisol production.
• Pasireotide, a somatostatin analog, can be used to reduce ACTH secretion from pituitary tumors.
• For ectopic ACTH syndrome, treatment focuses on removing the tumor that is producing ACTH, often through surgery, chemotherapy, or radiation therapy, depending on the type and location of the tumor.
• Medications to block cortisol production may also be used while treating the underlying tumor.
• For adrenal adenomas or carcinomas, surgical removal of the adrenal gland (adrenalectomy) is the primary treatment.
• Medications may be necessary to manage cortisol levels before surgery.
• Mitotane, an adrenolytic drug, can be used to treat adrenal carcinomas and reduce cortisol production.
• Following treatment, patients require long-term monitoring for recurrence and adrenal insufficiency.
• Hydrocortisone replacement therapy may be needed temporarily or permanently after surgery, especially if both adrenal glands were removed.

Addison's Disease

• Addison's disease, also known as primary adrenal insufficiency, is a rare endocrine disorder in which the adrenal glands do not produce enough cortisol and aldosterone.
• Cortisol is a glucocorticoid that regulates metabolism, stress response, and immune function.
• Aldosterone is a mineralocorticoid that regulates sodium and potassium balance, as well as blood pressure.
• Addison's disease is typically caused by autoimmune destruction of the adrenal cortex, where the body's immune system mistakenly attacks and damages the adrenal glands.
• Other less common causes include infections (such as tuberculosis), hemorrhage into the adrenal glands, tumors, genetic disorders, and certain medications.

Signs and Symptoms of Addison's

• Chronic and worsening fatigue.
• Muscle weakness.
• Loss of appetite and unintentional weight loss.
• Hyperpigmentation (darkening of the skin), particularly in skin creases, scars, and gums.
• Low blood pressure, which may cause dizziness or fainting upon standing (orthostatic hypotension).
• Salt craving due to aldosterone deficiency.
• Nausea, vomiting, and abdominal pain.
• Diarrhea or constipation.
• Muscle and joint pain.
• Irritability, depression, or other mood changes.
• In women, menstrual irregularities and loss of body hair.

Diagnosis of Addison's

• An ACTH stimulation test is the primary diagnostic test.
• The ACTH stimulation test involves measuring cortisol levels before and after an injection of synthetic ACTH.
• In healthy individuals, ACTH stimulates the adrenal glands to produce cortisol, resulting in a significant increase in cortisol levels.
• In Addison's disease, the adrenal glands are damaged and unable to respond to ACTH, resulting in little or no increase in cortisol levels.
• A baseline cortisol level may also be measured, but it is less reliable than the ACTH stimulation test.
• Plasma ACTH levels are typically elevated in primary adrenal insufficiency, as the pituitary gland attempts to stimulate the underactive adrenal glands.
• Electrolyte abnormalities, such as low sodium and high potassium, may be present due to aldosterone deficiency.
• An insulin-induced hypoglycemia test may be used to assess cortisol response to stress, but it is less commonly used due to potential risks.
• Imaging studies, such as CT scans of the adrenal glands, may be performed to look for structural abnormalities or other causes of adrenal insufficiency.
• Antibody testing may be done to detect antibodies against adrenal tissue, which are often present in autoimmune Addison's disease.

Treatment of Addison's

• Treatment involves hormone replacement therapy to replace the missing cortisol and aldosterone.
• Hydrocortisone is a synthetic glucocorticoid used to replace cortisol.
• It is typically taken two or three times daily to mimic the body's natural cortisol rhythm.
• Prednisone or dexamethasone may also be used, but hydrocortisone is preferred due to its shorter duration of action.
• Fludrocortisone is a synthetic mineralocorticoid used to replace aldosterone.
• It helps regulate sodium and potassium balance and maintain blood pressure.
• Patients with Addison's disease must be educated about the importance of taking their medications regularly and the need to increase their hydrocortisone dose during times of stress, illness, or surgery.
• Patients should carry a medical alert card or wear a medical alert bracelet to inform healthcare providers about their condition in case of an emergency.
• Patients should have an emergency injection of hydrocortisone available for use in situations where they are unable to take oral medication, such as during severe vomiting or trauma.
• Regular monitoring is needed to adjust medication dosages and assess for complications.
• Monitoring includes assessing blood pressure, electrolytes, and symptoms of both over- and under-replacement of hormones.

Adrenal Crisis

• Adrenal crisis is a life-threatening condition that occurs when cortisol levels are critically low.
• It can be triggered by sudden discontinuation of glucocorticoid medication, severe stress, trauma, infection, or surgery in individuals with adrenal insufficiency.
• Symptoms include severe weakness, abdominal pain, vomiting, diarrhea, dehydration, low blood pressure, and loss of consciousness.
• Treatment involves immediate injection of hydrocortisone, followed by intravenous fluids and electrolyte replacement.
• Identifying and treating the underlying cause of the crisis is also crucial.