CUSHING SYNDROME: CAUSES, SYMPTOMS, AND TREATMENT

Cushing Syndrome, also termed as Cushing’s Syndrome is a rare disorder that occurs due to exposure to high levels of the hormone cortisol for an extended period. It is named after the neurosurgeon Harvey Cushing, who first described the condition in 1932. Recently, actress Amy Schumer revealed her diagnosis of Cushing Syndrome after receiving high-dose corticosteroid injections, bringing attention to this often misunderstood disorder.

What is Cushing Syndrome?

Cushing Syndrome is an often reversible hormonal condition that is induced by prolonged exposure to high cortisol levels. Cortisol is a hormone produced by the adrenal glands. It is known as the "stress hormone" because it is released in response to stress and drives the body's "fight-or-flight" response. Chronic stress can lead to cortisol overproduction, adversely affecting the body.

Cortisol affects nearly every tissue and plays a vital role in the body's daily functions^[1], such as regulating blood pressure, metabolism, and the immune system. It also helps the body respond to stress by elevating blood glucose levels and suppressing immune function.

Under normal conditions, these are protective responses that help the person during an emergency. At the micro level, immune system suppression helps to limit any potential damage caused by excess inflammation and promotes optimal recovery.

Prolonged cortisol exposure can lead to a range of health problems, including weight gain, infection susceptibility, erratic blood glucose levels, impaired tissue renewal, and depression.

The prevalence of Cushing syndrome is unknown, yet is estimated to affect 40 to 70 people per million^[2]. It affects more women than men on average.

What Causes Cushing Syndrome?

There are three types of Cushing Syndrome with slightly different causes^[3]:

• Cushing's Disease: This type of Cushing Syndrome is caused by a pituitary gland tumor that secretes excess Adrenocorticotropic Hormone (ACTH). This hormone signals the adrenal glands to produce cortisol.
• Secondary Cushing Syndrome: This type is caused by a tumor outside the pituitary gland that elevates ACTH.
• Ectopic ACTH Syndrome: This type is caused by a tumor outside the pituitary gland that produces ACTH. The tumor may occur in the thyroid, pancreas, or thymus.

Cushing's syndrome is also classified as endogenous (body-derived) and exogenous (external intake). Exogenous cases are caused by prolonged glucocorticoid use, whereas Cushing's disease causes up to 80% of endogenous cases.

Glucocorticoids may be prescribed to treat long-term musculoskeletal pain, autoimmune diseases such as rheumatoid arthritis and lupus, severe chronic infections, and asthma. A doctor may also prescribe corticosteroids after surgery to suppress the immune system's response, especially after organ transplantation.

Cushing's disease and Ectopic ACTH syndrome are ACTH dependent, meaning that diagnostic tests will show higher than average ACTH levels. ACTH-independent Cushing's syndrome is not detectable by looking at ACTH levels. Common causes include adrenal gland enlargement (hyperplasia), adenoma, and carcinoma.

There are various types of hereditary Cushing's syndrome pertaining to specific hereditary tumors. These include^[4]:

• Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by an inactivating mutation in the MEN1 gene. People with MEN1 may develop tumors in the parathyroid glands, pituitary gland, and pancreatic islet cells.
• Multiple endocrine neoplasia type 4 (MEN4) is a rare condition caused by a CDKN1B gene mutation. It is similar to MEN1 but can also cause tumors in the adrenal glands. Mutations in the CDKN1B gene can increase the risk of developing this condition and Cushing syndrome.
• Familial isolated pituitary adenomas (FIPA) is a condition that causes pituitary tumors in multiple members of a family. A mutation in the AIP gene causes it.
• Carney complex is a rare genetic disorder that causes unusual skin pigmentation and increases the risk of developing various tumors, including heart tumors and hormone-producing gland tumors. Mutations in the PRKAR1A gene cause this condition and can be passed down within families.

Other mutations that increase the risk of developing Cushing's syndrome include PDE11A and PDE8B, yet their role is still under investigation.

There are many more gene mutations associated with the development of pituitary gland tumors and other tumors that can cause Cushing's syndrome.

Risk Factors

Other risk factors that can lead to chronically elevated cortisol levels and promote the development of Cushing's syndrome include^[5]:

• A severely traumatic life event
• Chronic extreme stress
• Post-Traumatic Stress Disorder (PTSD)^[6]
• Mania and bipolar disorder
• Chronic anxiety or related disorders, such as GAD (generalized anxiety disorder)
• Chronic inflammation, infections, or exposure to harmful substances
• Repeated traumatic injuries
• Cancer

What are the Differences Between Cushing's Disease and Adrenal Insufficiency (Addison's Disease)?

Cushing's disease and Addison's disease are both hormonal disorders that affect the adrenal glands. A pituitary gland tumor causes Cushing's disease, while the cause of Addison's disease is damage to the adrenal glands, giving rise to a cortisol production deficit and hypersensitivity to cortisol.

Symptoms of Cushing Syndrome

Chronic cortisol elevation in Cushing's syndrome wreaks havoc on the body's delicate hormonal balance, leading to a cascade of adverse effects^[7]:

1. Metabolic Disruption: Cortisol usually helps regulate blood sugar levels. When chronically elevated, it disrupts this process, leading to high blood sugar (hyperglycemia) and potentially diabetes.
2. Immune Suppression: Cortisol is a natural anti-inflammatory hormone, but too much suppresses the immune system, making you more susceptible to infections and hindering wound healing.
3. Muscle Wasting: Cortisol promotes the breakdown of muscle tissue for energy. Chronically high levels lead to muscle weakness and fatigue, making even simple tasks difficult.
4. Bone Loss: Cortisol inhibits the formation of new bone and promotes its breakdown. This weakens bones, increasing the risk of osteoporosis and fractures.
5. Cardiovascular Issues: Chronic cortisol can contribute to high blood pressure, increase cholesterol levels, and stiffen blood vessels, all of which raise the risk of heart disease and stroke.
6. Weight Gain and Fat Redistribution: Cortisol promotes fat storage, particularly in the abdomen, upper back, and face, leading to the characteristic "moon face" and "buffalo hump" (fatty lump between the shoulders) associated with Cushing's syndrome.
7. Neurological and Psychological Effects: Chronic cortisol exposure can impair memory, focus, and mood, leading to anxiety, depression, and difficulty sleeping. Some people experience intense mood swings or emotions that are difficult to control.

These are just some of the significant biological effects of chronic cortisol elevation in Cushing's syndrome. It is a complex condition with wide-ranging consequences, highlighting the significance of preserving a healthy hormonal profile.

Other physical symptoms of Cushing's syndrome may include^[8]:

• Thin, fragile skin that bruises easily
• Purple stretch marks on the skin
• Acne
• Fatigue or chronic exhaustion
• Loss of libido
• Irregular or absent menstrual periods in women
• Female hirsutism (abnormal unruly hair growth)
• Erectile dysfunction and breast development (gynecomastia) in men

How is Cushing's Syndrome Diagnosed?

Diagnosing Cushing's syndrome can be complex because its symptoms can mimic those of other conditions like depression, polycystic ovary syndrome, or metabolic syndrome.

The diagnosis often involves multiple tests and may require consultation with an endocrinologist (a specialist in hormone disorders). A doctor will review your medical history, discuss your symptoms, and perform a physical exam. They may observe signs of Cushing's, such as central obesity, a rounded face, easy bruising, or stretch marks.

Tests for Cushing's syndrome include:

Blood and Urine Tests: These tests measure cortisol levels in your blood and urine.

High cortisol levels suggest possible Cushing's syndrome. Blood tests may also reveal high ACTH levels, yet normal levels do not necessarily rule out Cushing's syndrome when other symptoms are present.

Other standard tests include:

• 24-Hour Urinary Free Cortisol Test: You collect urine over 24 hours for analysis.
• Late-Night Salivary Cortisol Test: Measuring cortisol levels in your saliva late at night can point towards abnormal cortisol production.

Suppression Tests to Assess Cortisol Levels: These tests help determine how your body responds to cortisol regulation:

• Low-Dose Dexamethasone Suppression Test (LDDST): You take a low dose of dexamethasone, a synthetic cortisol, at night. The following morning your cortisol level is measured. Usually, it registers as low. In Cushing's syndrome, it often won't drop^[9].
• High-Dose Dexamethasone Suppression Test (HDDST): This test is useful if the  LDDST results are unclear. It is similar but with a higher dose of dexamethasone to help pinpoint the cause of Cushing's syndrome.

Imaging Studies (CT Scan, MRI): Imaging tests can visualize your adrenal or pituitary glands, potentially locating tumors or other abnormalities. CT scans or MRIs are the standard diagnostic tools for Cushing’s disease^[10].

Petrosal Sinus Sampling: This specialized test helps determine if the excess cortisol is coming from the pituitary gland or elsewhere. It involves taking blood samples from veins that drain the pituitary gland and comparing cortisol levels to those in the rest of your body.

How to Treat Cushing Syndrome?

Cushing's syndrome treatment depends on the cause of the condition. If the cause is long-term use of corticosteroids, your doctor may gradually reduce your dosage or switch you to a different medication.

Other treatment options revolve around suppressing cortisol levels and tumor removal^[11]:

• Surgery: Surgical removal of a tumor that is elevating body cortisol is a popular treatment for cancer-related Cushing's syndrome and Cushing's disease. For tumors on the pituitary gland, transsphenoidal surgery is optimal.^[12] This minimally invasive procedure involves accessing the pituitary gland through the nose. With the aid of a microscope, the surgeon removes the tumor, potentially curing Cushing's syndrome.
• Medications: Certain medications can help control cortisol production or suppress the adrenal glands.
• Radiation Therapy: In some patients, radiation therapy may shrink tumors and prevent recurrence. Studies suggest that stereotactic radiation therapy may be safer for cortisol normalization in those with Cushing disease than conventional radiotherapy.
• Treating Underlying Conditions: If another medical condition contributes to cortisol production, such as a pituitary tumor causing secondary Cushing's syndrome, treatment for that condition may be necessary.

All of the above treatment options can cause side effects. It is crucial to have the doctor explain and discuss the risks and benefits with you.

Complications of Cushing Syndrome

If left untreated, Cushing Syndrome can lead to a range of complications, including:

• High blood pressure
• Type 2 diabetes
• Osteoporosis
• Increased risk of infections
• Depression and anxiety
• Infertility
• Increased risk of heart disease and stroke

Can Cushing's Syndrome be Prevented?

There is no known way to prevent Cushing Syndrome. However, if you are taking corticosteroids, it is essential to follow your doctor's instructions and not stop taking them suddenly.

Living With Cushing Syndrome

Living with Cushing Syndrome can be challenging, but there are ways to manage the symptoms and improve your quality of life. Some tips for living with Cushing Syndrome include:

• Cushing Syndrome Diet: A nutritious diet can help control some of the symptoms of Cushing Syndrome, such as weight gain and high blood pressure. Limiting salt, sugar, and processed food intake and focusing on whole, nutrient-dense foods is essential. Vitamin D supplementation, sunshine, and dietary calcium are necessary to prevent bone mineral loss.^[13]
• Exercise: Regular exercise can limit excessive weight gain and improve overall health. The ideal forms of exercise do not place pressure on the skeletal system, such as jogging and weight lifting. Gentle exercises, such as cycling, walking, or swimming are good for those with Cushing's syndrome^[14].
• Stress management: Since stress can exacerbate the symptoms of Cushing Syndrome, it is essential to manage stress with techniques such as meditation, yoga, or therapy.
• Stay informed: Stay current on Cushing Syndrome treatment and research advancements by referring to online resources or talking to your doctor.

Latest Advancements in Cushing Syndrome

Researchers are continually working to find new and improved treatments for Cushing Syndrome. Some recent advancements include:

• New medications: Researchers are studying medications that may help reduce cortisol levels in people with Cushing Syndrome.^[15]
• Pasireotide: This drug mimics somatostatin, a natural hormone that inhibits cortisol production, and shows promise^[16] in treating Cushing's disease.
• Next-Generation Pasireotide Analogues: New, longer-acting pasireotide analogs are underway to improve treatment adherence and efficacy.
• Lanreotide DEPOT: This long-acting somatostatin analog offers promise for treating Cushing's disease.
• Gene therapy: Scientists are exploring the applications of gene therapy to target and shrink tumors that cause Cushing Syndrome.
• Targeted Therapy with USP8 Inhibitors: Mutations in the ubiquitin-specific protease 8 (USP8) gene have been reported in corticotroph tumors. The mutations increase the enzyme's activity, producing excessive hormones. Given the role of USP8 mutations, researchers are developing drugs that inhibit USP8 activity. This offers a potential targeted therapy for Cushing's disease.
• Improved surgical techniques: Surgeons continually refine surgical methods to remove tumors more effectively and with fewer side effects.

Conclusion

Cushing Syndrome is a rare endocrine condition that can significantly impact a person's health and well-being. To manage the condition effectively, it is essential to understand the symptoms and tackle the underlying causes with an appropriate treatment plan. If you are experiencing symptoms of Cushing Syndrome, it is essential to consult with a specialist doctor for proper diagnosis and treatment.

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