What Is Cushing's Disease (Cushing’s Syndrome)?

Key differences between Cushing’s disease and Cushing’s syndrome include:

Cushing’s syndrome

• Excess cortisol due to either external or internal factors may cause Cushing’s syndrome.
• It can result, for example, from the use of corticosteroid medicines such as prednisone.
• It might be caused by an adrenal tumor or adrenal hyperplasia, which causes the body to produce too much cortisol.
• Cushing’s syndrome is due to mutations in genes such as CTNNB1, APC, and PRKACA.

Cushing’s disease

• This occurs due to, specifically, a pituitary tumor that causes the body to produce an excessive amount of cortisol.
• Cushing’s disease is the most frequent type of endogenous (from the body) Cushing’s syndrome, accounting for about 70 percent of people with Cushing’s syndrome.
• Cushing’s disease is due to mutations in genes such as Menin 1, NR3C1, AIP, TP53, and NR0B1.

Cortisol-like steroid treatment, such as prednisone, is the most prevalent cause of Cushing's syndrome. To treat various illnesses such as lupus and asthma, these drugs may be prescribed at a high dose for an extended period. Some people are genetically predisposed to be more susceptible to cortisol-like hormones than others.

Tumors or nodules in or around the pituitary and adrenal glands might possibly be the source of the problem.

Four common causes of Cushing’s syndrome include:

1. Cushing’s disease:
   • It is caused by noncancerous pituitary gland tumors that release adrenocorticotropic hormone (ACTH).
   • A high level of ACTH activates the adrenal glands, causing them to overproduce cortisol.
2. Ectopic ACTH syndrome:
   • It is linked with malignant or noncancerous tumors that form outside the pituitary and adrenal glands, most commonly in the lungs, and generate an excess of ACTH.
3. Cortisol-producing adrenal tumors:
   • Adrenal tumors (adrenal nodules) can produce an abnormally high level of cortisol.
   • Because symptoms might be modest at first, they may go unnoticed for many years.
4. Familial Cushing's syndrome:
   • The majority of Cushing's syndrome instances are not hereditary.
   • Some people, however, may acquire Cushing's syndrome owing to a genetic proclivity to develop tumors of one or more endocrine glands. 
   • Children or young adults with primary pigmented micronodular adrenal illness develop tiny cortisol-producing tumors of the adrenal glands.
   • Hormone-secreting tumors of the parathyroid glands, pancreas, and pituitary gland can arise in multiple endocrine neoplasia type I (MEN I).
   • Cushing's syndrome may be caused by the pituitary, ectopic, or adrenal tumor in MEN I.

Cushing’s disease or syndrome is uncommon. Each year, about 10 to 15 new cases per million people are diagnosed in the United States. It is more common in adults aged 20 to 50 years. Cushing’s disease or syndrome affects women nearly three times more than men.

Normally, our bodies maintain a healthy amount of cortisol through a complicated mechanism that involves three glands: the brain, pituitary gland, and adrenal glands.

When this mechanism is thrown off, our cortisol levels might become high. If they remain high for an extended period, they might create symptoms and lead to significant issues. Cortisol, when present in enough amounts, aids the body's response to stress, regulates vital bodily activities, and converts fat, carbs, and proteins into energy.

Too much cortisol can cause Cushing's syndrome, resulting in symptoms such as:

1. Central body obesity with relatively thin arms and legs
2. Buffalo hump (fat deposition between the shoulder blades)
3. Round, full face (moon facies)
4. Fatigue
5. Flushing in the face
6. Thin skin with a tendency to bruise
7. Acne and skin problems
8. Purple stretch marks over the stomach, upper arms, thighs, and breasts
9. Diabetes mellitus
10. High blood pressure
11. Osteoporosis
12. Excess facial hair and fewer menstrual periods in women
13. Female balding
14. Decreased libido or erection difficulties in men
15. Infertility in both men and women
16. Muscle weakness
17. Depression
18. Significant problems with memory and thinking
19. Headaches
20. Vertigo
21. Vision changes
22. Water retention
23. Thin skin
24. Easily bruised
25. Poor wound healing
26. Sleep disorders

Symptoms of Cushing's syndrome vary depending on the degree of excess cortisol in the body. Cushing's syndrome can be difficult to diagnose because symptoms do not always lead to the illness. In addition, other illnesses, such as polycystic ovary syndrome, are linked to Cushing's, making it difficult to diagnose.

Because Cushing's syndrome is an uncommon but significant illness, it is critical to rigorously rule out other disorders. This testing and exclusion procedure typically takes days to weeks and involves a great deal of patience and cooperation from the person being tested.

Doctors perform initial history, physical exam, and routine blood tests. The next step of Cushing’s syndrome diagnosis is to check the medications a person takes. Then, the next step consists of a variety of tests.

Three important tests to diagnose Cushing's syndrome include:

1. Urinary cortisol levels are measured to see if the body is producing too much cortisol. Urine can be collected for up to 24 hours. 
2. Cortisol levels fluctuate throughout the day. These levels fall dramatically in the evening in people who do not have Cushing's disease. If these levels are excessively high late at night, doctors may suspect Cushing's syndrome using a late evening saliva test. 
3. The dexamethasone suppression test is commonly used to diagnose Cushing's syndrome and involves measuring the cortisol level in the blood after taking dexamethasone.

The tumor is then located using localizing methods such as computed tomography scans or magnetic resonance imaging. Because pituitary tumors are often small and difficult to detect, a particular test of adrenocorticotropic hormone (ACTH) release from both sides of the pituitary (petrosal sinus sampling) may be required.

Small tumors that produce ectopic ACTH can be difficult to locate and need many scans and X-rays.

During your consultation sessions with your doctors, you may ask the following eight questions to help you further understand Cushing’s syndrome:

1. What is your underlying cause for Cushing’s syndrome?
2. How can you take care of your current symptoms?
3. What are the prevention tips for Cushing's syndrome? 
4. What treatment options can you expect after being diagnosed with Cushing's syndrome?
5. What can be the common side effects during treating Cushing's syndrome?
6. What is the life expectancy after successfully treating Cushing's syndrome?
7. What are the most common complications due to Cushing's syndrome?
8. How do I cope if I am diagnosed with Cushing's syndrome?

The best treatment for Cushing’s syndrome is determined by the reason for elevated cortisol levels in the body.

• When elevated levels are caused by the use of steroids, the syndrome is treated by gradually reducing medication use.
• When elevated levels are caused by an adrenal or pituitary tumor, treatment options may include:
  • Surgery to remove the tumor
  • Radiation therapy (in rare situations)
  • Cortisol replacement therapy following tumor removal
  • Medicines to prevent hormone release (if the tumor cannot be removed)

Surgery

• When a tumor causes Cushing’s syndrome, it is frequently removed surgically. 
• This is generally the initial step in therapy. Although surgery is typically effective, it does not always cure Cushing’s syndrome because the tumor may not always be well localized.
• Transsphenoidal surgery is the technique in which the pituitary tumor is removed through the nose, leaving the remaining pituitary function intact.
• If surgery is unsuccessful, you may require further therapies.
• The adrenal glands may not function properly straight away after surgery. 
• As a result, people have been prescribed cortisol replacement medicines. 
• The adrenal glands normally return to producing the physiological quantity of cortisol over time, implying that people can gradually wean themselves off the replacement medicines. This procedure might take a year or more.

Removal of the adrenal glands

• Some adrenocorticotropic hormone (ACTH)-secreting tumors are too tiny to be detected and removed. Cushing’s syndrome therapy in these situations entails removing both adrenal glands. This is known as bilateral adrenalectomy. 
• If people have severe Cushing’s syndrome manifestations and previous therapies have failed, they may require this procedure.
• If the person’s adrenal glands are removed, they will require hormone replacement (cortisol replacement) therapy for the remainder of their life.
• The drug provides the body with the hormones that the adrenal glands would ordinarily produce.

Radiation therapy

• If a surgeon is unable to remove the entire pituitary tumor, the person may require radiation therapy after surgery. 
• This therapy has the potential to kill what is left of the tumor. If it is not feasible to remove the entire tumor, the person may only get radiation therapy.

Medications

• If Cushing’s syndrome is severe, people may be given medication before surgery. 
• The doctor may offer medication before surgery to alleviate signs and symptoms and minimize the risks of the procedure.

Three pharmacologic strategies exist to treat Cushing’s syndrome which include:

1. Modulation of pituitary ACTH (decreasing cortisol secretion from the adrenal gland):
   • Cyproheptadine, octreotide, and valproic acid are among the medications used.
   • This technique has a low response rate, and these agents are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of Cushing’s syndrome. 
2. Inhibition of cortisol’s action (blocking cortisol’s action):
   • Mifepristone inhibits glucocorticoid, androgen, and progestin receptor binding competitively.
   • In the United States, mifepristone is currently solely approved as an abortifacient. Its usage in CS is an off-label use, and more research is needed.
3. Inhibition of steroid synthesis (preventing steroid production):
   • Ketoconazole, mitotane, metyrapone, and etomidate are among the medications utilized in this method.
   • These medications work by inhibiting the conversion of cholesterol to cortisol through various methods. This results in a reduction in cortisol levels and the elimination of symptoms.
   • However, these agents are not FDA-approved to many side effects of this strategy.

Because the current pharmaceutical treatment does not address the underlying cause of high cortisol, it is mainly used as a supplementary therapy. When surgery or radiation is not indicated or is delayed, pharmacologic therapy may be required. Following treatment, more examinations are required to determine the efficacy of therapy.

Cushing’s syndrome is a rare condition with potentially serious complications if left untreated. Proper diagnosis is important to assess the underlying cause of Cushing’s syndrome, allowing for appropriate treatment. Pharmacologic treatment, while not first-line, plays a vital role for selected people with Cushing’s syndrome.

Dietary and lifestyle adjustments are the best ways to take care of yourself if you are diagnosed with Cushing’s syndrome.

Three ways to care for yourself if you are diagnosed with Cushing’s syndrome include:

1. Anti-inflammatory diet: By naturally regulating hormones, aiding digestion, and decreasing inflammation, nutrient-dense, unprocessed food can help prevent issues and alleviate symptoms. Eating foods high in calcium, vitamin D, vitamin K, and magnesium is beneficial to bone health, as is limiting your intake of artificial additives, processed grains, caffeine, alcohol, sugar, and salt.
   • Some of the best foods for fighting the effects of high cortisol include adrenal fatigue diet foods such as:
     • Healthy fats and omega-3 fatty acids 
     • Foods high in B vitamins
     • Foods with calcium, potassium, and magnesium 
     • High-protein foods
2. Exercise:
   • Exercise, when done reasonably and healthily can be an excellent method to reduce stress, control cortisol and manage your weight.
   • Another advantage of exercise is that it serves as an excellent diversion from stressful situations, reduces the detrimental effects of blood pressure, and protects the heart.
   • Work with your doctor to develop an exercise program that incorporates cardiovascular/aerobic exercises, strength training, and stress management approaches.
3. Rest and lower your stress: Getting adequate sleep is important for controlling cortisol and other hormones. To help fight stress and, therefore, increase cortisol levels, try some of the following natural stress relievers:
   • Meditation
   • Acupuncture
   • Deep breathing exercises
   • Massage therapy
   • Essential oil massage 

Avoid falls, which can result in fractures and injuries. Remove any loose rugs or other tripping hazards from your house. Consult your doctor regularly to check for additional issues such as diabetes, high blood pressure, and osteoporosis.

Many people with Cushing's disease experience anxiety and sadness. It is beneficial to speak with a professional, such as a therapist or counselor, and seek support from family, friends, and others who are experiencing similar difficulties.

• Connecting with other people is one of the finest ways to naturally relieve stress and feel happy. 
• You may easily join a support group online that helps you learn about living with the illness, such as the one produced by the Cushing's Support & Research Foundation.
• If you'd prefer to work with a professional, research has shown that cognitive-behavioral therapy (CBT) is one of the most effective stress-reduction techniques. Identifying causes of stress, rearranging priorities, altering one's response to stress, and discovering ways for managing and lowering stress are all part of CBT.

Support groups might be beneficial in dealing with Cushing’s syndrome and recovering from it. They bring you together with other individuals who are facing similar struggles, as well as their families and friends, and provide a space in which you may discuss common issues. 

Inquire with your doctor about local support groups. Your local health department, public library, phone book, and the internet are all useful places to look for a support group in your neighborhood.

If you have symptoms of Cushing’s syndrome, make an appointment with your physician immediately. Tell them about all of your symptoms. Take pictures that show what you looked like before having symptoms of Cushing’s syndrome. 

• Diagnosis is not as easy as one would expect. Once Cushing’s syndrome has been diagnosed, it is important to find the cause of cortisol overproduction.
• Currently, a lot of research is being done on therapies. There have been several advances in the diagnosis and treatment of Cushing’s syndrome, such as novel magnetic resonance imaging methods for localizing tiny pituitary tumors, petrosal sinus sampling, endoscopic transnasal pituitary surgery, laparoscopic adrenalectomy, and stereotactic radiosurgery. 
• If left untreated, Cushing’s syndrome can be fatal.
• Cushing’s syndrome, with successful diagnosis and treatment, is generally associated with a good prognosis. 
• Many individuals can stop cortisol replacement therapy in less than one or two years although some individuals may have to continue therapy for the rest of their lives. Avoid using unproven supplements and herbs that claim to cure your condition. These may worsen your syndrome rather than relieve your symptoms.

If you think you have signs and symptoms that indicate Cushing’s syndrome, your care team should include:

• A general physician who evaluates your symptoms and then may refer you to other doctors
• An endocrinologist (a doctor who specializes in hormonal disorders)
• A neurosurgeon, once the diagnosis of Cushing’s syndrome is made
• A dietician and nutritionist to help you with your lifestyle modifications to have better outcomes during and after treatment
• A physical therapist who may help you with exercises that may suit your age and underlying health condition

It is always best to take a doctor’s appointment that is near to your community because the treatment of Cushing’s syndrome has some side effects that may need frequent hospital visits.