Cushing’s Disease: Everything you need to know

Fatigue, easy bruising, weight gain—sound familiar? Cushing’s disease is a relatively rare endocrine condition that affects 10 to 15 million people per year. While an increase in the hormone cortisol may seem minuscule, symptoms in nearly every bodily system could be the result of a small, benign tumor transforming the way the body manages stress. What is Cushing’s disease, how is it diagnosed, how is it treated?

Cushing's Disease
Cushing’s Disease Glucose Intolerance and Diabetes

What is Cushing’s Disease?

To understand Cushing’s disease, one must first know about cortisol. Cortisol is a stress hormone belonging to the glucocorticoid class. It is produced by the adrenal glands above the kidneys and released in intervals throughout the day. ACTH, a second hormone made by the pituitary gland, stimulates its release. Cortisol levels are the highest in the morning and lowest at night with the purpose to help the body cope in times of stress. By increasing energy, cortisol manages metabolism, controls the sleep-wake cycle, heals the body from illness, and regulates blood glucose and the cardiovascular system.

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Cushing’s disease refers to an overproduction of cortisol secondary to a tumor or hyperplasia on the pituitary gland. Although pituitary growths are typically benign (non-cancerous), it results in a surplus of the hormone ACTH. Excess ACTH from the pituitary triggers the adrenal glands to produce more cortisol than normal.

Cushing’s Disease VS. Cushing’s Syndrome

Cushing’s disease and Cushing’s syndrome are often used interchangeably by the public. However, the two are not to be confused. The difference between the terms is that Cushing’s disease has one single cause—a tumor on the pituitary gland. Contrarily, Cushing’s syndrome refers to the excess production of cortisol for any number of reasons. Examples of Cushing’s syndrome causes are autoimmune conditions that are treated with corticosteroid medication or tumors of the adrenal gland.

Cause of Cushing’s Disease: Pituitary Tumors

Although the size of a pea, the pituitary is a major endocrine gland located at the base of the brain. It is responsible for secreting hormones such as ACTH. A pituitary adenoma is the most common type of tumor to cause Cushing’s disease in 60 to 70% of cases. The growth is an extremely small, non-cancerous tumor on the pituitary gland that is slow growing and does not spread. Tumors less than 1 cm are microadenomas, and those over 1 cm are macroadenomas. Pituitary adenomas cause Cushing’s disease symptoms because they release large amounts of ACTH that stimulates the adrenal glands to produce cortisol.

How is Cushing’s Disease Diagnosed?

Trained in disease of the endocrine system, an endocrinologist diagnoses Cushing’s disease. Endocrinologists focus on glands that regulate daily functions through the release of hormones. There are a variety of medical tests are used for a Cushing’s disease diagnosis. The main tests measures levels of cortisol, as Cushing’s patients always show an elevation.

  • 24-hour Urine Cortisol—Urine collections over the course of a 24-hour period provide an accurate reading of overall cortisol levels.
  • Cortisol Blood Test—If a cortisol level is higher than it should be at the time of day the blood was drawn, Cushing’s is likely. The 24-hour urine collection is preferred, as the blood test measures the level in that exact moment instead of the entire day.
  • Cortisol Saliva Test—Cortisol level is occasionally tested via saliva samples rather than using blood or urine.
  • CT Scan or MRI—Computed tomography (CT) or magnetic resonance imaging (MRI) can locate tumors on the glands that cause Cushing’s.  
  • Corticotropin-releasing hormone test— A nurse administers Corticotropin-releasing hormone (CRH) through an IV into the patient with suspected Cushing’s disease. CRH should stimulate the release of cortisol to confirm the diagnosis of Cushing’s, but those without the disease will show no response.
  • Petrosal sinus sample— The petrosal sinus sample accesses the likelihood of a pituitary adenoma. The beginning of the procedure entails taking a blood sample from the sinuses. Blood from the pituitary gland collects in the sinus cavity and reflects ACTH elevations in those with Cushing’s. The patient is sedated, and a second sample is obtained from the blood vessels connected to the pituitary gland by inserting a catheter into the groin. ACTH levels from both locations are then compared. A higher level in the sinuses indicates Cushing’s disease.  

Symptoms of Cushing’s Disease

Too much cortisol in the body causes symptoms in nearly every organ system. The symptoms of Cushing’s disease are extensive.

  • DEPWeight gain (abdomen, face)
  • Obesity
  • Buffalo hump (fatty deposits on the upper shoulders and back)
  • Purple stretch marks
  • Acne
  • Fatigue
  • Slow wound healing
  • Easy bruising
  • Thinning skin
  • Headache
  • Depression
  • Anxiety
  • Cognitive impairments
  • Memory loss
  • Bone loss
  • Glucose intolerance
  • Increased thirst and urination
  • Muscle weakness
  • Frequent infections
  • High blood pressure
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Men with Cushing’s Disease

Many symptoms of Cushing’s disease are universal, but gender is a factor. Differences in symptoms between a man and a woman are due to fluctuations in the hormones. Men with the condition might experience erectile dysfunction, infertility, and a loss of sexual interest.

Women with Cushing’s Disease

Cushing’s disease is more common in women than men and primarily affects those aged 20-50 years. Females with Cushing’s disease are prone to irregular menstrual periods, an absence of menstruation, or facial and body hair.

Cushing’s Disease Cognitive Impairment

Cortisol is required for several functions in the body, particularly those controlled by the nervous system. An excess of the stress hormone disrupts the normal cognitive processes.

Cells called neurons comprise the whole human brain. The hippocampus, the area of the brain responsible for learning and memory, is vulnerable to a deficiency of glucocorticoids (cortisol). Experts agree that “excess glucocorticoids cause retraction and simplification of dendrites in the hippocampus” (Patil, Lad, Katznelson, & Laws, 2007). Neurons forming the hippocampus die off resulting in brain atrophy. Therefore, cognitive impairments are a common occurrence.

Memory in Cushing’s disease

Memory loss is a frequent complaint in Cushing’s disease. High cortisol levels change the way the brain stores information. Cortisol in normal amounts facilitates the brain capacity to encode incoming information by processing it through the five senses. The hippocampus temporarily stores that information for later retrieval. If the information is deemed important enough by the hippocampus, it is stored as long-term memories in the amygdala and other parts of the brain. With the hippocampus in charge of memory and home to glucocorticoid receptors, Cushing’s effect on the hippocampus from excess cortisol hinders the short-term memory process more significantly than long term memory. Memory loss ordinarily improves with treatment of Cushing’s and is not permanent.

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Learning in Cushing’s disease

With memory deficits prominent, Cushing’s disease interferes with the practices of learning. IQ scores of Cushing’s patients reveal noticeable delays in verbal learning and recall in comparison to healthy controls. The learning impairments are likely related to memory, as further studies “found that once material was learned, the percentage of retention one-half hour after learning was not different from that of control subjects” (Starkman, et al., 2001, p. 991). Cushing’s creates the tip-of-tongue phenomena—information cannot be expressed because of poor recall.

Neuropsychiatric Disorders in Cushing’s disease

The role of cortisol in the brain is so vast that not even psychological health is spared from the effects of Cushing’s disease. Symptoms differ from patient to patient, yet neuropsychiatric illness is frequently reported. Experts hypothesize that the neuropsychiatric disorders associated with Cushing’s disease are caused by the interrupted signaling of the glucocorticoid receptors in the hypothalamus, which regulates mood and emotion, as well as memory. Neuropsychiatric disorders as a Cushing ’s comorbidity do not respond to regularly prescribed psychiatric medications. Treating the underlying Cushing’s disease is crucial for symptom resolution.

  • Anxiety—Anxiety in Cushing’s disease is not rare. Elevated cortisol levels are a key component to the fight-or-flight response. The body of a patient with Cushing’s continually perceives the threat of a stressor and feelings of anxiousness go hand-in-hand with the stress response.
  • Depression—Depression, unusual sadness lasting more than two weeks, is the most common psychiatric disorder secondary to Cushing’s disease. 50-70% of Cushing’s patients exhibit depression symptoms.
  • Hypomania— Hypomania is considered a form of mania identified by elevated mood, increased activity, and a decreased need for sleep. Only  3% of Cushing’s disease patients have hypomania.
  • Psychosis— Few patients with Cushing’s report mild occurrences of psychosis thought to stem from changes in glucocorticoid signaling that reduce neurotransmitter levels. Psychosis describes a mental state that is out of touch with reality. Hallucinations, delusions, incoherent speech, and erratic behavior are its accompanying symptoms.

Cushing’s Disease Treatment

Left untreated, the symptoms of Cushing’s disease escalate in severity. Over time, the bone loss leads to osteoporosis, insulin resistance turns to diabetes, and poor wound healing drives recurring infections. Fortunately, treatment options for Cushing’s exist in the options of surgical intervention, medication, and lifestyle adjustments.

Surgical Interventions for Cushing’s Disease

Surgical intervention is the go-to treatment to pinpoint the pituitary tumor typically causing the Cushing’s disease. The preferred surgical procedure is to the discretion of a doctor.

Cushing's Disease
Surgical Treatment for Cushing’s Disease

Pituitary Tumor Removal

The treatment with the greatest success rate targets the true cause of Cushing’s disease—a pituitary tumor. Providing the tumor is confined to the pituitary gland and does not extend to outside structures, the tumor can be surgically removed. Modern day techniques provide access to the tumor via the sinus cavity to avoid large surgical incisions. If the entire tumor is removed leaving the pituitary gland intact, normal function will return to the endocrine system given time. There is a 15% chance of reoccurrence.

Adrenal Gland Removal

Removing the pituitary tumor may not be an option for some patients with Cushing’s disease, like in the case that the tumor on the pituitary gland has extended to outside structures. The surgical removal of the adrenal glands treats Cushing’s disease because it prevents the body from producing cortisol.

Cortisol is necessary for survival, so patients who undergo the removal of the adrenal glands are dependent on synthetic hormones to replace what the body would naturally make under normal conditions.

Radiosurgery

Radiosurgery is referred to as targeted radiation therapy. Using an MRI to locate the tumor, radiation is applied directly to the tumor on the pituitary gland. Medications to suppress the adrenal production of cortisol are used in combination with radiosurgery because the radiation treatment can take up to 10 years to prove beneficial. Radiation therapy has unwanted side effects. According to The Pituitary Society, it affects other pituitary cells that produce other hormones.

Medications to Treat Cushing’s Disease

If surgery is not a viable option or is unsuccessful, there are medications used to treat Cushing’s disease. Available medications reduce cortisol levels by blocking the production of cortisol, acting on glucocorticoid receptors, or decreasing ACTH levels.

Pituitary-directed Drugs

Pituitary-directed drugs are the ideal treatment for Cushing’s disease because they specifically target pituitary adenomas. Pituitary adenomas not only stimulate the adrenal glands to produce excess cortisol, but the tumors themselves produce too much of a hormone called prolactin. Some pituitary-directed drugs shrink the tumor by decreasing the secretion of prolactin, while others block the production of ACTH from the pituitary gland which stimulates the body to produce cortisol. In general, adrenal-directed drugs act as neurotransmitters like dopamine, serotonin, and GABA that are important for endocrine metabolism.

Examples of pituitary-directed drugs are bromocriptine, cabergoline, and pasireotide. Side effects include runny nose, numbness in fingers, and gastrointestinal complaints: nausea, vomiting, constipation, or diarrhea.

Adrenal-directed Drugs

Adrenal-directed medications act quickly to reduce cortisol levels at the adrenal gland and are not used for long-term, chronic cases. They are best suited for pre-surgical flares of the disease because they do not treat the underlying cause of the pituitary tumor. As they work to inhibit steroid enzymes, there are harsh side effects.

Examples of adrenal-directed drugs are ketoconazole and metyrapone. Side effects include severe dizziness, fainting, irregular heartbeat, liver problems, nausea and vomiting, loss of appetite, fatigue, dark urine, yellowing of the eyes or skin, and headaches.

Glucocorticoid Receptor-Directed Drugs

Glucocorticoid receptors are what cortisol binds to. Like adrenal-directed drugs, glucocorticoid medications act rapidly to reduce cortisol levels by inhibiting CRH and ACTH. Professionals are still researching glucocorticoid receptor-directed drugs for the treatment of Cushing’s disease. However, patients in the trials have shown favorable responses. Those with Cushing’s induced diabetes have the most benefit. Limitations thus far are side effects on both male and female sexual reproduction.

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Lifestyle Changes for Cushing’s Disease

While health is a precarious concept with Cushing’s disease, lifestyle aspects of treatment are not entirely out of the patient’s control. Simple changes in habits can have immense benefits.

  • Anti-inflammatory Diet—High levels of cortisol increases inflammation throughout the body. Inflammation is decreased by consuming a balanced diet of the following:
    • Healthy Fats—Healthy fats are required to support brain health. Nuts, seeds, avocado, coconut, and seafood contain omega-3 fatty acids to stabilize mood.
    • B Vitamins—Green leafy vegetables like spinach, romaine, and kale, poultry, and yeast are rich in B vitamins.
    • High Protein—Adequate amounts of protein regulate neurotransmitter levels, which are disrupted in Cushing’s disease. Green leafy veggies, low-fat meats, nuts and seeds ensure a diet with a complete amino acid profile.
    • Calcium—Beans, legumes, green vegetables, cruciferous vegetables (i.e. broccoli, cauliflower), avocado, yogurt, and fish have calcium to strengthen weakened bones and balance electrolytes.
  • Low impact exercise—Cushing’s disease, if untreated, results in bone loss. Low impact exercises like interval training, walking, yoga, or bike riding provide the body with the movement it needs for hormone products, yet reduces the chances for injury.
  • Vitamin D and Calcium supplementation—Vitamin D and calcium are both vital to bone health. If natural sunlight and diet are not sufficient, vitamin supplementation ensures levels remain in range to conserve bone health.
  • No smoking and reduced alcohol intake—Surgery is the first treatment option for Cushing’s disease. Smoking interferes with the safety of a procedure. Drinking in excess increases the probability for liver problems and is not safe with medications.  
  • Rest—The body cannot heal without proper rest. Although Cushing’s disease causes insomnia, resting when you can and not overworking your body facilitates the healing process.  

References

Patil, C.G., Lad, S.P., Katznelson, L., & Laws, E.R. (2007). Brain atrophy and cognitive deficits in Cushing’s disease. Neurosurg focus. 23(3):E11. DOI: 10.3171/foc.2007.23.3.13.

Pivonello, R., De Leo, M., Cozzolino, A., & Colao, A. (2015). The Treatment of Cushing’s Disease. Endocrine reviews, 36(4), 385-486.

Starkman, M. N., Giordani, B., Berent, S., Schork, A., Schteingart, D. E. (2001). Elevated Cortisol Levels in Cushing’s Disease Are Associated With Cognitive Decrements. Psychosomatic Medicine 63:985–993.

Tang, A., O’Sullivan, A. J., Diamond, T., Gerard, A., & Campbell, P. (2013). Psychiatric symptoms as a clinical presentation of Cushing’s syndrome. Annals of general psychiatry, 12(1), 23. doi:10.1186/1744-859X-12-23.