Cushings Syndrome

General Information:

Cushing’s syndrome is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol. Sometimes called hypercortisolism, Cushing’s syndrome occurs when the body’s tissues are exposed to high levels of cortisol for too long. (1) Many people develop Cushing’s syndrome because they take glucocorticoids—steroid hormones that are chemically similar to naturally produced cortisol—such as prednisone for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. (1) Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue. (1)

Other people develop Cushing’s syndrome because their bodies produce too much cortisol.  (1)

Normally, the production of cortisol follows a precise chain of events. First, the hypothalamus, a part of the brain about the size of a small sugar cube, sends corticotropin-releasing hormone (CRH) to the pituitary gland. (1) CRH causes the pituitary to secrete adrenocorticotropin hormone (ACTH), which stimulates the adrenal glands. (1) When the adrenals, which are located just above the kidneys, receive the ACTH, they respond by releasing cortisol into the bloodstream.  (1) Cortisol is a potent glucocorticoid released from the adrenal cortex.  This hormone affects the metabolism of carbohydrates, proteins, and fats. (2) Cortisol tends to increase glucose by stimulating gluconeogensis from glucose stores.  It also inhibits the effect of insulin and thereby inhibits glucose transport into the cells. (2)

Some of cortisol’s vital tasks in the body include; helping maintain blood pressure and cardiovascular function and reducing the immune system’s inflammatory response. (1) However, one of cortisol’s most important jobs is to help the body respond to stress. For this reason, women in their last 3 months of pregnancy and highly trained athletes normally have high levels of the hormone. (1) People suffering from depression, alcoholism, malnutrition, or panic disorders also have increased cortisol levels. (1) When the amount of cortisol in the blood is adequate, the hypothalamus and pituitary release less CRH and ACTH.  (1) This process ensures the amount of cortisol released by the adrenal glands is precisely balanced to meet the body’s daily needs. However, if something goes wrong with the adrenals or the regulating switches in the pituitary gland or hypothalamus, cortisol production can go awry. (1)

Most cases of Cushing syndrome are due to exogenous glucocorticoids. (3) The annual incidence of endogenous Cushing syndrome has been estimated at 13 cases per million individuals. (3) Of these cases, approximately 70% are due to Cushing disease, that is, a pituitary ACTH-producing tumor; 15% to ectopic ACTH; and 15% to a primary adrenal tumor. (3)

Diagnosis of Cushing’s Syndrome

Diagnosis is based on a review of a person’s medical history, a physical examination, and laboratory tests. X rays of the adrenal or pituitary glands can be useful in locating tumors.

Symptoms and Physical Manifestations of Cushing’s Syndrome

Symptoms of Cushing’s Syndrome usually include:

• Upper body obesity (above the waist) and thin arms and legs
• Central obesity with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio: greater than 1 in men and 0.8 in women; and, upon CT scan of the abdomen, increased visceral fat is evident.
• Round, red, full face (moon face)
• Slow growth rate in children (4)

Skin changes that are often seen:

• Acne or skin infections
• Purple marks (1/2 inch or more wide), called striae, on the skin of the abdomen, thighs, and breasts
• Thin skin with easy bruising (4)

Muscle and bone changes include:

• Backache, which occurs with routine activities
• Bone pain or tenderness
• Collection of fat between the shoulders (buffalo hump)
• Thinning of the bones, which leads to rib and spine fractures
• Weak muscles (4)

Women often have:

• Excess hair growth on the face, neck, chest, abdomen, and thighs
• Menstrual cycle becomes irregular or stops (4)

Men may have:

• Decreased fertility
• Decreased or no desire for sex
• Impotence (4)

Other symptoms that may occur include:

• Mental changes, such as depression, anxiety, or changes in behavior
• Fatigue
• Headache
• High blood pressure
• Increased thirst and urination (4)
• Sugar cravings (7)
• Shakiness between meals (7)
• Sleep disturbances  (7)

Other Systemic Changes Possible:

• Cardiovascular and renal:
  • Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention. (3)
  • According to researchers, increased total Cortisol exposure is independently associated with atherosclerosis of the carotid arteries. (5)
• Gastroenterologic:
  • Peptic ulceration may occur with or without symptoms. Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism). (3)
• Endocrine:
  • Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels. (3)
  • Signs of hypothyroidism, such as slow reflex relaxation, may occur from an anterior pituitary tumor whose size interferes with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function. Similarly, other pituitary function may be interrupted. (3)
• Visual:
  • Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasma. (3)

Patient History Associated with Cushing’s Syndrome

Patients with Cushing syndrome may complain of weight gain, especially in the face, supraclavicular region, upper back, and torso. (3) Frequently, patients notice changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning.  (3) Because of progressive proximal muscle weakness, patients may have difficulty-climbing stairs, getting out of a low chair, and raising their arms.  (3) Women may complain of menstrual irregularities, amenorrhea, infertility, and decreased libido due to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing hormone-releasing hormone (LHRH) pulse generation. (3)

Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop.  (3) New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur. (3) Patients with an ACTH-producing pituitary tumor may develop headaches, polyuria and nocturia, visual problems, or galactorrhea. (3) If sufficient mass effect from the tumor is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, and hypogonadism may develop. Rapid onset of symptoms of glucocorticoid excess in conjunction with virilization in women or feminization in men suggests an adrenal carcinoma as the underlying cause of the Cushing syndrome. (3)

Laboratory:

Laboratory abnormalities that may be associated with Cushing syndrome include the following:

• Elevated white blood cell count greater than 11,000/mm3
• Hyperglycemia

Hypokalemic metabolic alkalosis may occur in patients with markedly elevated cortisol due to cortisol activation of the renal mineralocorticoid receptor. (3)

Biochemical evaluation of Cushing syndrome:

The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high serum or urine cortisol levels.  Currently 4 methods are accepted for the diagnosis of Cushing syndrome: (3)

1. Urinary free cortisol level:

Urinary free cortisol (UFC) determination has been widely used as an initial screening tool for Cushing syndrome because it provides measurement of cortisol over a 24-hour period. A valid result depends on adequate collection of the specimen. Urinary creatinine excretion can be used to assess the reliability of the collection. Urine free cortisol values higher than 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome.  Multiple collections are necessary because patients with disease may have values that fall within the normal range. Three urine free cortisol levels in the normal range exclude the diagnosis of endogenous Cushing syndrome. (3) Normal urinary free Cortisol levels for an adult are <100mcg/24hr. (2)

2. Low-dose dexamethasone suppression test:

The rationale for the dexamethasone suppression tests is based on the normal physiology of the hypothalamic-pituitary-adrenal axis; glucocorticoids inhibit secretion of hypothalamic CRH and pituitary ACTH but do not directly affect adrenal cortisol production. Since cortisol production is controlled by ACTH, decreases in ACTH lead to decreases in plasma and urine cortisol. The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 PM with subsequent measurement of cortisol level at 8 am. (3) In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL. (3) To enhance the sensitivity of the test, a cutoff value of less than 1.8 mcg/dL (50 nmol/L) excludes Cushing syndrome. (3) Its ease of administration makes the 1-mg dexamethasone suppression test a widely used screening tool. (3) Patients with adrenal hyperplasia will suppress and patients with adrenal or ectopic tumors will not suppress. (2)

3. Evening serum and salivary cortisol level:

Late-night serum and salivary cortisol levels take advantage of the alterations in circadian rhythm of cortisol secretion in patients with Cushing syndrome. (3) Normally, cortisol values are at their lowest level late at night.  Individuals with Cushing’s syndrome often have upper normal plasma cortisol levels in the morning and do not exhibit a decline as the day proceeds. (2) High levels of cortisol indicate Cushing’s syndrome. (2) Results from a meta-analysis of 7 studies relating to late-night salivary cortisol testing in the diagnosis of Cushing syndrome (947 patients aged >18 years, including 339 persons with Cushing syndrome) indicated that such testing has a sensitivity of 92%, a specificity of 96%, and a diagnostic odds ratio of 311. (3) The report’s authors concluded that late-night salivary cortisol measurement “is a robust, convenient test for screening and diagnosis of Cushing syndrome.” (3)

4. Dexamethasone–corticotropin-releasing hormone test.

The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. (3) Dexamethasone (0.5 mg every 6 hours) is given 8 times starting at about 8 AM, CRH is administered intravenously 6 hours after the last dose of dexamethasone and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests. (3)

Once Cushing’s syndrome has been diagnosed, other tests are used to find the exact location of the abnormality that leads to excess cortisol production. The choice of test depends, in part, on the preference of the endocrinologist or the center where the test is performed.

Imaging Studies for Cushing’s Syndrome

Radiologic imaging: direct visualization of the endocrine glands. Imaging tests reveal the size and shape of the pituitary and adrenal glands and help determine if a tumor is present. Imaging procedures are used to find a tumor after a diagnosis has been made. Imaging is not used to make the diagnosis of Cushing’s syndrome because benign tumors are commonly found in the pituitary and adrenal glands. These tumors, sometimes called incidentalomas, do not produce hormones in quantities that are harmful. They are not removed unless blood tests show they are a cause of symptoms or they are unusually large. Conversely, pituitary tumors may not be detectable by imaging in almost half of people who ultimately need pituitary surgery for Cushing’s syndrome. (1)

Petrosal sinus sampling. This test is not always required, but in many cases, it is the best way to distinguish pituitary from ectopic causes of Cushing’s syndrome. Samples of blood are drawn from the petrosal sinuses—veins that drain the pituitary—by inserting tiny tubes through a vein in the upper thigh or groin region. A local anesthetic and mild sedation are given, and x rays are taken to confirm the correct position of the tubes. Often CRH, the hormone that causes the pituitary to release ACTH, is given during this test to improve diagnostic accuracy.  Levels of ACTH in the petrosal sinuses are measured and compared with ACTH levels in a forearm vein. Higher levels of ACTH in the sinuses than in the forearm vein indicate a pituitary adenoma. Similar levels of ACTH in the petrosal sinuses and the forearm suggest ectopic ACTH syndrome. (1)

Traditional Treatment and Prognosis

Treatment: Treatment involves surgery to remove the pituitary tumor, if possible. Patients with Cushing disease are usually treated with transsphenoidal surgery, as this approach leads to remission in 70-90% of cases and is associated with low morbidity when performed by experienced pituitary gland surgeons. (8)) After surgery, the pituitary may slowly start to work again and return to normal. (4) During the recovery process the patient may need cortisol replacement treatments. Radiation treatment of the pituitary gland may also be used. (4) Remission after radiation therapy occurs in ∼85% of patients with Cushing disease after a considerable latency period  (8).  If the tumor does not respond to surgery or radiation the patient may be given medications to stop the body from making cortisol. (4) If these treatments are not successful, the adrenal glands may need to be removed to stop the high levels of cortisol from being produced. (4)

Prognosis: Untreated, Cushing’s disease can cause severe illness, even death. Removal of the tumor may lead to full recovery, but the tumor can grow back. (4) The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of co-morbidities caused by the underlying pathology. (9)  Medical therapy for CS should be given with a tailor-made approach, involving relevant patient characteristics, in which potential clinical efficacy of a drug should be carefully weighed against its potential side effects.  (10)

Natural Supplements for Cushing’s Syndrome

DHEA

DHEA may help to protect against the overproduction of cortisol from the adrenal glands and enhance the immune system. This is an important factor since too much cortisol accelerates aging and causes immune system disorders. Studies show that DHEA deficiency may actually debilitate immune status (Wisniewski 1993; Morio et al. 1996). (6)

Vitamin C

Studies show that vitamin C and aspirin can attenuate and influence cortisol, inducing an anti-inflammatory response to prolonged exercise and stress. Vitamin C has been shown to reduce the elevation of cortisol in response to heavy exercise. In human studies, 3000 mg of vitamin C daily mitigated a rise in blood pressure, cortisol, and subjective response to acute psychological stress (Di Luigi et al. 2001; Peters et al. 2001a, 2001b; Brody et al. 2002). (6)

Phosphatidylserine (PS)

Phosphatidylserine is a phospholipid that is a structural component of the biological membranes in animals and plants. In studies, supplemental PS has been shown to improve mood and blunt the release of cortisol in response to physical stress (Monteleone et al. 1990; Kelly 1999; Benton et al. 2001). (6)

Calcium and Vitamin D

These nutrients help strengthen bones (important because bone loss is common with people who have Cushing’s syndrome). (11)

Melatonin

Melatonin is secreted by the pineal gland and functions to regulate circadian rhythm and induce sleep. Melatonin circadian secretion in patients with pituitary- or adrenal-dependent Cushing’s syndrome was shown to be significantly lower compared to healthy control groups. Studies also have shown that nightly administration of 2 mg of melatonin increased the DHEA-S-cortisol ratio after 6 months of treatment (Soszynski et al. 1989; Bruls et al. 2000; Pawlikowski et al. 2002). (6)

Ashwagandha and Schisandra: These herbs can be highly effective in promoting recovery from stress and stabilizing Cortisol levels. ((5) Ashwagandha is an adaptogenic herb and can help prevent enlargement of the adrenal glands and reduce the adrenal depletion of Cortisol released into the body to counteract the effects of stress. (5)

Lifestyle Tips For Patients with Cushing’s Syndrome: (11)

• Eat smart, balanced and choose nutritious foods. Keep Stress levels low and blow sugar balanced.
• Exercise gently. Exercise plays a significant role in any healthy lifestyle, but it’s important for you not to rush into it. Even if you think you’re feeling better, your body still needs time to heal.  Start off slowly.  Intense exercise can stress the body further.  Just start with movement therapy and comfortable exercise.
• Keep tabs on your mental health. Your mental health can take a toll when you have Cushing’s syndrome—depression is common. If you feel blue or you don’t feel like doing the things you used to and you’re not sure why, don’t ignore it. Talk to your doctor—he or she can recommend a psychologist who can help you cope with your feelings throughout your recovery.
• Keep a journal to record how you feel on a day-to-day basis.  Give yourself a break. Don’t be hard on yourself as your body recovers from Cushing’s syndrome. It’s important to get plenty of rest, relaxation, and sleep. Treat yourself to a gentle massage, warm bubble bath, meditation session or listen to soothing music.

Incorporating these lifestyle tips into your routine can not only help you live well, but they can help you thrive with Cushing’s syndrome.

Preventative Measures for Adrenal Fatigue

After an evaluation by a physician, if stress is determined to be the cause of adrenal fatigue, the first goal is to relieve the stressful situations as much as possible. Consider lifestyle changes, including diet modification and exercise. Limit the consumption of processed foods, and avoid alcohol and tobacco use because these substances put extra stress on the adrenal glands. Many supplements recommended for Cushing’s syndrome may also be taken for general adrenal fatigue because they can help to support healthy adrenal function, reduce stress, and blunt the release of excess cortisol during stress.

Consider the following:

• Vitamin C, 3000 mg a day
• DHEA, 50 mg a day
• L-theanine, 100-400 mg a day
• Pantothenic acid (vitamin B5), 1500 mg a day
• Melatonin, 300 mcg-6 mg (at bedtime)
• Phosphatidylserine capsules, 300 mg a day
• Licorice (Glycyrrhiza glabra), no more than 1000 mg of glycyrrhizin (6)

Resources:

1. Nieman L, Ilias I. Evaluation and treatment of Cushing’s syndrome. The American Journal of Medicine. 2005;118:1340–1346.
2. Pagana. Mosby’s Manual of Diagnostic and Laboratory Tests, fourth ed.
3. Adler, Gail, MD, PhD., Griffing, George, MD. Cooper,Mark, MBBS, PhD, FRACP. Cushings Syndrome. Medscape reference.
4. Stewart PM. The adrenal cortex. In: Kronenberg H, Melmed S, Polonsky K, Larsen PR, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: Saunders Elsevier; 2008:chap 14.
5. Meletis, Chris, ND.  The Heart Harming Effects of Elevated Cortisol.  2011.
6. LEF. ORG, Life Extension Foundation, Cushings Syndrome Protocols.
7. Lord, R. Bralley, J. Laboratory Evaluations for Integrative and Functional Medicine
8. Tritos NA1, Biller BM, Swearingen B. Management of Cushing disease. Nat Rev Endocrinol. 2011 May;7(5):279-89. doi: 10.1038/nrendo.2011.12. Epub 2011 Feb 8.
9. Ahmed Rizk, Juergen Honegger, Monika Milian, and Tsambika Psaras Treatment Options in Cushing’s Disease, Clin Med Insights Oncol. 2012; 6: 75–84. 2012 Jan 11.
10. R van der Pas, W W de Herder, L J Hofland and R A Feelders. New developments in the medical treatment of Cushing’s syndrome. Society for Endocrinology
11. Julie M. Gentile 4 Lifestyle Tips for Cushing’s Syndrome, endocrine web.com