Cushing’s Syndrome

By Janine Gilbert

Cushing’s Syndrome is a disease caused by an abnormally high presence of cortisol in the body. Cortisol is a steroid produced by the adrenal glands. Unfortunately, excess cortisol (hypercortisolism) lends to a myriad of unpleasant symptoms or side-effects; the most popular being drastic weight gain, especially in the mid-section, while maintaining thin arms and legs. Other symptoms may include but are not limited to; excessive body hair (hirsutism), buffalo hump, moon shaped face, purple stretch marks (striae), fragile skin that bruises easily, acne, slow healing, missing periods (ammenorrhia), high blood pressure, depression, diabetes, osteoporosis, fatigue and muscle weakness. cushing’s patients are often misdiagnosed, and can wait years for their diagnosis due to the overlapping of the symptoms with other diseases. Here’s what you need to know about Adrenal cushing’s and Ectopic cushing’s so that won’t happen to you. Knowledge is power and when you have or even suspect you have cushing’s you need to become your own advocate.

Adrenal cushing’s Syndrome is an endogenous form of hypercortisolism. This means that the disease is caused from a source within the body. Adrenal cushing’s is different from the other endogenous forms of cushing’s (Pituitary and Ectopic) because it is not ACTH (adrenocorticotropic hormone) dependent.  In ACTH dependent cushing’s, one or more tumors produce a hormone called ACTH that notify the adrenal glands to produce cortisol. Adrenal cushing’s is most commonly caused by a noncancerous tumor, or tumors (adenomas), of the adrenal cortex (usually only in one gland). The adrenal tumors produce cortisol without the stimulation of ACTH. In more rare occasions, Adrenal cushing’s is caused by a cancerous tumor or tumors (adrenocortical carcinoma) or by a benign nodular enlargement of both glands. However, in short, Adrenal cushing’s is most commonly caused by cortisol secreting tumor(s) on one of the adrenal glands.

What are the adrenal glands? We all have two adrenal glands situated above our right and left kidneys. The right is triangle shaped, while the left has more of a semi-lunar shape.  On average, they usually weigh about 5 grams each. To give you an example, one U.S. nickel weighs about 5 grams. Both adrenal glands are made up of the medulla and cortex. The medulla is located at the center of the adrenal gland and is responsible for synthesizing and secreting epinephrine and norepinephrine. But for the purpose of cushing’s, we must focus on the adrenal cortex, which produces two classes of steroids; mineralocorticoids and glucocorticoids. Aldosterone is the prime mineralocorticoid produced by the adrenal glands. It regulates the absorption of sodium, potassium and electrolytes in the body. Cortisol is the glucocorticoid produced by the adrenal glands. Glucocorticoids are a class of steroid hormone that regulate the metabolism of proteins, carbohydrates, and fats, while exerting an anti-inflammatory effect. Lastly, the adrenal cortex produces some sex steroids, particularly androgens. It really is amazing the effects two glands, each just the size of a nickel, can have on our bodies.

How do I get a diagnosis? Although the symptoms of Adrenal cushing’s are usually the same as Pituitary or Ectopic, the testing may progress differently. Initially, testing is the same, but first, and most importantly, you need to establish if your body is being excessively dosed with cortisol. Listed below are the preliminary tests for cortisol. They are also the beginning of the protocol for cushing’s testing.

8am Serum Cortisol Blood Test – Because cortisol is produced cyclically in the body; It is believed that cortisol begins reaching a diurnal peak around 7am. Diurnal variation is the natural occurrence of highs and lows of a substance during a 24 hour period. The peak is the highest point and levels are believed to slowly decrease throughout the day. Your doctor will ask you to have your blood drawn at about 8am to test and compare your levels with the norm at that time for your age group and sex. Make sure that you make an appointment with your local lab to ensure your blood is drawn at the proper hour.

Salivary Cortisol Test – Conversely to an 8am reading, and according to its diurnal variation; your cortisol is believed to be at its lowest point at midnight. The Salivary Cortisol Test is not only more convenient because it can be done at home; but is believed by some experts to supply more accurate results than a midnight blood draw. If your cortisol is supposed to be low at midnight, it’s partly because you are either getting ready for, or already, in bed. Some experts believe, if you have to get up and get dressed and drive to a lab to have your blood drawn; it can interrupt your natural diurnal variation. All those things, including a needle stick, can cause stress. Causing stress during a known diurnal low, can cause you to produce more cortisol than you would normally at this time and lead to inaccurate or falsely high results. I’m inclined to agree, but that is a discussion to have with your medical professional. The Midnight Salivary Test is non-invasive and can be done in your pajamas.  It simply requires placing a cotton swab under your tongue and allowing it to absorb your saliva. Make sure it is done at the stroke of midnight. You can pick up the proper swabs and tubes at your local lab along with more detailed instructions. You can freeze the specimen overnight and drop it off at the lab later that day. You will most likely be asked to perform a series of these tests to show consistent cortisol highs. This test is beneficial because it’s an easy way to record inappropriately high levels of cortisol at night.

24 Hour Urinary Free Cortisol Test – Another vital diagnostic tool for cortisol testing is a 24 hour urine collection, also known as a 24 hour UFC or urinary free cortisol. As we have learned, cortisol production goes up and down in your body throughout the day. The 24HR UFC is not based on any specific diurnal variation or specific times, just your average for the day. You will go to your lab and pick up a big (usually orange) jug. You may also want to ask for, what some people refer to as, a “hat”. It is a plastic container designed to sit securely under the seat of the toilet and collect your urine. (voiding into a large jug may prove tricky) The instructions are as follows:
When you wake do not collect your first void (urination) of the day. Then, for the rest of the day, every time you go; you must void into the jug. Be sure to keep the container refrigerated at all times. If you are uncomfortable with keeping urine in the refrigerator, place a cooler in the bathroom with some ice to store it in. The next morning when you wake, collect that first morning void in the jug. Then, bring it to the lab for testing. This can be a hard test to do if you are employed, so I always did it on a Saturday then dropped it off to the lab on my way to work on Monday.
As with the tests before, the number is compared with the normal range for your age group and sex.

If any of the above tests, combined with cushing’s symptoms come back higher than normal, your doctor may refer you for further testing to try and locate the source of the cortisol production.

ACTH Test – It is very possible that when you had your 8am Serum Cortisol Blood Test your ACTH was also measured. ACTH, as we mentioned earlier, is the hormone that stimulates your adrenal glands to produce cortisol. If you are producing excess cortisol it is either because of an ectopic tumor(s), pituitary tumor(s), or an adrenal tumor(s). If your ACTH was not tested during your 8am Serum Cortisol Blood Test; you may need to have that drawn at your lab in the same fashion, as it operates on the same diurnal variation. If it falls within a normal or below range, then you can postulate your hypercortisolism is not being caused by a pituitary tumor(s). When it is an adrenal source, ACTH should be low because it is not causing the hypercortisolism. In summation, if the cortisol is elevated and the ACTH is subnormal, that is a sure-fire indication of Adrenal cushing’s.

Here are some other tests that can confirm a cushing’s diagnosis and locate the source:

ACTH Stimulation Test or Cortrosyn Stimulation Test – This test requires an injection of Cortrosyn which is a synthetic version of ACTH. Your blood will be drawn prior to the injection and one hour after in order to measure your cortisol levels. The results will indicate the reaction of your adrenal glands.  An abnormal value of cortisol as a result of this test coupled with a low ACTH blood test (as we talked about above) can indicate Adrenal cushing’s.

Dexamethasone Suppression Test – There are two different types including a low-dose and a high-dose. The standard low-dose test requires a 72 hour urine collection. The first 24 hours require nothing more than collecting urine. On the second day, you take .5mg of dexamethasone every 6 hours for 48 hours. The jugs then are sent to the lab to measure the cortisol.

The alternative way to do the low-dose dexamethasone test is overnight.  You are given 1mg of dexamethasone at 11pm and the cortisol is measured in one blood draw at 8am.

The standard high-dose test is exactly the same as the standard low-dose test, however, instead of .5mg of dexamethasone, you’re given 2mg every 6 hours. The overnight high-dose is also the same, however you receive 8mg instead of 1mg at 11pm.

Dexamethasone is a corticosteroid like cortisol, however it is longer acting and will not skew cortisol test results. It is meant to suppress the amount of ACTH you are producing and allow your adrenals to function of their own volition. The dexamethasone suppression tests can help diagnose hypercortisolism and assist in locating the cause. If there is no effect on the amount of cortisol you are producing, your source is most likely adrenal. Therefore, not from an ACTH producing tumor(s).

CRH Stimulation Test -In a Corticotropin-releasing hormone stimulation test blood is drawn for baseline ACTH and cortisol levels initially and 15 minutes later. It is followed by a dose of CRH. CRH is the hormone that stimulates the pituitary to release ACTH. Then samples are drawn at 15, 30, 60, 90 and 120 minutes. In Adrenal cushing’s the low ACTH and high Cortisol levels at baseline are not affected by the CRH injection. This further proves that the tumor(s) is not ACTH dependent and possibly located in the adrenal glands.

Now that your doctor has performed some, or maybe even all of these tests, he may suspect an adrenal tumor(s) or adenoma(s) to be responsible for your hypercortisolism. Your doctor will most commonly order either a CT scan or an MRI of the adrenal glands to locate any anomalies.

Why wouldn’t my doctor just scan my adrenal glands in the first place? Many average people, are walking around with anomalies on their adrenal glands referred to as incidentalomas. Incidentalomas are adenomas or benign lesions that secrete no hormones and according to recent studies, have been found in upwards of 12% of autopsies of individuals with hypertension. It is further believed that because of our advances in radiological imaging pathologists are discovering all kinds of anomalies that once went unnoticed. A person without Adrenal cushing’s could easily have an anomaly appear on an adrenal scan, but without further diagnostic evidence to support the diagnosis of cushing’s; the findings may simply just be an incidentaloma.

Is Adrenal cushing’s common? According to the National Institute of Health Adrenal cushing’s is only responsible for 15% of all cushing’s cases.  Furthermore, UCLA research indicates adrenal tumors are not only more common in adults, but mostly in women. In fact they are 4 to 5 times more common in women than men. UCLA also cites that Adrenal cushing’s occurs in 6 out of 1,000,000 people. The question remains whether or not it really is that rare, or just often misdiagnosed or even missed altogether. That is why it is important to do your research and be your own advocate while being treated by a healthcare professional with a firm knowledge of Adrenal cushing’s.

Is there a cure for Adrenal cushing’s? That is a complicated question. Most often, the solution is surgery. Most commonly, but not always, there is one or more tumors on one of your adrenal glands. Since the adrenals are so small, the cure is usually a full unilateral adrenal ressection or an adrenalectomy. That is just the clinical way of saying, to remove the gland completely. The good news is that you are rid of that nasty life altering tumor(s), and you were born with two adrenal glands. Unlike ACTH dependent cushing’s, upon removal of the adrenal gland or tumor(s), your Adrenal cushing’s should be cured. In most cases, thanks to surgical advances, the procedure can be done via a laparascopic surgery, and requires three to five, 1/4 to 1/2 inch incisions. The small incisions allow your surgeon to insert a small camera and instruments through the abdomen and remove the tumor(s), or in most cases the whole gland. The incisions are so small, they don’t even require sutures–only steri-strips. The average hospital stay is 1-2 days. The surgery itself is seemingly simple, especially compared to recovery.

Recovery – Congratulations you have just been cured of your Adrenal cushing’s, but you’re not out of the woods yet. Although it may seem contradictory, you will mostly likely begin steroid replacement therapy quickly after surgery. The therapy includes replacing both the glucorticosteroids and mineralocorticoids that we read about earlier in the article. The steroids are necessary for both replacement and supplementation for weaning. Prior to surgery, your adrenal tumor(s) may have been producing devastatingly high amounts of cortisol. Therefore, removing the tumor(s) or gland can cause withdrawal symptoms. You must also keep in mind, your adrenal tumor(s) was producing such high levels of cortisol; it will have most likely, suppressed your ACTH production. That ACTH suppression will keep your second adrenal gland from working right away. The suppression is actually your body’s way of trying to correct the problem. Your pituitary, or master gland, recognized that excess cortisol you were making and tried to stabilize the problem on its own. Under the care of your doctor, you will slowly taper the dose of steroids until you are used to a reasonable level of cortisol again and your remaining adrenal gland restarts and begins to function normally. When you are tapering your steroids, it is important to be cognizant of the symptoms of Adrenal Insufficiency (AI). AI is when you are not receiving enough steroids to function and can be dangerous, even fatal. It must be taken very seriously. Be sure to ask your doctor for more information so you can watch for the warning signs.

How long will it take for me to taper my steroids and get back to “normal”? This is not an easy question to answer, because everyone is different. Some people can get off the replacement dose in 2 months, and others can take 2 years. Recovery is an individual journey, influenced by things like the state of your body, your tolerance, how high your cortisol was in the first place, and several other factors personal to you. Tapering is not an easy process. There may be ups and downs. Although it is a long and arduous journey, it’s important to remember that you are working towards your new life without cushing’s. It may not be the exact same life you remember, but it should be quite an improvement compared to the one you were living while dealing with the symptoms of cushing’s.

Ectopic cushing’s is an endogenous form of hypercortisolism, just like Adrenal cushing’s. The difference is that it’s ACTH dependent. The tumor(s) produces ACTH just like Pituitary cushing’s, minus the pituitary location. Adenomas that appear outside of the pituitary and still secrete ACTH are Ectopic. According to the Neuroendocrine Clinical Center and Pituitary Tumor Center at MGH/Harvard: “Lung tumors cause over 50% of these cases. Men are affected 3 times more frequently than women.The most common forms of ACTH-producing tumors are oat cell, or small cell lung cancer, which accounts for about 25% of all lung cancer cases, and carcinoid tumors. Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinoma of the thyroid.”

How will I know if I have Ectopic cushing’s? The first few steps of diagnosis are the same as Pituitary and Adrenal cushing’s. Your doctor must determine first, if you are producing excess cortisol and have the proper symptoms to fit the cushing’s profile. It is important to note, that since some cases of Ectopic cushing’s are cancerous, the weight gain may be less significant. If you fit this description and show elevated levels of ACTH (based upon the tests discussed earlier) you will first be scanned for a pituitary adenoma. (Pituitary cushing’s and testing is explained thoroughly in the Pituitary cushing’s Section of this site.) If no anomalies can be found on the pituitary, your doctor should discuss scanning other areas; usually beginning with the lungs. There are also certain blood tests that may indicate cancerous tumors prior to a scan.

How is Ectopic cushing’s treated? Ectopic cushing’s treatment is based on the type of tumor(s) and where it is located. If it is not cancerous, the first choice is usually surgical removal. Depending upon the tumor’(s) location and size, this can be a small laparascopic surgery or a more invasive surgery. The recovery would require a tapered dose of steroids like other cushing’s surgeries until your body resets. It is important to note that this type of tumor(s) does run the risk of recurrence, unlike Adrenal cushing’s. If the tumor(s) is cancerous and has metastasized, it may not be able to be removed. In that case you may require pharmaceuticals or radiation to attempt to suppress the cortisol production. You will also require cancer treatment under the advisement of an oncologist.
Aside from the operation location and impact on the pituitary, Ectopic cushing’s recovery (when benign) is very similar to Pituitary cushing’s recovery. Some Ectopic cushing’s patients may require a Bilateral Adrenalectomy (BLA) in order to cure the cushing’s. A BLA is the removal of both adrenal glands in order to stop the cortisol production for good. A BLA may be performed in cases where your doctor cannot seem to locate the tumor(s) or remove them all. A BLA may also be a good alternative for recurring tumors.  Either way, as we’ve learned with Adrenal cushing’s, everyone is different. With Ectopic cushing’s, every tumor is different, and most importantly, so is every recovery.