Alicia M. Held, MSW
The diagnosis of any illness can be a confusing and terrifying time, but it is even more so when you are diagnosed with a rare illness. While the diagnosis of diabetes can be scary and daunting, there is a wealth of knowledge at your fingertips; everything from websites, support groups and books at your local bookstore. Experts disagree about the prevalence of Cushing’s syndrome; a disorder generally caused by a pituitary or adrenal tumor which results in elevated levels of cortisol. Most articles will cite the prevalence of Cushing’s syndrome at 2-4 people per million, but the best estimates place it closer to 10-15 people per million, with more being mis- or un-diagnosed (Guaraldi & Salvatori, 2012). So when you are diagnosed with Cushing’s syndrome you become part of a new, very small, circle of people who have had to fight to find reliable sources of information (the number of articles about veterinary Cushing’s far outweighs those about the human form of the disease), and make your best guess as to the validity and reliability of the information with very little to compare it to. My hope is that the information you find here will help to relieve some of the panic inducing anxiety you likely are feeling right now, provide accurate and reliable information to help you make the best decisions for your care, and provide you with support and a group of people who understand what you are going through and genuinely care about you!
Once you have a diagnosis of Cushing’s syndrome there are a myriad of treatment options available to you. As part of the diagnosis process it is important to determine where the source of the elevated cortisol is coming from. There are multiple tests that help determine the location of the tumor, and once the location of the tumor is established this dictates the options for treatment that are available. Below I will delineate the treatment options currently available for Cushing’s syndrome based on the tumor location, either pituitary, adrenal, ectopic, or a non-tumor, exogenous source.
Treatments for pituitary tumors.
Let me start off by saying each case is unique, and the information that follows in no way is a substitute for the care of a physician who knows the details of your individual case. With that being said, the general, preferred initial treatment for a pituitary tumor causing Cushing’s disease (the word disease is used to specify the sub-set of Cushing’s syndrome caused by pituitary tumors) is to remove the tumor through surgical means. Surgery has made enormous strides since Harvey Cushing was practicing in the early 1900’s (Bliss, 2005), and an opening in the cranium, or skull, is no longer required. In fact today, the preferred method for accessing tumors at the base of the skull, which is where the pituitary gland is located anatomically, is actually by creating a small incision under the lip (sublabial), in the roof of the mouth, or by using the natural opening of the nose and entering the sphenoid sinus (endonasal transshpenoidal). Many neurosurgeons work in conjunction with ENT surgeons, who perform the first incisions to open the patient up and allow access for the neurosurgeon to then do the dissection of the tumor in the pituitary gland. Generally this surgery is only moderately painful, and requires only a short hospital stay. However, it is extremely important, this can not be stressed enough, that a neurosurgeon who performs a numerous amount of these types of surgeries be the person who performs the operation and not just someone who has done one or two previous surgeries (McCutcheon, 2008). Surgery on the pituitary gland is a fairly rare procedure in and of itself, and resecting a microadenoma from the pituitary takes tremendous skill, and many years of practice to perfect.
The first few days after surgery are very important for monitoring cortisol levels. Achieving a cortisol level of less than 2 μg/dl 72 hours after surgery appears to be the greatest predictor for long-term remission (Liu et al., 2007). Again, experts disagree as to the success rate of a singular pituitary surgery at achieving long-term remission, yet it is often cited at 70%. Studies that look at patients as far as ten years out from surgery generally report the number of patients achieving remission from a single pituitary surgery to be closer to 56% (Liu et al.).
If you have had an unsuccessful pituitary surgery, or in rare cases even as a first line of treatment, there are medications available that can lower cortisol or mitigate the effects of cortisol on the body systems. The first medication that endocrinologists will often try is Ketoconazole, Keto for short. Ketoconazole is in a class of drugs known as anti-fungals and as a side effect of its general action it also prevents the production of cortisol. The dose for Ketoconazole can range from 400 mg-1200mg daily, and it is important to monitor cortisol levels through UFC (urinary free cortisol) tests as adrenal insufficiency (cortisol levels that are too low) can sometimes occur (Liu et al.). Recently, however, the FDA has issued a “black box” warning for prescribing Ketoconazole, so the use of Ketoconazole in treating Cushing’s syndrome may see a decline in the coming months (Adler, 2014). Other drugs that work through this same mechanism of action, to inhibit cortisol production, but are not prescribed as often are: mitotane, trilostane, aminoglutethimide, and metyrapone (Liu et al.).
Another way drugs can work to help control Cushing’s syndrome is by acting on the nuerotransmitters in the brain itself and these drugs are called neuromodulatory agents. The most frequently used types of drugs in this class for Cushing’s disease are ones that affect the release of ACTH, which is the hormone produced by the pituitary gland that tells the adrenal glands to produce cortisol. In this sub-set of drugs octreotide was the previously most prescribed medication. However, its effectiveness in use in patients has not proved to be as good as in laboratory trials (Liu et al.). Currently, however, there is a new medication, SOM 230, which has a similar method of action as octreotide, but is showing much more promise at effectively reducing ACTH secretion in patients in early studies (Liu et al.). More long-term studies are needed, however, to reliably state whether this will be a viable option going forward.
Lastly, a new medication that has just been approved by the FDA in the past few years for treatment of Cushing’s syndrome is mifepristone, brand name Korlym. It acts in a novel way. Instead of changing the production or release of hormones, mifepristone acts as a competitor at the steroid receptor (Liu et al.). The receptor actually has a greater affinity for the medication than for the endogenous cortisol, and thereby works by blocking the excess cortisol from causing unwanted side effects.
In addition to surgery to remove the tumor and medical therapies, there is a third option that is sometimes used as the first line of treatment, but is often used instead after a failed pituitary surgery. Radiation therapy is a viable option for many people who have had a failed pituitary surgery, and for those rare cases where surgical intervention is too risky. Traditionally conventional fractionated radiation therapy was the preferred modality for treating pituitary adenomas, however, complications that cause hypopituitarism (loss of pituitary function) in approximately 50% of patients, has caused it to fall out of favor (Liu et al). Instead strereotactic radiosurgery (SRS), or gamma knife, is currently the preferred modality to treat pituitary adenomas. Unfortunately it takes approximately 2 years to see complete remission from radiation therapy, which is why radiation therapy is often used in conjunction with medical treatment.
The last line of treatment available to patients who have had failed pituitary surgeries or radiation therapy and have not had good results with the currently available medical treatments is to undergo a bilateral adrenalectomy (BLA). In a BLA procedure the adrenal glands are removed, so although the person might still have some tumor function in the pituitary gland, the adrenal glands, farther down the hormone cascade are not able to respond to the excess ACTH being produced and in turn produce too much cortisol. This surgery is not without risks, patients are left unable to make cortisol, aldosterone, and other adrenal hormones, and must supplement these hormones for life. However, I will not go into detail here as the bilateral adrenalectomy is discussed in length elsewhere on this site.
Treatments for adrenal tumors.
Besides being caused by a tumor in the pituitary gland which secretes ACTH, Cushing’s syndrome can also be caused by a tumor in the adrenal gland which produces excess cortisol. Adrenal tumors are generally benign adenomas in the sense that they do not spread their tumor cells beyond the adrenal gland, however, a small percentage of adrenal tumors causing Cushing’s syndrome are adrenal carcinomas and may require more intervention than just surgery. Oftentimes the tumor is only in one gland, as opposed to tumors present in both glands. The treatment is often straightforward, and the first line treatment is removal of the tumor and generally the removal of the entire affected gland. As compared to pituitary tumor removal surgery, patients with adrenal tumors generally have a high success rate and experience a high rate of remission (NLM, 2014). For more detailed information on Cushing’s due to an adrenal source please see information found elsewhere on this site.
Treatments for ectopic Cushing’s syndrome.
Ectopic Cushing’s syndrome refers to a diagnosis of Cushing’s in which the source of the disorder does not originate in either the pituitary or adrenal glands. Ectopic Cushing’s sydrome generally accounts for less than 10% of all cases of Cushing’s syndrome with half of those cases caused by small cell carcinomas in the lung and the rest of the cases stem from various other neuroendocrine tumors, generally bronchial and thymic carcinoids (Bhansali et al., 2007). The treatment of ectopic Cushing’s syndrome is heavily dependent upon the location of the tumor and whether or not the tumor is malignant. However, almost all treatment involves removal of the tumor in conjunction with medical treatment.
Treatments for exogenous Cushing’s syndrome.
Exogenous Cushing’s syndrome differs from other types of Cushing’s in that instead of being caused by a tumor, the symptoms of Cushing’s are caused by something outside of the body, generally the use of corticosteroid drugs. Corticosteroid medications include drugs used to treat illnesses such as lupus, rheumatoid arthritis, asthma and are also used in people receiving organ transplants or as injections for people with joint and muscle injuries. Medications include prednisone, dexamethasone (Decadron), and methylprednisolone (Medrol) (Nordqvist, 2009). Treatment for Cushing’s syndrome caused by an exogenous source generally includes tapering the current corticosteroid dose or switching to a non-steroidal treatment option.
Getting a diagnosis of Cushing’s disease can be a scary and confusing time, but I would like to leave you with these thoughts. Have hope. There are people who have been there before you, people who understand the turmoil you are going through, and people who will support you through this process. There are many decisions to be made in regards to treatment, and the amount of information out there can be overwhelming. Take a breath, feel free to ask questions, give yourself permission to grieve this diagnosis, but then find your strength and get ready to fight; you will not be alone!
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