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What’s New in Cushing’s Research? A Conversation with Dr. Constantine Stratakis of the NICHD

Dr. Stratakis gave one of the most highly rated presentations at the October 2017 Patient Education Day at the NIH in Bethesda, MD, when he discussed new strategies, research, and outcomes for Cushing’s in his breakout session.  The positive feedback led to our desire to share a version of this presentation in the newsletter.  What follows is a Q&A based on comments from some of the patients who attended.

Q: What kind of information is out there for long-term survivors of Cushing’s Disease / Syndrome?  There are patients now who have been post-surgery for 10, 20, 30, even 40 years.  Is there any new research on quality of life, long-term effects of hypercortisolism, or living long-term without adrenals or with hydrocortisone dependence?

A: There is quite a bit of information about quality of life (QoL) in Cushing’s syndrome (CS) after treatment. A lot of unknowns also remain. In brief, we know that life for patients with CS is not easy with or without cure. Children with CS (Keil M. J Clin Endocrinol Metab. 2013 Jul;98(7):2667-78) suffer through deterioration in academic performance after their cure from CS for the first few years post-operatively. Most children find it difficult to cope, even when they are young adults; we described a few of these patients that attempted suicide, despite being cured from CS for many years (Keil M et al. Pediatrics. 2016 Apr;137(4)). Adults with CS suffer similarly and there are several recent publications on this issue (Pivonello R et al.. Front Neurosci. 2015 Apr 20;9:129). Adults report fatigue and executive dysfunction even after cure (Papakokkinou E et al. Behav Neurol. 2015;2015:173653).

Although other patients with pituitary tumors experience similar problems, the issues of patients with CS stand out (Romijn JA. Nat Rev Endocrinol. 2016 Sep;12(9):547-56). There is a lot of new knowledge on what QoL is like for patients with CS which did not exist even a decade ago. Patients now do not have to deal with the ignorance and disbelief of previous years, as there is good documentation in the literature. But, of course, lots of questions remain: now that we know that QoL is impaired in patients with CS even after complete cure of their hypercortisolemia, we do not know why this is the case. Is it because cortisol caused some permanent damage in the neuronal circuits regulating specific brain functions? Or, is it all reversible albeit after many, many years?  There are no studies looking at 30-40 years after cure for CS. We just started a long-term study at the NIH that will attempt to study patients as long as 10 years after cure.

Finally, it is unclear whether all the effects are neuronal. Does the body change in a way that is irreversible if one has CS?  This is much harder to answer, as muscle mass, body strength, bone structure, and skeletal function all change with aging; it would require, therefore, the follow-up of many, many patients for a number of years and their respective age-adjusted controls to answer this question.      

Q: What types of advances in genetics are you seeing for Cushing’s?  How prevalent are genetics in pituitary vs. adrenal?

A: I have been studying the genetics of all forms of CS for the last 25 years. I am happy to report that what I was saying in the 1990s and sounded almost crazy back then, is now universally accepted: CS is frequently a genetic disease – not necessarily inherited but genetic, in the sense that it is due to mutations of specific genes (see a review by Lacroix et al Lancet 2015;386:913-927). This is all very good news: knowing the genes that cause pituitary or adrenal tumors that lead to CS may assist in the development of new medical therapies that will be far more effective than the currently available ones. There is really no difference between pituitary and adrenal tumors in terms of how frequently they can be genetically caused: for example, 50% of all pituitary tumors causing CS harbor mutations in the USP8 gene and 50% of all adrenal adenomas leading to CS have mutations in the PRKACA gene. There are other genes involved in predisposition to CS in forms of the disease that are inherited. These are much rarer in both the pituitary and the adrenal gland. Multiple endocrine neoplasia-type 1 (MEN1), Carney complex (CNC) and related diseases are some examples of these inherited conditions that may also lead to CS among other conditions. 

Q: What kinds of advancements are you seeing in imaging for this disease?

A: Currently, we rely on magnetic resonance imaging (MRI) and computed tomography (CT) for most lesions of the pituitary and the adrenal, respectively. The technology is clearly suboptimal, especially for pituitary tumors. MRI is simply not enough, knowing that it can miss as many as one third of all pituitary tumors causing CS. We hope that the developments in genetics will lead to the discovery of probes that may be used for imaging and allow for the earlier identification of these tumors. Likewise, in the adrenal gland, we need imaging modalities that are safe and allow for the differentiation of the various functions of adrenal lesions, distinguishing cortisol-, aldosterone- and androgen-producing lesions from non-secreting ones. 

Q: There’s lots of chatter about dental problems caused by Cushing’s.  What kind of research do you see happening in this area?

A: CS affects immunity and almost certainly the microbes that we all host in our body. Thus, I would not be surprised if patients with CS experience dental issues and/or increased severity of periodontal disease. There is paucity of data on this issue. 

Q:  Is there anything specific being done to try to reduce the statistic that approximately 50% of tumors come back?  How about the one where there is a 50% chance of getting a tumor somewhere else in the body after Cushing’s?

A: The best way of preventing a recurrence is being seen early and at an experienced medical center. For example, patients with pituitary tumors seen at the NIH have a less than 10% recurrence rate. This is because we go to an extreme length in diagnosing the right cause of CS in our patients the first time we see them. And then, a very experienced surgeon operates on them. Most recurrences of pituitary tumors are due to incomplete excision by an inexperienced surgeon. A great number of cases are due to the wrong diagnosis: if a tumor is not in the pituitary gland, temporary remission may occur after pituitary surgery, but CS will come back because a corticotropin-producing tumor may be elsewhere in the body. Finally, most benign adrenocortical tumors should be completely excised by an experienced endocrine surgeon. However, ectopic adrenocortical tissue can be left behind by an inexperienced surgeon.  

Q:  One patient recalls that you said that cortisol is so vital to the body that going without it for a very short period of time can lead to death.  This is obviously a huge deal for those of us who are adrenally insufficient or headed toward that because of radiation or other factors.  Do you have additional details to expand on this point? 

A: My point is that patients that do not have adequate cortisol secretion face a serious problem, one that is life-threatening. Fortunately, for patients with pituitary tumors this is temporary and adrenocortical insufficiency (AI) only lasts for up to 12-18 months. For patients with single adrenocortical tumors, AI after surgery also lasts for about 18 months, on average. However, patients that had bilateral adrenalectomy face a life-long need for cortisol replacement. AI also complicates the management of patients on adrenolytic medications or those on Korlym. Finally, permanent AI may develop in patients with pituitary tumors after complicated or multiple pituitary surgeries.

AI can lead to acute hypoglycemia, hypotension, or severe electrolyte abnormalities that, yes, can cause death in a few minutes. At the NIH, we spend a lot of time training our patients on signs of AI, recognizing and treating it, and preparing for its recognition by emergency medical services if the latter are called in the case of emergency. Fortunately, like patients with diabetes and on insulin, patients with AI also learn to live with their disease, prevent crises, and treat their needs, in a way that allows them to live full and healthy and productive lives.

Q: There are standard tests that most everyone is familiar with now – the standard physical symptoms, blood, urine, saliva, dexamethasone suppression test….but you mention a “squat test”.  What is that, and what are some other similar tests that may not be commonly listed but that are good tests for Cushing’s?

There are a few physical signs of CS that the average physician is not familiar with. All physicians know the extreme central obesity and thinning of the extremities, the full face, the stretch marks, the easy bruising, fatigue, hair loss and the overall appearance of the “classic” patient with CS. However, there are some subtler signs that appear early in the course of hypercortisolemia: weakness of the central body muscles that becomes only detectable by asking the patient to squat and get up without support. Most healthy adults are capable of completing this simple exercise; however, patients with CS are unable to complete it successfully even if the disease is in its early phases. Other soft and early signs of hypercortisolemia include soft, non-terminal hair in the face and elsewhere that can be felt rather than seen, fullness in the supraclavicular and/or temporal areas of the neck and head, respectively, brought upon from local fat accumulation, and facial plethora (redness).    

Q: Any final thoughts?

A: The good news is that CS is a disease that today can be cured. The goal should be to diagnose it early, correctly, and offer the proper treatment. As we find more and more about what causes CS including USP8 and PRKACA mutations in pituitary and adrenal tumors respectively, new diagnostic testing and therapies will be designed; in the future, every tumor causing CS will be genotyped and the information will be useful in defining treatment and prognosis.

In the meantime, we have to make sure that patients with CS do not suffer from the many side effects of hypercortisolemia that go beyond what we know as CS. For example, patients with CS can develop severe infections, sometimes lethal ones; these can be prevented by implementing measures in patients with CS such as those used in other diseases that compromise the immune system. Fractures and/or other effects on the myoskeletal system should also be prevented or dealt with early and with appropriate physical therapy. Hypertension should be treated; and so on…

All of the above can be taken care and offered at experienced centers where both diagnoses and therapies and multidisciplinary care are offered by experienced teams of doctors and other caretakers. The goal is to turn CS into yet another disorder that is totally treatable; our patients should be able to live full and healthy lives, as medicine and technology advance.

Thank you, Dr. Stratakis!

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