This year marked the 100^th anniversary of the Endocrine Society’s Annual Meeting and Expo. The event was held over several gorgeous days in Chicago from March 17-20. Endocrinologists, scientists, nurses, medical students, and other stakeholders gathered in the mutual pursuit of the latest theories, research, and developments in endocrinology. As in previous years, the CSRF reached out to attendees and sponsors on the exhibition floor, welcoming them into our booth for education and discussion. CSRF volunteers Leslie Edwin, Elissa Kline, Dr. Meg Keil, Joanie Kilbride, and Sabrina Whitt promoted awareness and the Foundation’s patient resources. This year’s conference did not disappoint, offering almost three dozen Cushing’s-related presentations in addition to more than 100 related endocrine study and discovery posters. 

The following is a summary of scientific information that was presented in nine sessions and four posters related to the Cushing’s journey.  Presenting doctors are listed as well as any specific research or trial references.  Scientific information is relayed from oral presentations, slides, and printed literature.

Reexamining the Diagnosis and Management of Hypercortisolism

Dr. Ty Carroll, Medical College of Wisconsin, Menomonee Falls, WI

Increased cortisol frequently causes a number of symptoms that are likely familiar to readers: muscle weakness, vertebral fractures, blood clotting disorders, cognitive and psychological changes, diabetes, and osteoporosis.  We know the diagnosis of Cushing’s, but a patient can have sustained, elevated cortisol (hypercortisolism) caused by sources other than tumors or steroid use. Hypertension is another frequent symptom of hypercortisolism, but there is a greater issue of cardiovascular health that can sometimes get put on the back burner while treating the more immediate threats of high cortisol.  Dr. Carroll stressed the significant effect of cortisol’s disruption of the natural circadian rhythm of our bodies, which is an essential natural regulator of everything from sleeping and feeding patterns to adequate management of glucose and insulin. 

It is an unfortunate fact that untreated Cushing’s leads to about a 50% mortality rate over five years.  According to Dr. Carroll’s research, there is a direct correlation between results of the dexamethasone suppression test (DST) and mortality – if a patient’s cortisol level suppresses on the low-dose DST with a reading of <1.8 mcg/dl, there is an average 91.2% survival rate; a reading of >1.8 mcg/dl drops the average survival rate to 57% as related to the patient’s hypercortisolism.  An individual with an adrenal adenoma that is ≥2.4 cm in size is three times more likely to have a cardiac event, and even those with non-secreting adrenal nodules have been found to have a much higher rate of developing diabetes than patients without adenomas of any type present.  This research was done on patients who presented with some signs of hypercortisolism but without a diagnosis of Cushing’s.

The dangers of hypercortisolism-related cardiovascular damage are enough to warrant careful consideration in patients where testing has indicated elevated cortisol.  On average, 4-7% of ALL imaged adults have an adrenal incidentaloma (defined as an adenoma, nodule, or “spot” found while doing a scan for another reason).  This number increases with age.  From this set of patients, an estimated 5-30% of those adenomas turn out to be cortisol-secreting.  According to the European Society of Endocrinology, all patients with adrenal nodules should be screened for hypercortisolism.  This is not standard procedure in the US yet, and we cannot stress enough that choosing an experienced, educated physician can make a big difference in the care you receive.  Physicians experienced with hypercortisolism tend to be more aware of less-commonly discussed screening and diagnostic standards.  Even without overt clinical signs of hypercortisolism, the presence of an adenoma and any Cushing’s-like symptoms are directly related to an increased risk of health problems.

Dr. Carroll encourages use of the low-dose DST and shared a word of caution against depending too heavily on the urinary free cortisol (UFC) test due to its low sensitivity in mild cases of hypercortisolism. As for blood tests, he prefers testing dehydroepiandrosterone-sulfate (DHEA-S) as opposed to adrenocorticotropic hormone (ACTH) because the level of DHEA-S in the blood remains relatively steady while ACTH is easily disrupted and varies throughout the day.

Editor’s note: Interestingly, the percentage of adrenal incidentalomas discovered during abdominal scans for other reasons seems to be higher in the U.S. (4-7%) than the 2% currently reported in a European trial mentioned by Dr. Carroll (NCT02364089 – clinicaltrials.gov).  

Diagnosis and Treatment of “Subclinical Cushing’s Syndrome”: Who, Why and How?

Dr. Antoine Tabarin, CHU Bordeaux, France

Dr. Irina Bancos, Mayo Clinic, Rochester, MN

The lecture began with a dissection of the word “subclinical” when referring to mild cases of Cushing’s with an adrenal source.  It can be useful for physicians with little experience dealing with hypercortisolism because it is a term that has been around for a long time and is easily understood to differentiate from overt or pituitary cases.  There was unanimous agreement on a recent panel of physicians to instead use the term “autonomous cortisol secretion”.

The doctors made the case that diagnosis of autonomous cortisol secretion can be problematic because UFC testing seems to be useful in only about 30% of adrenal cases, and there is a general lack of agreement among the various tests.  Their philosophy is to avoid overdiagnosis and overtreatment without missing relevant diseases and to establish a diagnosis at the time an adrenal mass is found.  They felt that the 1mg DST was the best tool for diagnosis of possible cortisol secretion in adrenal incidentalomas: a result under 1.8 mcg/dl excluded, above 5 mcg/dl confirmed, and the area in between was a solid “possible”.  Additional investigations can help to confirm, especially if repeated over a period of 3-12 months depending on the severity of the patient’s condition (if they can tolerate the wait).  The presence of comorbidities (simultaneous presence of two or more chronic conditions) and the age of the patient are relevant in making the decision on how to proceed.

Some patients are ready to head straight to removal of one or both adrenals when high cortisol is present.  There are a lot of potential problems with this approach when the source of high cortisol is not clear and might be something other than a secreting tumor.  As rote as it might seem, aggressive lifestyle changes that reduce weight, reduce A1C, and improve hypertension can sometimes lower cortisol in a patient with an adrenal incidentaloma that has questionable cortisol secretion.  Medication can sometimes help manage mild hypercortisolism.  Unfortunately there are few comparative studies of patients who have adrenalectomies vs. those who opt in favor of other interventions (lifestyle changes, medication, etc).  Post-adrenalectomy management is also a matter up for serious debate – there’s still quite a bit of “what now?” from both the patient and the physician, and this is not a condition that is beneficial to a person who just had surgery and frequently has other comorbidities to manage. 

The take home message from this session was that there is no cut and dried method to ensure success for a patient without clear symptoms and targets.  All options must be considered and tests must be repeated.  Patients sometimes do not want to wait and will change doctors during the testing process out of frustration.  It is vital that the communication between doctors and patients improves so both understand the other’s needs, limits, fears, and desired outcomes.  Studies have shown that patients with mild hypercortisolism cross in and out of “normal” and “high” cortisol states if tested over a period of time.  We hear patients discuss strategies to “catch highs” to prove they have Cushing’s, but this might be misleading with potentially adverse effects if the patient is pursuing a diagnosis that is not appropriate for their condition.  Also, one high or low test does not prove anything definitively.  Some patients with borderline, intermittent, or self-described “cyclic” cortisol excess have successfully changed their habits (diet and exercise) and seen their DST results return to and stay in a normal range.  It’s imperative for patients to understand that multiple tests over a period of time are essential to getting the diagnosis correct.  It is just as important for doctors to find better ways to make their patients feel that they are heard, believed, and recognized as an active partner in their journey to diagnosis and healthy outcomes.  It was encouraging to see so much interest in this subject that the presentation was given twice, in the ballroom (biggest session room), with at least 90% of the chairs filled.

Recent Progress In Adrenal Tumors

Dr. Constantine Stratakis, National Institutes of Health, Bethesda, MD

Annabel Berthon, PhD, National Institutes of Health, Bethesda, MD

Researchers are expressing special interest in adrenal tumors, their origins, and ways to prevent their formation early in development. Ms. Berthon presented her work with Dr. Stratakis and his team on Kisspeptin, the Kisspeptin Receptor, its role in adrenocortical development, and how that development affects the adrenal gland’s secretion of cortisol.  Kisspeptin is a hormone made in the hypothalamus and is involved in general endocrine function and puberty.  There is some evidence it is also involved in age-related hormone decline.

Studies have looked at the complexities of manipulating various proteins and receptors in their attempts to determine what causes an adrenal tumor to form and why it begins to oversecrete cortisol.  It has been determined that damage to the process involving the kisspeptin receptor can lead to hyperaldosteronism, which is the overproduction of aldosterone in the adrenal glands.  This condition can lead to hypertension and low potassium / high acidity in the blood.

Kisspeptin and Kisspeptin Receptor May Be Involved in the Regulation of Adrenocortical Development and Steroid Hormone Secretion, Annabel Sophie Berthon, PhD¹, Nikolaos Settas, PhD¹, Andreas Giannakou, MD¹, Angela Delaney, MD², Fabio Rueda Faucz, PhD³, Constantine A. Stratakis, MD, PhD⁴.  ¹NIH, Bethesda, MD, USA, ²National Institutes of Health, Bethesda, MD, USA, ³NIH/NICHD, Bethesda, MD, USA, ⁴NICHD/NIH, Rockville, MD, USA

Challenging Cushing’s

Dr. John A Wass, Oxford University, UK

Dr. Wass chose to do the majority of his presentation town hall style – with a brief presentation of data and then the floor opened up for questions and conversations with the physicians in attendance.  He described cases of patients who presented in clinic with a few Cushing’s-like symptoms and a request for testing.  Symptoms ranged from florid to patient-reported but clinically undetectable.  He asked attendees to tell him how they would proceed.  There were subtle differences in approach and speed, but the audience seemed committed to following established diagnostic guidelines.  Still, not everything was as it seemed initially with the patients, which is no surprise.

Dr. Wass shared concerns about the typical symptoms and challenges of Cushing’s.  He highlighted the fact that patients are more susceptible to infections, psychiatric problems, and clotting tendencies during and after treatment.  He feels that most patients need anti-clotting protection for surgeries and exploratory procedures such as the inferior petrosal sinus sampling (IPSS).  Dr. Wass was also very insistent that patients be allowed to benefit from a multidisciplinary approach to their symptoms (Dr. Harvey Cushing initially discovered “polyglandular syndrome”, which clearly lays out that Cushing’s is not a single narrow diagnosis).  Outcomes are optimized when specialists get involved and apply their expertise.  Centers of Excellence are offering better chances for patients who can use their services because specialists are “under the same roof” and share records.  A patient who is treated across the spectrum of specialties will have a much better prognosis. 

Another highly debatable topic is cyclical Cushing’s.  Excellent doctors have been demonized by an oddly self-confident yet totally uncredentialled portion of the online Cushing’s community for disagreeing with the increasingly frequent self-diagnosis of cyclical Cushing’s.  All available evidence points to cyclic being a rare form of an already rare disease.  Cushing’s is probably more prevalent than currently reported, but it is rare.  It is difficult to diagnose because many common factors can lead to intermittent high cortisol readings, and there is a growing knee-jerk reaction in patients to determine they have cyclic Cushing’s based on a single high test and online encouragement to fight for that specific diagnosis.  Frustration grows when further testing is done and does not back up the single, or occasional, high cortisol test(s).  In all cases, the patient can identify at least a few “Cushing’s symptoms” because they are so non-specific.  There is much work to be done in this arena.  The following is verbatim from one of Dr. Wass’s slides:

“Cyclic Cushing’s: A small group of patients with Cushing’s syndrome have alternating normal and abnormal cortisol levels on an irregular basis.  All causes of Cushing’s syndrome may be associated with cyclical secretion of cortisol.  Clearly, the results of dynamic testing can only be interpreted when the disease is shown to be active (elevated urinary cortisol secretion and loss of normal circadian rhythm and suppressibility on dexamethasone).”

Dr. Wass concluded with the bold statement that Cushing’s is one of the most challenging conditions for an endocrinologist to treat.  Treatment in experienced centers is practically mandatory for a successful outcome, as is long term follow-up of the patient.  This follow-up is intended to diagnose and treat recurrence, hormone deficiency, and psychological and other consequences of the disease as early as possible.

Adrenal Insufficiency: Impact of Patient Education and Choice of Replacement Options

Dr. Stefanie Hahner, Wurzburg Medical School, Germany

Dr. Hahner began with a patient example – a 38 year old female with adrenal insufficiency (AI) who complained about being tired and having to give up her love of flamenco dancing.  She asked the audience how they would proceed, and most agreed that they would individualize the patient’s replacement steroid dosing to ensure she was taking a small extra amount ahead of the intense physical exertion required of a flamenco dancer.  The patient did this and resumed her passion but still had reduced energy and eventually had to cut back on work hours.

What next?  The patient was switched to Plenadren, a once-a-day extended release form of hydrocortisone (Plenadren is not licensed for use in the US but has obtained orphan drug status).  She would then take a dose of hydrocortisone before her strenuous activity.  She felt more stable but still unable to work full time.  Her doctor added DHEA treatment – studies show moderate positive effects on depression, anxiety, and the way a patient feels overall when they take DHEA.  The patient reported acne and greasy hair about 10 weeks into treatment with DHEA, so the dose was reduced and the negative symptoms resolved.  Over the next six months the patient reported slight improvements in sexuality and mood, but she was still only working half time.

Unfortunately, this is a reality for a lot of people with AI.  In fact, it could be a best possible outcome for some when compared to the limitations and challenges they experience personally.  Not all doctors are comfortable adjusting doses of life-saving hydrocortisone, but this seems to be getting more attention and will hopefully evolve to benefit all patients with AI who do not feel that the standard two doses a day fit their particular life.  In the meantime, the squeaky wheel may very well be the one that gets the grease – there is enough research and information available so that patients who want to consider individualized dosing of their replacement cortisol should be able to discuss this approach with their endocrinologist.

In addition to individualized dosing, there are benefits and drawbacks to each of the types of cortisol replacements that are available in the US like prednisone, hydrocortisone, and dexamethasone.  In choosing the type of replacement a patient takes, factors like age, ability to remember to take doses regularly, and presence of diabetes should be taken into consideration.  If the patient takes a medication that accelerates the metabolism of hydrocortisone (ex. carbamazipine, phenobarbital), that is also very important to factor into replacement choice and dosing.

One last related note, and there is no way to state this too often: there is a high prevalence of psychiatric disorders and metabolic comorbidity in patients with AI.  It is vital that all aspects of the patient’s health are put under the spotlight and followed when they become adrenally insufficient.

Diabetes Insipidus: Challenges in Diagnosis and Management and Vasopressin, Falls & Fractures

Dr. Daniel Bichet, Universite de Montreal,  Canada

Dr. Joseph Verbalis, Georgetown University, Washington DC

Although diabetes insipidus (DI) is a fairly common occurrence after treatment for Cushing’s, providers face some surprising challenges in its management.  DI is not related to blood sugar but rather to the water balance involving the kidneys and vasopressin, the anti-diuretic hormone (ADH). Vasopressin affects cells in the collecting ducts of the kidneys. The synthetic replacement for vasopressin can quickly become a deficient patient’s best friend, as it helps prevent fluid loss from the body by reducing urine output and helping the kidneys reabsorb water into the body.

As soon as we become comfortable with a synthetic form of vasopressin to help us maintain our bodies’ fluid balances after damage to or removal of the pituitary, we find that this very medication has been shown to play a role in increased numbers of falls and fractures. Desmopressin, or DDAVP, can be a very effective and extremely useful drug, but this replacement hormone is powerful. Too little DDAVP can lead to DI. Too much can lead to congestive heart failure, cirrhosis of the liver, and syndrome of inappropriate ADH (SIADH).

Dr. Verbalis explained the danger behind a less common side effect of taking the drug: hyponatremia, or the condition of having an abnormally low concentration of sodium in the blood.  Excessive vasopressin affects the body’s sodium levels and can cause a condition in which the brain develops an area of edema (swelling) because of sodium imbalance. The patient will often develop gait instability because hyponatremia affects nerve conduction and leads to loss of muscle strength.

Since the body is an efficient user of its own resources, when it experiences chronic sodium deficiency, it can actually break down bones for nutrients.  In the persistent absence of enough sodium, the body will send bone-dissolving osteoclasts (similar to white blood cells) out of its bone marrow to do their job and free up sodium, which is found in bones along with calcium and Vitamin D. Due to this breakdown, the patient can experience bone weakness which often leads to falls and a sharp increase in fractures and breaks. The standard for diagnosis of hyponatremia is the Bone-Micro CT scan with treatment focused on targeting the underlying cause of the excessive ADH dosage. 

Unconventional Causes and Treatments of Adrenal Insufficiency

Dr. John Achermann, University College London,Great Ormond Street Institute of Child Health,  UK

Dr. Peter Kuhnen, Institute of Experimental Pediatric Endocrinology, Berlin, Germany

Although the following information discusses causes of adrenal insufficiency (AI) that are not related to Cushing’s, it is still very encouraging that scientists are looking into the ways this condition develops on a microscopic level.  Advances in genetics can lead to better understanding and beneficial outcomes for all AI patients – the researchers are attempting to understand what causes AI in the hopes that they may eventually develop a way around that mechanism and prevent it from happening in the first place.

Three mutations can contribute to symptoms of AI in adults and children.  These gene variants are present and detectable as early as four weeks post-conception and can accurately predict the incidence of primary AI.  AI that starts later is often a result of deficient genetic mutations in CYPIIA1 and the STAR gene. A third mutation, an endocrine regulator called SAMD9, leads to a progressive chromosome loss that ignites a series of events that will also cause AI, sometimes as late as 20 years down the road. 

 Another uncommon cause of AI is a deficiency of the proopiomelanocortin (POMC) gene, which is synthesized in the pituitary.  A lowered level of POMC produces low ACTH in addition to problems with obesity and achieving satiety.  POMC deficiency also affects the body’s melanocortin, frequently leading to pale skin (https://ghr.nlm.nih.gov/gene/POMC).   Further research has focused on treatment that might restore the action of POMC, ultimately returning the body’s ability to feel full and more effectively utilize its energy.

Debunking the Internet Myths: What is the best approach?

Dr. Jonathan Leffert, North Texas Endocrine Center, Dallas, TX

The internet is an amazing resource – what CAN’T you find online these days?  You never come up short, even with the most obscure of search topics.  According to a recent study, 60% of the public uses the internet for health information and 35% is actively engaged in “online diagnosis.” (J Med Internet Res. 2017 June 13;19(6):e202)

As with everything in life, there is a dark side to this stunning collection of information: steaming piles of disinformation, misleading advice, and opinions stated and promoted as facts.  You could say it is human nature to want to share our personal truths, even if we don’t realize that subtle methods to our storytelling can end up being detrimental to some of our audience.  Cushing’s patients and those pursuing a diagnosis are vulnerable in so many ways – just one example is the list of more than 30 symptoms that can accompany this disease.  A huge portion of the population could claim at least a few of those symptoms on a regular basis.  Does that mean that everyone has Cushing’s?  Of course not. 

Dr. Leffert noted that in the early years of his practice (from 1991 until a few years ago), patient referrals usually came from another physician or the insurance company.  In the last few years, many referrals have come from internet self-diagnoses, online ratings websites, and other online sources.  This is awesome in a way: expanded access to specialists you’d never know about without the internet is a priceless resource.  Helpful advice from patients who have come before you can comfort you throughout the excruciating period of diagnosis and provide wisdom for the “after”.  The downside is that patients desperate for an answer to what ails them frequently do not do thorough research to understand the functioning of the larger systems of the body.  Endocrinology is a perfect example.  Symptoms of endocrine disease are often vague and nonspecific.  Lab tests may be assay- or time-dependent, resulting in “abnormal” results when easy-to-confuse instructions are not followed precisely.  Agreeing to the wrong treatment at the patient’s insistence does not fix the underlying symptoms because the underlying disease is not addressed.

Doctors must strike a delicate balance between appropriate testing and the patient’s expectations.  If the two are not aligned, it’s going to be a difficult time for everyone involved.  Dr. Leffert advised the packed room to empathize with the patient but to stand firm in the conviction not to perform unnecessary tests or prescribe medications that are not clearly indicated.  Most important, physicians must remember that patients come to them out of a need to feel better.  They need help.  There may be therapies that can help with some symptoms while the patient begins a lengthy testing period. 

There is a lot of work to be done to help patients and doctors communicate and understand one another, to get the right tests done the first time, and to help the patient understand the process, especially in the case of hypercortisolism / Cushing’s.  Repeat testing over a period of time is essential to ensure that unnecessary, irreversible surgeries and treatments are not undertaken until all evidence supports the diagnosis.

Poster Highlights

Hundreds of posters representing recent research and case studies looking into various clinical aspects of Cushing’s were presented.  Some highlights:

• Elena Valassi (Universitat Autonoma de Barcelona, Spain) and colleagues examined quality of life (QoL) in patients with Cushing’s Disease versus patients with adrenal Cushing’s Syndrome using European registry data. They found that the single most important predictor for quality of life was achieving remission, rather than the origin.  There was sufficient data to conclude that patients with a pituitary source vs. an adrenal source had lower QoL at long-term follow up.  (Patients With Cushing’s Disease Have Worse Long-term Quality of Life Than Patients With Cortisol Producing Adrenal Adenoma.  Data From The European Registry On Cushing’s Syndrome (ECUSYN), Elena Valassi, MD, PhD, Universitat Autonoma de Barcelona, Barcelona, Spain et. al.)
• Irina Bancos (Mayo Clinic, Rochester, MN) and colleagues have been investigating expression of the FKBP5 gene and its potential future use as a biomarker for measuring cortisol activity. Increases in glucocorticoids in the body lead to increased expression of FKBP5. This correlation can be used not only for diagnosis, but also for monitoring response to medical or surgical treatments in patients with hypercortisolism. After successful surgical treatment, FKBP5 gene expression has been found to be comparable to gene expression in healthy subjects. It was their conclusion that FKBP5 gene expression could potentially be used as a clinical biomarker for evaluation and diagnosis in patients with Cushing’s. (FKBP5 Gene Expression Biomarker In ACTH-dependent Cushing Syndrome Patients Pre- and Post-curative Surgery, Irina Bancos, MD¹, Betul Ayse Hatipoglu, MD², Kevin Choong Ji Yuen, MD, FRCP (UK), FACE³, Andreas Moraitis, MD⁴.  ¹Mayo Clinic, Rochester, MN, USA, ²Cleveland Clinic, Beachwood, OH, USA, ³Swedish Pituitary Center, Swedish Neuroscience Institute, Seattle, WA, USA, ⁴Corcept Therapeutics, Menlo Park, CA, USA)
• Pejman Cohan (Specialized Endocrine Care Center, Beverly Hills, CA) and colleagues gave a case presentation of a patient believed to have spontaneously entered remission following treatment with mifepristone (Korlym), a glucocorticoid receptor antagonist. The 23-year-old woman experienced three recurrences, each time with symptoms of rapid excessive weight gain, hypertension, and depression along with multiple other conditions. She was repeatedly treated with transsphenoidal surgery, each time achieving only a temporary remission. It is believed by some that spontaneous nonsurgical remission of hypercortisolism in Cushing’s Disease patients can be a result of a sudden obstruction to the blood supply in the pituitary (apoplexy or infarction). The authors postulate that mifepristone may have played a role in this spontaneous remission of a non-visible pituitary tumor. (A Curious Case of Biochemical and Clinical Remission After Treatment with Mifepristone, a GR Antagonist, Pejman Cohan, MD¹, Daniel Kelly, MD², Precious J. Lim, PhD³.  ¹Specialized Endocrine Care Center, Beverly Hills, CA, USA, ²Pacific Neuroscience Institute, Santa Monica, CA, USA, ³Corcept Therapeutics, Menlo Park, CA, USA)
• Jennifer Cheng (Jersey Shore University Medical Center, Neptune, NJ) and her colleagues presented their endorsement of a combination treatment for the management of mifepristone-induced hypokalemia (low potassium) in a case study. The combination of potassium-sparing diuretics amiloride and spironolactone helped their subject lose weight, control his blood pressure, and also maintain his potassium level. He was able to significantly decrease or discontinue all of his previous medications. The patient reported improvements in mood, depression, and anxiety, and he no longer experienced suicidal ideations. Muscle strength improved, abdominal girth decreased, and striae greatly improved. (Combining Amiloride and Spironolactone to Manage Hypokalemia and Edema in Patients with Cushing Syndrome, Jennifer Cheng, DO¹, Rachel Bunta, MBA².  ¹Jersey Shore Univ Med Center, Neptune, NJ, USA, ²Corcept Therapeutics, Menlo Park, CA, USA)
• If you’d like to browse the summaries for all posters presented, and there are a LOT on Cushing’s-related issues, visit https://www.endocrine.org/endo-2018 and click the link for “Abstracts Presented” under the topic “View the ENDO2018 Abstracts”.

Summer, 2018