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Endo 2016 Historical Perspective Cushing’s Symposium

Cushing’s Disease: An Update on Pathogenesis, Diagnosis, and Medical Treatment

Historical note from Symposium Chair

By Dr. Beverly MK Biller, Professor of Medicine, Harvard Medical School; Neuroendocrine Unit, Massachusetts General Hospital

This year, The Endocrine Society celebrated 100 years of existence with a theme of: “1916-2016, 100 years of hormone science to health.” In keeping with the Centennial theme, selected Symposium Chairs were asked to provide a 5 minute Historical Note on the topic to be addressed before introducing the three speakers for the session.

Dr. Harvey Cushing Dr. Harvey Cushing

Dr. Cushing served as the 3rd President of the Endocrine Society from 1920 to 1921. In his Presidential Address, later published in The Journal of the American Medical Association, Dr. Cushing equated the early stages of discovery in endocrinology to the voyage of a sailing ship, writing, “We find ourselves embarked on the fog-bound and poorly charted sea of endocrinology.” (2)

In 1932, Dr. Cushing identified a new disorder by closely observing a number of patients who had similar problems, now referred to as Cushing’s disease and first described this condition in the Bulletin of the Johns Hopkins Hospital (3). He proposed (correctly) that the condition was likely due to a small tumor in the pituitary gland.Cushing book

He went on to say, “I am quite aware that in ascribing the disorder to the basophilic elements (of the pituitary gland)…may arise questions which are at present unanswerable” (3 – pg. 193). At that time, those questions included what caused these tumors to develop, what hormones were involved, how to measure them and how to treat the patients.

He noted, “for states due to over-secretion, our only recourse at present is surgery or some form of radiation” (2 – pg. 1723), predicting that, “the day is not too far distant when surgery will come to play a less…important role” (2 ). Nearly 90 years after Dr. Cushing made this statement, medications were approved by the FDA and EMA specifically to treat Cushing’s disease.

The speakers selected for this Symposium on Cushing’s Disease: An Update on Pathogenesis, Diagnosis, and Medical Treatment have all been involved in advances over recent years in the pathogenesis (causes), diagnosis and treatment of the disorder, answering some of Dr. Cushing’s questions from the early 1900s. Dr. Stalla has added to our knowledge about one of the molecular causes of Cushing’s disease, Dr. Raff has advanced the field of making the diagnosis of Cushing’s and Dr. Fleseriu has contributed to clinical trials of new medications to treat the disorder and they shared their knowledge in the Symposium as described below.

1) Cushing, H., The Pituitary Body and its Disorders, Clinical States Produced by Disorders of the Hypophysis Cerebri, J.B Lippincott Company, 1912.
2) Cushing, H., Disorders of the Pituitary Gland: Retrospective and Prophetic, JAMA, Vol. 76, No 25, June 18, 1921.
3) Cushing, H. The Basophil Adenomas of the Pituitary Body and their Clinical Maifestations(Pituitary Basophilism), Bulletin of the Johns Hopkins Hospital 1932; 50: 137-196.

Editor’s Note: Images provided courtesy of the Endocrine Society.

New Concepts in Corticotroph Adenoma Pathogenesis and Experimental Treatments

By Dr. Gunter K. Stalla, Department of Internal Medicine, Endocrinology and Clinical Chemistry Max Planck Institute of Psychiatry, Munich, Germany

In past years, many genetic studies have been performed in Cushing’s pituitary tumors in attempts to find mutations that explain how these tumors develop. This is important in identifying potential drug targets. However, mutations had been found only in very rare individual cases and in rare genetic syndromes.

USP8 Mutations and Epidermal Growth Factor Receptor

More recently, mutations were found in the ubiquitin-regulating gene USP8. In a large multicenter, retrospective study (that included our center plus the University Hospital Munich, as well as UK, NIH/US, France, Brazil, Serbia and Hungary) we showed that somatic (not inherited) USP8 mutations are found in 40% of cases of Cushing’s disease and are more frequent in younger women.

Cells have intricate mechanisms whereby growth is controlled. At the cellular level, many of these mechanisms involve proteins and the quantity of important proteins is very tightly regulated. When genes are mutated, proteins often times are not present in their normal quantity. USP8 is an enzyme known to interact with EGFR, which is known to regulate cell growth. It has been found that mutated USP8 results in increased quantities of EGFR in Cushing’s pituitary tumor cells. EGFR regulates p27 and Cyclin E; proteins that tightly control cell growth. Several independent lines of evidence show that Cyclin E and p27 are present in different quantities in Cushing’s pituitary tumors compared to normal pituitary tissue.

Starting in 1990, evidence has accumulated in the literature showing that the EGFR present in Cushing’s pituitary tumor cells also plays an important role in the regulation of ACTH production. Stimulation of EGFR increases ACTH secretion and inhibition reduces it. The evidence that EGFR controls cell growth and ACTH secretion makes it a high interest target for medical treatment of Cushing’s disease.

Hsp90 and Silibinin

Normally, when cortisol is elevated, the pituitary gland decreases secretion of ACTH in an attempt to maintain normal cortisol levels. This is termed negative feedback. It is well known that Cushing’s pituitary tumors continue to produce excess ACTH in the presence of excess cortisol. This likely means that tumor cells are resistant to some control mechanism involving the glucocorticoid receptor (GR), the protein that interacts with cortisol. Why this happens is not fully understood.

Proteins have a 3 dimensional structure that heavily influences how they function. A specific protein present in pituitary cells, called Hsp90, had been previously studied in normal pituitary cells, was found to influence the 3D structure of GR and to be necessary for the response to glucocorticoids (cortisol). We investigated Hsp90 in Cushing’s tumor cells and found it to be present in greatly increased quantities in tumor cells compared to normal pituitary cells. We hypothesized that increased levels of Hsp90 could lead to lower levels of the proper GR 3D structure required to respond to glucocorticoids. Thus, we investigated the influence of several Hsp90 inhibitors on tumor cells and found that in 5 out of 6 cell cultures, the inhibitor, silibinin, increased the number of properly functional GR, restored responsiveness to glucocorticoids and decreased ACTH secretion. This was also confirmed in a mouse model.

Silibinin is a natural substance. It is safe and very well tolerated. It is currently in use in human patients in high doses to treat mushroom poisoning. Therefore, we are planning to test the effects of silibinin in human patients with Cushing’s disease.

Laboratory Diagnosis of Cushing’s Disease: Advances and Pitfalls

By Dr. Hershel Raff, PhD, Aurora St Luke’s Medical Center Medical College of Wisconsin, Milwaukee, WI

This presentation focused on three major areas:

  • Screening tests for the diagnosis of endogenous hypercortisolism (Cushing’s syndrome)
  • Determination of the cause (differential diagnosis) of Cushing’s syndrome
  • An approach to detect surgical remission and long-term recurrence of Cushing’s disease.

Screening Tests

The three major screening tests to use when the diagnosis of Cushing’s syndrome is suspected are late-night salivary cortisol measurement, an overnight low dose dexamethasone suppression test, and a 24 hour urine free cortisol test. These three tests interrogate different aspects of the pathophysiology of Cushing’s syndrome:

Late-night salivary cortisol: Normally, cortisol is highest in the morning and lowest at bedtime or soon thereafter. An increased late-night salivary cortisol test indicates a disrupted diurnal rhythm. In general, measurement of late-night salivary cortisol is considered the simplest and most accurate approach.

Overnight dexamethasone test: Normally, when cortisol is too high, the body decreases production of cortisol to try to maintain normal levels. This is termed negative feedback. Dexamethasone is a potent synthetic steroid; thus, if blood cortisol remains increased in this test, it indicates decreased glucocorticoid negative feedback sensitivity which is typical behavior for most tumors causing Cushing’s syndrome.

24 hour urine free cortisol: Increased cortisol in the blood leads to increased filtration of free cortisol from the blood into the kidney and, hence, the urine. It is generally thought that this test is not as sensitive as the other two tests because it is often not increased until Cushing’s syndrome is more severe.

Differential Diagnosis

Once Cushing’s syndrome is established, it is critical to determine the cause. It can be due to a tumor in the adrenal gland making too much cortisol independently of ACTH or it can be due to ACTH overproduction either from a pituitary ACTH-secreting adenoma (Cushing’s disease) or a non-pituitary source of ACTH (ectopic ACTH). Although it is not always perfectly clear, usually measuring a morning plasma ACTH is sufficient to distinguish an adrenal cause (suppressed ACTH) and a pituitary or ectopic cause (non-suppressed ACTH). If ACTH-dependent Cushing’s syndrome is established, one must be able to differentiate a pituitary tumor from an ectopic tumor. If a pituitary tumor is clearly demonstrated by MRI, then a referral to a highly experienced and talented pituitary neurosurgeon is warranted. If the MRI is negative, then inferior petrosal sinus sampling is performed in which a thin tube (catheter) is inserted in veins in the groin and passed up to the venous outflow of the pituitary. By demonstrating increased ACTH in the pituitary venous outflow particularly in response to CRH injection, one can establish that the cause is a pituitary ACTH-secreting tumor (Cushing’s disease).

Once Cushing’s disease is established, the typical first approach as mentioned above is transsphenoidal (usually with an endoscope) pituitary surgery. This must be done by a very experienced neurosurgeon who has successfully performed this technique on many patients with Cushing’s disease.

Determination of Remission or Recurrence

Unfortunately, surgical failures occur even in the best of neurosurgical hands and are usually detected in the post-operative period by a failure to have decreases in cortisol or a persistently increased late-night salivary cortisol. However, recurrences may happen many years after successful pituitary surgery. The best way to monitor patients for recurrence is with occasional (perhaps every 6 – 12 months) measurements of late-night salivary cortisol. If the patient starts to experience a recurrence of symptoms, this should be done immediately.

Selecting a Target in Refractory Cushing’s Disease: Corticotroph Tumor, Adrenal Steroidogenesis, or Glucocorticoid Receptor?

By Dr. Maria Fleseriu, MD, FACE, Departments of Medicine and Neurological Surgery, Northwest Pituitary Center, Oregon Health & Science University, Portland Oregon

Transsphenoidal surgery represents the first line of treatment for Cushing’s disease (CD). However, even in the hands of the most experienced neurosurgeons, a significant number of patients do not achieve remission and approximately 25% of patients experience a recurrence. Medical treatment is most often used after an unsuccessful surgery, in patients who are not surgical candidates or while awaiting effects of radiation.
Medical treatment can target a pituitary tumor, the adrenal glands to decrease cortisol synthesis or block the glucocorticoid receptor which decreases the effects of cortisol.

Two medications, pasireotide and mifepristone, are currently approved for use in some Cushing’s patients. A full evaluation of available medical treatments is reviewed in an adjacent article (pg 8 of this newsletter) on the Endocrine Society treatment guidelines. This article will focus on new drugs on the horizon, especially drugs in late stage in clinical trials.

Pasireotide LAR

Twice daily pasireotide is approved and targets the pituitary tumor. A monthly, intramuscular long-acting-release (LAR) formulation of pasireotide approved for the treatment of acromegaly is now being evaluated for use in Cushing’s disease (CD). In a phase III trial of 150 patients with persistent, recurrent or de novo (if not surgical candidates) CD, normalization of 24 hr urinary free cortisol (UFC) was observed in 40% of patients treated with pasireotide LAR for a duration of 7 months. Median decrease in UFC was 48%. Similar to twice daily pasireotide, high blood sugar was noted in 68% or 80% depending on the dose. This led to discontinuation of treatment in only 5 patients. Pasireotide LAR has the advantage of being administered monthly, potentially improving patient compliance.

Osilodrostat (LCI699)

Osilodrostat is an inhibitor that blocks the final step in cortisol synthesis, similar to metyrapone. However, it is significantly more potent and its longer half-life allows twice daily oral administration. In a 10-week, proof of concept study, osilodrostat normalized UFC in 11 of 12 patients with CD. The extension phase study enrolled 4/12 of the original cohort and an additional 15 new patients with CD. Doses were adjusted until UFC normalized. At 22 weeks, response was seen in 78.9% and all responders had normal UFC levels. Adverse reactions were well tolerated, the most common of which were adrenal insufficiency, nasopharyngitis, nausea, diarrhea, and asthenia. Elevated testosterone levels and hirsutism or acne were noted in 3 of 11 females. Importantly, no new safety signals were identified after 22 weeks of treatment. Interim analysis of the open-ended extension study (LINC-2) points to sustained long-term efficacy of osilodrostat. Based on these results, osilodrostat shows promise as an alternative treatment in CD and two phase III studies (LINC-3 and LINC-4) are currently underway.

Levoketoconazole (COR-003)

Levoketoconazole, a specific form of ketoconazole, is an investigational new drug for CS that acts similarly to, but is hypothesized to provide better safety and efficacy than closely related ketoconazole. Higher potency theoretically leads to lower doses and fewer adverse events. In some instances, ketoconazole has been shown to have adverse effects on liver function. Levoketoconazole is 12 times less potent for inhibition of a key liver enzyme that influences liver function, thus less liver toxicity might be expected.

A recent pre-clinical study confirmed that levoketoconazole more potently inhibits several steps in cortisol synthesis. In a phase I study, levoketoconazole administered to healthy subjects reduced serum cortisol significantly by day 4 as compared to ketoconazole. The drug was well tolerated; headache, back pain and nausea were the most frequently reported adverse events. A phase III single-arm, open-label trial is currently underway to evaluate the efficacy, safety, tolerability, and pharmacokinetics of levoketoconazole in patients with Cushing’s.


R-roscovitine, an inhibitor of Cyclin E (discussed by Dr. Stalla), has been evaluated as a potential therapy for CD patients. R-roscovitine was first shown to be effective in reducing ACTH and corticosterone serum levels in a mouse model. Currently, a phase II clinical trial in human patients with CD is ongoing to evaluate the efficacy and safety of R-roscovitine.

Retinoic acid

Retinoic acid was proposed as a treatment for CD patients after it was shown to decrease ACTH secretion and pituitary tumor growth in cell culture and in animal models. A recent clinical trial demonstrated that a specific form of retinoic acid, isotretinoin, resulted in UFC normalization in 4 of 16 patients (25%) at 12 months, with UFC reductions up to 52% seen in the rest. Adverse events, though mild and reversible, were encountered in more than 40% of patients. Further randomized, double-blind, clinical trials are needed to evaluate its efficacy in patients with CD.

Epidermal growth factor receptor (EGFR) inhibitors

Recently, it has been discovered that mutations in pituitary tumors involve the USP8 gene, which interacts with EGFR. Gefitinib, an EGFR inhibitor currently approved for treatment of some cancers, reduced ACTH secretion and tumor size, resulting in clinical improvement in animal models. Thus, inhibition of EGFR has potential therapeutic application.

Editor’s Note: To find further information on any of these trials, visit and search for the drug name. Also, see the Clinical Trials section of this website.

CSRF Editor’s Thoughts on Endo 2016 Cushing’s Symposium

While at Endo 2016, I had the opportunity to attend this very interesting session. The room was filled to capacity with probably over 1,000 in attendance. Dr. Biller set the stage perfectly with her historical perspective and throughout the rest of the session, my mind continued to reflect on what it would have been like to have Cushing’s 50 or 100 years ago and how the understanding and treatment of Cushing’s has advanced. I wanted to pass on a few of my thoughts.

It is hard to imagine that when Harvey Cushing’s discoveries were made, there were no imaging or biochemical cortisol testing techniques available, thus, many of his findings were actually in the pituitary gland during autopsy and related to the clinical picture.

When Harvey Cushing practiced, surgery was not nearly as advanced as today. Now, there are modern techniques of MRI and advanced optics make transsphenoidal surgery possible using a microscope or endoscope. Cushing’s patients undergoing surgery prior to 1950, when hydrocortisone became commercially available, often did not survive due to adrenal insufficiency.

Dr. Stalla discussed findings that would not have been possible many years ago. Understanding why tumors form and why they grow involves unraveling genetics, biochemistry and how cells function normally and abnormally. Over the last 50 years or so, laboratory techniques have gradually evolved so that intensive study of how a cell does what it does is now possible. With these tools, significant progress has been made in understanding what genes and proteins are involved in Cushing’s.

Many of us have gone through the lengthy diagnostic testing process. Again, it is hard to imagine that, when Cushing’s was first described, there was no laboratory test available to diagnose this condition. Work done during in the 1950’s and 1960’s led to the development of modern day testing methods such as the radioimmunoassay, 24 hr urine free cortisol measurements, and the overnight dexamethasone suppression test. While initially described in the 1960’s, late-night salivary cortisol testing did not become widely used until more recently.

For many decades, there were no medical treatments available for Cushing’s. In the early 1980’s, an anti-fungal medication called ketoconazole was made commercially available (for another reason) and shortly after was shown to decrease cortisol production in the adrenal glands of some patients with Cushing’s. This drug and others have been used “off-label”, meaning that they were not specifically approved by the US FDA for Cushing’s. Now, there are two FDA approved medications pasireotide (Signifor) and mifepristone (Korlym) specifically for Cushing’s and others currently in clinical trials or development.

While great progress has been made in the last 100 years, there is still much work to do. As patients, we are fortunate to have many very talented physicians working in the area of Cushing’s! Who knows what the area of Cushing’s will look like in another 100 years!

By Karen Campbell, Director, Editor, CSRF

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