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Report from the Cushing’s Disease Symposium at ENDO 2016

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Beverly MK Biller, M.D.
By Beverly MK Biller, M.D.

NEPTCC Newsletter Volume 23, Issue 1, Winter 2016/2017 [PDF version]

The 98th Annual Meeting of The Endocrine Society was held in Boston April 1-4, 2016. This article, adapted with permission from the Cushing’s Support and Research Foundation Newsletter, summarizes talks given at a Symposium on the topic, “Cushing’s Disease: An Update on Pathogenesis, Diagnosis, and Medical Treatment.”

Historical Note from Symposium Chair

In 2016, The Endocrine Society celebrated 100 years since the founding of the professional organization, with a theme called: “1916-2016, 100 years of hormone science to health”. Selected Symposium Chairs were asked to provide a 5 minute Historical Note before introducing the three speakers for their sessions. For this Symposium on Cushing’s disease (CD), held on April 2, 2016, I had the pleasure of delivering the Historical Note.

Dr. Harvey Cushing, known as the “father of modern neurosurgery” and the physician for whom CD is named, graduated from Harvard Medical School (HMS) in 1895. He served an internship (then termed “house pupil”), at Massachusetts General Hospital. Dr. Cushing was a surgical resident at Johns Hopkins Hospital and then returned to Boston as a faculty member at HMS. Dr. Cushing made many key discoveries about the pituitary gland, publishing The Pituitary Body and its Disorders, Clinical States Produced by Disorders of the Hypophysis Cerebri in 1912 (1).

Despite the fact that he was a neurosurgeon, Dr. Cushing served as the 3rd President of the Endocrine Society from 1920 to 1921. In his Presidential Address, 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.”

In 1932, Dr. Cushing identified the disorder that now bears his name by closely observing a number of patients with similar problems, describing this condition in the Bulletin of the Johns Hopkins Hospital (2). He correctly hypothesized that the condition was likely due to a small tumor in the pituitary gland.

He wrote, “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” (2). 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”, predicting that, “the day is not too far distant when surgery will come to play a less…important role” (1). Nearly 90 years after Dr. Cushing made this statement, the first medications were approved by the FDA and EMA specifically to treat CD.

The speakers selected for this Symposium on Cushing’s Disease: An Update on Pathogenesis, Diagnosis, and Medical Treatment were all involved in advances over recent years in the pathogenesis, diagnosis and treatment of the disorder, and have played a role in answering some of Dr. Cushing’s questions from the early 1900s. They shared their knowledge about CD in this fascinating Symposium.

Talk 1: 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 for 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 (EGFR)

More recently, mutations were found in the ubiquitin-regulating gene USP8. A large multicenter, retrospective study in Germany, UK, NIH/US, France, Brazil, Serbia and Hungary showed that somatic USP8 mutations were found in 40% of cases of CD and were more frequent in younger women (3).

USP8 is an enzyme which interacts with EGFR, which in turn, regulates cell growth. Mutated USP8 results in increased quantities of EGFR in corticotroph tumor cells. EGFR regulates p27 and Cyclin E; proteins that tightly control cell growth; they are present in different quantities in Cushing’s pituitary tumors compared to normal pituitary tissue.

Data have shown 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 potential target for medical treatment of CD.

Hsp90 and Silibinin

Pituitary tumors causing CD continue to produce excess ACTH in the presence of excess cortisol as they are not responsive to normal feedback inhibition. This likely means that tumor cells are resistant to some control mechanism involving the glucocorticoid receptor (GR), the protein that interacts with cortisol. The mechanism whereby this occurs has not been fully understood.

A specific protein present in normal pituitary cells, called Hsp90, influences the 3D structure of GR and is necessary for tissue response to glucocorticoids. In tumors from CD patients, increased Hsp90 was noted in tumor cells compared to normal pituitary cells (4). Investigators hypothesized that increased levels of Hsp90 could lead to lower levels of the proper GR 3D structure required to respond to glucocorticoids; they investigated the effect of several Hsp90 inhibitors. In 5 out of 6 tumor cell cultures, silibinin (a natural substance used to treat mushroom poisoning in humans), increased the number of functional GR, restored responsiveness to glucocorticoids and decreased ACTH secretion. This was also confirmed in a mouse model (4). Studies in human patients with CD are expected.

Talk 2: Laboratory Diagnosis of Cushing’s Disease: Advances and Pitfalls

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

1) Screening Tests

The three major screening tests to use when the diagnosis of Cushing’s syndrome is suspected are late-night salivary cortisol measurement (LNSC), an overnight low dose dexamethasone suppression test, and a 24 hour urine free cortisol (5). 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 LNSC level indicates a disrupted diurnal rhythm. In general, measurement of LNSC is considered the simplest and most accurate approach.
  • Overnight dexamethasone test – When cortisol is too high, production of cortisol is decreased to maintain normal levels through negative feedback on pituitary ACTH production. Dexamethasone is a potent synthetic steroid; thus, if blood cortisol remains increased when a low dose of dexamethasone is administered, it indicates decreased glucocorticoid negative feedback sensitivity, a typical feature of most tumors causing Cushing’s syndrome.
  • 24 hour urine free cortisol - Increased cortisol in the blood leads to increased filtration of free cortisol through the kidney and, hence into the urine. This test is not as sensitive as the other two measurements because it is often not increased until Cushing’s syndrome is more severe.

2) 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 due to ACTH overproduction either from a pituitary ACTH-secreting adenoma (CD) or a non-pituitary source of ACTH (ectopic ACTH). Usually measuring a morning plasma ACTH is sufficient to distinguish an adrenal cause (suppressed ACTH) from a pituitary or ectopic cause (non-suppressed ACTH). If ACTH-dependent Cushing’s syndrome is established, one must differentiate a pituitary from an ectopic tumor. If a pituitary lesion is clearly demonstrated by MRI (there is controversy over what size this should be), then a referral to a highly experienced pituitary neurosurgeon is warranted. If the MRI is negative (or shows only a small lesion), then inferior petrosal sinus sampling is performed in which catheters are threaded from groin veins up to the veins draining the pituitary. By demonstrating increased ACTH in the pituitary venous outflow, one can determine whether the cause is a pituitary ACTH-secreting tumor (CD). Once CD is established, the typical first approach is transsphenoidal pituitary surgery. This must be done by an experienced neurosurgeon who has successfully operated on many patients with CD.

3) 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 serum or urine cortisol or a persistently increased LNSC. However, even when patients are placed in remission, recurrences may happen many years later. The best way to monitor patients for recurrence is with occasional (perhaps every 6 – 12 months) measurements of LNSC. If the patient starts to experience recurrent symptoms, this test should be done immediately.

Talk 3: Selecting a Target in Refractory Cushing’s Disease: Corticotroph Tumor, Adrenal Steroidogenesis, or Glucocorticoid Receptor?

By Maria Fleseriu, M.D., 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 CD. However, even with an experienced neurosurgeon, some patients do not achieve remission and approximately 25% of patients eventually experience a recurrence. Medical treatment may then be needed. Medications can target 1) a pituitary tumor, 2) the adrenal glands to decrease cortisol synthesis, or 3) block the glucocorticoid receptor which decreases the effects of cortisol. A comprehensive discussion of available medical treatments is found in the Endocrine Society Clinical Guidelines on treatment (6). This talk focused on new drugs in development.


Twice daily pasireotide is approved and targets the pituitary tumor. A once-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. Similar to twice daily pasireotide, high blood sugar was noted in 68% or 80% depending on the dose.


Osilodrostat is an oral inhibitor that blocks the final step in cortisol synthesis, similar to metyrapone. However, it is significantly more potent and has a longer half-life, allowing twice daily administration. In a 10-week, proof of concept study, osilodrostat normalized UFC in 11 of 12 patients with CD (7). An extension phase study enrolled an additional 15 new patients. At 22 weeks, response was seen in 78.9% and all responders had normal UFC levels (8). Common side effects were adrenal insufficiency, nasopharyngitis, nausea, diarrhea, and asthenia. Elevated testosterone levels and hirsutism or acne were noted in 3 of 11 females. Based on these results, osilodrostat shows promise and two phase III studies (; NCTO2180217 and NCT02697734) are currently underway.


Levoketoconazole 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 may allow lower doses and fewer adverse events. Levoketoconazole is 12 times less potent at inhibiting a key liver enzyme, thus less hepatic toxicity might be expected with this medication. A phase III single-arm, open-label trial is currently ongoing to evaluate the efficacy, safety, tolerability, and pharmacokinetics of levoketoconazole in patients with Cushing’s (; NCT01838551).


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 (9). Currently, a phase II clinical trial (; NCT02160730) in human patients with CD is underway to evaluate the efficacy and safety of R-roscovitine.


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 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. Mild and reversible adverse events, were reported in over 40% of patients (10). Further randomized, double-blind, clinical trials are needed in patients with CD.


As discussed by Dr. Stalla, mutations in corticotroph 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 in CD and a study is underway (; NCT02484755).


The symposium on Cushing’s Disease at ENDO 2016 highlighted recent advances in the pathophysiology, diagnosis and treatment of this challenging condition. As Karen Campbell, a leader of the patient support organization Cushing’s Support and Research Foundation, noted after attending the Symposium, “While great progress has been made in the last 100 years, there is still much work to do……who knows what the area of Cushing’s will look like in another 100 years!”

Dr. Biller has a consulting relationship with the following companies: Cortendo, Ipsen, and Novartis.