Saturday, December 31, 2011

Complications of endoscopic surgery of the pituitary adenomas: analysis of 570 patients and review of the literature


DOI: 10.1007/s11102-011-0368-2

Mustafa BerkerDerya Burcu HazerTaşkın YücelAlper Gürlek,Ayşenur CilaMustafa Aldur and Metin Önerci


Endoscopic transsphenoidal surgery is emerging as a minimally invasive and maximally effective procedure for pituitary adenomas. In this report we analyzed the complications in 624 procedures of endonasal transsphenoidal endoscopic surgery in the treatment of 570 patients with pituitary adenomas. The leading author (MB) operated pituitary adenomas via pure endoscopic endonasal transsphenoidal surgery between January 2006 and August 2011 at the Hacettepe University, Department of Neurosurgery in Ankara. Complications were assessed in 624 surgical procedures under five groups; rhinological, CSF leaks, infection, vascular and endocrinologic complications. We observed a total of 76 complications (12.1%). Rhinological complications occurred in 8 patients (1.3%): 4 epistaxis (0.6%) and 4 hyposmia (0.6%). Postoperative CSF leaks occurred in 8 patients (1.3%), and infectious complications occurred in 8 patients: 3 cases of sphenoidal sinusitis (0.4%), 5 cases of meningitis (0.8%). Only 1 case of internal carotid aneurysm rupture during the opening of sellar floor (0.16%) was observed. Endocrinologic complications occurred in 51 (8.1%) patients: Anterior pituitary deficiency in 12 (1.9%), transient diabetes insipidus (DI) in 29 (4.6%), permanent DI in 3 (0.4%) and inappropriate antidiuretic hormone secretion syndrome occurred in 7 (1.1%). There was no mortality directly related to the surgical procedure. The complication rates observed in our study suggests that the endoscopic pituitary surgery is at least as safe as microscopic transphenoidal surgery. These rates were obtained with due experience and well-coordinated teamwork. To further improve these rates, new technological developments will be helpful.

Keywords  Pituitary – Adenoma – Endonasal endoscopic surgery – Complication

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FDA Will Not Require a Risk Evaluation and Mitigation Strategy in Connection With Corcept's Proposed Distribution of Korlym(TM) for Cushing's Syndrome

MENLO PARK, CA, Dec 15, 2011 (MARKETWIRE via COMTEX) -- Corcept Therapeutics Incorporated CORT -0.02%  , a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders, today announced that it has been advised by the U.S. Food and Drug Administration (FDA) that no Risk Evaluation and Mitigation Strategy (commonly known as a "REMS" program) will be required in connection with Corcept's proposed distribution of its lead product candidate, mifepristone, to which Corcept has given the brand name Korlym. The FDA is currently reviewing Corcept's New Drug Application (NDA) for Korlym, a glucocorticoid receptor type II (GR-II) antagonist that blocks the cortisol receptor, for the treatment of the clinical and metabolic effects of hypercortisolism in patients with endogenous Cushing's Syndrome. The FDA's decision with respect to REMS does not alter the Prescription Drug User Fee Act (PDUFA) date for completion of FDA review, which remains February 17, 2012.

"We are focused intently on developing the commercial and logistical capabilities we will need to make Korlym available to patients suffering from Cushing's Syndrome, should the FDA approve our drug for this indication," said Joseph K. Belanoff, M.D., Chief Executive Officer at Corcept.

About Cushing's Syndrome

Endogenous Cushing's Syndrome is caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing's Syndrome is an orphan indication which most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients in the United States. An estimated 20,000 patients in the United States have Cushing's Syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's Syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Korlym

Corcept's first-generation compound, Korlym, also known as mifepristone, directly blocks the cortisol (GR-II) receptor and the progesterone (PR) receptor. Intellectual property protection is in place to protect important methods of use for Korlym. Corcept retains worldwide rights to its intellectual property related to Korlym.

About Corcept Therapeutics Incorporated

Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. The company has completed its Phase 3 study of Korlym for the treatment of Cushing's Syndrome, and has an ongoing Phase 3 study of Korlym for the treatment of the psychotic features of psychotic depression. Corcept also has a developed a portfolio of new selective GR-II antagonists that block the effects of cortisol but not progesterone and has an extensive intellectual property portfolio covering the use of GR-II antagonists in the treatment of a wide variety of psychiatric and metabolic disorders, including the prevention of weight gain caused by the use of antipsychotic medication, as well as composition of matter patents for our selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements, including, for example, statements relating to the potential benefit of Korlym for patients diagnosed with Cushing's Syndrome, the timing of completion and potential outcome of the FDA's review of our NDA filing, Corcept's clinical development and research programs, the timing of introduction of Korlym and future product candidates and the ability to create value from Korlym or other future product candidates. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances with respect to the timing of completion and outcome of the FDA's review of our NDA filing, the cost, rate of spending, completion or success of clinical trials; or that Corcept will pursue further activities with respect to the development of Korlym or any of its other selective GR-II antagonists. These and other risk factors are set forth in the Company's SEC filings, all of which are available from our website ( ) or from the SEC's website ( ). We disclaim any intention or duty to update any forward-looking statement made in this news release.



Charles Robb

Chief Financial Officer

Corcept Therapeutics


Email Contact

Original article

FDA Rare Disease Patient Advocacy Day

On March 01, 2012, the Food and Drug Administration (FDA) will celebrate the fifth annual Rare Disease Day by hosting a "FDA Rare Disease Patient Advocacy Day" to engage and educate the rare disease community on regulatory processes related to rare diseases.


This meeting is intended to enhance the awareness of the rare disease community as to FDA’s roles and responsibilities in the development of products (drugs, biological products and devices) for the diagnosis, prevention, and/or treatment of rare diseases or conditions. 


This educational meeting will consist of live and interactive simultaneous webcast of presentations provided by FDA experts from various Centers and Offices, as well as from outside experts. The interactive meeting will include two general panel discussion sessions, as well as afternoon breakout sessions for more in-depth information on the roles of FDA. In addition, on-site attendees will have an opportunity during lunch to engage with FDA and outside experts in a small group setting.


While attendance is free, registration is required to attend the event.

Register for FDA Rare Disease Patient Advocacy Day disclaimer icon

If you need sign language interpretation during this meeting, please contact Megan McNamee at by February 15, 2012.FDA Rare Disease Patient Advocacy Day logo

Location and Directions:

White Oak Campus
10903 New Hampshire Ave
Silver Spring, MD, 20993

Location, directions, and other information about White Oak


March 01, 2012


Event agenda is in preparation and will be posted prior to the meeting


To connect to the live webcast of the meeting please follow the Connect Pro instructions.



The FDA Rare Disease Patient Advocacy Day is supported by the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the National Organization for Rare Disorders (NORD), and the Genetic Alliance.

NIH 2012  Rare Disease Day logoThe FDA encourages all attendees to also plan on attending the National Institutes of Health (NIH) Rare Disease Day day-long celebration on February 29, 2012.


Rare Disease Day at NIH

Rare Disease Day at NIH (RDD@NIH)

On February 29, 2012, the National Institutes of Health (NIH) will celebrate the fifth annual Rare Disease Day with a day-long celebration and recognition of the various rare diseases research activities supported by the NIH Office of Rare Diseases Research, the NIH Clinical Center, other NIH Institutes and Centers; the Food and Drug Administration’s Office of Orphan Product Development; the National Organization for Rare Disorders; and the Genetic Alliance. Rare Disease Day at NIH (RDD@NIH) will be held in the Clinical Center’s Masur Auditorium (Building 10) from 8:30 a.m. to 5:00 p.m. Attendance is free and open to the public.

In addition to the various scheduled talks, we expect to have posters and exhibits from many groups relevant to the rare diseases research community. In association with the Global Genes Project, we again encourage all attendees to wear their favorite pair of jeans.

While attendance is free, we would like to know how many people are planning to attend to prepare accordingly. If you would like to display a poster or exhibit, please include that information on your registration form. You can contact Dr. David J. Eckstein at for more information.

The NIH Office of Rare Diseases Research encourages all attendees to also plan on attending the Food and Drug Administration’s Rare Disease Day activities on March 1, 2012.
Visit the NIH Visitors and Security website for the latest instructions and updates. Please allow 30 minutes to move through security.

Sign language interpreters will be provided. Individuals with disabilities who need reasonable accommodation to participate in this event should contact Kimberly Potter at or 301-251-4962.

About Rare Disease Day
Rare Disease Day was established to raise awareness with the public about rare diseases, the challenges encountered by those affected, the importance of research to develop diagnostics and treatments, and the impact of these diseases on patients' lives. The focus of Rare Disease Day 2010 was 'Patients and Researchers, Partners for Life!' and is aligned with ORDR's philosophy that researchers need to work closely with patients and patient advocacy groups to maximize chances for success. This philosophy has been put into practice in our very successful Rare Diseases Clinical Research Network.

There are about 7000 rare diseases identified in the United States. About 80 percent of rare diseases are genetic in origin and it is estimated that about half of all rare diseases affect children. Rare diseases can be chronic, progressive, debilitating, disabling, severe and life-threatening. Information is often scarce and research is usually insufficient. People affected face challenges such as delays in obtaining a diagnosis, misdiagnosis, psychological burden and lack of support services for the patient and family. The goals remain for rare disease patients to obtain the highest attainable standard of health and to be provided the resources required to overcome common obstacles in their lives.
By highlighting these issues, the NIH Office of Rare Diseases Research hopes to
  • Raise awareness of rare diseases
  • Strengthen the voice of patients and patient advocacy groups
  • Give hope and information to patients
  • Bring stakeholders closer together
  • Coordinate policy actions within the United States and with other countries
  • Inspire continued growth of the awareness of rare diseases
  • Emphasize rare disease research and the search for new therapeutics
  • Get equality in access to care and treatment

The first Rare Disease Day sponsored by EURORDIS was held in Europe on February 29, 2008. February 29th was chosen since it is a rare day and it is symbolic of rare diseases. 2009 was the first time that Rare Disease Day was observed in the U.S. In addition to 17 European countries participating in Rare Disease Day 2009, the United States was joined by Argentina, Australia, Canada, China, Colombia, and Taiwan in celebrating the first global Rare Disease Day. The National Organization for Rare Disorders serves as the coordinator of this activity in the United States.

The Global Genes Project

The Global Genes ProjectA video developed by a rare disease parent advocate circulated on YouTube as part of World Rare Disease Day 2009, making a connection between jeans and genes. This video inspired a group of individuals and rare disease organizations to take this connection to the next level by creating the Global Genes Project, a grassroots effort to use jeans to raise awareness for rare genetic disorders.<

This group has grown and continues to add individuals and organizations that want to be involved. The hope is that the rare disease community as a whole will view this initiative as an opportunity to build unity around this important cause. The goal is to create a platform for collaboration, while building awareness about the prevalence of rare diseases, educating the public about genes and the impact they play in rare diseases, and engaging support from the general public.

There are numerous organizations that are working to help some of the individual diseases. They are funding much needed research, helping drive policy and develop educational programs, all in an effort to bring hope to this underserved community. The Global Genes Project encourages those who are concerned and compelled to join the cause to help both individual rare disease organizations, children and their families affected, as well as the community as a whole.

More information:

Thursday, December 22, 2011

Subclinical Cushings syndrome: definition and management

Subclinical Cushing's syndrome is an ill-defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing's syndrome stands on the presence of ACTH-independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed-back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures.

However, the natural history of subclinical Cushing's syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing's syndrome and the surrounding controversy. The management of subclinical Cushing's syndrome, that remains a highly debated issue, is also addressed and discussed.

Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence.

Document Type: Research article


Affiliations: 1: Internal Medicine I, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy

Buy the article at

Investigational drugs may expand medical treatment of Cushing’s syndrome

Endocrinologists face many challenges when treating patients with Cushing’s syndrome. Diagnosis can be difficult because many of the disease’s characteristics, such as obesity, depression and hypertension, are also common in the general population.

Treating the disease presents hurdles as well. With its potential for total cure, transsphenoidal surgery remains the first-line treatment. However, the problems of achieving permanent remission in all cases demonstrate the need for medical therapies for this condition.

Currently, endocrinologists use several medical therapies to treat hypercortisolism, although none have FDA approval for that particular indication. Two new investigational drugs — mifepristone (Korlym, Corcept Therapeutics) and pasireotide (SOM230, Novartis) — have the potential to meet those unmet needs, according to experts interviewed by Endocrine Today.

“Recently completed research studies, which involved innovative medical therapeutic strategies that target the corticotroph adenoma itself or block the effects of cortisol in the periphery, should bring new treatment options in the future,” Maria Fleseriu, MDassociate professor, director of the Northwest Pituitary Center at Oregon Health & Science University, said in an interview.

Manufacturers of both new medications have submitted new drug applications to the FDA. Corcept expects to hear from the FDA on Feb. 17, according to a spokesperson for the company.

Mifepristone has a unique mode of action in that it blocks the cortisol receptor, Robert L. Roe, MD, president of Corcept Therapeutics, said in an interview.

“With that receptor blocked, many of the problems associated with Cushing’s syndrome can be greatly improved, including: obesity, diabetes, insulin resistance, high blood pressure, quality of life and depression,” Roe said.

The SEISMIC trial, a 24-week, multicenter, open-label study, included 50 patients with persistent or recurring Cushing’s disease, metastatic adrenal cortical carcinoma or ectopic adrenocorticotropic hormone (ACTH) syndrome that was not amenable to surgery, according to Fleseriu, who was an investigator on the study. There were two primary endpoints: blood sugar improvement in patients with glucose intolerance and an improvement in BP in patients with a diagnosis of hypertension but without abnormal blood sugar levels. The key secondary endpoint looked for global clinical improvement as determined by a three-member independent data review board.

Results from the phase 3 study showed that, overall, mifepristone yielded significant clinical and metabolic improvement in patients with refractory Cushing’s syndrome, Fleseriu said. Of the glucose-intolerant patients, 60% responded, and BP improved in 38% of patients. The global clinical endpoint was positive in 87% of patients, Roe said.


Maria Fleseriu, MD
Maria Fleseriu


“In addition, out of 34 patients who completed the main study, 30 elected to continue in the long-term extension study,” Fleseriu said.

She said mifepristone “offers a new approach for the treatment of Cushing’s syndrome that [has] failed other therapies. Keeping in mind that biochemical parameters will not be available for monitoring these patients, close clinical observation is recommended.”

Yet, there are aspects of mifepristone that are still unknown.

“There will be a learning curve with this drug on how to dose it and use it properly to get a good response,” said James Findling, MD, professor of medicine, Endocrinology Center and Clinics, Medical College of Wisconsin, Milwaukee, who was the principal investigator of the study.


James Findling, MD
James Findling


Also on the horizon is the investigational agent pasireotide, a multiligand somatostatin analogue with a high affinity for the somatostatin receptor type 5, which is often expressed by corticotroph adenomas in Cushing’s disease. Pasireotide blocks the secretions from ACTH-secreting pituitary tumors.

“Pasireotide works by attacking the pituitary tumor to reduce the ACTH level,” according to Laurence Katznelson, MD, professor of medicine and neurosurgery at Stanford University and medical director of the pituitary program at Stanford Hospital and Clinics. “Possibly, this drug could prevent tumor growth or lead to tumor shrinkage, although we await data to support that.”

Results of the multicenter, phase 3 PASPORT-CUSHINGS trial, presented at the Endocrine Society’s 93rd Annual Meeting & Expo in June, included 162 patients with persistent/recurrent or newly diagnosed Cushing’s disease who were ineligible for surgery. Researchers randomly assigned participants to receive twice-daily subcutaneous pasireotide injections of 600 mcg or 900 mcg. The primary endpoint was urinary-free cortisol levels at 6 months without dose up-titration.

Of the patients in the 900-mcg dose group, 26.3% had normal urinary-free cortisol levels at 6 months; at 12 months, 25% maintained normal levels. The median reduction from baseline in urine-free cortisol after 6 months of treatment was 47.9% for both dose groups.

The researchers noted significant clinical benefit in most patients, including lower BP and total cholesterol, as well as weight loss, Fleseriu said.

“It is noteworthy that while urinary-free cortisol normalization was seen in just a subset of patients, the rate of normalization was higher in patients with lower baseline urinary-free cortisol, making it, in my opinion, an attractive treatment for patients with mild elevations in urinary-free cortisol,” Fleseriu, who was also an investigator for this trial, told Endocrine Today.

Pasireotide was well tolerated in the studies, she added.

“Adverse events were comparable to the other somatostatin analogues, with the exception of a much higher incidence of hyperglycemia,” Fleseriu said. “Patients treated with this drug will require strict monitoring and prompt treatment of hyperglycemia.” The reasons for hyperglycemia are related to inhibition of insulin release from the pancreas by this multiligand somatostatin analogue. The type 5 receptor is abundant on pancreatic insulin secreting cells of the pancreas.

Timely diagnosis, treatment critical

Cushing’s syndrome is the result of chronic exposure to high levels of cortisol. Cortisol, typically released in stressful situations, controls how the body uses carbohydrates, fats and proteins. In addition, it helps decrease the immune system’s response to inflammation.

Untreated, Cushing’s syndrome can have serious consequences, including significant mortality and morbidity. Timely diagnosis and appropriate treatment are critical for this rare disorder, according to Fleseriu, who is also associate professor of medicine/endocrinology and neurological surgery at Oregon Health & Science University.

The endocrinologist uses the following tests to diagnose the disorder: 24-hour urinary-free cortisol levels; late-night salivary cortisol measurements; and low-dose dexamethasone suppression test.

After making the diagnosis of hypercortisolism, the next step is to determine the cause of excess cortisol secretion. There are several tests available for this purpose: corticotropin-releasing hormone (CRH) simulation test; direct radiologic visualization of the pituitary and adrenal glands; and inferior petrosal sinus sampling for ACTH.

The most common cause is long-term synthetic steroid use to treat inflammatory illnesses such as asthma or rheumatoid arthritis, according to Katznelson. In these cases, gradually reduction of the glucocorticoid will reverse the disorder.

Another cause is an ACTH-secreting pituitary adenoma. The excess stimulates the adrenals to produce and secrete excess cortisol release, Katznelson said. This is also known as Cushing’s disease.

Pituitary adenomas are responsible for 70% of Cushing’s syndrome cases, according to information from the National Institute of Diabetes and Digestive and Kidney Diseases.

Surgery is first-line treatment


John Carmichael, MD
John Carmichael


First-line therapy for Cushing’s disease is transsphenoidal adenomectomy, in which the surgeon approaches the pituitary through the nose and, using either a microscope or endoscope by trained neurosurgeons, according to John Carmichael, MD, assistant professor of medicine, The Pituitary Center, Cedars-Sinai Medical Center, Los Angeles.

The procedure boasts an excellent cure rate.

“In good hands, with a small tumor, you can get cure rates of about 85%,” Carmichael said. “It depends on a number of factors: the skill of the surgeon, the size of the tumor and the level of invasiveness.”

If surgery is curative, the patient will require cortisol replacement.

“Once you remove the tumor, the normal tissue has been suppressed by the activity of the tumor for so long that it takes a long time for patients to recover and start making cortisol on their own,” Carmichael said. “It can take as long as 6 to 12 months for patients to completely recover their normal cortisol secretion once they’ve been cured.”


David M. Cook, MD
David M. Cook


However, the surgery is associated with risks, including bleeding and infection, although they are “pretty rare,” according to Carmichael. One of the most common risks is a pituitary injury that can cause diabetes insipidus, which is almost always transient. Other postoperative problems include possible cerebrospinal fluid leaks and the possibility of recurrence, said David M. Cook, MD, an endocrinologist in the department of medicine, Oregon Health & Sciences University.

Sometimes the tumor is hard to find during the first surgery, Katznelson said.

“The problem is, in 40% to 50% of patients who have Cushing’s disease, the tumor is very small, if not almost invisible, on the MRI scan,” he said. As a result, the surgeon may remove normal gland or possibly the entire pituitary, resulting in hypopituitarism. The patient would require hormone replacement and would still have Cushing’s syndrome.

Radiation is a possible treatment for these cases.

“The role of radiation is in the patient who has already had surgery for Cushing’s syndrome. The tumor is visible but cannot be completely removed. Radiation is most useful when there is a target to irradiate,” Katznelson said, adding that even in these cases, radiation cannot promise 100% efficacy.

Unfortunately, radiation takes a significant amount of time to work.

“People are a little reluctant to use radiation because it takes years to help,” Cook said. “It is not curative and patients can relapse from radiation also; it is not foolproof.”

Ectopic ACTH syndrome

Sometimes, tumors located outside the pituitary can produce ACTH, resulting in the ectopic ACTH syndrome. The tumors are usually malignant. In more than half of the cases, the tumors are found in the lungs, according to information from the NIDDK.

“You would need surgery in that location to get rid of the tumor,” Carmichael said.

If an adrenal tumor is stimulating an overabundance of cortisol, the definitive cure is adrenalectomy.

“If we do adrenalectomy, all of the [symptoms of] Cushing’s syndrome go away, but the primary pituitary tumor, which may have been microscopic, can start to become more aggressive and grow and become more difficult to treat in the long run,” Katznelson said. “That is Nelson’s syndrome.”

The adrenal insufficiency that follows adrenalectomy is serious, Cook said.

“It is dangerous to not have your adrenals; it is the most dangerous disease that endocrinologists treat,” he said. “A number of sudden deaths have been reported in patients without adrenals.”

Katznelson also said that managing these patients can be challenging.

“Management of primary adrenal insufficiency is sometimes difficult, because not only does the patient lack cortisol, but will also lack aldosterone, which is important for maintaining electrolytes and volume status,” he said. “Patients often find it quite challenging to manage primary adrenal insufficiency.”

Fast Facts

Medical therapies for Cushing’s syndrome

Besides surgery and radiation, endocrinologists can use several medical therapies to treat Cushing’s syndrome; however, to date, none has obtained FDA approval to treat the disorder.

The medical treatment used most often in the United States is ketoconazole, an antifungal agent that blocks the enzymes in the adrenal glands that produce steroids, Findling told Endocrine Today.

Ketoconazole, administered two to three times daily, is generally successful.

“It is an effective therapy,” Findling said. “Probably 50% to 70% of patients will have a response.”

However, this drug is not the optimal choice for long-term use.

“Ketoconazole has been associated with some toxicity; liver function abnormalities can occur and, in fact, liver failure can occur,” he said.

Another medical treatment option is mitotane (Lysodren, Bristol-Myers Squibb), which blocks adrenal steroid enzymes, Findling said. This toxic agent takes considerable time to work; in fact, it may require roughly 3 or 4 months for cortisol levels to normalize. It is used rarely in the United States.

“Mitotane has a limited future as a therapy for Cushing’s syndrome, except for in patients who have adrenal cancer, at least in the US,” Findling said.

Metyrapone (Metopirone, Novartis), another agent, effectively blocks adrenal steroid enzymes; however, it is not commercially available in the United States, Findling said.

Etomidate is an anesthetic agent that also inhibits adrenal steroidogenesis and is employed successfully in patients with very severe hypercortisolism who are not ready for surgery.

“If etomidate were available in a pill, it would be an excellent medical treatment for Cushing’s syndrome,” Findling said. “With subhypnotic doses, etomidate lowers the cortisol level smoothly down into the normal range. … It is well tolerated, but has to be given as a continuous IV infusion, so it is not practical.”

All of these medications have severe adverse effect profiles, according to Carmichael.

No replacement for surgery … yet

Although mifepristone and pasireotide show some promise as treatments for Cushing’s syndrome, it is not time to put the scalpels in storage, the experts said.

“Neither of these drugs, at least for the foreseeable future, will replace surgical treatment of Cushing’s syndrome,” Findling said. “Like most disorders, if you have a surgical procedure that will resolve the endocrinopathy and restore normal hormonal function, it is usually the treatment of choice.”

However, these medications are a welcome addition to the armamentarium, Carmichael said.

“It remains to be seen exactly what their place will be and how they will be best used. But, certainly, in cases where surgery is not an option or where you need to control the disease in someone who has very severe disease, they would have a role,” he said. Currently, Carmichael sees medical therapy as an adjuvant treatment, which would follow surgery if it was not curative. Also, endocrinologists may use them in place of surgery if surgery was not an option.

“There is a lot more room for work,” Carmichael said. “The ideal paradigm of having a medication that is safe and controls the disease and in a sense would replace surgery would be an ideal goal, but we are certainly not there yet.”– by Colleen Owens

For more information:

  • Colao A. OR09-6. Presented at: The Endocrine Society 93rd Annual Meeting & Expo; June 4-7, 2011; Boston.
  • Fleseriu M. [OR09-5] Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with refractory Cushing syndrome: results from the Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome (SEISMIC). Presented at: The Endocrine Society 93rd Annual Meeting & Expo; June 4-7, 2011; Boston.
  • Gross BA. Neurosurg Focus. 2007;23:E10.
  • National Institute of Neurological Disorders and Stroke. NINDS Cushing’s syndrome information page. Available at:
  • National Endocrine and Metabolic Diseases Information Service. Cushing’s syndrome. Available at:

Disclosures: Dr. Fleseriu is principal investigator in multiple Cushing’s trials and past consultant for Novartis; she is also the principal investigator on Corcept Cushing’s trials. Dr. Findling is a paid consultant for Corcept Therapeutics. The other doctors in this article did not report any relevant financial disclosures.

Which is the most reliable screening method for Cushing’s syndrome?


Tests are equally accurate, but have limitations

The diagnosis of Cushing’s syndrome is problematic. It is one of the most difficult endocrine diseases to diagnose. Diagnosis includes assessing the symptoms and signs of Cushing’s syndrome because the symptoms and signs overlap with common disorders, including obesity, depression and polycystic ovary syndrome. Many patients consult websites in an attempt to find an explanation for their weight gain, fatigue, depression and other symptoms. They ask frequently after a Web search if their symptoms could be Cushing’s syndrome.

Screening tests for Cushing’s syndrome include three different tests: an 11 p.m. or midnight salivary cortisol level; a 24-hour urine free cortisol level; and an 8 a.m. cortisol level after ingestion of 1 mg of dexamethasone at midnight the previous night. How reliable are these tests? They are equally accurate — approximately 90% to 92% reliable, which is actually good for screening tests.

However, all three tests have limitations. Results of the nighttime salivary cortisol test are affected by laboratory accuracy (not all laboratories are equally reliable) and sleep patterns. In severe depression cases, the results may be falsely elevated. The 24-hour urine free cortisol test is an indicator of overall cortisol production. The most accurate method of measurement — tandem mass spectrometry with concomitant measurement of urine volume and urine creatinine — provides a good measure. It may take several 24-hour urine collections to confirm hypercortisolism. The 1-mg overnight dexamethasone suppression test is reliable, but with several caveats. The test is standardized according to administering dexamethasone at midnight and measurement of serum cortisol promptly at 8 a.m. the following day. However, while the patient may have gone to the lab at 8 a.m., the blood sample may have been obtained later, which invalidates the test. Additionally, if the patient is taking medications that alter dexamethasone metabolism, the results may not be valid. The endocrinologist must measure a serum dexamethasone level to confirm the validity of the test.

The diagnosis of Cushing’s syndrome is dependent upon confirming consistent overproduction of cortisol. The diagnosis may require repeated testing and this should be done in any patient in which there is a suspicion of Cushing’s syndrome.

Mary Lee Vance, MD, is professor of medicine and neurosurgery at University of Virginia Health System, Charlottesville, Va.

Disclosure: Dr. Vance reports no relevant financial disclosures.


Late-night salivary cortisol is best initial test


Ty Carroll, MD
Ty Carroll


No test is perfect for all patients. In addition, it is important to remember that some patients will require multiple, different tests to confirm or exclude Cushing’s syndrome. However, that being said, late-night salivary cortisol is the best initial screening for most patients with suspected Cushing’s syndrome.

Late-night salivary cortisol is the most specific test for Cushing’s syndrome. The sensitivity and specificity are very good. Multiple studies have examined late night salivary cortisol testing, and the majority of those studies show sensitivity of more than 95% and a specificity in the range of 90% to 100%. That is comparable to — or better than — other methods to diagnose Cushing’s syndrome.

Also important to note: It is easy for patients to perform late-night salivary testing. Patients are able to do the collection at home and mail in the completed samples to a reference lab, whereas urinary free cortisol and dexamethasone suppression testing can be difficult for some patients to complete. In addition, for the most part, late-night salivary cortisol is not affected by other medications that patients take, unlike dexamethasone suppression testing, which can be affected by several medications that patients often take to treat other conditions.

Ty Carroll, MD, is assistant professor of medicine at Endocrinology Center and Clinics, Menomonee Falls, Wisc.

Disclosure: Dr. Carroll is an investigator in Corcept’s clinical trials of mifepristone.



Friday, December 16, 2011

A Pill That Stops Stress In Your Brain Before You Feel It

Stress makes many of us miserable — but it can also kill you. Besides just causing horrible anxiety and depression, the physiological basis for stress has also been linked to diseases as varied as obesity, postpartum depression, Cushing's syndrome, epilepsy, and osteoporosis. But what if we could just turn your brain's stress response off?

Now, researchers from Tufts claim to have pinpointed the way that stress hormones hit specific receptors in your brain — and they've even been able to block them. This could lead to the next great psychopharmaceutical breakthrough.

The Tufts researchers discovered that stress pathways are activated by neurosteroids acting on corticotrophin-releasing hormone neurons in what's known as the Hypothalamus-Pituitary-Adrenal axis. By blocking the synthesis of the neurosteroids, they stopped the elevation of corticosterone, and prevented anxiety in mice.

"We have identified a novel mechanism regulating the body's response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety," said author Jamie Maguire, PhD.

Now the team is focusing on modulating the neuroreceptors to treat some of the diseases that accompany stress — be they depression, anxiety, or epilepsy.


Wednesday, December 14, 2011

P36 - Severe Osteoporosis in Cushing’s Syndrome

Clin Cases Miner Bone Metab. 2010 Sep-Dec; 7(3): 240.

PMCID: PMC3213844


Do patients with Type 2 Diabetes Mellitus have an increased prevalence of Cushing's Syndrome?

Therese Krarup,  Thure Krarup,  Claus Hagen

Copyright © 2011 John Wiley & Sons, Ltd.

Keywords: Type 2 diabetes; Cushing's syndrome; hypercortisolism


Many clinical features are common for patients with Type 2 Diabetes Mellitus (T2DM) and Cushing's Syndrome (CS) such as central obesity, hypertension and dyslipidaemia. Patients with CS often have T2DM. Since T2DM is much more frequent than CS it is possible that some patients with T2DM have increased production of cortisol and thus represent patients with CS.

The aim of this review is to evaluate the prevalence of CS in patients with T2DM.

A search was performed in Pubmed and Medline. We found 7 prospective studies, 2 case control studies and 2 cross sectional studies.

The difficulties in diagnosing subclinical Cushing's Syndrome is discussed.

The most frequent tests for diagnosing CS, late night salivary cortisol, 1 mg dexamethasone suppression test, and urinary free cortisol are discussed and put in relation to the results of the literature found.

The observed prevalence of CS in patients with T2DM varies widely between the different studies, ranging from 0% - 9,4%. This may be due to patient selection, differences in test methodology, including choice of test, cut off values and different cortisol assays. The true prevalence of CS in T2DM has not been determined. We need more studies investigating the prevalences of CS in T2DM patients. There is a need for developing more specific tests for diagnosing CS in patients with only slightly elevated cortisol secretion and subclinical CS.

We suggest that examination for hypercortisolism should only be performed in T2DM patients with a cushingoid appearance and hypertension or truncal obesity or dyslipidaemia. Copyright © 2011 John Wiley & Sons, Ltd.

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Saturday, December 10, 2011

Cushing’s Syndrome Clinical Analysis of 77 Cases

OBJECTIVE To analyze the cause of Cushing’s syndrome classification, the major clinical manifestations and laboratory features of frequency of occurrence, and the efficiency of various diagnostic methods to evaluate the clinical doctors to improve diagnosis and treatment of disease, improve patient prognosis.

METHODS from 2004 to 2009 in our hospital by clinical or pathological diagnosis of Cushing’s syndrome in patients with clinical data, of which 57 cases of females, 20 males. For the 77 cases of clinical manifestations, laboratory examination, imaging studies, clinical diagnostic tests, pathological characteristics and with the results of literature analysis and summary of them were analyzed retrospectively.

RESULTS 1. From 2004 to 2009 were diagnosed 77 cases of Cushing’s syndrome, of which 20 males, female 57 cases, male: female = 2:2.85, adrenal adenoma 80% of female patients of childbearing age women.

2. In Cushing’s disease causes the most common (35 cases), followed by adrenal cortical adenoma (30 cases, the left side of 21 cases), there is a growing trend in the latter. Cushing’s disease course and age of onset of adrenal adenomas were higher than those, the difference was statistically significant (P <0.05), the shortest duration of adrenal carcinoma.

3. Clinical performance, the performance of the diversity of its starter, Hypertension and central obesity were the most frequently occur in 75%, and 79.22% suffering from hypertension, Hypertension 1 11.48%, Hypertension 2 62.30%, Hypertension 3 grade 26.23%, and the incidence of abnormal glucose metabolism and hyperlipidemia, respectively 41% and 68%, of which the proportion of diabetes by 30%, 65% of patients had hypokalemia, mostly mild to moderate, adrenal cortex carcinoma 100% of patients with a low potassium, and is of moderate to severe hypokalemia. Cushing’s disease and adrenal adenoma in serum potassium, blood pressure and gender showed no significant difference.

4. In the diagnosis of Cushing’s syndrome test, blood cortisol circadian rhythm disappeared (98.65%), elevated midnight serum cortisol (98.55%), 4Pm serum cortisol increased (97.14%), low-dose dexamethasone suppression test (94.59%), 24hUFC increased (91.22%), morning serum cortisol increased (71.62%). Low-dose dexamethasone suppression of serum cortisol in the morning the next day the basis of 8:00 of serum cortisol of 50% and 275,200,138,50 nmol/Lthe sensitivity of the cut-off point were 94.6%, 95.9%, 97.3% , 97.3% and 100%.

5. Patients with Cushing’s syndrome in the differential diagnosis, 80% of Cushing’s patients can be high-dose dexamethasone suppression, while more than 95% of patients with adrenal cortical adenoma can not be high-dose dexamethasone suppression. Cushing’s patients compared with blood cortisol and ACTH levels were significantly higher in patients with adrenal tumors, while the latter’s rhythmic performance is worse, the differences were statistically significant (P<0.05). Both urinary free cortisol showed no significant difference.6. imaging examination, pituitary MRI can detect 88% of Cushing’s disease there is pituitary adenoma, while the adrenal CT 100% can find out the adrenal tumors, adrenal CT of adrenal tumors and hyperplasia pathology consistent rate of 97.5%.

CONCLUSION 1. The present study in Cushing’s disease and adrenal cortical adenoma is still the most common cause of this group a high proportion of cases of adrenal adenoma, left more common. Cushing’s syndrome more common in women of childbearing age women, more common adrenal adenoma, Hypertension is the most common symptoms, mostly moderate to severe hypertension, diabetes, low potassium, high incidence of dyslipidemia.

2. Diagnostic tests in the CS, the morning cortisol increase the sensitivity of the worst, and serum cortisol circadian rhythm disappeared, midnight serum cortisol increased, 4PM cortisol rise, low-dose dexamethasone suppression test, 24hUFC elevated. There was no significant difference。

3. Patients with Cushing’s disease course, age of onset, blood cortisol and ACTH levels were higher than the adrenal adenoma, the latter comparison rhythm of blood cortisol rhythm performance is worse. The serum potassium, blood pressure and no significant difference in gender.

4. High-dose dexamethasone suppression test is to identify Cushing’s disease and adrenal cortical adenoma of the most appropriate method, CT of the adrenal lesion positive rate and help confirm the diagnosis and localization, B super-positive rate was significantly lower than CT, head MRI in Cushing’s disease positive rate.


Friday, December 9, 2011

Book: Harvey Cushing: A Life In Surgery

Harvey Cushing: A Life In Surgery

Review by Dr. Alfredo Quiñones-Hinojosa.  Dr. Alfredo Quiñones-Hinojosa (also known as "Dr. Q") is the Associate Professor of Neurosurgery, Neuroscience, Oncology and Cellular and Molecular Medicine, and the Director of the Brain Tumor Stem Cell Laboratory at Johns Hopkins University School of Medicine.

Harvey Cushing

Michael Bliss, Paperback, 591 pages

Here is the first biography to appear in fifty years of Harvey Cushing, a giant of American medicine and without doubt the greatest figure in the history of brain surgery.

Drawing on new collections of intimate personal and family papers, diaries and patient records, Michael Bliss captures Cushing's professional and his personal life in remarkable detail. Bliss paints an engaging portrait of a man of ambition, boundless, driving energy, a fanatical work ethic, a penchant for self-promotion and ruthlessness, more than a touch of egotism and meanness, and an enormous appetite for life. Equally important, Bliss traces the rise of American surgery as seen through the eyes of one of its pioneers. The book describes how Cushing, working in the early years of the 20th century, developed remarkable new techniques that let surgeons open the skull, expose the brain, and attack tumors--all with a much higher rate of success than previously known. Indeed, Cushing made the miraculous in surgery an everyday event, as he and his team compiled an astonishing record of treating more than two thousand tumors.

This is the definitive Cushing biography, an epic narrative of high surgical adventure, capturing the highs and lows of an extraordinary life.


Review below by Dr. Alfredo Quiñones-Hinojosa.  Dr. Alfredo Quiñones-Hinojosa (also known as "Dr. Q") is the Associate Professor of Neurosurgery, Neuroscience, Oncology and Cellular and Molecular Medicine, and the Director of the Brain Tumor Stem Cell Laboratory at Johns Hopkins University School of Medicine.

Without the influence of Cajal and Halsted, the career of Harvey Cushing, born in 1869, might not have been possible. And without Cushing, many careers, including my own, would not exist. In this marvelous biography, Michael Bliss examines both the icon and the person. A genius with relentless ambition, Cushing was a mentor and tormentor, a perfectionist who often forgot the line between confidence and arrogance, yet ultimately he was a healer who once said that brain surgery amounts to "20 percent science, 75 percent artistry and 5 percent community benefit." Bliss vividly details Cushing's obsession with improving all aspects of surgical care, as well as clinical diagnostic methods. Cushing's life is like a great ghost story — it will haunt you long after it's over.

Adrenal glands: The reserve tank for stress?

Have you ever noticed that when you are "stressed" you can feel either emotionally/physically depleted or energized? When our body is under stress the brain responds by producing epheniphrine (aka adrenaline), sending signals to our adrenal glands, increasing the rate at which our heart beats while releasing oxygen to our muscles. The long term response to this process produces cortisol (aka the stress hormone) facilitating the release of energy throughout our body. However, when our body isn't properly balanced these hormones can wreak havoc on our wellness possibly resulting in one of three conditions: Cushing's syndrome, Cushing's disease or Addison's disease.

The actual Adrenal glands sit physically atop both kidneys, taking on a triangular shape and a roundish rectangular type shape. These glands are responsible for our sex hormones and cortisol, helping us respond to stress amongst other functions. When our body is under stress, physically and/or nutritionally, it responds one of two ways: Produces too much or too little of the cortisol hormone. Our Adrenal glands also contribute to regulating our blood sugar, blood pressure, salt and water.

Adrenal disorders can cause our body to make too much or not enough of these hormones, bringing about adrenal gland related syndromes and disease. Cushing's syndrome results from our body making too much versus Addison's disease produces too little.

Cushing's syndrome vs Cushing's disease

Glucocorticoids (naturally produced in our body or received through medicine) are groups of corticosteroids (cortisol or dexamethasone) involved in metabolizing our carbohydrates and proteins. When taken synthetically (i.e. treatment of allergies, skin problems, and respiratory problems) or over-produced naturally, the side effects can result in "Cushing's syndrome".

Cushing's syndrome can occur one of two ways: Endogenous or Exogenous. Endogenous is caused by the body (usually through tumors). Exogenous is caused by medication. In both cases, the body produces too much cortisol.

Symptoms: Severe fatigue/muscle weakness, high blood sugar and high blood pressure, upper body obesity, thin arms/legs, bruising easily.

Treatment: The cure and treatment for Cushing's Syndrome and disease can come through medicine, surgery, or by lowering the dosage of your current synthetic hormone treatment and can likely be cured.

Cushing's disease is the most common form of endogenous Cushing's syndrome and is likely treatable. Caused by a tumor in the pituitary gland secreting too much Adrenocorticotropic hormone (ACTH), this type of tumor does not spread and can be removed through surgery.

Nutrition: See a nutritionist or dietician for your condition. Mostly, avoid excess sodium. High blood sugar (hyperglycemia) and high blood pressure can easily occur with this condition. Bone loss density is common with this condition, so be extra aware of your calcium (800 – 1200 mg per day, based upon age) and Vitamin D intake (5mcg from age 0-50, increasing up to 10 mcg 50-71, and 15 mcg after 71). Eating healthy, balanced and whole food (versus processed) is extremely important. (Resource:

Addison's disease Opposite from Cushing's syndrome, Addison's disease doesn't make “enough” of the sex hormones and cortisol. The result of this disease causes our immune system to attack our tissue, damaging our adrenal glands.

Symptoms: Weight loss, muscle weakness, increasingly worse fatigue, low blood pressure and patchy or dark skin.

Treatment: If left untreated, the condition can be fatal. Lifetime hormone treatment is usually required. Addison disease patients should always carry medical/emergency ID on them, listing their medication, dosage and disease

Lab tests can confirm that you have Addison's disease. If you don't treat it, it can be fatal. Very likely, you will need to take hormone pills for the rest of your life. If you have Addison's disease, you should carry an emergency ID. It should say that you have the disease, list your medicines and say how much you need in an emergency.

(Ref:, NIH: National Institute of Neurological Disorders and Stroke)

If all of this sounds a little overwhelming there is hope. Learning how to balance our stress-filled lives is extremely important to our overall health. Healthy nutrition always contributes benefits to our overall wellness. We can overwhelm our endocrine system by simply not eating nutritionally. Understanding that “Food is a drug” is vitally important to how we help our body naturally heal itself. The above conditions are the result of our body not handling the stress we are putting it through, causing our body to producing too much or too little of the sex hormones and cortisol.

Unless we first address what we can do naturally through nutrition, the medicine we consume will only do so much in helping our body heal completely. You simply cannot continue doing the same thing over and over again, expecting the medicine to do all the work. Some diseases are brought upon us through our environment (emotionally as well as physically) as well as our diet/nutrition. Reviewing our entire wellness is always wisdom whenever we're diagnosed with anything.

Certainly listen to your doctor and their advice. But also ask your doctor to refer you to a nutritionist or clinical/registered dietician for a complete evaluation that includes a review of your nutritional diet/wellness. Too often we reach for a pill or a procedure to “fix” our health problems, ignoring what we should be doing on our own to help our body heal. Medical intervention is "sometimes" the result of providing our body with what it cannot produce on its own. Nutrition should always be the “natural” medicine we take, as well as what we might need through prescribed medication.

Quick Tips for Wellness: Living “well” requires living nutritionally balanced.

Adapted From

Tuesday, December 6, 2011

Overt immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature

J Clin Endocrinol Metab. 2011 Oct;96(10):E1670-4. Epub 2011 Aug 3.

Overt immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature.


Department of Medicine, University Health Network, Toronto, Ontario, Canada M5G 2M9.



Autoimmune diseases frequently improve during active Cushing's syndrome. Several studies have reported new onset or exacerbation of these conditions upon cortisol normalization.


Our objective was to investigate the incidence and clinical characteristics of patients with autoimmune or allergic diseases after Cushing's syndrome remission.


Consecutive cases of confirmed Cushing's syndrome were characterized. A review of the literature was conducted to identify previous descriptions of immune dysfunction upon remission and evidence of the hypothalamic-pituitary-adrenal axis influence on the immune system.


Among 66 patients who achieved Cushing's syndrome remission, the incidence of immune dysfunction was 16.7%, where eight cases (72.7%) were noted for the first time and three (27.3%) were exacerbated. All had an ACTH-dependent cause. Glucocorticoids reduce proinflammatory cytokines and interact with other transcription factors affecting T cell and mast cell survival.


Hypercortisolism induces a state of immunosuppression. After Cushing's syndrome remission, rebound immunity frequently results in overt conditions extending beyond thyroid dysfunction.


Video - Cushing's Disease Misdiagnosis (Sharmyn)

Misdiagnosed for seven years, Sharmyn takes control of her own health, finds the answers she's been searching for and a doctor that can help. Dr. Daniel Kelly, the Director of Saint John's Brain Tumor Center in Santa Monica, CA, successfully removes her tumor and gives her back her life.

View Sharm's video here: