Tuesday, March 31, 2009

People With Cushing's Are Usually Diagnosed with Something Else First...

...now here's someone with Lyme Disease being diagnosed with Cushing's (AND Addison's Disease) first.  Amazing.

Lyme - emerging disease or hidden epidemic?


Thomas Gray, the English poet once said, "Ignorance is truly bliss". "Bliss" is a wonderful form of denial if you are in the throes of disease, such as Lyme. The illness can be a painful and debilitating process, fraught with complicated treatments and medical ignorance. One can accept ignorance with an emerging disease, yet not from the organization that is responsible for setting guidelines for treatment such as the Infectious Diseases Society of America:

One gets angrier when you begin to question the root of that ignorance in the national governing body. Is the behavior based on lack of knowledge or more subversive? Is there an ulterior motive to hide the truth of this ailment? The IDSA guidelines are used by health practitioners to treat the disorder and by many health insurance companies to make coverage decisions. This is the point where ignorance turns into systematic deception, when two parties attempt to squelch doctors who in their treatment have discovered that these guidelines in many cases do not work. These doctors have come under fire, in some cases losing their licenses for assisting people debilitated by this disease. There has been widespread anger by "lymies" (this is what we call ourselves) about controversial treatment options and inadequate guidelines. Still, nothing is being done, and people continue to get sick.

Last May, Connecticut Attorney General Richard Blumenthal announced that his antitrust investigation "uncovered serious flaws in the Infectious Disease Society of America's process for writing its 2006 Lyme disease guidelines..." "The IDSA guidelines have sweeping and significant impacts on Lyme disease medical care," Blumenthal wrote. "They are commonly applied by insurance companies in restricting coverage for long-term antibiotic treatment or other medical care and also strongly influence physician treatment decisions." http://www.ilads.org/press_2_07.htm

Several doctors in key roles on the panel were found to have conflicts of interest. "The IDSA's 2006 Lyme disease guideline panel undercut its credibility by allowing individuals with financial interests -- in drug companies, Lyme disease diagnostic tests, patents and consulting arrangements with insurance companies -- to exclude divergent medical evidence and opinion."

It is not just the IDSA, The Center for Disease Control http://www.cdc.gov/ncidod/dvbid/lyme/states the following: "Most cases of Lyme disease can be treated successfully with a few weeks of antibiotics." For those of us who have Lyme disease, a few weeks of antibiotics would not begin to attack the source of bacteria let alone the co-infections and dormant phases of the illness. Unfortunately, without proper treatment, the disease takes a stronger hold on the infected; making it much more difficult to cure.

For those of you who are lucky enough to not have any interaction with the disease or people infected, let me explain what Lyme disease is. Lyme disease is a bacterial infection caused by the bacteria Borrelia burgdorferi (Bb) that is commonly contracted from a deer tick bite. Researchers are also discovering that other insects such as; mosquitoes, fleas and lice may also transmit the disease.

Early Lyme disease can produce a wide-range of symptoms and is different in each person. In addition to the initial diagnosis, Lyme can carry many co-infections which can make a person much sicker. The treatment options are varied and most aggressive treatment forms are not supported by traditional western medicine. For now, those of us who have the disease are left on our own to find a treatment that works. It is terribly frightening.

A few years back I had spinal surgery-so I know what serious, debilitating pain is-and I would gladly opt for additional spine surgeries if I could get rid of Lyme disease. It is that debilitating.

Other transmission confirmations that the general public may not be aware of; Lyme disease can be transmitted in uterus, through breast milk and blood transfusions. Some Lyme specialist believes that the disease can be sexually transmitted since the bacteria can be found in saliva and semen; this form of transmission is still in question.

Another troubling aspect of the disease is ability to diagnosis the illness. In many parts of the United States, (and Lyme disease is everywhere) the diagnosis and testing are faulty. In the documentary "Under our Skin" http://www.underourskin.com many of the issues behind this disease are discussed. At one point, in the documentary, a series of "Lymies" show up on the screen. Each person states the number of doctors it took to get a proper diagnosis. Some were searching for years. My search for a diagnosis took five months and twenty-one doctors. Twenty-one doctors in the heart of Silicon Valley and in Stanford Hospitals' backyard. Before I got the diagnosis, I was told that I was pre-menopausal, iron deficient, that I had Addison's disease, Cushing's disease, Adrenal Fatigue and post-trauma from my imprisonment in Zimbabwe: http://www.huffingtonpost.com/michealene-cristini-risley/gratitude-musings-after-_b_62791.html

Other myths that need to be challenged include the statistics on the prevalence of Lyme disease. I contacted the CDC and talked to the San Mateo County Health Department, for the most part they were less than helpful. I was told by the San Mateo County Health Department that I am the only case of Rocky Mountain spotted fever, (another co-infection) in the state of California in over 15 years. I don't believe them. Other thoughts to convey to your physician:

• The number of cases, the geographical scope and the proportion of afflicted that are severe cases needs to be reviewed. Lyme disease is not decreasing, it in increasing. You can get Lyme disease during the winter.
• Over 50% of those people infected by Lyme disease do not get the distinguishing rash or Bull's eye.
• Over 50% of those with Lyme disease get a false-negative on the testing.

We do know that Lyme disease can be debilitating. The disease needs to be researched to figure out all transmission modes for this illness. Since testing for this disease is inadequate, more research needs to be done to determine better testing mechanisms. In my own experience and in reading books such as "Cure Unknown": http://www.cureunknown.com/ so many stories of doctors and facilities that do not believe that the disease exists.

Insurance companies have typically refused paying for treatments. I personally know that insurance companies are refusing many of my costs. This weekend, my insurance company, Blue Shield of California would only pay for 6 pills to rid me of parasites caused by the immune system fallout from Lyme. In order for me to get the proper prescription of the full 30 pills and to rid the parasite, I had to pay over two-thousand dollars for the additional 24 pills. I purchased enough for the weekend and will start to call Blue Shield on Monday. I wish I was kidding.

Many people who have Lyme disease have sounded the alarm, yet the medical establishment is not listening. Why are there so many disbelievers in Western medicine? Why are insurance companies denying the very basic of claims? If the IDSA guidelines are in question, shouldn't the insurance companies be reviewing what is covered?

Two weeks ago, I was so ill with Lyme, that I thought I was going to die. I was getting neurological symptoms, my right leg was caving in, and my mind would not work. I called the following hospitals; Stanford Hospital, Mayo Clinic, University of California-San Francisco, not a one of these top institutions would take me as a Lyme patient. I start to get an inkling what is must have been like at the beginning of the AIDS epidemic.

There are many issues facing our country right now. For me, Lyme disease is at the top of that list. Too many people are becoming debilitated from this disease, some are dying. It is time that the medical establishment takes the politics out of lyme and start practicing they oath they took to help the sick. You can make a difference. Get on-line, call your congress-person, call the White House at (202) 456-1414. Have a conversation with someone who has LYME disease. Help us to take action before Lyme's disease spreads further.

To each his sufferings: all are men,
Condemned alike to groan,
the tender for another's pain;
the unfeeling for his own.
Yet ah! Why should they know their fate?
Since sorrow never comes too late,
And happiness too swiftly flies.
Thought would destroy their paradise.
No more; where ignorance is bliss,
'Tis folly to be wise.

Monday, March 30, 2009

Distinguishing PCOS and Cushing's

survive the journey: Distinguishing PCOS and Cushing's: Does ...
By survivethejourney@gmail.com (RobinS)

The treatment of CS is primarily the surgical removal of a pituitary, adrenal, or ectopic tumor. The treatment for PCOS is primarily medical and includes oral contraceptives, biguanides (metformin), thiazolidinediones (rosiglitazone or ...
survive the journey - http://survivethejourney.blogspot.com/

Sunday, March 29, 2009

Great Information from Robin and Dr Ted Friedman

Thanks, Robin!  She posted this in her blog survive the journey

survive the journey: Diagnosing and Treating Cushing's ...
By survivethejourney@gmail.com (RobinS)

Diagnosing and Treating Cushing's: Presentations by Dr. Theodore C. (Ted) Friedman. Dr. Friedman's original PowerPoints may be found at his website. These are very informative and easy to follow. ...

survive the journey - http://survivethejourney.blogspot.com/

Friday, March 27, 2009

Rare Care for a Rare Disease

Ellen is a member of the Cushing's Help Message Boards

From http://www.mywheaton.org/locations/elmbrook_memorial/EM_HG_surg_Ptstory1.asp

Cushing’s Disease is a rare condition where a non-cancerous tumor in the pituitary gland causes the production of excess cortisol, a stress hormone. This can lead to diabetes, obesity, high blood pressure, heart disease, suppression of the immune system, and much more.

“It basically ages you prematurely, affecting every system in the body” says Ellen, who, until recently, was suffering with Cushing’s Disease.

A resident of Colorado, Ellen went to her doctor complaining of many new symptoms, including fatigue and headaches. He suspected she might have Cushing’s Disease. He referred her to an endocrinologist in California for further testing.

The endocrinologist determined that Ellen’s condition would require surgery, removal of the tumor in her pituitary gland. Following the surgery, however, Ellen’s Cushing’s Disease persisted. Two options remained: another pituitary surgery, or a more definitive treatment, removal of her adrenal glands, the glands that sit atop each kidney and, in Ellen’s case, were producing the excess cortisol that was making her sick.

Ellen chose to remove her adrenals. Her endocrinologist immediately recommended the best doctor he knew of for the procedure: Dr. Manfred Chiang at Wheaton Franciscan Healthcare – Elmbrook Memorial.

Somewhat surprised that she was being referred to a hospital she’d never heard of in a small Wisconsin town, Ellen did some research. She discovered an online support group at www.cushings-help.com . She also learned that her endocrinologist was not steering her wrong.

“Dr. Chiang has a following,” explains Ellen. “Folks from all around the country had gone to him for their surgeries.” She decided to do the same.

When she met Dr. Chiang, she knew she had made the right choice. “He was wonderful; incredibly skilled and intelligent,” says Ellen. “He actively listened to me, followed through, and was exceptionally kind and compassionate.”

Her surgery went very well. Dr. Chiang performed the procedure laproscopically meaning it was minimally invasive. “There are very few hospitals in the country who regularly perform this unusual surgery,” says Ellen. “But fortunately, Dr. Chiang is considered one of the best bilateral adrenalectomy specialists in the nation.”

“I was up and about that same day,” says Ellen. “And I was finally free of Cushing’s!”

An excellent staff at Elmbrook Memorial enhanced Ellen’s experience.

“The entire experience was the most amazing I’ve ever had at a hospital,” Ellen says. “It was immaculately clean. I loved the warm colors, the layout, and the view. And the nurses were excellent; very intelligent, very willing and able to help. If I had an issue they figured out how to fix it and they fixed it. Every one of them introduced themselves to me, wrote their name on the board when they came into my room, and listened to me. That can be such a rare thing in a busy hospital. They really worked to make my hospital experience a good one.”

Ellen says at www.cushings-help.com she’s not the only one who feels this way. “I’ve never heard a negative word about Elmbrook Memorial.”

Saturday, March 21, 2009

Dr Ted Friedman: Why Diagnosis is Less Important in Endocrinology in the 21st Century

From http://www.empowher.com/news/herarticle/2009/03/20/why-diagnosis-less-important-endocrinology-21st-century

In the 14th century, William of Occam stated, "Plurality must not be posited without necessity." This led to the concept populated by the famous internist, William Osler, who posited that each patient should have one disease, and that disease can explain all the patient's symptoms. In medical school, young physicians learn this philosophy and continue that philospophy throughout their medical career.

They often look for a single, unifying diagnosis in each patient and expect that all the patient's problems are related to this single diagnosis. When that diagnosis is treated with a standard treatment, the problems should go away. Dr. Friedman feels this philosophy of Occam's Blade is detrimental to modern medicine, especially endocrinology.

Patients are becoming increasingly complex and have multiple subtypes. It is important to distinguish between the subtypes, as that may alter treatment. Additionally, not all patients with a single disease present similarly. For example, patients with Cushing's syndrome may manifest diverse symptoms including weight gain, trouble sleeping, severe fatigue, decreased libido, high blood pressure, and diabetes, but most patients with Cushing's syndrome do not have all of these conditions and they only have a few of them.

Many physicians only know about Cushing’s syndrome from a picture of a severe Cushing’s syndrome they see in a textbook and may say to a patient that they don’t have Cushing's syndrome, because they lack one or more signs from that textbook case. Therefore, it is important not to lump everyone together with a diagnosis of Cushing's syndrome but rather to recognize that there may be different subtypes. This is especially important in the field of diabetes, which can be due to problems such as insulin resistance, lack of insulin production, inflammation, or problems with glucose disposal. Currently in diabetes, all patients are treated with similar medicines regarding of their etiology of diabetes. Dr. Friedman expects this to change in the near future, and subtyping patients will be come standard of care. Additionally, recognizing that patients with a single disease may have different manifestations of that disease is becoming more prevalent.

While Dr. Friedman does like to try to provide a diagnosis to the patient, but sometimes it is more important to recognize a symptom complex that can be treated with different medications. Many diseases, such as polycystic ovarian syndrome (PCOS), are really grab-bags of different symptoms put together. Therefore, diagnosing someone with PCOS just means that other causes of the symptom complex of weight gain, extra hair growth and irregular periods, have been excluded. Dr. Friedman does not find it particularly useful to give someone a diagnosis of PCOS but rather to treat those initial symptoms and find out whether they are due to a laboratory value such as high testosterone that can be corrected with medications.

Hopefully Occam's Blade will be put to rest and more symptom- and laboratory-based specific treatments will come to the forefront of endocrinology in the future.


Dr Friedman's January 29, 2009 interview on Cushing's Help!

Dr Friedman's March 12, 2009 interview on Cushing's Help!!

Friday, March 20, 2009

How many people are aware that April 8th is National Cushings Awareness Day???

From http://health-website.com/how-many-people-are-aware-that-april-8th-is-national-cushings-awareness-day/

Cushing's syndrome (aka hypercortisolism or hyperadrenocorticism) is an endocrine disorder caused by high levels of the hormone cortisol. It is pretty rare and generally affects adults aged 20 to 50. Approximately 10 to 15 of every million people are affected every year. It was discovered by Harvey Cushing in 1932.

SOME of the symptoms may be:
rapid weight gain, moon face, excess sweating, easy bruising, purple or red striae, hirsutism, "buffalo hump", reduced libido, impotence, amenorrhoea, infertility, psychological disturbances, persistent hypertension, diabetes mellitus

Cushings may be caused by pituitary and/or adrenal adenomas or disease, ectopics ACTH-secreting tumors, treatment with corticosteroids

Kanzius left hope

From http://www.news-press.com/article/20090319/OPINION/903190319/1015

To all citizens, I wish to sincerely thank you for your generous support of the John Kanzius cancer treatment research project. You are making a difference in the fight against cancer.

As many know, John was initially motivated to action by witnessing the side-effects of current cancer treatment in children. Brain cancer has recently surpassed leukemia as the leading cause of cancer-related death in children.

In recent months a promising potential mechanism for applying The Kanzius Method to brain cancer has been identified, which integrates pioneering cancer research done at other medical research institutions (see transmolecular.com).

Synthetic chlorotoxin (TM601), which can be easily connected to gold nanoparticles has already been shown in a study at the University of Washington to selectively and specifically deliver metallic nanoparticles into brain cancer cells. Thus, the potential to deliver gold nanoparticles into brain cancer cells now exists, which would enable the application of The Kanzius Method to the leading cause of cancer-related death in children.

Furthermore, in addition to cancer, preliminary theoretical models have been recently designed to provide for the development of applying the Kanzius Method to life-threatening illnesses such as Cushing's Disease and Acromegaly, both caused by tumors in the pituitary gland.

Hopefully now, you may more clearly see how very important and how much appreciated your past and continued support of this research project is.


Fort Myers

MASEP gamma knife radiosurgery for secretory pituitary adenomas: experience in 347 consecutive cases

From http://7thspace.com/headlines/305020/masep_gamma_knife_radiosurgery_for_secretory_pituitary_adenomas_experience_in_347_consecutive_cases.html

Secretory pituitary adenomas are very common brain tumors. Historically, the treatment armamentarium for secretory pituitary adenomas included neurosurgery, medical management, and fractionated radiotherapy.

In recent years, MASEP gamma knife radiosurgery (MASEP GKRS) has emerged as an important treatment modality in the management of secretory pituitary adenomas. The goal of this research is to define accurately the efficacy, safety, complications, and role of MASEP GKRS for treatment of secretory pituitary adenomas.

Methods: Between 1997 and 2007 a total of 347 patients with secretory pituitary adenomas treated with MASEP GKRS and with at least 60 months of follow-up data were identified.

In 47 of these patients some form of prior treatment such as transsphenoidal resection, or craniotomy and resection had been conducted. The others were deemed ineligible for microsurgery because of body health or private choice, and MASEP GKRS served as the primary treatment modality.

Endocrinological, ophthalmological, and neuroradiological responses were evaluated.

Results: MASEP GKRS was tolerated well in these patients under the follow-up period ranged from 60 to 90 months; acute radioreaction was rare and 17 patients had transient headaches with no clinical significance.

Late radioreaction was noted in 1 patient and consisted of consistent headache. Of the 68 patients with adrenocorticotropic hormone-secreting(ACTH) adenomas, 89.7% showed tumor volume decrease or remain unchanged and 27.9% experienced normalization of hormone level.

Of the 176 patients with prolactinomas, 23.3% had normalization of hormone level and 90.3% showed tumor volume decrease or remain unchanged. Of the 103 patients with growth hormone-secreting(GH) adenomas, 95.1% experienced tumor volume decrease or remain unchanged and 36.9% showed normalization of hormone level.

Conclusions: MASEP GKRS is safe and effective in treating secretory pituitary adenomas.

None of the patients in our study experienced injury to the optic apparatus or had other neuropathies related with gamma knife. MASEP GKRS may serve as a primary treatment method in some or as a salvage treatment in the others.

However, treatment must be tailored to meet the patient's symptoms, tumor location, tumor morphometry, and overall health. Longer follow-up is required for a more complete assessment of late radioreaction and treatment efficacy.

Author: Heng Wan, Ohye Chihiro and Shu BIN Yuan
Credits/Source: Journal of Experimental &Clinical Cancer Research 2009, 28:36

Merits and pitfalls of mifepristone in Cushing's syndrome

From http://www.eje.org/cgi/content/abstract/EJE-09-0098v1

European Journal of Endocrinology (2009) In press
DOI: 10.1530/EJE-09-0098
Copyright © 2009 by European Society of Endocrinology

Frederic Castinetti, Martin Fassnacht, Sarah Johanssen, Massimo Terzolo, Philippe Bouchard, Philippe Chanson, Christine DoCao, Isabelle Morange, Antonio Pico, Sophie Ouzounian, Jacques Young, Stephanie Hahner, Thierry Brue, Bruno Allolio and Bernard Conte-Devolx

F Castinetti, Department of Endocrinology, La Timone Hospital, Marseille, France
M Fassnacht, Dept. of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Josef-Schneider-Str. 2, Wuerzburg, Germany
S Johanssen, Dept. of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Josef-Schneider-Str. 2, Wuerzburg, Germany
M Terzolo, Dipartimento di Scienze Cliniche e Biologiche, Medicina Interna I, Orbassano, Italy, Orbassano, Italy
P Bouchard, Service d'Endocrinologie, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, FR-75571 Paris Cedex 12 France, Paris, France
P Chanson, Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, Paris, France
C DoCao, Clinique Endocrinologique Marc Linquette, CHU, 59037 Lille-Cedex, Lille, France
I Morange, Department of Endocrinology, La Timone Hospital, Marseille, France
A Pico, Servicio de Endocrinología y Nutrición. Hospital General Universitario de Alicante, Alicante, Spain, Alicante, Spain
S Ouzounian, Service d'Endocrinologie, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, FR-75571 Paris Cedex 12 France, Paris, France
J Young, Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, Paris, France
S Hahner, Dept. of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Josef-Schneider-Str. 2, Wuerzburg, Germany
T Brue, Department of Endocrinology, La Timone Hospital, Marseille, France
B Allolio, Dept. of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Josef-Schneider-Str. 2, Wuerzburg, Germany
B Conte-Devolx, Department of Endocrinology, La Timone Hospital, Marseille, France

Correspondence: Frederic Castinetti, Email: CastiFred1@free.fr

Objective: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome.

Design: Retrospective study of patients treated in seven European centers.

Methods: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, 3 with ectopic ACTH secretion) or benign (n=5, 4 with Cushing's disease, 1 with bilateral adrenal hyperplasia) Cushing's syndrome (CS) were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day [200-1000]. Median treatment duration was 2 months [0.25-21] for malignant CS, and 6 months [0.5-24] for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency) and biochemical parameters (serum potassium and glucose) were evaluated.

Results: Treatment was stopped in 1 patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients.

Conclusion: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

Friday, March 13, 2009

Surgical Versus Conservative Management for Subclinical Cushing Syndrome in Adrenal Incidentalomas: A Prospective Randomized Study

From http://www.annalsofsurgery.com/pt/re/annos/abstract.00000658-200903000-00006.htm;jsessionid=J6BLG5jsTSGtvWX2pmJCN87cjMRWClGFHjBwhZ9G0G1MW1fXTcBT!-411160686!181195629!8091!-1

Fulltext  |  PDF (170 K)  |  Request Permission

Annals of Surgery:Volume 249(3)March 2009pp 388-391

Toniato, Antonio MD*; Merante-Boschin, Isabella MD*; Opocher, Giuseppe MD†; Pelizzo, Maria R. MD*; Schiavi, Francesca MD*; Ballotta, Enzo MD‡

From the *Surgical Pathology Clinic, Department of Medical and Surgical Sciences, University of Padua School of Medicine, Padova, Italy; †Familial Cancer Clinic, Istituto Oncologico Veneto I.R.C.C.S., Padua, Italy; and ‡Department of Surgical and Gastroenterological Sciences, University of Padua School of Medicine, Padova, Italy.

Correspondence: Antonio Toniato, MD, Surgical Pathology Clinic, Department of Medical and Surgical Sciences, University of Padua, School of Medicine, Via N. Giustiniani, 2 35128 Padova, Italy. E-mail: giorgiolina@libero.it, Phone: +39 (049) 821.2258, Fax: +39 (049) 821.2250.


Objective: To compare the clinical outcome of patients with subclinical Cushing syndrome (SCS) due to an adrenal incidentaloma (the autonomous hypersecretion of a small amount of cortisol, which is not enough to cause clinically-evident disease) who underwent surgery or were managed conservatively.

Summary Background Data: The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment.

Methods: Over a 15-year period, 45 SCS patients were randomly selected to undergo surgery (n = 23) or conservative management (n = 22). All surgical procedures were laparoscopic adrenalectomies performed by the same surgeon. All patients were followed up (mean, 7.7 years; range, 2-17 years) clinically by 2 experienced endocrinologists 6 and 12 months after surgery and then yearly, or yearly after joining the trial, particularly monitoring diabetes mellitus (DM), arterial hypertension, hyperlipidemia, obesity, and osteoporosis. The study end point was the clinical outcome of SCS patients who underwent adrenalectomy versus those managed conservatively.

Results: All 23 patients in the surgical arm had elective surgery. Another 3 patients randomly assigned to conservative management crossed over to the surgical group due to an increasing adrenal mass >3.5 cm. In the surgical group, DM normalized or improved in 62.5% of patients (5 of 8), hypertension in 67% (12 of 18), hyperlipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6). No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. On the other hand, some worsening of DM, hypertension, and hyperlipidemia was noted in conservatively-managed patients.

Conclusions: Based on the results of this study, laparoscopic adrenalectomy performed by skilled surgeons appears more beneficial than conservative management for SCS patients complying with our selection criteria. This trial is registered with Australian Clinical Trials Registry number, ANZCTR12608000567325.

© 2009 Lippincott Williams & Wilkins, Inc.

Circadian Rhythm

For more info on circadian rhythms listen to Robin's great podcast. In it Robin (Staticnrg) explains how diurnal variation and circadian rhythm is useful in diagnosing Cushing's.

Robin has also posted several informative posts on circadian rhythms in her blog.  Read them here: http://survivethejourney.blogspot.com/search/label/circadian

The article below is from http://www.nature.com/news/2009/090311/full/458142a.html

Circadian rhythms: Of owls, larks and alarm clocks

Could out-of-sync body clocks be contributing to human disease? Melissa Lee Phillips reports.

Melissa Lee Phillips

Download a PDF of this article
Download a PDF of this article

Ten years ago, researchers reported on three families with an extreme 'lark' problem. Larks are people who naturally wake up early in the morning, and are the opposite of 'owls', who wake up and go to sleep late. But many of the members of these families had particularly acute larkness, waking up on average around 4 a.m. and falling asleep around 7.30 p.m.1. The researchers later found that the families, who were diagnosed with familial advanced sleep-phase syndrome (FASPS), all carried mutations in a gene called PER2, which is involved in setting the human body clock2.

By some estimates, more than half of the population in industrialized societies may have circadian rhythms that are out of phase with the daily schedule they keep. Such people are said to have 'social jet lag' — a term coined by Till Roenneberg of Ludwig Maximilians University in Munich, Germany. Some of these are larks, some owls, and some have pretty standard human rhythms that are disrupted by shift work or travel. In modern societies, circadian-rhythm disruptions can arise from simply spending too much time indoors, something that can make such workers decidedly "owlish", Roenneberg says. Even the one-hour time change made by many countries at this time of year can take some adjusting to.

“You have to view your body as a whole collection of different clocks.”

Joseph Takahashi

If larks and owls are forced to follow normal schedules, they run into all kinds of problems with disabling insomnia and sleepiness. But disrupted rhythms could have graver consequences than that. In 2007, an expert working group at the World Health Organization's International Agency for Research on Cancer in Lyon, France, concluded that "shift-work that involves circadian disruption is probably carcinogenic to humans"3, after reviewing the existing evidence. Equally strong conclusions have been drawn from evidence that links circadian-rhythm problems to psychiatric disorders, metabolic syndrome and a range of other illnesses.

Researchers now are working to understand those links. Some suspect that health problems arise from a third kind of jet lag — one that arises when the circadian rhythms in different body tissues lose synchrony with each other. In 2006, the European Commission started funding EUCLOCK, a €16-million (US$20-million), five-year project involving some 34 researchers whose goal is to understand how the circadian clock synchronizes with cycles in the environment. In particular, the researchers are trying to work out what type of schedules are the healthiest fit for individuals' biological clocks. "People have been researching this for 50 years," says Anna Wirz-Justice at the Centre for Chronobiology in Basel, Switzerland, "but I think the methods are only now coming up to address this properly."

In nearly all organisms, patterns of biochemistry, physiology and behaviour oscillate with the daily cycles of light and dark, often with near-perfect timing. People forced to live in a 28-hour cycle still show fluctuations of almost exactly 24 hours in their core body temperature and levels of the hormones melatonin and cortisol4. In mammals, many of these cycles are directed by a 'master clock' in the brain's hypothalamus called the suprachiasmatic nucleus (SCN). The SCN receives information from the retina about light and coordinates rhythmic cycling of gene expression in the rest of the brain and body through neural signalling and hormones. Cycles of gene expression in the gastrointestinal tract, for example, ensure that digestive acids and enzymes are produced at the appropriate times.

In the past decade, researchers have identified some of the genes responsible for timekeeping, showing that expression of CLOCK, BMAL1, PER and CRY rises and falls over 24 hours in the SCN and elsewhere, and that mice with mutated versions of these genes abandon the 24-hour cycle for one that is shorter, longer or has no pattern at all. Such animals were "the key development that brought the field to its present exciting position", Wirz-Justice says, because it suggested that these were 'master genes' directing the clock and the physiological processes that follow it.


But for some individuals, the cycles of gene expression and behaviour do not adhere well to the cycles of night and day. The tendency to be a lark, an owl, or somewhere in between is referred to as individual's 'chronotype', and although it may shift over the course of a person's lifetime — adolescents and young adults tend to be more owl-like than either children or older adults — it doesn't usually change in comparison with peers and it is thought to be determined largely by genes. FASPS was the first human circadian disorder linked to a mutation in a specific clock gene. Not all such genes have been easy to find: researchers have found no simple mutation that accounts for people with the owlish delayed sleep-phase syndrome (DSPS), who can have trouble falling asleep before 6 a.m. and waking up before 2 p.m..

People with DSPS and FASPS often also have depression5,6, and this and other psychiatric conditions, such as bipolar disorder and schizophrenia, are commonly associated with abnormalities in circadian rhythms. "The vast majority of people with major depression have sleep abnormalities and interestingly it can be that they sleep too much or they have insomnia and can't sleep," says Colleen McClung of the University of Texas Southwestern Medical Center in Dallas. This connection raises a cause and effect question: are the circadian-rhythm disorders causing the depression or the other way around? In 2007, McClung and her colleagues found some support for the former idea when they studied mice that lack a working Clock gene and, they observed, exhibit symptoms of mania and hyperactivity that can be reversed by the mood stabilizer lithium7. "Every way we test them, they look like bipolar patients in the manic state," McClung says.

Circadian rhythms are known to affect the most basic of metabolic pathways, including protein synthesis, glycolysis and fatty-acid metabolism. And many patients who have circadian-rhythm disorders caused by shift work also develop gastrointestinal and metabolic disorders such as glucose intolerance, diabetes and high blood pressure, says Theodore Bushnell, a neurologist at the University of Washington Medicine Sleep Disorders Center in Seattle. "It seems like there's nobody who just has a shift-work issue."

The conclusion that shift work can be carcinogenic has grown largely from epidemiological work. A nationwide study in Denmark, for example, found that women who work mainly at night for at least six months are 1.5 times more likely to develop breast cancer than those who work regular hours8. Researchers suggest that the raised cancer risk could be because these people's cells start to divide at the wrong time and run amok, an idea supported by some cell-culture studies.

So far, these links haven't provided the details that biologists would like. Much like diet or stress, circadian rhythms affect so many cellular and physiological functions that it is extremely difficult to pinpoint a mechanism by which a given alteration to these rhythms could contribute to a particular disease. Much of the current work involves genetic association studies, in which scientists look for gene variants that pop up more often in people affected with a disorder than in those without it. Some such studies for psychiatric diseases, for example, have pulled out variants in clock genes. But researchers have also been making progress by dissecting the machinery of the various human body clocks.

Since the late 1990s, it has become apparent that the body has 'peripheral circadian oscillators' in tissues outside the SCN. These peripheral clocks receive input from the SCN, but are also influenced by other time-keeping signals. In 2004, a team led by Joseph Takahashi of the Center for Sleep and Circadian Biology at Northwestern University in Evanston, Illinois, measured cycles of gene expression in different mouse tissues in culture when placed in constant darkness. He found that the kidney cells followed a clock of 24.5 hours, whereas the corneal cells ran at about 21.5 hours9. "We used to think the clock was just in the brain — it was a neural process and the body just passively followed," Takahashi says. "But that's clearly not the case. You have to view your body as a whole collection of different clocks."

Like Greenwich Mean Time for the body, the SCN serves as a reference point for the peripheral clocks, and they usually run in sync. But sometimes — after stepping off a long-distance flight, for example — the synchrony breaks down. When simulating jet lag in rats, researchers at the University of Tokyo found that the SCN resets to local time in around one day based on light signals, but peripheral oscillators can take more than a week to adjust10. "So, during jet lag, your body is literally completely out of sync," Takahashi says. "Each organ shifts at a different rate."

Could it be that loss of synchrony between the body's tissues underlies some of the health problems seen in circadian-rhythm disorders and shift workers? To test this, researchers have used genetic tools to create an artificial mismatch between the central clock and a peripheral one. In one study11, researchers knocked out the gene Bmal1 in the liver of mice, effectively disabling the clock in that organ. When the animals developed low blood sugar for parts of the day, the researchers knew that the brain clock was not sufficient to maintain glucose levels — a working peripheral clock was needed too.

The SCN is synchronized during the daytime by light, whereas liver metabolism is also synchronized by food intake, Roenneberg says. So perhaps shift-workers have gastrointestinal problems because their liver and intestinal tracts are gearing up for a meal at the wrong time. "You can easily imagine that this is not exactly optimal for the system," he says.

Out of time

A mismatch between central and peripheral clocks has been linked to other health conditions too. Ongoing work by Christian Cajochen at the Centre for Chronobiology in Basel, suggests that the peripheral clocks of women with depression are not as well linked to sleep–wake cycles as they are in those without the condition. "Women with depression have a greater degree of variability in the timing of different physiological and endocrine rhythms," Wirz-Justice says.

Some researchers in the EUCLOCK consortium are planning to work out how the SCN is able to keep peripheral clocks and human physiology in time. In some experiments, mice will be put onto 'shift-work' schedules in which they are forced to 'work' and eat during the day rather than at night. The researchers will then examine how the schedule affects behaviour and the synchronization of various local body clocks.

“The vast majority of people with major depression have sleep abnormalities.”

Colleen McClung

In fact, peripheral oscillators have already proved to be a useful research tool. Last February, researchers from Steven Brown's lab at the University of Zurich and Achim Kramer's group at Charité Hospital in Berlin identified 11 larks and 17 owls based on a 'morningness–eveningness' questionnaire and then measured their molecular rhythms from the expression of Bmal1 in their skin cells12. The team wanted to find out why larks and owls naturally adopt the schedules that they do. For some people, the researchers found what they expected: cells from larks showed shorter periods than those from owls. But they also found that about half of the larks and owls actually had 'normal' circadian period lengths.

The researchers found that in this group, the owls had skin clocks that were more difficult to reset than those of people with more typical schedules, and that the larks had clocks that were easier to reset. This suggests that individual differences in chronotype result not just from innate differences in circadian period length but also from differences in how easily a person's rhythms can be synchronized to the night–day cycle — and that some larks and owls have clocks that are not reset normally each day. So perhaps these people's peripheral clocks stray from the central one easily.

Therapy options

With few firm mechanisms to go on, the question now is how to go about 'treating' circadian-rhythm disruptions. Intense-light therapy has been used to shift undesirable sleep schedules back to a more normal pattern. And Wirz-Justice says that researchers are working on other behavioural or pharmaceutical ways to alter circadian rhythms. Ramelteon, for instance, is a drug used to reduce the effects of insomnia by mimicking the action of melatonin — a hormone that tells the body it is sleep time. But no one knows yet whether such interventions will also prevent or reduce some of the other health risks associated with circadian-rhythm disruptions. Roenneberg is not convinced that it would be easy to solve even conventional jet lag with drugs. "The trouble is that we are still much too naive to have pharmacological success without messing something else up in the system," he says.

That means it could be up to individuals to consider their chronotype before choosing their schedule, or making other decisions that might affect their health. EUCLOCK researchers are developing ways to measure clock-gene expression from cheek swabs or other tissue that could provide a quick laboratory read-out of a person's chronotype. (Roenneberg says that so far these results agree with self-reported chronotype based on questionnaires.) Chronotype might be taken into account when administering drugs or medical tests: performing a blood test at 8 a.m. can yield completely different results on a morning person, who has been up for hours, than it will on an evening one. "You can get very different clinical blood values based on their chronotypes without anything being meaningfully different, because in one person, the system is up, and in the other, it's still down," says Roenneberg.

Working with EUCLOCK and another consortium called CLOCKWORK, Roenneberg and his colleagues are developing a computer model that works out a person's ideal schedule on the basis of his or her chronotype and sleep needs. The group is starting to test the model's predictions by asking people of each chronotype to try out a certain schedule in their daily lives, and measuring its effects in a range of physiological, behavioural and cognitive tests. They will then use their findings to refine the model. By repeating this process several times, Roenneberg says, "we are confident that we will finally put some sense into how to do shift-work properly — that is, with the fewest side effects on health".

Being a lark or owl should not, in itself, be a problem, Roenneberg adds. "Chronotype per se should have no health effects whatsoever. Health effects come from having to live against one's own clock."

Saturday, March 7, 2009

11th Doctor Sees 'Ghost'

Jackie is a local person (to me) :


From http://www.washingtonpost.com/wp-dyn/content/article/2007/08/10/AR2007081001808.html


By Sandra G. Boodman

Washington Post Staff Writer
Tuesday, August 14, 2007; Page HE01

The worst moment of Jacquelyn Silverman's two-year medical ordeal came on her 36th birthday. She had donned a new pair of earrings that were a gift from her husband and was trying to slip on her glasses to admire them when she realized her face had gotten so fleshy the spectacles no longer fit.

"I just started crying," she recalled. "I felt I was literally growing out of my skin."

Jacquelyn Silverman, second from right,  today shows no signs of her medical ordeal.

Jacquelyn Silverman, second from right, today shows no signs of her medical ordeal. (Provided By Jacquelyn Silverman)


As Silverman learned much later, the mystifying constellation of symptoms plaguing her -- unexplained weight gain, stomach pain, severe acne, an awful metallic taste in her mouth, aching joints, the red rash on her neck -- was caused by a rare disorder that can confound experienced physicians.

Even after a Washington specialist (the 11th doctor she consulted) told Silverman he suspected he knew what was wrong with her, it took four more months of testing to be certain of the diagnosis -- and more than a year for her to fully recover.

"Everyone was treating the individual symptoms, but no one put it all together," she said. Several doctors suggested her problem might be psychological, Silverman recalled, a notion she flatly rejected. "I knew it wasn't. I kept saying, 'Something is wrong with me.' At times it felt like there was a ghost inhabiting my body."

Now 52, Silverman, who lives in Montgomery County, said her symptoms surfaced gradually when she turned 35. She began gaining weight and couldn't lose the 20 pounds she quickly packed on. Her longtime internist recommended a low-fat diet and exercise. Silverman joined Weight Watchers and a gym, but after two months hadn't lost an ounce.

"The more I would exercise, the more I got bigger," she said. Her face and fingers looked especially puffy.

Silverman said she spent the next year shuttling back and forth to the internist, who referred her to a series of specialists: a dermatologist to treat the acne that suddenly blanketed her face and back; a rheumatologist to examine her joints, which ached so much it felt like a recurrence of the mononucleosis she'd had when she was young; and a gastroenterologist, who performed a colonoscopy after Silverman complained of abdominal pain and bloating. Her dentist considered removing her fillings and replacing them with porcelain to eradicate the constant awful metallic taste in her mouth. Silverman's regular periods became erratic. She developed insomnia and hypertension.

"I was constantly hyped up and yelling at my kids," she recalled.

But no doctor could explain what was wrong. "I felt as though everything was ruled out -- but nothing was diagnosed," Silverman said.

Finally her internist suggested she might be depressed and should see a psychiatrist.

Silverman refused. She was convinced that her problem was organic; her husband never suggested otherwise. "He was unbelievable," Silverman recalled. "He'd say, 'You just have to keep seeing doctors until they figure it out.' "

At last one did. Silverman's internist, suspicious that her problem might be metabolic, referred her to endocrinologist Ace Lipson.

Silverman vividly recalls her first meeting with Lipson, whom she credits with salvaging her life.

"I walked in and started telling him my symptoms," Silverman recalled. "He listened and then asked me whether I had a picture of what I used to look like, which I didn't. Then he said, 'I need to do a lot of tests, but I think I know what you have.' I was so happy and so relieved when he said that."

Lipson remembers their encounter somewhat differently. He insists he was merely following up on the internist's "inkling of what was wrong. I'm not the hero."

The endocrinologist said he was fairly sure Silverman had Cushing's disease, a rare disorder that strikes about one in 500,000 Americans. Cushing's results in the overproduction of the stress hormone cortisol, which can wreak havoc with multiple organ systems.

Silverman, Lipson recalled, had the round "moon face" that characterizes patients with Cushing's or those on high doses of corticosteroids. Many of her other symptoms were classic manifestations of the disease. The usual cause is a nonmalignant tumor on the pituitary gland at the base of the brain.

Cushing's affects more women than men and is sometimes hereditary. Left untreated, it can cause serious illness or even death, according to the National Institutes of Health. Surgery to remove the tumor is standard procedure, but not a sure-fire cure: In an estimated 20 to 50 percent of cases, the tumor grows back, Lipson says.

The endocrinologist, who estimates he has seen about 20 Cushing's patients in his career, said that it can be a "very difficult diagnosis because the individual symptoms can lead you in very different directions" and because it is so rare. The disease can masquerade as lung cancer or psychiatric disorders, both of which cause similar symptoms.

"There have been stories of patients hospitalized on psych wards for years who really had Cushing's," Lipson said.

Silverman said she suspects that her father, who died in his 50s of a disease reputed to be lung cancer, may also have had Cushing's, though it was never diagnosed.

In March 1993, Silverman underwent a four-hour operation at the University of Virginia Medical Center to remove the brain tumor. She endured a long and rocky recovery in which she developed a form of diabetes for a time and had to be slowly weaned off steroids to replace the high doses her body had been manufacturing. Eighteen months after the operation, she finally felt like her old self.

"I am fine now and have been ever since," she said. Every five years she undergoes an MRI just to be sure there has been no recurrence.

Looking back, she recalls, her quest for a diagnosis was "really hard. It consumes you and becomes your life. My message is to ask, ask, ask questions. And don't stop until you have an answer." ·

If you have a medical mystery that's been solved, e-mail us atmedicalmysteries@washpost.com.

GlaxoSmithKline submits European marketing authorisation application for Pazopanib in advanced kidney cancer

From http://www.pipelinereview.com/content/view/25590/109/

GlaxoSmithKline (GSK) today announced the submission of a Marketing Authorisation Application (MAA) tot he European Medicines Agency (EMEA) for pazopanib as an oral therapy for patients with advanced and/or metastatic renal cell carcinoma (RCC).

London, UK and Philadelphia, PA, USA | March 6, 2009 | GlaxoSmithKline (GSK) today announced the submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMEA) for pazopanib as an oral therapy for patients with advanced and/or metastatic renal cell carcinoma (RCC).

RCC is the most common type of kidney cancer.[1] The incidence of RCC is rising throughout the world[2] with 208,000 new cases diagnosed annually, and over 100,000 deaths.[3] More than 10 percent of new cases are diagnosed in Western Europe.[4]

Pazopanib is an investigational, oral, angiogenesis inhibitor which targets key proteins responsible for tumour growth and survival.[5]

The MAA submission is based on positive results from a randomised, double-blind, placebo-controlled Phase III study of pazopanib in treatment-naïve and cytokine-pre-treated patients with advanced RCC. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, response rate and safety.[6] From previously published studies the most common side-effects associated with pazopanib treatment include diarrhoea, hypertension, hair colour change, nausea, anorexia and vomiting.5 The complete results from the Phase III study will be presented at an upcoming medical conference.

In December 2008, GSK also completed the submission of a new drug application (NDA) to the US Food and Drug Administration (FDA) for pazopanib as an oral therapy for patients with advanced RCC. The filing is currently under regulatory review.

“If approved, pazopanib will offer physicians and patients a new therapeutic option for advanced kidney cancer and demonstrate our ongoing commitment to the development of innovative and personalised treatments for patients with cancer.” said Paolo Paoletti, Senior Vice President, R&D Oncology Unit.

“The MAA submission of pazopanib marks our fifth major submission since the formation of the R&D Oncology Unit in September 2008. Previous submissions included FDA filings for pazopanib and ofatumumab, and MAA submissions for ofatumumab and eltrombopag,” said Moncef Slaoui, Chairman, Research and Development. “These submissions underscore the value of a dedicated Oncology R&D Unit in capturing the many synergies that exist between discovery and development in oncology and in delivering more products of value.”

About Pazopanib

Pazopanib is an investigational, oral, once-daily angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit.5 VEGF and PDGF are growth factors critical to the development and growth of blood vessels[7],[8] – a process known as angiogenesis.[9] Angiogenesis plays a pivotal role in the growth and spread of several tumour types, with VEGF and PDGF overexpression linked to multiple cancers.8,9

Within a broad clinical program across multiple tumour types, there are three Phase III studies currently underway. Pazopanib is also being evaluated as a monotherapy,in combination with targeted therapies and in combination with cytotoxic chemotherapy.More than 2,000 patients have been treated to date in clinical trials.

For further details please visit www.clinicaltrials.gov.

GSK in Oncology

GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary ‘bench to bedside’ approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com

SOURCE GlaxoSmithKline

Friday, March 6, 2009

Pituitary Blog Posts March 6, 2009

With it being the way it is? | FAQ Sleep Apnea
By admin
Growth hormone, like a number of hormones, is produced by the pituitary gland. It is one in a series of hormones that control tissue growth .. Levels of growth hormone and related hormones also are affected by sleep, exercise, stress, ...
FAQ Sleep Apnea - http://www.faqsleepapnea.com/


Scientific Basis Of Fertility Awareness - MeDiCaLGeeK
By trimurtulu
The pituitary gland at the base of the brain secretes FSH (follicle-stimulating hormone) which, stimulates the ripening of follicles in the ovary. The ripening follicles produce increasing amounts of oestrogen. ...
MeDiCaLGeeK - http://www.medicalgeek.com/


Includes a video: Pituitary Tumors: A Neurosurgeon’s Perspective
By admin
There are non-surgical procedures (such as medication) that can shrink pituitary adenomas. These medicines are are often prescribed when a patient is exhibiting visual disturbances. If your MD or specialist is not helping or advising ...
Cure Tumor & Cancer - http://andridaulay.com/rs/


transsphenoidal pituitary adenoma - VKER Health
By vker.net
growth hormone deficiency, deficiency (also called GHD) of the pituitary gland disease (pygmy Pitu - itary dwarfism). The pituitary gland secretion of growth hormone, lobe adrenal cortical hormone, thyroid hormones and gonadal hormone ...
VKER Health - http://www.vker.net/


By Leigh Penman
This is a glycoprotein secreted by the anterior pituitary gland and is responsible for triggering the Leydig cells to produce Testosterone. By measuring LH levels it can be determined whether a low testosterone reading is caused by the ...
Muscle Sport Mag - http://www.musclesportmag.com/

Tuesday, March 3, 2009

A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate

From http://jcem.endojournals.org/cgi/content/abstract/jc.2008-2392v1


Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2008-2392

A N Paisley, S V Rowles, D Brandon,  and P J Trainer*

Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK; Department of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA

* To whom correspondence should be addressed. E-mail: peter.trainer@man.ac.uk.

Introduction: The decision to commence life-long glucocorticoid replacement therapy is often based on a cortisol stimulation test. We investigated the relationship between the peak cortisol response to insulin-induced hypoglycemia and daily cortisol production rate (CPR) to ascertain if provocative tests are accurate in indicating the need to initiate life-long glucocorticoid replacement.

Patients and Methods: Ten patients (5 male, mean age 44±13 yrs) with pituitary disease, with demonstrably suboptimal peak cortisol response (350–500 nmol/L) to insulin-induced hypoglycemia, underwent CPR measurement by isotope dilution using gas chromatography-mass spectrometry and 24 hour urinary free cortisol (UFC).

Results: The median baseline and peak cortisol attained with hypoglycemia was 284 (164–323) and 473.5 (366–494) nmol/L, respectively. A strong positive correlation was seen between peak stimulated cortisol and CPR (adjusted for body surface area)(r = 0.75, P = 0.02) and in all patients CPR (4.6 (2.9–15.1) mg/day per m2) was within the reference range (2.1–12 mg/day per m2) or elevated (1 patient). A wide range was found for 24 hr UFC (116.5 (20.5–265.9) nmol/L) in this group of patients, and this parameter lacked significant correlation with either serum cortisol concentration or CPR.

Conclusion: This is the first study to demonstrate a significant correlation between CPR and peak cortisol values during hypoglycemic challenge. An inadequate cortisol response to hypoglycemia suggests the need for glucocorticoid cover at times of stress, but these data indicate that a sub-optimal peak cortisol does not equate to a low CPR and should not be an automatic indication for life-long glucocorticoid replacement therapy. UFC bears no relation to serum cortisol or CPR and is therefore unhelpful in assessment of such patients.

Key words: Hypopituitarism • cortisol production rate

Pituitary: How to recognize depressive disorders in children and adolescents

From http://www.jaapa.com/How-to-recognize-depressive-disorders-in-children-and-adolescents/PrintArticle/128128/

Brett Reisman Greenberg, PA-C

March 02 2009

Depression was once thought to affect only adults. Clinical evidence has revealed that children and adolescents experience both depressive symptoms and depressive disorders.1,2 However, the limited language skills of young children and adolescents' reluctance to cooperate can make it difficult for clinicians to diagnose these disorders in the pediatric population. This article reviews the criteria used to make an accurate diagnosis and initiate the most appropriate treatments.

Depressive disorders are divided into three classifications: major depressive disorder (MDD), dysthymic disorder (DD), and depressive disorder not otherwise specified (NOS). Approximately 2% of children and 4% to 8% of adolescents suffer from MDD.3,4 Although only a few studies have reported on the prevalence of DD, it is reported to be 0.6% to 1.7% of children and 1.6% to 8% of adolescents.5 Combined, these statistics indicate a collective incidence of MDD during childhood and adolescence of 15% to 20%.6 Although the criteria for these classifications differ, treatment is fairly similar.

Major depressive disorder A diagnosis of MDD is made when the patient is in a depressed mood or has a consistent loss of interest in daily activities for at least 2 weeks. The disorder is characterized by one or more major depressive episodes with no manic, hypomanic, or mixed episodes of mood disturbance. An adolescent must exhibit at least five of the symptoms of depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), in order to meet the criteria for a diagnosis of MDD7 (see Table 1). These symptoms must not be the result of drug abuse, medications, a medical condition, or the loss of a loved one.

Dysthymic disorder DD in adolescents is characterized by an overwhelming and chronic state of depressed or irritable mood for at least 1 year. Other symptoms include poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions, and feelings of hopelessness. The adolescent must experience two or more of the symptoms, with a reduction of symptoms lasting for 2 months or less.7 Often, symptoms of DD are missed or overlooked because they are less severe than the symptoms of MDD. DD has an extended course, therefore early recognition is critical to prevent extensive impairment to the patient's ability to function.

Depressive disorder not otherwise specified Persons with depressive disorder NOS present with clinically significant symptoms of depression. However, these patients do not meet the criteria for any specific mood disorder.


Depression does not have specific symptoms in children and adolescents. In fact, depressive disorders may manifest differently in each age-group. For instance, infants and preschoolers have a limited ability to express feelings of sadness through language skills; therefore, psychiatric disorders are often difficult to diagnose at this young age. Depressive symptoms must be inferred from overt behavior such as apathy, withdrawal from caregivers, a delay in or regression of developmental milestones, and failure to thrive that has no organic cause.8,9 Clinicians must rely heavily on parental history, evaluation of parent-child interactions, and play interviews conducted by mental health specialists.10

School-age children are cognitively able to internalize environmental stressors and display low self-esteem and excessive guilt. Many times they may present with somatic complaints (headache, stomachaches), anxiety (school phobia, excessive separation anxiety), and irritability (temper tantrums, other behavioral problems).1,11,12 Teachers are a valuable source of information on the behaviors and attitudes of these children.

Common manifestations of depression in a teenager are a sudden drop in grades, a change in friends, participation in fewer social or recreational activities, frequent irritability, a recent change in eating or sleeping patterns, frequent fatigue, feelings of worthlessness or hopelessness, or suicidal thinking. Adolescents experience many challenges as they strive to establish their own identities. Patients in this age-group can be extremely challenging to treat because they tend to be struggling for autonomy from authoritative figures. A good rapport is absolutely essential to building the trust of an adolescent patient.


Pathogenic contributors to the risk of depression are supported by substantial clinical evidence; however, the proportion of contribution to the etiology varies from case to case. One of the most significant pathogenic factors is genetics. Depression is both polygenic and multifactorial.13 Genetic factors can predispose a person to depression, but additional nongenetic factors are required to produce the disorder. For example, an interaction between an allele of the serotonin transporter (5-HTT) gene and stressful life events can increase the risk of depression.14,15 Genetic factors may also influence response to treatment.

Many studies have shown that persons with depression have altered brain structure and function. Monoamine neurotransmitters, specifically norepinephrine and serotonin, have been researched; these agents are also used in the therapeutic approach to depressive disorders. Early study models postulated that hypoactivity occurs in the neurotransmitter systems. However, more complex dynamics involving intracellular cascades triggered by the monoamines appear to be involved in depression and a person's response to antidepressant medication.16 In addition, overproduction of corticotrophin-releasing hormone causes hyperactivity in the hypothalamic-pituitary-adrenal cortex axis in depressed persons,17 which may, in turn, lead to glucocorticoid-mediated hippocampal atrophy.18 Functional neuroimaging studies have shown altered brain function occurring in several regions, often including the frontal cortex and striatum.19 Neuropsychological findings also support the theory that functional abnormalities occur in these brain regions.

Social system dynamics such as isolation and negative or critical comments from family members may also contribute to depression onset or perpetuate a depressive episode.20-22 Societal and cultural factors strongly influence both the symptomatic expression and a person's willingness or ability to seek care for depression.23


The typical course of a major depressive episode in adolescence lasts 7 to 9 months. Young persons recover from a depressive episode within 1 to 2 years in 90% of cases;24,25 however, relapse is common, and the probability of recurrence within 2 years is 40% and within 5 years is 70%.1-3 Adolescents with depression are more likely to suffer depressive episodes or have other mental health issues in adulthood than are adolescents who do not have depression.26,27 Education can help patients and family members understand depression as an illness and emphasize the importance of adherence to treatment. Developing supportive and understanding relationships with the patient is key to improving treatment outcomes.28,29

Psychotherapy can be a useful initial therapy for children and adolescents with mild to moderate depression; it can also be an adjunct to medications for those patients with more severe depression.30 Psychotherapeutic approaches include play therapy, psychodynamic therapy, supportive therapy, interpersonal therapy, family therapy, group therapy, and cognitive behavior therapy (CBT). The Treatment for Adolescents with Depression Study (TADS) found that a combination of psychosocial and pharmacologic therapies is the most beneficial treatment for adolescents suffering from a depressive disorder.

TADS evaluated the efficacy of short-term (12 weeks) and long-term (36 weeks) treatment with fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI); CBT; fluoxetine plus CBT; and pill placebo in adolescents with MDD.31 The typical response rate for psychosocial or pharmacologic monotherapy for MDD is approximately 60%,32,33 and the rate of remission is 35% to 40%.32 However, TADS results support combination therapy with fluoxetine and CBT as the most effective treatment during the acute phase (the first 12 weeks).32

The outcomes were measured using the Children's Depression Rating Scale-Revised (CDRS-R) and a dichotomized Clinical Global Impression-Improvement (CGI-I) score.32 A positive response on the CGI-I was defined as a score of 1 (very much improved) or 2 (much improved). Outcomes based on the CDRS-R indicated that the most significant improvement in depressive symptoms occurred in the fluoxetine combined with CBT treatment group. However, outcomes based on the CGI-I indicated that fluoxetine alone was effective, although not as effective as fluoxetine/ CBT combination therapy. After 12 weeks of treatment, 71% of adolescents treated with combination therapy reported a much improved or very much improved mood on the CGI-I compared to 61% treated with fluoxetine monotherapy, 43% treated with CBT monotherapy, and 35% who received placebo.32 In addition, the patients treated with combination therapy or fluoxetine alone recovered earlier than those patients treated with CBT or placebo alone.34 Combination therapy showed favorable results at 12, 18, and 36 weeks; however, all the therapies showed similar results by 36 weeks.32


Tricyclic antidepressants are not beneficial in pediatric patients, therefore SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) are increasingly being used to treat depression in this patient population.35 Research on the efficacy and safety of antidepressants in children has increased dramatically over the last 10 years. Only 250 children and adolescents with depression were included in double-blind, randomized controlled trials (RCTs) of antidepressants before 1995, whereas more than 2,800 children and adolescents have been included in more recent RCTs of these medications.

Of the SSRIs and SNRIs that are used to treat depression, fluoxetine is the only drug with FDA approval for use in children and adolescents. However, the other SSRIs and SNRIs are used to treat depression in these patients. Although the outcomes of many of the antidepressant trials have been widely scrutinized, the Medicines and Healthcare Products Regulatory Agency and the FDA considered only the results of the fluoxetine trials, including the TADS study, as positive.

Interpretation of suicidal behavior in depression studies can be difficult because suicide attempts and suicidal ideation are common symptoms of depression. Determining if a suicide attempt made during treatment indicates a lack of improvement, a worsening of depressive symptoms, or a reaction to the medication is difficult. All children and adolescents with depression must be closely monitored during drug therapy, particularly in the early stages of treatment or after dose titrations. FDA recommendations state that patients should be monitored weekly for the first 4 weeks of antidepressant therapy and after any subsequent dose adjustments. In addition, patients and their families need to be fully informed about the risk of suicidal behaviors. Table 2 lists online resources for information about depression. Families must watch closely for signs of worsening depression, worsening or new suicidal ideation or behaviors, and other adverse behaviors.36 Referral to a psychiatrist, psychologist, or other mental health care provider is warranted whenever depression is recurrent or chronic, complicated by comorbid conditions, causes a high degree of functional impairment, or if the adolescent's presentation is unclear or guarded. If the need for psychopharmacologic medications is suspected, a referral to a psychiatrist is indicated.


Adolescents with depression typically present in primary care. Unfortunately, the disorder is underdiagnosed and undertreated;37 an estimated 70% of teenagers with depression do not receive any form of treatment.4,38 In the United States, suicide rates doubled among adolescents aged 15 to 19 years and tripled among those aged 10 to 14 years from the 1960s to the 1990s.39 Suicide is the fourth leading cause of death among all children and the third leading cause of death among children aged 10 to 19 years.40 From 2003 to 2004, suicide rates among females aged 10 to 14 years increased by 76%; among those aged 15 to 19 years, suicide rates increased by 32% in females and by 9% in males.41 Furthermore, approximately two-thirds of children and adolescents with MDD also suffer from another mental health disorder. Health care practitioners also need to recognize the associated psychiatric comorbidities, including DD, anxiety disorders, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and substance use disorder.42

Studies have shown that only one-third of parents who had concerns that their child may have a psychosocial disorder planned to discuss it with their child's pediatrician. In cases where parents initiated this discussion, only 40% of pediatricians responded; the response rate was even lower if the parents were less educated.43,44 This finding indicates that a majority of psychosocial disorders in children are being missed.

With appropriate evaluation, diagnosis, and treatment, primary care practitioners can do much to prevent the subsequent morbidity and mortality associated with depressive disorders. Prompt recognition ensures effective treatment of depressive disorders in children and adolescents; therefore, PAs must educate themselves, their patients, and their patients' families about the signs and symptoms of these disorders. JAAPA

Brett Reisman Greenberg works at the Cleveland Clinic of Florida, Weston, Florida. She has indicated no relationships to disclose relating to the content of this article.


1. Birmaher B, Ryan ND, Williamson DE et al. Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1427-1439.

2. Saluja G, Iachan R, Scheidt PC, et al. Prevalence of and risk factors for depressive symptoms among young adolescents. Arch Pediatr Adolesc Med. 2004;158(8):760-765.

3. Fleming JE, Offord DR. Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry. 1990;29(4):571-580.

4. Lewinsohn PM, Clarke GN, Seeley JR, Rohde P. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry. 1994;33(6):809-818.

5. Lewinsohn PM, Hops H, Roberts RE, et al. Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students. J Abnorm Psychol. 1993;102(1):133-144.

6. Carlson GA, Cantwell DP. Unmasking masked depression in children and adolescents. Am J Psychiatry. 1980;137(4):445-449.

7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Assoc; 2000.

8. Jellinek MS, Snyder JB. Depression and suicide in children and adolescents. Pediatr Rev. 1998;19(8):255-264.

9. Wolraich M, Felice ME, Drotar D. The Classification of Child and Adolescent Mental Diagnoses in Primary Care: Diagnostic and Statistical Manual for Primary Care (DSM-PC) Child and Adolescent Version. Elk Grove Village, IL: American Academy of Pediatrics; 1996.

10. Lewis M. Psychiatric assessment of infants, children, and adolescents. In: Lewis M, ed. Child and Adolescent Psychiatry: A Comprehensive Textbook. Baltimore, MD: Williams & Wilkins; 1991:447-463.

11. Ryan ND, Puig-Antich J, Ambrosini P, et al. The clinical picture of major depression in children and adolescents. Arch Gen Psychiatry. 1987;44(10):854-861.

12. Mitchell J, McCauley E, Burke PM, Moss SJ. Phenomenology of depression in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1988;27(1):12-20.

13. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry. 2006;163(1):109-114.

14. Kendler KS, Kuhn JW, Vittum J, et al. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry. 2005;62(5):529-535.

15. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.

16. Nutt DJ, Baldwin DS, Clayton AH, et al. Consensus statement and research needs: the role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry. 2006;67(suppl 6):46-49.

17. Gillespie CF, Nemeroff CB. Hypercortisolemia and depression. Psychosom Med. 2005;67(suppl 1): S26-S28.

18. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57(10):925-935.

19. Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med. 1998;49:341-361.

20. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8):1516-1518.

21. Paykel ES. Life events and affective disorders. Acta Psychiatr Scand Suppl. 2003;(418):61-66.

22. Hayhurst H, Cooper Z, Paykel ES, et al. Expressed emotion and depression. A longitudinal study. Br J Psychiatry. 1997;171:439-443.

23. Simon GE, VonKorff M, Piccinelli M, et al. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-1335.

24. Kovacs M, Feinberg TL, Crouse-Novak MA, et al. Depressive disorders in childhood: I. A longitudinal prospective study of characteristics and recovery. Arch Gen Psychiatry. 1984;41(3):229-237.

25. McCauley E, Myers K, Mitchell J, et al. Depression in young people: initial presentation and clinical course. J Am Acad Child Adolesc Psychiatry. 1993;32(4):714-722.

26. Harrington R, Fudge H, Rutter M, et al. Adult outcomes of childhood and adolescent depression. I. Psychiatric status. Arch Gen Psychiatry. 1990;47(5):465-473.

27. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA. 1999;281(18):1707-1713.

28. Asarnow JR, Goldstein MJ, Tompson M, Guthrie D. One-year outcomes of depressive disorders in child psychiatric in-patients: evaluation of the prognostic power of a brief measure of expressed emotion. J Child Psychol Psychiatry. 1993;34(2):129-137.

29. Asarnow JR, Tompson M, Hamilton EB, et al. Family-expressed emotion, childhood-onset depression, and childhood-onset schizophrenia spectrum disorders: is expressed emotion a nonspecific correlate of child psychopathology or a specific risk factor for depression? J Abnorm Child Psychol. 1994;22(2):129-146.

30. Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. AACAP. J Am Acad Child Adolesc Psychiatry. 1998;37(10 suppl):63S-82S.

31. Treatment for Adolescents With Depression Study Team. Treatment for Adolescents With Depression Study (TADS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry. 2003;42(5):531-542.

32. March J, Silva S, Vitiello B; TADS Team. The Treatment for Adolescents with Depression Study (TADS): methods and message at 12 weeks. J Am Acad Child Adolesc Psychiatry. 2006;45(12):1393-1403.

33. Goodyer I, Dubicka B, Wilkinson P, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. BMJ. 2007;335(7611):142.

34. Blackburn IM, Moore RG. Controlled acute and follow-up trial of cognitive therapy and pharmacotherapy in out-patients with recurrent depression. Br J Psychiatry. 1997;171:328-334.

35. Hazell P, O'Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev. 2002;(2):CD002317.

36. US Food and Drug Administration Web site. http://www.fda.gov. Accessed February 2, 2009.

37. Adolescent medicine: teen depression: overlooked and undertreated. Patient Care. 2002;12:37-47.

38. Flament MF, Cohen D, Choquet M, et al. Phenomenology, psychosocial correlates, and treatment seeking in major depression and dysthymia of adolescence. J Am Acad Child Adolesc Psychiatry. 2001;40(9):1070-1078.

39. Efforts to reduce the toll of injuries in childhood require expanded research. American Academy of Pediatrics. Committee on Injury and Poison Prevention. Pediatrics. 1996;97(5):765-768.

40. Hamilton BE, Minino AM, Martin JA, et al. Annual summary of vital statistics: 2005. Pediatrics. 2007;119(2):345-360.

41. Center for Disease Control and Prevention (CDC). Suicide trends among youths and young adults aged 10-24 years—United States, 1990-2004. MMWR Morb Mortal Wkly Rep. 2007;56(35):905-908.

42. Angold A, Costello EJ, Erkanli A. Comorbidity. J Child Psychol Psychiatry. 1999;40(1):57-87.

43. Cassidy LJ, Jellinek MS. Approaches to recognition and management of childhood psychiatric disorders in pediatric primary care. Pediatr Clin North Am. 1998;45(5):1037-1052.

44. Jellinek M, Little M, Murphy JM, Pagano M. The Pediatric Symptom Checklist. Support for a role in a managed care environment. Arch Pediatr Adolesc Med. 1995;149(7):740-746.

Cushing's Info From NIH

Published at http://www.endocrine.niddk.nih.gov/pubs/cushings/cushings.htm

Cushing’s Syndrome

On this page:

What is Cushing’s syndrome?

Cushing’s syndrome is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol. Sometimes called hypercortisolism, Cushing’s syndrome is relatively rare and most commonly affects adults aged 20 to 50. People who are obese and have type 2 diabetes, along with poorly controlled blood glucose—also called blood sugar—and high blood pressure, have an increased risk of developing the disorder.


What are the signs and symptoms of Cushing’s syndrome?

Signs and symptoms of Cushing’s syndrome vary, but most people with the disorder have upper body obesity, a rounded face, increased fat around the neck, and relatively slender arms and legs. Children tend to be obese with slowed growth rates.

Other signs appear in the skin, which becomes fragile and thin, bruises easily, and heals poorly. Purple or pink stretch marks may appear on the abdomen, thighs, buttocks, arms, and breasts. The bones are weakened, and routine activities such as bending, lifting, or rising from a chair may lead to backaches and rib or spinal column fractures.

Women with Cushing’s syndrome usually have excess hair growth on their face, neck, chest, abdomen, and thighs. Their menstrual periods may become irregular or stop. Men may have decreased fertility with diminished or absent desire for sex and, sometimes, erectile dysfunction.

Other common signs and symptoms include

  • severe fatigue
  • weak muscles
  • high blood pressure
  • high blood glucose
  • increased thirst and urination
  • irritability, anxiety, or depression
  • a fatty hump between the shoulders

Sometimes other conditions have many of the same signs as Cushing’s syndrome, even though people with these disorders do not have abnormally elevated cortisol levels. For example, polycystic ovary syndrome can cause menstrual disturbances, weight gain beginning in adolescence, excess hair growth, and impaired insulin action and diabetes. Metabolic syndrome—a combination of problems that includes excess weight around the waist, high blood pressure, abnormal levels of cholesterol and triglycerides in the blood, and insulin resistance—also mimics the symptoms of Cushing’s syndrome.


What causes Cushing’s syndrome?

Cushing’s syndrome occurs when the body’s tissues are exposed to high levels of cortisol for too long. Many people develop Cushing’s syndrome because they take glucocorticoids—steroid hormones that are chemically similar to naturally produced cortisol—such as prednisone for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. Glucocorticoids are also used to suppress the immune system after transplantation to keep the body from rejecting the new organ or tissue.

Other people develop Cushing’s syndrome because their bodies produce too much cortisol. Normally, the production of cortisol follows a precise chain of events. First, the hypothalamus, a part of the brain about the size of a small sugar cube, sends corticotropin-releasing hormone (CRH) to the pituitary gland. CRH causes the pituitary to secrete adrenocorticotropin hormone (ACTH), which stimulates the adrenal glands. When the adrenals, which are located just above the kidneys, receive the ACTH, they respond by releasing cortisol into the bloodstream.

Cortisol performs vital tasks in the body including

  • helping maintain blood pressure and cardiovascular function
  • reducing the immune system’s inflammatory response
  • balancing the effects of insulin, which breaks down glucose for energy
  • regulating the metabolism of proteins, carbohydrates, and fats

Drawing of the brain and adrenal glands with the hypothalamus, pituitary gland, and adrenal glands labeled and arrows diagramming the effect of CRH on ACTH and the effect of ACTH on cortisol.
The hypothalamus sends CRH to the pituitary, which responds by secreting ACTH. ACTH then causes the adrenals to release cortisol into the bloodstream.

One of cortisol’s most important jobs is to help the body respond to stress. For this reason, women in their last 3 months of pregnancy and highly trained athletes normally have high levels of the hormone. People suffering from depression, alcoholism, malnutrition, or panic disorders also have increased cortisol levels.

When the amount of cortisol in the blood is adequate, the hypothalamus and pituitary release less CRH and ACTH. This process ensures the amount of cortisol released by the adrenal glands is precisely balanced to meet the body’s daily needs. However, if something goes wrong with the adrenals or the regulating switches in the pituitary gland or hypothalamus, cortisol production can go awry.

Pituitary Adenomas

Pituitary adenomas cause 70 percent of Cushing’s syndrome cases,1 excluding those caused by glucocorticoid use. These benign, or noncancerous, tumors of the pituitary gland secrete extra ACTH. Most people with the disorder have a single adenoma. This form of the syndrome, known as Cushing’s disease, affects women five times more often than men.

Ectopic ACTH Syndrome

Some benign or, more often, cancerous tumors that arise outside the pituitary can produce ACTH. This condition is known as ectopic ACTH syndrome. Lung tumors cause more than half of these cases, and men are affected three times more often than women. The most common forms of ACTH-producing tumors are small cell lung cancer, which accounts for about 13 percent of all lung cancer cases,2 and carcinoid tumors—small, slow-growing tumors that arise from hormone-producing cells in various parts of the body. Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.

Adrenal Tumors

In rare cases, an abnormality of the adrenal glands, most often an adrenal tumor, causes Cushing’s syndrome. Adrenal tumors are four to five times more common in women than men, and the average age of onset is about 40. Most of these cases involve noncancerous tumors of adrenal tissue called adrenal adenomas, which release excess cortisol into the blood.

Adrenocortical carcinomas—adrenal cancers—are the least common cause of Cushing’s syndrome. With adrenocortical carcinomas, cancer cells secrete excess levels of several adrenocortical hormones, including cortisol and adrenal androgens, a type of male hormone. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.

Familial Cushing’s Syndrome
Most cases of Cushing’s syndrome are not inherited. Rarely, however, Cushing’s syndrome results from an inherited tendency to develop tumors of one or more endocrine glands. Endocrine glands release hormones into the bloodstream. With primary pigmented micronodular adrenal disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. With multiple endocrine neoplasia type 1 (MEN1), hormone-secreting tumors of the parathyroid glands, pancreas, and pituitary develop; Cushing’s syndrome in MEN1 may be due to pituitary, ectopic, or adrenal tumors.

1Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. The Journal of American Medicine. 2005;118(12):1340–1346.

2Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. Journal of Clinical Oncology. 2006;24:4539–4544.


How is Cushing’s syndrome diagnosed?

Diagnosis is based on a review of a person’s medical history, a physical examination, and laboratory tests. X rays of the adrenal or pituitary glands can be useful in locating tumors.

Tests to Diagnose Cushing’s Syndrome

No single lab test is perfect and usually several are needed. The three most common tests used to diagnose Cushing’s syndrome are the 24-hour urinary free cortisol test, measurement of midnight plasma cortisol or late-night salivary cortisol, and the low-dose dexamethasone suppression test. Another test, the dexamethasone-corticotropin-releasing hormone test, may be needed to distinguish Cushing’s syndrome from other causes of excess cortisol.

  • 24-hour urinary free cortisol level. In this test, a person’s urine is collected several times over a 24-hour period and tested for cortisol. Levels higher than 50 to 100 micrograms a day for an adult suggest Cushing’s syndrome. The normal upper limit varies in different laboratories, depending on which measurement technique is used.

  • Midnight plasma cortisol and late-night salivary cortisol measurements. The midnight plasma cortisol test measures cortisol concentrations in the blood. Cortisol production is normally suppressed at night, but in Cushing’s syndrome, this suppression doesn’t occur. If the cortisol level is more than 50 nanomoles per liter (nmol/L), Cushing’s syndrome is suspected. The test generally requires a 48-hour hospital stay to avoid falsely elevated cortisol levels due to stress.

    However, a late-night or bedtime saliva sample can be obtained at home, then tested to determine the cortisol level. Diagnostic ranges vary, depending on the measurement technique used.

  • Low-dose dexamethasone suppression test (LDDST). In the LDDST, a person is given a low dose of dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 2 days. Urine is collected before dexamethasone is administered and several times on each day of the test. A modified LDDST uses a onetime overnight dose.

    Cortisol and other glucocorticoids signal the pituitary to release less ACTH, so the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. If cortisol levels do not drop, Cushing’s syndrome is suspected.

    The LDDST may not show a drop in cortisol levels in people with depression, alcoholism, high estrogen levels, acute illness, or stress, falsely indicating Cushing’s syndrome. On the other hand, drugs such as phenytoin and phenobarbital may cause cortisol levels to drop, falsely indicating that Cushing’s is not present in people who actually have the syndrome. For this reason, physicians usually advise their patients to stop taking these drugs at least 1 week before the test.

  • Dexamethasone-corticotropin-releasing hormone (CRH) test. Some people have high cortisol levels but do not develop the progressive effects of Cushing’s syndrome, such as muscle weakness, fractures, and thinning of the skin. These people may have pseudo-Cushing’s syndrome, a condition sometimes found in people who have depression or anxiety disorders, drink excess alcohol, have poorly controlled diabetes, or are severely obese. Pseudo-Cushing’s does not have the same long-term effects on health as Cushing’s syndrome and does not require treatment directed at the endocrine glands.

    The dexamethasone-CRH test rapidly distinguishes pseudo-Cushing’s from mild cases of Cushing’s. This test combines the LDDST and a CRH stimulation test. In the CRH stimulation test, an injection of CRH causes the pituitary to secrete ACTH. Pretreatment with dexamethasone prevents CRH from causing an increase in cortisol in people with pseudo-Cushing’s. Elevations of cortisol during this test suggest Cushing’s syndrome.

Tests to Find the Cause of Cushing’s Syndrome

Once Cushing’s syndrome has been diagnosed, other tests are used to find the exact location of the abnormality that leads to excess cortisol production. The choice of test depends, in part, on the preference of the endocrinologist or the center where the test is performed.

  • CRH stimulation test. The CRH test, without pretreatment with dexamethasone, helps separate people with pituitary adenomas from those with ectopic ACTH syndrome or adrenal tumors. As a result of the CRH injection, people with pituitary adenomas usually experience a rise in blood levels of ACTH and cortisol because CRH acts directly on the pituitary. This response is rarely seen in people with ectopic ACTH syndrome and practically never in those with adrenal tumors.

  • high-dose dexamethasone suppression test (HDDST). The HDDST is the same as the LDDST, except it uses higher doses of dexamethasone. This test helps separate people with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. High doses of dexamethasone usually suppress cortisol levels in people with pituitary adenomas but not in those with ectopic ACTH-producing tumors.

  • Radiologic imaging: direct visualization of the endocrine glands. Imaging tests reveal the size and shape of the pituitary and adrenal glands and help determine if a tumor is present. The most common imaging tests are the computerized tomography (CT) scan and magnetic resonance imaging (MRI). A CT scan produces a series of x-ray pictures giving a cross-sectional image of a body part. MRI also produces images of internal organs but without exposing patients to ionizing radiation.

    Imaging procedures are used to find a tumor after a diagnosis has been made. Imaging is not used to make the diagnosis of Cushing’s syndrome because benign tumors are commonly found in the pituitary and adrenal glands. These tumors, sometimes called incidentalomas, do not produce hormones in quantities that are harmful. They are not removed unless blood tests show they are a cause of symptoms or they are unusually large. Conversely, pituitary tumors may not be detectable by imaging in almost half of people who ultimately need pituitary surgery for Cushing’s syndrome.

  • Petrosal sinus sampling. This test is not always required, but in many cases, it is the best way to distinguish pituitary from ectopic causes of Cushing’s syndrome. Samples of blood are drawn from the petrosal sinuses—veins that drain the pituitary—by inserting tiny tubes through a vein in the upper thigh or groin region. A local anesthetic and mild sedation are given, and x rays are taken to confirm the correct position of the tubes. Often CRH, the hormone that causes the pituitary to release ACTH, is given during this test to improve diagnostic accuracy.

    Levels of ACTH in the petrosal sinuses are measured and compared with ACTH levels in a forearm vein. Higher levels of ACTH in the sinuses than in the forearm vein indicate a pituitary adenoma. Similar levels of ACTH in the petrosal sinuses and the forearm suggest ectopic ACTH syndrome.


How is Cushing’s syndrome treated?

Treatment depends on the specific reason for excess cortisol and may include surgery, radiation, chemotherapy, or the use of cortisol-inhibiting drugs. If the cause is long-term use of glucocorticoid hormones to treat another disorder, the doctor will gradually reduce the dosage to the lowest dose adequate for control of that disorder. Once control is established, the daily dose of glucocorticoid hormones may be doubled and given on alternate days to lessen side effects. In some cases, noncorticosteroid drugs can be prescribed.

Pituitary Adenomas

Several therapies are available to treat the ACTH-secreting pituitary adenomas of Cushing’s disease. The most widely used treatment is surgical removal of the tumor, known as transsphenoidal adenomectomy. Using a special microscope and fine instruments, the surgeon approaches the pituitary gland through a nostril or an opening made below the upper lip. Because this procedure is extremely delicate, patients are often referred to centers specializing in this type of surgery. The success, or cure, rate of this procedure is more than 80 percent when performed by a surgeon with extensive experience. If surgery fails or only produces a temporary cure, surgery can be repeated, often with good results.

After curative pituitary surgery, the production of ACTH drops two levels below normal. This drop is natural and temporary, and patients are given a synthetic form of cortisol such as hydrocortisone or prednisone to compensate. Most people can stop this replacement therapy in less than 1 or 2 years, but some must be on it for life.

If transsphenoidal surgery fails or a patient is not a suitable candidate for surgery, radiation therapy is another possible treatment. Radiation to the pituitary gland is given over a 6-week period, with improvement occurring in 40 to 50 percent of adults and up to 85 percent of children. Another technique, called stereotactic radiosurgery or gamma knife radiation, can be given in a single high-dose treatment. It may take several months or years before people feel better from radiation treatment alone. Combining radiation with cortisol-inhibiting drugs can help speed recovery.

Drugs used alone or in combination to control the production of excess cortisol are ketoconazole, mitotane, aminoglutethimide, and metyrapone. Each drug has its own side effects that doctors consider when prescribing medical therapy for individual patients.

Ectopic ACTH Syndrome

To cure the overproduction of cortisol caused by ectopic ACTH syndrome, all of the cancerous tissue that is secreting ACTH must be eliminated. The choice of cancer treatment—surgery, radiation, chemotherapy, immunotherapy, or a combination of these treatments—depends on the type of cancer and how far it has spread. Because ACTH-secreting tumors may be small or widespread at the time of diagnosis, making them difficult to locate and treat directly, cortisol-inhibiting drugs are an important part of treatment. In some cases, if other treatments fail, surgical removal of the adrenal glands, called bilateral adrenalectomy, may replace drug therapy.

Adrenal Tumors

Surgery is the mainstay of treatment for benign and cancerous tumors of the adrenal glands. Primary pigmented micronodular adrenal disease and the inherited Carney complex—primary tumors of the heart that can lead to endocrine overactivity and Cushing’s syndrome—require surgical removal of the adrenal glands.


Points to Remember
  • Cushing’s syndrome is a disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol.

  • Typical signs and symptoms of Cushing’s syndrome include upper body obesity, a rounded face, skin that bruises easily and heals poorly, weakened bones, excess body hair growth and menstrual irregularities in women, and decreased fertility in men.

  • Cushing’s syndrome is caused by exposure to glucocorticoids, which are used to treat inflammatory diseases, or by the body’s overproduction of cortisol, most often due to tumors of the pituitary gland or lung.

  • Several tests are usually needed to diagnosis Cushing’s syndrome, including urine, blood, and saliva tests. Other tests help find the cause of the syndrome.

  • Treatment depends on the specific reason for excess cortisol and may include surgery, radiation, chemotherapy, or the use of cortisol-inhibiting drugs.


Hope through Research

Several components of the National Institutes of Health (NIH) conduct and support research on Cushing’s syndrome and other disorders of the endocrine system, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Center for Research Resources.

NIH-supported scientists are conducting intensive research into the normal and abnormal function of the major endocrine glands and the many hormones of the endocrine system. Researchers continue to study the effects of excess cortisol, including its effect on brain structure and function. To refine the diagnostic process, studies are under way to assess the accuracy of existing screening tests and the effectiveness of new imaging techniques to evaluate patients with ectopic ACTH syndrome. Researchers are also investigating jugular vein sampling as a less invasive alternative to petrosal sinus sampling. Research into treatment options includes study of a new drug to treat the symptoms of Cushing’s syndrome caused by ectopic ACTH secretion.

Studies are under way to understand the causes of benign endocrine tumor formation, such as those that cause most cases of Cushing’s syndrome. In a few pituitary adenomas, specific gene defects have been identified and may provide important clues to understanding tumor formation. Endocrine factors may also play a role. Increasing evidence suggests that tumor formation is a multistep process. Understanding the basis of Cushing’s syndrome will yield new approaches to therapy.

The NIH supports research related to Cushing’s syndrome at medical centers throughout the United States. Scientists are also treating patients with Cushing’s syndrome at the NIH Clinical Center in Bethesda, MD. Physicians who are interested in referring an adult patient may contact Lynnette Nieman, M.D., at NICHD, 10 Center Drive, Room 1–3140, Bethesda, MD 20892–1109, or by phone at 301–496–8935. Physicians interested in referring a child or adolescent may contact Constantine Stratakis, M.D., D.Sc., at NICHD, 10 Center Drive, Room 1–3330, Bethesda, MD 20892–1103, or by phone at 301–402–1998.


For More Information

The following articles about Cushing’s syndrome can be found in medical libraries, some college and university libraries, and through interlibrary loan in most public libraries.

Labeur M, Arzt E, Stalla GK, Páez-Pereda M. New perspectives in the treatment of Cushing’s syndrome. Current Drug Targets—Immune, Endocrine & Metabolic Disorders. 2004;4:335–342.

Lin D, Loughlin K. Diagnosis and management of surgical adrenal diseases. Urology. 2005;66:476–483.

Newell-Price J, Bertagna X, Grossman A, Nieman L. Cushing’s syndrome. The Lancet. 2006;367:1605–1617.

Nieman L, Ilias I. Evaluation and treatment of Cushing’s syndrome. The American Journal of Medicine. 2005;118:1340–1346.

The following organizations may also be able to assist with certain types of information:

American Association of Neurological Surgeons
5550 Meadowbrook Drive
Rolling Meadows, IL 60008
Phone: 1–888–566–AANS (2267) or 847–378–0500
Email: info@AANS.org
Internet: www.NeurosurgeryToday.org
To locate a board-certified neurosurgeon: www.neurosurgerytoday.org/findaneuro

Pituitary Network Association
P.O. Box 1958
Thousand Oaks, CA 91358
Phone: 805–499–9973
Fax: 805–480–0633
Email: PNA@pituitary.org
Internet: www.pituitary.org

The National Endocrine and Metabolic Diseases Information Service collects resource information about endocrine and metabolic diseases for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Reference Collection. This database provides titles, abstracts, and availability information for health information and health education resources. The NIDDK Reference Collection is a service of the National Institutes of Health.

You may view the results of the automatic search on Cushing’s syndrome.

If you wish to perform your own search of the database, you may access and search the NIDDK Reference Collection database online.

This publication may contain information about medications used to treat a health condition. When this publication was prepared, the NIDDK included the most current information available. Occasionally, new information about medication is released. For updates or for questions about any medications, please contact the U.S. Food and Drug Administration at 1–888–INFO–FDA (463–6332), a toll-free call, or visit their website at www.fda.gov. Consult your doctor for more information.


The National Endocrine and Metabolic Diseases Information Service

6 Information Way
Bethesda, MD 20892–3569
Phone: 1–888–828–0904
TTY: 1–866–569–1162
Fax: 1–703–738–4929
Email: endoandmeta@info.niddk.nih.gov
Internet: http://endocrine.niddk.nih.gov/

The National Endocrine and Metabolic Diseases Information Service is an information dissemination service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health, which is part of the U.S. Department of Health and Human Services.

The NIDDK conducts and supports biomedical research. As a public service the NIDDK has established information services to increase knowledge and understanding about health and disease among patients, health professionals and the public.

Publications produced by the NIDDK are carefully reviewed by both NIDDK scientists and outside experts. This publication was reviewed by George Chrousos, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

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NIH Publication No. 08–3007
July 2008