Aggressive Cushing's

I have been so sick for the 75 days with adrenal insufficiency. As a result, I have been unable to determine the right ketoconazole dose at 8 pm and 10 pm or stabilize my Cortef/ hydrocortisone replacement at 8 am. Only in the last few days have I even thought of looking to the medical journals for more knowledge. Today, I share this full article (pdf).

Journal of Oncololgy. 2012; 2012: 685213.

Published online 2012 August 9.

Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

Carlotta Pozza, Chiara Graziadio, Elisa Giannetta, Andrea Lenzi, and Andrea M. Isidori^*

Abstract

Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone "RU-486"). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ"PPAR-γ" ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.

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Articles from Journal of Oncology are provided here courtesy of Hindawi Publishing Corporation

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425913/pdf/JO2012-685213.pdf

Cushies can die after exhausting all treatment options

This makes me incredibly sad.  I have had two unsuccessful pituitary surgeries, and I am currently doing medication therapy (pm ketoconazole with am Cortef) until the tumor culprit comes out of hiding and presents itself on the pituitary MRI for a third pituitary surgery.  No one knows how long that will take.

After my first pituitary surgery, I developed ptosis, or drooping eyelid.

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Cushing’s: the worst case scenario

Viv Thornton-Jones

Churchill Hospital, Oxford, UK.
Endocrine Abstracts (2008) 15 S58

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We present the case of a 40-year-old female who was referred to our Department in 1993, for further management following the diagnosis of Cushing’s disease. She proceeded to a transsphenoidal adenenomatectomy (TSA, note: pituitary surgery) which resulted in a biochemical cure.

In 1998 she presented with recurrence of Cushing’s Disease, which was managed by a 2nd TSA (pituitary surgery) followed by external beam irradiation.

Bilateral adrenalectomy followed a year later, due to the inability to control her disease.

In 2001 she presented with Nelson’s Syndrome managed by a 3rd TSA (pituitary surgery) followed this time with Gamma Knife surgery.

In 2004 she presented with manifestations consistent with recurrence of Nelson’s Syndrome and proceeded to a 4th TSA (pituitary surgery). 

Despite the risk of blindness, the patient agreed to a second course of Gamma Knife treatment for the possibility of tumour control.

Over the next 2 years her clinical picture deteriorated, resulting in a right partial ptosis and a sixth nerve palsy.

She was referred to an Oncologist who offered her Chemotherapy, but she refused treatment.

The patient was then in the care of the Palliative Care Team and she died peacefully at home in 2006.

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Endocrine Abstracts (2008) 15 S58

Thank you to Ami and MaryO for finding this abstract.

Europe Continues to Lead Research on Cyclical Cushing's

It is my strong belief that European endocrinologists and research will pave the way for cyclical patients in the United States, who continue to struggle.

Don't believe me?

Well, I point you to many articles that consistently come out of Ireland, Italy, Germany, France, England, Serbia, Spain, and others I can't remember now. When I get a chance, I'll try to post a link with all of these articles in one place. Until then, please, I beg you. Trust me on this.

I have read many articles on cyclical Cushing's -- after searching high and low for them. These articles come primarily from our European friends. 

Common knowledge about cyclical Cushing's must be racing around the continent on those bullet trains (which I adore, by the way!).

A Comparison of the Use of Urinary Cortisol to Creatinine Ratios and Nocturnal Salivary Cortisol in the Evaluation of Cyclicity in Patients with Cushing's Syndrome Authors 1.    U. M. Graham, 2.    S. J. Hunter, 3.    M. McDonnell, 4.    K. R. Mullan and 5.    A. B. Atkinson 1.   Regional Centre for Endocrinology and Diabetes (U.M.G., S.J.H., K.R.M., A.B.A.) and Regional Endocrine Laboratory (M.McD.), Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom 1.    Address all correspondence and requests for reprints to: Dr. Una Graham, Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, United Kingdom. E-mail: qublbc8@hotmail.com. Abstract Context: Cyclical Cushing's syndrome is detected in our center by collecting sequential early morning urine (EMU)* samples for cortisol to creatinine ratio over 28 d. The Endocrine Society suggests that nocturnal salivary cortisol (NSC)* may be used to assess patients for cyclical Cushing's. However, there is only very limited evidence that it correlates with early morning urine testing or that it demonstrates cycling over 28 d. Objective: We sought to correlate nocturnal salivary cortisol with early morning urine results collected the following morning and to determine whether nocturnal salivary cortisol could be used to detect cyclical Cushing's. Design and Setting: An observation study of 28-d collections for nocturnal salivary cortisol and early morning urine was performed in a tertiary referral center over 1 yr. Patients: A 28-d collection of nocturnal salivary cortisol and early morning urine was performed in 10 patients with confirmed or suspected Cushing's syndrome. Main Outcome Measure: The main outcome of the study was the correlation of salivary and urinary cortisol with graphical assessment of results for cycling. Results: Eleven collections were performed. One patient with cyclical Cushing's completed the collection before and after cabergoline therapy. Two hundred seventy matched salivary and urinary results were correlated (r = 0.79; P < 0.001). In two patients with cyclical Cushing's, early morning urine and nocturnal salivary cortisol followed a similar cyclical pattern. In one patient with recurrent cyclical Cushing's, cortisol was elevated in both saliva and urine but with more prominent cycles in saliva. Conclusion: Nocturnal salivary cortisol correlated well with early morning urine (EMU). Nocturnal salivary cortisol detected all cases of cyclical Cushing's. Therefore, nocturnal salivary cortisol may prove to be an additional option or replacement for early morning urine in detecting cyclical Cushing's syndrome.

* For ease of reading, blogger changed all EMU to early morning urines and all NSC to nocturnal salivary cortisol. A Cushie brain is far too foggy to keep even these simple conventions straight even when reading a brief article. 

Dogs and Cortisol

Any person researching Cushing's is sure to come encounter as many articles about dogs as humans. Horses and cats get Cushing's as well. Wanna know which doctors seem to be the most compassionate and know the most about Cushing's? Veterinarians.

This morning, as cortisol woke me as it often does at 3:45 am on the dot, I was reading news online on my beloved and ever-present companion, my iPhone.

Fiona Apple cancels tour, citing dying dog: Read her handwritten note | The Music Mix Mobile | EW.com

http://music-mix.ew.com/2012/11/20/fiona-apple-cancels-tour-dog/

Fiona explains her dog has Addison's, a disease that plagues the patient with low cortisol (while Cushing's does it with high cortisol). She mentions her dog needing shots to keep her alive. Might this be the same Solu-cortef doses that we Cushing's patients need when we face secondary adrenal insufficiency, even years after pituitary surgery?

I admire Fiona Apple's love, compassion, and courage for her 14-year old "pacifist" rescue dog. While her music has never found its way to my speakers in the past, I will be sure that it soon will.  

Fiona, my thoughts are with you and your lovely canine friend at this time.

This Week, Give Thanks

ORIGINAL ARTICLE

Metabolic and cardiovascular outcomes in patients with Cushing's syndrome of different aetiologies during active disease and 1 year after remission

1. Roberta Giordano¹, 
2. Andreea Picu², 
3. Elisa Marinazzo², 
4. Valentina D'Angelo², 
5. Rita Berardelli², 
6. Ioannis Karamouzis², 
7. Daniela Forno¹, 
8. Domenico Zinnà², 
9. Mauro Maccario²,
10. Ezio Ghigo², 
11. Emanuela Arvat²

Article first published online: 5 AUG 2011

DOI: 10.1111/j.1365-2265.2011.04055.x

© 2011 Blackwell Publishing Ltd

Issue

Clinical Endocrinology

Volume 75, Issue 3, pages 354–360, September 2011

Summary

Objective  Cushing's syndrome is associated with several comorbidities responsible for the increased cardiovascular risk, not only during the active phase but also after disease remission.

Design  In 29 patients with Cushing's syndrome (14 Cushing's diseases and 15 adrenal adenomas), waist circumference, fasting and 2-h glucose after oral glucose tolerance test (OGTT), lipid profile and blood pressure were evaluated during the active disease and 1 year after remission and compared with those in 29 sex-, age- and BMI-matched controls.

Results  During the active disease, waist circumference, 2-h glucose after OGTT, total and LDL cholesterol were higher in patients with Cushing's syndrome than in controls (P < 0·001) but similar in Cushing's disease and adrenal adenomas. The prevalence of impaired glucose tolerance (IGT), diabetes mellitus, dyslipidaemia and hypertension was higher (P < 0·001) in patients with Cushing's syndrome (27%, 24%, 59% and 72%) than in controls (10%, 0%, 21% and 10%), with no significant difference between Cushing's disease and adrenal adenomas. One year following hormonal remission, waist circumference persisted higher than in controls (P < 0·05) in both Cushing's disease and adrenal adenomas. Metabolic and cardiovascular abnormalities were still present in both groups, although with a lower prevalence, as well as with a more marked decrease in adrenal adenomas (P < 0·05 vs active disease for IGT, dyslipidaemia and hypertension).

Conclusions  These results show that chronic hypercortisolism, independently of its aetiology, contributes to metabolic impairment and increased cardiovascular risk, while these abnormalities mostly persist in patients with previous Cushing's disease after hormonal remission. Pituitary hormonal deficiencies, hormonal replacement treatments and/or incomplete cure from Cushing's disease may account for these findings.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2011.04055.x/abstract;jsessionid=8826EEB2529F32D58CA4EABCCE3A75E6.d02t03

Insurance Questions Loom Over Cushing's Patients

Facing brain surgery, a health economist finds the health-care market hard to navigate

A health economist learns the hard way that picking the right insurance plan isn't easy at all.

By Dahlia K. Remler,  Published: NOVEMBER 05, 11:32 AM ET

"Who, when sick and scared, would be equipped to make wrenching decisions that interweave financial, technical, health and emotional threads?"


http://m.washingtonpost.com/national/health-science/facing-brain-surgery-a-health-economist-finds-the-health-care-market-hard-to-navigate/2012/11/05/0a931b5c-fcf1-11e1-b153-218509a954e1_story.html

PS  Thank you Dahlia for writing this article. These insurance decision trees are quite common and plague me and fellow Cushies for months and months as we find the most fitting juxtaposition between out-of-pocket cost and neurosurgeon skill/ chance for a better life and cure. 

Adrenal Crisis: The Danger That Looms over the Cushie's Head

Well, isn’t this what we patients have been trying to get folks to do for many moons.

The editorial concludes "listening to a well informed patient in adrenal crisis who says that he or she need steroids and taking urgent action will avoid unnecessary deaths from this eminently treatable medical problem."

How to avoid precipitating an acute adrenal crisis
     

Reference: BMJ 2012; 345: e6333

Source: British Medical Journal

Date published: 09/11/2012 16:53

Summary

by: Yuet Wan

An editorial in the BMJ highlights the risks of failing to recognize the need for hydrocortisone in patients at risk of adrenocortical insufficiency (adrenal or addisonian crisis).

The authors note that all too often, healthcare workers do not realize the urgency of treatment for acute adrenal crisis or fail to heed the requests of well informed patients for hydrocortisone. They reiterate that patients with adrenal insufficiency are at risk of developing life threatening adrenal crisis if steroids are reduced or stopped, or if glucocorticoid treatment is not increased during periods of increased stress.

In this article, they describe the situations in which acute adrenal crisis can occur, features of acute adrenal crisis, its treatment, and cite examples where patients with Addison's disease who present unwell to healthcare services have their requests for hydrocortisone administration turned down or delayed. The authors question why there is such mismanagement? They draw attention to guidelines for the perioperative management of such patients on the websites of the Society for Endocrinology (www.endocrinology.org/), the Addison's Disease Self Help Group (www.addisons.org.uk/) and the Pituitary Foundation (www.pituitary.org.uk/). In addition, the Addison's Disease Self Help Group can issue hospital stickers to be put on to drug charts to draw attention to a patient's steroid dependency.

The editorial concludes "listening to a well informed patient in adrenal crisis who says that he or she need steroids and taking urgent action will avoid unnecessary deaths from this eminently treatable medical problem."

Link to editorial

Letter in BMJ 2012; 345: e7436

http://www.nelm.nhs.uk/en/NeLM-Area/News/2012---November/09/BMJ-Editorial-How-to-avoid-precipitating-an-acute-adrenal-crisis/