HPA Axis: Accuracy of several parameters of hypothalamic–pituitary–adrenal axis activity in predicting before surgery the metabolic effects of the rem

European Journal of Endocrinology (2010) In press
DOI: 10.1530 / EJE-10-0602
Copyright © 2010 by European Society of Endocrinology

Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Claudia Battista, Massimo Torlontano, Francesca Coletti, Laura Iorio, Elisa Cairoli, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani and Iacopo Chiodini

C Eller-Vainicher, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
V Morelli, Milan, 20122, Italy
A Salcuni, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
C Battista, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
M Torlontano, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
F Coletti, Endocrinology Unit, Ospedale San Giuseppe Multimedica, Milan, Italy
L Iorio, Policlinico San Donato Institute, I.R.C.C.S.Depertment of Medical and Surgical Sciences, University of Milan, san Donato Milanese, Milan, Italy
E Cairoli, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
P Beck-Peccoz, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milan, Italy
M Arosio, University of Milan, Milan, Italy
B Ambrosi, Policlinico San Donato Institute, I.R.C.C.S.Depertment of Medical and Surgical Sciences, University of Milan, san Donato Milanese, Milan, Italy
A Scillitani, Endocrinology Unit, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
I Chiodini, Department of Medical Sciences, Endocrinology and Diabetology Unit, Fondazione Ospedale Maggiore Policlinico, I.R.C.C.S., Milano, 20123, Italy

Correspondence: Iacopo Chiodini, Email: iacopo.chiodini@email.it

Context: It is unknown if the metabolic effects of the removal of an adrenal incidentalomas (AI) can be predicted by the assessment of cortisol hypersecretion before surgery.

Objective: To evaluate the accuracy of several criteria of hypothalamic-pituitary-adrenal axis activity in predicting the metabolic outcome after adrenalectomy.

Design: Retrospective longitudinal study.

Patients: In 55 surgically-treated AI patients (Group 1) before surgery and in 53 non-treated AI patients (Group 2) at baseline, urinary free cortisol (UFC), cortisol after 1mg-overnight dexamethasone-suppression test (1mg-DST), ACTH and midnight serum cortisol (MSC) were measured. In Group 1 and 2, metabolic parameters were evaluated before and 29.6±13.8 months after surgery and at baseline and after 35.2±10.9 months, respectively.

Main Outcome Measures: The improvement/worsening of weight, blood pressure, glucose and cholesterol levels (endpoints) was defined in the presence of a >5% weight decrease/increase and following the European Society of Cardiology or the ATPIII criteria, respectively. The accuracy of UFC, 1mg-DST, ACTH and MSC, singularly taken or in combination, in predicting the improvement/worsening of ≥2 endpoints was calculated.

Results: The presence of ≥2 among UFC>70 µg/24h (193 nmol/L), ACTH<10>3.0 µg/dL (83 nmol/L) (UFC-ACTH-DST criterion) had the best accuracy in predicting the endpoints’ improvement (sensitivity 65.2%, specificity 68.8%) after surgery. In the non-treated AI patients, this criterion predicted the worsening of ≥2 endpoints (sensitivity 55.6%, specificity 82.9%).

Conclusions: The UFC-ACTH-DST criterion seems the best for predicting the metabolic outcome in surgically-treated AI patients.

From http://www.eje.org/cgi/content/abstract/EJE-10-0602v1

Gamma Knife Radiosurgery Is Effective in Improving Remission Rates in Patients With Cushing's Disease

By Ann Saul

LIEGE, Belgium -- September 26, 2010 -- Leksell gamma knife radiosurgery is effective for the treatment of Cushing's disease, researchers said here on September 22 at the 14th Congress of the European Neuroendocrine Association (ENEA).

Typical first-line treatment for Cushing's disease is usually transsphenoidal surgery, and the rate of remission following the initial surgery is between 70% to 90% in patients with microadenomas and 50% to 60% in patients with macroadenomas.

However, recurrence of the disease happened in approximately 10% to 30% of patients. In those cases, one of the treatment options is stereotactic radiosurgery with Leksell gamma knife (LGK).

"Leksell gamma knife is an integral part of the treatment approach in Cushing's disease," said Jana Jezkova, MD, Department of Medicine, First Medical Faculty, Charles University, Prague, Czech Republic. "LGK irradiation is used as a secondary treatment after surgery when a hormonally active residue is found or as a primary treatment in situations where surgery is contraindicated or is refused by the patient."

This study included 27 patients (24 females, 3 males) aged 16 to 65 years. They were followed for a mean period of 80.9 months (range, 24-168 months). Seventeen of the patients (63%) had previous neurosurgery, but none of them had conventional radiotherapy prior to LGK irradiation.

The target tumour volume for radiosurgery was between 13.4 to 2,700 mm³ with an average dose of 639.5 mm³ (median, 232 mm³). The central radiation dose range was 50 to 80 Gy, with an average dose of 68.3 Gy (media, 70 Gy). The minimal peripheral dose was 25 to 49 Gy, with an average dose of 37.2 Gy (median, 35 Gy). The dose for surrounding structures was 8 Gy for the edge of chiasma opticum and 14 Gy for the brainstem. The mean dose to the pituitary was 15 Gy.

Pituitary function was monitored at 6-month intervals post irradiation. The 3 criteria for hormonal normalisation included normalisation of 24-hour free urinary cortisol, suppressibility of plasma cortisol after an overnight dexamethasone (1 mg), and restitution of circadian variability of plasma cortisol levels.
At 1 year following treatment, 27 patients (25.9%) had achieved hormonal normalisation. After 3 years, 25 patients (36%) had achieved normalisation. Hormonal normalisation was achieved 5 years after LGK irradiation in 18 patients (66.7%) and 8 years later in 8 patients (75%).

The irradiation arrested the growth of all adenomas and caused the tumour to shrink in the majority of cases.

After 1 to 2 years, there was no change in 17.4% of tumours, a decrease in adenoma size in 69.7%, and disappearance of the adenoma in 13.0%. After 3 to 5 years, there was no change in only 13.3% of patients, 73.4% of adenomas had decreased, and 13.3% of adenomas had disappeared.

Three (11.1%) of the patients developed hypopituitarism within 12 to 72 months after LGK irradiation. However, hypopituitarism did not develop in patients who were irradiated with a mean dose to the pituitary of <15 Gy.

Until the effect of the irradiation is evident and the hormonal production halted, levels of excess hormones have to be suppressed pharmacologically. Keeping the mean radiation dose to the pituitary gland <15 Gy prevents the development of hypopituitarism, the researchers said.

[Presentation title: Gamma Knife Radiosurgery for Cushing's Disease. Abstract PC-118]

From http://www.docguide.com/news/content.nsf/news/852576140048867C852577AA0069717A?OpenDocument&id=48DDE4A73E09A969852568880078C249&c=Pituitary&count=10

Promising Phase III results of pasireotide, a new therapy for Cushing’s disease

Novartis’ pasireotide effective in Cushing’s disease trial

The Swiss pharmaceutical company Novartis reported the results of a Phase III study of an experimental therapy pasireotide, also known as SOM230, which showed reduced cortisol levels in patients with Cushing’s disease. Pasireotide is first medical therapy to show efficacy in a Phase III trial in Cushing’s disease. Detailed results will be presented at the 14th Congress of the European Neuroendocrine Association (ENEA).

As the largest clinical trial in Cushing’s disease, PASPORT-CUSHINGS study was conducted at 68 sites in 18 countries involving 162 patients with persistent or recurrent Cushing’s disease, and in patients with newly diagnosed Cushing’s disease who are not suitable for surgery. The goals of the phase III trial are to evaluate the efficacy and safety of the experimental drug pasireotide.

The study showed that the majority of evaluable patients (91/103) experienced a reduction from baseline in urinary free cortisol (UFC) levels at six months. The UFC levels, which are major biomarkers of biochemical control of the disease, were reduced to normal in 26% of patients randomized to pasireotide 900ug twice daily, meeting the primary endpoint of the study. Additionally, median UFC was reduced by 48% in both the 900ug and 600ug dose groups. After 12 months of treatment, results confirmed the durability of the effect. On average, as UFC levels were reduced, clinical symptoms of Cushing’s disease improved including reduction of blood pressure, total cholesterol, weight and body mass index (BMI).

The trial results gave Novartis’ development pipeline another boost, only a few days after the approval of its potential blockbuster drug Gilenya by FDA. The company said the trial will be basis for first regulatory filing planned by year end.

Cushing’s disease is caused by a benign tumor in the pituitary gland that secretes adrenocorticotropic hormone (ACTH), which triggers the adrenal glands to produce excess cortisol. Cushing’s disease can cause severe cardiovascular and metabolic-related illnesses or death. There are currently no approved medicines to treat Cushing’s disease.

“There is a critical need for a medical treatment for people with Cushing’s disease because currently available options, such as surgery or radiotherapy, are ultimately not effective for many of the patients who suffer from this debilitating disease,” said William H. Ludlam, MD, PhD, Director, Seattle Pituitary Center at the Swedish Neuroscience Institute in Seattle, WA. “The results of this study suggest that pasireotide may help patients achieve biochemical control of their Cushing’s disease and its symptoms by directly targeting the pituitary tumor that triggers excess cortisol production.”

Pasireotide is a metabolically stable cyclohexapeptide, which targets multiple subtypes of the receptor for somatostatin. Its highest affinity is to sst5, a receptor subtype frequently expressed by the pituitary tumors associated with Cushing’s disease. Pasireotide was assigned orphan drug designation for Cushing’s disease in Europe and the US.

From http://pharminfo.co.cc/2010/09/promising-phase-iii-results-of-pasireotide-a-new-therapy-for-cushings-disease/

ENEA 2010: Potential new options for the treatment of Cushing's disease: the dawn of a new era?

24/09/2010
Posted by Jo Armstrong, ecancer

Beverly Biller, Massachusetts General Hospital, USA

The goal of treatment of Cushing's disease is to normalise cortisol levels. However, current treatment options are limited and are associated with a variety of drug related adverse events and relapse. There are no approved medical therapies for Cushing's disease, and the efficacy of medical treatments that are used is limited, highlighting the unmet need in these patients.

Of great benefit would be a pituitary-directed medical treatment which targets the underlying cause of ACTH hypersecretion. There are a number of agents under investigation for the treatment of Cushing's disease, including pituitary targeted drugs and drugs targeting blockade of the glucocorticoid receptor.

Pasireotide, a new investigational drug with multi-serotonin subtype receptor affinity, is a pituitary targeted medical therapy that has been associated with rapid normalisation of UFC levels in a small number of patients in a Phase II study of patients with Cushing's disease. This has led to a Phase III, randomised, double-blind, multicentre study, the initial results of which were presented at ENEA 2010. This ongoing clinical trial is the largest study to evaluate a medical therapy in this patient population. After 6 months of treatment with pasireotide 600 or 900 µg sc bid, 14.6% and 26.3% of patients with moderate to severe hypercortisolism achieved UFC ≤ULN. At 12 months, 13.4% and 25.0% patients achieved UFC ≤ULN. Overall, there was a rapid and sustained improvement in clinical signs and symptoms from baseline, as well as improvements in patient health related quality of life. Around 50% of patients at ≥1.5 to <2 ULN achieved UFC ≤ULN with 900 at 6 months. In addition, systolic and diastolic blood pressure and weight improved in line with the decline in cortisol levels. Non-responding patients, based on UFC levels, were identified early after treatment initiation, which may be clinically useful for identifying patients inappropriate for this therapy.

With the exception of hyperglycaemia, the safety profile of pasireotide was similar to that of other somatostatin analogues. As expected with an active agent in Cushing's disease, some patients experienced symptoms of hypocortisolism, which was adequately managed in patients by decreasing the dose of pasireotide.

 

From http://www.ecancermedicalscience.com/blog.asp?postId=113

A new plastic model of endoscopic technique training for endonasal transsphenoidal pituitary surgery

CHEN Ge, LING Feng

CHEN Ge Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; LING Feng Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
Correspondence to: LING Feng  Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China  (Tel:86-10-83198836 Fax:86-10-83198836 Email:ling-feng@vip.163.com )

Keywords: anatomy·endoscopy·model·pituitary neoplasms·transsphenoidal approach

Abstract:

Background  Endoscopic transsphenoidal approach is a minimally invasive surgical technique for the removal of sellar and parasellar lesions, which has been progressively accepted by neurosurgeons. However, frustration is often expressed by neurosurgeons when first attempting endoscopic endonasal pituitary surgery. To overcome the learning curve from microscope to endoscope in a smooth way, a new human nasal model has been developed. The present study assessed this new model of the human paranasal sinuses for endonasal surgery training, particularly for endonasal pituitary surgery training.

Methods  The procedure for endonasal transsphenoidal endoscopy was performed using this model. Three approaches were used to observe the endonasal structures and sphenoidal sinus: paraseptal; middle turbinectomy; and middle meatal. Attempts were made to identify anatomical landmarks in the nasal cavity and sphenoidal sinus. Model landmarks were compared with those in a cadaver and a real patient.

Results  This model precisely reproduced nasal bone structure. Compared with cadavers and living bodies, intranasal structures displayed very good color and texture, providing a close facsimile of the operative environment, and good morphology, with similar hardness and tactile feel on resection. All intranasal anatomical landmarks were easily identified, including choanae, inferior, middle and superior turbinates, and even the natural ostium of the sphenoidal sinus.

Conclusion  This human nasal model is very useful for training neurosurgeons in endoscopic endonasal transsphenoidal pituitary surgery, but typical anatomical landmarks in the posterior wall of the sphenoidal sinus in this model should be improved.

2010;123(18):2576-2579

From http://www.cmj.org/Periodical/PaperList.asp?id=LW2010917610525406247

Management of Diabetes Mellitus in Cushing’s Syndrome

Free Abstract
Article (Fulltext)
Article (PDF 215 KB)

Novel Insights in the Management of Cushing's Syndrome.
Editor(s): Colao A. (Napoli), Gaillard R. (Lausanne)

Alia Munir, John Newell-Price
Academic Unit of Diabetes and Endocrinology, University of Sheffield, Sheffield, UK

Address of Corresponding Author

Neuroendocrinology 2010;92 (Suppl. 1):82-85 (DOI: 10.1159/000314316)

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Key Words

• Diabetes
• Metformin
• Cortisol
• Metyrapone
• Ketoconazole
• Insulin resistance

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Abstract

Active Cushing’s syndrome is associated with insulin resistance induced by the high and prolonged circulating level of glucocorticoids. In endogenous Cushing’s syndrome the overall incidence of diabetes mellitus and insulin resistance is very likely to be under-reported as not all patients are actively investigated with glucose tolerance tests. Whilst it is common clinical experience that management of diabetes mellitus is necessary in patients with Cushing’s syndrome there is a dearth of literature-based evidence to support which regimes are the most effective. Therefore, a pragmatic approach is necessary on an individualized patient basis, whereby patients are stratified according to the severity of their impaired glucose homeostasis. The most effective means of control of diabetes mellitus in a patient with active Cushing’s syndrome is to lower the levels of circulating cortisol. This may initially be achieved by using adrenal steroidogenesis blockade with drugs including metyrapone, ketaconazole, or, on occasion, mitotane. The rapid action of metyrapone is particularly suitable in this circumstance. Despite this, diabetes-specific therapy is often necessary and metformin and PPAR-γ agonists may be of use, but in the acute setting insulin therapy is frequently needed. Definitive management directed against source driving Cushing’s syndrome is often highly effective at either reducing the severity of diabetes, or allowing its complete resolution. Patients experiencing diabetes mellitus in the context of exogenously administered glucocorticoids may well require insulin therapy for the period that the high levels of steroids are being administered. Despite resolution of Cushing’s syndrome after definitive treatment patients may continue to exhibit insulin resistance. This and other cardiovascular risk factors require ongoing and long-term attention.

Copyright © 2010 S. Karger AG, Basel

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Author Contacts

J. Newell-Price
Academic Unit of Diabetes and Endocrinology, University of Sheffield
Room OU142, Floor O, Royal Hallamshire Hospital
Sheffield (UK)
Tel. +44 114 226 1409, Fax +44 114 271 1863, E-Mail j.newellprice@sheffield.ac.uk

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Article Information

Published online: September 10, 2010
Number of Print Pages : 4
Number of Figures : 2, Number of Tables : 1, Number of References : 10

From http://content.karger.com/ProdukteDB/produkte.asp?Doi=314316

Upcoming Event: Pituitary Day at Brigham & Women's Hospital

SAVE THE DATE
Saturday, November 13, 2010
A Workshop for Patients and Family Members on the East Coast!
Here is an opportunity you should not miss!

Pituitary Day
Brigham & Women’s Hospital
Saturday, November 13, 2010

The Brain Science Foundation, in collaboration with Shields MRI and the Brigham and Women’s Hospital Pituitary Neuroendocrine Center, is pleased to present Pituitary Day 2010.  This event will be held on Saturday, November 13, 2010 at the Brigham and Women’s Hospital Bornstein Amphitheater.

Pituitary Day is designed to provide information on the manifestations of pituitary disease which may lead to improvement in diagnosis and treatment.  Emphasis will also be placed on informing patients about their disease, and providing a forum for questions of experienced and knowledgeable faculty.

Longtime BSF Principal Investigator Edward R. Laws, Jr., MD has been a driving force in the California Pituitary Conference and the Pituitary Days Lecture Series for years, and he sought to bring the program to Boston so that more patients and their families could access this information.

Pituitary Day seeks to unite patients, caregivers, family and friends with leading clinicians, researchers, nurses and other experts to discuss the latest in pituitary diagnosis and treatment. By way of a series of presentations and panel discussions, participants will discuss basic and new information related to pituitary disorders, including physical and psychological aspects, and other important patient issues.

Scheduled presenters include: Edward R. Laws, MD, Steven Haley, Siobhan Shields Quinn, Zachary Litvack, MD, Ursula Kaiser, MD, Whitney Woodmansee, MD, Sherry Iuliano, NP, Valerie Golden, PhD, and Sashank Prasad, MD.

Tentative Agenda:
• Anatomy & Physiology of the Pituitary
• Clinical Aspects of Pituitary Tumors and Medical Management of Pituitary Tumors
• Hypopituitarism and Pituitary Replacement Medications
• Headaches Associated with Pituitary Tumors
• Surgical Management of Pituitary Disorders
• Panel: Clinical Trials and New Aspects of Management of Pituitary Disease
• Psychological Aspects of Pituitary Disease
• Effects of Pituitary Tumors on Vision Assessment and Outcomes
• Breakout Sessions: Hypopituitarism, Acromegaly, Cushings Disease, Prolactinoma
• Group Discussion: Psychological Challenges of Pituitary Disorders

For more information, go to http://www.brainsciencefoundation.org

The diagnosis of Cushing’s syndrome

Reviews in Endocrine & Metabolic Disorders

DOI: 10.1007/s11154-010-9143-3

Ty B. Carroll and James W. Findling

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Abstract

Spontaneous Cushing’s syndrome is well known but unusual clinical disorder. Many of the clinical features (central weight gain, glucose intolerance, hypertension, muscle weakness) are seen in other common conditions. Recognition of patients with multiple features, features unusual for their age (i.e. early onset osteoporosis or hypertension), patients with features more specific to Cushing’s syndrome (i.e. easy bruising, facial plethora, and violaceous striae), and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess. Late-night salivary cortisol, 1 mg overnight dexamethasone suppression testing, or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing’ syndrome. If this initial testing is abnormal, further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing’ syndrome.

Keywords  Cushing’s syndrome - Cushing’s disease - Diagnosis - Hypercortisolism

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From http://www.springerlink.com/content/k25125412307h623/

Comparison of three methods for the estimation of the pituitary gland volume using magnetic resonance imaging: a stereological study

Tolga Ertekin, Niyazi Acer, Ahmet T. Turgut, Kenan Aycan, Özlem Özçelik and Mehmet Turgut

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DOI: 10.1007 / s11102-010-0254-3

Abstract

Stereological techniques using point counting and planimetry have been used to estimate pituitary gland volume. However, many studies have estimated pituitary gland volume by the mathematical approach the elliptic formula. The objective of the current study was to determine pituitary gland volume using stereological methods and elliptic formula on magnetic resonance imaging (MRI). In this study, pituitary gland volumes were estimated in a total of 28 subjects (22 females, 6 males,) who were free of any pituitary or neurological symptoms and signs. The mean ± SD pituitary gland volumes for the point counting, planimetry and elliptic formulae groups were 582.14 ± 140.16 mm³, 610.08 ± 133.17 mm³, and 432.82 ± 147.38 mm³, respectively.

The mean CE for the pituitary gland volume estimates derived from the point counting technique was 8.07%. No significant difference was found between point counting and planimetric methods for the pituitary gland volume (P > 0.05). In addition, there was a 26.14 and 29.71% underestimation of pituitary volume as measured by the elliptic formula compared to the point counting and planimetric techniques, respectively. From these results, it can be concluded that stereological techniques are unbiased, efficient and reliable methods and are ideally suitable for in vivo examination of MRI data for pituitary gland volume estimation.

Hence, we suggest that estimating pituitary gland volume using MRI study and stereology may be clinically relevant for pituitary surgeons for the investigation of the structure and function of the pituitary gland.

Keywords Stereology - Planimetry - Pituitary gland volume - MRI

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From http://www.springerlink.com/content/m64g74183k31h8u7/

Overnight Dexamethasone Suppression Test in the Diagnosis of Cushing's Syndrome

Abstract- Realizing the cause of Cushing's Syndrome (CS) is one of the ... All of these tests had 100% specificity for the diagnosis of Cushing's disease.

Read the PDF at http://journals.tums.ac.ir/pdf/16196

Transient Schizophrenic Reaction as a Major Symptom of Cushing's Syndrome

Jack W. Hickman, M.D., Rosser P. Atkinson, M.D., Lloyd D. Flint, M.D., and Lewis M. Hurxthal, M.D.

N Engl J Med 1961; 264:797-800 April 20, 1961

This article has no abstract; the first 100 words appear below.

MENTAL symptoms, including nervousness, irritability, mild depression and paranoid tendencies, have long been known to be associated with Cushing's syndrome. The incidence varied from 20 to 67 per cent in four series described in reports dealing with this aspect of the disorder.1 2 3 The incidence of full-blown schizophrenia is much lower. Among 35 cases of Cushing's syndrome seen at the Lahey Clinic after the original description of the condition in 1932 up to 1958, 2 patients have had mental symptoms consistent with a diagnosis of schizophrenic reaction. The following is a report of the most recent case.

Case Report

A 35-year-old . . .

Source Information

BOSTON, MASSACHUSETTS

†Formerly, fellow in internal medicine, Lahey Clinic.

‡Member, Department of Neuropsychiatry, Lahey Clinic.

§Member, Department of Urology, Lahey Clinic.

¶Member, Department of Internal Medicine, Lahey Clinic.

Read this article at http://www.nejm.org/doi/pdf/10.1056/NEJM196104202641605