Cyclic Cushing’s syndrome: a clinical challenge

Posted on August 11, 2013 by MaryO
  1. J R Meinardi1,2,
  2. B H R Wolffenbuttel2 and
  3. R P F Dullaart2

+Author Affiliations


  1. 1Department of Internal Medicine, Canisius Wilhelmina Ziekenhuis, PO Box 9015, 6500 GS Nijmegen, The Netherlands and 2Department of Endocrinology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
  1. (Correspondence should be addressed to: R P F Dullaart; Email:r.p.f.dullaart@int.umcg.nl)

Abstract

Cyclic Cushing’s syndrome (CS) is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolism can occur regularly or irregularly with intercyclic phases ranging from days to years.

To formally diagnose cyclic CS, three peaks and two troughs of cortisol production should be demonstrated. Our review of 65 reported cases demonstrates that cyclic CS originates in 54% of cases from a pituitary corticotroph adenoma, in 26% from an ectopic ACTH-producing tumour and in about 11% from an adrenal tumour, the remainder being unclassified. The pathophysiology of cyclic CS is largely unknown.

The majority of patients with cyclic CS have clinical signs of CS, which can be either fluctuating or permanent. In a minority of patients, clinical signs of CS are absent. The fluctuating clinical picture and discrepant biochemical findings make cyclic CS extremely hard to diagnose. Clinicians should therefore be aware of this clinical entity and actively search for it in all patients with suspected CS but normal biochemistry or vice versa.

Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic CS. Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing. When cyclic CS is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency. In cases of suspected ectopic ACTH production, specific biochemical testing for carcinoids or neuroendocrine tumours is required, including measurements of serotonin in platelets and/or urine, chromogranin A and calcitonin.

Read the entire article here:  http://www.scribd.com/doc/159503297/Cyclic-Cushing%E2%80%99s-syndrome-a-clinical-challenge

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Prolactin Measure Didn’t Help Localize Pituitary Adenoma

Posted on August 10, 2013 by MaryO

By: SHERRY BOSCHERT, Clinical Endocrinology News Digital Network

SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.

The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.

Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.

A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).

The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.

At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.

MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.

Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.

“We did not find any difference in localization rates by measurement of prolactin during IPSS,” she said. The small size of the study and its retrospective design invite further research in a more robust study.

Dr. Sharma reported having no financial disclosures.

From Clinical Endocrinology News

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What is the Best Approach to Suspected Cyclical Cushing Syndrome?

Posted on August 2, 2013 by MaryO

Strategies for Managing Cushing’s Syndrome With Variable Laboratory Data

Brew Atkinson, Karen R. Mullan

Disclosures

Clin Endocrinol. 2011;75(1):27-30.

 

Abstract

Cyclical Cushing’s syndrome is a pattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This syndrome is often associated with fluctuating symptoms and signs. It is now being increasingly recognized. The phenomenon is important because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. The techniques and criteria, protocols and dynamic biochemical tools to detect cycling in patients with hypercortisolism are discussed as are the strategies for diagnosing and managing this important subgroup of patients with hypercortisolism.

Introduction

Cyclical Cushing’s syndrome (CS) is a pattern in hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This can also be associated with fluctuating symptoms and signs. This type of case was initially thought to be rare. However, it has recently been recognized as occurring much more frequently. The phenomenon is important because, if not recognized, it can lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. All of these can have very serious clinical consequences.

As a result of reading this article, it is hoped that readers will be better able to consider more carefully the risks associated with too wide a diagnostic trawl for the diagnosis of CS and the associated chances of finding some abnormality of steroid biochemistry.

In cases where the diagnosis is being strongly considered, the risks of not considering episodic secretion when laboratory results are discordant are discussed. Readers should be able to plan strategies to assess for variable and cyclical secretion and to use these in diagnosis, differential diagnosis and treatment assessments.

Read more here: What is the best approach to suspected cyclical Cushing syndrome?

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Long-term mifepristone associated with endometrial thickening, bleeding

Posted on August 2, 2013 by MaryO

SAN FRANCISCO – Long-term mifepristone therapy for Cushing’s syndrome was associated with endometrial thickening, with some women showing histologic changes consistent with progesterone receptor modulator–associated endometrial changes, in two studies of a total of 35 patients.

The women received 300-1,200 mg/day of mifepristone in the 24-week open-label Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) and in an extension of the study in 18 patients who continued for a median of 27 months (range, 14-43 months).

Mifeprex is used, with misoprostol, to end an early pregnancy (within 49 days of the start of a woman’s last menstrual period), according to the Food and Drug Administration’s website. The treatment of Cushing’s syndrome is an off-label use.

Transvaginal ultrasounds in 26 women at baseline and 27 women after the start of the study showed that mifepristone use was associated with endometrial thickening, especially in premenopausal women. The endometrium thickened by more than 5 mm in 8 of 26 premenopausal women (31%) and in two of nine postmenopausal women (22%), with thickening of more than 10 mm in 4 premenopausal women (15%) and one postmenopausal woman (11%), Dr. Ty Carroll reported.

Four (22%) of the 18 women in the extension study who’d been on mifepristone for 14 or more weeks and who had endometrial thickening greater than 20 mm developed clinically relevant endometrial bleeding and underwent hysterectomy (three patients) or dilation and curettage. The endometrial thickening ranged from 25 to 55 mm in these women, who remained on mifepristone therapy throughout the studies, Dr. Carroll and his associates reported in a featured poster presentation at the annual meeting of the Endocrine Society.

“Gynecologic consultation may be required in patients with persistent endometrial bleeding,” said Dr. Carroll of the Medical College of Wisconsin, Milwaukee.

Vaginal bleeding of any kind occurred in 10 premenopausal women (38.5%) and two postmenopausal patients (7%). Three premenopausal women reported minor bleeding upon starting mifepristone, and one premenopausal woman reported minor bleeding after stopping mifepristone. Two premenopausal and two postmenopausal women reported intermittent, self-limited spotting or bleeding during treatment.

Bleeding did not always occur following endometrial thickening. Three patients with endometrial thickening greater than 20 mm after 6 months reported no bleeding.

Mifepristone use was not associated with precancerous endometrial lesions. In 33 endometrial biopsies obtained from 15 patients (11 premenopausal and 4 postmenopausal women), 31 biopsies (94%) had benign histology with variable findings of inactive, atrophic, disordered, or mixed-pattern endometrium, and 18 biopsies (56%) showed findings of progesterone receptor modulator–associated endometrial changes. Simple hyperplasia in one patient could not be confirmed on a repeat biopsy, and complex atypical endometrial hyperplasia in a second patient was thought to have existed prior to the study, Dr. Carroll reported. No patients showed evidence of endometrial carcinoma.

Previous studies have reported progesterone receptor modulator–associated endometrial changes from the use of mifepristone, a competitive progesterone receptor antagonist, in doses of 5-200 mg/day that are not associated with glucocorticoid receptor antagonism.

In the current study, median endometrial thickness for the premenopausal women was 5 mm at baseline and 11 mm at 6 months, and for postmenopausal women, was 3 mm at baseline and 6.4 mm at 6 months. The gain was statistically significant for premenopausal but not postmenopausal women. Endometrial thickness continued to increase in the extension study.

The SEISMIC study included adult females with endogenous Cushing’s syndrome and type 2 diabetes or impaired glucose function and/or hypertension. It excluded premenopausal women with an endometrial thickness greater than 20 mm, postmenopausal women with an endometrial thickness greater than 5 mm, patients with ovarian cysts with diameters measuring greater than 5 cm (premenopausal) or 2 cm (postmenopausal), or women with free fluid pockets greater than 4 cm. Premenopausal participants had a mean age of 39 years, and postmenopausal participants had a mean age of 57 years.

Dr. Carroll has been a speaker and researcher for Corcept Therapeutics, which markets mifepristone. His coinvestigators were employees, contractors, or consultants for Corcept, which provided some funding for the study.

By: SHERRY BOSCHERT, Clinical Endocrinology News Digital Network

sboschert@frontlinemedcom.com

On Twitter @sherryboschert

From Clinical Endocrinology News

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When to think Cushing’s syndrome in type 2 diabetes

Posted on July 28, 2013 by MaryO

ESTES PARK, COLO. – Diabetes mellitus, osteoporosis, and hypertension are conditions that should boost the index of suspicion that a patient with some cushingoid features may in fact have endogenous Cushing’s syndrome, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

An estimated 1 in 20 patients with type 2 diabetes has endogenous Cushing’s syndrome. The prevalence of this form of hypercortisolism is even greater – estimated at up to 11% – among individuals with osteoporosis. In hypertensive patients, the figure is 1%. And among patients with an incidentally detected adrenal mass, it’s 6%-9%, according to Dr. McDermott, professor of medicine and director of endocrinology and diabetes at the University of Colorado.

“Endogenous Cushing’s syndrome is not rare. I suspect I’ve seen more cases than I’ve diagnosed,” he observed. “I’ve probably missed a lot because I failed to screen people, not recognizing that they had cushingoid features. Not everyone looks classic.”

There are three screening tests for endogenous Cushing’s syndrome that all primary care physicians ought to be familiar with: the 24-hour urine cortisol test, the bedtime salivary cortisol test, and the overnight 1-mg dexamethasone suppression test.

“I think if you have moderate or mild suspicion, you should use one of these tests. If you have more than moderate suspicion – if a patient really looks like he or she has Cushing’s syndrome – then I would use at least two screening tests to rule out endogenous Cushing’s syndrome,” the endocrinologist continued.

The patient performs the bedtime salivary cortisol test at home, obtaining samples two nights in a row and mailing them to an outside laboratory. The overnight dexamethasone suppression test entails taking 1 mg of dexamethasone at bedtime, then measuring serum cortisol the next morning. A value greater than 1.8 mcg/dL is a positive result.

Pregnant women constitute a special population for whom the screening method recommended in Endocrine Society clinical practice guidelines (J. Clin. Endocrinol. Metab. 2008;93:1526-40) is the 24-hour urine cortisol test. That’s because pregnancy is a state featuring high levels of cortisol-binding globulins, which invalidates the other tests. In patients with renal failure, the recommended screening test is the 1-mg dexamethasone suppression test. In patients on antiepileptic drugs, the 24-hour urine cortisol or bedtime salivary cortisol test is advised, because antiseizure medications enhance the metabolism of dexamethasone.

Dr. McDermott said that “by far” the most discriminatory clinical features of endogenous Cushing’s syndrome are easy bruising, violaceous striae on the trunk, facial plethora, and proximal muscle weakness.

“They’re by no means specific. You’ll see these features in people who don’t have Cushing’s syndrome. But those are the four things that should make you really consider Cushing’s syndrome in your differential diagnosis,” he stressed.

More widely recognized yet actually less discriminatory clinical features include facial fullness and the “buffalo hump,” supraclavicular fullness, central obesity, hirsutism, reduced libido, edema, and thin or poorly healing skin.

Endogenous Cushing’s syndrome can have three causes. An adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma accounts for 80% of cases. A cortisol-secreting adrenal tumor is the cause of 10%. And another 10% are due to an ectopic ACTH-secreting tumor, most commonly a bronchial carcinoid tumor.

Once the primary care physician has a positive screening test in hand, it’s typical to refer the affected patient to an endocrinologist in order to differentiate which of the three causes is present. This is accomplished based upon the results of a large, 8-mg dexamethasone suppression test coupled with measurement of plasma ACTH levels.

Dr. McDermott recommended as a good read on the topic of evaluating a patient with endogenous Cushing’s syndrome a recent review article that included a useful algorithm (N. Engl. J. Med. 2013;368:2126-36).

He reported having no financial conflicts.

bjancin@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com

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