Nora Albiger

Effect of protracted treatment with rosiglitazone, a PPARgamma agonist, in patients with Cushing's disease.

Objective  Cushings disease, hypercortisolism due to a pituitary ACTH‐secreting tumour, is a highly morbid illness as yet without effective medical therapy. Recent studies have demonstrated that peroxisome proliferator‐activated receptor gamma (PPARγ) agonists effectively suppress ACTH secretion in a murine tumoral corticotroph cell line, but the few studies conducted so far in patients with ACTH‐secreting pituitary adenomas have yielded variable results.

A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

OBJECTIVE The mechanisms inducing steroidogenesis in primary aldosteronism (PA) remain poorly defined. It was recently demonstrated that some G-protein-coupled receptors are abnormally expressed in aldosterone-producing adenomas (APA). We evaluated the potential role of LH and GNRH receptors (LHR (or LHCGR) and GNRHR) in regulating aldosterone secretion in a patient with APA arising during pregnancy (index case) and in a subset of other patients with PA. PATIENTS AND METHODS GNRH test was performed in the index case, 11 other PA, and 5 controls. GNRHR and LHR expressions were examined in 23 APA and 6 normal tissues. RESULTS Aldosterone response increased significantly (114%) in the index case after GNRH test was performed preoperatively, while it was blunted after adrenalectomy. Aldosterone also increased after human chorionic gonadotropin and triptorelin stimulation. A partial aldosterone response to GNRH was observed in other 7/11 PA, while a significant response was observed in two patients. Controls did not respond to GNRH test. GNRHR was overexpressed and LHR expression was moderate in the APA tissue from the index case. Moreover, LHR was found in normal adrenals and overexpressed in 6/22 APA. GNRHR was overexpressed in 6/22 APA, 2 of them with a 95- and 109-fold higher expression than normal. A correlation between the clinical and molecular findings was observed in five out of seven patients. CONCLUSION We describe a case of PA diagnosed during pregnancy, which appeared to correlate with aberrant LHR and GNRHR expression. Our findings suggest that a subset of patients with PA has aberrant LHR and GNRHR expression, which could modulate aldosterone secretion.

Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid-induced increase in von Willebrand factor: the lesson learned from Cushing syndrome

Cushing syndrome (CS) features high‐glucocorticoid secretion and an associated hypercoagulable state often involving an increase in von Willebrand factor (VWF). To identify any influence of VWF promoter on glucocorticoid haemostatic effects, four polymorphic positions (‐3267, ‐2708, ‐2659 and ‐2525) segregating as haplotypes 1 (GCAG) or 2 (CTGA) were analysed in 50 CS patients with high VWF (group I) and normal VWF (group II) levels, divided by ABO group. Genotype distribution differed significantly between the two groups: in group I, 25·8% had genotype 1/1, 22·6% had 2/2 and 38·7% had 1/2; in group II, 0% had genotype 1/1, 57·9% had 2/2 and 31·6% had 1/2 (P = 0·03). Patients’ genotypes also differed from those of controls (P = 0·003 for group I, P = 0·03 for group II). Haplotype 1 was prevalent in group I, haplotype 2 in group II (P = 0·002), both with frequencies differing from controls (P < 0·001 and P = 0·009). By odds ratio analysis, genotype 1/1 carried a 12 times greater risk of high‐VWF levels than genotype 2/2, and haplotype 1 carried a five times greater risk than haplotype 2. Our findings suggest that VWF promoter haplotypes influence the corticosteroid‐mediated increase in VWF.

Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS

INTRODUCTION AND AIM As initial screening for Cushings syndrome (CS), The Endocrine Society guidelines recommend one of the following: the 1-mg dexamethasone suppression test (DST) or late-night salivary cortisol (LNSC) or urinary free cortisol (UFC) measurement. We examined the diagnostic performance of the above-mentioned tests in a series of patients. MATERIALS AND METHODS We retrospectively analyzed 137 patients with clinical conditions suggestive of hypercortisolism: 38 with confirmed CS diagnosis and 99 without (termed non-CS). UFC was measured by liquid chromatography tandem-mass spectrometry, whereas LNSC by the radioimmunometric method and serum cortisol were measured by a chemiluminescence immunoassay. RESULTS Comparing CS vs non-CS, a cutoff of 138 nmol/L after 1-mg DST revealed the best specificity (SP; 97%), whereas the 50-nmol/L cutoff confirmed the best sensitivity (SE; 100%); the SE and SP for LNSC greater than 14.46 nmol/L were, respectively, 84% and 89%, whereas the SE and SP for UFC greater than 170 nmol per 24 hours, they were 97% and 91%. Overall, UFC revealed both a combined higher positive and a lower negative likelihood ratio among first-line tests (respectively 10.7 and 0.03). Computing a receiver-operating curve -contrast analysis to compare the power of each single test with that of the others, alone or combined (DST+LNSC, DST+UFC, and LNSC+UFC) or with that of all the tests together (DST+LNSC+UFC), the UFC assay was at least as good as all the other possible combinations. CONCLUSIONS Measuring UFC by liquid chromatography tandem-mass spectrometry achieves the best accuracy in diagnosing CS among patients presenting with suspected hypercortisolism.

Diagnosis and complications of Cushing's disease: gender‐related differences

Cushings disease (CD) presents a remarkable preponderance in female gender, with a female‐to‐male ratio of 3–8:1. The aim of this study was to evaluate gender‐related differences in the presentation of CD, as regards: biochemical indices of hypercortisolism; sensitivity of diagnostic tests; clinical features and complications of disease.

An analysis of different therapeutic options in patients with Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: a single‐centre experience

Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushings syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients, but little is known about recurrence during follow‐up.

Predicting late recurrence in surgically treated patients with Cushing's disease

Cushings disease (CD) has an uncertain prognosis because patients achieving remission after transsphenoidal pituitary neurosurgery (TSS) may relapse. We aimed to identify factors predicting relapse, focusing on desmopressin (DDAVP) and corticotropin‐releasing hormone (CRH) tests after surgery.

Cyclic Cushing's Syndrome: An Overview

Cyclic Cushings syndrome (CS) involves rhythmic fluctuations in ACTH secretion resulting in a cyclic variation of adrenal steroid production. In the majority of cases, cyclic CS is caused by an ACTH-secreting pituitary adenoma, but it can also be due to ectopic ACTH production or an adrenal adenoma. This condition should be strongly suspected in patients with symptoms or signs of hypercortisolism but normal cortisol levels and paradoxical responses to the dexamethasone test, that may reflect an increasing or decreasing endogenous hormone activity. Dynamic tests are best interpreted if they are performed during a sustained period of hypercortisolism. Sometimes, it is necessary to confirm the diagnosis over lengthy periods of observation. Responses to treatment must be closely monitored, interpreted and evaluated with caution because of the potential variations in steroidogenesis. An original case report of a cyclic Cushings syndrome is presented in this review.

Assessment of glucocorticoid therapy with salivary cortisol in secondary adrenal insufficiency

CONTEXT Appropriate glucocorticoid replacement therapy in adrenal insufficiency (AI) is crucial, given the risks of chronic under- or overtreatment, particularly in patients on multiple medications. Salivary sampling allows for non-invasive, stress-free cortisol measurement. OBJECTIVE To determine whether salivary cortisol measurement is helpful in assessing the adequacy of glucocorticoid therapy with cortisone acetate (CA) in patients with secondary AI. DESIGN A prospective cohort study at the Endocrinology Unit of Padua University Hospital. METHODS Six samples of salivary cortisol were collected from 28 patients with secondary AI on CA treatment and from 36 healthy volunteers at fixed times of the day, and used to calculate salivary cortisol levels at each time point and the area under the curve (AUC) across the different sampling times. RESULTS Salivary cortisol levels were lower in patients than in controls in the morning but no differences were found in the afternoon or at night before resting. Salivary cortisol levels were higher in patients immediately following CA administration. Ten patients showed an AUC above the 97.5th percentile of controls, without clinical signs of hypercortisolism, and salivary cortisol levels 90 min after each dose of CA predict the AUC. All patients had severe GH deficiency and there were no differences in salivary cortisol levels or AUC between patients treated or not with GH. CONCLUSIONS Two salivary cortisol determinations, able to predict the daily AUC, may allow for assessing the adequacy of glucocorticoid replacement therapy in secondary AI and for identifying cases of over- or undertreatment.

A comprehensive approach to adrenal incidentalomas

Improvements in abdominal imaging techniques have increased the detection of clinically inapparent adrenal masses, or incidentalomas (AI), the appropriate diagnosis and management of which have become a common clinical problem for health care professionals. Once an adrenal mass has been detected, the clinician needs to address two questions: 1) is the tumor hormonally active? and 2) is there any chance of the mass being malignant? The majority of AI is non-hypersecretory cortical adenomas, but an endocrine evaluation can lead to the identification of subtle hormone excess. An overnight low-dose dexamethasone suppression test, fractionated urinary or plasma metanephrine assay and, in hypertensive patients, establishing the upright plasma aldosterone/plasma renin activity ratio are recommended as preliminary screening steps. Masses greater than 4 cm are at greater risk of malignancy. Morphological imaging features may be helpful in the distinction between benign and malignant forms. Fine-needle aspiration biopsy is an important tool in the evaluation of oncological patients to establish any metastatic disease. Adrenalectomy is indicated by evidence of a functional adrenal mass, or a suspected malignant form. We advocate adrenalectomy of subtle hypercortisolism, especially in the presence of hypertension, obesity, diabetes or osteoporosis potentially aggravated by glucocorticoid excess. A close follow-up is needed, particularly in the first year after diagnosis.