Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery.

OBJECTIVE: The performance of late-night salivary cortisol (LNSC) to accurately screen for postoperative recurrence of Cushing's disease (CD) at an early stage is unknown. The aim of this study was to compare the accuracy of multiple sampling strategies to suggest the optimal number of LNSC samples needed for diagnosing post-surgical recurrences of CD at an early stage. DESIGN: Retrospective analysis in a single centre. PATIENTS AND MEASUREMENTS: Thirty-six patients in surgical remission of CD had successive measurements of LNSC, defined as 'sequences', using a locally modified RIA assay as part of long-term follow-up (69·2 ± 10·6 months). Patients underwent an extensive biochemical evaluation within 3 months before or after a sequence of saliva sampling and were classified as being in remission or in early-stage recurrence. The accuracy of three diagnostic strategies combining two, three or four LNSC results from a sequence was estimated using areas under the ROC curves (AUC), sensitivity, specificity and predictive values. RESULTS: Forty-four sequences of LNSC measurements were available. Fifty-two percent of sequences were performed during early-stage recurrence. The intrasequence variability of LNSC was higher during recurrence than during remission (medians of SDs: 2·1 vs 0·5 nm; P < 0·0001). AUCs from ROC curves ranged from 0·93 to 0·96 depending on the strategy. For 90% sensitivities, the best specificities (92·9% and 90·9%) were achieved by strategies taking into account three or four measurements summarized either by their mean or their maximum value. CONCLUSIONS: Increase in LNSC concentration is an early abnormality during post-surgical recurrence of CD. However, due to a major within-patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early-stage recurrence of CD with a high accuracy.

Phasing-in plasma metanephrines determination.

OBJECTIVES: We set up plasma normetanephrine (pNMA) and metanephrine (pMA) assays as they demonstrated their usefulness for diagnosing phaeochromocytomas. Our scope is to describe some practical laboratory aspects and the clinical relevance of these assays in our endocrinological or cardiological departments. METHODS: We retrospectively reviewed the results of MA from a population of in- and outpatients over a 7-year period. Subjects (n=2536) from endocrinological or cardiological departments were investigated (66 phaeochromocytomas). Urinary NMA (uNMA) and pNMA, and urinary MA (uMA) and pMA were assayed by HPLC with electrochemical detection. RESULTS: pNMA and pMA assays are now more frequently requested than uNMA and uMA. This changed our laboratory work load with improved delivery, sensitivity and reliability of plasma assays as well as reduced apparatus maintenance time. The pNMA and pMA upper reference limits (URLs) of subjects with no phaeochromocytoma were 1040 and 430 pmol/l respectively. Sensitivity and specificity based on receiver operating characteristic curves optimal points were 83 and 93% for pNMA at 972 pmol/l and 67 and 98% for pMA at 638 pmol/l. Sensitivity and specificity of paired tests of pMA (positive test: at least one analyte above its URLs) were 100 and 91% respectively. CONCLUSION: The very low concentration of analytes requires a sustained very good apparatus analytical sensitivity. This can be obtained in an up-to-date laboratory. In terms of clinical performances, assays in plasma or urine are equivalent. Depending on local preferences, populations, strategies or departments, requests for one or the other assay may sustain the need for specifically defined reference ranges.

Clinical review: Bariatric surgery following treatment for craniopharyngioma: a systematic review and individual-level data meta-analysis.

OBJECTIVES: Craniopharyngiomas are rare low-grade tumors located in the hypothalamic and/or pituitary region. Hypothalamic involvement and treatment resulting in hypothalamic damage are known to lead to development of "hypothalamic obesity" (HyOb) in 50% of cases. The management of HyOb, associated with eating disorders and rapid comorbidities, is an important issue. Bariatric surgery is the most effective therapy for weight loss in patients with severe exogenous obesity. The aim of this systematic review and meta-analysis was to determine the 12-month outcome of bariatric surgery for HyOb due to craniopharyngioma treatment. METHODS AND RESULTS: Relevant studies were identified by searches of the MEDLINE and EMBASE databases until January 2013. A total of 21 cases were included: 6 with adjustable gastric banding, 8 with sleeve gastrectomy, 6 with Roux-en-Y gastric bypass, and 1 with biliopancreatic diversion. After data pooling, mean weight difference was -20.9 kg after 6 months (95% confidence interval [CI], -35.4, -6.3) and -15.1 kg after 12 months (95% CI, -31.7, +1.4). The maximal mean weight loss was achieved by the gastric bypass group: -31.0 kg (95% CI, -77.5, +15.5) and -33.7 kg (95% CI, -80.7, +13.3) after 6 and 12 months, respectively. CONCLUSIONS: In this largest ever published study on the effect of bariatric surgery on obesity after craniopharyngioma treatment, we observed an important weight loss after 1 year of follow-up. Larger studies are warranted to establish appropriate selection criteria and the best surgical technique to perform bariatric surgery.

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients.

BACKGROUND: Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. DESIGN AND METHODS: A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. RESULTS: Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CONCLUSION: CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients.

CONTEXT: Neither precise evaluation of pertinent thresholds nor comparison of the diagnostic performance of late-night salivary cortisol (NSC) between inpatient and outpatient settings has been conducted. The usefulness of NSC for the screening of "subclinical" Cushing's syndrome is still unknown. OBJECTIVES: The aim of the study was to compare the influence of inpatient and outpatient settings on the diagnostic performance of NSC and assess its usefulness as a screening test for subclinical Cushing's syndrome. DESIGN: Consecutive patients were investigated prospectively with two salivary collections, first as inpatients and then as outpatients. PARTICIPANTS: Forty-two obese subjects participated in the study, as well as nine patients cured of Cushing's disease, 13 with overt Cushing's syndrome, 14 showing mild recurrence of Cushing's disease, and 48 with adrenal incidentalomas [23 subclinical cortisol-secreting adenomas (SCSA), 25 nonsecreting adenomas]. MAIN OUTCOME MEASURES: Reproducibility of NSC and diagnostic performance were measured using receiver operating characteristic analysis. RESULTS: NSC in controls was similar between inpatient and outpatient settings. The diagnostic performance of NSC across the different patient groups was similar irrespective of the setting. A threshold of 12 nmol/liter yielded 100% sensitivity and specificity in overt Cushing's syndrome. Optimal performance in subclinical Cushing's syndrome required lower thresholds. NSC showed acceptable performance in diagnosing recurrence of Cushing's disease (90% sensitivity, 91.8% specificity). On the contrary, NSC was similar between patients with SCSA and nonsecreting adenomas. CONCLUSIONS: Our data validate the outpatient bed sampling strategy for NSC with no need for specific outpatient threshold. NSC may be helpful to detect mild recurrence of Cushing's disease after surgery but is of little value in identifying SCSA amongst adrenal incidentalomas.

Bioavailable estradiol in man: relationship with age and testosterone.

Sex hormones undergo decreases in aging men. Several studies have shown the association of low levels of bioavailable estradiol with osteoporosis in man. To allow a better approach of sex hormones influences, we evaluated bioavailable estradiol concentrations in men and its correlation with age and testosterone. We show that bioavailable estradiol decreases significantly with age. We provide reference values in men with normal testosterone levels.

[Adrenal incidentalomas]. / Incidentalomes et tumeurs de la loge de la surrénale.

The adrenal incidentaloma is an adrenal mass, generally more than 1 cm in diameter, that is discovered serendipitously during a radiologic examination performed for indications other than an evaluation of adrenal disease. The prevalence of adrenal incidentalomas is at least 1% in patients who underwent abdominal CT examination. The main therapeutic issues are to select which patient should undergo surgical excision, and the optimal procedure and duration of follow-up for patients in whom surgery is not indicated. Surgery is mandatory in patients with secretory tumours (pheochromocytoma, secreting cortical adenomas) and with adrenal cancer. However, the vast majority of adrenal incidentalomas are benign cortical adenomas and surgery is mandatory only in a minority of patients. Systematic aetiological investigation of adrenal incidentalomas should therefore be performed in order to guide the decision on surgical or non surgical management. This investigation includes, at least, clinical assessment, biological endocrine evaluation and appropriate standardized CT scan examination of the mass. The optimal duration and modalities of follow-up for patients with adrenal incidentalomas are uncertain.

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Pituitary magnetic resonance imaging findings do not influence surgical outcome in adrenocorticotropin-secreting microadenomas.

The pituitary origin of ACTH secretion in ACTH-dependent hypercortisolism can be difficult to assess, as magnetic resonance imaging (MRI) frequently fails to identify ACTH-secreting microadenomas or, on the contrary, may give false positive images of microadenomas. The choice of therapeutic option for patients with such normal MRI findings is controversial. Some groups propose routinely pituitary surgery, whereas others consider that neurosurgical exploration may be less successful and more harmful, and therefore prefer other types of management. The aim of this study was to compare surgical outcomes between patients with Cushing's disease (CD) and normal vs. positive pituitary MRI findings. Fifty-four patients (44 women and 10 men) with CD, operated on after 1996 in two centers (Kremlin-Bicêtre and Bordeaux) and followed postoperatively during a mean period of 19.9 +/- 22.7 months (range, 1-89 months), were enrolled in this retrospective study. Twenty-eight patients had normal pituitary MRI findings, and the pituitary origin of ACTH was established by bilateral petrosal sinus sampling in all of these cases. Twenty-six patients had positive MRI findings clearly showing a microadenoma. The two groups were not significantly different in terms of the sex ratio, age, frequency of hypertension, or diabetes, basal 24-h urinary free cortisol levels and follow-up. All of the patients were operated on by two experienced neurosurgeons using the same surgical protocol. Selective adenomectomy was performed when a tumor was identified, and subtotal hypophysectomy was performed when the lesion was uncertain or when no tumor was found during surgical exploration. Respectively, 50% and 84% of patients with normal and positive MRI results underwent adenomectomy (P < 0.05). A pituitary adenoma (confirmed by pathological examination) was found at surgery in 53% and 88% of patients in the normal and positive MRI groups, respectively (P < 0.05). The early surgical success rate (combining patients with corticotropic deficiency and patients with eucortisolism) was similar in the normal and positive MRI groups (78% and 88%, respectively; P = 0.85). The recurrence rate was lower in the normal MRI group, but the difference did not reach statistical significance (9% vs. 30%; P = 0.07). The final remission rate at the last visit was similar in the normal and positive MRI groups (72% and 61%, respectively; P = 0.29). Postoperative complications were also similar: 10 patients (36%) with normal MRI and five patients (20%) with positive MRI had at least one postoperative complication (surgical and/or pituitary deficiency; P = 0.12). Thus, the outcome of pituitary surgery in CD appears to be similar regardless of whether pituitary MRI shows a microadenoma. We recommend neurosurgical pituitary exploration as the first-line treatment of CD, provided that the pituitary origin of ACTH secretion is confirmed by bilateral petrosal sinus sampling in patients with normal pituitary MRI findings.