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Diagnosis of secondary adrenal insufficiency in patients with hypothalamic–pituitary disease: comparison between serum and salivary cortisol during the high-dose short synacthen test

Timo Deutschbein, Nicole Unger, Klaus Mann, and Stephan Petersenn

Objective

Accurate assessment of adrenal function is essential in patients with hypothalamic–pituitary–adrenal (HPA) disease. The measurement of salivary cortisol (SaC) instead of serum cortisol (SeC) offers several advantages, such as the determination of the free hormone. We evaluated the diagnostic value of SeC and SaC both unstimulated and during a high-dose short synacthen test (HDT) in comparison to the insulin tolerance test (ITT).

Design

Comparative study between 2005 and 2007.

Methods

Fifty-five patients with HPA impairment and 21 healthy controls were enrolled. Samples were collected in the early morning and over 120 min during the HDT. Receiver operating characteristic analysis revealed individual thresholds for four HDT periods (0–30, 0–60, 0–90, and 0–120 min).

Results

The ITT identified 30 subjects as adrenal insufficient. With respect to the four HDT periods, sensitivity and specificity were 67–79% and 71–88% for SeC, compared with 63–72% and 72–86% for SaC. If upper and lower thresholds (with specificities >95%) were applied, patients were diagnosed in 40–45% by SeC and in 25–31% by SaC. The combination of basal cortisol and HDT allowed a diagnosis in 47–49% (SeC) and in 42–45% (SaC) respectively.

Conclusion

We suggest the determination of basal SeC or SaC as first-line test. In comparison to the ITT, the HDT has only limited value in screening for alterations of the HPA axis. If the HDT is performed, sampling may be limited to 30 min post-synacthen, using either SeC or SaC. Due to the ease of collection and the independence of binding proteins, SaC may be preferable.

Free access

Anthropometric factors have significant influence on the outcome of the GHRH–arginine test: establishment of normative data for an automated immunoassay specifically measuring 22 kDa human growth hormone

Timo Deutschbein, Martin Bidlingmaier, Jochen Schopohl, Christian J Strasburger, and Stephan Petersenn

Context

Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion.

Objective

To improve the diagnostic accuracy of GH-releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH.

Design/setting

Prospective multicenter study.

Participants

Eighty-seven patients with hypothalamic–pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when ≥2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with ≥95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI.

Interventions

All participants received GHRH and l-arginine.

Main outcome measures

GH was measured by immunoassay (iSYS, IDS).

Results

In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively.

Conclusion

BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs.

Free access

Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry

Wolfgang Saeger, Dieter K Lüdecke, Michael Buchfelder, Rudolf Fahlbusch, Hans-Jürgen Quabbe, and Stephan Petersenn

In 1996, the German Registry of Pituitary Tumors was founded by the Pituitary Section of the German Society of Endocrinology as a reference center for collection and consultant pathohistological studies of pituitary tumors. The experiences of the first 10 years of this registry based on 4122 cases will herein be reported. The data supplement former collections of the years 1970–1995 with 3480 surgically removed tumors or lesions of the pituitary region. The cases were studied using histology, immunostainings and in some cases also molecular pathology or electron microscopy. The adenomas were classified according to the current World Health Organization classification in the version of 2004. From 1996 on 3489 adenomas (84.6%), 5 pituitary carcinomas (0.12%), 133 craniophar-yngiomas (3.2%), 39 meningiomas (0.94%), 25 metastases (0.6%), 22 chordomas (0.5%), 115 cystic non-neoplastic lesions (2.8%), and 46 inflammatory lesions (1.1%, 248 other lesions or normal tissue (6.0%)) were collected by us. The adenomas (100%) were classified into densely granulated GH cell adenomas (9.2%), sparsely granulated GH cell adenomas (6.3%), sparsely granulated prolactin (PRL) cell adenomas (8.9%), densely granulated PRL cell adenomas (0.3%), mixed GH/PRL cell adenomas (5.2%), mammosomatotropic adenomas (1.1%), acidophilic stem cell adenomas (0.2%), densely granulated ACTH cell adenomas (7.2%), sparsely granulated ACTH cell adenomas (7.9%), Crooke cell adenomas (0.03%), TSH cell adenomas (1.5%), FSH/LH cell adenomas (24.8%), null cell adenomas (19.3%), null cell adenoma, oncocytic variant (5.8%), and plurihormonal adenomas (1.3%). Following the WHO classification of 2004, the new entity ‘atypical adenoma’ was found in 12 cases in 2005. Various prognostic parameters and clinical implications are discussed.

Free access

Late-night and low-dose dexamethasone-suppressed cortisol in saliva and serum for the diagnosis of cortisol-secreting adrenal adenomas

Timo Deutschbein, Nicole Unger, Jakob Hinrichs, Martin K Walz, Klaus Mann, and Stephan Petersenn

Objective

In patients with adrenal incidentalomas, hormonally active masses need to be considered, particularly cortisol-producing adenomas (CPA), aldosterone-producing adenomas, and pheochromocytomas. The screening for hypercortisolism relies on confirming excess cortisol secretion and insufficient suppression after dexamethasone. Because of its high correlation with free cortisol and its stress-free collection, salivary cortisol (SaC) may offer advantages over serum cortisol (SeC). We evaluated the value of SaC and SeC for the diagnosis of CPA.

Design

Comparative study between 2001 and 2006.

Methods

Thirty-eight patients with confirmed CPA were compared with 18 healthy subjects as well as 48 control patients suffering from aldosterone-producing adenomas (n=13), pheochromocytomas (n=16), or nonfunctioning adenomas (n=19). Sampling of saliva and serum was performed at 2300 and at 0800 h following low-dose dexamethasone suppression. Receiver operating characteristics analysis was used to calculate thresholds with at least 95% sensitivity for CPA.

Results

Regarding the cutoffs for late-night cortisol, SaC (4.8 nmol/l, sensitivity 97%, specificity 69%) was slightly more specific than SeC (115 nmol/l, sensitivity 97%, specificity 63%). In contrast, the cutoff for dexamethasone-suppressed SaC (3.7 nmol/l, sensitivity 97%, specificity 83%) was slightly less specific than SeC (94 nmol/l, sensitivity 97%, specificity 88%). However, the latter cutoffs demonstrated greater specificity when compared with the cutoffs for late-night cortisol.

Conclusion

The diagnostic accuracy of SaC is as good as SeC. Owing to its higher specificity, dexamethasone-suppressed cortisol is preferable to late-night cortisol when screening for Cushing's syndrome in patients with adrenal incidentalomas.

Free access

Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency

Sven Benson, Pia Neumann, Nicole Unger, Manfred Schedlowski, Klaus Mann, Sigrid Elsenbruch, and Stephan Petersenn

Objective

For secondary adrenal insufficiency (SAI), established biochemical parameters for dosage control are lacking and no optimal substitution dosage and daily distribution have been determined yet. Therefore, in clinical practice, the individual total dose is often adjusted based on patients' subjective well-being.

Design

Effects of three standard glucocorticoid replacement regimens on psychological variables were assessed in patients with SAI based on a randomized double-blind study design.

Methods

SAI patients (n=18) were treated with three different established glucocorticoid replacement regimens in a randomized, double-blind, crossover study (treatment A, hydrocortisone 10 mg-placebo-5 mg-placebo; treatment B, hydrocortisone 10 mg-5 mg-placebo-5 mg; and treatment C, prednisone 5 mg-placebo-placebo-placebo). Following each 4-week replacement regimen, quality of life (SF-36) and emotional distress (brief symptom inventory (BSI)) were assessed along with diurnal changes in current well-being (Bf-S) and alertness (Stanford Sleepiness Scale (SSS)) using validated questionnaires, and additionally compared with patient (patients with pituitary disease and adrenal sufficiency) and healthy control groups.

Results

SAI patients showed improvements in physical quality of life (i.e. SF-36 physical function, P<0.05; physical role function, P<0.05) and current well-being (at 1800 h, P<0.05) under treatment A (hydrocortisone 10-0-5-0 mg) compared with the other replacement regimens. Quality of life and current well-being were significantly impaired compared with healthy controls but did not differ from patient controls.

Conclusions

Although the observed improvements in psychological parameters were comparatively small, our results indicate beneficial effects of a 10-0-5-0 mg hydrocortisone replacement regimen. Nevertheless, treatment effects were insufficient to restore subjective health compared with healthy controls, indicating the need for improved replacement regimens and supportive psychosocial interventions in SAI patients.

Free access

Aggressive pituitary tumours and carcinomas: two sides of the same coin?

Jacqueline Trouillas, Pia Burman, Ann McCormack, Stephan Petersenn, Vera Popovic, Olaf Dekkers, and Gerald Raverot

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.

Free access

Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery

Christian Berg, Timo Meinel, Harald Lahner, Ali Yuece, Klaus Mann, and Stephan Petersenn

Objective

The glucagon stimulation test (GST) like the insulin tolerance test (ITT) stimulates both ACTH and GH secretion. However, there are limited data with modern assays on sensitivity and specificity for GST in comparison to ITT. The aim of this study was to evaluate the diagnostic utility of the GST for GH deficiency (GHD) and adrenal insufficiency (AI) in patients following pituitary surgery.

Design and patients

ITT and GST were performed within 7 days in 49 patients at least 3 months after transsphenoidal surgery. Serum GH and cortisol were measured by Immulite 2000 assay (Siemens AG). Receiver-operating characteristic (ROC) analysis was performed to identify the thresholds for GST.

Results

In ITT, 18/49 cases were classified as AI. ROC analysis revealed a peak cortisol value >599 nmol/l in GST for adrenal sufficiency with 100% specificity and 32% sensitivity, and a peak cortisol <277 nmol/l with >95% specificity and 72% sensitivity for AI. Of the 49 subjects, 25 (51%) demonstrated levels between these cut-offs and could not be diagnosed by GST alone with sufficient accuracy. Regarding GHD, 21/49 cases were classified as insufficient by ITT. ROC analysis revealed a cut-off of 2.5 ng/ml with 95% sensitivity and 79% specificity. Of the 49 cases, seven (14%) were discordant in terms of defining GHD, with six subjects being treated for GHD according to GST although being sufficient in ITT.

Conclusion

In our prospective series of patients with pituitary disease, GST is a potential alternative test for the assessment of GH reserve, but is a poor test for ACTH reserve. Test-specific cut-offs should be applied to avoid misinterpretation.

Free access

Salivary cortisol as a diagnostic tool for Cushing's syndrome and adrenal insufficiency: improved screening by an automatic immunoassay

Timo Deutschbein, Martina Broecker-Preuss, Jörg Flitsch, Andrea Jaeger, Ricarda Althoff, Martin K Walz, Klaus Mann, and Stephan Petersenn

Background

Salivary cortisol is increasingly used to assess patients with suspected hypo- and hypercortisolism. This study established disease-specific reference ranges for an automated electrochemiluminescence immunoassay (ECLIA).

Methods

Unstimulated saliva from 62 patients with hypothalamic–pituitary disease was collected at 0800 h. A peak serum cortisol level below 500 nmol/l during the insulin tolerance test (ITT) was used to identify hypocortisolism. Receiver-operating characteristic (ROC) analysis allowed establishment of lower and upper cutoffs with at least 95% specificity for adrenal insufficiency and adrenal sufficiency. Saliva from 40 patients with confirmed hypercortisolism, 45 patients with various adrenal masses, and 115 healthy subjects was sampled at 2300 h and after low-dose dexamethasone suppression at 0800 h. ROC analysis was used to calculate thresholds with at least 95% sensitivity for hypercortisolism. Salivary cortisol was measured with an automated ECLIA.

Results

When screening for secondary adrenal insufficiency, a lower cutoff of 3.2 nmol/l and an upper cutoff of 13.2 nmol/l for unstimulated salivary cortisol allowed a highly specific diagnosis (i.e. similar to the ITT result) in 26% of patients. For identification of hypercortisolism, cutoffs of 6.1 nmol/l (sensitivity 95%, specificity 91%, area under the curve (AUC) 0.97) and 2.0 nmol/l (sensitivity 97%, specificity 86%, AUC 0.97) were established for salivary cortisol at 2300 h and for dexamethasone-suppressed salivary cortisol at 0800 h.

Conclusions

The newly established thresholds facilitated initial screening for secondary adrenal insufficiency and allowed excellent identification of hypercortisolism. Measurement by an automated immunoassay will allow broader use of salivary cortisol as a diagnostic tool.

Free access

Computed tomography criteria for discrimination of adrenal adenomas and adrenocortical carcinomas: analysis of the German ACC registry

Stephan Petersenn, Paul-Ajoy Richter, Thomas Broemel, Christian O Ritter, Timo Deutschbein, Frank-Ulrich Beil, Bruno Allolio, Martin Fassnacht, and for the German ACC Study Group

Objective

Thresholds of 2–20 hounsfield units (HU) in unenhanced computed tomography (CT) are suggested to discriminate benign adrenal tumors (BATs) from malignant adrenal tumors. However, these studies included only low numbers of adrenocortical carcinomas (ACCs). This study defines a HU threshold by inclusion of a large cohort of ACCs.

Design

Retrospective, blinded, comparative analysis of CT scans from 51 patients with ACCs (30 females, median age 49 years) and 25 patients with BATs (12 females, median age 64 years) diagnosed during the period of 2005–2010 was performed.

Methods

Tumor density was evaluated in unenhanced CT by two blinded investigators.

Results

Median tumor size was 9 cm (range 2.0–20) for ACCs vs 4 cm (2.0–7.5) for BATs (P<0.0001). In ACCs, the median unenhanced HU value was 34 (range 14–74) in comparison with 5 (−13 to 40) in BATs (P<0.0001). ROC analysis revealed a HU of 21 as threshold with the best diagnostic accuracy (sensitivity 96%, specificity 80%, and AUC 0.89). However, two ACCs that were 5 and 6 cm in size would have been missed. Setting the threshold to 13.9 allowed for 100% sensitivity, but a lower specificity of 68%.

Conclusions

This first large study on ACCs confirmed that the vast majority of ACCs have unenhanced HU >21. However, to avoid misdiagnosing an ACC as benign, a threshold of 13 should be used.

Free access

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

Gerald Raverot, Pia Burman, Ann McCormack, Anthony Heaney, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Olaf M Dekkers, and The European Society of Endocrinology

Background

Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas.

Methods

We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36–58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline.

Selected recommendation

(i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.