Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays.

CONTEXT: The short ACTH stimulation test (250 µg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds. OBJECTIVE: To propose a morning baseline cortisol criterion of three of the most commonly used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency. DESIGN: Observational, retrospective cross-sectional study at two centres. PATIENTS AND MEASUREMENTS: Retrospective analysis of the results of 1019 Short Synacthen tests (SSTs) with the Advia Centaur, 449 SSTs with the Architect and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250 µg Synacthen and after 30 min. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients. RESULTS: Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilizing these criteria, 589, 158 and 578 SSTs, respectively, for Siemens, Abbott and Roche immunoassays could have been avoided. CONCLUSIONS: We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients.

Older Adults with Type 2 Diabetes Treated with Metformin: AME-MET Study - A Multicentric Real-world Study in Italy.

AIMS: Metformin is the most widely used drug for the first-line treatment of type 2 diabetes mellitus (T2DM), but its use and schedule have been poorly investigated in elderly patients. METHODS: We conducted an observational, cross-sectional, multicentric study on metformin in T2DM outpatients older than 65 years who were taking the drug for at least 6 months and referred to Italian Endocrinology and Diabetology Services. The primary endpoint was daily metformin dose, and secondary endpoints were the correlations between metformin dose and age, comorbidities, and concomitant use of other drugs. The study was open to all members of AME (Associazione Medici Endocrinologi). RESULTS: Fifteen Italian centers recruited 751 consecutive participants (42.9% older than 75 years, 48.6% females). T2DM duration was 12.9 ± 9.7 years (longer than 10 years in 53.8%). Metformin had been used for 10.3 ± 6.8 years (longer than 10 years in 52.4%). Metformin dose was 1.6 ± 0.9 g/day (>1.5 g/day in 63.4%). As compared to the youngest, participants older than 75 years did not differ for metformin daily dose or number of administrations. Metformin dose was significantly directly correlated to eGFR, diabetes duration, and metformin treatment duration. CONCLUSION: In this real-world study, the minimum daily effective dose of metformin was prescribed in more than half of older T2DM outpatients.

Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia: prevalence and sonographic, hormonal, and seminal characteristics.

OBJECTIVE: Testicular adrenal rest tumors have been described in patients with congenital adrenal hyperplasia (CAH). The aim of this work was to (1) evaluate the prevalence of testicular adrenal rest tumors in patients with CAH; (2) study the hormonal profile; (3) define the sonographic features; (4) assess the seminal profile; and (5) initiate a longitudinal study on the possible role of corticotropin (ACTH) plasma levels in the induction and persistence of testicular adrenal rest tumors. METHODS: Eighteen patients affected by CAH, aged 21 to 41 years, were studied. These were all patients referred to our endocrinology unit for the first time to undergo a clinical evaluation. All of the patients were taking long-term cortisone acetate and fludrocortisone replacement therapy. The study included (1) a physical examination, (2) testis sonography, (3) a hormonal profile, (4) semen analysis. RESULTS: Sonography showed testicular adrenal rest tumors in 11 patients (61.1%); of these, 9 cases (50.0%) were bilateral, and 2 (11.1%) were unilateral. The diameter ranged from 4 to 38 mm. In 9 patients, the lesions were hypoechoic, whereas in 2, they were hyperechoic. High plasma ACTH levels were detected in all of the patients with tumors despite long-term therapy. Semen analysis found 2 cases of azoospermia and 6 cases of oligoasthenoteratozoospermia; the 3 remaining patients were normospermic. The preliminary longitudinal study has shown 3 patients with a disappearance or reduction of the tumors after 6 months of modified treatment. CONCLUSIONS: This study confirms the high prevalence of testicular adrenal rest tumors in patients with CAH and the major role played in its pathogenesis by high plasma ACTH levels.

Intratesticular isolated anechoic areas: prevalence, seminal profile, and longitudinal study.

OBJECTIVE: The aim of this study was to evaluate the prevalence of intratesticular isolated anechoic areas (ITIAAs) in a large population, the seminal profile, and follow-up of patients with ITIAAs. METHODS: A total of 2223 patients underwent an andrologic examination and scrotal sonography. In the patients with ITIAAs, a hormonal profile was obtained, and screening for neoplastic markers was performed. In selected cases, standard semen analysis was performed. Finally, a longitudinal study was initiated. RESULTS: The prevalence of ITIAAs was 2.7% (59 of 2223 cases). In 48 of 59 cases (81.4%), a single ITIAA was found, whereas in the other 11 cases (18.6%), multiple ITIAAs were detected. Among the 59 patients with ITIAAs, we observed concomitant epididymal anechoic areas (EAAs) in 25 (42.4% of cases), specifically in 19 of 48 cases with a single ITIAA and 6 of 11 cases with multiple ITIAAs. Regarding age, 91.5% (54 of 59 cases) of the ITIAAs were found in patients older than 30 years; concomitant EAAs were present in about 50% of the cases. In patients younger than 30 years, no EAAs were detected. The seminal profile showed reduced sperm motility percentages in the patients with ITIAAs and concomitant EAAs. The longitudinal study did not show any significant variation of ITIAA patterns; all neoplastic markers remained negative. CONCLUSIONS: An ITIAA is a pattern occasionally observed on sonography. The findings suggest that an ITIAA with a concomitant EAA could have a microtraumatic or inflammatory pathogenesis, whereas an ITIAA without a concomitant EAA in young patients could have a dysontogenetic origin.

The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function.

Context: The 250-µg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. Objective: To use the SST results to predict adrenal recovery. Design: A retrospective analysis of 1912 SSTs data. Patients: Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Main Outcome Measures: Recovery of HPA axis function. Results: SST 30-minute cortisol levels above or below 350 nmol/L (12.7 µg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 µg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 µg/dL) recovered HPA axis function. Conclusions: Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines.

C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro-caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines.

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol.

CONTEXT: Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 µg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. METHODS: We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. RESULTS: In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. CONCLUSION: Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.