Expression Patterns of MOTS-c in Adrenal Tumors: Results from a Preliminary Study.

Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression.

[The value of dehydroepiandrosterone sulfate in the differential diagnosis of primary bilateral adrenal macronodular hyperplasia].

Objective: To investigate the value of serum dehydroepiandrosterone sulfate (DHEAS) in the differential diagnosis of primary bilateral macronodular adrenal hyperplasia (PBMAH) from nonfunctional adenoma tumors (NFA), adrenocortical adenoma (ADA) and Cushing's disease (CD). Methods: A cross-sectional study. The clinical data of 302 patients with PBMAH, NFA, ADA and CD diagnosed and treated in the First Medical Center of PLA General Hospital from January 2010 to June 2021 were retrospectively analyzed. Among them, 97 were males and 205 were females, aged (45.7±7.2) years. The area under receiver operating characteristic (ROC) curve was used to evaluate the DHEAS ratio (serum DHEAS value divided by the lower limit of normal reference range for the corresponding age and sex) and the 8∶00 adrenocorticotropic hormone (ACTH) level in the differential diagnosis of PBMAH from NFA, ADA and CD. The maximum value of Youden index was cut-off value. Results: Among the 302 patients, 33 were in PBMAH group, 125 were in NFA group, 67 were in ADA group, and 77 were in CD group. The DHEAS ratio in CD group, NFA group, PBMAH group and ADA group decreased successively, with values of 6.34(4.44, 9.93), 3.37(2.24, 4.79), 1.14(1.04, 2.40) and 0.58(0.27, 1.05), respectively. There was statistical significance among all groups (all P<0.01). The area under the ROC curve for distinguishing PBMAH from NFA, ADA and CD were 0.803, 0.741 and 0.930, and the cut-off value were 2.59, 0.99 and 2.92, respectively. The sensitivity was 66.1%, 64.2% and 87.9%, respectively. The specificity was 81.8%, 81.2% and 85.7%. According to the level of 8∶00 ACTH, PBMAH was divided into ACTH-inhibited group (ACTH<2.2 pmol/L,n=18) and ACTH-non-inhibited group (ACTH≥2.2 pmol/L, n=15).The DHEAS ratio in ACTH-non-inhibited PBMAH group was higher than that in ACTH-inhibited PBMAH group(P<0.01).The area under ROC curve of DHEAS ratio for identifying ACTH-non-inhibited PBMAH and CD was 0.877, the cut-off value was 4.55, the sensitivity was 93.3%, and the specificity was 75.3%. If the DHEAS ratio combined with 8∶00 ACTH was used as a differential diagnostic indicator, the area under the ROC curve for distinguishing ACTH-non-inhibitory PBMAH from CD can reach 0.967, with the sensitivity of 100.0% and the specificity of 81.8%. Conclusions: DHEAS ratios is different in PBMAH, NFA, ADA and CD patients, which can assist in the differential diagnosis of PBMAH from NFA、ADA and CD patients, especially in the differential diagnosis of ACTH-non-inhibited PBMAH patients and CD patients.

Predicting postoperative hypocortisolism in patients with non-aldosterone-producing adrenocortical adenoma: a retrospective single-centre study.

BACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1 mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6 days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1 mg dexamethasone suppression test (median 1 mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p < 0.001). Univariate analysis showed preoperative 1 mg dexamethasone suppression test negatively related with baseline ACTH levels (r = - 0.376; p = 0.041) and negatively associated with the 6-week baseline (r = - 0.395, p = 0.034) and 30-min cortisol levels during Short Synacthen test (r = - 0.534, p = 0.023). Logistic regression analysis demonstrated preoperative 1 mg dexamethasone suppression test as the only biochemical predictor for 6-week adrenal recovery: ROC curve identified a 1 mg dexamethasone suppression test threshold of 131 nmol/L predicting 6-week recovery with 89.5% sensitivity and 72.7% specificity (AUC 0.87; 95% CI 66.9-98.7, p < 0.001). Other preoperative assessments (tumor size, ACTH levels and anthropometrics) were not associated with postoperative hypothalamus-pituitary-adrenal axis function, but the presence of diabetes was associated with a lower probability of recovery (OR = 24.55, p = 0.036). ACTH levels increased postoperatively in all patients but did not predict hypothalamus-pituitary-adrenal axis recovery. CONCLUSIONS: The preoperative 1 mg dexamethasone suppression test cortisol value and presence of diabetes are the only relevant predictor of hypothalamus-pituitary-adrenal axis recovery in patients with non-aldosterone- producing adrenocortical adenoma undergoing surgery, regardless other clinical and biochemical variables. Notably, pre- and postoperative ACTH levels did not predict hypothalamus-pituitary-adrenal axis recovery. These findings point towards the potential for saving resources by optimizing their allocation during follow-up assessments for patients with non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy.

Correlation of Histopathologic Subtypes of Primary Aldosteronism with Clinical Phenotypes and Postsurgical Outcomes.

CONTEXT: Clinical implications of unilateral primary aldosteronism (PA) histopathology remain to be determined in various ethnic populations. OBJECTIVE: We examined the histopathology of unilateral PA using CYP11B2 immunostaining in relation to clinical phenotypes and postsurgical outcomes. METHODS: Patients consecutively operated for unilateral PA from 2010 to 2020 at 3 tertiary hospitals in South Korea were retrospectively enrolled. Adrenals with solitary aldosterone-producing adenomas and/or dominant aldosterone-producing nodules were classified as the classical and the others as the nonclassical groups. The classical group was subdivided into mixed or solitary group according to whether other aldosterone-producing lesions coexist or not. RESULTS: Of the 240 cases, 124 were solitary, 86 mixed, and 30 nonclassical. Baseline serum potassium concentration was lower in the solitary group than the mixed or nonclassical group. Plasma aldosterone concentration after saline loading was the highest in the solitary group (median 31.65 ng/dL), followed by the mixed group (median 25.40 ng/dL), and the lowest in the nonclassical group (median 14.20 ng/dL). Solitary and mixed groups showed higher lateralization indices and lower contralateral indices than the nonclassical group. The contralateral index was lower in the solitary group than the mixed group. At 6 to 12 months after adrenalectomy, fewer antihypertensive medications were required for the solitary and mixed groups than the nonclassical group. CONCLUSION: The solitary group, followed by the mixed group, was associated with more severe hyperaldosteronism and more suppressed aldosterone production from the contralateral side than the nonclassical group. Histopathologic phenotypes were related to the clinical manifestations and may suggest postoperative prognosis.

Targeted Mutational Analysis of Cortisol-Producing Adenomas.

CONTEXT: Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1. OBJECTIVE: This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and "subclinical" mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue. METHODS: We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3ß-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations. RESULTS: Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase). CONCLUSION: A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs.

Is there a role for the IGF system and epidermal growth factor (EGF) in the pathogenesis of adrenocortical adenomas? A preliminary case-control study.

Adrenal incidentalomas (AI) are very common and mostly they are non-functioning adenomas (NFA). NFAs are often associated with insulin resistance and metabolic syndrome. Several biomarkers, including certain growth factors, may participatein the pathogenesis ofmetabolic changes in patients with adrenal adenomas.Patients with NFA and age-matched control subjects were enrolled in the study. Data on age, gender, presence of metabolic syndrome or its components were obtained for each subject. Blood samples were obtained and glycemia, insulinemia, lipid profile, and selected growth factor levels were measured. Forty-three patients with NFA and 40 controls were included in the study. Differences were not found in the metabolic syndrome and its components prevalence or in the biochemical profile between patients and the control group. Significant differences were noticed in the levels of IGF1, IGF2, and IGFBP3 (p=0.016, p=0.005, p=0.004, respectively), but there were no differences in VEGF or EGF concentrations. In NFA patients, an association between glycemia and EGF levels was present (p=0.026). No significant correlations between tumor size and insulin or growth factor concentrations were present in AI patients. Significantly higher serum IGF1, IGF2, and IGFBP3 concentrations in NFA patients may support the role of the IGF axis in the pathogenesis of adrenocortical lesions.No correlation between IGFs or IGFBP3 and parameters of glucose or lipid metabolism was found. Present results may support the role of the growth hormone axis rather than hyperinsulinemia and insulin resistance in the pathogenesis of adrenocortical adenomas.

A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.

CONTEXT: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). OBJECTIVE: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. DESIGN, SETTING, AND PATIENTS: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. RESULTS: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. CONCLUSIONS: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.

The Concordance Between Imaging and Adrenal Vein Sampling Varies With Aldosterone-Driver Somatic Mutation.

BACKGROUND: Correct subtyping of primary aldosteronism (PA) is critical for guiding clinical management. Adrenal imaging is less accurate than adrenal vein sampling (AVS); nonetheless, AVS is invasive, technically challenging, and scarcely available. OBJECTIVE: To identify predictors of concordance between cross-sectional imaging and lateralized AVS in patients with PA that could help circumvent AVS in a subset of patients. METHODS: We retrospectively studied all patients with PA who underwent AVS in a tertiary referral center from 2009 to 2019. AVS was performed before and after cosyntropin stimulation. Patients with lateralized AVS in at least one condition were included. Aldosterone synthase-guided next-generation sequencing was performed on available adrenal tissue. Logistic regression was implemented to identify predictors of imaging-AVS lateralization concordance. RESULTS: A total of 234 patients (62% men), age 20 to 79 years, 73% white, 23% black, and 2% Asian were included. AVS lateralization was found: 1) both pre- and post-cosyntropin (Uni/Uni) in 138 patients; 2) only at baseline (Uni/Bi) in 39 patients; 3) only after cosyntropin stimulation (Bi/Uni) in 29 patients. Catheterization partially failed in 28 patients. AVS-imaging agreement was higher in patients with KCNJ5 versus other aldosterone-driver somatic mutations (90.3% versus 64.6%; P < 0.001); in Asian and white versus black Americans (75%, 70%, and 36%, respectively); in younger patients; and those with left adrenal nodules and contralateral suppression. Conversely, AVS-imaging agreement was lowest in Uni/Bi patients (38% vs. 69% in Uni/Uni, and 62% in Bi/Uni; P = 0.007). CONCLUSIONS: While AVS-imaging agreement is higher in young white and Asian patients, who have KCNJ5-mutated aldosterone producing adenomas, no predictor confers absolute imaging accuracy.

Basal contralateral aldosterone suppression is rare in lateralized primary aldosteronism.

CONTEXT: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. OBJECTIVES: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. METHODS: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. RESULTS: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. CONCLUSIONS: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.

Ectopic Cortisol-producing Adrenocortical Adenoma Detected by 131I-6ß-iodomethyl-norcholesterol Scintigraphy.

A 50-year-old man was referred to our department for overt Cushing's syndrome (CS). His plasma cortisol concentrations were 314 µg/L, and his urinary cortisol concentrations were 431 µg/day. The plasma adrenocorticotropic hormone (ACTH) concentration was below the detectable limit. Computed tomography revealed atrophy of both adrenal glands and the presence of a left pararenal tumor. 131I-6ß-iodomethyl-norcholesterol scintigraphy showed an intense uptake by the left pararenal tumor. These findings suggested that the left pararenal tumor was ectopic cortisol-producing adrenocortical adenoma. This case serves as a reminder that 131I-6ß-iodomethyl-norcholesterol scintigraphy is an effective method for diagnosing ACTH-independent CS in which no adrenal tumor has been found.

Developments in Primary Aldosteronism Subtyping Using Steroid Profiling.

Adrenal venous sampling is the standard of care for identifying patients with unilateral primary aldosteronism, which is often caused by an aldosterone producing adenoma and can be cured with surgery. The numerous limitations of adrenal venous sampling, including its high cost, scarce availability, technical challenges, and lack of standardized protocols, have driven efforts to develop alternative, non-invasive tools for the diagnosis of aldosterone producing adenomas. Seminal discoveries regarding the pathogenesis of aldosterone producing adenomas made over the past decade have leveraged hypotheses-driven research of steroid phenotypes characteristic of various aldosterone producing adenomas. In parallel, the expanding availability of mass spectrometry has enabled the simultaneous quantitation of many steroids in single assays from small volume biosamples. Steroid profiling has contributed to our evolving understanding about the pathophysiology of primary aldosteronism and its subtypes. Herein, we review the current state of knowledge regarding the application of multi-steroid panels in assisting with primary aldosteronism subtyping.

A clinical prediction score using age at diagnosis and saline infusion test parameters can predict aldosterone-producing adenoma from idiopathic adrenal hyperplasia.

PURPOSE: Accurate subtyping of the primary aldosteronism into aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH) is important to direct for specific treatment modalities. The objective of the study was to compare the clinical and biochemical parameters of APA and IAH patients to derive a Clinical Prediction Score reliably predicting APA from IAH. METHODS: This was a retrospective multi-centre study recruiting 38 APA patients and 42 IAH patients from four major hospitals in Hong Kong using database from Surgical Outcomes Monitoring and Improvement Programme and Clinical Data Analysis and Reporting System. Their clinical and biochemical parameters were evaluated. RESULTS: Patients in APA group were younger than IAH group (mean age 48.6 ± 9.2 vs. 57.1 ± 7.3 years old, p < 0.001), had more suppressed renin before saline infusion in saline infusion test (SIT) (median 0.19 [IQR 0.15-0.37] vs. 0.39 [IQR 0.19-0.69] ng/mL/h, p = 0.01), and higher aldosterone level after saline infusion in SIT (median 674 [IQR 498-1000] vs. 327 [IQR 242-483] pmol/L, p < 0.001). A clinical prediction score using three parameters was devised, comprising age at diagnosis < 50 years, PRA before saline infusion in SIT ≤ 0.26 ng/mL/h, and aldosterone level after saline infusion in SIT ≥ 424 pmol/L. A score of 2 would predict APA with a sensitivity of 84.2% and specificity of 88.1%, and a score of 3 would predict APA with a sensitivity of 31.6% and specificity of 100%. CONCLUSIONS: Clinical Prediction Score based on the combination of age at diagnosis, PRA, and aldosterone level in the saline infusion tests could reliably predict APA from IAH.

Insulin secretion and sensitivity before and after surgical treatment for aldosterone-producing adenoma.

AIM: Primary aldosteronism, which is usually caused by an aldosterone-producing tumour, affects glucose metabolism. The effects of this condition on insulin secretion and insulin sensitivity have remained unclear, however. To gain insight into the influence of primary aldosteronism on glucose tolerance, various parameters related to insulin secretion or insulin sensitivity in patients with an aldosterone-producing tumour were comprehensively analyzed. METHODS: To assess 14 patients with an aldosterone-producing tumour, hyperglycaemic and hyperinsulinaemic-euglycaemic clamp tests as well as oral glucose tolerance tests (OGTTs) were performed before and after tumour excision. Time between presurgical analysis and surgery was 27-559 (194±132) days, and 14-142 (51±38) days between surgery and postsurgical analysis. Various parameters related to insulin secretion or sensitivity as determined by OGTT as well as hyperglycaemic and hyperinsulinaemic-euglycaemic clamp analyses were evaluated. RESULTS: Surgical treatment of tumours ameliorated hypokalaemia and reduced plasma aldosterone levels. First and second phases of insulin secretion during the hyperglycaemic clamp, as well as the insulinogenic index and total insulin secretion measured during OGTT, were also improved after surgery. In addition, the insulin sensitivity index determined during the hyperinsulinaemic-euglycaemic clamp was reduced after surgery. CONCLUSION: Primary aldosteronism impairs insulin secretion.

Seated saline infusion test in predicting subtype diagnosis of primary aldosteronism.

CONTEXT: Although saline infusion test is widely used as a confirmatory test for primary aldosteronism (PA), it is reportedly less sensitive in patients in whom aldosterone is responsive to the upright position by performing it in recumbent position. Based on a single-centre experience, seated saline infusion test (SSIT) has been reported to be highly sensitive and superior to recumbent testing in identifying both unilateral and bilateral forms of PA. However, due to limited participants number, the utility of SSIT needs to be validated in other series. OBJECTIVE: This study aimed to evaluate the accuracy of SSIT in determining the PA subtypes compared with adrenocorticotropic hormone stimulation test under dexamethasone suppression (Dex-AT). PATIENTS AND SETTING: Sixty-four patients with PA who underwent both SSIT and Dex-AT were included. Subtype diagnosis of PA was determined by adrenal venous sampling (AVS) (16 unilateral and 48 bilateral forms). MAIN OUTCOME MEASURE: Plasma aldosterone concentrations (PACs) were measured after SSIT and Dex-AT. RESULTS: The area under the receiver operating characteristic (ROC) curve for diagnosing unilateral PA was greater in SSIT than that in Dex-AT (0.907 vs. 0.755; P = .023). ROC curve analysis predicted optimal cut-off PACs of 13.1 ng/dL (sensitivity, 93.8%; specificity, 79.2%) for SSIT and 34.2 ng/dL (sensitivity, 75.0%; specificity, 68.8%) for Dex-AT. CONCLUSIONS: Seated saline infusion test has superior accuracy in subtype diagnosis of PA compared with Dex-AT. SSIT can be a sensitive test for determining patients who require AVS prior to surgery.

Serum steroid profiling by mass spectrometry in adrenocortical tumors: diagnostic implications.

PURPOSE OF REVIEW: Liquid chromatography-tandem mass spectrometry (LC-MS/MS), allowing the reliable measurement of large panels of steroids, opened a new era in the characterization of adrenal diseases. This review summarizes the most recent findings on serum steroid profile in benign adrenocortical tumors and provides a focus on the most promising analytical developments. RECENT FINDINGS: Recently developed LC-MS/MS assays included challenging compounds, providing new knowledge on adrenal steroid secretion. Pioneering studies highlighted the potential of incoming technologies in increasing measurement selectivity and implementing the steroidomic approach. In primary aldosteronism, several studies highlighted the signature of aldosterone-producing adenomas, mainly characterized by secretion of hybrid steroids. The combination of steroid panel and radiological data reached an agreement with adrenal vein sampling-based classification in more than 80% of the cases. The serum steroid profiling in patients with Cushing's syndrome, mainly characterized by reduced androgens and increased 11-dexoycorticosterone in adrenal hypercortisolism, showed a good discriminant power for patients' subtyping (90% correct classification rate). Finally, a selected panel of steroids, including 11-deoxycortisol as the main discriminant compound, was able to achieve a good separation of patients with and without adrenocortical carcinomas. SUMMARY: The constantly evolving serum steroid profiling by MS may improve the diagnosis of different types of adrenocortical tumors.

A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman.

BACKGROUND: Hyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen-secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range. CASE PRESENTATION: A 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin α, melan A, ß-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided. CONCLUSIONS: Pure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.

Changes in glucose metabolism based on 75-g oral glucose tolerance tests before and after surgery for adrenal Cushing's syndrome.

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient ß-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 µg/day [interquartile range: 321.0-743.0 µg/day] to 31.3 µg/day [23.6-40.6 µg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.