Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic-pituitary-gonadal axis activation in Klinefelter syndrome.

PURPOSE: The role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism. METHODS: This retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement. RESULTS: The tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031). CONCLUSION: In KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults.

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.

Characterization of circulating immune cells and correlation with Tie2/Angiopoietins level in well differentiated neuroendocrine gastroenteropancreatic tumors: a cross-sectional analysis.

PURPOSE: The immune environment represents a new, but little explored, tool for understanding neuroendocrine neoplasms (NENs) behavior. An immunosuppressed microenvironment is hypothesized to promote NENs progression. A missing profiling of circulating leukocyte and peripheral blood mononuclear cells (PBMCs) subpopulations would open new perspectives in the still limited diagnostic-therapeutic management of NENs. METHODS: A cross-sectional case-control pilot study was performed recruiting 30 consecutive subjects: 15 patients naïve to treatment, with histologically proven gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and 15 healthy controls, matched for age and sex. PBMCs subpopulations were studied by flow cytometry. Soluble Tie2 (sTie2), Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) were evaluated by ELISA. RESULTS: Immune cell profiling revealed a significant lower CD3-CD56+ natural killer (NK) cell count in NETs vs controls (p = 0.04). NK subset analysis showed a reduced relative count of CD56+CD16+ NK cells (p =0.002) in NETs vs controls. Patients with NET showed a higher percentage of CD14+CD16++ non-classical monocytes (p = 0.01), and a lower percentage of CD14+CD16+ intermediate monocytes (p = 0.04). A decrease in percentage (p = 0.004) of CD4+ T-helper lymphocytes was found in NET patients. Evaluation of cellular and serum angiopoietin pathway mediators revealed in NET patients a higher relative count of Tie2-expressing monocytes (TEMs) (p < 0.001), and high levels of Ang-1 (p = 0.003) and Ang-2 (p = 0.002). CONCLUSIONS: Patients with GEP-NET presented an immunosuppressed environment characterized by a low count of cytotoxic NK cells, a high count of anti-inflammatory non-classical monocytes, and a low count of T-helper lymphocytes. Higher levels of TEMs and angiopoietins suggest a crosstalk between innate immunity and angiogenic pathways in NETs.

Bilateral testicular masses and adrenal insufficiency: is congenital adrenal hyperplasia the only possible diagnosis? First two cases of TARTS described in Addison-only X-linked adrenoleukodystrophy and a brief review of literature.

BACKGROUND: Testicular adrenal rest tumors (TARTs) are benign masses deemed to originate from pluripotent testicular steroidogenic cells that grow under chronic ACTH stimulation. These lesions, occasionally misdiagnosed as Leydig cell tumors (LCTs), are typically described in patients with congenital adrenal hyperplasia (CAH). X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of beta-oxidation with accumulation of very long chain fatty acids (VLCFAs) in various tissues, and a rare cause of primary adrenal insufficiency (PAI). TARTs have never been associated with X-ALD. CASE 1 DESCRIPTION: A 19-year old male, who had previously undergone bilateral enucleation of presumed LCTs, was referred to our unit. Follow-up scans showed persistent bilateral lesions compatible with TARTs. Biochemical exams revealed PAI but excluded CAH. A serum VLCFAs panel was consistent with X-ALD, with gene testing confirming the diagnosis. Histological revision of the previously resected testicular lesions was compatible with TARTs. Start of glucocorticoid replacement therapy was associated with a reduction of testicular masses. CASE 2 DESCRIPTION: A 26-year old X-ALD male was diagnosed with bilateral testicular lesions compatible with TARTs. These lesions increased after ACTH elevation following switch to modified-release hydrocortisone. Clinical and sonographic findings allowed for a "watchful-waiting" approach, avoiding unnecessary surgery. CONCLUSION: These are the first cases reported of TARTs in patients with X-ALD-associated PAI. Testicular lesions in patients with an early onset of ACTH elevation, regardless of the cause, should always be thoughtfully investigated, as they may reveal themselves as TARTs. We suggest that all patients affected from chronic ACTH elevation of a young age of onset should undergo testicular ultrasound in order to evaluate the presence of these lesions. GRT in these patients might also help preserving fertility.