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Context: It has been claimed that thyroid dysfunction contributes to the spectrum of Klinefelter syndrome (KS); however, studies are scarce., Objective: In a retrospective longitudinal study, we aimed at describing the hypothalamic-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span., Methods: A total of 254 patients with KS (25.9 ± 16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched individuals with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, antithyroid antibodies, US thyroid parameters, and in vitro pituitary type 2 deiodinase (D2) expression and activity., Results: Thyroid autoimmunity was more prevalent among individuals with KS at all ages, although the antibody (Ab)-negative vs Ab-positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in prepubertal, pubertal, and adult patients with KS, whereas thyrotropin values were lower only in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism., Conclusion: From infancy through adulthood, KS is characterized by increased morphofunctional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Klinefelter syndrome is the most common chromosomal disorder in males and the most common cause of hypergonadotropic hypogonadism. We describe the natural history of testicular dysfunction in patients with Klinefelter syndrome through the integration of clinical, hormonal, and quantitative ultrasound data in a life-course perspective., Design: Prospective semilongitudinal study., Methods: We included 155 subjects with 47,XXY karyotype (age range: 7 months-55 years) naïve to testosterone replacement therapy. Subjects were divided according to pubertal stage and age group (transition age and adults). Serial clinical, hormonal, and testicular ultrasound (US) assessments were performed., Results: Testicular development progresses until Tanner stage 4, with subsequent regression, whereas Sertoli and germ cell impairment is not hormonally detected before Tanner stages 3-4, as reflected by normal inhibin B values until stage 4 and the fall in the inhibin B/follicle-stimulating hormone ratio thereafter. The testosterone/luteinizing hormone ratio peaks during Tanner stages 2-3 and declines from Tanner stage 4 onward, preceding the development of overt hypogonadism. US echotexture progressively worsens until transition age, reflecting ongoing gonadal compromise, whereas quantitative US echotexture measures and the presence of both hypoechoic lesions and microlithiasis independently and significantly predict a lower circulating testosterone level., Conclusions: The findings from this large prospective study contribute to our understanding of the natural history of testicular dysfunction in Klinefelter syndrome, underlining the importance of quantitative testicular US in infancy and childhood, as well as during pubertal development and transition age, for the optimal care of Klinefelter syndrome patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Experimental studies on Klinefelter syndrome (KS) reported increased intratesticular testosterone (T) levels coexisting with reduced circulating levels. Abnormalities in testicular microcirculation have been claimed; however, no studies investigated in vivo testicular blood flow dynamics in humans with KS., Objective: To analyze the testicular microcirculation in KS by contrast-enhanced ultrasonography (CEUS) and correlate vascular parameters with endocrine function., Design and Setting: Prospective study. University setting., Patients: Sixty-eight testicular scans, 34 testes from 19 T-naïve subjects with KS and 34 testes from age-matched eugonadal men (control) who underwent CEUS for incidental nonpalpable testicular lesions., Main Outcomes: CEUS kinetic parameters., Results: CEUS revealed slower testicular perfusion kinetics in subjects with KS than in age-matched controls. Specifically, the wash-in time (P = 0.018), mean transit time (P = 0.035), time to peak (P < 0.001), and wash-out time (P = 0.004) were all prolonged. Faster testicular blood flow was associated with higher total T levels. Principal component analysis and multiple linear regression analyses confirmed the findings and supported a role for reduced venous blood flow as independent predictor of total T levels., Conclusions: Testicular venous blood flow is altered in KS and independently predicts T peripheral release., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Despite the pivotal role of calcium signaling in immune response, little is known about immune function in patients affected by hypoparathyroidism., Objective: This work aimed to evaluate immune function in hypoparathyroidism., Methods: The Evaluation of iMmune function in Postsurgical and AuToimmune HYpoparathyroidism (NCT04059380) is a case-control, cross-sectional study set in an Italian referral center. Participants included 20 patients with postsurgical hypoparathyroidism (12 females) and 20 age- and sex-matched controls. Main outcome measures included calcium metabolism assessment, peripheral blood mononuclear cells (PBMC) profiling via flow cytometry, parathyroid hormone receptor 1 (PTHr1) expression analysis using immunofluorescence and PrimeFlow RNA assay, gene expression analysis via real-time polymerase chain reaction, cytokine measurement, and evaluation of infectious disease frequency and severity., Results: Immune cell profiling revealed decreased monocytes, regulatory, naive, and total CD4+ T lymphocytes, which correlated with total calcium, ionized calcium, and PTH levels, in patients with hypoparathyroidism. Patients with hypoparathyroidism had a higher CD3-CD56+ natural killer (NK) cell count, which inversely correlated with calcium, PTH, and vitamin D levels. Furthermore, they exhibited decreased tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor gene expression and decreased circulating TNF levels. Gene expression and immunofluorescence analysis confirmed PTHr1 expression in all PBMC lineages; however, the percentage of cells expressing PTHr1 was lower, whereas the intensity of PTHr1 expression in monocytes, total T lymphocytes, CD8+CD4+ and CD4+ T lymphocytes, and total NK cells was higher in patients with hypoparathyroidism., Conclusions: This study describes for the first time the immune alterations in patients with hypoparathyroidism receiving conventional therapies, supporting the immunoregulatory role of PTH and proposing an explanation for the increased susceptibility to infections observed in epidemiological studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs., Objective: We hypothesized that 5α-RI may worsen the adverse effects of GCs., Design: Prospective, randomized study., Patients: A total of 19 healthy male volunteers (age 45 ± 2 years; body mass index 27.1 ± 0.7kg/m2)., Interventions: Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated., Main Outcome Measures: Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels., Results: Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482 ± 96 vs 761 ± 57 nmol/L, P = 0.029). Prednisolone alone did not alter Ra glucose (2.55 ± 0.34 vs 2.62 ± 0.19 mg/kg/minute, P = 0.86), M-value (3.2 ± 0.5 vs 2.7 ± 0.7 mg/kg/minute, P = 0.37), or glucose oxidation (0.042 ± 0.007 vs 0.040 ± 0.004 mmol/hr/kg/minute, P = 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67 ± 0.16 vs 3.05 ± 0.18 mg/kg/minute, P < 0.05) and decreased M-value (4.0 ± 0.5 vs 2.6 ± 0.4 mg/kg/minute, P < 0.05), and oxidation (0.043 ± 0.003 vs 0.036 ± 0.002 mmol/hr/kg, P < 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1 ± 28.9 vs 36.8 ± 14.3 μmol/L, P = 0.81), unless co-administered with a 5α-RI (49.8 ± 8.6 vs 88.5 ± 13.5 μmol/L, P < 0.01)., Conclusions: We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency., Objective: To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency., Design: Observational, retrospective, longitudinal analysis., Patients: A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed., Main Outcome Measures: PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose., Results: PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC., Conclusions: The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function., Objective: To assess timing and predictors of HPA axis recovery after TSA., Design: Single-center, retrospective analysis of consecutive pituitary surgeries performed between February 2015 and September 2018., Patients: Patients (N = 109) with short Synacthen test (SST) data before and at sequential time points after TSA., Main Outcome Measures: Recovery of HPA axis function at 6 weeks, and 3, 6, and 9 to12 months after TSA., Results: Preoperative SST indicated adrenal insufficiency in 21.1% Among these patients, 34.8% recovered by 6 weeks after TSA. Among the 65.2% (n = 15) remaining, 13.3% and 20% recovered at 3 months and 9 to 12 months, respectively. Of the 29% of patients with adrenal insufficiency at the 6-week SST, 16%, 12%, and 6% subsequently recovered at 3, 6, and 9 to 12 months, respectively. Preoperative SST 30-minute cortisol, postoperative day 8 cortisol, and 6-week postoperative SST baseline cortisol levels above or below 430 nmol/L [15.5 μg/dL; AUC ROC, 0.86]; 160 nmol/L (5.8 μg/dL; AUC ROC, 0.75); and 180 nmol/L (6.5 μg/dL; AUC ROC, 0.88), were identified as cutoffs for predicting 6-week HPA recovery. No patients with all three cutoffs below the threshold recovered within 12 months after TSA, whereas 92% with all cutoffs above the threshold recovered HPA function within 6 weeks (OR, 12.200; 95% CI, 5.268 to 28.255)., Conclusion: HPA axis recovery can occur as late as 9 to 12 months after TSA, demonstrating the need for periodic reassessment of patients who initially have SST-determined adrenal insufficiency after TSA. Pre- and postoperative SST values can guide which patients are likely to recover function and potentially avoid unnecessary lifelong glucocorticoid replacement., (Copyright © 2019 Endocrine Society.)

Context: Adrenal insufficiency (AI) requires lifelong glucocorticoid (GC) replacement. Conventional therapies do not mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the machinery controlling circadian functions and are influenced by GCs. However, clock gene expression has never been investigated in patients with AI., Objective: To evaluate the effect of the timing of GC administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients from the Dual Release Hydrocortisone vs Conventional Glucocorticoid Replacement in Hypocortisolism (DREAM) trial., Design: Outcome assessor-blinded, randomized, active comparator clinical trial., Participants and Intervention: Eighty-nine patients with AI were randomly assigned to continue their multiple daily GC doses or switch to an equivalent dose of once-daily modified-release hydrocortisone and were compared with 25 healthy controls; 65 patients with AI and 18 controls consented to gene expression analysis., Results: Compared with healthy controls, 19 of the 68 genes were found modulated in patients with AI at baseline, 18 of which were restored to control levels 12 weeks after therapy was switched: ARNTL [BMAL] (P = 0.024), CLOCK (P = 0.016), AANAT (P = 0.021), CREB1 (P = 0.010), CREB3 (P = 0.037), MAT2A (P = 0.013); PRKAR1A, PRKAR2A, and PRKCB (all P < 0.010) and PER3, TIMELESS, CAMK2D, MAPK1, SP1, WEE1, CSNK1A1, ONP3, and PRF1 (all P < 0.001). Changes in WEE1, PRF1, and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes, and CD16+ natural killer cells., Conclusions: Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).

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.

Context: Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients., Objective: To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs)., Design: Randomized, double-blind, placebo-controlled study in type 2 diabetes., Patients and Intervention: A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected., Main Outcome and Measures: Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT., Results: Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile., Conclusions: Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.