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BACKGROUND: cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy. METHODS AND RESULTS: Fifty-nine diabetic men (60.3±7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [], -12.6±3.1; increased left ventricular [LV] torsion [], 18.4±4.6°; and increased ratio of LV mass to volume, 2.1±0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro-B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion ([Delta]: sildenafil, -3.89±3.11° versus placebo, 2.13±2.35°; P<0.001) and strain ([Delta]: sildenafil, -3.30±1.86 versus placebo, 1.22±1.84; P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5±11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-[beta] were the only markers affected by active treatment ([Delta]monocyte chemotactic protein-1: -75.30±159.28 pg/mL, P=0.032; [Delta]transforming growth factor-[beta]: 5.26±9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism. CONCLUSIONS: The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00692237. [ABSTRACT FROM AUTHOR]

The syndrome of ectopic adrenocorticotrophin secretion (EAS) is rare and is due to excess adrenocorticotrophin (ACTH) production from a nonpituitary tumour. These tumours can be covert, where the tumours are not readily apparent, and very small making them challenging to image. It is clinically and biochemically difficult to distinguish between covert EAS and Cushing's disease. The first-line investigation in locating the source of ACTH production is computed tomography (CT). The aim of this pictorial review is to illustrate the likely covert sites and related imaging findings. We review the CT appearances of tumours resulting in covert EAS and the associated literature. The most common tumours were bronchial carcinoid tumours, which appear as small, well-defined, round or ovoid pulmonary lesions. Rarer causes included thymic carcinoids, gastrointestinal carcinoids and pancreatic neuroendocrine tumours. Awareness of the imaging characteristics will aid identification of the source of ACTH production and allow potentially curative surgical resection. [ABSTRACT FROM AUTHOR]

Purpose: Andrological pathologies in the adulthood are often the results of conditions that originate during childhood and adolescence and sometimes even during gestation and neonatal period. Unfortunately, the reports in the literature concerning pediatric andrological diseases are scares and mainly concerning single issues. Furthermore, no shared position statement are so far available., Methods: The Italian Society of Andrology and Sexual Medicine (SIAMS) commissioned an expert task force involving the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP) to provide an updated guideline on the diagnosis and management of andrological disorders from childhood and adolescence to transition age. Derived recommendations were based on the grading of recommendations, assessment, development, and evaluation (GRADE) system., Results: A literature search of articles in English for the term "varicoceles", "gynecomastia", "fertility preservation", "macroorchidism", "precocious puberty" and "pubertal delay" has been performed. Three major aspects for each considered disorder were assessed including diagnosis, clinical management, and treatment. Recommendations and suggestions have been provided for each of the mentioned andrological disorders., Conclusions: These are the first guidelines based on a multidisciplinary approach that involves important societies related to the field of andrological medicine from pediatric to transition and adult ages. This fruitful discussion allowed for a general agreement on several recommendations and suggestions to be reached, which can support all stakeholders in improving andrological and general health of the transitional age., Competing Interests: Declarations. Conflict of interest: Authors declare no competing interstest. Compliance with ethics standards: This article does not contain any studies with human or animal subjects. Research involving human participants and/or animals: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: For this type of study, formal consent is not required., (© 2024. The Author(s).)

Purpose: Although thyroid nodules are less common in the pediatric population, the risk of malignancy is higher than in adult patients. The aim of this study was to evaluate the ultrasonographic predictive factors of malignancy in thyroid nodules and to validate American College of Radiologists (ACR) TI-RADS performance in transition age patients., Methods: One hundred forty-two patients aged between 14 and 21 years referred to the participating centers for FNA biopsy of a thyroid nodule between 2007 and 2022 were included and ultrasound reports and sonographic images were retrospectively analyzed. Nodule features were defined according to the ACR-TIRADS lexicon. Two reference standards were applied: FNA cytology and surgical histology. The diagnostic performance of single sonographic features was estimated. Significant predictors were then included in a multivariate regression model., Results: Nodules included in ACR-TIRADS categories TR4 or TR5 had 10-fold increased risk of indeterminate or suspicious/malignant cytology [p < 0.001]. In univariate analysis, solid composition [p = 0.016] and presence of hyperechoic foci [p = 0.040] significantly increased the likelihood of malignant histology. In multivariate regression analysis, irregular margins [p = 0.011] and hyperechoic foci [p = 0.019] were independent predictors of indeterminate or suspicious/malignant cytology., Conclusion: Nodules included in ACR-TIRADS categories TR4 or TR5 had 10-fold increased risk of indeterminate or suspicious/malignant cytology in transition age. ACR-TIRADS was not able to rule-out malignancy compared to FNAB alone, suggesting the need to reconsider recommendations in the transition age group., Competing Interests: Compliance with ethical standards. Conflict of interest: G.G. and D.G. are associated editors of Endocrine. Cosimo Durante is a member of Endocrine Editorial Board. They will not be involved in the editorial review or the decision to publish this article. The other authors have no competing interest to declare that are relevant to the content of this article. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Sapienza University of Rome Ethics Committee, reference 7141, Prot. 0418/2023. Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Studies describing the coagulation profile in adrenal adenomas still need to be added., Objective: We explored how sex and mild autonomous cortisol secretion (MACS) affect coagulation parameters in patients with adrenal adenomas., Design: Cross-sectional study., Methods: From January 2019 until April 2023, participants in the Impact of Adrenal IncidenTalomas and Possible Autonomous Cortisol Secretion on Cardiovascular and Metabolic Alterations trial (NCT04127552) diagnosed with adrenal adenoma were categorised according to the 1 mg overnight dexamethasone-suppression test (1 mg-DST). Coagulation parameters were evaluated, and two-way ANOVA was used to elucidate the cortisol-by-sex interaction., Results: Of 153 patients screened, 90 were enrolled (62.2% female, mean age 62 ± 10 years): 41 with non-functioning adrenal tumour (1 mg-DST ≤ 1.8 µg/dL), and 49 with a MACS (1 mg-DST > 1.8 µg/dL). Platelet counts were higher in the MACS group ( P = .01). Regression analysis identified female sex (B = 36.603, P = .011), 1mg-DST (B = 0.238, P = .042), and younger age (B = -1.452, P = .038) as independent predictors for elevated platelet count. In patients with MACS, women exhibited higher levels of procoagulant factors fibrinogen ( P = .004) and factor VIII ( P < .001), and coagulation inhibitors protein C ( P = .003) and antithrombin III ( P = .005) than males. No differences were observed in the non-functioning adrenal tumour group, providing a cortisol-by-sex interaction regarding fibrinogen ( P = .047), factor VIII ( P = .046), and protein C ( P = .028)., Conclusion: Our findings revealed a worse coagulation profile in women with MACS, underscoring the need for a sex-specific approach in clinical practice to manage thrombotic risks effectively. Dedicated prospective studies are needed to validate and integrate these findings into clinical strategies for thromboprophylaxis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© 2024. The Author(s).)

Background: Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo., Methods: In a 12-month prospective case-control multicentre trial, the daily fluctuations in the number of circulating peripheral blood mononuclear cells (PBMCs) and the time-specific expression of clock-related genes were analysed in a cohort of 68 subjects, 34 affected by CS and 34 matched controls. Cosinor mixed effects model, rhythmicity algorithms and machine learning techniques were applied to the multi-level dataset., Findings: Multiple, 5-point daily sampling revealed profound changes in the levels, amplitude, and rhythmicity of several PBMC populations during active CS, only partially restored after remission. Clock gene analyses in isolated PBMCs showed a significant flattening of circadian oscillation of CLOCK, PER1, PER2, PER3, and TIMELESS expression. In active CS, all methods confirmed a loss of rhythmicity of those genes which were circadian in the PBMCs of controls. Most, but not all, genes regained physiological oscillation after remission. Machine learning revealed that while combined time-course sets of clock genes were highly effective in separating patients from controls, immune profiling was efficient even as single time points., Interpretation: In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity., Funding: The research leading to these results has received funding from the European Union in the context of the National Recovery and Resilience Plan, Investment PE8 - Project Age-It: "Ageing Well in an Ageing Society". This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022], the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health, and through internal funding to Sapienza University of Rome., Competing Interests: Declaration of interests None of the authors have received funding or have other fees to declare related to this project. SC is a PC member for the Association for Computational Linguistics (ACL)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hormones are chemical messengers that regulate a wide range of physiological processes including metabolism, development, growth, reproduction and mood. The concentration of hormones that orchestrate the numerous bodily functions is very low (1 nM or less). Efforts have been made to develop highly sensitive tools to detect them. This review represents a critical comparison between different types of nanoparticle-based electrochemical biosensors for the detection of various hormones, namely cortisol, sex hormones (estradiol, progesterone, testosterone), insulin, thyroid-stimulating hormone (TSH) and growth hormone (GH). The electrochemical biosensors investigated for each hormone are first divided on the basis of the biological fluid tested for their detection, and successively on the basis of the electrochemical transducer utilized in the device (voltammetric or impedimetric). Focus is placed on the nanoparticles employed and the successive electrode modification developed in order to improve detection sensitivity and specificity and biosensor stability. Limit of detection (LOD), linear range, reproducibility and possibility of regeneration for continuous reuse are also investigated and compared. The review also addresses the recent trends in the development of wearable biosensors and point-of-care testing for hormone detection in clinical diagnostics useful for endocrinology research, and the future perspectives regarding the integration of nanomaterials, microfluidics, near field communication (NFC) technology and portable devices.

Background: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH., Methods: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control., Results: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups., Conclusions: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Cardiac abnormalities are common in patients with acromegaly, contributing to the increased morbidity and mortality. Cardiac magnetic resonance (CMR) is the gold standard for measuring cardiac morpho-functional changes. This study aims to detect cardiac alterations in acromegaly through CMR, even when the disease is adequately controlled., Methods: In this, multicentre, case-control study, we compared consecutive patients with acromegaly, cured after surgery or requiring medical treatment, with matched controls recruited among patients harbouring non-functioning adrenal incidentalomas., Results: We included 20 patients with acromegaly (7 females, mean age 50 years) and 17 controls. Indexed left ventricular-end-diastolic volume (LV-EDVi) and LV-end-systolic volume (LV-ESVi) were higher in patients than in controls (p < 0.001), as were left ventricular mass (LVMi) (p = 0.001) and LV-stroke volume (LV-SVi) (p = 0.028). Right ventricle (RV) EDVi and ESVi were higher, whereas RV-ejection fraction (RV-EF) was lower (p = 0.002) in patients than in controls (p < 0.001). No significant differences were observed in the prevalence of cardiometabolic comorbidities, including hypertension, glucose and lipid metabolism impairment, obstructive sleep apnoea syndrome, and obesity. IGF1 x upper limit of normal significantly predicted LVMi (b = 0.575; p = 0.008). Subgroup analysis showed higher LVMi (p = 0.025) and interventricular septum thickness (p = 0.003) in male than female patients, even after adjusting cardiac parameters for confounding factors., Conclusions: The CMR analysis reveals a cluster of biventricular structural and functional impairment in acromegaly, even when the biochemical control if achieved. These findings appear specifically triggered by the exposure to GH-IGF1 excess and show sex-related differences advocating a possible interaction with sex hormones in cardiac disease progression., (© 2024. The Author(s).)

Purpose: Cushing's syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS., Methods: This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up., Results: Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure., Conclusion: CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors., (© 2024. The Author(s).)

Background: Bilateral testicular germ cell tumours (B-GCT) are rare, with an incidence of 2-5%, and can be classified as synchronous (sB-GCT) or metachronous (mB-GCT). Our study aimed to identify clinical, biochemical, and radiological risk factors for mB-GCT in a cohort of patients with GCT at a single tertiary referral centre., Methods: This retrospective case-control study included patients with GCT referred to Policlinico Umberto I-Sapienza University of Rome, from 2005 to 2023. We evaluated clinical history, testicular ultrasound features, hormone levels, semen analysis, histological characteristics, staging, and treatments. mB-GCTs were compared with unilateral GCT patients with a follow-up longer than the median time-to-onset of the second tumour., Results: Of 319 patients, 52 experienced B-GCT, with a median time-to-onset of the second tumour of 62 months (range: 8-229). The mB-GCT group showed higher gonadotropin levels (FSH 13.6mUI/mL vs. 7.4mUI/mL, p < 0.001; LH 6.6mUI/mL vs. 3.9mUI/mL, p = 0.004), lower sperm concentration (27 × 10 6 /ejaculate vs. 78 × 10 6 /ejaculate, p = 0.009), smaller residual testis volume (10.4 mL vs. 16.3 mL, p < 0.001), more inhomogeneous echotexture [57.5% vs. 14%, p < 0.001], and presence of microlithiasis (75% vs. 19.5%, p < 0.001). Kaplan-Meier curves confirmed that ultrasound features of the residual testis increased the cumulative risk of developing a second tumour. Microlithiasis was a strong independent predictor (OR 30.712, 95% CI 3.357-280.942, p = 0.002)., Conclusions: Histological features of the first tumour or its treatment do not influence the onset of a second tumour. However, low residual testis volume, inhomogeneous echotexture, and microlithiasis significantly increase this risk. A comprehensive evaluation of the residual testis at baseline is essential for developing a personalised surveillance programme in GCT survivors, with regular ultrasound follow-up recommended beyond the conventional 5-year limit., (© 2024 The Author(s). Andrology published by John Wiley & Sons Ltd on behalf of American Society of Andrology and European Academy of Andrology.)

Context: Data supporting successful and satisfactory penile prosthesis (PP) implantation outcomes are mainly based on subjective, rather than objective, analysis., Objective: To systematically review and objectively analyze, all available data related to patient and partner PP satisfaction., Evidence Acquisition: An extensive search was performed, including the following key-words: ("penile prosthesis" and "satisfaction"). The search, which accrued data from January 1, 1969, up to July 31, 2023, was restricted to English-language articles including human participants., Evidence Synthesis: Out of 663 retrieved articles, 83 were considered including, 12,132 subjects with a mean age and mean follow-up of 58.6 [range 20; 77.1] years and 47.6 [range 6; 374] months, respectively. Overall, a high patient satisfaction rate was observed 83[80; 86]%. The satisfaction rate increased in subjects with three-piece PP and in those with a higher rate of cardiovascular or neurological diseases and was independent of the patient's age. Partner's satisfaction rate was lower when compared to that observed in men and it increased according to the use of inflatable devices and the presence of patient Peyronie's disease. The long-term complication rate was limited ranging from 3% for erosion to 4.6% when mechanical failure was considered., Conclusions: Patient and partner satisfaction is excellent and increases with time. The number of complications is limited and is strongly associated with the presence of diabetes mellitus., Patient Summary: We found a high couple satisfaction score that was higher when reported by males compared to females. Patient satisfaction increased with time, and it was independent of age., (© 2024 American Society of Andrology and European Academy of Andrology.)