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. 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. 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. 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. 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.

Context: Medical therapy for Cushing syndrome (CS) typically aims to reduce daily cortisol output without addressing circadian rhythm restoration. No licensed drugs target this goal. Objective: We investigated the efficacy and safety of timed, once-daily osilodrostat administration in improving circadian cortisol profiles in CS. Methods: A prospective, multicenter study evaluated patients with well-controlled CS on a stable twice-daily osilodrostat therapy before and 60 to 90 days after transitioning to a single equivalent daily dose at 19:00 ± 1 hour. Circadian steroid analysis was performed on saliva, serum, and urine using ultra-high performance liquid chromatography–tandem mass spectrometry. Additional assessments included cardio-metabolic markers, quality of life, sleep function, and safety outcomes. Results: Sixteen patients (4 males; 7 pituitary, mean age 53.3 ± 11.8 years) were enrolled. At baseline, CS was well-controlled with a mean osilodrostat dose of 4.2 ± 1.3 mg. After transitioning, salivary cortisol exposure decreased significantly during the afternoon to early morning period (AUC16:00-08:00: −6.1 [−0.15 to −12.1] ng/mL/h, P = .029). Quality of life and sleep improved (CushingQoL: +4.2, P = .029; Pittsburgh Sleep Quality Index: −1.7, P = .049). Serum steroid precursors, including 11-deoxycorticosterone (−3.1 ng/mL/h, P = .008) and 11-deoxycortisol (−17.8 ng/mL/h, P = .005), decreased. Eight patients advancing dosing to 16:00 ± 1 hour showed comparable reductions, with phase shifts in acrophase and nadir. No patients developed adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control. Conclusion: Once-daily osilodrostat effectively and safely treats patients with biochemically controlled CS, improving circadian cortisol profiles, quality of life, and sleep. Findings support further exploration of chronotherapy-based approaches in CS management.

Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.

Purpose Dyslipidemias are highly prevalent metabolic disturbances and represent a major driver of atherosclerotic cardiovascular disease. Beyond primary forms, numerous endocrine diseases induce secondary dyslipidemias that substantially modify lipid metabolism and contribute to cardiometabolic risk. This Position Statement of the Nutrition Hormones and Metabolism Club of the Italian Society of Endocrinology (SIE) aims to provide an updated, evidence-based synthesis of the pathophysiology, biochemical profile, and clinical impact of dyslipidemias associated with endocrine disorders. Methods A comprehensive review of current literature was performed, integrating epidemiological, mechanistic, and clinical data on lipid alterations across major endocrine diseases. Expert consensus was used to interpret evidence and formulate recommendations for clinical practice. Results Distinct and disease-specific dyslipidemic patterns were identified across conditions involving the hypothalamic–pituitary, thyroid, adrenal, gonadal, and GH/IGF-1 axes. Disorders such as acromegaly, growth hormone deficiency, hypothyroidism, hyperthyroidism, Cushing’s syndrome, male and female hypogonadism, congenital adrenal hyperplasia, and polycystic ovary syndrome exhibit characteristic lipid abnormalities driven by hormonal dysregulation. These alterations contribute to increased cardiometabolic risk yet are frequently underrecognized and suboptimally managed. Early identification and tailored intervention may significantly improve outcomes. Conclusion Endocrine-related dyslipidemias represent a clinically relevant but often overlooked contributor to cardiovascular risk. By summarizing current evidence and expert perspectives, this Position Statement aims to support clinicians in improving diagnosis, risk stratification, and management of lipid disorders associated with endocrine diseases, fostering a multidisciplinary approach to cardiometabolic prevention.

The growing burden of obesity and diabetes underscores the need for innovative strategies to identify secondary causes. While hypercortisolism is traditionally considered rare, its broader spectrum - from mild autonomous cortisol secretion to overt Cushing's syndrome (CS) - may be under-recognized in these populations. We systematically searched MEDLINE, Scopus and Web of Science for original studies assessing hypercortisolism in obesity or diabetes. We included first-line screening tests for hypercortisolism, particularly the dexamethasone suppression test (DST), and subsequent confirmed CS. Data were pooled using random-effects models and are presented as 95%CIs. Certainty of evidence was assessed with GRADE. Of 3038 articles, 39 (14,995 screened participants) were included. In a pooled cohort of 8705 individuals with obesity (19 studies), the prevalence of an abnormal DST was 4.6% (95%CI: 3.2-6.4), and CS confirmed in 0.8% [0.4-1.5]. Among 6638 patients with diabetes (22 studies), 14.3% (95%CI: 10.9-18.4) had an abnormal DST, increasing to 23.3% (95%CI: 22.2-24.5) after heterogeneity adjustment; 2.1% (95%CI: 1.3-3.3) had confirmed CS. Younger age, recent weight gain, and diabetes were significant predictors of CS. One in six abnormal DST led to CS confirmation. Exploratory economic analyses supported broadening screening in selected cohorts. GRADE certainty ranged from low to moderate. In a clinically relevant subset of patients with obesity and diabetes, underlying hypercortisolism remains undiagnosed. The implications of abnormal DST without confirmed CS warrant further investigation. Screening strategies for secondary causes of obesity and type 2 diabetes might require reassessment, pending confirmation in unbiased cohorts.

Objective: To determine whether cardiac remodelling associated with mild autonomous cortisol secretion (MACS) is reversible after treatment and how trajectories compare with non-functioning adrenal incidentalomas (NFAI). Design: Five-year prospective cohort study (ITACA; NCT04127552). Methods: Sixty patients (35 MACS, 25 NFAI) underwent clinical, biochemical, and echocardiographic evaluations at baseline and after 1 and 5 years. MACS was managed with either active surveillance (AS, n = 22) or unilateral adrenalectomy (ADRX, n = 13). Longitudinal changes were analysed with linear mixed-effects models. Results: At baseline, MACS had a higher prevalence of left-ventricular (LV) hypertrophy (46% vs 16%, P = .013) and diastolic dysfunction (34% vs 12%, P = .050), and greater LV mass index (LVMi) (median 100 vs 85 g/m², P = .011). Over time, the change in LVMi differed between NFAI, MACS-AS and MACS-ADRX (P = .004). At 1 year, LVMi fell by −14.8 g/m² (95%CI −28.7 to −0.9) after ADRX and rose by 13.7 g/m² (0.8 to 26.5) under AS. By 5 years, LVMi returned to baseline in both MACS subgroups, whereas NFAI increased by 22.4 g/m² (12.3 to 32.5; P < .001). Right-ventricular systolic excursion (TAPSE) improved only in AS (3.6 mm, 1.8 to 5.4; P = .001). Global LV systolic and diastolic indices deteriorated similarly across groups. Major adverse cardiac events occurred in 13.3% of MACS-AS, 12.5% of ADRX, and 5.6% of NFAI patients. Conclusions: MACS is associated with early concentric LV remodelling that regresses after adrenalectomy but rebounds within 5 years, leaving surgical and surveillance patients with comparable cardiac geometry. Under AS, remodelling stabilizes, whereas NFA continue a slow, progressive hypertrophic course. These findings support serial echocardiographic monitoring and underscore the need to test other cortisol-lowering therapies, alone or in combination with surgery, for durable cardioprotection.