Prevalence and outcome of secondary hypogonadism in male patients with Cushing's syndrome and mild autonomous cortisol secretion.

BACKGROUND: Secondary hypogonadism (SH) is common in men with Cushing's syndrome (CS), but its impact on comorbidities is largely unknown and longitudinal data are scarce. If SH also affects men with mild autonomous cortisol secretion (MACS) is unknown. METHODS: We included 30 treatment-naïve adult men with CS and 17 men with MACS diagnosed since 2012. Hypogonadism was diagnosed based on total testosterone (TT) concentrations < 10.4 nmol/L and age-specific cut-offs. Outcomes were compared to age- and BMI-matched controls. In 20 men in remission of CS, a longitudinal analysis was conducted at 6, 12, and 24 months. RESULTS: Men with CS had significantly lower concentrations of TT, bioavailable T, and free T compared to controls (P < .0001) with lowest concentrations in ectopic CS. Likewise, TT was lower in men with MACS compared to controls. At baseline, 93% of men with CS and 59% of men with MACS had SH. Testosterone correlated negatively with late night salivary cortisol and serum cortisol pre- and post-1 mg dexamethasone suppression test. Following successful surgery, TT increased significantly (P = .001), normalising within 6 months. Despite normalisation, several RBC parameters remained lower in men with CS even 2 years after successful surgery. CONCLUSIONS: Secondary hypogonadism is common in men with CS and MACS but usually reversible after successful surgery. The persisting changes observed in RBC parameters need to be further investigated in larger cohorts and longer follow-up durations.

Biochemical Control in Cushing's syndrome: Outcomes of the treatment in a large single center cohort.

BACKGROUND: Normalization of hypercortisolism is essential to reduce morbidity and mortality in patients with Cushing's syndrome (CS). The aim of this analysis was to assess biochemical control rates in patients with Cushing's disease (CD), ectopic Cushing's syndrome (ECS) and adrenal Cushing's syndrome (ACS). METHODS: Patients with confirmed CS (n= 296) treated in a single tertiary care center were retrospectively analysed (185 CD, 27 ECS, 84 uni- and bilateral ACS). RESULTS: Firstline treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, IQR) was longer in CD (11.0 weeks, 5.6-29.8; p< 0.05) than in ACS (7.7 weeks, 4.1-17.1) and ECS (5.6 weeks, 4.1-23.3). Disease persistence or recurrence after first-line therapy was observed more often in CD (24% and 18%; p< 0.05) than in ECS (15% and 15%) and ACS (6% and 4%). Total time in hypercortisolism since diagnosis was significantly shorter in patients with CD diagnosed since 2013, after specialized patient care was implemented, compared to patients diagnosed before 2013 (13.5 weeks, vs. 26.1 weeks; p< 0.0070). Control of hypercortisolism at last follow up (76 months, 38-163) was achieved in 94% of patients with ACS, 100% of patients with ECS and 92% of patients with CD. CONCLUSIONS: Biochemical control can be achieved in most patients with different subtypes of CS within a reasonable time frame. Control of hypercortisolism has improved over time.

The Landscape of Androgens in Cushing's Syndrome.

Hyperandrogenemia in patients with Cushing's syndrome (CS) presents a diagnostic pitfall due to its rare occurrence and overlapping symptoms with more common conditions like polycystic ovary syndrome (PCOS). This review explores the significance of androgen dysregulation in CS, focusing on both classical and 11-oxygenated androgens. While classical androgens contribute to hyperandrogenism in CS, their levels alone do not fully account for clinical symptoms. Recent research highlights the overlooked role of 11oxC19 androgens, particularly 11OHA4 and 11KT, in driving hyperandrogenic manifestations across all CS subtypes. These adrenal-specific and highly potent androgens offer stable expression throughout the lifespan of a woman, serving as valuable diagnostic biomarkers. Understanding their prominence not only aids in subtype differentiation but also provides insights into the complex nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches and improve clinical management strategies for patients with CS.

Sleep disturbances in primary aldosteronism are associated to depressive symptoms - Could specific mineralocorticoidreceptors be a common pathway?

Symptoms of depression and anxiety are frequent in patients with primary aldosteronism (PA) and are supposed to be independent risk factors for cardiovascular diseases (CVD). As patients with PA have an increased cardiovascular risk compared to patients with essential hypertension, sleep disturbances, which often accompany depressive and anxiety symptoms, may be an additional contributor to the cardiometabolic consequences of PA. To clarify this possible link we investigated 132 patients with PA at baseline and after one year after initiation of treatment either by adrenalectomy (ADX) or mineralocorticoid-receptor-antagonist (MRA). Sleep disturbances and daytime sleepiness were assessed with Pittsburg sleep Inventory (PSQI) and Epworth sleepiness scale (ESS). Patients with PA showed pathological scores for sleep disturbances at baseline according to PSQI, with females being more affected (8.1 vs. 5.7 p < 0.001), which was significantly improved after initiation of specific treatment (p = 0.002). For ESS we found scores within the normal range, but higher than the general population, which significantly improved at follow-up (p < 0.001). The intensity of sleep disturbances was highly correlated with scores of anxiety and depression at baseline and follow-up. However, clinical and biochemical markers of PA (e.g. aldosterone, blood pressure) and metabolic markers did not show a consistent association with sleep changes. The degree of improvement in PSQI was significantly associated with the improvement of brief patients health questionnaire (PHQD) (p = 0.0151). Sleep disturbances seem not to be an independent risk factor for cardiovascular and metabolic problems in PA. They are strongly associated to depressive symptoms and maybe mediated by the same mineralocorticoid receptor circuits.

Delineating endogenous Cushing's syndrome by GC-MS urinary steroid metabotyping.

BACKGROUND: Diagnosing Cushing's syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. METHODS: We quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing's disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FINDINGS: Cluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11ß-OH-An + 11ß-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. INTERPRETATION: GC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FUNDING: The study was funded by the Else Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.