Katrin Ritzel

Context: Cushing’s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. Objective: Evaluation of lipid profiles during active CS and the early postoperative period. Patients and methods: In this single-center cohort study at LMU Hospital, Munich, we analyzed lipid profiles (total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein (a), triglycerides, and non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n = 23) after curative surgery and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. Results: Paradoxically, most lipid parameters worsened postoperatively. One month following surgery, HDL (1 month postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], P < .0001) and ApoA1 concentrations (1-month postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], P < .0001) were significantly lower compared to preoperative levels. Similarly, 1-month following surgery triglycerides concentrations (1-month postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, P < .0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed 3 distinct postoperative trajectories depending on BMI at baseline. Conclusion: During the early remission phase following curative surgery for CS, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provide the basis for targeted therapy.

Hypertension is the most frequent co-morbidity in active Cushing's syndrome (CS) and regarded as a major cardio-vascular risk factor. It is unknown whether blood pressure and related parameters, such as kidney function, recover in the long-term following remission of CS. Blood pressure and related co-morbidities were analyzed in a cohort of 81 patients with CS (Cushing's disease: 52, ectopic CS: 8, adrenal CS: 21) from a single tertiary care center. Patients were longitudinally evaluated at baseline, at 7.1 years (6.3-7.4) and at 14 years (13.5-14.4) after biochemical remission. Data were compared to a control group matched for BMI, age and sex (n = 243) from the "Cooperative Health Research in the Region of Augsburg" study (KORA) in a 1:3 fashion. Patients with CS showed a higher median blood pressure and lower median glomerular filtration rate (GFR) compared to the matched controls, at baseline, 7 and 14 years after biochemical remission. Although the prevalence of hypertension and chronic kidney disease increased over time in the KORA cohort, patients treated for CS had a significantly higher prevalence of both comorbidities. Notably, the number of patients on antihypertensive medication declined in the Cushing's cohort, resulting in significantly higher rates of uncontrolled hypertension at follow-up. The prevalence of hypertension and impaired kidney function remained elevated in patients with CS years after biochemical remission, potentially contributing to an unfavorable long-term clinical outcome. This highlights the critical need for increased monitoring and treatment of co-morbidities in patients with CS following surgical remission.

Context: Patients with Cushing's syndrome (CS) suffer from metabolic and cardiovascular comorbidities caused by hypercortisolism. The human gut microbiome responds to different pathological conditions. Objective: The aim of our study was to analyze the effect of chronic endogenous cortisol excess on the gut microbiome. Methods: We prospectively recruited 18 patients with endogenous CS of different etiologies (mainly pituitary CS, n = 13). Patients provided a stool sample during active CS and 1 to 2 years after successful surgical treatment being in biochemical remission. In addition, 36 patients, in whom CS was excluded, served as an obese control group and 108 samples from healthy lean students were used as a reference group. Amplicons of the V3/V4 region of the 16S ribosomal RNA gene, from every sample, were sequenced and clustered into operational taxonomic units. The microbial profiles of CS patients were then compared to the control and reference groups using R scripts. Results: In comparison to lean references, the gut microbiome of patients with florid CS demonstrated a disturbed microbial profile. Microbial dysbiosis of patients with CS was maintained even after biochemical remission following curative surgery. Conclusion: Patients with CS have a distinct and disturbed gut microbiome that persists even after surgery, indicating a possible target for additional probiotic interventions to accelerate convergence to a healthy microbiome.

Background: Cushing's syndrome (CS) can be difficult to diagnose. A timely diagnosis, however, is the cornerstone for targeted treatment, to reduce morbidity and mortality. One reason for the difficulties to identify early on patients with CS might be the presence of a mild phenotype. The aim of the study was to classify the phenotypic landscape of CS. We studied patients with overt CS and mild autonomous cortisol secretion (MACS). Method: The study was part of the German Cushing's registry. Patients were prospectively included at time of diagnosis and the number of comorbidities and clinical signs and symptoms were assessed in a standardized fashion. One hundred twenty-nine patients with CS (pituitary CS, n = 85, adrenal CS, n = 32, ectopic CS, n = 12, respectively) and 48 patients with MACS were included. Patients with clinical signs and/or comorbidities typical for CS and at least 2 pathological screening tests were classified as having CS. Patients with a 1 mg low-dose-dexamethasone-suppression test above 1.8 µg/dL without being clinically overt CS were classified as having MACS. Results: On average, patients with CS had 2 comorbidities (range 1-3) at time of diagnosis (pituitary CS: 2 [1-3], adrenal CS: 3 [2-4], ectopic CS: 3 [2-4]). Patients with MACS, however, had 3 comorbidities (range 2-3). Hypertension was the most common comorbidity in all subtypes of CS (78%-92%) and in patients with MACS (87%). Of a total of 11 clinical signs, patients with CS had on average 5 with 28% of patients having between 0 and 3 clinical signs, 50% 4-7 signs, and 22% more than 7 clinical signs. Patients with MACS had on average 2 clinical signs (range 1-3) at time of diagnosis. Conclusion: The phenotypic landscape of CS is quite variable. The frequency of comorbidities is similar between patients with CS and MACS. A relevant number of patients with overt CS have just a few clinical signs. There is also an overlap in frequency of symptoms and clinical signs between patients with CS and MACS. According to the current guidelines, 96% of our patients with MACS fall into the category “consideration of adrenalectomy”. This should be kept in mind when making treatment decisions in the latter group of patients.

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.

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 analyzed (185 CD, 27 ECS, 84 uni- and bilateral ACS). Results First-line treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, interquartile range) was longer in CD (11.0 weeks, 5.6-29.8; P < .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 < .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 < .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. Conclusion 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.