Ebbehøj, Andreas Ladefoged

Abstract Context Patients with mild autonomous cortisol secretion (MACS) have higher rates of vertebral fractures compared to patients with non-functioning adrenal nodules, yet bone density is not always reduced. Objective To characterize the effect of MACS on bone density, metabolism, and microstructure as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Design Cross-sectional study, 2019-2022 Setting Tertiary referral center Participants Seventy-five patients with MACS and 75 age-, sex-, and gonadal status–matched referent subjects. Measurements Bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan, and HR-pQCT. Outcomes Areal and volumetric bone mineral density (aBMD, vBMD), trabecular bone score (TBS), microstructural parameters including trabecular bone volume to total volume (BV/TV) ratio. Results While no differences in aBMD were observed at any skeletal site, patients with MACS had decreased TBS (1.389 vs 1.475, P < .001) and lower osteocalcin concentration (17.1 vs 19.5 ng/mL, P = .030) than referent subjects. On HR-pQCT at the tibia, patients with MACS had reduced trabecular BV/TV (0.220 vs 0.233, P = .015) compared to referent subjects. On multivariable analysis, MACS was associated with lower TBS (odds ratio [OR] per SD decrease 2.87 [1.65-5.00]), lower trabecular BV/TV at the radius (OR per SD decrease 2.58 [1.33-5.00]), and lower trabecular BV/TV at the tibia (OR per SD decrease 4.06 [2.10-7.86]). Conclusion Patients with MACS have microstructural deterioration that may not be evident on routine DXA aBMD testing.

Abstract Objectives The impact of mild autonomous cortisol secretion (MACS) on cognition is incompletely characterized. We aimed to assess cognition in patients with MACS, identify factors associated with lower cognition, and determine the impact of adrenalectomy on cognition. Methods We conducted a cross-sectional study (4/2019 to 10/2022) and a longitudinal cohort study (10/2021 to 9/2023) of adults with MACS and referent subjects. Cognition was assessed with National Institute of Health Toolbox Cognition Battery and reported as standardized T scores (adjusted for age, sex, race/ethnicity, and education) for fluid, crystallized, and total composite cognition. Participants were assessed with urine steroid profiling (liquid chromatography-tandem mass spectrometry), frailty index, Beck’s Depression Inventory (BDI), and Short Form-36 (SF-36). Results A total of 84 patients (median age 57 years, 67% women) and 201 referent subjects (median age 63 years, 58% women) were included. Patients with MACS demonstrated lower mean (SD) total composite (50.9 [9.3] vs 55.4 [8.9], P < .001) and fluid composite T score (49.3 [10.6] vs 55.2 [10.2], P < .001), but not crystallized composite T score (52.3 [8.4] vs 54.0 [8.4], P = .130) when compared with referent subjects. Multivariable analysis adjusted for age, sex, BDI, SF-36, frailty index, total glucocorticoids, and androgens demonstrated that MACS status was associated with lower cognition. When cognition was reassessed in 37 patients post-adrenalectomy and 31 referent subjects, adjusted group differences of cognition change were similar except for a higher comparative increase in attention and executive functioning in patients with MACS. Conclusion Patients with MACS demonstrate lower cognition than referent subjects. Adrenalectomy for MACS had a minor positive impact on cognition.

Abstract Context Mild autonomous cortisol secretion (MACS) is diagnosed based on postdexamethasone cortisol >1.8 µg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. Objective To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS vs referent subjects. Methods Cross-sectional study, 2018-2023, at a referral center. Patients with MACS and age-, sex-, body mass index–, and menopausal status–matched referent subjects were included. Urine was collected over a 24 hour period as separate daytime and nighttime collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects was admitted for serum measurements of free and total cortisol every 2 hours. Outcomes were steroids, steroid sums, and ratios. Results Patients with MACS (n = 72) had lower µg/24 hour median androgens (2084 vs 3283, P < .001), higher glucocorticoids (15 754 vs 12936, P < .001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P < .001) than referent subjects. Patients also had lower steroid day/night ratios than referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour areas under the curve for total and free serum cortisol were similar. However, evening mean total (5.3 vs 4.0 µg/dL, P = .056) and free (0.2 vs 0.1 µg/dL, P = .035) cortisol was higher in patients vs referent subjects. Conclusion Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.

Abstract Objective Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. Design Population-based cohort study, Olmsted County, MN, 1995-2017. Methods Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. Conclusions Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

Abstract Objective 11-oxygenated androgens significantly contribute to the circulating androgen pool. Understanding the physiological variation of 11-oxygenated androgens and their determinants is essential for clinical interpretation, for example, in androgen excess conditions. We quantified classic and 11-oxygenated androgens in serum and saliva across the adult age and body mass index (BMI) range, also analyzing diurnal and menstrual cycle-dependent variation. Design Cross-sectional. Morning serum samples were collected from 290 healthy volunteers (125 men, 22-95 years; 165 women, 21-91 years). Morning saliva samples were collected by a sub-group (51 women and 32 men). Diurnal saliva profiles were collected by 13 men. Twelve women collected diurnal saliva profiles and morning saliva samples on 7 consecutive days during both follicular and luteal menstrual cycle phases. Methods Serum and salivary steroids were quantified by liquid chromatography–tandem mass spectrometry profiling assays. Results Serum classic androgens decreased with age-adjusted BMI, for example, %change kg/m2 for 5α-dihydrotestosterone: men −5.54% (95% confidence interval (CI) −8.10 to −2.98) and women −1.62% (95%CI −3.16 to −0.08). By contrast, 11-oxygenated androgens increased with BMI, for example, %change kg/m2 for 11-ketotestosterone: men 3.05% (95%CI 0.08-6.03) and women 1.68% (95%CI −0.44 to 3.79). Conversely, classic androgens decreased with age in both men and women, while 11-oxygenated androgens did not. Salivary androgens showed a diurnal pattern in men and in the follicular phase in women; in the luteal phase, only 11-oxygenated androgens showed diurnal variation. Conclusions Classic androgens decrease while active 11-oxygenated androgens increase with increasing BMI, pointing toward the importance of adipose tissue mass for the activation of 11-oxygenated androgens. Classic but not 11-oxygenated androgens decline with age.

Abstract Context Urinary bladder paraganglioma (UBPGL) is rare. Objective We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL. Methods We conducted a multicenter study of consecutive patients with pathologically confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality. Results Patients (n=110 total; n=56 [51%] women) were diagnosed with UBPGL at a median age of 50 years (interquartile range [IQR], 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after the initial diagnosis. Development of metachronous metastases was associated with younger age (hazard ratio [HR] 0.97; 95% CI, 0.94-0.99), UBPGL size (HR 1.69; 95% CI, 1.31-2.17), and a higher degree of catecholamine excess (HR 5.48; 95% CI, 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR 20.80; 95% CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality. Conclusions Only a minority of patients were diagnosed before biopsy/surgery, reflecting need for better diagnostic strategies. All patients with UBPGL should have lifelong monitoring for development of recurrence and metastases.

Abstract Context While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking. Objective To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas. Design Population-based cohort study. Setting Olmsted County, Minnesota, USA. Patients Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas. Main outcome measure Prevalence, incidence of cardiometabolic outcomes, mortality. Results (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups. Conclusion Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.

Objective Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. Design Population-based cohort study, Olmsted County, Minnesota, USA, 1995–2017. Methods Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20–96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0–21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07–1.52) for developing a new fracture during follow up when compared to referent subjects. Conclusions Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Abstract Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Abstract Background: Adrenal tumors are reported in 5% of adults, with malignancy rates in 1–12%, and rates of overt hormonal excess in 1–15 %. However, most estimates originate from convenience samples. Our objective was to determine the incidence, prevalence and clinical presentation of adrenal tumors in a population-based setting. Methods: We used a centralized epidemiologic database to identify patients diagnosed with adrenal tumors in a local community 1995 to 2017. The database is a unique medical records linkage system that allows access to hospital and community medical records for local residents (population 137,000). We calculated incidence rates (IR) as the number of new patients diagnosed while living in the study area, and prevalence as the number of patients living in the study area on Dec 31 2017. IR and prevalence were sex- and age-adjusted to the 2010 US Census population. Results: Of 1,287 patients diagnosed with adrenal tumor, the median age of diagnosis was 62 years (IQR 52–72), 713 (55%) were women, and 13 (1%) were younger than 18 years at diagnosis. IR was highest in patients >65 YO, followed by patients 40–64 YO, 18–39 YO and <18 YO (142 vs 66 vs 9 vs 2 per 100,000 persons years). IR per 100,000 increased from 4.4 (CI95% 0.3–8.6) in 1995 to 47.8 (CI95% 36.9–58.7) in 2017. Overall prevalence in the population was 0.53% in 2017, ranging from 0.01% among 0–17 YO to 1.9% among +65 YO. Malignant adrenal mass was diagnosed in 8.7% patients (4 patients with adrenal cortical carcinoma (0.3%) and 108 (8.4%) patients with other malignant mass). Pheochromocytoma was diagnosed in 11 (1.1%) patients and benign adrenal mass was diagnosed in 1,175 (90.2%) patients (1,076 (83.6%) with adrenal adenoma and 85 (6.6%) with other benign mass). Median tumor size was 15 mm (range 5–255), and 184 (14%) of patients had bilateral tumors. Only 255 (20%) patients had dexamethasone suppression test, 93 (36%) with cortisol>1.8 mcg/dl. Of 1,076 adrenal adenomas, 53 (4.9%) had overt hormone excess, 140 (13%) had nonfunctioning adrenal adenomas, and 88 (8.2%) had mild autonomous cortisol secretion. Hormonal work up for was incomplete in 795 (73.9%) adenomas. Patients discovered incidentally (1,050, 81.6%) had a lower rate of malignancy and hormone excess (5.3% vs 52% of patients with non-incidental discovery, p <0.001). Rate of malignancy was highest in children (67% vs 8% >18YO, p<0.001), bilateral tumors (16% vs 8% unilateral, p<0.001), tumors ≥4 cm (33% vs 7% in < 4 cm, p<0.001). Conclusion: IR of adrenal tumors increased 10-fold since 1995, and was highest in patients >65 YO. 8.7% of tumors were malignant, with a majority represented by malignant adrenal tumors other than adrenal cortical carcinoma. The risk of malignancy was highest in non-incidental discovery, children, and tumors > 4 cm. Overt hormone excess was diagnosed in 4.5% of patients. The majority of patients with adrenal adenomas had a suboptimal work up for hormone excess.