Presentation, disease progression and outcomes of adrenal gland metastases.

OBJECTIVE: Data on the presentations and outcomes of patients with adrenal gland metastases are limited. Our objectives were to characterize the prevalence of adrenal metastases subtypes and investigate how varying clinical presentations affect disease progression, development of primary adrenal insufficiency (PAI) and mortality. DESIGN: Single institution tertiary centre, retrospective cohort study from 1997 to 2020. PATIENTS AND MEASUREMENTS: Adult patients with adrenal metastases. Clinical, radiologic and biochemical presentations and outcomes were reviewed. RESULTS: Of 579 patients (62.3% men, median age 67 years [range 25-92]) with adrenal metastases (median tumour size of 30 mm [range 5-200]), 339 (58.5%) were discovered during cancer staging, 210 (36.3%) were found incidentally, and 29 (5.0%) based on symptoms. Tumours originated from the lung (226, 39.0%), genitourinary (GU) (160, 27.6%), gastrointestinal (GI) (79, 13.6%) and other (114, 19.7%) organ systems. Bilateral metastases were found in 140 (24.2%) patients at the time of initial diagnosis, and 249 (43.0%) had bilateral disease throughout the study course. PAI developed in 12.4% of patients with bilateral disease and was associated with larger tumour size. Median follow-up time was 14 months (range 0-232), and 442 (76.3%) patients died. Higher mortality was independently associated with older age, adrenal metastases originating from the lung, bilateral disease, and the absence of adrenalectomy. CONCLUSIONS: Adrenal gland metastases originated most commonly from lung, GU and GI malignancies. Bilateral adrenal metastases occurred in 43% of patients, and PAI occurred in 12.4% of those with bilateral disease, warranting further case detection strategies.

Investigating the Role of G Protein ßγ in Kv7-Dependent Relaxations of the Rat Vasculature.

Objective- In renal arteries, inhibitors of G protein ßγ subunits (Gßγ) reduce Kv7 activity and inhibit Kv7-dependent receptor-mediated vasorelaxations. However, the mechanisms underlying receptor-mediated relaxation are artery specific. Consequently, the aim of this study was to ascertain the role of Gßγ in Kv7-dependent vasorelaxations of the rat vasculature. Approach and Results- Isometric tension recording was performed in isolated rat renal, mesenteric, and cerebral arteries to study isoproterenol and calcitonin gene-related peptide relaxations. Kv7.4 was knocked down via morpholino transfection while inhibition of Gßγ was investigated with gallein and M119K. Proximity ligation assay was performed on isolated myocytes to study the association between Kv7.4 and G protein ß subunits or signaling intermediaries. Isoproterenol or calcitonin gene-related peptide-induced relaxations were attenuated by Kv7.4 knockdown in all arteries studied. Inhibition of Gßγ with gallein or M119K had no effect on isoproterenol-mediated relaxations in mesenteric artery but had a marked effect on calcitonin gene-related peptide-induced responses in mesenteric artery and cerebral artery and isoproterenol responses in renal artery. Isoproterenol increased association with Kv7.4 and Rap1a in mesenteric artery which were not sensitive to gallein, whereas in renal artery, isoproterenol increased Kv7.4-AKAP (A-kinase anchoring protein) associations in a gallein-sensitive manner. Conclusions- The Gßγ-Kv7 relationship differs between vessels and is an essential requirement for AKAP, but not Rap-mediated regulation of the channel.

Emotional Distress Disparities Across Multiple Intersecting Social Positions: The Role of Bias-Based Bullying.

OBJECTIVES: To apply an intersectional lens to disparities in emotional distress among youth, including multiple social positions and experiences with bias-based bullying. METHODS: Data are from the 2019 Minnesota Student Survey (n = 80 456). Social positions (race and ethnicity, sexual orientation, gender) and 2 forms of bias-based bullying (racist, homophobic or transphobic) were entered into decision tree models for depression, anxiety, self-injury, suicidal ideation, and suicide attempts. Groups with the highest prevalence are described. Rates of emotional distress among youth with matching social positions but no bias-based bullying are described for comparison. RESULTS: LGBQ identities (90%) and transgender, gender diverse, and questioning identities (54%) were common among the highest-prevalence groups for emotional distress, often concurrently; racial and ethnic identities rarely emerged. Bias-based bullying characterized 82% of the highest-prevalence groups. In comparable groups without bias-based bullying, emotional distress rates were 20% to 60% lower (average 38.8%). CONCLUSIONS: Findings highlight bias-based bullying as an important point for the intervention and mitigation of mental health disparities, particularly among lesbian, gay, bisexual, transgender, gender-diverse, queer, and questioning adolescents. Results point to the importance of addressing bias-based bullying in schools and supporting lesbian, gay, bisexual, transgender, gender-diverse, queer, and questioning students at the systemic level as a way of preventing emotional distress.

Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia.

Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production.

Exploring Bias-Based Bullying and Intersecting Social Positions as Correlates of Sexual Risk Behaviors Among Adolescents.

Purpose: The current study extends the limited body of intersectional research on adolescents' sexual health by examining experiences of bias-based bullying and multiple intersecting social positions associated with engagement in sexual risk behaviors. Methods: Participants were 14,968 sexually active 9th and 11th grade students surveyed as part of the 2019 Minnesota Student Survey (15% lesbian/gay/bisexual/queer/pansexual/questioning [LGBQ] and/or transgender/gender diverse [TGD] or gender questioning). Exhaustive Chi-square Automatic Interaction Detection analysis was used to identify experiences (i.e., bias-based bullying victimization) and intersecting social positions (i.e., sexual orientation identity; gender identity/modality; race/ethnicity; physical disabilities/chronic illness; mental health/behavioral/emotional problems) associated with the highest prevalence of three sexual risk behaviors. Results: Overall, 18% of adolescents reported 3+ sex partners in the last year, 14% reported drug/alcohol use before last sex, and 36% reported not discussing protection from sexually transmitted infections with new sexual partners. Adolescents with 2+ marginalized social positions, some of whom also experienced bias-based bullying, were part of 53% of the highest prevalence risk groups. For example, 42% of Multiracial or Latina/x/o gender questioning adolescents who identified as LGBQ reported 3+ sex partners in the last year-twice the sample average. Adolescents who were Black, American Indian/Alaska Native, Latina/x/o, Multiracial, TGD, or gender questioning were in the highest prevalence nodes across all outcomes. Conclusion: Adolescents with multiple marginalized social positions and who experience bias-based bullying engage in high-risk sexual behaviors at higher-than-average rates. Findings underscore the importance of addressing intersecting experiences of stigma to reduce high-risk sex behaviors and promote health equity among adolescents.

Glucocorticoid withdrawal syndrome following surgical remission of endogenous hypercortisolism: a longitudinal observational study.

OBJECTIVE: Glucocorticoid withdrawal syndrome (GWS) is a scarcely studied phenomenon that complicates the recovery following surgical remission of hypercortisolism. We aimed to characterize the presence and trajectory of glucocorticoid withdrawal symptoms in the postoperative period and to determine presurgical predictors of GWS severity. DESIGN: Longitudinal observational study. METHODS: Glucocorticoid withdrawal symptoms were prospectively evaluated weekly for the first 12 weeks following surgical remission of hypercortisolism. Quality of life (CushingQoL and Short-Form-36) and muscle function (hand grip strength and sit-to-stand test) were assessed at the baseline and at 12 weeks after surgery. RESULTS: Prevalent symptoms were myalgias and arthralgias (50%), fatigue (45%), weakness (34%), sleep disturbance (29%), and mood changes (19%). Most symptoms persisted, while myalgias, arthralgias, and weakness worsened during weeks 5-12 postoperatively. At 12 weeks after surgery, normative hand grip strength was weaker than at baseline (mean Z-score delta -0.37, P = .009), while normative sit-to-stand test performance improved (mean Z-score delta 0.50, P = .013). Short-Form-36 Physical Component Summary score worsened (mean delta -2.6, P = .015), but CushingQoL score improved (mean delta 7.8, P < .001) at 12 weeks compared to baseline. Cushing syndrome (CS) clinical severity was predictive of postoperative GWS symptomology. CONCLUSION: Glucocorticoid withdrawal symptoms are prevalent and persistent following surgical remission of hypercortisolism with baseline CS clinical severity predictive of postoperative GWS symptom burden. Differential changes observed in muscle function and quality of life in the early postoperative period may reflect the competing influences of GWS and recovery from hypercortisolism.

Determinants of muscle function and health-related quality of life in patients with endogenous hypercortisolism: a cross-sectional study.

OBJECTIVE: Prospective data on determinants of muscle strength impairment and quality of life in patients with various subtypes and severity of endogenous hypercortisolism are lacking. DESIGN: Single-center cross-sectional study, 2019 to 2022. METHODS: Patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) were assessed with clinical and biochemical severity scores, muscle function (nondominant hand grip strength and sit-to-stand test), and quality of life (Short Form-36 [SF36] and CushingQoL). Referent subjects were recruited from the local population undergoing abdominal imaging for reasons other than suspected adrenal disorder. RESULTS: Of 164 patients, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age was 53 years (interquartile range: 42-63 years), and 126 (77%) were women. The SF36 mental component score was similarly low in patients with MACS vs CS, but physical component score was lower in CS when compared to MACS (mean of 34.0 vs 40.5, P = .001). Compared to MACS, patients with CS had lower scores on the standardized CushingQoL (mean of 47.1 vs 34.2, P < .001). Compared to referent subjects, patients with MACS demonstrated reduced muscle strength, similar to patients with CS (mean sit to stand Z-score of -0.47 vs -0.54, P = .822). Clinical severity (r = -0.22, P = .004) but not biochemical severity was associated with sit-to-stand test performance. CONCLUSIONS: Both patients with overt CS and MACS demonstrate reduced muscle strength and low quality of life. The clinical severity score utilized is associated with both physical and psychosocial components of CushingQoL and with the physical component of SF36.

Quality of Life and its Determinants in Patients With Adrenal Insufficiency: A Survey Study at 3 Centers in the United States.

CONTEXT: Current evidence on determinants of quality of life (QoL) in patients with adrenal insufficiency (AI) is limited. OBJECTIVE: This work aimed to identify the determinants of QoL in different subtypes of AI. METHODS: This multicenter cross-sectional survey study was conducted using a patient-centered questionnaire, the Short Form-36. RESULTS: Of 529 participants, 223 (42.2%) had primary AI, 190 (35.9%) had secondary AI, and 116 (21.9%) had glucocorticoid-induced AI. Median age was 58 years (interquartile range: 43-68 years) and 342 (64.8%) were women. In multivariable analyses, patients were more likely to report worse physical scores if they were women (odds ratio [OR]: 3.3; 95% CI, 1.8-6.0), had secondary AI or glucocorticoid-induced AI (OR: 2.5; 95% CI, 1.4-4.3), had shorter duration of AI (OR: 2.0; 95% CI, 1.1-3.6), were treated with more than 25 mg hydrocortisone equivalent daily (OR: 2.3; 95% CI, 1.2-4.6), had more comorbidities related to glucocorticoid excess (OR: 2.3; 95% CI, 1.3-4.0), reported a higher financial burden from AI (OR: 2.1; 95% CI, 1.3-3.6), and reported difficulties with AI management (OR: 2.5; 95% CI, 1.2-5.2). Women (OR: 2.1; 95% CI, 1.08-4.0), shorter duration of AI (OR: 2.4; 95% CI, 1.4-4.3), higher financial burden (OR: 2.3; 95% CI, 1.3-4.0), difficulties with AI management (OR: 2.6; 95% CI, 1.4-4.9), and lack of family support (OR: 9.1; 95% CI, 2.3-33.3) were associated with worse mental component scores. CONCLUSION: In patients with AI, QoL could be improved by addressing certain determinants, such as avoiding GC overreplacement, providing in-depth education on self-management, offering more comprehensive insurance coverage, and ensuring better family support.

The Impact of the COVID-19 Pandemic on Self-Reported Outcomes in Patients With Adrenal Insufficiency.

CONTEXT: The COVID-19 pandemic has impacted healthcare environment. OBJECTIVE: To determine the impact of the pandemic on self-reported outcomes in patients with adrenal insufficiency (AI). DESIGN AND SETTING: Prospective longitudinal survey study at 2 tertiary centers. PARTICIPANTS: Patients with AI. INTERVENTION: Patient-centered questionnaire. MAIN OUTCOME MEASURES: Depression Anxiety Stress Scales-21, Short Form-36, and AI self-management. RESULTS: Of 342 patients, 157 (46%) had primary AI, 109 (32%) had secondary AI, and 76 (22%) had glucocorticoid-induced AI. When compared to prepandemic, daily glucocorticoid dose and number of adrenal crises did not change. However, patients reported a higher financial impact from AI (34% vs 23%, P = 0.006) and difficulty accessing medical care (31% vs 7%, P < 0.0001) during the pandemic. A third of patients reported difficulty managing AI during the pandemic. After adjusting for duration and subtypes of AI, younger patients [odds ratio (OR) 2.3, CI 95% 1.3-4.1], women (OR 3.7, CI 95% 1.9-7.1), poor healthcare access(OR 4.2, CI 95% 2.3-7.7), lack of good insurance support (OR 2.8, CI 95% 1.3-5.9), and those with a higher financial impact (OR 2.3, CI 95% 1.3-4.3) reported greater difficulties managing AI. Patients were more likely to report a higher anxiety score (≥8) if they found managing AI challenging during the pandemic (OR 3.0, CI 95% 1.3-6.9), and had lower Physical Component Summary (OR 4.9, CI 95% 2.2-11.0) and Mental Component Summary (OR 4.1, CI 95% 1.8-9.5) scores prior to the pandemic. CONCLUSIONS: A third of patients with AI reported difficulties with management of AI during the pandemic, particularly in younger patients, women, and those with poor healthcare access.