Hamidi, Oksana

Abstract Objective The aim of this study is to assess whether clinical and imaging characteristics are associated with the hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACAs). Design This is a single-center cohort study. Methods Consecutive adult patients with incidental ACA were diagnosed between 2000 and 2016. Results Of the 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFAs), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome, 18 (1%) had PA and MACS, and 226 (15%) had incomplete work-up. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1 cm growth was associated with younger age (odds ratio [OR] = 0.8 per 5-year increase, P = .0047) and longer imaging follow-up (OR = 1.2 per year, P < .0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR = 0.79 per 5-year increase, P = .002), larger initial tumor size (OR = 2.3 per 1 cm increase, P < .0001), ≥1 cm growth (OR = 15.3, P < .0001), and higher postdexamethasone cortisol (OR = 6.6 for >5 vs <1.8 μg/dL, P = .002). Conclusions Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated postdexamethasone cortisol.

Abstract Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Abstract Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Abstract Disclosure: J.P. Frias: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. I. Bancos: None. L. Blonde: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.S. Busch: Consulting Fee; Self; Corcept Therapeutics. Speaker; Self; Bayer, Inc., Novo Nordisk, Amgen Inc, Eli Lilly & Company, AstraZeneca. J.B. Buse: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, GentiBio, Glycadia, Glyscend, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Stability Health, Valo, Zealand Pharma. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Janssen, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, Dasman Diabetes Center (Kuwait), Fortress Biotech, GentiBio, Glycadia, Glyscend, Mediflix, Medscape, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, ReachMD, Stability Health, Valo, Zealand Pharma. Grant Recipient; Self; Novo Nordisk, Sanofi, VTV Therapeutics, Nanotype, NIH, NovaTarg, Tolerion, Dexcom. Stock Owner; Self; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. Other; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk, Dasman Diabetes Institute, Zealand, Association for Clinical and Translational Science. R.A. DeFronzo: None. J.W. Findling: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. V. Fonseca: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Lantheus, Recordati Rare Diseases, Neurocrine Biosciences, Amryt, Novo Nordisk, Strongbridge. Consulting Fee; Self; Corcept Therapeutics. Y. Handelsman: Consulting Fee; Self; Amgen Inc, Applied Therapeutic, AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Corcept Therapeutics, Esperion, Mannkind Corporation, Merck, Pfizer, Inc., Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Vertis. Grant Recipient; Self; Amgen Inc, Applied Therapeutic, Ionis Pharmaceuticals Inc., Regor. Speaker; Self; AstraZeneca, Bayer, Inc., Esperion, Novo Nordisk, Vertis, Amarin. R.E. Pratley: Consulting Fee; Self; Bayer, Inc., Corcept Therapeutics, Gasherbrum Bio, Inc, Hanmi, Hengrui (USA) Ltd, Merck, Novo Nordisk, Pfizer, Inc., Rivus Pharmaceuticals Inc, Sun Pharmaceutical Industries, Sanofi, Scohia Pharma Inc, Dexcom. Grant Recipient; Self; Hanmi, Metavention, Novo Nordisk, Poxel SA. Speaker; Self; Novo Nordisk. J. Rosenstock: Advisory Board Member; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Consulting Fee; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Grant Recipient; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Merck, Oramed, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. I. Tudor: Employee; Self; Corcept Therapeutics. Stock Owner; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. D. Einhorn: Employee; Self; Corcept Therapeutics. Studies suggest that the prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) is higher than is currently appreciated. A recently published meta-analysis suggests that the prevalence of hypercortisolism is higher in persons with T2D who require a greater number of antihyperglycemic agents and/or who have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we describe a 2-part phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5-11.5%) despite receiving multiple antihyperglycemic agents. The study will be conducted at approximately 30 sites in the United States. In Part 1, approximately 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test. Those responding with serum cortisol >1.8 µg/dL (50 nmol/L) and dexamethasone levels ≥140 ng/dL (3.6 nmol/L) will have adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and cortisol measured in fasting blood samples obtained between 7-9 AM and a non-contrast adrenal computed tomography scan. Patients who may have ACTH-dependent hypercortisolism will be discontinued from the study and referred for further evaluation. The primary study endpoint is determining the prevalence of ACTH-independent hypercortisolism and will be evaluated in Part 1. Patients identified to have ACTH-independent hypercortisolism will advance to Part 2, a prospective, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the glucocorticoid receptor antagonist mifepristone. Patients will be randomized 2:1 to mifepristone or placebo, stratified by the presence or absence of adrenal adenomas on CT, and receive treatment for 24 weeks. The mifepristone dose will be 300 mg once daily for 4 weeks, then increased to 600 mg daily for 20 weeks based on clinical assessment of tolerability and degree of improvement. There will be an option to increase to mifepristone 900 mg. Placebo will be titrated accordingly from 1 up to 3 tablets. Part 2 will assess the secondary endpoint of change in HbA1c from baseline to 24 weeks, as well as changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life). This will be the first prospective study to assess the prevalence of ACTH-independent hypercortisolism in persons with difficult-to-control T2D and the first prospective, randomized, placebo-controlled trial to assess the potential benefits and safety of treatment with mifepristone in this patient population. Presentation: Friday, June 16, 2023

Abstract 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.

Abstract Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

Abstract Context: Quality of life (QoL) is impaired in patients with chronic adrenal insufficiency (AI) despite standard glucocorticoid (GC) replacement therapy. Current evidence on the determinants of QoL is scarce and limited in very few European countries, and how it relates to AI subtypes remains underexplored. Objective: We conducted the first survey study in patients with AI in the USA to determine the correlations between clinical parameters, adverse outcomes, patient education, socioeconomic factors, and QoL in different subtypes of AI. Design, Setting and Participants: Cross-sectional survey study of 529 patients with AI between 2015 and 2020, at three tertiary centers in the USA. Intervention: Patient-centered questionnaires. Main Outcome Measures: QoL scores using Short-Form 36. Results: Of 529 participants, 223 (42.2%) had primary AI (PAI), 190 (35.9%) had secondary AI (SAI), and 116 (21.9%) had glucocorticoid induced AI (GIAI). Median age at the time of survey was 58 years (IQR: 43–68), 342 (64.8%) were women and 483 (91.3%) were Caucasians. Median duration of AI was 6 years (IQR: 3–14.5), longest in patients with PAI (11 vs 4 years in SAI and GIAI, p=0.0001). Overall, Physical Composite Summary (PCS) score was lower than the Mental Composite Summary (MCS) (38.1±12.9 vs 46.5±11.8). Across the eight dimensions, each individual decade- and sex-adjusted Z-score (using the normative data of USA population) in patients with PAI was significantly higher than that of the other two AI subtypes (all p&lt;0.05), although all Z-scores were still below 0. In multivariate analyses, patients were more likely to report a worse PCS score (&lt;40) if they were women (OR: 3.3, CI 95%: 1.8–6.0), had SAI or GIAI (OR: 2.5, CI 95%: 1.4–4.3), had shorter duration of AI (&lt;6 years) (OR: 2.0, CI 95%: 1.1–3.6), were treated with &gt;25 mg hydrocortisone equivalent daily (OR: 2.3, CI 95%: 1.2–4.6), had more comorbidities related to GC excess (OR: 2.3, CI 95%: 1.3–4.0), reported higher financial burden due to AI (OR: 2.1, CI 95%: 1.3–3.6), and reported difficulties with AI management (OR: 2.5, CI 95%: 1.2–5.2). Women (OR: 2.1, CI 95%: 1.08–4.0), shorter duration of AI (OR: 2.4, CI 95%: 1.4–4.3), higher financial burden due to AI (OR: 2.3, CI 95%: 1.3–4.0), reporting difficulties with AI management (OR: 2.6, CI 95%: 1.4–4.9), and lack of family support during adrenal crisis (OR: 9.1, CI 95%: 2.3–33.3), were predictors of a worse MCS score (&lt;40). Conclusions: Patients with AI have substantially impaired QoL despite GC replacement therapy. Certain determinants of QoL are modifiable and achievable, such as avoiding GC over-replacement, offering detailed hands-on education in self-management, more comprehensive insurance coverage, and more robust domestic support. Our study calls for a multidimensional effort from patients, clinicians, and society to improve QoL in this vulnerable patient population.

Abstract Context Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia. Objective The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids. Data Sources We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018. Study Selection Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism. Data Extraction Pairs of independent reviewers extracted data and appraised studies. Data Synthesis Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration. Conclusions Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.