Hamidi, Oksana

Abstract Context Crinecerfont, a first-in-class corticotropin-releasing factor type 1 receptor antagonist, is FDA-approved as an adjunct to the physiologic glucocorticoid (GC) required to treat the underlying adrenal insufficiency in patients (≥4 years old) with classic congenital adrenal hyperplasia (CAH). By reducing elevated adrenocorticotropic hormone, crinecerfont controls excess adrenal androgens, thereby enabling lower GC doses. However, there are no published recommendations for how to reduce supraphysiologic GC doses after initiating crinecerfont. This manuscript aims to provide a framework developed by experienced endocrinologists for reducing supraphysiologic GC doses in patients taking crinecerfont. Evidence Acquisition An experienced panel of 11 endocrinologists discussed strategies and considerations when reducing GC doses and developed an algorithm to guide GC dose reductions after introducing crinecerfont in adults with CAH. Evidence Synthesis Approaches to GC reduction should be individualized based on the patient's therapeutic goals, cortisol needs, lifestyle preferences, and the clinician's experience to set appropriate targets for clinical parameters, androgens, and GC dose regimen. In general, GC doses should be reduced gradually to minimize the risks of developing symptoms of GC withdrawal or adrenal insufficiency. GC doses should be adjusted to the lowest level needed to maintain androgens at goal, without reducing below what is needed for cortisol replacement. Practical considerations during GC dose reduction include switching from longer- to shorter-acting GCs (eg, from dexamethasone to hydrocortisone), optimizing dose distribution to mimic normal circadian cortisol exposure, and consolidating or eliminating doses to improve adherence. Conclusion This framework for reducing supraphysiologic GC doses in adult patients taking crinecerfont may become increasingly relevant as treatment of CAH shifts toward physiologic GC replacement with adjunctive control of adrenal androgens.

Abstract Endogenous Cushing syndrome (CS) is a rare disorder resulting from chronic exposure to excessive concentrations of cortisol. It is likely underdiagnosed because many clinical signs and symptoms are non-specific and overlap with those of common conditions. Furthermore, biochemical testing to diagnose CS can be complex and challenging, especially in milder cases. CS is characterized by excessive daily cortisol production, but it is also associated with a disrupted circadian rhythm of cortisol secretion. Traditional cortisol monitoring techniques rely on single-time-point measurements or a cumulation of measurements, which are unable to capture the complete daily rhythm of cortisol fluctuations. Currently, the utility of assessing individual patients’ cortisol circadian rhythm during diagnosis and treatment of CS is not well characterized. In this review, we will discuss how cortisol is measured in clinical practice and the potential benefit of measurement and normalization of the cortisol circadian rhythm.

Abstract Context Patients with mild autonomous cortisol secretion (MACS) can develop adrenal insufficiency after unilateral adrenalectomy. Objective This work aimed to determine the prevalence, duration, and predictors of adrenal insufficiency, and compare postoperative basal cortisol and cosyntropin stimulation test (CST). Methods In this multicenter retrospective study of patients with MACS, adrenal insufficiency was diagnosed when postoperative basal cortisol was less than 10 µg/dL and/or CST < 18 µg/dL. The results were concordant when both tests met cutoffs. Biochemical (BSS) and clinical severity scores (CSS) were calculated. Results Among 281 patients with MACS (80% women), postoperative adrenal insufficiency was diagnosed in 153 (54.5%) patients. Adrenal insufficiency inversely correlated with age (odds ratio [OR] 0.67 per 10 years; 95% CI, 0.53-0.84). Low basal cortisol and CST were associated with younger age (OR 0.64 per 10 years for both) and higher BSS (OR 1.17 and 1.22, respectively). Basal cortisol and CST were discordant in 22% of patients, and the discordance rate was more common in patients with bilateral nodules (32% vs 19%; P < .001). The median time to adrenal insufficiency recovery was 3.9 months (IQR, 3-5.9 months), with longer duration associated with higher BSS and CSS: 3 months for mild, 4 to 5 months for moderate, and 12 to 14 months for severe BSS and CSS. Conclusion Approximately half of patients with MACS developed postoperative adrenal insufficiency, with 50% recovering by 3.9 months after surgery. BSS correlated with basal cortisol, CST, and duration of adrenal insufficiency. As discordant results were noted in 22%, performing both basal cortisol and CST postoperatively should be considered.

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 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.

AbstractObjectiveWe aimed to describe clinical course of myelolipoma and to identify predictors of tumour growth and need for surgery.DesignA retrospective study.PatientsConsecutive patients with myelolipoma.ResultsA total of 321 myelolipomas (median size, 2.3 cm) were diagnosed in 305 patients at median age of 63 years (range, 25‐87). Median follow‐up was 54 months. Most myelolipomas were incidentally detected (86%), whereas 9% were discovered during cancer staging and 5% during workup of mass effect symptoms. Thirty‐seven (12%) patients underwent adrenalectomy. Compared to myelolipomas <6 cm, tumours ≥6 cm were more likely to be bilateral (21% vs 3%, P < .0001), cause mass effect symptoms (32% vs 0%, P < .0001), have haemorrhagic changes (14% vs 1%, P < .0001) and undergo adrenalectomy (52% vs 5%, P < .0001). Among patients with ≥6 months of imaging follow‐up, median size change was 0 mm (−10, 115) and median growth rate was 0 mm/y (−6, 14). Compared to <1 cm growth, ≥1 cm growth correlated with larger initial size (3.6 vs 2.3 cm, P = .02), haemorrhagic changes (12% vs 2%, P = .007) and adrenalectomy (35% vs 8%, P < .0001).ConclusionsMost myelolipomas are incidentally discovered on cross‐sectional imaging. Myelolipomas ≥6 are more likely to cause mass effect symptoms, have haemorrhagic changes and undergo resection. Tumour growth ≥1 cm is associated with larger myelolipoma and haemorrhagic changes. Adrenalectomy should be considered in symptomatic patients with large tumours and when there is evidence of haemorrhage or tumour growth.