Citations

Abstract Context Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by the loss of physiological reserves and an increase in vulnerability, and it serves as a marker of declining health. Objective To compare frailty in patients with MACS versus patients with nonfunctioning adrenal tumors (NFAT). Design Retrospective study, 2003-2018 Setting Referral center Patients Patients >20 years of age with adrenal adenoma and MACS (1 mg overnight dexamethasone suppression (DST) of 1.9-5 µg/dL) and NFAT (DST <1.9 µg/dL). Main outcome measure Frailty index (range 0-1), calculated using a 47-variable deficit model. Results Patients with MACS (n = 168) demonstrated a higher age-, sex-, and body mass index–adjusted prevalence of hypertension (71% vs 60%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but a lower prevalence of asthma (5% vs 14%) than patients with NFAT (n = 275). Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared with NFAT. Age-, sex- and BMI-adjusted frailty index was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15; P = 0.009). Using a frailty index cutoff of 0.25, 24% of patients with MACS were frail, versus 18% of patients with NFAT (P = 0.028). Conclusion Patients with MACS exhibit a greater burden of comorbid conditions, adverse symptoms, and frailty than patients with NFAT. Future prospective studies are needed to further characterize frailty, examine its responsiveness to adrenalectomy, and assess its influence on health outcomes in patients with MACS.

AbstractObjectiveData 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.DesignSingle institution tertiary centre, retrospective cohort study from 1997 to 2020.Patients and MeasurementsAdult patients with adrenal metastases. Clinical, radiologic and biochemical presentations and outcomes were reviewed.ResultsOf 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.ConclusionsAdrenal 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.

Abstract Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

OBJECTIVE Cushing’s disease arises from functioning adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing’s disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing’s disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing’s disease. METHODS A single-institution database of Cushing’s disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing’s disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI. RESULTS Of the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61–6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002). CONCLUSIONS Empty sella syndrome is associated with an increased rate of MRI-negative Cushing’s disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.

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.

AbstractObjectiveComprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma.DesignA retrospective study at a tertiary care centre.PatientsAll patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015.MeasurementsTumour size, genetic testing, plasma/urine metanephrines and catecholamines.ResultsA total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4‐70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1‐38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical‐sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow‐up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy.ConclusionsBilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.

Abstract Background: Patients with primary adrenal insufficiency (PAI) and secondary adrenal insufficiency (SAI) report impaired quality of life. Predictors of adverse outcomes include duration of disease, supraphysiologic glucocorticoid (GC) use, and presence of other comorbidities. There is limited evidence to suggest that quality of life is disproportionately affected in one subtype of adrenal insufficiency. Objective: To identify determinants of quality of life in patients with PAI vs SAI. Method: Survey study of patients with the diagnosis of AI between 2015 and 2019 was evaluated at two large tertiary medical centers in the United States. Collected variables included data on circumstances of AI diagnosis, symptoms, management, burden of disease, and overall well-being. Patients with AI due to exogenous glucocorticoid use were excluded. Results: Patients with PAI (n=310, 65% women) were diagnosed at a younger age (37 ± 19 vs 48 ± 16 years, p<.01) than patients with SAI (n=255, 57% women). Patients with SAI were more likely not to understand their diagnosis (13% vs 4% in PAI, p<.01), or to report a discordant diagnosis (16% vs 9% in PAI, p=.02). Patients with PAI were on a higher dose of daily GC (23.8 mg vs 18.5 mg hydrocortisone (HC) equivalent, p <.01), with higher number of patients on HC> 25 mg/day (33% vs 15%, p<.01). Patients with PAI reported a higher compliance with wearing medical alert ID (79% vs 64%, p=.01) and higher availability of injectable GC (74% vs 58%, p<.01). Patients with PAI reported a higher frequency of at least one adrenal crisis within the last 12 months that required self- injectable GC (32% vs 16%, p<.01), or prompted ER visits (56% vs 29%, p<.01) compared to those with SAI. Nevertheless, patients with PAI were more likely to report good general health (78% vs 65% in SAI, p<.01). When adjusted for current age, sex, duration of disease, supraphysiologic GC use, number of current symptoms and recent adrenal crises, patients with SAI had HR of 2.6 (CI 95% 1.5-4.3) for poor health, 1.6 (CI 95% 0.95-2.8) for physical limitations, 1.7 (CI 95% 1.1-2.7) for fatigue, and 2.7 (CI 95% 1.5-4.9) for social limitations compared to those with PAI. Conclusions: Patients with PAI receive higher daily GC and experience a higher number of adrenal crises when compared to patients with SAI. However, patients with PAI report a better general perception of health, possibly due to a more robust knowledge of their disease and higher comfort level managing AI. More effort is needed to ensure patients with AI are appropriately educated regarding their medical condition and therapy.

Abstract Background: Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by diminished strength and endurance and serves as a marker of declining health and dependency. We hypothesized that patients with MACS are more frail when compared to patients with nonfunctioning adrenal tumors (NFAT). Methods: This is a retrospective study of adult patients with adrenal adenoma evaluated at a tertiary center from 2004 to 2018. MACS and NFAT were defined as cortisol after 1 mg overnight dexamethasone suppression (DST) between 1.8-5 mcg/dl and <1.8 mcg/dl, respectively. Frailty index (FI, range 0-1) was calculated using a 47 variables -deficit model (20 comorbidities, 14 activities of daily living, and 13 symptoms). Patients were excluded if treated with exogenous glucocorticoids, if diagnosed with overt adrenal hormone excess, another adrenal disorder, or if missing variables of interest. Results: MACS was diagnosed in 168 patients (67% women) at a median age 65 (30-91) years and NFAT in 275 patients (61% women) at a median age of 59 (21-84) years. Patients with MACS demonstrated higher prevalence of hypertension (73% vs 62%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but lower prevalence of asthma (5% vs 14%), when compared to patients with NFAT, p<0.05 for all. Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared to patients with NFAT, p<0.05 for all. Age, sex and BMI-adjusted FI was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15, p=0.009). Using cut-off FI of 0.2, 42% of patients with MACS were frail, versus 30% of patients with NFAT (p=0.01). Conclusion: Higher frailty in patients with MACS supports a more aggressive management, such as adrenalectomy over conservative follow up. Future prospective studies are needed to characterize frailty in greater detail in patients with MACS, as well as to examine frailty reversal by adrenalectomy.

Abstract Introduction: Low or borderline cortisol concentrations and impaired response to dynamic testing have been reported in patients with fibromyalgia, potentially related to hypothalamus-pituitary dysfunction.1,2 Superimposed adrenal insufficiency (AI) may contribute to some fibromyalgia symptoms or delay improvement in patients enrolled in fibromyalgia treatment programs. We hypothesized that a subset of patients with fibromyalgia have: 1) partial secondary AI and concomitant growth hormone (GH) deficiency 2) a discordance in Cosyntropin stimulation test and 3) improvement in fibromyalgia symptoms with initiation of glucocorticoid and/or GH replacement. Design: This was a retrospective study of patients with fibromyalgia diagnosed with partial secondary AI based on abnormal insulin tolerance test (peak cortisol < 18 mcg/dL) at our institution from June 2002 to August 2019. Patients were excluded if they had other reasons for adrenal insufficiency, including steroid exposure and opioid use. Results: We identified 22 patients (18 women, 82%) diagnosed with partial AI at a median age of 38 years (range 19-65). The fibromyalgia symptoms included fatigue (n=22, 100%), pain (n=22, 100%), sleep disturbance (n=15, 68%), and bowel changes (n=13, 59%). The median morning cortisol concentration was 8.6 mcg/dL (range 1.1-11); 9 patients (41%) had a morning cortisol concentration below the normal range (7 mcg/dL). The median ACTH level was 15.5 pg/mL (range 7.7-54). Nineteen patients had baseline IGF1 levels, with a median z-score of -0.94 (range -1.96 to 1.70). MRI pituitary imaging was performed in 20 patients and showed no significant pituitary pathology. All patients achieved hypoglycemia <=40 mg/dL during the insulin tolerance test. Peak median cortisol level was 11 mcg/dL (range 5.4-17). Nineteen patients (86%) also had partial GH deficiency (defined as a peak GH < 4 ng/mL) with a median GH level of 0.36 ng/mL (range 0.03-3.83). Cosyntropin stimulation test was performed in 13 patients (59%) with a 1 mcg dose in 2 patients and 250 mcg dose in 11 patients. The peak cortisol was >=18 mcg/dL in 10 (77%) patients. All patients were started on physiologic glucocorticoid replacement, and 12 patients were started on GH replacement. Endocrinology follow-up information was available for 13 patients, and 8 (62%) reported symptom improvement after starting treatment. Conclusions: Patients with fibromyalgia can have co-existing partial secondary AI and GH deficiency as defined by insulin-induced hypoglycemia. Cosyntropin stimulation test can be used in patients with fibromyalgia, but a normal test does not rule out partial secondary AI. Replacing the underlying deficiency improved symptoms in some patients demonstrating certain fibromyalgia symptoms may overlap with AI and GH deficiency. 1Gur et al. Ann Rheum Dis. 2004. 63(11):1504-1506. 2Kirnap et al. Clin Endocrinol (Oxf). 2001. 55(4):455-459.