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  1. Abstract Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease. References (27) 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing's syndrome: a population-based study. J Clin Endocrinol Metab 86: 117-123, 2001. 2. Starkman MN. Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration. Endocrinol Metab Clin N Am 42: 477-488, 2013. 3. Chen YF, Li YF, Chen X, Sun QF. Neuropsychiatric disorders and cognitive dysfunction in patients with Cushing's disease. CMJ 26: 3156-3160, 2013. 4. Priego T, Martín AI, González-Hedström D, Granado M, López-Calderón A. Role of hormones in sarcopenia. Vitam Horm 115: 535-570, 2021. 5. Grossman R, Mukherjee D, Chaichana KL, et al. Complications and death among elderly patients undergoing pituitary tumour surgery. Clin Endocrinol 73: 361-368, 2010. 6. Tiemensma J, Kokshoom NE, Biermasz NR, et al. Subtle cognitive impairments in patients with long-term cure of Cushing's disease. J Clin Endocrinol Metab 95: 2699-2714, 2010. 7. Brunetti A, Fulham MJ, Aloj L, et al. Decreased brain glucose utilization in patients with Cushing's disease. J Nucl Med 39: 786-790, 1998. 8. Liu S, Wang Y, Xu K, et al. Brain glucose metabolism is associated with hormone level in Cushing's disease: A voxel-based study using FDG-PET. Neuroimage Clin 12: 415-419, 2016. 9. Cheng H, Gao L, Hou B, et al. Reversibility of The cerebral blood flow in Patients with Cushing's Disease after Surgery Treatment. Metabolism 104: 154050, 2020. 10. Forget H, Lacroix A, Somma M, Cohen H. Cognitive decline in patients with Cushing's syndrome. J Int Neuropsychol Soc 6: 20-29, 2000. 11. Kim KJ, Filosa JA. Advanced in vitro approach to study neurovascular coupling mechanisms in the brain microcirculation. J Physiol 590: 1757-1770, 2012. 12. McEwen BS, Bowles NP, Gray JD, et al. Mechanisms of stress in the brain. Nat Neurosci 18: 1353-1363, 2015. 13. Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6: 219-233, 2007. 14. Iuchi T, Akaike M, Mitsui T, et al. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 92: 81-87, 2003. 15. Cheng H, Gao L, Hou B, et al. Reversibility of the cerebral blood flow in patients with Cushing's disease after surgery treatment. Metabolism 104: 154050, 2020. 16. Frimodt-Møller KE, Møllegaard Jepsen JR, Feldt-Rasmussen U, et al. Hippocampal volume, cognitive functions, depression, anxiety, and quality of life in patients with Cushing syndrome. J Clin Endocrinol Metab 104: 4563-4577, 2019. 17. Siegel S, Kirstein CF, Grzywotz A, et al. Neuropsychological functioning in patients with cushing's disease and Cushing's syndrome. Exp Clin Endocrinol Diabetes 129: 194-202, 2021. 18. Chow Y, Masiak J, Mikołajewska E, et al. Limbic brain structures and burnout-A systematic review. Adv Med Sci 63: 192-198, 2018. 19. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol Psychiatry 32: 756-765, 1992. 20. Goldberg AL, Tischler M, Demartina G, Griffin G. Hormonal regulation of protein degradation and synthesis in skeletal muscle. Fed Proc 39: 31-36, 1980. 21. Miller BS, Ignatoski KM, Daignault S, et al. A quantitative tool to assess degree of sarcopenia objectively in patients with hypercortisolism. Surgery 150: 1178-1185, 2011. 22. Delivanis D, Iñiguez-Ariza N, Zeb M, et al. Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas. Clin Endocrinol 88: 209-216, 2018. 23. Kim JH, Kwak MK, Ahn SH, et al. Alteration in skeletal muscle mass in women with subclinical hypercortisolism. Endocrine 61: 134-143, 2018. 24. Gonzalez Rodriguez E, Marques-Vidal P, Aubry-Rozier B, et al. Diurnal salivary cortisol in sarcopenic postmenopausal women: the OsteoLaus Cohort. Calcif Tissue Int 109: 499-509, 2021. 25. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 8: 748-761, 2020. 26. Lau D, Rutledge C, Aghi MK. Cushing's disease: current medical therapies and molecular insights guiding future therapies. Neurosurg Focus 38: E11, 2015. 27. Villar-Taibo R, Díaz-Ortega C, Sifontes-Dubo M, et al. Pituitary surgery in elderly patients: a safe and effective procedure. Endocrine 2: 814-822, 2021. From https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_8326-21/_article
  2. Abstract Context Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion. Objective Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD). Design Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission. Results Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], P = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], P = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), P = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status. Conclusions A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively. Cushing disease, copeptin, cortisol, remission Issue Section: Clinical Research Article Arginine vasopressin (AVP) and CRH act synergistically as the primary stimuli for secretion of ACTH, leading to release of cortisol [1, 2]. The role of AVP in the hypothalamic-pituitary-adrenal (HPA) axis is via release from the parvocellular neurons of the paraventricular nuclei (and possibly also from the magnocellular neurons of the paraventricular and supraoptic nuclei), the secretion of which is stimulated by stress [3-6]. AVP release results in both independent stimulation of ACTH release and potentiation of the effects of CRH [3, 7-9]. Additionally, there is evidence that glucocorticoids act by way of negative feedback to suppress AVP secretion [10, 11-20]. Further, parvocellular neurons of the hypothalamic paraventricular nuclei have been shown to increase AVP production and neurosecretory granule size after adrenalectomy, and inappropriately elevated plasma AVP has been reported in the setting of adrenal insufficiency with normalization of plasma AVP after glucocorticoid administration [21-24]. This relationship of AVP and its effect on the HPA axis has been used in the diagnostic evaluation of Cushing syndrome (CS) [14] and evaluation of remission after transsphenoidal surgery (TSS) in Cushing disease (CD) by administration of desmopressin [25]. Copeptin makes up the C-terminal portion of the AVP precursor pre-pro-AVP. Copeptin is released from the posterior pituitary in stoichiometric amounts with AVP, and because of its longer half-life in circulation, it is a stable surrogate marker of AVP secretion [26-28]. Plasma copeptin has been studied in various conditions of the anterior pituitary. In a study by Lewandowski et al, plasma copeptin was measured after administration of CRH in assessment of HPA-axis function in patients with a variety of pituitary diseases. An increase in plasma copeptin was observed only in healthy subjects but not in those with pituitary disease who had an appropriately stimulated serum cortisol, and the authors concluded that copeptin may be a sensitive marker to reveal subtle alterations in the regulation of pituitary function [7]. Although in this study and others, plasma copeptin was assessed after pituitary surgery, it has not, to the best of our knowledge, been studied as a marker of remission of CD before and after pituitary surgery [7, 29]. In this study, plasma copeptin levels were assessed as a surrogate of AVP secretion before and after TSS for treatment of CD. Because there is evidence that glucocorticoids exert negative feedback on AVP, we hypothesized that there would be a greater postoperative increase in plasma copeptin in those with CD in remission after TSS resulting from resolution of hypercortisolemia and resultant hypocortisolemia compared with those not in remission with persistent hypercortisolemia and continued negative feedback. In other words, we hypothesized that an increase in copeptin could be an early marker of remission of CD after TSS. We aimed to complete this assessment by comparison of the peak postoperative copeptin and change in copeptin from preoperative to peak postoperative copeptin for those in remission vs not in remission postoperatively. Subjects and Methods Subjects Adult and pediatric patients with CD who presented at the Eunice Kennedy Shriver National Institute of Child Health and Human Development under protocol 97-CH-0076 and underwent TSS between March 2016 and July 2019 were included in the study. Exclusion criteria included a prior TSS within 6 weeks of the preoperative plasma copeptin sample or a preoperative diagnosis of diabetes insipidus, renal disease, or cardiac failure. Written informed consent was provided by patients aged 18 years and older and by legal guardians for patients aged < 18 years to participate in this study. Written informed assent was provided by patients aged 7 years to < 18 years. The 97-CH-0076 study (Investigation of Pituitary Tumors and Related Hypothalamic Disorders) has been approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development institutional review board. Clinical and Biochemical Data Clinical data were extracted from electronic medical records. Age, sex, body weight, body mass index (BMI), pubertal stage (in pediatric patients only), and history of prior TSS were obtained preoperatively during the admission for TSS. Clinical data obtained postoperatively included TSS date, histology, development of central diabetes insipidus (DI) or (SIADH), time from TSS to most recent follow-up, and clinical remission status at postoperative follow-up. Preoperatively, serum sodium, 24-hour urinary free cortisol (UFC), UFC times the upper limit of normal (UFC × ULN), midnight (MN) serum cortisol, MN plasma ACTH, and 8 AM plasma ACTH were collected. Postoperatively, serum sodium, serum and urine osmolality, urine specific gravity, serum cortisol, and plasma ACTH were collected. For serum cortisol values < 1 mcg/dL, a value of 0.5 mcg/dL was assigned for the analyses; for plasma ACTH levels < 5 pg/mL, a value of 2.5 pg/mL was assigned. Additionally, plasma copeptin levels were obtained preoperatively and on postoperative days (PODs) 1 through 8 after TSS at 8:00 AM. Peak postoperative copeptin was the highest plasma copeptin on PODs 1 through 8. The delta copeptin (Δcopeptin) was determined by subtracting the preoperative copeptin from the peak postoperative copeptin; hence, a positive change indicated a postoperative increase in plasma copeptin. Plasma copeptin was measured using an automated immunofluorescent sandwich assay on the BRAHMS Kryptor Compact PLUS Copeptin-proAVP. The limit of detection for the assay was 1.58 pmol/L, 5.7% intra-assay coefficient of variation, and 11.2% inter-assay coefficient of variation, with a lower limit of analytical measurement of 2.8 pmol/L. For those with multiple preoperative plasma copeptin values within days before surgery, an average of preoperative copeptin levels was used for analyses. Diagnosis of CD was based on guidelines published by the Endocrine Society and as previously described for the adult and pediatric populations [30, 31]; diagnosis was further confirmed by either histologic identification of an ACTH-secreting pituitary adenoma in the resected tumor specimen, decrease in cortisol and ACTH levels postoperatively, and/or clinical remission after TSS at follow-up evaluation. All patients were treated with TSS at the National Institutes of Health Clinical Center by the same neurosurgeon. Remission after surgical therapy was based on serum cortisol of < 5 μg/dL during the immediate postoperative period, improvement of clinical signs and symptoms of cortisol excess at postoperative follow up, nonelevated 24-hour UFC at postoperative follow-up, nonelevated midnight serum cortisol at postoperative follow up when available, and continued requirement for glucocorticoid replacement at 3 to 6 months’ postoperative follow-up. Diagnosis of SIADH was based on development of hyponatremia (serum sodium < 135 mmol/L) and oliguria (urine output < 0.5 mL/kg/h). Diagnosis of DI was determined by development of hypernatremia (serum sodium > 145 mmol/L), dilute polyuria (urine output > 4 mL/kg/h), elevated serum osmolality, and low urine osmolality. Statistical Analyses Results are presented as median (interquartile range [IQR], calculated as 25th percentile-75th percentile) or mean ± SD, as appropriate, and frequency (percentage). Where appropriate, we compared results using parametric or nonparametric testing; however, the median (IQR) and the mean ± SD were both reported to allow for comparisons with the appropriate testing noted. Subgroup analyses were completed comparing those who developed water balance disorders included patients who developed DI only (but not SIADH), those who developed SIADH only (but not DI), and those with no water balance disorder; hence, for these subgroup analyses, those who developed both DI and SIADH postoperatively (n = 4) were excluded. Preoperative copeptin, peak postoperative copeptin, and Δcopeptin were compared between those with and without remission at follow-up, using either t test or Wilcoxon rank-sum test, depending on the distribution of data. These were done in all patients combined, as well as within each subgroup. The same tests were used for comparing other continuous variables (eg, age, BMI SD score [SDS], cortisol excess measures) between those with and without remission. Categorical data (eg, sex, Tanner stage) were analyzed using the Fisher exact test. Comparisons of copeptin levels among the subgroups (DI, SIADH, neither) were carried out using mixed models and the Kruskal-Wallis test, as appropriate. Post hoc pairwise comparisons were adjusted for multiplicity using the Bonferroni correction, and as applicable, only corrected P values are reported. Mixed models for repeated measures also analyzed copeptin, serum sodium, and cortisol data for PODs 1 through 8. In addition, maximum likelihood estimation (GENMOD) procedures analyzed the effects of copeptin and serum sodium on the remission at follow-up. Correlation analyses were done with Spearman ρ. All analyses were tested for the potential confounding effects of age, sex, BMI SDS, and pubertal status, and were adjusted accordingly. For plasma copeptin reported as < 2.8 pmol/L, a value of 1.4 pmol/L (midpoint of 0 and 2.8 pmol/L) was used; sensitivity analyses repeated all relevant comparisons using the threshold limit of 2.8 pmol/L instead of 1.4 pmol/L. Odds ratios (OR) and 95% CIs, other magnitudes of the effect, data variability, and 2-sided P values provided the statistical evidence for the conclusions. Statistical analyses were performed in SAS version 9.4 software (SAS Institute, Inc, Cary, NC). Results Patient Characteristics Forty-four adult and pediatric patients, aged 7 to 55 years (77.2% were < 18 years old), with CD were included in the study. The cohort included 28 female patients (64%), and the median BMI SDS was 2.2 (1.1-2.5). Thirty-four percent (15/44) had prior pituitary surgery (none within the prior 6 weeks). Seventy-five percent (33/44) had postoperative follow-up evaluations available, with median follow-up of 13.5 months (11.3-16.0). Of those 33 patients, 85% were determined to be in remission at follow-up. Comparing those in remission vs no remission, there was no difference in age, sex, BMI SDS, pubertal status (in pediatric ages only), preoperative measures of cortisol excess (UFC × ULN, PM serum cortisol, MN plasma ACTH, AM plasma ACTH), duration of follow-up, or development of DI or SIADH. There was a lower postoperative serum cortisol nadir in those in remission at follow-up compared with those not in remission at follow-up, as expected, because a postoperative serum cortisol < 5 μg/dL was included in defining remission status. Postoperatively, 8/44 (18%) developed DI, 13/44 (30%) developed SIADH, 4/44 (9%) developed both DI and SIADH, and 19/44 (43%) developed no water balance disorder (Table 1). There were no differences by remission status when assessing these subgroups (ie, DI, SIADH, and no water balance disorder) separately. Table 1. Demographic and clinical characteristics of subjects All subjects, n = 44 All subjects by remission status, n = 33 All subjects by remission status, excluding those with DI or SIADH, n = 13 Remission, n = 28 No remission, n = 5 P Remission, n = 10 No remission, n = 3 P Age, median (range), y 14.5 (7-55) 17.4 ± 10.7 14.5 (12.5-17.5) 15.6 ± 13.2 11.0 (9.0-12.0) 0.11 13.7 ± 3.1 14.0 (13.0-15.0) 19.7 ± 16.8 11.0 (9.0-39.0) 0.60a Sex  Female 28 (64%) 22 (78.6%) 3 (60.0%) 0.57 9 (90.0%) 2 (66.7%) 0.42 BMI SDS 2.2 (1.1-2.5) 1.7 ± 1.0 2.0 (0.9-2.5) 2.2 ± 0.4 2.2 (2.1-2.3) 0.70 1.7 ± 1.1 2.0 (0.7-2.5) 2.0 ± 0.4 2.1 (1.5-2.3) 0.65a Pubertal status Female (n = 19) (n = 15) (n = 2) 0.51 (n = 8) (n = 1) 0.44   Tanner 1-2 6 4 (26.7%) 1 (50.0%) 3 (37.5%) 1 (25.0%)   Tanner 3-5 13 11 (73.3%) 1 (50.0%) 5 (62.5%) 0 Male (n = 14) (n = 5) (n = 2) (n = 1) (n = 1) --- Testicular volume < 12, mL 10 4 (80.0%) 2 (10.00%) 1 (100.0%) 1 (100.0%) Testicular volume ≥ 12, mL 4 1 (20.0%) 0 1.0 0 0 Preoperative UFC ULN 3.3 (1.2-6.1) 4.9 ± 6.1 2.6 (1.0-7.6) 3.2 ± 1.3 3.7 (3.0-3.9) 0.70 7.2 ± 8.4 3.9 (1.8-9.1) 3.8 ± 0.7 3.9 (3.0-4.4) 0.93 Preoperative PM cortisol 11.9 (9.2-14.8) 13.3 ± 4.7 12.2 (9.2-16.8) 10.8 ± 2.1 11.5 (9.0-11.6) 0.30 13.3 ± 6.0 11.2 (8.4-16.5) 11.1 ± 2.6 11.6 (8.3-13.6) 0.57a Preoperative MN ACTH 43.4 (29.3-51.6) 44.2 ± 25.5 46.1 (27.6-50.5) 40.9 ± 15.3 11.5 (9.0-11.6) 0.74 36.6 ± 16.6 37.4 (29.1-48.8) 34.0 ± 9.4 39.3 (23.1-39.5) 0.67 Preoperative AM ACTH 44.6 (31.4-60.5) 46.9 ± 28.9 44.0 (29.8-56.2) 48.6 ± 28.8 58.7 (21.7-60.5) 0.84 35.2 ± 16.2 40.3 (28.0-44.0) 45.4 ± 24.6 58.7 (17.0-60.5) 0.41a Postoperative cortisol nadir 0.5 (0.5-0.5) 0.7 ± 0.7 0.5 (0.5-0.5) 7.8 ± 6.6 5.2 (2.2-12.3) <0.001 0.6 ± 0.3 0.5 (0.5-0.5) 8.1 ± 7.9 5.2 (2.1-17.0) 0.003 Duration of follow-up 13.5 (11.3-16.0) 15.3 ± 7.9 14.0 (12.0-16.5) 14.0 ± 13.0 11.0 (6.0-14.0) 0.30 18.6 ± 11.2 15.5 (12.0-27.0) 16.7 ± 17.2 11.0 (3.0-36.0) 0.82a DI only 8 (18%) 7/8 (87.5%) 1/8 (12.5%) 0.91 --- --- --- SIADH only 13 (30%) 8/9 (88.9%) 1/9 (11.1%) Neither DI/SIADH 19 (43%) 10/13 (76.9%) 3/13 (23.1%) Both DI and SIADH 4 (9%) 3/3 (100%) 0/3 Demographic and clinical characteristics of all subjects (n = 44) with Cushing disease. Data are also presented by remission status for all subjects with postoperative follow-up (n = 33) and by remission status after excluding those who developed DI or SIADH postoperatively with postoperative follow-up (n = 13). Both median (IQR) and mean ± SD reported to allow for comparisons, with P value provided using appropriate testing depending on distribution of data sets. Data are mean ± SD, median (25th-75th IQR), or frequency (percentage) are reported, except for age, which is presented as median (range). Abbreviations: AM, 7:30-8 PM; BMI, body mass index; DI, diabetes insipidus; IQR, interquartile range; MN, midnight; N/A, not applicable; SDS, SD score; SIADH, syndrome of inappropriate antidiuresis; UFC, urinary free cortisol; ULN, upper limit of normal. p-values below the threshold of 0.05 are in bold. aP value indicates comparison using parametric testing, as appropriate for normally distributed data. Open in new tab Preoperative copeptin levels were higher in males (7.0 pmol/L [5.1-9.6]) than in females (4.0 pmol/L [1.4-5.8], P = 0.004) (Fig. 1). Age was inversely correlated with preoperative copeptin (rs = -0.35, P = 0.030) and BMI SDS was positively correlated with preoperative copeptin (rs = 0.54, P < 0.001) (Fig. 2). Figure 1. Open in new tabDownload slide Preoperative plasma copeptin and sex. Preoperative plasma copeptin in all patients, comparing by sex. A higher preoperative plasma copeptin was found in males (7.0 pmol/L [5.1-9.6]) than in females (4.0 pmol/L [1.4-5.8], P = 0.004). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. Figure 2. Open in new tabDownload slide Preoperative plasma copeptin and BMI SDS. Association of preoperative plasma copeptin and BMI SDS in all patients. A BMI SDS was positively associated with a preoperative plasma copeptin (rs = 0.54, P < 0.001). Shaded area = 95% confidence interval. Copeptin Before and After Transsphenoidal Surgery for CD Among the 33 patients with postoperative follow-up, there was no difference in peak postoperative copeptin for patients in remission vs those not in remission (6.1 pmol/L [4.3-12.1] vs 7.3 pmol/L [5.4-8.4], P = 0.88). There was also no difference in the Δcopeptin for those in remission vs not in remission (2.3 pmol/L [-0.5 to 8.2] vs 0.1 pmol/L [-0.1 to 2.2], P = 0.46) (Fig. 3). Including all subjects, the mean preoperative copeptin was 5.6 pmol/L (±3.4). For patients with follow-up, there was no difference in preoperative copeptin for those in remission (4.8 pmol/L [±2.9]) vs no remission (6.0 pmol/L [±2.0], P = 0.47). POD 1 plasma copeptin ranged from < 2.8 to 11.3 pmol/L. Figure 3. Open in new tabDownload slide (A) Peak postoperative plasma copeptin in all patients, comparing those in remission with no remission (6.1 pmol/L [4.3-12.1] vs 7.3 pmol/L [5.4-8.4], P = 0.88). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) in all patients, comparing those in remission with no remission (2.3 pmol/L [-0.5 to 8.2] vs 0.1 pmol/L [-0.1 to 2.2], P = 0.46). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. When those who developed DI or SIADH were excluded, there was no difference in peak postoperative copeptin in those in remission vs no remission (10.2 pmol/L [6.9-21.0] vs 5.4 pmol/L [4.6-7.3], P = 0.20). However, because the distribution of the peak postoperative copeptins was borderline normally distributed, parametric testing was also completed for this analysis, which showed a higher peak postoperative copeptin in remission (14.6 pmol/L [±10.9]) vs no remission (5.8 [±1.4], P = 0.03). There was no difference in the Δcopeptin for those in remission vs not in remission (5.1 pmol/L [0.3-19.5] vs 1.1 pmol/L [-0.1 to 2.2], P = 0.39) (Fig. 4). Preoperative copeptin was not different for those in remission (4.7 pmol/L [±2.4]) vs no remission (4.9 pmol/L [±20.3], P = 0.91). There was no association between serum cortisol and plasma copeptin over time postoperatively (Fig. 5). Figure 4. Open in new tabDownload slide (A) Peak postoperative plasma copeptin excluding those who developed DI or SIADH, comparing those in remission with no remission (10.2 pmol/L [6.9-21.0] vs 5.4 pmol/L [4.6-7.3], P = 0.20). (B) ΔCopeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin) excluding those who developed DI or SIADH, comparing those in remission with no remission (5.1 pmol/L [0.3-19.5] vs 1.1 pmol/L [-0.1 to 2.2], P = 0.39). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. Figure 5. Open in new tabDownload slide Plasma copeptin and serum cortisol vs postoperative day for patients who did not develop DI or SIADH. Plasma copeptin (indicated by closed circle) and serum cortisol (indicated by “x”). Results shown as (median, 95% CI). All analyses here were repeated adjusting for serum sodium, and there were no differences by remission status for preoperative, peak postoperative, or Δcopeptin for all subjects or after excluding those who developed a water balance disorder (data not shown). Copeptin and Water Balance Disorders As expected, peak postoperative copeptin appeared to be different among patients who developed DI, SIADH, and those without any fluid balance disorder (P = 0.029), whereas patients with DI had lower median peak postoperative copeptin (4.4 pmol/L [2.4-6.9]) than those who developed no fluid abnormality (10.0 pmol/L [5.4-16.5], P = 0.04), the statistical difference was not present after correction for multiple comparisons (P = 0.13). Peak postoperative copeptin of patients with SIADH was 9.4 pmol/L (6.5-10.4) and did not differ from patients with DI (P = 0.32) or those with no fluid abnormality (P = 1.0). There was a difference in Δcopeptin levels among these subgroups (overall P = 0.043), which appeared to be driven by the lower Δcopeptin in those who developed DI (-1.2 pmol/L [-2.6 to 0.1]) vs in those with neither DI or SIADH (3.1 pmol/L [0-9.6], P = 0.05). However, this pairwise comparison did not reach statistical significance, even before correction for multiple comparisons (P = 0.16) (Fig. 6). Preoperative copeptin levels were also not different among the subgroups (P = 0.54). Figure 6. Open in new tabDownload slide (A) Peak postoperative plasma copeptin, comparing those who developed DI, SIADH, or neither (P = 0.029 for comparison of all 3 groups). (B) ∆ Copeptin (preoperative plasma copeptin subtracted from postoperative peak plasma copeptin), comparing those who developed DI, SIADH, or neither (P = 0.043 for comparison of all 3 groups). Horizontal lines = median. Whiskers = 25th and 75th interquartile ranges. Top brackets = pairwise comparisons. P values presented are after Bonferroni correction for multiple comparisons. Association of Sodium and Copeptin Longitudinal data, adjusting for subgroups (ie, DI, SIADH, neither), were analyzed. As expected, there was a group difference (P = 0.003) in serum sodium over time (all DI was missing preoperative serum sodium), with the difference being driven by DI vs SIADH (P = 0.007), and SIADH vs neither (P = 0.012). There was no group difference in plasma copeptin over POD by water balance status (P = 0.16) over time (Fig. 7). There was also no effect by remission status at 3 to 6 months for either serum sodium or plasma copeptin. Figure 7. Open in new tabDownload slide (A) Serum sodium and (B) plasma copeptin by POD and water balance status longitudinal data, adjusting for subgroups (ie, DI, SIADH, neither). Data points at point 0 on the x-axis indicate preoperative values. As expected, there was a group difference (P = 0.003) in serum sodium over time (all with DI were missing preoperative serum sodium), with the difference being driven by DI vs SIADH (P = 0.007), and SIADH vs neither (P = 0.012). There was no group difference in plasma copeptin over POD by water balance status (P = 0.16) over time. Higher serum sodium levels from PODs 1 through 8 itself decreased the odds of remission (OR, 0.56; 95% CI, 0.42-0.73; P < 0.001) in all CD patients. Copeptin levels from these repeated measures adjusting for serum sodium did not correlate with remission status at 3 to 6 months’ follow-up (P = 0.38). There were no differences in preoperative, peak postoperative, or delta sodium levels by remission vs no remission in all patients and in those with no water balance disorders. Discussion AVP and CRH act synergistically to stimulate the secretion of ACTH and ultimately cortisol [1, 2], and there is evidence that glucocorticoids act by way of negative feedback to suppress AVP secretion [10, 11-20]. Therefore, we hypothesized that a greater postoperative increase in plasma copeptin in those with CD in remission after TSS because of resolution of hypercortisolemia and resultant hypocortisolemia, compared with those not in remission with persistent hypercortisolemia and continued negative feedback, would be observed. Although a clear difference in peak postoperative and Δcopeptin was not observed in this study, a higher peak postoperative copeptin was found in those in remission after excluding those who developed DI/SIADH when analyzing this comparison with parametric testing, and it is possible that we did not have the power to detect a difference by nonparametric testing, given our small sample size. Therefore, postoperative plasma copeptin may be a useful early marker to predict remission of CD after TSS. The utility of this test may be limited to those who do not develop water balance disorders postoperatively. If a true increase in copeptin occurs for those in remission after treatment of CD, it is possible that this could be due to the removal of negative feedback from cortisol excess on pre-pro-AVP secretion, as hypothesized in this study. However, it is also possible that other factors may contribute to an increase in copeptin postoperatively, including from the stress response of surgery and postoperative hypocortisolism and resultant stimulation of pre-pro-AVP secretion from these physical stressors and/or from unrecognized SIADH. It was anticipated that more severe hypercortisolism to be negatively correlated with preoperative plasma copeptin because of greater negative feedback on AVP. However, no association was found between preoperative plasma copeptin and markers of severity of hypercortisolism (MN cortisol, AM ACTH, UFC × ULN) in this study. Similarly, we would expect that the preoperative plasma copeptin would be lower compared with healthy individuals. However, comparisons of healthy individuals may be difficult because the fluid and osmolality status at the time of the sample could influence the plasma copeptin, and depending on those factors, copeptin could be appropriately low. A healthy control group with whom to compare the preoperative values was not available for this study, and the thirsted state was not standardized for the preoperative copeptin measurements. Future studies could be considered to determine if preoperative plasma copeptin is lower in patients with CD, or other forms of CS, compared with healthy subjects, with all subjects thirsted for an equivalent period. Further, if preoperative plasma copeptin is found to be lower in thirsted subjects with CS than a thirsted healthy control group, the plasma copeptin could potentially be a diagnostic test to lend support for or against the diagnosis of endogenous CS. In the comparisons of those who developed DI, SIADH, or neither, no difference was found in the Δcopeptin. Peak copeptin was lower in DI compared with those without DI or SIADH (but not different from SIADH). Again, it is possible that there is a lower peak postoperative copeptin and change in copeptin in those with DI, but we may not have had the power to detect this in all of our analyses. These comparisons of copeptin among those with or without water balance disorders postoperatively are somewhat consistent with a prior study showing postoperative copeptin as a good predictor of development of DI, in which a plasma copeptin < 2.5 pmol/L measured on POD 0 accurately identified those who developed DI, and plasma copeptin > 30 pmol/L ruled out the development of DI postoperatively [29]. In the current study, 3 of 6 subjects with DI had a POD 1 plasma copeptin < 2.5 pmol/L, and none had a POD 1 plasma copeptin > 30 pmol/L. However, the study by Winzeler et al found that copeptin measured on POD 0 (within 12 hours after surgery) had the greatest predictive value, and POD 0 plasma copeptin was not available in our study. Further, we used the preoperative, peak, and delta plasma copeptin for analyses, so the early low copeptin levels may not have been captured in our data and analyses. Additionally, this study revealed that increasing levels of serum sodium have lower odds of remission. Those who have an ACTH-producing adenoma that is not identified by magnetic resonance imaging and visual inspection intraoperatively have lower rates of remission and are more likely to have greater manipulation of the pituitary gland intraoperatively [32-36], and the latter may result in greater damage to the pituitary stalk or posterior pituitary, increasing the risk for development of DI and resultant hypernatremia. A higher preoperative copeptin was associated with male sex and increasing BMI SDS. Increasing preoperative copeptin was also found in pubertal boys compared with pubertal girls, with no difference in copeptin between prepubertal boys and girls. It is particularly interesting to note that these associations were only in the preoperative plasma copeptin levels, but not the postoperative peak copeptin or Δcopeptin. Because the association of higher plasma in adult males and pubertal males in comparison to adult females and pubertal females, respectively, have been reported by others [26, 37-40], it raises the question of a change in the association of sex and BMI with plasma copeptin in the postoperative state. An effect of BMI or sex was not found by remission status, so it does not seem that the postoperative hypocortisolemic state for those in remission could explain this loss of association. However, this study may not have been powered to detect this. Strengths of this study include the prospective nature of the study. Further, this is the first study assessing the utility of copeptin to predict remission after treatment of CD. Limitations of this study include the small sample size because of the rarity of the condition, difficulty in clinically diagnosing DI and SIADH, potential effect of post-TSS fluid balance disorders (particularly for those who may have developed transient partial DI or transient SIADH), lack of long-term follow-up, lack of any postoperative follow-up in 11 of the 44 total subjects, as well the observational nature of the study. Further, it is possible that pubertal status, sex, and BMI may have affected copeptin levels, which may have not been consistently detected because of lack of power. Lack of data on the timing of hydrocortisone replacement is an additional limitation of this study because postoperative glucocorticoid replacement could affect AVP secretion via negative feedback. Additional studies are needed to assess to further assess the role of vasopressin and measurement of copeptin in patients before and after treatment of CD. A clear difference in peak postoperative plasma copeptin as an early marker to predict remission of CD after TSS was not found. Further studies with larger sample sizes are needed to further evaluate postoperative plasma copeptin as an early marker to predict remission of CD, though the utility of this test may be limited to those who do not develop water balance disorders postoperatively. Future studies comparing copeptin levels before and after treatment of adrenal CS would be of particular interest because this would minimize the risk of postoperative DI or SIADH which also influence copeptin levels. Additionally, comparison of thirsted preoperative plasma copeptin in those with endogenous CS and thirsted plasma copeptin in healthy controls could potentially provide evidence of whether or not preoperative plasma copeptin is lower in patients with CD, or other forms of CS, compared with healthy subjects. Further, if this is found to be true, it could potentially be a diagnostic test to lend support for or against endogenous CS. Abbreviations AVP arginine vasopressin BMI body mass index CD Cushing disease CS Cushing syndrome DI diabetes insipidus HPA hypothalamic-pituitary-adrenal IQR interquartile range MN midnight OR odds ratio POD postoperative day SDS SD score SIADH syndrome of inappropriate antidiuresis TSS transsphenoidal surgery UFC urinary free cortisol ULN upper limit of normal Acknowledgments The authors thank the patients and their families for participating in this study. Funding This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health. Disclosures C.A.S. holds patents on technologies involving PRKAR1A, PDE11A, GPR101, and related genes, and his laboratory has received research funding support by Pfizer Inc. for investigations unrelated to this project. C.A.S. is associated with the following pharmaceutical companies: ELPEN, Inc., H. Lunbeck A/S, and Sync. Inc. Clinical Trial Information ClinicalTrials.gov registration no. NCT00001595 (registered November 4, 1999). Data Availability Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. Published by Oxford University Press on behalf of the Endocrine Society 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US. From https://academic.oup.com/jes/article/6/6/bvac053/6564309?login=false
  3. https://doi.org/10.1016/j.aace.2022.04.003Get rights and content Under a Creative Commons license Open access Highlights • We describe a rare case of a patient with a sparsely granulated corticotroph pituitary macroadenoma with pituitary apoplexy who underwent transsphenoidal resection resulting in remission of hypercortisolism. • Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. • macroadenomas account for 7-23% of patients with pituitary corticotroph adenomas • Sparsely granulated corticotroph tumors are associated with longer duration of Cushing disease prior to diagnosis, larger tumor size at diagnosis, decreased immediate remission rate, increased proliferative marker Ki-67 and increased recovery time of hypothalamic-pituitary-adrenal axis after surgery. • Granulation pattern is an important clinicopathological distinction impacting the behavior and treatment outcomes of pituitary corticotroph adenomas Abstract Background /Objective: Pituitary corticotroph macroadenomas, which account for 7% to 23% of corticotroph adenomas, rarely present with apoplexy. The objective of this report is to describe a patient with a sparsely granulated corticotroph tumor (SGCT) presenting with apoplexy and remission of hypercortisolism. Case Report A 33-year-old male presented via ambulance with sudden onset of severe headache and nausea/vomiting. Physical exam revealed bitemporal hemianopsia, diplopia from right-sided third cranial nerve palsy, abdominal striae, facial plethora, dorsal and supraclavicular fat pad. Magnetic resonance imaging (MRI) demonstrated a 3.2 cm mass arising from the sella turcica with hemorrhage compressing the optic chiasm, extension into the sphenoid sinus and cavernous sinus. Initial investigations revealed plasma cortisol of 64.08 mcg/dL (Reference Range (RR), 2.36 – 17.05). He underwent emergent transsphenoidal surgery. Pathology was diagnostic of SGCT. Post-operatively, cortisol was <1.8ug/dL (RR, 2.4 – 17), adrenocorticotropic hormone (ACTH) 36 pg/mL (RR, 0 – 81), thyroid stimulating hormone (TSH) 0.07 uIU/mL (RR, 0.36 - 3.74), free thyroxine 1 ng/dL (RR, 0.8 – 1.5), luteinizing hormone (LH) <1 mIU/mL (RR, 1 – 12), follicle stimulating hormone (FSH) 1 mIU/mL (RR, 1 – 12) and testosterone 28.8 ng/dL (RR, 219.2 – 905.6) with ongoing requirement for hydrocortisone, levothyroxine, testosterone replacement and continued follow-up. Discussion Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. Sparsely granulated pattern is associated with larger tumor size and decreased remission rate after surgery. Conclusion This report illustrates a rare case of hypercortisolism remission due to apoplexy of a SGCT with subsequent central adrenal insufficiency, hypothyroidism and hypogonadism. Keywords pituitary apoplexy pituitary macroadenoma pituitary tumor sparsely granulated corticotroph tumor Cushing disease Introduction The incidence of Cushing Disease (CD) is estimated to be between 0.12 to 0.24 cases per 100,00 persons per year1,2. Of these, 7-23% are macroadenomas (>1 cm)3, 4, 5. Pituitary apoplexy is a potentially life-threatening endocrine and neurosurgical emergency which occurs due to infarction or hemorrhage in the pituitary gland. Apoplexy occurs most commonly in non-functioning macroadenomas with an estimated prevalence of 6.2 cases per 100,000 persons and incidence of 0.17 cases per 100,00 persons per year6. Corticotroph macroadenoma presenting with apoplexy is uncommon with only a handful of reports in the literature7. We present a case of a sparsely granulated corticotroph (SGCT) which presented with apoplexy leading to remission of hypercortisolism and subsequent central adrenal insufficiency. Case Presentation A 33-year-old male who was otherwise healthy and not on any medications presented to a community hospital with sudden and severe headache accompanied by hypotension, nausea, vomiting, bitemporal hemianopsia and diplopia. Computed Tomography (CT) scan of the brain demonstrated a hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica with extension into the right cavernous sinus and encasement of the right internal carotid arteries (Figure 1A). He was transferred to a tertiary care center for neurosurgical management with endocrinology consultation post-operatively. Download : Download high-res image (404KB) Download : Download full-size image Figure 1. hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica on unenhanced CT (A); MRI demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogeneous mass on T1 (B) and T2-weighted imaging (C) showing small hyperintense areas in solid part of the sella mass with flattening of the optic chiasm, remodeling/dehiscence of the floor of the sella and extending into the right cavernous sinus with at least partial encasement of the ICA In retrospect, he reported a 3-year history of ongoing symptoms of hypercortisolism including increased central obesity, dorsal and supraclavicular fat pad, facial plethora, abdominal purple striae, easy bruising, fatigue, decreased libido and erectile dysfunction. Notably, at the time of presentation he did not have a history of diabetes, hypertension, osteoporosis, fragility fractures or proximal muscle weakness. He fathered 2 children previously. His physical examination was significant for Cushingoid facies, facial plethora, dorsal and supraclavicular fat pads and central obesity with significant axillary and abdominal wide purple striae (Figure 2). Neurological examination revealed bitemporal hemianopsia, right third cranial nerve palsy with ptosis and impaired extraocular movement. The fourth and sixth cranial nerves were intact as was the rest of his neurological exam. These findings were corroborated by Ophthalmology. Download : Download high-res image (477KB) Download : Download full-size image Figure 2. Representative images illustrating facial plethora (A); abdominal striae (B, C); supraclavicular fat pad (D); dorsal fat pad (E) Initial laboratory data at time of presentation to the hospital included elevated plasma cortisol of 64.08ug/dL (RR, 2.36 – 17.05), ACTH was not drawn at the time of presentation, normal TSH 0.89 mIU/L (RR, 0.36 – 3.74), free thyroxine 0.91ng/dL (RR, 0.76 – 1.46), evidence of central hypogonadism with low total testosterone 28.8 ng/dL (RR, 219.2 – 905.6) and inappropriately normal luteinizing hormone (LH) 1mIU/mL (RR, 1 – 12) and follicle stimulating hormone (FSH) 3mIU/mL (RR, 1 – 12), low prolactin <1 ng/mL (RR, 3 – 20), and normal insulin growth factor – 1 (IGF–1) 179ng/mL (RR, 82 – 242). A pituitary gland dedicated MRI was performed to further characterize the mass, which re-demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogenous mass at the sella turcica extending superiorly and flattening the optic chiasm, remodeling of the floor of the sella and bulging into the sphenoid sinus and extending laterally into the cavernous sinus with encasement of the right internal carotid artery (ICA). As per the radiologist’s diagnostic impression, this appearance was most in keeping with a pituitary macroadenoma with apoplexy (Figure 1B – C). The patient underwent urgent TSS and decompression with no acute complications. Pathological examination of the pituitary adenoma showed features characteristic of sparsely granulated corticotroph pituitary neuroendocrine tumor (adenoma)8, with regional hemorrhage and tumor necrosis (apoplexy). The viable tumor exhibited a solid growth pattern (Figure 3A), t-box transcription factor (T-pit) nuclear immunolabeling (Figure 3B), diffuse cytoplasmic CAM5.2 (low molecular weight cytokeratin) immunolabeling (Figure 3C), and regional weak to moderate intense granular cytoplasmic ACTH immuno-staining (Figure 3D). The tumor was immuno-negative for: pituitary-specific positive transcription factor 1 (Pit-1) and steroidogenic factor 1 (SF-1) transcription factors, growth hormone, prolactin, TSH, FSH, LH, estrogen receptor-alpha, and alpha-subunit. Crooke hyalinization was not identified in an adjacent compressed fragment of non-adenomatous anterior pituitary tissue. Ki-67 immunolabeling showed a 1.5% proliferative index (11 of 726 nuclei). Download : Download high-res image (2MB) Download : Download full-size image Figure 3. Hematoxylin phloxine saffron staining showing adenoma with solid growth pattern (A); immunohistochemical staining showing T-pit reactivity of tumor nuclei (B); diffuse cytoplasmic staining for cytokeratin CAM5.2 (C); and regional moderately intense granular cytoplasmic staining for ACTH (D). Scale bar = 20 μm Post-operatively, he developed transient central diabetes insipidus requiring desmopressin but resolved on discharge. His postoperative cortisol was undetectable, ACTH 36 pg/mL (RR, 0 - 81), TSH 0.07 mIU/mL (RR, 0.36 - 3.74), free thyroxine 1 ng/dL (RR, 0.8 - 1.5), LH <1mIU/mL (RR, 1 - 12), FSH 1 mIU/mL (RR, 1 - 12) and testosterone 28.8 ng/dL (RR, 219.2 - 905.6) (Table 1 and Figure 4). One month later, he reported 15 pounds of weight loss and a 5-inch decrease in waist circumference. He also noted a reduction in the dorsal and supraclavicular fat pads, facial plethora, and Cushingoid facies as well as fading of the abdominal stretch marks. His visual field defects and right third cranial nerve palsy resolved on follow up with ophthalmology post-operatively. Repeat MRI six months post-operatively showed minor residual soft tissue along the floor of the sella. He is being followed by Neurosurgery, Ophthalmology, and Endocrinology for monitoring of disease recurrence, visual defects, and management of hypopituitarism. Table 1. Pre- and post-operative hormonal panel POD -1 POD 0 POD1 POD2 POD3 POD16 6 -9 months Comments Cortisol(2.4 – 17 ug/dL) 64↓ 32↓ 11↓ <1.8↓ <1.8↓ 1.8↓ HC started POD3 post bloodwork ACTH(0 – 81 pg/mL) 41↓ 36↓ 28↓ 13↓ TSH(0.36 - 3.74 uIU/mL) 0.89 0.43 0.12↓ 0.07↓ 0.05↓ 0.73 Thyroxine, free(0.8 – 1.5 ng/dL) 0.9 0.9 1.1 1 2.1↑ 1 Levothyroxine started POD4 LH(1 – 12 miU/mL) 1↓ <1↓ 1↓ 3 FSH(1 – 12 mIU/mL) 3↓ 1↓ 1↓ 3 Testosterone(219.2 – 905.6 ng/dL) 28.8↓ <20↓ 175.9↓ Testosterone replacement started as outpatient Testosterone, free(160 - 699 pmol/L) <5.8↓ 137↓ IGF-1(82 – 242 ng/mL) 179 79 GH(fasting < 6 mIU/L) 4.5 <0.3 Prolactin(3 – 20 ng/mL) <1↓ <1↓ POD, postoperative day; HC, hydrocortisone; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating hormone; LH, luteinizing Hormone; FSH, follicle stimulating hormone; IGF-1, insulin like growth factor - 1; GH, growth hormone Download : Download high-res image (259KB) Download : Download full-size image Figure 4. Trend of select pituitary hormonal panel with key clinical events denoted by black arrows. Discussion Microadenomas account for the majority of corticotroph tumors, but 7% – 23% of patients are diagnosed with a macroadenoma3, 4, 5. It is even rarer for a corticotroph macroadenoma to present with apoplexy with only a handful of case reports or series in the literature7. Due to its rarity, appropriate biochemical workup on presentation, such as including an ACTH with the blood work, may be omitted especially if the patient is going for emergent surgery. In this case, the undetectable prolactin can reflect loss of anterior pituitary function and also suggest a functioning corticotroph adenoma due to the inhibitory effect of long term serum glucocorticoids on prolactin secretion9. After undergoing TSS, the patient developed central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. Presumably, the development of adrenal insufficiency demonstrated the remission of hypercortisolism as a result of apoplexy and/or TSS. The ACTH remains detectable likely representing residual tumor that was not obliterated by apoplexy nor excised by TSS given it location near the carotid artery and cavernous sinus. The presence of adrenal insufficiency in the setting of detectable ACTH is not contradictory as the physiological hypothalamic-pituitary-adrenal axis has been suppressed by the long-term pathological production of ACTH. IGF-1 and prolactin also failed to recover post-operatively. In CD where the production of IGF-1 and prolactin are attenuated by elevated cortisol, it would then be expected that IGF-1 and prolactin recover after hypercortisolism remission. However, the absence of this observation in our case is likely a sequalae of the apoplexy and extensive surgery leading to pituitary hypofunction. We also want to highlight features of the pre-operative radiographical findings which can provide valuable insight into the subsequent histology. Previous literature has shown that, on T2-weight MRI, silent corticotroph adenomas are strongly correlated with characteristic a multimicrocystic appearance while nonfunctional gonadotroph macroadenomas are not correlated with this MRI finding10. The multimicrocystic appearance is described as small hyperintense areas with hyperintense striae in the solid part of the tumor (Figure 1C)10. This is an useful predictive tool for silent corticotroph adenomas with a sensitivity of 76%, specificity of 95% and a likelihood ratio of 15.310. The ability to distinguish between silent corticotroph macroadenoma and other macroadenomas is important for assessing rate of remission and recurrence risk. In 2017, the WHO published updated classification for pituitary tumors. In this new classification, corticotroph adenomas are further divided into densely granulated, sparsely granulated and Crooke’s cell tumors11. DGCT are intensely Periodic Acid Schiff (PAS) stain positive and exhibit strong diffuse pattern of ACTH immunoreactivity, whereas SGCT exhibit faintly positive PAS alongside weak focal ACTH immunoreactivity4,12. Crooke’s cell tumors are characterized by Crooke’s hyaline changes in more than 50% of the tumor cells4. In the literature, SGCT account for an estimated 19-29% of corticotroph adenomas13, 14, 15. The clinicopathological relevance of granulation pattern in corticotroph tumors was unclear until recently. In multiple studies examining granulation pattern and tumor size, SGCT were statistically larger13,15,16. Hence, we suspect that many of the previously labelled silent corticotroph macroadenomas in the literature were SGCT. The traditional teaching of CD has been “small tumor, big Cushing and big tumor, small Cushing” which reflects the inverse relationship between tumor size and symptomatology17. This observation appears to hold true as Doğanşen et al. found a trend towards longer duration of CD in SGCT of 34 months compared to 26 months in DGCT based on patient history13,17. It has been postulated that the underlying mechanism of the inverse relationship between tumor size and symptomatology is impaired processing of proopiomelanocortin resulting in less effective secretion of ACTH in corticotroph macroadenomas3. Doğanşen et al. also found that the recurrence rate was doubled for SGCT, while Witek et al. showed that SGCT were less likely to achieve remission postoperatively13,16. Similar to other cases of SGCT, the diagnosis was only arrived retrospective after pathological confirmation10. Interestingly, the characteristic Crooke’s hyaline change of surrounding non-adenomatous pituitary tissue was not observed as one would expect in a state of prolonged glucocorticoid excess in this case. Although classically described, the absence of this finding does not rule out CD. As evident in a recent retrospective study where 10 out of 144 patients with CD did not have Crooke’s hyaline change18. In patients without Crooke’s hyaline change, the authors found a lower remission rate of 44.4% compared to 73.5% in patients with Crooke’s hyaline change. Together with the detectable post-operative ACTH, sparsely granulated pattern and absence of Crooke’s hyaline change in surrounding pituitary tissue, the risk of recurrence is increased. These risk factors emphasize the importance of close monitoring to ensure early detection of recurrence. Declaration of Interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Conclusion We present a case of a sparsely granulated corticotroph macroadenoma presenting with apoplexy leading to remission of hypercortisolism and development of central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. References 1 J. Lindholm, S. Juul, J.O. Jørgensen, et al. Incidence and late prognosis of cushing's syndrome: a population-based study J Clin Endocrinol Metab, 86 (1) (2001), pp. 117-123 View Record in ScopusGoogle Scholar 2 J. Etxabe, J.A. Vazquez Morbidity and mortality in Cushing's disease: an epidemiological approach Clin Endocrinol (Oxf), 40 (4) (1994), pp. 479-484 View PDF CrossRefView Record in ScopusGoogle Scholar 3 L. Katznelson, J.S. Bogan, J.R. Trob, et al. Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas J Clin Endocrinol Metab, 83 (5) (1998), pp. 1619-1623 View Record in ScopusGoogle Scholar 4 L.V. Syro, F. Rotondo, M.D. Cusimano, et al. Current status on histological classification in Cushing's disease Pituitary, 18 (2) (2015), pp. 217-224 View PDF CrossRefView Record in ScopusGoogle Scholar 5 Y.S. Woo, A.M. Isidori, W.Z. Wat, et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas J Clin Endocrinol Metab, 90 (8) (2005), pp. 4963-4969 View PDF CrossRefView Record in ScopusGoogle Scholar 6 C. Briet, S. Salenave, J.F. Bonneville, E.R. Laws, P. Chanson Pituitary Apoplexy Endocr Rev, 36 (6) (2015), pp. 622-645 View PDF CrossRefView Record in ScopusGoogle Scholar 7 K. Siwakoti, S.B. Omay, S.E. Inzucchi SPONTANEOUS RESOLUTION OF PRIMARY HYPERCORTISOLISM OF CUSHING DISEASE AFTER PITUITARY HEMORRHAGE AACE Clin Case Rep, 6 (1) (2020), pp. e23-e29 ArticleDownload PDFCrossRefView Record in ScopusGoogle Scholar 8 S.L. Asa, O. Mete What's new in pituitary pathology? Histopathology, 72 (1) (2018), pp. 133-141 View PDF CrossRefView Record in ScopusGoogle Scholar 9 M.E. Freeman, B. Kanyicska, A. Lerant, G. Nagy Prolactin: Structure, Function, and Regulation of Secretion Physiological Reviews, 80 (4) (2000), pp. 1523-1631 View PDF CrossRefView Record in ScopusGoogle Scholar 10 L. Cazabat, M. Dupuy, A. Boulin, et al. Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas Clin Endocrinol (Oxf), 81 (4) (2014), pp. 566-572 View PDF CrossRefView Record in ScopusGoogle Scholar 11 M.B.S. Lopes The 2017 World Health Organization classification of tumors of the pituitary gland: a summary Acta Neuropathol, 134 (4) (2017), pp. 521-535 View PDF CrossRefView Record in ScopusGoogle Scholar 12 W. Saeger, J. Honegger, M. Theodoropoulou, et al. Clinical Impact of the Current WHO Classification of Pituitary Adenomas Endocr Pathol, 27 (2) (2016), pp. 104-114 View PDF CrossRefView Record in ScopusGoogle Scholar 13 S. Doğanşen, B. Bilgiç, G.Y. Yalin, S. Tanrikulu, S. Yarman Clinical Significance of Granulation Pattern in Corticotroph Pituitary Adenomas Turk Patoloji Derg, 35 (1) (2019), pp. 9-14 Google Scholar 14 O. Mete, A. Cintosun, I. Pressman, S.L. Asa Epidemiology and biomarker profile of pituitary adenohypophysial tumors Mod Pathol, 31 (6) (2018), pp. 900-909 View PDF CrossRefView Record in ScopusGoogle Scholar 15 B. Rak, M. Maksymowicz, M. Pękul, G. Zieliński Clinical, Biological, Radiological Pathological and Immediate Post-Operative Remission of Sparsely and Densely Granulated Corticotroph Pituitary Tumors: A Retrospective Study of a Cohort of 277 Patients With Cushing's Disease Front Endocrinol (Lausanne), 12 (2021) 672178 Google Scholar 16 P. Witek, G. Zieliński, K. Szamotulska, M. Maksymowicz, G. Kamiński Clinicopathological predictive factors in the early remission of corticotroph pituitary macroadenomas in a tertiary referral centre Eur J Endocrinol, 174 (4) (2016), pp. 539-549 View PDF CrossRefView Record in ScopusGoogle Scholar 17 A.M. McNicol Tumors of the pituitary gland. S. L. Asa. AFIP atlas of tumor pathology, third series The Journal of Pathology, 188 (1) (1999), pp. 115-116 View Record in ScopusGoogle Scholar 18 A. Akirov, V. Larouche, I. Shimon, et al. Significance of Crooke's Hyaline Change in Nontumorous Corticotrophs of Patients With Cushing Disease Front Endocrinol (Lausanne), 12 (2021) 620005 Google Scholar From https://www.sciencedirect.com/science/article/pii/S2376060522000268#!
  4. The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed. Key Takeaways A study of 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor or other lesions within the pituitary fossa at a single center in the UK suggests that postoperative plasma levels of copeptin — a surrogate marker for levels of arginine vasopressin (antidiuretic hormone) — can rule out development of central (neurogenic) diabetes insipidus caused by a deficiency of arginine vasopressin following pituitary surgery. The researchers suggest using as a cutoff a copeptin level of >3.4 pmol/L at postoperative day 1 to rule out diabetes insipidus. Such a cutoff yields the following: A high sensitivity of 91% for ruling out diabetes insipidus. A negative predictive value of 97%. Only 1 of 38 patients with a copeptin value >3.4 pmol/L at day 1 postoperatively developed diabetes insipidus. A low specificity of 55%, meaning that copeptin level is not useful for diagnosing diabetes insipidus Why This Matters An estimated 1% to 67% of patients who undergo pituitary gland surgery develop diabetes insipidus, often soon after surgery, although it is often transient. Diagnosing diabetes insipidus in such patients requires a combination of clinical assessment, the monitoring of fluid balance, and determining plasma and urine sodium and osmolality. Currently, clinical laboratories in the UK do not have assays for arginine vasopressin, which has a short half-life in vivo and is unstable ex vivo, even when frozen, and is affected by delayed or incomplete separation from platelets. Copeptin, an arginine vasopressin precursor, is much more stable and measurable by commercial immunoassays. The findings suggest that patients who have just undergone pituitary gland surgery and are otherwise healthy and meet the copeptin cutoff for ruling out diabetes insipidus could be discharged 24 hours after surgery and that there is no need for additional clinical and biochemical monitoring. This change would ease demands on the healthcare system. Study Design The study reviewed 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor from November 2017 to June 2020 at the John Radcliffe Hospital in Oxford, United Kingdom. Patients remained in hospital for a minimum of 48 hours after their surgery. Clinicians collected blood and urine specimens preoperatively and at day 1, day 2, day 8, and week 6 post surgery. The patients were restricted to 2 L of fluid a day postoperatively to prevent masking of biochemical abnormalities through compensatory drinking. Diabetes insipidus was suspected when patients' urine output was >200 mL/h for 3 consecutive hours or >3 L/d plus high plasma sodium (>145 mmol/L) and plasma osmolality (> 295 mosmol/kg) plus inappropriately low urine osmolality. Definitive diagnosis of diabetes insipidus was based on clinical assessment, urine and plasma biochemistry, and need for treatment with desmopressin (1-deamino-8-D-arginine vasopressin). Key Results The median age of the patients was 55, and 53% were men; 92% of the lesions were macroadenomas; the most common histologic type was gonadotroph tumor (47%). Among the 78 patients, 11 (14%) were diagnosed with diabetes insipidus postoperatively and required treatment with desmopressin; of these, seven patients (9%) continued taking desmopressin after 6 weeks (permanent diabetes insipidus), but the other four did not need to take desmopressin for more than a week. Patients who developed diabetes insipidus were younger than other patients (mean age, 46 vs 56), and 8 of the 11 patients who developed diabetes insipidus (73%) were women. Preoperative copeptin levels were similar in the two groups. At day 1, day 8, and 6 weeks postoperatively, copeptin levels were significantly lower in the diabetes insipidus group; there were no significant differences at day 2, largely because of an outlier result. An area under the receiver operating characteristic curve (AUC; C-statistic) analysis showed that on day 1 after surgery, copeptin levels could account for 74.22% of the incident cases of diabetes insipidus (AUC, 0.7422). On postop day 8, the AUC for copeptin was 0.8015, and after 6 weeks, the AUC associated with copeptin was 0.7321. Limitations Blood samples for copeptin tests from patients who underwent pituitary surgery were collected at specified times and were frozen for later analysis; performing the test in real time might alter patient management. The study may have missed peak copeptin levels by not determining copeptin levels sooner after pituitary gland surgery, inasmuch as other researchers have reported better predictive values for diagnosing diabetes insipidus from samples taken 1 hour after extubation or <12 hours after surgery. Disclosures The study did not receive commercial funding. The authors report no relevant financial relationships. This is a summary of a preprint research study, "Post-Operative Copeptin Analysis Predicts Which Patients Do Not Develop Diabetes Insipidus After Pituitary Surgery," by researchers from John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, in the United Kingdom. Preprints from Research Square are provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com. Read the article here: https://www.medscape.com/viewarticle/970357#vp_1
  5. This article was originally published here Front Surg. 2022 Feb 2;8:806855. doi: 10.3389/fsurg.2021.806855. eCollection 2021. ABSTRACT PURPOSE: Currently, endoscopic transsphenoidal surgery (ETS) and microscopic transsphenoidal surgery (MTS) are commonly applied treatments for patients with pituitary adenomas. This meta-analysis was conducted to evaluate the efficacy and safety of ETS and MTS for these patients. METHODS: A computer search of Pubmed, Embase, Cochrane library, Web of Science, and Google Scholar databases was conducted for studies investigating ETS and MTS for patients with pituitary adenomas. The deadline is March 01, 2021. RevMan5.1 software was used to complete this meta-analysis after literature screening, data extraction, and literature quality evaluation. RESULTS: A total of 37 studies including 5,591 patients were included. There was no significant difference in gross tumor removal (GTR) and hormone-excess secretion remission (HES remission) between two groups [RR = 1.10, 95% CI (0.99-1.22), P = 0.07; RR = 1.09, 95% CI (1.00-1.20), P = 0.05]. ETS was associated with lower incidence of diabetes insipidus (DI) [RR = 0.71, 95% CI (0.58-0.87), P = 0.0008], hypothyroidism [RR = 0.64, 95% CI (0.47-0.89), P = 0.007], and septal perforation [RR = 0.32, 95% CI (0.13-0.79), P = 0.01] than those with MTS. CONCLUSION: This meta-analysis indicated that ETS cannot significantly improve GTR and HES remission. However, ETS could reduce the incidence of DI, hypothyroidism, and septal perforation without increasing the rate of other complications. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/#myprospero, identifier: CRD42021241217. PMID:35187049 | PMC:PMC8847202 | DOI:10.3389/fsurg.2021.806855
  6. Best friends Charly Clive and Ellen Robertson thought carefully about what to call the tumour that was growing in Charly’s brain. The doctors had their own name for the golf-ball-sized growth sitting right behind Charly’s left eye — a pituitary adenoma — but the friends decided they needed something less scary. They flirted with calling it Terry Wogan (‘as in Pitui-Terry Wogan,’ says Ellen), but that didn’t seem quite right. So Britney Spears fan Charly, then 23, suggested Britney. Bingo! Not only was she ‘iconic and fabulous’, but Britney was also one of life’s survivors. From then on, they were a threesome — Charly, Ellen and Britney the brain tumour — although Ellen is at pains to point out that this Britney was never a friend. What a thing to have to deal with, so young. The pair, who met at school in rural Oxfordshire, are now actresses. Charly’s biggest role to date has been in the critically acclaimed 2019 Channel 4 series Pure, while Ellen starred in the Agatha Christie mini-series The Pale Horse. But this week they appeared together in Britney, a BBC comedy based on the story of Charly’s brain tumour. The TV pilot (and yes, they are hoping for a full series) is an expansion of a sell-out stage show they performed at the Edinburgh Fringe in 2016. The production is admittedly surreal. Viewers are led inside Charly’s brain and the show includes a scene where Charly dons an inflatable sumo-wrestler suit on the day of her diagnosis. Poetic licence? No, it really happened. ‘My dad’s mate had given him a sumo suit as a silly Christmas present and so, on Doomsday, we took photos of me in it.’ The tone was set for how these friends would deal with the biggest challenge of their lives: they would laugh through it, somehow. As the women, now 28, point out, what was the alternative? Charly says: ‘It was that thing of laughing at the monster so you are not scared of it. If you cry when do you stop? It was easier to make light of it.’ Their show is not really about a brain tumour. It’s a celebration of friendship. Ellen pretty much moved in with Charly’s family during this time (‘To be in place when I exploded, so she could pick up the debris,’ says Charly). The pair live together today, finishing each other’s sentences as we speak on Zoom — and at one point both miming Charly’s brain surgery (with gruesome sound effects). This sort of silliness rooted their friendship, which started at the age of 14 when they wrote their own plays (Finding Emo, anyone?) while at school together in Abingdon. Charly later moved to New York to study dramatic arts, and Ellen studied at Cambridge. In 2015, Charly came home for a visit, and went to see her GP (played in the drama by Omid Djalili) about her lack of periods and a blind spot in her peripheral vision. An MRI scan showed a mass on her brain. ‘They said it had eroded the bone in my nose and was pressing on the optic nerve, and it was lucky we had caught it,’ she says. ‘The next step would have been discovering it because I’d gone blind.’ Even worse, the tumour was so close to her carotid artery that removal might kill her — and they still had no idea if it was cancerous. Into the breach stepped Ellen. ‘I saw it as my job to make her laugh, which is what I’d always done anyway,’ she says. They both talk of toppling into limbo, ‘almost like a fantasy world’, says Charly. ‘As I was going through the tests, we’d do impressions of the doctors and create our own scenarios.’ The friends talk about sitting up into the night, watching TV. There is a touching moment when Charly admits she was afraid to sleep, and Ellen knew it. ‘It’s hard when you are thinking “What if the tumour grows another inch in the night and I don’t wake up?” ’ Charly was operated on in March 2016, and Ellen remembers the anaesthetist confiding that Charly’s heart had stopped on the operating table. ‘He wasn’t the most tactful person we’ve ever met. He said “Oh my God, guys, she died”.’ Charly makes a jazz hands gesture. ‘And guess who is alive again?’ Even at that darkest moment, there were flashes of humour. Ellen laughs at the memory of the surgeon in his scrubs, with wellies on. ‘They had blood on them. I was transfixed. I wanted to ask “Is that Charly’s . . . brain blood?” ’ In the stage version of the show, the anaesthetist gets two full scenes. ‘He’s the heartthrob of the piece,’ says Charly. ‘A sexy rugger bloke who is crap at talking to people.’ The days that followed the surgery were hideous — and yet they, too, have been mined for comedy. Charly’s face was bandaged, ‘as if I’d had a Beverly Hills facelift’, and she was warned that she could not sneeze. ‘If I did, bits of my brain would come out my nose,’ she says. Ellen read her extracts from Harry Potter but ‘made them smutty’, which confused the already confused Charly further. ‘I was drug-addled and not myself, and in the most bizarre pain, concentrated in my face’. ‘That week after the surgery was the worst part of all,’ says Ellen, suddenly serious. ‘She was behaving oddly and there was this unacknowledged fear: was this Charly for ever?’ Oh, the relief when the old Charly eventually re-emerged — albeit a more fragile, often tearful version. It was Ellen who persuaded Charly to take their stage show about her illness public — and it went on to win much critical acclaim. ‘I wanted Charly to see it as something other than just this rubbish chapter that needed to be forgotten about,’ says Ellen. For her part, Charly credits her best friend as her saviour: ‘I don’t know how I would have got through it all without Ellen.’ The good news is that Britney was not cancerous, although surgery did not obliterate her entirely. ‘She’s still there, but tiny — just a sludge. I’ve been told that she won’t grow though. If I ever do get another brain tumour, it won’t be Britney.’ Off they go again, imagining what is happening now inside Charly’s brain. ‘Britney is still in there, trying on outfits for a comeback tour, but it won’t happen,’ says Charly. Ellen nods. ‘It’s over,’ she says. ‘But she’s just left a pair of shoes behind.’ Britney is available to watch on BBC Three and BBC iPlayer Adapted from https://www.dailymail.co.uk/femail/article-10264203/I-laughed-brain-tumour-Id-never-stop-crying-Actress-Charly-Clive.html
  7. Headaches are a common complaint in patients with pituitary tumors. Although many patients presumably have headaches which are unrelated to their pituitary tumor, there are several important direct and indirect mechanisms by which pituitary tumors may elicit or exacerbate headaches. Pituitary tumors may directly provoke headaches by eroding laterally into the cavernous sinus, which contains the first and second divisions of the trigeminal nerve, by involvement of the dural lining of the sella or diaphragma sella (which are innervated by the trigeminal nerve), or via sinusitis, particularly after transsphenoidal surgery. Headache pain in these situations is typically characterized by steady, bifrontal or unilateral frontal aching (ipsilateral to tumor). In some instances, pain is localized in the midface (either because of involvement of the second division of the trigeminal or secondary to sinusitis). In contrast to the insidious, subacute development of headaches in most patients with pituitary tumors, patients with pituitary apoplexy may experience acute, severe headaches, perhaps associated with signs and symptoms of meningeal irritation (stiff neck, photophobia), CSF pleocytosis or occulomotor paresis. Routine CT scans of the head occasionally skip the sella, hence the presence of blood or a mass within the sella may not be detected and patients can be misdiagnosed with meningitis or aneurysm. Because pituitary apoplexy represents a neurosurgical emergency, MRI should be used in patients with symptoms suggestive of this disorder. A subacute form of pituitary apoplexy has also been reported. Patients with subacute pituitary apoplexy experience severe and/or frequent headaches over weeks to months and have heme products within the sella on MRI scans. In most instances, headaches are not attributable to direct effects of the pituitary tumor and indirect causes must be considered. Generally, indirect effects of pituitary tumors are caused by reduced secretion of pituitary hormones and are manifested by promotion of "vascular" headaches (e.g., migraine). The major exception to this rule relates to the potential for acromegalic patients to develop headaches secondary to cervical osteoarthritis. Vascular headaches may be exacerbated in association with disruption of normal menstrual cyclicity and impaired gonadal steroid secretion (e.g., from hyperprolactinemia or gonadotropin deficiency). Hyperprolactinemia, hypothyroidism and hyperthyroidism may also have direct effects, independent of gonadal hormones. Headaches are common in acromegaly, and in the majority of cases the etiology is not well understood. Finally, drug management of pituitary tumors may inadvertently impact headaches. Octreotide results in extremely rapid headache improvement with patients with acromegaly. The rapid time course suggests it is not due to lowering of GH levels. Octreotide also has a dramatic beneficial effect on migraine and may be producing relief of headache by vascular mechanisms. Occasionally severe headaches surface in acromegalic patients after reduction or discontinuation of octreotide, as a "withdrawal" phenomenon.| Bromocriptine or other dopamine agonists occasionally trigger severe headaches. When this occurs, it is important to recognize that bromocriptine has been reported as a cause of pituitary apoplexy, and it may be necessary to perform an MRI or CT to rule out infarction or hemorrhage within the pituitary. Once it is established that the patient is not infarcting the pituitary, it is generally safe to treat the headaches symptomatically (not with an ASA containing drug) and consider alternative therapies for the prolactinoma if the problem remains severe. Pituitary tumor patients with vascular headaches are generally quite responsive to standard prophylactic migraine drugs (e.g., tricyclic antidepressants, verapamil and beta-blockers). It is best to begin therapy with very low-dose medication (e.g., 10 mg of amitriptyline at bedtime) and resist the impulse to escalate the dose rapidly to higher levels. Often patients have an excellent response to 10-30 mg of a tricyclic antidepressant, although it may take up to six or more weeks to reach the ultimate benefit. The choice of tricyclic antidepressant should be based upon the desired side effects (e.g., either more sedation or less sedation) The newer, serotonin-selective antidepressants are generally less effective for headaches than tricyclics, although some patients do respond nicely to these agents. In some cases it may be necessary to use combination therapy (e.g., verapamil plus a tricyclic). From https://www.massgeneral.org/neurosurgery/treatments-and-services/pituitary-tumors-and-headaches?fbclid=IwAR2iBMjf5VNvw2_ucalXikyIZIh3dJuYu0Kk6P1jhQ2IDnDj9ubkPO4Zl9A
  8. https://doi.org/10.1016/j.aace.2021.10.004Get rights and content Under a Creative Commons license open access Highlights • Cushing’s Disease (CD) in pregnancy is rare, but poses many risks to the mother and fetus • Although surgery is still considered first line, this CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure • The dose of metyrapone can be titrated to a goal urinary free cortisol of < 150 ug/24 hours given the known rise in cortisol during gestation • Though no fetal adverse events have been reported, metyrapone does cross the placenta and long-term effects are unknown. ABSTRACT Background Cushing Disease (CD) in pregnancy is a rare, but serious, disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with CD. Case Report 34-year-old woman with hypertension who was diagnosed with adrenocorticotropic hormone-dependent CD based on a urinary free cortisol (UFC) of 290 μg/24hr (reference 6-42μg/dL) and abnormal dexamethasone suppression test (cortisol 12.4 μg/dL) before becoming pregnant. She conceived naturally 12 weeks post-transsphenoidal surgery, and was subsequently found to have persistent disease with UFC 768μg/dL. Surgery was deemed high risk given the proximity of the tumor to the right carotid artery and high likelihood of residual disease. Instead, she was managed with metyrapone throughout her pregnancy and titrated to goal UFC of <150μg/24hr due to the known physiologic rise in cortisol during gestation. The patient had diet-controlled gestational diabetes, and well-controlled hypertension. She gave birth at 37 weeks gestation to a healthy baby boy, without adrenal insufficiency in the baby or mother. Discussion This CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure. While metyrapone is effective, close surveillance is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, this medication crosses the placenta and long-term effects are unknown. Conclusion We describe a CASE of CD during pregnancy that was successfully treated with metyrapone. Key words Cushing disease metyrapone pregnancy cortisol INTRODUCTION Cushing disease (CD) is caused by endogenous overproduction of glucocorticoids due to hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. CD in pregnancy is very rare, and when it occurs, it is considered a high-risk pregnancy with many potential adverse outcomes for both the mother and fetus.1 Infertility is common in CD due to cortisol and androgen excess leading to hypogonadotropic hypogonadism.1 Due to the rarity of CD in pregnancy, there is little guidance in terms of treatment for this patient population. Similar to non-pregnant patients, the first-line treatment is transsphenoidal pituitary adenoma resection, with medical therapy as a second-line treatment option. This report presents a CASE that highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor. CASE REPORT A 34-year-old woman with a past medical history of hypertension and infertility for six years presented to endocrinology for evaluation. Aside from difficulty conceiving, her only complaints were nausea and easy bruising. On exam she did not have clinical features of CD –abdominal violaceous striae, moon facies or a dorsocervical fat pad were absent. Her laboratory results revealed an elevated prolactin level (50-60ng/mL, reference range 1.4-24), an elevated ACTH level (61 pg/mL, reference range 0-46), and low FSH and LH levels (1.7mIU/mL and 1.76mIU/mL, respectively). Further testing demonstrated an elevated urinary free cortisol level (UFC) (290μg/24 hour, reference range 6-42) and her cortisol failed to suppress on a 1mg dexamethasone suppression test (cortisol 12.4μg/dL). Magnetic resonance imaging (MRI) of the pituitary with and without contrast showed a T2 hyperintense, hypoenhancing lesion within the right side of the sella touching the right cavernous internal carotid artery measuring 8x8x9 mm consistent with a pituitary adenoma (Figure 1). Download : Download high-res image (247KB) Download : Download full-size image Figure 1. Caption: T1 weighted post gadolinium coronal image of the pituitary gland with a small hypoenhancing lesion within the right side of the sella. After the presumed diagnosis of CD was made, she was referred to neurosurgery for transsphenoidal resection of the adenoma, which she underwent a few months later. Intra-operatively, a white friable tumor was found, and otherwise the surgery was uneventful. Three months later, however, she was found to have a persistent 8x8x9mm hypoenhancing lesion extending laterally over the right cavernous carotid artery on MRI. The mass approximated but did not contact the right intracranial optic nerve. The pathology from resected tissue was consistent with normal pituitary tissue with staining for growth hormone (80%), ACTH (30%), prolactin (40%), follicle stimulating hormone (5%), luteinizing hormone (40%) and thyroid stimulating hormone (15%), proving the surgery to have been unsuccessful. Twelve weeks post-operatively, the patient discovered she was pregnant. At 12 weeks gestation, her UFC was 768μg/24h and two midnight salivary cortisol levels were elevated at 0.175 and 0.625μg/dL (reference <0.010-0.090). She was experiencing easy bruising and taking labetalol 400 mg twice daily for hypertension. She had gained 10 pounds by 12 weeks gestation. A second transsphenoidal surgery during pregnancy was deemed high risk, with a high likelihood of residual disease due to the proximity of the tumor to the right carotid artery. The decision was made to treat the patient medically with metyrapone which was started at 250 mg twice per day at 12 weeks gestation and was eventually uptitrated based on UFC levels every 3-4 weeks (goal of <150μg /24h) to 1000 mg three times per day by the time of delivery with an eventual UFC level of 120μg/24h (Figure 2) . Morning ACTH and serum cortisol levels were monitored for potential adrenal insufficiency. Download : Download high-res image (375KB) Download : Download full-size image Figure 2. Caption: This figure depicts the patient’s 24 hour urinary cortisol levels over time as well as the titration of metyrapone dosage in mg/day. Her hypertension was well controlled throughout pregnancy on labetalol with the addition of nifedipine XL 30mg daily in the second trimester. She remained normokalemic with potassium ranging from 3.8-4.1mEq/L. She was diagnosed with gestational diabetes at 24 weeks by an abnormal two-step oral glucose tolerance test, which was diet-controlled. The patient was induced at 37 weeks gestation due to cervical insufficiency with cerclage in place, and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy vaginally without complications. His Apgar scores were 9 and 9 and he weighed 6 pounds and 5 ounces. At the time of delivery and one week later, the baby’s cortisol levels were normal (6 μg/dL, normal 4-20), without evidence of adrenal insufficiency. The patient’s metyrapone dose was reduced to 500mg three times a day after pregnancy and her 2 month postpartum 24 hour UFC was 42μg/24hr. The patient stopped the metyrapone on her own four months later and her UFC was found to be elevated at 272ug/24hr (normal 6-42μg/24hr). An MRI one year postpartum revealed a 10x10x9 mm adenoma in the right sella with some suprasellar extension without compression of the optic chiasm, but with abutment of the right carotid artery. Due to the persistently elevated cortisol, large size of the tumor, and potential for cure, especially if followed by radiation therapy, a second transsphenoidal surgery was recommended. However, due to the COVID-19 pandemic the patient underwent a delayed surgery 1.5 years postpartum. The pathology was consistent with a pituitary adenoma that stained strongly and diffusely for ACTH and synaptophysin, only. Her postoperative day 2 cortisol was 1.1μg/dL (reference range 6.7-22.6) and hydrocortisone 20mg in the morning and 10mg in the afternoon was started. She remains on hydrocortisone replacement and went on to conceive again, one month after her second surgery. DISCUSSION We describe a patient with pre-existing CD who became pregnant and was managed successfully with metyrapone throughout her pregnancy. Although CD is rare in pregnancy, it can occur, and poses risks to both the mother and fetus.1,2 Potential maternal complications include hypertension, preeclampsia, diabetes, fractures and more uncommonly, cardiac failure, psychiatric disorders, infection and maternal death.1,2 There is also increased fetal morbidity including prematurity, intrauterine growth retardation and less commonly CD can lead to stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism.1,2 It is, therefore, imperative that these patients receive prompt care to control cortisol levels. The treatment of CD in pregnancy is challenging as there are no large research trials studying the efficacy and safety of medications in CD during pregnancy. Pituitary surgery is first-line recommendation and should be done late in the first trimester or in the second trimester to prevent spontaneous pregnancy loss.3 In this CASE, however, it was felt that a second surgery would be high-risk given the proximity of the tumor to the right carotid artery and possibly not curative, and thus surgery was not a feasible option. She was therefore successfully managed with medical therapy with metyrapone alone throughout her pregnancy. Metyrapone use in pregnancy has been previously reported in the literature and has been shown to be effective in reducing cortisol levels.4,5,6 Although not approved for use in pregnancy, this steroidogenesis inhibitor is the most commonly used medication to treat Cushing’s syndrome in pregnant women.3,5 Due to metyrapone’s inhibition of 11-beta-hydroxylase, there is a buildup of steroidogenesis precursors such as 11-deoxycorticosterone, which can worsen hypertension, increase frequency of preeclampsia, and cause hypokalemia.3 Metyrapone also leads to elevation of adrenal androgens, which in conjunction with accumulation of 11-deoxycorticosterone, can cause hirsutism and virilization. 8 Though the use of Cabergoline has been reported in cases with Cushing disease during pregnancy, no long term safety data is available regarding it effects on pregnancy as well as the fetus. Moreover, studies assessing the effect of cabergoline in persistent or recurrent CD show a response rate of 20-30% only in cases with mild hypercortisolism. 9 There is no consensus on how to medically treat patients with CD during pregnancy. We chose a goal UFC of <150μg/24 hours because of the physiological rise of cortisol to two to three times the upper limit of normal during pregnancy.3,7 During pregnancy, there is an increase in corticotropin-releasing hormone from the placenta, which is identical in structure to the hypothalamic form.7 This leads to increased levels of ACTH which stimulates the maternal adrenal glands to become slightly hypertrophic and accounts for the rise in serum cortisol levels in pregnancy.7 Corticosteroid-binding globulin also increases in pregnancy, along with serum free cortisol, leading to urinary free cortisol increasing to 3-fold the normal range.7 We therefore aimed to keep our patient’s urinary free cortisol approximately 3 times the upper limit of normal on our assay, to maintain normal cortisol levels for pregnancy. Close surveillance of patients is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency.3 Although no fetal adverse events from metyrapone have been reported, the medication does cross the placenta, leading to the potential for fetal adrenal insufficiency, and long-term effects are unknown.3 CONCLUSION This CASE demonstrates the successful use of metyrapone alone to treat CD throughout pregnancy resulting in the birth of a healthy baby without adrenal insufficiency. These cases are particularly challenging given the lack of FDA-approved therapies and the lack of consensus on directing titration of medications and the duration of therapy. Uncited reference 4., 6.. REFERENCES: 1 T. Brue, V. Amodru, F. Castinetti MANAGEMENT OF ENDOCRINE DISEASE: Management of Cushing's syndrome during pregnancy: solved and unsolved questions Eur J Endocrinol, 178 (6) (2018 Jun), pp. R259-R266, 10.1530/EJE-17-1058 Epub 2018 Mar 9. PMID: 29523633 View PDF CrossRefView Record in ScopusGoogle Scholar 2 F. Caimari, E. Valassi, P. Garbayo, C. Steffensen, A. Santos, R. Corcoy, S.M. Webb Cushing's syndrome and pregnancy outcomes: a systematic review of published cases Endocrine, 55 (2) (2017 Feb), pp. 555-563, 10.1007/s12020-016-1117-0 Epub 2016 Oct 4. PMID: 27704478 View PDF CrossRefView Record in ScopusGoogle Scholar 3 M.D. Bronstein, M.C. Machado, M.C. Fragoso MANAGEMENT OF ENDOCRINE DISEASE: Management of pregnant patients with Cushing's syndrome Eur J Endocrinol, 173 (2) (2015 Aug), pp. R85-91, 10.1530/EJE-14-1130 Epub 2015 Apr 14. PMID: 25872515 View PDF View Record in ScopusGoogle Scholar 4 Azzola A, Eastabrook G, Matsui D, Berberich A, Tirona RG, Gray D, Gallego P, Van Uum S. Adrenal Cushing Syndrome Diagnosed During Pregnancy: Successful Medical Management With Metyrapone. J Endocr Soc. 2020 Nov 5;5(1):bvaa167. doi: 10.1210/jendso/bvaa167. PMID: 33305159; PMCID: PMC7712789. Google Scholar 5 W.H. Lim, D.J. Torpy, W.S. Jeffries The medical management of Cushing's syndrome during pregnancy Eur J Obstet Gynecol Reprod Biol, 168 (1) (2013 May), pp. 1-6, 10.1016/j.ejogrb.2012.12.015 Epub 2013 Jan 8. PMID: 23305861 ArticleDownload PDFView Record in ScopusGoogle Scholar 6 Gormley MJ, Hadden DR, Kennedy TL, Montgomery DA, Murnaghan GA, Sheridan B. Cushing's syndrome in pregnancy--treatment with metyrapone. Clin Endocrinol (Oxf). 1982 Mar;16(3):283-293. doi: 10.1111/j.1365-2265.1982.tb00718.x. PMID: 7074978. Google Scholar 7 M.C. Machado, M.C.B.V. Fragoso, M.D. Bronstein Pregnancy in Patients with Cushing's Syndrome Endocrinol Metab Clin North Am, 47 (2) (2018 Jun), pp. 441-449, 10.1016/j.ecl.2018.02.004 PMID: 29754643 ArticleDownload PDFView Record in ScopusGoogle Scholar 8 Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser GM. Metyrapone in long-term management of Cushing's disease. Br Med J. 1977 Jul 23;2(6081):215-217. doi: 10.1136/bmj.2.6081.215. PMID: 195666; PMCID: PMC1631369. Google Scholar 9 Stalldecker G, Mallea-Gil MS, Guitelman M, Alfieri A, Ballarino MC, Boero L, Chervin A, Danilowicz K, Diez S, Fainstein-Day P, García-Basavilbaso N, Glerean M, Gollan V, Katz D, Loto MG, Manavela M, Rogozinski AS, Servidio M, Vitale NM. Effects of cabergoline on pregnancy and embryo-fetal development: retrospective study on 103 pregnancies and a review of the literature. Pituitary. 2010 Dec;13(4):345-350. doi: 10.1007/s11102-010-0243-6. PMID: 20676778. Google Scholar Clinical Relevance: Cushing’s Disease (CD) in pregnancy is a rare, but serious, disease that has potential adverse effects on maternal and fetal health. Surgery is considered first line therapy, and there is little consensus on medical treatment of CD in pregnancy. This CASE demonstrates the successful use and titration of metyrapone throughout pregnancy. From https://www.sciencedirect.com/science/article/pii/S2376060521001164
  9. The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background. Introduction Endogenous Cushing´s syndrome (CS) is a rare disorder with an incidence of 0.2–5.0 per million people per year (1, 2). The predominant subtype (accounting for about 80%) is adrenocorticotropic hormone (ACTH)-dependent CS. The vast majority of this subtype is due to an ACTH-secreting pituitary adenoma [so called Cushing´s disease (CD)], whereas ectopic ACTH-secretion (e.g. through pulmonary carcinoids) is much less common. In contrast, ACTH-independent CS can mainly be attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease (PPNAD) may account for some of these cases as well (3, 4). Coexistence of different subtypes of endogenous CS in single individuals is even rarer but has been described in few reports. These cases were usually observed in the context of prolonged ACTH stimulation on the adrenal glands, resulting in micronodular or macronodular hyperplasia (5–9). A sequence of CD and PPNAD was also described in presence of Carney complex, a genetic syndrome characterized by the loss of function of the gene encoding for the regulatory subunit type 1α of protein kinase A (PRKAR1A) (10). Moreover, another group reported the case of a patient with Cushing's disease followed by ectopic Cushing's syndrome more than 30 years later (8). To our knowledge, however, we here describe the first case report on a single patient with a cortisol-producing adrenocortical adenoma and subsequent CD. Read the rest of the article at https://www.frontiersin.org/articles/10.3389/fendo.2021.731579/full
  10. This article was originally published here J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print. ABSTRACT CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection. OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD. MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI. RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion. CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing. PMID:34478542 | DOI:10.1210/clinem/dgab659
  11. Christina Tatsi, Maria E. Bompou, Chelsi Flippo, Meg Keil, Prashant Chittiboina, Constantine A. Stratakis First published: 25 August 2021 https://doi.org/10.1111/cen.14560 Abstract Objective Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD. Patients Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included. Measurements Clinical, imaging and biochemical data were analysed. Results One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1–6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7–5.8). Conclusions Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings. Full text at https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14560
  12. Zarina Brady, Aoife Garrahy, Claire Carthy, Michael W. O’Reilly, Christopher J. Thompson, Mark Sherlock, Amar Agha & Mohsen Javadpour BMC Endocrine Disorders volume 21, Article number: 36 (2021) Cite this article 160 Accesses Metricsdetails Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. Results A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4–79) months. Conclusion Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus. Peer Review reports Introduction With an estimated annual incidence of 1.7 per million [1], Cushing’s disease is rare. Untreated, it poses serious complications including osteoporosis, hypertension, dyslipidaemia, insulin resistance, and hypercoagulability [2] and is associated with a 4.8 fold increase in mortality rate [3,4,5]. Patients who are in remission from CD have a mortality rate which decreases towards (although not reaching) that of the general population [6]. Endoscopic transsphenoidal surgery (ETSS) offers patients potential remission from Cushing’s disease, although long term surveillance is required as recurrence rates range from 5 to 22%% [7,8,9,10,11,12]. Since the first report in 1997 [13], the selective removal of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma by endoscopic transsphenoidal surgery has gained popularity as the first line treatment for Cushing’s disease. The primary goal of ETSS treatment in Cushing’s disease is to produce disease remission and to provide long-term control, while minimising complications. Remission rates are dependent on tumour size, preoperative MRI, cavernous sinus invasion, intraoperative visualisation of the tumour and pre- and postoperative ACTH and cortisol concentration [11]. Several studies also report pituitary neurosurgeon experience as a major factor for operative success [2, 14, 15]. Reported remission and recurrence rates after TSS for CD vary widely according to the criteria utilised to define remission [11], and in some studies due to limited patient numbers or short follow-up periods. Indeed, there is no clear consensus on how best to define post-operative remission; an early morning serum cortisol concentration < 138 nmol/L (5μg/dl) within 7 days of TSS is quoted in the 2015 Endocrine Society Clinical Practice Guideline as indicative of remission [16]. A more strict day 3 cut-off of 50 nmol/L (1.8 μg/dl) has been reported in paediatric studies [17], and also included in the Endocrine Society Guideline [16]; the literature suggests this cut-off is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. The main objective of this study was to assess the outcomes of endoscopic transsphenoidal surgery for Cushing’s disease in a tertiary pituitary centre; remission using two widely accepted criteria [16], recurrence and postoperative complications. Methods Study design This is a retrospective analysis of a prospectively-maintained database of patients operated on by a single neurosurgeon (MJ), via image-guided endoscopic transsphenoidal approach for Cushing’s disease. Patient data was gathered over 8 years (January 2012 to February 2020) and identified from the institution’s prospective database. Clinical and biochemical data during the follow-up period was reviewed. Approval was granted by the Hospital Audit Committee. Study population Patients were screened for Cushing’s syndrome by the presence of typical clinical features, together with failure to adequately suppress cortisol to < 50 nmol/L following overnight dexamethasone suppression test (ONDST) and/or elevated late night salivary cortisol (LNSF) concentration and/or elevated 24 h urinary free cortisol measurements. As per standard guidelines, Cushing’s disease was diagnosed on the basis of elevated serum ACTH measurements, along with confirmatory hormone responses to peripheral corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS). Patients with previous TSS prior to the study period were excluded. Surgical procedure A single neurosurgeon subspecialising in endoscopic pituitary and anterior skull base surgery, M.J, carried out all ETSS surgical procedures. The surgical technique has been described in detail in publications by Cappabianca et al. (1998, 1999) and Jho et al. (1997, 2000, 2001) [13, 18,19,20,21]. In summary, the procedure consists of a binostril endoscopic transsphenoidal approach. A selective adenomectomy was performed on patients with adenomas noted on pre-operative MRI. In cases of negative pre-operative MRI, exploration of the pituitary gland was performed. To confirm the diagnosis of ACTH-secreting adenoma or hyperplasia, all specimens removed underwent histopathological and immunohistochemical staining for pituitary hormones. Postoperative assessment Patients received empiric oral hydrocortisone on day 1 and on the morning of day 2 post-operatively, prior to assessment of 0800 h serum cortisol on day 3. A blood sample for serum cortisol was drawn at 0800 h on the morning of day 3, if clinically stable, prior to administration of hydrocortisone. The Endocrine Society Clinical Practice Guideline define post-operative biochemical remission as morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively [16], ‘standard criteria’. In our institution, we also apply a biochemical cut-off of < 50 nmol/L (1.8 μg/dl) at day 3 postoperatively to allow early indication of biochemical remission, ‘strict criteria’. If serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical sequalae of hypercortisolaemia made (such as improvement in blood pressure or glycaemic control), before repeat endoscopic transsphenoidal surgery is considered. Transient cranial diabetes insipidus (DI) was defined as the development of hypotonic polyuria postoperatively requiring at least one dose of desmopressin [22], which resolved prior to discharge. Permanent DI was confirmed by water deprivation test according to standard criteria [23]. Thyroid stimulating hormone (TSH) deficiency was defined by low fT4 with either low or inappropriately normal TSH. Growth hormone (GH) deficiency was confirmed using either Insulin Tolerance Test or Glucagon Stimulation Test [24]. Gonadotrophin deficiency was defined in premenopausal women as amenorrhoea with inappropriately low FSH and LH concentration, and in postmenopausal patients as inappropriately low FSH and LH concentration. Recovery of hypothalamic-pituitary-adrenal axis was assessed by short synacthen (250 μg) test or insulin tolerance test 3 months post-operatively, and every 3–6 months thereafter in cases of initial fail or borderline result. Patients were assessed annually for recurrence of Cushing’s disease, recurrence was defined by failure to suppress cortisol to < 50 nmol/L following an 1 mg overnight dexamethasone suppression test, an elevated late night salivary cortisol (LNSF) or urinary free cortisol (UFC) in patients no longer taking hydrocortisone. Laboratory analysis Prior to 2019, serum cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter UniCel Dxl 800. Intra-assay CV for serum cortisol was 8.3, 5 and 4.6% at concentrations of 76, 438 and 865 nmol/L, respectively. From January 2019 onwards, serum cortisol was measured using Elecsys® Cortisol II assay on the Roche Cobas e801; intra-assay precision for serum cortisol was 1.2, 1.1 and 1.6% at concentrations of 31.8, 273 and 788 nmol/L, respectively. Statistics Data are expressed as median (range) and number (%). The Fishers Exact test was used to compare categorical variables between groups. All p-values were considered statistically significant at a level < 0.05. Statistical analysis was performed using GraphPad Prism 8 statistical software (GraphPad Software, La Jolla, California, USA). Results Demographics Forty-three endoscopic transsphenoidal procedures were performed in 39 patients. Demographics are summarised in Table 1. Median (range) age was 37 years (8–75), 30 were female. Median (range) duration of symptoms was 24 months (6–144), 72% (28/39) had hypertension, and 28% (11/39) had type 2 diabetes. Table 1 Summary of demographics and post-operative outcomes Full size table Preoperative imaging and IPSS Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). No adenoma was identified in 17 patients (44%). IPSS was carried out in 33 (85%) patients. Postoperative remission Post-operative outcomes are summarised in Table 1 and Fig. 1. Using standard criteria (0800 h serum cortisol < 138 nmol/l within 7 days of operation and improvement in clinical features of hypercortisolism), postoperative remission rates for initial surgery were 87% (34/39) for the entire group and 89% (31/35) when patients with macroadenomas were excluded, Fig. 1. Three patients had an early repeat ETSS for persistent disease; day 3 serum cortisol ranged from 306 to 555 nmol/L and interval to repeat ETSS from 10 days–3 months. When the outcome of early repeat ETSS was factored in, overall remission rate was 92% (36/39) overall, and 94% (33/35) when patients with macroadenomas were excluded. Fig. 1 Schema of patients who underwent ETSS. *Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids Full size image Using strict criteria of early remission (day 3 serum cortisol concentration < 50 nmol/L), postoperative remission rates were 58% (22/38) overall, and 62% (21/34) excluding macroadenomas. Including the three patients with early repeat ETSS, remission rate was 61% (23/38) overall, and 65% excluding macroadenomas (22/34). Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids. Eleven patients (28%) had a cortisol measurement between 50 and 138 nmol/L on day 3, seven of whom had received metyrapone therapy prior to ETSS. Six patients had serial measurements of 0800 h cortisol up to a maximum follow-up of 14 days post-op, serum cortisol concentration fell after day 3 in all six patients. Ten (91%) were glucocorticoid-dependent at 3 months based on synacthen/ITT; 0800 h cortisol had fallen to < 50 nmol/L in six patients. Predictors of remission No statistical difference was found in the rates of remission in those patients with or without tumour target on preoperative MRI, using either strict criteria for remission (12/21 target vs 10/17 no target, p > 0.99) or standard criteria (19/22 target vs 15/17 no target, p > 0.99). Similar results were found when the four patients with macroadenoma were excluded. Persistent disease Five patients (13%) had persistent hypercortisolaemia after the initial endoscopic transsphenoidal surgery (Table 2). Three patients underwent a repeat early endoscopic transsphenoidal surgery, Fig. 1. Remission rate after repeat early ETSS was 67% (2/3) using standard criteria, and 33% (1/3), using the strict criteria. Of the patients with persistent disease following repeat ETSS, one received radiosurgery, while the other has been commenced on medical therapy, with a view to refer for radiotherapy. Table 2 Outcome of five patients with persistent hypercortisolaemia after initial ETSS Full size table Postoperative complications The rate of transient diabetes insipidus after first ETSS was 33% (13/39), while permanent diabetes insipidus occurred in 23% (9/39). Postoperatively, there were five cases of new thyroid stimulating hormone deficiency (13%) and four cases of gonadotrophin deficiency (10%) (in pre-menopausal females). There were no cases of postoperative CSF leak, no cases of meningitis and no visual complications. There were no other complications. Recurrence No patients were lost to follow-up. Over a median (range) duration of follow-up of 24 (4–79) months, one patient had recurrence of Cushing’s disease. Pre-operative MRI had shown a macroadenoma; serum cortisol on day 3 after the initial ETSS was 71 nmol/L, which fulfilled standard criteria for remission, but not the more strict criteria. The patient underwent a second ETSS 13 months later. No tumour was visible intra-operatively so no tissue was removed, day 3 serum cortisol concentration was 308 nmol/L and the patient was commenced on a trial of metyrapone. Recovery of the hypothalamic-pituitary-adrenal axis Recovery of the hypothalamic-pituitary-adrenal axis occurred in nine patients (27%), at median 13 (3–27) months post-operatively. There was no statistical difference in rates of recovery of HPA axis in patients with day 3 cortisol < 50 nmol/l, and those who only passed standard criteria for remission (< 138 nmol/l) [7/20 (follow-up 25 (3–59) months) versus 2/11 (follow-up 16 (3–79) months) respectively, p = 0.43]. One patient died 5 weeks post-operatively; post-mortem revealed bilateral haemorrhagic adrenal necrosis. Discussion Reported remission rates following ETSS in patients with Cushing’s disease (CD) vary widely, predominantly due to differences in criteria used to define remission [11]. There is no uniform consensus on the criteria used to define ‘remission’, with institutions using a combination of biochemical and clinical criteria; this makes comparing surgical outcome studies challenging. The normal corticotroph cells of the pituitary gland are suppressed due to sustained hypercortisolaemia, therefore following successful removal of the ACTH-secreting adenoma, serum ACTH and cortisol concentrations should fall postoperatively. A morning serum cortisol concentration < 138 nmol/L (5 μg/dl) within 7 days of ETSS is usually indicative of remission, and this biochemical cut-off is quoted in the Endocrine Society Clinical Practice Guideline [16], and many surgical outcome studies [8, 11, 25]. Other studies have applied a more strict serum cortisol cut-off of < 50 nmol/L (1.8 μg/L) at day 3 postoperatively to allow early indication of biochemical remission [10, 11, 26,27,28]; the literature suggests this cutoff is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. Our practice is to apply this latter approach; if serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical signs of hypercortisolaemia made, before repeat endoscopic transsphenoidal surgery is considered. It is important to ensure that serum cortisol has reached a nadir, before further intervention is considered. In this single-centre single-surgeon study, we report two very different remission rates using these two widely accepted criteria. Our remission rate, including those patients who had an early second ETSS, using standard guidelines, is 92%, on par with other larger studies [7, 8, 11, 25, 29]. When patients with corticotroph macroadenomas were excluded, the remission rate was even higher at 94%. In comparison, when we applied the more strict criteria of day 3 cortisol < 50 nmol/L, the remission rate was considerably lower at 61%. This criteria is in place in our institution so that we can safely identify patients who have early signs of remission to facilitate discharge on day 3 post-operatively; however reporting these rates in isolation lead to a misleadingly low remission rate compared to the more lenient criteria proposed by the Endocrine Society [16]. Evidence has suggested that higher day 3 cortisol concentration is associated with greater risk of recurrence of CD. A recent retrospective cohort analysis of 81 ETSS for CD by Mayberg et al. reported significantly higher recurrence rates in patients with post-operative cortisol nadir between 58 and 149 nmol/L (2.1–5.4 μg/dL) compared with those with cortisol < 55 nmol/L (2 μg/dL) (33% vs 6%, p = 0.01) [30]. Recurrence of CD was low in our series at 3%, and occurred in a patient with a corticotroph macroadenoma, which have been shown to be associated with higher rates of recurrence [31]. On post-operative assessment, serum cortisol fell between the two criteria for remission and if remission was strictly defined as a day 3 cortisol < 50 nmol/L, then this patient had in fact persistent hypercortisolaemia. This case highlights the difficulty when comparing studies reporting ETSS outcomes in CD – the distinction between persistent post-operative hypercortisolism and early recurrence of CD is not always clear-cut, and is dictated by the local protocol. Whilst our recurrence data are encouraging in comparison to other reports on CD recurrence, which published rates of up to 22% [11], longer term follow-up is necessary before recurrence rates can be accurately defined. The criteria used to define long term recurrence of CD also varies widely in the literature; a large systematic review (n = 6400) by Petersenn et al. (2015) reported decreased recurrence rates when studies used UFC with ONDST vs. UFC only, and UFC with morning serum cortisol vs. UFC only [11]. This highlights the requirement for standardization of remission and recurrence criteria, for consistency in clinical practice and in the literature. The post-operative surgical complication rate in our series was very low, with no cases of CSF leak, vascular injury or visual compromise. Other published case series have reported incidence rates for CSF leakage and meningitis of 0–7.2% and 0–7.9% [2, 12, 32, 33] respectively. Postoperative meningitis is strongly associated with CSF leakage [34]. Some studies suggest that the endoscopic approach results in higher rates of carotid artery injury compared with the microscopic approach, which could be attributed to the nature of the extended lateral approach [35]. However, in this series of 43 ETSS, we report no cases of surgical related carotid artery injury, similar to other studies reporting 0% serious morbidity or mortality due to carotid artery injury [33, 36]. Finally, postoperative visual disturbance is a major concern, as it can be life changing for patients. Factors linked with visual complications include tumour size, patient age and any pre-existing visual conditions [37,38,39]. Visual deterioration after TSS for Cushing’s disease has been reported to occur in some large case series at rates of 1.9% [32] and 0.86% [12]. There were no cases of postoperative visual disturbance in our series. While the surgical complication rate was low, our endocrine complication rate was higher than that reported in other studies, particularly the rate of DI. Transient DI occurred in 33% of cases, and permanent DI in 23%. These relatively high rates of transient DI may be due to the diagnostic criteria used in our protocol; we defined transient post-operative DI as one episode of hypotonic polyuria in the setting of normal or elevated plasma sodium concentration, requiring at least one dose of desmopressin. In contrast, some studies discount any polyuria which lasts less than 2 days [10], while others require the documentation of hypernatremia for the diagnosis of DI [40]. These more stringent criteria will not capture cases of mild transient DI; therefore it is not surprising that the rates of transient DI reported in a 2018 meta-analysis were lower than that in our study, 11.3% [29]. The rates of permanent DI in our study merits particular attention. TSS for CD has been shown to be associated with a higher risk of post-operative DI [41, 42]. It may be that a more aggressive surgical approach resulted in high remission rates, but at a cost of higher rates of DI. All patients are reviewed post-operatively in the National Pituitary Centre, where there is a low threshold for water deprivation testing and/or 3% saline testing. We did not routinely re-test patients for resolution of DI after their initial water deprivation test at 3 months, and it is possible that some cases subsequently resolved after 3 months [41, 43]. Regardless, the rate reported in this study is significant, and emphasises the importance of counselling the patient about the risk of DI long-term. Strengths and limitations The reporting of two remission rates based on widely accepted criteria is a strength of this study, and allows for direct comparison of our outcomes with other studies. All ETSS were performed by a single pituitary surgeon; while this removes bias from surgeon experience, the disadvantage of this is that the sample size is relatively low. Furthermore, because we included patients who were recently operated on to maximise numbers for analysis of surgical complications, the follow-up period is relatively short. A longer follow-up is required to comment accurately on recurrence of CD. We did not have full ascertainment of longitudinal post-operative data including dexamethasone suppression tests, and this has highlighted the need for protocolised follow-up to allow for consistency when reporting our results. Conclusion Endoscopic transsphenoidal surgery in patients with Cushing’s disease offers excellent remission rates and low morbidity. Remission rates are much higher when standard criteria [morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively] are used compared with day 3 cortisol < 50 nmol/l. Higher remission rates were found for patients with microadenomas. Patients should be counselled regarding risk of post-operative endocrine deficiencies, in particular permanent diabetes insipidus. Longer follow-up is required to accurately assess recurrence rates. Availability of data and materials The data that support the findings of this study are not publicly available due to restrictions by General Data Protection Regulation (GDPR), but are available from the corresponding author on reasonable request. Abbreviations TSS: Transsphenoidal surgery ACTH: Adrenocorticotropic hormone CD: Cushing’s disease ETSS: Endoscopic transsphenoidal surgery ONDST: Overnight dexamethasone suppression test LNSF: Late night salivary cortisol CRH: Corticotropin releasing hormone IPSS: Inferior petrosal sinus sampling DI: Diabetes insipidus TSH: Thyroid stimulating hormone GH: Growth hormone UFC: Urinary free cortisol References 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23. CAS PubMed PubMed Central Google Scholar 2. Broersen LHA, van Haalen FM, Biermasz NR, et al. 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  13. Sherry passed away this afternoon, naturally and peacefully in her sleep. She loved her community and we know how grateful she was to every one of her friends on here for the genuine love and support she’s received over the years. We (her family) are processing, but will share details about her celebration of life when we’ve worked it out. Sherry's bio: I have been very ill for many years now, since 1999 that I know of. But it had always come and gone, until 2004 when it decided to stay. At first it was a mystery as to what was wrong. I was seeing a psychiatrist that felt very strong that what I was dealing with was endocrine related. He mentioned a few things that it could be and one was Cushing’s, so I looked it up on the internet and sure enough I had many of the symptoms of Cushing’s disease, moon face, buffalo hump, weight gain, big round belly, red face, very ruddy complexion, acne, nausea, depression, fatigue, hirsutism, depression, anxiety, hypertension, unusual bruising, and highs and lows of energy. I found this support group on the internet at Cushings-help.com and they helped me find Dr.William Ludlam at OHSU. He told me I had a suddle case of Cushing’s and had a pituitary tumor on the right side displacing the pituitary to the left. Although Dr.Ludlam originally saw tumors on both sides, I had a pituitary tumor that seemed to be cyclic. When it turned on I had major Cortisol energy, when it turned off I got very achy, nausea, and very tired. In March of 2006 I was officially diagnosed after 1 long year of testing, and went on to have my first unsuccessful Transphenoidal pituitary surgery 3/23/2006 with Dr. Johnny Delashaw at OHSU. I had a second unsuccessful pituitary surgery 10/12/06 and finally a BLA 11/7/06. I am now cured of Cushing’s disease 2 1/2 years out from my BLA and I am still very sick, I traded Cushing’s disease for Addison’s disease, and my body does not like it. Cushing’s did a lot more damage than ever thought; I have permanent nerve damage to my lower back, damage to soft tissues throughout my body, Diabetes, High lipids, Fatty liver, I have no usable veins, I have permanent port-a-cath in now so they can access my veins for blood draws and any IV stuff I may need in emergency’s. I had my period for 1 year straight so I had a full hysterectomy 8/20/08. I am permanently panhypopituitary now, no working hormones any more. I am on all replacement hormones, except DDAVP. I ended up with a new doctor that gave me a severe case of steroid induced Cushing’s. I am still dealing with this aftermath; the details are in my timeline. My timeline will update you as to where I am at now. I will try to keep the timeline updated so you know where I am at as far as getting better. Please don’t let this scare you, most people are cured and go on to live lives as best they can, and a lot of people are doing very well. Towards the end of my Cushing’s I went full blown, Dr.Ludlam told me this was a progressive disease and in me this was the case. So if you believe you have Cushing’s, get to a specialist that knows Cushing’s disease, don’t waste time on doctors that do not know the disease, it is so worth it in the end to get to the right doctor. This disease is one of the hardest endocrine diseases to diagnose. Cushings_help.com/ founder MaryO has been a lifesaver for me and still is, I have met people from all over the country, over the years I have made many friends that have, had or are still in the diagnostic phase. I live in a small town of around 10,000 people and I hear all the time, oh I know so and so that had or has a pituitary tumor. What I am finding out is there are a lot of people in this town that have this disease, it is suppose to be rare, one in a million, my next goal is to get my story out and have local people contact me, then start a support group. Maybe get some accurate numbers of actual pituitary/brain tumors and find out why this is happening in this small town. It will be a big adventure but if it saved even one life it will be worth it. I know of 3 definite pituitary Cushing’s cases so far. My Timeline of illness to diagnosis 3rd pregnancy 1994 pre-term labor again, stopped, gestational diabetes, son born 3 weeks early and I got toxemia after my son was born, was told this is very rare. I should have known RARE would be a word I would hear a lot in my future. 1995-Left breast discharge, surgical biopsy done, lump removal of marble size, this should have signaled a full hormonal work-up, but didn’t. No cancer. 1997-1999 Depression and severe anxiety with panic attacks…Diagnosis of Fibromyalgia. Weight 130# 1999- First occurrence of unknown mystery illness. Hypertension, fatigue, flushing, swelling of face, hives, and much more that lasted several months. Sick on and off with mystery illness. Tumor was turning on and off. April 1999-2004-Severe nausea and vomiting, extreme fatigue, weight gain of 50# in about 1 years time, headaches, dizziness, hypertension, tachycardia, muscle and bone pain, malor rash, other rashes, IBS, occasional unexplained low grade fevers, anxiety and depression much worse, increased hirsutism, almost constant mouth sores, memory loss, cognitive difficulties, loss of coordination, syncope, excessive energy spurts, insomnia. **Off work for 3 months April-June due to symptoms…Saw PCP, Gastroenterologist, Rheumatologist and Cardiologist… diagnosis Peptic ulcer/Chronis Gastritis and Chronic pain Syndrome and Tachycardia/Hypertension. Abdominal/Pelvic Cat scan done and fatty liver noted. High Cholesterol and Triglycerides discovered. Nov-2004 My Psychiatrist was the first to mention Cushing’s or a Pheochromocytoma; he felt all my symptoms where due to endocrinology. He did not want to see me again until I was seen at OHSU. I have never seen him again due to insurance change. I really need to thank him. Dec-2004 10# weight gain in 1 week with severe abdominal distention….another Cat scan done, lymph nodes around vena cava where enlarged. Jan-2005 Went to OHSU for diagnosis….First saw an endocrinologist that was not experienced with Cushing’s, she ordered 1 UFC and 2 midnight saliva tests, and told me to test when I felt my worst; Tests where low so she felt my symptoms where not due to my endocrine system. Boy was she wrong. I needed to test when I felt good, or high. Feb-2005 Went to the Pituitary Unit at OHSU and saw Dr.Ludlam, he believed that I had Cushing’s but we needed to prove it. MRI saw adenoma on right side displacing pituitary to the left. He originally thought he saw tumors on both sides, he was right. Lot’s of testing done. Testing did not prove it yet. Dr believes I am Cyclic. It took 1 year for diagnoses from Dr.Ludlam. April-2005 Peripheral vision test done by local optometrist, showed some peripheral loss in left eye. May 2005-Lot’s more Cushing’s testing, PICC line in all month. Major dizziness, passed out and fell this month. Diagnosed with Type 2 Diabetes but cannot treat due to extreme highs and lows, trying to control glucose with diet. I have very high and low Cortisol days. I am very cyclic at this point. June/July 2005-Three TIA like event’s… left sided weakness and numbness. Saw Neurologist that sent me to Neurologist at OHSU. Found three new white matter lesions seen on my brain MRI. Unknown cause. 5 in all now. August 2005-Had to leave my beloved job teaching Medical Assistants due to symptoms. I had one more TIA like event. Sep-2005 Neurologist at OHSU ran several tests and came to the conclusion that if in fact we could prove Cushing’s, all of my symptoms where due to this disease. I stopped all medications by choice. Nov-2005 I went back for extensive testing at OHSU with Dr.Ludlam and sure enough the numbers started proving my case. Very high midnight serum Cortisol’s among other high tests. Jan/Feb 2006-PICC line in and extensive Cushing’s testing done with CSS in Feb. CSS showed left sided gradient strongly. Cortisol numbers have proven my case, finally…. I had a midnight serum Cortisol of 34.1, the Midnight Salivaries, Midnight Serum Cortisol, UFC’s and CSS all positive for Cushing’s disease. March 23, 2006 I finally had Pituitary surgery at OHSU, they found the tumor on the left side bigger than originally though and removed the whole left half of my Pituitary gland. I was in the hospital for 6-days due to complications of Diabetes Insipitus and Adrenal Insuffiency. April-2006 Seen in the ER 3 times. Hospitalized for 4 days again due to complications, Blood cultures showed infection. I am on very high doses of Hydrocortisone and also taking DDAVP for the Diabetes Insipitus. April 2006- I am finally getting better somewhat…..This has been one heck of a roller coaster ride. I am now on Hydrocortisone 40/40/30. I am told we won’t know if I am cured for 3-6 month’s. June 5, 2006- Off Hydrocortisone stimulated my Cortisol to 24 on the ACTH stim test. August, 2006- Not cured, testing again!!! I had that gut feeling when I woke from the first surgery. I just knew… October 12, 2006- Second Pituitary surgery, more tumor on right side, most of my pituitary gland removed. Surgery unsuccessful, still have Cushing’s disease. November 7, 2006- BLA ...soon to be cured of Cushing's. Dec 2006/Jan 2007- Very sick due to another blood infection. Lot’s of adrenal crises due to infections. 3 blood infections to date. November 2008- 2 years out from my BLA and I am still very sick, I traded Cushing’s disease for Addison’s disease, and my body does not like it. Towards the end of my Cushing’s I went full blown, Dr.Ludlam told me this was a progressive disease and in me this was the case. Cushing’s did a lot more damage than ever thought; I have permanent nerve damage to my lower back requiring permanent narcotic pain relief through a pain center, damage to soft tissues throughout my body, diabetes, high lipids, fatty liver (NASH), Osteopenia, I have no usable veins, they are destroyed due to the high Cortisol, I have permanent port-a-cath in now so they can access my veins for blood draws and any IV stuff I may need, I had my period for 1 year straight because of lack of appropriate hormones after my surgeries so I had a full hysterectomy 8/20/08. I am permanently panhypopituitary now, no working pituitary hormones any more at all. I must replace all pituitary hormones, except DDAVP. Please don’t let this scare you, most people are cured and go on to live lives as best they can, and a lot of people are doing very well. June 21, 2009-Since writing in November I sat on the couch in severe AI until around September when I was put with a doctor that has been seeing Cushing’s patients for 38 years, he put me a on a very high dose of Dexamthasone and Florinef and forgot about me, he ended up with cancer and is no longer seeing patients. In the meantime, I got severe steroid induced Cushing’s and have had severe complications from it. I started falling from atrophied muscles and broke both hips, I ended up in a wheelchair, which I am happy to say I am out of now, had to have surgery on my left hip to pin it, it is still not healing, I am having absorption issues with calcium, iron, vitamins, minerals and meds. So I have to do my DEX by injections. We are now trying to find out why I am having absorption issues. I have a new endo at OHSU Dr.V and he is wonderful. He has brought my steroids down to a safe level and did it slow. He really seems to know his stuff as far as after care. I do not think he does the diagnosis process for Cushing’s. I would definitely go back to Dr.Ludlam if I had to go through it again. But I know there are many other great Cushing’s experts out there, this was just my experience. I know I will get better, but it may be a while. I am still at home handicapped, can barely go to the grocery store and I do not drive as I am on a high dose of Morphine. My goal is to get my pain under a 5 and be able to drive myself around. That is a good goal for now. Then on to finding out why my small town has so many tumors and starting a support group. I just need to get to a point where I feel I can be a good advocate for Cushing’s and right now I can’t. But that is the goal. Nov 16, 2009 I am still not well, I have broken my ankle, have no idea how, woke up one morning and it was broken. I am almost down to my 1/2 mg of DEX and am happy about that. had 2 surgeries in Sep and Oct on both elbows for ulnar nerve decompression. The first surgery got infected and a week later I had sepsis, which they think I had a small bowel preferation that healed itself. I was ambulanced up to OHSU and was in AI. It was a very rare bowel bacteria running through my blood stream, I was very sick. I just want to get well, but for some reason I am going through one thing after another. I am praying that 2010 will be my year of healing and I will have a good quaility of life then.That is what I am counting on. UPDATE January 23, 2016 2016: wow has the past few years have been a roller coaster. I don't know dates because I'm having memory issues at 47 years old. I have had 5 port-a-caths. I kept getting sepsis and every time they would take me to surgery and remove my port. Then place another when I was better. I have no veins that work. So I received IV port fluids 2-3x a week. I just recently had sepsis, when I get it I have a 50/50 % chance of survival. They removed my port and did not place another. So no more fluids which was for Pots. I had labs done through my port every 2 weeks. Now everything stopped. I am producing small amounts of cortisol. After a BLA. Intermittently. I am just now starting to feel good for 2 weeks now. I have started the exercise program called T-Tapp. I love it. No jumping or hard moves. 15 min and that's it. I am a grandma of 2 and one due any day. So for now I hope I'm on the road to recovery at least the best I can. HOME | Sitemap | Abbreviations | Adrenal Crisis! | Glossary | Forums | Bios | Add Your Bio | Add Your Doctor | MemberMap | CushieWiki
  14. First published:03 May 2020 Read the entire article at https://doi.org/10.1002/alr.22540 Potential conflict of interest: None disclosed. Presented at the 65th Annual Meeting of the American Rhinologic Society, on September 14, 2019, in New Orleans, LA. Abstract Background Endoscopic transsphenoidal surgery (ETS) for the resection of pituitary adenoma has become more common throughout the past decade. Although most patients have a short postoperative hospitalization, others require a more prolonged stay. We aimed to identify predictors for prolonged hospitalization in the setting of ETS for pituitary adenomas. Methods A retrospective chart review as performed on 658 patients undergoing ETS for pituitary adenoma at a single tertiary care academic center from 2005 to 2019. Length of stay (LoS) was defined as date of surgery to date of discharge. Patients with LoS in the top 10th percentile (prolonged LoS [PLS] >4 days, N = 72) were compared with the remainder (standard LoS [SLS], N = 586). Results The average age was 54 years and 52.5% were male. The mean LoS was 2.1 days vs 7.5 days (SLS vs PLS). On univariate analysis, atrial fibrillation (p = 0.002), hypertension (p = 0.033), partial tumor resection (p < 0.001), apoplexy (p = 0.020), intraoperative cerebrospinal fluid (ioCSF) leak (p = 0.001), nasoseptal flap (p = 0.049), postoperative diabetes insipidus (DI) (p = 0.010), and readmission within 30 days (p = 0.025) were significantly associated with PLS. Preoperative continuous positive airway pressure (CPAP) (odds ratio, 15.144; 95% confidence interval, 2.596‐88.346; p = 0.003) and presence of an ioCSF leak (OR, 10.362; 95% CI, 2.143‐50.104; p = 0.004) remained significant on multivariable analysis. Conclusion For patients undergoing ETS for pituitary adenomas, an ioCSF leak or preoperative use of CPAP predicted PLS. Additional common reasons for PLS included postoperative CSF leak (10 of 72), management of DI or hypopituitarism (15 of 72), or reoperation due to surgical or medical complications (14 of 72). From https://onlinelibrary.wiley.com/doi/abs/10.1002/alr.22540?af=R
  15. Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146. January 5, 2020 Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology. “The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.” In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing. Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy. Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy. Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy. During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis. “The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood
  16. In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research. But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found. The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery. Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS. A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months. Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density. As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma. Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS. Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS. The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%). Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months). Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test. The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%). Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy. A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission. Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.” From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/
  17. Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows. Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes. The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections. Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence. While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone. Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery. Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term. Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases. Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge. While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission. Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months. Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis. Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission. And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis. “In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said. Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded. PATRICIA INACIO, PHD EDITOR Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. From https://cushingsdiseasenews.com/2019/08/29/acth-levels-after-surgery-help-predict-remission-recurrence-in-cushings-study-suggests/
  18. Recovery of the hypothalamus-pituitary-adrenal (HPA) axis can occur as late as 12 months after transsphenoidal adenomectomy (TSA), according to study results published in The Journal of Clinical Endocrinology & Metabolism. These findings emphasize the need to periodically assess these patients to avoid unnecessary hydrocortisone replacement. The primary treatment for most pituitary lesions is TSA. After pituitary surgery, the recovery of pituitary hormone deficits may be delayed; limited data are available regarding the postsurgical recovery of hormonal axes or predictors of recovery. The goal of this study was to assess HPA axis dysfunction and predictive markers of recovery following TSA, as well as time to recovery, to identify subgroups of patients who may be more likely to recover. This single-center observational retrospective study enrolled 109 patients in the United Kingdom (71 men; mean age, 56 years; range, 17 to 82 years) who underwent TSA between February 2015 and September 2018 and had ≥1 reevaluation of the HPA axis with the short Synacthen (cosyntropin) test. The primary outcome was recovery of HPA axis function 6 weeks, 3 months, 6 months, and 9 to 12 months after TSA. In 23 patients (21.1%), there was no evidence of pituitary hormone deficit before TSA. In 44 patients (40.4%), there was 1 hormone deficiency and in 25 patients (22.9%), preoperative evaluation showed >1 hormone deficiency. Of the 23 patients with abnormal HPA function before surgery, 8 patients (34.8%) had recovered 6 weeks after the surgery. Patients who recovered were younger (mean age, 50±14 vs 70±9 years; P =.008) compared with patients who did not respond. Of the 15 remaining patients, 2 (13.3%) recovered at 3 months and 3 (20%) recovered at 9 to 12 months. With regard to HPA function in the entire cohort 6 weeks after surgery, 32 patients (29.4%) did not pass the short Synacthen test. Of this group, 5 patients (15.6%) recovered at 3 months, 4 (12.5%) at 6 months, and 2 (6.2%) recovered 9 to 12 months after the surgery. Predictors of future adrenal recovery at 6 weeks included having preoperative 30-minute cortisol >430 nmol/L (P <.001) and a day 8 postoperative cortisol >160 nmol/L (P =.001). With these cutoffs, 80% of patients with preoperative 30-minute cortisol >430 nmol/L (odds ratio [OR], 7.556; 95% CI, 2.847-20.055) and 80% of patients with day 8 postoperative cortisol >160 nmol/L (OR, 9.00; 95% CI, 2.455-32.989) passed the short Synacthen test at 6 weeks postsurgery. In addition, a 6-week baseline short Synacthen test cortisol level above or below 180 nmol/L (P <.001) predicted adrenal recovery at that time point. None of the patients with all 3 variables below the aforementioned cutoffs recovered HPA axis within 1 year. On the other hand, 91.8% of patients with all 3 variables above those cutoffs had normal adrenal function at 6 weeks (OR, 12.200; 95% CI, 5.268-28.255). In addition to the retrospective design, the study had other limitations, including the potential for selection bias, a heterogeneous patient cohort, and no data beyond 12 months after the surgery. “[T]hese data offer the opportunity for patients who may have been given life-long replacement, to safely come off therapy and therefore avoid unnecessary glucocorticoid exposure,” wrote the researchers. Reference Pofi R, Gunatilake S, Macgregor V, et al. Recovery of the hypothalamo-pituitary-adrenal axis following transsphenoidal adenomectomy for non-ACTH secreting macroadenomas [published online June 21, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00406 From https://www.endocrinologyadvisor.com/home/topics/adrenal/recovery-of-hpa-axis-can-occur-late-after-transsphenoidal-adenomectomy/
  19. Removal of pituitary adenomas by inserting surgical instruments through the nose (transsphenoidal resection) remains the best treatment option for pediatric patients, despite its inherent technical difficulties, a new study shows. The study, “Transsphenoidal surgery for pituitary adenomas in pediatric patients: a multicentric retrospective study,” was published in the journal Child’s Nervous System. Pituitary adenomas are rare, benign tumors that slowly grow in the pituitary gland. The incidence of such tumors in the pediatric population is reported to be between 1% and 10% of all childhood brain tumors and between 3% and 6% of all surgically treated adenomas. Characteristics of patients that develop these pituitary adenomas vary significantly in different studies with regards to their age, gender, size of adenoma, hormonal activity, and recurrence rates. As the pituitary gland is responsible for hormonal balance, alterations in hormone function due to a pituitary adenoma can significantly affect the quality of life of a child. In most cases, pituitary adenomas can be removed surgically. A common removal method is with a transsphenoidal resection, the goal of which is to completely remove the growing mass and cause the least harm to the surrounding structures. In this study, the researchers report the surgical treatment of pediatric pituitary adenomas at three institutions. They collected data from 27 children who were operated for pituitary adenoma using one of two types of transsphenoidal surgeries — endoscopic endonasal transsphenoidal surgery (EETS) and transsphenoidal microsurgery (TMS) — at the University Cerrahpasa Medical Faculty in Istanbul, Turkey, at San Matteo Hospital in Pavia, and at the University of Insubria-Varese in Varese, Italy. The study included 11 males (40.7%) and 16 females (59.3%), with a mean age of 15.3 (ranging between 4 and 18). Medical records indicated that 32 surgical procedures were performed in the 27 patients, as six children required a second operation. Among the patients, 13 had Cushing’s disease, while the rest had growth-hormone-secreting adenomas, prolactinomas, or non-functional adenomas. The researchers found that most patients underwent remission following their surgery. Among the 27 patients, 22 patients (81.4%) underwent remission while five patients (18.5%) did not. Four patients underwent remission after a second operation. Based on these findings, the team believes that the transsphenoidal surgical approach adequately removes pituitary tumors and restores normal hormonal balance in the majority of pediatric patients with pituitary adenomas. “Satisfactory results are reported with both EETS and TMS in the literature,” they wrote. “Despite the technical difficulties in pediatric age, transsphenoidal resection of adenoma is still the mainstay treatment that provides cure in pediatric patients.” From https://cushingsdiseasenews.com/2019/05/30/transsphenoidal-surgery-effective-remove-pituitaty-adenomas-children-study/
  20. In patients with a diagnosis of Cushing disease in whom magnetic resonance imaging (MRI) shows either no abnormalities or nonspecific abnormalities, surgery is preferable to medical treatment, according to study results published in The Journal of Clinical Endocrinology & Metabolism. There is a consensus that the first line of treatment for Cushing disease is transsphenoidal surgery to remove the pituitary adenoma causing the disease, with an 80% remission rate following the intervention. However, in the absence of clear evidence of a pituitary adenoma on imaging, there is some controversy regarding the best treatment. The goal of this retrospective single-center study was to assess the outcomes of surgery in patients with Cushing disease with clear evidence of a pituitary adenoma on MRI compared with outcomes in patients with inconclusive or normal MRI. The cohort included 195 patients treated with transsphenoidal surgery between 1992 and 2018 (156 women; mean age at surgery, 41 years) classified into 4 MRI groups: 89 patients were found to have microadenoma, 18 had macroadenoma, 44 had nonspecific/inconclusive abnormalities on MRI results, and 44 had normal imaging results. The researchers reported that MRI performance in their neuroradiology department improved with time; the proportion of inconclusive or normal MRI results decreased from 60% in 1992 to 1996 to 27% in 2012 to 2018 (P =.037). In analyzing the influence of MRI findings on remission rates, the researchers found no significant difference among the 4 groups: remission rate was 85% for microadenomas, 94% for macroadenomas, 73% for inconclusive MRI, and 75% for negative MRI (P =.11). This finding indicates the overall percentage of patients in remission after transsphenoidal surgery is only slightly lower in those with normal or inconclusive MRI results compared with patients with clear evidence of microadenoma or macroadenoma. There was no difference in remission rate after a microscopic vs endoscopic surgical approach (P =.16). The researchers found that endoscopic-assisted surgery allowed a higher visualization rate than microscopic-assisted surgery. Although the neurosurgeon had a better visualization rate than MRI (100% vs 72%, respectively), there were some false-positive findings; thus, positive predictive value was similar (84% vs 78%, respectively). The study had several limitations including the retrospective design. In addition, in light of the long study duration, the researchers noted that changes in MRI technology and surgical procedures occurred over time. The researchers proposed that after exclusion of nonneoplastic hypercortisolism, patients with Cushing disease, an inconclusive or normal MRI, and a pituitary adrenocorticotropic hormone gradient at bilateral inferior petrosal sampling be directed to an expert neurosurgeon for transsphenoidal surgery rather than treated medically. Reference Cristante J, Lefournier V, Sturm N, et al. Why we should still treat by neurosurgery patients with Cushing’s disease and a normal or inconclusive pituitary MRI [published online May 14, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00333 From https://www.endocrinologyadvisor.com/home/topics/adrenal/transsphenoidal-surgery-recommended-for-cushing-disease-with-inconclusive-or-normal-mri/
  21. Cushing’s disease patients whose pituitary tumors carry a USP8 mutation are more likely to achieve remission after surgery than those without such mutations, a retrospective Italian study found. The study, “Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas,” was published in the journal Endocrine. Cushing’s disease is a condition where a tumor on the pituitary gland produces too much of the adrenocorticotropin hormone (ACTH), which will act on the adrenal gland to make cortisol in excess. While rare, the condition can be life-threatening, as excess cortisol is linked to an increased risk of infections and cardiovascular complications, along with an increased likelihood of obesity and diabetes. The reasons some patients develop these pituitary adenomas are far from understood, but researchers recently found that some of these patients show mutations in the USP8 gene. These appear to increase EGFR signaling which, in turn, has a stimulatory role for the synthesis of ACTH. But more than influencing the development of Cushing’s disease, researchers believe the USP8 mutations may also determine response to treatment. Thus, a team in Italy examined whether patients with USP8 mutations presented different clinical features and responded differently to the standard surgical procedure, called transsphenoidal pituitary surgery. The study included 92 patients with ACTH-secreting pituitary tumors who received surgery at the neurosurgical department of the Istituto Scientifico San Raffaele in Milan between 1996 and 2016. “All surgical procedures were performed by the same experienced neurosurgeon, which is one of the most important factors affecting early and late surgical outcome of pituitary adenomas,” researchers explained. Among study participants, 22 (23.9%) had mutations in the USP8 gene, but these mutations were significantly more common in women than in men — 28.7% vs. 5.3%. Researchers think estrogens — a female sex hormone — may have a role in the development of mutated pituitary tumors. Overall, the two groups had similar tumor size and aggressiveness and similar ACTH and cortisol levels before surgery. But among those with microadenomas — tumors smaller then 10 mm in diameter — USP8-mutated patients had significantly larger tumor diameters. After receiving surgery, 81.5% of patients achieved surgical remission — deemed as low cortisol levels requiring glucocorticoid replacement therapy, normal cortisol levels in urine, and normal response to a dexamethasone-suppression test. But remission rates were significantly higher among those with USP8 mutations — 100% vs. 75.7%. Also, USP8 mutation carriers required steroid replacement therapy for shorter periods, despite ACTH and cortisol levels being similar among the two groups after surgery. Among patients who entered remission, 12 (16%) saw their disease return. While more patients with USP8 mutations experienced a recurrence — 22.7% vs. 13.2% — this difference was not significant. After five years, 73.8% of UPS8-mutated patients remained alive and recurrence-free, which researchers consider comparable to the 88.5% seen in patients without the mutation. Researchers also tested sex, age at surgery, and post-surgical ACTH and cortisol levels as possible predictors of disease recurrence, but none of these factors was associated with this outcome. “ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated on by a single neurosurgeon. Recurrence rates are not related with USP8-variant status,” researchers concluded. From https://cushingsdiseasenews.com/2018/10/23/cushings-disease-patients-usp8-mutations-more-likely-achieve-remission-after-surgery/
  22. A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary. “Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.” In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies. On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3. At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests. The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve. The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas. Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers. The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers. “A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission
  23. The chemotherapy temozolomide partially improved a case of an aggressive pituitary tumor that caused symptoms of Cushing’s disease (CD), according to a new study in Poland. However, after tumor mass and cortisol levels were stabilized for a few months, the patient experienced rapid progression, suggesting that new methods for extending the effects of temozolomide are needed. The study, “Temozolomide therapy for aggressive pituitary Crooke’s cells corticotropinoma causing Cushing’s Disease: A case report with literature review,” appeared in the journal Endokrynologia Polska. Aggressive pituitary tumors are usually invasive macroadenomas, or benign tumors larger than 10 mm. A very rare subset of pituitary adenoma — particularly corticotropinoma, or tumors with excessive secretion of corticotropin (ACTH) — exhibit Crooke’s cells. These tumors are highly invasive, have a high recurrence rate, and are often resistant to treatment. Information is not widely available about the effectiveness of treating aggressive pituitary tumors, particularly those that cause Cushing’s disease. The management of these tumors usually requires neurosurgery, followed by radiotherapy, and pharmacotherapy. However, the chemotherapy medication temozolomide has been increasingly used as a first-line treatment after initial evidence of its effectiveness in treating glioblastoma, the most common form of brain cancer. In this study, researchers at the Jagiellonian University, in Poland, discussed the case of a 61-year-old man with ACTH-dependent Cushing’s syndrome caused by Crooke’s cell corticotropinoma. The patient first presented with symptoms of severe hypercorticoidism — the excessive secretion of steroid hormones from the adrenal cortex — in December 2011. He also showed advanced heart failure, severe headaches, and impaired vision, which had started two or three years before diagnosis. Examinations revealed osteoporosis and a fracture in the Th5 vertebra. His morning ACTH levels were high. The same was observed for mean cortisol levels even after dexamethasone treatment, which was suggestive of a pituitary tumor secreting ACTH. MRIs showed the existence of a tumor mass, later identified as a macroadenoma with high cell polymorphism, the presence of Crooke’s cells, and ACTH secretion. The patient was referred for transsphenoidal nonradical neurosurgery, performed through the nose and the sphenoid sinus, and bilateral adrenalectomy, or the surgical removal of the adrenal glands, in 2012-2013. However, he developed fast, postoperative recurrence of hypercorticoidism and tumor regrowth. This led to three additional transsphenoidal neurosurgeries and radiotherapy. The patient’s clinical status worsened as he developed severe cardiac insufficiency. Doctors began temozolomide treatment in April 2015, which did not result in adverse effects throughout treatment. The initial standard dose (150–200 mg/m2) was given once daily in the morning for five consecutive days, in a 28-day cycle. The patient also received 600 mg of ketoconazole, an antifungal medication. Ondansetron was administered to prevent nausea and vomiting. Subsequent examinations revealed clinical and biochemical improvements, including a reduction in ACTH and cortisol levels. In addition, the patient also showed reduced cardiac insufficiency, less frequent and less severe headaches, visual field improvements, and better physical fitness and mood. However, clinical symptoms worsened after the eighth temozolomide cycle. The tumor size also suddenly increased after the ninth cycle, reaching the inner ear. Temozolomide was then discontinued and ACTH levels increased by 28 percent one month later. The patient also demonstrated deteriorated vision, hearing loss, and strong headaches. Clinicians then decided to start treatment with the Cushing’s disease therapy Signifor (pasireotide), but a worsening of diabetes was observed, and the patient died in February 2016. “The most probable reason for death was compression of the brainstem, which had been observed in the last MRI of the pituitary,” the researchers wrote, adding that “due to the very short duration of treatment, any conclusions on the treatment with Signifor cannot be drawn.” Overall, “the results of the presented case suggest that [temozolomide] treatment monotherapy could have only partial response in aggressive corticotroph adenoma causing Cushing’s disease, followed by sudden progression,” the investigators wrote. This contrasts with mostly responsive cases reported in research literature, they noted. “Therefore, further research on the factors of responsiveness and on novel methods to extend the duration of the effect of [temozolomide] should be carried out,” they wrote. From https://cushieblog.com/2018/02/10/temozolomide-may-partially-improve-aggressive-pituitary-tumors-causing-cushings-disease/
  24. Today is the anniversary of MaryO's pituitary surgery at NIH in 1987. Read more at https://cushingsbios.com/2016/11/03/29-years-giving-thanks/
  25. Nearly half of adults with Cushing’s disease that persists or recurs after surgical treatment require second and sometimes third therapeutic interventions, including pituitary surgical reintervention, radiotherapy, pharmacotherapy or bilateral adrenalectomy, study data from Mexico show. Moisés Mercado, MD, FRCPC, of the ABC Hospital Neurological and Cancer Centers in Mexico City, and colleagues evaluated 84 adults (median age, 34 years; 77 women) with Cushing’s disease to determine the long-term efficacy of secondary interventions for persistent and recurrent Cushing’s disease. Median follow-up was 6.3 years. Overall, 81 participants were primarily treated with transsphenoidal surgery. More than half experienced long-lasting remission (61.7%); disease remained active in 16%, who were diagnosed with persistent Cushing’s disease; and 22% experienced relapse after remission and were diagnosed with recurrent Cushing’s disease. After the initial procedure, 18 participants required pituitary surgical reintervention, including 10 with recurrent and eight with persistent disease. Radiation therapy was administered to 14 participants, including two as primary therapy and 12 after failed pituitary surgery. Pharmacologic treatment with ketoconazole was prescribed for 15 participants at one point during the course of disease. Bilateral adrenalectomy was performed in 12 participants. Pituitary surgical reintervention was the most commonly used secondary treatment (22.2%), followed by pharmacologic therapy with ketoconazole (16%), radiotherapy (14.8%) and bilateral adrenalectomy (14.8%). More than half of participants experienced early remissions after a second operation (66.6%) and radiotherapy (58.3%), whereas long-lasting remission was reached in only 33.3% of participants who underwent a second surgery and 41.6% of participants who underwent radiotherapy. Half of participants who underwent bilateral adrenalectomy were diagnosed with Nelson’s syndrome. Overall, 88% of participants achieved remission, and disease was biochemically controlled with pharmacologic treatment in 9.5% of participants after their initial, secondary and third-line treatments. “The efficacy of treatment alternatives for recurrent or persistent [Cushing’s disease] vary among patients, and often, more than one of these interventions is required in order to achieve a long-lasting remission,” the researchers wrote. – by Amber Cox Disclosure: The researchers report no relevant financial disclosures. From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B5519b312-5912-4c65-b2ed-2ece3f68e83f%7D/postsurgical-treatment-often-necessary-in-persistent-recurrent-cushings-disease
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