Prediction of remission and recurrence of Cushing’s disease following transsphenoidal surgery (TSS): A single center, 20-year, retrospective series

Prediction of remission and recurrence of Cushing’s disease following transsphenoidal surgery (TSS): A single center, 20-year, retrospective series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prediction of remission and recurrence of Cushing’s disease following transsphenoidal surgery (TSS): A single center, 20-year, retrospective series Dana Bar Natan, Merav Serebro, Zvi Ram, Rachel Grossman, Naomi Even Zohar, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6277838/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jun, 2025 Read the published version in Endocrine → Version 1 posted 6 You are reading this latest preprint version Abstract Purpose Cushing's disease (CD) is a rare condition with variable surgical outcomes. This study aimed to assess remission and recurrence rates in CD patients undergoing transsphenoidal surgery (TSS) at a major Israeli referral center, and to identify predictive factors for these outcomes. We hypothesized that microadenomas would have higher remission rates than macroadenomas. Methods This retrospective analysis included 97 CD patients who underwent TSS at Tel Aviv Sourasky Medical Center (2002–2022). Remission was defined by biochemical criteria and clinical improvement. Suspected recurrence was confirmed by pathological dexamethasone suppression and/or elevated urinary free cortisol. Univariate and multivariate analyses identified predictors of remission, while Kaplan-Meier survival analysis and Cox proportional hazard modeling determined factors associated with recurrence. Results The overall remission rate was 63.9%, with no significant difference between microadenomas (58.7%) and macroadenomas (73.5%). Multivariate logistic regression showed predictors of remission were adenoma presence in pathology specimens (OR = 31.25, P < 0.001) and first-time surgery status (OR = 9.42, P = 0.002), while younger age was a contributory factor (OR = 0.963, P = 0.05). The relapse rate was 22.6% over a median follow-up of 63 [IQR 35-109.5] months. Glucocorticoid withdrawal syndrome emerged as a novel protective factor against recurrence (P = 0.045). Conclusions This largest analysis of TSS outcomes for CD in Israel challenges established notions about remission predictors, including our initial hypothesis about microadenomas. The identification of glucocorticoid withdrawal syndrome as a predictor of long-term remission provides a potential avenue for post-operative monitoring in the local healthcare context. Cushing’s disease Transphenoidal Surgery-TSS microadenomas macroadenomas remission recurrence glucocorticoid withdrawal syndrome Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 14 Figure 15 Introduction Cushing's disease (CD), a rare condition of endogenous hypercortisolism, results from an ACTH-secreting pituitary tumor and accounts for 70%-75% of all endogenous Cushing's syndrome cases [ 1 ]. Recent estimates place the annual global incidence of CD at 2.4/million, though this figure may be rising [ 2 , 3 ]. A comprehensive nationwide study from Iceland suggests an even higher rate of 5.2/million/year [ 4 ]. This potential increase could reflect growing recognition of the disease, spurred by the need to address a condition that carries significant morbidity and elevated mortality risks [ 1 ]. While recent years have seen remarkable progress in medical approaches to managing endogenous hypercortisolism [ 5 – 7 ], pituitary surgery remains the primary intervention for CD, offering the prospect of enduring recovery without life-long medical therapy [ 8 ]. The transsphenoidal surgical (TSS) technique, introduced by Wilson and Hardy nearly five decades ago [ 9 , 10 ], has become the gold standard approach. Recently, endoscopic visualization has largely superseded the original microscopic method, though this shift hasn't consistently improved surgical outcomes or remission rates [ 11 , 12 ]. Early remission rates from CD with TSS vary widely, from below 60–95%, with generally quoted figures of 80% for primary surgeries and 58% for repeat procedures [ 13 ]. Recurrence rates after initial remission range from 10–50%, with most studies reporting around 20%. These recurrences have been observed up to 5 years post-surgery, and in some cases as late as 10 years [ 13 , 14 ]. This variability in outcomes stems from factors including series size, study design, surgical expertise, and follow-up duration [ 13 – 15 ]. Given these variations, region- and institution-specific data are crucial for informed patient decision-making. To date, only one retrospective series from Israel, published over 20 years ago, has reported outcomes of 82 CD patients undergoing 90 TSS procedures (including 13 repeat surgeries) between 1990 and 2000 [ 16 ]. Our study aims to provide an updated assessment of remission and recurrence rates in CD patients undergoing TSS at a major Israeli referral center with a dedicated pituitary surgery unit. We hypothesized higher remission rates in subjects with microadenomas and sought to identify potential predictive factors for both remission and recurrence. Methods Study Design and Inclusion Criteria We conducted a single-center, retrospective analysis of adult patients (18 y or older) with Cushing's disease (CD) who underwent transsphenoidal surgery (TSS) at the Neurosurgery Department of Tel Aviv Sourasky Medical Center between January 1, 2002, and December 31, 2002. Initial patient identification utilized computerized medical records, searching for ICD-9 diagnoses 255.0 (Cushing's syndrome), 227.3 and 253.1 (pituitary tumors and excessive pituitary secretion), cross-referenced with procedure code 07.62 (TSS). Subsequent individual chart review was performed to retain only patients with a confirmed diagnosis of CD who had undergone surgery at our center during the study period, and whose pituitary tumors could be classified as micro or macroadenomas (based on imaging and/or surgical report). Patients on whom such information was not available were excluded. Subjects undergoing reoperation were included. The institutional ethics committee approved the study in accordance with the Declaration of Helsinki and waived the requirement for informed consent due to the retrospective design (IRB approval #TLV-0576-22). Data Extraction We comprehensively reviewed charts of included subjects (selection process flow chart detailed in the Results section) to extract pre-surgical demographic, clinical, biochemical, and imaging data (including tumor size, suprasellar extension and invasiveness). We also collected information on the TSS procedure (microscopic or endoscopic), perioperative complications, and immediate or early post-operative remission status. Endocrine follow-up data, including remission duration, recovery of the hypothalamic-pituitary-adrenal axis (HPA) and recurrence, were similarly extracted. Notably, the data extraction process was challenging due to incomplete computerization of hospitalization records before 2008 and outpatient endocrine clinic records before 2014, necessitating review of numerous handwritten documents. Criteria for adenoma classification, remission, recovery of the HPA axis, and recurrence Tumors were classified as microadenomas if their largest diameter on pituitary MRI was less than 10 mm, while macroadenomas measured 10 mm or greater. In a few cases where size was not explicitly mentioned, the records' specification of micro- or macroadenoma was used for classification. As patients did not receive routine peri-operative glucocorticoid coverage, immediate remission was determined based on a post-surgical morning serum cortisol nadir below 55 nmol/L or 138 nmol/L (typically observed on the third post-operative day), confirmed by suppressed cortisol and glucocorticoid-dependence at the first follow-up endocrine clinic visit, usually within 4 weeks of surgery. Additionally, a clinical course suggestive of overt acute hypoadrenalism, accompanied by low blood pressure and hyponatremia prompting immediate in-hospital hydrocortisone initiation and later confirmed by post-discharge suppressed cortisol, was also considered evidence of remission. In some cases, delayed remission was documented at the first outpatient follow-up visit, and in one instance, almost 3 months post-surgery due to admission for acute hypoadrenalism. Continued remission was assessed through persistently suppressed serum cortisol concentrations and glucocorticoid-dependence, pending recovery of the HPA axis. HPA axis function was deemed recovered when a normal morning serum cortisol level was complemented by an ACTH-stimulated serum cortisol exceeding 497 nmol/L. After discontinuation of glucocorticoid replacement and full recovery of the HPA axis, continued remission was periodically evaluated by 24-hour urinary free cortisol measurement within the normal range (which varied according to the assaying laboratory), an overnight 1 mg dexamethasone suppression test with serum cortisol below 55 nmol/L, and a midnight salivary cortisol measurement below 5.2 nmol/L (salivary cortisol measurements were exclusively performed in our department core lab), often using a combination of these tests. Recurrence was typically suspected upon return of clinical complaints and confirmed by a combination of a pathological overnight 1 mg dexamethasone suppression test and elevated 24-hour urinary free cortisol secretion. Sample size computation and statistics We hypothesized a higher remission rate among subjects with microadenomas. Based on an expected 75% prevalence of microadenomas and using conservative remission rates of 83% for microadenomas versus 68% for macroadenomas [ 17 ], we calculated that a cohort of 123 patients would provide 80% power to detect this difference (α = 0.05). This sample size was consistent with our clinic's annual referral rate at the time of study design. We present continuous variables as mean ± SD or median [IQR] based on their distribution, and categorical variables as frequencies and percentages. For remission analysis, we first conducted univariate analyses to identify potential predictors, comparing various independent variables between remission and non-remission groups. We used Student's t-test or Mann-Whitney test for continuous variables and chi-square or Fisher's exact test for categorical variables, as appropriate. We then performed multivariate logistic regression to identify independent predictors of remission. For recurrence analysis, we employed Kaplan-Meier survival analysis with log-rank tests for categorical variables and Cox regression for continuous variables to account for varying follow-up durations. We conducted all statistical analyses using IBM SPSS Statistical Software Version 29.0 (IBM Corp., Armonk, NY), setting statistical significance at P < 0.05. Graphs were created using GraphPad Prism 10.2.3 (GraphPad Software, San Diego, CA). Results Patient Selection, Cohort Composition, and Baseline Characteristics Initial screening using diagnosis codes identified 301 patients. After applying inclusion criteria and reviewing charts, we included 97 patients with clear tumor type classification (Fig. 1 ). To assess temporal trends, we divided the study period into three 7-year intervals, revealing a steady increase in patient numbers: 16 in 2002–2008, 38 in 2009–2015, and 43 in 2016–2022. As expected, the cohort was predominantly female (77/97, 79.4%), with a median age of 42 years [IQR: 33.5–57]. Notably, macroadenomas constituted a substantial portion of the cohort (34/97, 35%), higher than what we had anticipated. Each subject underwent a single operation at our center during the study period. However, for 13 subjects (13.4%), this represented a repeat TSS due to either a failed previous procedure elsewhere or disease recurrence. Table 1 presents the clinical, biochemical, and imaging characteristics of the entire cohort, stratified by adenoma classification. As expected, tumor size differed between groups, with macroadenomas showing significantly higher rates of cavernous sinus invasion compared to microadenomas (23.5% vs 3.2%, P = 0.002). No other characteristics differed significantly between the groups. Table 1 Demographic, clinical, and laboratory data of CD patients at the time of presentation. Data are presented as mean ± SD if normally distributed, or median [IQR], and frequencies including the denominator (N), as appropriate. The micro and macroadenomas were compared by the student’s T-test, the Mann-Whitney test, or by the Chi-square test for proportions, as appropriate. Significance was assumed for P < 0.05 Variable All (n = 97) Micro (n = 63) Macro (n = 34) P Women; n/N (%) 77/97 (79.4) 50/63 (79.4) 27/34 (79.4) NS Age (y) 42 [33.5–57] 41 [32–55] 47 [36-57.8] NS Weight gain; n/N (%) 75/90 (83.3) 47/57 (63.3) 28/33 (84.8) NS Obesity; n/N (%) 51/88 (58) 28/55 (50.9) 23/33 (69.7) 0.084 Hypertension; n/N (%) 62/96 (64.5) 40/62 (64.5) 22/32 (64.7) NS Diabetes; n/N (%) 35/96 (36.5) 22/62 (35.5) 13/34 (38.2) NS Hyperlipidemia; n/N (%) 44/96 (45.8) 24/62 (38.7) 20/34 (58.8) 0.059 No. catabolic signs; mode (range) a 1 (0–4) 1 (0–4) 0 (0–3) NS N o .fat redistribution signs; mode (range) b 1 (0–4) 1 (0–4) 1 (0–4) NS N o . neuropsychiatric comorbidities; mode (range) c 0 (0–3) 0 (0–3) 0 (0–2) NS N o . hyperandrogenic signs; mode (range) d 1 (0–3) 1 (0–3) 1 (0–3) NS Adenoma size (mm) 7 [ 5 – 11 ] 5.4 ± 2.1 17 ± 6.5 < 0.001 Invasive; n/N (%) 10/91 (10.9) 2/63 (3.2) 8/22 (23.5) 0.002 8:00 am cortisol (nmol/L) 712 [555–890] 710 [553.8–903] 742 [555–829] NS ACTH (pg/ml) 66 [42.5–94.1] 63[39.6–88.6] 69.3 [51.4-104.4] NS Mean UFC e (micg/24h) 245.5 [156-375.5] 260 [160-375.5] 175.8 [115.3–393] NS Relative UFC/upper limit f 2.7 [1.8–4.5] 2.95 [1.9–4.5] 2.25 [1.5–4.75] NS ONDST cortisol (nmol/L) 360 [165.5-567.5] 351 [230–587] 363 [85–492] NS Salivary cortisol (micg/dl) 0.49 [0.29–1.09] 0.57 [0.33–1.18] 0.28 [0.13–0.65] 0.05 a Included: osteoporosis, fractures, nephrolithiasis, muscle weakness, striae and easy bruising; b included: dorsocervical fat pad, moon face, supraclavicular fullness; c included: Anxiety, depression, psychosis, insomnia; d in women only, included: hirsutism, alopecia, acne, menstrual disturbances; e ONDST-Overnight dexamethasone suppression test; f UFC-Urinary free cortisol Remission Rates: Microadenomas vs. Macroadenomas We initially sought to test our hypothesis that subjects with microadenomas would achieve remission more frequently than those with macroadenomas. Table 2 provides a comprehensive overview of the immediate post-operative indicators used to evaluate remission and the ultimate remission status of each patient. Table 2 Pathology findings, post-operative indicators of remission, and remission rates in subjects with micro- and macroadenomas. Comparisons were done with the chi-square or the Fisher exact test. Variable All (n = 97) Micro (n = 63) Macro (n = 34) P Adenoma on pathology; n/N (%) 78/94 (83) 45/60 (75) 33/34 (97.1) 0.006 Nadir cortisol < 2.0 n/N (%) 23/93 (24.7) 21/61 (34.4) 2/32 (6.3) 0.003 Nadir cortisol < 5.0 n/N (%) 37/93 (39.8) 27/61 (44.3) 10/32 (31.3) NS Discharge with GC; n/N (%) 60/96 (62.5) 28/55 (50.9) 22/33 (66.7) NS GCSW syndrome a ; n/N (%) 34/96 (35.4) 29/63 (46) 5/33 (15.2) 0.003 Remission; n/N (%) 62/97 (63.9) 37/63 (58.7) 25/34 (73.5) 0.148 a GCSW: Glucocorticoid withdrawal syndrome Contrary to our assumption, subjects with microadenomas did not achieve a higher rate of remission. Overall, 62 subjects (63.9%) reached remission following surgery. As previously shown, while microadenomas were significantly less invasive than macroadenomas, the remission rates between the two groups were essentially the same. A potential explanation lies in the pathology results: adenoma tissue was found in only 75% of the microadenoma cases, compared to virtually all macroadenomas (P = 0.006). Among the 60 subjects with microadenomas for whom pathological reports were available, 15 cases yielded material that was not adenoma but instead consisted of either normal pituitary tissue or unrelated material. By contrast, in the macroadenoma group, with a single exception, all surgical specimens were confirmed as pituitary adenoma tissue. To further explore the relationship between adenoma size and surgical outcomes, we refined our classification. Rather than the binary distinction between microadenomas and macroadenomas, we stratified tumors into four categories based on size: small microadenomas (< 6 mm), large microadenomas (6–9 mm), small macroadenomas (10–19 mm), and large macroadenomas (≥ 20 mm). Notably, among the 49 microadenomas whose size was documented in the charts, 28 (57.1%) were small microadenomas, while 21 (42.9%) were 6 mm or larger. However, even with this more nuanced approach, we found no statistically significant differences in remission rates across these groups. Factors Associated with Remission Not having found the expected difference in remission rates between micro- and macroadenomas, we conducted a more comprehensive analysis to identify factors associated with remission. We first performed univariate analyses, focusing on variables frequently cited in the literature as influencing remission in Cushing's disease. These included: demographics, treatment period (2002–2008, 2009–2015, 2016–2022), surgical approach (endoscopic vs. microscopic TSS), previous TSS, indices of activity severity at presentation, tumor characteristics (size and invasiveness), and histopathology findings. An overview of this univariate analysis is presented in Table 3 . Our results revealed that most factors appeared to have no statistically significant impact on remission. In keeping with the previous comparison, neither adenoma size nor tumor invasiveness was associated with remission. Importantly, various biochemical markers of disease severity also showed no significant association with surgical outcomes. Contrary to our expectation, patients operated on in later years were not significantly more likely to achieve remission, suggesting no observable learning curve effect over time. Similarly, the general adoption of endoscopic transsphenoidal surgery (TSS) in 2009 did not emerge as a turning point for surgical success, a finding which, broadly speaking, aligns with the available literature. Table 3 Demographic, clinical, laboratory and surgery data of CD patients. Data are given for the entire cohort and stratified by remission status. Variable All (n = 97) Remission (n = 62) No Remission (n = 35) P Women; n/N (%) 77/97 (79.4) 48/62 (77.4) 29/35 (82.9) NS Age (y) 42 [33.5–57] 40 [32.75-52] 50 [35–60] 0.069 Period of presentation; n (1/2/3) 16/38/43 11/23/28 5/15/15 NS Adenoma size (mm) 7 [ 5 – 11 ] 10.1 ± 7.3 7.8 ± 5.8 NS Adenoma invasive; n/N (%) 10/91 (10.9) 5/58 (8.6) 5/35 (14.3) NS 8:00 am cortisol (nmol/L) 712 [555–890] 738 [537–913] 708 [579–820] NS ACTH (pg/ml) 66 [42.5–94.1] 68.6 [47-96.3] 62.8 [39.7–91.5] NS Mean UFC (micg/24h) 245.5 [156-375.5] 246.7 [158.5-370.7] 234.5 [146-420.1] NS Relative UFC/upper limit 2.7 [1.8–4.5] 2.7 [1.9–4.6] 2.7 [1.5–4.6] NS ONDST cortisol (nmol/L) 360 [165.5-567.5] 370 [235–582] 326 [98–561] NS Salivary cortisol (mcg/dl) 0.49 [0.29–1.09] 0.48 [0.29–1.13] 0.5 [0.29–1.1] NS Endoscopic TSS; n/N (%) 76/97 (78.4) 47/62 (75.8) 29/35 (82.9) NS Repeat TSS; n/N (%) 13/97 (13.4) 4/62 (6.5) 9/35 (25.7) 0.012 Adenoma on pathology; n/N (%) 78/94 (83) 58/60 (96.7) 20/34 (58.8) < 0.001 Adenoma ACTH positive; n/N (%) 73/78 (93.6) 55/58 (94.8) 18/21 (85.7) NS Table 4 Final multivariate logistic regression model to explain remission Predictor B S.E. Wald df Sig. Exp(B) 95% CI for Exp(B) Age at presentation -0.038 0.019 3.855 1 0.050 0.963 (0.927, 1.000) Repeat TSS (Yes) 2.243 0.718 9.773 1 0.002 9.419 (2.305, 38.493) Pituitary adenoma present -3.438 0.754 20.820 1 < 0.001 0.032 (0.007, 0.141) Constant 0.758 1.172 0.419 1 0.518 2.135 - Predicting remission We subsequently conducted multivariate logistic regression analyses to identify independent predictors of remission. Our initial model included variables based on the univariate analysis results and potential clinical relevance: presence of adenoma in pathology, repeat surgery status, patient age, gender, period of presentation, and surgery type (endoscopic vs. microscopic). Using backward elimination based on likelihood ratio, we identified three significant independent predictors of remission. The presence of adenoma at pathology was the strongest predictor of remission (OR = 31.25, 95% CI: 7.09-142.86, p < 0.001), although the wide confidence interval suggests considerable uncertainty in the effect's magnitude. Conversely, repeat surgeries significantly reduced the likelihood of remission (OR = 9.42, 95% CI: 2.31–38.49, p = 0.002). Age at presentation also played a role, with younger patients having slightly better odds of remission; each additional year of age was associated with a 3.7% decrease in remission odds (OR = 0.963, 95% CI: 0.927-1.000, p = 0.050). Other factors, including gender, treatment period, and surgery type, did not significantly influence remission outcomes in our cohort. To validate these findings, we constructed several alternative models, consistently including the three main predictors while varying other variables. Across all models, the same three factors remained significant, with stable Nagelkerke R² values (0.455–0.458), reinforcing the robustness of the results. Disease Recurrence To investigate the long-term outcomes of surgical intervention, we conducted a follow-up analysis on the cohort of 62 patients who initially achieved remission following transsphenoidal surgery (TSS). The follow-up period extended from 6 to 225 months post-initial remission, with a median duration of 63 [IQR 35-109.5] months. During this observational period, 14 patients (22.6%) experienced disease recurrence after a mean remission duration of 47 ± 33.4 months (range 6-112). To optimize the statistical power of our analysis, we implemented a 120-month censoring point, as the limited number of patients with extended follow-up (n = 12) yielded no additional cases of relapse beyond this timeframe. Our investigation started with a Kaplan-Meier survival analysis comparing microadenomas and macroadenomas (Fig. 2 ). This analysis revealed no statistically significant difference between these groups (P = 0.24). We subsequently expanded our inquiry to include various categorical variables. Gender emerged as a potentially influential factor (Fig. 3 ); notably, none of the 14 men who achieved remission experienced recurrence, in contrast to 29.2% of women (P = 0.084). Other variables, including tumor invasiveness (P = 0.285) and surgical approach (microscopic vs. endoscopic, P = 0.689), demonstrated no significant association with recurrence development. Similarly, metabolic comorbidities such as obesity, diabetes, hypertension, and hyperlipidemia showed no predictive value for disease recurrence. Intriguingly, the of glucocorticoid withdrawal syndrome (GCSW) emerged as a statistically significant significant protective factor against disease recurrence (P = 0.045, Fig. 4 ). Additionally, a suppressed cortisol nadir suggested a trend towards long-term protection, although not achieving statistical significance (P = 0.105 for nadir < 55 nmol/L, and P = 0.108 for nadir < 138 nmol/L). Of note, the occurrence of GCSW demonstrated a moderate correlation with a cortisol nadir below 55 nmol/L, Spearman's rho = 0.372, P < 0.001. To evaluate the potential influence of continuous variables on recurrence risk, we employed Cox proportional hazards regression analysis. This method assessed factors including age, time to hypothalamic-pituitary-adrenal (HPA) axis recovery, and adenoma size as measured by pituitary MRI. However, none of these variables reached statistical significance, yielding P-values of 0.641, 0.331, and 0.210, respectively. Discussion In this retrospective study of 97 Cushing's disease patients undergoing TSS at Tel Aviv Sourasky Medical Center from 2002 to 2022, we found that surgery achieved remission in 63.9% of cases, with a 22.6% relapse rate over a mean follow-up of 63 [IQR 35-109.5] months. Significant predictors of remission were adenoma presence in pathology specimens (p < 0.001) and first-time surgery status (p = 0.012). Younger age also tended to correlate with higher remission rates. Post-remission recurrence was less common in patients who experienced glucocorticoid withdrawal syndrome, while women seemed to be prone to relapse more than men. Remission Our remission rate (63.9%) aligns with contemporary series [ 17 – 19 ], though lower than some reported rates [ 20 ]. This discrepancy likely reflects the inclusion of reoperated patients, known to have lower remission rates than first-time surgery subjects [ 13 – 15 ]. Contrary to our hypothesis, we found no significant difference between microadenomas (58.7%) and macroadenomas (73.5%). Tumor size, whether considered as a continuous variable or categorized, did not affect remission rates. This surprising finding warrants an explanation. Macroadenomas are easier to target, while microadenomas can elude detection. The introduction of endoscopic TSS at our hospital in 2009, expected to improve outcomes, did not change remission rates, mirroring reports from the literature [ 21 ]. In our series, adenoma tissue was retrieved from virtually all macroadenomas but only 75% of microadenomas. Given the established link between adenoma identification in pathology and remission [ 13 – 15 ], this discrepancy could negate the theoretical advantage of smaller tumors. Of the 49 microadenomas with size documented, 57.1% were smaller than 6 mm. While other imaging and testing modalities were used to exclude ectopic ACTH sources with high reliability, as proposed by others as an alternative to IPSS [ 22 ], lack of inferior petrosal sinus sampling (IPSS) at out center until recently might have led to misclassification of some ectopic ACTH cases as microadenomas. However, given the rarity of ectopic ACTH secretion without fulminant CS [ 23 ], this likely affected very few cases. Surprisingly, tumor invasiveness, suspected by MRI, did not predict poorer remission outcomes. This may be due to overestimation of cavernous sinus invasion by MRI, as previously documented [ 14 , 24 – 26 ]. Notably, no standard invasiveness classification like the Knosp system was consistently applied during the study period. While some studies have linked ACTH staining in histological specimens with remission [ 16 , 26 ], we did not find this association. This might be due to a small number of presumably ACTH-negative adenomas in our cohort (4/78, 5%), which could have been immunohistochemistry procedure failures rather than truly ACTH-negative tumors. Our study suggested a possible role of age in predicting remission, with younger patients showing better outcomes in both univariate and multivariate analyses. While age has not been a major focus in most remission studies, this finding has been observed in some [ 20 ] but was not supported by a large retrospective study [ 27 ]. It may be a chance finding in our smaller cohort. Relapse The relapse rate of 22.6% in our study falls within the literature's reported range of 5–27% after initial remission [ 14 , 28 , 29 ]. All relapses occurred within 10 years (range 6-112 months). Although survival analysis was censored at 120 months, 12 patients were followed for up to 225 months. Since some reports have shown relapse occurring more than 10 years post-surgery, long-term follow-up remains essential [ 8 ]. The literature is replete with studies have proposed factors to predict relapse. Many variables and mathematical models, including machine learning-derived algorithms, have been suggested to predict this outcome. Among the proposed variables early post-operative hypocortisolism (particularly nadir cortisol < 55 nmol/L) and prolonged suppression of the HPA axis have been emphasized [ 30 ]. Additionally, elevated preoperative ACTH levels, larger adenoma size, exaggerated desmopressin response, and USP8 mutations have also been proposed as predictors of relapse [ 31 ]. However, there is no consensus on these predictors. In our analysis, glucocorticoid withdrawal syndrome (GCSW) emerged as a significant predictor of long-term remission. Though GCSW has been alluded to as a marker of prolonged remission [ 32 ], no study has directly examined it as a predictor. The lack of an obvious mechanism behind this association makes further investigation necessary. In our cohort, GCSW predicted long-term remission better than any of the post-operative cortisol nadir thresholds. Our data showed an interesting trend of gender differences in relapse rates, though it was not statistically significant (P = 0.084). None of the 14 men who achieved remission relapsed, compared to 30% of women. This finding, inconsistent in the literature, could also be a chance observation given the small number of men in our study. Limitations The main limitation is our sample size [97], which is smaller than our initial estimate of 120–140 subjects. This was due to the study period encompassing pre-electronic record-keeping years, surgeries done elsewhere, or patients not meeting inclusion criteria. Despite this, the cohort remains substantial for a single-center study of this rare condition. The retrospective design may have introduced selection bias and missing data points. The single-center design may also limit the generalizability of our findings to other settings. Strengths This study presents a relatively large cohort of Cushing's disease patients from a single center, with most surgeries performed by a single neurosurgeon, reducing variability in technique. It identified GCSW as a predictor of long-term remission, adding new insights to the field. Importantly, it represents the largest and most comprehensive analysis of TSS outcomes for Cushing’s disease in Israel to date, expanding on previous work [ 16 ]. Conclusions This 20-year retrospective study provides the most up-to-date analysis of TSS outcomes for Cushing's disease in Israel. It offers insights into remission and relapse patterns and possible predictors. The potential role of glucocorticoid withdrawal syndrome in predicting long-term remission warrants further investigation, highlighting the importance of evaluating outcomes in the context of patient-specific and local healthcare factors. Declarations Ethical Approval This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Tel Aviv Sourasky Medical Center (Approval Number: TLV-0576-22). The requirement for informed consent was waived due to the retrospective nature of the study. Study design [KT, YG] Data collection [DBN, KT, MS, YS, ZR, RG, IY] Data analysis [KT, YG, DBN] Interpretation of results [KT, YG, DBN] Manuscript drafting [KT] Manuscript revision and critical review [KT, YG, DBN, MS, YS, ZR, RG, IY ] Supervision [KT, TG] Final approval of the manuscript All authors Author Contribution Conceptualization: [KT, YG]Study design: [KT, YG]Data collection: [DBN, KT, MS, YS, ZR, RG, IY]Data analysis: [KT, YG, DBN]Interpretation of results: [KT, YG, DBN]Manuscript drafting: [KT]Manuscript revision and critical review: [KT, YG, DBN, MS, YS, ZR, RG, IY ]S Statements The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose . Ethical Approval This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Tel Aviv Sourasky Medical Center (Approval Number: TLV-0576-22). The requirement for informed consent was waived due to the retrospective nature of the study. Authors contribution Conceptualization: [KT, YG] Study design: [KT, YG] Data collection: [DBN, KT, MS, YS, ZR, RG, IY] Data analysis: [KT, YG, DBN] Interpretation of results: [KT, YG, DBN] Manuscript drafting: [KT] Manuscript revision and critical review: [KT, YG, DBN, MS, YS, ZR, RG, IY ] Supervision: [KT, TG] Final approval of the manuscript: All authors upervision: [KT, TG]Final approval of the manuscript: All authors References Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281–93. https://doi-org.eur.idm.oclc.org/ 10.2147/CLEP.S44336 Giuffrida, G., Crisafulli, S., Ferraù, F., Fontana, A., Alessi, Y., Calapai, F., Ragonese, M., Luxi, N., Cannavò, S., & Trifirò, G. (2022). Global Cushing's disease epidemiology: a systematic review and meta-analysis of observational studies. Journal of endocrinological investigation, 45 (6), 1235–1246. https://doi-org.eur.idm.oclc .org/10.1007/s40618-022-01754-1 Ragnarsson, O., Olsson, D. S., Chantzichristos, D., Papakokkinou, E., Dahlqvist, P., Segerstedt, E., Olsson, T., Petersson, M., Berinder, K., Bensing, S., Höybye, C., Edén Engström, B., Burman, P., Bonelli, L., Follin, C., Petranek, D., Erfurth, E. M., Wahlberg, J., Ekman, B., Åkerman, A. K., … Johannsson, G. (2019). The incidence of Cushing's disease: a nationwide Swedish study. Pituitary, 22 (2), 179–186. https://doi-org.eur.idm.oclc.org/10.1007/s11102-019-00951-1 Matthiasdottir, A. M., Hardarson, T. O., Arnardottir, S., & Sigurjonsdottir, H. A. (2024). Cushing's Disease May Have Higher Incidence than Previously Thought: A Nationwide Study in Iceland 2010–2019. Neuroendocrinology, 114 (10), 950–957 https://doi-org.eur.idm.oclc.org/10.1159/000540205 Colao, A., Petersenn, S., Newell-Price, J., Findling, J. W., Gu, F., Maldonado, M., Schoenherr, U., Mills, D., Salgado, L. R., Biller, B. M., & Pasireotide B2305 Study Group (2012). A 12-month phase 3 study of pasireotide in Cushing's disease. The New England journal of medicine, 366 (10), 914–924. https://doi-org.eur.idm.oclc.org/10.1056/NEJMoa1105743 Pivonello, R., Fleseriu, M., Newell-Price, J., Bertagna, X., Findling, J., Shimatsu, A., Gu, F., Auchus, R., Leelawattana, R., Lee, E. J., Kim, J. H., Lacroix, A., Laplanche, A., O'Connell, P., Tauchmanova, L., Pedroncelli, A. M., Biller, B. M. K., & LINC 3 investigators (2020). 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. The lancet. Diabetes & endocrinology, 8 (9), 748–761. https://doi-org.eur.idm.oclc.org/10.1016/S2213-8587(20)302 Pivonello, R., Zacharieva, S., Elenkova, A., Tóth, M., Shimon, I., Stigliano, A., Badiu, C., Brue, T., Georgescu, C. E., Tsagarakis, S., Cohen, F., & Fleseriu, M. (2022). Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary, 25 (6), 911–926. https://doi-org.eur.idm.oclc .org/10.1007/s11102-022-01263-7 Fleseriu, M., Auchus, R., Bancos, I., Ben-Shlomo, A., Bertherat, J., Biermasz, N. R., Boguszewski, C. L., Bronstein, M. D., Buchfelder, M., Carmichael, J. D., Casanueva, F. F., Castinetti, F., Chanson, P., Findling, J., Gadelha, M., Geer, E. B., Giustina, A., Grossman, A., Gurnell, M., Ho, K., … Biller, B. M. K. (2021). Consensus on diagnosis and management of Cushing's disease: a guideline update. The lancet. Diabetes & endocrinology, 9 (12), 847–875. https://doi-org.eur.idm.oclc.org/10.1016/S2213-8587(21)00235-7 Wilson, C. B., & Dempsey, L. C. (1978). Transsphenoidal microsurgical removal of 250 pituitary adenomas. Journal of neurosurgery, 48 (1), 13–22. https://doi-org.eur.idm.oclc .org/10.3171/jns.1978.48.1.0013 Bigos, S. T., Robert, F., Pelletier, G., & Hardy, J. (1977). Cure of Cushing's disease by transsphenoidal removal of a microadenoma from a pituitary gland despite a radiographically normal sella turcica. The Journal of clinical endocrinology and metabolism, 45 (6), 1251–1260. https://doi-org.eur.idm.oclc.org/10.1210/jcem-45-6-1251 Qiao N. (2018). Outcome of endoscopic vs microsurgical transsphenoidal resection for Cushing's disease. Endocrine connections, 7 (1), R26–R37. https://doi-org.eur.idm.oclc .org/10.1530/EC-17-031 Little, A. S., Karsy, M., Evans, J. J., Kim, W., Pacione, D. R., Kim, A. H., Gardner, P. A., Hendricks, B. K., Sarris, C. E., Torok, I. E., Low, T. M., Crocker, T. A., Valappil, B., Kanga, M., Abdallah, H., Collopy, S., Fernandez-Miranda, J. C., Vigo, V., Ljubimov, V. A., Zada, G., … RAPID Consortium (2024). Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics. Neurosurgery, 95 (2), 372–379. https://doi-org.eur.idm.oclc.org/10.1227/neu.0000000000002888 Stroud, A., Dhaliwal, P., Alvarado, R., Winder, M. J., Jonker, B. P., Grayson, J. W., Hamizan, A., Harvey, R. J., & McCormack, A. (2020). Outcomes of pituitary surgery for Cushing's disease: a systematic review and meta-analysis. Pituitary, 23 (5), 595–609. https://doi-org.eur.idm.oclc .org/10.1007/s11102-020-01066-8 Koh, C. H., Khan, D. Z., Digpal, R., Layard Horsfall, H., Ali, A. M. S., Baldeweg, S. E., Bouloux, P. M., Dorward, N. L., Drake, W. M., Evanson, J., Grieve, J., Stoyanov, D., Korbonits, M., & Marcus, H. J. (2023). The clinical outcomes of imaging modalities for surgical management Cushing's disease - A systematic review and meta-analysis. Frontiers in endocrinology, 13 , 1090144. https://doi-org.eur.idm.oclc.org/10.3389/fendo.2022.1090144 Dai, C., Feng, M., Sun, B. et al. Surgical outcome of transsphenoidal surgery in Cushing’s disease: a case series of 1106 patients from a single center over 30 years. Endocrine 75, 219–227 (2022). https://doi-org.eur.idm.oclc .org/10.1007/s12020-021-02848-1 Shimon, I., Ram, Z., Cohen, Z. R., & Hadani, M. (2002). Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery, 51 (1), 57–62. https://doi-org.eur.idm. oclc.org/10.1097/00006123-200207000-00008 Parksook, W. W., Laichuthai, N., & Sunthornyothin, S. (2020). Clinical Characteristics and Treatment Outcomes in Endogenous Cushing's Syndrome: A 15-Year Experience from Thailand. Case reports in endocrinology , 2020 , 2946868. https://doi- Mondin, A., Ceccato, F., Voltan, G., Mazzeo, P., Manara, R., Denaro, L., Scaroni, C., & Barbot, M. (2023). Complications and mortality of Cushing's disease: report on data collected over a 20-year period at a referral centre. Pituitary, 26 (5), 551–560. https://doi-org.eur.idm.oclc .org/10.1007/s11102-023-01343-2 Johnston, P. C., Kennedy, L., Hamrahian, A. H., Sandouk, Z., Bena, J., Hatipoglu, B., & Weil, R. J. (2017). Surgical outcomes in patients with Cushing's disease: the Cleveland clinic experience. Pituitary, 20 (4), 430–440. https://doi-org.eur.idm.oclc .org/10.1007/s11102-017-0802-1 Shirvani, M., Motiei-Langroudi, R., & Sadeghian, H. (2016). Outcome of Microscopic Transsphenoidal Surgery in Cushing Disease: A Case Series of 96 Patients. World neurosurgery, 87 , 170–175. https://doi-org.eur.idm.oclc.org/ 10.1016/j.wneu.2015.11.046 Broersen, L. H. A., van Haalen, F. M., Biermasz, N. R., Lobatto, D. J., Verstegen, M. J. T., van Furth, W. R., Dekkers, O. M., & Pereira, A. M. (2019). Microscopic versus endoscopic transsphenoidal surgery in the Leiden cohort treated for Cushing's disease: surgical outcome, mortality, and complications. Orphanet journal of rare diseases, 14 (1), 64. https://doi-org.eur.idm.oclc.org/10.1186/s13023-019-1038-0 Frete, C., Corcuff, J. B., Kuhn, E., Salenave, S., Gaye, D., Young, J., Chanson, P., & Tabarin, A. (2020). Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome. The Journal of clinical endocrinology and metabolism, 105 (10), dgaa409. https://doi-org.eur.idm .oclc.org/10.1210/clinem/dgaa409 Ragnarsson, O., Juhlin, C. C., Torpy, D. J., & Falhammar, H. (2024). A clinical perspective on ectopic Cushing's syndrome. Trends in endocrinology and metabolism: TEM, 35 (4), 347–360. https://doi-org.eur.idm.oclc.org/ 10.1016/j.tem.2023.12.003 Zhang, W., Sun, M., Fan, Y., Wang, H., Feng, M., Zhou, S., & Wang, R. (2021). Machine Learning in Preoperative Prediction of Postoperative Immediate Remission of Histology-Positive Cushing's Disease. Frontiers in endocrinology, 12 , 635795. https://doi-org.eur.idm.oclc.org/10.3389/fendo.2021.635795 Dhandapani, S., Singh, H., Negm, H. M., Cohen, S., Anand, V. K., & Schwartz, T. H. (2016). Cavernous Sinus Invasion in Pituitary Adenomas: Systematic Review and Pooled Data Meta-Analysis of Radiologic Criteria and Comparison of Endoscopic and Microscopic Surgery. World neurosurgery, 96 , 36–46. https://doi-org.eur.idm.oclc.org/10.1016/j.wneu.2016.08.088 Erfe, J. M., Perry, A., McClaskey, J., Inzucchi, S. E., James, W. S., Eid, T., Bronen, R. A., Mahajan, A., Huttner, A., Santos, F., & Spencer, D. (2018). Long-term outcomes of tissue-based ACTH-antibody assay-guided transsphenoidal resection of pituitary adenomas in Cushing disease. Journal of neurosurgery, 129 (3), 629–641. https://doi-org.eur.idm.oclc.org/10.3171/2017.3.JNS162245 Dai, C., Fan, Y., Liu, X., Bao, X., Yao, Y., Wang, R., & Feng, M. (2021). Predictors of Immediate Remission after Surgery in Cushing's Disease Patients: A Large Retrospective Study from a Single Center. Neuroendocrinology, 111 (11), 1141–1150. https://doi-org.eur.idm.oclc.org/10.1159/000509221 Alexandraki, K. I., Kaltsas, G. A., Isidori, A. M., Storr, H. L., Afshar, F., Sabin, I., Akker, S. A., Chew, S. L., Drake, W. M., Monson, J. P., Besser, G. M., & Grossman, A. B. (2013). Long-term remission and recurrence rates in Cushing's disease: predictive factors in a single-centre study. European journal of endocrinology, 168 (4), 639–648. https://doi-org.eur.idm.oclc.org/10.1530/EJE-12-0921 Ramm-Pettersen, J., Halvorsen, H., Evang, J. A., Rønning, P., Hol, P. K., Bollerslev, J., Berg-Johnsen, J., & Helseth, E. (2015). Low immediate postoperative serum-cortisol nadir predicts the short-term, but not long-term, remission after pituitary surgery for Cushing's disease. BMC endocrine disorders, 15 , 62. https://doi-org.eur.idm.oclc.org/10.1186/s12902-015-0055-9 Catalino, M. P., Moore, D. T., Ironside, N., Munoz, A. R., Coley, J., Jonas, R., Kearns, K., Min, L., Vance, M. L., Jane, J. A., Jr, & Laws, E. R., Jr (2023). Postoperative Serum Cortisol and Cushing Disease Recurrence in Patients With Corticotroph Adenomas. The Journal of clinical endocrinology and metabolism, 108 (12), 3287–3294. https://doi-org.eur.idm.oclc.org/10.1210/clinem/dgad347 Miao, H., Wang, L., Gong, F., Duan, L., Wang, L., Yao, Y., Feng, M., Deng, K., Wang, R., Xiao, Y., Ling, Q., Zhu, H., & Lu, L. (2024). A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours. Clinical endocrinology, 101 (1), 32–41. https://doi-org.eur.idm.oclc.org/10.1111/cen.15065 He, X., Findling, J. W., & Auchus, R. J. (2022). Glucocorticoid Withdrawal Syndrome following treatment of endogenous Cushing Syndrome. Pituitary, 25 (3), 393–403. https://doi-org.eur.idm.oclc .org/10.1007/s11102-022-01218-y Additional Declarations No competing interests reported. Supplementary Files S.Table1.docx Cite Share Download PDF Status: Published Journal Publication published 18 Jun, 2025 Read the published version in Endocrine → Version 1 posted Reviews received at journal 20 Apr, 2025 Reviewers agreed at journal 10 Apr, 2025 Reviewers invited by journal 30 Mar, 2025 Editor assigned by journal 23 Mar, 2025 Submission checks completed at journal 23 Mar, 2025 First submitted to journal 21 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Recent estimates place the annual global incidence of CD at 2.4/million, though this figure may be rising [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A comprehensive nationwide study from Iceland suggests an even higher rate of 5.2/million/year [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This potential increase could reflect growing recognition of the disease, spurred by the need to address a condition that carries significant morbidity and elevated mortality risks [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile recent years have seen remarkable progress in medical approaches to managing endogenous hypercortisolism [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], pituitary surgery remains the primary intervention for CD, offering the prospect of enduring recovery without life-long medical therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The transsphenoidal surgical (TSS) technique, introduced by Wilson and Hardy nearly five decades ago [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], has become the gold standard approach. Recently, endoscopic visualization has largely superseded the original microscopic method, though this shift hasn't consistently improved surgical outcomes or remission rates [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEarly remission rates from CD with TSS vary widely, from below 60\u0026ndash;95%, with generally quoted figures of 80% for primary surgeries and 58% for repeat procedures [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recurrence rates after initial remission range from 10\u0026ndash;50%, with most studies reporting around 20%. These recurrences have been observed up to 5 years post-surgery, and in some cases as late as 10 years [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis variability in outcomes stems from factors including series size, study design, surgical expertise, and follow-up duration [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Given these variations, region- and institution-specific data are crucial for informed patient decision-making. To date, only one retrospective series from Israel, published over 20 years ago, has reported outcomes of 82 CD patients undergoing 90 TSS procedures (including 13 repeat surgeries) between 1990 and 2000 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study aims to provide an updated assessment of remission and recurrence rates in CD patients undergoing TSS at a major Israeli referral center with a dedicated pituitary surgery unit. We hypothesized higher remission rates in subjects with microadenomas and sought to identify potential predictive factors for both remission and recurrence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Inclusion Criteria\u003c/h2\u003e \u003cp\u003eWe conducted a single-center, retrospective analysis of adult patients (18 y or older) with Cushing's disease (CD) who underwent transsphenoidal surgery (TSS) at the Neurosurgery Department of Tel Aviv Sourasky Medical Center between January 1, 2002, and December 31, 2002. Initial patient identification utilized computerized medical records, searching for ICD-9 diagnoses 255.0 (Cushing's syndrome), 227.3 and 253.1 (pituitary tumors and excessive pituitary secretion), cross-referenced with procedure code 07.62 (TSS). Subsequent individual chart review was performed to retain only patients with a confirmed diagnosis of CD who had undergone surgery at our center during the study period, and whose pituitary tumors could be classified as micro or macroadenomas (based on imaging and/or surgical report). Patients on whom such information was not available were excluded. Subjects undergoing reoperation were included.\u003c/p\u003e \u003cp\u003e The institutional ethics committee approved the study in accordance with the Declaration of Helsinki and waived the requirement for informed consent due to the retrospective design (IRB approval #TLV-0576-22).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003e We comprehensively reviewed charts of included subjects (selection process flow chart detailed in the Results section) to extract pre-surgical demographic, clinical, biochemical, and imaging data (including tumor size, suprasellar extension and invasiveness). We also collected information on the TSS procedure (microscopic or endoscopic), perioperative complications, and immediate or early post-operative remission status. Endocrine follow-up data, including remission duration, recovery of the hypothalamic-pituitary-adrenal axis (HPA) and recurrence, were similarly extracted. Notably, the data extraction process was challenging due to incomplete computerization of hospitalization records before 2008 and outpatient endocrine clinic records before 2014, necessitating review of numerous handwritten documents.\u003c/p\u003e\n\u003ch3\u003eCriteria for adenoma classification, remission, recovery of the HPA axis, and recurrence\u003c/h3\u003e\n\u003cp\u003eTumors were classified as microadenomas if their largest diameter on pituitary MRI was less than 10 mm, while macroadenomas measured 10 mm or greater. In a few cases where size was not explicitly mentioned, the records' specification of micro- or macroadenoma was used for classification.\u003c/p\u003e \u003cp\u003eAs patients did not receive routine peri-operative glucocorticoid coverage, immediate remission was determined based on a post-surgical morning serum cortisol nadir below 55 nmol/L or 138 nmol/L (typically observed on the third post-operative day), confirmed by suppressed cortisol and glucocorticoid-dependence at the first follow-up endocrine clinic visit, usually within 4 weeks of surgery. Additionally, a clinical course suggestive of overt acute hypoadrenalism, accompanied by low blood pressure and hyponatremia prompting immediate in-hospital hydrocortisone initiation and later confirmed by post-discharge suppressed cortisol, was also considered evidence of remission. In some cases, delayed remission was documented at the first outpatient follow-up visit, and in one instance, almost 3 months post-surgery due to admission for acute hypoadrenalism.\u003c/p\u003e \u003cp\u003eContinued remission was assessed through persistently suppressed serum cortisol concentrations and glucocorticoid-dependence, pending recovery of the HPA axis. HPA axis function was deemed recovered when a normal morning serum cortisol level was complemented by an ACTH-stimulated serum cortisol exceeding 497 nmol/L. After discontinuation of glucocorticoid replacement and full recovery of the HPA axis, continued remission was periodically evaluated by 24-hour urinary free cortisol measurement within the normal range (which varied according to the assaying laboratory), an overnight 1 mg dexamethasone suppression test with serum cortisol below 55 nmol/L, and a midnight salivary cortisol measurement below 5.2 nmol/L (salivary cortisol measurements were exclusively performed in our department core lab), often using a combination of these tests.\u003c/p\u003e \u003cp\u003eRecurrence was typically suspected upon return of clinical complaints and confirmed by a combination of a pathological overnight 1 mg dexamethasone suppression test and elevated 24-hour urinary free cortisol secretion.\u003c/p\u003e\n\u003ch3\u003eSample size computation and statistics\u003c/h3\u003e\n\u003cp\u003eWe hypothesized a higher remission rate among subjects with microadenomas. Based on an expected 75% prevalence of microadenomas and using conservative remission rates of 83% for microadenomas versus 68% for macroadenomas [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], we calculated that a cohort of 123 patients would provide 80% power to detect this difference (α\u0026thinsp;=\u0026thinsp;0.05). This sample size was consistent with our clinic's annual referral rate at the time of study design.\u003c/p\u003e \u003cp\u003eWe present continuous variables as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median [IQR] based on their distribution, and categorical variables as frequencies and percentages.\u003c/p\u003e \u003cp\u003eFor remission analysis, we first conducted univariate analyses to identify potential predictors, comparing various independent variables between remission and non-remission groups. We used Student's t-test or Mann-Whitney test for continuous variables and chi-square or Fisher's exact test for categorical variables, as appropriate.\u003c/p\u003e \u003cp\u003eWe then performed multivariate logistic regression to identify independent predictors of remission.\u003c/p\u003e \u003cp\u003eFor recurrence analysis, we employed Kaplan-Meier survival analysis with log-rank tests for categorical variables and Cox regression for continuous variables to account for varying follow-up durations.\u003c/p\u003e \u003cp\u003eWe conducted all statistical analyses using IBM SPSS Statistical Software Version 29.0 (IBM Corp., Armonk, NY), setting statistical significance at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Graphs were created using GraphPad Prism 10.2.3 (GraphPad Software, San Diego, CA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection, Cohort Composition, and Baseline Characteristics\u003c/h2\u003e \u003cp\u003eInitial screening using diagnosis codes identified 301 patients. After applying inclusion criteria and reviewing charts, we included 97 patients with clear tumor type classification (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). To assess temporal trends, we divided the study period into three 7-year intervals, revealing a steady increase in patient numbers: 16 in 2002\u0026ndash;2008, 38 in 2009\u0026ndash;2015, and 43 in 2016\u0026ndash;2022. As expected, the cohort was predominantly female (77/97, 79.4%), with a median age of 42 years [IQR: 33.5\u0026ndash;57]. Notably, macroadenomas constituted a substantial portion of the cohort (34/97, 35%), higher than what we had anticipated.\u003c/p\u003e \u003cp\u003eEach subject underwent a single operation at our center during the study period. However, for 13 subjects (13.4%), this represented a repeat TSS due to either a failed previous procedure elsewhere or disease recurrence.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the clinical, biochemical, and imaging characteristics of the entire cohort, stratified by adenoma classification. As expected, tumor size differed between groups, with macroadenomas showing significantly higher rates of cavernous sinus invasion compared to microadenomas (23.5% vs 3.2%, P\u0026thinsp;=\u0026thinsp;0.002). No other characteristics differed significantly between the groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, clinical, and laboratory data of CD patients at the time of presentation. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD if normally distributed, or median [IQR], and frequencies including the denominator (N), as appropriate. The micro and macroadenomas were compared by the student\u0026rsquo;s T-test, the Mann-Whitney test, or by the Chi-square test for proportions, as appropriate. Significance was assumed for P\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;97)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMicro\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;63)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacro\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77/97 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50/63 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27/34 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 [33.5\u0026ndash;57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 [32\u0026ndash;55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47 [36-57.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight gain; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75/90 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47/57 (63.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28/33 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51/88 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28/55 (50.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23/33 (69.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62/96 (64.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40/62 (64.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22/32 (64.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35/96 (36.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22/62 (35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13/34 (38.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidemia; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44/96 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24/62 (38.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20/34 (58.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. catabolic signs; mode (range) \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003csup\u003eo\u003c/sup\u003e.fat redistribution signs; mode (range) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003csup\u003eo\u003c/sup\u003e. neuropsychiatric comorbidities; mode (range) \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003csup\u003eo\u003c/sup\u003e. hyperandrogenic signs; mode (range) \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (0\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10/91 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/63 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8/22 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8:00 am cortisol (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e712 [555\u0026ndash;890]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e710 [553.8\u0026ndash;903]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e742 [555\u0026ndash;829]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACTH (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 [42.5\u0026ndash;94.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63[39.6\u0026ndash;88.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.3 [51.4-104.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean UFC\u003csup\u003ee\u003c/sup\u003e (micg/24h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245.5 [156-375.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e260 [160-375.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175.8 [115.3\u0026ndash;393]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelative UFC/upper limit\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.7 [1.8\u0026ndash;4.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.95 [1.9\u0026ndash;4.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.25 [1.5\u0026ndash;4.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eONDST cortisol (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360 [165.5-567.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e351 [230\u0026ndash;587]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e363 [85\u0026ndash;492]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalivary cortisol (micg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.49 [0.29\u0026ndash;1.09]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.57 [0.33\u0026ndash;1.18]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.28 [0.13\u0026ndash;0.65]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eIncluded: osteoporosis, fractures, nephrolithiasis, muscle weakness, striae and easy bruising; \u003csup\u003eb\u003c/sup\u003eincluded: dorsocervical fat pad, moon face, supraclavicular fullness; \u003csup\u003ec\u003c/sup\u003eincluded: Anxiety, depression, psychosis, insomnia; \u003csup\u003ed\u003c/sup\u003ein women only, included: hirsutism, alopecia, acne, menstrual disturbances; \u003csup\u003ee\u003c/sup\u003eONDST-Overnight dexamethasone suppression test; \u003csup\u003ef\u003c/sup\u003eUFC-Urinary free cortisol\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRemission Rates: Microadenomas vs. Macroadenomas\u003c/h3\u003e\n\u003cp\u003eWe initially sought to test our hypothesis that subjects with microadenomas would achieve remission more frequently than those with macroadenomas. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e provides a comprehensive overview of the immediate post-operative indicators used to evaluate remission and the ultimate remission status of each patient.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePathology findings, post-operative indicators of remission, and remission rates in subjects with micro- and macroadenomas. Comparisons were done with the chi-square or the Fisher exact test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;97)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMicro\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;63)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacro\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma on pathology; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78/94 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45/60 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33/34 (97.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNadir cortisol\u0026thinsp;\u0026lt;\u0026thinsp;2.0 n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23/93 (24.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21/61 (34.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2/32 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNadir cortisol\u0026thinsp;\u0026lt;\u0026thinsp;5.0 n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37/93 (39.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27/61 (44.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10/32 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDischarge with GC; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60/96 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28/55 (50.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22/33 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCSW syndrome\u003csup\u003ea\u003c/sup\u003e; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34/96 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29/63 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5/33 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62/97 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37/63 (58.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25/34 (73.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eGCSW: Glucocorticoid withdrawal syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eContrary to our assumption, subjects with microadenomas did not achieve a higher rate of remission. Overall, 62 subjects (63.9%) reached remission following surgery. As previously shown, while microadenomas were significantly less invasive than macroadenomas, the remission rates between the two groups were essentially the same. A potential explanation lies in the pathology results: adenoma tissue was found in only 75% of the microadenoma cases, compared to virtually all macroadenomas (P\u0026thinsp;=\u0026thinsp;0.006). Among the 60 subjects with microadenomas for whom pathological reports were available, 15 cases yielded material that was not adenoma but instead consisted of either normal pituitary tissue or unrelated material. By contrast, in the macroadenoma group, with a single exception, all surgical specimens were confirmed as pituitary adenoma tissue.\u003c/p\u003e \u003cp\u003eTo further explore the relationship between adenoma size and surgical outcomes, we refined our classification. Rather than the binary distinction between microadenomas and macroadenomas, we stratified tumors into four categories based on size: small microadenomas (\u0026lt;\u0026thinsp;6 mm), large microadenomas (6\u0026ndash;9 mm), small macroadenomas (10\u0026ndash;19 mm), and large macroadenomas (\u0026ge;\u0026thinsp;20 mm). Notably, among the 49 microadenomas whose size was documented in the charts, 28 (57.1%) were small microadenomas, while 21 (42.9%) were 6 mm or larger. However, even with this more nuanced approach, we found no statistically significant differences in remission rates across these groups.\u003c/p\u003e\n\u003ch3\u003eFactors Associated with Remission\u003c/h3\u003e\n\u003cp\u003eNot having found the expected difference in remission rates between micro- and macroadenomas, we conducted a more comprehensive analysis to identify factors associated with remission.\u003c/p\u003e \u003cp\u003eWe first performed univariate analyses, focusing on variables frequently cited in the literature as influencing remission in Cushing's disease. These included: demographics, treatment period (2002\u0026ndash;2008, 2009\u0026ndash;2015, 2016\u0026ndash;2022), surgical approach (endoscopic vs. microscopic TSS), previous TSS, indices of activity severity at presentation, tumor characteristics (size and invasiveness), and histopathology findings.\u003c/p\u003e \u003cp\u003eAn overview of this univariate analysis is presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Our results revealed that most factors appeared to have no statistically significant impact on remission. In keeping with the previous comparison, neither adenoma size nor tumor invasiveness was associated with remission. Importantly, various biochemical markers of disease severity also showed no significant association with surgical outcomes. Contrary to our expectation, patients operated on in later years were not significantly more likely to achieve remission, suggesting no observable learning curve effect over time. Similarly, the general adoption of endoscopic transsphenoidal surgery (TSS) in 2009 did not emerge as a turning point for surgical success, a finding which, broadly speaking, aligns with the available literature.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, clinical, laboratory and surgery data of CD patients. Data are given for the entire cohort and stratified by remission status.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;97)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRemission\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo Remission\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77/97 (79.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48/62 (77.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29/35 (82.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 [33.5\u0026ndash;57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 [32.75-52]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 [35\u0026ndash;60]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriod of presentation; n (1/2/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16/38/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11/23/28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/15/15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma size (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma invasive; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10/91 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/58 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/35 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8:00 am cortisol (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e712 [555\u0026ndash;890]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e738 [537\u0026ndash;913]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e708 [579\u0026ndash;820]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACTH (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 [42.5\u0026ndash;94.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.6 [47-96.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62.8 [39.7\u0026ndash;91.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean UFC (micg/24h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245.5 [156-375.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e246.7 [158.5-370.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e234.5 [146-420.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelative UFC/upper limit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.7 [1.8\u0026ndash;4.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7 [1.9\u0026ndash;4.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.7 [1.5\u0026ndash;4.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eONDST cortisol (nmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360 [165.5-567.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e370 [235\u0026ndash;582]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e326 [98\u0026ndash;561]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalivary cortisol (mcg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.49 [0.29\u0026ndash;1.09]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.48 [0.29\u0026ndash;1.13]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5 [0.29\u0026ndash;1.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndoscopic TSS; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76/97 (78.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47/62 (75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29/35 (82.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRepeat TSS; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13/97 (13.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/62 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9/35 (25.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma on pathology; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78/94 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58/60 (96.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20/34 (58.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenoma ACTH positive; n/N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73/78 (93.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55/58 (94.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18/21 (85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFinal multivariate logistic regression model to explain remission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePredictor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eS.E.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWald\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003edf\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSig.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eExp(B)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI for Exp(B)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at presentation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.963\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.927, 1.000)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRepeat TSS (Yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e9.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(2.305, 38.493)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePituitary adenoma present\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-3.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.754\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.820\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.007, 0.141)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.172\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.518\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePredicting remission\u003c/h2\u003e \u003cp\u003eWe subsequently conducted multivariate logistic regression analyses to identify independent predictors of remission. Our initial model included variables based on the univariate analysis results and potential clinical relevance: presence of adenoma in pathology, repeat surgery status, patient age, gender, period of presentation, and surgery type (endoscopic vs. microscopic).\u003c/p\u003e \u003cp\u003eUsing backward elimination based on likelihood ratio, we identified three significant independent predictors of remission.\u003c/p\u003e \u003cp\u003eThe presence of adenoma at pathology was the strongest predictor of remission (OR\u0026thinsp;=\u0026thinsp;31.25, 95% CI: 7.09-142.86, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), although the wide confidence interval suggests considerable uncertainty in the effect's magnitude. Conversely, repeat surgeries significantly reduced the likelihood of remission (OR\u0026thinsp;=\u0026thinsp;9.42, 95% CI: 2.31\u0026ndash;38.49, p\u0026thinsp;=\u0026thinsp;0.002). Age at presentation also played a role, with younger patients having slightly better odds of remission; each additional year of age was associated with a 3.7% decrease in remission odds (OR\u0026thinsp;=\u0026thinsp;0.963, 95% CI: 0.927-1.000, p\u0026thinsp;=\u0026thinsp;0.050).\u003c/p\u003e \u003cp\u003eOther factors, including gender, treatment period, and surgery type, did not significantly influence remission outcomes in our cohort. To validate these findings, we constructed several alternative models, consistently including the three main predictors while varying other variables. Across all models, the same three factors remained significant, with stable Nagelkerke R\u0026sup2; values (0.455\u0026ndash;0.458), reinforcing the robustness of the results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDisease Recurrence\u003c/h2\u003e \u003cp\u003eTo investigate the long-term outcomes of surgical intervention, we conducted a follow-up analysis on the cohort of 62 patients who initially achieved remission following transsphenoidal surgery (TSS). The follow-up period extended from 6 to 225 months post-initial remission, with a median duration of 63 [IQR 35-109.5] months. During this observational period, 14 patients (22.6%) experienced disease recurrence after a mean remission duration of 47\u0026thinsp;\u0026plusmn;\u0026thinsp;33.4 months (range 6-112).\u003c/p\u003e \u003cp\u003eTo optimize the statistical power of our analysis, we implemented a 120-month censoring point, as the limited number of patients with extended follow-up (n\u0026thinsp;=\u0026thinsp;12) yielded no additional cases of relapse beyond this timeframe. Our investigation started with a Kaplan-Meier survival analysis comparing microadenomas and macroadenomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This analysis revealed no statistically significant difference between these groups (P\u0026thinsp;=\u0026thinsp;0.24). We subsequently expanded our inquiry to include various categorical variables. Gender emerged as a potentially influential factor (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e); notably, none of the 14 men who achieved remission experienced recurrence, in contrast to 29.2% of women (P\u0026thinsp;=\u0026thinsp;0.084). Other variables, including tumor invasiveness (P\u0026thinsp;=\u0026thinsp;0.285) and surgical approach (microscopic vs. endoscopic, P\u0026thinsp;=\u0026thinsp;0.689), demonstrated no significant association with recurrence development. Similarly, metabolic comorbidities such as obesity, diabetes, hypertension, and hyperlipidemia showed no predictive value for disease recurrence.\u003c/p\u003e \u003cp\u003eIntriguingly, the of glucocorticoid withdrawal syndrome (GCSW) emerged as a statistically significant significant protective factor against disease recurrence (P\u0026thinsp;=\u0026thinsp;0.045, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Additionally, a suppressed cortisol nadir suggested a trend towards long-term protection, although not achieving statistical significance (P\u0026thinsp;=\u0026thinsp;0.105 for nadir\u0026thinsp;\u0026lt;\u0026thinsp;55 nmol/L, and P\u0026thinsp;=\u0026thinsp;0.108 for nadir\u0026thinsp;\u0026lt;\u0026thinsp;138 nmol/L). Of note, the occurrence of GCSW demonstrated a moderate correlation with a cortisol nadir below 55 nmol/L, Spearman's rho\u0026thinsp;=\u0026thinsp;0.372, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003cp\u003eTo evaluate the potential influence of continuous variables on recurrence risk, we employed Cox proportional hazards regression analysis. This method assessed factors including age, time to hypothalamic-pituitary-adrenal (HPA) axis recovery, and adenoma size as measured by pituitary MRI. However, none of these variables reached statistical significance, yielding P-values of 0.641, 0.331, and 0.210, respectively.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective study of 97 Cushing's disease patients undergoing TSS at Tel Aviv Sourasky Medical Center from 2002 to 2022, we found that surgery achieved remission in 63.9% of cases, with a 22.6% relapse rate over a mean follow-up of 63 [IQR 35-109.5] months. Significant predictors of remission were adenoma presence in pathology specimens (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and first-time surgery status (p\u0026thinsp;=\u0026thinsp;0.012). Younger age also tended to correlate with higher remission rates. Post-remission recurrence was less common in patients who experienced glucocorticoid withdrawal syndrome, while women seemed to be prone to relapse more than men.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRemission\u003c/h2\u003e \u003cp\u003eOur remission rate (63.9%) aligns with contemporary series [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], though lower than some reported rates [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This discrepancy likely reflects the inclusion of reoperated patients, known to have lower remission rates than first-time surgery subjects [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Contrary to our hypothesis, we found no significant difference between microadenomas (58.7%) and macroadenomas (73.5%). Tumor size, whether considered as a continuous variable or categorized, did not affect remission rates. This surprising finding warrants an explanation.\u003c/p\u003e \u003cp\u003eMacroadenomas are easier to target, while microadenomas can elude detection. The introduction of endoscopic TSS at our hospital in 2009, expected to improve outcomes, did not change remission rates, mirroring reports from the literature [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our series, adenoma tissue was retrieved from virtually all macroadenomas but only 75% of microadenomas. Given the established link between adenoma identification in pathology and remission [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], this discrepancy could negate the theoretical advantage of smaller tumors.\u003c/p\u003e \u003cp\u003eOf the 49 microadenomas with size documented, 57.1% were smaller than 6 mm. While other imaging and testing modalities were used to exclude ectopic ACTH sources with high reliability, as proposed by others as an alternative to IPSS [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], lack of inferior petrosal sinus sampling (IPSS) at out center until recently might have led to misclassification of some ectopic ACTH cases as microadenomas. However, given the rarity of ectopic ACTH secretion without fulminant CS [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], this likely affected very few cases.\u003c/p\u003e \u003cp\u003eSurprisingly, tumor invasiveness, suspected by MRI, did not predict poorer remission outcomes. This may be due to overestimation of cavernous sinus invasion by MRI, as previously documented [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Notably, no standard invasiveness classification like the Knosp system was consistently applied during the study period.\u003c/p\u003e \u003cp\u003eWhile some studies have linked ACTH staining in histological specimens with remission [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], we did not find this association. This might be due to a small number of presumably ACTH-negative adenomas in our cohort (4/78, 5%), which could have been immunohistochemistry procedure failures rather than truly ACTH-negative tumors.\u003c/p\u003e \u003cp\u003eOur study suggested a possible role of age in predicting remission, with younger patients showing better outcomes in both univariate and multivariate analyses. While age has not been a major focus in most remission studies, this finding has been observed in some [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] but was not supported by a large retrospective study [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. It may be a chance finding in our smaller cohort.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eRelapse\u003c/h2\u003e \u003cp\u003eThe relapse rate of 22.6% in our study falls within the literature's reported range of 5\u0026ndash;27% after initial remission [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. All relapses occurred within 10 years (range 6-112 months). Although survival analysis was censored at 120 months, 12 patients were followed for up to 225 months. Since some reports have shown relapse occurring more than 10 years post-surgery, long-term follow-up remains essential [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe literature is replete with studies have proposed factors to predict relapse. Many variables and mathematical models, including machine learning-derived algorithms, have been suggested to predict this outcome. Among the proposed variables early post-operative hypocortisolism (particularly nadir cortisol\u0026thinsp;\u0026lt;\u0026thinsp;55 nmol/L) and prolonged suppression of the HPA axis have been emphasized [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additionally, elevated preoperative ACTH levels, larger adenoma size, exaggerated desmopressin response, and USP8 mutations have also been proposed as predictors of relapse [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, there is no consensus on these predictors.\u003c/p\u003e \u003cp\u003eIn our analysis, glucocorticoid withdrawal syndrome (GCSW) emerged as a significant predictor of long-term remission. Though GCSW has been alluded to as a marker of prolonged remission [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], no study has directly examined it as a predictor. The lack of an obvious mechanism behind this association makes further investigation necessary. In our cohort, GCSW predicted long-term remission better than any of the post-operative cortisol nadir thresholds.\u003c/p\u003e \u003cp\u003eOur data showed an interesting trend of gender differences in relapse rates, though it was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.084). None of the 14 men who achieved remission relapsed, compared to 30% of women. This finding, inconsistent in the literature, could also be a chance observation given the small number of men in our study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThe main limitation is our sample size [97], which is smaller than our initial estimate of 120\u0026ndash;140 subjects. This was due to the study period encompassing pre-electronic record-keeping years, surgeries done elsewhere, or patients not meeting inclusion criteria. Despite this, the cohort remains substantial for a single-center study of this rare condition. The retrospective design may have introduced selection bias and missing data points. The single-center design may also limit the generalizability of our findings to other settings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStrengths\u003c/h2\u003e \u003cp\u003eThis study presents a relatively large cohort of Cushing's disease patients from a single center, with most surgeries performed by a single neurosurgeon, reducing variability in technique. It identified GCSW as a predictor of long-term remission, adding new insights to the field. Importantly, it represents the largest and most comprehensive analysis of TSS outcomes for Cushing\u0026rsquo;s disease in Israel to date, expanding on previous work [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis 20-year retrospective study provides the most up-to-date analysis of TSS outcomes for Cushing's disease in Israel. It offers insights into remission and relapse patterns and possible predictors. The potential role of glucocorticoid withdrawal syndrome in predicting long-term remission warrants further investigation, highlighting the importance of evaluating outcomes in the context of patient-specific and local healthcare factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthical Approval\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Tel Aviv Sourasky Medical Center (Approval Number: TLV-0576-22). The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e[KT, YG]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData collection\u003c/strong\u003e \u003cp\u003e[DBN, KT, MS, YS, ZR, RG, IY]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData analysis\u003c/strong\u003e \u003cp\u003e[KT, YG, DBN]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInterpretation of results\u003c/strong\u003e \u003cp\u003e[KT, YG, DBN]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eManuscript drafting\u003c/strong\u003e \u003cp\u003e[KT]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eManuscript revision and critical review\u003c/strong\u003e \u003cp\u003e[KT, YG, DBN, MS, YS, ZR, RG, IY ]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSupervision\u003c/strong\u003e \u003cp\u003e[KT, TG]\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFinal approval of the manuscript\u003c/strong\u003e \u003cp\u003eAll authors\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: [KT, YG]Study design: [KT, YG]Data collection: [DBN, KT, MS, YS, ZR, RG, IY]Data analysis: [KT, YG, DBN]Interpretation of results: [KT, YG, DBN]Manuscript drafting: [KT]Manuscript revision and critical review: [KT, YG, DBN, MS, YS, ZR, RG, IY ]S\u003cp\u003e\u003cstrong\u003eStatements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Tel Aviv Sourasky Medical Center (Approval Number: TLV-0576-22). The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConceptualization:\u003c/strong\u003e [KT, YG]\u003cbr\u003e\u003cstrong\u003eStudy design:\u003c/strong\u003e [KT, YG]\u003cbr\u003e\u003cstrong\u003eData collection:\u003c/strong\u003e [DBN, KT, MS, YS, ZR, RG, IY]\u003cbr\u003e\u003cstrong\u003eData analysis:\u003c/strong\u003e [KT, YG, DBN]\u003cbr\u003e\u003cstrong\u003eInterpretation of results:\u003c/strong\u003e [KT, YG, DBN]\u003cbr\u003e\u003cstrong\u003eManuscript drafting:\u003c/strong\u003e [KT]\u003cbr\u003e\u003cstrong\u003eManuscript revision and critical review:\u003c/strong\u003e [KT, YG, DBN, MS, YS, ZR, RG, IY ]\u003cbr\u003e\u003cstrong\u003eSupervision:\u003c/strong\u003e [KT, TG]\u003cbr\u003e\u003cstrong\u003eFinal approval of the manuscript:\u003c/strong\u003e All authors\u003c/p\u003eupervision: [KT, TG]Final approval of the manuscript: All authors\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSharma ST, Nieman LK, Feelders RA. 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Pituitary, \u003cem\u003e25\u003c/em\u003e(3), 393\u0026ndash;403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi-org.eur.idm.oclc\u003c/span\u003e\u003cspan address=\"https://doi-org.eur.idm.oclc\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.org/10.1007/s11102-022-01218-y\u003c/span\u003e\u003cspan address=\".10.1007/s11102-022-01218-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cushing’s disease, Transphenoidal Surgery-TSS, microadenomas, macroadenomas, remission, recurrence, glucocorticoid withdrawal syndrome","lastPublishedDoi":"10.21203/rs.3.rs-6277838/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6277838/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eCushing's disease (CD) is a rare condition with variable surgical outcomes. This study aimed to assess remission and recurrence rates in CD patients undergoing transsphenoidal surgery (TSS) at a major Israeli referral center, and to identify predictive factors for these outcomes. We hypothesized that microadenomas would have higher remission rates than macroadenomas.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective analysis included 97 CD patients who underwent TSS at Tel Aviv Sourasky Medical Center (2002\u0026ndash;2022). Remission was defined by biochemical criteria and clinical improvement. Suspected recurrence was confirmed by pathological dexamethasone suppression and/or elevated urinary free cortisol. Univariate and multivariate analyses identified predictors of remission, while Kaplan-Meier survival analysis and Cox proportional hazard modeling determined factors associated with recurrence.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe overall remission rate was 63.9%, with no significant difference between microadenomas (58.7%) and macroadenomas (73.5%). Multivariate logistic regression showed predictors of remission were adenoma presence in pathology specimens (OR\u0026thinsp;=\u0026thinsp;31.25, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and first-time surgery status (OR\u0026thinsp;=\u0026thinsp;9.42, P\u0026thinsp;=\u0026thinsp;0.002), while younger age was a contributory factor (OR\u0026thinsp;=\u0026thinsp;0.963, P\u0026thinsp;=\u0026thinsp;0.05). The relapse rate was 22.6% over a median follow-up of 63 [IQR 35-109.5] months. Glucocorticoid withdrawal syndrome emerged as a novel protective factor against recurrence (P\u0026thinsp;=\u0026thinsp;0.045).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis largest analysis of TSS outcomes for CD in Israel challenges established notions about remission predictors, including our initial hypothesis about microadenomas. The identification of glucocorticoid withdrawal syndrome as a predictor of long-term remission provides a potential avenue for post-operative monitoring in the local healthcare context.\u003c/p\u003e","manuscriptTitle":"Prediction of remission and recurrence of Cushing’s disease following transsphenoidal surgery (TSS): A single center, 20-year, retrospective series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 10:35:08","doi":"10.21203/rs.3.rs-6277838/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-04-20T12:09:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"127424812138636634417530885424706215973","date":"2025-04-10T14:22:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-31T00:44:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-24T03:20:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-24T03:19:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2025-03-21T12:55:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"47961694-161a-49c3-b10a-a60c2a6a52db","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-23T16:00:02+00:00","versionOfRecord":{"articleIdentity":"rs-6277838","link":"https://doi.org/10.1007/s12020-025-04304-w","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2025-06-18 15:57:01","publishedOnDateReadable":"June 18th, 2025"},"versionCreatedAt":"2025-04-21 10:35:08","video":"","vorDoi":"10.1007/s12020-025-04304-w","vorDoiUrl":"https://doi.org/10.1007/s12020-025-04304-w","workflowStages":[]},"version":"v1","identity":"rs-6277838","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6277838","identity":"rs-6277838","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}