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  1. Ahmed Saeed Mubarak Mohamed1, Ahmed Iqbal2, Suveera Prasad3, Nigel Hoggard4, Daniel Blackburn1 Correspondence to Dr Daniel Blackburn, Sheffield Teaching Hospitals NHS Foundation Trust Department of Clinical Neurology, Sheffield S10 2JF, UK; d.blackburn@sheffield.ac.uk Abstract Cushing’s disease is a rare endocrine condition in which a pituitary corticotroph adenoma drives excess adrenal cortisol production, and is one cause of endogenous Cushing’s syndrome. We present a young woman with 3 weeks of headaches and cognitive disturbance who subsequently developed florid psychosis requiring multiple admissions under neurology and psychiatry. Her clinical stigmata of hypercortisolism and biochemical abnormalities prompted an MR scan of the pituitary, which confirmed a pituitary microadenoma. Treatment with metyrapone and subsequent surgery led to complete recovery within 2 months. Cushing’s disease commonly causes neuropsychiatric symptoms and can present with psychosis. Diagnosing Cushing’s disease can be challenging, but with early diagnosis and treatment it has an excellent prognosis. http://dx.doi.org/10.1136/practneurol-2021-002974 Get the full text
  2. Eleni Papakokkinou, Marta Piasecka, Hanne Krage Carlsen, Dimitrios Chantzichristos, Daniel S. Olsson, Per Dahlqvist, Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye, Britt Edén Engström, Pia Burman, Cecilia Follin, David Petranek, Eva Marie Erfurth, Jeanette Wahlberg, Bertil Ekman, Anna-Karin Åkerman, Erik Schwarcz, Gudmundur Johannsson, Henrik Falhammar & Oskar Ragnarsson Abstract Purpose Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing's disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development. Data sources Systematic literature search in four databases. Study Selection Observational studies reporting the prevalence of NS after BA in adult patients with CD. Data extraction Data extraction and risk of bias assessment were performed by three independent investigators. Data synthesis Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)]. Conclusions Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS. Introduction Cushing´s disease (CD) is a rare disorder associated with excess morbidity and increased mortality [1, 2]. Previously, bilateral adrenalectomy (BA) was the mainstay treatment for CD. During the last decades, however, other treatment modalities have emerged, including pituitary surgery, radiotherapy and medical treatments. Despite this, BA is still considered when other treatment options have failed to achieve remission, or when a rapid relief of hypercortisolism is necessary [3]. BA is considered to be a safe and effective treatment for CD [4], especially after the laparoscopic approach was introduced during the 1990s [5]. There are, however, significant drawbacks with BA, mainly the unavoidable chronic adrenal insufficiency, as well as the risk for Nelson’s syndrome (NS), i.e., growth of the remaining pituitary tumor and excessive production of ACTH, that may cause optic nerve or chiasmal compression and mucocutaneous hyperpigmentation [6]. The prevalence of NS varies between studies, mainly due to a lack of consensus on the definition and diagnostic criteria for the syndrome [7, 8]. Previously published studies are also inconsistent as to whether factors such as previous radiotherapy, age at BA, gender and duration of CD, may affect the risk of developing NS. Furthermore, high ACTH concentrations after BA have been suggested as a risk factor for developing NS [9,10,11,12]. Thus, the primary aim of this systematic review and meta-analysis was to estimate the prevalence of NS after BA for CD, both the total prevalence of NS as well the prevalence of NS requiring treatment with pituitary surgery and/or radiotherapy. The secondary aim was to investigate risk factors associated with development of NS. Methods A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13]. The PICO process was applied for the definition of the research question and eligibility criteria for the literature search. The protocol of this review was registered in the PROSPERO database (CRD42020163918). Search strategy We searched PubMed, Embase, Cochrane Library and Web of Science on February 25th 2020, with no start date restriction, for relevant articles by using the following terms: “Cushing´s syndrome” or “Cushing´s disease” or “Hypercortisolism” or “Pituitary ACTH hypersecretion” or “corticotroph tumor” or “corticotroph tumors” or “corticotroph adenoma” or “corticotroph adenomas” or “corticotropinoma” or “corticotropinomas” or “corticotrophinoma” or “corticotrophinomas” or “ACTH pituitary adenoma” or “ACTH pituitary adenomas” or “adrenocorticotropin pituitary adenoma” or “adrenocorticotropin pituitary adenomas” AND “bilateral adrenalectomy” or “bilateral adrenalectomies” or “total adrenalectomy” or “total adrenalectomies”. A detailed description of the search strategy is given in the Supplementary. Also, references of the included studies and relevant review articles were checked manually for additional articles. A new search was performed on January 12th 2021, prior submission, to identify any new publications. Study selection and eligibility criteria Eligible studies were observational studies (cohort or cross-sectional studies) reporting the prevalence of NS in adult patients with CD treated with BA. Studies including only children (age < 18 years), review articles, letters, commentaries and meeting abstracts were excluded. Moreover, case reports, case-series and studies with a population of fewer than 10 cases were excluded. Also, studies written in languages other than English were not considered for inclusion. Data collection process and data extraction Titles and abstracts from all identified articles were screened for eligibility and further full-text assessment by three independent investigators (EP, MP, OR). Discrepancies were resolved through discussion and consensus. Duplicate articles and studies with overlapping populations were excluded. In the latter case, the publication with the largest population, more comprehensive information on relevant clinical variables and/or lowest risk of bias was included. Full-text assessment and data extraction were conducted independently by the same investigators as above. Data on the following predefined variables were extracted: first author, year of publication, region/hospital, study period, characteristics of the study population (number of patients, gender, follow-up, age at CD, age at BA, previous treatment with radiotherapy and/or pituitary surgery, ACTH concentrations at BA, MRI findings at CD and at BA), intervention (BA as primary or secondary treatment, remission status) and outcome (criteria for NS, number of patients with NS, age at NS, time from BA to NS, ACTH concentrations one year after BA, number of patients treated for NS, type of treatment; pituitary radiotherapy and/or pituitary surgery). One of the studies included in the meta-analysis is our nationwide Swedish study on CD [2]. Additional clinical data, not provided in the original publication, was retrieved and used in the current analysis (Table 1). Table 1 Characteristics of the included studies Full size table Risk of bias assessment The Newcastle–Ottawa Scale [14], modified to suit the current study, was used for assessment of risk of bias of all included studies. Three investigators (EP, MP, OR) assessed the studies independently, and any disagreements were resolved by discussion. Selection, comparability and outcome were assessed through predefined criteria. All studies that provided information on NS as outcome, and/or corticotroph tumor progression, were included, and the definition as well as the treatment of NS were recorded (Table 1 and Table S1). A clear definition of NS and information on treatment were considered to be two of the most important components of the quality assessment. We considered the definition of NS to be clear when it included either a new visible pituitary tumor or progression of a pituitary tumor remnant following BA, alone, or in combination with high ACTH concentrations and/or hyperpigmentation. Detailed description of the criteria for the risk of bias assessment is provided in the Supplementary file. Studies with an overall score ≥ 5 (max overall grade 😎 and a clear definition of NS, were considered to have a low risk of bias. Data synthesis and statistical analysis Primary endpoints were the prevalence of NS, as well as the prevalence of pituitary-specific treatment for NS. Descriptive data are presented as median (range or interquartile range; IQR). Meta-analysis was performed by using the meta package in R (version 4.0.3) [15]. Statistical pooling was performed according to random-effects model due to the clinical heterogeneity among the included studies [16]. For all analyses, indices of heterogeneity, I2 statistics and Cochrane’s Q test, are reported. For the primary outcomes we estimated pooled prevalence with 95% confidence intervals (95% CI). Statistical significance was defined as P < 0.05. The possibility of publication bias was assessed by visual inspection of funnel plots as well as with the Egger’s test [17]. Sensitivity analyses were performed by excluding studies with an overall risk of bias < 5, and studies where information on diagnostic criteria for NS was lacking. By choosing the overall risk of bias < 5, all studies without adequate follow-up were also excluded (Table S2). Also, another sensitivity analysis was performed by including all studies reporting the number of patients with NS who received treatment for NS (Table 1). Subgroup analyses were performed to investigate factors that may affect the prevalence of NS, namely pituitary radiotherapy prior to BA, prophylactic pituitary radiotherapy, overall radiotherapy (prior to BA or prophylactic), pituitary surgery (transcranial or transsphenoidal surgery) prior to BA, and BA as primary or secondary treatment. For these outcomes, we estimated relative risks (RRs), or pooled prevalence, with 95% CIs. Also, in a subgroup analysis, the prevalence (with 95% CI) of NS and treatment for NS were estimated in studies where MRI was used at diagnosis and during follow-up. Uni- and bivariate meta-regression was used to investigate whether the prevalence of NS was influenced by median follow-up time or age at BA. The meta-analysis was performed by using the Metareg command in R. The estimated association is reported as β coefficient. Role of funding source The funding source had no role in the design and conduction of the study; i.e., collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Results Identification and description of included studies After removal of duplicates, 1702 articles were identified (Fig. 1). Three additional articles were found after checking the reference lists of identified articles and review papers. After reviewing titles, abstracts and full-text articles, 48 articles were considered eligible for further analysis. Of these, however, 11 articles were excluded due to overlapping or identical patient cohorts. Thus, 37 studies published between 1976 and 2020, were included in the current meta-analysis (Fig. 1). All studies had a retrospective observational design. Characteristics of the included studies are presented in Table 1. Two of the included studies had an overlapping cohort where one was used for the main outcome [18] and one [19] for the subgroup analyses on the influence of radiotherapy on the development of NS. An overview of risk of bias assessment of the eligible studies is provided in Table S2. Fig. 1 Flowchart of study selection Full size image In total, 1316 patients with CD treated with BA were included. The median follow-up after BA was 7 years (23 studies, range 3.3–22). Median age at BA in patients with NS was 31 years (13 studies, IQR 26–34). Median time from BA to the diagnosis of NS was 4 years (19 studies) with the shortest reported time being 2 months [20] and the longest 39 years [2]. At diagnosis of NS, hyperpigmentation was reported in 155 of 188 (82%) patients (19 studies) and chiasmal compression in 24 of 129 (19%) patients [11 studies]. Prevalence of NS Thirty-six of 37 studies, with total 1316 patients with CD treated with BA, were included [2, 18, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Reported prevalence of NS ranged from 4 to 60%. The mean pooled prevalence was 26% (95% CI 22–31%) with a moderate to high heterogeneity (I2 67%, P < 0.01) (Fig. 2). The Egger’s test was statistically significant (P = 0.01), but visual inspection showed no obvious asymmetry. The significant Egger’s test indicates publication bias, probably explained by the fact that case reports and cohorts with fewer than 10 participants were excluded (Fig. S1). Fig. 2 Forest plot showing individual studies and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease. *Additional data Full size image In a sensitivity analysis, excluding all studies with high risk of bias (overall score < 5) and no clear definition of NS, the pooled prevalence was 31% (95% CI 24–38%; I2 76%, 17 studies, 822 patients; P < 0.01) (Fig. S2). In a subgroup analysis, the prevalence of NS in studies where MRI was used at diagnosis and during follow-up was 38% (Fig. 3; 95% CI 27–50%; I2 71%, 7 studies, 280 patients; P < 0.01). Fig. 3 Forest plot showing individual studies using magnetic resonance imaging and pooled prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with Cushing’s disease Full size image Prevalence of treated NS The pooled prevalence of treatment for NS was 21% (95% CI 18–26%; I2 52%, P < 0.01) (Table 1; 29 studies with 1074 patients). Thus, the pooled prevalence was slightly lower, compared to the pooled prevalence of NS in total, as well as the heterogeneity (Fig. S3). The funnel plot showed no asymmetry and Egger’s test was not statistically significant, indicating low possibility of publication bias (Fig. S4). In a subgroup analysis, the prevalence of treated NS in studies where MRI was used at diagnosis and during follow-up was 25% (95% CI 17–35%; I2 61%, 7 studies; P = 0.02). The indication for treatment was progression of the pituitary tumor in 23 out of 28 patients (82%, five studies), optic chiasmal compression in 11 out of 91 patients (12%, 11 studies), while four patients out of 14 (one study) had both these indications for treatment. Twenty-six studies provided information on treatment modalities (pituitary surgery and/or radiotherapy). Seventy-three out of 201 patients with NS (36%) were treated with pituitary surgery, 86 (43%) with radiotherapy and 41 (20%) received both treatments. Radiotherapy Nineteen studies provided information on radiotherapy prior to BA. However, nine studies had no events and no patients in one of the arms (radiotherapy or no radiotherapy) (Table S3). Thus, ten studies were eligible for further estimation, showing that the risk for NS in patients treated with radiotherapy prior to BA was comparable to the risk in patients not treated with radiotherapy (RR 0.9, 95% CI 0.5–1.6; 10 studies with 564 patients) (Fig. 4). Fig. 4 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with radiotherapy prior to bilateral adrenalectomy versus no radiotherapy. RR could not be calculated when there were no cases in the RTX or no RTX arms, and when no events in either arm. *Additional data. RTX, radiotherapy prior to bilateral adrenalectomy or prophylactic radiotherapy Full size image Thirteen studies provided information on prophylactic radiotherapy. However, only one study provided applicable data for calculating RR, thus subgroup analysis was not performed (Table S4). In that study [20], none of the seventeen patients who received prophylactic radiotherapy developed NS, while 11 of 22 patients without radiotherapy developed NS after a mean follow-up of 4.4 years (range 10–16 years). By using studies with information on either previous or prophylactic radiotherapy (11 studies with 603 patients; Table S5), the pooled RR was 0.8 (95% CI 0.5–1.5). Pituitary surgery prior to BA Of 21 studies with information on pituitary surgery prior to BA (Table S6), only ten provided information for estimation of RR. A pooled RR of 0.6 (10 studies with 430 patients; 95% CI 0.4–1.0) was found (Fig. 5), indicating that the risk for developing NS was not influenced by previous pituitary surgery. Fig. 5 Forest plot showing the RR (relative risk) and 95% CI for Nelson’s syndrome in patients treated with pituitary surgery prior to bilateral adrenalectomy versus no pituitary surgery. RR could not be calculated when there were no cases in the surgery or no surgery arms, and when no events in either arm. *additional data. Abbreviations: Surgery, pituitary surgery prior to bilateral adrenalectomy Full size image BA as primary or secondary treatment for CD Information on whether patients with NS were treated primarily with BA or not, was provided in ten and nine studies, respectively (Fig. S5 and S6). The pooled prevalence of NS was 26% (95% CI 20–33%) for patients treated primarily with BA and 22% (95% CI 15–31%) for patients who had been treated with pituitary surgery and/or radiotherapy prior to BA. ACTH concentrations one year after BA Four studies provided information on ACTH concentrations during the first year after BA [45, 49, 52, 53]. In a study by Assié et al. the median ACTH concentration in patients who developed NS was 301 pmol/L, compared to 79 pmol/L in patients without NS (upper range of limit; URL 13 pmol/L) [52]. The median ACTH concentration in a study by Cohen et al. was 105 pmol/L in the NS group compared to 18 pmol/L in patients without NS (P = 0.007) (URL 10 pmol/L) [49]. Also, in a study by Das et al., there was a statistically significant difference in ACTH concentrations one year after BA between patients with and without NS (110 vs 21 pmol/L respectively; P = 0.002) [53]. On the contrary, Espinosa-de-Los-Monteros et al.found no difference in ACTH concentrations between the patients with NS and those without NS [45]. Thus, three of four studies found that high ACTH concentrations one year after BA were associated with the development of NS. However, since the ACTH assays and the conditions when ACTH was collected were different in these studies (Table S7), further comparison or a meta-analysis on ACTH levels after BA was not considered feasible. Influence of age at BA and duration of follow-up on prevalence of NS In a meta-regression analysis, age at BA (β-coefficient = – 0.03, P = 0.4; Fig. 6) and median duration of follow-up (β-coefficient = 0.01, P = 0.7; Fig. S7) were not associated with prevalence of NS. After adjustment for follow-up, age at BA was still not associated with prevalence of NS (β-coefficient = -0.03, P = 0.4). Fig. 6 Bubble plot showing the influence of age at BA on the prevalence of Nelson’s syndrome. The bubble sizes are proportional to the weight of the studies in the meta-analysis. Coefficient estimate (β) and p value for the effect of age at BA are indicated by the regression line Full size image Discussion In this study we have for the first time evaluated the pooled prevalence of NS by using a meta-analysis on data from 36 studies, including more than 1300 patients with CD treated with BA. The overall prevalence of NS was 26% and the median time from BA to diagnosis of NS was 4 years, ranging from 0.2 to 39 years. The prevalence of patients requiring pituitary-specific treatment for NS was 21%. Furthermore, radiotherapy and pituitary surgery prior to BA, as well as age at BA, did not seem to affect the risk of developing NS. Various definitions have been used for NS over the past decades [12]. Historically, the diagnosis was based on clinical findings related to mucocutaneous hyperpigmentation and chiasmal compression, together with signs of an enlarged sella turcica on skull radiography [6]. Since then, the diagnosis of NS in most studies has been based on (i) radiological evidence of a pituitary tumor that becomes visible, or a progression of a preexisting tumor, (ii) “high” ACTH concentrations, and (iii) hyperpigmentation [54]. In the studies with the highest prevalence of NS [45, 46], the diagnosis was based on rising ACTH concentrations and an expanding pituitary mass, where 2 mm increment in tumor size on MRI was considered to be a significant growth. On the contrary, the criteria for NS in studies with the lowest prevalence were based on hyperpigmentation, often but not always combined with a pituitary tumor responding to radiotherapy and/or a radiographic evidence of pituitary tumor on skull radiography [21, 23]. Thus, the great variance in the prevalence of NS between studies can, at least partly, be explained by the different definitions of NS. Consequently, in an expert opinion published in 2010, it was suggested that the diagnosis of NS should be based on an elevated level of ACTH >500 ng/L (110 pmol/L) in addition to rising levels of ACTH on at least three consecutive occasions and/or an expanding pituitary mass on MRI or CT following BA [54]. Similarly, in a recently published expert consensus recommendation, based on a systematic review, it was suggested that NS should be defined as radiological progression or new detection of a pituitary tumor on a thin-section MRI [55]. Furthermore, the authors recommend active surveillance with MRI three months after BA, and every 12 months for the first 3 years, and every 2–4 years thereafter, based on clinical findings. The meta-regression of the current analysis did not show an association between median follow-up time and prevalence of NS. Nevertheless, NS occurred as early as 2 months [20], and up to 39 years after BA [2], supporting that life-long surveillance after BA is necessary for patients with CD. Active surveillance with MRI was more common in studies published during the last two decades. In fact, the use of MRI in recent studies resulted in earlier detection of a growing pituitary adenoma and, subsequently, contributed to a higher prevalence of NS. Namely, the seven studies including patients treated with BA after 1990 and using MRI reported higher prevalence of NS, both overall NS and treated NS. Whether factors such as pituitary radiotherapy affects the risk for development of NS has been evaluated in several studies. Some studies have shown that radiotherapy prior to BA, or administrated prophylactically, can prevent or delay the development of NS [20, 39]. On the contrary, other studies have not demonstrated a protective effect of radiotherapy prior to BA [18, 37] and, moreover, one study found an association with tumor progression [46]. Nevertheless, the current meta-analysis indicates that radiotherapy prior to BA does not decrease the risk of developing NS. Neither did previous pituitary surgery affect the risk for NS. Elevated ACTH concentrations during the first year after BA have been considered to be a strong predictor of NS [49, 52]. In fact, seven studies in the current analysis included cut-off levels for ACTH concentration, arbitrarily defined, for the diagnosis of NS [18, 25, 34, 36, 41, 45, 49]. Due to the different ACTH assays, and different conditions when ACTH was collected, no further analysis on ACTH levels was performed. Nevertheless, four studies [45, 49, 52, 53] reported ACTH concentrations one year after BA in both patients with and without NS. Three of these studies found that high ACTH concentrations one year after BA [49, 52, 53] were associated with pituitary tumor progression. Thus, these findings support the suggestion that ACTH should be monitored following BA in patients with CD [54, 55]. The prevalence of treatment for NS (21%), and the heterogeneity index (52%), were slightly lower than in the analysis of total prevalence of NS (26%, I2 67%). The majority of the patients was treated with radiotherapy, followed by pituitary surgery and combination of pituitary surgery and radiotherapy. Today, surgical removal of the pituitary tumor is considered to be the first-line therapy of NS whereas radiotherapy is considered if surgery has failed or is not possible [12, 54, 56]. In a large multi-center study by Fountas et al., the 10-year progression-free survival rates after surgery alone, or with radiotherapy, for patients with NS was 80% and 81%, respectively [57]. In comparison, progression-free survival rate in patients who did not receive treatment was 51%. Reports on the efficacy of medical therapy for NS have shown inconsistent results [56]. Strengths and limitations This is the largest systematic review, and the first meta-analysis, on NS published to date. However, some limitations have to be acknowledged. Most important are the different diagnostic methods used to detect NS, and the different definitions of the syndrome between the studies. The majority of the studies have used the combination of hyperpigmentation, high ACTH concentrations and radiological findings for the diagnosis of NS. Notwithstanding these common criteria, there were still differences in the cut-offs of ACTH levels, the use of different radiological modalities over time as well as the radiological definition of progress of pituitary tumors. Moreover, in some studies radiological findings were used solely or in combination with either hyperpigmentation and/or bitemporal hemianopsia, ACTH concentrations or response to treatment of NS. Furthermore, in several studies a clear definition of NS was not provided. Nevertheless, we consider our attempt to address the heterogeneity of the included studies, through systematic review, quality assessment, and sensitivity and subgroup analyses to be a strength. Conclusions The risk of NS after BA in patients with CD is considerable and may first become clinically evident many decades later. Thus, life-long close follow-up is necessary for an early detection of a growing pituitary tumor, and adequate treatment when needed. Although this meta-analysis did not find prior surgery or radiotherapy to be associated with risk of NS, the findings are based on a limited number of studies. Thus, in order to individualize the treatment for patients with CD, further studies are needed where these and other factors possibly associated with risk of NS are evaluated. Data availability The data generated or analyzed during this study are included in this published article or in the Supplementary file. Abbreviations CD: Cushing's disease BA: Bilateral adrenalectomy NS: Nelson’s syndrome ACTH: Adrenocorticotropic hormone RR: Relative risk MRI: Magnet resonance imaging CT: Computer tomography References 1. Papakokkinou E, Olsson DS, Chantzichristos D, Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K, Bensing S, Hoybye C, Eden-Engstrom B, Burman P, Bonelli L, Follin C, Petranek D, Erfurth EM, Wahlberg J, Ekman B, Akerman AK, Schwarcz E, Bryngelsson IL, Johannsson G, Ragnarsson O (2020) Excess morbidity persists in patients with cushing's disease during long-term remission: a swedish nationwide study. J Clin Endocrinol Metab 105(8):2616–2624 2. 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Author information Affiliations Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson The Department of Endocrinology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, Sweden Eleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson Department of Environmental and Occupational Health School of Public Health and Community Medicine, University of Gothenburg, 4053, Gothenburg, Sweden Hanne Krage Carlsen Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, Sweden Per Dahlqvist Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology, Karolinska University Hospital, 171 76, Stockholm, Sweden Maria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar Department of Endocrinology and Diabetes, Uppsala University Hospital, and Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, 751 85, Uppsala, Sweden Britt Edén Engström Department of Endocrinology, Skåne University Hospital, University of Lund, 205 02, Malmö, Sweden Pia Burman Department of Endocrinology, Skåne University Hospital, 222 42, Lund, Sweden Cecilia Follin, David Petranek & Eva Marie Erfurth Department of Endocrinology and Department of Medical and Health Sciences, Linköping University, 581 83, Linköping, Sweden Jeanette Wahlberg & Bertil Ekman Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 702 81, Örebro, SE, Sweden Jeanette Wahlberg, Anna-Karin Åkerman & Erik Schwarcz Corresponding author Correspondence to Oskar Ragnarsson. 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If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions About this article Cite this article Papakokkinou, E., Piasecka, M., Carlsen, H.K. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary (2021). https://doi.org/10.1007/s11102-021-01158-z Download citation Accepted18 May 2021 Published25 May 2021 DOIhttps://doi.org/10.1007/s11102-021-01158-z Share this article Anyone you share the following link with will be able to read this content: Get shareable link Provided by the Springer Nature SharedIt content-sharing initiative Keywords Bilateral adrenalectomy Cushing’s disease Corticotroph adenoma Nelson’s syndrome From https://link.springer.com/article/10.1007/s11102-021-01158-z
  3. Data from LINC3 and LINC4 provide insight into the impact of dosing titration schedules on risk of hypocortisolism-related adverse events associated with osilodrostat use in patients with Cushing's disease. Data from a pair of phase 3 studies presented at the American Academy of Clinical Endocrinology’s 30th Annual Meeting (AACE 2021) is providing insight into the effect of dose titration schedules with use of osilodrostat (Isturisa) in patients with Cushing’s disease. Presented by Maria Fleseriu, MD, of Oregon Health and Science University, the analysis of the LINC3 and LINC4 demonstrated the more gradual titration occurring in LINC4 resulted in a lower proportion of hypocortisolism-related adverse events, suggesting up-titration every 3 weeks rather than every 2 weeks could help lower event risk without compromising mean urinary free cortisol (mUFC) control. “For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response/tolerability aimed at normalizing cortisol levels,” concluded investigators. With approval from the US Food and Drug Administration in March 2020 for patients not eligible for pituitary surgery or have undergone the surgery but still have the disease, osilodrostat became the first FDA-approved therapy address cortisol overproduction by blocking 11β-hydroxylase. Based on results of LINC3, data from the trial, and the subsequent LINC4 trial, provide the greatest available insight into use of the agent in this patient population. The study presented at AACE 2021 sought to assess whether slow dose up titration might affect rates of hypocortisolism-related adverse events by comparing titration schedules from both phase 3 trials. Median osilodrostat exposure was 75 (IQR, 48-117) weeks and 70 (IQR, 49-87) weeks in LINC3 and LINC4, respectively. The median time to first mUFC equal to or less than ULN was 41 (IQR, 30-42) days in LINC3 and 35 (IQR, 34-52) days in LINC4. Adverse events potentially related to hypocortisolism were more common among patients in LINC3 (51%, n=70) than LINC4 (27%, n=20). Upon analysis of adverse events, investigators found the most commonly reported type of adverse event was adrenal insufficiency, which included events of glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased urinary free cortisol. Results incited the majority of hypocortisolism-related adverse events occurred during the dos titration periods of each trial. In LINC3, 54 of the 70 (77%) hypocortisolism-related adverse events occurred by week 26. In comparison, 58% of hypocortisolism-related adverse events occurring in LINC4 occurred prior to week 12. Investigators noted most of events that occurred were mild or moderate and managed with dose interruption or reduction of osilodrostat or concomitant medications. This study, “Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients with Cushing's Disease (CD): Results from Two Phase III Trials (LINC3 and LINC4),” was presented at AACE 2021. From https://www.endocrinologynetwork.com/view/fda-panels-votes-to-support-teplizumab-potential-for-delaying-type-1-diabetes
  4. Dr. Irmanie Hemphill, who first thought her weight gain was due to having a baby. Doctors at Cleveland Clinic Florida in Weston diagnosed her with a tumor in the pituitary gland in her brain. In the summer of 2019, Irmanie Hemphill gained a lot of weight, developed acne and had high blood pressure. She attributed it to her body adjusting from giving birth just six weeks prior. “I was thinking maybe it was just hormonal changes from having a baby,” said Hemphill, 38, of Pembroke Pines. But when Hemphill, a family medicine physician, saw that her nails were turning dark and she gained five pounds within a week, she knew it was something more serious. Blood tests ordered by her physician came back normal, with the exception of high levels of cortisol detected via a urine cortisol test, which she requested after researching her symptoms online. The next step was to find out where the excess cortisol was coming from: either her kidneys or her adrenal glands, which produce hormones in response to signals from the pituitary gland in the brain. The first MRI of her brain did not detect anything abnormal, so her endocrinologist attributed her symptoms to her body adjusting post-pregnancy. Hemphill sought a second opinion at Cleveland Clinic Weston, where more MRIs of her brain, combined with an Inferior Petrosal Sinus Sampling (IPSS) procedure, detected she had a tumor on her pituitary gland. That led her to be diagnosed with Cushing’s Disease — caused by excess cortisol. TWO TYPES OF PITUITARY TUMORS There are two types of pituitary tumors: those that produce active hormones, like the one Hemphill had, and those that do not, which grow in size over time and do not manifest symptoms right away. Hemphill’s tumor was producing adrenocorticotropic hormone (ACTH), which causes the adrenal gland to produce more cortisol. Many people with Cushing’s Disease experience high blood pressure and high blood sugar, muscle fatigue, easy bruising and brain fog. If left untreated, the condition can lead to pulmonary embolisms, diabetes, osteoporosis, strokes and heart attacks. “It was a little bit of relief but also sadness,” said Hemphill, of finding out her diagnosis. “I was very happy that I got a diagnosis but now it’s like, what’s the next step?” LESS INVASIVE WAY TO REMOVE A PITUITARY TUMOR Hospitals in South Florida are at the forefront in developing new research, techniques and technologies for pituitary tumors. The tiny bean-shaped pituitary gland is located at the base of the brain and controls many of the body’s hormonal and metabolic functions. Last June, neurosurgeon Dr. Hamid Borghei-Razavi of Cleveland Clinic Weston removed Hemphill’s pituitary tumor through her nose. This type of procedure allows surgeons to remove the tumor without damaging the brain. “It’s a less-invasive approach compared to 20 years ago, when pituitary tumors were removed through the cranium,” he said. “Now, with new technologies, more than 95% of pituitary tumors can be removed through the nose.” The procedure takes just a few hours to complete, based on the size and location of the tumor. Patients usually stay at the hospital for one to two days afterward for observation. The removal of Hemphill’s tumor, which was three to four millimeters in size, put an end to her Cushing’s Disease and her symptoms, though it took six months to a year for Hemphill to feel normal. (She was prescribed cortisol for six months until her adrenal glands could restart producing cortisol on their own.) “Sometimes it’s very hard to make a diagnosis for pituitary tumors because we don’t see them in the MRIs,” said Borghei-Razavi. “We call it MRI Negative Cushing’s Syndrome. It means we don’t see it in the MRI, but the cells are there,” he said. Borghei-Razavi and Hemphill credit the Inferior Petrosal Sinus Sampling (IPSS) test as pinpointing her tumor. Cleveland Clinic Weston is among only a handful of medical practices in South Florida that use this technique. Three Ways to Remove the Tumor Most pituitary tumors are benign. The challenge is when it comes to removing the tumor. “Pituitary tumors come in all shapes and sizes,” says Dr. Zoukaa Sargi, a head and neck surgeon at Sylvester Comprehensive Cancer Center at the University of Miami. “There are non-functional tumors that do not secrete hormones that can reach extreme sizes of up to 10 centimeters before coming to medical attention. This is the equivalent of the size of a grapefruit,” he says. “Then there are functional tumors that produce hormones that are typically discovered much sooner and can be only a few millimeters in size before coming to medical attention. A small proportion, less than 1%, are malignant,” he adds. There are three treatment options for pituitary tumors: surgical removal, medical therapy and radiation. “Medical therapy is only applicable in certain functional tumors that produce hormones,” says Dr. Ricardo Komotar, a neurosurgeon who is director of the Sylvester Comprehensive Cancer Center Brain Tumor Initiative. “Radiation is an option primarily for inoperable tumors with high surgical risk. Surgical removal is the optimal treatment in the vast majority of pituitary cases, conferring the greatest benefit with the lowest morbidity,” he says. Dr. Rupesh Kotecha, chief of radiosurgery at Miami Cancer Institute (MCI), part of Baptist Health South Florida, says there are a number of different hormones that the pituitary gland can secrete. “Prolactin is the most common form of pituitary adenoma that’s functioning and accounts for 30% to 50%,” he said. Excess prolactin can cause the production of breast milk in men and in women who are not pregnant or breastfeeding. Kotecha said the next most common are growth-hormone secreting tumors, which occur in 10% of patients. ACTH-secreting adenomas — the kind that Hemphill had — account for 5% of patients, while 1% secrete TSH, which causes the thyroid gland to be overactive. MCI’s Proton Therapy delivers high-dose radiation that treats the tumor’s area, allowing for surrounding tissues and organs to be spared from the effects of radiation. “The pituitary gland essentially sits in the middle of the brain,” says Kotecha. “It’s sitting in the middle of all of these critical structures.” From https://www.miamiherald.com/living/health-fitness/article251653033.html
  5. Decreased visual functions and severe headache may be signs of a brain tumor. The pituitary gland is a pea-sized gland located in the bone structure at the base of the brain called Sella Turcica. The pituitary gland, which has a great effect on our body, is a vital organ that regulates the secretion of many hormones such as growth hormone, prolactin hormone, and thyrotropin. Head of Department of Brain and Nerve Surgery, Yeni Yüzyıl University Gaziosmanpaşa Hospital, Assoc. Dr. Mete Karatay said, 'Tumors in the pituitary gland cause many disorders. Therefore, the symptoms should be taken into account and the tumor should be intervened before it grows. ' He gave information about the subject. Pituitary adenomas take the 3rd place after all tumors located in the head, after those originating from the brain itself and its membrane. So it is a relatively common tumor. The reasons for its occurrence are not fully understood. Rarely, they are seen together with inherited diseases. Tumors arising in the pituitary gland show symptoms either due to excessive hormone secretion or due to excessive growth and compression and spread to the surrounding tissues. Adenomas that do not secrete hormones usually grow slowly and can remain asymptomatic for years. Those who secrete hormones show early symptoms due to the effects of hormones in the body. In pituitary adenomas, headache, weakness, decreased visual clarity, vision loss, limitation of eyeball movements, double vision, drooping of the eyelid or visual field (especially loss of the outer quadrants of the eye) can be seen, and brain tumors such as pituitary adenoma should come to mind in these cases. . Other common complaints are the following complaints that develop due to the hormone secretion of the pituitary gland. In excess of prolactin; menstrual irregularities, milk secretion from breast tissue, development in breast tissue, sexual dysfunction in men, decrease in sperm quantity In excess of growth hormone; excessive elongation in adolescence; In adulthood, it causes elongation of the extremities of the body parts such as the chin, tip of the nose, hands and feet, heart problems, sweating, high blood sugar and joint problems. Cushing's - In ACTH excess; fat in abnormal areas of the body, muscle weakness, high blood pressure and blood sugar, skin oily and acne development, stretch marks, psychological problems In excess of TSH; weight loss, palpitations, bowel problems, sweating, restlessness, and irritability In the excess of FSH - LH; menstrual irregularities, sexual function problems, infertility The treatment of pituitary adenomas is done by the endocrinology and neurosurgery units. From an endocrinological standpoint, it is important to restore the body's hormonal balance. Neurosurgeons focus on relieving the pressure on nerve structures. Therefore, these patients are usually treated with a team of endocrinologists and neurosurgeons. Surgery is usually performed in the nasal cavity and is considered one of the difficult neurosurgical operations. The surgeon uses what we call a microscope and endoscope to reach and remove the tumor. Today, the method we call endoscopic surgery is used more frequently. With this method, there is no external scar and shortens the length of stay in the hospital. From https://www.raillynews.com/2021/05/gorme-kaybi-beyin-tumorunun-habercisi-olabilir/
  6. Abstract Background: Cushing’s syndrome is a condition caused by excessive glucocorticoid with insomnia as one of its neuropsychiatric manifestation. Cushing’s syndrome may be caused by excessive adrenocorticotropin hormone (ACTH-dependent), for example from ACTH producing pituitary tumors, or by overproduction of cortisol by adrenocortical tumors. In this report, we presented a case with Cushing’s syndrome manifesting as chronic insomnia with adrenal cortical adenoma and pituitary microadenoma. Case presentation: A 30-year-old woman was consulted from the Neurologic Department to the Internal Medicine Department with the chief complaint of insomnia and worsening headache for 6 months prior to the admission. She had undergone head MRI and abdominal CT scan previously and was found to have both pituitary microadenoma and left adrenal mass. From the physical examination she had clinical signs of Cushing’s syndrome like Cushingoid face and purplish striae on her stomach. Midnight cortisol serum examination was done initially and showed high level of cortisol. High dose dexamethasone suppression test or DST (8 mg overnight) was later performed to help determine the main cause of Cushing’s syndrome. The result failed to reach 50% suppression of cortisol serum, suggestive that the Cushing’s syndrome was not ACTH-dependent from the pituitary but potentially from overproduction of cortisol by the left adrenal mass. Therefore, left adrenalectomy was performed and the histopathological study supported the diagnosis of adrenal cortical adenoma. Conclusion: Chronic insomnia is a very important symptoms of Cushing’s syndrome that should not be neglected. The patient had both microadenoma pituitary and left adrenal mass thus high dose DST test (8 mg overnight) needed to be performed to differentiate the source of Cushing’s syndrome. The result showed only little suppression therefore the pituitary microadenoma was not the source of Cushing’s syndrome and more suggestive from the adrenal etiology. Keywords: Cushing’s syndrome; insomnia; adrenal cortical adenoma; pituitary microadenoma; dexamethasone suppression test Permalink/DOI: https://doi.org/10.14710/jbtr.v7i1.9247I Read the entire article here: https://ejournal2.undip.ac.id/index.php/jbtr/article/view/9247/5440
  7. Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds. Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an "unacceptable" three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting. Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom. "While mortality has improved since 2000, it is still significantly compromised compared to the background population.... The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level," she said. Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show "we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet.... This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery." She noted that although she wasn't surprised by the overall results, "the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded." Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, "Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care. "But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment," she stressed. In addition, she noted, "Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications.... We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS." Largest Study in Scale and Scope of Cushing Syndrome Mortality Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available. Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease. "In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome," Limumpornpetch noted. The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906). Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84). This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (P = .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (P < .001). The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (P = .004). The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas. Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04). Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%). Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25). Preventing Perioperative Mortality: Consider Thromboprophylaxis Fleseriu told Medscape Medical News that she believes hypercoagulability is "the least recognized complication with a big role in mortality." Because most of the perioperative mortality is due to venous thromboembolism and infections, "thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding." Recently, Fleseriu's group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively. The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population. "Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk," Fleseriu advised. A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted. Limumpornpetch commented, "We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population." Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge. ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021 Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker. From https://www.medscape.com/viewarticle/949257
  8. Zarina Brady, Aoife Garrahy, Claire Carthy, Michael W. O’Reilly, Christopher J. Thompson, Mark Sherlock, Amar Agha & Mohsen Javadpour BMC Endocrine Disorders volume 21, Article number: 36 (2021) Cite this article 160 Accesses Metricsdetails Abstract Background Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing’s disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. Methods A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012–February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. Results A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4–79) months. Conclusion Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus. Peer Review reports Introduction With an estimated annual incidence of 1.7 per million [1], Cushing’s disease is rare. Untreated, it poses serious complications including osteoporosis, hypertension, dyslipidaemia, insulin resistance, and hypercoagulability [2] and is associated with a 4.8 fold increase in mortality rate [3,4,5]. Patients who are in remission from CD have a mortality rate which decreases towards (although not reaching) that of the general population [6]. Endoscopic transsphenoidal surgery (ETSS) offers patients potential remission from Cushing’s disease, although long term surveillance is required as recurrence rates range from 5 to 22%% [7,8,9,10,11,12]. Since the first report in 1997 [13], the selective removal of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma by endoscopic transsphenoidal surgery has gained popularity as the first line treatment for Cushing’s disease. The primary goal of ETSS treatment in Cushing’s disease is to produce disease remission and to provide long-term control, while minimising complications. Remission rates are dependent on tumour size, preoperative MRI, cavernous sinus invasion, intraoperative visualisation of the tumour and pre- and postoperative ACTH and cortisol concentration [11]. Several studies also report pituitary neurosurgeon experience as a major factor for operative success [2, 14, 15]. Reported remission and recurrence rates after TSS for CD vary widely according to the criteria utilised to define remission [11], and in some studies due to limited patient numbers or short follow-up periods. Indeed, there is no clear consensus on how best to define post-operative remission; an early morning serum cortisol concentration < 138 nmol/L (5μg/dl) within 7 days of TSS is quoted in the 2015 Endocrine Society Clinical Practice Guideline as indicative of remission [16]. A more strict day 3 cut-off of 50 nmol/L (1.8 μg/dl) has been reported in paediatric studies [17], and also included in the Endocrine Society Guideline [16]; the literature suggests this cut-off is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. The main objective of this study was to assess the outcomes of endoscopic transsphenoidal surgery for Cushing’s disease in a tertiary pituitary centre; remission using two widely accepted criteria [16], recurrence and postoperative complications. Methods Study design This is a retrospective analysis of a prospectively-maintained database of patients operated on by a single neurosurgeon (MJ), via image-guided endoscopic transsphenoidal approach for Cushing’s disease. Patient data was gathered over 8 years (January 2012 to February 2020) and identified from the institution’s prospective database. Clinical and biochemical data during the follow-up period was reviewed. Approval was granted by the Hospital Audit Committee. Study population Patients were screened for Cushing’s syndrome by the presence of typical clinical features, together with failure to adequately suppress cortisol to < 50 nmol/L following overnight dexamethasone suppression test (ONDST) and/or elevated late night salivary cortisol (LNSF) concentration and/or elevated 24 h urinary free cortisol measurements. As per standard guidelines, Cushing’s disease was diagnosed on the basis of elevated serum ACTH measurements, along with confirmatory hormone responses to peripheral corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS). Patients with previous TSS prior to the study period were excluded. Surgical procedure A single neurosurgeon subspecialising in endoscopic pituitary and anterior skull base surgery, M.J, carried out all ETSS surgical procedures. The surgical technique has been described in detail in publications by Cappabianca et al. (1998, 1999) and Jho et al. (1997, 2000, 2001) [13, 18,19,20,21]. In summary, the procedure consists of a binostril endoscopic transsphenoidal approach. A selective adenomectomy was performed on patients with adenomas noted on pre-operative MRI. In cases of negative pre-operative MRI, exploration of the pituitary gland was performed. To confirm the diagnosis of ACTH-secreting adenoma or hyperplasia, all specimens removed underwent histopathological and immunohistochemical staining for pituitary hormones. Postoperative assessment Patients received empiric oral hydrocortisone on day 1 and on the morning of day 2 post-operatively, prior to assessment of 0800 h serum cortisol on day 3. A blood sample for serum cortisol was drawn at 0800 h on the morning of day 3, if clinically stable, prior to administration of hydrocortisone. The Endocrine Society Clinical Practice Guideline define post-operative biochemical remission as morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively [16], ‘standard criteria’. In our institution, we also apply a biochemical cut-off of < 50 nmol/L (1.8 μg/dl) at day 3 postoperatively to allow early indication of biochemical remission, ‘strict criteria’. If serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical sequalae of hypercortisolaemia made (such as improvement in blood pressure or glycaemic control), before repeat endoscopic transsphenoidal surgery is considered. Transient cranial diabetes insipidus (DI) was defined as the development of hypotonic polyuria postoperatively requiring at least one dose of desmopressin [22], which resolved prior to discharge. Permanent DI was confirmed by water deprivation test according to standard criteria [23]. Thyroid stimulating hormone (TSH) deficiency was defined by low fT4 with either low or inappropriately normal TSH. Growth hormone (GH) deficiency was confirmed using either Insulin Tolerance Test or Glucagon Stimulation Test [24]. Gonadotrophin deficiency was defined in premenopausal women as amenorrhoea with inappropriately low FSH and LH concentration, and in postmenopausal patients as inappropriately low FSH and LH concentration. Recovery of hypothalamic-pituitary-adrenal axis was assessed by short synacthen (250 μg) test or insulin tolerance test 3 months post-operatively, and every 3–6 months thereafter in cases of initial fail or borderline result. Patients were assessed annually for recurrence of Cushing’s disease, recurrence was defined by failure to suppress cortisol to < 50 nmol/L following an 1 mg overnight dexamethasone suppression test, an elevated late night salivary cortisol (LNSF) or urinary free cortisol (UFC) in patients no longer taking hydrocortisone. Laboratory analysis Prior to 2019, serum cortisol was measured using a chemiluminescent immunoassay with the Beckman Coulter UniCel Dxl 800. Intra-assay CV for serum cortisol was 8.3, 5 and 4.6% at concentrations of 76, 438 and 865 nmol/L, respectively. From January 2019 onwards, serum cortisol was measured using Elecsys® Cortisol II assay on the Roche Cobas e801; intra-assay precision for serum cortisol was 1.2, 1.1 and 1.6% at concentrations of 31.8, 273 and 788 nmol/L, respectively. Statistics Data are expressed as median (range) and number (%). The Fishers Exact test was used to compare categorical variables between groups. All p-values were considered statistically significant at a level < 0.05. Statistical analysis was performed using GraphPad Prism 8 statistical software (GraphPad Software, La Jolla, California, USA). Results Demographics Forty-three endoscopic transsphenoidal procedures were performed in 39 patients. Demographics are summarised in Table 1. Median (range) age was 37 years (8–75), 30 were female. Median (range) duration of symptoms was 24 months (6–144), 72% (28/39) had hypertension, and 28% (11/39) had type 2 diabetes. Table 1 Summary of demographics and post-operative outcomes Full size table Preoperative imaging and IPSS Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). No adenoma was identified in 17 patients (44%). IPSS was carried out in 33 (85%) patients. Postoperative remission Post-operative outcomes are summarised in Table 1 and Fig. 1. Using standard criteria (0800 h serum cortisol < 138 nmol/l within 7 days of operation and improvement in clinical features of hypercortisolism), postoperative remission rates for initial surgery were 87% (34/39) for the entire group and 89% (31/35) when patients with macroadenomas were excluded, Fig. 1. Three patients had an early repeat ETSS for persistent disease; day 3 serum cortisol ranged from 306 to 555 nmol/L and interval to repeat ETSS from 10 days–3 months. When the outcome of early repeat ETSS was factored in, overall remission rate was 92% (36/39) overall, and 94% (33/35) when patients with macroadenomas were excluded. Fig. 1 Schema of patients who underwent ETSS. *Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids Full size image Using strict criteria of early remission (day 3 serum cortisol concentration < 50 nmol/L), postoperative remission rates were 58% (22/38) overall, and 62% (21/34) excluding macroadenomas. Including the three patients with early repeat ETSS, remission rate was 61% (23/38) overall, and 65% excluding macroadenomas (22/34). Day 3 cortisol was not measured in one patient due to intercurrent illness requiring treatment with intravenous glucocorticoids. Eleven patients (28%) had a cortisol measurement between 50 and 138 nmol/L on day 3, seven of whom had received metyrapone therapy prior to ETSS. Six patients had serial measurements of 0800 h cortisol up to a maximum follow-up of 14 days post-op, serum cortisol concentration fell after day 3 in all six patients. Ten (91%) were glucocorticoid-dependent at 3 months based on synacthen/ITT; 0800 h cortisol had fallen to < 50 nmol/L in six patients. Predictors of remission No statistical difference was found in the rates of remission in those patients with or without tumour target on preoperative MRI, using either strict criteria for remission (12/21 target vs 10/17 no target, p > 0.99) or standard criteria (19/22 target vs 15/17 no target, p > 0.99). Similar results were found when the four patients with macroadenoma were excluded. Persistent disease Five patients (13%) had persistent hypercortisolaemia after the initial endoscopic transsphenoidal surgery (Table 2). Three patients underwent a repeat early endoscopic transsphenoidal surgery, Fig. 1. Remission rate after repeat early ETSS was 67% (2/3) using standard criteria, and 33% (1/3), using the strict criteria. Of the patients with persistent disease following repeat ETSS, one received radiosurgery, while the other has been commenced on medical therapy, with a view to refer for radiotherapy. Table 2 Outcome of five patients with persistent hypercortisolaemia after initial ETSS Full size table Postoperative complications The rate of transient diabetes insipidus after first ETSS was 33% (13/39), while permanent diabetes insipidus occurred in 23% (9/39). Postoperatively, there were five cases of new thyroid stimulating hormone deficiency (13%) and four cases of gonadotrophin deficiency (10%) (in pre-menopausal females). There were no cases of postoperative CSF leak, no cases of meningitis and no visual complications. There were no other complications. Recurrence No patients were lost to follow-up. Over a median (range) duration of follow-up of 24 (4–79) months, one patient had recurrence of Cushing’s disease. Pre-operative MRI had shown a macroadenoma; serum cortisol on day 3 after the initial ETSS was 71 nmol/L, which fulfilled standard criteria for remission, but not the more strict criteria. The patient underwent a second ETSS 13 months later. No tumour was visible intra-operatively so no tissue was removed, day 3 serum cortisol concentration was 308 nmol/L and the patient was commenced on a trial of metyrapone. Recovery of the hypothalamic-pituitary-adrenal axis Recovery of the hypothalamic-pituitary-adrenal axis occurred in nine patients (27%), at median 13 (3–27) months post-operatively. There was no statistical difference in rates of recovery of HPA axis in patients with day 3 cortisol < 50 nmol/l, and those who only passed standard criteria for remission (< 138 nmol/l) [7/20 (follow-up 25 (3–59) months) versus 2/11 (follow-up 16 (3–79) months) respectively, p = 0.43]. One patient died 5 weeks post-operatively; post-mortem revealed bilateral haemorrhagic adrenal necrosis. Discussion Reported remission rates following ETSS in patients with Cushing’s disease (CD) vary widely, predominantly due to differences in criteria used to define remission [11]. There is no uniform consensus on the criteria used to define ‘remission’, with institutions using a combination of biochemical and clinical criteria; this makes comparing surgical outcome studies challenging. The normal corticotroph cells of the pituitary gland are suppressed due to sustained hypercortisolaemia, therefore following successful removal of the ACTH-secreting adenoma, serum ACTH and cortisol concentrations should fall postoperatively. A morning serum cortisol concentration < 138 nmol/L (5 μg/dl) within 7 days of ETSS is usually indicative of remission, and this biochemical cut-off is quoted in the Endocrine Society Clinical Practice Guideline [16], and many surgical outcome studies [8, 11, 25]. Other studies have applied a more strict serum cortisol cut-off of < 50 nmol/L (1.8 μg/L) at day 3 postoperatively to allow early indication of biochemical remission [10, 11, 26,27,28]; the literature suggests this cutoff is associated with remission, and a low recurrence rate of approximately 10% at 10 years [14]. Our practice is to apply this latter approach; if serum cortisol on day 3 is 50–138 nmol/L, serial measurements are taken daily to determine if cortisol will fall further, and assessment for improvement/resolution of clinical signs of hypercortisolaemia made, before repeat endoscopic transsphenoidal surgery is considered. It is important to ensure that serum cortisol has reached a nadir, before further intervention is considered. In this single-centre single-surgeon study, we report two very different remission rates using these two widely accepted criteria. Our remission rate, including those patients who had an early second ETSS, using standard guidelines, is 92%, on par with other larger studies [7, 8, 11, 25, 29]. When patients with corticotroph macroadenomas were excluded, the remission rate was even higher at 94%. In comparison, when we applied the more strict criteria of day 3 cortisol < 50 nmol/L, the remission rate was considerably lower at 61%. This criteria is in place in our institution so that we can safely identify patients who have early signs of remission to facilitate discharge on day 3 post-operatively; however reporting these rates in isolation lead to a misleadingly low remission rate compared to the more lenient criteria proposed by the Endocrine Society [16]. Evidence has suggested that higher day 3 cortisol concentration is associated with greater risk of recurrence of CD. A recent retrospective cohort analysis of 81 ETSS for CD by Mayberg et al. reported significantly higher recurrence rates in patients with post-operative cortisol nadir between 58 and 149 nmol/L (2.1–5.4 μg/dL) compared with those with cortisol < 55 nmol/L (2 μg/dL) (33% vs 6%, p = 0.01) [30]. Recurrence of CD was low in our series at 3%, and occurred in a patient with a corticotroph macroadenoma, which have been shown to be associated with higher rates of recurrence [31]. On post-operative assessment, serum cortisol fell between the two criteria for remission and if remission was strictly defined as a day 3 cortisol < 50 nmol/L, then this patient had in fact persistent hypercortisolaemia. This case highlights the difficulty when comparing studies reporting ETSS outcomes in CD – the distinction between persistent post-operative hypercortisolism and early recurrence of CD is not always clear-cut, and is dictated by the local protocol. Whilst our recurrence data are encouraging in comparison to other reports on CD recurrence, which published rates of up to 22% [11], longer term follow-up is necessary before recurrence rates can be accurately defined. The criteria used to define long term recurrence of CD also varies widely in the literature; a large systematic review (n = 6400) by Petersenn et al. (2015) reported decreased recurrence rates when studies used UFC with ONDST vs. UFC only, and UFC with morning serum cortisol vs. UFC only [11]. This highlights the requirement for standardization of remission and recurrence criteria, for consistency in clinical practice and in the literature. The post-operative surgical complication rate in our series was very low, with no cases of CSF leak, vascular injury or visual compromise. Other published case series have reported incidence rates for CSF leakage and meningitis of 0–7.2% and 0–7.9% [2, 12, 32, 33] respectively. Postoperative meningitis is strongly associated with CSF leakage [34]. Some studies suggest that the endoscopic approach results in higher rates of carotid artery injury compared with the microscopic approach, which could be attributed to the nature of the extended lateral approach [35]. However, in this series of 43 ETSS, we report no cases of surgical related carotid artery injury, similar to other studies reporting 0% serious morbidity or mortality due to carotid artery injury [33, 36]. Finally, postoperative visual disturbance is a major concern, as it can be life changing for patients. Factors linked with visual complications include tumour size, patient age and any pre-existing visual conditions [37,38,39]. Visual deterioration after TSS for Cushing’s disease has been reported to occur in some large case series at rates of 1.9% [32] and 0.86% [12]. There were no cases of postoperative visual disturbance in our series. While the surgical complication rate was low, our endocrine complication rate was higher than that reported in other studies, particularly the rate of DI. Transient DI occurred in 33% of cases, and permanent DI in 23%. These relatively high rates of transient DI may be due to the diagnostic criteria used in our protocol; we defined transient post-operative DI as one episode of hypotonic polyuria in the setting of normal or elevated plasma sodium concentration, requiring at least one dose of desmopressin. In contrast, some studies discount any polyuria which lasts less than 2 days [10], while others require the documentation of hypernatremia for the diagnosis of DI [40]. These more stringent criteria will not capture cases of mild transient DI; therefore it is not surprising that the rates of transient DI reported in a 2018 meta-analysis were lower than that in our study, 11.3% [29]. The rates of permanent DI in our study merits particular attention. TSS for CD has been shown to be associated with a higher risk of post-operative DI [41, 42]. It may be that a more aggressive surgical approach resulted in high remission rates, but at a cost of higher rates of DI. All patients are reviewed post-operatively in the National Pituitary Centre, where there is a low threshold for water deprivation testing and/or 3% saline testing. We did not routinely re-test patients for resolution of DI after their initial water deprivation test at 3 months, and it is possible that some cases subsequently resolved after 3 months [41, 43]. Regardless, the rate reported in this study is significant, and emphasises the importance of counselling the patient about the risk of DI long-term. Strengths and limitations The reporting of two remission rates based on widely accepted criteria is a strength of this study, and allows for direct comparison of our outcomes with other studies. All ETSS were performed by a single pituitary surgeon; while this removes bias from surgeon experience, the disadvantage of this is that the sample size is relatively low. Furthermore, because we included patients who were recently operated on to maximise numbers for analysis of surgical complications, the follow-up period is relatively short. A longer follow-up is required to comment accurately on recurrence of CD. We did not have full ascertainment of longitudinal post-operative data including dexamethasone suppression tests, and this has highlighted the need for protocolised follow-up to allow for consistency when reporting our results. Conclusion Endoscopic transsphenoidal surgery in patients with Cushing’s disease offers excellent remission rates and low morbidity. Remission rates are much higher when standard criteria [morning serum cortisol < 138 nmol/L (5μg/dl) within 7 days postoperatively] are used compared with day 3 cortisol < 50 nmol/l. Higher remission rates were found for patients with microadenomas. Patients should be counselled regarding risk of post-operative endocrine deficiencies, in particular permanent diabetes insipidus. Longer follow-up is required to accurately assess recurrence rates. Availability of data and materials The data that support the findings of this study are not publicly available due to restrictions by General Data Protection Regulation (GDPR), but are available from the corresponding author on reasonable request. Abbreviations TSS: Transsphenoidal surgery ACTH: Adrenocorticotropic hormone CD: Cushing’s disease ETSS: Endoscopic transsphenoidal surgery ONDST: Overnight dexamethasone suppression test LNSF: Late night salivary cortisol CRH: Corticotropin releasing hormone IPSS: Inferior petrosal sinus sampling DI: Diabetes insipidus TSH: Thyroid stimulating hormone GH: Growth hormone UFC: Urinary free cortisol References 1. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23. CAS PubMed PubMed Central Google Scholar 2. Broersen LHA, van Haalen FM, Biermasz NR, et al. Microscopic versus endoscopic transsphenoidal surgery in the Leiden cohort treated for Cushing's disease: surgical outcome, mortality, and complications. Orphanet J Rare Dis. 2019;14(1):64. PubMed PubMed Central Article Google Scholar 3. Hammer GD, Tyrrell JB, Lamborn KR, et al. Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J Clin Endocrinol Metab. 2004;89:6348–57. CAS PubMed Article PubMed Central Google Scholar 4. Nieman LK. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol/Eur Fed Endoc Soc. 2015;173:M33–8. CAS Article Google Scholar 5. Swearingen B, Biller BM, Barker FG, et al. Long-term mortality after transsphenoidal surgery for Cushing disease. Ann Intern Med. 1999;130:821–4. CAS PubMed Article PubMed Central Google Scholar 6. Clayton RN, Jones PW, Reulen RC, et al. Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol. 2016;4(7):569–76. PubMed Article PubMed Central Google Scholar 7. Berker M, Işikay I, Berker D, et al. Early promising results for the endoscopic surgical treatment of Cushing's disease. Neurosurg Rev. 2014;37:105–14. Article Google Scholar 8. Cebula H, Baussart B, Villa C, et al. Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing's disease in 230 patients with positive and negative MRI. Acta Neurochir. 2017;159(7):1227–36. PubMed Article PubMed Central Google Scholar 9. Shimon I, Ram Z, Cohen ZR, et al. Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients. Neurosurgery. 2002;51(1):57–62. PubMed Article PubMed Central Google Scholar 10. Wagenmakers MA, Boogaarts HD, Roerink SH, et al. Endoscopic transsphenoidal pituitary surgery: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas. Eur J Endocrinol. 2013;169(3):329–37. CAS PubMed Article PubMed Central Google Scholar 11. Petersenn S, Beckers A, Ferone D, et al. Therapy of endocrine disease: outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol. 2015;172(6):R227–39. CAS PubMed Article PubMed Central Google Scholar 12. Atkinson AB, Kennedy A, Wiggam MI, et al. Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin Endocrinol. 2005;63:549–59. Article Google Scholar 13. Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg. 1997;87(1):44–51. CAS PubMed Article PubMed Central Google Scholar 14. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93:2454–6. CAS PubMed PubMed Central Article Google Scholar 15. Ciric I, Ragin A, Baumgartner C, et al. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery. 1997;40(2):225–36. CAS PubMed Article PubMed Central Google Scholar 16. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807–31. CAS PubMed PubMed Central Article Google Scholar 17. Storr H, Alexandraki K, Martin L, et al. Comparisons in the epidemiology, diagnostic features and cure rate by transsphenoidal surgery between paediatric and adult-onset Cushing's disease. Eur J Endocrinol. 2011;164(5):667–74. CAS PubMed Article PubMed Central Google Scholar 18. Cappabianca P, Alfieri A, de Divitiis E. Endoscopic endonasal transsphenoidal approach to the Sella: towards functional endoscopic pituitary surgery (FEPS). Minim Invasive Neurosurg. 1998;41(2):66–73. CAS PubMed Article PubMed Central Google Scholar 19. Cappabianca P, Alfieri A, Thermes S, et al. Instruments for endoscopic endonasal transsphenoidal surgery. Neurosurgery. 1999;45(2):392–6. CAS PubMed Article PubMed Central Google Scholar 20. Jho H. Endoscopic transsphenoidal surgery. J Neuro-Oncol. 2001;54:187–95. CAS Article Google Scholar 21. Jho HD, Alfieri A. Endoscopic transsphenoidal pituitary surgery: various surgical techniques and recommended steps for procedural transition. Br J Neurosurg. 2000;14(5):432–40. CAS PubMed Article PubMed Central Google Scholar 22. Seckl J, Dunger D. Postoperative diabetes insipidus. Br Med J. 1989;298:2. CAS Article Google Scholar 23. Garrahy A, Moran C, Thompson CJ. Diagnosis and management of central diabetes insipidus in adults. Clin Endocrinol. 2019;90(1):23–30. Article Google Scholar 24. Glynn N, Agha A. Diagnosing growth hormone deficiency in adults. Int J Endocrinol. 2012;2012:972617. PubMed PubMed Central Article CAS Google Scholar 25. Starke RM, Reames DL, Chen CJ, et al. Pure endoscopic transsphenoidal surgery for Cushing’s disease: techniques, outcomes, and predictors of remission. Neurosurgery. 2013;72:240–7. PubMed Article PubMed Central Google Scholar 26. McCance DR, Besser M, Atkinson AB. Assessment of cure after transsphenoidal surgery for Cushing's disease. Clin Endocrinol. 1996;44:1–06. CAS Article Google Scholar 27. Trainer PJ, Lawrie HS, Verhelst J, et al. Transsphenoidal resection in Cushing's disease: undetectable serum cortisol as the definition of successfuI treatment. Clin Endocrinol. 1993;38:73–8. CAS Article Google Scholar 28. Yap LB, Turner HE, Adams CBT, et al. Undetectable postoperative cortisol does not always predict long-term remission in Cushing’s disease: a single Centre audit. Clin Endocrinol. 2002;56:25–31. CAS Article Google Scholar 29. Broersen LHA, Biermasz NR, van Furth WR, et al. Endoscopic vs. microscopic transsphenoidal surgery for Cushing's disease: a systematic review and meta-analysis. Pituitary. 2018;21(5):524–34. PubMed PubMed Central Article Google Scholar 30. Mayberg M, Reintjes S, Patel A, et al. Dynamics of postoperative serum cortisol after transsphenoidal surgery for Cushing's disease: implications for immediate reoperation and remission. J Neurosurg. 2018;129(5):1268–77. PubMed Article PubMed Central Google Scholar 31. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93:358–62. CAS PubMed Article PubMed Central Google Scholar 32. Fahlbusch R, Buchfelder M, Müller OA. Transsphenoidal surgery for Cushing's disease. J R Soc Med. 1986;79(5):262–9. CAS PubMed PubMed Central Article Google Scholar 33. Sarkar S, Rajaratnam S, Chacko G, et al. Pure endoscopic transsphenoidal surgery for functional pituitary adenomas: outcomes with Cushing's disease. Acta Neurochir. 2016;158(1):77–86. PubMed Article PubMed Central Google Scholar 34. Magro E, Graillon T, Lassave J, et al. Complications related to the endoscopic Endonasal Transsphenoidal approach for nonfunctioning pituitary macroadenomas in 300 consecutive patients. World Neurosurg. 2016;89:442–53. PubMed Article PubMed Central Google Scholar 35. Ammirati M, Wei L, Ciric I. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2013;84(8):843–9. PubMed Article PubMed Central Google Scholar 36. Dehdashti AR, Gentili F. Current state of the art in the diagnosis and surgical treatment of Cushing disease: early experience with a purely endoscopic endonasal technique. Neurosurg Focus. 2007;23:E9. PubMed Article PubMed Central Google Scholar 37. Barzaghi LR, Medone M, Losa M, et al. Prognostic factors of visual field improvement after trans-sphenoidal approach for pituitary macroadenomas: review of the literature and analysis by quantitative method. Neurosurg Rev. 2012;35(3):369–78. PubMed Article PubMed Central Google Scholar 38. Mortini P, Losa M, Barzaghi R, et al. Results of transsphenoidal surgery in a large series of patients with pituitary adenoma. Neurosurgery. 2005;56(6):1222–33. PubMed Article PubMed Central Google Scholar 39. Nomikos P, Buchfelder M, Fahlbusch R. Current management of prolactinomas. J Neuro-Oncol. 2001;54(2):139–50. CAS Article Google Scholar 40. Mamelak AN, Carmichael J, Bonert VH, et al. Single-surgeon fully endoscopic endonasal transsphenoidal surgery: outcomes in three-hundred consecutive cases. Pituitary. 2013;16(3):393–401. PubMed Article PubMed Central Google Scholar 41. Hensen J, Henig A, Fahlbusch R, et al. Prevalence, predictors and patterns of postoperative polyuria and hyponatraemia in the immediate course after transsphenoidal surgery for pituitary adenomas. Clin Endocrinol. 1999;50:431–9. CAS Article Google Scholar 42. Nemergut EC, Zuo Z, Jane JA Jr, et al. Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg. 2005;103(3):448–54. PubMed Article PubMed Central Google Scholar 43. Adams JR, Blevins LS Jr, Allen GS, et al. Disorders of water metabolism following transsphenoidal pituitary surgery: a single institution's experience. Pituitary. 2006;9(2):93–9. PubMed Article PubMed Central Google Scholar
  9. A CORONER has recorded a verdict of accidental death at the inquest held into the death of a 40-year-old Wrexham mother. Marie Richardson, of Bryn Hafod, died in March at the Maelor Hospital. A post mortem examination found that she had died as a result of a haemorrhage involving the pituitary gland, which plays a key role in the body's hormonal system. The inquest was told a post mortem examination had been conducted by Dr Anthony Burdge. Giving evidence, Dr Burdge said that it was probable the bleeding had been caused as a result of thinning of the blood and not a trauma such as a fall. Contributory factors in Mrs Richardson's death had been Cushing's disease, a very rare condition involving a hormone disorder, and bronchial pneumonia. The court was told by Mrs Richardson's husband, Andrew, that his wife had started to experience ill health, including swollen legs and constant backache. Her mobility was badly affected. Mrs Richardson was admitted to the Maelor Hospital. Consultant physician Dr Stephen Stanaway said that as part of the treatment, Mrs Richardson received a small dose of a blood-thinning drug to help ensure she did not fall victim to clots. She had been given a scan involving the pituitary and there was no evidence of a tumor. It transpired the post-mortem had found Mrs Richardson did have a tumor, which had experienced bleeding. Dr Stanaway said that Mrs Richardson had not liked the scanning process and moved at one point – it was important for patients to remain still. Acting coroner John Gittins asked if Mrs Richardson would have been administered with blood thinner if the tumour had been known about at the time of treatment. Dr Stanaway said it would have to be a balanced decision but he felt that she would have been. Legal representatives for Mrs Richardson's family and the NHS Trust were present at the inquest. Dr Stanaway was asked a series of questions about whether anything further could have been done about Mrs Richardson's treatment while at the Maelor. He said that with hindsight the only potential other avenue may have been if she had been given steroids. But Dr Stanaway stressed he doubted this would have been successful, emphasizing Mrs Richardson was a very poorly woman and it would be impossible to say that administering steroids would have saved her. Recording his verdict of accidental death Mr Gittins emphasized: "This is not an indication of responsibility, blame or judgment. "That is not my jurisdiction. My very sincere condolences go to the family." HOME | Sitemap | Adrenal Crisis! | Abbreviations | Glossary | Forums | Donate | Bios | Add Your Bio | Add Your Doctor | MemberMap | CushieWiki
  10. From board member @sharm Please Join Us to Celebrate 20 Years-Pituitary Patient Support Group. Saturday April 10, 2021: 9:00am-11:00am (PST) (Scroll below for Zoom meeting links) We invite you to join the conversation with our experts: Pejman Cohan, neuro-endocrinologist & Daniel Kelly, neurosurgery. Email me or leave your questions in the chat below. We will answer as many questions as time allows. We can't wait to see you on Zoom! Thank you, Sharmyn McGraw, patient advocate, community outreach. pituitarybuddy@hotmail.com Meeting ID: 849 6356 9824 Passcode: 596170 Zoom: https:/zoom.us/join One tap mobile +16699006833,,84963569824#,,,,*596170# US (San Jose) +12532158782,,84963569824#,,,,*596170# US (Tacoma) Dial by your location +1 669 900 6833 US (San Jose) +1 253 215 8782 US (Tacoma) +1 346 248 7799 US (Houston) +1 929 205 6099 US (New York) +1 301 715 8592 US (Washington DC) +1 312 626 6799 US (Chicago) Meeting ID: 849 6356 9824 Passcode: 596170 Find your local number: https://us02web.zoom.us/u/kdgrvRLBP7
  11. From board member @sharm - Please Join Us to Celebrate 20 Years-Pituitary Patient Support Group. Saturday April 10, 2021: 9:00am-11:00am (PST) (Scroll below for Zoom meeting links) We invite you to join the conversation with our experts: Pejman Cohan, neuro-endocrinologist & Daniel Kelly, neurosurgery. Email me or leave your questions in the chat below. We will answer as many questions as time allows. We can't wait to see you on Zoom! Thank you, Sharmyn McGraw, patient advocate, community outreach. pituitarybuddy@hotmail.com Meeting ID: 849 6356 9824 Passcode: 596170 Zoom: https:/zoom.us/join One tap mobile +16699006833,,84963569824#,,,,*596170# US (San Jose) +12532158782,,84963569824#,,,,*596170# US (Tacoma) Dial by your location +1 669 900 6833 US (San Jose) +1 253 215 8782 US (Tacoma) +1 346 248 7799 US (Houston) +1 929 205 6099 US (New York) +1 301 715 8592 US (Washington DC) +1 312 626 6799 US (Chicago) Meeting ID: 849 6356 9824 Passcode: 596170 Find your local number: https://us02web.zoom.us/u/kdgrvRLBP7
  12. Yu Wang, Zhixiang Sun, Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, People’s Republic of China Correspondence: Zhiquan Jiang Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Bengbu, Anhui 233004, People’s Republic of China Tel +86-13966075971 Email bbjiangzhq@163.com Abstract: Cushing’s disease (CD), also known as adrenocorticotropic hormone (ACTH)-dependent pituitary Cushing’s syndrome, is a rare and serious chronic endocrine disease that is usually caused by a pituitary adenoma (especially a pituitary microadenoma). Meningioma is the most common type of primary intracranial tumor and is usually benign. The patient in this case report presented with CD coexisting with pituitary microadenoma and meningioma, which is an extremely rare comorbidity. The pathogenesis of CD associated with meningioma remains unclear. Here, we describe the case of bilateral lower extremity edema, lower limb pain, abdominal purplish striae, and abdominal distension for 9 months in a 47-year-old woman. Two years ago, the patient underwent a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. Magnetic resonance imaging of her head revealed a sellar lesion (7.8 mm × 6.4 mm) and a spherical mass (3.0 cm × 3.0 cm) in the right frontal convexity. Her level of serum adrenocorticotropic hormone (ACTH) was 169 pg/mL, and her cortisol levels were 933 nmol/mL and 778 nmol/mL at 8 am and 4 pm, respectively. Preoperatively, she was diagnosed with ACTH-secreting pituitary microadenoma and meningioma. Excision of the meningioma was performed through a craniotomy, while an endoscopic endonasal transsphenoidal approach was used to remove the pituitary adenoma. Meningioma and pituitary adenoma were confirmed by postoperative pathology. On the basis of this unusual case, the relevant literature was reviewed to illustrate the diagnosis and treatment of Cushing’s disease and to explore the pathogenesis of pituitary adenoma associated with meningioma. Keywords: Cushing’s disease, pituitary adenoma, meningioma Introduction Cushing’s disease (CD) is a severe condition caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor that accounts for approximately 70% of all cases of endogenous Cushing’s syndrome. It has a total incidence of 1–2 cases per million per year and a prevalence rate of approximately 30 patients per million per year, making it an uncommon disease.1 Meningiomas account for 15–25% of all intracranial tumors, with an annual incidence of 6 cases per 100,000 persons.2 CD combined with meningioma is a rare condition, and even rarer in patients who have no previously known risk factors for either tumor. To the best of our knowledge, its pathogenesis have not been clearly described to date. Case Presentation Clinical History and Laboratory Findings A 47-year-old woman was admitted to the endocrinology department of our hospital with chief complaints of bilateral lower extremity edema, left lower limb pain, abdominal purplish striae, and abdominal distension for 9 months. Two years ago, the patient had a hysterectomy at a local hospital for hysteromyoma. She had no previous radiotherapeutic treatment or other medical history. She weighed 90 kg and was 165 cm tall with a body mass index (BMI) of 33. Physical examination showed typical features of Cushing’s syndrome, including centripetal obesity, moon face, pedal edema, and buffalo hump. Her skin was thin and dry, with acne and hirsutism. On admission, her blood pressure was 146/115 mmHg and routine biochemical blood tests confirmed comorbidity with diabetes mellitus, hyperlipidemia, and hypokalemia. Endocrine measurements showed that her serum ACTH was 169 pg/mL (reference value: 5–50 pg/mL), cortisol (8 am) was 933 nmol/L (reference value: 138–690 nmol/L), and cortisol (4 pm) was 778 nmol/L (reference value: 69–345 nmol/L), indicating that her ACTH and cortisol levels were dramatically increased. Cortisol secretion was increased and had lost its circadian rhythm. The low-dose dexamethasone suppression test showed that cortisol suppression was < 50%, while a >50% suppression of cortisol was found in the high-dose dexamethasone suppression test. Serum prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone, free thyroid hormone (FT3 and FT4), and thyrotropin values were normal. Endocrinological evaluation suspected that pituitary lesions caused Cushing syndrome. Imaging Analysis The patient underwent a magnetic resonance imaging (MRI) scan to image her head. T1-weighted MRI with contrast enhancement showed a spherical enhancing mass (3.0 cm × 3.0 cm) in the right frontal convexity and a dural tail sign (Figure 1A). In the sellar area, the enhancement degree of the lesion (7.8 mm × 6.4 mm) was significantly lower than that of the surrounding pituitary tissue, and the pituitary stalk was displaced to the right (Figure 1A and B). No abnormalities were found on plain or enhanced adrenal computed tomography scans. Figure 1 Enhanced magnetic resonance imaging (MRI) of the patient’s head: (A) Coronal view of the gadolinium-enhanced T1-weighted image showing a spherical enhancing mass in the right frontal convexity and a dural tail sign. A round low-intensity lesion can be seen on the right side of the pituitary gland, and the pituitary stalk is displaced to the right. (B) Sagittal T1-weighted sequence with contrast showing the degree of enhancement is lower than that of the pituitary in the sellar region. Treatment and Pathological Examination Physical examination, endocrine examination, and head MRI successfully proved that pituitary microadenoma caused Cushing’s syndrome (specifically CD) comorbid with asymptomatic meningioma. In order to receive surgical treatment, the patient was referred from the endocrinology department to neurosurgery. She underwent neuroendoscopic transsphenoidal surgery and the pituitary microadenoma was removed. The sellar floor was reconstructed with artificial dura mater, and after this reconstruction, no cerebrospinal fluid leakage was observed. The pathological specimen was examined and was determined to be consistent with a pituitary microadenoma (Figure 2A). One month later, excision of the meningioma was performed through a right frontal trephine craniotomy. Histological examination revealed a WHO grade I meningioma (Figure 2B). Figure 2 (A) Histopathologic examination revealed a pituitary adenoma (Hematoxylin and eosin staining, 100×). (B) Histopathologic examination revealed a meningioma (Hematoxylin and eosin staining, 100×). Outcome and Follow Up On the second day after the operation, her cortisol level dropped below the normal range in the morning. Hydrocortisone replacement therapy was started on the same day. In addition, she had developed transient diabetes insipidus, which was treated with desmopressin. Three months postoperatively, after hydrocortisone replacement therapy, the symptoms of Cushing’s disease were alleviated, and the cortisol level returned to normal, which was 249nmol/L (reference value: 138~690nmol/L). At the 1-year follow-up, no lesions were observed on the MRI scan and the symptoms of Cushing’s syndrome were in remission. The use of hydrocortisone supplements were discontinued and hormone levels remained normal, indicating recovery of the hypothalamic–pituitary–adrenal (HPA) axis. The patient had lost 30 kg and her BMI had dropped to 22, while her blood glucose, triglyceride level, and blood pressure had all returned to normal. Physical changes in the patient pre- and post-treatment are shown in Figure 3A and B. Figure 3 Abdominal appearance with striae (A) preoperation and (B) 4 months postoperation. Discussion Cushing’s Disease CD is a serious clinical condition caused by a pituitary adenoma secreting a high level of ACTH, leading to hypercortisolism. The proportion of ACTH-secreting pituitary adenomas (corresponding to CD) among hormone-secreting pituitary adenomas is 4.8%–10%, which affects women three times more frequently than men, mainly occurs in those 40–60 years old.3,4 Exposure to excessive cortisol can lead to various manifestations of Cushing’s syndrome and increases in morbidity and mortality.5 Therefore, early diagnosis and treatment of CD are very important. The diagnosis and differential diagnosis of CD is very complicated, and these have always been challenging problems in clinical endocrinology. Once Cushing’s syndrome is diagnosed, its etiology should be determined. A diagnosis of Cushing’s disease is made based on a biochemical examination confirming the pituitary origin of the condition and exclude other sources (namely, ectopic ACTH secretion and adrenocortical tumors).3 High-dose dexamethasone suppression and corticotropin-releasing-hormone stimulation tests may be used to distinguish high-secretion sources of pituitary and ectopic ACTH. More than 90% of the pituitary adenomas that cause CD are microadenomas (≤10 mm in diameter), and 40% of the cases cannot be located by radiological examination.5 Examination with bilateral inferior petrosal sinus sampling (BIPSS) is necessary for CD patients in whom noninvasive biochemical and imaging examinations do not lead to a definitive diagnosis.6 The first-line treatment for CD is transsphenoidal selective tumor resection (TSS) with approximately 78% of the patients in remission after the operation, and 13% of patients relapse within 10 years after surgery. Therefore, there are a considerable number of patients who have experienced long-term surgical failure and require additional second-line treatment, such as radiotherapy, bilateral adrenalectomy, or medication.4 The pathogenesis of CD is unclear, but recent studies have confirmed that there are somatic activation mutations of multiple genes in adrenocorticotropin adenomas, while ubiquitin specific peptidase 8 (USP8) is the most common, accounting for about 50% of the mutations in these adenomas.7 Pituitary Adenoma Associated with Meningioma Radiotherapy used to treat pituitary tumors is a well-known reason for the development of meningiomas. Gene mutations are a common molecular characteristic of meningiomas, with inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene found in 55% of meningiomas, and a further 25% of meningiomas accounted for by recently described mutations in other genes.8 Simultaneous occurrence of pituitary adenoma and meningioma without a history of radiotherapy is a rare condition clinically, having only been described in 49 cases before 2019,9 while ACTH-secreting pituitary adenomas (CD) comorbid with meningioma have been reported even less frequently. In the reported cases, the most common site of meningioma is parasellar, accounting for 44.9%, while meningioma located in the distant part of the adenoma is rare.9,10 A number of clinicians have suggested that the coexistence of meningiomas and pituitary adenomas is incidental, with no relationship between the two diseases.2,11 Genetic imbalances have been found in pituitary adenomas, including in particular the chromosomal deletions of 1p, 2q, 4, 5, 6, 11q, 12q, 13q, and 18q, and the overexpression of 9q, 16p, 17p, 19, and 20q. Functional adenomas have more such imbalances than nonfunctional adenomas, corresponding in particular to deletions of chromosomes 4 and 18q, and the overexpression of chromosomes 17 and 19.12 Meanwhile, estrogen receptor positive de novo meningiomas significantly involve chromosomes 14 and 22.13 The study by Hwang et al14 reported that the expression levels of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins were significantly higher in pituitary adenomas and meningiomas than that in normal brain tissues. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) and its downstream signaling pathways play an pivotal role in pituitary tumor, meningioma, and other brain tumors. Zhu et al15 reported that multiple endocrine neoplasia type 1 (MEN1) plays an important role in pituitary adenoma associated with meningioma by upregulating the mammalian target of rapamycin signaling pathway. They found that rapamycin treatment promotes apoptosis in primary cells of the pituitary adenoma and meningioma in cases of pituitary adenoma associated with meningioma. Recurrence of pituitary adenoma, younger age, and larger size of meningioma have been shown to be significantly associated with MEN1 mutation.16 Mathuriya et al17 suggested that hormones may contribute to the occurrence of meningiomas. de Vries et al9 reported that compared with other types of adenomas, the proportion of growth hormone adenomas is higher, accounting for about one third of cases. Meanwhile, Friend et al18 demonstrated that activation of GH/insulin-like growth factor-1 (IGF-1) axis clearly increased the growth rate of meningiomas. However, in the present case, we observed the coexistence of ACTH-secreting adenoma and meningioma. Further studies are required to understand whether ACTH or cortisol are related to the occurrence and development of meningioma. In our case, pituitary microadenoma was the cause of Cushing’s syndrome, while the meningioma was an incidental imaging observation. With the popularity and technological progress of high-resolution imaging technology, the reported prevalence of intracranial lesions related to dominant pathology has increased.2 However, when imaging examinations are limited to specific regions, the diagnosis of lesions in other locations is likely to be omitted. For example, in our case, performing MRI of the sellar region alone may have meant that the meningioma was missed. Conclusion Cushing’s disease is the most common cause of endogenous Cushing’s syndrome and is caused by ACTH-secreting pituitary adenoma.It is associated with severe complications and reduced quality of life, so early diagnosis and treatment are critical. The coexistence of CD, pituitary adenoma, and meningioma is very rare, and the exact mechanisms underlying such comorbidity are currently unclear and need further study. Data Sharing Statement The data that support the findings of this study are available on request from the corresponding author, Zhiquan Jiang. Ethics and Consent Statement Based on the regulations of the department of research of the Bengbu Medical College, institutional review board approval is not required for case reports. Consent for Publication Written informed consent has been provided by the patient to have the case details and any accompanying images published. Author Contributions All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. Funding The authors declared that this case has received no financial support. Disclosure The authors report no conflicts of interest in this work. References 1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–927. doi:10.1016/S0140-6736(14)61375-1 2. Curto L, Squadrito S, Almoto B, et al. MRI finding of simultaneous coexistence of growth hormone-secreting pituitary adenoma with intracranial meningioma and carotid artery aneurysms: report of a case. Pituitary. 2007;10(3):299–305. doi:10.1007/s11102-007-0011-4 3. Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762–773. doi:10.1093/neuonc/now130 4. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36(4):385–486. doi:10.1210/er.2013-1048 5. Tritos NA, Biller BMK. Current management of Cushing’s disease. J Intern Med. 2019;286(5):526–541. doi:10.1111/joim.12975 6. Fan C, Zhang C, Shi X, et al. Assessing the value of bilateral inferior petrosal sinus sampling in the diagnosis and treatment of a complex case of Cushing’s disease. Intractable Rare Dis Res. 2013;2(1):24–29. doi:10.5582/irdr.2013.v2.1.24 7. Sbiera S, Kunz M, Weigand I, Deutschbein T, Dandekar T, Fassnacht M. The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight. Cancers. 2019;11(11):1761. doi:10.3390/cancers11111761 8. Apra C, Peyre M, Kalamarides M. Current treatment options for meningioma. Expert Rev Neurother. 2018;18(3):241–249. doi:10.1080/14737175.2018.1429920 9. de Vries F, Lobatto DJ, Zamanipoor Najafabadi AH, et al. Unexpected concomitant pituitary adenoma and suprasellar meningioma: a case report and review of the literature. Br J Neurosurg. 2019:1–5. doi:10.1080/02688697.2018.1556782. 10. Gosal JS, Shukla K, Praneeth K, et al. Coexistent pituitary adenoma and frontal convexity meningioma with frontal sinus invasion: a rare association. Surg Neurol Int. 2020;11:270. doi:10.25259/SNI_164_2020 11. Cannavo S, Curto L, Fazio R, et al. Coexistence of growth hormone-secreting pituitary adenoma and intracranial meningioma: a case report and review of the literature. J Endocrinol Invest. 1993;16(9):703–708. doi:10.1007/BF03348915 12. Szymas J, Schluens K, Liebert W, Petersen I. Genomic instability in pituitary adenomas. Pituitary. 2002;5(4):211–219. doi:10.1023/a:1025313214951 13. Pravdenkova S, Al-Mefty O, Sawyer J, Husain M. Progesterone and estrogen receptors: opposing prognostic indicators in meningiomas. J Neurosurg. 2006;105(2):163–173. doi:10.3171/jns.2006.105.2.163 14. Hwang M, Han MH, Park HH, et al. LGR5 and downstream intracellular signaling proteins play critical roles in the cell proliferation of neuroblastoma, meningioma and pituitary adenoma. Exp Neurobiol. 2019;28(5):628–641. doi:10.5607/en.2019.28.5.628 15. Zhu H, Miao Y, Shen Y, et al. The clinical characteristics and molecular mechanism of pituitary adenoma associated with meningioma. J Transl Med. 2019;17(1):354. doi:10.1186/s12967-019-2103-0 16. Zhu H, Miao Y, Shen Y, et al. Germline mutations in MEN1 are associated with the tumorigenesis of pituitary adenoma associated with meningioma. Oncol Lett. 2020;20(1):561–568. doi:10.3892/ol.2020.11601 17. Mathuriya SN, Vasishta RK, Dash RJ, Kak VK. Pituitary adenoma and parasagittal meningioma: an unusual association. Neurol India. 2000;48(1):72. 18. Friend KE, Radinsky R, McCutcheon IE. Growth hormone receptor expression and function in meningiomas: effect of a specific receptor antagonist. J Neurosurg. 1999;91(1):93–99. doi:10.3171/jns.1999.91.1.0093 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. From https://www.dovepress.com/cushingrsquos-disease-caused-by-a-pituitary-microadenoma-coexistent-wi-peer-reviewed-fulltext-article-IJGM
  13. For years before and after their diagnosis, people with Cushing’s disease use more psychotropic medications — those that affect mood, thoughts, or perception — for mental health problems than their healthy peers, a study in Sweden found. Notably, patients experiencing long-term disease remission still showed higher use of antidepressants and sleeping pills than healthy individuals. These findings highlight Cushing’s persistent negative effects on mental health, according to researchers. Additionally, the results of this study, based on prescribed medication dispenses in Sweden, support the importance of earlier diagnoses of Cushing’s disease — and the need for close and long-term monitoring of neuropsychiatric symptoms in this patient population, the researchers said. The study, “Psychotropic drugs in patients with Cushing’s disease before diagnosis and at long-term follow-up — a nationwide study,” was published in the Journal of Clinical Endocrinology & Metabolism. Mental health issues such as anxiety, depression, sleep disturbances, and cognitive impairments are part of the wide range of symptoms caused by the abnormally high levels of the cortisol hormone that characterize Cushing’s syndrome. Of note, Cushing’s disease is a form of Cushing’s syndrome caused by a tumor in the pituitary gland. A “few” studies have reported the elimination or partial lessening of neuropsychiatric symptoms after successful Cushing’s treatment, according to the researchers. But others noted that “impaired cognitive function and quality of life seemed to persist for a long time after biochemical [cortisol level-based] remission had been achieved,” the team wrote. Now, these researchers, from several universities in Sweden, have assessed the use of psychotropic medications — reflecting mental health burden — in 372 people with Cushing’s disease. The use of such medications was assessed five years before diagnosis, at the time of diagnosis, and at five and 10 years post-diagnosis. The patients, diagnosed between 1990 and 2018, were identified through the Swedish Pituitary Register, which covers 95% of all people with Cushing’s disease in the country. Most of the patients (76%) were women. Altogether, the patients’ mean age at diagnosis was 44 years. For each individual with Cushing’s, four sex-, age-, and residential area-matched healthy individuals were used as controls for comparative analyses. Data on each individual’s dispenses of medications commonly used for neuropsychiatric issues were obtained from the Swedish Prescribed Drug Register. This register, which fully covers all prescribed medications given throughout the country, also was used to determine each patient’s dispenses of other medications for Cushing’s disease symptoms, such as high blood pressure, also called hypertension, and diabetes. The results showed that the use of antidepressants, anxiolytics — medications to lessen anxiety — and sleeping pills was at least twofold higher in Cushing’s patients than in healthy individuals during the five-year period before diagnosis, and at the time of diagnosis. Five years after diagnosis, the proportion of patients using antidepressants (26%) and sleeping pills (22%) remained unchanged, and even individuals in remission showed significantly higher use of such medications than did controls (20–26% vs. 8.6–12%). According to the results, one-third of the patients on antidepressants since their diagnosis were able to discontinue treatment before the five-year assessment — most having achieved disease remission. However, 47% of those receiving antidepressants at five years had initiated such treatment at a median of 2.4 years after diagnosis. During the five-year follow-up, older age and being a woman appeared to increase the risk of antidepressant use among Cushing’s disease patients. At 10 years of follow-up, the use of antidepressants and sleeping pills was not significantly different between groups, despite the fact that antidepressants use remained about the same among patients. Notably, researchers conducted an analysis of 76 patients with sustained remission for a median of 9.3 years, and 292 matching controls. That analysis showed that the use of antidepressants and sleeping pills was significantly higher among patients. The use of other medications, such as those for hypertension and diabetes, also was significantly more common among Cushing’s disease patients before, at diagnosis, and at five years post-diagnosis — although the post-diagnosis numbers dropped by half during that period. After 10 years, only the use of anti-diabetic medications remained significantly higher in patients as compared with controls. These findings suggest that other conditions associated with Cushing’s disease, such as hypertension and diabetes, are effectively lessened with treatment. However, they also highlight that “many patients with CD [Cushing’s disease] will have persistent mental health problems,” the researchers wrote. In addition, visits to a psychiatrist and hospital admissions for treatment of psychiatric disorders tended to be more common among Cushing’s disease patients, even before diagnosis, the team noted. “This nationwide register-based study shows that use of psychotropic drugs in CD patients is increased from several years before diagnosis,” the researchers wrote, adding that this use “remained elevated regardless of remission status, suggesting persisting negative effects on mental health,” the researchers wrote. These findings highlight the importance of early diagnosis of Cushing’s disease and of considering neuropsychiatric symptoms “as an important part of the disease,” they concluded. There is a “need for long-term monitoring of mental health” in Cushing’s, they wrote. From https://cushingsdiseasenews.com/2021/02/24/cushings-found-to-cause-persistent-negative-mental-health-effects-swedish-study/
  14. until
    Register Now! 2nd annual WAPO eSummit March 19 & 20, 2021 World Alliance of Pituitary Organizations represents the voice of 37 patient advocacies around the globe. This event is also translated into Español, there’s something for everyone! The World Alliance of Pituitary Organizations (‘WAPO’) represents the voice of 37 patient advocacies around the globe. We seek to empower and improve the Quality of Life of Pituitary Patients, by sharing knowledge and inform you about treatment choices. By registering to the WAPO eSummit 2021, you will have a unique opportunity to learn about the latest medical research, raise questions and dialogue with international experts on the pituitary gland! Get involved and register in one of the provided languages. We are looking forward to meeting you! For more information visit the link below. https://web.cvent.com/event/aaf5e35f-793d-49ff-9f4b-138f155dbbc2/summary?fbclid=IwAR0-ah0tkUnx7HmBkQlEoIMOEBvQOGxnvz_XP7fC7BDKhEKkuBhgXfVQL04
  15. Register Now! 2nd annual WAPO eSummit March 19 & 20, 2021 World Alliance of Pituitary Organizations represents the voice of 37 patient advocacies around the globe. This event is also translated into Español, there’s something for everyone! The World Alliance of Pituitary Organizations (‘WAPO’) represents the voice of 37 patient advocacies around the globe. We seek to empower and improve the Quality of Life of Pituitary Patients, by sharing knowledge and inform you about treatment choices. By registering to the WAPO eSummit 2021, you will have a unique opportunity to learn about the latest medical research, raise questions and dialogue with international experts on the pituitary gland! Get involved and register in one of the provided languages. We are looking forward to meeting you! For more information visit the link below. https://web.cvent.com/event/aaf5e35f-793d-49ff-9f4b-138f155dbbc2/summary?fbclid=IwAR0-ah0tkUnx7HmBkQlEoIMOEBvQOGxnvz_XP7fC7BDKhEKkuBhgXfVQL04
  16. The cancer medicine bexarotene may hold promise for treating Cushing’s disease, a study suggests. The study, “Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT‐20 cells,” was published in the Journal of Cellular and Molecular Medicine. Cushing’s disease is caused by a tumor on the pituitary gland, leading this gland to produce too much adrenocorticotropic hormone (ACTH). Excess ACTH causes the adrenal glands to release too much of the stress hormone cortisol; abnormally high cortisol levels are primarily responsible for the symptoms of Cushing’s. Typically, first-line treatment is surgical removal of the pituitary tumor. But surgery, while effective in the majority of cases, does not help all. Additional treatment with medications or radiation therapy (radiotherapy) works for some, but not others, and these treatments often have substantial side effects. “Thus, the development of new drugs for CD [Cushing’s disease] treatment is extremely urgent especially for patients who have low tolerance for surgery and radiotherapy,” the researchers wrote. Recent research has shown that a protein called testicular receptor 4 (TR4) helps to drive ACTH production in pituitary cancers. Thus, blocking the activity of TR4 could be therapeutic in Cushing’s disease. Researchers conducted computer simulations to screen for compounds that could block TR4. This revealed bexarotene as a potential inhibitor. Further biochemical tests confirmed that bexarotene could bind to, and block the activity of, TR4. Bexarotene is a type of medication called a retinoid. It is approved to treat cutaneous T-cell lymphoma, a rare cancer that affects the skin, and available under the brand name Targretin. When pituitary cancer cells in dishes were treated with bexarotene, the cells’ growth was impaired, and apoptosis (a type of programmed cell death) was triggered. Bexarotene treatment also reduced the secretion of ACTH from these cells. In mice with ACTH-secreting pituitary tumors, bexarotene’s use significantly reduced tumor size, and lowered levels of ACTH and cortisol. Cushing’s-like symptoms also eased; for example, bexarotene treatment reduced the accumulation of fat around the abdomen in these mice. Additional cellular experiments suggested that bexarotene specifically works on TR4 by changing the location of the protein. Normally, TR4 is present in the nucleus — the cellular compartment that houses DNA — where it helps to control the production of ACTH. But with bexarotene treatment, TR4 tended to go outside of the nucleus, leading to lower ACTH production. The researchers noted that other mechanisms may also be involved in the observed effects of bexarotene. “In summary, our work demonstrates that bexarotene is a potential inhibitor for TR4. Importantly, bexarotene may represent a new drug candidate to treat CD,” the researchers concluded. From https://cushingsdiseasenews.com/2021/02/05/bexarotene-cancer-drug-t-cell-lymphoma-acth-production/?preview_id=39289
  17. Researchers conducted this retrospective cohort study to investigate acute and life-threatening complications in patients with active Cushing syndrome (CS). Participants in the study were 242 patients with CS, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. In patients with benign pituitary CS, the prevalence of acute complications was 62%, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Infections, thromboembolic events, hypokalemia, hypertensive crises, cardiac arrhythmias and acute coronary events were complications reported in patients with benign CS. The whole spectrum of acute and life-threatening complications in CS and their high prevalence was illustrated in this study both before disease diagnosis and after successful surgery. Read the full article on Journal of Clinical Endocrinology and Metabolism.
  18. From message board member @sharm - Sharmyn McGraw: Hi All, I hope you can join us on Zoom this Saturday, Nov. 14, 2020 starting at 9:00 a.m. (PST). For those that can't make it, I will record the meeting and post it later on our Facebook page. I look forward to seeing you! Contact @sharm if you have questions or email her here: pituitarybuddy@hotmail.com
  19. From message board member @sharm - Sharmyn McGraw: Hi All, I hope you can join us on Zoom this Saturday, Nov. 14, 2020 starting at 9:00 a.m. (PST). For those that can't make it, I will record the meeting and post it later on our Facebook page. I look forward to seeing you! Contact @sharm if you have questions or email her here: pituitarybuddy@hotmail.com
  20. Presented by Dr. Magge, Assistant Professor of Neurology at Weill Cornell Medical College and an Assistant Attending Neurologist at New York-Presbyterian Hospital. Dr. Ranakrishna, Chief of Neurological Surgery at NewYork-Presbyterian Brooklyn Methodist Hospital, Associate Professor of Neurological Surgery at Avina and Willis Murphy at Weill Cornell Medicine Click here to attend. Date: Tuesday, October 13, 2020 Time: 10:00 AM Eastern Daylight Time Learning objectives: - the basic characteristics of the different types of pituitary adenomas - the potential predictors of recurrence and aggressiveness in pituitary adenomas - the surgical and radiotherapy options for recurrent pituitary adenomas - the potential medical interventions, including chemotherapy, for recurrent pituitary adenomas
  21. Presented by Dr. Magge, Assistant Professor of Neurology at Weill Cornell Medical College and an Assistant Attending Neurologist at New York-Presbyterian Hospital. Dr. Ranakrishna, Chief of Neurological Surgery at NewYork-Presbyterian Brooklyn Methodist Hospital, Associate Professor of Neurological Surgery at Avina and Willis Murphy at Weill Cornell Medicine Click here to attend. Date: Tuesday, October 13, 2020 Time: 10:00 AM Eastern Daylight Time Learning objectives: - the basic characteristics of the different types of pituitary adenomas - the potential predictors of recurrence and aggressiveness in pituitary adenomas - the surgical and radiotherapy options for recurrent pituitary adenomas - the potential medical interventions, including chemotherapy, for recurrent pituitary adenomas
  22. This event has been postponed to Dec. 5, 2020 You are Cordially Invited! The PNA is pleased to announce our participation in this event! Saturday, December 5, 2020 8:30am – 4:30pm Zuckerman Research Center 417 E. 68th St. New York, NY Memorial Sloan Kettering Cancer Center Target Audience This course is intended for endocrinologists, neurosurgeons, otolaryngologists, radiation oncologists, neurologists, ophthalmologists, neuro-oncologists, family medicine and internal medicine physicians, physicians in training and other allied health professionals who treat and manage patients with pituitary diseases. We also invite patients with pituitary disease and their caregivers to attend this educational activity and participate in our interactive afternoon breakout sessions. Overall this course aims to improve patient care and outcomes through evidence-based discussion of clinical practice guidelines and emerging therapies. Our goal is to assess and update current practices to promote earlier diagnosis and treatment of pituitary diseases. The multidisciplinary nature of the course will allow for the dissemination of knowledge across the variety of practitioners caring for pituitary patients, and for the patients themselves. Pituitary patients will be able to review treatment options, learn about ongoing clinical trials, and discuss their comprehensive care with providers and other patients. The educational objective of this patient session is to provide a forum for pituitary patients to discuss treatment options and new therapies with providers and other patients. Patients with pituitary disease and their caregivers are invited to attend this educational activity FREE of charge. If you are a patient or caregiver interested in attending, please email cme@mskcc.org to register (registration is required in order to attend). Medical Professionals who wish to attend must register online: mskcc.org/PituitaryCourse View Course Flyer
  23. The Barrow Pituitary Center is dedicated to educating patients, caregivers, and loved ones by providing information which is current and non-biased. Experts at this conference will address management of the emotional and physical elements of living with pituitary disorders. We hope attendees will leave empowered to make better-informed decisions about their healthcare and achieve their goals for a long and fruitful life. In Person and Online Registration Options This conference will be offered in person and through live online format with Zoom. We reserve the right to transition to a solely live online format as a result of health concerns as we move into the fall. Participants will be notified if this change develops. Register here
  24. Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced ‘lockdowns’ are the new ‘norm’ as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population. Introduction In many centers worldwide, the evaluation and treatment of pituitary disorders has already been substantially impacted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic. With reduced access to routine clinical services, patients with suspected or confirmed pituitary disease face the prospect of delays in diagnosis and implementation of effective treatment plans. Furthermore, patients undergoing surgery may be at increased risk from COVID-19, whilst the risk of infection to healthcare providers during pituitary surgery is of particular concern. Herein, we discuss several clinical scenarios where clinical care can be adjusted temporarily without compromising patient outcomes. For this expert guidance, The Pituitary Society Professional Education Committee, which includes neuroendocrinologists and neurosurgeons from four continents, held an online video conference call with subsequent discussions conducted through email communications. The suggestions are not evidence-based due to the novelty and timing of the pandemic; furthermore, re-evaluation every few months in light of emerging data, is recommended. The approach will also likely vary from country to country depending on the risk of viral infection, local rules for “lockdown”, and the capabilities of individual health care systems. Pituitary surgery challenges during the COVID-19 pandemic The significant challenges to pituitary surgery presented by COVID-19 can be considered in terms of the phase of the pandemic, the patient, the surgeon, and the healthcare institution (Table 1). Table 1 Pituitary surgery challenges and recommendations during COVID-19 pandemic Full size table The World Health Organization (WHO) recognizes several phases of a pandemic wave [1]. When the pandemic is in progress (WHO pandemic phase descriptions; Phase 6) [2] there is a high prevalence of active cases. In the immediate post-peak period, the pandemic activity appears to wane, but active cases remain, and additional waves may follow. Previous pandemics have had many such waves, each separated by several months (www.cdc.gov). The corollary is that there will remain a significant possibility of patients and surgeons contracting COVID-19 until a vaccine is developed or herd immunity is achieved by other means. The patient requiring pituitary surgery may be especially vulnerable to COVID-19 due to age and/or comorbidities. This is particularly true of patients with functioning pituitary adenomas such as those with Cushing’s disease (CD), where cortisol excess results in immunosuppression, hypercoagulability, diabetes mellitus and hypertension, and acromegaly which is also frequently complicated by diabetes mellitus and hypertension. Moreover, the risk for patients undergoing surgery that develop COVID-19 in the perioperative period appears to be very high. In a retrospective analysis of 34 patients who underwent elective—non pituitary—surgeries during the incubation period of COVID-19, 15 (44.1%) patients required admission to the intensive care unit, and 7 (20.5%) died [3]. Although this study included cases of variable technical difficulty, complexity and risk—from excision of breast lump to total hip replacement—we would suggest that patients undergoing pituitary surgery that develop COVID-19 are likely to be at similar or greater risk. These risks must be balanced carefully against the natural history of pituitary disease and, in particular, whether undue delay may result in irreversible morbidity such as visual loss in patients with pituitary apoplexy. The surgeon remains in direct contact with the patient throughout their operation and is therefore at risk of contracting COVID-19 if the patient has an active infection. Iorio-Morin et al. [4] suggest that surgeons performing transsphenoidal pituitary surgery (TSS) may be at the greatest risk, because such surgery is performed under general anesthesia, requiring intubation and extubation, exposes the colonized nasal mucosa, and usually involves sphenoid drilling, which can result in aerosolization of contaminated tissues. The healthcare institution will invariably divert resources from elective services to support the care of patients with COVID-19, with a knock-on effect on the capacity to manage patients with pituitary disease (Table 1). Bernstein et al. [5] suggest that surgery is particularly affected in such reorganization, because of both the need for redeployment of anesthesiologists able to manage patient airways, and availability of protective physical resources such as masks, gowns, and gloves (personal protective equipment; PPE). Furthermore, in areas with high number of infections, several operating rooms (OR)s were converted into intensive care units (ICU) to treat patients with COVID-19, thus limiting patients’ access to elective surgery even more. Recommendations for pituitary surgery When the viral risk is decreasing in a specific geographic area, we would advocate a stepwise, but flexible normalization of activity, addressing each of the aforementioned factors. Burke et al. [6] proposed a staged volume limiting approach to scheduling surgical cases depending on the number of community cases and inpatients with COVID-19, and staffing shortages. In extreme cases, where significant assistance is required from outside institutions, only emergent cases can proceed. Until further data become available, all patients undergoing pituitary surgery should undergo screening for COVID-19, until a vaccine is developed or herd immunity is achieved by other means. At the least, we recommend screening patients for cough, fever, or other recognized symptoms of infection with SARS-CoV-2, and taking swab samples for testing if there is any clinical suspicion. Depending on the level of COVID-19 activity in the community, and available resources, a more exhaustive strategy may be appropriate, including isolation of patients for up to 2 weeks before surgery, paired swabs and/or serological tests for all patients irrespective of symptoms, and routine chest X-ray or chest computed tomography (CT), depending on local guidance. In patients with COVID-19 in whom surgery is indicated, in general we recommend delaying surgery if possible, ideally until patients no longer have symptoms and have a negative swab test result. The nature of the patient’s pituitary disease is an important consideration, and we propose stratifying cases as emergent, urgent, or elective. We recommend that patients continue to be operated on in an emergent fashion if they present with pituitary apoplexy, acute severe visual loss, or other significant mass effect, or if there is concern regarding malignant pathology. Selected patients with slowly progressive visual loss, functioning tumors with aggressive clinical features, and those with an unclear diagnosis, may also benefit from urgent (but not emergent) surgery, with decisions made on a case-by-case basis. Patients with incidental and asymptomatic tumors, known nonfunctioning adenomas [7] or functioning tumors, which are well controlled with medical therapy, can be scheduled as elective cases. In most cases, TSS remains the safest, most effective, and most efficient approach to pituitary tumors. In a series of 9 consecutive patients without COVID-19 undergoing pituitary and skull base surgery during the pandemic, Kolias et al. [8] reported that none of the patients or staff contracted COVID-19 following adoption of a standardized risk-mitigation strategy. In the rare instances where a patient with COVID-19 requires emergent surgery that cannot be deferred, alternative transcranial approaches may be considered (avoiding nasal mucosa). To replace high-speed drilling, the use of non-powered tools such as rongeurs and chisels has been recommended. If this is not possible large suction tubes can be used to aspirate as much particulate matter as possible [9]. In such cases, the availability and use of PPE, and in particular filtering facepiece (FFP3) respirators, is mandated. Depending on the level of COVID-19 activity in the community, and the availability and effectiveness of testing, PPE may be appropriate in all cases. At an institutional level, there must remain flexibility in anticipation of further waves of COVID-19. This necessitates a reduction in capacity, particularly in available ICU beds, that must be recognized when scheduling challenging surgical cases. In the long term, resumption of full elective workloads depends on wider national and international factors, including widespread testing, and widespread immunity through vaccination or other means. Pituitary diseases diagnosis and management Acromegaly Acromegaly, a condition that arises from growth hormone (GH) excess, generally occurs as a result of autonomous GH secretion from a somatotroph pituitary adenoma [10, 11], is associated with substantial morbidity and excess mortality, which can be mitigated by prompt and adequate treatment [12]. Diagnosis is often delayed because of the low prevalence of the disease, the frequently non-specific nature of presenting symptoms, and the typically subtle progression of clinical features [10, 11]. During the COVID-19 pandemic many outpatient clinics have closed or limited work hours. Patients are often reluctant to seek care out of fear of possible exposure to the coronavirus. Therefore, even longer diagnostic delays are anticipated. In addition, patients who present with vision loss and larger tumors encroaching upon the optic apparatus are at risk for experiencing persistent visual compromise unless the optic chiasm and nerves are promptly decompressed. To improve patient access to care and minimize potentially deleterious delays in diagnosis and treatment, clinicians may conduct virtual visits (VV) using secure, internet-based electronic medical record platforms. A detailed history can be obtained and a limited physical examination is possible, including inspection of the face, skin and extremities. Diagnosis Establishing the diagnosis of acromegaly requires testing of serum insulin-like growth factor-I (IGF-I) levels [11] (Box 1). Access to accurate IGF-I assays is critical in light of the substantial analytical and post-analytical problems that have plagued several IGF-I immunoassays. While the oral glucose tolerance test (OGTT) is considered the diagnostic “gold standard”, this test is not essential in many patients, including those with a clear-cut clinical picture and an unequivocally elevated serum IGF-I level. Deferring the lengthy (2-h) OGTT may minimize the risk of potential exposure to infectious agents. Given the over-representation of macroadenomas in patients with acromegaly, pituitary imaging is indicated, preferably by a pituitary-specific magnetic resonance imaging (MRI) protocol, although CT may be performed to rule out a large tumor if MRI is not feasible. Obtaining imaging at satellite sites detached from major hospitals may also decrease the risk of infection exposure. Management Transsphenoidal pituitary surgery remains the treatment of choice for most patients with acromegaly [10, 11], and patients with visual compromise as a result of a pituitary adenoma compressing the optic apparatus should still undergo pituitary surgery promptly. Other patients could be treated medically until the pandemic subsides. Medical treatment options are somatostatin receptor ligands (SRLs), octreotide long-acting release (LAR), lanreotide depot and pasireotide LAR, pegvisomant and cabergoline (used off-label) [13]. Medical therapies can be effective in providing symptomatic relief, control GH excess or action, and potentially reduce tumor size (except pegvisomant, which does not have direct antiproliferative effects). Preoperative medical therapy has been reported to improve surgical outcomes in some, but not all studies. Pasireotide, which potentially can induce QTc prolongation, should be used with caution in patients who are taking, either as prophylaxis or treatment, medications for COVID-19 (azithromycin, hydroxychloroquine), which can also have an effect on QTc interval. Furthermore, as hyperglycemia is very frequent in patients treated with pasireotide and needs close monitoring at start of the treatment, this treatment should be reserved for truly resistant cases, with large tumors and who cannot have surgery yet. Notably, lanreotide depot, cabergoline or pegvisomant can be administered by the patient or a family member and therefore an in-person visit to a clinic is not required. If SRLs that require health care professional administration are required, raising the dose may allow the interval between injections to be extended beyond 4 weeks while maintaining disease control. Virtual visits can be implemented to monitor the patient’s course and response to medical therapy during the pandemic. Careful management of comorbidities associated with acromegaly remains an essential part of patient care [14, 15]. Prolactinomas Hyperprolactinemia may be physiological in origin or arise because of an underlying pathophysiologic cause, medication use or laboratory artifact. Therefore, an initial evaluation for hyperprolactinemia should include a comprehensive medication history, a thorough evaluation for secondary causes, including primary hypothyroidism, and a careful assessment for clinical features of hyperprolactinemia, including hypogonadism and galactorrhea. Unless a secondary cause of hyperprolactinemia can be established definitively, further investigation is indicated to evaluate the etiology of hyperprolactinemia. Diagnosis The diagnosis of a lactotroph adenoma can be inferred in most patients based on the presence of a pituitary adenoma and an elevated prolactin level, which is typically proportionate in magnitude to adenoma size. Pituitary imaging (MRI or CT) is therefore a key step in the investigation of hyperprolactinemia. Evaluation for hypopituitarism is also necessary. Management Although observation and routine follow-up with serial prolactin levels and imaging is acceptable for patients who are asymptomatic and who have a microadenoma, most patients diagnosed with a prolactinoma will require treatment. Dopamine-agonists (DA) can normalize prolactin levels and lead to reduction in size of the lactotroph adenoma [16]. In patients who have a microadenoma and who are not seeking fertility, hormone-replacement therapy may also be appropriate if serum prolactin is routinely followed and imaging performed as necessary. Medical therapy can be managed effectively and efficiently via VVs coupled with laboratory/imaging studies as needed. However, in all patients in whom a DA will be initiated, it is critical that a comprehensive psychiatric history is obtained prior to commencing treatment. Patients may not readily volunteer their psychiatric history and may not appreciate the relevance of such information. For example, until specifically questioned about their psychiatric history, the patient described in the illustrative case (Box 2) did not report a history of severe depression, suicide attempt and prolonged psychiatric hospitalization 8 months prior to presentation with hyperprolactinemia. At the time of the visit, he was not taking any psychiatric medications and was not under the care of a mental health team. Given this patient’s significant psychiatric history, lack of ongoing psychiatric care, and the well-recognized adverse effects of DA therapy, including increased impulsivity, depression and psychosis [17], a DA was not initiated. Counseling on potential DA side-effects is crucial, as they may also present in individuals with no prior psychiatric history [17]. Furthermore, during the COVID-19 pandemic when there is reduced access to routine medical and mental health care, patients who develop symptoms of severe depression may not have ready access to mental health services, or may not seek care. Therefore, it is particularly important to make patients aware of these potential side effects and the critical importance of reporting them. In the small number of patients for whom medical therapy is not possible and where surveillance is not appropriate (e.g., macroprolactinoma with visual loss) the risks and benefits of surgical intervention will need to be carefully weighed. Cushing’s disease Left untreated, CD has significant morbidity and mortality, and delays in diagnosis (from a few months to even years) are common. Clinical presentation is also very variable with some patients having subtle symptoms while others present with more striking/classical features. Severe hypercortisolemia induces immunosuppression, which may place patients with untreated CD at particular risk from COVID-19. New patients referred for endocrinology evaluation with clinical suspicion of Cushing’s Diagnosis Screening for, and confirmation of Cushing’s syndrome (CS) and, furthermore, localization for CD is laborious and requires serial visits and testing procedures [18, 19]. If initial laboratory abnormalities are consistent with hypercortisolemia, a VV should allow for an estimate of the severity of clinical presentation and facilitate planning for further testing and treatment. Careful questioning for potential causes of exogenous CS (including, but not limited to, history of high-dose oral corticosteroids, intraarticular injections or topical preparations) is an important first step. Subsequently, establishing the likelihood and pretest probability of CS is more important than ever now, when testing may be delayed. While presentation varies significantly between patients, some features, although not all highly sensitive, are more specific, e.g. easy bruising, facial plethora, large wide > 1 cm violaceous striae, proximal weakness and hypokalemia. Diagnosis of CS is often challenging even under normal circumstances, however, a diagnosis by VV is more nuanced and difficult. Conversely, if a patient has a high likelihood of CS, we recommend limited laboratory evaluation (urinary free cortisol (UFC), adrenocorticotropic hormone (ACTH), liver panel, basic metabolic panel), preferably at a smaller local laboratory rather than a Pituitary Center, to reduce viral risk exposure. Salivary cortisol samples could represent a hazard for laboratory staff and they are prohibited in some countries [18, 19]. In the US, laboratories have continued to process salivary cortisol samples and salivary cortisol has higher sensitivity compared with UFC and has the convenience of mailing multiple specimens at a time, without travel [18, 19]. Though usually we strongly recommend sequential laboratory testing under normal circumstances, limiting trips to a laboratory is preferred during COVID-19. If preliminary assessment confirms ACTH-dependent CS [18, 19] and no visual symptoms are reported, imaging may be delayed. However, in the presence of any visual symptoms, and recognizing the challenges of undertaking a formal visual field assessment, proceeding directly with MRI or CT (shorter exam time and easier machine access) imaging, will allow confirmation or exclusion of a large pituitary adenoma compressing the optic chiasm. If the latter is confirmed, the patient will need to be evaluated by a neurosurgeon. In contrast, a small pituitary adenoma may not be visible on CT, but in such cases MRI may be deferred for a few months until COVID-19 restrictions limiting access to care are lifted. Another VV will help to decide, in conjunction with patient’s preference, the best next step, which in cases of more severe clinical Cushing’s, and in the absence of a large pituitary adenoma, would be medical therapy. The magnitude of 24 h-UFC elevation could also represent a criterion for primary therapy, since higher values have been associated with increased risk of infection. In parallel, it is also important to address comorbidities including diabetes mellitus, hypertension and hyperlipidemia. In light of the increased risk of venous thromboembolism, in discussion with primary care providers, plans for regular mobilization/exercise as permitted (including at home when orders to stay in are in place) and/or prophylactic low weight molecular heparin should be considered. Management First line medical therapy options vary, depending on country availability, regulatory approval and patient comorbidities. Ideally, an oral medication, which is easier to administer is preferred; options include ketoconazole, osilodrostat or metyrapone [20, 21]. Cabergoline therapy, which has lesser efficacy [20, 21] compared with adrenal steroidogenesis inhibitors, can be also attempted in very mild cases. The initial laboratory profile should be reviewed to exclude significant abnormalities of renal and/or liver function prior to commencing treatment. Starting doses of all medications should be the lowest possible to avoid adrenal insufficiency (AI) and up titration should be slow, with VVs weekly if possible. All patients with CS on any type of medical therapy should have prescribed glucocorticoids (GC) both in oral and injectable forms available at home and information regarding AI should be provided during a VV when starting therapy for CS. Down titration of other medications for diabetes and hypertension may also be needed over time. Pasireotide (both subcutaneous and LAR preparations) would be a second line option, reflecting higher risk of significant hyperglycemia that would require treatment [22]. If the clinical features of CS are mild and longstanding, with no acute deterioration, another possibility is to aggressively treat the associated comorbidities for a few months; depending on local circumstances, this may actually be less risky for the patient by avoiding the risk of AI/crisis and the need for an emergency department (ED) visit and/or admission. For patients with Cushing’s disease with endocrinology chronic care Patients in remission after surgery with adrenal insufficiency on glucocorticoid replacement These patients are likely to remain at slightly higher risk of COVID-19 infection due to immunosuppression from previous hypercortisolemia. Furthermore, GC doses should be adjusted to prevent adrenal crisis and visits to an ED. Lower GC daily doses (10–15 mg hydrocortisone/day) are now frequently used for replacement and virtual and/or phone visits are encouraged to evaluate an appropriate regimen and sufficient supplies of medication and injectable GC (at home) should be prescribed. Patients with potential symptoms of under replacement may require an increase in daily dose, while balancing any risk of GC over replacement and possible consequent immunosuppression. Patients in non-remission treated with medical therapy (dependent on country availability) Doses may need to be adjusted to reduce the risk of AI/crisis and reduce the need for serial laboratory work. Monthly or bimonthly VVs are appropriate for clinical evaluation and up titration should be slower than usual. Patients with CD on medical therapy need to have at home prescriptions for oral and injectable GC and instruction on AI surveillance. Patients should also be advised, that if they develop a fever, to stop Cushing’s medication for few days; if they develop AI symptoms, GC administration will be required. In some countries, block and replace regimens are also employed to avoid risk of AI. Of note, for mifepristone, a glucocorticoid receptor (GR) antagonist, patients will require much higher doses of GC to reverse the blockade (1 mg of dexamethasone approximately per 400 mg of mifepristone) and for several days, as drug metabolites also have GR antagonist effects. Furthermore, for all patients who have made dose changes or discontinued medications for Cushing’s, it is essential to follow very closely and consider adjustments in the doses of concomitant medications, especially insulin, other antidiabetic and antihypertensive medications, and potassium supplements. If patients have history of radiotherapy and are still on medications for CD, a VV every few months should be performed to determine if anti-Cushing’s treatment can be slowly down-titrated (to avoid AI). A morning serum cortisol would be ideal to rule out AI off medications, however, if laboratory testing cannot be undertaken safely, clinical evaluation by serial VVs can be helpful. While head-to-head data will never be available, in COVID-19 hotspots, given the higher risk of infection with laboratory testing or face to face visits, mild hypercortisolemia might be “better” than adrenal crisis, especially in the short term! Patients with CD have increased rates of depression, anxiety and can have decreased quality of life (QoL) even when in long-term remission, thus in the challenging circumstances of the current pandemic it is it even more important to focus on psychological evaluation during virtual endocrinology visits, with referral to virtual counseling as needed. From https://link.springer.com/article/10.1007/s11102-020-01059-7?utm_source=newsletter_370
  25. Presented by Georgios A. Zenonos, MD Assistant Professor of Neurological Surgery Associate Director, Center for Skull Base Surgery University of Pittsburgh Medical Center 200 Lothrop Street, Pittsburgh PA, 15217 Presbyterian Hospital, Suite B400 No Registration is Required. It will be webcast by Microsoft Teams. Click here to attend. Date: Friday, July 17, 2020 Time: 10:00 AM Pacific Daylight Time, 1:00 PM Eastern Daylight Time
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