Women with type 1 diabetes experience changes in insulin requirements in pregnancy and throughout the menstrual cycle. It remains to be explored whether women with type 1 diabetes perceive changes in glucose regulation during and after the menopausal transition, another period of marked hormonal change in a woman’s life. We conducted a cross-sectional survey to investigate whether women with type 1 diabetes perceive changes in glucose regulation after their final menstrual period. The online questionnaires were distributed through advertisements in hospitals and through online platforms for people living with type 1 diabetes in the Netherlands. Postmenopausal women (≥1 year of amenorrhoea) with type 1 diabetes, aged 45–65 years, were included. Participants with primary amenorrhoea, premenopausal hysterectomy or a postmenopausal diabetes diagnosis were excluded from the study. The primary outcome was the extent to which participants perceived changes in their glucose regulation following their final menstrual period, assessed using a five-point Likert scale. Menopausal symptom severity was estimated using the Greene climacteric scale (GCS). Questionnaires from a total of 159 women were eligible for inclusion. Participants had a mean age of 54.9 years (SD 3.8), a mean diabetes duration of 30.3 years (SD 12.8), and had their final menstrual period at a mean age of 50.1 years (SD 5.0). Overall, 67.4 https://doi.org/10.34894/84QJOO .

Purpose Given the ongoing need to reduce the delay in diagnosis of acromegaly, the aim of the current study was to develop a screening algorithm that: finds as many patients as possible who have already been diagnosed with acromegaly (=sensitivity), while identifying a limited number of additional patients who are at risk for acromegaly as a proxy for specificity. Methods CTcue data mining software (version 4.7, IQVIA Inc., USA) was used to develop a screening algorithm. Data were extracted from the electronic health records of a tertiary centre. Multiple sources (literature review, real-world evidence and expert opinion) were used to identify predictors such as clinical manifestations, comorbidities and frequently consulted specialists, for inclusion in the algorithm. Based on different combinations of predictors, several exploratory search strategies were constructed in CTcue and algorithms with the highest sensitivity were further adapted. Results A total of 68 predictors were identified and grouped into 5 categories. After exploratory analysis and fine-tuning, an algorithm combining pathognomonic changes in clinical appearance with manifestations considered by medical experts to be most characteristic of acromegaly (hyperhidrosis, sleep apnoea, arthralgia, headache and type 2 diabetes mellitus) detected 48/90 of patients with previously diagnosed acromegaly, while identifying an additional 1844/1,7 million of possible at-risk patients. Conclusion We found that our best algorithm led to the detection of more than half of patients with previously diagnosed acromegaly. The same algorithm identified 0.1 % of the hospital population as potentially having acromegaly, which is approximately 10 times higher than the estimated worldwide prevalence. These results seem promising but need further improvement and validation.

OBJECTIVES:One of the recommended initial tests for diagnosing neoplastic hypercortisolism is the measurement of late-night salivary cortisol (CortisolLNSa). Published cut-off values for CortisolLNSa and late-night salivary cortisone (CortisoneLNSa) vary widely between studies. This study aims to establish cut-off values for CortisolLNSa and CortisoneLNSa using liquid chromatography-tandem mass spectrometry and to determine which salivary hormone performs better in distinguishing between people with and without neoplastic hypercortisolism. METHODS:A retrospective study was conducted on subjects screened for endogenous hypercortisolism at Amsterdam UMC between December 2015 and February 2022. 25 subjects with and 430 subjects without neoplastic hypercortisolism were included. The diagnosis neoplastic hypercortisolism was confirmed by histology and postoperative clinical features, not on biochemical tests, and excluded based on a follow-up of at least 12 months without progressive clinical signs of neoplastic hypercortisolism. Salivary samples were collected between 22:00-23:59 h and CortisolLNSa and CortisoneLNSa concentrations were measured using liquid chromatography-tandem mass spectrometry. RESULTS:The median CortisolLNSa was 7.8 nmol/L for subjects with and 0.8 nmol/L for subjects without neoplastic hypercortisolism (p < 0.001). The median CortisoneLNSa was 35.5 nmol/L and 5.3 nmol/L, respectively (p < 0.001). Optimal diagnostic accuracy was established at 2.25 nmol/L for CortisolLNSa (sensitivity 92 %, specificity 89 %, positive predictive value 32.9 %, negative predictive value 99.5 %) and 15.5 nmol/L for CortisoneLNSa (sensitivity 93.8 %, specificity 94.5 %, positive predictive value 46.9 %, negative predictive value 99.7 %). CONCLUSIONS:We established cut-off values for CortisolLNSa and CortisoneLNSa for the diagnosis of neoplastic hypercortisolism. CortisoneLNSa provided the highest diagnostic accuracy and we therefore recommend it as the preferred salivary measurement.

Context and Objective:The lack of efficacy of somatostatin receptor subtype 2 (SST2) preferring somatostatin analogs in patients with Cushing's disease (CD) results from a downregulating effect of hypercortisolism on SST2 expression. Our objective is to evaluate the efficacy of a strategy with sequential treatment of ketoconazole to reduce cortisol levels and potentially restore SST2 expression followed by octreotide as maintenance therapy in patients with CD. Patients and Design:Fourteen adult patients with CD were prospectively enrolled. Patients started with ketoconazole. Once cortisol levels were normalized, octreotide was initiated. After 2 months of combination therapy, patients were maintained on octreotide monotherapy until the end of the study period (9 months). Treatment success was defined by normalization of urinary free cortisol (UFC) levels. Results:Ketoconazole was able to normalize UFC levels in 11 (79%) patients. Octreotide effectively sustained normal levels of UFC in 3 patients (27%) (responders). Four patients (36%) showed a partial response. The remaining 4 (36%) patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders). Octreotide responders had lower UFC levels at baseline when compared to partial responders and nonresponders (1.40 ± 0.07 vs 2.05 ± 0.20 UNL, P = 0.083). SST2 mRNA was highly expressed in adenomas of 2 responder patients (0.803 and 0.216 copies per hprt). Conclusion:Sequential treatment with ketoconazole to lower cortisol levels followed by octreotide to maintain biochemical remission according to UFC may be effective in a subset of patients with mild CD, suggesting that cortisol-mediated suppression of SST2 expression is a reversible process.

OBJECTIVE:Both tinnitus and sellar masses are common disorders in the general population and sometimes occur together. However, little is known about their relationship. We investigated the prevalence, clinical aspects, and impact of tinnitus in patients with sellar masses, and evaluated the effect of surgical tumor resection on these variables. METHODS:A prospective, controlled, single-center study was conducted, including 57 patients (aged 53.1 ± 16.4 years; 47% male) and 29 of their partners as controls (aged 54.8 ± 14.9 years; 55% male). Participants completed a questionnaire consisting of case history items and the Mini-Tinnitus Questionnaire-Dutch version twice: 1 month preoperatively and 3 months postoperatively. RESULTS:Prior to transsphenoidal surgery, 24/57 (42%) of patients and 8/29 (28%) of controls reported having tinnitus (P = 0.19). After surgery, the prevalence of tinnitus in the patient group decreased to 12/49 (24%), while 4 patients reported an increase in tinnitus. The impact of tinnitus on daily life remained low. No differences were found in the prevalence, characteristics, and impact of tinnitus before and after surgery compared with controls. CONCLUSIONS:In this study, we found no association between tinnitus and (resection of) sellar masses. However, as the decrease in tinnitus prevalence was more pronounced in patients than in controls, and tinnitus resolved in 1 patient after resection of a giant nonfunctioning pituitary adenoma, and worsened in 2 patients with perioperative bleeding complications, tinnitus may be associated with sellar masses in selected cases.

The circadian rhythm of the central brain clock in the suprachiasmatic nucleus (SCN) is synchronized by light. White adipose tissue (WAT) is one of the metabolic endocrine organs containing a molecular clock, and it is synchronized by the SCN. Excess WAT is a risk factor for health issues including type 2 diabetes mellitus (DM2). We hypothesized that bright-light exposure would affect the human WAT transcriptome. Therefore, we analyzed WAT biopsies from two previously performed randomized cross-over trials (trial 1: n = 8 lean, healthy men, and trial 2: n = 8 men with obesity and DM2). From 7:30 h onwards, all the participants were exposed to either bright or dim light. Five hours later, we performed a subcutaneous abdominal WAT biopsy. RNA-sequencing results showed major group differences between men with obesity and DM2 and lean, healthy men as well as a differential effect of bright-light exposure. For example, gene sets encoding proteins involved in oxidative phosphorylation or respiratory chain complexes were down-regulated under bright-light conditions in lean, healthy men but up-regulated in men with obesity and DM2. In addition to evident group differences between men with obesity and DM2 and healthy lean subjects, autonomic or neuroendocrine signals resulting from bright-light exposure also differentially affect the WAT transcriptome.

The circadian timing system controls glucose metabolism in a time-of-day dependent manner. In mammals, the circadian timing system consists of the main central clock in the bilateral suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks in peripheral tissues. The oscillations produced by these different clocks with a period of approximately 24-h are generated by the transcriptional-translational feedback loops of a set of core clock genes. Glucose homeostasis is one of the daily rhythms controlled by this circadian timing system. The central pacemaker in the SCN controls glucose homeostasis through its neural projections to hypothalamic hubs that are in control of feeding behavior and energy metabolism. Using hormones such as adrenal glucocorticoids and melatonin and the autonomic nervous system, the SCN modulates critical processes such as glucose production and insulin sensitivity. Peripheral clocks in tissues, such as the liver, muscle, and adipose tissue serve to enhance and sustain these SCN signals. In the optimal situation all these clocks are synchronized and aligned with behavior and the environmental light/dark cycle. A negative impact on glucose metabolism becomes apparent when the internal timing system becomes disturbed, also known as circadian desynchrony or circadian misalignment. Circadian desynchrony may occur at several levels, as the mistiming of light exposure or sleep will especially affect the central clock, whereas mistiming of food intake or physical activity will especially involve the peripheral clocks. In this review, we will summarize the literature investigating the impact of circadian desynchrony on glucose metabolism and how it may result in the development of insulin resistance. In addition, we will discuss potential strategies aimed at reinstating circadian synchrony to improve insulin sensitivity and contribute to the prevention of type 2 diabetes.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Purpose Graves’ disease (GD) is an auto-immune cause of hyperthyroidism. First-line treatment often consists of a 12–18 month course of antithyroid drugs (ATD). After discontinuation of ATD, GD relapses in approximately 50% of patients. The ‘Graves recurrent event after therapy+ ’ (GREAT+) score may predict individual relapse chances after ATD discontinuation more accurately based on clinical and laboratory parameters at diagnosis. We investigated the need for the GREAT+ score through an online questionnaire among GD patients and physicians treating GD. Methods An anonymous online questionnaire was distributed to patients and physicians between June 2022 and August 2023. Results The questionnaire was completed by 532 patients and 44 physicians. Results showed that 94% of patients were interested in knowing their GREAT+ score at the start of treatment. 55% would consider definite treatment (radioiodine/thyroidectomy) as first-line treatment in case of a high relapse chance. 98% of the physicians indicated the GREAT + score would support patient counseling. 84% may change their advice for first-line treatment if a patient has a high relapse chance based on the score. Conclusion Patients and physicians considered the GREAT+ score as a valuable addition to the current available information which could change treatment decisions. Therefore, external validation of the GREAT+ score is justified to implement this score in clinical practice.

Entrustable Professional Activities (EPAs) are an important tool to support individualisation of medical training in a competency-based setting and are increasingly implemented in the clinical speciality training for endocrinologist. This study aims to assess interrater agreement and factors that potentially impact EPA scores. Five known factors that affect entrustment decisions in health profesions training (capability, integrity, reliability, humility, agency) were used in this study. A case-vignette study using standardised written cases. Case vignettes (n = 6) on the topics thyroid disease, pituitary disease, adrenal disease, calcium and bone disorders, diabetes mellitus, and gonadal disorders were written by two endocrinologists and a medical education expert and assessed by endocrinologists experienced in the supervision of residents in training. Primary outcome is the inter-rater agreement of entrustment decisions for endocrine EPAs among raters. Secondary outcomes included the dichotomous interrater agreement (entrusted vs. non-entrusted), and an exploration of factors that impact decision-making. The study protocol was registered and approved by the Ethical Review Board of the Netherlands Association for Medical Education (NVMO-ERB # 2020.2.5). Nine endocrinologists from six different academic regions participated. Overall, the Fleiss Kappa measure of agreement for the EPA level was 0.11 (95% CI: 0.03–0.22) and for the entrustment decision 0.24 (95% CI 0.11–0.37). Of the five features that impacted the entrustment decision, capability was ranked as the most important by a majority of raters (56%–67%) in every case. There is a considerable discrepancy between the EPA levels assigned by different raters. These findings emphasise the need to base entrustment decisions on multiple observations, made by a team of supervisors and enriched with factors other than direct medical competence.

PURPOSE:Pituitary surgery can lead to post-surgical adrenal insufficiency with the need for glucocorticoid replacement and significant disease related burden. In patients who do not receive hydrocortisone replacement before surgery, at our center, an early morning plasma cortisol concentration using a cut-off value of 450 nmol/L 3 days after surgery (POD3) is used to guide the need for hydrocortisone replacement until dynamic confirmatory testing using metyrapone. The aim of this study was to critically assess the currently used diagnostic and treatment algorithm in patients undergoing pituitary surgery in our pituitary reference center. METHODS:Retrospective analysis of all patients with a POD3 plasma cortisol concentration < 450 nmol/L who received hydrocortisone replacement and a metyrapone test after 3 months. Plasma cortisol concentration was measured using an electrochemiluminescence immunoassay (Roche). All patients who underwent postoperative testing using metyrapone at Amsterdam UMC between January 2018 and February 2022 were included. Patients with Cushing's disease or those with hydrocortisone replacement prior to surgery were excluded. RESULTS:Ninety-five patients were included in the analysis. The postoperative cortisol concentration above which no patient had adrenal insufficiency (i.e. 11-deoxycortisol > 200 nmol/L) was 357 nmol/L (Sensitivity 100%, Specificity 31%, PPV:32%, NPV:100%). This translates into a 28% reduction in the need for hydrocortisone replacement compared with the presently used cortisol cut-off value of 450 nmol/L. CONCLUSION:Early morning plasma cortisol cut-off values lower than 450 nmol/L can safely be used to guide the need for hydrocortisone replacement after pituitary surgery.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

ABSTRACTIntroductionSellar masses are common intracranial neoplasms. Their clinical manifestations vary widely and include headache. We aimed to determine whether the prevalence and characteristics of headache in patients with sellar tumours differ from the general population and to investigate the effect of tumour resection on this complaint.MethodsWe performed a prospective, controlled study in a single tertiary centre and included 57 patients that underwent transsphenoidal resection for a sellar mass (53% females, mean age 53.5 ± 16.4) and 29 of their partners (controls; 45% females, mean age 54.8 ± 14.9). Outcome measures were prevalence, characteristics and impact of headache 1 month preoperatively and at neurosurgical follow‐up 3 months postoperatively.ResultsPreoperatively, the prevalence of regular headache (≥1 time per month) was higher in patients than in controls (54% vs. 17%, p < 0.001), and patients scored higher on headache impact questionnaires (all p ≤ 0.01). At postoperative follow‐up, headache prevalence decreased in both groups, but the decrease in regular headache frequency and impact was larger in patients than in controls, and no between‐group differences remained.ConclusionsMore than half of patients with sellar tumours suffer from at least once‐monthly headaches, and both regular headache occurrence and impact are higher compared with controls. The more pronounced decrease in headache complaints in patients versus controls at postoperative follow‐up suggests an additional effect of tumour resection next to the factor time.