Disclosure: W. Gallardo: Ipsen, Merck, Novartis Pharmaceuticals, Pfizer, Inc., Recordati Rare Diseases. C. De Block: A Menarini Diagnostics, Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Indigo Diabetes. Z. Hussein: Abbott Laboratories, Boehringer Ingelheim, Novartis Pharmaceuticals, Novo Nordisk, Zuellig Pharma Therapeutics. E. Grineva: Ipsen, Pfizer, Inc., Recordati Rare Diseases, Merck. N. Kapoor: None. J.M. Escalante Pulido: None. G. Rollin: Abbott Laboratories, AstraZeneca, Bayer, Inc., Merck Serono, Novo Nordisk. R. Baggenstoss: None. A. Piacentini: Recordati. A. Mueller: Recordati Rare Diseases. M. Gadelha: Crinetics Pharmaceuticals, Ipsen, Novo Nordisk, Recordati Rare Diseases. Introduction: The long-term safety of pasireotide (a second-generation, multireceptor-targeted somatostatin receptor ligand) in patients (pts) with Cushing’s disease (CD), acromegaly and other rare endocrine disorders was assessed in an open-label, multicenter, Phase IV rollover study (B2412; NCT01794793). Final data are reported for CD pts who received pasireotide for ≤10 years during the rollover. Methods: Pts who were judged by the investigator to be benefiting from pasireotide at parent study end were eligible to enter the rollover and initially remained on the same pasireotide dose. Data are reported for CD pts from 4 parent studies who received pasireotide long-acting release (LAR; n=33) or subcutaneous (sc; n=29) and ≥1 dose during the rollover (except for 1 pt who only received pasireotide sc in the parent study). The primary objective of the rollover was to evaluate long-term pasireotide safety, assessed by frequency of adverse events (AEs)/serious AEs (SAEs). Data are reported from start to end of the rollover, unless otherwise stated. Results: Overall, 62 CD pts from 15 countries entered the rollover to receive pasireotide LAR or sc; 66.1% (n=41) completed treatment and 33.9% (n=21) discontinued, most commonly because of unsatisfactory therapeutic effect (12.9%, n=8). Median (min-max) duration of exposure and average dose from parent study baseline to rollover end was 7.4 years (2.7-9.9) and 32.6 mg/month (6-49) for pasireotide LAR and 5.8 years (0.6-15.8) and 469.3 µg/day (0-1661) for pasireotide sc. AEs, regardless of study drug relationship (pasireotide LAR and sc), were reported in 77.4% (n=48) of pts, most commonly (≥10% of pts) nasopharyngitis (24.2%, n=15), pharyngitis, diarrhea (each 14.5%, n=9), hypoglycemia, urinary tract infection and back pain (each 12.9%, n=8). Hyperglycemia and diabetes mellitus (DM) were reported in 2 and 4 pts, respectively. 62.9% (n=39) of pts required additional therapy to manage AEs, most commonly for nasopharyngitis (16.1%, n=10). 1 and 4 pts required additional therapy to manage hyperglycemia and DM, respectively. 9.7% (n=6) of pts required dose interruption/adjustment to manage AEs, most commonly for endocrine disorders (Cushing’s syndrome and hyperadrenocorticism, each 1.6%, n=1). In total, 4 pts (6.5%) discontinued treatment because of AEs (COVID-19, hyperglycemia, increased glycated hemoglobin, muscular weakness; each n=1). SAEs were reported in 33.9% (n=21) of patients, most commonly cholelithiasis (4.8%, n=3). 4 patients died during the rollover (colon cancer, COVID-19, pneumonia, septic shock; each n=1). No new safety signals were identified. Conclusion: Pasireotide is a well-tolerated long-term treatment option for CD pts, with pts having received treatment for ≤16 years from parent study entry. Few pts discontinued because of AEs, including hyperglycemia, and hyperglycemia was infrequent during the study. Presentation: Sunday, July 13, 2025

We developed a prediction model for postprandial glycemic response (PPGR) in pregnant women, including those with diet-treated gestational diabetes mellitus (GDM) and healthy women, and explored the role of gut microbiota in improving prediction accuracy. The study involved 105 pregnant women (77 with GDM, 28 healthy), who underwent continuous glucose monitoring (CGM) for 7 days, provided food diaries, and gave stool samples for microbiome analysis. Machine learning models were created using CGM data, meal content, lifestyle factors, biochemical parameters, and microbiota data (16S rRNA gene sequence analysis). Adding microbiome data increased the explained variance in peak glycemic levels (GLUmax) from 34 to 42% and in incremental area under the glycemic curve (iAUC120) from 50 to 52%. The final model showed better correlation with measured PPGRs than one based only on carbohydrate count (r = 0.72 vs. r = 0.51 for iAUC120). Although microbiome features were important, their contribution to model performance was modest.

Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a common endocrine disorder. Minimal invasive parathyroidectomy (PTX) is favorable surgical approach in PHPT treatment. Its success is highly dependent on accurate preoperative localization of all causative parathyroid adenomas. Despite the fact that wide range of visualization methods are applied in PHPT diagnostics, PHPT persistence occurs. Therefore, the search for additional visualizing tools of parathyroid adenomas remains relevant. Recently, positron emission tomography/computed tomography (PET/CT) has been used in order to improve PHPT diagnostics. OBJECTIVE: To evaluate the diagnostic effectiveness of PET/CT with 11 C-methionine and 11 C-choline in patients with PHPT based on the intensity of both tracers uptake in parathyroid adenomas. MATERIALS AND METHODS: The data of 26 patients diagnosed with PHPT was analyzed. PET/CT with 11 C-choline was performed in 14 patients, with 11 C-methionine — in 10 patients, with two radiopharmaceuticals — in two patients. All patients underwent PTX. Histological examination’s results were compared with the results of PET/CT. Using the software, the standardized uptake value of radiopharmaceuticals in histologically verified parathyroid adenomas/hyperplasias and in the trapezius muscle was obtained, then tumor-to-background ratios (TBR) of 11 C-methionine and 11 C-choline were calculated.Statistics: Software STATISTICA 10 was used in statistical analysis.RESULTS: 11 C-choline TBR median was of 2.3 (1.6; 3.2), median of 11 C-methionine TBR showed slightly higher values — 2.5 (1.9; 3,6). However, no significant difference was found between the two radiopharmaceuticals’ uptake in parathyroid adenomas.DISCUSSION: The scientific impact of current study is determined by the diagnostic effectiveness comparison between PET/CT with 11 C-methionine and 11 C-choline, which is based on the accumulation intensity of both radiopharmaceuticals in parathyroid adenomas.CONCLUSION: The intensity of accumulation of 11 C-methionine and 11 C-choline by hyperfunctioning parathyroid tissue does not differ significantly. Thus both tracers might be successfully applied for topic diagnosis of parathyroid adenomas in patients with PHPT.

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

Background. Currently, the “gold standard” of differential diagnosis of Cushing’s disease is inferior petrosal sinus sampling and measurement of the adenocorticotropic hormone (ACTH) level. The studied literature data indicate a wide variability in the sensitivity and specificity of inferior petrosal sinus sampling in the range of 85–100 and 67–100 %, respectively, which can lead to an erroneous diagnosis of the source of ACTH hyperproduction and, as a consequence, to incorrect and untimely treatment.Aim.To improve the results of differential diagnosis of Cushing»s disease by using bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses.Materials and methods. Cohort single-center retro/prospective study of 70 patients with confirmed ACTH-dependent Cushing’s syndrome. For the purpose of differential diagnosis, a number of indicators were calculated: central-peripheral ratio, prolactin-normalized ACTH ratio, successful catheterization. Sampling results were evaluated in comparison with contrast-enhanced pituitary magnetic resonance imaging data and intraoperative data.Results. The study of the central-peripheral ratio showed the need to assess it simultaneously at the level of the cavernous and inferior petrosal sinuses. This approach makes it possible to significantly increase the sensitivity and specificity of the applied gradient to 93.1 and 85.7 %, respectively. Prolactin-normalized ACTH ratio is a second line predictor in the differential diagnosis of Cushing’s disease with sensitivity and specificity reaching 94.7 and 28.6 %, respectively. The gradient of successful catheterization is a reflection of possible hemodynamic features of a particular sinus, does not serve as an indicator of the correct positioning of microcatheters in the vascular bed.Conclusion. Bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses is an effective method of differential diagnosis of Cushing’s disease and ectopic ACTH-dependent syndrome.

CONTEXT:Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE:To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS:We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS:The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION:This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.

Background: Parathyroid tumors are classified as parathyroid neuroendocrine neoplasia (NEN) by the IARC-WHO classification. These tumors can occur with NENs from other sites, which often require total-body [68Ga]-DOTA-peptides PET/CT. This study aimed to assess the utility of [68Ga]-DOTA-peptide PET/CT in imaging parathyroid NENs and to evaluate the underlying mechanisms. Methods: Fifty patients with primary hyperparathyroidism (PHPT) and parathyroid NENs histologically confirmed as parathyroid adenomas (PAs) were included. PET/CT with [68Ga]-DOTA-peptide was performed in 16 patients with localized PAs, including 10 with MEN1 syndrome. Somatostatin receptor types 2 and 5 (SST2 and SST5) staining was performed on PAs from 48 patients. Somatostatin analogs (SSA) were prescribed in four patients with MEN 1 syndrome and 1 with persistent acromegaly, all with PAs and PHPT. The therapy effects on calcium and parathyroid hormone (iPTH) were evaluated. Results: [68Ga]-DOTA-peptide PET/CT detected 20 PAs with high radiopharmaceutical uptake. SST2 expression was negative on PA cell membranes in all cases and positive on endothelium in 39 (81%) PAs. Membrane SST5 expression was positive in 25 (52%) PAs and endothelial was positive in 40 (83%). Serum calcium levels decreased in patients on SSA therapy, while iPTH did not. Conclusions: PET/CT with [68Ga]-DOTA-peptides can detect parathyroid NENs. The incidental detection of high [68Ga]-DOTA-peptide uptake in the parathyroid region during whole-body PET/CT may prompt biochemical evaluation for PHPT. We suggest that endothelial SST expression mediates high radiopharmaceutical uptake by PAs and that SSA treatment can reduce hypercalcemia in PHPT patients.

We aimed to develop a prediction model for postprandial glycemic response (PPGR) in pregnant women with gestational diabetes mellitus (GDM) and to explore the influence of gut microbial data on prediction accuracy. We enrolled 105 pregnant women (70 GDM and 35 healthy). Participants underwent continuous glucose monitoring (CGM) for 7 days and provided detailed food diaries. Stool samples were collected at 28.8 ± 3.6 gestational weeks, followed by 16S rRNA gene sequence analysis. We developed machine learning algorithms for predicting PPGR, incorporating CGM measurements, meal content, lifestyle factors, biochemical parameters, anthropometrics, and gut microbiota data. The accuracy of the models with and without gut microbiota were compared. PPGR prediction models were created based on 2,706 meals with measured PPGRs. The integration of microbiome data in models increased the explained variance in peak glycemic levels (GLUmax) from 34–42% and the explained variance in the incremental area under the glycemic curve 120 minutes after meal start (iAUC120) from 50–52%. The final model performed better than the model based solely on carbohydrate count in terms of correlation between predicted and measured PPGRs (r = 0.72 vs r = 0.51 for iAUC120 and r = 0.66 vs r = 0.35 for GLUmax). After summing the SHAP values of associated features, the microbiome emerged as the fourth most impactful parameter for GLUmax and iAUC120 prediction, following meal composition, CGM measurements, and meal context. Microbiome features rank among the top 5 most impactful parameters in predicting PPGR in women with GDM.

Introduction: Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. Methods: In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. Results: Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. Conclusion: Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity >= 2, BMI >= 40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

BACKGROUND:Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. METHODS:We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. RESULTS:The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. CONCLUSION:We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

We recommend acromegaly to be ruled in all patients with characteristic changes in appearance (A3). In all patients without characteristic changes in appearance, we recommend to rule out acromegaly, if several clinical signs suspicious for acromegaly are present (B3). We recommend acromegaly to be ruled out in all patients with pituitary adenoma (B3). We recommend to rule out acromegaly in all patients with prolactin-secreting adenomas (C4). For laboratory confirmation of acromegaly, we recommend to measure serum insulin-like growth factor-1 (IGF-1, somatomedin C) level (A3). In patients without obvious clinical signs of acromegaly and/or with a moderate increase in IGF-1 levels (IGF-1 index less than 1.3), we recommend to assess the response of somatotropic hormone (GH) to hyperglycemia (GH during an oral glucose tolerance test) (B3). In all patients with biochemically confirmed acromegaly, magnetic resonance imaging of the pituitary gland with intravenous contrast is recommended to assess pituitary adenoma size, location and growth pattern (A3). We recommend to measure blood glucose and glycated hemoglobin in all patients with confirmed acromegaly (B3). We recommend to measure serum prolactin levels in all patients with acromegaly (B3).In all patients with acromegaly and pituitary adenoma, transnasal transsphenoidal adenomectomy is recommended as first-line treatment if the patient’s consent is given and there are no contraindications (A1). For all patients with acromegaly for whom neurosurgical treatment is indicated, surgical intervention is recommended in medical centers, specializing in pituitary diseases, by neurosurgeons who perform at least 50 such operations per year (A3). We recommend that morphological and immunohistochemical examination of the removed pituitary adenoma is performed in all patients with acromegaly (A3). We do not recommend routine medical therapy for acromegaly before surgery as a mean to reduce tumor size (B2).For patients with acromegaly in whom neurosurgical treatment is not indicated or ineffective or while patient awaiting for the effect of radiation therapy, we recommend medical therapy (A1). Long-acting first-generation somatostatin analogues are recommended as first-line drug therapy for acromegaly. In case of partial/complete resistance to or intolerance to somatostatin analogs, pegvisomant is recommended as a second-line medical therapy for acromegaly (A1). We recommend starting pegvisomant from a single dose of 40–80 mg per day subcutaneously, then continue injections at a starting dose of 10 or 15 mg per day with IGF-1 monitoring after 4–6 weeks and dose adjustment if necessary (B2). In patients with acromegaly and a moderate increase in IGF-1 levels, we recommend to initiate cabergoline as medical monotherapy or, if somatostatin analogs are ineffective, in combination with them (B2).In patients with acromegaly, if the disease remains active after surgical treatment, if drug treatment is unavailable, intolerable or ineffective, and repeated neurosurgical intervention is inappropriate, it is we recommend radiation therapy (A1). A multidisciplinary approach is recommended in the management of acromegaly complications (C3).

Context Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations.Methods We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines.Results The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches.Conclusion Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

The ectopic ACTH syndrome (EAS) is a constellation of clinical signs and symptoms caused by chronic excess production of cortisol by the adrenal glands due to stimulation by adrenocorticotropic hormone (ACTH) of extrapituitary origin. EAS is a rare pathology, it accounts for approximately 20% of all cases of ACTH-dependent hypercortisolism and up to 10% of all causes of endogenous autonomic cortisol production, however, it is often associated with severe hypercortisolism and is a life-threatening condition. The sources of ectopic secretion of ACTH are neuroendocrine tumors (NET), which differ in histological type, malignant potential, clinical course, and also have different, often difficult to detect localization. Early identification of ACTH -producing NET reduces the risk of death of the patient both from severe hypercortisolism and the tumor itself. The paper describes the features of the course of EAS, the possibilities of its diagnosis, and presents an algorithm for EAS diagnosis, created on the basis of the latest achievements of Russian and world medicine.

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

In the current work, we aimed to evaluate the association of clinical data of Cushing's disease (CD) patients with USP8 mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in USP8 revealed variants in eighteen adenomas, two of which were described for the first time in CD. USP8 variants were more common in women (94% vs. 76%; p = 0.001), and microadenomas and tumor recurrence were prevalent in the USP8-mutant group (44% vs. 29%; p = 0.04 and 44% vs. 22%; p = 0.0015). Preoperative ACTH and serum cortisol did not differ in the USP8-WT and USP8-mutant patients. All USP8-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of USP8-WT adenomas were double-negative (SST5-/SST2-), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine USP8-mutant and six USP8-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the USP8-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors' trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring USP8 variants.