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Introduction Thyrotropin-secreting pituitary adenoma (TSH-oma) is a rare cause of thyrotoxicosis and represents 0.5-3% of all pituitary adenomas. Given the rarity of the disease and the lack of extensive clinical experience in world practice, the analysis of each case of TSH-secreting pituitary tumors is extremely relevant. Materials and methods: We enrolled consecutive patients with TSH secreting pituitary adenoma. TSH (0,25-3,5 mIU/L), FT4 (9-20 pmol/l) FT3 (2,5-5,5 pmol/l) were measured by Architect i2000SR (Abbott Laboratories, Abbott Park, Illinois, U.S.A). An octreotide test consisted of injecting short-acting somatostatin analogue (SSA) at a dose of 100 μg 3 times a day subcutaneously during 3 days or long-acting SSA 20 mg in 28 days minimum for two months and measuring thyroid profile blood tests before and at the end of the test. MRI was performed on GE Optima MR450w 1.5T. Results: We present 28 case series with TSH-omas followed in our center from 2010 to 2019, the median age - 46 (from 10 to 71 years) with a predominance of a female (21 cases) over a male (7 cases). Clinical manifestations included cardiac arrhythmias (82.1%), neurological changes (60.7%), visual impairment (39.3%), osteoporosis (28.6%), hypopituitarism (7.1%). At first admission, 17 patients had increased TSH, FT3 and FT4; in 7 patients - FT3 and FT4 only, and in 4 - an increase was in one of the hormones; mean value of TSH was 5,04 mIU/L, FT4 - 24,46 pmol/l, FT3 - 8,9 pmol/l. SSBG, CTx, osteocalcin were elevated in 60.9%, 57.9% and 31.6% of cases, respectively. In 88.5% of cases octreotide test led to thyroid hormones normalization. On MRI macroadenomas was registered in 67.9%. In 12 patients, diagnosis was confirmed by immunohistochemical examination. In 12 patients, the diagnosis verification was based on remission after surgical and medical treatment. In the remaining four cases, the diagnosis was made on clinical and laboratory data, however, confirmation was inconceivable due to inefficacy of medical treatment. Remission was achieved in 23 patients: 17 of 21 after neurosurgery (81%), 3 of 7 after primary administration of SSA, and 3 after administration of SSA after surgery (100% remission in cases of combined treatment and 42.9% of monotherapy); 3 out of 5 patients who did not achieve remission were lost for observation. Two patients died: in one case due to the brain herniation and cachexia in active thyrotoxicosis. In second case, the patient developed a mental disorder (catatonia) after the second transphenoidal adenomectomy, which led to death. Conclusion The diagnosis of TSH-oma should be based on all thyroid hormones assessment, since biochemical thyrotoxicosis can manifest itself in various ways. The most effective treatment is transphenoidal adenomectomy. If a neurosurgery is not effective or contraindicative, preoperative preparations SSA can be used.

Objective: The phase 3 CHIASMA OPTIMAL study assessed efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly controlled on injectable somatostatin receptor ligands (SRLs). Sensitivity analyses were conducted for efficacy endpoints using two methods of imputation (i.e., the process of replacing clinical data with substitution values) to address missing data points due to some subjects reverting back to their prior injectable SRL treatment. Methods: Patients were ≥18 years of age and had evidence of active acromegaly with an average IGF-I ≤ 1.0 x ULN (utilizing the IDS iSYS assay calibrated to WHO recombinant reference standard 02/254). At baseline, patients were randomized to receive OOC or placebo for 36 weeks. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (2-value average at weeks 34 and 36) (Samson et al. ENDO 2020). Per study protocol, patient study discontinuations were considered non-responders regardless of clinical response at the time of discontinuation (non-response imputation). Additional exploratory analyses were performed utilizing the last observation carried forward (LOCF) analysis, as well as a completers analysis of response among the subgroup that completed the entire 36 weeks on study drug. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Twenty-eight patients received OOC and 12 failed to maintain biochemical response based on the primary endpoint. Seven of these 12 patients discontinued treatment early - 5 due to treatment failure and 2 due to AEs. The remaining 5 patients completed the 36-week protocol on study drug. Of these 5 patients, 4 had IGF-I values between >1.0 and ≤1.3 x ULN and 1 completed the study with an IGF-I of 1.7 x ULN with no clinical symptoms. 58.2% of patients in the OOC group met the primary endpoint of maintenance of biochemical response at the end of study using the non-response imputation. Using LOCF imputation, 64.3% (18/28) of patients met this endpoint. Of those completing the study (N=21), 76.2% maintained response. Conclusion: CHIASMA OPTIMAL primary endpoint was assessed using the non-response imputation for patients who discontinued treatment early, with a 58.2% response rate. However, when assessing the response rate based on LOCF imputation, or in study completers, similar to other phase 3 studies for acromegaly, the rate was imputed at 64.3% and 76.2%, respectively.

Thyrotropinomas (TSHomas) are rare pituitary tumours, comprising 1-2% of all pituitary adenomas. Thyrotropinomas in pregnancy are exceedingly rare and management of these in pregnancy can be challenging due to the potential for maternal and foetal harm. We report the case of a 35 year old woman who was found to have a pituitary macroadenoma on imaging whilst being evaluated for headaches and sinusitis. She had felt more stressed than usual but no other overt thyrotoxic symptoms. There were no visual field abnormalities or symptoms to suggest other endocrine hypo or hypersecretion. Pituitary MRI revealed a macroadenoma and biochemistry demonstrated raised free T4 24 pmol/L and free T3 6.8 pmol/L and inappropriately elevated TSH of 4.2 mIU/L, in keeping with secondary hyperthyroidism. She was scheduled for transsphenoidal (TSA) pituitary surgery, however on review she had naturally fallen pregnant. After a multi-disciplinary discussion, it was decided that surgery should be deferred and close observation be undertaken under the care of a multidisciplinary team. During the first half of pregnancy she suffered hyperemesis gravidarum with ongoing thyrotoxicosis but declined carbimazole. Her visual fields were normal throughout pregnancy. She delivered vaginally at 38 weeks, weight 3.395kg and had no malformations. Post birth was complicated by post-partum haemorrhage requiring multiple blood transfusions and intensive care. One week later after recovering, she was able to commence breastfeeding. She went on to TSA at 6months post partum with complete tumour resection. This case demonstrates the complexity of managing TSHomas in pregnancy and the potential cross reactivity of the early hCG rises with the already elevated TSH levels, likely exacerbating her hyperemesis gravidarum.

Introduction Cushing’s syndrome is associated with significant chronic and acute comorbidities including acute thromboembolic and cardiovascular events. To date, there are no data on the prevalence and predictors of acute and perioperative complications in patients with active Cushing’s syndrome. Methods In a single-center cohort analysis we evaluate predictors and outcomes of acute, life-threatening and perioperative complications in patients with active biochemically verified Cushing’s syndrome attending our endocrine department between 1978 and 2016. Any medical complications necessitating hospitalization, including admission to intensive care units (ICUs), from the time of appearance of first symptoms of hypercortisolism until one year after biochemical remission by surgery (or where surgical remission was not achieved, during continuing follow-up) were recorded and classified. Baseline factors related to and predicting acute complications were tested using uni- and multivariate analysis. Results The study included 242 patients (m/f n=54/188) with Cushing’s syndrome (pituitary n=99, adrenal n=116, ectopic n=27), 14.0% of which had malignant disease. At least one acute complication was observed in 54.5% of patients; these included electrolyte disturbances (24.4%), infections (27.7%), thromboembolic events (14.9%), cardiac arrhythmias necessitating medical intervention (5.4%), hypertensive crises (8.7%), acute coronary events (3.3%) and cerebrovascular events (4.1%). At least one ICU admission (excluding post-surgical observance) was required in 13.2% of patients. The majority of complications occurred prior to surgery (60-90%); infections occurred pre- and postoperatively (51.7% vs 48.3%, respectively). Patients with ectopic Cushing’s syndrome demonstrated a higher likelihood of infection (p The total number of acute complications and the number of days at ICU correlated positively with parameters of cortisol excess including urinary free cortisol and the time of hypercortisolism. Conclusion This cohort analysis identifies a significantly high prevalence of acute and perioperative complications in Cushing’s syndrome, with one in eight patients suffering a life-threatening situation necessitating ICU admission. These acute complications are positively predicted by the degree of hypercortisolism, emphasizing the necessity for acute interventions aiming to reduce cortisol excess even before definitive disease cure is achieved.

Background: Bilateral inferior petrosal sinus sampling (BIPSS) has been the gold standard in differentiating a pituitary vs. an ectopic source of ACTH in Cushing’s syndrome however, it has many limitations. The ON-HDDST being simple to perform and the tests of choice in resource poor setting. The primary aim of our study was to consolidate the present knowledge regarding the diagnostic utility of ON-HDDST in localizing the source of ACTH. Method: We retrospectively studied 88 patients with ACTH dependent Cushing syndrome who underwent ONHDDST. Patient were considered as Cushing disease (CD) if either of the 3 criteria were met a) histopathological confirmed b) a central to peripheral gradient >2 was seen in BIPSS or c) pituitary adenoma ≥ 6mm seen in MRI of pituitary. Patient were considered as ectopic ACTH syndrome if the tumor was localized at any peripheral location by imaging or histopathological confirmed after surgery or if BIPSS shown a central to peripheral gradient of Result: Out of total 88 ACTH dependent Cushing syndrome patients, 68 (77.3%) were proven CD and 20 (22.7%) were ectopic. There was no difference in basal serum cortisol however, S. Cortisol after ONHDDST was significantly different between the two with a median of 547.7 nmol/l (341-770) in ectopic vs 273.5 nmol/l (142-689) in CD (p=0.02). A positive response to ONHDDST (≥50% suppression) was seen in about 44 (65%) patients with CD and 5 (25%) patients with ectopic disease (p = 0.002). Among CD patient, 35 (76.1%) of those with microadenoma, 7 (43.8%) amongst macroadenoma and 2 (33%) patient with no visible tumor on MRI shown positive response to ONHDDST. In ectopic group, cortisol suppressibility was seen in 3 (50%) patient with occult tumor but only in 2(14.3%) patient with. ROC curve plotted for percentage suppression of cortisol after ONHDDST shown as AUC equal to 0.68 (p = 0.01). The best test parameters with sensitivity (65%), specificity (85%) and Accuracy (69%) were seen at 50% cutoff level as were the likelihood ratio for positive test (4.3), AUC (0.75), PPV (93.6%), NPV (41.4%). Conclusion: Our study has shown that ONHDDST has poor diagnostic value in differentiating between CD and ectopic ACTH syndrome whatever be the cutoff level of the cortisol suppression. However, this can still be utilized in setups where no alternative is available. For etiologic confirmation, another test with better sensitivity and specificity is preferable.

Prolactinomas are the most common type of functioning pituitary adenomas and up to 50% of all adenomas in clinical practice. Prolactinomas are more prevalent in women; nonetheless, they may occur at any age and in both genders, and represent the most common cause non-physiological hyperprolactinemia. Prolactin-secreting adenomas are classified by their tumor size as follows: microprolactinomas (1cm) and giant prolactinomas (>4 cm). The clinical presentation of these tumors might differ from age, sex and size. Dopamine agonists, such as cabergoline or bromocriptine, have become the first line of treatment, since these agents decrease tumor size and prolactin (PRL) secretion. In Mexico, recent studies have focused on giant prolactinomas but there is missing data of the clinical and biochemical manifestations of the tumor size-effect within the three types of prolactinomas in our population. Objective: To determine the effect of the tumor size in the clinical and biochemical presentation, and the follow up in prolactinomas. Methods: This an observational, retrospective, retrolective study. Results: Patients were classified according to their tumor size and 489 patients with confirmed diagnosis of prolactinoma were included. The mean age was 36+-12 years old and 86% were women. The size was different among sex with 14 (2.9%) and 259 (52.9%) patients with microprolactinoma and 34 (6.9) and 152 (31.1%) with macroprolactinoma in men and women, respectively (p References 1. Lopes M.B.S. (2019). Pathology of prolactinomas: any predictive value? Pituitary doi: 10.1007/s11102-019-00997-1

Background Acromegaly is a complex disease, primarily treated with pituitary surgery or long-acting somatostatin analogues (LA-SSA). Few studies have examined real-world use of LA-SSA. This analysis evaluated LA-SSA treatment patterns in Sweden for patients with acromegaly. Methods Data were obtained from nationwide health care registers. Patients were included if they had diagnosis codes for acromegaly and neoplasm of the pituitary gland between Jul 1, 2005 and Dec 31, 2017, and at least one purchase of LA-SSA (lanreotide [LAN] 60, 90, or 120 mg, or octreotide [OCT] 10, 20, or 30 mg). Cox regression models were used for analyses of persistence and switching. Results The analysis included 176 pts treated with LA-SSA in 2005-2017. The cohort was subgrouped on year of initiation of LA-SSA (2005-2011, n=90, 51%; 2012-2017, n=86, 49%). In the first period, 36 pts (40%) initiated LAN while 54 pts (60%) initiated OCT while in the later period, 44 pts (51%) initiated LAN and 42 pts (49%) initiated OCT (p=0.17). No patients initiated pasireotide. Patient characteristics were similar between LAN and OCT initiators, but history of pituitary surgery was more common for LAN as compared to OCT (LAN 62%; OCT 46%, p The mean (95%CI) dose interval was not significantly different, 30.5 (28.7; 32.6) days for LAN vs 29.5 (28.5; 30.3) days for OCT. The median (95%CI) duration of 1st-line LA-SSA treatment was 14.4 (10.8; 21.6) months for LAN and 12.0 (7.2; 19.2) months for OCT. Fifty-one pts (64%) discontinued 1st-line LAN while 70 pts (73%) discontinued 1st-line OCT (hazard ratio (HR) LAN vs. OCT 0.80; 95% CI: 0.56-1.15). Due to the use of register data, the reason for therapy change could not be determined. Eight pts (10%) switched LAN to OCT while 29 pts (30%) switched OCT to LAN. Patients initiated on OCT were more likely to switch to LAN than the other way around (HR for switch for 1st-line LAN vs. OCT 0.33; 95% CI 0.15-0.72). Among patients who switched OCT to LAN, 67% of LAN dispensing was 120 mg, 21% 90 mg, and 12% 60 mg. Among patients who switch LAN to OCT, 84% of OCT dispensing was 30 mg, and 16% 20 mg. Conclusions There was no significant difference in the number of patients initiated on LAN or OCT despite the later introduction of LAN in Sweden. Patient characteristics were similar but LAN initiators were more likely to have undergone surgery and be diagnosed with visual field defects which could indicate that physicians initiate LAN in patients with more aggressive disease. Extended dose intervals with LAN (dosing every 6-8 w) do not seem to be commonly used in Sweden. In comparison to OCT, patients initiated on LAN were significantly less likely to change LA-SSA therapy.

Relevance. Cushing’s Syndrome (CS) is a serious risk factor for developing impaired glucose tolerance disorder (GTD) and a manifestation of secondary diabetes mellitus (DM). On the other hand, the development of impaired glucose metabolism affects not only the course but also the outcome of SC. Moreover, their frequency varies from 10% to 45% of all cases of SC. The aim of investigation - to evaluate the frequency of various forms of impaired glucose metabolism in patients with SC according to the national registry in the Republic of Uzbekistan. Materials and methods. The object of the study was 264 patients included in the register, 182 women (68.9%); men 82 (31.1%) aged 16 to 49 years. Including ACTH dependent CS (ACTH-DS) 219 (82.9%), ACTH independent CS (ACTH-IS) 41 (15.5%), ACTH ectopic CS (ACTH-ES) 4 (1.5%). The levels of ACTH, cortisol, insulin, glucose, glycated hemoglobin were studied, tests with dexamethasone and an oral glucose tolerance test (OGTT) were performed; MSCT of the adrenal gland and MRI of the pituitary gland. Fasting glucose (IH), NTG and diabetes were determined according to international criteria (EASD 2019, IDF 2018) Results. It was found that out of 264 patients with SC, 136 (51.5%) had various disorders of carbohydrate metabolism (CM), including diabetes in 32.6 ± 2.9% (86 bp), GTD in 18, 6 ± 2.4% (49 bp) and NGN - in 0.4 ± 0.4% (1 bp). At the same time, diabetes developed in 33.3% of cases in patients with ACTH-DS, 24.4% of ACTH-IS and 75% with ACTH-ESC (p˂ 0.01; p˂ 0.001). Cases of prediabetes were mainly found in the form of NTG in 17.4% of ACTH-DS and 26.8% in ACTH-IS. Conclusions. In the Republic of Uzbekistan, CM took place in the overwhelming majority of patients with CS (51.5%) and clearly depended on the type of CS (ACTH-ES, AKTG-DS, AKTG-IS) and correlated with the degree of hypercortisolism.

Background and objective: Hypercortisolism is the hall mark of ACTH Cushing’s syndrome, which is a benign ACTH secreting tumor resulting in high morbidity and mortality. The diagnosis is based on an elevated serum ACTH, elevated 24h urinary cortisol or a non-suppressible ACTH after dexamethasone suppression test. Confirmation of ACTH hypersecretion is followed by localization of the adenoma which can be pituitary in origin or peripheral. Dynamic MRI of the pituitary gland is the gold standard for diagnosis of pituitary tumors, and contrast enhanced CT scan is the gold standard for ectopic lesions which are usually lung tumors. The localization of the lesion is often a challenge because conventional MRI fail to show pituitary lesions and sometimes requiring inferior petrosal sinus sampling to confirm pituitary origin. Transsphenoidal surgery is the treatment of choice for Cushing’s disease, even without MRI evidence of pituitary tumors, if pituitary origin is confirmed by inferior petrosal sinus sampling. This causes increase in the incidence of treatment failure and complications. Thus, the diagnosis of Cushing’s disease urges exploring new diagnostic modalities. In our study we test the sensitivity of 11C methionine PET CT together with dynamic pituitary MRI in localization of ACTH dependent Cushing’s disease. Materials and methods This is an interventional, prospective study, forty-one subjects: newly diagnosed ACTH dependent Cushing’s Syndrome (n=29). (indicated by non-suppressible ACTH on dexamethasone suppression test) or persistent hypercortisolism following transsphenoidal surgery (n=12). 11C methionine PET CT was done in all cases in addition to dynamic pituitary MRI. All patients underwent 11 C-methionine PET-CT in addition to dynamic pituitary MRI This allowed us to determine whether suspected adenomas seen on structural imaging exhibited focal tracer uptake on functional imaging.Inclusion Criteria:• Aged 18 years old or over• Patient with a diagnosed Cushing’s disease confirmed by non-suppressible ACTH on dexamethasone suppression test.• Patient with persistent ACTH dependent Cushing’s disease following transsphenoidal surgery.• Patient not enrolled in other interventional studies.Exclusion Criteria:• Contraindication to MRI• Pregnant woman, breastfeeding RESULTS: Patients with newly diagnosed ACTH dependent Cushing: 24 out of 29 of the cases showed adenoma on dynamic MRI of the pituitary; 5 out of 29 cases failed to showed any lesions on dynamic MRI of the pituitary; Inferior petrosal sampling was done and confirmed pituitary origin in 4 out of 5 and 1 out of 5 was found to have ectopic ACTH secretion. In patients with persistent hypercortisolism following transsphenoidal surgery; 3 out of 12 of the cases showed adenoma on dynamic MRI of the pituitary and 7 out of 12 cases failed to showed any lesions on dynamic MRI of the pituitary and inferior petrosal sampling was done and confirmed pituitary origin in all 12 cases. All 41 cases underwent 11C methionine PET CT scan; 39 patients showed tracer uptake on 11c methionine PET CT scan in the pituitary area, 36 of which had unilateral asymmetrical tracer uptake. All 40 subjects with suspected pituitary lesions were confirmed to be of pituitary origin by histopathological examination of biopsies taken intraoperatively. CONCLUSIONS 11C methionine PET CT has proven to be of very high sensitivity in detecting ACTH secreting adenomas, further studies should be done on a larger scale as this modality can address the pitfalls in localization of ACTH secreting lesions.

Data on the impact of withdrawal from long-acting somatostatin receptor ligand (SRL) injections on disease activity in patients with acromegaly are limited. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study assessed the efficacy and safety of oral octreotide capsules in adult patients with acromegaly responding to injectable SRL therapy. The placebo-controlled arm of this study allowed for assessment of acromegaly biochemical and disease activity in patients after withdrawal from SRL treatment. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Patients were ≥ 18 years of age, had evidence of active disease (defined as IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤ 1.0 x ULN in response to a stable dose of SRL injection. Patients were randomized, 1 month following their last injection, to octreotide capsule or placebo for 36 weeks, with an option to enroll in an open-label extension. The primary aim was to determine the proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (average of week 34 and 36). The trial met the primary endpoint, with 58% (16/28) of patients receiving octreotide capsules maintaining IGF-I response vs 19% (5/28) receiving placebo (P=0.008). The median time to loss of response (2 criteria evaluated: IGF-I >1.0 and ≥ 1.3 x ULN for 2 consecutive visits) was 16 weeks in the placebo group, while it was not reached in the octreotide capsule group. Of the 5 patients in the placebo group who maintained their biochemical response at 36 weeks, only 2 (7% of placebo group) did not meet loss of response criteria. When IGF-I values for any 2 consecutive visits were analyzed for patients receiving placebo, 93% (26/28) lost response based on IGF-I > 1 x ULN and 79% (22/28) lost response based on IGF-I ≥ 1.3 x ULN. Irrespective of biochemical control of acromegaly, 26/28 patients receiving placebo experienced active disease-related symptoms reported as AEs of special interest (AESIs). Most common AESIs (≥ 5%) included arthralgia/arthritis (60.7%), soft tissue swelling (35.7%), headache (32.1%), hyperhidrosis (25%), carpal tunnel (14.3%), musculoskeletal pain (14.3%), weight increased (7.1%) and tongue disorders (7.1%). The 5 patients receiving placebo with controlled IGF-I at 36 weeks received active medical treatment in the open label extension by decision of their study PIs, as they were deemed to have either lost their response during the study or had continuing active acromegaly symptoms. 93% of patients receiving placebo lost response following withdrawal of injectable SRLs, with a median duration of 16 weeks. All 5 patients receiving placebo who met the primary endpoint criteria at the end of the study were assessed clinically to have active disease and were continued on oral SRL treatment in the open label extension.

Introduction: Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard test to differentiate Cushing’s disease (CD) and ectopic ACTH syndrome (EAS). Stimulation test for diagnosis may be unnecessary in some cases and the diagnostic yield of the stimulation test may be similar to the basal measurement. Methods: 34 adult patients referred for diagnosis of ACTH dependent Cushing syndrome. Basal simples for prolactin and ACTH were taken from bilateral inferior petrosal sinus and from peripheral vein. Stimulation test with desmopressin (32 subject) or CRH (2 subjects) was performed. Samples were taken at 0, 3, 5 and 10 minutes. To compare the percentage of diagnosis with each measurement the MacNemar test was done. Results: Right basal ACTH was 465 pg./ml (ICR 62-1250), ACTH at 3 minutes was 647 (ICR 227-2610), ACTH at 5 minutes was 1250 (ICR 245-1965), ACTH at 10 minutes was 230 (71-550). Left basal ACTH was 230 (71-550), at 3 minutes was 453 (ICR 116-1250), at 5 minutes was 431 (91-1250), at 10 minutes was 534 (140-1250). Median basal ACTH ratio was 13.8 (ICR 5.1-26), at 3 minutes was 34.5 (ICR 13-82), at 5 minutes was 30.6 (11.4-49.8), at 10 minutes was 18.5 (8.2-48.2). The higher ratio was at 3 minutes. Basal ACTH ratio was 3 after stimulation test. CD was diagnosed with basal ratio in 88.6% of cases, and at 3, 5 and 10 minutes in 94.3% of cases. There was no difference in percentage of CD diagnosis at 3, 5 or 10 minutes (p=1.0). Discussion: Basal ACTH ratio was able to differentiate CD from ECS in most cases (88.6%). At least one additional sample with CRH or desmopressin stimuli identify 94.3% of CD cases with the higher increases at 3 minutes. Additional stimuli do not improve overall diagnosis, therefore, a basal ratio and additional stimulation test at 3 minutes is enough for CD diagnosis. This may decrease the cost of BIPSS and total duration of the procedure.

BACKGROUND: Transsphenoidal surgery is the cornerstone of acromegaly treatment. However, cure is obtained in only ~50% of the cases. Until today, no biochemical marker has been identified to preoperatively predict surgical outcome and long-term remission. Recently, soluble alpha klotho (αKL) was proposed as new biomarker for diagnosis and follow-up of acromegaly. Therefore, we aimed to evaluate the potential of pre-surgery αKL concentrations as a prognostic factor to predict remission by surgery alone. Methods: We measured αKL concentrations (IBL-ELISA) and classical biomarkers (IGF-I and GHrandom, both by IDS-iSYS, GHnadir measured by IDS-iSYS (n=13) or DiaSorin-Liaison® (n=7)) in samples from a prospective study in treatment-naïve patients with acromegaly (total n=25). Patients were then followed for at least 6 months after surgery (median (range) 30.1 (6–142) months). Outcome was evaluated and classified as non-remission (NR: IGF-I>1.2xULN (n=2) or continued need for medical treatment with somatostatin analogues (n=10)) or remission (R: improvement on clinical signs and symptoms and IGF-I1.2xULN), GHnadir (>0.4 ng/mL) and GHrandom (>1.0 ng/mL). As expected, αKL (pg/mL) was also high (>1.2xULN) in 92% patients. Before surgery, αKL was significantly higher in NR compared to R [6648 (4408–13951) vs. 3389 (2132–6837); p0.05 for both comparisons). ROC analysis indicated that concentrations of αKL>4470pg/mL (~3.5xULN) (75% specificity, 62% sensitivity, AUC=0.72) and IGF-I>3.8xULN (67% specificity, 85% sensitivity, AUC=0.79) indicate lack of long-term remission. Conclusion: High αKL (>4470pg/mL, ~3.5xULN) and IGF-I (>3.8xULN) concentrations before surgery are significantly associated with persistent disease activity after surgery. However, both biomarkers alone or in combination have insufficient specificity (though acceptable sensitivity) as predictors of surgical outcome.

Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

Introduction: somatostatin receptor ligands (SRL) represent the first-line medical therapy in acromegaly patients who were not cured by surgery and in those where surgical remission is unlikely. It is well known that SRL may negatively act on insulin secretion, with consequent hyperglycemia and diabetes mellitus (DM). Purpose: To evaluate whether the degree of response to surgical pre-treatment with SRL predicts alterations in blood glucose levels.Patients and Methods: We retrospectively studied 181 patients attending the Unit of Neurosurgery of our Hospital prior to transsphenoidal surgery. All patients had a biochemical and radiological diagnosis of acromegaly (nadir GH during OGTT >0.4 ng/mL; IGF-I above age-standardized UNL and pituitary adenoma at MRI scans); diagnosis of DM and impaired fasting glucose (IFG) was performed on fasting blood glucose (FBG) according to the American Diabetes Association guidelines; all parameters of the pituitary axes were determined. The response to SRL treatment was determined as percent change of GH levels. Data are presented as mean±SD; Continuous data normally distributed were analyzed using a two-tailed Student’s t-test to compare two groups, and one-way ANOVA to compare several groups, followed by the Bonferroni post-hoc procedure for pairwise comparison of groups after the null hypothesis was rejected (p

Background: Acromegaly is a disorder characterized by excessive growth hormone (GH) secretion, which, in most cases, is caused by a GH secreting adenoma. Surgical removal of the tumor via a transsphenoidal approach is the first choice treatment for most patients. The remission rate after an initial resection is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas. Objective: To analyze predictive factors of remission in acromegaly patients who underwent transsphenoidal surgery for GH secreting adenoma. Methods: From January 2006 to October 2019, 75 patients with GH secreting pituitary adenoma were evaluated at our center. Patients who had undergone medical treatment or radiotherapy as first treatment were excluded. A total of 60 patients were included in the analysis. Remission was defined as normal serum insulin-like growth factor-1 (IGF-1) age and sex adjusted and a random serum GH less than 1 ng/mL and/or nadir GH during oral glucose tolerance test Results: We evaluated 60 patients (41 females and 19 males), with a mean age at diagnosis of 49.6 (ranged from 23 to 77 years). Mean initial IGF-1 was 905.3 ng/mL (range 100-324) and mean initial GH was 25.0 ng/mL ( Conclusions: In our study, predictors of biochemical remission after surgery were smaller tumor size, lower Knosp grade, and lower preoperative GH and IGF-1 levels.

Background: Injectable somatostatin receptor ligands (SRLs) are currently the most widely used medical therapy for acromegaly worldwide. Oral octreotide capsules (OOC) have been formulated as a potential therapy for this disorder and the safety and efficacy were evaluated in the CHIASMA OPTIMAL pivotal study (Samson et al. ENDO 2020). As reported, mean IGF-I levels of the OOC treatment group were maintained within normal range at the end of treatment in all patients. However, some patients may not respond to OOC treatment (25% of OOC group and 68% of placebo groups required rescue, P=0.003). This analysis describes the degree and rapidity with which patients achieve biochemical control (IGF-I ≤1.0 x ULN) when reverted to their prior injectable SRL treatment. Methods: Patients with confirmed acromegaly and receiving a stable dose of injectable SRL (≥3 months) were randomized to OOC (40mg/day; N=28) or placebo (N=28) for 36 weeks. Patients were dose titrated to 60 or 80mg of OOC (or placebo) through week 24 at investigator discretion based on increased IGF-I levels and/or worsening acromegaly signs/symptoms. Patients could be rescued via reversion to prior injectable SRL therapy if they met the predefined withdrawal criteria (i.e., IGF-I ≥1.3 x upper limit of normal [ULN] for 2 consecutive visits on the highest dose, and exacerbation of clinical signs/symptoms) or discontinued treatment early for any other reason. In the study, 7 patients in the OOC group and 19 in the placebo group required rescue. The change in IGF-I from Baseline was compared to the end of the Double-blind Placebo Controlled period. Results: In patients rescued up to week 32 and in whom there were at least 4 weeks of follow up, baseline IGF-I levels (mean of Screening Visit 2 and Baseline) were 0.80 and 0.87 x ULN in the OOC and placebo groups, respectively. In patients receiving rescue therapy, the end of study IGF-I levels (mean of week 34 and 36) were 0.80 and 0.89 x ULN in the OOC and placebo groups, respectively, virtually unchanged. The median time to return to normal baseline IGF-I values following loss of response was 4.0 weeks after discontinuing OOC and 4.0 weeks after discontinuing placebo treatment. Therefore, most patients who required rescue following a short trial of therapy with OOC returned to their baseline values following a single SRL injection. Conclusion: Most treatment failures in the CHIASMA OPTIMAL trial (on either OOC or placebo) rescued with injectable SRL re-established their baseline response levels after a single injectable SRL administration (at pre-study dose). Based on this data, patients may potentially be treated with OOC and for those not responding, either not biochemically controlled or who have adverse effects, they may be able to return to injectable SRLs with immediate IGF-I control after one SRL injection.

The aim- to study the characteristic of the reproductive function in patients with ACTH-dependent Cushing Syndrome in (CS) in all regions of the RUz and RKK. Material and methods. Under our supervision in the all regions of RUz and Tashkent-city there are 120 women of fertile age with ACTH-dependent Cushing Syndrome were observed in the framework of project. Middle age of patients was 27,6 ± 3, 4 years. The complex of researches, including clinical, biochemical hormonal (ACTH, LH, FSH, cortizol, prolactin), ultrasound investigations, pituitary and adrenals CT/MRI was executed all patients. Results. The patients were divided into 2 groups: 1 group - patients with conservative treatment - 47 cases (39,1%), 2 group -patients with pituitary surgery - 65 cases.(54,1%), 3 group - combined therapy - 8 patients (6,6%). The reproductive disorders had 63 women from 120 (52,5%): amenorrhoea -35%), oligomenorrhoea (30%), polimenorrhoea (7,5%). It was found that with ACTH - dependent Cushing’s syndrome, primary infertility was 17,6%, secondary 23.5%, We found hyperandrogenemiya and hypercortizolemiya in patients of all groups before treatment. Estradiol levels were significantly inversely correlated with cortisol levels. One year after surgery we established normal range of LH, FSH, ACTH, cortizol, prolactin in all women of 2 group, but in 1 and 3 group we didn’t achieve compensation yet. After 1 year only 1 (2,1)% women from 1 group can pregnant. After 1 year 30 women from 65 patients of second group after pituitary surgery (46,1%) achieved pregnancy without stimulation therapy. There are 2 (25%) women of 3 group achieved pregnancy. The restoration of reproductive function in women with CS was observed in 3,5% of cases in patients treated with medical therapy, 33,3% in patients with adrenalectomy and combination therapy, and 50% after transsphenoidal adenomectomy of pituitary tumor. Conclusions. The fertility function in women with ACTH-dependent CS can improve after pituitary surgery without stimulation therapy. In 46,1% of cases, in patients with combined therapy -in 25%and in women after conservative therapy - in 2,1%.

Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenoma. A well-known complication of TSS is hypopituitarism with a reported risk of 5-25% after resection of pituitary adenomas. A decrease in postoperative prolactin concentration was shown to be associated with postoperative hypopituitarism in a previous report. We hypothesized that in addition to clinical factors (preoperative hypofunction and adenoma size), biochemical factors (change in prolactin concentration and immediate post-operative hypofunction) can aid in predicting long term hypopituitarism as defined as ≥1 biochemically confirmed hypofunctioning pituitary axes 3 years after resection. A retrospective analysis of all patients undergoing TSS for both functioning and non-functioning pituitary adenomas at a tertiary center from January 2013 through December 2015 was performed. Prolactinomas were excluded. Of the 75 patients included, 21.3% (n=16) had at least one pituitary axis requiring replacement at 3 years post operatively. Mean age at presentation was 55 ± 16 years, 55% were female and 81% were Caucasian. Mean adenoma size was no different between normal pituitary function and hypopituitary groups (24.0 ± 11.9 mm versus 25.3 ± 10, p=0.7). Factors associated with long term hypopituitarism were older age (mean age 64 ± 4 years versus 53 ± 2 years, p = 0.02), preoperative secondary adrenal insufficiency (AM cortisol 6.4 ± 3.7 vs 12.0 ± 6.5 µg/dL; p = 0.03), preoperative secondary hypothyroidism (0.8 ± 0.2 vs 12.0 ± 6.5 ng/dL; p < 0.01), low immediate postoperative cortisol (5.3±3.1 vs 26.1±18.3 µg/d; p

Background Patients (pts) with acromegaly (A) require long term follow up, as up to 15% will develop recurrence. Current guidelines for MRI surveillance recommend 12 week post-operative (postop) imaging for all pts and yearly if on pegvisomant (PEG). Many pts with residual tumor postop undergo repetitive imaging even when controlled with pituitary (PIT) directed therapies. However, gadolinium retention and healthcare costs are of increased concern. Aim Assess tumor growth postop and necessity of serial MRI in medically treated A pts. Methods Retrospective, IRB-approved, data analysis of pathology-proven A pts. Included were pts with at least 1 MRI at ≥1 year postop. Initial tumor size, invasion status, pathology, postop remission, MRIs, radiation and medical therapy data were collected. Biochemical (biochem) remission = normal IGF-1 and GH 1 year (9 on PEG alone.) 11/83 (13.25%) had tumor growth at median 3.5 years (range 1-11). Tumors that grew were larger at diagnosis (25.21±10.93 mm vs 17.45±8.37 mm, p=0.004), had larger residuals postop (23.83±5.0 mm vs 11.86±7.47 mm, p=0.0003), and tended to be invasive (77.78% (7/9) vs 53.03% (35/66), p=NS). 7/11 were sparsely granulated and 4 mixed GH-PRL. Of 11 that grew, 8 had postop residual tumor, 3 in remission, 4 with discrepant IGF-1/GH, 2 uncontrolled and 2 with no data at 3 months postop. At the time of growth, 9/11 pts were untreated (6 had active A, 1 with discrepant IGF-1/GH and 2 with no IGF-1/GH data), 1 was controlled on pasireotide and one in biochem remission. Only 1/50 (2%) pts on pasireotide had growth and no pts on PEG >1 year. Discussion 86.75% of pts with A did not have tumor growth after surgery. Only one pt on PIT-targeted medications and none on PEG experienced tumor growth. Almost all pts who had growth had large invasive adenomas, majority were sparsely granulated, residual tumor postop, were biochemically uncontrolled and not on medication at the time of growth. A previous metanalysis of SRLs in A showed that tumor increase occurs in 1.4% (follow up 3-36 months). In our study pt follow up was longer and 1.82% (1/55) of pts who were on SRL/Cab had growth. Conclusion We recommend less frequent MRI monitoring for pts treated with PIT-targeted medications. Conversely, pts with residual adenoma not on medical therapy should be closely monitored biochemically and by serial MRIs. Further studies are needed to identify appropriate imaging interval for pts on medications and based on characteristics of aggression (such as sparsely granulated, large residual tumors, lack of biochemical control despite medications).

Endogenous Cushing’s syndrome (CS) is a rare, serious disorder caused by chronically elevated cortisol. A phase 3, open-label study (SONICS) of levoketoconazole in adults with CS and mean urinary free cortisol (mUFC) ≥1.5 × upper limit of normal (ULN) at baseline demonstrated normalization of mUFC in 62% of those completing 6 months of maintenance treatment (Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7[11]:855-865). LOGICS is an ongoing, phase 3, double-blind, placebo-controlled, randomized-withdrawal study further investigating the safety and efficacy of levoketoconazole in patients who completed the SONICS study, or patients with CS who are levoketoconazole treatment-naive (ClinicalTrials.gov identifier: NCT03277690). The primary objective of LOGICS is to evaluate the effect of withdrawing levoketoconazole treatment to placebo, versus continuing treatment with levoketoconazole, on the cortisol therapeutic response established during open-label levoketoconazole therapy. The study includes (1) a screening phase (up to 13 weeks to allow for washout of CS medications); (2) a dose titration-maintenance phase (150-600 mg BID [dosed as needed to target mUFC normalization]) of ≥14 weeks, with at least the final 4 weeks demonstrating mUFC normalization prior to advancing to the randomized-withdrawal (R-W) phase; (3) a double-blind, placebo-controlled R-W phase (levoketoconazole or placebo; up to 8 weeks); and (4) a double-blind restoration phase (levoketoconazole and placebo; 8 weeks). Patients are randomized 1:1 in the R-W phase to continue their therapeutic dose of levoketoconazole, established during the dose titration-maintenance phase, or to receive an equivalent number of placebo tablets. Up to ~54 subjects are targeted for randomization. The primary efficacy endpoint, assessed at the completion of R-W phase, is the proportion of patients with loss of therapeutic response to levoketoconazole (mUFC ≥1.5x ULN, >40% above baseline if baseline value is >ULN [SONIC-completer cohort only], or early rescue criterion met) upon withdrawing to placebo, compared with continuing treatment with levoketoconazole, during the R-W phase. Secondary endpoints include changes from baseline to all postbaseline visits in R-W phase for mUFC, late-night salivary cortisol, CS cardiovascular biomarkers (fasting glucose, fasting insulin, hemoglobin A1c, homeostatic model assessment-insulin resistance, total and LDL cholesterol, high-sensitivity C-reactive protein), CS clinical signs and symptoms (acne, hirsutism [women only], and peripheral edema scores), and patient-reported outcomes of QoL (Cushing QoL questionnaire score) and depression (Beck Depression Inventory II). Potential liver toxicity, QT prolongation, and adrenal insufficiency are prespecified adverse events of special interest.

Introduction: Prolactinomas are the most frequent pituitary-secreting tumors. Medical therapy with cabergoline (CAB), a dopamine agonist (DA), is the first line treatment, but 10% of prolactinomas are resistant to CAB. Recently, in vitro studies have shown anti-tumoral activity of metformin and other biguanids in human prolactinomas1, which prompted us to investigate that possibility in vivo. Aim: To evaluate the effect of metformin (MET) on Prolactin (PRL) secretion in patients with CAB resistant prolactinomas. Design and Setting: Prospective interventional study in a single referral center. Subjects: Ten patients (7 M; mean age: 44 ± 12y) with CAB resistant (PRL: 148 ± 125ng/ml; range: 38 - 386) prolactinomas (all macroadenomas) and metabolic syndrome on maximally tolerated CAB doses (4.3 ± 1.2 mg/week; range: 2.0-7.0) for ≥ 6 months (45 ± 39mo; range: 6-120). Intervention: Oral extended release metformin (p.o.) was prescribed according to patient’s tolerance (mean dose: 1.3 ± 0.4 g; range: 1.0-2.0). Main Outcome Measurements: Serum PRL (Elecsys, Roche, Indianapolis, USA), body weight (BW), fasting glycemia (FG) and HbA1C were evaluated before and at two time points during metformin treatment (30-60 and 120-180 days). Results: BW, FG, and/or HbA1C reductions were observed in 9/10 patients and mean FG decreased significantly (P=0.04). No significant changes were observed in serum PRL levels during metformin treatment [134 ± 124 ng/ml vs 138 ± 132 ng/ml vs 144 ± 129 ng/ml, before, at 30-60 days and at 120-180 days, respectively (P=0.499, mixed-effects analysis with the Geisser-Greenhouse correction)]. Individually, two patients exhibited a ≥ 50% decrease in PRL levels at a single timepoint (one at 30-60 days, with a further increase at 120-180 days and the other at 120-180 days). Conclusion: Metformin, at usual doses, did not inhibit prolactin secretion in patients with cabergoline-resistant prolactinomas. The discrepancy between our results and in vitro studies is not clear, but may be related to the much higher concentrations of metformin used in vitro1 as compared to the serum concentrations observed in patients during metformin treatment2. References: 1Gao J et al. Metformin inhibits growth and prolactin secretion of pituitary prolactinoma cells and xenografts. J Cell Mol Med. 2018 22:6368-79; 2 Frid A et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 2010 33:1291-3.

Acromegaly is a rare, chronic disorder characterized by hypersecretion of growth hormone (GH) that stimulates the production of insulin-like growth factor 1 (IGF-1). In addition to the physical manifestations, such as acral soft-tissue enlargement and maxillofacial changes, patients may develop a number of comorbidities, often prior to diagnosis. The goal of acromegaly treatment is to achieve biochemical control (normalization of GH and IGF-1 levels), which may resolve or prevent worsening of comorbid conditions. The objective of this study was to quantify the economic burden of comorbidities associated with acromegaly, including diabetes, hypertension, colon cancer, sleep apnea, and hypopituitarism. Comparisons were made between patients with acromegaly and biochemical control, patients with acromegaly without biochemical control, and the general population. Literature was reviewed to identify the prevalence of comorbidities among the groups, as well as the influence of each comorbidity on healthcare costs, quality of life, and mortality. Inputs from the literature were synthesized using a decision-analytic cohort model with a starting age of 55 years old and 55% female and extrapolated over a lifetime. Acromegaly-associated morbidity and mortality were not modeled due to possible double counting between acromegaly and other comorbidities. The average comorbidity count measure (range from 0 to 5) was a sum across all 5 comorbidity prevalence rates for all those living in the cohort per year of survival. Comorbidity prevalence was higher among acromegalic patients vs the general population for all comorbidities. Within acromegaly, uncontrolled disorder was associated with a higher prevalence of diabetes, hypertension, and sleep apnea. Lifetime discounted comorbidity costs were ~$121,000, ~$313,000, and ~$406,000 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted life years were 17.6, 16.9, and 16.7 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted quality-adjusted life years were 14.6, 11.7, and 10.4 in in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted average comorbidity count was 0.8, 1.9, and 2.4 in each group, respectively. Compared with controlled acromegaly, uncontrolled disorder resulted in $93,000 additional comorbidity-related costs, 1.3 fewer years of perfect health, and 0.5 more comorbidities across the remaining lifespan. This simulation model suggests achieving biochemical control seems to be associated with improvements in cost, quality of life, and mortality. A multimodal treatment strategy including biochemical control and management of comorbidities is necessary to promote optimal patient outcomes.

Background: Macroprolactinoma is an uncommon pituitary tumor which presents mainly in males. The usual presentation is headache, bitemporal hemianopia, and signs/symptoms of hypogonadism. Ours is a case report of 5.5 –cm macroprolactinoma presented with unilateral optic nerve atrophy and asymptomatic hypogonadism. Clinical case: A 50-year-old male with past medical history of type 2 diabetes mellitus and essential hypertension presented with progressive blurred vision of the left eye for 6 months. He was able to perceive color but had difficulty reading. There was occasional headache with left periorbital pain. He was seen by an optometrist and was found to have left optic disc atrophy with suspicion of glaucoma. Subsequent visual field test showed entire left and right superior temporal loss. MRI of the pituitary showed 5.5 x 5.6 x 5.3 cm enhancing mass centered in the sellar/suprasellar region. There was significant mass effect with compression of the optic chiasm, temporal lobe and brainstem. The patient reported mood changes, normal libido, but loss of morning erection. He has family history of pituitary macroadenoma with left optic nerve compression. On physical examination, there were left visual field defect and decreased visual acuity. There were no signs of Cushing’s syndrome, hypothyroidism, acromegaly, or hypogonadism. Laboratory tests showed prolactin of >200 ng/ml and 16,610 ng/ml after dilution (male Conclusion: Even though profoundly hypogonadal by labs, the presentation for this 5.5-cm prolactinoma was acute vision loss. The highly elevated prolactin level correlates with the size of macroadenoma. The typical presentation of local mass effect is bitemporal hemianopia, but in our case the patient presented with unilateral optic nerve atrophy. Despite a 5.5-cm lesion, there is partial hypopituitarism; hypogonadism. Based on the size, one would have expected panhypopituitarism. Given a family history of macroadenoma, there might be genetic predisposition. Molecular testing is planned.

Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Introduction: Silent corticothop adenomas (SCAs) account for 9 to 19% of nonfunctioning pituitary adenomas and behave as the most agressive pituitary tumors with more invasiveness and high recurrence rate. The identification of these patients during the preoperative stage could predict better surgery results. Some authors refer to high basal ACTH level in the preoperative evaluation as the only marker but until this date, there are no clinical and hormonal markers that could predict its occurrence. The aim of this study is to evaluate the response to desmopressin test and the presence of silent corticothoph tumors. Patients and methods: Among 475 patients with pituitary lesion, which underwent surgery, 332 were pituitary adenomas, (82 were acromegaly, 40 Cushing disease, 178 nonfunctioning adenomas). Twenty-three patients, 17 with Cushing disease, (CD), mean age: 31 y, 13 female and 4 male) and 6 patients with SCA (mean age: 47 y, 5 female and 1 male) had positive ACTH confirmed by immunohistochemical analysis. Clinical characteristics: in the CD group, 53% had hypertension (9/17), 42% diabetes (7/17), 100% dyslipidemia, BMI was 30.7 kg/m2. Among SCA group, 67% hypertension, 50% diabetes, 50% dyslipidemia, BMI was 28 kg/m2. All patients were evaluated with basal ACTH and DHEAS before surgery. Patients with SCA underwent desmopressin test and were compared to CD. Dexamethasone suppression test (DST 1 mg) and 24-hour free urinary test was performed in patients with CD and in two patients with SCA. Response to desmopressin test was considered positive when increase in cortisol was above 20% and in ACTH of 35% using chemiluminescence assay (Immulite 2000). Results: Among CD group, the median (med) basal ACTH was 75.9 pg/mL (30.9 to 211), the med basal cortisol was 22.5 µg/dL (14.5 to 43.5), the med DHEAS was 170 µg/dL (33 to 465), the med 24h urinary free cortisol of 454.5 µg/24 h (149 to 1673) and med basal cortisol after DST 1mg of 15.4 µg/dL (4.7 to 31.5). Among SCA, med basal ACTH was 19.4 pg/mL (9.5 to 65.5), the med basal cortisol was 9.5 µg/dL (7.8 to 16.4) and the med DHEAS was 104.5 µg/dL (82 to 127). Only 4 patients with CD had macroadenomas. All of them responded with ACTH increase (med increase of 98%, 31.6 to 377%), and only 4 did not respond to cortisol increase (med increase of 54.4%, 0 to 167%). All patients with SCA had macroadenomas. Only one patient did not respond to ACTH increase (med increase of 123.5%, 9.5 to 1522%, 9.5 to 1522%), and 3 patients did not respond to cortisol increase (med increase of 17.9%, 0 to 234%). Discussion: SCA are invasive tumors, with high recurrence and tests predicting their occurrence are missing. We hypothesized that as ACTH is present in the adenoma a response to desmopressin test could exist (like CRH). Conclusion: The desmopressin test can be a useful tool in the evaluation of SCA and can predict pathological phenotype in preoperative tumors.

Surgical removal of the GH-secreting tumor is the initial treatment of choice for acromegaly. Outcome of surgery is assessed by measuring IGF-1 and glucose-suppressed GH levels. IGF-1 normalization is an essential biochemical criterion for remission. The cut-off for nadir GH after oral glucose that signifies remission, however, is debated. It also remains unclear whether GH levels provide additional prognostic or clinically relevant information when IGF-1 results are definitive. To address this question, we examined how initial postoperative glucose-suppressed GH levels change over time on serial testing in patients who achieve initial remission as defined by IGF-1 normalization. We studied 87 acromegaly patients (48M, 39F) who achieved a normal IGF-1 level after surgery alone longitudinally from 1996 to 2019. All had GH measured before and 60, 90 and 120 minutes after 75 or 100 mg oral glucose (OGTT) at ≥ 3 months after surgery and GH and IGF-1 repeated ≥ 1 year later. GH was by measured by sensitive, 22KDa GH specific assays, either a IRMA (DSL, International Reference Standard (IRS) 88/624) or a chemiluminescence immunoassay (IDS-iSYS, IRS 98/574). OGTT Nadir GH levels were also measured in healthy subjects; n=46 (26 M, 20 F, ages 19-71 yr.) by DSL and n=46 (29 M, 17 F; ages 20-66 yr.) by IDS-iSYS. Nadir GH levels in acromegaly patients were compared to the 95%CI of healthy subjects’ mean and categorized relative to healthy subjects’ 97.5 percentile, which was 0.14 µg/L for both assays. IGF-1 levels were compared to age and gender adjusted normal ranges. Subjects were grouped based on initial nadir GH ≤ or > 0.14 µg/L and the patterns of change in nadir GH and IGF-1 at last follow up or until IGF-1 became elevated (i.e. recurrence). Follow up durations are given as median(range). In follow up, 73 patients remained in remission (normal IGF-1) and 14 had a recurrence (elevated IGF-1). Of the 73 in remission, 55 had initial nadir GH ≤ 0.14 µg/L that persisted to 10 yr.(1-22yr.) of follow up, 5 had initial GH ≤ 0.14 µg/L that rose to > 0.14 µg/L by 9(3-21)yr., 10 had GH > 0.14 µg/L that persisted at 5.5(2-22)yr., and 3 had GH > 0.14 µg/L that fell to ≤ 0.14 µg/L at 5(4-7)yr. of follow up. Of the 14 that recurred, 11 had an initial and persistent GH > 0.14 µg/L and developed an elevated IGF-1 level after 6(1-23) yr.. The 3 other patients that recurred had an initial GH ≤ 0.14 µg/L that rose to > 0.14 µg/L by 1-6 years later and subsequently developed an elevated IGF-1 level by 14-16 years of follow up. In summary, we found that the pattern of normal IGF-1 along with nadir GH > 0.14 µg/L on initial testing or developing with time, was associated with recurrence in 14/32 patients. We also found that initial nadir GH ≤ 0.14 µg/L was highly predictive of long-term persistent remission: 60/63 such patients remained in remission. In conclusion, glucose-suppressed GH levels are of prognostic value in acromegaly patients with normal IGF-1 after surgery.

Background: Single- and multi-center studies have shown an increased incidence of malignancies in patients with acromegaly. These findings may be affected by selection bias. Our aim was therefore to investigate the incidence of malignancies in a nationwide unselected cohort of patients with acromegaly. Methods: Adult patients diagnosed with acromegaly due to a pituitary tumor between 1987 and 2017 were identified in the Swedish National Patient Registry. All malignancies following the diagnosis of acromegaly were identified in the Swedish Cancer Registry that has a coverage of over 96%. Standardized incidence ratios (SIRs) for malignancies, with 95% confidence intervals (CI), were calculated by using the Swedish general population as a reference. Incidence of malignancies was also analyzed in sub-groups of patients treated with radiotherapy and in those having diabetes mellitus and hypopituitarism. Results: A total of 1,296 patients with acromegaly were included (621 men, 675 women). The mean age (±SD) at diagnosis was 51.6±14.7 years. The mean follow-up was 12.7±8.3 years, with a total of 16,395 person years at risk. Pituitary surgery was performed in 842 (65%) patients and radiation therapy in 152 (12%) patients. The diagnosis of hypopituitarism and diabetes mellitus was recorded in 29% and 16% of patients, respectively. Overall, 186 malignancies were identified in patients with acromegaly as compared to 179 expected malignancies in the general population (SIR 1.04; 95% CI 0.90-1.20). Incidence of malignancies was similar in men and women [SIR 1.08 (95% CI 0.88-1.32) vs 1.00 (95% CI 0.80-1.23)]. Incidence of colorectal cancer (SIR 1.12; 95% CI 0.75-1.62) or malignancies of the respiratory system (SIR 1.22; 95% CI 0.76-1.84) was not increased. Incidence of kidney and ureter cancer (n=17) was, however, increased (SIR 3.81; 95% CI 2.22-6.11). In the entire study cohort, only three cases of thyroid cancer were recorded. SIR for malignancies in patients treated with radiotherapy (1.12; 95% CI 0.56-2.01) and in patients with hypopituitarism (SIR 0.91; 95% CI 0.68-1.18) or diabetes (SIR 1.08; 95% CI 0.78-1.45) did not differ from the general population. Conclusions: This large nationwide population-based study showed that the overall incidence of malignancies in patients with acromegaly was not different from the general population. In particular, incidence of colorectal and thyroid cancer was not increased. Incidence of malignancies of the urinary tract was, however, increased.

The prevalence of growth hormone (GH)-secreting pituitary adenoma is around 11-13% of all pituitary adenomas. Giant GH-secreting pituitary adenomas (≥ 4 cm) are rare tumors, and its prevalence of among acromegalic patients is This is a retrospective cohort study including patients with giant GH-secreting pituitary adenomas. The study population consisted of 10 patients (5 M/5 F). The mean age at diagnosis was 33.0±12.9 yrs (11-55 yrs). The mean delay between first symptom onset and diagnosis was 2.9 years. The most frequent symptoms were acral enlargement and facial changes (80%), followed by headache (70%) and visual deterioration (50%). One patient had epilepsy. Amenorrhea was presented in three females but obvious galactorrhea in two. The mean adenoma diameter was 42.6±4.7 mm (40-51 mm) at diagnosis. The vast majority of adenomas presented suprasellar extension (100%) or cavernous sinus invasion (80%). Cystic adenomas accounted for 50%. At presentation, mean GH and IGF-1 levels were 40.0±21.4 ng/mL (14.8-51.0) and 2.62±1.09 x ULN (1.08-3.96), respectively. Six patients presented with PRL cosecretion. At diagnosis maximal tumor diameter was not correlated with GH or IGF-1 levels. All patients underwent pituitary surgery as first-line treatment. Three cases were treated with an endoscopic approach and four cases with a microscopic approach. Transcranial approach was also employed in three cases. Postoperative mean GH and IGF-1 levels were 14.9±16.1 ng/mL (0.6-51.0) and 2.25.±0.82 x ULN (1.48-3.74), respectively. After first surgery, only one patient had more than 50% reduction in IGF-1 levels. Five patients (50%) underwent repeat surgery on two to three procedures because remission was not achieved. Postoperative somatostatin receptor ligands (SRLs) were used by all patients. Six patients were treated with dopamine agonist in combination with SRL. Six patients (60%) received postoperative radiotherapy. The mean follow-up period was 12.6±5.3 yrs (4-21 yrs). The mean GH and IGF-1 levels were 1.47±1.54 ng/mL (0.08-5.25) and 0.73±0.44 x ULN (0.08-1.56), respectively at the last visit. Residual adenoma was present at the last MRI in eight patients (mean diameter 9.0±3.6 mm). Panhypopituitarism rose from 10% at baseline to 30% at the last visit. During follow-up, one patient diagnosed breast cancer, while another diagnosed thyroid papillary cancer. Giant GH-secreting pituitary adenomas can have a clinically aggressive behavior with mass effect. Moreover, treatment in patients with giant GH-secreting pituitary adenoma is complex and multimodal therapy is necessary.

The aim of investigation to determine clinical aggressiveness diagnostic markers in patients with non-functional pituitary adenomas (NFPA) in the formation of gravity neuroendocrine disease symptoms. Material and Methods: We observed in 87 patients (including man - 44 women -43) of which have a verified diagnosis of NFPA after surgery - 31 which were subjected transnasal adenomectomy of the pituitary (TAG). Further analysis was performed on these patients, who were followed from 1 to 3 years. Results. After the analysis of the frequency of remission and relapse NFPA data selectively in patients we studied the correlation between various parameters and the frequency of relapses. NFPA developed the scale of aggressiveness allowed to identify the risk factors of markers on the 3rd degrees, allowing to create a set of measures of tumor growth relapse prevention. According to MRI data of the brain and pituitary gland, in 15 patients an endosellar tumor was found, in 16 - an endo-extrasellar tumor. In an MRI study, the structure of the NFPA had a predominantly soft tissue (n = 16) and cystic (n = 11) structure. In 4 cases (13%), the structure of the NFPA was represented by a hemorrhagic component, and in 2 (6.4%) of them, both cystic and hemorrhagic components were present. In 18 patients, microadenoma was revealed, in 12 - pituitary macroadenoma and in 1 - a giant pituitary adenoma. The developed scale of aggression markers of NFPA allowed identifying factors by 3 degrees, which allows developing a complex of measures for the prevention of tumor growth recurrence. Conclusions. 1) According to our data, the number of patients with large-cell chromophobic pituitary adenoma predominated - 24 (77.5%). In 2nd place were patients with small cell NFPA - 6 cases (19.3%). And only in 1 case was observed (3.2%) a giant malignant pituitary macroadenoma with recurrence of growth and metastasis in the brain of a teenage girl, in which dark-cell pituitary adenoma was histologically determined, 2) According to our preliminary data, the markers of aggressiveness of the course of NFPA are: young patient age, first symptoms of the disease manifest, large tumor size, asymmetry and deformation of the pituitary gland, signs of tumor invasion into adjacent tissues / arteries / cavernous sinus, presence of small cell and / or dark extracellular chromophobic adenomas, STH hypopituitarism, panhypopituitarism.

Cushing’s disease (CD) is characterized by chronic exposure to excess glucocorticoids due to an ACTH-producing tumor. Obesity is a prominent feature of CD, although the mechanisms of weight gain have not been completely elucidated. In some patients, obesity persists despite appropriate medical or surgical treatment of CD and normalization of cortisol levels (1). Few studies have followed patients prospectively to understand the effect of CD remission and cortisol normalization on appetite and body weight. Previous studies have not shown a correlation between appetite or food cravings and circulating total peptide YY (PYY), ghrelin, or leptin concentrations, leading to interest in other hormones which may regulate appetite in CD (2). One of these is the neuropeptide Agouti-related protein (AgRP). AgRP is known to promote appetite and decrease energy expenditure by acting as a melanocortin antagonist at the level of the hypothalamus. Plasma AgRP may be elevated in patients with active CD and decreases with normalization of cortisol levels (3). We sought to determine if AgRP may play a role in regulating appetite or food cravings in CD. Plasma AgRP was measured before and prospectively after treatment in 19 patients with CD. Patients completed surveys on appetite and food cravings at these same time points. As expected, AgRP significantly decreased following treatment for CD, with mean AgRP before treatment 128.72 pg/mL (SD 55.41) and mean AgRP after treatment 75.23 pg/mL (SD 23.46). Using a paired t-test, the mean difference of 53.5 pg/mL was significant (p=0.0006). In addition, there were significant decreases in BMI, weight, and waist circumference with CD treatment. We found that plasma AgRP concentrations did not correlate with an 8-question visual analogue scale (VAS) used to assess hunger and satiety. However, treatment of CD significantly reduced Trait Food Craving Questionnaire scores in parallel with circulating AgRP levels using a one-way analysis of variance (p=0.004). Our data suggest that AgRP may play a role in food craving, rather than appetite, in patients with CD. Further research may clarify the relationship between AgRP and food cravings in CD patients before and after treatment. References: 1. Geer et al. Endocrinol Metab Clin North Am. 2014; 43: 75-102. Geer et al. Pituitary. 2016; 19: 117-126.Page-Wilson et al, J Clin Endocrinol Metab. 2019; 104 (3): 961-969.

Craniopharyngioma (CP) is a rare embryonic tumor of the sellar and parasellar region with benign histology (World Health Organization grade I) thought to arise from embryonic remnants of Rathke’s pouch. Despite its high survival rates, this tumor can lead to severe morbidity secondary to destruction of adjacent structures. Hypothalamus (HT) is a brain region that has a central role in regulating body weight through a complex mechanism involving central and peripheral signaling pathways. Destruction of its distinctive nuclei induces hyperphagia, hyperinsulinemia and weight gain. Seventy-five patients with CP who underwent first surgical resection in a single center by the same neurosurgeon between February 2005 and March 2019 were screened; those who have had prior radiation, were aged below 18 years, or did not have follow up body mass index (BMI) after surgery were excluded. Ultimately, this study included 45 patients with a mean age 50.5 years, 73.3% women. Pre and post-operative MRI were independently reviewed by three neuroradiologists to determine involvement of the hypothalamic regions: anterior, anterior and posterior, or no hypothalamic involvement. Body mass index were recorded pre operatively and subsequently after TSS up to 24 months post operation. Association between hypothalamic region involvement and BMI as well as endocrine function were examined. Posterior hypothalamic involvement seen in pre operative MRI (N=28) was significantly associated with higher BMI at 3-6 month, 7-12 month, and 13-24 month follow up (p < 0.05) in comparison to involvement of anterior hypothalamic alone or no hypothalamic involvement. Similarly, posterior hypothalamic involvement in the pre and post-operative MRI was significantly associated with development of diabetes insipidus (DI) (p < 0.05) compared to anterior or no hypothalamic involvement. There was no association between pre-operative BMI and hypothalamic involvement. Although the weight gain was accelerated after surgery, there was no association between post operative MRI and ensuing BMI, suggesting that the damage of the hypothalamic nuclei was done by the CP rather than surgical procedure. Conclusion: Assessment of hypothalamic involvement by anterior and posterior regions on pre operative MRI can be helpful in predicting development of obesity in patients with CP.

Acromegaly is associated with increased morbidity and mortality primarily attributed to cardiovascular and cerebrovascular diseases, thus demonstrating the negative arterial impact of chronic GH and IGF-1 excess. There are limited and conflicting data regarding coronary artery disease (CAD) in acromegaly that consists mainly of heterogeneous cohorts and pathological reviews of old case series. Increased arterial stiffness is associated with an increased risk of cardiovascular events such as myocardial infarction. Arterial stiffness may measured from pulse wave velocity(PWV). In this study we aimed to evaluate the association between pulse wave velocity and aortic augmentation index in acromegalic patients. Methods: Our study population consists of a consecutive subset of 32 acromegalic patients and 19 control. Acromegalic patients IGF 1 levels were noted. All patients BMI, age, blood pressure, gender also were noted. Also pulse pressure, central blood pressures were measured by non-invasive central blood pressure measurement device (SphygmoCor). Pulse wave velocity and aortic augmentation index were measured by the same device. Results: A total of 32 acromegalic patients and 19 control were enrolled in the study. Body mass index and gender were not significantly different between the groups. Aortic augmentation index (5 vs. 6, p =0,685) variables weren’t significantly different in the study. Systolic and diastolic blood pressures were significantly high in the acromegalic group. (130/82 vs. 120/70) PWV was significantly high in the acromegalic group. (13 vs 11,5 p=0,002)Conclusions: Our study results suggest that acromegaly patients have worse arterial stiffness due to increased pulse wave velocity. Acromegaly is associated with increased morbidity and mortality primarily attributed to cardiovascular problems. We thought that it may be a guiding method in disease management since it can be an early marker of cardiovascular risk.Keywords: acromegaly, pulse wave velocity, aortic augmentation index

Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.

Cushing’s disease is a severe multimorbid pathology affecting mainly people of young working age. In most cases, the diagnosis of the disease is acute and the patient is observed for a long time by doctors of different specialties with complications of hypercorticism. Purpose: To identify the most frequent clinical manifestations of hypercorticism at the time of diagnosis of Cushing’s disease, to analyze the relationship of clinical manifestations of hypercorticism with the main clinical and laboratory indicators. Material and methods: 25 patients were examined, including 15 women and 10 men with Cushing’s disease, registered in Samarkand Endocrinology Clinic. Results: Majority of patients (68%) were in age 25-40, the average age was 37. The median duration of the disease was 35,5 months. Matronism, the most characteristic manifestation of hypercortisolism was observed in 36% (9 patients). This is most often associated with hypercorticism symptoms were striae and acne, which were found in 56% (14 patients), osteoporosis 40% (10). The most frequent complaints were weight gain, fatigue, headache, menstrual disturbances. A number of symptoms had a positive correlation with cortisol levels. Conclusion: Clinical manifestations of hypercorticolism are mainly nonspecific. Striae and acne were found in high frequency. Therefore these key features, namely a change in facial appearance, weight gain, elevation of BMI and the presence of genital virilisation should alert the clinician to the possibility of Cushing’s disease and initiate laboratory evaluation

Introduction: Acromegaly is a potentially fatal neuro-endocrinopathy caused by a growth hormone (GH)-secreting pituitary adenoma (PA). A lack of consensus on factors that reliably predict patient outcomes in acromegalic patients following endoscopic endonasal approaches (EEA) warrants additional investigation. Methods: Pre- and postoperative tumor and endocrinological characteristics from 55 acromegalic patients who underwent EEA for resection of a GH-secreting PA were evaluated as potential predictors of postoperative hormonal remission (defined as age- and sex- normalized IGF-1 levels). Results: The 55 patients included had a mean age of 50.1 ± 13.5 years and a mean follow-up time of 18 ± 17.4 months. Fifty-three patients (96%) presented with dysmorphic craniofacial features, with 22 (40%) presenting with prognathism, 22 (40%) exhibiting frontal bossing, and 18 (33%) presenting with macroglossia. Ten (18%) had microadenomas and 45 (82%) had macroadenomas. Five (9.4%) had giant adenomas. Forty-five (92%) tumors were invasive, with 44 (83%) exhibiting infrasellar invasion, 17 (32%) extending above the sella, and 9 (18%) with cavernous sinus invasion. Thirty-three patients (66%) underwent gross total resection (GTR; mean maximal tumor diameter = 1.52 cm), and 17 (34%) underwent subtotal resection (STR; mean maximal tumor diameter = 2.77 cm). Invasive tumors were significantly larger and Knosp scores were negatively correlated with GTR. Thirty-three patients (65%) achieved hormonal remission after EEA resection alone, which increased to 80% with adjunctive medical therapy. Additionally, 90% of patients who underwent GTR and 63% of patients who underwent STR demonstrated postoperative remission. Six patients (11%) exhibited biochemical remission after postoperative medical therapy with an average time to remission of 5.2 months. These patients all had significantly higher preoperative IGF-1 levels and larger tumors than patients who remitted immediately postoperatively. In all patients preoperative IGF-1 levels were inversely correlated with hormonal remission. Conclusions: This study indicates that endoscopic transsphenoidal resection of growth hormone secreting pituitary adenomas is a safe and highly effective management strategy for achieving hormonal remission and tumor control for patients with acromegaly. When combined with postoperative medical therapy, we observed endocrinological remission rates of 80% based on normalized IGF-1 levels. Our results support the conclusions of current literature that smaller and less invasive tumors are more likely to be fully resected. We additionally suggest that patients with lower preoperative IGF-1 are more likely to undergo postoperative biochemical remission, irrespective of tumor size and invasion.

Background: A new lanreotide autogel/depot (LAN) syringe was developed based on feedback from a human factors study to improve user experience. Methods: PRESTO was a multinational, simulated-use study in nurses with ≥2 years’ experience injecting LAN or octreotide long-acting release (OCT LAR) in patients with acromegaly and/or neuroendocrine tumors, which aimed to assess injector preference between the LAN new syringe and the current OCT LAR syringe. Participating nurses were invited to test both the LAN new syringe (120 mg) and the current OCT LAR syringe (20 mg or 30 mg), using injection pads. The sponsor was not involved in these sessions. In an anonymous web-based questionnaire, nurses reported overall preference (‘strong’ or ‘slight’; primary endpoint), and rated and ranked the importance of nine attributes for each syringe (1 [not at all] to 5 [very much]). Results: In total, 90 nurses attended injection sessions and completed valid questionnaires. Overall, 97.8% of nurses expressed a preference (85.6% ‘strong’, 12.2% ‘slight’) for LAN new syringe (p Conclusions: The PRESTO study showed that nurses preferred the user experience of the LAN new syringe over the current OCT LAR syringe across all attributes tested.

Objective: Childhood-onset craniopharyngiomas (CP) are diagnosed due to clinical symptoms (symCP) or incidentally (incCP). We investigated clinical manifestations and outcome in incCPs and symCPs. Design and methods: IncCP were discovered in 4 (3m/1f) and symCP in 214 CP (101m/113f) recruited 2007–2014 in KRANIOPHARYNGEOM 2007. Age, sex, height, body mass index (BMI), tumor size, degree of resection, pre- and postsurgical hypothalamic involvement/lesions, pituitary function and outcome were compared between both subgroups. Results: Reasons for imaging in incCP were cerebral palsy, head trauma, nasal obstruction, and tethered-cord syndrome, whereas headache (44%) visual impairment (25%), and growth retardation (17%) lead to imaging in symCP. Tumor size at diagnosis was smaller in incCP (median tumour size 3.26 cm2; range: 0.56–5.13 cm2) when compared with symCP (median tumour size 12.16 cm2; range: 0.004–79.54 cm2). Age, gender, BMI, height, hydrocephalus, tumor location, and hypothalamic involvement at diagnosis of incCP were within the range of these parameters in symCP. Complete resections were achieved more frequently (3/4 patients) in incCP when compared with symCP (20%). Surgical hypothalamic lesions were distributed similar in incCP and symCP. Irradiation was performed only in symCP (33%). No noticeable differences were observed concerning survival rates, endocrine deficiencies, BMI, height, functional capacity and quality of life of the 4 incCP cases when compared with the symCP cohort. Conclusions: IncCP are rare (1.8%) and characterized by lack of endocrine deficiencies, resulting in normal height and BMI, no hydrocephalus, and smaller tumor size at diagnosis when compared with symCPs. Outcome of the observed incCP is similar with symCP.

Silent corticotroph adenomas (SCAs) are tumors of the TPIT anterior pituitary cell lineage that do not lead to biochemical or clinical Cushings syndrome. Thus, they present as clinically nonfunctioning pituitary adenomas (CNFPAs) and are only diagnosed pathologically. Since they are often aggressive tumors, identification of a peripheral blood marker of SCA activity would be useful for diagnosis and monitoring. Some data suggest that aberrant processing of POMC, the precursor of ACTH, underlies the lack of elevated biologically active ACTH and thus cortisol excess in SCAs. We hypothesized that these tumors could secrete POMC, resulting in elevated plasma levels of POMC in patients with SCAs. Therefore, we investigated plasma POMC levels as a potential marker of this tumor type and correlated with tumor ACTH immunoreactivity (IR), which may be detecting unprocessed POMC. We studied 267 patients (134M, 133F, age 56.3±13.6yr) with CNFPAs (Cushings excluded) prior to surgery and at enrollment in a prospective, observational study. We also studied 9 patients with known SCAs with residual macroadenomas after surgery. Peripheral blood was sampled for POMC, ACTH and cortisol levels. POMC was measured by in-house two-site ELISA (detects POMC and 22kD pro-ACTH) and ACTH and cortisol by Immulite(Siemens). POMC levels were compared to the 95%CI of the mean of 70 healthy subjects and considered elevated if ≥ the 97.5 percentile of 39 fmol/mL. Of the CNFPA cohort, 12/267 had elevated POMC levels (range 39-166 fmol/mL) and 4 of the 12 had elevated ACTH levels (> 50 pg/ml)(range 53.6-76 pg/ml). Of the 12 with elevated POMC, 9 underwent surgery and 6 of them had positive ACTH IR in their tumors. An additional 13 patients in the CNFPA cohort had weak ACTH IR tumors, but POMC

Background Insulinomas are rare life-threatening pancreatic neuroendocrine tumors. Surgical removal continues to be the treatment of choice for such benign cases with a high cure rate. However, surgery is associated with a considerable risk of morbidity and mortality.Here we describe a case of benign solitary insulinoma successfully treated with RFA in a patient who strongly refused surgery. Case Description A 56-year- old non- diabetic, male is known to have hypertension and lymphoma diagnosed at age of 20 years, in remission. He presented with recurrent episodes of transient ischemic attack and stroke over the last three years. A change in his cognitive function, behavior, and memory was noticed. During his hospital stay for the second episode of stroke, he was found to have hypoglycemia which was asymptomatic. Insulinoma was confirmed based on the followings: low plasma glucose level of 2.04 mmol/l (4.0- 5.6), inappropriately elevated plasma f insulin and C-peptide 68.9 mU/l (3-13) and 4.08 ug/l (1.0-3.1); respectively. Sulfonylurea screening test was negative. MRI of the abdomen showed a 3.2x2.5 cm, well-circumscribed hypervascular lesion at the uncinate process of the pancreas, which is compatible with neuroendocrine tumor. Treatment modalities have been explained to the patient who was fully informed about the risk and benefit of each treatment option. However, he strongly refused surgery. Meanwhile, he was admitted with a third attack of stroke with concurrent hypoglycemia. In view of his refusal of the surgical treatment and due to his recent stroke and high-risk status for surgery, the option of radiofrequency ablation was decided. RFA of the pancreatic tumor using 40.75 GY fractions was carried out with a favorable outcome. The patient achieved biochemical normalization and remains euglycemic during his follow up. Reversal of his cognitive, behavioral, and memory changes was recognized. CT abdomen during a follow-up of 2 months after radiation showed a mild regression of the size of the tumor with no evidence of new lesions or distance metastasis. He remained under close follow up at the neuroendocrine clinic. Conclusion This case shows a treatment challenge which required the use of an alternative treatment option other than the standard of care in managing a case of benign insulinoma. Successful treatment was achieved in our case with the use of RFA rather than surgery. This report highlights the evolving evidence of nonsurgical RFA being a potential safe, feasible therapeutic modality option or even an alternative to surgery in selected cases of benign insulinoma. Because of the rarity of this tumor and low rate of therapeutic application of RFA in similar cases, the role of RFA had not been extensively studied. Large studies are needed to evaluate the long-term outcomes of RFA in this setting.

Introduction: Transsphenoidal surgery is recommended as first line therapy in the vast majority of patients with acromegaly. Successful surgical intervention is determined by normalization of insulin like-growth factor (IGF) - 1 and adequate suppression of growth hormone (GH) during glucose GH suppression test or random GH levels Aim: To determine if IGF-1 levels at 6 weeks were equally predictive of surgical outcomes when compared to IGF-1 levels at 3–6 months postoperative. Methods: Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2010–2019 and had post-operative IGF-1 level measured at 6 weeks and 3–6 months. IGF-1 was measured using the Siemens Immulite assay until 2016 when it was replaced by a LC-MS/MS assay. IGF-1 measurements at 6 weeks are obtained based on clinician discretion. Results: 69 patients (mean age 49 ± 14.8, female 31/69, 44.9%) with acromegaly had surgery and IGF-1 follow-up measurements at 6 weeks and 3–6 months. Persistent acromegaly was noted in 45/69 at 3–6 months. The median IGF-1 pre-operative was 701 ng/ mL (289–1600), 6 weeks postoperative was 286 ng/ mL (109–1038) and at 3–6 months was 267 ng/ mL (77–996). The median pre-operative IGF-1 was significantly higher than the median IGF-1 level at 6 weeks and 3–6 months (P= Conclusion: In the vast majority of patients, 6 weeks post-operative IGF-1 can be used to assess response to surgery avoiding a delay in treatment. However, we would recommend repeating IGF-1 levels at 3–6 months in those who have marginally elevated IGF-1 above normal (≤ 1.12), without cavernous sinus invasion and a post-operative GH of

Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited. Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X. Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion. Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T>A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation. ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.

Background MRI T2 hypointensity of growth hormone (GH) secreting pituitary adenomas (PA) has been associated with better biochemical response to somatostatin receptor ligands and has been suggested to be useful in selecting patients with expected favorable response for pre- and post-surgery medical therapy. However, in most imaging centers, T2 intensity measurement is not part of standard neuroradiologist (NR) reporting. Objective To assess whether endocrinologists (Es) can reliably measure PA T2 signal intensity by calculating inter-rater reliability between Es and NR. Methods Retrospective review of MRI in 20 patients with pituitary somatotroph macroadenoma randomly selected from an IRB-approved PA database who had preoperative MRI available. T2 MRI intensity of the solid portion of the PA was compared to the temporal gray matter (GM) and white matter (WM): hypo- (PA< WM), hyper- (PA> GM), and isointense (WM

Distinguishing non-specific signs and symptoms of acromegaly from treatment emergent adverse events (TEAEs) in patients treated with somatostatin receptor ligands has proven difficult given limited data from placebo-controlled studies. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study provides a novel data set to evaluate the incidence of adverse events from patients randomized to octreotide capsules or placebo. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥18 years of age, had active disease (IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤1.0 x ULN in response to a stable dose of somatostatin receptor ligand injection. Patients were randomized to octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label extension for up to 1 year. Safety and tolerability were evaluated based on incidence of AEs, including incidence of new or worsening adverse events of special interest (AESIs). In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide (Melmed et al 2015). No new or unexpected safety signals were detected. Nearly all patients (55/56) experienced a TEAE (28 patients [100.0%] in the octreotide capsule group and 27 patients [96.4%] in the placebo group). Thirty-three patients (58.9%) experienced a TEAE considered to be related to study drug by the blinded PI (64.3% of the octreotide capsule group [18 patients, 40 events] and 53.8% of the placebo group [15 patients, 41 events]). TEAEs with an incidence ≥5% that were more common in the octreotide capsule group vs placebo group included GI disorders, increased blood glucose, sinusitis, osteoarthritis, and cholelithiasis. TEAEs with an incidence ≥5% that were more common in the placebo group vs octreotide capsule group included arthralgia, headache, fatigue, hyperhidrosis, and peripheral swelling. GI disorders were the most common TEAE, reported in 64% of all patients (36/56) and at similar rates between octreotide capsule (68%) and placebo groups (61%). AESIs (defined as new or worsening signs of acromegaly) were observed in 15 patients (53.6%, 34 events total) in the octreotide capsule group and more frequently in 26 patients (92.9%, 82 events total) in the placebo group. In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide. Most patients receiving octreotide capsules or placebo demonstrated TEAEs, although the profile of most common TEAEs varied between groups. TEAEs observed in the placebo group may be indicative of underlying disease activity. Further analysis may elucidate the difference between treatment related AEs and signs/symptoms of active disease in acromegaly.