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Purpose: Arthropathy is a common and disabling complication of acromegaly. Since in this condition radiological findings rarely correspond to functional impairment, we elected to quantify in a large cohort of acromegalic patients: the degree of motor disability compared with data from general population, the impact of joint involvement on quality of life and work productivity, and to look for associated factors. Methods: In 211 acromegalic patients, 131 with controlled disease and 80 with active disease, eight validated scales were used to evaluate the (i) prevalence and distribution of arthropathy, (ii) degree of motor disability and joint symptoms (VAS, AIMS symptoms and WOMAC), (iii) quality of life (AcroQoL and PASQ) and work capability (WPAI:GH) as consequences of joint complications. Results: Using the WOMAC questionnaire, for which population based normative values are available, a significantly higher prevalence and severity of motor disability was detected in acromegalics compared to the general population from literature. The results provided by the different questionnaires turned out to be highly concordant. All measures of motor disability correlated both with impaired quality of life and motor disability and were worse in females and in patients with higher BMI. Conclusions: The questionnaires VAS, AIMS symptoms, and WOMAC (this latter both as a whole and with its functionality subscale), with their scores, proved to be the most adequate tools to evaluate motor disability and its consequences on both quality of life and work productivity in acromegaly. Female gender and higher BMI are associated with worse articular symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long-standing active acromegaly undergoing treatment with Pegvisomant.Subjects and methods: Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed.Results: Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site.Conclusion: Vertebral fractures are a frequent complication of long-standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteoporosis is a very common bone disorder and accounts for 1.4 million vertebral compression fractures (VCFs) per year,mostly in post-menopausal women. AIM: The aim of this study was to develop a risk scoring system to identify and gauge the risk of osteoporotic VCFs in post-menopausal women. MATERIALS AND METHODS: We conducted a retrospective cross-sectional study on 477 post-menopausal women consecutively visited at our institution.We studied 15 different clinical variables, i.e. age, body mass index (BMI), weight, L1-L4 lumbar T-Score, L1-L4 lumbar ZScore, L1-L4 lumbar bone mineral density (BMD), femoral neck T-Score, femoral neck ZScore, femoral neck BMD, smoking habit, alcohol consumption, 25-OH-vitamin D, total alkaline phosphatase, bone alkaline phosphatase, and L4 vertebral volume. Study population was split in a derivation and a validation cohort. A logistic regression model was used to develop a predictive score of osteoporotic VCFs in the derivation cohort, finally the performance of the score was tested in the validation cohort. RESULTS: Age, L1-L4 lumbar T-Score, femoral neck T-Score, L4 vertebral volume, and smoking habit were found to be predictors of VCFs.To each variable a score from 0 to +12 was assigned to the magnitude of regression coefficient. A score ≤ 22 identified VCFs with a sensitivity of 87%/89% and a specificity of 87%/90% in the derivation and validation cohorts, respectively. CONCLUSIONS: Our findings indicate that a simple score derived from clinical history and routine diagnostic workout can be usefully employed to gauge the risk of fragility VCFs in postmenopausal women. [ABSTRACT FROM AUTHOR]

Introduction: Insulin autoimmune syndrome (IAS) is a rare condition characterized by hypoglycemia due to autoantibodies against endogenous insulin. It is correlated, in approximately 50% of cases, to specific drugs intake. Hypoglycemia occurs typically during the late post-prandial period. Aim(s): We report two cases of IAS patients who came to our attention because of recurrent and severe hypoglycemia. Materials and methods: Case 1: A 29-year-old female, affected by Graves disease and treated with methimazole, was evaluated in 2006 because of recurrent hypoglycemia. Insulinemia was > 1000 µUI/ml. Fasting test was negative as well as abdomen MRI. After total thyroidectomy glycemic and insulin levels normalized. Case 2: A 45-year-old female came to our attention in 2011 because of recurrent post-prandial hypoglycemia. Insulinemia was >1000 µUI/ml. An OGTT revealed late reactive hypoglycemia, while fasting test was normal as well as EUS. Dosing of insulin antibodies was 658 U/ml (<0.4). With an adequate diet and acarbose treatment the symptoms improved. Results: In these two cases, inappropriately high levels of insulin were associated with late post-prandial hypoglycemia, with no evidence of pancreatic lesions and negative fasting tests. Conclusion: In the evaluation of patients with hypoglycemia and inappropriate secretion of insulin, IAS should be considered in the differential diagnosis, especially in patients with late post-prandial hypoglycemia with a history of specific drugs intake and negative imaging. [ABSTRACT FROM AUTHOR]

Inositols have demonstrated a role in cancer prevention and treatment in many kinds of neoplasms. Their molecular mechanisms vary from the regulation of survival and proliferative pathways to the modulation of immunity and oxidative stress. The dysregulation of many pathways and mechanisms regulated by inositols has been demonstrated in endocrine and neuroendocrine tumors but the role of inositol supplementation in this context has not been clarified. The aim of this review is to summarize the molecular basis of the possible role of inositols in endocrine and neuroendocrine tumors, proposing it as an adjuvant therapy.

Introduction: Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity., Methods: We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization., Results: At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered., Conclusion: The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mormando, Galiè, Bianchini, Lauretta, Puliani, Tanzilli, Anceschi, Simone, Petreri, Graziano, Pace and Appetecchia.)

Background: To evaluate the ability of therapeutic intensity score (TIS) in predicting the clinical outcomes of partial (PA) and total adrenalectomy (TA) for UPA., Methods: Between 2011 and 2022, a four-center adrenalectomy dataset was queried for "unilateral adrenal mass" and "UPA" (n = 90). Preoperative TIS of each antihypertensive medication were individually calculated and merged to create a single, cumulative variable. Probability of complete clinical, partial, and absent pooled success rates according to TIS were assessed for the overall cohort by Kaplan-Meier. Cox analyses were used to identify predictors of complete clinical and partial/absent success, respectively. For all analyses, a two-sided p < 0.05 was considered significant., Results: At a median follow-up of 42 months (IQR 27-54) complete partial, and absent clinical success were observed in 60%, 17.7%, and 22.3%, respectively. On Kaplan-Meier analysis, TIS < 1 predicted higher complete success rates ( p < 0.001), while TIS ≥ 1 was predictor of either partial and absent clinical success ( p = 0.008). On multivariable analysis, TIS < 1 (HR 0.25; 95% CI 0.11-0.57; p = 0.001) and adenoma size (HR 1.11; 95% CI 1-1.23; p = 0.0049) were independent predictors of complete clinical success, while TIS ≥ 1 (HR 2.84; 95% CI 1.32-6.1; p = 0.007) was the only independent predictor of absent clinical success., Conclusions: TIS score and adenoma size may help to identify patients who are likely to be at risk of persistent hypertension after surgery.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has been used for over two decades for the treatment of well-differentiated neuroendocrine tumors (NETs), and the publication of the NETTER-1 trials has further strengthened its clinical use. However, many aspects of this treatment are still under discussion. The purpose of this review is to collect and discuss the new available evidence, published in 2021, on the use of 177 Lu-Oxodotreotide (DOTATATE) or 90 Y-Edotreotide (DOTATOC) in adult patients with NETs focusing on the following hot topics: 1) PRRT use in new clinical settings, broaden its indications; 2) the short- and long-term safety; and 3) the identification of prognostic and predictive factors. The review suggests a possible future increase of PRRT applications, using it in other NETs, as a neoadjuvant treatment, or for rechallenge. Regarding safety, available studies, even those with long follow-up, supported the low rates of adverse events, even though 1.8% of treated patients developed a second malignancy. Finally, there is a lack of prognostic and predictive factors for PRRT, with the exception of the crucial role of nuclear imaging for both patient selection and treatment response estimation., Competing Interests: MA does consultancy and has received research grants from Bayer, Eisai, and Eli-Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Puliani, Chiefari, Mormando, Bianchini, Lauretta and Appetecchia.)

Background: To propose a trifecta that summarizes endpoints and predicts their maintenance after adrenalectomy ( n = 90) for unilateral primary aldosteronism (UPA)., Methods: Trifecta was defined as coexistence of: ≥50% antihypertensive therapeutic intensity score reduction (∆TIS), no hypokalemia at 3 months, and no Clavien grade 2-5. Logistic regression was used to identify predictors of trifecta. Probability of clinical, biochemical, and simultaneous success according to trifecta were assessed by Kaplan-Meier. Cox regression was used to identify predictors of long-term clinical, biochemical, and simultaneous success. For all analyses, a two-sided p < 0.05 was considered significant., Results: Simultaneous success rate was 50%. On multivariable analysis, TIS was an independent predictor of trifecta achievement (HR 3.28; 95% CI 1.07-10.9; p = 0.03). At Kaplan-Meier, trifecta predicted higher success for all endpoints (each p < 0.03). On multivariable Cox analysis, adenoma size (AS) ≥6 cm and trifecta were independent predictors of biochemical (AS: HR 2.87; 95% CI 1.53-5.36; trifecta: HR 2.1; 95% CI 1.13-3.90; each p < 0.02) and simultaneous success (AS: HR 3.81; 95% CI 1.68-8.65; trifecta: HR 4.29; 95% CI 2.08-8.86; each p < 0.01), while trifecta was an independent predictor of complete clinical success (HR 2.84; 95% CI 1.45-5.58; p < 0.01)., Conclusions: Trifecta and AS are independent predictors of either long-term complete clinical, biochemical, or combined success after adrenalectomy for UPA.

Introduction: Several predictive scores to evaluate outcomes of adrenal surgery for unilateral primary aldosteronism (UPA), have been conceived. We compared a novel trifecta that summarizes outcomes of adrenal surgery for UPA with the clinical cure proposed by Vorselaars., Material and Methods: Between March 2011 and January 2022, a multi-institutional dataset was queried for UPA. Baseline, perioperative and functional data were collected. Clinical and biochemical complete and partial success rates according to Primary Aldosteronism Surgical Outcome (PASO) criteria were assessed for the overall cohort. Clinical cure was defined either as normotension without antihypertensive medications or normotension with lower or equal use of antihypertensive medications. Trifecta was defined as the coexistence of ≥50% antihypertensive therapeutic intensity score (TIS) reduction (ΔTIS), no electrolyte impairment at 3-months and no Clavien-Dindo (2-5) complications. Cox regression analyses were used to identify predictors of long-term clinical and biochemical success. For all analyses, a two-sided p <0.05 was considered significant., Results: Baseline, perioperative and functional outcomes were analyzed. Out of 90 patients, at a median follow-up of 42 months (IQR 27-54) a complete and partial clinical success was observed in 60% and 17.7% of cases while a complete and partial biochemical success was achieved in 83.3% and 12.3% of cases, respectively. Overall trifecta and clinical cure rates were 21.1% and 58.9%, respectively. On multivariable Cox regression analysis, trifecta achievement (HR 2.87; 95% CI 1.45-5.58; p = 0.02) was the only independent predictor of complete clinical success at long-term follow-up., Conclusions: Despite its complex estimation and more restrictive criteria, trifecta but not clinical cure allows to independently predict composite PASO endpoints on the long run., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this systematic review is to collect the available evidence on the side effects of mitotane on the endocrine and metabolic systems in both children and adults affected by adrenal carcinoma. Sixteen articles on 493 patients were included. Among the adrenal insufficiency, which is an expected side effect of mitotane, 24.5% of patients increased glucocorticoid replacement therapy. Mineralocorticoid insufficiency usually occurred late in treatment in 36.8% of patients. Thyroid dysfunction is characterized by a decrease in FT4, which occurs within 3-6 months of treatment in 45.4% of patients, while TSH seems to not be a reliable marker. Dyslipidemia is characterized by an increase in both LDL-c and HDL-c (54.2%). Few studies have found evidence of hypertriglyceridemia. In males, gynecomastia and hypogonadism can occur after 3-6 months of treatment (38.4% and 35.6%, respectively), while in pre-menopausal women, mitotane can cause ovarian cysts and, less frequently, menstrual disorders. Most of these side effects appear to be reversible after mitotane discontinuation. We finally suggest an algorithm that could guide metabolic and endocrine safety assessments in patients treated with mitotane for ACC.

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

The original version of the article contained an error in the results section of the Abstract. The vertebral fractures (VFs) odds ratio is incorrectly published as 61.0 and the correct value is 6.10.

Purpose: Acromegalic osteopathy is an emerging complication of acromegaly characterized by increase in bone turnover, deterioration in bone microarchitecture and high risk of vertebral fractures (VFs). Somatostatin receptor ligands (SRLs) and pegvisomant (PegV) are used for treatment of acromegaly and there is evidence that both drugs may exert direct effects on peripheral targets regardless of biochemical control of disease. However, whether or not SRLs and PegV may directly influence skeletal health its is unknown., Methods: In this longitudinal study, we evaluated the incidence of radiological VFs in 83 patients (48 females, 35 males; median age 47 years, range 18-80 years) who were treated with SRLs alone (42 cases), PegV alone (6 cases) or in combination with SRLs (35 cases) for median period of 82 months (range 36-126). PegV was given when acromegaly was not controlled by SRLs alone., Results: During the follow-up, 29 patients (34.9%) developed incident VFs. In patients receiving PegV due to active disease during SRL therapy, incidence of VFs decreased significantly from 43.9 to 26.8% (p = 0.039). When acromegaly was controlled by PegV, the incidence of VFs was slightly but not significantly lower as compared to that observed in patients with biochemical control of disease by SRLs (10.0 vs. 26.7%; p = 0.09). In the multivariate logistic regression analysis, incident VFs were independently predicted by pre-existing VFs (odds ratio 61.0; p = 0.009), duration of active acromegaly (odds ratio 1.01; p = 0.05) and mean serum IGF-I during the follow-up (odds ratio 5.26; p = 0.03), regardless of the therapeutic regimen (odds ratio 1.05; p = 0.94)., Conclusions: PegV and SRLs had comparable effects on VF risk in acromegaly. The activity of disease was the main determinant of VFs independently of the drug used to control acromegaly.

Background: Autoimmune hypophysitis is a rare disease with a natural progression that is not well known., Aim: To collect representative data on clinical features of autoimmune hypophysitis and better characterize the disease., Patients and Methods: A prospective single-center study was designed. Autoimmune hypophysitis-affected patients evaluated from 2011 at our tertiary care Pituitary Unit were enrolled. After ruling out other pituitary masses and secondary causes of hypophysitis, autoimmune hypophysitis was the diagnosis of exclusion. Autoimmune hypophysitis was classified as adenohypophysitis, panhypophysitis, and infundibuloneurohypophysitis according to clinical and neuroradiological findings., Results: A total of 21 patients met the inclusion criteria: 9 were diagnosed with adenohypophysitis, 4 with panhypophysitis, and 8 with infundibuloneurohypophysitis. The frequency of secondary hypoadrenalism was similar in adenohypophysitis, panhypophysitis, and infundibuloneurohypophysitis. Growth hormone deficit and secondary hypogonadism occurred more frequently in infundibuloneurohypophysitis than in adenohypophysitis and panhypophysitis (p = 0.009; p = 0.04). All cases of multiple pituitary secretion deficits occurred in cases of infundibuloneurohypophysitis (p = 0.04). No correlations between hypophysitis subtype and anti-pituitary and anti-hypothalamus autoantibodies were found. A higher frequency of extractable nuclear antigens (ENA) and anti-nuclear antibodies (ANA) was found in cases of panhypophysitis (OR 5.0, 95% CI 0.86-28.8, p < 0.001, and OR 1.8, 95% CI 1.1-3.2, p = 0.02, respectively) as compared to adenohypophysitis and infundibuloneurohypophysitis., Conclusion: Infundibuloneurohypophysitis should be taken into account in the etiological diagnosis of hypopituitarism, particularly if it is associated with diabetes insipidus and in cases of growth hormone deficit, secondary hypogonadism, or multiple hormone deficits. Contrast-enhanced MRI is crucial for the clinical and noninvasive diagnosis of hypophysitis. Screening for autoantibodies, particularly anti-ENA and anti-ANA, is strongly suggested in the clinical context of hypophysitis., (© 2016 S. Karger AG, Basel.)

Aim: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly., Patients and Methods: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR., Results: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04)., Conclusion: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients., (© 2016 European Society of Endocrinology.)