Gonadotropic status in adult women with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

BACKGROUND: Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. METHODS: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. RESULTS: Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. CONCLUSIONS: We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

Position statement on the diagnosis and management of congenital pituitary deficiency in adults: The French National Diagnosis and Treatment Protocol (NDTP).

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

Assessment of the Impact of Subcutaneous Catheter Change on Glucose Control in Patients with Type 1 Diabetes Treated by Insulin Pump in Open- and Closed-Loop Modes.

Introduction: Most continuous subcutaneous insulin infusion (CSII) catheters (KT) are changed every 3 days. This study aims at evaluating whether KT changes impact glucose control while under open-loop (OL) or automated insulin delivery (AID) modes. Methods: We included patients with type 1 diabetes who used Tandem t:slim x2 insulin pump and Dexcom G6 glucose sensor for 20 days in OL, then as AID. CSII and sensor glucose data in OL and for the past 20 days of 3-month AID were retrospectively analyzed. The percentage of time spent with sensor glucose above 180 mg/dL (%TAR180) was compared between the calendar day of KT change (D0), the next day (D1), and 2 days later (D2). Values were adjusted for age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) at inclusion, and %TAR180 for the 2 h before KT change. Results: A total of 1636 KT changes were analyzed in 134 patients: 72 women (54%), age: 35.6 ± 15.7 years, BMI: 25.2 ± 4.7 kg/m2, and HbA1c: 7.5 ± 0.8%. %TAR180 in the 2 h before the KT change was 51.3 ± 37.0% in OL and 33.2 ± 30.0% in AID mode. In OL, significant absolute increases of %TAR180 at D0 versus D1 (+6.9%; P < 0.0001) or versus D2 (+6.8%; P < 0.0001) were observed. In AID, significant absolute increases of %TA180R at D0 versus D1 (+4.8%; P < 0.0001) or versus D2 (+4.2%; P < 0.0001) were also observed. Conclusion: This study shows an increase in time spent in hyperglycemia on the day of the KT change both in OL and AID modes. This additional information should be taken into account to improve current AID algorithms. ClinicalTrials.gov: NCT04939766.

Updates on the genetics of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.

Relationship Between Lipohypertrophy, Glycemic Control, and Insulin Dosing: A Systematic Meta-Analysis.

Background: Lipohypertrophy is a common complication in patients with diabetes receiving insulin therapy. There is a lack of consensus regarding how much lipohypertrophy affects diabetes management. Our study aimed to assess the potential correlation between lipohypertrophy and glycemic control, as well as insulin dosing in patients with diabetes. Methods: We performed a systematic review followed by a meta-analysis to collect data about glycemic control and insulin dosing in diabetic patients with and without lipohypertrophy. To identify relevant studies published in English, we searched medical databases (MEDLINE/PubMed, Embase, and CENTRAL) from 1990 to January 20, 2023. An additional hand-search of references was performed to retrieve publications not indexed in medical databases. Results of meta-analyses were presented either as prevalence odds ratios (pORs) or mean differences (MDs) with 95% confidence intervals (95% CIs). This study was registered on PROSPERO (CRD42023393103). Results: Of the 5540 records and 240 full-text articles screened, 37 studies fulfilled the prespecified inclusion criteria. Performed meta-analyses showed that patients with lipohypertrophy compared with those without lipohypertrophy were more likely to experience unexplained hypoglycemia (pOR [95% CI] = 6.98 [3.30-14.77]), overall hypoglycemia (pOR [95% CI] = 6.65 [1.37-32.36]), and glycemic variability (pOR [95% CI] = 5.24 [2.68-10.23]). Patients with lipohypertrophy also had higher HbA1c (MD [95% CI] = 0.55 [0.23-0.87] %), and increased daily insulin consumption (MD [95% CI] = 7.68 IU [5.31-10.06]). Conclusions: These results suggest that overall glycemic control is worse in patients with lipohypertrophy than in those without this condition.

Should people with type 2 diabetes treated by multiple daily insulin injections with home health care support be switched to hybrid closed-loop? The CLOSE AP+ randomized controlled trial.

AIM: The study aim was to evaluate the feasibility, safety and efficacy of automated insulin delivery (AID) assisted by home health care (HHC) services in people with type 2 diabetes unable to manage multiple daily insulin injections (MDI) at home on their own. PATIENTS AND METHODS: This was an open label, multicentre, randomized, parallel group trial. In total, 30 adults with type 2 diabetes using MDI and requiring nursing support were randomly allocated to AID or kept their usual therapy over a 12-week period. Both treatments were managed with the support of HHC services. The primary outcome was the percentage time in the target glucose range of 70-180 mg/dl (TIR). Secondary outcomes included other continuous glucose monitoring metrics, glycated haemoglobin (HbA1c) levels, daily insulin doses, body weight, and of quality of life scores, fear of hypoglycaemia and satisfaction questionnaires. RESULTS: Age (69.7 vs. 69.3 years) and HbA1c (9.25 vs. 9.0) did not differ in MDI and AID at baseline. Compared with MDI, AID resulted in a significant increase in TIR by 27.4% [95% CI (15.0-39.8); p < .001], a decrease in time above range by 27.7% and an unchanged time below range of <1%. A between-group difference in HbA1c was 1.3% favouring AID. Neither severe hypoglycaemia nor ketoacidosis occurred in either group. Patient and caregiver satisfaction with AID was high. CONCLUSIONS: AID combined with tailored HHC services significantly improved glycaemic control with no safety issues in people with type 2 diabetes previously under an MDI regimen with HHC. AID should be considered a safe option in these people when lacking acceptable glucose control.

Safety and Efficacy of Sustained Automated Insulin Delivery Compared With Sensor and Pump Therapy in Adults With Type 1 Diabetes at High Risk for Hypoglycemia: A Randomized Controlled Trial.

OBJECTIVE: Assess the safety and efficacy of automated insulin delivery (AID) in adults with type 1 diabetes (T1D) at high risk for hypoglycemia. RESEARCH DESIGN AND METHODS: Participants were 72 adults with T1D who used an insulin pump with Clarke Hypoglycemia Perception Awareness scale score >3 and/or had severe hypoglycemia during the previous 6 months confirmed by time below range (TBR; defined as sensor glucose [SG] reading <70 mg/dL) of at least 5% during 2 weeks of blinded continuous glucose monitoring (CGM). Parallel-arm, randomized trial (2:1) of AID (Tandem t:slim ×2 with Control-IQ technology) versus CGM and pump therapy for 12 weeks. The primary outcome was TBR change from baseline. Secondary outcomes included time in target range (TIR; 70-180 mg/dL), time above range (TAR), mean SG reading, and time with glucose level <54 mg/dL. An optional 12-week extension with AID was offered to all participants. RESULTS: Compared with the sensor and pump (S&P), AID resulted in significant reduction of TBR by -3.7% (95% CI -4.8, -2.6), P < 0.001; an 8.6% increase in TIR (95% CI 5.2, 12.1), P < 0.001; and a -5.3% decrease in TAR (95% CI -87.7, -1.8), P = 0.004. Mean SG reading remained similar in the AID and S&P groups. During the 12-week extension, the effects of AID were sustained in the AID group and reproduced in the S&P group. Two severe hypoglycemic episodes occurred using AID. CONCLUSIONS: In adults with T1D at high risk for hypoglycemia, AID reduced the risk for hypoglycemia more than twofold, as quantified by TBR, while improving TIR and reducing hyperglycemia. Hence, AID is strongly recommended for this specific population.

Effects on the Hypothalamo-Pituitary Axis in Patients with CNS or Head and Neck Tumors following Radiotherapy.

BACKGROUND: Knowledge about the precise effects of radiotherapy on hypothalamo-pituitary functions is limited. Reduction of side effects is a major goal of advanced radiotherapy modalities. We assessed strategies for monitoring and replacement of hormone deficiencies in irradiated patients. METHODS: A search strategy was systematically conducted on PubMed®. Additional articles were retrieved to describe endocrine mechanisms. RESULTS: 45 studies were evaluated from 2000 to 2022. They were predominantly retrospective and highly heterogeneous concerning patient numbers, tumor types, radiotherapy technique and follow-up. Endocrine deficiencies occurred in about 40% of patients within a median follow-up of 5.6 years without a clear difference between radiotherapy modalities. Somatotropic and thyrotropic axes were, respectively, the most and least radiosensitive. CONCLUSIONS: Current pituitary gland dose constraints may underestimate radiation-induced endocrine deficiencies, thus impairing quality of life. Little difference might be expected between radiation techniques for PG tumors. For non-PG tumors, dose constraints should be applied more systematically.

Evidence of Persistent Mild Hypercortisolism in Patients Medically Treated for Cushing Disease: the Haircush Study.

CONTEXT: Cortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD). OBJECTIVE: This work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement. METHODS: This multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF. RESULTS: Despite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05). CONCLUSION: Despite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized.

Use of insulin pumps and closed-loop systems among people living with diabetes: A narrative review of clinical and cost-effectiveness to enable access to technology and meet the needs of payers.

The use of continuous subcutaneous insulin infusion (CSII) via insulin pumps is today considered standard of care for type 1 diabetes (T1D). Closed-loop systems combining continuous glucose monitoring with automated algorithm-driven insulin delivery have been shown to be safe and efficacious in randomized controlled trials and real-life studies in both paediatric and adult participants with T1D. Implementation of hybrid closed-loop (HCL) systems has shown incremental effectiveness, with further reduction of hypoglycaemia and hyperglycaemia. Although less extensively studied in type 2 diabetes (T2D), insulin pumps have demonstrated their effectiveness in glucose control, along with a reduction in need for insulin and a neutral effect on weight. Recent studies have also shown promising results with the use of HCL systems in T2D. Cost-effectiveness studies in both T1D and T2D have shown that pump use is cost-effective in several countries, leading to improvements in quality-adjusted life-years. Insulin pumps are currently reimbursed for T1D in many European countries, but in only a few for individuals with T2D. HCL systems are to be evaluated in future trials performed in T2D to compare their incremental efficacy and cost-effectiveness in comparison with available intensification tools which include multiple daily insulin injections, metformin, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. There is a need for updated guidelines for the use of CSII and HCL in individuals living with T2D based on the emerging evidence, with identification of and recommendations for the people who would benefit the most, which would eventually form a basis for reimbursement and health policies.

Congenital adrenal hyperplasia: New biomarkers and adult treatments.

Congenital adrenal hyperplasia (CAH) is a genetic disease caused by an enzyme deficiency interrupting adrenal steroidogenesis. It most frequently involves 21-hydroxylase, which induces adrenal insufficiency with hyperandrogenism. Restoring hormonal balance is difficult with glucocorticoids, which are the gold-standard treatment. Strict normalization of conventional biomarkers (17-hydroxyprogesterone and delta-4 androstenedione) is often obtained at the cost of iatrogenic hypercortisolism. Optimizing the management of these patients first involves using more specific biomarkers of adrenal steroidogenesis in difficult situations, and secondly using therapeutics targeting the induced hypothalamic-pituitary-adrenal axis disorder. 11-oxygenated androgens are candidates for biochemical monitoring of Congenital adrenal hyperplasia (CAH), in particular 11-ketotestosterone. Numerous new therapeutic agents are currently being explored, the prime goal being to reduce glucocorticoid exposure, as no strategy can fully replace it at present. They can be divided into 3 categories. The first includes "more physiological" hydrocortisone administration (modified-release hydrocortisone and continuous subcutaneous infusion of hydrocortisone hemisuccinate); the second includes corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) receptor antagonists and anti-ACTH antibodies; and the third includes steroidogenesis inhibitors. Finally, experiments on gene and cell therapies suggest the possibility of lasting remission or even cure in the future.

Needle Technology for Insulin Administration: A Century of Innovation.

Innovations in syringe and pen needle (PN) technology over the last 100 years have led to important advances in insulin delivery for people with diabetes, paralleling the strides made in developing recombinant DNA human insulin and insulin analogs with varying onset and duration of action. In this review, the history of advances in insulin delivery is described, focusing on progress in syringe, needle, and PN technologies. The early glass and metal syringes that required sterilization by boiling have been replaced by disposable, single-use syringes or pens with clear labeling for precise insulin dosing. The early needles ranging in length from 19 to 26 mm that required manual sharpening against a whetstone have been replaced by syringe needles of 6 mm and PNs of 4 mm in length as slender as 34 gauge. Imaging studies using ultrasound and computed tomography measured the thickness of skin and subcutaneous tissue layers to show feasibility of targeted insulin administration with shorter needles. These developments, coupled with innovations in needle/PN wall and tip structure, have led to improved injection experience for people with diabetes. It is also important to acknowledge the role of injection technique education, together with these advances in injection technology, for improving clinical outcomes and patient satisfaction. With continued projected growth of diabetes prevalence, particularly in developing countries where expensive and complex insulin delivery systems may not be practical, insulin syringes and pens will continue to serve as reliable and cost-effective means of insulin delivery for people with diabetes.

Epidemiology and health impact of diabetes in France.

OBJECTIVES: Diabetes is a growing health concern. An update on epidemiology and health outcomes is mandatory to devise strategies to alleviate the burden of diabetes. The objective of this study was to assess the prevalence of diabetes and associated complications in France in 2017. METHODS: Demographics and healthcare data from a representative permanent secondary database were analyzed. Patients with at least 2 national health insurance payments for anti-diabetic drugs in 2017 were selected, with the index date set to the last payment date. Patients were grouped as diabetes treated with insulin only (DTi), diabetes treated with anti-diabetic drugs other than only insulin (DT2) or gestational diabetes. Comorbidities, diabetes-related complications and hospital admissions, healthcare consumption and medical follow-up were extracted for a 5- or 2-year period prior to the index date and summarized using descriptive statistics. RESULTS: Overal, 29,288 patients were included in the study population: 1964 (6.7%) were categorized as DTi and 27,243 (93.0%) as DT2. Patients with gestational diabetes (81 [0.3%]) are not further described here. Prevalence was estimated at 4.9%. For DT2, marked geographic disparities were observed, with prevalence being highest in the northeast France. Diabetes-related complications were more frequent in DTi than in DT2 over a 5-year period (52.2% vs 34.7%). Diabetes-related admissions were also more common in DTi than in DT2 over a 2-year period (29.8% vs 16.9%). In the DT2 category, another antidiabetic drug was added during the 3 months prior to the index date in 16.5% of cases overall and in 25% of patients with recent hospital admission or diabetes-related complications. Although more than 80% of patients in the DTi and DT2 categories had at least 1 healthcare consultation during 2 years prior to the index date, only 10% to 20% of patients complied with guidelines for all 5 recommended examinations. CONCLUSIONS: Prevalence of diabetes is high in the French population, while compliance with recommended healthcare consultations falls short of the 80% goal set by regulations. New strategies are mandatory in order to reduce the burden of diabetes-related complications and admissions, focusing on patient and physician information and education in order to increase proactive treatment adjustment and reduce therapeutic inertia.

Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France.

CONTEXT: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). OBJECTIVE: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. METHODS: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11). RESULTS: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients. CONCLUSION: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect.

Sensor-Augmented Insulin Pump with Predictive Low-Glucose Suspend (PLGS): Determining Optimal Settings of Pump and Sensor in a Multicenter Cohort of Patients with Type 1 Diabetes.

INTRODUCTION: The use of predictive low-glucose suspend (PLGS) sensor-augmented pumps has been shown to lead to a significant reduction in hypoglycemic episodes in patients with type 1 diabetes (T1D), but their effects on hyperglycemia exposure are heterogeneous. The aim of this study was to determine the settings of the Medtronic 640G system to obtain the optimal balance between occurrence of both hypoglycemia and hyperglycemia. METHODS: The hypo- and hyperglycemia area under the curve (AUC), as well as system settings [hypoglycemic threshold, mean insulin total daily dose (TDD), mean basal insulin percentage, and mean daily duration of PLGS] were collected between 2 and 12 times during 1 year in patients from four university hospital centers. Univariate/multivariate analyses and receiver operating characteristics (ROC) curves were performed to determine factors associated with hyper- and hypoglycemia AUC. RESULTS: A total of 864 observations were analyzed from 110 patients with T1D. Two preselected settings predictive of low hyperglycemia AUC were a basal insulin percentage < 52.0% [sensitivity (Se) = 0.66 and specificity (Sp) = 0.53] and a PLGS duration > 157.5 min/day (Se = 0.47 and Sp = 0.73). The preselected setting predictive of a low hypoglycemia AUC was a PLGS duration ≤ 174.4 min (Se = 0.83 and Sp = 0.51). Between-visit variation of PLGS and TDD was positively correlated (r = 0.61; p < 0.0001). CONCLUSION: The most important Medtronic 640G setting was the mean daily PLGS duration, where a value between 157.5 and 174.4 min/day was associated with the best reduction in both hypo- and hyperglycemia AUC. In this study, we showed that PLGS duration could be indirectly modified through total daily insulin dose adaptation. TRIAL REGISTRATION: This study is registered in clinicaltrials.gov (NCT03047486).

Local aromatase excess with recruitment of unusual promoters of CYP19A1 gene in prepubertal patients with gynecomastia.

OBJECTIVES: Gynecomastia may be due to aromatase excess in several diseases such as obesity and cancer. Aromatase excess syndrome (AEXS) is an autosomal dominant disorder caused by overexpression of CYP19A1. Germinal mutations occurring in AEXS include various genomic rearrangements including duplication, deletion, and inversion identified in the upstream region of CYP19A1. Aromatase overexpression caused by a CYP19A1 somatic mutation has been rarely described. METHODS: Breast adipose tissue biopsies or surgical specimens were obtained from 19 subjects with gynecomastia. Aromatase quantification was performed by digital PCR and CYP19A1 sequencing by RACE PCR products. RESULTS: We observed localized aromatase overexpression (>10 fold greater than normal) in breast adipose tissue from three prepubertal males with gynecomastia out of the 19 cases. One carried a chromosomal rearrangement between CYP19A1 and DMXL2, consistent with AEXS. In the 2 others, the first exon of CYP19A1 contained 11 different tissue-specific promoter subtypes, specifically I.4 or I.3 normally expressed by adipose tissue, but also the placental I.2 promoter and the more ubiquitous I.7 which is usually expressed in breast cancer, uterine, and endothelial tissues. No differences in clinical or biochemical characteristics were observed between these 3 subjects and 16 others without aromatase overexpression. CONCLUSIONS: We describe two cases of aromatase overexpression in breast adipose tissue associated with nonspecific promoter recruitment. Further investigations are necessary to understand the mechanisms involved in aberrant promoter selection.