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Aims: Testosterone therapy (TTh) has been postulated to increase the risk of prostate adverse events (PAEs) and erythrocytosis, risk further exacerbated in high-risk obese patients with type 2 diab...

We evaluated long-term effects of testosterone undecanoate on glycemic control, metabolic syndrome, vascular function and morphology in obese men with functional hypogonadism (FH) and type 2 diabetes (T2D) in a 2-year prospective clinical trial.A total of 55 participants were enrolled in this study; group P (FPG, HbATwo-year of TTh resulted in normalized serum testosterone levels, improved glycemia, endothelial function, lipids and insulin sensitivity, and quelled the symptoms of hypogonadism, potentially reducing cardiovascular risk in obese men with FH and T2D.

Objectives Adult growth hormone deficiency (AGHD) is a rare disease characterised by abnormal body composition, reduced strength and exercise capacity and impaired psychological wellbeing. An advisory board of leading Central and Eastern European (CEE) endocrinologists was assembled to gain insights into the status of AGHD care in the CEE region. Topics of discussion included the position of adult hypopituitarism/AGHD in health system priorities, availability and affordability of treatments, awareness of AGHD, practice guidelines used in CEE countries and provisions for long-term care of patients. Design Prior to the meeting, the advisors were asked to summarise, using an itemised survey questionnaire, the usual standards of care for patients with AGHD in their country. At the meeting, the panel of experts discussed the findings and thereby elucidated similarities and differences among CEE countries; these were compared with international guideline-recommended practices for AGHD. Results All CEE countries involved reported having some type of infrastructure in place for care of patients with GHD transitioning from adolescence to adulthood. Most countries reported having at least one specialist centre for patients with AGHD. The main variations across the region included initial entry into healthcare systems, tests required to confirm AGHD diagnosis and medication reimbursement by health authorities. Most CEE countries relied on international society-led guidelines, while some countries have developed national guidelines. Conclusion The CEE Adult Endocrinology Advisory Board meeting recognised considerable diversity in the care and patient pathways for AGHD across CEE countries. Additional work is needed to optimise care of patients with AGHD in the CEE region.

We herein report two cases of primary adrenal insufficiency (AI) associated with antiphospholipid syndrome (APS). In both patients, the main finding that led to the diagnosis was hyponatraemia. The major difference between the two cases was the time at which AI evolved during the course of APS. In the first patient, AI developed acutely along with other presenting features of APS. In the second patient, the AI was unmasked during a stressful situation induced by severe inflammation that occurred 7 years after the first APS manifestation and had probably evolved slowly during the previous few years. These cases emphasise the importance of considering AI in patients with either suspected or newly diagnosed APS as well as in patients who have long been known to have APS. The symptoms and signs alerting the clinician to possible AI are general abdominal complaints, fever, hypotension, and hyponatraemia. Conversely, patients with primary AI should be questioned about the signs and symptoms of APS.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2).Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n = 28) was treated with testosterone undecanoate (1000 mg i.m. every 10 weeks) while group P (n = 27) received placebo.Anthropometrical and vascular measurements - flow-mediated dilatation (FMD) and intima media thickness (IMT) - biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated.TRT resulted in reduction of HOMA-IR by 4.64 ± 4.25 (p .001), HbA1c by 0.94 ± 0.88% points (p .001), and an increase in FMD by 2.40 ± 4.16% points (p = .005).TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population.

Objective Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults. Design 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A. Results Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects. Conclusions Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

WOS: 000439200100008, PubMed ID: 29794110, Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

Background: Adrenalectomy is standard of care for phaeochromocytomas, but for bilateral phaeochromocytoma, the recommendations are inconsistent. However, large studies systematically investigating long-term outcomes for total adrenalectomies compared to those for patients with adrenal-sparing operations are lacking. Methods: A multi-center consortium-based registry was established to study clinical, genetic and surgical data in 623 patients with bilateral phaeochromocytomas. Findings: Of 623 patients, median age at diagnosis was 30 (range 3-79) years and 48% were female. Synchronous bilateral phaeochromocytomas were diagnosed in 396 patients and metachronousphaeochromocytomas in 227 (36%); interval to second operations were up to 40 (median 6) years. In 96% of tested patients germline mutations were detected in the genes RET (56%), VHL (34%), and others (10%). Of 849 operations, 385 (45%) surgeries in 326 patients were planned as adrenal-sparing which was successful in 251. 372 patients became steroid-dependent. Follow-up was up to 53 (median 11) years. Adrenal crises developed in 67 patients (18%) during follow-up, and 49 (13%) had manifestations of iatrogenic Cushing syndrome. Of the steroid-independent patients, 34 (14%) had developed another phaeochromocytoma within the remnant adrenal after up to 27, median 8 years, all treated with removal of the new phaeochromocytoma. Overall survival was mainly influenced by non-phaeochromocytoma comorbidities, whereas only 1% died of metastatic phaeochromocytoma. Cortical-sparing operations did not affect survival. Interpretation: Cortical-sparing operations avert lifelong steroid-dependency without affecting survival. Preoperative genetic testing is recommended even in unilateral phaeochromocytoma presentations to identify patients at heritable risk, to guide surgical approach, and inform for gene-specific extra-adrenal morbidities. Funding Statement: Supported in part by the grant AZV 16-32665A to Sarka Dvorakova and Petr Vlcek, and the Blank Foundation to Charis Eng. Declaration of Interests: None of the authors have relevant conflicts of interest. Ethics Approval Statement: The institutional review boards for human subjects’ protection or ethical committees of all participating centers approved this study. Patients provided written informed consent according to the protocols of respective institutional review boards. In The Netherlands data were collected anonymously, and no further Institutional Review Board approval is required.

Background Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. Objective (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). Patients and methods 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Results Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P P P P Conclusions PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) stimulate satiety leading to reductions in food intake and body weight. The effects of long- acting GLP-1 RA liraglutide on eating behavior of women with PCOS have not been investigated yet.Thirty-six obese women with PCOS (mean ± SD, aged 31.2 ± 7.8 years, with BMI 38.7 ± 0.1 kg/m(2)), pretreated with metformin (1000 mg BID) were switched to liraglutide 1.2 mg QD sc for 12 weeks. Adiposity parameters and eating behavior as assessed by Three-Factor Eating Questionnaire (TFEQ-R18) were examined at baseline and after 12 weeks.Subjects treated with liraglutide lost on average 3.8 ± 0.1 kg (p 0.001). Significant reductions of waist circumference and visceral adipose tissue (VAT) mass, volume and area were demonstrated from liraglutide induction to the end of the study. TFEQ-R18 scores were significantly different pre- and post-liraglutide intervention. After treatment with liraglutide the uncontrolled eating (UE) score decreased from 36.8 ± 24.5 to 19.6 ± 18.4 (p 0.001) and emotional eating (EE) score decreased from 49.9 ± 33.3 to 28.5 ± 26.9 (p 0.001). Scores for cognitive restraint (CR) were not changed.Short-term liraglutide treatment was associated with weight loss and significantly improved eating behavior in obese women with PCOS.

ObjectiveThe effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost MethodsA total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight.ResultsThirty six patients (aged 31.3±7.1 years, BMI 37.1±4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5±2.8 kg compared with a 3.8±3.7 kg loss in the LIRA group and a 1.2±1.4 kg loss in the MET group (PPP=0.029). Subjects treated with liraglutide experienced more nausea than those treated with metformin, but severity of nausea decreased over time and did not correlate with weight loss.ConclusionsShort-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.

Obesity was categorized as a chronic disease by the World Health Organization (WHO) in 1997 because the problem had reached at pandemic level and presented a serious risk factor with respect to people who have been developing type-2 diabetes, hyperdyslipidaemia and hypertension. These four risk factors tend to accelerate the development of cardiovascular diseases. As a result, obesity has also become a significant social and economic burden. An important observation with regard to the population exhibiting increased body mass is the fact that they would like to decrease their weight, although they are frequently not successful. In this paper, a modelling-and-simulation approach is used for the presentation, analysis and explanation of the reasons that have an important influence on the treatment’s efficacy. The presented modelling results are based on the observation and treatment experiences of patients in a specialized institution over a period of 15 years, where each year around 100 new patients enter ...

Objective To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing’s syndrome (ERCUSYN), and to examine if their use differs from the current guidelines. Patients and methods We analyzed data on the diagnostic tests performed in 1341 patients with Cushing’s syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS). Results Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years (P P P Conclusions Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD). Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2. Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C—the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2−/− mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2−/− mice. Conclusions: The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.

ObjectiveThe European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).Design and methodsBaseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).ResultsProportion of men in the ECT-CS group was higher than in the other groups (PPPPPPPPPPPPConclusionsThe ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

Objectives Cardiovascular disease is the leading cause of death in postmenopausal women and estrogen deficiency may be an important factor in its development. The selective estrogen receptor modulator, raloxifene, exerts a part of its actions through the estrogen receptor alpha (ESR1) activation. We explored if polymorphisms of the ESR1 modify the effects of 6 months raloxifene treatment on endothelial function. Methods A total of 53 postmenopausal women, mean age 59.7 ± 6.2, finished the prospective clinical trial. The PvuII, XbaI, and P325P polymorphisms of the ESR1 gene were analyzed. In all subjects endothelium-dependent flow mediated dilatation (FMD) and cell adhesion molecules (CAM) ICAM-1, VCAM-1 and E-selectin were measured before and after 6 months of raloxifene treatment. Results There was no difference in FMD between the ESR1 genotypes, at baseline. After raloxifene treatment, the FMD was significantly greater in subjects with XX genotype of XbaI polymorphism compared to xx (p = 0.03) and borderline greater when compared to Xx genotype (p = 0.053). The FMD increased significantly with raloxifene treatment in women with Xx genotype of XbaI and Pp genotype of PvuII polymorphisms (p = 0.027 and p = 0.034, respectively). The P325P polymorphism did not influence the FMD after raloxifene. None of the ESR1 gene polymorphisms had any impact on the levels of CAM before or after the treatment. When analysing the whole group, a significant decrease in E-selectin (p

ObjectiveThe insulin-resistant state of the polycystic ovary syndrome (PCOS) was found to be associated with a decreased glucose transporter GLUT4 expression in the insulin target tissues. This study was performed to explore whether the well-known clinical, hormonal and metabolic efficacy of metformin or rosiglitazone treatment is reflected in the modulation of adipocyte GLUT4 mRNA expression in patients with PCOS.MethodsWe enrolled 35 women with PCOS. They received either metformin or rosiglitazone for 6 months. A history, blood samples for the measurement of androgens and s.c. adipose tissue samples were taken at baseline and end point. Quantification of GLUT4 mRNA expression in adipose tissue was performed using real-time quantitative PCR. Homeostasis model assessment (HOMAIR) score calculation was applied as a measure for insulin resistance (IR).ResultsGLUT4 mRNA expression in adipose tissue increased significantly in both groups (PP=0.040). There was a statistically significant improvement of HOMAIRin both groups (P=0.008). After treatment, frequencies of menstrual bleeding were significantly higher (PP=0.001).ConclusionsA 6-month therapy with insulin sensitizers resulted in marked improvement in adipose tissue GLUT4 mRNA expression in PCOS patients, rosiglitazone being more effective when compared with metformin. The augmentation of the insulin signal transduction was accompanied by a significant improvement of HOMAIR, menstrual pattern and androgen profile.

AB0 blood groups are inherited markers on blood cells. Since their discovery, there were numerous attempts to be attributed a wide variety of biological functions they don’t possess. The purpose of this article is primarily to inform the professional, as well as lay public that the theory of healthy nutrition based on AB0 blood groups represents nothing more than a pseudoscience used for mass exploitation and commercial purposes. ABO blood groups were attributed such characteristics by naturopathic doctor Peter D'Adamo, who on the basis of false methods and erroneous assumptions wrote a bestseller "Eat Right For Your Type". It claims that the blood groupsAB0 represent a "key to the functioning of our immune system" and that the blood group based diet represents a “key to the health of every man”. As in the case of nutrition based on the ABO blood groups, the scientific knowledge in the field of immunohematology is misused to mislead the lay public, we are obliged to explain the real meaning and the role of blood groups in health and disease, the misuse of blood groups in relation to healthy nutrition.

We describe 4 consecutive hypertensive women with polycystic ovary syndrome, classified according to the National Institute of Child Health and Human Development (NICHD) criteria, treated with telmisartan 40 mg/d for six months. Blood pressure, menstrual pattern, body mass index (BMI), homeostasis model assessment of insulin resistance, testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were recorded and measured before and after telmisartan treatment. Obese hypertensive polycystic ovary syndrome patients had a decrease in systolic blood pressure. Marked drop-off in serum androgen concentrations was observed in all four patients. Three patients improved their menstrual cyclicity. The improvements were independent of changes in weight. The reduction of androgen concentrations and improvement in menstrual pattern was achieved despite a non-significant change of fasting insulin levels in patients, who were not considered severely insulin resistant at baseline. These findings may provide a new basis for a proper choice of the antihypertensive drug in hypertensive women with polycystic ovary syndrome.

The long-acting glucagon-like peptide 1 receptor agonist liraglutide is linked to progressive and sustained weight loss in obese people with diabetes. However, its efficacy and safety in women with polycystic ovary syndrome (PCOS) has not yet been addressed.Thirty-two obese women (aged 27.6±7.2 years, BMI 39.5±6.2 kg/m(2)) with newly diagnosed PCOS were randomized to receive either liraglutide 1.2 mg QD sc (n=17) or metformin 1000 mg BID po (n=15) for 12 weeks; 28 patients completed the study (14 on liraglutide and 14 on metformin). The main outcome was change in body weight.Intention-to-treat analysis showed significant BMI (-0.98 kg/m(2); p0.001), body weight (-2.52 kg; p0.001), waist circumference (-3.38 cm; p0.001) and whole-body fat mass (-1.26%; p0.001) reduction in both treatment arms without significant differences between therapeutic groups. However, in a subgroup of patients (n=9) with insulin resistance (HOMA(IR)2), severe obesity and higher odds ratio for the metabolic syndrome (OR=3.9), the patients fared much better with liraglutide than with metformin (mean BMI decreased 2.13 kg/m(2) vs. 0.62 kg/m(2), respectively).Short-term liraglutide treatment was associated with significant weight loss in a subset of obese patients with newly diagnosed PCOS and a higher metabolic risk profile.

Inzulinska rezistencija je stanje poremećene sposobnosti odgovora na djelovanje inzulina. Najčešći osnovni uzrok je središnja pretilost, iako je primarna inzulinska rezistencija moguća i u osoba s normalnom težinom. Suvišno abdo-minalno masno tkivo otpušta povećane količine faktora tumorske nekroze α i slobodnih masnih kiselina, što izravno utječe na inzulinsko signaliziranje, smanjuje preuzimanje glukoze u mišićima, dovodi do pretjerane sinteze trigliceri-da i izaziva glukoneogenezu u jetri. Ostali čimbenici za koje se pretpostavlja da igraju ulogu u inzulinskoj rezistenciji su adiponektin (sniženje), leptin, IL-6 i neki drugi adipokini. Smatra se da je obična pretilost poligenog podrijetla uz utjecaj "pretilogene" okoline - povećan unos hrane i nedostatak tjelesne aktivnosti. Današnja visoka učestalost pretilosti mogla bi se objasniti evolucijskim pritiskom za odabir gena koji promiču pohranu masti za preživljenje u vrijeme gladovanja. Inzulinska rezistencija je prisutna zajedno sa središnjom pretilosti, hipertenzijom i dislipidemijom, koje se skupno označavaju kao metabolički sindrom. Ove pojavnosti predstavljaju snažne čimbenike rizika za šećernu bolest tipa 2 i kardiovaskularnu bolest., Insulin resistance is a state of impaired responsiveness to insulin action. The most common underlying cause is central obesity although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of tumor necrosis factor α and free fatty acids, which directly affect insulin signaling, diminish glucose uptake in the muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play a role in insulin resistance are adiponectin (a decrease), leptin, IL-6 and some other adipokines. Common obesity is thought to be of polygenic origin with influence of "obesogenic" environment, i.e. increased food intake and the lack of physical activity. Today's high prevalence of obesity could be explained by evolutionary pressure for selection of genes promoting fat storage to survive in starvation. Insulin resistance frequently coexists with central obesity, hypertension and dyslipidemia, which have collectively been denoted as metabolic syndrome. These manifestations represent strong risk factors for diabetes mellitus type 2 and cardiovascular disease.

In this study we sought to determine whether intracytoplasmic sperm injection (ICSI) could improve the efficacy of treatment with gonadotrophins in gonadotrophin-deficient men in terms of pregnancy. A series of six adult men (aged 26-47 years) with hypogonadotrophic hypogonadism (HH) is reported: four men with prepubertal isolated idiopathic HH (IIHH) and two adult-onset HH, as part of hypopituitarism secondary to surgical treatment of a pituitary tumour. All were azoospermic. To restore spermatogenesis, all received hormonal treatment with intramuscular human menopausal gonadotrophins (HMG) and human chorionic gonadotrophin (HCG) for 2 to 23 months. High basal serum inhibin B was predictive of rapid and complete recovery of spermatogenesis. In the two adult-onset HH, a natural pregnancy was achieved within 3 months. The four men with IIHH underwent ICSI because of poor sperm quality. ICSI using fresh or frozen-thawed ejaculated spermatozoa was performed after 6-23 months of gonadotrophin treatment. ICSI provided good clinical results in terms of fertilization and embryo quality, and resulted in three pregnancies that ended in three term deliveries. In men with oligozoospermia related to prepubertal IIHH, ICSI shortens the hormonal treatment and enhances the chances of pregnancy.

International audience; Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

BackgroundThere is evidence for differences between endocrinologists and other specialists in their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).ObjectiveA mailed survey consisting of a simple questionnaire aiming to understand current practice for diagnosis and management of the PCOS by specialists across Europe.MethodsThe questionnaire consisted of 23 questions grouped to achieve information on i) the general characteristics of the respondents, ii) patients with PCOS seen by endocrinologists, iii) the main diagnostic criteria, iv) biochemical parameters used in the differential diagnosis of hyperandrogenism, v) long-term concerns, and, finally vi) treatment choices. A total of 357 questionnaires representing 13.3% of the members of European Society of Endocrinology (ESE) were available for final analysis; 93% of the respondents were endocrinologistsResultsIn relation to the diagnostic criteria, respondents were most likely to select menstrual irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that the NIH criteria were followed by the majority of respondents. The most frequent biochemical parameters in the differential diagnosis of hyperandrogenism were total testosterone or free androgen index. Obesity and type 2 diabetes were regarded as the principal long-term concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%), lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility include clomiphene citrate alone or in combination with metformin, prescribed by 9 and 23%, respectively, whereas only 6% used other methods for induction of ovulation.ConclusionThe survey produced by ESE is a good start for evaluating the perspective in the diagnosis and treatment of PCOS by endocrinologists in Europe.

OBJECTIVE The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin-like growth factor 1 (IGF-1) levels were also assessed for reproducibility on each occasion. DESIGN and PATIENTS Three consecutive ITTs were performed in seven normal adult men (ages 22–27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23–48 years). MEASUREMENTS Serum GH and IGF-1 were measured by immunoradiometric and cortisol by immunofluorimetric assays. RESULTS In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4·6 and 59·3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 µg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations

Patients with hypopituitarism have increased carotid artery intima-media thickness and reduced arterial distensibility. The effect of 2 years of growth hormone (GH) replacement therapy on these parameters was studied in 11 GH-deficient men (age range, 24-49 years) with hypopituitarism and compared with 12 healthy, age-matched men with no evidence of pituitary or vascular disease. Before treatment the intima-media of the common carotid arteries and the carotid bifurcations were significantly thicker in patients (P < 0.001) than in the control group. Treatment with GH normalized the intima-media thickness of the common carotid artery within 6 months and of the carotid bifurcation within 3 months. The changes in intima-media thickness of the carotid artery were negatively correlated with changes in serum levels of insulin-like growth factor I during treatment. There was a significant improvement in flow-mediated, endothelium-dependent dilation of the brachial artery at 3 months, which was sustained at 6, 18 and 24 months of GH treatment (P < 0.05). Thus, GH replacement therapy in GH-deficient men reverses early morphological and functional atherosclerotic changes in major arteries, and may reduce rates of vascular morbidity and mortality.

Purpose: To contribute to a better understanding of the physiological role of P-glycoprotein (P-gp) in the adrenal gland, we initiated our studies in rabbits. The aim of our study was to explore the effect of the selective multidrug resistance (MDR) modulator PSC 833 (valspodar) on serum cortisol in rabbits. Methods: Baseline and corticotropin-stimulated serum cortisol levels were measured before and after valspodar treatment in adult male rabbits. Seven rabbits were treated with 50 mg/kg per dose and seven, with 75 mg/kg per dose of valspodar subcutaneously. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values. Results: Serum cortisol levels (baseline as well as corticotropin-stimulated) increased after both valspodar treatment regimens. The increase was dose-dependent and was higher for the baseline than for the corticotropin-stimulated values. Serum valspodar levels exceeding 1000 ng/ml were achieved in all except one animal in each group. We hypothesize that the increased serum cortisol levels were due to increased adrenocorticotropic hormone (ACTH) secretion after valspodar treatment, but, unfortunately, we could not measure ACTH properly in rabbits by means of the commercially available kits. Conclusions: Our study indicates that P-gp is not involved in steroid hormone secretion in the adrenal gland. This is evident from observations that serum cortisol levels were found to have increased rather than decreased in rabbits treated with a P-gp blocker and that the treated animals appeared healthy and normal. Since P-gp was found to play an important role in protection against xenobiotics in some other organs, further studies to explore the protective role of P-gp in the adrenal gland are warranted.

Background The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. Methods This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients' RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. Findings 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6–13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0·57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. Interpretation The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications. Funding European Union, German Cancer Foundation, Arthur Blank Foundation, Italian Government, Charles University, Czech Ministry of Health, Nanjing Military Command, National Science Centre Poland, National Research Council for Scientific and Technological Development, and State of São Paulo Research Foundation Fil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina

In addition to its effects on reproductive health, it is now well recognized that polycystic ovary syndrome (PCOS) is a metabolic disorder, characterized by decreased insulin sensitivity which leads to an excess lifetime risk of type 2 diabetes and cardiovascular disease. PCOS patients are often obese, hypertensive, dyslipidemic and insulin resistant; they have obstructive sleep apnea and have been reported to have higher aldosterone levels in comparison to normal healthy controls. These are all components of an adverse cardiovascular risk profile. Many studies exploring subclinical atherosclerosis using different methods (flow-mediated dilatation, intima media thickness, arterial stiffness, coronary artery calcification) as well as assessing circulating cardiovascular risk markers, point toward an increased cardiovascular risk and early atherogenesis in PCOS. The risk and early features of subclinical atherosclerosis can be reversed by non-medical (normalization of weight, healthy lifestyle) and medical (metformin, thiazolidinediones, spironolactone, and statins) interventions. However, the long-term risk for cardiovascular morbidity and mortality as well as the clinical significance of different interventions still need to be properly addressed in a large prospective study.

ObjectiveAccumulating evidence connects polycystic ovary syndrome (PCOS) with increased risk of cardiovascular disease. Endothelial dysfunction is present in PCOS and represents an early, reversible marker of cardiovascular damage. As androgens and renin–angiotensin–aldosterone system are implicated in the atherogenesis process of PCOS, we tested the hypothesis that treatment with spironolactone, an androgen and mineralocorticoid receptor blocking drug, might reverse endothelial dysfunction in PCOS.PatientsA total of 30 non-obese PCOS patients, compared with 20 body mass index matched control subjects, were evaluated. PCOS patients were given spironolactone 100 mg daily in 21-day long intervals followed by a 7-day pause, for 6 months.MeasurementsFlow-mediated dilatation (FMD), glyceryl trinitrate-induced dilatation, free testosterone, androstenedione, DHEA-sulfate, total, low-density lipoprotein (LDL)-, high-density lipoprotein-cholesterol, and triglycerides were determined at baseline and after 6 months.ResultsResults are expressed as median (25–75th percentile). At baseline, FMD was significantly lower in PCOS patients than in controls: 6.0 (0.0–11.7) vs 10.2 (6.8–15.9) %, P=0.018. This difference disappeared after 6 months of spironolactone treatment, as FMD in PCOS patients significantly increased to 8.3 (5.7–10.3) %, P=0.034, and was no longer different from controls. In PCOS patients, serum androgen levels did not change during treatment, while total and LDL-cholesterol decreased significantly from 4.8 (4.1–5.1) mmol/l to 4.4 (3.9–4.8) mmol/l and from 2.5 (2.1–3.1) to 2.2. (2.1–2.5) mmol/l, PPConclusionTreatment with spironolactone normalized endothelial function and improved cholesterol levels in non-obese PCOS patients.

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance (IR) and central obesity. The impact of adipose tissue cortisol reactivation by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) on markers of obesity and IR was assessed in PCOS patients. Eighty-five PCOS patients and 43 controls were enrolled for subcutaneous adipose tissue biopsy; 25/85 patients and 29/43 controls underwent also visceral adipose tissue biopsy. HSD11B1 gene expression and expression of lipid metabolism genes were measured in subcutaneous and visceral adipose tissues. Anthropometric and biochemical markers of IR and PCOS were also assessed. HSD11B1 expression in visceral and subcutaneous adipose tissue was increased in PCOS patients compared to controls (p

ObjectiveIn polycystic ovary syndrome (PCOS), insulin resistance (IR) appears with high prevalence and represents the major cause of cardiometabolic complications. Lipin 1β regulates lipid metabolism and augments insulin sensitivity. The impact of lipin 1β expression in visceral and subcutaneous adipose tissue of PCOS patients on IR was studied for the first time.MethodsEighty-five PCOS patients and 44 controls were enrolled for subcutaneous tissue biopsy, of whom 25 patients and 30 controls also underwent visceral adipose tissue biopsy. Gene expression of lipin 1β was measured, together with that of peroxisome proliferator-activated receptor γ, lipoprotein lipase, hormone-sensitive lipase, adiponectin and glucose transporter 4 in subcutaneous and visceral adipose tissue. Markers of obesity, IR and PCOS were also measured.ResultsIn PCOS patients, lipin 1β expression in both adipose depots was lower than in controls: 0.76 (0.67–0.84) vs 1.16 (0.90–1.43) for visceral and 0.91 (0.73–1.10) vs 1.30 (1.03–1.57) for s.c. depot (both P−4). The difference remained significant after adjustment for body mass index (BMI) and also when comparing only lean patients with lean controls. In PCOS patients, visceral adipose lipin 1β expression correlated negatively with homeostasis model assessment–IR (r=−0.474, P=0.017), BMI (r=−0.511, P=0.009) and waist circumference (r=−0.473, P=0.017), waist circumference remaining significant (P=0.027) in multiple regression. Subcutaneous lipin 1β expression in PCOS correlated negatively with BMI, waist circumference and plasma triglycerides, and positively with high density lipoprotein-cholesterol. Subcutaneous, but not visceral lipin 1β expression, correlated positively with the studied genes.ConclusionsLipin 1β appears to be involved in the pathogenesis of IR in PCOS.

ObjectiveThere is evidence of preclinical cardiovascular disease even in young women with polycystic ovary syndrome (PCOS). The aim of our study was to assess and compare the effects of metformin (MET) and rosiglitazone (ROSI) on endothelial function in PCOS patients.MethodsFor 6 months, 26 women with PCOS received either MET or ROSI. Blood samples for assessment of androgens, lipids, and high-sensitive C-reactive protein were taken at baseline and at endpoint. Endothelium-dependent flow-mediated dilation (FMD) and glyceryl trinitrate-induced endothelium-independent dilation of brachial artery were studied before and after treatment. Homeostasis model assessment (HOMAIR) calculation was applied as a measure of insulin resistance (IR).ResultsWith treatment, FMD of brachial artery improved significantly from 4.2±6.6 to 10.2±5.9% in MET group (P=0.036) and from 2.9±3.2 to 7.6±4.9% in ROSI group (P=0.026), MET being as effective as ROSI (P=0.70). The endothelium-independent dilation did not change. Additionally, administration of MET was associated with a significant decrease in HOMAIR (P=0.003), serum total and serum-free testosterone (P=0.045 and P=0.008 respectively) and significantly higher frequencies of menstrual bleeding (P=0.006).ConclusionsA 6-month therapy with insulin sensitizers, MET and ROSI, resulted in marked improvement of endothelial function in young PCOS patients without clinically evident atherosclerosis who were not severely insulin resistant. Neither drug was superior to the other. We conclude that therapeutic intervention with either insulin sensitizer may reverse the atherosclerotic process in PCOS patients at its early stage.

To determine whether serum levels of potential markers could detect insulin resistance (IR) in young women with polycystic ovary syndrome (PCOS).Serum levels of fasting glucose, insulin, intact proinsulin, resistin, and adiponectin were measured in 50 women with PCOS and known homeostatic model assessment (HOMA)-IR values (or=2 indicating IR). The women were all younger than 25 years.Of the 50 women, 49 had undetectable levels of resistin, 50 had intact proinsulin levels within the normal range, and 50 had adiponectin levels of 8.4+/-3.3 mg/L, just below the normal range. When groups were compared, however, the 26 women (52%) with IR (HOMA-IR valuesor=2) had significantly higher intact proinsulin levels (3.2+/-2.0 pmol/L vs 1.8+/-1.0 pmol/L; P0.005) and significantly lower adiponectin levels (7.2+/-2.9 mg/L vs 9.7+/-3.3 mg/L; P0.01), than the 24 women (48%) without IR.Serum levels of intact proinsulin, resistin, or adiponectin were not detectors of IR in individual young women with PCOS.

Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases.

In addition to diabetes mellitus and obesity, acromegaly, Cushing's syndrome, hypopituitarism, hypo- and hyperthyroidism, hyperparathyroidism and polycystic ovary syndrome are associated with either increased mortality from, or increased prevalence of, cardiovascular disease (CVD). Recently, endothelial dysfunction has been identified as an early marker of CVD and has been shown to predict future coronary artery disease, before atherosclerotic changes appear in arteries. Thus, measurement of endothelial function might identify at-risk individuals early and be a useful means of assessing response to treatment aimed at reducing long-term morbidity and/or mortality from CVD. Such studies are being undertaken in hypopituitarism and other endocrinopathies, and are reviewed herein. Endothelial function in large vessels can be measured noninvasively by ultrasound measurement of flow-mediated endothelium-dependent dilation (FMD). Serum markers of endothelial function, such as von Willebrand's factor, thrombomodulin, E-selectin and intercellular adhesion molecule 1, could be increased and be useful for evaluation of treatment, because they correlate inversely with FMD.