Bilateral pheochromocytomas: clinical presentation and morbidity rate related to surgery technique and genetic status.

Background: Pheochromocytomas (PHEOs) are rare catecholamine-secreting adrenal tumors. Approximately 60-90% of bilateral PHEOs are hereditary. We retrospectively analyzed the clinical characteristics of patients with bilateral PHEOs and the morbidity rate (malignancy, tumor recurrence and adrenal insufficiency (AI) rate) related to surgery technique and genetic status of the patients. Results: Fourteen patients (12.5%, nine women, five men) had synchronous or metachronous bilateral PHEOs (out of 112 PHEO patients who underwent surgery between 1976 and 2021). The median age at diagnosis was 32 years (9-76) (three were children). Nine patients (64.2%) presented synchronous bilateral tumors, five (35.7%) contralateral metachronous tumors, 2-12 years after the first surgical intervention; three (21.4%) were metastatic. Median follow-up: 5 years (1-41), IQR 19 months. A total of 78.5% had a germline mutation (eight RET gene with MEN2A syndrome, three VHL syndrome, three not tested). Post-surgery recurrence was noted in 16.6% of patients (one with MEN2A syndrome and metastatic PHEOs, one with VHL syndrome), with similar rates after total adrenalectomy or cortical-sparing adrenal surgery. AI was avoided in 40% after cortical-sparing surgery. Conclusion: Bilateral PHEOs are usually associated with genetic syndromes. The surgical technique for patients with hereditary bilateral PHEOs should be chosen based on a personalized approach, as they are at higher risk for developing new adrenal tumors requiring additional surgeries.

Radiotherapy in aggressive or dopamine agonists resistant prolactinomas; is it still worthwhile?

Radiotherapy, conventional or radiosurgery, has been used to control prolactin secretion and tumour growth in prolactinomas both as part of multimodal therapy or rarely as primary treatment. However, considering the radiotherapy side effects, notably hypopituitarism, as opposed to the high efficacy and low toxicity of dopamine agonists (DA) treatment and neurosurgery, radiotherapy is recommended mostly for patients with aggressive or high-risk prolactinomas or in those resistant or intolerant to medical therapy, usually after surgical failure. We provide an overview of the published literature on the efficacy and toxicity of radiotherapy (conventional fractionated or radiosurgery), in aggressive, high-risk, or DA resistant prolactinomas. Radiotherapy has shown a good efficacy and a reasonable toxicity profile in prolactinomas where other treatment modalities failed. In aggressive and high-risk prolactinomas, the cumulative percentage for tumour control (reduction plus stable) ranged from 68% to 100%. Most studies reported global hormonal control rates over 50%. In resistant prolactinomas, the global secretion control rate (on, but also off DA) ranged from 28% to 89%-100%; in most studies over 80%. The 5-year rate of hypopituitarism was around 12%-25%. To date there are no controlled study on the use of radiotherapy as a prophylactic treatment in patients with clinical, radiological or pathological markers of aggressiveness. In conclusion, our review supports the use of radiotherapy in patients with growing, clinically aggressive or truly DA resistant prolactinomas. In patients with high-risk or invasive prolactinomas or in those harboring pathological markers of aggressiveness, the prophylactic use of radiotherapy should be individualized.

Hyperthyroidism in Pregnancy: The Delicate Balance between Too Much or Too Little Antithyroid Drug.

Overt hyperthyroidism (HT) during pregnancy is associated with a risk of maternal-fetal complications. Antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal-neonatal hypothyroidism. This study evaluated ATD treatment and thyroid function control during pregnancy, and pregnancy outcome in women with HT. PATIENTS AND METHODS: A retrospective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with HT diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. RESULTS: Twenty-six women had Graves' disease (GD, 33 pregnancies), 1 had a hyperfunctioning autonomous nodule, and 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical HT, 5 euthyroid with previous GD remission before conception). In the 8 pregnancies of GD patients diagnosed during gestation or shortly before (<6 weeks), i.e., with fetal exposure to uncontrolled HT, there was 1 spontaneous abortion at 5 weeks (3.4% of all ATD-treated pregnancies), and 1 premature delivery at 32 weeks with neonatal death in 24 h (3.4%); 1 child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). In women treated more than 6 months until conception (20 pregnancies): (a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; (b) ATD was withdrawn in 40% of pregnancies in trimester (T)1, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in T3; (c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T1, T2 and T3 respectively; FT4 was increased in 5.8% (T1) and subnormal in 11.75% in T2 and T3; (d) no fetal birth defects were recorded; one fetal death due to a true umbilical cord knot was registered. Mean birth weight was similar in both ATD-treated and control groups. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). CONCLUSION: In hyperthyroid women with long-term ATD treatment before conception, drugs could be withdrawn in T1 in 40% of them, the thyroid function control was better, and pregnancy and fetal complications were rarer, compared to women diagnosed during pregnancy. Frequent serum TSH and FT4 monitoring is needed to maintain optimal thyroid function during pregnancy.

Updates in the outcomes of radiation therapy for Cushing's disease.

External radiation therapy (RT) directed to the pituitary gland is generally recommended in patients with Cushing's disease (CD) as adjuvant to transsphenoidal surgery, among other second-line therapies offered to patients with residual or recurrent hypercortisolism (i.e., medical treatment, repeat surgery or bilateral adrenalectomy). RT is effective for the control of tumor growth, even in invasive tumors and in Nelson's syndrome. Progress in radiation stereotactic techniques lead to improved tumor targeting and radiation delivery, thus sparing the adjacent brain structures. Stereotactic RT is associated with a 55-65% rate of cortisol normalization after several months to a few years and potentially with a lower risk of long-term complications, compared with conventional RT. Cortisol-lowering medical therapy is recommended while awaiting the radiation effects. Hypopituitarism is the most frequent side-effect, damage to optic or cranial nerves or second brain tumors are rarely reported. This review presents the updates in the efficacy and safety of the stereotactic radiation techniques in CD patients. Practical points which should be considered by the clinician before recommending RT are also presented.

Standardized Map of Iodine Status in Europe.

Background: Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods: We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results: In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 µg/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 µg/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC <150 µg/L. Conclusions: We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.

Selenium involvement in mitochondrial function in thyroid disorders.

Selenium (Se), an important oligoelement, is a component of the antioxidant system. Over the last decade, it has been ever more frequently discussed in the context of thyroid disorders. Graves' disease and Hashimoto's thyroiditis, differentiated thyroid cancer, and even endemic goiter may have common triggers that are activated by excess reactive oxygen species (ROS), which are involved in various stages of the pathogenesis of thyroid disorders. Most oxidative events occur in mitochondria, organelles that contain enzymes with Se as a cofactor. Mitochondria are responsible for the production of ATP in the cell and are also a major site of ROS production. Thyroid hormone status (the thyroid being the organ with the highest concentration of Se in the body) has a profound impact on mitochondria biogenesis. In this review, we focus on the role of Se in mitochondrial function in thyroid disorders with impaired oxidative stress, since both thyroid hormone synthesis and thyroid dysfunction involve ROS. The role of Se deficiency or its excess in relation to mitochondrial dysfunction in the context of thyroid disorders is therefore of interest.

Updates in the Medical Treatment of Pituitary Adenomas.

Pituitary adenomas represent approximately 15% of brain tumors; incidence is significantly on the increase due to widespread use of magnetic resonance imaging. Surgery remains the first-line treatment for most tumors overall. The role of dopaminergic agonists (DAs) and somatostatin receptor ligands (SRLs) in the treatment of pituitary adenomas is quite well established for prolactinomas and growth hormone (GH) excess. However, over the last decade new multi-receptor binding SRLs are increasingly used for treatment of acromegaly and Cushing's disease. SRLs/DA chimeric compounds seem to have enhanced potency and efficacy when compared to that of individual SRLs or DA receptor agonists according to preclinical data. However, following negative results, more research is needed to determine if this interesting mechanism will translate into positive clinical effects for acromegaly patients. Furthermore, new agents that block adrenal steroidogenesis have been developed in phase III clinical trials for Cushing's disease and several new compounds working at the pituitary level and/or blocking the glucocorticoid receptor are also in development. Combination therapy of drugs with similar or different mechanisms (possibly synergistic) are also on the increase. A growing awareness regarding all mechanisms involved in both control of pituitary secretion and cellular proliferation might allow for sole medical treatment of pituitary adenomas, especially macroadenomas, rather than surgery and/or radiation therapy, in the future. Moreover, the underlying decision on how to treat patients with pituitary adenomas should be individualized on a case-by-case basis with not only a goal of tumor shrinkage and biochemical control, but also of improving patients' quality of life.

Fine-scale haplotype mapping of MUT, AACS, SLC6A15 and PRKCA genes indicates association with insulin resistance of metabolic syndrome and relationship with branched chain amino acid metabolism or regulation.

Branched chain amino acids (BCAA) are essential elements of the human diet, which display increased plasma levels in obesity and regained particular interest as potential biomarkers for development of diabetes. To define determinants of insulin resistance (IR) we investigated 73 genes involved in BCAA metabolism or regulation by fine-scale haplotype mapping in two European populations with metabolic syndrome. French and Romanians (n = 465) were genotyped for SNPs (Affymetrix) and enriched by imputation (BEAGLE 4.1) at 1000 genome project density. Initial association hits detected by sliding window were refined (HAPLOVIEW 3.1 and PHASE 2.1) and correlated to homeostasis model assessment (HOMAIR) index, in vivo insulin sensitivity (SI) and BCAA plasma levels (ANOVA). Four genomic regions were associated with IR located downstream of MUT, AACS, SLC6A15 and PRKCA genes (P between 9.3 and 3.7 x 10-5). Inferred haplotypes up to 13 SNPs length were associated with IR (e.g. MUT gene with P < 4.9 x 10-5; Bonferroni 1.3 x 10-3) and synergistic to HOMAIR. SNPs in the same regions were also associated with one order of magnitude lower P values (e.g. rs20167284 in the MUT gene with P < 1.27 x 10-4) and replicated in Mediterranean samples (n = 832). In French, influential haplotypes (OR > 2.0) were correlated with in vivo insulin sensitivity (1/SI) except for SLC6A15 gene. Association of these genes with BCAA levels was variable, but influential haplotypes confirmed implication of MUT from BCAA metabolism as well as a role of regulatory genes (AACS and PRKCA) and suggested potential changes in transcriptional activity. These data drive attention towards new regulatory regions involved in IR in relation with BCAA and show the ability of haplotypes in phased DNA to detect signals complimentary to SNPs, which may be useful in designing genetic markers for clinical applications in ethnic populations.

Branched-Chain Amino Acid Database Integrated in MEDIPAD Software as a Tool for Nutritional Investigation of Mediterranean Populations.

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration.

Acromegaly treatment in Romania. How close are we to disease control?

INTRODUCTION: In Romania, no nationwide data for acromegaly treatment and control rate are available. Our objective was to assess the acromegaly control rate in a tertiary referral centre, which covers an important part of Romanian territory and population of patients with acromegaly. MATERIALS AND METHODS: We reviewed the records of all 164 patients (49 males and 115 females; median age 55 [47, 63.5] years) with newly or previously diagnosed acromegaly, who have been assessed at least once in our tertiary referral centre between January 1, 2012 and March 31, 2016. This sample represents 13.6% of the total expected 1200 Romanian patients with acromegaly and covers 82.9% of the counties in Romania. Control of acromegaly was defined as a random serum growth hormone (GH) < 1 ng/mL and an age-normalised serum insulin-like growth factor-I (IGF-I) value. The GH and IGF-I values used for calculation of the control rate were those at the last evaluation. The same assays for GH and IGF-I measurement were used in all patients. RESULTS: There were 147 treated and 17 untreated patients. Of the 147 patients assessed after therapy, 137 (93.2%) had pituitary surgery, 116 (78.9%) were on medical treatment at the last evaluation, and 67 (45.5%) had radiotherapy. Seventy-one (48.3%) had a random GH < 1 ng/mL, 54 (36.7%) had a normalised, age-adjusted IGF-I, and 42 (28.6%) had both normal random serum GH and IGF-I. CONCLUSIONS: In Romania, acromegaly benefits from the whole spectrum of therapeutic interventions. However, the control rate remains disappointing.

Updates in outcomes of stereotactic radiation therapy in acromegaly.

Purpose Treatment of acromegaly has undergone important progress in the last 20 years mainly due to the development of new medical options and advances in surgical techniques. Pituitary surgery is usually first-line therapy, and medical treatment is indicated for persistent disease, while radiation (RT) is often used as third-line therapy. The benefits of RT (tumor volume control and decreased hormonal secretion) are hampered by the long latency of the effect and the high risk of adverse effects. Stereotactic RT methods have been developed with the aim to provide more precise targeting of the tumor with better control of the radiation dose received by the adjacent brain structures. The purpose of this review is to present the updates in the efficacy and safety of pituitary RT in acromegalic patients, with an emphasis on the new stereotactic radiation techniques. Methods A systematic review was performed using PubMed and articles/abstracts and reviews detailing RT in acromegaly from 2000 to 2016 were included. Results Stereotactic radiosurgery and fractionated stereotactic RT (FSRT) for patients with persistent active acromegaly after surgery and/or during medical therapy provide comparable high rates of tumor control, i.e. stable or decrease in size of the tumor in 93-100% of patients at 5-10 years and endocrinological remission in 40-60% of patients at 5 years. Hypofractionated RT is an optimal option for tumors located near the optic structures, due to its lower toxicity for the optic nerves compared to single-dose radiosurgery. The rate of new hypopituitarism varies from 10 to 50% at 5 years and increases with the duration of follow-up. The risk for other radiation-induced complications is usually low (0-5% for new visual deficits, cranial nerves damage or brain radionecrosis and 0-1% for secondary brain tumors) and risk of stroke may be higher in FSRT. Conclusion Although the use of radiotherapy in patients with acromegaly has decreased with advances in medical treatments, it remains an effective treatment option after unsuccessful surgery and/or resistance or unavailability of medical therapy. Long-term studies evaluating secondary morbidity and mortality rate after the new stereotactic techniques are needed, in order to evaluate their potential brain-sparing effect.

Beneficial effect of dose escalation and surgical debulking in patients with acromegaly treated with somatostatin analogs in a Romanian tertiary care center.

BACKGROUND: Somatostatin analogs (SSA) are now considered standard therapy for acromegaly, as primary or adjunctive treatment after pituitary surgery. OBJECTIVE: To evaluate the efficacy of SSA and the effect of dose escalation in non-operated patients with acromegaly as compared to patients treated after pituitary surgery in a Romanian tertiary care center. DESIGN: Retrospective study of 73 consecutively evaluated patients with acromegaly treated with SSA, divided into 2 groups: 11 patients (4M/7F, 21-62 years) with primary treatment and 62 patients (22M/40F, 21-68 years) treated after surgery. They received Octreotide LAR 20-30 mg i.m./28 days or Lanreotide SR 30 mg i.m./14/10/7 days. Random serum growth hormone (GH) was measured using IRMA, sensitivity 0.2-0.01 µg/L IGF-1 was measured using different assays and compared with ULN for age and sex. RESULTS: Overall, random GH ≤2.5 µg/L was attained in 39 patients (53.4%) and optimal GH ≤1 ng/mL) in 30 patients (41%), while normal IGF-1 was recorded in 22/72 patients (30.5%). The final random GH ≤2.5 µg/L was achieved in 27.2% of non-operated patients (3/11) as compared with 58% (36/62) of patients treated medically after pituitary surgery, p<0.05. Escalation of doses of SSA applied in 43 patients improved the number of controlled patients by 5 (12.1%, p=0.059) and the number of optimally controlled patients by 9.7%. Of the 8 patients who switched from Lanreotide to Octreotide, 2 patients achieved GH normalization. CONCLUSION: The rate of biochemical control via SSA treatment in patients with acromegaly could be improved by rise of the SSA dose or by debulking surgery. Occasionally, substituting one SSA for another may be of benefit.

Dense mapping of the region of insulin gene VNTR in polycystic ovary syndrome in a population of women from Central Europe.

INTRODUCTION: Insulin gene VNTR was associated with polycystic ovary syndrome (PCOS) in some studies but not in others. This couldb be due to the heterogeneity of the definition of PCOS and/or the use of inappropriate gene mapping strategies. MATERIAL AND METHODS: In this investigation, the association of VNTR with PCOS was explored in a population of women from Central Europe (377 cases and 105 controls) in whom PCOS was diagnosed according to Rotterdam criteria. Seven SNPs: rs3842756 (G/A), rs3842755 (G/T), rs3842754 (C/T), rs3842753 (A/C), rs3842752 (C/T), rs3842748 (G/C), and rs689 (T/A) were genotyped in a portion of the population (160 cases and 95 controls) by sequencing or by SSO-PCR. Analysis of linkage disequilibrium (LD) pattern allowed selecting three tagSNPs (rs3842754, rs3842748, and rs689), which were genotyped in the rest of the population by KASPar. RESULTS: Six haplotypes were reconstructed, among which three (h1, h2 and h6) were more frequent. Statistical analysis allowed observation of the association of the SNP rs3842748, through its GC genotype, with obesity in PCOS (P = 0.049; OR CI95% 1,59 [1.00-2.51]) and in classical PCOS (YPCOS) (P = 0.010), as well as the correlation of the SNP rs689 and the pair of haplotypes h1/h1 with higher levels of testosteronaemia in the PCOS group, although this was at the limit of significance (P = 0.054) CONCLUSION: These results are in accordance with some studies in literature and highlight the role of insulin gene VNTR in complex metabolic disorders.

Endocrine dysfunction in sepsis: a beneficial or deleterious host response?

Sepsis is a systemic, deleterious inflammatory host response triggered by an infective agent leading to severe sepsis, septic shock and multi-organ failure. The host response to infection involves a complex, organized and coherent interaction between immune, autonomic, neuroendocrine and behavioral systems. Recent data have confirmed that disturbances of the autonomic nervous and neuroendocrine systems could contribute to sepsis-induced organ dysfunction. Through this review, we aimed to summarize the current knowledge about the endocrine dysfunction as response to sepsis, specifically addressed to vasopressin, copeptin, cortisol, insulin and leptin. We searched the following readily accessible, clinically relevant databases: PubMed, UpToDate, BioMed Central. The immune system could be regarded as a "diffuse sensory organ" that signals the presence of pathogens to the brain through different pathways, such as the vagus nerve, endothelial activation/dysfunction, cytokines and neurotoxic mediators and the circumventricular organs, especially the neurohypophysis. The hormonal profile changes substantially as a consequence of inflammatory mediators and microorganism products leading to inappropriately low levels of vasopressin, sick euthyroid syndrome, reduced adrenal responsiveness to ACTH, insulin resistance, hyperglycemia as well as hyperleptinemia. In conclusion, clinical diagnosis of this "pan-endocrine illness" is frequently challenging due to the many limiting factors. The most important benefits of endocrine markers in the management of sepsis may be reflected by their potential to be used as biomarkers in different scoring systems to estimate the severity of the disease and the risk of death.

Association of insulin receptor genetic variants with polycystic ovary syndrome in a population of women from Central Europe.

To assess the role of the insulin receptor gene in polycystic ovary syndrome (PCOS) we performed a case-control study in a female population (n=226) from Central Europe by examining the genetic associations of single nucleotide polymorphisms (rs8107575, rs2245648, rs2245649, rs2963, rs2245655, and rs2962) and inferred haplotypes around exon 9 of this gene. The ancestral T allele of single nucleotide polymorphism rs2963 or the corresponding haplotype (GGTC-C) showed association with PCOS with odds ratio 2.99, 95% confidence interval 1.4-6.3, independent of obesity but related to the presence of Acanthosis nigricans and insulin resistance, metabolic syndrome, or hyperandrogeny, thus providing a frame for future fine mapping of the susceptibility loci in PCOS.

FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome.

The FTO (Fat mass and obesity associated) locus has recently been associated with obesity and type 2 diabetes (T2D) in humans. To understand the role of the FTO gene in polycystic ovary syndrome (PCOS) we genotyped single nucleotide polymorphism (SNP) rs1421085 (C/T) in women with PCOS (n=207) and controls (n=100) from a Central European population. The homozygous C/C genotype showed increased prevalence in PCOS patients either obese or with metabolic syndrome (MetS) compared to lean PCOS patients or controls (27.6%, 38.9%, 22.3%, and 16.3%, respectively). In logistic regression, this genotype strongly associated with MetS (P<0.0001, OR 3.2, 95% CI 1.8-5.7) and impaired fasting glucose (IFG) with P<0.0007, OR 7.7, 95% CI 2.1-28.6, independently of BMI or age, and to AUC(gluc) during OGTT (P<0.0001, alpha=0.99), indicating an influential role of the FTO gene in the glucose intolerance component of MetS.