Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Paediatric-onset and adult-onset Graves' disease share multiple genetic risk factors.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disease (AITD) with a peak incidence between 30 and 50 years of age. Although children and adolescents may also develop the disease, the genetic background of paediatric-onset GD (POGD) remains largely unknown. Here, we looked for similarities and differences in the genetic risk factors for POGD and adult-onset GD (AOGD) as well as for variants associated with age of GD onset. MATERIALS AND METHODS: A total of 1267 GD patients and 1054 healthy controls were included in the study. Allele frequencies of 40 established and suggested GD/AITD genetic risk variants (39 SNPs and HLA-DRB1*03) were compared between POGD (N = 179), AOGD (N = 1088) and healthy controls. Subsequently, multiple linear regression was used to explore the relationship between age of GD onset and genotype for each locus. RESULTS: We identified six POGD risk loci, all of them were also strongly associated with AOGD. Although for some of the analysed variants, including HCP5 (rs3094228), PRICKLE1 (rs4768412) and SCGB3A2 (rs1368408), allele frequencies differed nominally between POGD and AOGD patients, these differences were not significant after applying multiple testing correction (Pcor  = 0.05/40 = 1.25 × 10-3 ). Regression analysis showed that patients with higher number of HCP5 risk alleles tend to have a significantly earlier onset of GD (P = 6.9 × 10-5 ). CONCLUSIONS: The results of our study revealed that POGD and AOGD share multiple common genetic risk variants. Moreover, we demonstrated for the first time that HCP5 polymorphism is associated with an earlier age of GD onset in a dose-dependent manner.

Role of Obesogens in the Pathogenesis of Obesity.

Obesity is considered to be a 20th century pandemic, and its prevalence correlates with the increasing global pollution and the presence of chemical compounds in the environment. Excessive adiposity results from an imbalance between energy intake and expenditure, but it is not merely an effect of overeating and lack of physical activity. Recently, several compounds that alter the mechanisms responsible for energy homeostasis have been identified and called "obesogens". This work presents the role of obesogens in the pathogenesis of obesity. We reviewed data from in vitro animal and human studies concerning the role of obesogens in the disturbance of energy homeostasis. We identified (i) the main groups and classes of obesogens, (ii) the molecular mechanisms of their action, (iii) their deleterious effect on adipose tissue function and control of appetite, and (iv) possible directions in limiting their influence on human metabolism. Obesogens have a multifactorial detrimental influence on energy homeostasis. Focusing on limiting exposure to obesogens and improving early life nutrition seems to be the most reasonable direction of action to prevent obesity in future generations.

High dose intravenous methylprednisolone pulse therapy causes transient increase of serum calcium and phosphate levels.

High and very high doses of intravenous methylprednisolone (IVMP) administered in pulses are the first-line treatment for active, moderateto- severe, as well as sight-threatening Graves' orbitopathy (GO). However, glucocorticoid therapy is associated with side effects, among others, it affects bone metabolism. AIM: The aim of study was to assess the acute effects of high and very high doses of IVMP on calcium (Ca) and phosphate (P) balance in euthyroid patients with moderate-to-severe GO and sight-threatening GO due to dysthyroid optic neuropathy (DON). MATERIALS AND METHODS: Thirty-six patients with active, moderate-tosevere GO were treated with twelve once-weekly pulses (with cumulative dose of 4.5 g IVMP) and 11 patients with DON received 3 intravenous pulses of 1.0 g IVMP on three consecutive days. We measured serum levels of Ca and P at baseline and on the following days after the beginning of the IVMP therapy. RESULTS: We observed a significant increase in serum Ca level on the next day after the 1st IVMP pulse both in patients with moderate-tosevere GO and with DON. Then, on the day 3, the decrease of serum Ca was noticed. In patients with moderate-to-severe GO, on the day 2 serum P showed a significant increase and then, it returned to basal level on the day 3. CONCLUSIONS: We observed a significant increase in serum Ca level on the next day after the 1st IVMP pulse both in patients with moderate-tosevere GO and with DON. Then, on the day 3, the decrease of serum Ca was noticed. In patients with moderate-to-severe GO, on the day 2 serum P showed a significant increase and then, it returned to basal level on the day 3.

Primary pigmented nodular adrenocortical disease (PPNAD) as an underlying cause of symptoms in a patient presenting with hirsutism and secondary amenorrhea: case report and literature review.

Hypercortisolemia in females may lead to menstrual cycle disturbances, infertility, hirsutism and acne. Herewith, we present a 18-year-old patient, who was diagnosed due to weight gain, secondary amenorrhea, slowly progressing hirsutism, acne and hot flashes. Thorough diagnostics lead to a conclusion, that the symptoms was the first manifestation of primary pigmented nodular adrenocortical disease (PPNAD). All symptoms of Cushing syndrome including hirsutism and menstrual disturbances resolved after bilateral adrenalectomy. Our report indicates that oligo- or amenorrhea, hirsutism, acne in combination with weight gain, growth failure, hypertension and slightly expressed cushingoid features in a young woman requires diagnostics towards hypercortisolemia. Despite PPNAD is a very rare cause of ACTH-independent Cushing syndrome, it has to be taken into consideration, especially when adrenal glands appear to be normal on imaging and paradoxical rise in cortisol level in high-dose dexamethasone test is observed. Unlike in our patient, in vast majority of patients, PPNAD is associated with Carney complex (CC). Therefore, these patients and their first-degree relatives should be always carefully screened for symptoms of PPNAD, CC and genetic mutations of PRKAR1A, PDE11A, and PDE8B genes.

Blood Pressure Profile and N-Terminal-proBNP Dynamics in Response to Intravenous Methylprednisolone Pulse Therapy of Severe Graves' Orbitopathy.

Hypercortisolemia is associated with increased risk of hypertension. Natural and synthetic glucocorticoids (GCs) have different effects on blood pressure (BP). The effect of synthetic GCs on BP depends on the dose, treatment duration, type of GCs, and route of administration. Intravenous methylprednisolone (IVMP) pulse therapy is the first line of treatment for severe Graves' orbitopathy (GO). The aim of this study was to evaluate influence of IVMP pulses on BP and N-terminal pro-brain natriuretic peptide (NT-proBNP) dynamics. A total of 32 patients with GO were treated with one IVMP pulse every week for 12 weeks. We performed 48-h BP monitoring (24-h before and 24-h after IVMP) and measured NT-proBNP before, 24 h, and 48 h after the 1st, 6th, and 12th IVMP pulse. Mean BP did not change after any of the pulses. We did not observe an increase in maximal systolic BP or mean nocturnal BP, except after the last pulse. Additionally, the dipping phenomenon was less frequent after the last pulse. We found a significant increase in median NT-proBNP levels after all analyzed pulses. Our study suggests that IVMP may have an unfavorable cumulative effect on BP. Variation in NT-proBNP concentration indicates a compensatory effect of brain natriuretic peptide secretion.

Clinical utility of TSH receptor antibody levels in Graves' orbitopathy: a comparison of two TSH receptor antibody immunoassays.

INTRODUCTION: Thyroid stimulating hormone (TSH) receptor antibodies (TRAB) play a role in the development of Graves' orbitopathy (GO), and measurements of the TRAB level may be helpful in monitoring GO treatment. AIM OF THE STUDY: To assess the correlation of TRAB levels measured with two different assays: third-generation TRAB assay (TRAB Cobas) and novel Immulite assay (TRAB Immulite), in patients with moderate-to-severe GO treated with intravenous glucocorticoid pulse therapy (ivGCs). MATERIAL AND METHODS: Forty patients with active, moderate-to-severe GO underwent clinical and laboratory evaluation before, in the middle, and after ivGCs therapy. The correlation of TRAB levels with GO signs was evaluated. Laboratory and clinical findings were compared according to the response to ivGCs. TRAB concentration was measured with Immulite TSI assay and with Elecsys IMA. RESULTS: All patients were TRAB positive in both assays at the beginning of the treatment. The decrease of both TRAB Immulite and Cobas levels in serum during ivGCs was statistically significant. We observed strong correlation between both TRAB levels before and after ivGCs. There was no statistically significant difference in antibody levels between patients with good response and no response to the treatment. We did not find any correlation between antibody levels and GO features before the therapy, but measurements during ivGCs showed comparable correlation of both TRAB levels with GO activity. CONCLUSIONS: We found similarity between Immulite assay and third-generation TRAB assay in the assessment of patients with GO treated with ivGCs. Both TRAB levels showed comparable correlation with GO activity during ivGCs therapy.

Accuracy of the European Thyroid Imaging Reporting and Data System (EU-TIRADS) in the valuation of thyroid nodule malignancy in reference to the post-surgery histological results.

PURPOSE: To assess the clinical usefulness of the European Thyroid Imaging and Reporting Data System (EU-TIRADS) in the valuation of thyroid nodules malignancy in reference to post-surgery histological results. MATERIAL AND METHODS: Pre-operative ultrasound was performed in consecutive patients admitted for thyroid surgery between June 2017 and January 2018. Thyroid nodules were classified according to EU-TIRADS to five groups: 1-5. At least one fine-needle aspiration biopsy (FNAB)/patient (dominant or suspected nodule) was performed in an outpatient clinic. The final diagnosis was based on the histological result. The percentage of cancers in each EU-TIRADS group was evaluated. Finally, sensitivity, specificity, accuracy, as well as positive and negative predictive values for malignancy were assessed. RESULTS: Fifty-two patients with a total of 140 thyroid nodules (median: 3 nodules/thyroid [minimum-maximum: 1-6]) were enrolled in the study. Thyroid cancer was diagnosed in 0% (0/6) in EU-TIRADS 2; 0% (0/92) in EU-TIRADS 3; 5.9% (2/34) in EU-TIRADS 4, and 75% (6/8) in EU-TIRADS 5. In nodules assessed as EU-TIRADS ≥ 4 sensitivity, specificity, positive and negative predictive values for malignancy were, respectively: 75% (CI 95%: 40.7-93.5), 94.1% (CI 95%: 86.0-98.5), 75% (CI 95%: 40.7-93.5), and 94.1% (CI 95%: 86.0-98.5). CONCLUSIONS: EU-TIRADS is a valuable and simple tool for assessment of the risk of malignancy of thyroid nodules and demonstrates a high ultrasound correlation with histological post-surgery results. FNAB should be performed in all nodules assessed as EU-TIRADS ≥ 4, due to higher risk of malignancy.

Gender-dependent and age-of-onset-specific association of the rs11675434 single-nucleotide polymorphism near TPO with susceptibility to Graves' ophthalmopathy.

The role of TPO gene polymorphism in the susceptibility to Graves' disease (GD) remains unclear. However, single-nucleotide polymorphisms (SNPs) near TPO have been recently associated with serum levels of thyroid peroxidase (TPO) antibody in two independent genome-wide association studies. Moreover, we have observed a strong association between the rs11675434 SNP located near TPO and the presence of clinically evident Graves' ophthalmopathy (GO). The aim of the current study was to reevaluate and dissect this association in an extended group of 1231 well-characterized patients with GD (1043 adults and 188 children) and 1130 healthy controls from the Polish Caucasian population, considering possible gender-dependent and age-of-onset-specific effects of the studied SNP. We found that the T allele of rs11675434 was significantly more frequent in GD patients with than without GO (odds ratio (OR)=1.26, 95% confidence interval (CI)=1.05-1.51, P=0.012), which was consistent with our previous findings. Further analyses performed in subgroups of patients showed that the association with GO was significant in adult patients with age of GD onset ⩾45 years (OR=1.34, 95% CI=1.03-1.75, P=0.031), but not in children and adolescents or adult patients with earlier onset of the disease (OR=1.72, 95% CI=0.77-3.84, P=0.18 and OR=1.05, 95% CI=0.79-1.40, P=0.75, respectively). Moreover, a strong association with GO was present in males (OR=2.06, 95% CI=1.40-3.02, P=0.0002), whereas it was absent in females (OR=1.10, 95% CI=0.90-1.35, P=0.35). The results of our study further suggest that rs11675434 SNP located near TPO is associated with the development of GO, especially in males and patients with later age of GD onset.

Total testosterone to dihydrotestosterone ratio assessed by LC-MS/MS predicts a worse metabolic profile not only in PCOS patients.

OBJECTIVES: Total testosterone/dihydrotestosterone ratio (TT/DHT) was found to determine metabolic risk in polycystic ovary syndrome (PCOS). The aim of this study was to analyze whether (TT/DHT) may be helpful in predicting metabolic risk not only in PCOS patients but also in healthy women. MATERIAL AND METHODS: Total testosterone (TT), dihydrotestosterone (DHT), androstendione and dehydroepiandrosterone sulphate (DHEA-S) were measured by LC-MS/MS in 36 women with PCOS and in 29 age-matched controls without clinical hyperandrogenism. In all participants, anthropometric data, lipids, adipose tissue percent (%fat), HOMA-IR were also assessed. RESULTS: The studied groups were not different in terms of age, BMI, waist circumference, %fat and HOMA-IR. In the patients group, mean TT and androstendione levels were significantly higher as compared to controls (1.4 nmol/L vs. 1.0 nmol/L, P < 0.001) and (6.6 nmol/L vs. 4.9 nmol/L, P < 0.01), respectively. In the patients group, mean TT/DHT ratio was significantly higher compared to controls (3.6 vs. 2.7, P < 0.01) and correlated with BMI (r = 0.37, P < 0.05), waist circumference (r = 0.44, P < 0.01), %fat (r = 0.30, P < 0.05), as well as with insulin levels (r = 0.38, P < 0.05) and HOMA-IR (r = 0.44, P < 0.05). The association between TT/DHT ratio and unfavorable metabolic parameters was also seen in controls. CONCLUSION: Total testosterone/dihydrotestosterone ratio assessed by LC-MS/MS correlates with a worse metabolic profile not only in PCOS patients, but also in healthy women.

The morning and late-night salivary cortisol ranges for healthy women may be used in pregnancy.

OBJECTIVES: The diagnosis of adrenal dysfunction in pregnancy and in women taking oral contraceptives remains a diagnostic challenge. Salivary cortisol seems to be a useful tool for the diagnosis of Cushing's syndrome and adrenal insufficiency. However, the changes in salivary cortisol concentration in healthy pregnancy are not clearly defined. DESIGN: The aim of our study was to compare diurnal changes in salivary cortisol in healthy pregnant women, healthy controls and women on oral contraceptives. PATIENTS: The study groups consisted of (i) 41 healthy pregnant women, (ii) 42 healthy women and (iii) 12 healthy women on oral contraceptives. MEASUREMENTS: Serum and salivary cortisol in the morning and salivary late-night cortisol were measured with Roche ECLIA cortisol test (Elecsys 2010) in each trimester and postpartum. RESULTS: Despite the elevation of morning serum cortisol in the second and third trimesters of pregnancy, the morning salivary values as well as late-night salivary cortisol throughout all trimesters were not significantly different from control values (P > 0·5). In the postpartum period, the morning and late-night salivary cortisol values were significantly lower than in late pregnancy. The morning and late-night salivary cortisol values in women on contraceptives were also not different from those in the healthy women group. CONCLUSION: The results of our study suggest that reference values for salivary cortisol established for a healthy adult population can be used for pregnant women and women on oral contraceptives in the initial diagnostic testing for Cushing's syndrome and adrenal insufficiency.

The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease.

BACKGROUND: Despite great progress, the genetic basis of Graves' disease (GD) remains poorly understood. Recently, a population-based genomewide association study (GWAS) identified five novel loci (ATXN2/SH2B3, MAGI3, BACH2, TPO and KALRN) as significantly associated with the presence of thyroid peroxidase autoantibodies (TPOAbs), whereas several other loci showed suggestive association. METHODS: In this study, we investigated 16 single nucleotide polymorphisms (SNPs) associated with TPOAbs for the association with susceptibility to and phenotype of GD in a cohort of 647 patients with GD and 769 controls from a Polish Caucasian population. RESULTS: SNPs within/near HCP5 (rs3094228, P = 1·6 × 10(-12) , OR = 1·88), MAGI3 (rs1230666, P = 1·9 × 10(-5) , OR = 1·51) and ATXN2/SH2B3 (rs653178, P = 0·0015, OR = 1·28) loci were significantly associated with susceptibility to GD. Allele frequencies differed significantly in subgroups of patients with GD stratified by age of GD onset for HCP5 (P = 0·0014, OR = 1·50) and showed a suggestive difference for MAGI3 (P = 0·0035, OR = 1·50) SNPs. Although rs11675434 located near TPO showed no association with GD susceptibility, it was significantly associated with the presence of clinically evident Graves' ophthalmopathy (GO, P = 5·2 × 10(-5) , OR = 1·64), and this effect was independent from smoking status, age of GD onset and gender. CONCLUSIONS: This is the first study showing an association of the ATXN2/SH2B3 locus with susceptibility to GD. Furthermore, we observed a novel significant association within the HLA region at a SNP located near HCP5 and confirmed the association of the MAGI3 locus with GD susceptibility. HCP5 and MAGI3 SNPs were further correlated with age of GD onset. Finally, we identified TPO as a new susceptibility locus for GO.

HLA DQ2 HAPLOTYPE, EARLY ONSET OF GRAVES DISEASE, AND POSITIVE FAMILY HISTORY OF AUTOIMMUNE DISORDERS ARE RISK FACTORS FOR DEVELOPING CELIAC DISEASE IN PATIENTS WITH GRAVES DISEASE.

OBJECTIVE: The diagnosis of celiac disease (CD) in patients with different autoimmune diseases including Graves disease (GD) remains a challenge. The aims of our study were to: (1) assess the prevalence of CD in Polish patients with GD and (2) evaluate the prevalence of CD in the subgroups of patients with GD divided on the basis of clinical and human leukocyte antigen (HLA) typing criteria. METHODS: The prospective study was conducted at an academic referral center. The study groups consisted of consecutive, euthyroid patients with GD (n = 232) and healthy volunteers without autoimmune thyroid diseases (n = 122). The diagnosis of CD was based on elevated immunoglobulin A autoantibodies to the enzyme tissue transglutaminase (IgA-TTG) and small intestine biopsy findings. RESULTS: CD was diagnosed in 8 patients with GD (3.4%) and 1 healthy volunteer (0.8%). The development of CD in patients with GD was strongly associated with HLA-DQ2 haplotype (as predicted from linkage disequilibria, 14.6% vs. 1.5%, P = .009; odds ratio [OR] = 11.3; 95% confidence interval [CI] 1.3-252.7): 6 patients with CD carried HLA-DRB1(*)03, 1 carried an HLA-DRB1(*)04 allele, and 1 had an HLA-DRB1(*)07/(*)11 genotype. Multivariate analysis showed independent associations between CD and early GD onset (P = .014, OR = 9.6), autoimmunity in family (P = .029, OR = 6.3) and gastroenterologic symptoms (P = .031, OR = 8.1). CONCLUSIONS: The results of our study suggest that serologic screening for CD may be considered in GD patients (1) with the HLA alleles typical for CD, (2) with an early onset of GD, or (3) a family history of autoimmunity. Moreover, the diagnosis of CD should be explored in euthyroid GD patients with nonspecific gastrointestinal symptoms.

LC-MS/MS improves screening towards 21-hydroxylase deficiency.

Basal serum 17OHP measurement remains the first screening step for nonclassic congenital adrenal hyperplasia (NCCAH) and the accuracy of the test is of high value. The aim of this study was to compare the accuracy of immunoassays to LC-MS/MS in the assessment of serum 17OHP and androgens concentration in women with hyperandrogenism and controls. 17OHP, total testosterone, androstendione and DHEA-S were measured in 39 women with clinically and/or biochemically evident hyperandrogenism and in 29 age-matched controls without clinical hyperandrogenism. 17OHP and androgens were measured by immunoassays and by LC-MS/MS. In patients group median 17OHP level measured by immunoassays was significantly higher compared to LC-MS/MS (5.49 nmol/l-ELISA NovaTec® and 3.57 nmol/l-ELISA DRG® versus 1.56 nmol/l-LC-MS/MS p < 0.0001) as well as in the control group (2.58 nmol/l-ELISA DRG® versus 1.14 nmol/l-LC-MS/MS p < 0.0001). Additional, unnecessary diagnostic procedures explaining elevated 17OHP level were undertaken in 85% of patients when NovaTec® test was used, in 50% when ELISA DRG® and in none when LC-MS/MS method was applied. Total testosterone, androstendione and DHEA-S concentrations in the patients and the controls assessed by the immunoassays were also significantly higher compared to LC-MS/MS. LC-MS/MS is more reliable diagnostic tool in the measurement of serum 17OHP and androgens concentrations compared to immunoassays in women with hyperandrogenism.

The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia.

Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) influence hair follicles through paracrine and intracrine routes. There is significant evidence that PTH and PTHrP influence the proliferation and differentiation of hair follicle cells. The PTH/PTHrP receptor signalling plays an important role in the hair follicle cycle and may induce premature catagen-telogen transition. Transgenic mice with an overexpression or blockade (PTH/PTHrP receptor knockout mice) of PTHrP activity revealed impaired or increased hair growth, respectively. Some findings also suggest that PTHrP may additionally influence the hair cycle by inhibiting angiogenesis. Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth. A hair-stimulating effect of a PTH/PTHrP receptor antagonist applied topically to the skin has been observed in hairless mice, as well as in mice treated with cyclophosphamide. These data indicate that the PTH/PTHrP receptor may serve as a potential target for new (topical) hair growth-stimulating drugs, especially for chemotherapy-induced alopecia.

Increased concentration of T-cell receptor rearrangement excision circles (TREC) in peripheral blood in Graves' disease.

BACKGROUND: T-cell receptor rearrangement excision circles (TREC) are circular DNA molecules generated during T-cell maturation in the thymus. Recent studies suggested that a decreased TREC concentration in peripheral blood may be a general feature of autoimmunity. Our purpose was to assess the TREC concentration in Graves' disease (GD). METHODS: TREC concentration was assessed by real time PCR in DNA samples isolated from peripheral blood leucocytes among younger (n = 94, age range 6-29 years) and older patients with GD (n = 93, age range 57-80 years) and age-matched controls (n = 206). RESULTS: TREC concentration decreased with age in all subjects, but it was significantly higher in GD compared with controls (P = 9·4 × 10(-10) ). TREC concentration was higher (P = 0·0038) in hyperthyroid (n = 78) than euthyroid (n = 82) patients with GD, but in both groups, it remained increased relative to controls (P = 2·2 × 10(-11) and P = 4·4 ×10(-7) , respectively). CONCLUSIONS: Patients with GD, particularly those with hyperthyroidism, have increased concentration of TREC which may suggest increased rather than decreased thymic activity. Thus, GD does not follow the paradigm suggested for other autoimmune disorders which links autoimmunity with thymic senescence.

LanroNET, a non-interventional, prospective study to assess the resource utilization and cost of lanreotide autogel 120 mg in Polish patients with neuroendocrine tumors - results of interim analysis.

AIM OF THE STUDY: To examine characteristics and treatment patterns of symptomatic neuroendocrine tumors (NETs) patients who received lanreotide Autogel 120 mg (ATG120) administered as part of routine clinical practice. MATERIAL AND METHODS: Lanro-NET is a national, multicenter, non-interventional, observational study in the population of adult patients with symptomatic NETs treated with ATG120 for at least three months before inclusion. Data on demographic and clinical characteristics of the population, dosing interval regimen and aspects of administration were collected prospectively during 12 months. Costs were calculated from the perspective of public payer for the year 2014. RESULTS: Fifty-two patients were enrolled in the study. Primary tumors were located predominantly in gastrointestinal tract (51.2%), all tumors were metastatic. The most commonly reported disease symptoms were flushing and diarrhea (55.8% of patients). 86% of patients had undergone surgery, chemotherapy and radioisotope therapy were used in 11.6% and 46.5% of patients, respectively. During the 12-months observation 12 (28%) patients received ATG120 at an extended dosing interval (> 4 weeks), the mean number of days between injections was 31.75 (SD 6.74). The cost of ATG12 was estimated at 4273.17 PLN patient/month. In all patients ATG120 was administered by nurse, 51.6% of injections in out-patient setting, 48.4% - in hospital. CONCLUSIONS: This study presents the current use of ATG120 in the population of Polish NETs patients in a realistic clinical settings. Finding that 28% of patients could be treated with extended dose intervals supports the potential for ATG120 of reducing treatment burden.

Long-term remission of corticosteroid-resistant Graves' orbitopathy after therapy with tocilizumab.

Not required for Clinical Vignettes.

Towards personalized TSH reference ranges: A genetic and population-based approach in three independent cohorts.

BACKGROUND: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual, but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. METHODS: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically-determined TSH reference ranges in a thyroid disease-free cohort (N=6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (N=3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (N=26,321) as well as individuals on levothyroxine (LT4) treatment (N=1,132). RESULTS: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other non-genetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically-determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically-determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7x10-8). CONCLUSIONS: Individual genetic profiles have potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.