Determination of the levels and possible associations of alpha2-macroglobulin with autoantibodies in the serum of patients with various forms of autoimmune thyroiditis.

Antibodies to thyroid peroxidase (AB-TPO), antibodies to thyroglobulin (AB-TG), and the content of α2-macroglobulin (α2-MG) have been studied in serum samples of patients with autoimmune thyroiditis (AIT). All the patients were divided into 3 groups depending on age: 25-35, 36-50, 51-65 years. We found a significant change in the thyroid panel parameters in AIT, but without significant changes in the average concentration of α2-MG in the age groups of patients. This may be due to the accumulation and retention of complexes of defective forms of α2-MG in the circulation associated with their decreased ability to bind to receptors.

Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Impact of Antithyroperoxidase Antibodies (Anti-TPO) on Ovarian Reserve and Early Embryo Development in Assisted Reproductive Technology Cycles.

Autoimmune thyroid disease (AITD) is one of the most common endocrinopathies and is more prevalent in women. It becomes evident that the circulating antithyroid antibodies that often follow AITD have effects on many tissues, including ovaries, and therefore that this common morbidity might have an impact on female fertility, the investigation of which is the aim of the present research. Ovarian reserve, ovarian response to stimulation and early embryo development in infertile patients with thyroid autoimmunity were assessed in 45 women with thyroid autoimmunity and 45 age-matched control patients undergoing infertility treatment. It was demonstrated that the presence of anti-thyroid peroxidase antibodies is associated with lower serum anti-Müllerian hormone levels and antral follicle count. Further investigation revealed the higher prevalence of sub-optimal response to ovarian stimulation in TAI-positive women, lower fertilization rate and lower number of high-quality embryos in this group of patients. The cut-off value for follicular fluid anti-thyroid peroxidase antibody affecting the above-mentioned parameters was determined to be 105.0 IU/mL, highlighting the necessity of closer monitoring in couples seeking infertility treatment with ART.

Prunella vulgaris can improve the pregnancy outcomes of experimental autoimmune thyroiditis rats by inhibiting Th1/Th17 immune responses.

Autoimmune thyroiditis (AIT), one of the most common autoimmune diseases among women of reproductive age, is closely associated with reproductive failure and other obstetric complications. However, effective clinical strategies for the management of pregnant women with AIT are limited. It has been shown that Prunella vulgaris (PV), a traditional herbal medicine, can ameliorate AIT and other common thyroid disorders. Therefore, using an experimental autoimmune thyroiditis (EAT) rat model, we investigated the potential effects of PV on AIT-related pregnancy outcomes. According to the administered dose of PV, EAT rats were randomly divided into the untreated EAT and PV-treated EAT groups. We found that thyroid peroxidase antibody and thyroglobulin antibody serum levels and the inflammatory infiltration of the thyroid were reduced in all PV-treated groups. Increased splenic Tgfb1 mRNA levels and Treg cell proportions were associated with decreased Th1/Th17 cell proportions, and Ifng mRNA levels were reduced in rats that received low and medium doses of PV. Moreover, in the low-dose PV group, fetal development retardation and placental injuries were reversed. Overall, our findings indicated that PV could alleviate AIT and improve pregnancy outcomes in EAT rats by downregulating Th1/Th17 immune responses and inducing Treg cell proliferation.

Determinants and Clinical Implications of Thyroid Peroxidase Antibodies in Middle-Aged and Elderly Individuals: The Rotterdam Study.

Background: Thyroid peroxidase antibodies (TPO-Abs) play an important role in autoimmune thyroid disease, but are also prevalent in healthy individuals. However, it is unclear what determinants may influence the occurrence of TPO-Abs in healthy individuals and how TPO-Abs may affect health outcomes in these individuals. We aimed to identify determinants of TPO-Abs in a large, prospective population-based cohort of middle-aged and elderly individuals and to subsequently assess the association between TPO-Abs and risk of overall and cause-specific mortality. Methods: We performed binomial and multinomial logistic regression analyses to obtain odds ratios (ORs) and 95% confidence intervals [95% CIs] for the association of potential determinants based on previous literature with TPO-Ab positivity (>35 kU/L), TPO-Ab detectability (>5 kU/L), and TPO-Ab categories. Cox proportional hazards regression analyses were performed to obtain hazard ratios (HRs) and CIs for the association between TPO-Abs and mortality risk. Results: In 9685 participants (57% women, median baseline age 63.3 years, median follow-up time 10.1 years), we identified female sex (OR = 2.47 [CI 2.13-2.86]) and current smoking (OR = 3.10 [CI 2.66-3.62]) as determinants of TPO-Ab positivity and TPO-Ab detectability, respectively. Higher age (OR = 0.98 [CI 0.97-0.98]) and all categories of alcohol consumption (ORs ranging from 0.71-0.78) were associated with lower odds of TPO-Ab detectability. TPO-Ab detectability was associated with a higher risk of overall (HR = 1.09 [CI 1.01-1.17]), cancer-related (HR = 1.18 [CI 1.01-1.38]), and cardiovascular mortality (HR = 1.21 [CI 1.01-1.45]). Interestingly, this was more prominent in men compared with women (HR for cardiovascular mortality 1.50 vs. 0.99, respectively). Conclusions: In community-dwelling middle-aged and elderly individuals, female sex and current smoking are the most important determinants associated with TPO-Ab levels in the detectable and positive range, whereas alcohol consumption is associated with lower odds of TPO-Abs. The clinical importance of detectable TPO-Ab levels is illustrated by the association with an increased mortality risk, mainly in men. Our results warrant further exploration of the clinical applicability of detectable TPO-Ab levels, potentially as a marker for low-grade inflammation. The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.

Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3.

OBJECTIVE: Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. METHODS: Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9-16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery. RESULTS: Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7-74.9%) for TSH, 67.5% (59.8-75.3%) for fT4, 59.7% (54.4-65.0%) for fT3 and 48.8% (40.6-56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. CONCLUSION: Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Relationship between autoimmune thyroid disease and nephropathy: A clinicopathological study.

ABSTRACT: The association of nephropathy with autoimmune thyroid disease (AITD) has been reported previously. However, there is limited information on the relationship between thyroid autoantibodies and nephropathy. A retrospective study was conducted using the medical records of 246 patients with nephropathy, 82 of whom had concurrent AITD. General characteristics, thyroid function, autoantibodies, and the pathological types of nephropathy were analyzed. Immunohistochemistry was used to detect the thyroglobulin antibody (TG-Ab) and thyroid peroxidase antibody (TPO-Ab) in the kidneys. We found nephropathy patients with AITD exhibited higher serum levels of TPO-Ab, TG-Ab, thyroid-stimulating hormone receptor antibody (TR-Ab), and immunoglobulin G (IgG) (P < .05). Compared with the nephropathy without AITD group, the nephropathy with AITD group exhibited higher proportions of membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), and relatively lower proportions of mesangial proliferative glomerulonephritis (MsPGN) and minimal change nephropathy (MCN) (P = .005). TPO-Ab and TG-Ab levels in the kidney were more prevalent in nephropathy patients with AITD than those without AITD (P = .015 and P = .026, respectively). Subgroup analysis demonstrated that serum levels of thyroid stimulating hormone (TSH), TG-Ab, TPO-Ab, immunoglobulin M (IgM), and IgG in the MN group were significantly higher, whereas the levels of free thyroxine (FT4) and estimated glomerular filtration rate (eGFR) were lower, as compared with MN with Hashimoto thyroiditis (HT) group (P < .05). TPO-Ab and TG-Ab expression levels in the kidneys were more prevalent in the MN group than in the MN with HT group (P = .034). The expression levels of FT4, TG-Ab, TPO-Ab, and thyroid-stimulating hormone receptor antibody (TSHR-Ab) in the serum were significantly higher in the MN group than in the MN with Graves disease (GD) group (P < .05). The expression of TPO-Ab in the kidneys was more prevalent in the MN group than in the MN with GD group (P = .011). In sum, the expressions of TPO-Ab and TG-Ab were more prevalent in the kidneys of patients with nephropathy and AITD. Our findings indicate that TPO-Ab and TG-Ab may play a role in the development of AITD-related nephropathy.

The impact of exogenous vitamin D on thyroid autoimmunity in euthyroid men with autoimmune thyroiditis and early-onset androgenic alopecia.

BACKGROUND: Early-onset androgenic alopecia is regarded as the phenotypic equivalent of polycystic ovary syndrome in men. Women with polycystic ovary syndrome are at high risk of autoimmune thyroiditis. The aim of the current study was to investigate whether early-onset androgenic alopecia determines the impact of exogenous vitamin D on thyroid autoimmunity and thyroid function in men with autoimmune thyroiditis. METHODS: The study included 67 young men with autoimmune thyroiditis, 25 of whom had early-onset androgenic alopecia (group A). All 25 men with alopecia and 23 out of the 42 men with no evidence of hair loss, matched for age, antibody titers and thyrotropin levels (group B), were then treated with vitamin D (100 µg daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, serum levels of thyrotropin, free thyroid hormones, total and calculated free testosterone, dehydroepiandrosterone-sulfate, estradiol, prolactin and 25-hydroxyvitamin D, as well as the calculated parameters of thyroid homeostasis were assessed before vitamin D treatment and 6 months later. RESULTS: At baseline, thyroid antibody titers were higher in subjects with than without alopecia and correlated with calculated free testosterone levels. Vitamin D reduced antibody titers in both groups but this effect was stronger in group B than group A. Only in group B, vitamin D increased SPINA-GT. The impact of vitamin D on antibody titers correlated with 25-hydroxyvitamin D levels, calculated free testosterone, treatment-induced increase in 25-hydroxyvitamin D levels and the improvement in insulin sensitivity. CONCLUSION: This study suggests that euthyroid men with early-onset androgenic alopecia may benefit to a lesser degree from vitamin D treatment than other subjects with autoimmune thyroiditis.

Cordyceps sinensis-derived fungus Isaria felina ameliorates experimental autoimmune thyroiditis in mice.

AIMS: This study aimed to investigate the therapeutic effect of Cordyceps sinensis-derived fungus Isaria felina on experimental autoimmune thyroiditis (EAT). METHODS: A NaI-induced EAT mouse model was established. The mice received oral administration of vehicle, low-dose Isaria felina (300 mg/kg), or high-dose Isaria felina (600 mg/kg) once a day for four weeks before euthanasia. Enzyme-linked immunosorbent assays (ELISA) was performed to measure serum thyroid-stimulating hormone (TSH) levels, thyroid antibodies, and cytokines. Hematoxylin and eosin (H&E) staining was conducted to assess histopathological changes in the thyroid tissue samples of mice. TUNEL and Bcl-2 immunohistochemistry (IHC) were performed to evaluate cell apoptosis, and cleaved caspase-3 IHC was performed to detect the relative expression in the thyroid tissue samples. RESULTS: Compared with KIO3 and KI water, NaI water consumption successfully induced EAT in mice, as evidenced by significantly increased circulating TSH and thyroid antibody levels, along with typical histopathological abnormalities of autoimmune thyroiditis (AIT) in the thyroid tissue samples. Compared with vehicle or low-dose Isaria felina, high-dose Isaria felina treatment resulted in significant reductions in white cell counts and circulating TSH, thyroid antibody, and cytokine levels of EAT mice. High-dose Isaria felina also alleviated histopathological abnormalities and attenuated TUNEL staining, Bcl-2 protein expression, and cleaved caspase-3 expression in the thyroid tissue samples. CONCLUSION: High-dose Isaria felina treatment alleviates thyroid inflammation and cell apoptosis in EAT, serving as a novel, promising therapeutic agent for AIT.

Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report.

BACKGROUND: Hypothyroidism is diagnosed on the basis of laboratory tests because of the lack of specificity of the typical clinical manifestations. There is conflicting evidence on screening for hypothyroidism. CASE PRESENTATION: We report a case of an apparently healthy 19-year-old Kuwaiti woman referred to our clinic with an incidental finding of extremely high thyroid-stimulating hormone (TSH), tested at the patient's insistence as she had a strong family history of hypothyroidism. Despite no stated complaints, the patient presented typical symptoms and signs of hypothyroidism on evaluation. Thyroid function testing was repeated by using different assays, with similar results; ultrasound imaging of the thyroid showed a typical picture of thyroiditis. Treatment with levothyroxine alleviated symptoms and the patient later became biochemically euthyroid on treatment. CONCLUSION: There is controversy regarding screening asymptomatic individuals for hypothyroidism; therefore, it is important to maintain a high index of suspicion when presented with mild signs and symptoms of hypothyroidism especially with certain ethnic groups, as they may be free of the classical symptoms of disease.

Association of thyroid autoimmunity and the response to recombinant human growth hormone in Turner syndrome.

OBJECTIVES: Short stature and thyroid autoimmunity are common comorbidities in Turner syndrome (TS). Recombinant human growth hormone (rhGH) significantly improves height growth in TS individuals. This study aims to investigate the association of thyroid autoimmunity and the response to rhGH treatment in TS patients. METHODS: Medical records of 494 patients with TS were reviewed. Among 126 patients who regularly tested for thyroid autoantibodies, 108 patients had received rhGH treatment. Clinical characteristics, including karyotype and the presence of autoimmune thyroid diseases, as well as rhGH treatment records were analyzed. Height velocity (HV) of patients with or without thyroid autoimmunity was compared to assess the response to rhGH treatment. For patients who developed thyroid autoantibodies during rhGH treatment, HV before and after antibody presence were compared. RESULTS: 45XO monosomy presented in 36% (176/496) of patients. 42.1% of patients (53/126) had elevated circulating anti-thyroid peroxidase antibody and anti-thyroglobulin antibody. In 108 patients who received rhGH treatment, HVs were significantly correlated to age, height, weight and BMI at the initiation of treatment. For patients who developed thyroid autoantibodies during rhGH treatment, HVs after thyroid autoantibody presence significantly decreased compared with HVs before thyroid autoantibody detection (n=44, p=0.0017). CONCLUSIONS: Our data suggested that in TS patients who developed thyroid autoantibodies during rhGH treatment, the response to rhGH is negatively associated with the development of thyroid autoimmunity.

Primary hypothyroidism and autoimmune thyroiditis alter the transcriptional activity of genes regulating neurogenesis in the blood of patients.

Objective. Thyroid hormones play an important role in the development and maturation of the central nervous symptom and their failure in the prenatal period leading to an irreversible brain damage. Their effect on the brain of adult, however, has not been fully studied. With the discovery of neurogenesis in the adult brain, many recent studies have been focused on the understanding the basic mechanisms controlling this process. Many neurogenesis regulatory genes are not only transcribed but also translated into the blood cells. The goal of our study was to analyze the transcriptional activity of neurogenesis regulatory genes in peripheral blood cells in patients with thyroid pathology.Methods. The pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) was used to identify and validate the neurogenesis regulatory genes expression in patients with thyroid pathology and control group.Results. The results showed that GFRA3, NGFR, NRG1, NTF3, NTRK1, and NTRK2 significantly decreased their expression in patients with autoimmune thyroiditis with rising serum of autoantibodies. The patients with primary hypothyroidism, as a result of autoimmune thyroiditis and postoperative hypothyroidism, had significantly lower expression of FGF2, NGFR, NRG1, and NTF3. The mRNA level of CNTFR was markedly decreased in the group of patients with postoperative hypothyroidism. No change in the ARTN, PSPN, TFG, MT3, and NELL1 expression was observed in any group of patients.Conclusion. The finding indicates that a decrease in thyroid hormones and a high level of autoantibodies, such as anti-thyroglobulin antibody and anti-thyroid peroxidase antibody, affect the expression of mRNA neurogenesis-regulated genes in patients with thyroid pathology.

Subclinical Hypothyroidism as the Most Common Thyroid Dysfunction Status in Children With Down's Syndrome.

Introduction: Thyroid dysfunctions are one of the most common abnormalities coexisting in children with Down's syndrome (DS) and have been reported in up to 54% of cases. Aim of the Study: The purposes of this retrospective study were to investigate the course of subclinical hypothyroidism in children with DS, to evaluate the thyroid function of these subjects in relation to the risk of developing overt thyroid disease and autoimmunity, and to identify clinical and biochemical characteristics of patients prescribed L-T4 therapy in children and adolescents with DS and SH. Material and Methods: The records of DS patients referred to the Endocrinology Outpatient Clinic between 2010 and 2015 for screening of thyroid function were observed till the end of 2019 June and analyzed retrospectively. The children diagnosed with congenital hypothyroidism, acute lymphoblastic leukemia, and seizures and treated with drugs that may have interfered with thyroid function like lithium, antiepileptic, or iodinated drugs and glucocorticoids were excluded from the study. Results: The data of 77 DS patients were collected, evaluated, and analyzed. The study group consisted of 73 patients (32 girls and 41 boys with the mean age at baseline of 3.0 ± 4.5 years). A total of 63/73 (87%) children were diagnosed with SH. The 16/63 (25.4%) patients were followed-up without the treatment (group SH-T0), and therapy with levothyroxine (L-T4) was introduced in 47/63 (74.6%) SH children with a mean dosage of 1.8 ± 1.0 µg/kg/day (group SH-T1). Thyroxine supplementation did not improve growth expressed as ΔhSDS (0.1 ± 1.3, ranged -2.1 to 3.8 in SH-T0 vs. 0.0 ± 0.7, ranged -1.7 to 1.4 in SH-T1, p = 0.96) and ΔBMI Z-score (0.3 ± 0.9, ranged -0.9 to 2.6 in SH-T0 vs. 0.3 ± 1.1, ranged -2.1 to 2.9 in SH-T1, p = 0.65). Positive anti-TPO and anti-TG antibodies were detected in 7/63 (11.1%) DS cases. Conclusions: SH is the most frequent presentation of thyroid gland dysfunction in DS children. A small percentage of patients develop an overt hypothyroidism, particularly in females with mostly positive titer of antithyroid autoantibodies.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model.

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.

Antithyroid antibodies may predict serum beta HCG levels and biochemical pregnancy losses in euthyroid women with IVF single embryo transfer.

OBJECTIVE: To investigate the relationship between thyroid autoimmunity and early pregnancy serum ß-HCG levels in intracytoplasmic sperm injection patients. METHODS: The study subjects were 85 female euthyroid patients undergoing intracytoplasmic sperm injection embryo transfer cycles with GnRH antagonist treatment. Patients who received transfer of more than one embryo, those with serum TSH levels of greater than 2.5 IU/ml and subjects using levothyroxine were excluded. Normal responder patients under the age of 40 years were randomly selected from the patient files retrospectively. Subjects were divided into two groups: those with autoimmune thyroid disease (thyroid autoimmunity group; n = 39) and those without the disease (control group; n = 46). RESULTS: The age, body mass index, trial number, total rFSH treatment dose, the number of cumulus oophorus complexes, number of metaphase II oocytes, and number of 2-pronuclei embryos were similar in the thyroid autoimmunity and control groups. Serum ß-HCG levels measured on the 14th day after oocyte pickup were significantly lower in the thyroid autoimmunity group than in the control group (93.8 ± 35.8 versus 128.5 ± 55.8 mlU/ml, respectively; p < .001). The miscarriage rate was higher in the thyroid autoimmunity group than in the control group (34.4% versus 21.7%, respectively; p = .034). CONCLUSION: We found that early-stage pregnancy serum ß-HCG hormone levels among euthyroid patients undergoing intracytoplasmic sperm injection were lower in subjects with thyroid autoimmunity than in those without thyroid autoimmunity. This result, reported for the first time in the literature on euthyroid pregnant women with thyroid autoimmunity, may be predictor of early pregnancy losses in pregnant women with thyroid autoimmunity.Key messageIn intracytoplasmic sperm injection (ICSI)/IVF patients, due to lack of evidence-based data about the relationship between thyroid autoimmunity and pregnancy loss the current research was conducted. Early-stage pregnancy serum ß-HCG hormone levels in euthyroid ICSI patients with thyroid autoimmunity are lower than those without autoimmunity which may be associated with early pregnancy losses.

Thyroid peroxidase in human endometrium and placenta: a potential target for anti-TPO antibodies.

Autoimmune thyroid disease is the most common endocrine disorder during pregnancy. Thyroid autoantibodies (TAs) have been suggested to serve a role in implantation failure and spontaneous abortion. Until now, there are no data on the potential interaction of TAs with human reproductive organs. Here, we set out for the first time to test this hypothesis by studying the expression of thyroid peroxidase (TPO) at gene and protein level in human reproductive organs. Endometrial samples were taken from normal women, and placenta tissues were collected after full-term caesarian section. Expression of TPO messenger RNA (mRNA) was investigated by qRT-PCR. In addition, polyclonal anti-TPO antibodies were produced and the expression of TPO protein in mentioned tissues was evaluated by immunohistochemistry and Western blot analysis. The reactivity of anti-TPO antibody in human embryos was evaluated by immunofluorescent staining. For the first time, our study showed that TPO is expressed at gene and protein levels in endometrium and placenta. TPO expression was mainly localized to glandular and luminal epithelial cells in the endometrium. In placenta, the syncytiotrophoblasts and invasive trophoblast cells were the main cell types that expressed TPO protein. Specific band of approximately 110 kDa was observed in all endometrial and placental tissues by Western blot analysis. However, no expression of TPO protein was observed in human embryo. TPO expression in endometrium and placenta may explain higher frequency of abortion and infertility in patients with thyroid autoimmunity.

Predicting response and toxicity to PD-1 inhibition using serum autoantibodies identified from immuno-mass spectrometry.

Background: Validated biomarkers are needed to identify patients at increased risk of immune-related adverse events (irAEs) to immune checkpoint blockade (ICB). Antibodies directed against endogenous antigens can change after exposure to ICB. Methods: Patients with different solid tumors stratified into cohorts received pembrolizumab every 3 weeks in a Phase II trial (INSPIRE study). Blood samples were collected prior to first pembrolizumab exposure (baseline) and approximately 7 weeks (pre-cycle 3) into treatment. In a discovery analysis, autoantibody target immuno-mass spectrometry was performed in baseline and pre-cycle 3 pooled sera of 24 INSPIRE patients based on clinical benefit (CBR) and irAEs. Results: Thyroglobulin (Tg) and thyroid peroxidase (TPO) were identified as the candidate autoantibody targets. In the overall cohort of 78 patients, the frequency of CBR and irAEs from pembrolizumab was 31% and 24%, respectively. Patients with an anti-Tg titer increase ≥1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without this increase in unadjusted, cohort adjusted, and multivariable models (OR=17.4, 95% CI 1.8-173.8, p=0.015). Similarly, patients with an anti-TPO titer ≥ 1.5x from baseline to pre-cycle 3 were more likely to have irAEs relative to patients without the increase in unadjusted and cohort adjusted (OR=6.1, 95% CI 1.1-32.7, p=0.035) models. Further, the cohort adjusted analysis showed patients with anti-Tg titer greater than median (10.0 IU/mL) at pre-cycle 3 were more likely to have irAEs (OR=4.7, 95% CI 1.2-17.8, p=0.024). Patients with pre-cycle 3 anti-TPO titers greater than median (10.0 IU/mL) had a significant difference in overall survival (23.8 vs 11.5 months; HR=1.8, 95% CI 1.0-3.2, p=0.05). Conclusions: Patient increase ≥1.5x of anti-Tg and anti-TPO titers from baseline to pre-cycle 3 were associated with irAEs from pembrolizumab, and patients with elevated pre-cycle 3 anti-TPO titers had an improvement in overall survival.

Anti-thyroid peroxidase antibody and subclinical hypothyroidism in relation to hypertension and thyroid cysts.

Hypertension frequently occurs in subclinical hypothyroidism (SCH). By bolstering thyroid inflammation, anti-peroxidase antibody (TPO-Ab) causes autoimmune thyroiditis, which is one of the most common causes of SCH. Since the absence of thyroid cysts is associated with TPO-Ab (+) based on the indication of latent thyroid damage, we explored the potential mechanism underlying the association among TPO-Ab, SCH, hypertension, and thyroid cysts. A cross-sectional study of 1,483 Japanese aged 40-74 years was conducted. Thyroid cysts were defined as those having a maximum diameter of ≥ 2.0 mm, containing no solid component. TPO-Ab (+) was positively associated with SCH with hypertension (adjusted odds ratio [OR] and 95% confidence interval [CI], 2.62 [1.40, 4.89]) but not with SCH without hypertension (0.84 [0.37, 1.89]), respectively. Moreover, among participants without thyroid cysts, SCH was positively associated with hypertension (2.15 [1.23, 3.76]) but not among participants with thyroid cysts (0.58 [0.16, 2.16]), respectively. TPO-Ab was positively associated with SCH with hypertension, but not with SCH without hypertension. In addition, status of thyroid cysts might act as a determinant factor on the association between SCH and hypertension. These findings are efficient tools to clarify the background mechanism that underlies SCH.

Does thyroid autoimmunity affect the reproductive outcome in women with thyroid autoimmunity undergoing assisted reproductive technology?

PROBLEM: Our study aims to investigate whether the anti-thyroperoxidase antibody (TPO-Ab) and TSH level in euthyroid women have any association with reproductive outcomes after the ART cycle. METHODS OF STUDY: A total of 1107 patients who were enrolled in the study were divided into four groups based on serum TSH level and TPO-Ab status: group A, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab- ; group B, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab+ ; group C, 2.5 ≤ TSH < 4.2 mIU/L, and TPO-Ab- ; and group D, 2.5 ≤ TSH < 4.2 mIU/L, TPO-Ab+ . The differences in ART cycles and pregnancy outcomes were analyzed between study groups. RESULTS: The fertilization rate in group D (73%) was significantly lower than that in groups A (83% P < .001), B (84% P = .001), and C (82% P = .002). The biochemical pregnancy rates of groups B (7%) and D (12%) were significantly higher than those of group A (2%) (P = .028 and P = .017, respectively). TPO-Ab was related to a higher biochemical pregnancy rate (P = .002, OR = 5.311, 95% CI 1.859-15.169) and TSH over 2.5 mIU/L was related to higher ICSI rate (P = .001, OR = 1.759, 95% CI 1.250-2.476) by logistic regression analysis. The receiver operating characteristic (ROC) also verified the results. CONCLUSION: The impacts of TSH ≥ 2.5 mIU/L on the intracytoplasmic sperm injection (ICSI) rate, TSH ≥ 2.5 mIU/L and TPO-Ab+ on the fertilization rate, and TPO-Ab+ on the biochemical pregnancy rate, rather than the effect on abortion, clinical pregnancy, and live birth, were emphasized.

Ovarian Reserve and Serum Concentration of Thyroid Peroxidase Antibodies in Euthyroid Women With Different Polycystic Ovary Syndrome Phenotypes.

Objective: It has been shown that women with polycystic ovary syndrome (PCOS), as well as Hashimoto's thyroiditis (HT), are characterized by increased incidence of infertility. Serum anti-Müllerian hormone (AMH), which reflects ovarian reserve, is elevated in PCOS women and is decreased in women with HT. The Rotterdam criteria recognize four clinical PCOS phenotypes, i.e., phenotypes A, B, C, and D. The aim of the present study was to investigate the relation between serum concentrations of thyroid peroxidase antibodies (TPOAbs) and ovarian reserve in different PCOS phenotypes. Patients and methods: We examined 141 women with PCOS [phenotype A was diagnosed in 67 (47.5%) women, phenotype B in 30 (21.3%), phenotype C in 28 (19.9%), and phenotype D in 16 (11.3%)] and 88 control subjects of similar age; all women were euthyroid. Serum concentrations of AMH, thyroid-stimulating hormone (TSH), thyroid hormones, and TPOAbs were assessed. Results: We observed positive serum TPOAbs in 21.9% women with PCOS and in 23.9% controls (p = 0.07). We did not find differences in the frequency of detection of positive serum TPOAbs between phenotypes A, B, and C and the control group (p > 0.05). We did not observe a difference in AMH levels between TPOAbs-positive and TPOAbs-negative women, both in the control group and the PCOS women (all p > 0.05). However, serum AMH concentration was markedly higher in the whole PCOS group (p < 0.01) and in phenotype A (p < 0.01) vs. controls when the serum concentration of TPOAbs was negative. In the groups with positive serum levels of TPOAbs, serum concentration of AMH did not differ between PCOS phenotypes and controls (p = 0.23). Additionally, we observed that serum AMH concentration was related to the level of TPOAbs in the PCOS group (r = -0.4, p = 0.02). Conclusions: The frequency of serum detection of positive TPOAbs did not differ between PCOS phenotypes with clinical/biochemical hyperandrogenism and the control group. The observation of the difference in serum AMH between the PCOS and control groups only in TPOAbs negative women together with the inverse relation of TPOAbs with serum AMH only in the PCOS group might suggest that ovarian reserve is influenced by TPOAbs in PCOS.