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Competing Interests: C.D.: member of the Sling Therapeutics Scientific Advisory Board; consultant for Amgen/Horizon, Immunovant, and Third Rock Ventures; performs research with Viridian Therapeutics and Sling Therapeutics. M.S.: his institution received grants from Immunovant, Viridian, Sling and Lassen; and he received consulting fees from Third Rock Ventures, Septerna, Grifols, Tshaka Bio, MingHui Pharma, Lundbeck, Lasses, Tourmaline, Avilar, Genentech, and ArgenX. A.L.K.: consultant/advisor for Amgen/Horizon Therapeutics, Immunovant Inc., Aceylrin, Kriya Therapeutics, Viridian Therapeutics, Lassen Therapeutics, Genentech, and Argenx; performs research with Sling Therapeutics, Amgen/Horizon Therapeutics, Kriya Therapeutics, Viridian Therapeutics, and Lassen Therapeutics. M.K. has no financial or conflicts of interest to disclose.

Subclinical hypothyroidism and thyroid autoimmunity in pregnancy are common conditions. They are both associated with adverse maternal and offspring outcomes. Women with thyroid autoimmunity should be monitored with regular thyroid function tests preconception and during gestation to identify women who develop hypothyroidism. The effectiveness of thyroid hormone treatment in reducing adverse outcomes in pregnancy has been studied in a number of randomized controlled trials. Current evidence shows obstetrical benefits of levothyroxine treatment in pregnant women with a thyroid-stimulating hormone level greater than 4 mU/L., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

Purpose: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab., Design: Multicenter, retrospective, observational cohort study., Participants: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab., Methods: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit., Main Outcome Measures: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement., Results: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8)., Conclusions: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: The COVID-19 pandemic and a movement away from traditional lecture-based learning have increased the use of online flipped classroom (FC) and active learning models in medical education. The Community of Inquiry (CoI) framework for online learning may be used to evaluate the effectiveness and strengths of the online FC model compared with other learning formats., Methods: An observational survey study was conducted to measure medical student and facilitator perceptions of an online FC endocrinology tutorial compared with online lecture experiences. For the tutorial, students were instructed to watch short, pre-recorded lecture videos on thyroid pathophysiology prior to class. During class, small groups of students were paired with a faculty facilitator in online Zoom rooms for case discussion. Students were surveyed using the CoI framework to assess elements of cognitive, social, and teaching presence between the two online learning modalities. Facilitators were also surveyed. Survey questions were rated on a 5-point Likert scale., Results: Fifty-three out of 92 students (58% response rate) and seven out of eight facilitators (88% response rate) completed surveys. In general, students felt that online FC learning improved cognitive, teaching, and social presence compared with online lecture. Areas of cognitive presence (mean score 3.9 ± 1.0 SD), such as stimulating curiosity and applying concepts, were highly rated. Certain elements of social presence (3.6 ± 0.9) and teaching presence (3.7 ± 0.9), such as expression of emotion and communication of expectations, garnered lower ratings. All surveyed facilitators felt that online FC was more effective and enjoyable to teach than online lectures but did not feel it was superior to in-person instruction., Conclusion: Medical students and facilitators viewed an online FC tutorial in endocrinology positively. Most, but not all, areas of the CoI framework were enhanced with the online FC tutorial compared with online lecture-based learning., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Chang et al.)

Teprotumumab has been shown to be effective in the treatment of thyroid eye disease, a potentially vision-threatening condition. Adverse events, including sensorineural hearing loss, have been associated with teprotumumab. The authors present the case of a 64-year-old female who discontinued teprotumumab due to significant sensorineural hearing loss after 4 infusions, along with other adverse events. The patient was unresponsive to a subsequent course of intravenous methylprednisolone and orbital radiation, during which she experienced worsening thyroid eye disease symptoms. Teprotumumab was restarted 1 year later, at a half dose of 10 mg/kg for 8 infusions. Three months post-treatment, she retains resolution of double vision and orbital inflammatory signs, and significant improvement in proptosis. She tolerated all infusions with an overall reduction in the severity of her adverse events and without return of significant sensorineural hearing loss. The authors conclude that a lower dose of teprotumumab can be effective for patients with active moderate-severe thyroid eye disease who experience significant or intolerable adverse events., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Context: Occurrence of Graves' disease (GD) has been reported following SARS-CoV-2 vaccine administration, but little is known about thyroid eye disease (TED) after SARS-CoV-2 vaccination., Objective: We describe 2 cases of TED activation following mRNA SARS-CoV-2 vaccination and review additional cases reported in the literature., Methods: We report 2 cases of TED activation following SARS-CoV-2 vaccination: 1 case of TED worsening in a patient with GD, and 1 of de novo active TED progressing to dysthyroid optic neuropathy in a patient with a history of Hashimoto hypothyroidism. Our literature search revealed 8 additional reported TED cases associated with SARS-CoV-2 vaccination until June 2022. We review the characteristics, duration, and management of TED following SARS-CoV-2 vaccination in these cases., Results: Of all 10 reported TED cases following SARS-CoV-2 vaccination, 4 developed new-onset TED and 6 previously stable TED cases experienced significant deterioration. Six patients had known GD and 2 patients had Hashimoto thyroiditis. Two cases progressed to dysthyroid optic neuropathy, 6 had moderate/severe active disease, and 2 had mild disease that did not require treatment. Seven TED cases received teprotumumab and had a favorable response, 2 of whom had prior limited response to initial prednisone or methylprednisolone and tocilizumab therapy., Conclusion: New diagnosis or deterioration of TED after mRNA SARS-CoV-2 vaccination can occur, with most cases described in patients with underlying autoimmune thyroid disease. Our report raises awareness to this potential complication to promote early recognition and prompt management of TED associated with mRNA SARS-CoV-2 vaccines. Further studies are needed to explore the mechanism, risk factors, prevention, and treatment of TED following mRNA SARS-CoV-2 vaccination., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials., Objective: Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort., Methods: This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months., Results: Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up., Conclusion: While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The thyroid eye disease (TED) treatment landscape is rapidly evolving. How new treatment options have impacted practice is unknown. Methods: We conducted a cross-sectional electronic survey of American and European Thyroid Association members between June 2 and June 30, 2021. The survey included TED questions about resources for its management, index cases for different severities and presentations of TED, barriers for the management of TED, and participants' concerns about TED. We classified respondents into three geographic categories: North America, Europe, or other regions. Results: Two hundred fifty-two eligible participants started the survey (15% response rate), and 227 completed it. Participants were mostly men (50.2%, 114/227), white (79.7%, 181/227), endocrinologists with a thyroid focus (66.1%, 150/227), practicing in a tertiary academic center (46.7%, 106/227), caring for 10 or more TED patients over the last 12 months (40.5%, 92/227), and reported not having a multidisciplinary TED clinic in their institution (52.8%, 120/227). The majority reported that new TED cases per annum have not changed in the past 10 years (47.5%, 108/227), and that TED patients are found in practice during the management of hyperthyroidism (41.8%, 95/227). For mild active TED, participants from Europe reported a higher use of selenium (73%[96/132] vs. 32%[20/62] of respondents from North America and 24%[8/33] of respondents from other regions). For moderate-to-severe active TED, there was a modest preference for teprotumumab as first-line therapy (37%, 23/62) among North American participants and intravenous (IV) steroids (73%[96/132], and 42%[14/33]) for participants from Europe and other regions, respectively. These treatment preferences did not change in patients with moderate-to-severe active TED with poorly controlled diabetes. In contrast, participants from the three geographic categories preferred IV steroids for optic neuropathy and women planning pregnancy. The three top "very important" concerns about TED management according to participants were: the cost of TED treatment (31.3%, 71/227), lack of effective TED treatments (19.8%, 45/227), and difficulty in predicting whether TED will develop (18.9%, 43/227). Conclusions: There is a marked geographic practice variation in the management of TED. Clinicians' concerns about TED management demand ongoing research on more effective treatment, TED predictive tools, and policy changes to improve the affordability of new TED therapies.

Context: Thyroid eye disease (TED) is a sight-threatening and debilitating autoimmune condition, with limited therapies available, that often poses diagnostic and therapeutic challenges. In recent years, the treatment landscape has shifted to early intervention with targeted therapy., Methods: A PubMed review of the literature was conducted for the period between 1979 and 2021. Search terms included thyroid eye disease, teprotumumab, targeted therapy, Graves disease, Graves ophthalmopathy, dysthyroid optic neuropathy, and related terms in different combinations. Novel biologic therapies for TED have emerged as alternatives to traditional steroid regimens in recent years. New insights into TED pathophysiology have uncovered the role of the insulin-like growth factor 1 receptor (IGF-1R) and led to the development of teprotumumab, an IGF-1R-inhibiting monoclonal antibody., Results: Randomized clinical trials demonstrating the efficacy of teprotumumab for TED led to Food and Drug Administration approval. Teprotumumab is gradually replacing immunosuppressive agents as first-line therapy in the United States for active moderate-to-severe TED, while emerging reports also show its use in other stages of the disease. Recent data highlight risk factors for adverse events and screening protocols to maximize patient safety. Personalized therapeutic plans developed through effective partnership between endocrinologists and ophthalmologists aim to enhance the safety and outcomes of TED treatments and improve care for this complex disease., Conclusion: TED management is shifting to an era of targeted therapy with multidisciplinary care. Teprotumumab has demonstrated superior efficacy to conventional treatments and has transformed our therapeutic and surgical algorithms. Clinical guidelines and additional studies are needed to further guide and refine therapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: To characterize the frequency, severity, and resolution of hearing dysfunction in patients treated with teprotumumab for thyroid eye disease (TED)., Design: Prospective observational case series., Methods: Ophthalmic examination and adverse event assessment, including otologic symptoms, were performed at baseline, after infusions 2, 4, and 8, and at 6-month follow-up in consecutive patients who received at least 4 teprotumumab infusions. Laboratory test results were collected at baseline and during treatment. Audiometry, patulous eustachian tube (PET) testing, and otolaryngology evaluation were obtained for patients with new or worsening otologic symptoms, with a subset obtaining baseline and posttreatment testing., Results: Twenty-seven patients were analyzed (24 females, 3 males, average 56.3 years old). Twenty-two patients (81.5%) developed new subjective otologic symptoms, after a mean of 3.8 infusions (SD 1.8). At 39.2-week average follow-up after the last infusion, most patients with tinnitus (100%), ear plugging/fullness (90.9%), and autophony (83.3%) experienced symptom resolution, whereas only 45.5% (5 of 11) of patients with subjective hearing loss/decreased word comprehension experienced resolution. Six patients underwent baseline and posttreatment audiometry, 5 of whom developed teprotumumab-related sensorineural hearing loss (SNHL) and 1 patient also developed PET. Three of the 5 patients with teprotumumab-related SNHL had persistent subjective hearing loss at last follow-up. A prior history of hearing loss was discovered as a risk factor for teprotumumab-related SNHL (P = .008)., Conclusions: Hearing loss is a concerning adverse event of teprotumumab, and its mechanism and reversibility should be further studied. Until risk factors for hearing loss are better understood, we recommend baseline audiometry with PET testing and repeat testing if new otologic symptoms develop. Screening, monitoring, and prevention guidelines are needed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: Broad genomic analyses among thyroid histologies have been described from relatively small cohorts., Objective: Investigate the molecular findings across a large, real-world cohort of thyroid fine-needle aspiration (FNA) samples., Design: Retrospective analysis of RNA sequencing data files., Setting: Clinical Laboratory Improvement Amendments laboratory performing Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) testing., Participants: A total of 50 644 consecutive Bethesda III-VI nodules., Intervention: None., Main Outcome Measures: Molecular test results., Results: Of 48 952 Bethesda III/IV FNAs studied, 66% were benign by Afirma GSC. The prevalence of BRAF V600E was 2% among all Bethesda III/IV FNAs and 76% among Bethesda VI FNAs. Fusions involving NTRK, RET, BRAF, and ALK were most prevalent in Bethesda V (10%), and 130 different gene partners were identified. Among small consecutive Bethesda III/IV sample cohorts with one of these fusions and available surgical pathology excision data, the positive predictive value of an NTRK or RET fusion for carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features was >95%, whereas for BRAF and ALK fusions it was 81% and 67%, respectively. At least 1 genomic alteration was identified by the expanded Afirma XA panel in 70% of medullary thyroid carcinoma classifier-positive FNAs, 44% of Bethesda III or IV Afirma GSC suspicious FNAs, 64% of Bethesda V FNAs, and 87% of Bethesda VI FNAs., Conclusions: This large study demonstrates that almost one-half of Bethesda III/IV Afirma GSC suspicious and most Bethesda V/VI nodules had at least 1 genomic variant or fusion identified, which may optimize personalized treatment decisions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

A 45-year-old male presented with active progressive thyroid eye disease refractory to intravenous steroids and right orbital radiation. Visual acuity, left relative afferent pupillary defect, and Humphrey visual field defects were consistent with worsening left dysthyroid optic neuropathy. Orbital MRI demonstrated extraocular muscle enlargement and effacement of the left optic nerve sheath. After 2 infusions of teprotumumab, the patient's visual acuity, relative afferent pupillary defect, Humphrey visual fields, proptosis, and extraocular muscle size improved. This is the first report of dysthyroid optic neuropathy responsive to teprotumumab, and it supports the need for further studies to better understand the role of teprotumumab in treating sight-threatening thyroid eye disease., Competing Interests: Dr. Andrea Kossler is a consultant for Horizon Therapeutics. The other authors report no conflicts of interest., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Thyroid eye disease (TED) is a complex inflammatory disease that can have a long clinical course with sight-threatening and debilitating ocular sequelae. Until recently, there were limited therapeutic options available. In the last decade we have gained a deeper understanding of the underlying pathophysiology, which has led to the development of novel effective targeted therapies. This article discusses the challenges encountered in the clinical evaluation and treatment of TED patients, with the goal to empower endocrinologists and ophthalmologists to work together to provide effective multidisciplinary care. We will review recommendations of past clinical guidelines around evaluation and management of TED patients, discuss the randomized controlled trials of new biologic therapies, and explore how to navigate the emerging therapeutic landscape., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Every year, 500,000 youths in the U.S. with chronic disease turn 18 years of age and eventually require transfer to adult subspecialty care. Evidence-based interventions on the organization of transfer of care are limited, although engagement and retention in adult clinic are considered appropriate outcomes. Sustained continuity of care improves patient satisfaction and reduces hospitalization. Methods: We conducted a prospective, nonrandomized cohort study of patients with pediatric endocrine conditions, age 16 to 26 years, enrolled upon referral to the adult endocrine clinic of a physician trained in both adult and pediatric endocrinology (Med+Peds endocrinologist). Patients differed based on whether their referral originated from another pediatric endocrinologist (traditional transfer) or if the Med+Peds endocrinologist previously saw the patient in his pediatric endocrine clinic (guided transfer). Rather than relying on arbitrary age criteria, guided transfer to adult clinic occurred when physician and patient considered it appropriate. The primary outcome was show rate at the first and second adult visits. Results: Of 36 patients, 21 were referred by another pediatric endocrinologist and 15 underwent guided transfer. For traditional transfer, show rate to the first and second visit was 38%, compared to 100% in the guided transfer group ( P = .0001). Subgroup analysis of 27 patients with diabetes revealed that both groups had similar initial hemoglobin A1c ( P = .38), and the guided transfer group maintained hemoglobin A1c. Conclusion: Most traditional transfers were unsuccessful. Guided transfer was significantly more effective, with every patient successfully transferring, and could be implemented with adult endocrinologists willing to see patients in the pediatric clinic. Abbreviations: DKA = diabetic ketoacidosis; HbA1c = hemoglobin A1c; Med+Peds = Internal Medicine and Pediatrics.

Background: Thyroid disease is prevalent in women of reproductive age, while infertility is common in women with thyroid dysfunction. In this study, we review the recent advances in the field of thyroid and fertility since the publication of the 2017 American Thyroid Association pregnancy guidelines. Summary: Recent studies have confirmed associations of thyrotropin (TSH) elevation and/or thyroid autoimmunity with infertility and low ovarian reserve in subsets of women, and have led to a better understanding of the pathogenesis linking thyroid autoimmunity with infertility. Even though the benefit of treating patients with TSH >4 mIU/L has been confirmed in a large retrospective cohort study, two large randomized controlled trials have failed to show benefit of thyroid hormone on obstetrical outcomes in euthyroid women with thyroid autoimmunity. New data have emerged regarding the potential gonadal toxicity of radioactive iodine (RAI), based on its impact on ovarian reserve and sperm chromosomal abnormalities. Conclusions: There is continued evidence supporting an important role of thyroid hormone in regulation of reproductive tissues at many levels. Recent randomized trials have failed to identify a benefit of thyroid hormone in euthyroid women with thyroid autoimmunity. Further research in the field is needed to more completely delineate the relevant pathways and identify women who may benefit from levothyroxine treatment. The impact of RAI on fertility also merits further investigation.

Radioactive iodine (RAI) is a key component in the treatment of differentiated thyroid cancer. RAI has been recommended more selectively in recent years as guidelines evolve to reflect risks and utility in certain patient subsets. In this study we sought to evaluate the survival impact of radioactive iodine in specific thyroid cancer subgroups. Nationwide retrospective cohort study of patients using the National Cancer Database (NCDB) from 2004 to 2012 and Surveillance, Epidemiology, and End Results (SEER) database from 1992 to 2009 examining patients with differentiated thyroid cancer treated with or without RAI. Primary outcomes included all-cause mortality (NCDB and SEER), and cancer-specific mortality (SEER). Cox multivariate survival analyses were applied to each dataset, and in 135 patient subgroups based on clinical and non-clinical parameters. A total of 199,371 NCDB and 77,187 SEER patients were identified. RAI was associated with improved all-cause mortality (NCDB: RAI hazard ratio (HR) 0.55, P < 0.001; SEER: HR 0.64, P < 0.001); and cancer-specific mortality (SEER: HR 0.82, P = 0.029). Iodine therapy showed varied efficacy within each subgroup. Patients with high-risk disease experienced the greatest benefit in all-cause mortality, followed by intermediate-risk, then low-risk subgroups. Regarding cancer-specific mortality, radioactive iodine therapy was protective in high-risk patients, but did not achieve statistical significance in most intermediate-risk subgroups. Low-risk T1a subgroups demonstrated an increased likelihood of cancer-specific mortality with iodine therapy. The efficacy of RAI in patients with differentiated thyroid cancer varies by disease severity. A negative cancer-specific survival association was identified in patients with T1a disease. These findings warrant further evaluation with prospective studies.

Objectives: The use of I whole body scintigraphy (WBS) before I radioiodine ablation (RIA) of the post-surgical thyroid remnant in patients with papillary thyroid cancer (PTC) remains debated. The American Thyroid Association's guidelines state that WBS may be useful before RIA (rating C-expert opinion). Some institutions do not use I WBS before RIA in their routine clinical protocol. We were therefore prompted to evaluate the impact of I WBS prior to ablation of thyroid remnant in patients with PTC., Methods: We reviewed data from 152 consecutive patients with PTC who had total thyroidectomy and were referred for RIA between August 2007 and February 2009 at our institution. The group included 107 women and 45 men, 13-82 years old (mean ± SD: 45.5 ± 18.3). Three endocrinologists blinded to the results of the I WBS reviewed patients' data including sex, age, pathology, thyroglobulin (Tg) level, anti-Tg antibodies, thyroid stimulating hormone (TSH) level and ultrasound results. Each endocrinologist then returned a form with the recommended I dose for each participant, according to the following rules: 50-75 mCi (remnant ablation), 75-125 mCi (lymph nodes metastases), 150 mCi (lung metastases), and 200 mCi (bone metastases). We compared their recommended doses with the actual I doses prescribed after the pre-therapy I WBS., Results: All three endocrinologists recommended the same dose in 98.7% of the cases. The dose prescribed by the endocrinologists matched the dose administered after analyzing the I WBS in 77 patients (51%). However, for 46 patients (30%) the endocrinologists would have given a lower dose, for 18 patients (12%) a higher dose than that administered based on the results of the I WBS, while 11 patients (7%) would have been treated unnecessarily (5/11 had no I uptake and 6/11 had I uptake in the breasts)., Conclusions: Our study suggests a significant role of the pre-therapy I WBS in PTC patients referred for I ablation post-thyroidectomy. The actual I dose that was administered based on the I WBS differed from the dose recommended in the absence of the I WBS in 49% of the cases.

Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period., Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members., Results: The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research., Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.

Isolated maternal hypothyroxinemia (IMH) during pregnancy is defined as a low maternal T 4 in the absence of TSH elevation. As IMH is common, with a prevalence of 1-2% in iodine-sufficient populations, and early research has suggested adverse effects on fetal neurodevelopment, it has been the focus of many studies in the last decade. In the current review, we first discuss the significance of IMH based on data from animal models and recent discoveries regarding the role of thyroid hormone on neurodevelopment. We address issues surrounding the definition and prevalence of this entity and discuss new insights into the etiologies, clinical consequences and management of IMH. A number of large cohort studies have investigated the effects of IMH on the risk of various pregnancy complications and child neurodevelopment. We review these studies in detail and describe their limitations. We discuss the available research on management of IMH, including two recent randomized controlled trials (RCTs). Finally, we delineate the remaining uncertainties in this field and emphasize the need for a sufficiently powered, placebo-controlled RCT on the treatment of IMH early in the first trimester of pregnancy., (© 2017 European Society of Endocrinology.)

Background: The incidence of Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, has risen rapidly worldwide. PTC usually has an excellent prognosis. However, the rising incidence of PTC, due at least partially to widespread use of neck imaging studies with increased detection of small cancers, has created a clinical issue of overdiagnosis, and consequential overtreatment. We investigated how molecular data can be used to develop a prognostics signature for PTC., Methods: The Cancer Genome Atlas (TCGA) recently reported on the genomic landscape of a large cohort of PTC cases. In order to decrease unnecessary morbidity associated with over diagnosing PTC patient with good prognosis, we used TCGA data to develop a gene expression signature to distinguish between patients with good and poor prognosis. We selected a set of clinical phenotypes to define an 'extreme poor' prognosis group and an 'extreme good' prognosis group and developed a gene signature that characterized these., Results: We discovered a gene expression signature that distinguished the extreme good from extreme poor prognosis patients. Next, we applied this signature to the remaining intermediate risk patients, and show that they can be classified in clinically meaningful risk groups, characterized by established prognostic disease phenotypes. Analysis of the genes in the signature shows many known and novel genes involved in PTC prognosis., Conclusions: This work demonstrates that using a selection of clinical phenotypes and treatment variables, it is possible to develop a statistically useful and biologically meaningful gene signature of PTC prognosis, which may be developed as a biomarker to help prevent overdiagnosis.

Background: Thyroid cancer incidence is increasing worldwide. Incorporating 22 years of incidence data through 2009, we extend examination of these trends among a wide array of subgroups defined by patient (age, sex, race/ethnicity, and nativity), tumor (tumor size and stage), and neighborhood (socioeconomic status and residence in ethnic enclaves) characteristics, to identify possible reasons for this increase., Methods: Thyroid cancer incidence data on 10,940 men and 35,147 women were obtained from the California Cancer Registry for 1988-2009. Population data were obtained from the 1990 and 2000 U.S. Census. Incidence rates and 95% confidence intervals (CI) were calculated and incidence trends were evaluated using Joinpoint regression to evaluate the timing and magnitude of change [annual percentage change (APC) and rate ratios]., Results: The incidence of papillary thyroid cancer continues to increase in both men (APC, 5.4; 95% CI, 4.5-6.3 for 1998-2009) and women (APC, 3.8; 95% CI, 3.4-4.2 for 1998-2001 and APC, 6.3; 95% CI, 5.7-6.9 for 2001-2009). Increasing incidence was observed in all subgroups examined., Conclusions: Although some variation in the magnitude or temporality of the increase in thyroid cancer incidence exists across subgroups, the patterns (i) suggest that changes in diagnostic technology alone do not account for the observed trends and (ii) point to the importance of modifiable behavioral, lifestyle, or environmental factors in understanding this epidemic., Impact: Given the dramatic and continued increase in thyroid cancer incidence rates, studies addressing the causes of these trends are critical. Cancer Epidemiol Biomarkers Prev; 23(6); 1067-79. ©2014 AACR., (©2014 American Association for Cancer Research.)

Context: Hypothyroidism in pregnancy can lead to adverse maternal and fetal outcomes. Although screening of high-risk women is advocated, universal screening remains controversial., Objective: The objective of the study was to compare the cost-effectiveness of universal screening of pregnant women for autoimmune thyroid disease (AITD) with screening only high-risk women and with no screening., Design, Setting, and Participants: A decision-analytic model compared the incremental cost per quality-adjusted life-year (QALY) gained among the following: 1) universal screening, 2) high-risk screening, and 3) no screening. Screening consisted of a first-trimester thyroid-stimulating hormone level and antithyroid peroxidase antibodies. Women with abnormal results underwent further testing and, when indicated, levothyroxine therapy. Randomized controlled trials provided probabilities for adverse obstetrical outcomes. The model accounted for the development of postpartum thyroiditis and overt hypothyroidism. Additional scenarios in which therapy prevented cases of decreased child intelligence quotient were explored., Main Outcome Measures: Medical consequences of AITD in pregnancy, QALY, and costs were measured., Results: Risk-based screening and universal screening were both cost-effective relative to no screening, with incremental cost-effectiveness ratios (ICERs) of $6,753/QALY and $7,138/QALY, respectively. Universal screening was cost-effective compared with risk-based screening, with an ICER of $7,258/QALY. Screening remained cost-effective in various clinical scenarios, including when only overt hypothyroidism was assumed to have adverse obstetrical outcomes. Universal screening was cost-saving in the scenario of untreated maternal hypothyroidism resulting in decreased child intelligence, with levothyroxine therapy being preventive., Conclusions: Universal screening of pregnant women in the first trimester for AITD is cost-effective, not only compared with no screening but also compared with screening of high-risk women.

Objective: Untreated maternal hypothyroidism during pregnancy can have adverse consequences on maternal health and child intelligence quotient (IQ). Our objective was to examine the cost-effectiveness of screening pregnant women for autoimmune thyroid disease., Design: We developed a state-transition Markov model and performed a cost-effectiveness analysis of screening pregnant US women, aged 15-45 years, with no known history of thyroid disease, in the first trimester., Methods: Three strategies were compared: 1) no screening, 2) one-time screening using anti-thyroid peroxidase (anti-TPO) antibodies, and 3) one-time screening using TSH. Screening tests were added to the laboratory tests of the first prenatal visit. Abnormal screening tests were followed by further testing and subsequent thyroxine treatment of hypothyroid women., Results: Screening pregnant women in the first trimester using TSH was cost-saving compared with no screening. Screening using anti-TPO antibodies was cost-effective compared with TSH screening with an incremental cost-effectiveness ratio of $15,182 per quality-adjusted life year. Screening using TSH remained cost-saving across a wide range of ages at screening, costs of treatment, and probabilities of adverse outcomes. The cost-effectiveness of anti-TPO screening compared with TSH screening was mostly influenced by the probability of diagnosing hypothyroidism in unscreened subjects or subjects with a normal screening test. Screening remained highly cost-effective in scenarios where we assumed no improvement of child IQ outcomes by levothyroxine treatment., Conclusion: Screening all pregnant women for autoimmune thyroid disease in the first trimester is cost-effective compared with not screening.

The endocrine system and the immune system interact closely during implantation and maintenance of pregnancy. One of the most striking examples of this communication is at the level of the decidua (endometrium of pregnancy). Here, under the influence of sex steroids, there is a dramatic increase of a unique population of lymphocytes, the uterine natural killer (uNK) cells, in early pregnancy. These cells derive predominantly from a subset of peripheral blood NK cells, which under hormonal influence gets recruited to the uterus. In mice, uNK cells play an important role in the development of placental vasculature. The role of these cells in human pregnancy is still not definitively established; however, they are believed to promote placental and trophoblast growth and provide immunomodulation at the maternal-fetal interface. In contrast to their presumptive role in the maintenance of a healthy pregnancy, uNK cells and peripheral NK cells are dysregulated in unexplained recurrent pregnancy loss. Herein, we review NK cell populations, their changes in number and function in altered endocrine environments during the menstrual cycle and pregnancy, the current data on their potential role in unexplained recurrent pregnancy loss, and mechanisms for potential therapies targeted to NK cell function for this enigmatic disorder.

Problem: Changes in the immune environment in the endometrium are believed to be important for successful implantation and maintenance of pregnancy. We have previously investigated global gene profiling in human endometrium during the window of implantation by oligonucleotide microarray technology, and analysis of these data underscore the regulation of a group of immune-related genes. The present study was therefore conducted to examine the pattern of expression and regulation of these genes including decay accelerating factor (DAF), indoleamine 2,3 dioxygenase (IDO), interleukin-15 (IL-15), IL-15 receptor alpha subunit (IL-15Ralpha), interferon regulatory factor-1 (IRF-1), lymphotactin (Lpn), natural killer-associated transcript 2 (NKAT2) and NKG5 in secretory and proliferative human endometrium., Method of Study: Endometrial biopsies were obtained from normally cycling women in the late proliferative and mid-secretory phase of the menstrual cycle. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot analysis were used to determine the expression and regulation of these genes in secretory and proliferative human endometrium. Cellular localization of NKG5, Lpn and IDO by in situ hybridization in secretory-phase endometrium was also examined., Results: Semi-quantitative RT-PCR and Northern blot results demonstrate that there is a coordinated upregulation of this group of genes during the window of implantation., Conclusions: We demonstrate the upregulation of immune-related genes IL-15Ralpha, Lpn and NKG5 in secretory versus proliferative human endometrium. We also demonstrate a similar upregulation in secretory endometrium of other immune-related genes, viz, DAF, IDO, IL-15, IRF-1 and NKAT2. The functions of these genes include stimulation of proliferation of uterine natural killer (uNK) cells, inhibition of cytolytic activity of uNK cells, inhibition of cell growth of T cells and other pathogens and inhibition of the classical complement pathway. Upregulation of these immune-related genes in the window of implantation suggests their role during the process of implantation and in immune tolerance of the implanting conceptus.

Silencing of a target mRNA by small interfering RNA (siRNA) has emerged as a new and powerful tool to study gene function, and post-transcriptional gene silencing can now be accomplished with 21-23 nucleotide RNA that mediate sequence-specific mRNA degradation. In the current study we employed lamin A/C siRNA to silence lamin A/C expression in cultured human endometrial stromal cells and investigated downstream cellular markers for proof of concept. Human endometrial stromal cells from three subjects were transfected with lamin A/C siRNA or non-silencing fluorescein-labelled siRNA, and flow cytometric analysis revealed 95-98% transfection efficiency after 6 h of treatment. RT-PCR and quantitative RT-PCR were used to measure mRNA degradation of lamin A/C, and 75-88% silencing was observed 48 h post-transfection. Western blotting and immunocytochemistry confirmed corresponding decrease in lamin A/C protein within 48 h of gene silencing. The downstream effect of lamin A/C silencing was investigated by immunocytochemical analysis of the cellular localization of the protein, emerin, an important component of the nuclear lamina and known to be regulated by lamin expression. Marked displacement of emerin from the nuclear lamina to the cytoplasm was observed when lamin A/C was silenced in human endometrial stromal cells, confirming functional silencing of lamin A/C resulting in a nuclear lamina assembly defect. Silencing target mRNA by siRNA in human endometrial stromal cells can be more broadly applied to investigate the function and regulation of other genes in this cell type, and the methodology and data presented herein strongly support the more widespread use of this powerful tool in endometrial biology research.

Interaction between the endocrine and the immune systems has been suggested by observations of sexual dimorphism of the immune response, differential susceptibility to autoimmunity between the sexes, changes in autoimmune disease activity during the menstrual cycle and in pregnancy and in vitro studies of hormonal influence on cytokine production.We hypothesized that if there is hormonal regulation of the immune response, this would be manifest in peripheral blood leukocytes (PBLs) at different phases of the menstrual cycle. In this study, we describe gene profiling of PBLs from the follicular and luteal phases of the menstrual cycle. We observe important differences in immune gene expression, with significant down-regulation of the Th1 immune response in the luteal phase. A significant number of interferon (IFN)-related genes are amongst the downregulated genes. These results support significant hormonal regulation of the immune system and may have therapeutic implications in diseases of autoimmunity in women.