Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

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.

Reduction of Teprotumumab-Induced Hearing Loss With Comparable Efficacy Using Half-Dose Therapy.

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.

Teprotumumab for Dysthyroid Optic Neuropathy: Early Response to Therapy.

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.

THE GUIDED TRANSFER OF CARE IMPROVES ADULT CLINIC SHOW RATE.

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.

Development of prognostic signatures for intermediate-risk papillary thyroid cancer.

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.

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.

New Onset or Deterioration of Thyroid Eye Disease After mRNA SARS-CoV-2 Vaccines: Report of 2 Cases and Literature Review.

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.

Use of the Community of Inquiry Framework to Measure Student and Facilitator Perceptions of Online Flipped Classroom Compared with Online Lecture Learning in Undergraduate Medical Education.

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.

Teprotumumab-Related Hyperglycemia.

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.

Oral Corticosteroids for Teprotumumab-Related Hearing Loss: A Case Report.

Teprotumumab is a novel insulin-like growth factor-1 receptor inhibitor approved for the treatment of thyroid eye disease, but growing reports of hearing loss require further investigation. To date, an effective protocol for managing hearing loss in this setting has not been determined. Here, we present the first report of the resolution of teprotumumab-related hearing loss with prompt oral prednisone. A 70-year-old woman on teprotumumab experienced sudden hearing loss and tinnitus after her first infusion. An audiogram demonstrated a mild down-sloping to moderately severe mixed conductive and sensorineural hearing loss that was promptly treated with prednisone 60 mg for 6 days with a 1-week gradual taper. An audiogram 3 weeks later demonstrated return of hearing to normal thresholds, and the whole teprotumumab treatment course was completed without further issue. This case highlights the importance of audiometric monitoring, prompt identification of hearing symptoms, and the potential for oral steroids to reverse teprotumumab-related hearing loss.

Teprotumumab and the Evolving Therapeutic Landscape in Thyroid Eye Disease.

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.

A Survey on the Management of Thyroid Eye Disease Among American and European Thyroid Association Members.

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.

Hearing Dysfunction After Treatment With Teprotumumab for Thyroid Eye Disease.

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.

Thyroid Eye Disease: Navigating the New Treatment Landscape.

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.

Afirma Genomic Sequencing Classifier and Xpression Atlas Molecular Findings in Consecutive Bethesda III-VI Thyroid Nodules.

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.

Thyroid and Fertility: Recent Advances.

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.

Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives.

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.