Dr. Dosiou specializes in the treatment of patients with thyroid disease. She has a special interest in the evaluation and treatment of thyroid disease in the setting of pregnancy and the care of patients with thyroid-eye disease.
- Thyroid Dysfunction in Pregnancy
- Graves' Disease
- Thyroid eye disease
- Diabetes and Metabolism
Clinical Professor, Medicine - Endocrinology, Gerontology, & Metabolism
Medical Director, Thyroid Eye Clinic, Stanford University School of Medicine (2009 - Present)
Program Director, Endocrinology Fellowship, Stanford University School of Medicine (2014 - Present)
Fellowship: Stanford University Endocrinology Fellowship (2003) CA
Fellowship: Stanford University Hematology and Oncology Fellowship (2001) CA
Residency: UCSF Department of Medicine (2000) CA
Internship: UCSF Department of Medicine (1998) CA
Board Certification: American Board of Internal Medicine, Endocrinology, Diabetes and Metabolism (2003)
Medical Education: Harvard Medical School (1997) MA
MS, Stanford University, Epidemiology (2006)
BA, Harvard College, Biology (1993)
MD, Harvard Medical School, Medicine (1997)
Current Research and Scholarly Interests
I am highly interested in the interactions between the endocrine and immune systems in women. Current clinical research interests lie in the field of autoimmune thyroid disease, especially thyroid autoimmunity in pregnancy.
Graduate and Fellowship Programs
Endocrinology (Fellowship Program)
- NTRK, RET, BRAF, and ALK fusions in thyroid fine-needle aspirates (FNAs). LIPPINCOTT WILLIAMS & WILKINS. 2021
Afirma Genomic Sequencing Classifier & Xpression Atlas Molecular Findings in Consecutive Bethesda III-VI Thyroid Nodules.
The Journal of clinical endocrinology and metabolism
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: CLIA laboratory performing Afirma Genomic Sequencing Classifier (GSC) and Xpression Atlas (XA) testing.PARTICIPANTS: 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 non-invasive follicular thyroid neoplasm with papillary-like nuclear features was >95%, while for BRAF and ALK fusions it was 81% and 67%, respectively. At least one 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 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.
View details for DOI 10.1210/clinem/dgab304
View details for PubMedID 34009369
Thyroid Eye Disease: Navigating the New Treatment Landscape.
Journal of the Endocrine Society
2021; 5 (5): bvab034
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.
View details for DOI 10.1210/jendso/bvab034
View details for PubMedID 33948524
Thyroid and Fertility: Recent Advances.
Thyroid : official journal of the American Thyroid Association
BACKGROUND: Thyroid disease is quite prevalent in women of reproductive age, while infertility is common in women with thyroid dysfunction. In this study we will review the recent advances in the field of thyroid and fertility since the publication of the 2017 American Thyroid Association (ATA) pregnancy guidelines.SUMMARY: Recent studies have confirmed associations of thyroid-stimulating hormone (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 on 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.
View details for DOI 10.1089/thy.2019.0382
View details for PubMedID 31903865
Teprotumumab for Dysthyroid Optic Neuropathy: Early Response to Therapy.
Ophthalmic plastic and reconstructive surgery
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.
View details for DOI 10.1097/IOP.0000000000001831
View details for PubMedID 32976335
THE GUIDED TRANSFER OF CARE IMPROVES ADULT CLINIC SHOW RATE.
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
Objective Every year 500,000 youths in the U.S. with chronic disease turn 18 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 non-randomized cohort study of patients with pediatric endocrine conditions, age 16-26 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 = 0.0001). Subgroup analysis of 27 patients with diabetes revealed that both groups had similar initial HbA1c (p = 0.38) and the guided transfer group maintained HbA1c. Conclusions 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.
View details for DOI 10.4158/EP-2019-0470
View details for PubMedID 32045296
A Novel G385E Variant in the Cold Region of the T3-Binding Domain of Thyroid Hormone Receptor Beta Gene and Investigations to Assess Its Clinical Significance.
European thyroid journal
2019; 8 (6): 293–97
Background: Resistance to thyroid hormone beta (RTHbeta) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene (THRB) defects. Most mutations producing RTHbeta phenotype are located in CG-rich regions of THRB, encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384-425 is virtually devoid of RTHbeta-causing mutations, termed "cold region."Case: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated. During LT4 treatment she had slightly elevated free thyroxine and TSH levels, suggesting the possibility of RTHbeta.Results: Sequencing of THRB identified a heterozygous missense variant c.1154G>A producing p.G385E in the proband. Since this variant of unknown significance (VUS) has not been reported in RTHbeta individuals and considering its location in the "cold region" of THRB, we questioned its relevance. In silico functional prediction algorithms showed conflicting results: PolyPhen-2 predicted this VUS to be probably damaging with a score of 1.000, while SIFT predicted it to be tolerated with a score of 0.07, thus making additional investigations necessary. Genotyping of family members revealed that the proband's mother and sister, without RTHbeta phenotype, also harbored the same variant. This indicates that the THRB G385E variant is unlikely to manifest RTHbeta phenotype and confirms its "cold" status.Conclusions: This study illustrates that assigning causality of a THRB VUS for RTHbeta based only on in silico prediction algorithms is not always fully reliable. Additional phenotype-genotype segregation in family members can assist in predicting functional consequences of missense mutations.
View details for DOI 10.1159/000503860
View details for PubMedID 31934554
- The TABLET trial: limitations and implications. BMC medicine 2019; 17 (1): 126
- The Guided Transition of Care AMER DIABETES ASSOC. 2019
Radioactive iodine in differentiated thyroid cancer: a national database perspective.
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 2004-2012 and Surveillance, Epidemiology, and End Results (SEER) database from 1992-2009 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.
View details for DOI 10.1530/ERC-19-0292
View details for PubMedID 31443087
Diagnostic 123I Whole Body Scan Prior to Ablation of Thyroid Remnant in Patients With Papillary Thyroid Cancer: Implications for Clinical Management
CLINICAL NUCLEAR MEDICINE
2018; 43 (10): 705–9
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.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.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).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.
View details for PubMedID 30153149
2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum.
2017; 27 (3): 315-389
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.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.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.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.
View details for DOI 10.1089/thy.2016.0457
View details for PubMedID 28056690
CHALLENGE TO THE PARADIGM OF PRENATAL TESTOSTERONE EXPOSURE ON GENDER IDENTITY DEVELOPMENT
KARGER. 2017: 478
View details for Web of Science ID 000412595405113
MANAGEMENT OF ENDOCRINE DISEASE Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns
EUROPEAN JOURNAL OF ENDOCRINOLOGY
2017; 176 (1): R21-R38
Isolated maternal hypothyroxinemia (IMH) during pregnancy is defined as a low maternal T4 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.
View details for DOI 10.1530/EJE-16-0354
View details for Web of Science ID 000391957300003
Development of prognostic signatures for intermediate-risk papillary thyroid cancer.
2016; 16 (1): 736-?
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.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.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.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.
View details for DOI 10.1186/s12885-016-2771-6
View details for PubMedID 27633254
Craniosynostosis and risk factors related to thyroid dysfunction.
American journal of medical genetics. Part A
2015; 167A (4): 701-707
Thyroid disease is a common problem among women of reproductive age but often goes undiagnosed. Maternal thyroid disease has been associated with increased risk of craniosynostosis. We hypothesized that known risk factors for thyroid disease would be associated with risk of craniosynostosis among women not diagnosed with thyroid disease. Analyses included mothers of 1,067 cases and 8,494 population-based controls who were interviewed for the National Birth Defects Prevention Study. We used multivariable logistic regression to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). After excluding women with diagnosed thyroid disease, younger maternal age (AOR 0.7, 95% CI 0.6-0.9, for <25 years versus 25-29), black or other race-ethnicity (AOR 0.3, 95% CI 0.2-0.4 and AOR 0.6, 95% CI 0.4-0.8, respectively, relative to non-Hispanic whites), fertility medications or procedures (AOR 1.5, 95% CI 1.2-2.0), and alcohol consumption (AOR 0.8, 95% CI 0.7-0.9) were associated with risk of craniosynostosis, based on confidence intervals that excluded 1.0. These associations with craniosynostosis are consistent with the direction of their association with thyroid dysfunction (i.e., younger age, black race-ethnicity and alcohol consumption are associated with reduced risk and fertility problems are associated with increased risk of thyroid disease). This study thus provides support for the hypothesis that risk factors associated with thyroid dysfunction are also associated with risk of craniosynostosis. Improved understanding of the potential association between maternal thyroid function and craniosynostosis among offspring is important given that craniosynostosis carries significant morbidity and that thyroid disease is under-diagnosed and potentially modifiable. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36953
View details for PubMedID 25655789
Continued rapid increase in thyroid cancer incidence in california: trends by patient, tumor, and neighborhood characteristics.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
2014; 23 (6): 1067-1079
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.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].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.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.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.
View details for DOI 10.1158/1055-9965.EPI-13-1089
View details for PubMedID 24842625
Cost-Effectiveness of Universal and Risk-Based Screening for Autoimmune Thyroid Disease in Pregnant Women
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2012; 97 (5): 1536-1546
Hypothyroidism in pregnancy can lead to adverse maternal and fetal outcomes. Although screening of high-risk women is advocated, universal screening remains controversial.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.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.Medical consequences of AITD in pregnancy, QALY, and costs were measured.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.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.
View details for DOI 10.1210/jc.2011-2884
View details for Web of Science ID 000303915900044
View details for PubMedID 22399510
Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis
EUROPEAN JOURNAL OF ENDOCRINOLOGY
2008; 158 (6): 841-851
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.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.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.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.Screening all pregnant women for autoimmune thyroid disease in the first trimester is cost-effective compared with not screening.
View details for DOI 10.1530/EJE-07-0882
View details for Web of Science ID 000256812800009
View details for PubMedID 18505905
Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone
JOURNAL OF ENDOCRINOLOGY
2008; 196 (1): 67-77
Although there is significant evidence for progesterone's role as an immunomodulator, nuclear progesterone receptors have not been consistently identified in immune cells. Recently, three new putative membrane progesterone receptors (mPRs), mPRalpha, mPRbeta, and mPRgamma have been described. The objective of this study was to examine whether mPRs are expressed in peripheral blood leukocytes (PBLs) in women of reproductive age, and to further characterize them in T lymphocytes and immortalized T cells (Jurkat cells). Transcripts for mPRalpha and mPRbeta but not mPRgamma, were detected by RT-PCR in PBLs, T lymphocytes, and Jurkat cells. Western blot analysis showed the presence of the mPRalpha and mPRbeta proteins on cell membranes of T lymphocytes and Jurkat cells. Expression of the mPRalpha mRNA was upregulated in the luteal phase of the menstrual cycle in cluster of differentiation (CD)8+, but not in CD4+, T lymphocytes. Radioreceptor assays revealed specific [(3)H]progesterone binding to T- and Jurkat cell membranes (K(d) 4.25 nM) characteristic of steroid membrane receptors. Progesterone activated an inhibitory G-protein (G(i)), suggesting that mPRs are coupled to G(i) in Jurkat cells. These results suggest a potential novel mechanism for progesterone's immunoregulatory function through activation of mPRs.
View details for DOI 10.1677/JOE-07-0317
View details for PubMedID 18180318
Decidual stromal cell response to paracrine signals from the trophoblast: Amplification of immune and angiogenic modulators
BIOLOGY OF REPRODUCTION
2007; 76 (1): 102-117
During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.
View details for DOI 10.1095/biolreprod.106.054791
View details for Web of Science ID 000243057200013
View details for PubMedID 17021345
Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women
2006; 147 (3): 1097-1121
Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping (54,600 genes and expressed sequence tags) of this tissue sampled across the cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. Unsupervised principal component analysis of all samples revealed that samples self-cluster into four groups consistent with histological phenotypes of proliferative (PE), early-secretory (ESE), mid-secretory (MSE), and late-secretory (LSE) endometrium. Independent hierarchical clustering analysis revealed equivalent results, with two major dendrogram branches corresponding to PE/ESE and MSE/LSE and sub-branching into the four respective phases with heterogeneity among samples within each sub-branch. K-means clustering of genes revealed four major patterns of gene expression (high in PE, high in ESE, high in MSE, and high in LSE), and gene ontology analysis of these clusters demonstrated cycle-phase-specific biological processes and molecular functions. Six samples with ambiguous histology were identically assignable to a cycle phase by both principal component analysis and hierarchical clustering. Additionally, pairwise comparisons of relative gene expression across the cycle revealed genes/families that clearly distinguish the transitions of PE-->ESE, ESE-->MSE, and MSE-->LSE, including receptomes and signaling pathways. Select genes were validated by quantitative RT-PCR. Overall, the results demonstrate that endometrial samples obtained by two different sampling techniques (biopsy and curetting hysterectomy specimens) from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods. Also, the results enable global identification of biological processes and molecular mechanisms that occur dynamically in the endometrium in the changing steroid hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore the potential of gene expression profiling for developing molecular diagnostics of endometrial normalcy and abnormalities and identifying molecular targets for therapeutic purposes in endometrial disorders.
View details for DOI 10.1210/en.2005-1075
View details for Web of Science ID 000235350100008
View details for PubMedID 16306079
Natural killer cells in pregnancy and recurrent pregnancy loss: Endocrine and immunologic perspectives
2005; 26 (1): 44-62
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.
View details for DOI 10.1210/er.2003-0021
View details for Web of Science ID 000226748400002
View details for PubMedID 15689572
The immune environment in human endometrium during the window of implantation
AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
2004; 52 (4): 244-251
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.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.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.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.
View details for Web of Science ID 000224562200003
View details for PubMedID 15494045
Silencing lamin A/C in human endometrial stromal cells: a model to investigate endometrial gene function and regulation
MOLECULAR HUMAN REPRODUCTION
2004; 10 (10): 705-711
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.
View details for DOI 10.1093/molehr/gah105
View details for Web of Science ID 000223945600001
View details for PubMedID 15347737
Interferon-related and other immune genes are downregulated in peripheral blood leukocytes in the luteal phase of the menstrual cycle
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2004; 89 (5): 2501-2504
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.
View details for DOI 10.1210/jc.2003-031647
View details for Web of Science ID 000221220100076
View details for PubMedID 15126584
B7-1 is superior to B7-2 costimulation in the induction and maintenance of T cell-mediated antileukemia immunity - Further evidence that B7-1 and B7-2 are functionally distinct
JOURNAL OF IMMUNOLOGY
1996; 156 (3): 1126-1131
Although intact, viable tumor cells rarely induce a clinically significant immune response in vivo, immunogenicity can be elicited by irradiated tumor cells that protect against subsequent challenge with wild-type intact viable tumor cells. Genetic modification of murine tumor cells, by transfection of cDNAs encoding either cytokines, MHC molecules, or costimulatory molecules, has been capable of inducing antitumor immunity. We and others have previously demonstrated that expression of the B7-1 costimulatory molecule, in either immunogenic or nonimmunogenic tumors, can protect against subsequent challenge with wild-type tumor cells. In this work, using a murine model of acute myeloid leukemia, we demonstrate that the B7-1 costimulatory molecule is superior to the B7-2 molecule in its capacity to protect against wild-type tumor challenge and eradicate minimal residual disease. These results provide compelling evidence that the B7-1 and B7-2 costimulatory signals are functionally distinct, thus resulting in clinically significant differences in the induction of antitumor immunity in vivo.
View details for Web of Science ID A1996TR32700031
View details for PubMedID 8557988
ROLE OF B7-1 IN MEDIATING AN IMMUNE-RESPONSE TO MYELOID-LEUKEMIA CELLS
1995; 85 (9): 2507-2515
A costimulatory signal from B7-1 (CD80) to its counter-receptor CD28 is required for T-cell activation. Many tumors, including most human leukemias, lack expression of B7-1, and this has been suggested to contribute to the failure of immune recognition of these diseases. A murine leukemia model system was developed to assess the potential role of B7-1 in the induction immunity to leukemia cells. The nonleukemic 32Dc13 myeloid cell line was transformed by transfection of the BCR/ABL gene, generating a subline (32Dp210/clone 26) that was leukemic and rapidly lethal to syngeneic, immunocompetent C3H/HeJ mice or T-cell-deficient nude mice. B7-1-modified leukemic cells remained lethal in nude mice, but caused only a transient, nonlethal leukemia in C3H/HeJ mice. After a single exposure to live, nonirradiated B7-1-modified leukemic cells, C3H/HeJ mice developed protective immunity against subsequent challenge with B7-1(-) leukemic cells. Further, hyperimmunization with B7-1(+) leukemic cells prolonged the survival of mice previously injected with a lethal number of B7-1(-) leukemic cells. These results indicate that myeloid leukemic cells may be attractive candidates for B7-1 gene transfer.
View details for Web of Science ID A1995QW60200027
View details for PubMedID 7537118
A POPULATION OF EARLY FETAL THYMOCYTES EXPRESSING FC-GAMMA-RII/III CONTAINS PRECURSORS OF LYMPHOCYTES-T AND NATURAL-KILLER-CELLS
1992; 69 (1): 139-150
We have identified a dominant fetal thymocyte population at day 14.5 of gestation in the mouse that lacks CD4 and CD8 but expresses Fc gamma RII/III several days prior to acquisition of the T cell receptor (TCR) in vivo. If maintained in a thymic microenvironment, this population of CD4-CD8-TCR-Fc gamma RII/III+ thymocytes differentiates first into CD4+CD8+TCRlowFc gamma RII/III- thymocytes and subsequently CD4+CD8-TCRhighFc gamma RII/III- and CD4-CD8+TCRhighFc gamma RII/III- mature Ti alpha-beta lineage T cells. However, if removed from the thymus, the CD4-CD8-TCR-Fc gamma RII/III+ thymocyte population selectively generates functional natural killer (NK) cells in vivo as well as in vitro. These findings show that a cellular pool of Fc gamma RII/III+ precursors gives rise to T and NK lineages in a microenvironment-dependent manner. Moreover, they suggest a hitherto unrecognized role for Fc receptors on primitive T cells.
View details for Web of Science ID A1992HM44500013
View details for PubMedID 1532536