Bio

Clinical Focus


  • Parathyroid Diseases
  • Hyperparathyroidism
  • Thyroid Dysfunction in Pregnancy
  • Endocrinology
  • Thyroid Nodules
  • Graves' Disease
  • Diabetes andMetabolism
  • Hyperthyroidism

Academic Appointments


Professional Education


  • Board Certification: Endocrinology, Diabetes andMetabolism, American Board of Internal Medicine (2003)
  • Fellowship:Stanford University School of Medicine (2003) CA
  • Residency:UCSF School of Medicine (2000) CA
  • Fellowship:Stanford University School of Medicine (2001) CA
  • Internship:UCSF School of Medicine (1998) CA
  • Medical Education:Harvard Medical School (1997) MA
  • MS, Stanford University, Epidemiology (2006)
  • BA, Harvard College, Biology (1993)
  • MD, Harvard Medical School, Medicine (1997)

Research & Scholarship

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.

Teaching

2013-14 Courses


Publications

Journal Articles


  • Cost-Effectiveness of Universal and Risk-Based Screening for Autoimmune Thyroid Disease in Pregnant Women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Dosiou, C., Barnes, J., Schwartz, A., Negro, R., Crapo, L., Stagnaro-Green, A. 2012; 97 (5): 1536-1546

    Abstract

    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 Dosiou, C., Sanders, G. D., Araki, S. S., Crapo, L. M. 2008; 158 (6): 841-851

    Abstract

    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 Dosiou, C., Hamilton, A. E., Pang, Y., Overgaard, M. T., Tulac, S., Dong, J., Thomas, P., Giudice, L. C. 2008; 196 (1): 67-77

    Abstract

    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 Web of Science ID 000252803000007

    View details for PubMedID 18180318

  • Decidual stromal cell response to paracrine signals from the trophoblast: Amplification of immune and angiogenic modulators BIOLOGY OF REPRODUCTION Hess, A. P., Hamilton, A. E., Talbi, S., Dosiou, C., Nyegaard, M., Nayak, N., Genbecev-Krtolica, O., Mavrogianis, P., Ferrer, K., Kruessel, J., Fazleabas, A. T., Fisher, S. J., Giudice, L. C. 2007; 76 (1): 102-117

    Abstract

    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 ENDOCRINOLOGY Talbi, S., Hamilton, A. E., Vo, K. C., Tulac, S., Overgaard, M. T., Dosiou, C., Le Shay, N., Nezhat, C. N., Kempson, R., Lessey, B. A., Nayak, N. R., Giudice, L. C. 2006; 147 (3): 1097-1121

    Abstract

    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 ENDOCRINE REVIEWS Dosiou, C., Giudice, L. C. 2005; 26 (1): 44-62

    Abstract

    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 Lobo, S. C., Huang, S. T., Germeyer, A., Dosiou, C., Vo, K. C., Tulac, S., Nayak, N. R., Giudice, L. C. 2004; 52 (4): 244-251

    Abstract

    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 Tulac, S., Dosiou, C., Suchanek, E., Giudice, L. C. 2004; 10 (10): 705-711

    Abstract

    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 Dosiou, C., Lathi, R. B., Tulac, S., Huang, S. T., Giudice, L. C. 2004; 89 (5): 2501-2504

    Abstract

    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 Matulonis, U., Dosiou, C., Freeman, G., Lamont, C., Mauch, P., Nadler, L. M., Griffin, L. D. 1996; 156 (3): 1126-1131

    Abstract

    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 BLOOD Matulonis, U. A., Dosiou, C., Lamont, C., Freeman, G. J., Mauch, P., Nadler, L. M., GRIFFIN, J. D. 1995; 85 (9): 2507-2515

    Abstract

    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 CELL Rodewald, H. R., Moingeon, P., Lucich, J. L., Dosiou, C., Lopez, P., REINHERZ, E. L. 1992; 69 (1): 139-150

    Abstract

    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

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