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      Possible Role of Autoimmunity in Patients with Premature Ovarian Insufficiency

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          Abstract

          Background:

          To evaluate the involvement of immune abnormality in patients with idiopathic premature ovarian insufficiency (POI). In addition to the known etiology, autoimmune disorders may be a pathologic mechanism for POI.

          Materials and Methods:

          Our study was a prospective controlled trial. Twenty women with POI, reasons other than autoimmune excluded, were enrolled in this study. The control group consisted of 17 healthy women. In both groups, family and personal history were taken and the levels of follicle stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, prolactin, anti-Müllerian hormone, inhibin B, antithyroglobulin and antithyroid peroxidase antibodies were determined. Antiovarian antibodies and subpopulations of peripheral blood T-lymhocytes were also determined.

          Results:

          Participants in the study group exhibited hypergonadotropichypogonadism, while high levels of follicle stimulating hormone and low levels of inhibin B and anti-Müllerian hormone were observed. In 16 (80%) patients, POI was associated in their personal and familial history with another autoimmune disease. Fifty percent of patients presented highly elevated antithyroid antibodies. The lymphocyte subset, especially B cells, was significantly higher (p=0.014), and peripheral regulatory lymphocytes CD25+ high were significantly lower (p=0.015) in the study group than in the control group. Anti- ovarian antibodies were detected in 20% of patients with POI.

          Conclusion:

          We presume that the presence of anti-ovarian antibodies together with abnormalities of cellular immunity may in some cases potentially represent the involvement of an autoimmune mechanism in idiopathic POI.

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          Most cited references69

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          Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study.

          The aim of this study was to assess which of the basal ovarian reserve markers provides the best reflection of the changes occurring in ovarian function over time (i.e., reproductive aging). Prospective longitudinal study. Healthy volunteers in an academic research center. Eighty-one women with normal reproductive performance during the course of their lives were longitudinally assessed. In this select group of women, becoming chronologically older was considered as a proxy variable for becoming older from a reproductive point of view. The women were assessed twice, with on average a 4-year interval (T(1) and T(2)). The number of antral follicles on ultrasound (AFC) and blood levels of antimullerian hormone (AMH), FSH, inhibin B, and E(2) were assessed. Longitudinal changes of the markers mentioned and the consistency of these parameters over time. The mean ages at T(1) and T(2) were 39.6 and 43.6 years, respectively. Although AFC was strongly associated with age in a cross-sectional fashion, it did not change over time. The AMH, FSH, and inhibin B levels showed a significant change over time, in contrast to E(2) levels. The AMH and AFC were highly correlated with age both at T(1) and T(2), whereas FSH and inhibin B predominantly changed in women more than 40 years of age. To assess the consistency of these parameters over time, we investigated whether a woman's individual level above or below the mean of her age group at T(1) remained above or below the mean of her age group at T(2). Serum AMH concentrations showed the best consistency, with AFC as second best. The FSH and inhibin B showed only modest consistency, whereas E(2) showed no consistency at all. These results indicate that serum AMH represents the best endocrine marker to assess the age-related decline of reproductive capacity.
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            CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game.

            Regulatory T cells (Treg) play a dominant role in suppression of autoimmune pathology, as rescue of Treg number and/or function in model systems can both prevent and reverse disease. These findings have generated a series of studies addressing the role of defects in Treg number and function in human autoimmunity. However, demonstrating global defects in Treg of individuals diagnosed with autoimmune diseases has been challenging. These challenges are founded, in part, in the complexity of human autoimmune diseases in which various genetic factors and environmental triggers contribute to disease susceptibility. Moreover, contribution of failed Treg-mediated suppression to pathogenesis can extend to multiple mechanisms. In this article, we discuss what is known with respect to the number and function of CD4(+)FOXP3(+) Treg in human autoimmunity, focusing on representative autoimmunediseases in which there are diverse Treg-mediated defects. We also highlight the need to better understand Treg plasticity and function in the context of autoimmunity.
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              Premature ovarian failure and ovarian autoimmunity.

              Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oöphoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oöphoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by the immune system will lead to new approaches in the treatment of infertility of these patients. There are already a few reports on a successful ovulation-inducing treatment of selected POF patients (those with other autoimmune phenomena) with immunomodulating therapies, such as high dosages of corticosteroids (288-292).
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                Author and article information

                Journal
                Int J Fertil Steril
                Int J Fertil Steril
                Royan Institute
                International Journal of Fertility & Sterility
                Royan Institute
                2008-076X
                2008-0778
                Jan-Mar 2014
                22 December 2013
                : 7
                : 4
                : 281-290
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana, Slovenia
                [2 ]Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
                [3 ]Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
                Author notes
                * Corresponding Address: Department of Obstetrics and GynecologyUniversity Medical Centre Ljubljana Šlajmerjeva 3SI-1000 LjubljanaSlovenia Email: renata.kosir@ 123456inbox.com
                Article
                Int-J-Fertil-Steril-7-281
                3901183
                24520498
                c48d68ce-5a0b-4864-9af5-f31d540b523e
                Any use, distribution, reproduction or abstract of this publication in any medium, with the exception of commercial purposes, is permitted provided the original work is properly cited

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 17 November 2012
                : 7 April 2013
                Categories
                Original Article
                Immunology
                Gynecology and Female Infertility
                Custom metadata
                Košir Pogačnik R, Meden Vrtovec H, Vizjak A, Uršula Levičnik A, Slabe N, Ihan A. Possible role of autoim- munity in patients with premature ovarian insufficiency. Int J Fertil Steril. 2014; 7(4): 281-290.

                t-lymphocyte,premature ovarian insufficiency,cell immunity,thyroid stimulating antibody,autoantibody

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