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Controversies and Current Research The immune system in menopause and infertility Northside Hospital WomenFirst February 26, 2002 Mark Perloe, M.D., mpmd@ivf.com www.ivf.com

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Controversies and Current Research The immune system in menopause and infertility <ul><li>Immunology 101 </li></ul><ul><li>Sex hormones and the immune system </li></ul><ul><li>Pregnancy </li></ul><ul><li>Recurrent pregnancy loss </li></ul><ul><li>Infertility </li></ul><ul><ul><li>Sperm Antibodies </li></ul></ul><ul><ul><li>Endometriosis </li></ul></ul><ul><ul><li>Premature Ovarian Failure </li></ul></ul><ul><li>Getting information </li></ul><ul><li>Evaluating medical research </li></ul>

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Immune Cells <ul><li>Adaptive Immune Response </li></ul><ul><li>Lymphocytes </li></ul><ul><li>B-Cells </li></ul><ul><ul><li>Antibody production </li></ul></ul><ul><li>T-Cells </li></ul><ul><ul><li>Helper/inducer </li></ul></ul><ul><ul><li>Suppressor </li></ul></ul><ul><ul><li>Cytotoxic </li></ul></ul><ul><li>Innate Immune Response </li></ul><ul><li>Phagocytes </li></ul><ul><li>Macrophages </li></ul><ul><li>Neutrophils, basophils, eosinophils, mast cells </li></ul><ul><li>Natural Killer Cells </li></ul><ul><ul><li>Activated & inactivating receptors </li></ul></ul>

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Immune Cells

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Human Leukocyte Antigens HLA <ul><li>Cell surface molecule assists recognition of antigens by T-lymphocytes </li></ul><ul><li>Determines individual tissue typing </li></ul><ul><li>HLA Class I </li></ul><ul><ul><li>A, B, C, G </li></ul></ul><ul><ul><li>CD8+ cytotoxic T cells </li></ul></ul><ul><li>HLA Class II </li></ul><ul><ul><li>DP, DQ, DR </li></ul></ul><ul><ul><li>CD4+ Helper T cells </li></ul></ul><ul><li>T cells recognizing self-antigens undergo apoptosis in thymus </li></ul>

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Cytokines <ul><li>Soluble molecular mediators responsible for many of the intercellular collaborations that take place during the development of the immune response </li></ul><ul><li>Involved in cell growth, differentiation & function </li></ul><ul><li>Short half-life </li></ul><ul><li>Act locally </li></ul>

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Cytokine Response

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Complement <ul><li>Soluble components of the innate immune system </li></ul><ul><ul><li>Enhanced phagocytosis </li></ul></ul><ul><ul><li>Stimulates chemokines and proinflammatory cytokines </li></ul></ul><ul><ul><li>Membrane attack complex leads to cell death </li></ul></ul><ul><li>Triggered by: </li></ul><ul><ul><li>Antigen-antibody complex </li></ul></ul><ul><ul><li>Bacterial cell walls </li></ul></ul>

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Immune System Sexual Dimorphism <ul><li>Males are more susceptible to infection </li></ul><ul><li>Androgens increase susceptibility to infection </li></ul><ul><li>Women 2.7-fold risk to develop autoimmune disorders </li></ul>

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Autoimmune Disorders 20/1 792 Hashimoto’s Thyroiditis 3/1 860 Rheumatoid Arthritis Not known 151 Pernicious Anemia 1/1 192 IDDM 8/1 1152 Grave’s Disease Female-Male Ratio Prevalence Rate/100,000 Disease

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Systemic Lupus Erythematosus <ul><li>Significantly higher risk of pregnancy loss </li></ul><ul><li>Excess loss due to second trimester loss </li></ul><ul><li>Poor prognosis group </li></ul><ul><ul><li>Severe renal insufficiency </li></ul></ul><ul><ul><li>Pre-pregnancy flare or newly diagnosed within 6 m. </li></ul></ul><ul><li>Higher rate of pre-eclampsia & premature delivery </li></ul><ul><li>May worsen during pregnancy </li></ul>

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Role of Sex Steroid Hormone <ul><li>RA improves with pregnancy </li></ul><ul><ul><li>Potential for postpartum flare </li></ul></ul><ul><ul><li>Flares during menopause </li></ul></ul><ul><li>Effect of pregnancy on SLE more variable </li></ul><ul><li>Estrogen accelerates and androgens reduce SLE, Sjögrens’ syndrome & thyroiditis (rodents) </li></ul><ul><li>Effect may vary by subject and organ </li></ul><ul><li>Th2 pregnancy response may reduce Th1 mediated diseases & increase Th2 mediated conditions </li></ul><ul><ul><li>Th1: Multiple sclerosis and rheumatoid arthritis </li></ul></ul><ul><ul><li>Th2: Systemic Lupus Erythematosus </li></ul></ul>

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Estrogen <ul><li>Estrogen </li></ul><ul><ul><li>Promote antibody production </li></ul></ul><ul><ul><li>Alters peripheral T-cell activity ↑CD4+ cells </li></ul></ul><ul><ul><li>Reduce NK cell activity </li></ul></ul><ul><ul><li>Reduces vascular macrophage activity MCP-1 </li></ul></ul><ul><ul><li>Inhibits bone resorption </li></ul></ul><ul><ul><ul><li>Reduces osteoclast stimulation: IL-1, TNF- α , IL-6 </li></ul></ul></ul>

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Progesterone <ul><li>Inhibits lymphocyte activation </li></ul><ul><li>Inhibits killer-T cell generation and activity (PIBF) </li></ul><ul><li>Reduces macrophage proliferation & oxygen free radical generation </li></ul><ul><li>Inhibits peripheral antibody production </li></ul><ul><li>Promotes allograft survival </li></ul><ul><li>Reduces Th1 cytokines </li></ul>

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Androgens <ul><li>Increases cytotoxic CD8+ T cells </li></ul><ul><li>Reduces pre-B cell population in bone marrow </li></ul><ul><li>No effect on peripheral B cells </li></ul><ul><li>Reduce NO synthetase </li></ul><ul><ul><li>Immune defense </li></ul></ul><ul><ul><li>Atherosclerosis </li></ul></ul><ul><li>Decreases macrophage Fc  receptor </li></ul><ul><li>Stimulates Th1 response </li></ul>

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Pregnancy <ul><li>Why didn’t your mother’s body reject you? </li></ul><ul><ul><li>1950 Medawar: maternal-fetal tolerance </li></ul></ul><ul><ul><li>1991 Colbern & Main: maternal-placental tolerance </li></ul></ul>

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Is the pregnant uterus an immune-privileged site? <ul><ul><li>Mechanical barrier to placenta </li></ul></ul><ul><ul><ul><li>Cell traffic exists across placenta in both directions </li></ul></ul></ul><ul><ul><li>Suppression of the maternal immune system during pregnancy </li></ul></ul><ul><ul><ul><li>Maternal antiviral immunity not affected by pregnancy </li></ul></ul></ul><ul><ul><ul><li>Progesterone is immunosuppressive </li></ul></ul></ul><ul><ul><li>Absence of polymorphic MHC class I and II molecules on the placenta (HLA-G is expressed) </li></ul></ul><ul><ul><li>Cytokine shift </li></ul></ul><ul><ul><ul><li>Regulate immune response and control placental growth and implantation </li></ul></ul></ul><ul><ul><li>Local immunosuppression </li></ul></ul><ul><ul><ul><li>Cytokine FAS-FASL induces programmed cell death (apoptosis) in harmful cytotoxic T cells directed against paternally derived HLA antigens </li></ul></ul></ul>

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Pregnancy Loss Prevalence <ul><li>30-40% occult pregnancy loss </li></ul><ul><li>15-20% clinical pregnancy loss </li></ul><ul><li>1-2% recurrent pregnancy loss </li></ul>

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Spectrum of Pregnancy Loss <ul><li>Pre-clinical occult pregnancy loss </li></ul><ul><ul><li>Developmental failure: fertilized egg fails to divide </li></ul></ul><ul><ul><li>Failure to implant: blastocyst does not implant </li></ul></ul><ul><ul><li>Preclinical: failure after implantation </li></ul></ul><ul><li>Clinical loss </li></ul><ul><ul><li>Embryonic: loss before the 9 th week of pregnancy </li></ul></ul><ul><ul><li>Fetal: loss after the 9 th week of pregnancy </li></ul></ul><ul><ul><li>Miscarriage: loss after before the 20 th week of pregnancy </li></ul></ul><ul><ul><li>Stillbirth: loss after 20 weeks </li></ul></ul>

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Recurrent pregnancy loss autoimmunity and pregnancy loss <ul><li>Diagnosis </li></ul><ul><ul><li>Antiphospholipid antibody syndrome ACL, APS, API, APE </li></ul></ul><ul><ul><li>Anti Nuclear Antibodies ANA </li></ul></ul><ul><ul><li>Anti Thyroid Antibodies ATA </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Heparin and baby aspirin </li></ul></ul><ul><ul><li>Prednisone </li></ul></ul><ul><ul><li>IViG </li></ul></ul>

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Recurrent pregnancy loss Alloimmunity: pregnancy as an allograft <ul><li>Immunosuppression in pregnancy </li></ul><ul><ul><li>Role of NK-cells </li></ul></ul><ul><ul><li>TH1 vs. TH2 response </li></ul></ul><ul><ul><li>HLA-G, Progesterone Blocking Factor </li></ul></ul><ul><li>Diagnosis </li></ul><ul><ul><li>Embryo toxic factor </li></ul></ul><ul><ul><li>Immunophenotype and NK-cell activity </li></ul></ul><ul><ul><li>Cytoxicity </li></ul></ul><ul><ul><li>HLA </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>IViG </li></ul></ul><ul><ul><li>LIT </li></ul></ul>

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Antiphospholipid Antibodies & Infertility <ul><li>There is no evidence to suggest that APA are a cause of infertility or IVF failure </li></ul>

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NK-Cells and Infertility

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Sperm Antibodies <ul><li>Causes </li></ul><ul><ul><li>Obstruction of sperm egress </li></ul></ul><ul><ul><li>Testicular trauma </li></ul></ul><ul><ul><li>Sexually transmitted diseases </li></ul></ul><ul><ul><li>Polyglandular autoimmune failure </li></ul></ul><ul><li>Fertility impaired only when a majority of sperm are coated with antibody </li></ul><ul><li>No prospective studies that demonstrate decreased fecundity in couples where sperm Ab are detected </li></ul><ul><li>Present in 3-5% of infertile population </li></ul>

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Sperm Antibodies <ul><li>May inhibit or promote zona binding </li></ul><ul><li>Alter sperm longevity </li></ul><ul><li>Adverse effect on sperm-mucus interaction and sperm transport </li></ul><ul><li>Polyclonal antibodies </li></ul><ul><ul><li>May be specific to an individual </li></ul></ul><ul><ul><li>React to several different sperm proteins/locations </li></ul></ul><ul><li>May be present in serum but not semen </li></ul>

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Cumulative Pregnancy Rates OR….. Will I ever conceive ?

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ICSI maximizes fertilization

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Endometriosis

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Endometriosis

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Endometriosis

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Estrogen & Natural Killer Activity

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Anti-Ovarian Antibodies <ul><li>Indications for testing </li></ul><ul><ul><li>Diminished ovarian reserve </li></ul></ul><ul><ul><li>Poor response to ovulation induction </li></ul></ul><ul><li>What causes AOA? </li></ul><ul><ul><li>Ovarian surgery </li></ul></ul><ul><ul><li>Infection </li></ul></ul><ul><ul><li>Immune system activation </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Medrol therapy </li></ul></ul><ul><ul><li>Oocyte donation </li></ul></ul>

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Internet Resources <ul><li>Where to find information </li></ul><ul><ul><li>National Library of Medicine </li></ul></ul><ul><ul><ul><li>Medline, PubMed </li></ul></ul></ul><ul><ul><li>Expert Chats </li></ul></ul><ul><ul><li>Bulletin Boards & Newsgroups </li></ul></ul><ul><ul><li>Organization Websites </li></ul></ul><ul><ul><li>Mail Lists & eGroups </li></ul></ul><ul><ul><li>Other Websites </li></ul></ul>

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Caveats & Limitations <ul><li>Limitations </li></ul><ul><ul><li>Credentials may not evident </li></ul></ul><ul><ul><li>Financial bias Self promotion </li></ul></ul><ul><ul><li>Dumbing down information provided </li></ul></ul><ul><ul><li>Is material current? </li></ul></ul><ul><ul><li>No two cases are identical </li></ul></ul><ul><li>Keyboard + monitor  Pelvic Exam  Ultrasound </li></ul><ul><li>Evaluating medical literature </li></ul><ul><ul><li>Press and public get access at before physicians! </li></ul></ul>

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Clinical Study Types <ul><li>Experimental Studies </li></ul><ul><ul><li>Randomized Control Trials (RCT) </li></ul></ul><ul><ul><li>Randomized Cross-Over Trial </li></ul></ul><ul><li>Observational Studies </li></ul><ul><ul><li>Cohort (Incidence, Longitudinal) </li></ul></ul><ul><ul><li>Case-Control </li></ul></ul><ul><ul><li>Cross-Sectional (Prevalence) </li></ul></ul><ul><ul><li>Case Series </li></ul></ul><ul><ul><li>Case Report </li></ul></ul>

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Evaluating Medical Studies <ul><li>Validity: Truth </li></ul><ul><ul><li>External Validity: Can the study be generalized to the population of the reader </li></ul></ul><ul><ul><li>Internal Validity: Study is well designed. Results not due to chance, bias or confounding factors </li></ul></ul><ul><ul><li>Symmetry Principle: Groups are similar </li></ul></ul>

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Evaluating Medical Studies <ul><li>Confounding: distortion of the effect of one risk factor by the presence of another </li></ul><ul><li>Bias: Any effect from design, execution, & interpretation that shifts or influences results </li></ul><ul><ul><li>Confounding bias: failure to account for the effect of one or more variables that are not distributed equally </li></ul></ul><ul><ul><li>Measurement bias: measurement methods differ between groups, lack of blinding </li></ul></ul><ul><ul><li>Sampling (selection) bias: design and execution errors in sampling </li></ul></ul><ul><ul><li>Reader/Investigator bias: human tendency to accept information that supports pre-conceived opinions and reject studies that don’t </li></ul></ul><ul><ul><li>Sponsorship bias: studies designed to support sponsors views </li></ul></ul>

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What’s a Meta-analysis? <ul><li>Meta-analysis provides an overview of clinical trials </li></ul><ul><li>Meta-analysis is a set of statistical procedures designed to accumulate experimental and correlational results across independent studies that address a related set of research questions. </li></ul>

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Meta-Analysis <ul><li>Variability in populations </li></ul><ul><li>Variability in study design </li></ul><ul><ul><li>Study quality </li></ul></ul><ul><ul><li>Endpoint reportage </li></ul></ul><ul><ul><li>Availability of data </li></ul></ul><ul><li>Variability in interventions </li></ul>

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Clinical Decision-making <ul><li>What is my RISK ? </li></ul><ul><ul><li>of the event the treatment strives to prevent? </li></ul></ul><ul><ul><li>of the side-effect of treatment? </li></ul></ul><ul><li>What is my chance of RESPONDING? </li></ul><ul><li>What is the treatment’s FEASIBILITY in my MD’s practice/setting? </li></ul><ul><li>What are my VALUES ? </li></ul>