Controversies and Current Research The immune system in menopause and infertility

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

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

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

4. Immune Cells

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

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

7. Cytokine Response

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

9. Immune System Sexual Dimorphism Males are more susceptible to infection Androgens increase susceptibility to infection Women 2.7-fold risk to develop autoimmune disorders

10. Autoimmune Disorders

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

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

13. Estrogen Estrogen Promote antibody production Alters peripheral T-cell activity ?CD4+ cells Reduce NK cell activity Reduces vascular macrophage activity MCP-1 Inhibits bone resorption Reduces osteoclast stimulation: IL-1, TNF-a, IL-6

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

15. Androgens Increases cytotoxic CD8+ T cells Reduces pre-B cell population in bone marrow No effect on peripheral B cells Reduce NO synthetase Immune defense Atherosclerosis Decreases macrophage Fc? receptor Stimulates Th1 response

16. Pregnancy Why didn�t your mother�s body reject you? 1950 Medawar: maternal-fetal tolerance 1991 Colbern & Main: maternal-placental tolerance

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

18. Pregnancy Loss Prevalence 30-40% occult pregnancy loss 15-20% clinical pregnancy loss 1-2% recurrent pregnancy loss

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

20. Recurrent pregnancy loss autoimmunity and pregnancy loss Diagnosis Antiphospholipid antibody syndrome ACL, APS, API, APE Anti Nuclear Antibodies ANA Anti Thyroid Antibodies ATA Treatment Heparin and baby aspirin Prednisone IViG

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

22. Antiphospholipid Antibodies & Infertility There is no evidence to suggest that APA are a cause of infertility or IVF failure

23. NK-Cells and Infertility

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

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

26. Cumulative Pregnancy Rates OR�.. Will I ever conceive?

27. ICSI maximizes fertilization

28. Endometriosis

29. Endometriosis

30. Endometriosis

31. Estrogen & Natural Killer Activity

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

33. Internet Resources Where to find information National Library of Medicine Medline, PubMed Expert Chats Bulletin Boards & Newsgroups Organization Websites Mail Lists & eGroups Other Websites

34. Caveats & Limitations Limitations Credentials may not evident Financial bias Self promotion Dumbing down information provided Is material current? No two cases are identical Keyboard + monitor � Pelvic Exam + Ultrasound Evaluating medical literature Press and public get access at before physicians!

35. Clinical Study Types Experimental Studies Randomized Control Trials (RCT) Randomized Cross-Over Trial Observational Studies Cohort (Incidence, Longitudinal) Case-Control Cross-Sectional (Prevalence) Case Series Case Report Assignment of individuals is randomized RCT: Individuals similar at the beginning RCOT: Prospective analytical, susceptible to bias if carry over effects occur Observational: allocation or assignement is not under investigator control; weaker potential evidence; potential for large confounding variables Cohort: prospective, follow-up period to determine effect of exposure and outcome, stronger than case-control but more expensive Case-Control: retrospective, secondary data from chart review, useful for rare conditions, inexpensive, many forms of bias Cross-Sectional: descriptive study of relationship between factors at one point in time Case-Series: series of cases, lack of comparability, source of hypothesis, most common study type Case-Report: anecdotal evidence, Assignment of individuals is randomized RCT: Individuals similar at the beginning RCOT: Prospective analytical, susceptible to bias if carry over effects occur Observational: allocation or assignement is not under investigator control; weaker potential evidence; potential for large confounding variables Cohort: prospective, follow-up period to determine effect of exposure and outcome, stronger than case-control but more expensive Case-Control: retrospective, secondary data from chart review, useful for rare conditions, inexpensive, many forms of bias Cross-Sectional: descriptive study of relationship between factors at one point in time Case-Series: series of cases, lack of comparability, source of hypothesis, most common study type Case-Report: anecdotal evidence,

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

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

38. What�s a Meta-analysis? Meta-analysis provides an overview of clinical trials 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.

39. Meta-Analysis Variability in populations Variability in study design Study quality Endpoint reportage Availability of data Variability in interventions

40. Clinical Decision-making What is my RISK ? of the event the treatment strives to prevent? of the side-effect of treatment? What is my chance of RESPONDING? What is the treatment�s FEASIBILITY in my MD�s practice/setting? What are my VALUES ?