400 likes | 513 Views
Controversies and Current Research The immune system in menopause and infertility. Immunology 101Sex hormones and the immune systemPregnancyRecurrent pregnancy lossInfertilitySperm AntibodiesEndometriosisPremature Ovarian FailureGetting informationEvaluating medical research. Immune Cells
E N D
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, Sjgrens 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 didnt your mothers 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 dont
Sponsorship bias: studies designed to support sponsors views
38. Whats 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 treatments FEASIBILITY in my MDs practice/setting?
What are my VALUES ?