Controversies and Current Controversies and Current Research Research The immune system in menopause and The immune system in menopause and infertility infertility Northside Hospital WomenFirst February 26, 2002 Mark Perloe, M.D., [email protected]www.ivf.com
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Controversies and Current ResearchControversies and Current Research The immune system in menopause and infertilityThe immune system in menopause and infertility
Controversies and Current ResearchControversies and Current Research The immune system in menopause and infertilityThe immune system in menopause and infertility
Immunology 101Sex hormones and the immune systemPregnancyRecurrent pregnancy lossInfertility– Sperm Antibodies– Endometriosis– Premature Ovarian Failure
Human Leukocyte Antigens Human Leukocyte Antigens HLAHLA
Cell surface molecule assists recognition of antigens by T-lymphocytesDetermines individual tissue typingHLA 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
CytokinesCytokines
Soluble molecular mediators responsible for many of the intercellular collaborations that take place during the development of the immune responseInvolved in cell growth, differentiation & functionShort half-life Act locally
Cytokine ResponseCytokine Response
ComplementComplement
Soluble components of the innate immune system– Enhanced phagocytosis– Stimulates chemokines and proinflammatory cytokines– Membrane attack complex leads to cell death
Significantly higher risk of pregnancy lossExcess loss due to second trimester lossPoor prognosis group– Severe renal insufficiency– Pre-pregnancy flare or newly diagnosed within 6 m.
Higher rate of pre-eclampsia & premature deliveryMay worsen during pregnancy
Role of Sex Steroid HormoneRole of Sex Steroid Hormone
RA improves with pregnancy– Potential for postpartum flare– Flares during menopause
Effect of pregnancy on SLE more variableEstrogen accelerates and androgens reduce SLE, Sjögrens’ syndrome & thyroiditis (rodents)Effect may vary by subject and organTh2 pregnancy response may reduce Th1 mediated diseases & increase Th2 mediated conditions– Th1: Multiple sclerosis and rheumatoid arthritis– Th2: Systemic Lupus Erythematosus
Increases cytotoxic CD8+ T cellsReduces pre-B cell population in bone marrowNo effect on peripheral B cellsReduce NO synthetase– Immune defense– Atherosclerosis
Decreases macrophage Fc receptorStimulates Th1 response
PregnancyPregnancy
Why didn’t your mother’s body reject you?– 1950 Medawar: maternal-fetal tolerance– 1991 Colbern & Main: maternal-placental tolerance
Is the pregnant uterus an Is the pregnant uterus an immune-privileged site?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
Pregnancy Loss Pregnancy Loss PrevalencePrevalence
30-40% occult pregnancy loss15-20% clinical pregnancy loss1-2% recurrent pregnancy loss
Spectrum of Pregnancy LossSpectrum 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
Recurrent pregnancy lossRecurrent pregnancy loss autoimmunity and pregnancy lossautoimmunity 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
Recurrent pregnancy lossRecurrent pregnancy loss Alloimmunity: pregnancy as an allograftAlloimmunity: pregnancy as an allograft
Immunosuppression in pregnancy– Role of NK-cells– TH1 vs. TH2 response– HLA-G, Progesterone Blocking Factor
Fertility impaired only when a majority of sperm are coated with antibodyNo prospective studies that demonstrate decreased fecundity in couples where sperm Ab are detectedPresent in 3-5% of infertile population
Sperm AntibodiesSperm Antibodies
May inhibit or promote zona bindingAlter sperm longevityAdverse effect on sperm-mucus interaction and sperm transportPolyclonal antibodies– May be specific to an individual– React to several different sperm proteins/locations
May be present in serum but not semen
Cumulative Pregnancy RatesCumulative Pregnancy Rates OR….. Will I ever conceiveOR….. Will I ever conceive??
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
Internet ResourcesInternet Resources
Where to find information– National Library of
Medicine• Medline, PubMed
– Expert Chats – Bulletin Boards &
Newsgroups– Organization Websites– Mail Lists & eGroups– Other Websites
Caveats & LimitationsCaveats & 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 ExamUltrasoundEvaluating medical literature– Press and public get access at before physicians!
Clinical Study TypesClinical 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
Evaluating Medical StudiesEvaluating 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
Evaluating Medical StudiesEvaluating Medical Studies
Confounding: distortion of the effect of one risk factor by the presence of anotherBias: 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
What’s a Meta-analysis?What’s a Meta-analysis?
Meta-analysis provides an overview of clinical trialsMeta-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.
Meta-AnalysisMeta-Analysis
Variability in populationsVariability in study design– Study quality– Endpoint reportage– Availability of data
Variability in interventions
Clinical Decision-makingClinical 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 ?