Controversies and Current ResearchControversies and Current Research The immune system in menopause and infertilityThe immune system in menopause and infertility

Northside Hospital WomenFirstFebruary 26, 2002

Mark Perloe, M.D., mpmd@ivf.com www.ivf.com

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

Getting informationEvaluating medical research

Immune CellsImmune Cells

Adaptive Immune Response

LymphocytesB-Cells– Antibody production

T-Cells– Helper/inducer– Suppressor– Cytotoxic

Innate Immune Response

Phagocytes

MacrophagesNeutrophils, basophils, eosinophils, mast cellsNatural Killer Cells– Activated & inactivating

receptors

Immune CellsImmune Cells

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

Triggered by:– Antigen-antibody complex– Bacterial cell walls

Immune System Immune System Sexual DimorphismSexual Dimorphism

Males are more susceptible to infectionAndrogens increase susceptibility to infectionWomen 2.7-fold risk to develop autoimmune disorders

Autoimmune DisordersAutoimmune Disorders

Disease Prevalence Rate/100,000

Female-Male Ratio

Grave’s Disease 1152 8/1

IDDM 192 1/1

Pernicious Anemia 151 Not known

Rheumatoid Arthritis 860 3/1

Hashimoto’s Thyroiditis

792 20/1

Systemic Lupus ErythematosusSystemic Lupus Erythematosus

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

EstrogenEstrogen

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-α, IL-6

ProgesteroneProgesterone

Inhibits lymphocyte activationInhibits killer-T cell generation and activity (PIBF)Reduces macrophage proliferation & oxygen free radical generationInhibits peripheral antibody productionPromotes allograft survivalReduces Th1 cytokines

AndrogensAndrogens

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

Diagnosis– Embryo toxic factor– Immunophenotype and NK-cell activity– Cytoxicity – HLA

Treatment– IViG– LIT

Antiphospholipid Antibodies & InfertilityAntiphospholipid Antibodies & Infertility

There is no evidence to suggest that APA are a cause of infertility or IVF failure

NK-Cells and InfertilityNK-Cells and Infertility

Sperm AntibodiesSperm 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 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??

ICSI maximizes fertilizationICSI maximizes fertilization

Endometriosis Endometriosis

EndometriosisEndometriosis

EndometriosisEndometriosis

Estrogen & Natural Killer ActivityEstrogen & Natural Killer Activity

Anti-Ovarian AntibodiesAnti-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

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 ?