understanding infertility basic sciences a/prof r gyaneshwar franzcog, mh.ed clinical director of...
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Understanding Understanding InfertilityInfertility
Basic SciencesBasic SciencesA/Prof R GyaneshwarA/Prof R GyaneshwarFRANZCOG, MH.EdFRANZCOG, MH.Ed
Clinical Director of Obstetrics & GynaecologyClinical Director of Obstetrics & GynaecologyLiverpool Health ServiceLiverpool Health Service
Conjoint Associate ProfessorConjoint Associate ProfessorUniversity of New South WalesUniversity of New South Wales
2A/Prof R Gyaneshwar
3A/Prof R Gyaneshwar
AcknowledgementAcknowledgement
Dr Antony Lighten – Dr Antony Lighten – IVF AustraliaIVF Australia
Dr Derek Lok – Dr Derek Lok – Sydney IVFSydney IVF
4A/Prof R Gyaneshwar
Reproductive PhysiologyReproductive Physiology
5A/Prof R Gyaneshwar
Endometriosis
Fibroids
Blocked or damaged Fallopian tubes eg
Ectopic pregnancy
Failure of Ovulation
Polycystic Ovarian
Syndrome
Miscarriage
6A/Prof R Gyaneshwar
Causes of InfertilityCauses of Infertility
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The Causes of Infertility and The Causes of Infertility and their Approximate Frequency their Approximate Frequency (adapted from Hull et al 1985)(adapted from Hull et al 1985)
CausesCauses Frequency %Frequency %
Sperm defects or dysfunctionSperm defects or dysfunction 3030
Ovulation failureOvulation failure (amenorrhoea or oligomenorrhoea)(amenorrhoea or oligomenorrhoea) 2525
Tubal infective damageTubal infective damage 2020
Unexplained infertilityUnexplained infertility 2525
EndometriosisEndometriosis (causing damage)(causing damage) 55
Coital failure or infrequencyCoital failure or infrequency 55
Cervical mucus defects or dysfunctionCervical mucus defects or dysfunction 33
Uterine abnormalitiesUterine abnormalities (eg fibroids or abnormalities of (eg fibroids or abnormalities of shape)shape)
11
15% of couples have more than one sub-fertility factor15% of couples have more than one sub-fertility factor
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InfertilityInfertility
DefinitionDefinition 12 months of attempting to conceive12 months of attempting to conceive
Incidence 1 in 6 couplesIncidence 1 in 6 couples Incidence increases with ageIncidence increases with age
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Natural Cumulative Pregnancy Natural Cumulative Pregnancy RateRate
1
2
34
56
78
910
1112
24
0
10
20
30
40
50
60
70
80
90
1 2 3 4 5 6 7 8 9 10 11 12 24
% pregnant/month
Months of trying
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Natural Pregnancy RateNatural Pregnancy Rate
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Ovarian ReserveOvarian Reserve
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Anovulation Anovulation
LHRH
FSHLH
Hypothalamo-Hypothalamo-pituitarypituitary
WHO Type 1:WHO Type 1: HypogonadotrophicHypogonadotrophicNearly everyone conceivesNearly everyone conceives
AnovulationAnovulation WHO Type 2:WHO Type 2: NormogonadotrophicNormogonadotrophicMost women conceiveMost women conceive
Ovarian failureOvarian failure WHO Type 3:WHO Type 3: HypergonadotrophicHypergonadotrophicConception remote chance Conception remote chance without donated oocyteswithout donated oocytes
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The CluesThe Clues
Hot flushesHot flushes
Irregular/absent periodsIrregular/absent periods
Short cycleShort cycle
AmenorrhoeaAmenorrhoea
Weight loss/Exercise/StressWeight loss/Exercise/Stress
Drug-inducedDrug-induced
Other diseaseOther disease
LHRH
FSHLHIrregular mensesIrregular menses
Weight gainWeight gain
PCOS signs/symptomsPCOS signs/symptoms
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Ovulation Tests – Ovulation Tests – Luteal Luteal ProgesteroneProgesterone
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Tubal FactorTubal Factor
PeristalsisPeristalsis Ciliary dysfunctionCiliary dysfunction NarrowingNarrowing BlockageBlockage
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Lap / DyeLap / Dye
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EctopicEctopic
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Pelvic Infection and Tubal Pelvic Infection and Tubal DiseaseDisease
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Pelvic Infection and Tubal Pelvic Infection and Tubal DiseaseDisease
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EndometriosisEndometriosis
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Minimal / Mild EndometriosisMinimal / Mild Endometriosis
Monthly fecundity rate 6.1 (laparoscopic surgery) vs 3.2 (diagnostic laparoscopy) per 100 person month
The Canadian Collaborative Group on Endometriosis 1997 NEJM 337:217
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HysteroscopyHysteroscopy
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Septate uterusSeptate uterus
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Congenital AnomaliesCongenital Anomalies
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Failure of sperm production
Blocked/absent vas deferens
Low sperm numbers and/or poor sperm movement
High numbers of abnormal shaped sperm
Antisperm antibodies
Erectile dysfunction
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Male FactorMale Factor
Primary Testicular DiseasePrimary Testicular Disease Most common cause of male factor infertilityMost common cause of male factor infertility AetiologyAetiology
66% unknown66% unknown 20% testicular maldescent20% testicular maldescent 7% trauma and torsion7% trauma and torsion 5% Klinefelter’s Syndrome5% Klinefelter’s Syndrome 1% mumps orchitis1% mumps orchitis 1% chemo1% chemo
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Male FactorMale Factor
Endocrine causesEndocrine causes HyperprolactinaemiaHyperprolactinaemia Hypogonadotrophic hypogonadismHypogonadotrophic hypogonadism HypothrooidismHypothrooidism
RareRare Present with sexual dysfunctionPresent with sexual dysfunction
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Sperm CountSperm Count
VolumeVolume 2 – 5 mls2 – 5 mls
Density/ConcentrationDensity/Concentration > 20 mill/ml> 20 mill/ml
MotilityMotility > 50%> 50%
MorphologyMorphology > 14% > 14% normalnormal
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Male InfertilityMale Infertility
Semen Analysis Semen Analysis (WHO 1999)(WHO 1999) 3 days of abstinence, collection technique, 72 3 days of abstinence, collection technique, 72
days for sperm to be ejaculateddays for sperm to be ejaculated Vol > 1 mlVol > 1 ml Concentration > 20 x 10Concentration > 20 x 106 6 / mL/ mL Motility > 50%Motility > 50% Morphology Morphology (WHO Strict Criteria 99)(WHO Strict Criteria 99) > > 15% 15%
normalnormal Note:Note: SA best performed in andrology lab; If SA best performed in andrology lab; If
abnormalabnormal always repeatalways repeat
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Sperm Count Variation in a Sperm Count Variation in a Healthy ManHealthy Man
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Important ConceptsImportant Concepts
AgeAge Duration of infertilityDuration of infertility Primary versus secondary infertilityPrimary versus secondary infertility Multiple causes of infertilityMultiple causes of infertility Sub-fertility versus sterilitySub-fertility versus sterility
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HistoryHistory DurationDuration Previous pregnanciesPrevious pregnancies Wt / Ht / BMIWt / Ht / BMI Full menstrual historyFull menstrual history Androgenising signsAndrogenising signs Pelvic painPelvic pain Previous investigationsPrevious investigations Past medical historyPast medical history Past surgical historyPast surgical history Medications / cigarettes / alcoholMedications / cigarettes / alcohol
34A/Prof R Gyaneshwar
HistoryHistory Previous paternitiesPrevious paternities Sexual dysfunctionSexual dysfunction Mumps / STDMumps / STD TraumaTrauma Undescended testesUndescended testes Previous investigationsPrevious investigations Past medical historyPast medical history Past surgical historyPast surgical history Medications / cigarettes/ alcoholMedications / cigarettes/ alcohol
35A/Prof R Gyaneshwar
RANZCOG Statement RANZCOG Statement C-Obs 3 March 2004C-Obs 3 March 2004
Tests recommended at the first antenatal visit of Tests recommended at the first antenatal visit of each pregnancy:each pregnancy:
Blood group and antibody screenBlood group and antibody screen Full blood examinationFull blood examination Rubella Antibody statusRubella Antibody status Syphilis serologySyphilis serology Hepatitis B serologyHepatitis B serology Midstream urine examination by culture: Midstream urine examination by culture: eg dipslideeg dipslide HIV serologyHIV serology Hepatitis C serologyHepatitis C serology Cervical cytologyCervical cytology
36A/Prof R Gyaneshwar
Prognostic FactorsPrognostic Factors
AgeAge Duration of infertilityDuration of infertility Primary versus secondary infertilityPrimary versus secondary infertility Multiple causes of infertilityMultiple causes of infertility Sub-fertility versus sterilitySub-fertility versus sterility
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Duration of InfertilityDuration of Infertility
The longer the duration of infertility, the The longer the duration of infertility, the greater the likelihood of a cause of greater the likelihood of a cause of infertility; infertility; ie the less likely that the situation ie the less likely that the situation is due to bad luckis due to bad luck
Treatment is more successful in patients Treatment is more successful in patients where a specific treatable cause is foundwhere a specific treatable cause is found
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PrognosisPrognosis
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Effect of Multiple Minor Effect of Multiple Minor AbnormalitiesAbnormalities
Number of Number of FactorsFactors
Monthly Monthly ChanceChance
% Pregnancy % Pregnancy in 2 yearsin 2 years
Mean Years Mean Years to Pregnancyto Pregnancy
00 20%20% 93.693.6 0.3 (4m)0.3 (4m)
11 5%5% 63.863.8 1.5 - 21.5 - 2
22 1%1% 20.720.7 77
33 0.2%0.2% 4.74.7 4040
40A/Prof R Gyaneshwar
InvestigationsInvestigations
Tubal PatencyTubal PatencyHSGHSGLap & DyeLap & DyeOvulationOvulationMidluteal P4Midluteal P4Testosterone, TSH,Testosterone, TSH,Prolactin, LH, FSH asProlactin, LH, FSH asindicatedindicatedRubella, VaricellaRubella, VaricellaHep B, C, HIV, VDRLHep B, C, HIV, VDRL
Semen AnalysisSemen Analysis
LH, FSH, Prolactin as LH, FSH, Prolactin as indicatedindicated
KaryotypeKaryotype
Hep B, C, HIV, VDRLHep B, C, HIV, VDRL
41A/Prof R Gyaneshwar
Hormone / Ovulatory TestsHormone / Ovulatory Tests Day 2-3 hormonesDay 2-3 hormones
FSH, LH, OestradiolFSH, LH, Oestradiol Testosterone, SHBGTestosterone, SHBG Others:Others:
17-OH P, DHEAS, Androstenedione, cortisol17-OH P, DHEAS, Androstenedione, cortisol TSH, prolactinTSH, prolactin 75g GTT & fasting insulin75g GTT & fasting insulin
Luteal ProgesteroneLuteal Progesterone 7 days prior to estimated date of period if regular7 days prior to estimated date of period if regular If irregular, start 7 days prior to shortest cycle date If irregular, start 7 days prior to shortest cycle date
and repeat every 5-7 days till next period arrivesand repeat every 5-7 days till next period arrives
42A/Prof R Gyaneshwar
Treatment OptionsTreatment Options
AdviceAdvice AssessmentAssessment
OIOI Ovulation InductionOvulation Induction
IUIIUI Intrauterine InseminationIntrauterine Insemination
IVFIVF In Vitro FertilisationIn Vitro Fertilisation
ICSIICSI Intra Cytoplasmic Sperm InjectionIntra Cytoplasmic Sperm Injection
SSCSSC Surgical Sperm CollectionSurgical Sperm Collection
DonorDonor Sperm, Eggs or EmbryosSperm, Eggs or Embryos
43A/Prof R Gyaneshwar
Ovulation InductionOvulation Induction
PCOSPCOS
11stst line lineClomiphene – 60% pregnant after 6 monthsClomiphene – 60% pregnant after 6 months
22ndnd line lineMetforminMetformin
FSHFSH
Surgical Ovarian DrillingSurgical Ovarian Drilling
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Ovarian DrillingOvarian Drilling
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Ovarian InductionOvarian Induction
Hypothalamic amenorrhoeaHypothalamic amenorrhoeaFSHFSH
Pulsatile GnRHPulsatile GnRH
HyperprolactinaemiaHyperprolactinaemiaCarbergolideCarbergolide
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Intrauterine InseminationIntrauterine Insemination
IndicationsIndicationsUnexplainedUnexplained
Mild male factorMild male factor
Success/CycleSuccess/CycleNatural 10-15%Natural 10-15%
Stimulated 15-20%Stimulated 15-20%
47A/Prof R Gyaneshwar
In Vitro FertilisationIn Vitro Fertilisation
IndicationsIndicationsProlonged unexplainedProlonged unexplained
Tubal factorTubal factor
Severe male factorSevere male factor
Unsuccessful OI / IUI / fertility surgeryUnsuccessful OI / IUI / fertility surgery
48A/Prof R Gyaneshwar
In Vitro FertilisationIn Vitro Fertilisation
Success / CycleSuccess / Cycle40 – 5-%40 – 5-%
Single embryo transferSingle embryo transferNow gold standardNow gold standard
Twin rate 1%Twin rate 1%
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Sperm Preparation
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52A/Prof R Gyaneshwar52
53A/Prof R Gyaneshwar53
Day surgery for egg collection
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IVF (In Vitro Fertilisation) ICSI (Intra Cytoplasmic
Sperm Injection)
55A/Prof R Gyaneshwar55
IVF (In Vitro Fertilisation
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ICSI (Intra Cytoplasmic Sperm Injection)
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Fertilisation Day 2 Day 3
Day 4Day 5
BlastocystDay 5
Blastocyst
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Fate of recovered eggs (averages)
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Embryo transfer
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Pregnancy blood test
2 weeks after embryo transfer
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Embryo freezing
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Oocyte Oocyte CryopreservationCryopreservation
AuthorAuthor MethodMethod Survival Survival rate, n (%)rate, n (%)
Fertilisation Fertilisation rate, n (%)rate, n (%)
No. of No. of oocytes per oocytes per pregnancypregnancy
Fabbri (2001)Fabbri (2001) Slow-FreezeSlow-Freeze 796/1,502 (53)796/1,502 (53) 632/796 (79)632/796 (79) 9494
Chen (2005)Chen (2005) Slow-FreezeSlow-Freeze 119/159 (75)119/159 (75) 80/119 (67)80/119 (67) 2323
Boldt (2006)Boldt (2006) Slow-FreezeSlow-Freeze 218/361 (60)218/361 (60) 124/218 (61)124/218 (61) 2626
Yoon (2003)Yoon (2003) VitrificationVitrification 325/474 (69)325/474 (69) 142/198 (72)142/198 (72) 7979
Kuwayama Kuwayama (2005)(2005)
VitrificationVitrification 58/64 (91)58/64 (91) 52/58 (90)52/58 (90) 55
Jain. Fertil Steril 2006
63A/Prof R Gyaneshwar63
Any Questions?