Understanding Infertility Basic Sciences A/Prof R Gyaneshwar FRANZCOG, MH.Ed Clinical Director of Obstetrics & Gynaecology Liverpool Health Service Conjoint

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


AcknowledgementAcknowledgement

Dr Antony Lighten – Dr Antony Lighten – IVF AustraliaIVF Australia

Dr Derek Lok – Dr Derek Lok – Sydney IVFSydney IVF


Reproductive PhysiologyReproductive Physiology


Endometriosis

Fibroids

Blocked or damaged Fallopian tubes eg

Ectopic pregnancy

Failure of Ovulation

Polycystic Ovarian

Syndrome

Miscarriage


Causes of InfertilityCauses of Infertility


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


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


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


Natural Pregnancy RateNatural Pregnancy Rate


Ovarian ReserveOvarian Reserve


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


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


Ovulation Tests – Ovulation Tests – Luteal Luteal ProgesteroneProgesterone


Tubal FactorTubal Factor

PeristalsisPeristalsis Ciliary dysfunctionCiliary dysfunction NarrowingNarrowing BlockageBlockage


Lap / DyeLap / Dye


EctopicEctopic


Pelvic Infection and Tubal Pelvic Infection and Tubal DiseaseDisease


Pelvic Infection and Tubal Pelvic Infection and Tubal DiseaseDisease


EndometriosisEndometriosis


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


HysteroscopyHysteroscopy


Septate uterusSeptate uterus


Congenital AnomaliesCongenital Anomalies


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


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


Male FactorMale Factor

Endocrine causesEndocrine causes HyperprolactinaemiaHyperprolactinaemia Hypogonadotrophic hypogonadismHypogonadotrophic hypogonadism HypothrooidismHypothrooidism

RareRare Present with sexual dysfunctionPresent with sexual dysfunction


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


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


Sperm Count Variation in a Sperm Count Variation in a Healthy ManHealthy Man



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


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


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


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


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


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


PrognosisPrognosis


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


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


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


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


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


Ovarian DrillingOvarian Drilling


Ovarian InductionOvarian Induction

Hypothalamic amenorrhoeaHypothalamic amenorrhoeaFSHFSH

Pulsatile GnRHPulsatile GnRH

HyperprolactinaemiaHyperprolactinaemiaCarbergolideCarbergolide


Intrauterine InseminationIntrauterine Insemination

IndicationsIndicationsUnexplainedUnexplained

Mild male factorMild male factor

Success/CycleSuccess/CycleNatural 10-15%Natural 10-15%

Stimulated 15-20%Stimulated 15-20%


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


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%

49A/Prof R Gyaneshwar49

Sperm Preparation





Day surgery for egg collection


IVF (In Vitro Fertilisation) ICSI (Intra Cytoplasmic

Sperm Injection)


IVF (In Vitro Fertilisation


ICSI (Intra Cytoplasmic Sperm Injection)


Fertilisation Day 2 Day 3

Day 4Day 5

BlastocystDay 5

Blastocyst


Fate of recovered eggs (averages)


Embryo transfer


Pregnancy blood test

2 weeks after embryo transfer


Embryo freezing


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


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Understanding Infertility Basic Sciences A/Prof R Gyaneshwar FRANZCOG, MH.Ed Clinical Director of Obstetrics & Gynaecology Liverpool Health Service Conjoint