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

2A/Prof R Gyaneshwar

3 Acknowledgement Dr Antony Lighten – IVF Australia Dr Antony Lighten – IVF Australia Dr Derek Lok – Sydney IVF Dr Derek Lok – Sydney IVF

4A/Prof R Gyaneshwar Reproductive 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 Infertility

7A/Prof R Gyaneshwar The Causes of Infertility and their Approximate Frequency (adapted from Hull et al 1985) Causes Frequency % Sperm defects or dysfunction 30 Ovulation failure (amenorrhoea or oligomenorrhoea) 25 Tubal infective damage 20 Unexplained infertility 25 Endometriosis (causing damage) 5 Coital failure or infrequency 5 Cervical mucus defects or dysfunction 3 Uterine abnormalities (eg fibroids or abnormalities of shape) 1 15% of couples have more than one sub-fertility factor

8A/Prof R Gyaneshwar Infertility Definition Definition 12 months of attempting to conceive 12 months of attempting to conceive Incidence 1 in 6 couples Incidence 1 in 6 couples Incidence increases with age Incidence increases with age

9A/Prof R Gyaneshwar Natural Cumulative Pregnancy Rate Months of trying

10A/Prof R Gyaneshwar Natural Pregnancy Rate

11A/Prof R Gyaneshwar Ovarian Reserve

12A/Prof R Gyaneshwar Anovulation LHRH FSHLH Hypothalamo- pituitary WHO Type 1: Hypogonadotrophic Nearly everyone conceives Anovulation WHO Type 2: Normogonadotrophic Most women conceive Ovarian failure WHO Type 3: Hypergonadotrophic Conception remote chance without donated oocytes

13A/Prof R Gyaneshwar The Clues Hot flushes Irregular/absent periods Short cycle Amenorrhoea Weight loss/Exercise/Stress Drug-induced Other disease LHRH FSHLH Irregular menses Weight gain PCOS signs/symptoms

14A/Prof R Gyaneshwar Ovulation Tests – Luteal Progesterone

15A/Prof R Gyaneshwar Tubal Factor Peristalsis Peristalsis Ciliary dysfunction Ciliary dysfunction Narrowing Narrowing Blockage Blockage

16A/Prof R Gyaneshwar Lap / Dye

17A/Prof R Gyaneshwar Ectopic

18A/Prof R Gyaneshwar Pelvic Infection and Tubal Disease

19A/Prof R Gyaneshwar Pelvic Infection and Tubal Disease

20A/Prof R Gyaneshwar Endometriosis

21A/Prof R Gyaneshwar Minimal / 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

22A/Prof R Gyaneshwar Hysteroscopy

23A/Prof R Gyaneshwar Septate uterus

24A/Prof R Gyaneshwar Congenital Anomalies

25A/Prof R Gyaneshwar 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

26A/Prof R Gyaneshwar Male Factor Primary Testicular Disease Primary Testicular Disease Most common cause of male factor infertility Most common cause of male factor infertility Aetiology Aetiology 66% unknown 66% unknown 20% testicular maldescent 20% testicular maldescent 7% trauma and torsion 7% trauma and torsion 5% Klinefelter’s Syndrome 5% Klinefelter’s Syndrome 1% mumps orchitis 1% mumps orchitis 1% chemo 1% chemo

27A/Prof R Gyaneshwar Male Factor Endocrine causes Endocrine causes Hyperprolactinaemia Hyperprolactinaemia Hypogonadotrophic hypogonadism Hypogonadotrophic hypogonadism Hypothrooidism Hypothrooidism Rare Rare Present with sexual dysfunction Present with sexual dysfunction

28A/Prof R Gyaneshwar Sperm Count Volume2 – 5 mls Volume2 – 5 mls Density/Concentration> 20 mill/ml Density/Concentration> 20 mill/ml Motility> 50% Motility> 50% Morphology> 14% normal Morphology> 14% normal

29A/Prof R Gyaneshwar Male Infertility Semen Analysis (WHO 1999) Semen Analysis (WHO 1999) 3 days of abstinence, collection technique, 72 days for sperm to be ejaculated 3 days of abstinence, collection technique, 72 days for sperm to be ejaculated Vol > 1 ml Vol > 1 ml Concentration > 20 x 10 6 / mL Concentration > 20 x 10 6 / mL Motility > 50% Motility > 50% Morphology (WHO Strict Criteria 99) > 15% normal Morphology (WHO Strict Criteria 99) > 15% normal Note: SA best performed in andrology lab; If abnormal always repeat Note: SA best performed in andrology lab; If abnormal always repeat

30A/Prof R Gyaneshwar Sperm Count Variation in a Healthy Man

31A/Prof R Gyaneshwar

32A/Prof R Gyaneshwar Important Concepts Age Age Duration of infertility Duration of infertility Primary versus secondary infertility Primary versus secondary infertility Multiple causes of infertility Multiple causes of infertility Sub-fertility versus sterility Sub-fertility versus sterility

33A/Prof R Gyaneshwar History Duration Duration Previous pregnancies Previous pregnancies Wt / Ht / BMI Wt / Ht / BMI Full menstrual history Full menstrual history Androgenising signs Androgenising signs Pelvic pain Pelvic pain Previous investigations Previous investigations Past medical history Past medical history Past surgical history Past surgical history Medications / cigarettes / alcohol Medications / cigarettes / alcohol

34A/Prof R Gyaneshwar History Previous paternities Previous paternities Sexual dysfunction Sexual dysfunction Mumps / STD Mumps / STD Trauma Trauma Undescended testes Undescended testes Previous investigations Previous investigations Past medical history Past medical history Past surgical history Past surgical history Medications / cigarettes/ alcohol Medications / cigarettes/ alcohol

35A/Prof R Gyaneshwar RANZCOG Statement C-Obs 3 March 2004 Tests recommended at the first antenatal visit of each pregnancy: Tests recommended at the first antenatal visit of each pregnancy: Blood group and antibody screen Blood group and antibody screen Full blood examination Full blood examination Rubella Antibody status Rubella Antibody status Syphilis serology Syphilis serology Hepatitis B serology Hepatitis B serology Midstream urine examination by culture: eg dipslide Midstream urine examination by culture: eg dipslide HIV serology HIV serology Hepatitis C serology Hepatitis C serology Cervical cytology Cervical cytology

36A/Prof R Gyaneshwar Prognostic Factors Age Age Duration of infertility Duration of infertility Primary versus secondary infertility Primary versus secondary infertility Multiple causes of infertility Multiple causes of infertility Sub-fertility versus sterility Sub-fertility versus sterility

37A/Prof R Gyaneshwar Duration of Infertility The longer the duration of infertility, the greater the likelihood of a cause of infertility; ie the less likely that the situation is due to bad luck The longer the duration of infertility, the greater the likelihood of a cause of infertility; ie the less likely that the situation is due to bad luck Treatment is more successful in patients where a specific treatable cause is found Treatment is more successful in patients where a specific treatable cause is found

38A/Prof R Gyaneshwar Prognosis

39A/Prof R Gyaneshwar Effect of Multiple Minor Abnormalities Number of Factors Monthly Chance % Pregnancy in 2 years Mean Years to Pregnancy 020% (4m) 15% % %4.740

40A/Prof R Gyaneshwar Investigations Tubal Patency HSG Lap & Dye Ovulation Midluteal P4 Testosterone, TSH, Prolactin, LH, FSH as indicated Rubella, Varicella Hep B, C, HIV, VDRL Semen Analysis LH, FSH, Prolactin as indicated Karyotype Hep B, C, HIV, VDRL

41A/Prof R Gyaneshwar Hormone / Ovulatory Tests Day 2-3 hormones Day 2-3 hormones FSH, LH, Oestradiol FSH, LH, Oestradiol Testosterone, SHBG Testosterone, SHBG Others: Others: 17-OH P, DHEAS, Androstenedione, cortisol 17-OH P, DHEAS, Androstenedione, cortisol TSH, prolactin TSH, prolactin 75g GTT & fasting insulin 75g GTT & fasting insulin Luteal Progesterone Luteal Progesterone 7 days prior to estimated date of period if regular 7 days prior to estimated date of period if regular If irregular, start 7 days prior to shortest cycle date and repeat every 5-7 days till next period arrives If irregular, start 7 days prior to shortest cycle date and repeat every 5-7 days till next period arrives

42A/Prof R Gyaneshwar Treatment Options AdviceAssessment OI Ovulation Induction IUI Intrauterine Insemination IVF In Vitro Fertilisation ICSI Intra Cytoplasmic Sperm Injection SSC Surgical Sperm Collection Donor Sperm, Eggs or Embryos

43A/Prof R Gyaneshwar Ovulation Induction PCOS 1 st line Clomiphene – 60% pregnant after 6 months 2 nd line MetforminFSH Surgical Ovarian Drilling

44A/Prof R Gyaneshwar Ovarian Drilling

45A/Prof R Gyaneshwar Ovarian Induction Hypothalamic amenorrhoea FSH Pulsatile GnRH HyperprolactinaemiaCarbergolide

46A/Prof R Gyaneshwar Intrauterine Insemination IndicationsUnexplained Mild male factor Success/Cycle Natural 10-15% Stimulated 15-20%

47A/Prof R Gyaneshwar In Vitro Fertilisation Indications Prolonged unexplained Tubal factor Severe male factor Unsuccessful OI / IUI / fertility surgery

48A/Prof R Gyaneshwar In Vitro Fertilisation Success / Cycle 40 – 5-% Single embryo transfer Now gold standard Twin rate 1%

49A/Prof R Gyaneshwar 49 Sperm Preparation

50A/Prof R Gyaneshwar 50

51A/Prof R Gyaneshwar 51

52A/Prof R Gyaneshwar 52

53A/Prof R Gyaneshwar 53 Day surgery for egg collection

54A/Prof R Gyaneshwar 54 IVF (In Vitro Fertilisation) ICSI (Intra Cytoplasmic Sperm Injection)

55A/Prof R Gyaneshwar 55 IVF (In Vitro Fertilisation

56A/Prof R Gyaneshwar 56 ICSI (Intra Cytoplasmic Sperm Injection)

57A/Prof R Gyaneshwar Fertilisation Day 2 Day 3 Day 4 Day 5 Blastocyst Day 5 Blastocyst

58A/Prof R Gyaneshwar 58 Fate of recovered eggs (averages)

59A/Prof R Gyaneshwar 59 Embryo transfer

60A/Prof R Gyaneshwar 60 Pregnancy blood test 2 weeks after embryo transfer

61A/Prof R Gyaneshwar 61 Embryo freezing

62A/Prof R Gyaneshwar 62 Oocyte Cryopreservation AuthorMethod Survival rate, n (%) Fertilisation rate, n (%) No. of oocytes per pregnancy Fabbri (2001) Slow-Freeze 796/1,502 (53) 632/796 (79) 94 Chen (2005) Slow-Freeze 119/159 (75) 80/119 (67) 23 Boldt (2006) Slow-Freeze 218/361 (60) 124/218 (61) 26 Yoon (2003) Vitrification 325/474 (69) 142/198 (72) 79 Kuwayama (2005) Vitrification 58/64 (91) 52/58 (90) 5 Jain. Fertil Steril 2006

63A/Prof R Gyaneshwar 63 Any Questions?