Infertility—A Clinical Dilemma……

1. Infertility—A Clinical Dilemma…… Dr.Kundan V.Ingale. MBBS, DGO, DNB(Mumbai) Obstetrician & Gynecologist Consultant in Assisted Reproduction & Genetics LOKMANYA HOSPITAL, CHINCHWAD LOKMANYA HOSPITAL, PRADHIKARAN

2. Introduction • Traditionally, infertility is defined as the inability to conceive for one year. • Worldwide, 10 to 14% of couples in the reproductive age group (20-40) face difficulty in conceiving • 90% of infertility is treatable with advances in medicines and clinical procedures • Line of treatment includes medical and surgical intervention, Assisted Reproduction Techniques (ART) or a combination of these modalities. Infertility is an extraordinarily common medical problem.

3. INCIDENCE • Female Factor: - 40-45% • Male Factor: -25-40% • Both: - 10% • Unexplained: - 10%.

4. HSG – Septate uterus HSG – Bicornuate uterus Causes of Infertility Female • Anovulation (accounts for 25% of infertility) • Tubal factors (accounts for 25% - 40%of infertility) • Uterine & cervical factor (accounts for 10% of infertility) • Immunological cases, age and other factors (accounts for 25% of infertility) Tubal factor is a common cause of infertility in our country.

5. Causes of Infertility Male • Low sperm count • Low motility • Poor sperm morphology • Other factors such as • stress • varicocoele • chromosomal abnormality Both female and male factors contribute to infertility.

6. Infertility Rise in infertility : - - increased women employment - Late marriages - Preferring weekend sex - highly stressful job - Onset of childbearing at later age.

7. Male Infertility • Volume: 2-5ml • pH: 7.2-7.8 • Liquefaction time: within 40 mins. • Sperm Count: -20-120 million/ml (WHO Criteria) • Sperm motility: >50% after ½ hour. • Sperm Morphology: >50% normal.

8. Abnormal Semen Parameters. • Oligospermia: - sperm count <20 million/ml • Mild: -10-20 million/ml • Moderate: -5-10million/ml • Severe: -<5 million/ml. • Azoospermia: - Absence of single sperm in ejaculate. • Asthenospermia: -Sperm motility <50% • Teratospermia: - <4% normal sperms associated with poor fertility prognosis.

9. POLYCYSTIC OVARIAN SYNDROME • Heterogeneous complex condition – Hyperandrogenemia and chronic anovulation. • Associated with Hirsuitism , Hyperinsulinemia & insulin resistance. • Commonest cause of anovulation. • 50% patient of PCOS need assistance in reproduction.

10. Epidemiolgy of PCOS. • Affect 5-10%of all reproductive age group women. • 50% women attending infertility cilinics. • 50% women with recurrent miscarriages. PCO – LEADING CAUSE OF INFERTILITY.

11. Abnormal Estrogen Clearance / Metabolism Inability of H-P axis to respond to adequate & timely feedback signals LOW FSH Chronic anovulation Persistently Elevated Estrogen Increased Estrogen secretion Intrinsic follicular weakness / Impaired follicular-Gonadotropin interaction. High LH/Inadequate LH surge Gonadal (Ovary& Adrenal) Extragonadal (Adipose tissue) Failed local ovarian autocrine / paracrine factor

12. INSULIN RESISTANCE & HYPERINSULINEMIA • Causes: - • Peripheral target tissue resistance. Decreased insulin receptor number Decreased insulin binding Post-receptor failure • Decreased hepatic clearance. • Increased pancreatic sensitivity. INSULIN RESISTANCE – OBESE & NON-OBESE WOMEN.

13. PCO – THE SIGN Partial suppressed FSH Hyperplastic theca cells New Follicular growth Luteinized due to LH Follicular atresia Repeated follicular atresia & anovulation Thickened stroma PCO PCO : Sign , not a disease.

14. MAJOR Chronic anovulation Hyperandrogenemia Clinical signs of Hyperandrogenemia. MINOR Insulin resistance Perimenarchal onset of hisuitism and obesity Elevated LH and FSH ratio Intermittent anovulation assoc with Hyperandrogenemia PCOS- DIAGNOSIS

15. Tubal Factor • Fallopian tube blockage: Sites : Cornual end, interstitial, isthmus, ampulla, fimbrial end.

16. Tubo-Cornual region: - Tubal spasm Salphingitis Isthmica nodosa(SIN) Endometriosis Polyps Isthmus: - Occlusion-Prior sterilization,tubalpregnancy, SIN, T.B. Endometriosis. Ampulla: - Intraluminal adhesions, Tubal pregnancy Infundibulum: - Hydrosalphinx, phimosis of distal tubal ostium sec to PID. Intraperitoneal spread: - Adhesions. FALLOPIAN TUBE BLOCKAGE

17. Patency of tube Laparoscopic chromotubation Hysterosalphingo graphy Falloposcopy Methylene blue test Gas hydrotubation Sonosalphingography Direct cannulation Functioning of tubal mucosa Microsphere migration Descending tests Starch & Gold. DIAGNOSIS

18. MANAGEMENT OF TUBAL BLOCK • Proximal tubal disease: -Tubal cannulation IVF • Mid tubal disease: - Tubal reconstruction Microsurgery/IVF • Fimbrial / distal tubal disease: - Fimbrioplasty • Peritubal disease: -Adhesiolysis/IVF • T-O mass / multiple tubal block: -IVF/ICSI

19. Assisted Reproductive Techniques Intrauterine insemination (IUI) In Vitro Fertilization (IVF) Intracytoplasmic sperm Injection (ICSI) Laser Assisted hatching (LAH) Pre-implantation genetic diagnosis.(PGD) In vitro Maturation Donor oocyte programme.

20. IUI : Stimulation protocols • Natural cycle • Stimulated cycle CC CC+HMG CC+HMG/FSH+hCG FSH/HMG+hCG GnRHa + FSH/HMG + hCG • Follicle monitoring • Timing of IUI Success rate is high if more then one egg is produced.

21. Clomiphene Citrate Occupies the Estrogen receptor Concentration of Estrogen receptor is reduced No Negative feedback HPO axis is blind to Estrogen GnRH secretion activated FSH & LH pulse frequency increased Maturation of follicles

22. Results with Clomiphene Citrate • 70% Ovulation rate • 40% Pregnancy rate • 5% have multiple pregnancy • 60% conceive during first three cycles. If there is no pregnancy in 6 cycles, alternative therapy to be chosen.

23. IUI with Gonadotropin treatment • Gonadotropins : contain naturally occurring pituitary hormones (FSH & LH) • Daily injections: creates higher than normal levels of FSH, simulating the ovaries to produce multiple follicles and multiple eggs. • Transvaginal sonography: to check the growing follicles. Subcutaneous self injection into the thigh or abdomen.

24. Gonadotropins : Indications Indications: -Failure to respond to antiestrogen therapy • At least 3 cycles of C.C. and no ovulation • Dose: 0-200mg/day for 7 days. • At least 6 Ovulatory cycles and not conceived. -Side effects to antiestrogen therapy irrespective of ovulation -Two or more miscarriage after C. therapy.

25. Step Up protocols • Ovulation in PCO pts remains a challenge • OHSS, multiple pregnancy & LUF’s are a problem. • Allows right amount of FSH to connect the hormonal imbalance within the PCOS ovary. • Fewer follicles per cycle • Safer successful ovulation induction • OHSS reduced.

26. Step Down Protocols Principle : Activating pre-Ovulatory follicles and limiting the number of growing follicles by hormonal therapy. Advantages: Reduced risk of OHSS & multiple pregnancy. Disadvantages: Needs tight monitoring. Increased cancellation cycles.

27. Metformin in PCO patients • In cases diagnosed to have insulin resistance. • 1500mg/day till pregnancy achieved. • Given for at least 2 mths prior to ovulation induction programme.

28. INTRAUTERINE INSEMINATION(IUI)

29. What is IUI? • Direct placement of processed highly motile, concentrated sperm, washed free of seminal plasma and other debris, into the uterus as close to the ovulated oocytes as possible. • Reduces distance of travel Artificial insemination.

30. IUI The Goal is to place as many active, well-formed sperms as close to the ovulated eggs as possible, thereby increasing their chances of meeting.

31. Female factor: Anatomic defects Cervical factors Ovulatory dysfunction Unexplained infertility Minimal endometriosis Antisperm antibodies in cervix Psychological & Psychogenic sexual dysfunction Male Factor: Anatomic defects of the penis Sexual or ejaculatory dysfunction Retrograde ejaculation Impotency Immunological increased viscosity Oligoasthenoteratozoospermia Azoospermia Indications for IUI

32. Steps involved in COH & IUI Monitoring of a natural or stimulated cycle: so that the time of ovulation is apparent Preparation of Sperm wash: From either male partner or donor Procedure of Insemination: Sperm sample is then inserted into woman’s uterus via a catheter through the cervix.

33. IUI : Complications • Uterine cramping -5% • Spotting -1% • G I upset -0.5% • Infection -0.2% • OHSS -1% • Multiple gestation • Ectopic gestation Artificial Insemination

34. Efficacy of superovulation & IUI

35. IUI Results 751 cycles in 322 couples Chaffkin L.M.;Nulsen,J.C.,1991

36. IUI Failures • Poor responders • Hyperstimulation • LUF • Endometrial problems • Insatisfactory semen preparations

37. INTRACYTOPLASMIC SPERM INJECTION(ICSI)

38. ICSI Procedure ICSI involves injection of single sperm into the egg

39. Success Rates If 4 good quality embryos are produced following ICSI and the age of the woman is < 37 years, the pregnancy rates are 45% The hallmark to success is good quality embryos

40. Intra Cytoplasmic Sperm Injection (ICSI) • Revolutionary treatment for patients with severe male factor infertility • Fertilisation rate of mature eggs injected with immobilised sperm reached levels comparable to those obtained in conventional IVF • Also used to treat couples experiencing failure or low fertilisation rates under conventional IVF conditions The advent of ICSI has revolutionised male factor fertility.

41. Phases of IVF Cycle • Pituitary suppression (Down regulation) Done with Day 21 Lupride inj followed by stimulation with HMG or r-FSH. • Ovarian stimulation Fixed regimen - Step up and Step Down • Egg retrieval 34-36 hours after ovarian trigger One cycle is spread over a period of 25-30 days.

42. Phases of IVF Cycle • Fertilisation by ICSI • Embryo transfer • Luteal phase and pregnancy One cycle is spread over a period of 25-30 days.

43. Donor Programme • Donor sperms : - • azoospermia • Donor oocyte : - • Premature ovarian failure • Advanced maternal age with poor ovarian reserve • Donor embryo : - • Severe male as well as female factor.

44. 1 2 3 4 5 6 7 8 9 250bp 78bp 100bp 50bp 861bp 285bp 250bp 242bp 50bp Preimplantation genetic Diagnosis (PGD) The Micromanipulator FISH -Trisomy 18, X, Y PCR - Cystic Fibrosis  F 508 Mutation Cleavage stage Embryo Biopsy FISH - Polyploidy Polar Body Biopsy PCR -  Thalassemia PGD - Earliest form of prenatal diagnosis.

45. Cryopreservation For future fertilisation attempts

46. Laparoscopy Looking inside the abdominal cavity

47. Hysteroscopy Looking inside the uterus

48. Myths about infertility • Timing of intercourse • Frequency of intercourse • Certain coital positions improve chances of conception • Orgasm, libido, stress & tension • IUI improves chances of conception • Drugs to improve sperm count • Cold baths, loose pants • Unexplained infertility

49. Assisted Reproduction mimics human reproduction Getting close to nature

50. “The greatest motivational act one person can do for another is to listen.” Roy Moody THANK YOU