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 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. INCIDENCE • Female Factor: - 40-45% • Male Factor: -25-40% • Both: - 10% • Unexplained: - 10%. Causes of Infertility Female HSG – Septate uterus 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) HSG – Bicornuate uterus Tubal factor is a common cause of infertility in our country. 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. Infertility Rise in infertility : - increased women employment - Late marriages - Preferring weekend sex - highly stressful job - Onset of childbearing at later age. 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. 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. 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. 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. Abnormal Estrogen Clearance / Metabolism Inability of H-P axis to respond to adequate & timely feedback signals LOW FSH Persistently Elevated Estrogen Increased Estrogen secretion Chronic anovulation High LH/Inadequate LH surge Gonadal Extragonadal (Ovary& Adrenal) (Adipose tissue) Intrinsic follicular weakness / Impaired follicular-Gonadotropin interaction. Failed local ovarian autocrine / paracrine factor 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. PCO – THE SIGN Hyperplastic theca cells Luteinized due to LH Partial suppressed FSH New Follicular growth Follicular atresia Repeated follicular atresia & anovulation Thickened stroma PCO PCO : Sign , not a disease. PCOS- DIAGNOSIS 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 Tubal Factor Fallopian tube blockage: Sites : Cornual end, interstitial, isthmus, ampulla, fimbrial end. FALLOPIAN TUBE BLOCKAGE Tubo-Cornual region: Ampulla: Tubal spasm Intraluminal adhesions, Salphingitis Isthmica Tubal pregnancy nodosa(SIN) Infundibulum: Endometriosis Hydrosalphinx, phimosis of Polyps distal tubal ostium sec to Isthmus: PID. Occlusion-Prior Intraperitoneal spread: sterilization,tubal Adhesions. pregnancy, SIN, T.B. Endometriosis. DIAGNOSIS Functioning of of tube tubal mucosa – Laparoscopic chromotubation – Microsphere – Hysterosalphingo migration graphy – Descending tests – Falloposcopy Starch & Gold. – Methylene blue test – Gas hydrotubation – Sonosalphingography – Direct cannulation Patency 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 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. 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. 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 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. 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. 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. 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. 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. Metformin in PCO patients In cases diagnosed to have insulin resistance. 1500mg/day Given till pregnancy achieved. for at least 2 mths prior to ovulation induction programme. INTRAUTERINE INSEMINATION (IUI) 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. 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. Indications for IUI Female factor: Male Factor: Anatomic defects Cervical factors Ovulatory dysfunction Unexplained infertility Minimal endometriosis Antisperm antibodies in cervix Psychological & Psychogenic sexual dysfunction Anatomic defects of the penis Sexual or ejaculatory dysfunction Retrograde ejaculation Impotency Immunological increased viscosity Oligoasthenoteratozoospermia Azoospermia 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. IUI : Complications Uterine cramping Spotting G I upset Infection OHSS Multiple gestation Ectopic gestation Artificial Insemination -5% -1% -0.5% -0.2% -1% Efficacy of superovulation & IUI Treatment Intracervical insemination No.of pregnancies Pregnancy rate/couple 23 10 Intrauterine insemination 42 18 Super ovulation & Intracervical insemination Super ovulation & intrauterine insemination 44 19 77 33 IUI Results 751 cycles in 322 couples Treatment Fecundity/Cycle COH 6.3% IUI 3.4% COH + IUI 19.6% Chaffkin L.M.;Nulsen,J.C.,1991 IUI Failures Poor responders Hyperstimulation LUF Endometrial problems Insatisfactory semen preparations INTRACYTOPLASMIC SPERM INJECTION (ICSI) ICSI Procedure ICSI involves injection of single sperm into the egg 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 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. 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. Phases of IVF Cycle Fertilisation by ICSI Embryo transfer Luteal phase and pregnancy One cycle is spread over a period of 25-30 days. 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. Preimplantation genetic Diagnosis (PGD) 1 2 3 4 5 6 7 8 9 The Micromanipulator 250bp FISH -Trisomy 18, X, Y 78bp 100bp 50bp PCR - Cystic Fibrosis F 508 Mutation Cleavage stage Embryo Biopsy 861bp 285bp 250bp FISH - Polyploidy 242bp 50bp Polar Body Biopsy PCR - Thalassemia PGD - Earliest form of prenatal diagnosis. Cryopreservation For future fertilisation attempts Laparoscopy Looking inside the abdominal cavity Hysteroscopy Looking inside the uterus 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 Assisted Reproduction mimics human reproduction Getting close to nature “The greatest motivational act one person can do for another is to listen.” Roy Moody