Partnership Between the Patient, the ObGyn, and the Fertility Specialist ObGyn Patient Fertility Specialist 1 There Are Multiple Causes of Infertility Causes of Infertility 14% 18% Tubal factor Ovulatory dysfunction 6% 6% Diminished ovarian reserve Endometriosis Uterine factor 13% 7% Male factor Other causes 1% Unexplained 11% Multiple female factors 6% 19% Multiple factors male + female Centers for Disease Control. http://www.cdc.gov/ART/ART02/sect2_fig14-24.htm#Figure%2014. 2006. 2 Assisted Reproductive Technology (ART) Infertility treatment options In vitro fertilization Associated technology Efficacy of ART Partnership for better outcomes • Weight management • Surgical interventions • Pharmacologic interventions • • • • Ovulation induction (CC) Ovulation induction (gonadotropin) Controlled ovarian stimulation protocols ICSI • Preimplantation genetic diagnosis • Cryopreservation • Oncology considerations • Pregnancies/deliveries IVF • Pregnancies/deliveries ICSI • Rate of complications • • • • Need for partnership Management algorithm Recommendations Transition of patient 3 Treatment Options for Female Infertility ● Weight management ● Surgical interventions – Tubal reconstruction/flushing – Adhesiolysis, salpingectomy, laparoscopic treatment of endometriosis – Correction of uterine abnormalities ● Pharmacologic interventions (non–ovulation induction) – Selective estrogen receptor modulators, insulin-sensitizing agents, aromatase inhibitors, etc ● Ovulation induction – Natural or intrauterine insemination ● Assisted reproductive technologies – In vitro fertilization • Controlled ovarian stimulation • Intracytoplasmic sperm injection 4 Managing Obesity in Women Can Improve Fertility Odds ratio for subfertilitya 2.0 1.7% 1.5 1.4% 1.0% 1.0% <18.5 18.5 to <25.0 1.0 0.5 0 25.0 to <30.0 ≥30 BMI (kg/m2) aTime to pregnancy >12 months. Ramlau-Hansen et al. Hum Reprod. 2007;22:1634. 5 PCOS BMI >25 Anovulatory infertility Anthropometric and echographic evaluation Diet 1200 kcal BMI reduction by 5% then by 10% Ovulation Anthropometric and echographic evaluation Anovulation Residual time for spontaneous conception End of the study Rate of regular cycles, ovulatory cycles, and pregnancy Weight Loss as Treatment for Infertility 1.0 0.8 Ovulatory cycles 0.6 Regular menstrual cycles 0.4 0.2 Pregnancy 0 0 2 4 6 8 10 Months Treating obesity appears to reinstate normal ovulatory functions Crosignani et al. Hum Reprod. 2003;18:1928. 6 Tubal Reconstruction ● Tubal reconstruction appears less effective than IVF for treatment of tubal factor infertility – Series of 83 women with distal tube occlusion treated surgically and followed for 1 year1 • Pregnancy within 1 year: 15.7% • Live births from the above pregnancies: 9.6% – Overall delivery rate per transfer for IVF patients with tubal factor: 28.9%2 1. Nichols and Steinkampf. Prim Care Update Ob Gyns. 1998;5:168. 2. Benadiva et al. Fertil Steril. 1995;64:1051. 7 Adhesions Can Affect Infertility Origin ● Endometriosis ● Pelvic inflammatory disease (PID) ● Peritoneal infections – Appendicitis – Tuberculosis ● Surgery Effects ● Distortion of tubo-ovarian relationships, preventing ovum capture ● May hinder oocyte development and maturation – Decreased ovarian blood supply – Inadequate delivery of gonadotropins and growth factors to follicles Diamond and Freeman. Hum Reprod Update. 2001;7:567. 8 Uterine Structural Abnormalities ● Congenital abnormalities (Incidence %) – – – – – – Hypoplasia/agenesis (n/a) Unicornuate (6.2%) Bicornuate (20.3%) Didelphys (6.2%) Arcuate (32.8%) Septate (33.6%) Didelphys ● Endometrial polyps ● Myomas (fibroids) Taylor and Gomel. Fertil Steril. 2008;89:1. Raga et al. Hum Reprod. 1997;12:2277. 9 Uterine Abnormalities, Reproductive Effects, and Common Treatments Abnormality Effects on Reproduction Treatment Congenital Uterine Abnormalities Unicornuate 45% loss of pregnancies Removal of rudimentary horn by laparotomy or laparoscopy Bicornuate 45% loss of pregnancies Rarely requires surgical treatment Didelphys 42% loss of pregnancies Resection of vaginal septum, Strassman reunification Septate 79% loss of pregnancies Hysteroscopic resection Polyps 28% pregnancy rate Myomas - Polypectomy GnRH agonist, mifepristone, uterine artery embolization, myolysis, myomectomy Taylor and Gomel. Fertil Steril. 2008;89:1. 10 Possibly Useful Pharmacologic Interventions ● Selective estrogen receptor modulator (clomiphene/tamoxifen)—antagonizes estrogen feedback activity at hypothalamic-pituitary axis ● Insulin-sensitizing drugs (metformin/troglitazone)—insulin resistance may play a key role in the pathogenesis of ovarian dysfunction ● Aromatase inhibitor (letrozole)—blocks conversion of androstenedione and testosterone to estriol and estradiol Stadtmauer et al. Fertil Steril. 2001;75:505. Mitwally and Casper. J Soc Gynecol Investig. 2004;11:406. 11 Indications for In Vitro Fertilization ● Absent or blocked fallopian tubes ● Failed tuboplasty ● Concomitant pelvic disease ● Severe male factor infertility ● Endometriosis ● Diminished ovarian reserve ● Unexplained infertility – Failed intrauterine insemination (IUI) Diedrich et al. Hum Reprod. 1992;7(suppl 1):115. 12 Ovulation Induction ● Useful in patients with anovulatory infertility as well as unexplained infertility – WHO class I: hypogonadotropic hypogonadism – WHO class II: PCOS ● Goal – Stimulate development of a single follicle that will be able to reach preovulatory size and rupture ● Options – Clomiphene citrate (CC) – Gonadotropins (LH, FSH, gonadotropin-releasing hormone [GnRH], human chorionic gonadotropin [hCG]) Messinis. Hum Reprod. 2005;20:2688. 13 Pharmacology of Clomiphene Citrate (CC) ● Nonsteroidal triphenylethylene derivative ● Binds to estrogen receptors (ER) throughout the reproductive system – Both agonist and antagonist properties – Efficacy in ovulation induction attributed to binding to hypothalamic ER – Increases both LH and FSH – Considered best initial treatment for the majority of women whose infertility is associated with ovulatory dysfunction ● Some deleterious effects on endometrium and cervical mucous (due to systemic antiestrogen effects) Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(suppl 5):S187. Sereepapong et al. Fertil Steril. 2000;73:287. 14 Clomiphene 50-250 mg/d 5 days Standard CC Treatment Regimen 5 days Coitus every other day 7 days Progesterone LH FSH 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Menses Clomiphene therapy Home Fertility Network. Ovulation induction. http://www.homefertility.com/ovulind.htm. 2007. 15 Efficacy of CC: Meta-Analysis of Clinical Results 70 69.4% % of patients 60 50 40 30 20 6.2% 10 8.8% 0 Ovulation per cycle Pregnancy per cycle Pregnancy per ovulatory cycle Steiner et al. Hum Reprod. 2005;20:1511. 16 CC Summary ● Simplest initial treatment for majority of women ● Reported outcomes are variable, but in general, pregnancy rates 6% per cycle ● Limit treatment to 6 (3 if poor ovulation induction) cycles (low probability of success beyond this) ● Monitor patients to ensure effectiveness of ovulation induction (basal body temperature, urinary LH, serum progesterone) ● Principal risk associated with CC is multifetal gestation (<10%) Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(suppl 5):S187. National Institute for Clinical Excellence. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. 2004. Hanson and Dumesic. Mayo Clin Proc. 1998;73:681. Imani et al. J Clin Endocrinol Metab. 1999;84:1617. 17 Gonadotropin Therapy ● Represents a more physiologic approach to multifollicular recruitment than CC ● Agents – Purified or recombinant human FSH – Human menopausal gonadotropins (hMG): 75 IU each of FSH and LH – Human chorionic gonadotropin (hCG) ● Gonadotropin preparations constitute the principal agents for ovulation induction and COS – Significantly higher odds of pregnancy per woman (OR=0.41, 95%CI: 0.17-0.80) vs antiestrogen induction – Maximum control • Ovarian response • Risk of multiples Davis and Rosenwaks. Sem Reproductive Med. 2001;19:207. Athaullah et al. Cochrane Database Syst Rev. 2002:CD003052. 18 Ovulation Induction: Gonadotropin Treatment ● Starting dose of FSH usually 50 or 75 IU ● Increments of 25-50 units after 7-14 days ● May include IUI or natural intercourse OI hCG Homberg and Insler. Hum Reprod Update. 2002;8:449. Lambalk et al. Hum Reprod. 2006;21:632. 19 Ovulation Induction vs In Vitro Fertilization ● Ovulation induction (OI) – Goal: induce growth of 1 or 2 mature follicles – Low doses of gonadotropins – Clomiphene citrate (CC) – Natural insemination or IUI fertilization ● In vitro fertilization (IVF)/COS – Goal: induce growth of multiple mature follicles – Higher doses of gonadotropins – Oocytes removed, fertilized in laboratory setting, then returned to uterus 20 In Vitro Fertilization (IVF) Procedure ● Initially used in women with fallopian tube blockage or damage Risks ● – ● Now employed for many causes of infertility (eg, endometriosis, male factor) ● Involves – Controlled ovarian stimulation (COS) – Egg retrieval – Insemination, fertilization, embryo culture – Embryo transfer – Cryopreservation of extra embryos Ovarian hyperstimulation syndrome (OHSS) – – Usually not serious and resolves with outpatient management 1%-2% severe requiring hospitalization Dose-dependent, avoided by careful titration ● Anesthesia ● Multiple births ● Ectopic pregnancy ● Psychologic distress American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ART.pdf. 2008. 21 Typical IVF Protocol Controlled ovarian stimulation Embryo cryopreservation PGD screening Follicular aspiration IVF or ICSI Oocyte freezing Embryo cleavage Embryo transfer Pregnancy diagnosis Oehninger. J Soc Gynecol Investig. 2005;12:222. 22 Key Concepts in Controlled Ovarian Stimulation ● Prospective identification of ovarian response (high, intermediate, low) ● Individualization of treatment ● Prevention of complications by careful dose titration: – Ovarian hyperstimulation syndrome (OHSS) ● Optimization of the total reproductive potential by embryo cryopreservation Arslan et al. Fertil Steril. 2005;84:555. 23 Gonadotropin Releasing Hormone (GnRH) ● Released from the hypothalamus in small amounts about once every 90 minutes ● Stimulates the pituitary gland to secrete LH and FSH ● A GnRH analogue often is used to prevent spontaneous ovulation when gonadotropins are given to women undergoing IVF – Agonists • Leuprolide, nafarelin, goserelin, buserelin, deslorelin, triptorelin – Antagonists • Ganirelix, cetrorelix American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. 2006. van Loenen et al. Semin Reprod Med. 2002;20:349. 24 Native GnRH pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2 ● Synthesized and secreted in the hypothalamus ● Released in coordinated pulses by the hypothalamus ● Reaches the pituitary via the HP portal system ● Stimulates the release of FSH, LH, and GnRH receptors of the anterior pituitary ● Quickly metabolized with a half-life of <5 minutes 25 Controlled Ovarian Stimulation (COS): Gonadotropin Treatment ● Starting dose of FSH usually 150 or 225 IU ● Needs GnRH analogue treatment to prevent premature LH surge ● Ovarian stimulation followed by oocyte pick-up, in vitro fertilization, and transfer of embryos COS hCG Arslan et al. Fertil Steril. 2005;84:555. Borini and Dal Prato. Reprod Biomed Online. 2005;11:283. Yong et al. Fertil Steril. 2003;79:308. 26 Potential Adverse Effects of Gonadotropin Treatment ● Deliveries after IVF and ICSI combined are multiple – Twins: 21.7% – Triplets: 1% ● Premature delivery ● OHSSa ● Breast tenderness ● Swelling or rash at the injection site ● Abdominal bloating and/or pain ● Mood swings aDose-dependent. Andersen et al. Hum Reprod. 2008;23:756. American Society for Reproductive Medicine. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. 2006. 27 Typical GnRH Agonist Protocols Long follicular protocol FSH Agonist Cycle day M 3 5 7 9 11 13 hCG Long luteal protocol FSH Agonist Cycle daya 15 17 19 21 23 25 27 M 3 5 7 9 11 hCG Short/flare-up protocol FSH Agonist hCG Ultrashort protocol FSH Ag Ag hCG FSH Early cessation protocol Agonist hCG aPrior cycle. van Loenen et al. Semin Reprod Med. 2002;20:349. 28 GnRH Antagonist Protocols Single-dose protocol FSH Antagonist hCG Multiple-dose protocol FSH Antagonist hCG van Loenen et al. Semin Reprod Med. 2002;20:349. 29 Antagonist Protocol Is Shorter Than Agonist Protocol Day 2 or 3 of menses hCG Day 6 of FSH Embryo transfer GnRH antagonist Cycle day 21-24 rFSH IVF or Luteal phase support GnRH agonist rFSH ICSI Downregulation Luteal phase (prior cycle) Luteal phase (current cycle) Start of cycle 30 GnRH Agonists vs Antagonists: No Difference in Live-Birth Outcomes Citation Year Albano European 0.01 0.1 Effect P Value 2000 0.83 0.56 2000 0.75 0.12 Olivennes 2000 0.80 0.61 North American 2001 0.78 0.32 Middle East 2001 0.97 0.91 Akman 2001 0.76 0.71 Hohmann 2003 0.93 0.86 Martinez 2003 1.57 0.59 Franco 2003 0.55 0.57 Hwang 2004 1.11 0.87 Sauer 2004 1.07 0.91 Xavier 2005 0.85 0.76 Loutradis 2005 0.70 0.47 Malmusi 2005 1.00 1.00 Marci 2005 10.36 0.06 Cheung 2005 1.55 0.64 Check 2005 1.82 0.35 Barmat 2005 0.65 0.36 Bahceci 2005 0.84 0.60 Badrawi 2005 0.80 0.64 Schmidt 2005 1.00 1.00 Lee 2005 0.70 0.52 0.86 0.08 Favor agonists 1 10 100 Favor antagonists Kolibianakis et al. Hum Reprod Update. 2006;12:651. 31 GnRH Agonists vs Antagonists: Other Outcomes Outcome Duration of treatment Difference (Antagonist vs Agonist) Shorter for antagonist (difference >19 days) FSH requirement No difference Oocytes retrieved Lower for antagonist (difference 1.2 per cycle) OHSS associated with hospital admission Lower with antagonist (odds ratio = 0.46) LH surge Higher with antagonist (odds ratio = 4.05) LH rise Higher with antagonist (odds ratio = 8.27) Kolibianakis et al. Hum Reprod Update. 2006;12:651. 32 Intracytoplasmic Sperm Injection (ICSI) Success Rate and Complications Indications ● Very low numbers of motile sperm ● Severe teratospermia ● Problems with sperm binding to and penetrating the egg ● Antisperm antibodies ● Prior or repeated fertilization failure with standard IVF methods ● Frozen sperm limited in number and quality ● Obstruction of the male reproductive tract not amenable to repair ● Fertilization rate: 50%-80% ● Live offspring: 20%-40% (40% in younger women, success declines with maternal age) American Society for Reproductive Medicine. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf. 2001. Palermo et al. Sem Reprod Med. 2000;18:161. Campbell and Irvine. Br Med Bull. 2000;56:616. 33 Oocyte Retrieval ● Transvaginal ultrasound-guided oocyte retrieval (TVOR) during IVF treatment is the gold standard for IVF therapy1,2 – May be performed without general anesthesia – Generally well tolerated ● Complications1 – Aspiration needle injury to adjacent pelvic organs and structures leading to serious complications1 – Infection3 – Hemorrhage3 – Adnexal torsion3 – Rupture of endometriotic cysts3 – Hyperprolactinemic stress when performed under general anesthesia4 – Vertebral osteomyelitis3 1. 2. 3. 4. El-Shawarby et al. Hum Fertil (Camb). 2004;7:127. Yuzpe et al. J Reprod Med. 1989;34:937. Bennett et al. J Assist Reprod Genet. 1993;10:72. Robinson et al. Hum Reprod. 1991;6:1291. 34 Preimplantation Genetic Diagnosis (PGD) and Screening Indications ● Recurrent miscarriage or unsuccessful IVF cycles ● Unexplained infertility ● Advanced maternal age ● Male factor infertility ● Fertile couples carrying single gene disorders Evaluations ● Mosaicism ● Chromosome aberrations – Aneuploidy – Structural chromosome aberrations – Reciprocal translocations – Robertsonian translocations – Inversions – Deletions – Duplications – Genomic imprinting and uniparental trisomy – Single gene disorders Kearns et al. Semin Reprod Med. 2005;23:336. 35 ESHRE Consensus Meeting on Genetic Risks and Complications in ART ● Both partners should be examined (female by a gynecologist, male by an andrologist) ● All couples with severe male subfertility or repeated fertilization failure should be counseled by a genetically trained specialist ● Genetic counseling should be offered ● Possible laboratory testing – Chromosomal analysis and microdeletion testing in nonobstructive azoospermia and oligozoospermia – Karyotype is suggested when sperm count is <5 million/mL and highly recommended when sperm count is <1 million/mL – Cystic fibrosis transmembrane regulation (CFTR) gene analysis in congenital bilateral absence of the vas deferens and related conditions – In pregnancy, mid-trimester ultrasound screening for congenital malformations and amniocentesis may be considered Land and Evers. Hum Reprod. 2003;18:455. 36 Common PGD Single-Gene Testing ● Autosomal dominant – Myotonic dystrophy = 35% – Huntington disease = 29% – Charcot-Marie-Tooth = 8% – Other = 29% ● X-linked – Fragile X = 26% – Duchenne/Becker muscular dystrophy = 23% – Hemophilia = 9% – Other = 42% Image courtesy of David Hill. Ph.D. Most common PGD single-gene tests performed ● Autosomal recessive – Cystic fibrosis = 38% – Thalassemia = 18% – Spinal muscular dystrophy = 17% – Other = 27% Kearns et al. Sem Reprod Med. 2005;23:336. 37 Two Basic Techniques Developed for Cryopreservation Slow Freezing Vitrification Physiologic solution Before cooling Cryoprotectant solution Vitrification solution Ice seeding After cooling Slow cooling Rapid cooling Rapid cooling In LN2 Kasai and Mukaida. Reprod Biomed Online. 2004;9:164. 38 Pregnancy and Deliveries After IVF in Europe (2004) Pregnancies Deliveries 40 35 30.1% % of patients 30 25 20 26.6% 24.1% 17.4% 18.8% 21.1% 15 10 5 0 Per cycle Per aspiration Per transfer Andersen et al. Hum Reprod. 2008;23:756. 39 Pregnancy and Deliveries After ICSI in Europe (2004) Pregnancies Deliveries 40 35 % of patients 30 29.8% 27.1% 25.1% 25 20 17.2% 18.4% 19.8% 15 10 5 0 Per cycle Per aspiration Per transfer Andersen et al. Hum Reprod. 2008;23:756. 40 Complications and Fetal Reductions With ART in Europe (2004) Number of cases (incidence rate) (From 29 countries, 785 clinics reported 367,066 cycles) 3000 2858 2500 (0.77%) 2000 1500 1125 1000 (0.30%) 500 520 (0.14%) 0 OHSS Oocyte Bleeding retrieval complications 526 362 (0.09%) 4 (0.14%) Infection Maternal death Fetal reduction Andersen et al. Hum Reprod. 2008;23:756. 41 Assisted Reproductive Technologies: Summary ● Improvement in knowledge and technology has made it possible to optimize ovarian development, retrieve and fertilize oocytes, and preserve embryos with a minimal risk to patient ● Despite all these advances, younger maternal age has the most successful impact on outcomes 42 How can the ObGyn and fertility specialist together make sure that patients get the most appropriate treatment as soon as possible? ObGyn Patient Fertility Specialist 43 Management Algorithm for ObGyn Couple attempting conception Female <35 years of age 1 year of infertility Female >35 years of age 6 months of infertility Determine progesterone level 7 days after presumed ovulation Ovulation Anovulation or oligo-ovulation without hirsutism Consider referral for COS Female physiology: serum sensitive TSH, FSH, and prolactin levels Abnormal Refer to fertility specialist Normal Male evaluation: semen analysis Abnormal Female anatomy: hysterosalpingography Abnormal Treatment: clomiphene citrate 50-100 mg/d orally for 5 days during menses, for 3 cycles Unsuccessful Successful Initiate prenatal care Hanson and Dumesic. Mayo Clin Proc. 1998;73:681. 44 Lifestyle Changes Can be Recommended ● Avoid smoking and secondhand smoke to improve fertility (both male and female) and to reduce required dose of fertility medication ● Lose weight ● Reduce stress Kelly-Weeder and O’Connor. J Am Acad Nurse Pract. 2006;18:268. Younglai et al. Hum Reprod Update. 2005;11:43. 45 Reasons for Referral to a Fertility Specialist ● Factors indicating immediate referral to a fertility specialist – Older female age – Tubal occlusion – Abnormal semen parameters – Insulin resistance – Abnormal ovarian reserve testing – CC failure – Suspected or confirmed infertility Potter. http://www.infertilityspecialist.com/acrobat/The%20Contemporary%20Fertility%20.pdf. 2008. Olive and Hammond. Postgrad Med. 1985;77:205. 46 Transition From Clomiphene Citrate (CC) to Specialist-Guided Therapy and Back ● CC is widely used for ovulation induction in women with PCOS and in couples with unexplained infertility to induce follicular development ● Because of the potential side effects associated with CC, all patients should be monitored to assess response to treatment ● Without ultrasound monitoring, the number of CC cycles should probably be limited to 3 (or less), and early referral should be considered ● After successful ART, transition of patient back to ObGyn and prenatal care should be initiated PCOS = Polycystic ovary syndrome. Case. Can Fam Physician. 2003;49:1465. 47 Summary ● Infertility treatment protocol depends on female age ● Conduct diagnostic tests after – 1 year of infertility for female aged <35 years – 6 months of infertility for female aged >35 years ● Refer to fertility specialist after 3 (or fewer) unsuccessful CC cycles 48