INFERTILITY: Update on Evaluation & Treatment

1. INFERTILITY: Update on Evaluation & Treatment LaTasha B. Craig, M.D. Assistant Professor Division of Reproductive Endocrinology University of Oklahoma Health Sciences Center

2. Objectives • Understand the different causes of infertility and the specific evaluations to diagnose each cause. • Comprehend the available infertility treatment options including their chance of pregnancy, complications and chance of multiple gestations. • Have an understanding of the process and success of in vitro fertilization (IVF) & the concerns for long term outcomes of children born from IVF.

3. I have no financial relationships or affiliations to disclose. Many of the medications used in in vitro fertilization are not FDA approved for this indication. Speaker Disclosure

4. Considerations Pre-Pregnancy • Nutritional issues • Medical conditions • Medications • Immunization history • Family history and genetic risk • Tobacco, alcohol, caffeine & substance use • Occupational & environmental exposures

5. How to time conception • Cycle Day (CD) 1 is the first day of full-flow bleeding • Have intercourse every 2 -3 days (especially between CD 10-20) • Avoid most over-the-counter lubricants • Things to consider: • Ovulation Predictor Kits • Basal Body Temperature Charting • Things to avoid: • Over the counter fertility tests • Salivary hormone tests • Hormonal supplements

6. Basal Body Temperature Monitoring • Newill RG, Katz M. The basal body temperature chart in artificial insemination by donor pregnancy cycles. Fertil Steril 1982 Oct;38(4):431-8

7. Ovulation Predictor Kits:

8. What to Expect--Fecundability:Cumulative pregnancy rate Guttmacher, 1956

9. Definition of Infertility • Failure to conceive after 1 year of unprotected intercourse • The exception: For women ≥ 35 years old, 6 months unprotected intercourse without conception

10. Infertility • Incidence • Diagnostic evaluation • Treatment options

11. In 1790 U.S. census, birth rate was 55 per 1000 population with avg. of 8 births per woman 1995 National Survey of Family Growth (NSGF), birth rate of 15.5 per 1000, with avg. births of 1.2 per woman Popular explanations for declining U.S. fertility Changing roles & aspirations for women Postponement of marriage Delayed age of childbearing Increasing use of contraception Liberalized abortion Historical perspective on fertility Speroff. Clinical Gynecologic Endocrinology & Infertility. Sixth edition.

12. Components of Normal Fertility

13. Etiologies by percent in couples presenting for infertility

14. Male Infertility Evaluation: Semen Analysis

15. Female Infertility Evaluation: Tubal/Pelvic Factor

16. Hysterosalpingogram (HSG) Normal Bilateral Blocked Tubes

17. Female Infertility Evaluation: Ovulation Dysfunction Confirm ovulation by • History of regular cycles • Symptoms of ovulation • Ovulation predictor kits • Basal body temperature • Progesterone level around CD 21 • Ultrasound monitoring

18. Ovarian Aging:Depletion of primordial follicles Picture from: http://embryology.med.unsw.edu.au/Notes/images/week1/ovary/oocytenumber.jpg

19. Marital fertility rates by 5-year age groups Ten various populations ranging from 17th to mid-20th century. Menken J, Trussel J, Larsen U. Age and infertility. Science 1986;23:1389-1394.

20. 2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

21. 2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

22. Assessment of Ovarian Reserve • Female age • Cycle day 3 FSH & estradiol • AMH level • Vaginal ultrasound for antral follicles

23. Treatment Options • Directly correcta problem if possible (i.e. thyroid tx, Bromocriptine, weight loss, etc) • If unable to correct the underlying problem, then use empiric treatment: • Intrauterine insemination (IUI or AI) • Ovulation Induction • Assisted Reproductive Technology (i.e. in vitro fertilization – IVF)

24. Treatment Options: Intrauterine Insemination (IUI) Picture from Familydoctor.co.uk

25. Treatment Options: Ovulation Induction • By mouth: Clomiphene (Clomid) or Letrozole (Femara) • Pregnancy rate is 10% per cycle (higher in PCOS patients). • Risk of twins 8-10% and risk of triplets or more less than 1% • Side Effects: hot flushes, nausea, headaches, mood swings, blurred vision, thin uterine lining, poor cervical mucus.

26. Treatment Options: Ovulation Induction • Injectable medications: Gonadotropins (FSH, LH) • Pregnancy rate is 10-20% each cycle (controversial) • Risk of twins up to 30% and risk of triplets or more 5-10% • Side effects of medication are minimal because it is a natural hormone. Chance of overstimulation and canceling cycle.

27. Gonadotropins

28. Polycystic Ovarian Syndrome (PCOS)

29. 1500-2000 mg/ day May not be covered by insurance in non-diabetics Re-introduce clomid Adjunct to Ovulation Induction in PCOS Metformin • Ovulation rates, 50-80% • Adhesion risk, 10-15% • Longest study, 5 year follow-up1 (206 patients) • 70% Pregnancy rate (1/2 treated) • 50% Live birth rate Ovarian Drilling 1 Naether OG et al., Human Reprod 9(12):2342-9, 1994

30. Which of the following do you believe: • All patients with PCOS should be on metformin • All PCOS patients wanting to conceive should be on metformin • Metformin is only indicated if a patient has diabetes or impaired glucose tolerance.

31. Metformin in PCOS Nestler JE, et al. NEJM 338(26):1876-80, 1998

32. Metformin in PCOS Glueck CJ, et al. Metabolism Apr;48(4):511-9, 1999

33. Is metformin more effective than clomid? • Randomized controlled trial of metformin 850 mg bid vs. clomiphene citrate 150 mg qd cycle days 5-9 • Cumulative ovulation rate not different (63 vs. 67%) • Pregnancy rate/cycle = 15.1% metformin; 7.2% clomiphene (p = 0.009) Palomba et al. JCEM 90(7): 4068-74, 2005

34. Does metformin decrease the spontaneous miscarriage rate in PCOS? • Randomized controlled trial of metformin 850 mg bid vs. clomiphene citrate 150 mg qd cycle days 5-9 • Metformin group miscarriage = 3/31 (9.7%) • Clomid group miscarriage = 6/16 (37.5%) • P = 0.045 Palomba et al. JCEM 90(7): 4068-74, 2005

35. Is metformin more effective than clomid? Legro et al. NEJM 356,6: 551-66, 2007

36. What if all the tests are normal? Unexplained Infertility ~10% of couples

37. Guzick et al. Efficacy of treatment for unexplained infertility.Fertil Steril. 1998 Aug;70(2):207-13.) Treatment Options: Unexplained Infertility See next slide

38. OU Reproductive Medicine IVF Statistics( (Delivered per embryo transfer in 2010) % Pregnant or Delivered Age group (years) * A comparison of clinic success rates may not be meaningful because patient medical characteristics, treatment approaches and entrance criteria for ART may vary from clinic to clinic.

39. Treatment Options: In Vitro Fertilization (IVF) & ART • Blocked tubes • Severe male factor • Unexplained infertility • Endometriosis/peritoneal factor infertility • Failure to conceive with less aggressive treatment • Ovarian failure/ ovarian reserve (donor eggs)

40. ART Team Office & Clinic Staff MDs Lab• Embryology• Andrology• Endocrine NursingStaff

41. Assisted Reproductive Technology—ART • 1978/1981 In vitro fertilization—IVF • 1984 Donor oocyte (egg) cycle • 1985 Cryopreserved Embryo Transfer • 1990 Preimplantation Genetic Diagnosis—PGD • 1992 Intracytoplasmic Sperm Injection—ICSI As of 2004, more than 1 million children born worldwide as a result of ART

42. IVFLuteal Leuprolide Protocol Transfer Retrieval hCG 2days 3-6days Gonadotropins8-12 days Lupron24-30 days OCPs14-28 days

43. Monitoring FolliclesIVF Ultrasound

44. Sonographic Egg Recovery

45. Sonographic Egg Recovery

46. Discovered “by accident” in 1991 in a Belgian IVF lab Successfully treats almost all forms of severe male factor infertility Intracytoplasmic sperm injection—ICSI

47. ICSI

48. Day 3 Embryo Transfer Day 5–6 Embryo Transfer “Blastocyst Transfer” Timing of Embryo Transfer Veeck LL, Zaninovic N. An Atlas of Human Blastocysts. 1st ed. New York: Parthenon Publishing, 2003;118.

49. Embryo Transfer

50. Loading Catheter