10/20/2017 Disclosure No one involved in the planning or presentation of this activity has any relevant financial relationships with a commercial interest to disclose. Infertility Evaluation and ART Center for Reproductive Health Center for Reproductive Health Evelyn Mok-Lin, MD Assistant Professor, Obstetrics, Gynecology and Reproductive Sciences Medical Director, UCSF Center for Reproductive Health 2 Infertility is a Common Disease Age is the #1 Predictor of Fertility • 12% of reproductive age women in the US have • Women are less likely to conceive and more infertility likely to miscarry as they get older • WHO ranks infertility as the 3 rd most serious disease worldwide Center for Reproductive Health Heffner, NEJM 2004 3 4 1
10/20/2017 Decreasing Egg Quantity with Age Abnormal Spindles in Older Eggs 20-25 year old eggs – 17% of eggs with abnormal spindle assembly 40-45 year old eggs Center for Reproductive Health – 83% of eggs with abnormal spindle assembly • Finite number of follicles at birth • 12% remaining at age 30 • 3% remaining at age 40 Battaglia et al, Human Reproduction 1996 Wallace and Kelsey, PLoS 2010 5 6 Increasing Rates of Chromosomal Aneuploidy Rates in Couples Abnormalities with Age Undergoing IVF Franasiak et al. Fertility and Sterility 2014 7 8 2
10/20/2017 Age at which to start trying to Evaluation of the Infertile Couple conceive Center for Reproductive Health Habbema et al. Human Reproduction 2015 9 10 Evaluation of the Infertile Couple Ovarian Reserve Testing • Ovarian Reserve Testing • Anti-Mullerian Hormone (AMH) • Tubal Patency Assessment – The most reliable predictor – Produced by granulosa cells of pre-antral and small • Semen Analysis antral follicles • Other Indicated Testing – Drawn at any time in the menstrual cycle – Can be drawn while on hormonal contraceptives (long-term use may suppress levels) Center for Reproductive Health Center for Reproductive Health – The higher the level, the higher the reserve – “Normal” level is age-dependent 11 12 3
10/20/2017 Ovarian Reserve Testing Ovarian Reserve Testing • Follicle Stimulating Hormone (FSH) • Antral Follicle Count (AFC) – Indirect marker of ovarian reserve – The number of follicles <10mm – Produced by the pituitary in response to negative – Assessed via transvaginal ultrasound at any time in feedback from estradiol and inhibin B the cycle – Drawn on day 2-3 of the menstrual cycle along with – The higher the AFC, the higher the reserve an estradiol (E2) – The higher the level, the lower the reserve Center for Reproductive Health Center for Reproductive Health – Normal is <10-12 IU/L There is no screening test for egg QUALITY, only quantity 13 14 Tubal Patency Assessment Tubal Patency Assessment • Hysterosalpingogram (HSG) • Hysterosalpingogram (HSG) • Sono HSG (FemVue) – Oil-based better than water-based Center for Reproductive Health Center for Reproductive Health Dreyer et al. NEJM 2017 15 16 4
10/20/2017 Evaluation of the Infertile Couple Optimizing Natural Fertility • Semen Analysis • Other Indicated Testing – Thyroid – Prolactin – PCOS labs Center for Reproductive Health Center for Reproductive Health – Other imaging 17 18 Assisted Reproductive Technology Assisted Reproductive Technology (ART) Options (ART) Options • Superovulation – Ovulation of >1 egg to overcome the age effect – Oral agents (Clomid, Letrozole) – Injectable FSH/LH (Gonal-F, Follistim, Menopur) – Often used in conjunction with intrauterine insemination (IUI) Center for Reproductive Health Center for Reproductive Health 19 20 5
10/20/2017 Clomiphene Citrate (Clomid) Clomid Instructions Based on a 28 day cycle • Selective Estrogen Take 50-150mg (1-3 tabs) daily x 5 days Receptor Modulator Start on cycle day 3 (days 3-7) (SERM) • ER antagonist at the hypothalamus • Inhibits negative feedback of Check ovulation kit Center for Reproductive Health Center for Reproductive Health Ultrasound on day 10 estrogen starting day 10 until + • Increased GnRH hCG trigger pulsatility • Increased pituitary Intercourse or IUI 12-24 Intercourse or IUI 24-36 FSH and LH hours after +kit hours after hCG trigger secretion 21 22 Artificial Insemination (AI) or Potential Side Effects of Clomid Intrauterine Insemination (IUI) • Increased multiple pregnancy rate (7%) • Mood swings • Hot flushes • Headaches • Bloating • Visual symptoms and light sensitivity Center for Reproductive Health Center for Reproductive Health • Decreased endometrial thickness • Decreased cervical mucus 23 24 6
10/20/2017 Letrozole (Femara) Letrozole (Femara) • Aromatase inhibitor • 2.5-7.5mg (1-3 tabs) daily x 5 days (AI) • Not FDA approved for fertility use • Blocks conversion • More expensive of androgens into estrogen • Fewer side effects (fatigue and dizziness) • Inhibits negative feedback of • Increased success rates in PCOS patients Center for Reproductive Health Center for Reproductive Health estrogen – Legro et al., NEJM 2014 • Increased GnRH – 750 infertile women 18-40 years of age pulsatility – Randomized to Letrozole or Clomid with intercourse • Increased pituitary for up to 5 cycles FSH and LH – Higher ovulation, pregnancy and live-birth rates in secretion Letrozole group 25 26 IVF Center for Reproductive Health Center for Reproductive Health Veeck, Atlas of Human Gametes and Conceptuses 27 28 7
10/20/2017 IVF Procedure IVF Procedure Egg Retrieval FSH+LH 1 3 5 7 9 11 13 Days Center for Reproductive Health Center for Reproductive Health hCG trigger 29 30 Intracytoplasmic Sperm Injection Preimplantation Genetic Screening (ICSI) • PGS vs PGD • Benefits of PGS for women > 37: – Decreased risk of early miscarriages from aneuploidy – Decreased risk of chromosomally abnormal pregnancies Center for Reproductive Health Center for Reproductive Health – Decreased number of embryo transfer attempts – Decreased risk of multiple gestation 31 32 8
10/20/2017 Preimplantation Genetic Screening Summary • Risks of PGS: • Fertility rates decrease and miscarriage rates increase as women get older – Increased cost – Increased manipulation of the embryo • Initiate infertility evaluation and refer to REI after 12 months of trying to conceive in a woman < 35 yrs, – Decreased total number of embryos for transfer and after 6 months in a woman > 35 yrs (possible decrease in cumulative pregnancy rate) – Error rates and mosaicism Center for Reproductive Health Center for Reproductive Health • Treatment options include superovulation / IUI and IVF (+/- PGS) 33 34 Thank you 9
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