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Predicting Ovarian Response in Clinical Practice

Predicting Ovarian Response in Clinical Practice. Ege University Family Planning and Infertility Treatment and Research Center Ege University Dept. of OB&GYN İZMIR TURKEY. Prof. Dr. Ege TAVMERGEN GÖKER. ART SUCCESS. pregnancy. Ovulation induction. Male factor. Embryo quality.

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Predicting Ovarian Response in Clinical Practice

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  1. Predicting Ovarian Response in Clinical Practice Ege University Family Planning and Infertility Treatment and Research Center Ege University Dept. of OB&GYN İZMIR TURKEY Prof. Dr. Ege TAVMERGEN GÖKER

  2. ART SUCCESS pregnancy Ovulation induction Male factor Embryo quality Embryo transfer Implantation

  3. Ovulation induction is performed to obtain mature and good quality oocytes to ensure a good quality embryo • To provide adequate endocrine milieu

  4. Ovarian Reserve Ovarian reserve is a term to describe the functional potential of the ovary Reflects the number and may reflect quality of the oocytes (1). It refers to whatever remains in the declining pool of primordial follicles It reflects the reproductive potential of each oocyte(2) 1-Maheshwari A et al: RBM Online,18(5) ,717-734,2009 2-Broekmans FJ et al:Trends Endocrinol Metab 18:58-65 2007

  5. Why is prediction of ovarian reserve important in clinical practice? - To plan better induction protocoles for success and safety of ART -To counsel women regarding their reproductive potential

  6. Ovarian Reserve Screening Indications • Advanced womans age (>35y) • Ovarian surgery, frosen pelvis • Single ovary • Smoking • Family history • Otoimmune disease • Chemotherapy, radiotherapy • DM, HT, systemic diseases

  7. Poor Responder Incidence % 10 of women stimulated by gonadotrophins Up to 40% of women over age 35

  8. Hyperresponder Incidence 0.5-5% of the women have OHSS (Delvigne 2002,Aboulghar 2003)

  9. Predictors of ovarian performance The Ideal Ovarian Reserve Screening Method • Accurate/Predictive • Highly sensitive • Objective • Reproducible • Easily measurable • Independent of other factors • Cost-effective

  10. Ovarian Reserve - Tests • Static • Age, Basal FSH (1988), E2 (1995), FSH/LH (1996) - Inhibin-B (1989) • AMH (Anti Müllerian Hormone) • Dinamic • Clomifen citrate test (1987) • GnRHa test (1991) (GAST) • Gn stimulation test (1994) (EFORT) • Ultrasonography • Ovarian volume • Antral follicle count • Ovarian doppler exam • Ovarian biopsy

  11. Pretreatment assessment of ovarian reserve allows identification of women who are likely to have low, intermediate or exaggerated ovarian response • Modification of treatment protocoles • Ovarian volume and AFC provide direct measures of ovarian reserve where as inhibin B, FSH, AMH and E2 indirectly reflect early stages of follicles

  12. Age and Fertility Optimal Fertility Declining Fertility End of Fertility Menopause Irregular Cycles ART

  13. Ovarian Reserve & ReproductiveAge Primordial foll. pool At birth ~12000,000 At puberty ~ 300,000 Reproductive age ~ 400 ovulations

  14. ART Results According to Age PGT Results - Age

  15. Basal FSH – pregnancy(IVF) %24 30 %13.6 %10.7 20 10 • Pregnancy Delivery 0 <15 <15 15-25 15-25 >25 >25 Basal FSH Scott TR, 1989

  16. D(3) FSH– Intercycle variability Scott et al. Fertil Steril 1990; 53: 297-302 Martin et al. Fertil Steril 1996; 65: 1238-40 Abdalla H, Thum MY. Hum Reprod 2006;21,171-174 Age  Oocyte quality bFSH  Oocyte quantity

  17. FSH receptor polimorphismAsn680Ser • Serin has replaced asparagine at the 680. position of the FSH receptor. • This receptor is less active • Due to it FSH levels rise miss evaluations... Lambalk CB, Benjamins T, Harms P, van Montfrans JM, Gromoll J,Simoni M. Association of basal follicle stimulating hormone (FSH)levels with FSH receptor variants in subfertile women with normalmenstrual cycle:implications for ovarian sensitivity to FSH [abstract].In: Proceedings of the 2002 ASRM Annual Meeting, Seattle, Washington.Fertil Steril 2002;78(Suppl 1):S107.

  18. Basal E2 • High E2, can suppress FSH • Can predict ovarian response (>80 pg/ml) • Smotrich et al. Fertil Steril 1995; 64: 1136-40 • Scott et al-1997 • Buyalos et al. Fertil Steril 1997; 68: 272-7

  19. Inhibin • Dimeric peptid;  ve  subunit • A-subünit = inhibin A Secreted by the dominant follicle.Rises at late follicular phase after estradiol rise. Is a sign of follicular maturation. Due to smaller amount of granulosa cell production in older women inhibin A decreases • B-subünit = inhibin B Is secreted from the developing follicles at the mid luteal phase. Gives information about the developing follicles.

  20. AMH AMH is a member of transforming growth factor B family Is produced in the granulosa cells of preantral and small antral foll(up to 4mm) Is a direct marker of the primordial ovarian follicle pool Is a direct marker of the primordial ovarian follicle pool AMH is almost undetectable at birth, slightly increases in the weeks after birth , peaks in late puberty, undetectable after menapause (Kini 2010)

  21. Anti-Müllerian Hormone (AMH) • Produced by the granulosa cells of follicles 2-6 mm • Decreases the sensitivity of antral follicles to FSH • Is a direct marker of the primordial ovarian follicle pool • Is highly reproducible (cycle-to-cycle consistency) • Correlates significantly with the response to gonadotrophins

  22. Serum AMH levels are not stable during the cycle -rapidly decrease in early luteal phase -declines gradually during COH Streuli 2009,Kini 2010

  23. AMH and PCOS Nardo et al. Hum Reprod

  24. Conclusions AMH is similarly related to insulin resistance and androgens in women with and without PCOS. This effect appears to be independent of age although an indirect causal effect due to ageing or some other mechanisms cannot be ruled out. Excessive granulosa cell activity may be implicated in the abnormal follicular dynamic of the syndrome

  25. High serum AMH levels correlate with high IR’s and PR’s • A cut-off value of 0.75 or 0.5ng/ml has a sensitivity of 80-85% in predicting poor response (Marca 2007) • AMH >2.7ng/ml indicate good oocyte quality (Marca 2007,Silberstein 2006)

  26. Women with a ‘normal’ AMH (5 to ,15 pmol/l) treated with a long GnRH-agonist protocol • (both centres) showed a low incidence of excess response (0%) and poor response (0%). • In women with ‘high’ AMH (>15 pmol/l),the antagonist protocol eliminated the need for all • cryopreservation of embryos due to excess response (P , 0.001) and showed a higher • fresh cycle clinical pregnancy rate than agonist cycles [OR 4.40 (95% CI 1.95–9.93), P , 0.001]. Hum. Reprod. Advance Access published January 10, 2009

  27. Clomiphenecitratechallenge test(Navot, et al, 1987) • Dinamic test • Basal D3 FSH • Day 5.-9. 100 mg/g CC • 10. day FSH • Abnormal test is highly due to decreased E2 and inhibin-B production from granulosa cells. (Hoffman et al. Fertil Steril 1998; 69: 474-7)

  28. ExogenousFSHOvarianReserveTest (EFORT)(Fanchin et al, 1994) bFSH E2Result 11 30 Normal >11 30 Moderate 11 <30 Moderate >11 <30 Bad bFSH E2 (pg/mL) Single dosis FSH 300 IU 4 3 Cycle day YÜT, 52 patient +LR: 2.0

  29. GAST(GnRHa Stimulation Test) • Difference of E2 levels between D2-D3 after GnRH a Padilla et al., 1990, Windslow et al.,1991

  30. Ovarian ReserveAntral follicle count antral follicle

  31. 106 105 104 103 Follicular counts 102 101 100 0 10 20 30 40 50 60 70 80 Age (years) Gougeon et al. Biol Reprod 1994 50:653-663

  32. Antral Follicle Count (AFC) • Predicts the quantitative aspect of ovarian reserve • AFC is easy to determine by transvaginal ultrasound • Has low intercycle variability • Has low to moderate interobserver variability • < 6 follicles predicts poor response • > 16 follicles predicts excessive response • Correlates significantly with the response to gonadotrophins • Is significantly higher in women with PCOS • Correlates with age and AMH • Suffers from inter-observer and inter-cycle variability

  33. 1049 stimulated cycles(LA,microdose) AFC is a marker of ovarian response, has no predictive value for implantation rate AFC is a better predictor of ovarian response than age

  34. Inhibin B and AFC had the same predictive value for poor ovarian response Inhibin B on day 5 of OI is a better predictor for live birth rate than AFC

  35. AMH levels >7ng/ml are at risk of OHSS (La Marca 2007) AFC 14> may predict hyperresponse with a sesitivity of .82 and specifity of 0.89 (Kwee 2007)

  36. AMH and AFC seem equally predictive for poor response AFC is operator dependent

  37. Ovarian vascularity isnot predictive for Poor ovarian response

  38. Conclusions Prediction of ovarian response is important in IVF cycles as it helps to individualise and optimise the protocoleThere is no optimal test and treatment should not be denied based on the results. Instead, patients can be counselled and warnedThe purpose of any ovarian reserve test is the identification of poor response or hyperresponse according to age

  39. Conclusions Basal FSH is of less value than age in predicting pregnancy especially in young women AMH is superior to basal FSH and AFCAMH is easily measurable, accessible, accurate and relatively inexpensive AFC is one of the most reliable tests for ovarian reserve prediction Pregnancy prediction is more complicated than ovarian reserve, and the chance of pregnancy depends on many more factors other than ovarian reserve -

  40. Conclusions Pregnancy is not only related only to ovarian reserve;also embryo quality, ET transfer, endometrial receptivity…….

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