1. ADJUVANTS IN ART Inci KAHYAOGLU, MD
Ankara Etlik Zubeyde Hanım Women’s Health Research and Education Hospital
Center of Assisted Reproduction

2. Poor responder (%9-24)
Number of retrieved oocytes
Pregnancy rate
Hyperresponder
OHSS (iatrogenik and mortal complication of COS)
Repeated implantation failure

3. Why we use adjuvants?
To optimize the ovarian response in order to permit fresh embryo transfer
Prevent ovarian hyperstimulation syndrome
In order to prevent repeated implantation failure

4. Androgens
Growth hormone
Coenzyme Q10
Metformin
Low molecular weight heparin
Aspirin
Corticosteroids

5. ANDROgens

6. İncrease follicular IGF-1, promote folliculogenesis (Vendola et al, 1998, J Clin Invest)
Potentiate gonadotropin effect (Casson et al, 2000, Human Reprod)
Reduce follicular arrest (Sen et al, 2010, Mol Endocrinol)

7. TESTOSTERONE

8. Testosterone
Massin et al; increase in plasma T levels, no difference in ovarian response parameters (2006, Human Reprod)
Fabregues et al; decrease in total gonadotropin dose and stimulation duration (2009, Human Rep)
Kim et al; decrease in total gonadotropin dose and stimulation duration, increase in number of retrieved total and mature oocytes, increase in clinical pregnancy rates (2011, Fertil Steril)

9. González-Comadran M, 2012, RBM Online

10. Definition of poor responder different
Live birth rate
Çalışma sayısı az
Poor responder tanımı farklı
Few studies included
Definition of poor responder different
Gonzales-Comadran M, 2012, RBM Online

11. Quality of evidence moderate
Live birth rate
N=345 4 RCT
Kanıt düzeyi orta
RCT’lere ihtiyaç var
Quality of evidence moderate
Conclusion: Need for randomized controlled trials!
Nagels HE, 2015, Cochrane Database

12. DEHYDROEPIANDROSTERONE

13. Increased number of oocyte number (Barad et al, 2005 Fertil Steril)
Increased fertilized oocytes (Barad&Gleicher, 2006, Human Reprod)
Improved embryo morphological grading (Barad&Gleicher, 2006, Human Reprod)
Increased pregnancy rates (Barad et al, 2007, J Assist Reprod Genet)
Lower miscarriage rates (Gleicher et al, 2009, Reprod Biol Endocrinol)

14. Definition of poor responder?
Clinical pregnancy
Definition of poor responder?
Insufficient data to support beneficial role of DHEA as an adjuvant !
Number of retrieved oocytes
Narcwichean A, 2013, Reprod Biol Endocrinol

15. Increase in live birth rate (OR 1.81)
RCT’ler alınmı, canlı doğum için 8 RCT, 878 hasta
Increase in live birth rate (OR 1.81)
Nagels HE, 2015, Cochrane Database

16. DHEA may be associated with improved live birth rate
Miscarriage rate
DHEA may be associated with improved live birth rate
BUT insufficient evidence to draw conclusions!
Nagels HE, 2015, Cochrane Database

17. Zhang M, 2016, Assist Reprod Genet

18. Clinical pregnancy Live birth rate Zhang M, J2016, Assist Reprod Genet
RCT ve case
Zhang M, J2016, Assist Reprod Genet

19. Need for high quality clinical trials!
Miscarriage rate
Need for high quality clinical trials!
Zhang M, J2016, Assist Reprod Genet

20. GROWTH HORMON

21. Mechanism Increase in local production of ILGF-1
Increase in sensitivity of granulosa cells to FSH (Zhou J, 1997, J Molecular Endocrinol)
Increase in steroidogenesis in granulosa cells (Masson HD, 1990, Jendocrinol)
Nuclear and cytoplasmic maturation of oocytes (Nardo LG, 2015, Human Fertilty)
Increase in DNA repair mechanism of oocytes (Thompson BJ, 2000, Endocrinology)

22. Duration: started at 21st day of the previous cycle or during stimulation
Dose: 4-24 U
Kolibianakis EM, 2009, Human Reprod Update

23. Clinical pregnancy
Live birth rate

24. Live birth rate Pregnancy rate Duffy JM, 2010, Cochrane Review
10 çalışma 440 hasta
Pregnancy rate
Duffy JM, 2010, Cochrane Review

25. Definition of “poor responder” heterogenous
GH increases live birth rate but is there any subgroup that GH works better?

26. Bayoumi et al; increased number of retrieved oocytes, mature oocytes and fertilized oocytes (2015, Int J Gynaecol Obstet)
Bassiouny et al; decreased duration of stimulation, increased number of total and mature oocytes (2016, Fertil Steril)
Eftekhar et al, increased number of retrieved oocytes and embryos (2013, Arch Gynecol Obstet)
LIGHT study; (2016) stimulation parameters better
NO difference in live birth rate!

27. Number of retrieved oocytes
Hart RJ, 2017, Current Opinion

28. Duration of stimulation
Pregnancy rate
Stimülasyon süresi daha kısa.
gebelik testi pozitiflik oranı daha fazla
Hart RJ, 2017, Current Opinion

29. Live birth rate Clinical pregnancy Hart RJ, 2017, Current Opinion
Klinik gebelik oranları daha iyi
FAKAT daha önceki analizlerden farklı olarak canlı doğum oranları arasında anlamlı fark yok
Hart RJ, 2017, Current Opinion

30. COENZYME Q10

31. Advanced age; dysfunctional mitochondria in oocyte or granuloza cells reduced energy production by OXP and abnormal chromosome segregation (Wilding et al, 2001, Human Reprod)
CoQ10 levels were higher in follicular fluids associated with mature oocyte and high grade embryos than dysmorphic and poor quality embryos (Turi et al, 2012, Arch Gynecol Obstet)

32. lowering aneuploidy rates
CoQ10 improve energy
production and reduce
free oxygen radicals,
lowering aneuploidy rates
Bentov Y, 2014, Clinical Med Insights: Reproductive Health

33. Decreased total gonadotropin dose
78 IVF cycles DHEA /75 mg) + CoQ10 (600 mg) vs
175 cycles DHEA
Decreased total gonadotropin dose
Gat I, 2016, Gynecol Endocrinol

34. METFORMIN

35. Androgens increase sensitivity to gonadotrophins
Metformin decrease intraovarian hyperandrogenism
Number of periovulatory follicles
E2 level

36. OR= 1.69 (95% CI: 0.85-3.34) OR= 0.27 (95% CI: 0.16-0.46)
Live birth rate (7 RCT)
OR= 1.69 (95% CI: )
OHSS (9 RCT )
OR= 0.27 (95% CI: )
Miscarriage
OR= 0.50 (95% CI: )
Palomba S, 2013, BJOG

37. 12 RCT, 1516 PCOS
Pregnancy rate ( RR 1.11, 95% CI )
LBR (RR 1.12, )
Spontaneous abortion (RR 1.00, )
OHSS (RR 0.44, )
Huang X, 2015, Int J Gynecol Obstet

38. OHSS
Tso LO, 2015, Fertil Steril

39. ASRM, 2016, Fertil Steril
mg/day at least 2 months before the stimulation (Palomba S, BJOG, 2013; Costello MF, 2006, Human Reprod)

40. ASPİRİN

41. Live birth rate Clinical pregnancy
Siristatidis CS, 2016, Cochrane Database Syst Rev

42. HEPARIN

43. Live birth rate
Clinical pregnancy
Akhtar MA, 2013, Cochrane Database

44. UNEXPLAINED RECURRENT IMPLANTATION FAILURE
Live birth rate
Potdar, 2013, Human Reprod Update

45. İmplantation rate
Miscarriage rate

46. CORTICOSTEROID

47. Antiinflamatory and immunosupressive actions
Decrease in intrauterine proinflammatory cytokines and NK activity
Improved intrauterine environment
Success

48. Live birth rate
Boomsma , 2012, Cochrane

49. Pregnancy rate )
Boomsma , 2012, Cochrane

50. IVF
Pregnancy rates
ICSI
Boomsma , 2012, Cochrane

51. Autoantibody (+)
Beneficial effect with with antinuclear Ab(+) (Taniguchi F, 2005, J Reprod Med; Geva et al, 2000, Am J Reprod Med)
Prospective studies with improved pregnancy rates (Ando et al, 1996, J Assist Reprod Genet; Kim CH,1997, J Obstet Gynecol Res)

52. Conclusion DHEA & Testosteron increase in pregnancy rates
Garcia-Velasco J, 2014, RBM Online

53. Conclusion
Growth Hormon; pregnancy rates and live birth rates (?) but most effective in which subgroup ?
Coenzyme Q10 insufficient evidence
Metformin; decrease in OHSS incidence

54. Conclusion
Aspirin; no difference in pregnancy or clinical pregnancy rates
Heparin; insufficient evidence for routine use, repeated implantation failure can
Steroid; insufficient evidence for routine use, may be beneficial in autoantibody (+)