This document provides an update on poor ovarian response and approaches to improving outcomes for women with poor ovarian reserve undergoing IVF treatment. The key points summarized are: 1) The PRIMA study found no difference in pregnancy outcomes between a mild ovarian stimulation protocol using 150 IU of FSH daily versus a conventional stimulation protocol using 450 IU of HMG daily for women with poor ovarian reserve, despite the mild protocol requiring fewer days of stimulation and lower gonadotropin doses. 2) While increasing gonadotropin doses does not improve pregnancy rates, supplementation with LH during stimulation may provide benefits for women with poor ovarian reserve based on prior studies. 3) A new approach called "dual stimulation"

1. Update on Poor Ovarian
Response
Hesham Al-Inany, M.D, PhD

2. Outline
• Introduction
• Prediction
• Gn dose : PRIMA study
• Adjuvants
• New Approaches
• Conclusion

3. POR: variety of definitions
Surrey & Schoolcraft Fertil Steril 2000
Polyzos & Devroey Fertil Steril 2011
41 definitions
in 47 RCTs
28 different criteria

4. Clarity with Bologna Consensus?
Ferraretti et al Hum Reprod 2011

5. Outline
• Introduction
• Prediction
• Gn dose : PRIMA study
• Adjuvants
• New Approaches
• Conclusion

6. AMH
• most useful
• It is done at any day of cycle
• It is expensive
• tips

7. AMH
• Between 1-5
• Below 1
• Above 5

8. Low AMH : Subgroup
CLASSIFICATION
• Elderly patients .
• Young patients .
• Young patients with a normal basal
hormonal profile.

9. AFC and AMH best predictors
Poor
Broer et al Fertil Steril 2008
Broer et al Hum Reprod Update 2013
Iliodromiti et al Hum Reprod Update 2014

10. Outline
• Introduction
• Prediction
• PRIMA study 2017
• Adjuvants
• New Approaches
• Conclusion

11. Protocols for IVF
GnRH Antagonist
Protocols
GnRH Agonist
Protocols
225 IU per day
(150 IU Europe)
Individualized Dosing of FSH/HMG
250 mg per day antagonist
Individualized Dosing of FSH/HMG
GnRHa 1.0 mg per day
up to 21 days
0.5 mg per day of GnRHa
225 IU per day
(150 IU Europe)
Day 6
of FSH/HMG
Day
of hCG
Day 1
of FSH/HMG
Day 6
of FSH/HMG
Day
of hCG
7 – 8 days
after estimated ovulation
Down regulation
Day 2 or 3
of menses
Day 1
FSH/HMG
OCP

12. PRIMA trial
• To evaluate the effectiveness and safety of a mild
stimulation IVF versus a conventional simulation IVF in
women with poor ovarian reserve undergoing IVF
treatment

13. 394 couples poor ovarian reserve
197 couples
Mild IVF
197 couples
Conventional IVF
treatmenttime
150 IU FSH + GnRH
antagonist
Long GnRH agonist
+ 450 IU HMG
Ongoing Pregnancy
recruitmentendpoint
PRIMA trial design

14. 450 IU HMG /day
mid-luteal GnRH agonist
hCG OPU ET
Menstr.
 Mild Ovarian stimulation IVF
 Conventional Ovarian stimulation/IVF
Interventions
150 IU FSH/day
5 days
After laatste pil
GnRH antagonist
Sd 6
hCG OPU ET
PIL (  10 days)
Cd2-3
Menstr.

15. Outcomes
Primary outcome
• Ongoing pregnancy rate
Secondary outcomes
• Clinical pregnancy
• Biochemical pregnancy
• Multiple pregnancy
• Mmiscarriage rate,
• Total FSH/HMG doses used for ovarian stimulation,
• Cancellation rate
• No. oocytes retrieved, no. metaphase II oocytes,
• Fertilization rate
• No. embryos obtained, embryo transfers, embryos frozen
• Drop-out rate

16. Baseline characteristics
Mild stimulation
(N=197)
conventional stimulation
(N=197)
Age in years (µ ±SD) 36.52± 3,963 36.63±4.287
BMI in Kg/m2 (µ ±SD) 27.19±4.486 27.45±5.282
D. Infertility in years ( µ ±SD) 9.43±5.6 9.28±5.7
Primary infertility, n (%) 143 (74.9) 138 (71.9)
AFC (µ ±SD) 6.2±2.8 6.5± 2.9
FSH (µ±SD) 11.4±4.3 10.5±4.0
E2(µ±SD) 43.8±22.6 42.8±25.7
AMH (µ ±SD) (n= 301) 0.52±0.62 0.6±0.66

17. Baseline characteristics
Mild stimulation
(N=197)
Conventional stimulation
(N=197)
poor ovarian response
Expected n (%) 143 (74.9) 145 (75.5)
Non expected n (%) 48 (25.1) 47 (24.5)
Previous IVF/ICSI cycles
Yes 89 (47.6%) 94 (50.3)
No 98 (52.4) 93 (49.7)
Causes of infertility, n (%)
Diminished ovarian reserve (IOF) 99 (51.8) 98 (52.0)
IOF + Poor semen quality 47 (24.6) 46 (24)
IOF+ Tubal 16 (8.4) 11 (5.7)
IOF+ Endometriosis 5.0 (2.6) 5.0 (2.6)
IOF+ Multiple factors 16 (8.4) 22 (11.5)
IOF+ Others (..i.e. failed IUI) 8.0 (4.1) 10 (5.2)

18. Pregnancy outcomes
Mild ovarian
stimulation
(N=197)
Conventional
stimulation
(N=197)
RR (95% CI)
Ongoing pregnancy rate, n (%) 23 (12) 28 (14.6) 0.82 (0.49-1.37)
Clinical pregnancy rate, n (%) 30 (15.7) 35 (18.2) 0.86 (0.55-1.34)
Biochemical pregnancy rate, n (%) 41 (21.5) 38 (19.8) 1.08 (0.73- 1.60)
Early Miscarriage rate, n (%) 7.0 (23) 7.0 (20) 1.0 (0.36-2.80)
Multiple pregnancy rate 2.0 (6.0) 2.0 (5.0) 1.0 (0.14- 7.03)

19. Ovarian stimulation outcomes
Mild stimulation
(N=197)
Conventional
stimulation (N= 197)
p
No. of stimulation days ( µ ±SD) 95% CI) 8.9±2.6 10.2± 2.5 0.00
Total amount of FSH ( µ ±SD) 1394.4 ±366.4 ---
0.00
Total amount of HMG (µ ±SD) ----- 4852.4±3650.6
No. cycle cancellation rate due to poor ovarian
response, n (% )
35 (18.7) 26 (13.9) 0.32
No. of follicles ≥ 15 mm on hCG day ( µ ±SD) 3.4± 3.0 4.7± 3.6 0.06

20. So
• No difference as regards pregnancy outcomes
• shorter duration of stimulation and lower amount of
gonadotropins.

21. So
Increasing dose of Gn does not improve pregnancy
outcome in women with poor reserve undergoing IVF
treatment

22. Outline
• Introduction
• Prediction
• PRIMA study 2017
• Adjuvants
• New Approaches
• Conclusion

23. LH supplementation
Favours r-hFSH Favours r-hFSH + r-hLH
Mochtar MH, Cochrane Database, 2014.
Study or subgroup
rLH and rFSH
n/N
rFSH alone
n/N
Odds Ratio
M-H, Fixed, 95% CI
Weight
Odds Ratio
M-H, Fixed, 95% CI
Barrenetxea 2006 8/36 7/36 25.7% 1.18 [0.38,3.70]
DePlacido 2005 19/65 13/65 43.5% 1.65 [0.74,3.71]
Ferraretti 2004 22/54 11/54 30.8% 2.69 [1.14,6.33]
Total (95%CI) 155 155 100.0% 1.85 [1.10,3.11]
Total events: 49 (rLH andr FSH), 31 (rFSH alone)
Heterogeneity: Chi2=1.40, df=2 (P=0.50); I2=0.0%
Test for overall effect: Z=2.32 (P=0.020)
Review: Recombinant Luteinizing Hormone (rLH) for controlled ovarian hyperstimulation in assisted
reproductive cycles
Comparison: 3 rLH and rFSH versus rFSH alone for COH in GnRH agonist dowregulated IVF/CSI cycles in poor
responders
Outcome: 1 Ongoing pregnancy per woman randomised

24. Natural and Modified natural not
effective in RCTs
Polyzos et al Hum Reprod 2012
Kedem et al Fertil Steril 2014

25. Use of Growth Hormone reported as beneficial
Yovich and Stanger (2010) RMBO 21:37-49
10 IU of GH on days 21 (previous cycle), 2, 6, 8, 10 and 12th

26. But few RCTs to confirm a five fold
positive effect?

27. DHEA – no evidence of effect
Xu et al Plos One 2014
DHEA group ControlsParameter Significance

28. pretreatment with transdermal
AndroGel(r)

29. 2017

30. 2018

31. Outline
• Introduction
• Prediction
• Gn dose : PRIMA study
• Adjuvants
• New Approaches
• Conclusion

32. Accumulate oocytes first to avoid
disappointing negative pregnancy tests
+
oocytes Fresh oocytes form
the following cycle
Mixt cohort
ICSI
VitMixt
Types of ET
Fresh

33. 36.4 vs 23.7 %
• Does it worth??

34. Dual Stimulation

35. Why to waste these?

37. Requirements
• GnRH antagonist
• Triggering with GnRHa
• Start stimulation within 2 days of OPU

38. Persistence may be the key
Smith et al 2014
Analysis of >250,000 IVF cycles

39. Conclusions
 Antagonist is the protocol of choice
 mild dose of Gn is enough
 Dual stimulation is good option
 Persistence is critical

40. THANK YOU