Controlled Ovarian Hyper stimulation in ART By Dr Mamta Dighe Director- Xenith Advanced Fertility Centre- Pune

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Welcome to
XENITH-CONNECT - 3

2. Xenith Connect
Controlled Ovarian Hyperstimulation in ART
Dr Mamta Dighe
Director- Xenith Advanced Fertility Centre- Pune

3. Dr Mamta Dighe
Director- Xenith Advanced Fertility Centre , Pune
Past Director -IVFPune- Deenanath Mangeshkar Hospital, Pune
Fellow of National Board in Reproductive Medicine and working exclusively in the field
of Infertility for more than 15 years
Awarded ‘Icons of Pune –Women -2016’- Lokmat Group
Invited Faculty- World Gene Conference 2016
Scientific Chairperson ISAR 2009, Joint Organizing Secretary, IFS, Western
Maharashtra Chapter, 2014, Convenor- OI Workshop Fertitech 2017, AMOGS 2018
Invited Faculty at many National and International Conferences
Special Interests include Reproductive Endocrinology, Poor responders and
Endometriosis

4. Goals of COH
 Depends on the type of treatment planned- IUI or IVF
 To obtain a regular cohort of follicles
 To establish a single, healthy (euploid) pregnancy
 To maintain safety and to optimize the total reproductive potential

5. Goals of IVF
[1] to obtain multiple fertilizable oocytes of good quality than can
lead to diploid fertilization and early embryo development;
[2] to establish a single, healthy (euploid) pregnancy following embryo
transfer to the uterine cavity; and
[3] to cryopreserve excess embryos of good quality to optimize the
total reproductive potential

6. Complexity of COH
 This requires two major components:
 accurate means of predicting ovarian responses
 appropriate strategic approaches to COS adapted to that
response
Adaptive strategic approach using different GnRH
analogue control protocols has advantage over
simple modification of FSH dose,

7. >120 days 85 days
Paracrine Control Small
Antral
2–5 mm
Growth
FSH and LH
Independent
30 yr old
10 per day
or
2 per day
AMH
AMH
Low High
Ovarian Reserve
Adapted from Visser JA, Themmen APN. Mol Cell Endocrinol 2005;234:81–86.
Follicular development:
AMH secretion and circulation

8. Antral Follicle Count

9. Prediction of Response
The predicted ‘normal’ response category
(AMH -1.3 to 3.5ng/ml, AFC- 9-14)
The predicted ‘reduced’ response category
(AMH - <1.3ng/ml, AFC < 8)
The predicted ‘high’ response category
(AMH >3.6ng/ml, AFC > 15

10. COH in IUI
Where should we do COS
• 3 cycles of CC or Letroz with TR no improvement over expectant Rx
• IUI has much high preg rate
• If female > 35 then Gn stimulation increases preg rate
Anovulatory- 21% Unexplained- 15% Male- 10-12%
• CC or Letroz with IUI same results in Unexplained Infertility
• Gn with IUI also not recommended due to higher multiple pregnancy
rates
• Letroz should be first choice in PCOS

11. Clomiphene in IUI


12. Clomiphene Citrate
CC how to use
 Higher dose
 Longer duration
 Luteal phase CC Don’t wait for withdrawal after progesterone.
Start immediately after Prog stop
 Adjuvants
Pregnancy Rates
 50% in first cycle
 15% in second
 5% third cycle

15. Gn in IUI

16. Gn in IUI

17. Antagonist in IUI

18. Premature LH
surge occurs in
25-30% of IUI
cycles
Antagonists
completely abolish
LH surge
Increase in LBR is
5.3%
NUMBER NEEDED
TO TREAT (NNT)
is 20

19. Antagonist in IUI

20. hCG Trigger in IUI


21. hCG Trigger in IUI

22. hCG Trigger in IUI

24. Doppler and Timing of IUI

25. Luteal Support in IUI

26. Modified Natural Cycle IUI

27. Complexity of COH in IVF

28. Efficacy of Ovarian Stimulation
COS
improves
LBR

29. COH and Live Birth

30. COH and Live birth rates

31. Complexity of COH

32. Complexity of COH

33. Complexity of COH

34. COH strategy in Normal Responders
The predicted ‘normal’ response category
(AMH -1.3 to 3.5ng/ml, AFC- 9-14)
 Agonist cycles work well
 But so may antag
Human Reproduction, Vol.24, No.4 pp. 867–875, 2009

35. COH strategy in Poor Responders
The predicted ‘reduced’ response category
(AMH - <1.3ng/ml, AFC < 8)
 antagonist protocols were associated with a substantial drop in
cycle cancellation
 trend towards higher pregnancy rates
 Flare or Microdose flare protocols with GnRH agonists
 GnRH downregulation protocol- resurgence
Human Reproduction, Vol.24, No.4 pp. 867–875, 2009

36. COH in Hyperesponders
The ‘high’ response category (AMH >3.6ng/ml, AFC > 15)
With Antagonist cycles
 Clinical PR higher ( 61.7% vs 31.8%)
 Fewer cycle cancellations
 More fresh cycle transfers
 Equal numbaer of embryos for cryopreservation
 Reduced hospitalization for OHSS (0% vs13.9% )
 Ability to Use Agonist trigger
Human Reproduction, Vol.24, No.4 pp. 867–875, 2009

37. Gonadotropin Dose

38. COH as per predicted response

39. Normograms for Dose calculation-AFC

40. Normograms for Dose calculation- AMH

41. Complexity of COH

42. Long Agonist Protocol
Ideal in good
responders;
Not suitable in poor responders – increases the duration of treatment and dose of
gonadotropins without any increase in PR
Not suitable in hyper-responders as it increases the size of recruited follicular pool thus
increasing the risk of OHSS

43. Key Points in the Long Protocol

44. Drawbacks of the Long Protocol

45. Antagonist: Treatment Protocols
Hurine Judith, Lambalk Cornelis. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001; 358:
1793-803
d8
0.25 mg Cetrorelix/day
FSH 150
hCG/GnRHad2-3
d5/6
3 mg
FSH
hCG/GnRHad2-3
Multi-dose regimen
Single-dose regimen
• Ideal for hyper-responders, as antagonists do not influence follicular recruitment.
• Also, option of using GnRHa for ovulation trigger is feasible if the follicular recruitment is high
despite low starting dose of FSH.
• Multi-dose daily regime from day 6 of the stimulation is the most widely used antagonitst
protocol.

46. Antagonist Effects

47. Key Points in Antagonist Protocol

48. Agonist Trigger in Antag Cycles

49. Effects of dose changes

50. Complexity of COH

51. Short Agonist Protocol
d21-24
GnRH agonist
FSH/ HMG 300-375
hCGd2-3
OR ET
Suitable for Poor Responders
High FSH starting dose (300-375 iu)
Initial flare may help in increasing the recruitment.
Generally accepted that LH component is required in addtion to
FSH in older women with POR

52. Modified Natural / Minimal
Stimulation
/ Clomiphne
Poor Responders
Very low ovarian reserve

53. Individualized COH
AMH sub-categories Treatment protocol Comments
High
>3.6ng/ml
GnRH antagonist:
150 Iu r-FSH or HP-hMG daily
Maintains efficacy with sub
maximal response
Normal & “safe”
>1.26-3.6ng/ml
GnRH agonist long downreg:
200/225 IU r-FSH or HP-hMG
daily
Good response expected
Low
<1.26ng/ml
GnRH agonist or antagonist:
300-450 IU rFSH daily/ more
consider rLH addition
Remains the biggest challenge

54. Understanding POSEIDON Criteria
GROUP 1
Youngpatients<35yearswith
adequate ovarian reserve
parameters(AFC≥5;AMH≥1.2ng/
ml) and with an unexpected
poor or suboptimal ovarian
response
GROUP2
Olderpatients≥35yearswithade
quateovarianreserveparameter
s(AFC≥5;AMH≥1.2ng/ml)andwit
hanunexpectedpoororsuboptim
alovarianres
GROUP3
Youngpatients(<35years)withpoorova
rianreservepre-
stimulationparameters(AFC <5; AFC<
1.2ng/ml
GROUP4
Olderpatients(≥35years)withpoo
rovarianreservepre-
stimulationparameters(AFC
<5;AMH <1.2ng/ml)

55. Type of Poor Responder
PROBLEM: Women with Low Oocyte Quantity may have different clinical characteristics

56. Understanding Ovarian Response
Existing POR criteria NOT able to identify patients with
low/suboptimal ovarian responseto COS due to inherent ovarian
resistance (genetic polymorphisms)
Low Follicular Output RaTe
Genroet al. 2011; Gallotet al. 2012

57. Poor Response vs Hypo Response
POOR RESPONDER
At least twoof the following three features
must be present:
•Advanced maternal age(≥40 years) or
anyother risk factor for POR (Turner
syndrome, X-fragile mutations, history of
chemotherapyetc.)
•A previous poor ovarian response(POR) (≤3
oocytes with a conventional stimulation
protocol)
•An abnormalovarianreservetest (i.e., AFC 5
–7 folliclesor AMH 0.5 –1.1 ng/ml)
HYPO RESPONDER
Young,normogonadotrophic
women,with norma lovarian reserve
who show sub-optimal or
unexpected poor response to
exogenousFSH
•Thesewomen,evenwhentheovarianres
ponseisnormal(i.e.,>5eggs)tendtoshow
anincreaseinthecumulativeFSHdose(i.
e.>2500-
3000IU)andinthestimulationlength(hyp
o-sensitivityto

58. Gonadotropin Receptor Polymorphism and
Hypo-response
FSH-R Ser680 carriers have low FORT and require more FSH
V-beta-LH carriers have low FORT and require more FSH
Gonadotropin Receptor Polymorphisms influence ovarian response and
determine FORT

59. Hypo Responders
Groups 1 and 2 POSEIDON
The Role of LH in women with low FORT
R-hLH significantly increases implantation rate
R-hLH significantly increases FORT
In women between 35-40 r-hLH supplementation improves
implantation rate compared with r-hFSH
LH in 35-39 years : Increase in implantation rate is associated with
similar number of oocyte

60. Management of POSEIDON Group 1 and 2
The concept of low prognosis should be developed considering new categories of
abnormal ovarian response(i.e.,unexpected poor or sub-optimal responders)
Hypo-sensitivity to standard FSH dose(lowFORT) is a polygenic trait and can cause
unexpected poor or suboptimal response
There is evidence that FSHR polymorphism Ser680 plays a crucial role in determining
sensitivity to standard doses of FSH
Polymorphisms of LH and LH-R also seem to involved in determining hypo-response
There is evidence(Level1) that LH improves implantation rate in hypo-responders
consistent with groups1–2 Poseidon and women aged 35-39 with good ovarian
reserve(consistent with Group2 Poseidon)

61. POSEIDON Groups 3 and 4
GROUP3
Youngpatients(<35years)withpoorova
rianreservepre-
stimulationparameters(AFC <5; AFC<
1.2ng/ml
GROUP4
Olderpatients(≥35years)withpoo
rovarianreservepre-
stimulationparameters(AFC
<5;AMH <1.2ng/ml)

62. Poor Reserve Young Age
“Poor reserve -good quality”
iCOS Treatment:
•Flare protocol
•GnRHantagonist (E2, OCP)
•Stimulation up to 300 IU/d rFSH
•DuoStim(Ubaldiet al., 2015)
•Androgens? (DHEA, testosterone)
•Fresh transfer
•Oocyte/embryo accumulation and FET
Reasons for low Response:
•Poor ovarian reserve
•Asynchronous development
•

63. Poor Reserve –Advanced Age
“Poor reserve –poor quality”
iCOS Treatment:
•Flare GnRHaprotocol
•GnRHantagonist (E2, OCP)
•Stimulation up to 300 IU/d rFSHand LH
•Androgens (DHEA, testosterone)?
•GH?
•DuoStim(Ubaldiet al., 2015)
•Fresh transfer
•Segmentation –oocyte/embryo
accumulation and FET
•(Oocyte donation)
Poseidon Group, Fertil Steril 2016
Reasons for low Response:
•Poor ovarian reserve
•Asynchronous development
•Older age

64. DUO STIM PROTOCOL
Ubaldi, Alviggi ASRM 2015

65. Duo- Stim
In 2003 based on USG studies it was shown that follicular development occurs in
waves and that follicles developing during luteal phase could be developed further
Previous studies have shown that existing antral follicles in the luteal phase enable
ovarian stimulation (Huang et al., 2013)
Luteal-phasestimulation was originallyused to produce mature oocytes and
embryos for cryopreservation in case reports of emergency fertility preservation
and letrozole cycle (Huang et al. 2013; Bedoschiet al. 2010; Sonmezeret al.2011)

66. Duo- Stim
Luteal phase stimulatiom gives competent oocytes with live
birth rates
In low prognosis patients(Groups3 –4 Poseidon) Duo stim can
maximize the numbe rof oocytes per menstrual cycle increasing
the chance of obtaining the embryo that can give a live birth
and can minimize time to pregnancy

67. Role of LH

68. Role of LH
No difference in oocyte number
Basic severity score: Mild –moderate –severe POR
Higher LBR with r-hFSH+r-LHin moderate/severe
POR compared with mild POR
Lower pregnancy loss with r-hFSH+r-LH
Suggesting an effect on oocyte/embryo quality

69. Strategies in Group 3 and 4
Recombinant LH supplementation –”Bologna POR”
-Effect in POR subgroups, BSC 2 and 3 -Humaidanet al., ESPART 2017
DHEA
More studies needed
Transdermal testosterone
–LBR increased by 11% (95% CI: +0.3% to +22%); 2 RCT
–Bosdouet al. HR update 2012
–LBR increased RR 1.9 (95% CI: 1.01 -3.63)
–Gonzalez-Comadran, RBMO 2012
T-Transport NCT02418572 ongoingRCT –400 Bologna POR to berandomized
Growth hormone
–LBR increased (OR: 5.39; 95% CI:1.89-15.35); 4 RCT Cochrane 2010
–Bassiounyet al., 2016 –No effectin Bologna POR

70. COH in Poor Responders
Stratifying our patients based on their prognosis for pregnancy, using
the most relevant predictive parameters:
Oocyte quantity (ovarian reserve and genetic-related ovarian resistance)
Oocyte Quality (age)
Finding remedies to change the fate of our low prognosis patients
undergoing ART.

71. Takehome of COH

72. Conclusion
• COH is the central part of an ART procedure
• Choosing the most appropriate protocol is very important for optimizing the
success and minimizing the complications
• Individualiztion is now possible before the first attempt at IVF (AMH and AFC)
• Certain patient characteristics may influence ovarian reserve or ovarian response
to COH and hence may necessitate modifications in the COH protocol
• It is important to differentiate between poor reserve and poor response
• While deciding the starting dose of FSH / HMG for ovarian stimulation, the impact
of age, ethnicity, BMI and smoking need to be taken into consideration.

73. Thank you

74. Complexity of COH

75. Complexity of COH

76. Complexity of COH

77. Complexity of COH

78. Complexity of COH