we are now entering the fourth generation for Assisted reproduction

1. 4G Ovarian
stimulation
2021
• Hesham Al-Inany, M.D, PhD
• Kaainih@yahoo.com
• Mobile : 01112220298

2. Outline
• Introduction
• Mono follicular development
• Multifollicular development
• LPS

3. ‫الجيل‬
‫األول‬
‫الجيل‬
‫الثانى‬
‫الجيل‬
‫الثالث‬
‫الجيل‬
‫الرابع‬
IUI
IVF
ICSI
PGD + NGS
4G
ART

5. ‫الجيل‬
‫األول‬
‫الجيل‬
‫الثانى‬
‫الجيل‬
‫الثالث‬
‫الجيل‬
‫الرابع‬
Female
male
cryo
Fertile couples
4G
Service

6. Fertile couples
Transfer only unaffected embryos to the woman
affected affected
affected

7. ‫الجيل‬
‫األول‬
‫الجيل‬
‫الثانى‬
‫الجيل‬
‫الثالث‬
‫الجيل‬
‫الرابع‬
CC
Gn
recFSH
All + cost
effectiveness
4G
O.I

8. ‫الجيل‬
‫األول‬
‫الجيل‬
‫الثانى‬
‫الجيل‬
‫الثالث‬
‫الجيل‬
‫الرابع‬
Tablets
Injections
Suppositories
SC
4G
LPS

9. Outline
• Introduction
• Mono follicular development
• Multifollicular development
• LPS

10. • Pregnancies and live births are achieved more effectively and
faster after OI with low-dose FSH than with CC.
• This result has to be balanced by convenience and cost in
favour of CC.
• FSH may be an appropriate first-line treatment for some
women with PCOS and anovulatory infertility, particularly
older patients. Homburg et al, 2012
CC vs low-dose FSH for treatment of infertile
women with PCOS: a randomized multinational
study

11. CC Gn P-value
Clinical
pregnancies (per
patient)
54 (44%) 76 (58%) 0.03
Ongoing
pregnancies (per
patient)
48 (39%) 68 (52%) 0.04
Clinical
pregnancies (per
cycle)
54 (17.4%) 76 (26.4%) 0.008
Ectopic
pregnancies 1 1
Miscarriage rate
per pregnancya 5 (9.2%) 7 (9.2%)
Multiple
pregnancies
(twins only)
0 2 (3.4%)
Cumulative pregnancy rate
Cycle 1 12.9% 25.6%
Cycle 2 29.3% 44.8%
Cycle 3 41.2% 52.1% 0.02

12. The M-OVIN (Lancet, Dec. 2017)

13. 666 Women
• Gn group had more livebirths than CC
• [52%] vs [41%] p=0·012
• Addition of IUI did not increase
livebirths compared with intercourse
p=0·11
• But what about cost ??

14. The M-OVIN (Hum Reprod. 2019)
• Although Gn is more effective
• CC is more cost effective
• More twins with Gn

15. Network Meta-analysis

17. NATURE, 2017

18. Network Results

19. PCOS : Gn is the best
• Followed by Letrozol + Metformin
• Letrozol box ~ equal to one ampoule Fostimon
150 iu

20. hMG 150IU (50 /day for 3 days)
50 IU/day
CD3 CD6
150 mg CC
hCG
DF ≥ 18 mm
34-36h

21. Reversed hMG/CC
(Al-Inany et al)
(ACTRN12607000568415)

22. Assessed for eligibility (n= 245)
Excluded (n= 15)
Not meeting inclusion criteria (n=7)
Refused to participate (n=5)
Social reasons (n=3)
Received IUI (110)
Analyzed (n=110)
Cycles cancelled (n=5)
Inadequate response (n=4)
Hyper-response (n=1)
Group I (n=115) received Merional + CC
Cycles cancelled (n=8)
Inadequate response (n=6)
Hyper-response (n=2)
Group II (n=115) received Merional alone
Received IUI (107)
Analyzed (n=107)
Allocation
Analysis
Follow-Up
Enrollment
Randomized (n=230)

23. Both groups
• Folliculometry
• hCG when follicle reach 18mm or more
• Serum LH on day of hCG
• IUI 34-36hs later
• Micronised progesterone for 18 days

24. Results
Variable HMG/CC
(n=110)
HMG
(n=107)
P value
LH on day of hCG (miu/ml) for
cases with no premature LH surge
7.3 ± 1.8 7.8 ± 2.2 NS
Number of Follicles ≥ 16 mm 2.4 ± 0.97 1.3 ± 1.1 P < 0.05*
Number of patients with premature
LH surge
6 (5.45%) 17 (15.89%) P<0.001*
End. Thickness (mm) 5.9 ± 0.7 4.9 ± 1.9 NS
Clinical Pregnancy 11 (10%) 9 (8.41%) NS

25. So
• Reversed hMG /CC is a valid option
• Cost effective

26. NEJM

27. CPR

28. LBR

29. 4G O.I strategy
• Initial use of Gn for 3 days
followed by CC seems to be
cost effective regimen
• Avoid CC resistance
• Maintain one follicle growing

30. Outline
• Introduction
• Mono follicular development
• Multifollicular development
• LPS

31. 31
IVF/ICSI cycles
• Multifollicular development is
still an integral component for
ovarian stimulation in IVF /
ICSI cycles (Keck et al, 2005)

32. Which Gonadotropin?
• Human menopausal gonadotropin(hMG)
• Highly purified FSH
• Recombinant FSH (r FSH)

33. 2008

34. Meta-analysis

35. Gn: 2016 Final Word
Madelon van Wely1, Irene Kwan2,
Anna L Burt3, Jane Thomas4, Andy
Vail5, Fulco Van der Veen6, Hesham G
Al-Inany

36. Live Birth Rate

37. Conclusion : 7339 women
• Gonadotrophins
are
Gonadotrophins
are
Gonadotrophins

38. Cost Effectiveness
VS
cost of Live Birth rate in IVF /ICSI cycle
HP-hMG recFSH

39. Simulating IVF cycle : 1st cycle
Start Cycle
10,000
Ovum Pickup
No OHSS
Ovum Pickup
OHSS
9810
190
Fertilization
& Transfer
No Oocytes
380
9620
Clinical
Pregnancy
-ve βHCG
2982
6638
Ongoing
Pregnancy
Miscarriage
405
2577
3246
3392
Continue
Stop
Goa
l!

40. IVF Transition Probabilities
• Probability of
discontinuation at
the end of the cycle
(failed clinical
pregnancy) for non-
medical reasons 1
Cycle Value
1 0.489
2 0.524
3 0.571
1 Schröder et al. Cumulative pregnancy rates and drop-out rates in a
German IVF programme: 4102 cycles in 2130 patients. May 2004

41. Miscarriage
p_miscar_rFSH
Start Cycle
Pregnancy
#
Ongoing Pregnancy
Clinical Pregnancy
p_clin_preg_rFSH
continue
#
Start Cycle
stop
t_discon_nomed[ _stage]
Stop IVF
-ve bHCG
#
Fertilization &
Embryo Transfer
#
No Oocytes
p_cancel_rFSH
Start Cycle
Ovum Pickup
No OHSS
#
Miscarriage
p_miscar_rFSH
Start Cycle
Pregnancy
#
Ongoing Pregnancy
Clinical Pregnancy
p_clin_preg_rFSH
continue
#
Start Cycle
stop
t_discon_nomed[ _stage]
Stop IVF
-ve bHCG
#
Fertilization &
Embryo Transfer
#
No Oocytes
p_cancel_rFSH
Start Cycle
Ovum Pickup
OHSS
p_OHSS_rFSH
Start Cycle
1
Ongoing Pregnancy
0
Stop IVF
0
rFSH
Miscarriage
p_miscar_hMG
Start Cycle
Pregnancy
#
Ongoing Pregnancy
Clinical Pregnancy
p_clin_preg_hMG
continue
#
Start Cycle
stop
t_discon_nomed[ _stage]
Stop IVF
-ve bHCG
#
Fertilization &
Embryo Transfer
#
No Oocytes
p_cancel_hMG
Start Cycle
Ovum Pickup
No OHSS
#
Miscarriage
p_miscar_hMG
Start Cycle
Pregnancy
#
Ongoing Pregnancy
Clinical Pregnancy
p_clin_preg_hMG
continue
#
Start Cycle
stop
t_discon_nomed[ _stage]
Stop IVF
-ve bHCG
#
Fertilization &
Embryo Transfer
#
No Oocytes
p_cancel_hMG
Start Cycle
Ovum Pickup
OHSS
p_OHSS_hMG
Start Cycle
1
Ongoing Pregnancy
0
Stop IVF
0
hMG
Ovarian
Stimulant

42. Rec FSH
rFSH : By the end of the 3rd cycle, the individual’s
probability of ending at re-starting the cycle is 2.2%,
in live birth rate is 34.6%, and in discontinuing IVF is
66.3 %
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability

43. hMG
% Start Cycle
% Pregnancy
% Stop IVF
0
0.2
0.4
0.6
0.8
1
1.2
1 2 3 stop
Cycle
Probability
hMG: By the end of the 3rd cycle, the individual’s
probability of ending at re-starting the cycle is 6%, in
live birth is 45.2%, and in discontinuing IVF is 60.3 %

44. Dose : 300 IU max

45. 4G COH strategy
• Gn: No specific type
• Dose : max 300 iu
• Cost matters

46. Outline
• Introduction
• Mono follicular development
• Multifollicular development
• LPS

47. Rationale
1. Aspiration of granulosa cells at egg retrieval
2. Achievement of supraphysiologic levels of E2
with current stimulation protocols

48. Delaying the Initiation of LPS Results in
Lower Pregnancy Rates after IVF:
Day 3 Day 6 P
N 59 67
Age, yrs 34.8 34.5
Peak E2 pg/mL 2223 2232
Oocytes 8.3 9.8
Clinical Preg/Tr % 61 44.8 0.05
Clinical Preg/Tr %
Agonist Cycles
71.4 47.5 0.03
Implantation Rate %
Agonist Cycles
34 21 0.02
Williams, Muasher, Fertil Steril 2001; 76: 1140-3.

49. Duration of LPS After IVF/ET:
Standard Protocol
6 weeks
Study Protocol
11 days
N 46 51
Age, yrs 31.8 ± 3.2 32.7 ± 3.1
Embryos Tr. 2.12 2.13
Clinical Preg. / Tr. % 63 62.7
Ongoing Preg. / Tr. % 58.7 51
Implantation Rate % 17.2 18.3
No statistically significant differences
Goudge et al, Fertil Steril 2010; 94: 946-51.

52. Meta-analysis

54. Convenience and Side Effects of
Route of P4 Administration
Intramuscular
pain
Local Reaction,
Severe Allergic Reaction (rare)
Vaginal
irritation, and soreness

55. 4G LPS
• S.C injection
• Twice Daily
• High cost
• Convenient
• Effective ????

56. Day 2 of cycle
RIGHT OVARY
AFC: 18 Follicles <10mm.
TVS
LEFT OVARY
AFC: 14 Follicles <10mm.

57. Our patient
• Glucose 81
• LH 4.17
• FSH 3.8
• PRL 5.75
• AMH 5.5

58. What Next ? Anovulatory
• Semen:
16 million /ml
35% motility
90% abnormal forms
• HSG

59. HSG

60. What could be the Treatment?
• O.I
• Weight loss
• Bariatric surgery
• IVF

61. O.I
• Gonadotrophin : one ampoule / day
for 5 days

62. 0 6 9 14
FSH ui/day
Step up regimen
8 …
75? 75?
Days
Gn
E2
<10
12
14
16
18
37.5 37.5 37.5 37.5 37.5
1 2 3 4 … 7
End Lineal Lineal
B-C
5mm
105
13 12
150?
C
8mm
242
13 14
C
11mm
410
190
10 …
112.5? 112.5?
C
7mm

63. 0 6 9 14
FSH ui/day
Step up protocol
8 9
75 75
C
7mm
150
10 11
112.5? 112.5
12 13
C
8mm
234
14 15
C
11mm
495
Days
Gn
E2
<10
12
14
16
18
75 75 75 75 75
1 2 3 4 … 7
End Lineal Lineal
C
6mm
75

64. Final conclusion
• Changing attitude
• Yes
• No
• Any questions?

65. Business Model : 6 Oct.
• El Wadi Hospital
• Division of Obstetrics & Gynecology
• 16 room
• 4 O.R
• X 50,000 Corporate
• Target 2 million
• Access to Hospital – IVF center

66. Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com
Mobile : 01112220298