Medicine is changing and so ovulation induction : we present here the changing attitude in ovarian stimulation to be up to date

1. Ovulation Stimulation
2021
• Hesham Al-Inany, M.D, PhD
• Kaainih@yahoo.com
• Mobile : 01112220298

2. 2
Why Do We Need This Talk
• To update our knowledge and
understanding
• To provide evidence for decision-
makers
• To provide our patients with best
care based on Evidence

3. Outline
• Introduction
• Paradigm shift
• Gn/CC
• Supporting evidence

4. WHO Groups I to III
4
FSH usually
normal
FSH
usually
high
Hypothalamic
pituitary
dysfunction
(often PCOS)
Ovarian failure
Hypothalamic
pituitary failure
(hypogonadotrophi
c hypogonadism)
Group III 10%
Group II >85%
Group I : <5%
Normal
estrogen and
prolactin
1.World Health Organization. World Health Organ Tech Rep Ser. 1973;514:1–30.
2.Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
FSH usually
low
Estrogen
deficient and
low prolactin

5. OI can be achieved by2
Gn
Overcoming Infertility: Group I
5
FSH usually
low
Hypothalamic pituitary failure
(hypogonadotrophic hypogonadism)
Group I1
Low
Estrogen
Low
prolactin
1.Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
2.Messinis. Hum Reprod. 2005;20(10):2688–2697.

6. Overcoming Infertility: Group II
6
1. Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
2. Messinis. Hum Reprod. 2005;20(10):2688–2697.
FSH usually
normal
Hypothalamic pituitary dysfunction
(often PCOS)
Group II1
Normal
estrogen
Normal
prolactin
OI can be achieved by :
(clomiphene citrate)
Aromatase
inhibitors Gn Metformin LOD

7. O.I : other indications
7
1.Messinis. Hum Reprod. 2005;20(10):2688–2697.
2.Homburg et al. Hum Reprod. 2002;8(5):449–462.
3.Casper et al. J Clin Endocrinol Metabol. 2006;91(3):760–771.
• Group I: Anovulation related to hypogonadotrophic hypogonadism
• Group II: Anovulation related to PCOS
• Multifactorial subfertility: Production of one to three preovulatory follicles,
usually in combination with intrauterine insemination2,3
– Mild endometriosis
– Transient anovulation
– Mild OAT
– Cervical mucus inadequacy or hostility,
– Unilateral tubal occlusion

8. CC – LTZ : Pros & Cons
• CC may induce flushes and mood
swings
• letrozole can give headache and
abdominal cramps.
• ~25% of cases are resistant
(Legro et al., 2014)

9. Gn
• tend to have fewer side effects
than clomiphene citrate (Legro,
2016).
• the treatment with oral agents
is less costly (Balen, 2013)

10. Outline
• Introduction
• Paradigm shift
• Gn/CC
• Supporting evidence
• Case presentation

11. O.I
• New era
• Based on evidence

12. Randomisation
Participants
R
a
n
d
o
m
l
y
A
s
s
i
g
n
e
d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
O
u
t
c
o
m
e
C
o
m
p
a
r
e
d

13. • 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

14. 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

15. The M-OVIN (Lancet, Feb. 2018)

16. 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

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

18. Outline
• Current practice
• Paradigm shift
• Gn/CC
• Supporting evidence
• Case presentation

19. Reversed Gn/CC
(Al-Inany et al)
(ACTRN12607000568415)

20. Gn (4 days) then CC
75 IU/Gn
CD3 CD7
150 mg CC
hCG IUI
DF ≥ 18
mm
34-36h

21. 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)

22. 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

23. Results
Variable Gn/CC
(n=110)
Gn
(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

24. So
• Reversed Gn /CC is a valid option
• Cost effective

25. Outline
• Current practice
• Paradigm shift
• Gn/CC
• Supporting evidence
• Case presentation

26. Meta-analysis

27. Traditional
MA results

28. Network Meta-analysis

29. NATURE, 2017

30. Network Results

31. PCOS : Gn is the best
• Followed by Letrozol + Metformin

32. NEJM

33. CPR

34. LBR

35. Conclusion
• There is a clear evidence
that justify shift from CC to
Gn low dose for O.I
• Gn for 4 days followed by CC
seems to be cost effective
regimen

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

37. 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

38. 0 6 9 14
FSH ui/day
Step down regimen
Days
Gn
E2
<10
12
14
16
18
112.5
1 2 3 4 5 6
End Lineal Lineal
IVF? CANCELLATION?
hCG? COASTING?
196
7 8
75?
B-C
7mm
11 12
A
13mm
920
490
37.5?
9 10
B
10mm

39. hCG
• Dose ?
• When ?
• GnRHa?

40. Few days later (day 6 of hCG)
 She was presenting with:
Abdominal pain
Nausea and vomiting

41. What could be the reason?
• Gastroenteritis
• OHSS
• Pyelitis or pyelonepheritis

42. Inv.
• CBC
• Urine analysis
• U/S

43. CBC
 Hb: 14 g /dL,
 Hematocrit: 41%
 WBC count: 9,000/ml
 Platelet count : 350,000/mm3

44. Urine analysis
• Pus cells > 100
• culture : >100,000 bacteruria

45. U/S

46. What to do?
• Outpatient management ??
• Uro-vaxom for seven days
• Analgesia and antiemetics
• Follow up

47. But
 Vomiting &abdominal discomfort persist
 Haematocrite : 45%
 Platelet : 420,000
Intravenous fluid infusion is decided

48. Which is the Best Initial IV Fluid
A. Lactated ringer's
B. Dextrose 5% in normal saline
C. Normal saline
D. Human albumin
E. Hydroxy-ethyl-starch (HES)

49. Patient was improved
• Discharged with normal CBC

50. 5 days later
• She returned with more abdominal pain
 Hematocrit 46% WBC 12,000/ml
 Clinical ascites
 Dyspnea

51. What could be the diagnosis
• Late OHSS

52. What to do?
• HES
• Heparin
• IV glucose
• Aspocid

53. B-hCG
• 1200 !!!!
• What to do?
• Progesterone?
• Analgesic?
• Monitoring

54. Two weeks later
• U/S was done : Triplet ?
• What to do:-
• SER
• Cercelage

55. Urine analysis
• Again >100 pus cells
• What to do?
• Uro-Vaxom® is administered orally as one capsule daily
for
• (90 days).

56. 34ws gestation

57. 57
IVF/ICSI cycles
• Multifollicular development is
still an integral component for
ovarian stimulation in IVF /
ICSI cycles (Keck et al, 2005)

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

59. 2008

60. Meta-analysis

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

62. Live Birth Rate

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

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

65. 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!

66. 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

67. 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

68. Dose : 300 IU max

69. 4G COH strategy
• Gn: No specific type
• Dose : max 300 iu
• Cost matters

70. • Changing attitude in O.I
• Are u ready ?

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