The document provides an update on ovulation stimulation, discussing the need for evidence-based treatments for infertility, particularly for patients with conditions such as PCOS and hypogonadotrophic hypogonadism. It outlines various treatment groups, compares the efficacy of different drugs like clomiphene citrate and gonadotropins, and highlights a recent study that shows gonadotropins lead to higher pregnancy rates than clomiphene citrate. Additionally, it emphasizes the importance of considering cost-effectiveness when choosing treatment options for patients.

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