An integral step in assisted reproduction is the prevention of premature LH surge. This presentation illustrate a novel way that may help in prevention of LH surge

1. New Modality for suppression of
LH surge
Why & How?
Hesham Al-Inany, PhD (Amsterdam)

2. Why LH suppression?
• The original concept of the existence of a
therapeutic window for LH during ovarian
stimulation was first put forward by Hillier.
• According to this, there is not only a threshold
requirement for LH to guarantee an optimal
cycle but also a ceiling level beyond which LH
might be deleterious to ovarian stimulation.

3. The criteria for premature luteinization
• Decreased cycle outcome has been reported
when LH is >10 IU/L and P>1.0 ng/L
• others elected to choose a cut-off value of
>1.2 ng/mL for progesterone to define
premature luteinization

4. The ideal IVF protocol
• a high chance of embryo transfer
• a low cancellation rate,
• a reasonable pregnancy rate
• few side-effects,
• low costs
• practical convenience both for the patient and
the clinician

5. History
• 1970 Clomifen
hMG
• 1980 GnRH-agonist / hMG
• 1990 recFSH / hMG
GnRH-antagonist / hMG or recFSH

6. 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

7. How Science is advancing!!

8. Observation

9. Further Observation

10. Then search the medical literature

14. How Science is advancing!!

15. Idea
• CC antiestrogenic effect may suppress
premature LH rise while maintaining a positive
influence on ovarian follicle development if
continued till the day of hCG

16. How Science is advancing!!

17. Then performing a Trial

18. Current practice of O.i in IUI
Clomiphene Citrate
hMG or FSH
______________________________________________

19. Emerging protocol: Reversed hMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________

20. • Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY

21. If true : Double Benefits
• The use of hMG at start of cycle for few
days will avoid CC resistant cases
• use of CC till the day of hCG will prevent
LH surge

22. Outcome Parameters
Primary outcome parameters
Clinical pregnancy rate per women randomised (i.e.
fetal heart pulsations demonstrated by TVS at 6 –7
weeks’ gestation)
Premature LH
Secondary outcome parameters
E2 levels,
Number of mature follicles
Endometrial thickness
On day of HCG

23. Sample size calculation
• if premature LH surge rate among the hMG only
group is 20%.
• Assuming CC is effective by reducing it by 15%
• Then hMG + CC group will be 5%,
• So we will need to study 75 couples in each arm in
order to reach a power of 80%.

24. Drop out cases
• In order to compensate for discontinuations, we
recruited 115 women in each arm
• If more than 10% drop out cases, this would
affect the validity of the trial

25. 25
New concept has to be tested
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group

26. Novel protocol
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm

27. Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7

28. Results
Variable Group I
(n=115)
Group II
(n=115)
P value
Age (years) 27.3 ± 4.7 28.4 ± 2.7 NS
Duration of infertility (years) 3.1 ± 1.9 2.4 ± 1.6 NS
Cause of infertility
Mild male factor
Unexplained infertility
61 (53%)
54 (47%)
58 (50.4%)
57 (49.6%)
NS
NS
BMI 28.5 ± 1.6 28.1 ± 3.1 NS

29. Results (cont.)
Variable Group I
(n=110)
Group II
(n=107)
P value
Number of cancelled cycles
Inadequate response
Hyper response
5/110
4/5
1/5
8/107
6/8
2/8
NS
NS
NS
Basal LH (mIU/mL) 6.4 ± 2.2 5.8 ± 2.4 NS
Basal FSH (mIU/mL) 6.7 ± 2.5 7.2 ± 4.8 NS
Days of stimulation 7.2 ± 1.8 8.1 ± 1.3 NS
E2 at time of HCG (pg/mL) 360.3 ± 162.9 280 ± 110.0 P <.05*

30. Results (cont.)
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

31. How Science is advancing!!

32.  No OCP pretreatment
 Check patient cycle day 2
 FSH 100-225 IU
 Antagonist earlier than later
 LH not necessary
Suggested GnRH Antagonist Protocol
Cycle day 2
Transvaginal US +
(if desired) hormonal profile
This suggested protocol represents a “best estimate” given current
data and clinical experience. Further data are required before more
concrete recommendations can be made.
For regular IVF patients:
 5-9 antral follicles per
ovary
 Age <35 years
 No PCOS
 No history of poor
responses
 No endometriosis
Duration of treatment
based on clinical judgment
in consultation with patient
(usually 2 USs)
Cycle day 2/3
Start FSH 150-200 IU. Continue
Stimulation days 5-6
Start GnRH antagonist
administered daily. Continue
Monitoring according to clinic practice
 US (+ blood test if required)
 FSH dose adjustments may be considered
3 follicles 17 mm
Day of triggering
 Ensure interval between antagonist and hCG does not exceed 30 h
 hCG 5000-10,000 IU
Oocyte retrieval
36 h
YES
NO
US = ultrasonogram; OCP = oral contraceptive pill. Devroey et al. Hum Reprod. 2009;24:764.

33. How Science is advancing!!

34. Antagonist shortage

35. How Science is advancing!!

36. Proof of concept study
• Not a RCT • Small number
• To proof the theory

37. Proof of concept study
• Seven cases undergoing ICSI
• Strict criteria: young age
• Unexplained infertility
• Mild male factor
• Failed 2-3 IUI cycles • No PCOS
• No endometriomas

38. • 2-3 ampoules daily
• CC staring from follicle diameter 11mm
• Usually for 3-4 d
• hCG if follicle 17mm

39. Results
• No premature lutenisation was reported
till now
• Number of retrieved oocytes ranged
between 7-16
• MII oocytes more than 50%
Waiting for pregnancy rate

40. Should we rush?
• To apply it
• Too early
• Needs more cases
• Not magic

41. There was enthusiasm for PGS
• Advanced maternal age
• Gianaroli 1999, Munne 1999, Kahraman 2000, Obasaji 2001, Munne 2003;
Montag 2004; Platteau 2005
• Repeated IVF failure
• Gianaroli 1999, Kahraman 2000, Pehlivan 2003,Munne 2003,
Wilding 2004
• Recurrent miscarriage
• Pellicer 1999, Rubio 2003, Rubio 2005, Munne 2005
• Severe male factor
• Silber 2003, Platteau 2004

42. Preimplantation genetic screening
for advanced maternal age –
reduced live birth rates
OR 0.59
(0.44, 0.81)

43. Triggering – GnRH agonist or hCG?
Youssef et al, updated CR 2013
• 17 RCTs
– 9 report OHSS
– 5 report live birth rate
• Risk of bias
– Only 2/17 used blinding
– 4/17 studies stopped prematurely for differing
reasons
– All studies were either funded by pharmaceutical
companies or did not report their funding

44. Ovarian hyperstimulation rate is
reduced with agonist trigger in high
risk women only
OR 0.06
(0.01, 0.34)
Youssef et al, updated 2013
*4 studies no events in either arm

45. Live birth rate reduced with GnRHa
triggering

46. Conclusion
• It is a valid idea with scientific background
evidence
• Needs more cases to ensure its validity

47. For whom
• for young women,
• for those with unexplained infertility
• mild male factor
•i.e good responders