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
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Cc for suppression 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
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
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
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
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
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.
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
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