cc for suppression of lh surge
DESCRIPTION
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 surgeTRANSCRIPT
New Modality for suppression of LH surge
Why & How?Hesham Al-Inany, PhD (Amsterdam)
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.
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
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
History
• 1970 ClomifenhMG
• 1980 GnRH-agonist / hMG
• 1990 recFSH / hMGGnRH-antagonist / hMG or recFSH
Protocols for IVF GnRH AntagonistProtocols
GnRH AgonistProtocols
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 6of FSH/HMG
Dayof hCG
Day 1 of FSH/HMG
Day 6of FSH/HMG
Dayof hCG
7 – 8 daysafter estimated ovulation
Down regulation
Day 2 or 3of menses
Day 1 FSH/HMG
How Science is advancing!!
Observation
Further Observation
Then search the medical literature
How Science is advancing!!
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
How Science is advancing!!
Then performing a Trial
Current practice of O.i in IUI
Clomiphene Citrate
hMG or FSH
______________________________________________
Emerging protocol: Reversed hMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________
• Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY
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
Outcome Parameters
Primary outcome parametersClinical pregnancy rate per women randomised (i.e. fetal
heart pulsations demonstrated by TVS at 6 –7 weeks’ gestation)
Premature LH
Secondary outcome parametersE2 levels, Number of mature follicles Endometrial thickness
On day of HCG
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%.
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
25New concept has to be tested
Participants
R a
n d
o m
l y
A
s s
i g
n e
dIntervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
Novel protocol
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm
Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7
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%)
NSNS
BMI 28.5 ± 1.6 28.1 ± 3.1 NS
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*
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
How Science is advancing!!
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 5-6Start 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.
How Science is advancing!!
Antagonist shortage
Why not Clomiphe citrate?
How Science is advancing!!
Proof of concept study
• Not a RCT • Small number
• To proof the theory
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
• 2-3 ampoules daily• CC staring from follicle diameter 11mm• Usually for 3-4 d• hCG if follicle 17mm
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
Should we rush?
• To apply it• Too early• Needs more cases• Not magic
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
Preimplantation genetic screening for advanced maternal age – reduced live birth rates
OR 0.59 (0.44, 0.81)
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
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
Live birth rate reduced with GnRHa triggering
Conclusion
• It is a valid idea with scientific background evidence
• Needs more cases to ensure its validity
For whom
• for young women,
• for those with unexplained infertility
• mild male factor
• i.e good responders