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
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New Modality for suppression of LH surge
Why & How?Hesham Al-Inany, PhD (Amsterdam)
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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.
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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
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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
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History
• 1970 ClomifenhMG
• 1980 GnRH-agonist / hMG
• 1990 recFSH / hMGGnRH-antagonist / hMG or recFSH
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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
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How Science is advancing!!
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Observation
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Further Observation
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Then search the medical literature
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How Science is advancing!!
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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
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How Science is advancing!!
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Then performing a Trial
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Current practice of O.i in IUI
Clomiphene Citrate
hMG or FSH
______________________________________________
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Emerging protocol: Reversed hMG/CC
Clomiphene Citrate
hMG or FSH
______________________________________________
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• Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY
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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
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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
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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%.
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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
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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
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Novel protocol
75 IU/HMG
CD3 CD?7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
DF ≥ 12 mm
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Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
DF ≥ 12 mm
CD?7
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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
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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*
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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
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How Science is advancing!!
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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.
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How Science is advancing!!
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Antagonist shortage
Why not Clomiphe citrate?
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How Science is advancing!!
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Proof of concept study
• Not a RCT • Small number
• To proof the theory
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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
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• 2-3 ampoules daily• CC staring from follicle diameter 11mm• Usually for 3-4 d• hCG if follicle 17mm
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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
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Should we rush?
• To apply it• Too early• Needs more cases• Not magic
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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
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Preimplantation genetic screening for advanced maternal age – reduced live birth rates
OR 0.59 (0.44, 0.81)
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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
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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
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Live birth rate reduced with GnRHa triggering
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Conclusion
• It is a valid idea with scientific background evidence
• Needs more cases to ensure its validity
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For whom
• for young women,
• for those with unexplained infertility
• mild male factor
• i.e good responders