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