OVULARIAN STIMULATION PROTOCOLS

Ovulation Induction

Monofollicular development Multifollicular development Complications Novel protocol

Ovulation Induction

Monofollicular development Multifollicular development Complications Novel protocol

Clomiphene Citrate

Dose: 50-100 mg./day. starting day 2,3,4 or 5 for 5 days. Monitoring: ultrasound BBT, LH kits day 21 progesterone.

Unexplained Infertility

CC appears to improve pregnancy rates in women with unexplained subfertility

Meta-analysis by Hughes et al, 2000

Anovulatory cycles

Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle

Meta-analysis by Hughes et al, 2000

hCG vs. LH monitoring

If normoovulatory (e.g male factor), LH monitoring is preferred

If ovulatory dysfunction: hCG is preferred

Meta-analysis by Kosmos et al, 2007

CC Resistant

If still anovulatory after 6 months of continuous use the case is considered “clomiphene resistant”

No ovulation:

dose. duration of treatment (10 days). add hMG.

Tamoxifen

No significant benefit of Tamoxifen over CC

Meta-analysis by Stiener et al, 2005

Combination therapies

CC and other agents (metformin, NAC) can be used in CC resistant cases.

Alternative strategies for the CC-resistant woman include : ovarian drilling

So what do we use in Practice?

Clomiphene Citrate

TI AIH

hMG or FSH

______________________________________________

hMG or FSH

Ovulation Induction

Monofollicular development Multifollicular development Complications Novel protocol

Your Aim should be .. ..

PROTOCOL

RESULTS

COMPLICATIONS

BEST

Most SUITABLE

AVOID

IVF / ICSI cycles

Multifollicular development with

gonadotropin administration is still an

integral component for ovarian stimulation in

IVF / ICSI cycles

Gonadotrophins

hMG, FSH, rec-FSH

+GnRHa

-long-short-u-short

+GnRH antagonist

Always LP++

IVF ICSI

Protocols for IVF

GnRH AntagonistGnRH AntagonistProtocolsProtocols

GnRH GnRH AgonistAgonistProtocolsProtocols

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe) Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

250 250 g per day antagonistg per day antagonist

Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG

GnRHa 1.0 mg per day GnRHa 1.0 mg per day up to 21 daysup to 21 days 0.5 mg per day of GnRHa0.5 mg per day of GnRHa

225 IU per day225 IU per day(150 IU Europe)(150 IU Europe)

Day 6Day 6of FSH/HMGof FSH/HMG

DayDay

of of hCGhCG

Day 1 Day 1 of FSH/HMGof FSH/HMG

Day 6Day 6of FSH/HMGof FSH/HMG

DayDayof hCGof hCG

7 – 8 days7 – 8 daysafter estimated ovulationafter estimated ovulation

Down regulationDown regulation

Day 2 or 3Day 2 or 3of mensesof menses

Day 1 Day 1 FSH/HMGFSH/HMG

OCP

Starting dose

Depends on Age, weight

Usually 3 amp / day in average weight women between 28-35 ys

GnRH-a protocols:

down regulation of the pituitary gonadotrophic function

This will allow prevention of premature LH surge, until full oocyte maturity can be reached.

Short (flare up protocol):

GnRH-a is started on day one or two of the cycle.

Exogenous FSH administration, then is started on day 3 of the cycle to continue follicular stimulation, meanwhile complete pituitary desensitization occur.

Advantages of short protocol

1) 1. Shortening the stimulation time.

2) 2. Reducing the amount of GnRH used.

3) 3. Reducing the amount of hMG used. Thus the total cost of the procedure will be lower.

The protocol was criticized for being unphysiological, and increases the LH levels in the early stages of the follicular phase, which might be harmful to the growing follicles.

The long protocol

GnRH-a is given for two to three weeks. Down regulation of the pituitary gland is achieved as confirmed by the very low level of serum E2.

The GnRH is usually started in the mid luteal phase or early in the early follicular phase.

hMG therapy is started after down regulation

Disadvantages of long protocol

It is more expensive takes longer time. Larger dose of GnRH analogue larger number of ampoules of hMG

A meta analysis of 22 randomized trials comparing long and short protocols demonstrated the superiority of the long protocol of GnRH agonist regarding clinical pregnancy rate.

(Daya 1999)

Ultra-short protocol

GnRHa is given for only three days with the flare up technique

LH could be suppressed till the mid cycle This protocol will help to retrieve more

oocytes with a minimal risk of premature LH surge.

Ultra-long protocol

GnRH could be given for three months before the start of hMG.

May be used in patients with severe endometriosis before the start of the treatment

Pregnancy rate appears to be improved in this sub-group of patients. (Sallam et al, 2004)

Protocols for poor responders

Long protocol with large doses of gonadotropins

Clomiphene / hMG / antagonist protocol

Type of Gonadotropin

/ / / 3% glycoproteins

97% other proteins

FSH 75 I.ULH 75 I.U.+ detectableamountsof hCG

Recombinant FSH

Batch to batch consistency Free from urinary proteins Can be produced in limitless quantities

In 1995 € 5.0 million

volume increased by <100%

In 2000 € 26.8million

Zwart-van Rijkom et al,2002

Concerns Price

Impact of high cost

The decision to adopt a more expensive

treatment could result in a lower number of

cycles of IVF/ICSI treatment especially if

patients are paying for it.

LH supplementation: is it needed!!

Lisi et al., 2001Filicori et al, 2001Westergaard et al., 2001Tesarik and Mendoza, 2002Commenges-Ducos et al, 2002

Schats et al,2000

Balasch et al, 2001

Daya 2002

Balasch et al, 2003

Efficacy

Should be based upon most up to date evidence

RCTs are considered the gold standard

Most important outcome

Live birth rate

Per

woman

Effectiveness

Meta-analysis of: Truly randomized controlled trials IVF/ICSI cycles

Al-Inany et al, 2005

Live Birth / Ongoing Pregnancy rate

O.R.: 1.21 (95% CI 0.95-1.54)

Significant result with Long Protocol

O.R.: 1.26 (95% CI 1.00-1.60)

NNT

23

How to Explain!!

LH was shown to improve the implantation rateGordon et al, 2001 Ganirelix dose-finding study ,1998 Schoolcraft et al, 1999

How To ExplainGnRH agonist down-regulation may result in profound suppression of LH concentration (< 1 IU/l) , impairing adequate oestradiol synthesis

Fleming et al, 2000

Agonist vs antagonist

ongoing pregnancy/ live-birth rate

O.R = 0.82, 95% CI = 0.69 to 0.98

Pregnancy per woman

O.R = 0.80, 95% CI = 0.69 to 0.92

The absolute treatment effect (ATE) was calculated

to be 4.5%.

number needed to treat (NNT) 22

This means That

for every 22 subfertile couples undergoing IVF/ ICSI program, one additional pregnancy can be expected in the GnRH agonist treated group

Incidence of OHSS

R.R. = 0.61, 95% CI = 0.42 to 0.89

No difference

Spontaneous miscarriage Rate Multiple pregnancy rate

In Favor of Antagonist

much shorter duration of GnRH analogue treatment (OR -20.90, 95% CI -22.20 to -19.60)

less days of stimulation (OR -1.54, 95% CI -2.42 to -0.66).

reduction in the amount of gonadotrophins (OR -4.27, 95% CI -10.19 to 1.65)

The Future

Prevention of severe OHSS in women downregulated with GnRH agonist and with high risk of OHSS

(GnRH) antagonists

A unique Idea Administration when follicle reach 16 mm Continue hMG (step down protocol) Monitor by E2 Not more than 3 days

Luteal Phase Support

Micronised Progesterone tablets Oral: 100-200 mg 2-4X/day Vaginal: 100-200 mg 2X/day Rectal: 100-200 mg 2X/day

Progesterone Sup. 200-400 mg vag. or rectally 1-2X/day

Progesterone gel (8%)

IM Progesterone 100 mg 1x/day

Ovulation Induction

Monofollicular development Multifollicular development Complications Novel protocol

Complications of Ovulation Stimulation Drugs.

OHSSMultiple Gestation

OHSS.

-large fragile ovaries.

-haemoconcentration

-oliguria

-ascites

-pleural effusion

Complications of Ovulation Stimulation Drugs.

OHSSPrevention of

TI/IUI

withhold hCG use “coasting”

use Antagonist

IVF

Complications of Ovulation Stimulation Drugs.

4-folds higher incidence of twins & HRMG

Multiple Gestation

Ovulation Induction

Monofollicular development Multifollicular development Complications Novel protocol

Reversed hMG/CC

HP-hMG 75 IU starting from the 3rd day of

cycle for four days.

Followed by 50 mg of CC (Clomid,

Aventis Pharm) three times daily starting

from the fourth day of hMG and continued

until the day of hCG injection.

Novel protocol

75 IU/HMG

CD3 CD7

150 mg CC

hCG

IUI

DF ≥ 18 mm

34-36h

Control group

75 IU/HMG

CD3hCG

IUI

DF ≥ 18 mm

CD7

34-36h

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

For whom

This protocol is especially suitable for

young women, for those with

unexplained infertility or mild male factor

i.e good responders

it may also be suitable for PCOS women

to avoid the risk of severe OHSS

This is a novel protocol for OI

The protocol is simple, safe and appears

to be very cost effective.

Take Home Message

Monofollicular development: CC Multifollicular development :

hMG/agonist Complications: OHSS Novel protocol: hMG / CC

THANK YOU