IUI indications, Ovarian stimulation protocols CC, aromatase inhibitors, gonadotropins
Ovarian Stimulation Protocols
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Transcript of Ovarian Stimulation Protocols
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OVULARIAN STIMULATION PROTOCOLS
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Ovulation Induction
Monofollicular development Multifollicular development Complications Novel protocol
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Ovulation Induction
Monofollicular development Multifollicular development Complications Novel protocol
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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.
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Unexplained Infertility
CC appears to improve pregnancy rates in women with unexplained subfertility
Meta-analysis by Hughes et al, 2000
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Anovulatory cycles
Clomiphene citrate (all doses) was associated with an increased pregnancy rate per treatment cycle
Meta-analysis by Hughes et al, 2000
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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
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CC Resistant
If still anovulatory after 6 months of continuous use the case is considered “clomiphene resistant”
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No ovulation:
dose. duration of treatment (10 days). add hMG.
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Tamoxifen
No significant benefit of Tamoxifen over CC
Meta-analysis by Stiener et al, 2005
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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
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So what do we use in Practice?
Clomiphene Citrate
TI AIH
hMG or FSH
______________________________________________hMG or FSH
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Ovulation Induction
Monofollicular development Multifollicular development Complications Novel protocol
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Your Aim should be .. ..
PROTOCOL
RESULTS
COMPLICATIONS
BEST
Most SUITABLE
AVOID
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IVF / ICSI cycles
Multifollicular development with
gonadotropin administration is still an
integral component for ovarian stimulation in
IVF / ICSI cycles
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Gonadotrophins
hMG, FSH, rec-FSH
+GnRHa
-long-short-u-short +GnRH
antagonist
Always LP++
IVF ICSI
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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
DayDayof 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
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Starting dose
Depends on Age, weight
Usually 3 amp / day in average weight women between 28-35 ys
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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.
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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.
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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.
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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.
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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
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Disadvantages of long protocol
It is more expensive takes longer time. Larger dose of GnRH analogue larger number of ampoules of hMG
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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)
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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.
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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)
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Protocols for poor responders Long protocol with large doses of
gonadotropins Clomiphene / hMG / antagonist protocol
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Type of Gonadotropin
/ / / 3% glycoproteins
97% other proteins
FSH 75 I.ULH 75 I.U.+ detectableamountsof hCG
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Recombinant FSH Batch to batch consistency Free from urinary proteins Can be produced in limitless quantities
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In 1995 € 5.0 million
volume increased by <100%
In 2000 € 26.8million
Zwart-van Rijkom et al,2002
Concerns Price
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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.
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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
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Efficacy
Should be based upon most up to date evidence
RCTs are considered the gold standard
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Most important outcome
Live birth rate Per
woman
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Effectiveness
Meta-analysis of: Truly randomized controlled trials IVF/ICSI cycles
Al-Inany et al, 2005
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Live Birth / Ongoing Pregnancy rate
O.R.: 1.21 (95% CI 0.95-1.54)
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Significant result with Long Protocol
O.R.: 1.26 (95% CI 1.00-1.60)
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NNT
23
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How to Explain!!
LH was shown to improve the implantation rateGordon et al, 2001 Ganirelix dose-finding study ,1998 Schoolcraft et al, 1999
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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
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Agonist vs antagonist
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ongoing pregnancy/ live-birth rate
O.R = 0.82, 95% CI = 0.69 to 0.98
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Pregnancy per woman
O.R = 0.80, 95% CI = 0.69 to 0.92
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The absolute treatment effect (ATE) was calculated
to be 4.5%.
number needed to treat (NNT) 22
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This means That
for every 22 subfertile couples undergoing IVF/ ICSI program, one additional pregnancy can be expected in the GnRH agonist treated group
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Incidence of OHSS
R.R. = 0.61, 95% CI = 0.42 to 0.89
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No difference
Spontaneous miscarriage Rate Multiple pregnancy rate
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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)
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The Future
Prevention of severe OHSS in women downregulated with GnRH agonist and with high risk of OHSS
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(GnRH) antagonists
A unique Idea Administration when follicle reach 16 mm Continue hMG (step down protocol) Monitor by E2 Not more than 3 days
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Luteal Phase Support
Micronised Progesterone tablets Oral: 100-200 mg 2-4X/day Vaginal: 100-200 mg 2X/day Rectal: 100-200 mg 2X/dayProgesterone Sup. 200-400 mg vag. or rectally 1-2X/dayProgesterone gel (8%)
IM Progesterone 100 mg 1x/day
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Ovulation Induction
Monofollicular development Multifollicular development Complications Novel protocol
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Complications of Ovulation Stimulation Drugs.
OHSSMultiple Gestation
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OHSS.
-large fragile ovaries.-haemoconcentration-oliguria-ascites-pleural effusion
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Complications of Ovulation Stimulation Drugs.
OHSSPrevention of
TI/IUI
withhold hCG use “coasting”
use Antagonist
IVF
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Complications of Ovulation Stimulation Drugs.
4-folds higher incidence of twins & HRMGMultiple Gestation
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Ovulation Induction
Monofollicular development Multifollicular development Complications Novel protocol
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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.
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Novel protocol
75 IU/HMG
CD3 CD7
150 mg CC
hCG IUI
DF ≥ 18 mm
34-36h
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Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18 mm
CD7
34-36h
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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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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
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This is a novel protocol for OI
The protocol is simple, safe and appears
to be very cost effective.
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Take Home Message
Monofollicular development: CC Multifollicular development :
hMG/agonist Complications: OHSS Novel protocol: hMG / CC
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THANK YOU