Download - ovulation induction protocols update 2014
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حمن الر الله بسمحيم الر
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Induction of Ovulation
Hesham Al-Inany, M.D, PhD (Amsterdam)
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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Ovulation
• Day 14?
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Basic fertility work up
referral gyn
HistoryPhysical examination
Ovulation evaluation Semen analysisTubal
patency:CATHSGDLS
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How to estimate ?
•Chance to conceive naturally (home conception) (treatment independent pregnancy)
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http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel
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Clinical consequences
•Couples with prognosis <30% = IVF
•Couples with prognosis > 40% = expectant management
•Couples with prognosis 30-40% = IUI
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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Evaluation of Ovulation
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Diagnostic studies to confirm Ovulation
•Basal body temperature Inexpensive Accurate
•Endometrial biopsyExpensiveStatic information
•Serum progesteroneAfter ovulation
risesCan be measured
•Urinary ovulation-detection kitsMeasures changes
in urinary LHPredicts ovulation
but does not confirm it
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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Anovulation
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OVULATION DISORDERS WHO Classification
• Group 1 (10%) Hypothalamic pituitary failure low gonadotrophins - low oestrogen
• Group 2 (85%) polycystic ovaries two of the following three criteria-presence of at least 10 follicles measuring 2–9 mm in diameter and/or-clinical and/or biochemical hyperandrogenism-oligo- and/or anovulation
• Group 3 (5%) Ovarian failure high gonadotrophins - low oestrogen
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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Ovulation Induction
•Monofollicular development•Multifollicular development
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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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hCG vs. LH monitoring
• If normoovulatory (e.g male factor), LH monitoring is preferred
• If ovulatory dysfunction: hCG is preferredMeta-analysis by Kosmos et al, 2007
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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, 2011
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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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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•Gn for O.I•Novel protocol
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Tamoxifen Citrate
• Nolvadex 10 mg
•May be used alone or
• In combination with CC to act in synergy for better response or in cases resistant to CC alone.
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Meta-analysis
•Clomiphene citrate and tamoxifen are equally effective in inducing ovulation.
• There does not appear to be a significant benefit of one medication over the other
Meta-analysis by Stiener et al, 2005
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The Aromatase Inhibitors
• Letrozole (Fimara 2.5 mg)
• effective in anovulatory infertility. • It has the following advantages:• 1- It reduce E2 level. • 2- It avoids the unfavorable
effects on the endometrium frequently seen with CC
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Effect of letrozole on ovulation rate per cycle in PCOS (Requena et al , 2008)
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Metformin
• The addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction.
Meta-analysis by Siebert et al, 2013
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Prolactin Reducing Medications- For Hyperprolactinaemia associated infertility.
Causes:• Pituitary adenoma (prolactinoma).• Hyperactive lactotrophs.• Medications: tranquilizers, hallucinogens, painkillers, alcohol,..
• Diseases of the kidney or thyroid gland.
Dopamine agonist: - Bromocriptine.- Quinagolide.- Cabergoline
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CC resistance : what to do ?
Clomiphene Citrate
hMG or FSH
______________________________________________
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• Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC.
• This result has to be balanced by convenience and cost in favour of CC.
• FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients. Homburg et al, 2012
CC or low-dose FSH for the first-line treatment of infertile women with PCOS: a randomized multinational study
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CC FSH P-value
Number of patients randomized 143 159
Number of patients per protocol 123 132
Cycles 310 288Clinical pregnancies (per patient) 54 (44%) 76 (58%) 0.03
Ongoing pregnancies (per patient) 48 (39%) 68 (52%) 0.04
Clinical pregnancies (per cycle) 54 (17.4%) 76 (26.4%) 0.008
Ectopic pregnancies 1 1
Miscarriage rate per pregnancya 5 (9.2%) 7 (9.2%)
Multiple pregnancies (twins only) 0 2 (3.4%)
Cumulative pregnancy rate Cycle 1 12.9% 25.6% Cycle 2 29.3% 44.8% Cycle 3 41.2% 52.1% 0.02
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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PCOS
hMG or FSH ???
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Gn ?
hMG or FSH
______________________________________________
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Role of LH
The results of ovulation induction with hMG or FSH-only regimens did not differ in studies conducted in patients with polycystic ovary syndrome.
hMG was clearly superior to purified FSH for the treatment of hypogonadotropic hypogonadism.
hMG was superior to FSH in women above 37 yrs old Miscarriage rates were not affected by the use of hMG. Thus, low but detectable LH concentrations positively influence
the outcome of ovulation induction in patients with ovulatory disorders and women undergoing assisted reproductive techniques.
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HMG versus Rec FSH in PCOS Undergoing IVF
Ovarian stimulation with hMG and rFSH provides similar clinical pregnancy rates in PCOS patients treated with a long GnRH agonist protocol in IVF cycles. Turkcapar, M.D., 2013
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Role of LH
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Role of LH
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Role of LH
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•PCOS•Gn for O.I•Novel protocol
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Standard Protocol
May fit PCOS patients
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Step-Down Protocol
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Step-Up Protocol
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Outline of this talk
•Ovulation : Introduction•Evaluation of Ovulation•Anovulation: causes •How To Treat•Gn for O.I•Novel protocol
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Reversed hMG/CC Protocol
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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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Double Benefits
•The use of hMG at start of cycle for few
days will avoid CC resistant cases
•CC will continue the growth of the
dominant follicle and may prevent LH
surge
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New concept has to be tested
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Study
•Setting: Kasr Al-Aini hospital.
•Registered : (ACTRN12607000568415)
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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
• Each couple were included only once in this trial
in order to prevent a possible unit-of-analysis
error in interpreting the results
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Randomisation
ParticipantsR
a n
d o
m l
y
A s
s i
g n
e d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
O u
t c
o m
e
C
o m
p a
r e
d
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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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Treatment assignment
•Couples assigned to the intervention
group received hMG/CC protocol while
couples assigned to the control group
received hMG only.
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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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Both groups
• Folliculometry
• hCG when follicle reach 18mm or more
•Serum LH on day of hCG
• IUI 34-36hs later
•Micronised progesterone for 18 days
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Assessed for eligibility (n= 245)
Excluded (n= 15)
Not meeting inclusion criteria (n=7)
Refused to participate (n=5)
Social reasons (n=3)
Received IUI (110)
Analyzed (n=110)
Cycles cancelled (n=5)
Inadequate response (n=4)
Hyper-response (n=1)
Group I (n=115) received Merional + CC
Cycles cancelled (n=8)
Inadequate response (n=6)
Hyper-response (n=2)
Group II (n=115) received Merional alone
Received IUI (107)
Analyzed (n=107)
Allocation
Analysis
Follow-Up
Enrollment
Randomized (n=230)
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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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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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Conclusion
• This is a novel protocol for O.I in IUI
• The protocol is simple, safe and appears to
be very cost effective.
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Take Home message
• Low dose Gn is the main stay in ovulation induction to achieve the best results