ovulation induction protocols update 2014

‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬

Induction of
Ovulation
Hesham Al-Inany, M.D, PhD
(Amsterdam)

Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•PCOS
•Gn for O.I
•Novel protocol

Basic fertility work up
referral gyn
History
Physical examination
Ovulation evaluation Semen analysis
Tubal
patency:
CAT
HSG
DLS

How to estimate ?
•Chance to conceive naturally (home
conception) (treatment independent
pregnancy)

http://www.amc.nl/prognosticmodelhttp://www.amc.nl/prognosticmodel

Clinical consequences
•Couples with prognosis <30% = IVF
•Couples with prognosis > 40% =
expectant management
•Couples with prognosis 30-40% = IUI

Diagnostic studies to confirm
Ovulation
•Basal body
temperature
 Inexpensive
 Accurate
•Endometrial biopsy
 Expensive
 Static information
•Serum progesterone
 After ovulation rises
 Can be measured
•Urinary ovulation-
detection kits
 Measures changes in
urinary LH
 Predicts ovulation but
does not confirm it

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

Ovulation Induction
•Monofollicular development
•Multifollicular development

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.

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

Anovulatory cycles
•Clomiphene citrate (all doses) was
associated with an increased
pregnancy rate per treatment cycle
• Meta-analysis by Hughes et al, 2011

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

Outline of this talk
•Ovulation : Introduction
•Evaluation of Ovulation
•Anovulation: causes
•How To Treat
•Gn for O.I
•Novel protocol

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.

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

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

Effect of letrozole on ovulation rate per cycle in PCOS (Requena
et al , 2008)

Metformin
•The addition of metformin in the CC-
resistant patient is highly effective in
achieving ovulation induction.
Meta-analysis by Siebert et al, 2013

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

CC resistance : what to do ?
Clomiphene Citrate
hMG or FSH
______________________________________________

• 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

CC FSH P-value
Number of patients randomized 143 159
Number of patients per
protocol 123 132
Cycles 310 288
Clinical 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

Gn ?
hMG or FSH
______________________________________________

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.

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

Standard Protocol
May fit PCOS patients

•Some cases are CC resistant
• about 25% of IUI cycles suffer from
premature LH surge cancellation.
WHY

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

Study
•Setting: Kasr Al-Aini hospital.
•Registered : (ACTRN12607000568415)

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
•Each couple were included only once in this trial
in order to prevent a possible unit-of-analysis
error in interpreting the results

Randomisation
Participants
RandomlyAssigned
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
OutcomeCompared

Outcome Parameters
Primary outcome parameters
Clinical pregnancy rate per women randomised
( i.e. fetal heart pulsations demonstrated by TVS
at 6 –7 weeks’ gestation)
Premature LH
Secondary outcome parameters
E2 levels,
Number of mature follicles
Endometrial thickness
On day of HCG

Treatment assignment
•Couples assigned to the intervention
group received hMG/CC protocol while
couples assigned to the control group
received hMG only.

Novel protocol
75 IU/HMG
CD3 CD7
150 mg CC
hC
G
IUI
DF ≥ 18
mm
34-36h

Control group
75 IU/HMG
CD3 hCG IUI
DF ≥ 18
mm
CD7
34-36h

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

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)

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%)
NS
NS
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

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

Conclusion
•This is a novel protocol for O.I in IUI
•The protocol is simple, safe and appears to
be very cost effective.

Take Home message
•Low dose Gn is the main stay in
ovulation induction to achieve the best
results

Thank you
Dr. Hesham Al-Inany MD, PhD
e-mail : kaainih@yahoo.com

ovulation induction protocols update 2014

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