Controlled Ovarian Hyperstimulation With IUI

Patient selection and work-up
Ovarian stimulation
Monitoring of follicular growth and
endometrial development
Timing of insemination
Number of inseminations
Semen preparation
Insemination procedure
Luteal support

Age < 40 years
Patient capable of spontaneous or induced
ovulation
Atleast one patent fallopian tube with good
tubo- ovarian relationship
Sperm count of more than 10 million/ml
pre-wash or a post-wash count of >3-5
million motile sperms with percentage
motility of more than 40%
Easy access to the uterine cavity via a
negotiable cervical canal

Controlled ovarian stimulation along with
intrauterine insemination –effective form of
treatment - select group of couples.

Male factor
Female factor

 Subnormal semen parameters
oligozoospermia, asthenozoospermia,
teratozoospermia, hypospermia, highly viscous
semen
 Retrograde ejaculation.
 Ejaculatory failure-
 Anatomical
 Neurological
 Psychological
 Drug induced

Unexplained infertility
Cervical factor, Antisperm antibodies
Ovulatory dysfunction (ovulating but no
pregnancy and associated with male
factor-ESHRE/ASRM)
Minimal to mild endometriosis
Vaginismus
Allergy to seminal plasma

 Absentee husband
Anti – neoplastic treatment
Vasectomy
Poor semen parameters
Drug therapy

Severe abnormal semen parameters.
Azoospermia.
Hereditary disease in male.
Repeated failure at IVF/ICSI.

Tubal pathology
Genital tract infection
Severe male factor infertility
Severe endometriosis
Genetic abnormality in husband
Unexplained genital tract bleeding
Older women more than 40 years
Multiple failures at IUI

Oral drugs
Oral drugs with gonadotropins
Gonadotropins alone
Gonadotropins with Gnrh analogs
Gonadotropins with Gnrh antagonists

Anovulatory women –monofolliculogenisis.
Ovulatory women– super ovulation to
increase the chance of pregnancy as more
eggs will be available for the sperms to
fertilize.

Maximizes conception- ideally expressed
as singleton live birth at term.
Minimizes multiple pregnancy and OHSS.
Avoiding risks of preterm delivery, perinatal
morbidity and mortality to the neonate and
risks to the mother from OHSS

Basic protocol
DAY 3-5
Ultrasound- AFC , ENDO , CYST
Dose 50mg
Sexual relation every other day from day
10 onwards
If menses occurred within usual frame
work of 26-32 days- ovulation is assumed
to occurred.
If no ovulation then increase 50 mg tab
each succeeding cycle

 Effectiveness and safety of OI are increased.
 Starting day determined by day 2 -E2 and P4.
 Initial dose according to body weight.
 Monitoring by USG and E2 levels.
 Day and Time of IUI or timed intercourse-
regulated by triggering ovulation with HCG .

 PCOS -Ovulation in 60-80% and conception
rate of 50%-60% for upto 6 cycles
(ESHRE/ASRM GUIDELINE on PCOS-2008)
 Overall cycle fecundability is 15%-22% in those
ovulating with CC in first 3 cycles .
(Eijkeman---Human Rep 2003)
 Unexplained infertility-CC alone-5%, CC+IUI-
10%
(Deaton etal-fert ster 1990)

Extended course.
CC+ Glucocorticoids.
Preliminary suppressive therapy.
CC+ Insulin sensitizer .
Letrazole / Tamoxifen.
Gonadotropin therapy .
LOD .

 Extended course---50% who are resistant may
respond to 7-10 day course .FDA approves only
750mg of CC per treatment cycle.
(Isac etal-Fert stert 1997).
 CC+ Glucocorticoids
Continuous/follicular phase
Prednisolone-5mg or dexa-0.5-2mg/day -
normal or raised DHEAS level- increased
ovulation(75-80%) and pregnancy rates(40-
40.5%)
(RCT-Parsanezhad etal-fert stert 2002, human
reprod 2006 .)

 Preliminary suppressive therapy -in
women with excess LH and androgen
levels-continuous OC pills for 2
months(70% ovulation rates and 50%
pregnancy rates)
(Branigan etal RCT Fert stert 2003)
 Gnrh alone or in combination with OC
pill can also be used.
(Genazzani—J Asst rep gen 2000)

 No evidence of difference in live birth
rate comparing Metformin plus CC with
CC alone(meta analysis 2007 ).
 Highly effective in achieving ovulation
induction in CC resistant cases (fertil
steril 2006 )
 Metformin with gonadotropin did not
improve ovulation or pregnancy rates
but did reduce risk of OHSS. (RCT hum
reprod 2006 )

 Metformin treatment for 12 weeks before and
during IVF or ICSI in non-obese women with
PCOS significantly increases pregnancy and
LBRs compared with placebo. However, there
was no effect on the outcome of ART per se.
(randomized,multi-centre study 2011 )
 Metformin is still of benefit in improving clinical
pregnancy and ovulation rates although no
clear evidence exists that metformin improves
live birth rates (LBRs) whether it is used alone,
in combination with clomiphene or compared
with clomiphene. Cochrane analysis (Tang et
al., 2010)

 May have a role in OI after CC failure or as
first line.
 Similar in efficacy to CC in terms of ovulatory
rates.
(Nikolaos etal-systematic review reprod
biomed online-oct-2009)
 ESHRE/ASRM consensus-
Off label option, currently not licensed for use
in infertility . Further studies are needed
regarding safety before wide spread use .

 The long letrozole protocol (10 days)
can produce more mature follicles and
subsequently more pregnancies than
the short letrozole therapy (5 days).
(Fertil Steril_ 2009 )
 use of higher doses of letrozole offers
no advantage in terms of pregnancy
rates over the lower (2.5 mg)
dose(2007 Reproductive BioMedicine)

 Aromatase inhibitors are as effective as
or superior to CC in ovulation induction
and in superovulation. Unlike CC, they
do not carry an antiestrogenic effect on
the endometrium. Given the
advantages of aromatase inhibitors,
they can be used to replace CC as
ovulation-inducing drugs. (Fertil Steril_
2006.)

 The step-up letrozole protocol was
associated with multifollicular ovarian
development similar to CC. Higher
clinical pregnancy rate/treatment cycle
compared with CC was also observed
with the letrozole step-up treatment
(27.3% vs. 11.8%).
 Pregnancy rates treated with CC and
LET were identical . (RCT FERTIL STER
2007 )

 Concurrent protocol
 Overlap protocol
 Sequential protocol
 Cycle fecundability better than CC alone
(Dickey et al-Human rep 1993)
 Monitoring similar to gonadotropin cycle
 Lower incidence of multiple pregnancy
(Ron et al Human rep 1989)

 GROUP I
 CC RESISTANT(15-25%)
 50% of PCOS women who have undergone LOD
need CC or gonadotropin
 If no ovulation after 6 months use CC for
stimulation (ESHRE/ASRM in PCOS-2008).
 CLASS IV - if intolerant to dopamine agonists.

Conventional step up
Low dose protocol
Step up
Step down
Sequential protocol

Initial daily doses of 2 amp of HMG used,
(150IU FSH) increased by >50% every 3-5
days until an ovarian response occurs.
It is effective but is associated with
increased rate of OHSS and multiple
pregnancy
Disadvantage- does not take into account
the difference in the response of the follicle
to FSH and LH.

Low initial daily FSH of 75IU and the dose
is increased by small amount usually
37.5IU/day
Starting dose may be lower – clinical
features, previous OHSS, history of
multiple follicles developing in the first
week.
The first increase in dose is done only after
14 days

CYCLE DAY3 -75 IU FSH/DAY
7 DAYS
7 DAYS
Follicle<10 mm Maintain dose
Follicle<10 mm ,increase
dose By 37 .5 IU/day
Follicle > 10mm
Follicle> 10mm
Maintain Dose until follicle>mm
HCG Injection
7 DAYS
Follicle<10 mm ,increase
dose By 37 .5 IU/day weekly
to a max. of 225 IU/day
Follicle > 10mm
Follicle<10mm
Cancel cycle
Start new cycle
Increasing starting dose by 37.5
IU/day
Follicle>10mm

 Gonadotropins have a very narrow therapeutic
range.
 These regimens allow FSH to rise slowly to just
above the threshold level and at the same time
avoiding the explosive ovarian response.-
Threshold concept(BROWN etal)
 Initiation of follicular growth requires only 10-
30% of increase in the dose of exogenous FSH

Low complications of OHSS and multiple
pregnancy and fair pregnancy rates.
Pregnancy rate of 10% per initiated cycle
with a mean rate of 0.3% of higher order
multiple pregnancy.
(Ragni etal-6670 IUI cycles-Fert ster
2006)

Cycle day 3: 150-250 IU FSH/day/5 days
Ultrasonography (every 2-3 days)
Follicle> 9mm Follicle< 9mm
Decrease 37.5 IU/day every 3 days Increase 37.5 IU/day maintain 10 days
Maintain 75 IU/day
Until HCG injection
Follicle>9mm-------Follicle<9mm
Cancle cycle
STEP DOWN PROTOCOL

Concept-approximate physiologic
circumstances mimicking natural intercycle
FSH elevation and the subsequent
decreasing dependence of the DF on FSH.
Duration rather than the magnitude of FSH
increase affects follicle development

Monitoring is more intense .
Difficult to judge the correct dose reduction
in daily clinical practice.
Protocol is effective but the rate of OHSS
is more compared to step up regimen.

 Low dose step up regimens are superior to step down
regimens in terms of mono folliculogenisis, ovulation
rates and ovarian hyperstimulation in PCOS
(Christian Maitre –RCT stepup Vs stepdown in PCOS-
Huma rep-2003)
 Step up regimen-duration of therapy and the amount of
gonadotropins required are more compared to step down
regimens
 Even in step up regimens results are better if the starting
dose is low and the increments are also smaller doses

Combines an initial step up followed by a
step down regimen after follicular selection
(leading follicle >14mm ).

2-3
1
1.5-2
2-2.5
2.5-3
3
Ampoules/Day
(1amp.=75IU FSH+75 IULH)
COMBINED STEP DOWN AND STEP UP APPROACH
2 7 7 7 7

 Starting dose is 37.5-50 IU/day.
 Adherence to the 14 day starting period in
atleast the first cycle is less likely to result in
excessive stimulation.
 Small FSH dose increments of 50% of the initial
or previous FSH dose.
 Duration not to exceed 6 ovulatory cycles
 Intense ovarian response monitoring.
 Strict cycle cancellation criteria should be agreed
upon with the patient before therapy is started.

43 RCT TRIALS- 3597 WOMEN
- Gonadotropins Vs Antiestrogens-significant increase in
pregnancy rates(OR-1.8)
- Anti estrogens Vs Aromatase inhibitors -no significant
difference in pregnancy rates(OR-1.2,CI-0.65 to 2.1)
- Gonadotropins Vs Gonadotropins – no difference
- Addition of Gnrh agonist-No increase in pregnancy rates
but increase in OHSS.
- No evidence for the addition of Gnrh antagonist to
gonadotropins

HCG
Gnrh AGONIST
Recombinant HCG.
Routine administration of HCG adds little
to improving conception rates .Indicated
only when absent or delayed ovulation or
for timing IUI or intercourse.
(Fertil steril 2007)

Standard sperm wash
swim up
swim down method
Density gradient

 Single IUI.
 36 hrs after HCG .
 After follicle rupture .
 Within 24 hrs of LH surge.
 Double IUI.
 At 24 and 48hrs after HCG adminst.
 Day 6 and day 8 of last pill .
 NO statistical difference in pregnancy rates in
different timing regimens.
(Esra et al –Fert ster 2009)

 RATIONALE-increase opportunity for longer
fertilisation period (22-47hrs).
 No clear benefit in terms of LBR.
(TafunBagis etal-Human rep ,may 2010)
 Systematic review of 3RCT-No difference.
(NICE guideline-fertility-2004)
 No clear benefit in terms of pregnancy rates.
(meta analysis-Nikalaos-Fert stert Aug.2009.)

Pre- ovulatory USG.
Fresh unwashed semen- 6-8 hrs before
ovulation.
Washed semen –No sooner than 4 hrs
after ovulation.
Cryopreserved semen – As close to
ovulation.
LH testing kit.
Within 24 hrs of color change .

Intra vaginal insemination
Intra cervical insemination
Intra uterine insemination
Intra uterine tuboperitoneal insemination
Direct intra peritoneal insemination
Fallopian tube perfusion .

The patient is positioned .
Cervix exposed with cuscos bivavle
speculum, excessive vaginal secretions
are wiped away and the cervical os is
cleansed with the standard buffer solution
using a cotton swab.
IUI cannula is flushed with 1-2 ml of
flushing media to wash away any toxic
factors present.

 Specimen ( 0.4- 0.5ml) drawn into the
catheter and syringe.
 The catheter is gently introduced into the
cervix to pass beyond cervical os until the
catheter enters the uterus.
 The catheter is advanced to a depth of at
least 4cm but no more than 6cm to avoid
trauma to the endometrium
 When the catheter is in place and before
ejecting the specimen , the opened forceps is
positioned on either side of the cervix and the
opposing ends gently squeezed together with
just enough pressure to prevent fluid
escaping .

• The specimen is slowly ejected from the
syringe.
• The air remaining in the syringe is
expressed as the catheter is withdrawn, to
form an air block in the cervix.
• Pressure on the forceps should be
maintained until the cramping subsides,
usually within one minute

2 ml of buffered solution is drawn up into
the syringe before drawing up the
specimen suspended in 0.4- 0.5ml wash
media
The specimen and buffered solution are
injected slowly
The specimen propelled by the 2ml of
media, will fill the endometrial cavity and
partially fill the fallopian tubes.

FSP involves injecting 4.0 or 6.0 ml of a
washed specimen under pressure while
sealing the cervix to prevent reflux.
Increasing the insemination volume to 10
ml ensures peritoneal delivery of sperm
FSP resulted in significantly higher
pregnancy rates than IUI. ( cochrane
database 2004 ).

15 min of bed rest after IUI has shown to
improve ongoing pregnancy and LBR
(RCT-Custers etal BMJ2009).

 08 -14% per cycle for all causes of infertility.
 Semen parameters- count , motility and
morphology
(Van etal—fert&ster 2001)
(lee etal –int.j.andr,2002)

Age
Semen source and quality
No of follicles
Reason for treatment
Previous treatment cycles

 Threshold
 Pre wash
 Total count- 10 million
 Motility -30 %
 Total motile forms- 5
million
 Morphology - 5%
 8% VS 2.5%
Pregnancy rate per
cycle
 Post wash
 4 – 5 million
 50 %

COH WITH IUI CC WITH IUI P VALUE
WHO 18.4 % 12.9 NS
IUI-THRESHOLD 16.9 11.4 NS
SUB- IUI
THRESHOLD
8.9 3.2 <O.OO1
DONOR 22.2 16.5 NS

<32 19% 14.6 NS
32-34 19.2 13.9 NS
35-37 16.1 11.8 NS
38-40 12.9 12.1 NS
41-43 6.0 3.8 NS

CERVICAL ,
UNEXPLAINED
19.2 % 14 NS
OVULATORY
DYSFUNCTION
19.5 14 NS
ENDOMETRIOSI
S
16.1 7.9 <O.OO1
DICKEY ET ALL
2005

1 11.3 % 9.8 NS
2 13.2 14.3 NS
3 16.8 17.7 <O.O1
4 19.7
5-6 21.8
7-8 22.0
>9 26.0

First 16.4 % 10.4 NS
Second 15.1 9.1 NS
Third 10.9 8.9 NS
> Fourth 4.6 2.8 <0.005

 Luteal support in IVF cycles is associated with
increased pregnancy rates
 Luteal support is necessary when Gnrh
agonist,hcg and antagonist is used.
 Luteal support in the form of various forms of
progesterone and hcg can be given depending
on the clinical situation.

Oral dydrogesterone 10 mg bd from day of
IUI.
Micronized progesterone 100 mg bd orally
or vaginally.
Inj. Hcg 3000iu i.m. once every 3days.
 Role of estradiol is not clearly defined.

Failure of treatment
Pelvic infection: 0.01-0.2%
Uterine contractions and anaphylaxis
OHSS < 1%
Multiple pregnancy
Ectopic pregnancy
Miscarriages
Pain and vaso vagal attack

Controlled Ovarian Hyperstimulation With IUI

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Controlled Ovarian Hyperstimulation With IUI