1

In the Management of Subfertile

Couples

Dr. JEHAD YOUSEF

FICS, FRCOG
ALHAYAT ART CENTER
AMMAN – JORDAN
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Objectives of the Presentation

 To examine the current indications,

clinical and laboratory methodologies
used in IUI and the impact of female
and male factors on success.
 Emphasis is centered in questioning
the following: - The value of IUI
against timed intercourse.
- IUI application with or without COH.
-
Timing and frequency of IUI.
- Impact of various parameters on
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Artificial Insemination (A.I.H)

 Intra-vaginal insemination (IVI)

 Intra-cervical insemination (ICI)
 Intrauterine insemination (IUI)
 Fallopian tube sperm perfusion (FSP)
 Sperm Intra-fallopian insemination
(SIFI)
 Direct Intra-peritoneal insemination
(DIPI)
 Intra-follicular insemination (IFI)
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Intrauterine Insemination

 The rationale
is that
increasing
the density
of both eggs
and sperm
near the site
of
fertilization
will increase
the likelihood
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Indications for IUI

• The impossibility • Abnormal male

of vaginal factor
ejaculation - oligospermia
- psychogenic or - asthenospermia
organic - teratospermia
impotence • Unexplained

- severe infertility
hypospadias, • Cervical factor

retrograde infertility
ejaculation • Husband is away

- cry preservation from wife for long

time (work abroad)
of sperm in cases
• HIV negative women
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IUI : Step by Step

 Patient’s selection
 Natural cycle or
 Controlled Ovarian stimulation.
 Monitoring of treatment, to measure
the growth of follicles, individualize
drug doses, and prevent hyper
stimulation.
 Sperm preparation
 Insemination
 Luteal support.
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Selection of patients
 A Valid indication for IUI
 Normal or mildly abnormal semen
parameters (Semen analysis within 3
months of the planned IUI)
 No evidence of intrauterine disease and
patent tubes (at least one) as
shown in a Recent HSG or (laparoscopy /
hysteroscopy)
 Female age < 43 years ?
(Day 3 FSH < 10-15
mIU/Ml, if age > 37 yrs)
 Protocol of natural
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cycle IUI
 Monitoring begins 16 days before
expected menses by TVS for follicular
maturation.
 Once a mature sized follicle of 18-24
mm & > 9mm trilaminar endometrium
are obtained the woman will monitor
urinary LH every 4-5 hours.
 Intrauterine insemination is timed 36-
40 hours from the LH surge and will be
repeated within 12 hours if the oocyte
had not released as yet.
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Controlled ovarian hyperstimulation

before IUI
The rationale
• ↑ Number of oocytes available
( ↑ chance of fertilization )
• ↑ Steroid production
( ↑ chance of implantation )
• It may correct subtle ovulatory
disorders, such as luteinized
unruptured follicle syndrome, not
detected with routine diagnostic
studies
 Synchronization of the
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menstrual cycle

n
io
Brown 1978

at
ul
ov
 •
e
Intercycl
FSH 

- Menses is the marker for onset of

uterine/endometrial cycle.
- inter-cycle ↑FSH is the marker for functional
onset of ovarian cycle.
- Only those antral follicles which coincide with
 Synchronization of the
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menstrual cycle
Controlling the timing of occurrence of
inter-cycle increase in FSH :
 Timely use of E2 (2 mg estradiol
valerate, PO BID starting 3 days before
the onset of menses of the previous
cycle.
 Short-term use of the OC pill for 7 to 21
days in the cycle preceding stimulation
cycle.
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Ovarian Stimulation Protocols

 Clomiphene citrate or similar drugs
 u-hMG or highly purified u-hMG
 Purified u-FSH or highly purified u-FSH
 Recombinant (r-FSH)
 Combinations
----------------------------------------------------------------------
GnRH agonists in combination with hMG
and/or FSH (long, short or ultra short
protocol)
GnRH antagonists in combination with
hMG and/or FSH (fixed or variable
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Which ovarian stimulation to
chose before intra-uterine
insemination?
Drug Cost; Drug availability and Patient
acceptability
 CC is an effective alternative for young
women with good prognosis, whereas in
the remaining cases hMG or FSH would
be the preferable drug.
 rFSH Vs Urinary preparations : No
difference in clinical pregnancy rate.
 There is no advantage in routinely using
GRh-a in conjunction with
gonadotrophins for ovulation
stimulation
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Monitoring ovarian stimulation

Transvaginal ultrasound scanning :

. No. & size of follicles
. Pattern & thickness of endometrium
Estrogen blood level
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Endometrial thickness & Monitoring

ovarian stimulation

3500
E2
3000 n = 183
(pmol/L)
2500
2000
1500
1000
500
0
0 5 10 15 20
After Zeev Shoham Endometrium (mm)

Correlation between E2 and

endometrial thickness
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Optimum ovarian stimulation

For IUI
 2 - 4 follicules with Ø 18 – 19 mm.
 Estradiol blood level :
150-250 pgm / ml per ≥ 15 mm follicle.
 Endometrium ≥ 9 mm thick & trilaminar.
 IUI between Cycle D13 and D16.

Cancellation :
 ≥ 6 follicles ≥ 15 mm irrespective of E2
level
 Estradiol ≥ 1500 pg/ml.
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Sperm processing
Rationale
 Concentration of progressively motile
and morphologically normal
spermatozoa into a small volume of
culture fluid.
 Elemination of seminal PG,
lymphokines, cytokines and infectious
agents
 Reduce the number of free oxygen
radicals.
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Sperm processing

 Simple Sperm wash

 Swim-up following
sperm wash once or
twice.
 Density gradient
column separation
(filtration in Percoll
gradients, PureSperm
or Isolate).
 Adding chemicals to
the washed sperms
(caffeine ,
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Sperm processing

 Samples with an acceptable number of

motile sperm ( > 20 millions / ml ) can
be processed efficiently by sperm wash
twice and swim-up.
 Poor quality semen samples should be
processed using density gradient
centrifugation DGC.

Morshedi M et al, 2003

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Timing and Frequency of IUI

Fixed protocol:
• Single insemination:
36 – 40 hrs post – hCG
• double insemination:
within 12 & 48 hrs post - hCG

Variable protocol:
• TVS 36 h post hCG:- Ovulated → single IUI
- Not Ovulated→ IUI at once
→ IUI 24 hrs
later
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IUI technical aspects

- Partially filled urinary bladder; lithotomy position

& abdominal US
- Gently and atrumatically clean the cervix with
saline soaked swab
introduce IUI catheter through cervix; no touch to
fundus
- Slowly inject 0.3-.05 ml of processed semen
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Management following IUI

 Bed rest
A 10 minutes
bed rest after IUI has a positive effect
on PR.
 Intercourse within 12-18 hours of IUI.
 Luteal phase support, OPTIONS:
- hCG: 1.500 IU hCG 3 & 6 days after 1st
hCG
- Duphastone 10 mg PO / 8 hourly after
IUI x 14 days
- Cyclogest 400 mg supp. PV or PR;
once daily after IUI x 14 days
 Evidence based recommendations for
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practicing IUI
Grade A recommendations*
NICE Guidance Feb. 2004
 Couples with mild male factor fertility
problems, unexplained fertility
problems or minimal to mild
endometriosis should be offered up to
six cycles of intra-uterine insemination
because this increases the chance of
pregnancy.
* Grade A : based on randomised controlled trials
 Evidence based recommendations for
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practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004
 Where intra-uterine insemination is
used to manage male factor fertility
problems, ovarian stimulation should
not be offered because it is no more
clinically effective than unstimulated
intra-uterine insemination and it
carries a risk of multiple pregnancy.
 Evidence based recommendations for
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practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004
 Where intra-uterine insemination is
used to manage unexplained fertility
problems, both stimulated and
unstimulated intra-uterine
insemination are more effective than
no treatment. However, ovarian
stimulation should not be offered, even
though it is associated with higher
pregnancy rates than unstimulated
intra-uterine insemination, because it
 Evidence based recommendations for
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practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004
 Where intra-uterine insemination is
used to manage minimal or mild
endometriosis, couples should be
informed that ovarian stimulation
increases pregnancy rates compared
with no treatment, but that the
effectiveness of unstimulated intra-
uterine insemination is uncertain.
 Evidence based recommendations for
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practicing IUI
Grade A recommendations
NICE Guidance Feb. 2004
 Where intra-uterine insemination is
undertaken, single rather than double
insemination should be offered.
 Where intra-uterine insemination is
used to manage unexplained fertility
problems, fallopian sperm perfusion
for insemination (a large-volume
solution, 4 ml) should be offered
because it improves pregnancy rates
compared with standard insemination
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Number of trials of IUI ?

 Pregnancies resulting from IUI occur

during early treatment cycles.
Eighty-eight percent of pregnancies
occur in the first three cycles of IUI and
95.5% within the first four cycles
(Morshedi M et al, 2003).

Continued IUI beyond four trials

is not recommended
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Measures to improve
results
 Use of Aspirin in IUI Cycles Hsieh YY et al, 2000
RCT: Higher
pregnancy rate and better endometrial pattern
were achieved in patients with thin endometrium
after aspirin administration.
 Type of catheter Smith et al, 2002, RCT :
No difference in PR when using softer Wallace
catheter or the less pliable Tomcat catheter
 Vaginal misoprostol at the time IUI Brown et al.
2001 RCT :
200 - 400 μg of misoprostol vaginal insertion at
the time
of insemination is associated with higher PR.
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Measures to minimize
risk of
OHSS
 Shalev E, et al, 1995 RCT :

s.c. injection of 0.1 mg GnRHa

(decapeptyl) instead of hCG in IUI
treatment cycles at high risk of OHSS.
 De Geyter, et al 1996 RCT :

Transvaginal aspiration of
supernumerary follicles (more than
three follicles sized > 14 mm) does
not reduce the PRs and reduce
multiple pregnancy rate.
 What is the upper age limit
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for IUI ?
 Most studies have suggested that
it is an effective treatment option
for women under the age of 40 yrs
Success of intrauterine insemination,
in women aged 40-42 years, Hawbe, et al,
Fertility and Sterility, Vol 78, No 1, July 2002

se researchers found in their review that it ma

easonable approach for women under the age
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Where IUI should be done?

 Although IUI can be performed in an

optimized office but Patients need to
run from gynecologist to the lab.
Fragmented care because of poor
coordination.
 Ideally in an optimized clinic in
cooperation with an IVF unit
- IVF choice & Freezing any extra
embryos in case of over-response
- ? Selective follicular reduction in
case of over-response
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SUMMARY
 IUI is relatively simple, non-invasive,
cheap & easily repeatable.
 Careful selection of patient is important.
 There is good evidence in the literature in
favor of IUI as a cost-effective treatment
for unexplained and mild, moderate male
factor sub fertility.
 Although it may take relatively more
treatment cycles to achieve pregnancy,
there are considerable advantages to the
patient in terms of risk / benefit ratio and
financial cost as compared with other
ARTs.
 Failure of 4 - 6 trials of Gn. stimulated IUI
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Dr. J.Yousef FICS,FRCOG

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