Middle East Fertility Society Journal
1, 2005
Copyright Middle East Fertility Society
DEBATE
The current role of intrauterine insemination for the treatment
of male factor and unexplained infertility
Comment by: P.G. Crosignani. M.D.
E. Somigliana, M.D.
M. Colombo, M.D.
A. Riccaboni , M.D.
G. Ragni , M.D.
Milan, Italy
Introduction
For couples with male or unexplained
infertility, intrauterine insemination (IUI) is more
effective than timed intercourse and cervical
insemination (Farquhar et al., 2004). In women
with idiopathic infertility IUI in stimulated cycles
further improves the pregnancy rate compared with
natural cycle IUI (Table 1).
The need for milder ovarian stimulation
The following have a negative impact on IUI
outcome:
- duration of infertility
- age of the female partner
- history of pelvic inflammation
- presence of severe male factor(s).
Nevertheless, the most important risk
associated with IUI after ovarian stimulation is the
incidence of multiple gestation that can be as high
as 29% (Gleicher et al., 2000). This is why in the
presence of more than three follicles it has been
suggested the procedure should be stopped or the
cycle converted to IVF, but despite this risk the
method is still widely used.
Vol. 10, No. 1, 2005 Debate
Vol. 10, No.
Milder ovarian stimulation methods have been
recently introduced in order to reduce the risk of
iatrogenic twin pregnancies.
Reduced FSH dose
Simply lowering the follicle stimulating
hormone (FSH) dose can give an acceptable rate of
pregnancy per cycle (10%) with a lower rate of
twins and triplet (Table 2).
Low dose FSH + antagonist
In a pilot study carried out by our group, the
combined use of low-dose recombinant FSH and a
GnRH antagonist induced the growth of 1-2
follicles in the vast majority of the cycles (Ragni et
al., 2004).
Starting on day 3 of the cycle, patients were
given recombinant FSH (Puregon(R)) 50 IU per
day, and the GnRH antagonist Ganirelix
(Orgalutran(R)) at the dose of 0.25 mg per day was
started from the day when a leading follicle 14
mm in mean diameter was visualized, until HCG
administration.
Despite the presence of only one or two
follicles IUI produced an unexpectedly high
number of clinical pregnancies (11 in 32 cycles).
As unexplained infertility is the best diagnosis
for IUI and was the indication for treatment of the
majority of patients in this study, this could be the
reason for the high rate of pregnancies.
Nevertheless, taking into account that in idiopathic
infertility after multifollicular ovarian stimulation
the expected rate of pregnancy after IUI is 10%,
IUI for male factor and unexplained infertility 29
 Protocol of the pilot study

Day 3 Leading follicle Leading follicle

of the cycle Diam. 14 mm Diam. 18 mm

Recombinant FSH
hCG
GnRH antagonist

Table 1. Pregnancies after intrauterine insemination: stimulated versus natural cycles (Cohlen and Te Velde, 2002).

IUI in COH-cycles IUI in natural cycles O.R. (95% C.I.)

(pregnancies/cycles) (pregnancies/cycles)

Unexplained infertility (6 studies 1990-2000) 97/1007 52/1069 2.0 (1.4-2.8)

Male subfertility (5 studies 1990-2000) 40/349 28/337 1.4 (0.86-2.4)

and considering the small number of mature and it will be possible to achieve good clinical
follicles (1-2), an improvement in the quality of results without the unacceptable risk of multiple
oocytes could be another reason for the success pregnancies.
rate.
A better quality of follicles stimulated by low-
dose FSH and controlled by the antagonist is also REFERENCES
suggested by a recent study in previously poorly
responsive ICSI patients (12) observed during a 1. Cohlen JC, Te Velde ER. Mild ovarian hyperstimulation
second "spontaneous" ICSI cycle. These women for intrauterine insemination. In: Ovulation Induction,
Tarlatzis B. ed., Elsevier, pp.55-63, 2002.
were treated when the follicle reached a diameter 2. Farquhar C, Prentice A, Barlow D, et al. Menstrual
of 14-15 mm with low-dose FSH and a GnRH disorders and subfertility group. The Cochrane Library,
antagonist (for a few days) and the new method of Issue 3. Chichester, UK: Wiley, 2004.
pharmacological treatment normalized the ovarian
response, leading to a good normo-responder
success rate (Ubaldi et al., in press). Table 2. Clinical pregnancies in 510 controlled ovarian
Similarly the use of a GnRH antagonist hyperstimulation* and intrauterine insemination cycles (Healy
improved the IVF-ICSI results in patients who had et al., 2003).
already undergone ovarian hyperstimulation in
Outcome No. (%)
previous cycles (Somigliana et al., 2004).
To corroborate the findings of the pilot study a Clinical pregnancies 46 (9% per cycle)
multicenter European trial has been recently started Births 36 (7% per cycle)
and if its results confirm these data the rigid rule\ Twins (+ 1 triplet) 5 (14% of deliveries)
more oocytes, more pregnancy will be broken *
FSH 112 IU (day 2-6), then small increments

30 Debate IUI for male factor and unexplained infertility MEFSJ

3. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande
V. Reducing the risk of high-order multiple pregnancy
after ovarian stimulation with gonadotrophins. N Engl J
Med 2000; 343: 2-7
4. Healy D, Rombauts L, Vollenhoven B, Kovaks G,
Burmeister L. One triplet pregnancy in 510 controlled
ovarian hyperstimulation and intrauterine insemination
cycles. Fertil Steril 2003; 79: 1449-51
5. Ragni G, Alagna F, Brigante C, Riccaboni A, Colombo
M, Somigliana E, Crosignani PG. GnRH anatgonists and
mild ovarian stimulation for intrauterine insemination: a
randomized study comparing different gonadotrophin
dosages. Hum Reprod 2004;19: 54-8
6. Somigliana E, Ragni G, Riccaboni A, Engl B, Brigante
C, Crosignani PG. Is a protocol with GnRH antagonists
more suitable than a long protocol in patients at high risk
of OHSS? A preliminary study. 60 ASRM Conference,
Philadelphia, Pennsylvania, October 16-20, 2004
7. Ubaldi F, Rienzi L, Ferrero S, Baroni E, Iacobelli M,
Sapienza F, Greco E. Use of GnRH antagonists with
minimal stimulation in natural ICSI cycles in poor-
responder patients. RBM Online, in press.
P.G. Crosignani, E. Somigliana, M. Colombo, A.
Riccaboni, and G. Ragni
First Department of Obstetrics and Gynecology,
University of Milan,
Via Commenda 12,
Milan, Italy
Comment by: Ibrahim Fahmy, M.D.
Cairo, Egypt
Intrauterine inseminations (IUI) have been
performed since the beginning of the past century
for the treatment of infertility. Despite its
widespread use, the overall success rate of IUI
remains controversial. In general, the most
common indications for IUI are unexplained
infertility, mild to moderate male-factor infertility,
and other cases of infertility in which the woman
has an unobstructed genital tract and some ovarian
function and the man has motile sperm (1). Other
indications that may apply to male factor infertility
include; immunological infertility, coital and
ejaculatory problems due to different sexual
dysfunctions and anatomical defects (2). With the
Vol. 10, No. 1, 2005 Debate
advent of more sophisticated assisted reproductive
techniques (ART), offering IUI for infertile couple
become a matter of debate. The reported pregnancy
rate after IUI showed profound variations in the
literature ranging from 0 to over 50% (3).
However, many confrontations are challenging the
use of IUI on the ground of evidence-based
medicine.
The rationale for IUI in the treatment of male
subfertility is to increase the density of normal
motile spermatozoa at the site of fertilization.
Removal of nonmotile spermatozoa, leucocytes
and immature germ cells, might contribute to an
enhanced sperm quality by a decreased release of
lymphokines, cytokines, and free oxygen radicals
that may have a negative effect on the fertilizing
ability of spermatozoa. On the other hand, the
reservoir effect of the cervical mucus and the
natural selection of normal fertile spermatozoa are
compromised thus decreasing the window of
opportunity for sperm oocyte interaction and
fertilization. Before insemination, semen has to be
processed using one of the established sperm
preparation techniques to select a sperm population
with best quality. The techniques used for sperm
processing vary across the centers worldwide. The
most commonly used are the simple wash using
various culture media, swim-up, and discontinuous
gradient centrifugation (DGC). However, Other
less commonly used methods such as; glass bead
column, swim-down, and sperm select system have
been used in several studies. Despite the diversity
in sperm processing techniques, few randomized
controlled trials (RCT) could demonstrate a
borderline advantage for DGC, while others failed
to demonstrate such advantage (4). Large high
quality randomized controlled trials, comparing the
effectiveness of a gradient and/ or a swim-up and/
or wash and centrifugation techniques on clinical
outcome are lacking. Concerning the frequency of
insemination some studies favored double
insemination (2). On the other hand, double
intrauterine insemination showed no significant
benefit over single intrauterine insemination (5).
In male factor infertility due to impaired semen
parameters the results are contradictory. Ideally
evidence should be gained from large multi-center
well-designed randomized studies in clearly
defined populations of subfertile males. Despite
IUI for male factor and unexplained infertility 31