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Human Reproduction vol.10 no.l pp.

142-147, 1995

Intra-uterine insemination versus cyclic, low-dose


prednisolone in couples with male antisperm antibodies

A.Lahteenmaki1'2, J.Veilahti3 and O.Hovatta1

To whom correspondence should be addressed

A total of 46 couples with male immunological infertility


entered the trial at the infertility clinic of the Family
Federation of Finland. The men all showed a positive mixed
antiglobulin reaction to immunoglobulin G in their semen;
31 men were also tested for sperm-bound IgA inimunoglobulins by flow cytometry. Serum antisperm antibodies
were checked in a tray agglutination test. The women
showed normal reproductive endocrinology and at least
one patent Fallopian tube. The couples were randomized
to undergo either up to three intra-uterine inseminations
(IUI), or timed intercourse with cyclic, low-dose (20 mg)
prednisolone therapy of the men. Cross-over was carried
out if no pregnancy occurred in the first stage. Timing of
ovulation was based on urinary luteinizing hormone assay
and transvaginal ultrasonographic measurements. In all,
40 couples either completed the study or the female partner
conceived. IUI was significantly better (P = 0.04) with nine
pregnancies than timed intercourse with prednisolone (one
pregnancy). There were no significant associations between
antibody levels, sperm count or motility versus the incidence
of pregnancy. In male immunological infertility, well-timed
IUI is an effective treatment method: results are obtained
rapidly and steroidal side-effects can be avoided.
Key words: antisperm antibodies/intra-uterine insemination/
prednisolone

Introduction
It is known that auto-antibodies to spermatozoa impair fertility.
Those bound to the sperm surface are considered to be
especially important (Eggert-Kruse et ai, 1991). The presence
of such antibodies in men has been shown to be associated
with genital infections, vasectomy, trauma or certain anatomical
abnormalities (for a review see Isidori et ai, 1988). The effects
that male antisperm antibodies have on fertility are still not
very well known, which is reflected in the various treatment
modalities. In addition, the results of these treatments are
sometimes difficult to interpret because this condition is
anything but absolute. Spontaneous pregnancies occur,
although long periods are often involved (Shulman, 1986).
142

Materials and methods


Patients
A total of 46 couples, who had been trying to achieve
pregnancy for at least a year, entered the trial between
September 1989 and October 1993 at the infertility clinic of the
Family Federation of Finland, Helsinki, after giving informed
consent. Male partners had to show a positive mixed antiglobulin reaction (MAR) to immunoglobulin G (IgG) in their semen.
The men all had sufficient spermatozoa in their semen, so that
at baseline there were at least 1X106 spermatozoa with mean
progressive motility of 72% (range 19-99) after preparation.
A tray agglutination test (TAT), for detecting the presence of
circulating antisperm antibodies, was also carried out before
the trial. A sub-group of men (n = 31) was checked by flow
cytometry for IgA antibodies in their semen. The men were
healthy, except for one man who had diabetes. He was under
medical surveillance during the study. No X-ray examinations
were performed, since the prevalence of tuberculosis at present
is very small in the Finnish population.
The female partners had to be <40 years old and in good
general condition. Serum antibodies were also checked in the
women, and four women had a slightly elevated titre (TAT
1:16), which we considered to be insignificant. Tubal patency
was assessed by laparoscopic chromopertubation (41 women)
or hysterosalpingography (four women). One woman was not
assessed by either method as she had two children from her
previous marriage. Two women showed some pathological
results in their left Fallopian tubes, and one in the right
tube but no other abnormalities were seen. Ovulation and
reproductive endocrinology were assessed before the start of
the study. Oligo-ovulation occurred in five women. Serum
Oxford University Press

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'infertility Clinic, The Family Federation of Finland, Kalevankatu


16 B, 00100 Helsinki and department of Biomedicine, University
of Helsinki, Siltavuorenpenger 20 J, 00170 Helsinki, Finland

However, couples that have been trying to achieve a pregnancy


for several years are anxious for assistance.
Assisted reproductive techniques have been employed to
achieve pregnancy, with variable success rates. Intra-uterine
insemination (IUI) with washed spermatozoa has been used to
bypass the cervix, one of the possible sites of action of
antisperm antibodies (Mahony and Alexander, 1991). Better
results have been achieved by in-vitro fertilization (IVF)
treatment (Clarke etai, 1985). Immunosuppression by corticosteroids, introduced by Shulman in 1976, has been used with
various regimens. However, the results are inconclusive. In
this study we compared the efficacy of oral, low-dose cyclic
prednisolone with IUI, when the male partners had various
levels of sperm-bound antibodies in their semen.

IUI versus prednisolone in male immunological infertility

concentrations of prolactin and thyroid-stimulating hormone


were in their normal ranges, even though one woman had had
substitution for mild hypothyreosis for several years. One
woman had medication for epilepsy. Post-coital test results
were abnormal in 38 couples and positive in three. Results of
the tests with five couples were not obtained.

Sperm preparation and immunological tests


Semen specimens were collected by masturbation after 2-3
days of abstinence. The liquefied samples were analysed
using a Makler counting chamber according to World Health
Organization (WHO) guidelines (1987). At first, a swim-up
technique (24 men) was used to recover motile spermatozoa.
During the course of the study, superior results were achieved
with a discontinuous Percoll gradient technique. Hence it was
decided to switch to this method for the rest of the study. Only
one type of preparation method was used for each couple. In
the swim-up procedure, the ejaculate was diluted 1:2 with
Earle's balanced salt solution (EBSS-P-SR2) containing 1%
human serum albumin (HSA, MedicultR; Medi-Cult a/s, Copenhagen, Denmark) and centrifuged at 320 g for 10 min. The
supernatant was discarded, the pellet was resuspended in 2 ml
of medium and centrifugation was repeated at 370 g for 5

Statistical analyses
Fisher's exact test was used to compare the pregnancy rates
before cross-over and also in the whole material, based on the
assumption that a couple's probability of pregnancy using one
method did not depend on the conditions in which the previous
method had been applied unsuccessfully. This test was also
employed for comparison of sperm washing methods between
the groups, and for analysis of previous female fertility.
To test the homogeneity of the couples as regards antibody
levels, semen parameters and duration of infertility between
the two groups, the Mann-Whitney rank sum test was used.
It was also used to assess the differences in antibody levels
and in duration of infertility between pregnant and nonpregnant couples.
Student's paired Mest was employed to determine significant
changes in antibody levels (IgG-MAR and TAT), sperm count
and motility before and after treatment. Using multiple analysis
of variance, semen parameters were analysed between the
couples who first started with IUI and those who were treated
by IUI after cross-over.
The chosen level of significance was P < 0.05.
143

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Trial design
The ethical committee of the Family Federation of Finland
approved the study protocol. By drawing a sealed envelope,
the couples were randomized to undergo either up to three
IUI, or oral prednisolone therapy of the men combined with
timed intercourse in three consecutive menstrual cycles of the
female partner. Cross-over to the other treatment was carried
out if no pregnancy occurred in the first stage.
Prednisolone treatment was modified from the regimen
described by Hendry et al. (1986). A dose of 20 mg of
prednisolone (Prednisolon 5 mg; Leiras Oy, Turku, Finland)
was taken once a day with meals on days 1-10 of the female
partner's menstrual cycle, followed by 5 mg on days 11 and
12. In the pre-treatment visit the couples were informed about
the side-effects associated with this steroid. The men were
advised to abstain from alcohol and heavy sports during the
study period. After three cycles, the antibody levels were remeasured and semen analysis performed. The couples were
then seen and asked a non-leading question about the possible
side-effects.
Clomiphene citrate was used in 62% (67/108) of IUI
cycles and 54% (52/96) of timed intercourse cycles. Ovulation
detection was performed daily by use of urinary luteinizing
hormone (LH) home test kits (ClearplanR; Unipath, Bedford,
UK), beginning 3-4 days before expected ovulation. During
the three-cycle prednisolone therapy, couples were instructed
to have intercourse in each cycle in the evening of the day of
the LH rise and on the following day. In IUI cycles, timing
of ovulation was also checked by transvaginal ultrasonography.
IUI was performed the day after onset of the LH surge, by
injecting ~1 ml of spermatozoa in culture medium with a
Kremer-Delafontaine catheter (Prodimed, Neuilly-en-Thelle,
France). If no pregnancy occurred, up to three IUI cycles took
place, after which antibody tests were repeated.

min. The final pellet was then gently overlaid with 1 ml of


medium and incubated in 5% CO2 in air at 37C for 30-60
min, to allow motile spermatozoa to swim up into the medium.
The upper fraction was used for analysis and insemination.
In discontinuous Percoll gradients, isotonic Percoll (Pharmacia AB, Uppsala, Sweden) solutions were prepared using
Ham's F-10 10X(Gibco Ltd, Paisley, UK) medium containing
1% HSA (Finnish Red Cross, Helsinki, Finland). Percoll
suspensions of 40 and 90% were overlaid with undiluted
semen and centrifuged at 550 g for 20 min. The upper two
layers were discarded and the pellet in the 90% layer was
resuspended in 4-6 ml of Medicult culture medium. Centrifugation at 320 g for 10 min was repeated and the final pellet was
resuspended in ~1 ml of medium for analysis and insemination.
The spermMAR test (Ortho Diagnostic Systems, Beerse,
Belgium) for sperm-bound IgG antibodies was used as a MAR
test as described by Jager et al. (1978). The test, usually
performed twice before the study, was considered weakly
positive if >10 but <50% of motile spermatozoa were bound
to the latex particles (n = 6). When ^50% were bound, the
test result was clearly positive (n = 40).
The TAT was performed according to Friberg (1974) by
serially diluting serum samples and incubating each dilution
with washed donor spermatozoa in microchambers (Oriola,
Helsinki, Finland) at 37C for 2 h. The serum sample was
considered positive if agglutination of spermatozoa was seen
under the microscope at a dilution of 1:16 or above (n = 42).
A group of 31 men was assessed for sperm-bound IgA
antibodies by flow cytometry. This was done from native
semen samples by using fluorescein isothiocyanate-conjugated
F(ab')2 fragments of polyclonal antibodies. Antibody labelling
and estimation of the sperm IgA load have been described
previously (Rasanen et al., 1992). As dead spermatozoa were
excluded by propidium iodide staining, the antibody proportion
was calculated only from live cells. In all, 26 men tested
positive (>5%) for IgA antibody.

A.Lahteenmaki, J.Veilahti and O.Hovatta

of 10 pregnancies resulted: nine from IUI cycles, and one


from the timed intercourse regime during which the men had
prednisolone therapy. Numbers of couples starting the study
with IUI and with timed intercourse were 19 and 21 respectively. There were no significant differences in semen parameters, antibody levels or duration of infertility between these
groups (Table II). Before cross-over, the pregnancy rate after
three cycles of IUI was 16.7% (8/48), whereas no pregnancies
occurred in 63 timed intercourse cycles. The difference in
pregnancy rates per couple was highly significant (P = 0.001),
and remained also after cross-over (P = 0.04 for the whole
study), when two more pregnancies occurred, one in both
groups. The results of these treatments are shown in Table III.
Six IUI pregnancies resulted from 67 clomiphene citrateinduced cycles (9%) and three from 41 natural cycles (7%).
Clomiphene citrate was not used in those 44 timed intercourse
cycles which resulted in one pregnancy (2%).
There were no significant differences in IgG-MAR or TAT
values before and after three cycles of IUI. This was also the
case with IgG-MAR after three-cycle steroid therapy. However,
a reduction in serum TAT values (P = 0.03) was noticed after
the prednisolone treatment, although total disappearance of
antibody was not observed. This fall in serum antibody levels

Table I. Reason for withdrawal of six couples and some immunological characteristics of the men
Patient no.

Reason for withdrawal

Randomized
to start with

No. of treated
cycles

IgGa

IgAb

TAT

28

spontaneous pregnancy after the


first IUI
endometrial polyps discovered during
the study; later IUI pregnancy
male partner could not produce semen
samples for IUI
ovarian endometrioma discovered
during the study; later IVF
pregnancy
no longer wished to participate in the
study; later pregnancy with
prednisolone
no longer wished to participate in the
study

IUI

100

ND

1:256

IUI

76

ND

1:64

IUI

95

ND

1:64

TI

70

1:128

TI

98

89

1:512

IUI

95

64

1:128

40
41
43

45
46

Ig = immunoglobulin; TAT = tray agglutination test; IUI = intra-uterine insemination; TI = timed intercourse;
ND = not done
Direct mixed antiglobulin reaction (MAR) test.
b
Flow cytometry.
a

Table II. Comparison of initial semen parameters, antibody levels and duration of infertility in couples who first started with intra-uterine insemination (IUI),
with those starting with timed intercourse (TI)a
IUI first (n = 19)
b

IgG (%)
IgAc (%)
Total sperm count per ejaculate (X10 6 )
Progressive motility (%)
Duration of infertility (years)
a

Values are mean SD.


"Direct mixed antiglobulin reaction (MAR) test.
c
Flow cytometry.
d
n = 14.
e
= 17.

144

82 25
38 9d
258 248
57 19
5.2 4.4

TI first (n = 21)
80 27

51 T
174 127
46 21
5.4 3.6

P
0.9
0.3
0.5
0.05
0.8

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Results
In all, 40 couples either completed the study or the female
partner conceived and treatment was stopped. The reasons for
withdrawal of six couples are given in Table I. None of
them withdrew because of steroidal side-effects. One- man
complained of mild dyspepsia; two others of erythema on the
face and chest. No sleeplessness or irritability was reported.
Of the 40 men above, 19 (48%) had had some predisposing
factors for antisperm antibodies in their past: eight men had
had genital tract infections, five had had operations because
of inguinal hernias, three had suffered from cryptorchidism
and two from left-sided varicocele. One man had a unilateral
obstruction of the epididymis as a result of surgery. Interestingly, operated inguinal hernias predisposed the subjects to
very strong IgG-MAR positivity (>90%), whereas the other
factors were associated with more variable MAR values. In
these five men, serum TAT results were also clearly positive
(1:64-1:1024).
The mean duration of infertility in these couples up to the
start of the study was 5.3 years (SD 3.4; range 1-18). Infertility
was primary in 32 couples (80%). Previous fertility of the
female partner was not a significant predictor of pregnancy,
even though a slight association was noted (P = 0.09). A total

IUI versus prednisolone in male immunological infertility

Table III. Pregnancies per cycle and couple before cross-over and for the whole study
Before cross-over

IUI
Prednisolone + TI

The whole study

Per cycle
(%)

Per couple
(%)

Per cycle
(%)

Per couple
(%)

8/48 (17)
0/63 (0)

8/19 (42)a
0/21 (0)

9/108 (8)
1/96(1)

9/40 (23)b
1/32 (3)

IUI = intra-uterine insemination; TI = timed intercourse.


"P = 0.001.
b
P = 0.04.

Discussion
In the present study, IUI proved to be superior to low-dose,
cyclic prednisolone therapy with timed intercourse when the
male partner had sperm-associated IgG and/or IgA immunoglobulins. Limited success with IUI has been reported by
Kremer et al. (1978). On the other hand, Francavilla et al.

Table IV. Immunological characteristics of the men whose female partner


conceived
Method

IgGa

IgAb

Prednisolone + TI
IUI
IUI
IUI
IUI
IUI
IUI
IUI
IUI
IUI

10
98
94
63
97
100
95
55
77
95

ND
ND
24
34
13
51
ND
ND
73
0

TAT
:16
: 128
:1024
:64
:64
: 128
:16
: 128
:256
: 128

Ig = immunoglobulin; TAT = tray agglutination test; TI = timed intercourse;


IUI = intra-uterine insemination;
ND = not done
"Direct mixed antiglobulin reaction (MAR) test.
b
Flow cytometry.

(1992) failed to obtain pregnancies by IUI when all spermatozoa were IgG and/or IgA antibody-coated, irrespective of the
other semen parameters. In our study, timing of ovulation
was based on urinary LH rise and checked by transvaginal
ultrasonography, thus optimizing the timing of insemination.
When monitoring the female partner during these cycles, it is
possible to recognize and avoid problems that may be involved.
The importance of adequate ovulation has been reported by
Margalioth et al. (1988), who had some success with IUI,
especially when gonadotrophin stimulation of the female
partner was employed.
IUI may be of help if the primary obstacle to fertility is
sperm penetration through the cervical mucus, as suggested
with regard to locally produced IgA antibody (Jager et al.,
1980). The benefit of IUI may also be in overcoming problems
in sperm capacitation and acrosome reaction. As Lansford
et al. (1990) showed, premature acrosomal loss shortly after
ejaculation may be associated with sperm-bound antibodies.
If the lifespan of these spermatozoa is decreased, IUI with
appropriate timing has to be performed to enhance the probability of achieving pregnancy.
The effect of semen preparation on sperm-associated
immunoglobulins is interesting. Simply centrifuging and resuspending specimens has been considered to be inadequate in
separating antibodies from the sperm surface. This has been
shown by Haas et al. (1988), who used a radioimmunoassay
method to measure antibody levels after multiple washings.
However, flow cytometric data suggest that the first wash
145

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was not associated with the occurrence of pregnancy. The total


count and progressive motility of spermatozoa remained almost
unchanged after steroid therapy.
Table IV illustrates some antisperm antibody characteristics
of those men whose partners conceived during the study
period. There were no significant differences in sperm-bound
IgG or humoral antibody levels between pregnant and nonpregnant couples. The man undergoing steroid treatment whose
partner conceived had minimal amounts of seminal and serum
antibodies (MAR 10%, TAT 1:16). Of the IUI pregnancies,
five occurred in IgA-positive cases and one in an IgA-negative
case. Of the 31 cases tested for IgA, 26 were positive and five
were negative. The difference in IgA antibody levels between
pregnant and non-pregnant couples was not significant.
The semen parameters, i.e. total count and progressive
motility before and after washing, were analysed in the partners
of those women who first started with IUI (n = 19). This was
done because motility in native semen was slightly but not
significantly better in these men compared with those who
started with timed intercourse. However, there was no significant difference in sperm motility in IUI between pregnant and
non-pregnant couples. As Table III shows, most pregnancies
(n = 8) occurred in the IUI cycles before cross-over. Thus,
we also analysed the semen parameters in the IUI cycles after
cross-over. These cycles did not differ as regards sperm count
and progressive motility, although initially the difference in
progressive motility was close to significance (Table II).
Overall, the IUI cycles that led to a pregnancy were slightly
better as regards washed sperm progressive motility (mean
SD; 83 17%) than those which did not (mean SD; 73
19%, P = 0.08). Sperm preparation with Percoll gradients
produced relatively more pregnancies than swim-up, 5/16 and
4/24 respectively.
After the study period, one spontaneous pregnancy occurred
within 3 months. In this specific case, the man showed strong
IgG-MAR positivity (100%), and also by flow cytometry
clearly positive IgG (92%) and IgA (93%) antibody values.
Later, two more spontaneous pregnancies occurred.

A.Lahteenmaki, J.Veilahti and O.Hovatta

146

poor pregnancy results in the whole study compared with the


before cross-over groups for IUI is likely to reflect intraindividual variation rather than a negative effect of corticosteroid.
Even though previous fertility of the female partner and
duration of the couple's infertility were not significant predictors of pregnancy in this study, a weak association was
noted. This has been shown by Duleba et al (1992), who
analysed couples with male factor infertility. As they explained,
there is a chance of including a sub-fertile female population
which may not be identified in a standard infertility study. In
addition, Hendry etal. (1986) found that in male immunological
infertility, there was a preponderance of successful couples
among those whose duration of infertility was <2 years.
In conclusion, our results show that IUI is an effective
method for couples with male antisperm antibodies. The
method used for sperm preparation may be important. Slightly
better pregnancy rates achieved with a discontinuous Percoll
gradient than with swim-up suggest that the former technique
may remove some surface-bound antibodies on spermatozoa.
Monitoring the LH surge and checking ovulation by transvaginal ultrasonography makes it possible to exclude ovulatory
problems. As the majority of pregnancies usually occur within
the first two or three well-timed IUI cycles (te Velde et al,
1989), corticosteroid therapy and the steroidal side-effects that
may appear even with low doses (Spector and Sambrook,
1993) can be avoided.
Acknowledgements
We thank Dr Pekka Lahteenmaki for his critical review of the
manuscript, Dr Marita Rasanen for the flow cytometric analyses of
IgA antibodies and Dr Nicholas Bolton for revising the language.
The nursing assistance of Ms Ulla-Riitta Ripatti, the technical
assistance of Ms Kisse Johansson and Ms Kaisu Lavikka and the
secretarial assistance of Miss Anne Kaljunen are greatly appreciated.

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IUI versus prednisolone in male immunological infertility

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Received on May 26, 1994; accepted on September 14, 1994

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