fertilitzation rate in couples with ui

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Human Reproduction vol 7 no.2 pp.223-226, 1992

Fertilization rate in couples with unexplained infertility

A.I.Mackenna 1, F.Zegers-Hochschild,E.O.Fernandez, C.V.Fabres, C.A.Huidobro,J.A.Prado, L.S.Roblero, E.L.Altieri,A.R.Guadarrama and T.H.Lopez

Department of Obstetrics and Gynaecology, Climca Las Condes,Institute Chileno de Medicina Reproductiva, Santiago, Chile

'Present address and address for correspondence: The University ofSheffield, Department of Obstetrics and Gynaecology, JessopHospital for Wom en, Sheffield S3 7RE, UK

A group of 24 couples with unexplained infertility wasscheduled for in-vitro fertilization and tuba] embryo transfer

between May 1989 and September 1990. In the same period,

in-vitro fertilization and intrauterine transfer of embryos was

planned in a control grou p of women with tubal infertility.

The m ean age and d uration of infertility were similar in both

groups and the sam e scheme of ovarian stimulation was used.

No statistically significant difference was obtained comparing

oestradiol levels and numbers of mature oocytes retrieved

between the group of patients with unexplained infertility and

those with tubal infertility. The fertilization rate of the oocytes

obtained from women with unexplained infertility (60.4%)

was significantly lower P < 0.001) than that of the oocytes

obtained from patients with tubal infertility (87.3%). Therewas n o statistically significant difference in the cleavage rates

between patients with unexplained infertility and those with

tubal infertility. It is concluded that lack of fertilization is

an unexplored cause of infertility in couples with unexplained

infertility.

Key words: unexplained infertility/fertilization rate

Introduction

Unexplained infertility refers to those couples who have failed

to establish a pregnancy despite no cause of infertility being

identified or after correction of the factor presumed to be

responsible for infertility (Moghissi and Wallach, 1983). Its

reported incidence has varied between 6% and 27% (Moghissi

and W allach, 1983). This wide variability inevitably depends on

the methodology used to reach the diagnosis. Clearly, the more

exhaustive the evaluation of the infertile couple, the less will be

the possibility of reaching this diagnosis because more causes

of infertility can be identified (Navot et al., 1988).

Even when a com plete evaluation of the couple is performed,

there are some processes necessary for conception which are

inaccessible to traditional diagnostic methods and therefore, in

some cases, the cause of infertility remains unknown. Two

important unexplored events in human reproduction are sperm

transport through the upper genital tract (Taylor and Kredentser,

1989) and in-vivo fertilization.

In-vitro gamete interaction seems to be a good alternative for

the treatment of unexplained infertility (Navot et al., 1988;

Audibert et al., 1989), as well as for the investigation of this

condition (Trounson et al., 1980). However, the latter advantage

of in-vitro fertilization procedures has not received enough

attention.

The main objective of this study is to evaluate the in-vitro

fertilization rate in couples with unexplained infertility.

Materials and methods

A study group of 24 women with unexplained infertility was

scheduled for in-vitro fertilization and tubal embryo transfer

between May 1989 and September 1990 at the Unit of

Reproductive Medicine of Clinica Las Condes (Santiago, Chile).

The mean age of the patients was 33 (SD = 3.1) years and they

had a mean of 6 (SD = 1.3) years of infertility. A com plete

diagnostic work-up of the infertile couple was performed before

the procedure was indicated and for the diagnosis of unexplained

infertility, the findings had to be entirely normal. The analysisincluded ultrasound monitoring of follicular growth and samples

of cervical mucus, obtained in the fertile period, for scoring

(WH O, 1987) and for in-vitro spe rm -m uc us interaction (WHO,

1987). Semen analysis and the sperm mixed antiglobulin reaction

(MAR)-test, as well as homologous and heterologous in-vitro

penetration tests were performed, considering as normal

parameters those described by the World Health Organization

(1987). Two blood samples for measurement of prolactin and

progesterone were obtained in the mid-luteal phase. Results of

hysterosalpingography, hysteroscopy and laparoscopy performed

in all patients were normal.

Simultaneously a control group of 44 women with tubal

infertility was scheduled for in-vitro fertilization and intrauterineembryo transfer (IVF). These were all the patients with tuba

infertility and whose husbands had normal semen parameters

Table I. Age and duration

Unexplained infertility

Tubal infertility

of infertility

Women

(n)

24

44

Age-f(SD)

3 3 ( 3 . 1 ) '

33 (3.3)'

Years of infertility* ( S D )

6 (1 3)b

7 ( 1 . 9 )b

a/b = NS

© Oxford University Press 223



A.I.Mackenna el al.

TaWe D. N umb er of follicles S: 16

undergoing the same superovulation

Unexplained infertility*

Tubal infertility

mm, oestradiol values andscheme

Women

(")

23

44,

number of mature oocytes

Folliclesa 16 mm onday of HCGJ ( S D )

6 8 \2 f

7 0 (1 7)1

retrieved in patients with unexplained

Oestradiol/folliclea 16 mm on dayof HCG (pmol/l),f (SD)

1440 (540)"

1350 (560)"

infertility or tubal infertility

Mature oocytes

retrieved

x (SD)

6. 8 (1.3)c

7.5 (1.8)c

*24 minus 1 empty follicle syndrome .HCG = human chorionic gonadotrophin.a/b/c = NS.

(W HO , 1987) who were treated in the same period of time. Th e

mean age of these patients was 33 (SD = 3.3) years and they

had a mean of 7 (SD = 1.9) year s of infertility.

The same ovulation induction scheme was used in the study

and control groups for induction of multiple follicular maturation.

Leuprolide acetate (Lupron, Abbott Laboratories), human

menopausal gonadotrophin (Pergonal, Serono Laboratories) and

human chorionic gonadotrophin (HCG; Profasi, Serono

Laboratories) were used. Transvaginal ultrasound (Aloka, model

630, 5.0 MHz probe) was performed and daily blood samples

were taken for oestradiol measurement starting on day 6 of the

treatment cycle. Oocyte retrieval was performed, by transvaginal

aspiration of the follicles, 34 —36 h after the HCG injection.

Oocyte quality was assessed by light microscopy, considering

mature oocytes to be those with an expanded cumulus, radiant

corona, distinct zona pellucida, clear ooplasm and also expanded

granulosa cells. Only mature oocytes were inseminated with

100 000 spermatozoa each, thus ensuring these factors were not

variables interfering with the fertilization rate. Spermatozoa were

prepared using a standard swim-up technique (Cohen ex al., 1985)

and the mean final sperm count was 31.1 (range = 2. 4- 79 .2 )

million and 26.1 (range = 2.0—73.0) million in the unexplainedand tubal infertility groups respectively (NS). Fertilization was

assessed 18 h later and, if cleavage was observed, 48 - 5 0 h after

insemination tubal or intrauterine embryo transfer was performed.

The luteal phase was supplemented with daily intramuscular

injections of progesterone (50 mg), and blood samples for HCG

measurement were obtained on days +12, +15, +18 and +21

after transfer. For calculation of the pregnancy rate, all

pregnancies confirmed by sonographic evidence of a gestational

sac and embryo were counted.

For statistical analysis, Student's f-test, Fisher's exact test, chi-

square test, Mann -W hit ne y U test and power analysis were used.

The level of statistical significance was fixed at P < 0.05.

Results

No statistically significant difference was obtained comparing the

age and duration of infertility between the two groups (Table I).

The data of Table II provide a comparison of the number of

follicles > 16 mm in diame ter and the oestradiol levels on the

day of the HC G injection, and show no significant differences

between the study and control groups. In the group with

unexplained infertility, oocytes were obtained from 66.7%

(188/282) of the aspirated follicles compared with 71.3%

TaWe HI. Fertilization

Unexplained infertility*

Tubal infertility

rate and cleavage rate

Inseminatedoocytes

149

292

Fertilization

rate

(%)

60.4 '

87 3"

Cleavage

rate

(%)

92.2"

93.7"

2co

3tn

a>

5

25

J

•24 minus 1 empty follicle syndrome,a = P < 00 01 , b = NS.

H

75

Unexplainedinfertility

Tubal

infertility

Fig. 1. Fertilization rate for each couple treated in a group of

patients with unexplained infertility (n = 23. median = 70% andrange = 0-100%) or tubal infertility (n = 44, median = 90%and range = 0-1 00 %) Ma nn-W hitney U test P < 0.001.

(381/534) successful retrievals in the group with tubal infertility

(NS). No statistically significant difference was observed

comparing the mean numbers of mature oocytes retrieved bet-

ween the two groups. One patient with the diagnosis of

unexplained infertility presented empty follicle syndrome (Coulam

et al., 1986) and no oocytes were obtained after transvaginal

aspiration of 10 follicles.

224

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y ,

p

j

g

http://humrep.oxfordjournals.org/
















Unexplained infertility

A total of 149 mature oocytes from the group with unexplained

infertility were inseminated and in 90 of them fertilization was

observed (60 .4%); in the control group, 292 mature oocytes were

inseminated and 255 of them fertilized (87.3% ) (Table HI). This

difference is highly significant (P < 0.001). The cleavage rate

(the percentage of fertilized oocytes undergoing cleavage) was

similar in the two groups.

The rate of failed fertilization (patients who did not fertilize

any of the inseminated oocytes) was 13% (3/23) in the groupwith unexplained infertility and 4.5 % (2/44) in the control group

(NS). Figure shows the fertilization rate for each couple treated.

There is a highly significant difference between the two groups

(P < 0.001).

Twenty women with unexplained infertility underwent tubal

embryo replacement and intrauterine embryo transfer was

performed in 42 patients with tubal infertility. A clinical

pregnancy rate of 40% (8/20) and 33% (14/42) was observed

in the unexplained and tubal infertility groups respectively. Only

one first trimester abortion was observed in both groups occurring

in a patient with unexplained infertility.

Discussion

In comparison with patients with tubal infertility, the fertilization

rate in couples with unexplained infertility was significantly lower

(unexplained = 60.4% and tubal = 87.3%). Similar results have

been reported by Navot et al. (1988) and Audibert et al. (1989).

Since there were no differences between the two groups with

respect to the age of the patients, duration of infertility, number

of follicles developed, oestradiol values, numbers of oocytes

retrieved and light microscopic characterization of the oocytes,

it is resonable to conclude that in couples with unexplained

infertility there is an unknown factor which decreases the

fertilization rate. Another unexplored, but uncommon, cause of

unexplained infertility could be the empty follicle syndrome(Coulam etai., 1986).

Recently, Calvo et al. (1989), assessing the ability in 15 men

with unexplained infertility of capacitated spermatozoa to undergo

the acrosome reaction, found a sub-group of six with a lack of

acrosome reaction; Fenichel et al. (1991) concluded that an

impaired acrosomal status can be associated with unexplained

unsuccessful fertilization. Further studies must be developed to

assess whether the lack of fertilization demonstrated in couples

with unexplained infertility is due to functional defects in

spermatozoa and/or to oocyte defects.

When fertilization occurred, the cleavage rate was similar in

the unexplained and tubal groups of infertile p atients, suggestingthat fertilization rather than the subsequent development of the

fertilized oocyte is altered. Moreover, other authors using

intrauterine embryo transfer for both groups of patients have

observed that the implantation rate is also similar in women with

tubal or unexplained infertility (Audibert et al., 1989). In the

present study, it is impossible to compare both groups in terms

of pregnancy rate because different routes of embryo replacement

were used.

Although there was a trend towards a higher rate of failed

fertilization in the group with unexplained infertility, with the

number of patients included in this study (total = 67) this failed

to reach the level of statistical significance. Power analysis shows

that if this trend was maintained, 212 patients would be needed

to obtain a statistically significant difference (P < 0.05 ). On the

other hand, looking at the fertilization rate for each couple treated,

a statistically significant difference was obtained between the

study and control groups. As shown in Figure 1, most of the

couples with unexplained infertility had low fertihzation rates and

the majority of patients with tubal infertility had high fertilization

rates.

In spite of failing to identify a treatable condition, various

empirical treatments can be used in couples with unexplained

infertility (Chan and Ratnam, 1989). The good results obtained

in this series com pare favourably with the results in other series,

in which assisted fertilization techniques have also been used

(Leeton etai, 1987; Navot et al., 1988; Wong et al., 1988;

Audibert etai., 1989; Devroey etai, 1989; Sharma etai.,

1991). Th ese results are probably attributable to either the greater

chance of obtaining fertilization when more than one oocyte is

inseminated, or to by-passing the impaired sperm transport

through the upper genital tract, as has been suggested by Cefalu

et al. (1988) and Templeton et al. (1982). On the other hand,

Ramsewak et al. (1990) have demonstrated that spermatozoa areconsistently able to traverse the reproductive ract in patients with

unexplained infertility. This finding, however, does not

necessarily imply that the spermatozoa were competent to achieve

fertilization. The interaction between the spermatozoa and the

upper human female tract is a matter of present and future

research (Barratt and Cooke, 1991).

It is concluded that lack of fertilization is an unexp lored cause

of infertility in couples with unexplained infertility. This study

also suggests that in-vitro fertilization procedures have an

important role in both the investigation and the treatment of these

infertile couples.

Acknowledgements

We are very grateful for the advice given by Professor I.D.Cooke andDr J.P.Balmaceda.

References

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Received on August 8, 1991; accepted on October 28, 1991

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