Endometrial polyps and their implication in the pregnancy rates of patients undergoing intrauterine insemination: a prospective, randomized study

Tirso Pérez-Medina1, José Bajo-Arenas, Francisco Salazar, Teresa Redondo, Luis Sanfrutos, Pilar Alvarez and Virginia Engels

Department Of Gynaecology, Santa Cristina University Hospital, Universidad Autónoma de Madrid, C/O'Donnell 59, 28009 Madrid, Spain

1 To whom correspondence should be addressed. Email: tperezm{at}meditex.es


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: It was our intention to determine whether hysteroscopic polypectomy before intrauterine insemination (IUI) achieved better pregnancy outcomes than no intervention. METHODS: A total of 215 infertile women from the infertility unit of a university tertiary hospital with ultrasonographically diagnosed endometrial polyps (EP) undergoing IUI were randomly allocated to one of two pretreatment groups using an opaque envelope technique with assignment determined by a random number table. Hysteroscopic polypectomy was performed in the study group. Diagnostic hysteroscopy and polyp biopsy was performed in the control group. RESULTS: Total pregnancy rates and time for success in both groups after four IUI cycles were compared by means of contingency tables and life-table analysis. A total of 93 pregnancies occurred, 64 in the study group and 29 in the control group. Women in the study group had a better possibility of becoming pregnant after polypectomy, with a relative risk of 2.1 (95% confidence interval 1.5–2.9). Pregnancies in the study group were obtained before the first IUI in 65% of cases. CONCLUSIONS: These data suggest that hysteroscopic polypectomy before IUI is an effective measure.

Key words: endometrial polyps/hysteroscopic polypectomy/infertility/intrauterine insemination


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The biological mechanisms that regulate implantation still remain unexplained in their entirety, in spite of being the key point related to the outcome of the reproductive process (Li and Cooke, 1992Go).

Implantation is the process by which the free-floating blastocyst attaches to the endometrium, invades the stroma and establishes the trophoblast. The process involves a complex dialogue between the endometrium and the conceptus that is mediated by soluble growth factors, hormones, adhesion molecules, the extracellular matrix and prostaglandins. These elements coordinate the steps by which the embryo attaches to the epithelium, breaches the basement membrane and invades into the stroma (Sharkey and Smith, 2003Go).

In the transvaginal sonography (TVUS) habitually performed in reproductive medicine, images compatible with endometrial polyps (EP) often appear, although their ability to interfere with fertility potential is unknown. They have never been seriously considered as a cause of infertility in the reproductive process, although concern has existed since Foss and Wallach first published their retrospective series (Foss et al., 1958Go; Wallach, 1972Go).

EP used to be difficult to diagnose. Hysterosalpingography (HSG) has a sensitivity of between 50% (Soares et al., 2000Go) and 98% (Preuthippan and Linasmita, 2003Go) for intrauterine lesions, but it is unable to reliably distinguish between submucosal myomas and EP. Nowadays, with the advent of the TVUS (Pérez-Medina et al., 1999Go), sonohysterography (Syrop and Sahakian, 1992Go) and improved Doppler technology (Goldstein et al., 2002Go; Alcazar et al., 2004Go), the sonographic diagnosis of EP is highly accurate, with diagnostic hysteroscopy being the standard of reference (Brown et al., 2000Go).

Once EP have been diagnosed, the next problem was how best to remove them, as the classical dilatation and curettage leaves EP in situ in most cases (Word, 1954Go). Once more, hysteroscopy came to our aid when therapeutic hysteroscopy with working channel was developed, allowing the easier removal of polyps in an office environment (Pérez-Medina et al., 2000Go).

To the best of our knowledge, this is the first randomized, prospective study designed to discover whether polypectomy before intrauterine insemination (IUI) affects pregnancy rates.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient groups
Four hundred and fifty-two patients fulfilling the inclusion criteria were selected from 2800 new patients attending the infertility unit of our reference centre hospital during a 50-month period (January 2000 to February 2004). Patients were informed of the study characteristics, and were recruited for the study. Two hundred and fifteen of them agreed to participate and informed consent was obtained. The study was approved by the hospital's ethics committee.

The sonographic diagnosis of EP has been described elsewhere (Pérez-Medina et al., 1999Go). Concisely, EP was suspected when a hyperechogenic image with regular contours, occupying the uterine lumen either partly or in full, outlining the endometrial walls on which it rests, surrounded by a small hypoechogenic halo, was observed. A thin, hyperechogenic line in the midline, reflecting the interface between the endometrium and the polyp translating the displacement of the endometrial line acted as a trigger for the diagnosis and stated the diagnosis of EP. The positive colour Doppler map was assessed when even a minimal colour signal was found inside the formation. We then scanned carefully all around the formation to detect the stalk until the colour Doppler around the image revealed a straight, vascular pattern transducing the vascular stalk of the attachment area.

Inclusion criteria were women with at least 24 months of sterility, with a sonographic diagnosis of EP and who were candidates for IUI.

Exclusion criteria were patients >39 years of age, those with anovulation, azoospermia, uncorrected tubal disease or previous unsuccessful use of r-FSH.

Patients underwent a complete infertility evaluation that included TVUS in the early proliferative phase, basal body temperature recording to assess ovulation, postcoital test (PCT), HSG, semen analysis and, in some patients, diagnostic laparoscopy.

Female factor infertility was diagnosed in patients with ovulatory dysfunction, cervical factor or endometriosis.

Male factor infertility was diagnosed if two semen analyses obtained at least 1 month apart were subnormal according to the World Health Organization criteria for normality (WHO, 1999Go).

Idiopathic infertility was diagnosed in patients with normal ovulatory cycles, semen analysis, HSG and PCT in infertile couples for >24 months.

Patients were randomized to one of the two groups with use of an opaque envelope technique, with assignment determined by a computerized random number table.

The study group was composed of 107 women in whom EP was extracted during hysteroscopy. The polypectomy was performed by means of a 5.5-mm Olympus continuous flow office hysteroscope with a 5 Fr working channel. The formations were resected by means of a rigid 5 Fr scissors and forceps and submitted for pathologic study. When resection was not possible during the diagnostic hysteroscopy, the patient was scheduled for operative hysteroscopy under anaesthesia. All the hysteroscopies were performed by T.P.-M.

The control group was composed of 108 women in whom EP was not extracted during diagnostic hysteroscopy and polyp biopsy was performed.

Women were scheduled to receive four cycles of IUI, and the first IUI was planned for three cycles after hysteroscopy in both groups.

Semen preparation, ovulation induction, monitoring, triggering of ovulation and IUI
All of the IUIs were performed with spermatozoa selected after in-vitro treatment of the semen. A volume of 0.3–0.4 mL was used for insemination.

Patients received subcutaneous injection of recombinant FSH 50 IU daily from the third day. TVUS was performed daily to monitor the follicles.

Ovulation was triggered by intramuscular injection of 7500 IU HCG when the leading follicle reached a diameter of >18 mm.

IUI was performed 36 h after triggering the ovulation. To reduce the risk of multiple pregnancy and/or serious ovarian hyperstimulation, ovulation was not induced and the IUI cycle was stopped if there were more than three follicles with a diameter >15 mm at the time of induction.

Luteal phase was supported with 200 mg of intravaginal progesterone capsules twice daily.

If no menses had occurred by the 16th day after IUI, a semiquantitative {beta}-HCG pregnancy test was performed. Women with a positive pregnancy test had TVUS performed 2 weeks later. If menses occurred or the pregnancy test was negative, progesterone was stopped and another cycle was initiated on the third day. Four IUI cycles were attempted before finishing the trial.

Outcome measures
Clinical pregnancy was the main outcome measure analysed to determine the effectiveness of treatment. We studied the crude pregnancy rate in both groups. The secondary outcomes were to compare the time for success in each group and to determine whether the size of the EP influenced the pregnancy rate.

Statistical analysis
To detect an expected difference in pregnancy rate between the groups of 15% at a level of 0.05 with a power of 80%, a sample size of 200 (100 per group) was required.

Subjects were randomized into one of two groups in a 1:1 ratio using a restricted randomization. A descriptive study was performed for each variable of the study, as well as a bivariate analysis between the dependent variable and each of the independent variables with contingency tables, with {chi}2-test for categorical variables and t-test for continuous variables.

The relative risk (RR) of achieving pregnancy was calculated along with 95% confidence intervals (CI).

Survival analysis (Kaplan–Meier) was performed to determine the time influence (number of cycles) on the probability of conceiving in the two levels of the factor (polypectomy yes/no). Curves were compared with the Mantel–Haenzsel log-rank test.

With the report of the pathologist, EP in the study group were subdivided into four groups based in their quartiles (<5 mm, 5–10 mm, 11–20 mm and >20 mm), and pregnancy rates were compared between groups.

Significance was defined as P<0.05. Analyses were performed with the SPSS 12.0 statistical package.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Two hundred and fifteen patients were undergoing IUI because of infertility for a period >24 months [ovulatory factor (n=71), cervical factor (n=24), endometriosis (n=23), male factor (n=46), idiopathic infertility (n=105)]. In some cases multiple factors were present in same patient.

HSG suggested EP in 145 of the cases (sensitivity 67.4%) but failed to diagnose EP in the rest of the patients (38 patients informed as submucosal myoma, 32 informed as no intrauterine lesion), for a total of 70 false negatives.

Hysteroscopy in an office setting was not possible in seven patients (3.2%), so they were performed in the theatre under spinal anaesthesia. The cause for the failure was severe pain due to cervical conditions in all cases.

Eleven patients were lost from the study, six in the study group [three lost to follow-up, two pathologic reports of submucosal myoma and in one patient in whom the polyp was not confirmed (pathologic report of secretory endometrium)] and five in the control group (one lost to follow-up, two patients in whom the polyp was not confirmed and two pathologic reports of myoma), and were excluded of the study, leaving 101 patients in the study group and 103 in the control group.

Table I summarizes the baseline characteristics of the patients in both groups. There were no statistically significant differences between groups, including the size of the polyps, which was similar in the two groups (mean 16 mm, range 3–24) (P>0.05).


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Table I. Patients characteristics (n=204)

 
A total of 93 pregnancies occurred, 64 in the study group and 29 in the control group. Women in the study group had a better possibility of becoming pregnant after polypectomy with an RR of 2.1 (95% CI 1.5–2.9) (Table II).


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Table II. Number and percentage of pregnancies after hysteroscopic polypectomy (n=204)

 
The survival analysis shows that after four cycles the pregnancy rate was 51.4% in the study group and 25.4% in the control group (P<0.001). Interestingly, pregnancies in the study group were obtained before the first IUI in 65% of cases. The rest were obtained over the four-cycle period, without a clear distribution between the cycles. The pregnancies in the control group were obtained during the IUIs without predominance for any cycle, as shown in the survival analysis (Figure 1).



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Figure 1. Kaplan–Meier survival analysis and Mantel–Haenzsel log rank test * log rank test.

 
When comparing by the size of the EP in the study group, 19 pregnancies out of 25 patients (76%) were obtained in the >5 mm group, 18 of 32 (56.2%) in the 5–10 mm, 16 of 26 (61.5%) in the 11--20 mm group, and 11 of 18 (61.1%) in the >20 mm group. No significant difference was found between the groups (P=0.32).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There are very few reports in the literature concerning infertility and EP, and in none of them is any conclusion reached. Sillo-Seidl reported polyps in 10.8% of patients in his series on 1000 sterile patients (Sillo-Seidl, 1971Go). Pregnancy was obtained after polypectomy in eight patients. In contrast, Hereter, in his series of 33 patients with EP compared with 280 without EP, found no difference between the groups with respect to implantation and abortion in IVF cycles (Hereter et al., 1998Go).

In the study by Varastéh in a series of 23 sterile women, there was a correlation between the polypectomy and the accumulated rate of pregnancies of 65.2%, but polyps and myomas were mixed and the study was not randomized, so their conclusions raise some questions (Varastéh et al., 1999Go). In another series, 19 out of 25 infertile patients (76%) in whom polypectomy was performed conceived in a 12-month period (Spiewankiewicz et al., 2003Go). In our study, the proportion of patients pregnant in the study group was 64%, nearly twice that of the control group.

The cause for this disturbance is unknown. Richlin et al., (2002)Go demonstrated an increase in glycodelin levels in the periovulatory period in women with EP. Glycodelin is a protein that facilitates implantation by decreasing natural killer cell activity. During the normal periovulatory phase of a functional cycle, glycodelin decreases because inhibits sperm–oocyte binding. In this situation, the EP produces significant amounts of glycodelin, thus impairing implantation (Richlin et al., 2002Go).

Although cervical dilatation may be an added benefit of a recent hysteroscopy (McManus et al., 2000Go), in our study the hysteroscopy was performed in both groups, thus controlling this potentially confounding factor. It is also possible that irrigation of the uterine cavity with saline at the time of a recent hysteroscopy may have a beneficial effect on implantation, as suggested by a study reported by Takahashi et al., (2000)Go.

In the case of myomas, it is well known that the size and location of myomas are important factors for the occurrence of repeated gestational loss (Farrer-Brown et al., 1971Go; Forssman, 1976Go), but their association with infertility is more discussed (Buttram and Reiter, 1985Go). In his classical study in a series of 677 surgically treated sterile patients, only 2% of patients could attribute their infertility to myomas. Even in the case of submucosal myoma, a well-known factor for recurrent pregnancy loss, the controversy persists, with Varastéh reporting a 42% gestation rate after hysteroscopic myomectomy in his retrospective study and Fernandez concluding in his series of 59 infertile patients that the effect of myomectomy in infertility seems limited (Fernandez et al., 2001Go). Both authors found a significant relationship with the size of the myoma, as the probability of pregnancy increases proportionally with the size of the resected myoma, suggesting a space-occupying lesion mechanism for infertility. This is not consistent with our results in EP; we did not find any relationship between the size of the polyp and the chance of pregnancy. However, longer studies are needed to address this question.

We consider it to be worth performing polypectomy in an infertile woman whose only known problem is the presence of an EP, as stated by Spiewankiewicz and others (Mooney and Milki, 2003Go; Oliveira et al., 2003Go) in their studies in assisted reprodutive technology patients.

A second important conclusion in our study is that pregnancies after polypectomy are frequently obtained spontaneously while waiting for the treatment, suggesting a strong cause–effect of the polyp in the implantation process. This led us to defer the first IUI to three menstrual cycles after the polypectomy is performed. Longer series are needed to verify these results.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on November 9, 2004; resubmitted on January 17, 2005; accepted on January 27, 2005.





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