Objective
The purpose of this study was to compare the pregnancy rate in an artificial insemination donor program in women with minimal endometriosis and in women without endometriosis.
Study Design
A prospective double-blinded study was conducted in women with azoospermic partners.
Results
The per-cycle pregnancy rate was 8.6% (9/104 women) in the minimal endometriosis group vs 13.3% (26/196 women) in the control group. The per-woman pregnancy rate was 37.5% (9/24 women) in the minimal endometriosis group and 51.0% (26/51 women) in the control group.
Conclusion
Pregnancy rates were statistically similar in normal women and in women with minimal endometriosis.
The prevalence of endometriosis ranges from 0-82%, depending on the populations studied and probably on the diagnostic criteria and diagnostic scrupulousness. There is little doubt that extensive anatomic distortion and tubal obstruction, which frequently is attributed to severe endometriosis, do impair fertility. However, a great controversy exists about the association between minimal endometriosis and symptoms, especially as regards infertility. Some authors make a distinction between 2 different entities: endometriosis disease and the physiologic endometriosis or “nondisease endometriosis.”
We previously reported a similar frequency of minimal endometriosis in infertile women and in women who had not been exposed previously to spermatozoa. In baboons, fecundity was also similar in animals with stage I endometriosis and in cases with a normal pelvis. On the other hand, a number of studies are quoted as if they showed an association was stated between minimal/mild endometriosis and infertility. However, all such studies were methodologically imperfect and far from conclusive. Finally, laparoscopic surgery for minimal/mild endometriosis has been reported to increase the pregnancy rates (PRs), but such an increase was not seen in another study with a similar design. Indeed, endometriosis stages I and II may not have the same fertility impairment.
Human fertility may be evaluated in different settings, but many of the settings are hardly comparable with each other. A number of reports have addressed fertility rates in “minor endometriosis”: expectant management, mainly expectant management, controlled ovarian hyperstimulation with intrauterine insemination (IUI), controlled ovarian hyperstimulation after laparoscopic surgery, in vitro fertilization in natural cycle, or intracytoplasmic sperm injection (ICSI).
We chose a setting very similar to natural fertility in couples who are looking for pregnancy. Such couples are usually recommended to have sexual intercourse every other day around the ovulation day, very similar from a methodological point of view to couples undergoing an artificial insemination donor (AID) in a natural cycle. The purpose of the present study was to ascertain whether an association exists between minimal endometriosis and infertility in the setting of an AID program with 3 specific characteristics: (1) laparoscopy performed systematically before undertaking AID, (2) unstimulated AID cycles with 3 paracervical inseminations per cycle, and (3) only women with azoospermic partners with no associated infertility factors.
Materials and Methods
The study population consisted of 75 women who underwent 300 AID cycles at our unit because of azoospermia of their partners. All of them had a systematic diagnostic laparoscopy (video-laparoscopy) before starting AID, as reported previously. Laparoscopy was performed by our staff laparoscopists, all of whom have >15 years of experience in infertility laparoscopy.
The study was conducted prospectively from January 1994 to December 2007. Diagnostic laparoscopy and unstimulated AID were offered to all women whose partner had azoospermia. The study was undertaken in consecutive cycles without breaks. Our reproductive unit is the only public center in the Basque Country with a sperm bank. When the study was started, ICSI with testicular spermatozoa was not available at our unit. When ICSI with testicular spermatozoa became available (in 1998 in our geographic area; in 2002 at our unit), there was a marked reduction in the recruitment of study patients.
Endometriosis was investigated systematically and staged according to the classification that was designed by the former American Fertility Society, now the American Society for Reproductive Medicine. The diagnosis of endometriosis was established by the visualization of typical endometriosis lesions or of subtle lesions. Laparoscopy was performed 2-3 months before AID was started.
Institutional board approval and written informed consent were obtained (date of approval January 4, 1994; project number CEICHC 8/94) . Previous infertility work-up information included: pelvic examination, vaginal ultrasound, hysterosalpingography, and hormonal assays (follicle-stimulating hormone, luteinizing hormone, estradiol, and prolactin levels on days 3, 14, and 22 of the menstrual cycle and progesterone on days 14 and 22).
Inclusion criteria were (1) woman >18 years and <40 years old, (2) infertility duration >1 year, (3) 2 sperm analyses that showed azoospermia, (4) laparoscopic findings that were consistent with stage I (minimal) endometriosis (study group) or with absence of endometriosis, (5) normal tubal patency, (6) no evidence of dysovulation, (7) day 3 follicle-stimulating hormone levels <10 mIU/ mL, (8) cycle length between 24 and 35 days, (9) no evidence of intrauterine disease, (10) no previous infertility treatments, and (11) willingness to participate in the study. Two populations were established: women with stage I endometriosis (n = 24) and control group (patients with no endometriosis; n= 51). Endometriosis stages II-IV were not included in the study.
Until the conduct of this study, AID management at our unit consisted of up to 6 cycles of IUI (1 insemination per cycle) under gonadotropin stimulation. In the present study, patients were invited to undergo 6 AID cycles, according to the following protocol: (1) unstimulated ovarian cycle, (2) 3 paracervical inseminations performed on days −2, 0, and +2, with the day 0 of every cycle being calculated by subtracting 14 from the number of days of duration of the immediately preceding cycle, and (3) no luteal phase support. No ovulation detection kits were used. Frozen donor sperm was always used. Both laboratory staff and the gynecologists who performed and timed the inseminations were blinded to the women’s status (stage I endometriosis or control). Women were also blinded to their condition. Donors were used indifferently in both groups. Paracervical inseminations were performed with a Milex cervical reservoir (Milex, Chicago, IL). The cervical reservoir remained in place for 16-18 hours after insemination, at which time it was removed by the patient. In all cases 6 AID cycles were completed if pregnancy was not achieved. No changes in the protocol were made during the period of study, and no changes were made in the method of semen preparation or donor selection.
If pregnancy was not achieved after 6 unstimulated paracervical insemination cycles, 6 additional cycles under gonadotropin stimulation and with IUI were offered. Our AID methods with gonadotropins and IUI have been reported previously. Pregnancy was defined as the visualization of the gestational sac at week 6 of amenorrhea.
Power calculation was performed with the assumption of a per-cycle PR of 16% in control group and a 8% in stage I endometriosis; the ratio of control subjects/cases was 2/1, with a power of 80% and an alpha of .05 . With the arcsin approximation, the obtained sample consisted of 784 cycles in women without endometriosis and 258 cycles in women with stage I endometriosis. The calculated sample size was not reached because of the aforementioned recruitment constraints.
Statistical analyses were performed by means of χ 2 and Student t tests according to the standard criteria of applicability. PRs were tested with the odds ratio (OR) and its 95% confidence interval (CI). Cumulative PRs were calculated according to the Nelson-Aalen estimator, which is a nonparametric estimator of the cumulative hazard function based on a sample that is subject to right censoring. Statistical significance limit was defined as α = .05.
Results
The main demographic characteristics were similar in both groups ( Table 1 ). The mean endometriosis score in women with stage I endometriosis was 2.8 ± 1.7.
| Group | ||
|---|---|---|
| Variable | Minimal endometriosis (n = 24) | Normal (n = 51) |
| Age, y a | 32.33 ± 3.94 | 32.22 ± 3.82 |
| Infertility duration, y a | 4.79 ± 3.41 | 4.43 ± 2.98 |
| Mean artificial insemination donor cycles per patient, n a | 4.33 ± 1.99 | 3.94 ± 2.30 |
| Per-cycle pregnancy rate, n/N (%) | 9/104 (8.6) | 26/191 (13.3) |
| Per-woman pregnancy rate, n/N (%) | 9/24 (37.5) | 26/51 (51.0) |
The per-cycle PR was somewhat lower in the stage I endometriosis group (8.6%) than in the control group (13.3%), but statistical significance was not reached (OR, 0.62; 95% CI, 0.28–1.34; P > .05). The per-woman PR was 37.5% (9/24 women) in the stage I endometriosis vs 51.0% (26/51 women) in the control group; the differences lacked statistical significance ( P > .05; OR, 0.6; 95% CI, 0.22–1.62; Table 2 ).
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