women and in women who had not been exposed previously to spermatozoa. 3 In baboons, fecundity was also

Transcription

1 Research REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY Fertility in women with minimal endometriosis compared with normal women was assessed by means of a donor insemination program in unstimulated cycles Roberto Matorras, MD, PhD; Beatriz Corcóstegui, BS; Judith Esteban, MD; Olga Ramón, MD; Begoña Prieto, MD; Antonia Expósito, PhD; José Ignacio Pijoan, MD 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. Key words: AID, azoospermia, cumulative pregnancy rate, infertility, insemination, minimal endometriosis, pregnancy rate, stage I Cite this article as: Matorras R, Corcóstegui B, Esteban J, et al. Fertility in women with minimal endometriosis compared with normal women was assessed by means of a donor insemination program in unstimulated cycles. Am J Obstet Gynecol 2010;203:345.e1-6. The prevalence of endometriosis ranges from 0-82%, depending on the populations studied and probably on the diagnostic criteria and diagnostic scrupulousness. 1-3 There is little doubt that extensive anatomic distortion and tubal obstruction, which frequently is attributed to severe endometriosis, do impair fertility. 4 However, a great controversy exists about the association From the Human Reproduction Unit, Department of Obstetrics and Gynecology (Drs Matorras, Esteban, Ramón, Prieto, and Expósito and Ms Corcóstegui), Hospital from Cruces, Basque Country University, Baracaldo; the Clinical Epidemiology Unit (Dr Pijoan), Hospital from Cruces, Basque Country University, Baracaldo; and IVI- Bilbao, Leioa (Drs Matorras and Prieto), Vizcaya, Spain. Received May 5, 2009; revised Feb. 19, 2010; accepted May 7, Reprints: Roberto Matorras, MD, PhD, María Diaz de Haro 7, 6 iz, Bilbao, Spain. roberto.matorras@osakidetza.net. Authorship and contribution to the article is limited to the 7 authors indicated. There was no outside funding or technical assistance with the production of this article /$ Mosby, Inc. All rights reserved. doi: /j.ajog 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. 5 We previously reported a similar frequency of minimal endometriosis in infertile women and in women who had not been exposed previously to spermatozoa. 3 In baboons, fecundity was also similar in animals with stage I endometriosis and in cases with a normal pelvis. 6,7 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), 13 but such an increase was not seen in another study with a similar design. 14 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, 15 mainly expectant management, 16 controlled ovarian hyperstimulation with intrauterine insemination (IUI), 17,18 controlled ovarian hyperstimulation after laparoscopic surgery, 19 in vitro fertilization in natural cycle, 20 or intracytoplasmic sperm injection (ICSI). 21 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 OCTOBER 2010 American Journal of Obstetrics & Gynecology 345.e1

2 Research Reproductive Endocrinology and Infertility 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. 3 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 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, 22 now the American Society for Reproductive Medicine. 23 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. 2,3,24 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 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. 2,24 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 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, 25 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.05. RESULTS The main demographic characteristics were similar in both groups (Table 1). The mean endometriosis score in women with stage I endometriosis was 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, ; 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, ; Table 2). In the first cycle, a 4-fold higher PR was seen in women without endometriosis, but the difference was not statistically significant (Table 2). In cases with no endometriosis, the cumulative PR after 2 AID cycles was similar to the cumulative PR in the minimal endometriosis group after 5 AID cycles. In women without endometriosis, the cumulative PR after 3 AID cycles was similar to the cumulative PR after 6 AID cycles in women with stage I endometriosis (Figure). However, the differences were not statis- 345.e2 American Journal of Obstetrics & Gynecology OCTOBER 2010

3 Reproductive Endocrinology and Infertility Research tically significant (log-rank test for equality of survivors functions). To demonstrate that, in women with stage I endometriosis, the per-cycle PR was statistically lower than in women without endometriosis (with a power of 80% and an alpha of.05) with the arcsin approximation, 510 cycles in women with stage I endometriosis and 1021 cycles in women without endometriosis would be required. Couples who did not conceive in unstimulated cycles were offered IUI-AID under gonadotropin stimulation. Of the 40 couples who did not achieve pregnancy (25 women with endometriosis and 15 women with minimal endometriosis), 31 couples underwent IUI-AID under gonadotropin stimulation (22 couples in the no-endometriosis group and 9 couples in the endometriosis group). Among the women with no endometriosis, the PR per cycle was 26.1% (6/23 women), which was similar to the 34.3% (12/65 women) in the endometriosis group. There was no difference in the IUI- gonadotropin per-woman PR: 66.7% (6/9 women) with stage I endometriosis vs 54.5% (12/22 women) with no endometriosis. COMMENT In advanced endometriosis, pelvic adhesions, tubal distortion, and ovarian damage may cause in infertility. Thus, the frequency of endometriosis stages III and IV is much higher among infertile women than in unselected women. 3 A similar situation has been reported in nonhuman primates. 6,7 Concerning stage I endometriosis and infertility, virtually every area within the reproductive process has been investigated in an attempt to describe a causal relationship between endometriosis and infertility. Most of such studies were in direct contradiction to one another; other studies showed either normal results or no clinical significance. 4 Although a number of treatments have been proposed for minimal endometriosis, the association between stage I endometriosis and infertility had not been proved; a number of reports have been quoted to show an association between TABLE 1 Demographic characteristics and pregnancy rates in women with minimal endometriosis and in normal women Group Minimal endometriosis Variable (n 24) Normal (n 51) Age, y a Infertility duration, y a Mean artificial insemination donor cycles per patient, n a... 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)... There were no significant differences. a Values are expressed in mean SD. Matorres. Fertility and a donor insemination program. Am J Obstet Gynecol minimal endometriosis and infertility. 26 A number of studies jointly have analyzed minimal and mild endometriosis, although it has been suggested that it would be more accurate to analyze them separately. 3 Minimal endometriosis has been considered to cause infertility because it is much more frequent among infertile patients than among patients who undergo sterilization. 27 However, the search for endometriosis is much more meticulous in infertile women than in women who undergo tubal sterilization. Thus, when the same endometriosis diagnostic protocol was used, similar frequencies of stage I endometriosis were found among infertile women and normal women who were unexposed to spermatozoa. 3 In a multivariate analysis of infertility factors, lower live birth rates were reported in stage I and II endometriosis, but laparoscopy was performed as the initial assessment in the presence of some clinical data; in the remaining cases, it was performed after 1 year of follow-up evaluation. 11 Thus, the possibility that endometriosis was not detected in some cases because pregnancy occurred before the planned date of laparoscopy cannot be excluded. A number of reports have addressed fertility rates in minor endometriosis : expectant management, 15 mainly expectant management, 16 controlled ovarian hyperstimulation with IUI, 17,18 controlled ovarian hyperstimulation after laparoscopic surgery, 19 natural cycle in vitro fertilization, 20 or ICSI. 21 Reported PRs range from significantly lower, 15,17,18 lower but not significantly so, 16 and equal 19,21 to significantly higher. 20 It is difficult to draw conclusions because of the heterogeneity of the trials, the study design, the effect of associated procedures and patient recruitment, and the fact that only 2 reports were directed towards stage I endometriosis. 20,21 Apart from the aforementioned constraints, all of the women in the control group had unexplained infertility, which obviously does not represent normal fertility accurately. It TABLE 2 Per-cycle pregnancy rates in women with minimal endometriosis and women with no endometriosis Per-cycle pregnancy rate, n (%) Cycle Minimal endometriosis No endometriosis (1/24) 17.6 (9/51) (4/23) 16.7 (7/42) (2/19) 8.6 (3/35) 4 0 (0/17) 9.4 (3/32) 5 0 (0/17) 10.3 (3/29) (2/17) 3.6 (1/28) There were no significant differences. Matorres. Fertility and a donor insemination program. Am J Obstet Gynecol OCTOBER 2010 American Journal of Obstetrics & Gynecology 345.e3

4 Research Reproductive Endocrinology and Infertility FIGURE Cumulative pregnancy rate in artificial insemination donor (AID) cycles No endometriosis AID cycle number Matorres. Fertility and a donor insemination program. Am J Obstet Gynecol seems clear that the best gold standard is normal unselected women. AID is probably the best model to test the association between endometriosis and infertility. A number of authors have addressed this issue, but most studies have some methodologic constraints. Hammond et al 9 reported, in a series of 226 women (9 with endometriosis), that the per-cycle PR in women with endometriosis was only one-third of the per-cycle PR found in women without endometriosis. However, in this study, endometriosis was diagnosed at laparoscopy before or during AID, and no mention was made to staging. Clomiphene was used when needed. Toma et al 12 reported a significantly lower per-cycle PR in endometriosis stages I and II (analyzed together), when compared with a control group. However, endometriosis was diagnosed by laparoscopy only after the failure of 6 AID cycles; some cases experienced expectant management, and other cases had medical or surgical treatment. In women with minimal endometriosis 28 and no other infertility factors, compared with the normal population, the PRs were similar in cases in which AID was performed, whereas PRs were remarkably lower when, with normal sperm, they were treated expectantly. 29,30 Minimal endometriosis Chauhan et al 10 reported some apparently paradoxic results. In azoospermia cases, PRs were higher in normal women, compared with women with endometriosis. However, in cases with no azoospermia, PRs were lower in normal women, compared with women with endometriosis. In addition, there was no clear description of endometriosis stages included, and stage I endometriosis was treated with danazol. In a prospective study, Jansen 8 compared the PRs in 7 women who had been diagnosed of minimal endometriosis before the start of AID with 91 ideal women with no endometriosis. In both cases, partners had azoospermia or severe oligozoospermia. There were no differences in the per-woman PRs. Concerning the per-cycle PR, in endometriosis cases, it was less than one-third of the PR seen in ideal women. Although statistical significance was claimed, a 2 test that was applied to Jansen s data gave a probability value of.05. Furthermore, no mention was made to the staging method, except that the inclusion criterion for minimal endometriosis was the presence of minimal endometriosis considered too trivial to have been treated by their referring gynecologist. In addition, the population under study was recruited between 1978 and 1981, before revised American Fertility Society staging was published (1985), although the first American Fertility Society staging was published in 1979, when the study had already started. 31 It has been well documented that women with azoospermic partners have a higher fecundability than those whose partners have severe male subfertility. 32,33 This has been attributed to the fact that, in oligozoospermia cases, some infrequent pregnancy could be possible, particularly among women of high reproductive potential. Thus, when seeking reproductive assistance, although all partners of azoospermic males will seek consultation, the proportion of women with oligozoospermic partners with a good reproductive prognosis will be lower; this difference could be responsible for the lower PRs. 3 However, this potential confounding factor has never been addressed in the previously cited studies. Thus, the aforementioned studies (all of which were performed some 20 years ago), although classically quoted as proving that stage I endometriosis causes infertility, are not solid enough to demonstrate such a statement in the era of evidence-based medicine. Some methodologic aspects of our study should be stressed. First, only partners of azoospermic men were included in the study. Selection bias thus was avoided, because inclusion of severe oligozoospermia cases could have excluded some women of high reproductive potential who spontaneously achieved pregnancy. Second, no ovarian intervention or ovulation monitoring or detection was performed. The PRs, therefore, were analyzed in the setting of a completely natural cycle, and any hypothetic effect of ovarian stimulation on subtle ovulatory disorders in patients with endometriosis was avoided. Paracervical inseminations were preformed in the mid cycle (3 in total: 1 every 2 days), similar to the behavior of couples seeking pregnancy. Although it is well known that PRs dramatically decrease when the single natural intercourse occurs after ovulation, 34,35 we added the third insemination (on day 2) to cover unpredicted and delayed ovulations. Third, laparoscopy was performed systematically in all patients before the start of 345.e4 American Journal of Obstetrics & Gynecology OCTOBER 2010

5 Reproductive Endocrinology and Infertility Research AID, because it is part of our diagnostic work-up in AID. 3 Fourth, an eventual difference in PRs cannot be attributed to any differential in sexual behavior between the 2 groups (in terms of more frequent sexual intercourse in the group with no endometriosis) because PR was not dependent on the couple s behavior but on the AID program, which was blinded to patient status. Finally, diagnosis of endometriosis relied on the laparoscopic appearance only, to avoid a hypothetic beneficial effect of the removal of lesions by biopsy, because it is a form of surgical treatment, particularly in women who have few lesions. 13 If any women without endometriosis had been included nevertheless, the differences between endometriosis and nonendometriosis groups would be underestimated. According to our data, the per-cycle PRs among women with minimal endometriosis were 60% lower, compared with women with no endometriosis, whereas the per-woman PRs were 40% lower. However, statistical significance was not reached. Differences were more striking for the first cycle PR that was 4.2% in the minimal endometriosis group vs 17.6% in the no-endometriosis group, but again there were no significant differences. An analysis of cumulative PRs showed that pregnancy was achieved early in women without endometriosis; the cumulative PRs after 2 AID cycles in the no-endometriosis group was similar to the cumulative PRs after 5 AID cycles in women with minimal endometriosis, and the cumulative PRs after 3 cycles in the no-endometriosis group was similar to the cumulative PRs after 6 cycles in the minimal endometriosis population. In any case, the differences that were found were substantially lower than previously reported in the literature, in which PRs in minimal endometriosis have been reported to be one-third of the PRs that were found in the normal population. 8,9 However, somewhat 1500 AID cycles would be required to demonstrate that the differences that we found in PRs were statistically significant. Such a number is hardly attainable by most single study centers. Our study met with an unexpected difficulty in patient recruitment; because when ICSI with testicular spermatozoa was available, the number of recruited patients markedly decreased. Thus, a beta error could not be discarded because of the relatively small sample size. In our population, the aforementioned trend in unstimulated cycles to higher PRs among women with no endometriosis disappeared when IUI-AIDs under gonadotropin stimulation were analyzed. We can speculate that (if present) some mild infertility factor could have been overcome by IUI and especially by gonadotropin stimulation. However, the possibility of a selection bias should be taken into account, because many women with no endometriosis achieved pregnancy before IUI-AID under gonadotropin stimulation. Our study found no significant differences in PRs in natural cycles between women without endometriosis and those with minimal endometriosis in the absence of associated infertility factors. Although a trend to lower PRs was observed in women with minimal endometriosis, PR reduction was considerably lower than previously suggested. The trend to lower PRs was more evident when cumulative PRs were analyzed. In women without endometriosis, the PRs that were obtained at 2 and 3 cycles were equivalent to those obtained in minimal endometriosis after 5 and 6 cycles, respectively. f REFERENCES 1. Matorras R, Rodríguez F, Pijoan JI, Ramón O, Gutierrez de Terán G, Rodríguez- Escudero FJ. Epidemiology of endometriosis in infertile women. Fertil Steril 1995;63: Matorras R, Gorostiaga A, Diez J, et al. Intrauterine insemination with frozen sperm increases pregnancy rates in donor insemination cycles under gonadotropin stimulation. Fertil Steril 1996;65: Matorras R, Rodríguez F, Pijoan JI, et al. Women who are not exposed to spermatozoa and infertile women have similar rates of stage I endometriosis. Fertil Steril 2001;76: Hunter MI, Huang A, DeCherney AH. Endometriosis and ART. In: Gardner DK, Weissman A, Howles CM, Shoham Z, eds. Textbook of assisted reproductive techniques: laboratory and clinical perspectives, 2nd ed. London: Taylor & Francis; 2004: Koninckx PR. Is mild endometriosis a condition occurring intermittently in all women? Hum Reprod 1994;9: D Hooghe TM, Bambra CS, Koninckx PR. Cycle fecundity in baboons of proven fertility with minimal endometriosis. Gynecol Obstet Invest 1994;37: D Hooghe TM, Bambra CS, Raeymaekers BM, Riday AM, Suleman MA, Koninckx PR. The cycle pregnancy rate is normal in baboons with stage I endometriosis but decreased in primates with stage II and stage III-IV disease. Fertil Steril 1996;66: Jansen RPS. Minimal endometriosis and reduced fecundability: prospective evidence from an artificial insemination by donor program. Fertil Steril 1986;41: Hammond MG, Jordan S, Sloan CS. Factors affecting pregnancy rates in a donor insemination program using frozen sperm. Am J Obstet Gynecol 1986;155: Chauhan M, Barratt CL, Cooke SMS, Cooke ID. Differences in the fertility of donor insemination recipients: a study to provide prognostic guidelines as to its success and outcome. Fertil Steril 1989;51: Collins JA, Burrows EA, William AR. The prognosis for live birth among untreated infertile couples. Fertil Steril 1995;64: Toma SK, Stovall DW, Hammond MG. The effect of laparoscopic ablation or danocrine on pregnancy rates in patients with stage I or II endometriosis undergoing donor insemination. Obstet Gynecol 1992;80: Marcoux S, Maheux R, Bérubé M, the Canadian Collaborative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997;337: Parazzini F. Ablation of lesions or not treatment in minimal-mild endometriosis in infertile women: a randomized trial. Hum Reprod 1999;14: Akande VA, Hunt LP, Cahill DJ, Jenkins JM. Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis. Hum Reprod 2004;19: Berube S, Marcoux S, Langevin M, Maheux R, the Canadian Collaborative Group on Endometriosis. Fecundity of infertile women with minimal or mild endometriosis and women with unexplained infertility. Fertil Steril 1998;69: Omland AK, Tanbo T, Dale PO, Abyholm T. Artificial insemination by husband in unexplained infertility compared with infertility associated with peritoneal endometriosis. Hum Reprod 1998;13: Kunz G, Kallat-Sabri S. Treatment of women with endometriosis and subfertility: results of a meta-analysis. Geburts Frauenheilk 2008;66: Werbrouck E, Spiessens C, Meuleman C, D Hooghe T. No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild OCTOBER 2010 American Journal of Obstetrics & Gynecology 345.e5

6 Research Reproductive Endocrinology and Infertility endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril 2006;86: Omland AK, Fedorcsák P, Storeng R, Dale PO, Abyholm T, Tanbo T. Natural cycle IVF in unexplained, endometriosis-associated and tubal factor infertility. Hum Reprod 2001;16: Omland AK, Bjercke S, Ertzeid G, et al. Intracytoplasmic sperm injection (ICSI) n unexplained and stage I endometriosis- associated infertility after fertilization failure with in vitro fertilization (IVF). J Assist Reprod Genet 2006;23: The American Fertility Society. Revised American Fertility Society classification of endometriosis: Fertil Steril 1985;43: The American Society for Reproductive Medicine classification. Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Matorras R, Diaz T, Corcóstegui B, Ramón O, Pijoan JI, Rodriguez-Escudero FJ. Ovarian stimulation in intrauterine insemination with donor sperm: a randomized study comparing clomiphene in fixed protocol versus highly purified urinary FSH. Hum Reprod 2002;17: Aalen OO. Nonparametric inference for a family of counting processes. Ann Statist 1978;6: D Hooge T, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med 2003;21: Sangi-Haghpeykar H, Poindexter AN 3rd. Epidemiology of endometriosis among parous women. Obstet Gynecol 1995;85: Acosta AA, Buttram VC Jr, Besxh PK, Malinak RL, Franklin RR, Vanderheyden JD. A proposed classification of endometriosis. Obstet Gynecol 1973;42: Portuondo JA, Echanojauregui A, Herrán C. Alijarte I. Early conception in patients with untreated mild endometriosis. Fertil Steril 1983; 39: Rodriguez-Escudero FJ, Neyro JL, Corcóstegui B. Benito JA. Does minimal endometriosis reduce fecundity? Fertil Steril 1988,50: The American Fertility Society. Classification of endometriosis. Fertil Steril 1979;32: Emperaire JC, Gauzere- Soumireu E, Audebert AJM. Female fertility and donor insemination. Fertil Steril 1982;37: Albrecht BH, Cramer D, Schiff I. Factors influencing the success of artificial insemination. Fertil Steril 1982;37: Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation: effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med 1995;333: Wilcox AJ, Dunson DB, Weinberg CR, Trussell J, Day Baird D. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives. Contraception 2001;63: e6 American Journal of Obstetrics & Gynecology OCTOBER 2010