Increased pregnancy rates after ultralong postoperative therapy with gonadotropinreleasing hormone analogs in patients with endometriosis

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1 FERTILITY AND STERILITY VOL. 78, NO. 4, OCTOBER 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Increased pregnancy rates after ultralong postoperative therapy with gonadotropinreleasing hormone analogs in patients with endometriosis Dagmar Rickes, M.D., a Ingrid Nickel, M.D., a Siegfried Kropf, Ph.D., b and Jürgen Kleinstein, M.D. a Clinic for Reproductive Medicine and Gynecologic Endocrinology, Faculty of Medicine, Otto-von-Guericke University, Magdeburg, Germany Received April 9, 2002; revised and accepted June 7, Supported by AstraZeneca GmbH, Wedel, Germany. Presented at the Eighth World Congress on Endometriosis, San Diego, California, February 24 27, Reprint requests: Dagmar Rickes, M.D., Clinic for Reproductive Medicine and Gynecologic Endocrinology, Gerhart- Hauptmann-Strasse 35, D Magdeburg, Germany (FAX: ; juergen. kleinstein@medizin.unimagdeburg.de). a Clinic for Reproductive Medicine and Gynecologic Endocrinology, Faculty of Medicine, Otto-von- Guericke University. b Institute for Biometry and Medical Informatics, Faculty of Medicine, Ottovon-Guericke University /02/$22.00 PII S (02) Objective: To examine whether ultralong GnRH analog (GnRH-a) therapy after surgical treatment of endometriosis and before ART influences the pregnancy rate. Design: Prospective, randomized, controlled study. Setting: University clinic for reproductive medicine and gynecologic endocrinology. Patient(s): One hundred ten patients with stage II to IV endometriosis according to ASRM criteria. Intervention(s): Fifty-five patients received GnRH-a for 6 months after surgery and subsequently underwent up to 3 cycles of ART, and 55 patients received 3 cycles of ART alone immediately after surgery. Main Outcome Measure(s): Clinical pregnancy rates. Results: The pregnancy rate per patient was higher among patients who received follow-up treatment with GnRH-a. The same results were found in patients with stage III or IV endometriosis who were undergoing IUI or IVF/ICSI. Conclusion(s): Ultralong GnRH-a therapy increases the pregnancy rate of ART in patients with severe endometriosis. (Fertil Steril 2002;78: by American Society for Reproductive Medicine.) Key Words: GnRH-agonists, endometriosis, pregnancy rate, ART Because the etiology of endometriosis is unknown, no definitive treatment for this disease has been developed. In infertile patients with endometriosis who wish to conceive, expectant management, medical treatment, surgical treatment, or a combination of surgical and medical treatment may be attempted. Up to 37.4% of the patients with mild endometriosis become pregnant by expectant management alone. However, this success rate decreases to 3.1% in more severe forms of endometriosis. Medical treatment alone produces pregnancy rates of 29.2% to 47.2%, depending on the degree of severity. Surgical treatment alone produces pregnancy rates of approximately 41.3% to 51.8% in patients with advanced endometriosis (1). Evidence indicates that in stage I or II endometriosis, laparoscopic treatment produces significantly higher pregnancy rates compared with no surgical treatment (2). This result is supported by meta-analyses showing increased pregnancy rates after surgical treatment with or without medical treatment compared to no treatment at all or medical treatment alone (1). Patients with endometriosis who wish to conceive therefore seem to benefit most from microsurgical treatment followed by medical treatment. A few retrospective studies have examined use of surgical treatment followed by medical treatment using GnRH analogs (GnRH-a) before ART. Additional treatment with GnRH-a after surgery and before ART was associated with higher pregnancy rates. Marcus and Edwards (3) found that the pregnancy rate after ART was 42.8% for women who additionally received GnRH-a and 12.7% for women with no medical treatment. Nakamura et al. (4) reported analogous results (pregnancy rate per 757

2 FIGURE 1 Randomization of patients. Rickes. Ultralong GnRH-a therapy before ART. Fertil Steril patient, 67% vs. 27%; P.05) with use of GnRH-a after surgical treatment before ART. Other investigators were not able to confirm this benefit of GnRH-a pretreatment in a mixed sample with various indications for ART (5). We sought to investigate prospectively whether ultralong GnRH-a therapy after surgical treatment with laparoscopy or microsurgery affects the pregnancy rate of ART in women with stage II to IV endometriosis. MATERIALS AND METHODS Patients and Randomization We enrolled 110 women in whom stage II to IV endometriosis had been diagnosed by videolaparoscopy (Fig. 1). Patients were randomized by computer in blocks of six to receive treatment with GnRH-a after surgery or to undergo surgery alone. Neither patients nor physicians were blinded to treatment assignment. Three women who had been assigned to GnRH-a therapy and 7 assigned to undergo surgery alone chose to leave the study. Exclusion criteria were lack of desire to conceive, age older than 40 years, and dependence on testicular sperm in ART. Patients were allocated to the two main treatment groups and four subgroups based on ART and disease stage: IUI and stage II disease, IUI and stage III or IV disease, IVF/ICSI and stage II disease, and IVF/ICSI and stage III or IV disease. Because the sample was small, we could not randomize patients according to stage of endometriosis, but we examined this factor in statistical analysis. The study was approved by the Institutional Ethics Committee, Medical Faculty of the Otto-von-Guericke-University. All patients gave their informed consent. Surgical Procedure One of our primary objectives was the surgical treatment endometriosis. We aimed to completely remove all endometrial implants and adhesiolysis of all pelvic organs involved. Diagnostic laparoscopy and the corrective laparoscopic or microsurgical (by laparotomy) procedure was performed between May, 1999 and May, In cases of doubt about whether the pathologic findings represented endometriosis, biopsy was done for histologic confirmation by sharp dissection without cauterization of the foci. Endometriosis was classified on the basis of the ASRM guidelines (6). We followed all patients through February, 2002, until all surgical procedures, postoperative therapy with GnRH-a, up to 3 ART cycles, and 4 weeks of follow-up were completed. In 42 of 62 women (68%) with stage II endometriosis, videolaparoscopy was used according to the technique of Cook and Rock (7). Microsurgical procedures were used in 20 women with stage II endometriosis and all women with stage III or IV endometriosis (8). GnRH-a Therapy Fifty-five women randomized to therapy with goserelin (Zoladex-Gyn; AstraZeneca, Wedel, Germany), 3.6 mg, received their first s.c. dose on day 3 after surgery. All patients were informed about the potential side effects of GnRH-a, including hot flushes, depression, vaginal dryness, and slight but reversible bone loss. These women received GnRH-a monthly over 5 or 6 cycles. 758 Rickes et al. Ultralong GnRH-a therapy before ART Vol. 78, No. 4, October 2002

3 Assisted Reproductive Technologies Intrauterine insemination was performed in patients without fallopian tube disease who had optimum mobility of the tube around the ipsilateral ovary. Otherwise, IVF or ICSI was performed. Intrauterine Insemination Patients scheduled for IUI had patent and optimally movable fallopian tubes after surgery. For ovarian stimulation, the patients received a daily injection of recombinant FSH (Gonal-F75; Serono, Unterschleissheim, Germany), 75 IU, on day 3 of the first postoperative cycle or the first menstrual cycle after termination of GnRH-a therapy. Ovulation was induced by administering 10,000 IU of hcg (Pregnesin; Serono). Intrauterine insemination was performed 36 to 38 hours later. The luteal phase was supported by vaginal application of progesterone (Utrogest; Kade-Bessin, Berlin, Germany), 300 mg/d. A maximum of 3 IUI cycles per patient were included in the analysis. In Vitro Fertilization and Intracytoplasmic Sperm Injection Patients scheduled for IVF or ICSI had patent but poorly movable fallopian tubes, an unfavorable position of the fallopian tubes with respect to the ipsilateral ovary, or up to grade III oligoasthenoteratozoospermia in the partner. Intracytoplasmic sperm injection was performed if the progressive motile sperm count in the processed semen was less than cells/ml. In patients who had surgery only, ovarian stimulation began after down-regulation with 0.1 mg of GnRH-a in the long protocol. The women received daily s.c. injections of GnRH-a (Decapeptyl 0.1; Ferring, Kiel, Germany) from cycle day 18. Starting on day 3 of the new cycle, daily injections of recombinant FSH (Gonal-F; Serono), 150 IU to 300 IU, were given. Ovulation was induced with 10,000 IU of hcg (Pregnesin; Serono). Ultrasonography-guided follicular puncture was performed 35 to 36 hours later. After processing of the eggs and sperm and cultivation of the pronuclei, embryos were transferred intrauterinely 72 hours later. At least two but no more than three embryos were transferred per cycle. The luteal phase was supported by vaginal application of progesterone (Utrogest; Kade-Bessin), 300 mg/d, and hcg, 1,500 to 2,500 IU, on days 1, 3, and 6 after transfer. In patients who received GnRH-a treatment, ovarian stimulation was begun exactly 2 weeks after the last depot injection of GnRH-a by giving daily injections of recombinant FSH (Gonal-F; Serono), 150 IU to 300 IU. The remainder of the course was identical to the procedure described above, including luteal phase support. A maximum of three IVF/ICSI cycles were included in the analysis. Assessment of Pregnancy Fourteen days after IUI or ET, all patients were screened for pregnancy by -hcg assay and measurement of endometrial depth. Only clinical pregnancies with increasing -hcg levels and valid ultrasonographic evidence of an amniotic sac were recorded. Statistical Analysis The main outcome of interest was the pregnancy rate at the end of the treatment (without considering the number of cycles). To avoid a bias caused by unequal proportions of cases with mild and severe endometriosis in the two treatment groups, analysis was done according to four strata: IUI and stage II disease, IUI and stage III or IV disease, IVF/ ICSI and stage II disease, and IVF/ICSI and stage III or IV disease. In each stratum, percentages of pregnant women were calculated and compared between the two treatment arms by using Fisher s exact test. Results from these four strata were then combined in the Mantel Haenszel test to give an overview of the effect of GnRH-a with regard to ART technique and stage of endometriosis. In addition, the Tarone test was used to examine whether the effect of GnRH-a differs significantly among the four strata. Odds ratios and 95% CIs combined over all strata were determined. All analyses were performed by using SPSS software, version (SPSS, Inc., Chicago, IL). P.05 was considered statistically significant. RESULTS The youngest patient was 23 years of age, and the oldest was 40 years of age. The demographic characteristics of the two randomized groups did not differ statistically in terms of mean age, duration of infertility, ratio of primary to secondary infertility, mean stage of endometriosis, and mean endometriosis score. In three of the four strata, the pregnancy rate was higher in the treatment arm with administration of GnRH-a. This effect was significant (P.037) in women with stage III or IV endometriosis undergoing IVF/ICSI and approached significance (P.055) in patients with stage II endometriosis undergoing IUI. A slight, nonsignificant reversion of this effect was seen only in patients with stage II endometriosis undergoing IVF/ICSI (Fig. 2). When effects were combined over all strata, pregnancy rates did not differ significantly among the four strata (P.325, Tarone test). The overall test for dependence of the pregnancy rates on GnRH-a administration was highly significant (P.006, Mantel Haenszel test). The estimate of the common odds ratio over all four strata was 3.87 (95% CI, ) in favor of GnRH-a therapy. The results in the individual ART treatment groups are discussed below. FERTILITY & STERILITY 759

4 FIGURE 2 Pregnancy rates at different stages of endometriosis. (A), Patients undergoing IUI. (B), Patients undergoing IVF or ICSI. *P.05. Shaded bar with GnRH-a; open bar without GnRH-a. ( vs ). Moreover, the groups did not differ in the mean sperm count ( cells/ml vs cells/ml) or sperm count of the male partners of women who became pregnant ( cells/ml vs cells/ml). In Vitro Fertilization or Intracytoplasmic Sperm Injection The overall pregnancy rate with ART using IVF or ICSI after ultralong GnRH-a therapy was 75% compared with 47% in patients who had surgery only (Table 1). The number of patients undergoing IVF or ICSI did not differ between the two groups (16/12 vs. 10/9). According to analyses of the national registry (Deutsches IVF Register), the overall pregnancy rate at our center was 34.7% after IVF and 35.1% after ICSI at that time. In patients who received GnRH-a follow-up therapy, an average of embryos were transferred, compared with embryos in patients who had surgery only. The mean endometriosis score of both groups did not differ significantly ( vs ). Rickes. Ultralong GnRH-a therapy before ART. Fertil Steril Intrauterine Insemination Sixty-three patients underwent IUI. Twenty-seven patients received ultralong postoperative GnRH-a therapy, and 36 received no follow-up therapy (Fig. 1). Pregnancy rates were much higher in the GnRH-a group than the surgeryonly group (89% vs. 61%; P.05) (Table 1). Endometriosis score did not differ significantly between the two groups Stage-Related Pregnancy Rate After ART The positive effect of ultralong GnRH-a therapy on the outcome of the ART treatment did not distribute uniformly among all stages of endometriosis (Fig. 2). The pregnancy rate was increased in patients with stage II endometriosis who had IUI and received postoperative the GnRH-a therapy compared with similar patients who had surgery alone (86% vs. 58%), but this benefit was not statistically significant. In patients with stage II endometriosis who had IVF or ICSI, the pregnancy rate was slightly lower in those who received GnRH-a than in those who had surgery only (50% vs. 56%; P value not significant). In patients with stage III or IV endometriosis who underwent IVF or ICSI, GnRH-a treatment significantly increased pregnancy rates compared with patients who had surgery alone (82% vs. 40%; P.05). TABLE 1 Pregnancy rates for IUI and IVF/ICSI with and without GnRH-a pretreatment. IUI IVF/ICSI With GnRH-a (n 27) Without GnRH-a (n 36) With GnRH-a (n 28) Without GnRH-a (n 19) No. of cycles overall No. of cycles per patient No. of pregnancies (%) 24 (89) a 22 (61) a 21 (75) 9 (47) a P.05. Rickes. Ultralong GnRH-a therapy before ART. Fertil Steril Rickes et al. Ultralong GnRH-a therapy before ART Vol. 78, No. 4, October 2002

5 DISCUSSION We found that ultralong GnRH-a therapy before ART may improve results of surgical treatment of advanced endometriosis (stages III and IV) in terms of pregnancy rates after ART. Nonrandomized (3, 4) and randomized studies (9) have reported similar results. In the study by Marcus and Edwards (3), pretreatment with GnRH-a over at least 4 cycles was required to obtain a significantly higher IVF pregnancy rate compared with ultrashort (GnRH-a administration from day 2 of the stimulation cycle) or long (GnRH-a administration from day 20 of the preceding cycle) goserelin protocols. On the basis of these results, we administered ultralong GnRH-a therapy, lasting 5 to 6 months. Most investigators believe that a multifactorial process explains the benefit of ultralong GnRH-a therapy before ART. Prolonged amenorrhea after GnRH-a pretreatment produces an endocrine environment similar to that of hypogonadotropic hypogonadism. These women are known to have a high fertilization and implantation potential while receiving ovarian stimulation therapy with gonadotropins. High fertilization rates can be expected when the influence of FSH is suppressed (10, 11). The vital mechanism seems to be inhibition of the migration of primordial follicles to the pool of mature follicles after FSH depletion (12). The high implantation rates and increased rates of multiple births after ovarian stimulation in patients with hypogonadotropic hypogonadism can be explained by improved endometrial responsiveness following amenorrhea (13, 14). During amenorrhea, the pinopodes, which are highly important for implantation, recover. The advantages of uterine amenorrhea are known from oocyte donation programs in agonadal recipients and women with GnRH-a-induced amenorrhea. These women have higher pregnancy rates than do recipients with cyclic endometrial function (11, 15 17). On the basis of our results, however, a general benefit of GnRH-a treatment before ART on the pregnancy rate cannot be postulated. In our sample, only women with severe stage III and IV endometriosis benefited from ultralong GnRH-a therapy between surgical treatment and the ART treatment cycle. Women with stage II endometriosis did not benefit from this additional therapy. Fàbregues et al. (5) confirmed that GnRH-a does not generally improve results of ART. This prospective study in matched pairs included three main indications for IVF treatment: tubal, unexplained, and endometriosis-related (mild) infertility. After 4 months of GnRH-a therapy, the pregnancy rates per embryo transfer were no higher than those obtained with conventional GnRH-a therapy in the long protocol before IVF-ET. However, we found a benefit of GnRH-a treatment in patients with severe endometriosis. Surgical treatment of all patients with stage III and IV endometriosis was performed by an experienced surgeon using microsurgical techniques. Complete removal of all endometrial implants was attempted. However, in severe endometriosis, it must be assumed that some implants remain after surgery or that microscopic endometriosis may go undetected (18). Moreover, microsurgical procedures cannot completely prevent the spreading of endometrial material during surgery, and uterine adenomyosis escapes surgical therapy. In all these cases, ultralong postoperative therapy with GnRH-a may improve the chances of fertility. The overall pregnancy rate was relatively high, and 73% of patients undergoing IUI and 64% of patients undergoing IVF/ICSI became pregnant. The outcome of ART was based on cumulative pregnancy rates after three attempts in each ART group (IUI and IVF/ICSI). In addition, all men in the IUI program were normozoospermic. Because the pregnancy rates were high, additional benefit of GnRH-a therapy would not be expected. Nevertheless, our evidence indicates that GnRH-a therapy for 5 to 6 months after surgery and before ART program is beneficial in women with severe endometriosis. In summary, our data demonstrate that postoperative ultralong GnRH-a therapy may increase the pregnancy rate of ART cycles in patients with advanced endometriosis. This finding was especially evident for patients undergoing IVF or ICSI. Thus, patients with severe endometriosis should be prepared with an ultralong GnRH-a protocol. In contrast, patients with stage II endometriosis did not benefit uniquely from this treatment. Therefore, the ideal pretreatment before ART in these women is surgery alone using laparoscopy or laparotomy. References 1. Adamson GD. Treatment of endometriosis-associated infertility. Semin Reprod Endocrinol 1997;15: Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337: Marcus SF, Edwards RG. High rates of pregnancy after long-term down-regulation of women with severe endometriosis. Am J Obstet Gynecol 1994;171: Nakamura K, Oosawa M, Kondou I, Inagaki S, Shibata H, Narita O, et al. Menotropin stimulation after prolonged gonadotropin releasing hormone agonist pretreatment for in vitro fertilization in patients with endometriosis. J Assist Reprod Genet 1992;9: Fàbregues F, Balasch J, Creus M, Civico S, Carmona F, Puerto B, et al. Long-term down-regulation does not improve pregnancy rates in an in vitro fertilization program. Fertil Steril 1998;70: Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Cook AS, Rock JA. The role of laparoscopy in the treatment of endometriosis. Fertil Steril 1991;55: Hohl MK. Endometriose. In: Scheidel P, Hepp H, DeCherney AH (eds). Operative Techniken der Reproduktionsmedizin. Baltimore: Urban & Schwarzenberg. 1990: Dicker D, Goldman JA, Levy T, Feldberg D, Ashkenazi J. The impact of long-term gonadotropin-releasing hormone analog treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization-embryo transfer. Fertil Steril 1992;57: Edwards RG, Marcus S, Macnamee M, Balmaceda JP, Walters DE, Asch R. High fecundity of amenorrhoeic women in embryo-transfer programmes. Lancet 1991;338: Borini A, Violini F, Bianchi L, Bafaro MG, Trevisi MR, Flamigni C. FERTILITY & STERILITY 761

6 Improvement of pregnancy and implantation rates in cyclic women undergoing oocyte donation after long-term down-regulation. Hum Reprod 1995;10: Ataya K, Tadros M, Ramahi A. Gonadotropin-releasing hormone agonist inhibits physiological ovarian follicular loss in rats. Acta Endocrinol 1989;121: Edwards RG. Why are agonadal and post-amenorrhoeic women so fertile after oocyte donation? Hum Reprod 1992;7: Edwards RG. Clinical approaches to increasing uterine receptivity during human implantation. Hum Reprod 1995;10(2 Suppl): Navot D, Drews MR, Bergh PA, Guzman I, Karstaedt A, Scott RT, et al. Age-related decline in female fertility is not due to diminished capacity of the uterus to sustain embryo implantation. Fertil Steril 1994;61: Lydic ML, Liu JH, Rebar RW, Thomas MA, Cedars MI. Success of donor oocyte in in-vitro fertilization-embryo transfer in recipients with and without premature ovarian failure. Fertil Steril 1996;65: Abdalla HI, Wren ME, Thomas A, Korea L. Age of the uterus does not affect pregnancy or implantation rates; a study of egg donation in women of different ages sharing oocytes from the same donor. Hum Reprod 1997;12: Murphy AA, Green WR, Bobbie D, de la Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46: Rickes et al. Ultralong GnRH-a therapy before ART Vol. 78, No. 4, October 2002