Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial

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1 FERTILITY AND STERILITY VOL. 79, NO. 6, JUNE 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial Paolo Vercellini, M.D., Laura Trespìdi, M.D., Barbara Zaina, M.D., Sarah Vicentini, M.D., Giovanna Stellato, M.D., and Pier Giorgio Crosignani, M.D. Clinica Ostetrica e Ginecologica I, Istituto Luigi Mangiagalli, University of Milan, Milan, Italy Objective: To ascertain whether adjuvant gonadotropin-releasing hormone (GnRH) agonist therapy decreases blood loss during abdominal myomectomy. Design: Randomized controlled trial. Setting: Academic reproductive surgery center. Patient(s): One hundred premenopausal women requiring first-line conservative surgery for symptomatic intramural or subserous fibroids. Intervention(s): Eight weeks of treatment with depot triptorelin before myomectomy or immediate surgery. Main Outcome Measure(s): Intraoperative blood loss, operating time, degree of difficulty of the procedure, and short-term rate of fibroid recurrence. Result(s): Mean ( SD) intraoperative blood loss was ml in triptorelin recipients and in patients who had immediate surgery (mean difference, 31 ml [95% CI, 108 to 46 ml]). No significant differences were observed in blood loss according to uterine volume, number of fibroids removed, or total length of myometrial incisions. Most procedures in either group were of routine difficulty. On ultrasonography 6 months after myomectomy, four women in the GnRH agonist group and one in the immediate surgery group had tumor recurrence. Conclusion(s): Treatment with a GnRH agonist before abdominal myomectomy has no significant effect on intraoperative blood loss. Thus, systematic use of medical therapy before abdominal myomectomy does not seem to be justified. (Fertil Steril 2003;79: by American Society for Reproductive Medicine.) Key Words: Uterine leiomyoma, fibroid, myomectomy, conservative surgery, GnRH agonists, menorrhagia, infertility Received September 11, 2000; revised and accepted November 13, Reprint requests: Paolo Vercellini, M.D., Clinica Ostetrica e Ginecologica I, Istituto Luigi Mangiagalli, Università di Milano, Via Commenda 12, Milan, Italy (FAX: ; paolo.vercellini.@unimi.it) /03/$30.00 doi: /s (03) A considerable proportion of uterine leiomyomas are associated with symptoms requiring therapy (1 4). The standard treatment in women who desire pregnancy is myomectomy, which is performed abdominally if the tumors are not intracavitary (1 3). This surgical procedure may be associated with substantial morbidity, in particular major blood loss, because fibroid removal implies ample myometrial incision with exposure of numerous severed vessels. Prompt and meticulous hemostasis is not always feasible, particularly when large or multiple fibroids are present. Mechanical devices to limit blood loss may be awkward to apply or not always successful because of differences in uterine conformation (2, 3, 5). Vasoconstrictive agents (e.g., vasopressin or epinephrine) may cause severe cardiovascular side effects (3), and their use is prohibited in some countries. In the past decade, the use of gonadotropinreleasing hormone (GnRH) agonists before myomectomy became popular (5 10). The main purported advantages of these hypoestrogenizing hormones are limitation of blood loss and surgical trauma due to substantial reduction of fibroid volume and uterine artery blood flow (5 10). On the other hand, myomectomy after treatment with GnRH agonists is more cumbersome because it is difficult to identify the cleavage plane. In a gross anatomical and histopathologic study of uteri excised because of fibroids, De- 1390

2 ligdisch et al. (11) observed that pretreatment with GnRH agonists was associated with a blurred interface between myoma and myometrium, with obliteration of the cleavage plane. Moreover, it has been suggested that pretreatment with GnRH agonists may make identification of small intramural tumors more difficult and therefore increase the shortterm recurrence rate of myoma (12). Randomized controlled trials could verify the above findings, but the results of the six small randomized controlled trials published in the English-language literature are inconsistent (5, 12 16). We performed an adequately sized controlled trial to evaluate the effect of GnRH agonist administration before myomectomy at laparotomy on intraoperative blood loss. Secondary outcomes were operating time, degree of difficulty of the intervention, postoperative morbidity, and myoma recurrence. A short-term treatment was chosen to maintain the advantages of GnRH agonists (reduction in uterine blood flow and fibroid volume) while limiting side effects and costs (7, 9, 10, 14). MATERIALS AND METHODS Our open-label, parallel-group randomized controlled trial evaluated the effect of 2 months of treatment with a GnRH agonist before abdominal myomectomy on intraoperative blood loss compared with immediate surgery. The minimum duration of GnRH agonist treatment before myomectomy needed to accomplish the desired results is thought to be 2 months (9). The study was conducted in an academic department specializing in conservative and reconstructive gynecologic surgery. Institutional review board approval was obtained, and the participants were given oral and written information and signed a consent form. Selection Criteria Eligible patients were premenopausal women 18 to 40 years of age (serum FSH levels 30 miu/ml) who were referred to our center for symptomatic intramural or subserous fibroids (menorrhagia, infertility, or pelvic compression) larger than 3 cm that required first-line conservative surgery. The women underwent a complete physical examination, urine pregnancy test, and transvaginal ultrasonography. Uterine volume was calculated ultrasonographically by using the usual formula for a prolate ellipsoid (length width depth ). The number, diameter, and site of tumors were also assessed. Women with predominantly intracavitary fibroids were excluded. Other exclusion criteria were previous pelvic surgery for leiomyomas or other genital anomalies, uterine malformations, present or past pelvic inflammatory disease, use of GnRH agonists up to 6 months before study entry, ultrasonographic signs of uterine calcifications, coagulation disorders, and unstable general conditions. Women with a serum hemoglobin level 10 g/dl were also excluded because it was deemed inappropriate to preclude preoperative GnRH agonist treatment when moderate to severe irondeficiency anemia was present. Oral iron supplementation was systematically prescribed to mildly anemic patients (17). Treatments After pretrial screening, eligible patients were randomized in a proportion of 1:1 to treatment with intramuscular depot injections of triptorelin, 3.75 mg (Decapeptyl; IPSEN Biotech, Paris, France), on two occasions 28 days apart starting during the midluteal phase, or to immediate surgery. Treatment allocation was performed with a computer-generated randomization sequence using serially numbered, opaque, sealed envelopes. The operation was scheduled in the proliferative phase within 4 weeks of randomization in the immediate surgery group and within 4 weeks of the second triptorelin injection in the preoperative medical treatment group. The day before surgery, women allocated to the GnRH agonist group underwent a second ultrasonographic scan to evaluate variations in uterine and myoma volume. Myomectomies were performed at laparotomy by six expert staff surgeons and by four residents specializing in reproductive surgery. The residents were closely supervised by the six staff surgeons. Only mechanical and electrical instruments were used according to a standard technique described elsewhere (1 3). Fibroids were removed through a vertical incision as close to the midline of the uterine corpus as possible. Hemostasis was achieved with meticulous ligation of bleeders and obliteration of dead spaces with interrupted 2-0 or 3-0 polyglactic sutures. Vasoactive drugs, hemostatic tourniquets, and forceps or clamps on major pelvic arteries were not used. An oxidized regenerated cellulose surgical adhesion barrier was applied on the basis of the gynecologists experience and preference. Ultrashort antibiotic prophylaxis with intravenous cefuroxime, 2 g (clarithromycin in allergic patients), was systematically administered 30 minutes before surgery. Assessment of Efficacy The effect of treatment with triptorelin before myomectomy was based on blood loss, as measured in the operating room by weighing swabs and adding the estimated volume of blood to that removed by suction. The volume of lactated Ringer s solution used to irrigate the pelvis was estimated precisely and then subtracted from the fluid collected in the suction unit. No attempt was made to measure the amount of blood lost during abdominal wall opening because, in our experience, it is minimal and practically not evaluable. The number of myomas removed and their location was recorded. A tumor was defined as subserous if its greatest diameter lay outside the uterine contour, or as intramural in cases of marginal submucosal extension, provided that the greatest diameter was outside the uterine cavity (18). To accurately measure the length of uterine incisions, small marks corresponding to the extremes of the planned incision FERTILITY & STERILITY 1391

3 were made on the perimetrium with a needle-point electrode. A silk suture was stretched on the uterine surface and cut in correspondence with the marks. The pieces of surgical thread were collected and measured. Total operating time was measured from skin incision to closure; myomectomy time was measured from opening the peritoneum to start of closure. At the end of the intervention, the degree of difficulty of the procedure was graded according to a three-level scale (easier than usual, routine difficulty, or more difficult than usual). In addition, the surgeon was asked to state if the cleavage planes between the fibroids and the surrounding myometrium were clearly identifiable or not. Intraoperative or postoperative complication, blood transfusion, and duration of hospital stay were recorded. Serum hemoglobin and hematocrit were assessed before and 24 hours after the operation. Febrile morbidity was defined as a body temperature of 38 C or greater recorded on any 2 of the first 10 postoperative days, excluding the first 24 hours. To test the hypothesis that GnRH agonist treatment before myomectomy increases the risk of short-term tumor recurrence (12), the women underwent clinical evaluation and vaginal ultrasonography 6 months after the operation. Statistical Analysis According to previous experience at our institution, the standard deviation of blood loss in women undergoing abdominal myomectomy without adjuvant medical therapy is around 300 ml (18). A difference of 200 ml in intraoperative blood loss between treatment groups was considered clinically significant. To have an 80% chance of detecting such a difference at an overall significance level of 5%, about 40 subjects per study arm were required. Allowing for withdrawals, the aim was to recruit approximately 50 women per treatment group. Differences in blood loss, operating time, number and length of myometrial incisions, number of tumors removed, serum hemoglobin and hematocrit values, and duration of hospital stay were analyzed with the Student t-test for unpaired data. Degree of difficulty of the intervention was compared by using the Mann Whitney U test, and the 2 test or Fisher exact test was used to analyze the frequencies of identifiable cleavage planes, febrile morbidity, and postoperative myoma recurrence. All statistical tests were two-sided. P.05 was considered significant. When appropriate, 95% CIs were calculated for the observed differences. RESULTS A total of 162 subjects evaluated in an academic outpatient clinic were eligible. Fifty-one declined randomization (39 were unwilling to undergo treatment with a GnRH agonist and 12 requested preoperative treatment), and 11 were lost to further contact. Fifty of the remaining patients were TABLE 1 Baseline characteristics of women undergoing abdominal myomectomy with or without preoperative GnRH agonist treatment. Characteristic Triptorelin group (n 49) Immediate surgery group (n 48) Age (y) Body mass index (kg/m 2 ) No. of parous women (%) 15 (31) 18 (37) Uterine volume At clinical evaluation (gestational wk) At sonography (ml) Diameter of the largest myoma (mm) Note: Data are presented as mean ( SD) or number (%) of patients. Vercellini. GnRH agonist treatment before myomectomy. Fertil Steril allocated to the triptorelin group and the other 50 to the immediate surgery group. After randomization and before surgery, 2 women in the latter group were withdrawn from the study (1 became pregnant and 1 decided to undergo surgery at another hospital). Myomectomy was converted to hysterectomy in 1 patient allocated to triptorelin because of intraoperative diagnosis of disseminated uterine leiomyomatosis. Thus, 49 patients in the preoperative medical treatment group and 48 in the immediate surgery group were available for the efficacy analysis. Table 1 shows the baseline clinical characteristics of participants. The distribution of the variables under study was similar in the two groups. Mean SD uterine volume in GnRH agonist recipients decreased by 22% to ml at preoperative ultrasonographic assessment. All women were operated through a Pfannenstiel or a Küstner transverse suprapubic incision. No major intraoperative complications occurred, and no homologous blood transfusions were required. The mean number of fibroids removed, number of myometrial incisions and their mean total length, and operating time did not significantly differ in the two groups (Table 2). Most procedures were judged to be of usual difficulty, and easy or difficult interventions were equally distributed between the two groups. In both groups, identification of cleavage planes was difficult in about 1 of 10 women. Mean ( SD) intraoperative blood loss was ml in the pretreated group and in the immediate surgery group (mean difference, 31 ml [95% CI, 108 to 46 ml]). The amount of blood loss was 500 ml or more in 6 of 49 (12%) women in the triptorelin group and 8 of 48 (17%) in the immediate surgery group. The maximum blood loss was 700 ml in 1 triptorelin recipient and 900 ml in 1 patient who had immediate surgery Vercellini et al. GnRH agonist treatment before myomectomy Vol. 79, No. 6, June 2003

4 TABLE 2 Results of abdominal myomectomy with or without preoperative gonadotropin-releasing hormone agonist treatment. Result Triptorelin group (n 49) Immediate surgery group (n 48) Blood loss (ml) Total operating time (min) Myomectomy time (min) No. of myomas removed No. of myometrial incisions Total length of incisions (mm) Degree of difficulty at surgery Easier than usual 3 (6) 2 (4) Usual 38 (78) 39 (81) More difficult than usual 8 (16) 7 (15) Prompt identification of cleavage planes Yes 44 (90) 43 (90) No 5 (10) 5 (10) Note: Data are presented as mean SD or n (%) of patients. No differences between groups was statistically significant. Vercellini. GnRH agonist treatment before myomectomy Fertil Steril No significant differences were observed in subgroup analyses. Mean blood loss was ml in the GnRH agonist group (n 22) and ml in the immediate surgery group (n 22) when uterine volume assessed preoperatively at bimanual examination was up to 12 gestational weeks and ml (n 27) and ml (n 26), respectively, in women with larger uteri. In the triptorelin and immediate surgery groups, respectively, blood loss was ml (n 25) and ml (n 26) when only one or two fibroids were present and ml (n 24) and ml (n 22) when three or more tumors were removed. Blood loss did not differ between groups when patients were stratified on the basis of length of myometrial incisions: It was ml (n 22) in the triptorelin group and ml (n 18) in the immediate surgery group when the total length of incisions was 10 cm and ml (n 27) and ml (n 30) when the total length was 10 cm or greater. Nor was blood loss influenced by the surgeon s expertise: It was ml and ml in pretreated patients in whom surgery was done by staff or residents, respectively, compared with ml and ml in those undergoing immediate surgery. To determine whether the above variables were associated with the amount of blood loss independent of GnRH agonist use, data from patients in both groups were pooled. Uterine volume and total length of myometrial incisions were reliable predictors of blood loss: Values were ml (n 44) in women with a uterine size less than 12 gestational weeks and ml (n 53) in those with uterine size 12 weeks or larger (P.011, unpaired t-test), and ml (n 40) when the myometrial surface incision was smaller than 10 cm and (n 57) when the incision was 10 cm or large (P.043). Unexpectedly, blood loss was not significantly influenced by number of myomas removed. Values were ml (n 51) when one or two fibroids were excised and ml (n 46) when three or more tumors were present (P.761). Mean serum hemoglobin and hematocrit values in the GnRH agonist group decreased from g/dl and 38.4% 3.4% before surgery to g/dl and 35.2% 3.1% 6 hours after surgery and to g/dl and 34.1% 2.9% 24 hours after surgery. At the same time points, serum hemoglobin and hematocrit values in the immediate surgery group were, respectively, , , and g/dl and 37.6% 3.3%, 34.5% 3.3%, and 33.1% 3.9%. None of the above between-group differences was statistically significant. One woman in the immediate surgery group underwent a second intervention to treat an expanding subfascial hematoma. Febrile morbidity occurred in 9 (18%) patients treated with triptorelin and 10 (21%) who underwent immediate surgery. Mean duration of hospital stay was days in the preoperative GnRH agonist group and days in the immediate surgery group. The number of women who did not attend the 6-month follow-up evaluation was small (8 of 97) and equally distributed between the study groups. One patient in the immediate surgery group was excluded from evaluation of shortterm tumor recurrence because a deep 1-cm intramural myoma was deliberately left untreated. The procedures were otherwise deemed radical. Patients in the GnRH agonist group were more likely to have persistence or recurrence of their fibroids 6 months after myomectomy than were those who underwent immediate surgery (4 of 45 patients vs. 1 of 43 patients; P 0.361, Fisher exact test (odds ratio, 4.10 [95% CI, 0.44 to 38.25]). DISCUSSION Because GnRH agonists considerably decrease uterine blood flow and myoma volume (19 21), it seems reasonable to expect that their use would reduce the length of the uterine incision, duration of surgery, and, most important, blood loss in women undergoing myomectomy (6, 8, 9). In six randomized controlled trials published in the English literature, the mean between-group difference in blood loss ranged from 37 to 156 ml, always in favor of the GnRH agonist group (5, 12 16). However, because a vasoconstrictor was used in the two trials on laparoscopic myomectomy, those data on blood loss are biased (15, 16). Reduction in operating time varied from 6 to 16 minutes in favor of the FERTILITY & STERILITY 1393

5 GnRH group in five studies, whereas in one trial on laparoscopic myomectomy, the difference was in favor of the immediate surgery group (16). The combined proportion of women who had transfusion was 7% (9 of 133) of pretreated patients compared with 8% (8 of 102) of those undergoing immediate surgery. The cumulative rate of postoperative complications was also similar: 20% (13 of 64) in the former group and 21% (14 of 66) in the latter group. No difference in duration of hospitalization was observed (10, 21). We observed a minimal between-group difference in blood loss; even the 95% confidence limit of about 100 ml is of marginal clinical importance. Pooling of data from patients in both groups indicated that uterine volume and total length of myometrial incisions were important predictors of intraoperative blood loss. However, subgroup analyses of the above variables demonstrated no benefit of preoperative triptorelin therapy over immediate surgery. Thus, our findings disagree with those of Friedman et al. (5), who observed a major reduction in blood loss after preoperative GnRH agonist use only in patients with pretreatment mean uterine volume greater than 600 cm 3 (roughly the size of a 16-week gestation). A 2-month course of GnRH agonist was used to limit side effects and costs without lessening efficacy. Greater reduction in operative blood loss after extension of the treatment period with triptorelin to 3 or 6 months cannot be excluded but seems unlikely, as most of the reduction in uterine volume and blood flow is observed in the first weeks of therapy (6, 9, 19, 20). Furthermore, our findings are consistent with the conclusions of recent systematic literature reviews (10, 21). Finally, because we excluded women with moderate or severe anemia and prescribed oral iron supplementation to those with mild anemia, extension of the treatment period with the aim of normalizing hematologic values was not justified (17, 22, 23). A double-blind, placebo-controlled study would have been preferable but was not feasible because of local organizational difficulties. However, our primary aim was determination of blood loss at surgery, an outcome that should be considered sufficiently objective. Hemostasis should not be influenced by the surgeon s personal opinions. Our trial was adequately sized, and only three women were withdrawn from the study. We expected a standard deviation of mean blood loss of 300 ml, which is larger than the standard deviation of around 200 ml observed in both study groups. However, the former figure was based on historical data collected retrospectively, which are likely to be less accurate. We believe that this should not affect interpretation of the results, because the sample size as calculated was larger than that needed to identify the planned difference in blood loss. Assessment of the degree of difficulty of the procedure was subjective. However, the turnover of surgeons should have avoided a systematic bias. Moreover, operating time, a reasonable indirect measure of surgical difficulty, was almost identical in the two study groups. Finally, the definition of cleavage planes was deliberately dichotomous to limit undue operator influence. Our data do not support the idea that preoperative administration of GnRH agonists makes identification of the cleavage planes and myomectomy more difficult. Gonadotropin-releasing hormone agonist induced uterine volume reduction is reported to limit the rate of midline vertical abdominal incisions needed to perform myomectomy when large tumors are present (21). This was not the case in our series, as all women underwent surgery through a lower transverse suprapubic incision independent of treatment allocation. No difference between groups in postoperative morbidity and hospital stay was observed. A policy of early discharge after conservative surgery at laparotomy has not yet been implemented in our department, and the postoperative course of the enrolled women was managed routinely. The overall incidence of febrile morbidity was well within the rates reported in the literature, and preoperative medical treatment was of no benefit in limiting this specific complication of abdominal myomectomy (24). Some investigators speculate that the decrease in myoma volume and consistency induced by hypoestrogenism makes smaller tumors unidentifiable during operation (12). In a previous small study from our institution (12), ultrasonography performed 6 months after myomectomy revealed recurrence or persistence of intramural fibroids smaller than 1.5 cm in diameter in 5 of 8 pretreated patients (63%) compared with 2 of 16 controls (13%). Such a difference was not confirmed in the study by Friedman et al. (25), in which the postoperative fibroid recurrence rate was high (6 of 9 [67%] pretreated patients and 5 of 9 [56%] controls); however, follow-up exceeded 2 years. The distribution of myoma recurrence in our trial was unbalanced. However, because of limited number of events (5 of 88 patients [5.7%]), the CI of the odds ratio is wide and includes unity, which precludes useful conclusions. Of note, the odds ratio of myoma recurrence in our study (4.2) is similar to that calculated by the Cochrane Collaboration (4.0) in a recent meta-analysis (21). Accordingly, we cannot rule out the possibility that use of GnRH agonists before myomectomy increases the risk of small tumor persistence. An unanswered question is whether preoperative hormonal therapy facilitates conception after conservative surgery (21). In a large observational study of determinants of reproductive outcome after myomectomy for infertility (18), the 24-month cumulative probability of conception was independent of the preoperative use of GnRH agonists: The 1394 Vercellini et al. GnRH agonist treatment before myomectomy Vol. 79, No. 6, June 2003

6 rate was 67% in 40 pretreated women compared with 66% in 98 patients who underwent immediate surgery. Only patient age, duration of infertility, and presence of other, minor infertility factors in addition to myomas were significantly associated with postoperative conception rate. We are continuing to follow the patients enrolled in the current trial with the aim of clarifying this matter. In conclusion, GnRH agonist treatment before myomectomy has no significant effect on intraoperative blood loss. Use of adjuvant medical therapy is justified in anemic women, as amenorrhea facilitates normalization of hematologic values (2, 8, 17, 22, 23). Otherwise, a modest increase in blood loss of even 100 ml has no demonstrated practical consequence (10). Homologous transfusions were not needed in our series. No effect on operating time, degree of difficulty of the procedure, and postoperative morbidity was observed. Larger trials are needed to verify the hypothesis that hypoestrogenism induced before surgery increases the risk of small tumor persistence (12). The main advantage of combining medical with surgical treatment in nonanemic women seems to be that patients could be admitted at any time, thus avoiding the problem of scheduling the operation during a few postmenstrual days. In theory, a reduction of fibroid volume may increase the feasibility of laparoscopic myomectomy, but our trial was not designed to clarify this matter. Moreover, myomectomy at laparoscopy remains controversial, and it has not yet been demonstrated that the endoscopic approach constitutes a definite advantage. Acknowledgments: The authors thank the operating theatre personnel for their collaboration throughout the study period and IPSEN Biotech Pharmaceuticals, Milan, Italy, for providing triptorelin depot injections used in the trial. References 1. Buttram VC, Reiter RC. 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