Gestrinone versus danazol as preoperative treatment for hysteroscopic surgery: a prospective, randomized evaluation

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1 REPRODUCTIVE SURGERY versus danazol as preoperative treatment for hysteroscopic surgery: a prospective, randomized evaluation Onofrio Triolo, M.D., Antonio De Vivo, M.D., Vincenzo Benedetto, M.D., Salvatore Falcone, M.D., and Francesco Antico, M.D. Department of Gynecological, Obstetrical Sciences and Reproductive Medicine, University of Messina, Messina, Italy Objective: To compare danazol and gestrinone treatment as preoperative endometrial preparation for operative hysteroscopy. Design: Prospective, randomized clinical study. Setting: University department of gynecological, obstetrical sciences and reproductive medicine. Patient(s): One hundred thirty-five patients with endouterine pathologies (endometrial polyps, submucous myoma, septate uterus). Intervention(s): Patients pretreated with gestrinone and with danazol (n 67) underwent operative hysteroscopy. Main Outcome Measure(s): Endometrial response to the medical pretreatment, side effects, procedure time, intraoperative bleeding, infusion volume, patient satisfaction. Result(s): Side effects were infrequent in both groups, though the patients personal satisfaction was in favor of gestrinone. The rate of endometrial response was higher for the gestrinone group (97.1% vs. 83.6%). Operative time (mean SD) was and minutes for the gestrinone and danazol groups, respectively. The gestrinone group showed a lower incidence of moderate bleeding (3% vs. 22.4%) and a lower infusion volume (2, ml vs. 2, ml). Regarding cervical dilatation time, no significant difference was found between the two groups ( minutes vs minutes). Conclusion(s): Both treatments are good ways to prepare the endometrium for operative hysteroscopy. However, the data suggest that gestrinone pretreatment is preferable to danazol. (Fertil Steril 2006;85: by American Society for Reproductive Medicine.) Key Words:, gestrinone, preoperative treatment, operative hysteroscopy Hysteroscopic surgery is considered the gold standard for the treatment of a number of endouterine pathologies, such as fibroids, polyps, synechiae, septa, and endometrial resection and/or destruction (1, 2). In fertile women, preoperative pharmacologic treatment has been recommended to reduce endometrial thickness, intraoperative bleeding, and difficulties and duration of surgery (3 5). Several drugs have been proposed (3, 6), although only danazol and GnRH analogues have clearly been demonstrated to be effective (6, 7). Preoperative treatment with GnRH analogues or danazol for 2 to 3 months has been recommended to remove large intramural submucous myomas or perform endometrial resection (6). Because GnRH analogues might be considered too expensive and an over-treatment in cases of minor hysteroscopic Received February 5, 2005; revised and accepted September 10, Reprint requests: Onofrio Triolo, M.D., Policlinico Universitario G. Martino, Dipartimento di Scienze Ginecologiche, Ostetriche e Medicina della Riproduzione, Via Consolare Valeria, Messina 98124, Italy (FAX: ; otriolo@unime.it). surgery, such as removal of small endocavitary fibroids, endometrial polyps, or uterine septa, danazol, which is a less expensive, shorter treatment for preoperative endometrial preparation, might be considered more suitable and sufficient to obtain satisfactory results. Several studies have reported that gestrinone, a tri-enic steroid with antiestrogenic and antiprogestinic activities, also is capable of reducing uterine volume, menorrhagia, and endometrial thickness (7, 8). The aim of this prospective, randomized study was to compare danazol and gestrinone treatments as preoperative endometrial preparation for hysteroscopic surgery for a variety of conditions. MATERIALS AND METHODS Between January 2002 and November 2004, patients with endouterine pathologies, identified by diagnostic hysteroscopy, were evaluated for this study. All patients underwent diagnostic hysteroscopy during the precocious endometrial proliferative phase (cycle days 7 to 8). The characterization /06/$32.00 Fertility and Sterility Vol. 85, No. 4, April 2006 doi: /j.fertnstert Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. 1027

2 of endometrium on hysteroscopic examination followed the criteria reported by Baggish et al. (9). The appearance of the endometrium, under direct vision, was described as normal if compatible with the proliferative phase, normal with small hyperplastic areas if only small areas of thickness were present, and hyperplastic if the entire endometrium was thick. All patients underwent endometrial biopsy for histologic examination to confirm the visual observation and to exclude any possible malignancy. The following exclusion criteria were applied: [1] presence of submucous (type I, type II) or endocavitary (type 0) fibroids (according to the European Society of Hysteroscopy Classification of Submucous Fibroids) (10) with a diameter exceeding 3 cm, for which preoperative treatment with GnRH agonists is indicated (11); [2] hormonal therapies in the previous 8 weeks (including the drugs of the study); [3] uterine and/or concomitant adnexal pathologies (including malignancy) for which hysteroscopic surgery was not considered either safe or the method to resolve the problem; [4] cardiovascular, hepatic, or renal impairment; and [5] any medical condition that would have increased the surgical risk. The 136 patients meeting these requirements were enrolled in the study and were given detailed information about the study and the surgical procedure, to which they gave their written, informed consent. They were then assigned at random to two treatment groups on a one-to-one basis, by a computer-generated randomization table, with an open study. One group (67 patients) was treated with danazol, whereas the other (69 patients) received gestrinone. Subjects in both groups took the medication orally for a period of 4 to 5 weeks, starting on day 1 of menstruation. The dosage given for danazol (Danatrol; Sanofi-Syntelabo, Milan, Italy) was 200 mg three times daily, whereas for gestrinone (Dimetrose; Pharmacia, Milan, Italy) the dosage was 2.5 mg twice weekly (Monday and Thursday). Electrocardiogram and routine blood tests were performed on the day before surgery. On the following day, at time of admission, the side effects from danazol and gestrinone experienced during treatment were recorded, and each patient was asked to define whether their personal experience with the pharmacologic treatment taken had been good or bad. All patients received amoxicillin/clavulanate (Augmentin; GlaxoSmith- Kline, Verona, Italy) in a single administration (2 g IV) 30 minutes before surgery as antibiotic prophylaxis. Operative hysteroscopies were performed in the inpatient day surgery, under general anesthesia, by the same hysteroscopist (O.T.), who was blind to the preoperative treatment allocated. The cervix was dilated up to Hegar 10.5, and a mannitol sorbitol solution was used at a continuous pressure of mm Hg for distension of the uterine cavity. The surgery was carried out with a rigid hysteroresectoscope with an external diameter of 10 mm (Karl Storz, Tuttlingen, Germany). At the time of surgery, endometrial appearance was assessed by direct vision and was classified as normal if compatible with a normotrophic endometrium, hypotrophic with normotrophic areas if not completely atrophic, and atrophic if entirely atrophic. An endometrial sample was taken from each patient by resection so that the visual evaluation could be compared with a histologic examination. The histologic results at the time of surgery were compared with those found at time of enrollment. Precise records were taken of both the time required for each cervical dilatation, from the insertion of Hegar 4 up to 10.5, and the duration of each surgical procedure, from the insertion to the removal of the resectoscope. Intraoperative bleeding was defined as light when bleeding did not interfere with surgery, moderate when bleeding required the coagulation of vessels, and severe when hemorrhage required immediate suspension of hysteroscopy. Measurements of inflow, outflow, and amount of distension liquid absorbed by the patient were taken meticulously. Postoperative complications were defined as the appearance of any complications occurring from the termination of the surgery to discharge (4 to 5 hours after surgery). At follow-up 4 weeks later, all women had sonographic evaluation of endometrial thickness. Statistical analysis was performed with SPSS 11 (SPSS, Chicago, IL). To compare data between the two groups, Student s t-test was used for parametric data and the Mann- Whitney test for nonparametric data. Dichotomous variables were analysed with the 2 test and the Fisher exact test, when appropriate. A P value of.05 was considered statistically significant. RESULTS In all, 136 women (danazol, 67; gestrinone, 69) were randomized. One patient in the gestrinone group (GG), affected by septate uterus, withdrew after randomization and hormonal treatment but before surgery. Data for a total of 135 patients (danazol, 67; gestrinone, 68) were thus available for analysis. All women were menstruating regularly, and the mean ( SD) age of the whole sample was years. No significant differences were found between the two groups in terms of age, parity, and body mass index (Table 1). Endouterine pathologies according to diagnostic hysteroscopy were endometrial polyps in 53 patients, uterine septum in 11 patients, and submucous myoma in 4 patients for the GG, whereas in the danazol group (DG) 54 patients had polyps, 8 uterine septum, and 5 submucous myoma. No significant TABLE 1 Characteristics of patients. P value Age (y) BMI Parity 2 (0 4) 2 (0 4).8 Note: Data are presented as mean SD or median (range). BMI body mass index Triolo et al., danazol, and hysteroscopy Vol. 85, No. 4, April 2006

3 TABLE 2 Endouterine pathologies in the two groups. TABLE 4 Endometrial patterns after treatment. Pathologies (n 67) P value Endometrial pattern (n 67) P value Endometrial 53 (77.9) 54 (80.6).86 polyp Uterine septum 11 (16.2) 8 (11.9).64 Submucous myoma 4 (5.9) 5 (7.5).49 Normotrophic 2 (2.9) 11 (16.4) nonresponders Hypotrophic with 3 (4.4) 13 (19.4).018 a thickened areas Atrophic 63 (92.7) 43 (64.2) a Normotrophic nonresponders vs. responders (hypotrophic atrophic). differences were found between the two groups for any of the above pathologies (Table 2). Hysteroscopic patterns of endometrial mucosa before treatment were as follows: endometrium compatible with the proliferative phase in 49 GG patients and 43 DG patients (P.82), proliferative with small hyperplastic area in 6 GG patients and 10 DG patients (P.42), and hyperplastic with pseudopolipoid areas in 13 and 14 patients, respectively (P.96) (Table 3). In all cases, hysteroscopic visual assessments were confirmed by the histologic results. Assessment of the visual appearance of the endometrium at time of surgery, after hormonal treatment, showed that 2 GG and 11 DG patients were normotrophic nonresponders; the remaining 66 GG patients and 56 DG patients responded to the treatment, with a significant difference between the two treatment groups (P.01) (Table 4). In particular, the endometrium was hypotrophic with small trophic areas in 3 and 13 patients and atrophic in 63 and 43 patients for GG and DG, respectively. Once again, all visual evaluations were confirmed by histologic findings. No cases of severe intraoperative bleeding occurred in either group; it was moderate in 2 GG patients and in 15 DG patients and light in 66 GG patients and 52 DG patients (P.002). Regarding intraoperative data, significant differences emerged relating to the operating time, which took longer in the DG ( minutes vs minutes; P.001) and for the infusion volume used, which was greater for the DG (2, ml vs. 2, ml; P.001). In contrast, no differences were found between the two groups for the time taken for cervical dilatation (GG: minutes; DG: minutes; P.1) (Table 5). Moreover, surgical procedures were performed without any postoperative complications in both groups. In terms of cost, the difference between the two groups was minimal, with a single preoperative treatment lasting 5 weeks requiring an outlay of $109 for GG and $111 for DG. In consideration of the short duration of administration, side effects reported by patients were minimal, transient, and well tolerated in both groups, and no significant differences were found, although they were more frequent in the DG (P.98) (Table 6). Two GG patients and one DG patient suffered from dual side effects. However, the satisfaction expressed by patients came out in favor of gestrinone: 92% of GG patients defined the treatment as good, taking into consideration side effects, dosage, and cost, compared with 60% of DG patients (P.001). At follow-up, no significant differences between the two groups were found in endometrial thickness evaluated by TABLE 3 Endometrial patterns before treatment. Endometrial pattern (n 67) P value Proliferative endometrium a 49 (72.1) 43 (64.2).82 Proliferative endometrium with hyperplastic areas 6 (8.8) 10 (14.9).42 Hyperplastic endometrium with pseudopolypoid areas 13 (19.1) 14 (20.9).96 In line with the proliferative phase. Fertility and Sterility 1029

4 TABLE 5 Intraoperative data: comparison between the two groups. Variable P value Cervical dilatation time (min) Operative time (min) Infusion volume (ml) 2, , Light bleeding 66 (97) 52 (77.6) Moderate bleeding 2 (3) 15 (22.4).002 Note: Data are presented as mean SD or n (%). sonography (GG: mm vs. DG: mm; P.45). DISCUSSION The success of hysteroscopic surgery is heavily dependent on good and constant endouterine visibility during the procedure, bearing in mind that the surgical field is extremely limited and very often narrowed by endometrial thickness and by the endouterine pathology itself. A preoperative pharmacologic treatment for hormonal suppression and endometrial mucosa thinning is recommended to achieve the best conditions of visibility (12). The efficacy of GnRH agonists and danazol administration for thinning the endometrium before hysteroscopic surgery has been reported by several investigators (6, 13). Histologic examination of endometrial specimens revealed that a single dose of GnRH analogues is sufficient to produce the best effect in the hormonal inhibition of endometrium, resulting in marked thinning and vascularity reduction (14). therapy (200 mg three times daily for 6 weeks) has resulted in a significant increase in both the pulsatility index and the resistance index of uterine artery blood flow by color Doppler, suggesting a reductive and/or suppressive effect on TABLE 6 Side effects in the two treatment groups. Side effect P value No. of cases 5 (7.3) 6 (8.9).98 Headache 3 (4.4) 4 (6) Swelling 2 (2.9) 2 (3) Nausea 1 (1.5) 2 (3) Body weight gain 1 (1.5) 2 (3) Two patients in the gestrinone group and one in the danazol group had dual side effects. local angiogenic or growth factors involved in endometrial and subendometrial angiogenesis, which might result in the reduction of the cyclic regeneration of the mucosa and consequent endometrial atrophy (15)., a tri-enic steroid with both antiestrogen and antiprogesterone activities, used in the treatment of endometriosis, has been shown to reduce uterine volume, uterine leiomyomata, and menorrhagia (16 18). Histologic and ultrastructural studies of endometrium performed in women being treated with danazol or gestrinone for endometriosis revealed a series of cellular involutive alterations (e.g., chromatin condensation, pyknosis, rupture of the cell membrane, an increased number of lysosomes, mitochondrial cristae fragmentation, and dilated Golgi complexes) resulting in irregular secretory transformation and mucosal hypotrophy (8, 19). Our study, not only by visual inspection on operative hysteroscopy but also histologic examination, confirms the effects of these drugs in atrophying endometrium. This was more evident in the gestrinone group, in which the mucosa appeared to be very thin, atrophic in 63 patients (92.7%), compared with 43 danazol-treated patients (64.2%). Moreover, the reduction of vascularity was confirmed by the low incidence of hemorrhage in both groups, though it was lower with gestrinone treatment (P.002). The histologic examination of endometrial strips confirmed these patterns, demonstrating that gestrinone treatment produced the best endometrial effect in atrophying endometrial mucosa, making hysteroscopic surgery easier. Our data suggest that presurgical treatment with gestrinone also improves surgical performance, with a reduction of time taken to perform surgery. This is a very important finding because a shorter operative time means less infusion liquid is used, with a lower risk of absorption and consequently a lower risk of electrolytic alterations, and it also lessens patients exposure to anesthesiologic drugs. Side effects, owing to the short period over which the two drugs were administered, were infrequent in both treatments, without significant differences between the two groups. However, regarding patient satisfaction, the acceptability of gestrinone was higher (P.001) because of its being administered twice weekly, as compared with danazol, which is administered three times daily Triolo et al., danazol, and hysteroscopy Vol. 85, No. 4, April 2006

5 In conclusion, our data suggest that both treatments, used for a brief period, are good ways to prepare the endometrium for operative hysteroscopy. However, the advantages in terms of dosage (twice weekly vs. three times daily), the better results achieved for atrophying the endometrium, and improved performance in relation to surgical matters (operative time, incidence of hemorrhage, volume of infusion liquid used) suggest that a gestrinone-based preparation is preferable to danazol. REFERENCES 1. Bieber EJ, Loffer FD. Gynecologic resectoscopy. London: Blackwell Scientific, Mazzon I, Sbiroli C. Manuale di chirurgia resettoscopica in ginecologia. Milan, Italy: Unione Tipografico-Editrice Torinase (UTET), Rai VS, Gillmer MDG, Gray W. Is endometrial pre-treatment of value in improving the outcome of transcervical resection of the endometrium? Hum Reprod 2000;15: Vercellini P, Perino A, Consonni R, Trespidi L, Parazzini F, Crosignani PG. Treatment with a gonadotrophin releasing hormone agonist before endometrial resection: a multicentre, randomised controlled trial. Br J Obstet Gynaecol 1996;103: Donnez J, Vilos G, Gannon MJ, Stampe-Sorensen S, Klinte I, Miller RM, et al. Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large randomized, double-blind study. Fertil Steril 1997;68: Parazzini F, Vercellini P, De Giorgi O, Pesole A, Ricci E, Crosignani PG. Efficacy of preoperative medical treatment in facilitating hysteroscopic endometrial resection, myomectomy and metroplasty: literature review. Hum Reprod 1998;13: Fedele L, Bianchi S, Gruft L, Bigatti G, Busacca M. versus a gonadotropin-releasing hormone agonist as preoperative preparation for hysteroscopic metroplasty. Fertil Steril 1996;65: Marchini M, Fedele L, Bianchi S, Di Nola G, Nava S, Vercellini P. Endometrial patterns during therapy with gestrinone for endometriosis: structural and ultrastructural study. Hum Pathol 1992;23: Baggish MS, Barbot J, Valle RF, eds. Diagnostic and operative hysteroscopy. A text and atlas. Philadelphia: Saunders, Wamsteker K, Emanuel MH, de Kruif JH. Transcervical resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 1993;82: Romer T. Benefit of GnRH analogue pre-treatment for hysteroscopic surgery in patients with bleeding disorders. Gynecol Obstet Invest 1998;45: Lewis BV. Guidelines for endometrial ablation. British Society of Gynaecological Endoscopy. Br J Obstet Gynaecol 1994;101: Sowter MC, Singla AA, Lethaby A. Preoperative endometrial thinning agents before hysteroscopic surgery for heavy menstrual bleeding. Cochrane Database Syst Rev 2002;(3):CD Brooks PG, Serden SP. Preparation of endometrium for ablation with a single dose of leuprolide depot. J Reprod Med 1991;36: Pepper J, Dewart PJ, Oyesanya OA. Altered artery blood flow impedance after danazol therapy: possible mode of action in dysfunctional uterine bleeding. Fertil Steril 1999;72: Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. versus danazol in the treatment of endometriosis. Fertil Steril 1989;51: Coutinho EM. Treatment of large fibroids with large doses of gestrinone. Gynecol Obstet Invest 1990;30: Turnbull AC, Rees MC. in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97: Fedele L, Bianchi S, Marchini M, Di Nola G. Histological impact of medical therapy clinical implications. Br J Obstet Gynaecol 1995;102:8 11. Fertility and Sterility 1031