Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis

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1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 42, No. 9: , September 2016 Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis Yotaro Takaesu 1,2, Hirotaka Nishi 1, Junya Kojima 1, Toru Sasaki 1, Yuzo Nagamitsu 1, Rina Kato 1 and Keiichi Isaka 1 1 Department of Obstetrics and Gynecology, Tokyo Medical University, and 2 St. John s Society Sakuramachi Hospital, Tokyo, Japan Abstract Aim: Although there are various hormone therapies, including gonadotropin-releasing hormone agonist, danazol, levonorgestrel-releasing intrauterine system, dienogest, and low-dose estrogen progestin, no consensus opinion has been reached in terms of which medication should be used and for how long it should be administered. We aimed to determine whether dienogest or goserelin is the better postoperative therapy to prevent recurrence of endometriosis. Methods: A prospective cohort randomized study were conducted, including 198 patients diagnosed as having endometriosis. A total of 111 patients were randomly assigned into two groups: the dienogest-administered group (n = 56) and the goserelin-administered group (n = 55). Patients were followed for 24 months after laparoscopic surgery. Those who gave consent but desired no postoperative therapy were assigned to the non-treatment group (n = 79). Recurrence, side-effects, degrees of menstrual pain and chronic pelvic pain measured by the Visual Analogue Scale were compared among the three groups: the dienogest, goserelin, and non-treatment groups. Results: No significant difference was observed in the postoperative recurrence rate between the dienogest and goserelin groups. No significant difference was found in the recurrence rate between the goserelin group and nontreatment group; however, a significant difference was found in the recurrence rate between the dienogest group and the non-treatment group (P =0.027).Menstrualpainandchronicpelvicpainweresignificantly improved in both treatment groups. Side-effects were markedly observed in the goserelin group as compared with the dienogest group. Conclusion: Dienogest is available for prolonged administration of more than 6 months, so it is more useful than goserelin, which is available only for short-term administration. Key words: dienogest, endometriosis, goserelin, recurrence, surgery, Visual Analogue Scale. Introduction Endometriosis is an estrogen-dependent benign disease developed in about 3 10% of females of reproductive age, and an increase in the incidence has recently been pointed out. 1 There are a variety of symptoms, including menstrual pain, chronic pain, coital pain, and infertility. These symptoms markedly impair the patient s quality of life. 2 7 Endometriosis shows various pathological conditions, such as ovarian endometriosis cyst, deep pelvic lesion, peritoneal lesion and adhesion. Recently, it has been pointed out that endometriosis also causes malignant transformation to ovarian cancer. 8 Surgical therapy is the most effective therapy for endometriosis; however, Received: December Accepted: March Correspondence: Dr Hirotaka Nishi, Department of Obstetrics and Gynecology, Tokyo Medical University, Nishishinjuku, Shinjuku-ku, Tokyo , Japan. nishih@tokyo-med.ac.jp 1152

2 Comparison between dienogest and GnRHa complete remission is difficult and recurrence is not negligible, even after the lesions have been removed as much as possible. 9 Accordingly, a variety of postoperative treatments are conducted to control the condition. Although there are various hormone therapies, including gonadotropin-releasing hormone (GnRH) agonist, danazol, levonorgestrel-releasing intrauterine system, dienogest, and low-dose estrogen progestin (LEP), no consensus opinion has been reached in terms of which medication should be used and for how long it should be administered Here, we report on a prospective cohort study examining the efficacy and adverse events of goserelin (a GnRH agonist) and dienogest, used as a postoperative therapy. Methods Patients and study design Subjects were 198 patients who were diagnosed as having endometriosis at the Tokyo Medical University Hospital and Sakuramachi Hospital between April 2009 and June 2013 and gave informed consent. The research protocol was approved by the Institutional Review Boards of the hospitals. Operative procedures included laparoscopic resection of ovarian cyst, lesion-removal surgery and synechiotomy, and the legions were removed as much as possible. Subjects were aged from 18 years to before menopause (median of 34.5 years). Patients who received no hormone therapies, such as GnRH agonist, danazol, LEP, dienogest, and progestin, within 6 months before the surgery were included. Subjects with complication of uterine fibroids or adenomyosis were not excluded. Of 198 subjects, eight cases refused to enter the study. Of the 190 subjects, the non-treatment group included 79 cases who denied the postoperative therapy, and 111 cases were randomly divided into two groups: the dienogest group (56 cases) and the goserelin group (55 cases) (Fig. 1). Administration of dienogest or goserelin was started at the first menstruation after surgery. For dienogest, oral administration of 2 mg daily was continued every day for 24 weeks. For goserelin, 1.8 mg of subcutaneous injection was given once every 4 weeks a total of six times. Furthermore, consent for a follow-up study was obtained from patients who desired no postoperative therapy. They were assigned to the non-treatment group (79 patients). A follow-up study for the recurrence rate and the degree of improvement of pain was conducted in the same manner. Age, body mass index (BMI), cancer antigen (CA)-125 value, and revised American Society for Reproductive Medicine (rasrm) score were compared among the three groups. Regular observations of the progression of each group were implemented for more than 24 months. Transvaginal ultrasonography and vaginal examination were conducted at 1, 3, 6, 12, 18, and 24 months after surgery. In addition, magnetic resonance imaging was conducted at 24 months after the surgery and was also implemented when recurrence of endometriosis was suspected by transvaginal ultrasonography Figure 1 Study profile. 1153

3 Y. Takaesu et al. and other examinations. The diagnostic imaging was implemented by at least two physicians. Comparison survey between before and after the surgery was conducted for subjective end-points, which consisted of menstrual pain, chronic pelvic pain, coital pain, painful urination, and painful defecation. The Visual Analogue Scale (VAS; 0 mm = absence of pain = 0, 100 mm = unbearable pain = 10) was used for evaluation of menstrual pain and chronic pelvic pain. The endometriosis severity profile scoring system, based upon the Biberoglu and Behrman Scale, was used for evaluation of coital pain, painful urination, and painful defecation. 19 The primary efficacy end-point was recurrence of endometriosis. The secondary end-points were the degrees of improvement after the surgery in menstrual pain, chronic pelvic pain, coital pain, painful urination, and painful defecation. Recurrence of endometriosis was determined based on magnetic resonance imaging findings. group dropped out of the study because of side-effects or for economic reasons (Fig. 1). Recurrence of endometriosis was observed within 24 months after the surgery in four cases who received dienogest (7.4%) and eight cases who received goserelin (15.7%). First, the age, BMI, rasrm score, and CA-125 value were compared between the treatment groups (dienogest group and goserelin group) and the non-treatment group, but no significant difference was observed. Furthermore, the recurrence rate of the combined treatment groups was 11.4%, and on the other hand, the recurrence rate of the non-treatment group was 21.5% (17 cases). However, there was no statistically significant difference between these two groups (Table 1, Fig. 2). Then, comparisons between the two treatment groups, the dienogest and goserelin groups, were conducted. Age showed a significant difference (P = ), whereas no significant differences were observed in the BMI, rasrm score, and CA-125 value. The recurrence rates for the dienogest and goserelin groups were 7.4% and 15.7%, respectively. The Statistical analysis Statistical analyses were conducted with the Student s t-test for age, BMI, rasrm score and CA-125 value, and asignificant difference was defined as P < The χ 2 -test was used for the recurrence rate and the Welch t-test for the VAS score, and a significant difference was defined as P < 0.05 in the same manner. Results Comparison among the dienogest, goserelin, and non-treatment groups Of the 111 subjects who participated in the study, 56 and 55 cases were randomly assigned into the dienogest and goserelin groups, respectively. There were 79 subjects who denied the postoperative therapy but gave consent for the follow-up study after the surgery, and they were assigned into the non-treatment group. Two cases of the dienogest group and four cases of the goserelin Figure 2 Comparison of the recurrence rate between treatment and non-treatment groups. Recurrence of endometriosis was observed within 24 months after surgery in 17 cases in the non-treatment group (n = 79, 21.5%) and in 12 cases in the treatment group (n = 105, 11.4%). Table 1 Comparison between treatment and non-treatment groups Non-treatment group n =79 Treatment group n =105 Statistical analysis Age(average ± SD) 34.6 ± ± 6.6 Student s t-test (P =0.5685) BMI(average ± SD) 20.7 ± ± 2.0 Student s t-test (P =0.1625) rasrm score(average ± SD) 55.5 ± ± 30.7 Student s t-test (P =0.5187) CA-125 level(average ± SD) 92.6 ± ± 59.1 Student s t-test (P =0.5110) Recurrence rate (%) χ 2 -test (P = ) BMI, body mass index; CA-125, cancer antigen 125; rasrm, revised American Society for Reproductive Medicine. 1154

Comparison between dienogest and GnRHa recurrence rate of the dienogest group was lower; however, no significant difference was observed between the two groups (P =0.1555) (Table 2).

The recurrence rates for the dienogest and non-treatment groups were 7.4% and 21.5%, respectively; and the recurrence rate of the dienogest group was significantly lower (P = 0.027) (Tables 1,,2,Fig.

4 Comparison between dienogest and GnRHa recurrence rate of the dienogest group was lower; however, no significant difference was observed between the two groups (P =0.1555) (Table 2). In comparisons between the dienogest group and the non-treatment group, no significant differences were observed in age, BMI, rasrm score, or CA-125 value. The recurrence rates for the dienogest and non-treatment groups were 7.4% and 21.5%, respectively; and the recurrence rate of the dienogest group was significantly lower (P = 0.027) (Tables 1,,2,Fig.3).No statistical significance was observed in the age, BMI, rasrm score, CA-125 score, or recurrence rate in comparisons between the goserelin and nontreatment groups (Tables 1, 2, Fig. 3). rasrm scores in dienogest and goserelin groups Patients who had recurrent disease in the dienogest group tended to have higher rasrm scores than patients without recurrence; however, no significant difference was observed between patients with recurrence and without recurrence in the goserelin group (Fig. 4). Pain relief by dienogest and goserelin Objective evaluation of menstrual pain, chronic pelvic pain, coital pain, painful urination, and painful defecation, which are prominent symptoms of endometriosis, was implemented, and improvement in menstrual pain and chronic pelvic pain were observed after the surgery in both of the treatment groups and the non-treatment group, according to VAS scores (Fig. 5). Menstrual pain and chronicpelvicpainweresignificantly improved during drug administration in both the dienogest and goserelin groups (Fig. 5). However, menstruation returned at about 3 months after the end of drug administration, and then menstrual pain and chronic pelvic pain gradually became worse (Fig. 5). The degree of pain exacerbation was almost the same in the two treatment groups (Fig. 5). In the nontreatment group, menstrual pain and chronic pelvic pain also improved from immediately after the surgery for 6 months, but it was gradually exacerbated after that and showed notable exacerbation as compared with the treatment groups (Fig. 5). Figure 3 Comparison of the recurrence rates in the dienogest, goserelin and non-treatment groups. Recurrence of endometriosis was observed within 24 months after surgery in four cases in the dienogest group (n = 54, 7.4%), eight cases in the goserelin group (n = 51, 15.7%) and 17 cases in the non-treatment group (n = 79, 21.5%). *P < **P > Figure 4 The revised American Society for Reproductive Medicine (rasrm) score in the dienogest and goserelin groups in regards to the recurrence of endometriosis. ( )Recurrence.( ) Non-recurrence. For coital pain, no great improvement was observed in either of the treatment groups or the non-treatment group. The number of subjects who had sexual intercourse after Table 2 Dienogest versus goserelin Dienogest n =54 Goserelin n =51 Statistical analysis Age(average ± SD) 32.4 ± ± 6.2 Student s t-test (P =0.0074) BMI(average ± SD) 20.3 ± ± 2.0 Student s t-test (P =0.3895) rasrm score(average ± SD) 51.6 ± ± 29.0 Student s t-test (P =0.8427) CA125 level(average ± SD) 81.2 ± ± 34.6 Student s t-test (P =0.4072) Recurrence rate (%) χ 2 -test (P =0.1555) BMI, body mass index; CA-125, cancer antigen 125; rasrm, revised American Society for Reproductive Medicine. 1155

5 Y. Takaesu et al. improved after the surgery, although they answered mild. Only four cases had suffered from painful defecation before the surgery in the entire cohort of subjects, and these four cases were evaluated as mild. Of these four subjects, three cases were unchanged, and improvement was observed in one subject. No painful urination was observed in any subject. Figure 5 (a) Postoperative Visual Analogue Scale (VAS) scores for menstrual pain over 24 months in the dienogest, goserelin and non-treatment groups. (b) Postoperative VAS scores for chronic pelvic pain over 24 months in the dienogest, goserelin and non-treatment groups. ( ) Non-treatment. ( ) Goserelin. ( ) Dienogest. *P < **P > the surgery was 16 (30%) in the dienogest group and 14 (27%) in the goserelin group. The results of evaluation of coital pain before surgery by patients who also had sexual intercourse after surgery in the dienogest group were: 12 subjects for absence of pain, four cases for mild, no subjects for moderate, and no subjects for severe. One of the four patients who had answered that the coital pain had been mild indicated that the pain had been reduced by the surgery. The results of evaluation of coital pain before surgery by patients who also had sexual intercourse after surgery in the goserelin group were: eight subjects for absence of pain, three subjects for mild, two subject for moderate, and one subject for severe. One patient who answered severe indicated that the pain had been improved to mild by surgery. Patients who answered moderate or mild experienced almost no change in the pain. In the non-treatment group, 34 subjects (43%) responded to the query on coital pain. Of these 34 subjects, 26 subjects answered absence of pain and eight subjects answered mild. Only three subjects were determined as Side-effects Side-effects were notably observed in the goserelin group as compared with the dienogest group. Irregular vaginal bleeding occurred in 54 cases (100%) in the dienogest group and three cases (6%) in the goserelin group. Hot flash occurred in six cases (11%) in the dienogest group and 48 cases (94%) in the goserelin group. Headache was observed in five cases (9%) in the dienogest group and two cases (4%) in the goserelin group. Joint pain occurred in no cases (0%) in the dienogest group and one case (2%) in the goserelin group. Alopecia occurred in no cases (0%) in the dienogest group and one case (2%) in the goserelin group. Irregular bleeding was observed in all patients who received dienogest, but all cases were mild and no cases developed anemia. No serious side-effects were observed in either of the treatment groups (Table 3). Discussion There are a number of reports about postoperative therapy for endometriosis. However, there is no consensus opinion about which medication is the best. In addition, it is unclear for how long the medication should be administered. Busacca et al. reported that administration of GnRH agonist for 6 months after conservation surgery for endometriosis significantly extended the period until pain recurrence. 20 Strowitzki et al. conductedastudy comparing GnRH agonist and dienogest in patients with established diagnosis of endometriosis. However, they reported that there was no significant difference in symptom relief between the medications, and there were strong side-effects in the GnRH agonist group. Table 3 Adverse effects Dienogest n (%) Goserelin n (%) Total n Irregular 54 (100%) 3 (6%) 57 bleeding Hot flash 6 (11%) 48 (94%) 54 Headache 5 (9%) 2 (4%) 7 Joint pain 0 (0%) 1 (2%) 1 Alopecia 0 (0%) 1 (2%)

6 Comparison between dienogest and GnRHa Significant improvement of symptoms, such as various pains after surgery, was observed by drug administration in this study. It was also revealed that pain score gradually becomes worse after the end of the drug administration. This suggests minute recurrence of endometriosis, although no obvious recurrence of endometriosis is observed. After all, long-term postoperative therapy would be required to suppress symptoms. Recurrence of endometriosis could not be prevented by administration of goserelin as compared with the cases without drug administration after the endometriosis surgery in this study. However, recurrence of endometriosis was successfully prevented by administration of dienogest. In this regard, no statistically significant difference was observed in direct comparison of the recurrence rate between the medications. We assume that this was caused by a small number of registered cases. Furthermore, we consider that the reasons that there are many patients in the non-treatment group include: (i) the level of understanding of hormone therapy is low in Japan (due to bias regarding side-effects and other reasons); (ii) many of the patients desired early childbearing; and (iii) economic reasons (both goserelin and dienogest are expensive). We believe that the superiority of dienogest in comparison to goserelin will be apparent when more patients are examined. The guideline from the European Society of Human Reproduction and Embryology shows that secondary prevention is defined as interventions to prevent the recurrence of pain symptoms or the recurrence of disease in the long term, which is defined as more than 6 months after surgery. 21 Prolonged administration of goserelin for more than 6 months is not allowed because of concern that goserelin causes osteoporosis and other conditions, but dienogest may be administrated for a prolonged period of more than 6 months. In comparison to goserelin, dienogest more effectively prevents recurrence of endometriosis after surgery and has fewer side-effects. Hence, dienogest administration could be a first choice to prevent recurrence of endometriosis after surgery in the future. There are some reports that low-dose estrogen progestin (LEP), which can also be administered for a prolonged period, also contributes to recurrence prevention of endometriosis after surgery. 22,23 Vercellini et al.reported that recurrence risk of development of chocolate cyst was drastically reduced by continuous administration of LEP after conservation surgery for endometriosis as compared with the treatment without LEP administration. 23 In addition, Cho et al. showed that levonorgestrel releasing intrauterine system (LNG-IUS) has a similar degree of inhibitory effect to LEP on recurrence of endometriosis after surgery. 24 Future research trials should compare prolonged administration of LEP, LNG-IUS, and dienogest after surgery. Acknowledgments Funding for the present study was provided by Tokyo Medical University. Disclosure The authors declare no conflicts of interest. References 1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24: Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial analysis of private payer administrative claims data for women with endometriosis. JManagCarePharm2007; 13: Rogers PA, D Hooghe TM, Fazleabas A et al. Priorities for endometriosis research: Recommendations from an international consensus workshop. Reprod Sci 2009; 16: Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal antiinflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev 2009; CD Denny E. Women s experience of endometriosis. JAdvNurs 2004; 46: Kennedy S. What is important to the patient with endometriosis? Br J Clin Pract Suppl 1991; 72: Sepulcri RP, do Amarai VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 2009; 142: Kobayashi H, Sumimoto K, Moniwa N et al. Risk of developing ovarian cancer among women with ovarian endometrioma: A cohort study in Shizuoka, Japan. Int J Gynecol Cancer 2007; 17: Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009; 15: Momoeda M, Harada T, Terakawa N et al. Long-term use of dienogest for the treatment of endometriosis. JObstetGynaecol Res 2009; 35: Huntington A, Gilmour JA. A life shaped by pain: Women and endometriosis. J Clin Nurs 2005; 14: Davis L, Kennedy SS, Moore J, Prentice A. Modern combined oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev 2007: CD Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril 2008; 90: S260 S Heinrichs WL, Henzl MR. Human issues and medical economics of endometriosis: Three- vs six-month GnRH-agonist therapy. JReprodMed1998; 43 (Suppl 3): Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seikz C. 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7 Y. Takaesu et al. 16. Seracchioli R, Mabrouk M, Frasca C et al. Long-term cyclic and continuous oral contraceptive therapy and endometrioma recurrence: A randomized controlled trial. Fertil Steril 2010; 93: Koga K, Yutaka O, Yuri T, Masashi T, Yuji T. Recurrence of endometrioma after laparoscopic excision and its prevention by medical management. Front Biosci 2013; 1: Kikuchi I, Takeuchi H, Kitade M, Shimanuki H, Kumakiri J, Kinoshita K. Recurrence rate of endometriomas following a laparoscopic cystectomy. Acta Obstet Gynecol Scand 2006; 85: Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: Short-term and long-term effectiveness. Am J Obstet Gynecol 1981; 139: Busacca M, Somigliana E, Bianchi S et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: A randomized controlled trial. Hum Reprod 2001; 16: Dunselman GA, Vermeulen N, Becker C et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod 2014; 29: KogaK,TakamuraM,FujiiT,OsugaY.Preventionoftherecurrence of symptom and lesions after conservative surgery for endometriosis. Fertil Steril 2015; 104: Vercellini P, De Matteis S, Somigliana E, Buggio L, Frattaruolo MP, Fedele L. Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: A systematic review and meta-analysis. Acta Obstet Gynecol Scand 2013; 92: Cho S, Jung JA, Lee Y et al. Postoperative levonorgestrelreleasing intrauterine system versus oral contraceptives after gonadotropin-releasing hormone agonist treatment for preventing endometrioma recurrence. Acta Obstet Gynecol Scand 2014; 93:

Pre and post surgical medical therapy. Mauro Busacca M.D. Dept of Obstetrics and Gynecology University of Milan- Italy

Pre and post surgical medical therapy Mauro Busacca M.D. Dept of Obstetrics and Gynecology University of Milan- Italy introduction A disease is an open problem when two conditions are nor satisfied: The