Gynecol Surg (2016) 13:451–456 DOI 10.1007/s10397-016-0966-0

ORIGINAL ARTICLE

Effectiveness of treatment for infertility using clinical investigation of laparoscopy cytoreductive surgery combined with in adenomyosis

Mutangala Muloye Guy1,2 & Wang Zhan Ying1 & Wang Xiao Yan3 & Fang Zheng Hui 1 & Wu Xi Hai1 & Liu Yan Ping 1 & Zhang Ying Chun4 & Kasangye Kangoy Aurelie5,6 & Wei Zeng Tao1

Received: 7 January 2016 /Accepted: 23 June 2016 /Published online: 8 July 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract Adenomyosis is generally treated by medicine used for statistical analysis: measurement data was ana- and surgery; this study aims to explore the effectiveness lyzed by one-factor analysis of variance (ANOVA), LSD t of laparoscopic cytoreductive surgery combined with test was used for two to three groups’ comparison, and gestrinone on the treatment of adenomyosis. This is a chi-square test and Fisher probability method were used retrospective analysis (Jan. 2008 to Apr. 2011), on 82 for categorical data. The pregnancy rate (24 months after) patients who were diagnosed with adenomyosis and ac- was 57.14 % in group A, 41.67 % in group B, and cepted treatment, and who were divided into three groups. 15.38 % in group C. Recurrence in the three groups after Group A is composed by 27 patients who underwent lap- treatment was statistically significant (p < 0.05). All pa- aroscopic cytoreductive surgery and postoperative treat- tients who are undergoing laparoscopic surgery did not ment of gestrinone; group B, 25 patients who only present serious postoperative complications. But after 3 underwent laparoscopic cytoreductive surgery; and group and 6 months of treatment, patients present side ef- C, 30 patients who only received gestrinone. fects, and the difference was significant (p =0.046).The Postoperative complications, pregnancy rate, recurrence, study shows that surgical-medical treatment provided and drug side effects were respectively recorded after sur- more effective symptom control compared with surgery gery or drug treatment. SPSS 17.0 statistical software was alone. Surgical curative effect was better than alone; it can increase pregnancy rate for the patients with fertility requirements.

* Wei Zeng Tao Keywords Laparoscopic . Adenomyosis . Cytoreductive [email protected] surgery . Gestrinone

1 School of Medicine, Department of Obstetrics and Gynecology, Jinan Central Hospital, Shandong University, 44, Wenhua Xi Road, PO Box: 250012, Jinan, Shandong, China Introduction 2 School of Medicine, Department of Obstetrics and Gynecology, Cliniques Universitaires de Lubumbashi, University of Lubumbashi, Adenomyosis is an important clinical challenge in gynecology Lubumbashi, Democratic Republic of the Congo and healthcare economics, in its fully developed form. 3 School of Medicine, Department of Immunology, Shandong Symptoms of adenomyosis typically include menorrhagia, University, Shandong, China pelvic pain, and dysmenorrhea [1]. In adenomyosis, basal en- 4 School of Medicine, Department of Infertility, Jinan Central Hospital, dometrium penetrates into hyperplastic myometrial fibers. Shandong University, Shandong, China Adenomyosis may involve the uterus focally, creating an 5 School of Public Health, Social Medicine Department, Shandong adenomyoma [2]. University, Shandong, China The first description of the condition initially referred 6 School of Public Health, University of Lubumbashi, to as Badenomyoma^ was provided in 1860 by the Lubumbashi, Democratic Republic of the Congo German pathologist Carl von Rokitansky, who found 452 Gynecol Surg (2016) 13:451–456 endometrial glands in the myometrium and subsequently Methodology referred to this finding as Bcystosarcoma adenoids uterinum.^ The modern definition of adenomyosis was This is a retrospective study. provided in 1972 by Bird who stated BAdenomyosis may be defined as the benign invasion of endometrium Study population into the myometrium, producingadiffuselyenlargeduter- us which microscopically exhibits ectopic non-neoplastic, The study population constituted of women with age between endometrial glands and stroma surrounded by the hyper- 25 and 50 years, who were diagnosed with adenomyosis (fo- trophic and hyperplastic myometrium^ [3, 4]. cal adenomyosis) and accepted treatment in Jinan Central In the past, the diagnosis of adenomyosis was made Hospital (Shandong, China) from January 2008 to April 2011. solely based on histological analysis; an accurate deter- Ultrasound was used as the main imaging method for mination of its incidence or prevalence has therefore not diagnosis of adenomyosis. Patients were allocated into been carried out [5]. Though the general incidence of three groups of treatment based only on their preference adenomyosis has not been accurately determined, in hys- and consent on the treatment method. A first group con- terectomy specimens, the incidence of adenomyosis re- stituted of women who underwent laparoscopic ported in the literature varies, ranging from 5 to 70 % cytoreductive surgery, and accept postoperative treatment [6–11]. Adenomyosis is typically found in women be- of gestrinone (group A, average age 35.90 ± 7.4 and tween the ages of 35 and 50. However, newer reports motherhood times, 0–5 times); a second group of women using MRI criteria for diagnosis suggest that the disease who only received laparoscopic cytoreductive surgery may cause dysmenorrhea and chronic pelvic pain in ad- (group B, average age 36.50 ± 7.93 and motherhood olescents and women of younger reproductive age than times, 1–7times);andthelastgroup,womenwhoonly previously appreciated [12, 13]. received oral gestrinone (group, average age 38.73 ± 6.62 A causal relation between adenomyosis and infertility and motherhood times, 0–6 times). Dysmenorrhea, men- has been repeatedly suggested [14], but definitive dem- strual volume, menstrual period, trouble of menstrual cy- onstrations are still lacking. The reported prevalence of cle, uterine size, serum carcinoembryonic antigen adenomyosis in the infertile population varies widely 125(CA125), anemia, pregnancy rate and recurrence, [15]. Before the advent of laparoscopy, only symptomatic and drug side effects will be respectively recorded after adenomyosis was treated, but now, it is becoming in- surgery or drug treatment. creasingly common to diagnose asymptomatic disease, The inclusion criteria are as follows: especially in infertile women [16]. Treatment of adenomyosis use hormonotherapy; sur- – Women who were diagnosed with adenomyosis. (The gery and hysterectomy may be warranted in some cases diagnosis of adenomyosis was done after a comprehen- where fertility is not desired, and all other treatments sive analysis of the clinical symptoms, ultrasound, and have failed, such as androgens, , luteinizing hor- the checking level of serum CA125) mone, and endometrial ablation which have never been – Women who wanted to receive a treatment for infertility described for the treatment of infertile patients. The main caused by adenomyosis, with a demand of pregnancy, conservative options include GnRHa alone or after sur- and her husband semen examination was normal gical treatment. – Women who receive either gestrinone combined with lap- A new treatment of adenomyosis has been introduced; aroscopic cytoreductive surgery (during 3 months after gestrinone, a synthetic with mixed surgery), or only gestinone (one medication for 6 months) and antiprogestogen (partial ) effects and has or laparoscopic cytoreductive surgery as treatment to some mild androgenic activity [17]. Its mechanism of adenomyosis action consists on suppression of the release of pituitary – Women with progressive dysmenorrhea history and (or) gonadotropins. Gestrinone also interacts with the endo- menorrhagia history of infertility; gynecological exami- metrium, inhibiting its growth. The inhibition is the re- nation revealed enlarged uterus, such as pregnant 6– sult of gestrinone’s interaction with the androgen recep- 12 weeks; diagnosis of adenomyosis really pathologically tor; this is also the reason for androgenic side effects. confirmed Gestrinone has been shown to interact with the estrogen receptor, the androgen receptor, and the re- The exclusion criteria are as follows: ceptor [18]. (1) Hysteroscopy and curettage cervical or endometri- This study will aim to find out the clinical efficacy and al malignant lesions; (2) medical or other chronic dis- safety of laparoscopic cytoreductive surgery combined with eases (including other causes of anemia, such as hered- gestrinone on the treatment of adenomyosis. itary anemia, blood system diseases, etc.); (3) extensive Gynecol Surg (2016) 13:451–456 453 pelvic endometriosis; (4) the liver, kidney, endocrine or Statistical methods metabolic disorders, malnutrition, and other diseases; (5) history of primary dysmenorrhea All data were analyzed using SPSS 17.00 statistical software; measurement data are analyzed by one factor analysis of var- Procedures and methods of drug administration iance (ANOVA) for comparison between the three groups. Categorical data will be analyzed by chi-square test and Concerning the group A, a week after the start of oral Fisher probability method; α = 0.05 level, with a 95 % confi- gestrinone (Beijing Zizhu Pharmaceutical Co., Ltd., each cap- dence interval. sule containing gestrinone 2.5 mg), taken two times a week during 3 months, once a month during the treatment, review of liver and kidney function was performed. And for group C, Result oral gestrinone (2.5 mg), two times a week during 6 months (for the first time, the drug was taken on the first day of men- – Table 1 shows that the comparison of menstrual flow struation, and taking for the second time 3 days after and so within the three groups of patients, before treatment, the week after). was not statistically significant (F = 0.039, p = 0.962), but it was statistically significant (p < 0.05) after 6, 12, Surgical procedure and 24 months of treatment. After 6 and 12 months within group A and group B, it was not statically significant The type of the surgical treatment and operation steps (p =0.448;p = 0.432). After treatment, it was statistically used for adenomyosis is laparoscopy cytoreductive sur- significant (p < 0.05), for group B compared with group gery which includes the following steps: (1) relieve pelvic C. After 24 months of treatment, the comparison of group adhesions, recover normal pelvic anatomy; (2) recognition A, B, and C pairwise differences were statistically signif- of the lesion’s location and borders by inspection and icant (p <0.05). palpation; (3) longitudinal incision of the uterine wall – Table 2 shows that the comparison in the three groups of along the adenomyoma; (4) grasp adenomyotic tissues patients, concerning the menstrual period, was not statis- and excise them from normal myometrium, leaving a tically significant (p > 0.05). It means there is not a statis- myometrial thickness of 1 cm from the serosa above and tical difference in the three groups concerning the men- endometrium below; (5) carefully remove all non- strual cycle before and after treatment. microscopic lesions, after that, the uterine cavity was su- – Figure 1 (comparison of pregnancy rate in the three tured and closed; (6) closure of myometrium is performed groups of patients after treatment) shows that the number in no less than two layers and closure of the serosa in one of patients with pregnancy requirements, in the three layer with interrupted sutures; (7) use of an anti-adhesion groups, was respectively 14 cases (A), 12 cases (B), and membrane separation to prevent peritoneal adhesions. 13 cases (C). Within 24 months of treatment, the percent- age of pregnancy in the group was 57.14 % (8 cases) in Other indicators of treatment group A, 41.67 % (5 cases) in group B, and 15.38 % (2 cases) in group C. Pregnancy rate after treatment in group After respectively 6, 12, and 24 months of treatment, the fol- A was higher than in group B; the difference was not lowing indicators were recorded: statistically significant (p = 0.695). The difference be- tween group A and group C was statistically significant – Menstrual changes include menstrual flow, menstrual cy- (p = 0.046); the other group was not statistically signifi- cle phase, and the number of days; the amount of men- cant (p >0.05). strual bleeding was calculated using Statistical Methods – Figure 2 (recurrence rate in the patients after treatment) illustration score (PBAC), a menstrual flow >80 ml for demonstrates that 12 months after treatment, the recur- menorrhagia [19, 20]. rence rate was respectively 3.7 % (1/27) in group A, – Uterine volume: Using ultrasound as the main imaging 12 % (3/25) in group B, and 40 % (12/30) in group C. method, uterine volume of patients was examined and And 24 months after treatment, the recurrence rate was measured; it is calculated according to the oval uterine respectively 22.2 % (6/27) in group A, 40 % (10/25) in volume formula = (a × b × C × 0.523) cm3 (where a, b, C, group B, and 66.7 % (20/30) in group C; The difference are respectively, are the three-dimensional diameter, line, in the three groups was statistically significant (p <0.05). and radius of the uterus) [21]. – After 2 years of treatment, record of pregnancy rate to see Comparison between groups A and B after 12 month of the efficiency of treatment. treatment was not significant (χ corrected 2 = 0.361, – Recurrence: relapse or aggravate existing symptoms. p = 0.548). And the comparison in the three groups (A, B, 454 Gynecol Surg (2016) 13:451–456

Table 1 Changes in menstrual flow (ml, x ± s) before and after Groups A B C treatment in the three groups (A, B, and C) Before treatment 101.07 ± 23.21 100.36 ± 24.42 99.50 ± 16.56 6 months after treatment 39.07 ± 12.06 42.32 ± 9.87 64.10 ± 20.72 12 months after treatment 45.67 ± 14.74 49.52 ± 12.39 78.37 ± 22.78 24 months after treatment 44.37 ± 10.81 72.68 ± 22.16 83.93 ± 14.35

After 24 months of treatment, the comparison of group A, B, and C pairwise differences were statistically significant (p < 0.05) and C) was statistically significant (χ2 = 10.634, p = 0.001; laparoscopy cytoreductive main to retain the integrity of the χ2 =5.390,p = 0.020). And after 24 months of treatment, the uterus. difference was not significant between group A and group B Drug therapy of infertility associated with adenomyosis is (χ2 = 1.926, p = 0.165), but the difference was statistically generally done with hypoestrogenic agents including hormon- significant between group A and group C (χ2 = 11.315, al therapy with gonadotropin-realizing hormone (Gn- p = 0.001) and between group B and group C (χ2 = 3.911, RHa). Many case reports in the literature of successful preg- p =0.048). nancy rate and delivery have resulted from this therapy [24, 28, 29]. However, its effect is often transient and is used main- ly along with an operative therapy. Once the treatment with Discussion Gn-RHa has been stopped, recurrence of adenomyosis occurs [30]. In this study, gestrinone was used as the hormonal ther- The main method of treatment of adenomyosis includes , apy as referred to a study done in 1987 Thomas et al. who has surgery, and interventional therapy. Surgical treatment con- shown a beneficial impact of gestrinone in the treatment of sists of radical surgery and conservative surgery; the radical asymptomatic endometriosis [31]. surgery is total hysterectomy for older patients, with no fertil- Simple surgery or drug therapy alone has its limitations; its ity requirements after failure of conservative treatment. To therapeutic effect is still not satisfactory. A lot of study has date, conservative surgical intervention hardly plays a role in shown the efficacy of combining cytoreductive surgery and the management of infertile patients with adenomyosis. Gn-RHa in the treatment of infertility caused by adenomyosis: Cytoreductive surgery becomes the most commonly used Ben SH et al. demonstrated that the combination of careful method in this situation (performed via laparotomy or laparos- conservative surgery and Gn-Rh agonist therapy might pro- copy). A review of English literature shows a successful preg- vide some benefits in the patients with unexplained infertility nancy rate after cytoreductive surgery of infertile women with and presume severe adenomyosis [32]. And Al jama F.E adenomyosis [22–25]. However, reduction surgery for shows also in his study in which he compared two groups of adenomyosis has not been standardized. Fujishita et al. pro- women—a first group constituted of patients who were treated posed a modified H incision technique with an average sur- with Gn-RhA alone and a second group constituted of women gery time of 117 min and a blood loss of 373 ml. Symptom who received combined conservative cytoreductive surgery control was maintained for 2 years in five of six women with Gn-RHa therapy—that combined conservative surgery (83 %), and postoperative normal pregnancy rate was 50 % and Gn-RHa may provide effective symptoms relief, better [26]. Wood reported a detailed laparoscopic conservative ap- reductive performance in infertile patients with uterine proach for adenomyosis, with 63 % of patients symptom-free adenomyosis, and longer period of pregnancy prospects after at 2 years after surgery and a 56 % pregnancy rate [27]. These treatment than patients who received Gn-RHa alone [33]. studies show a tolerable but not quite satisfactory treatment However, another study done by Wang et al. compared the outcome of cytoreductive surgery used in the treatment of efficacy of surgical-medical (GnRH-a) treatment and surgery adenomyosis. In this study, conservative surgery consists on alone in the treatment of uterine symptomatic adenomyoma.

Table 2 Comparison table of menstrual cycle phase in the three Groups Cases Before 6 months 12 months 24 months groups of patients before and after treatment after treatment after treatment after treatment treatment (day, x ± s) Menstrual cycle of group A 27 28.8 ± 3.9 27.7 ± 3.4 29.1 ± 3.9 28.4 ± 3.9 Menstrual cycle of group B 25 27.5 ± 3.3 28.4 ± 3.9 29.0 ± 3.9 28.8 ± 3.7 Menstrual cycle of group C 30 28.9 ± 3.4 29.1 ± 3.9 28.9 ± 3.4 29.0 ± 3.7

Comparison in the three groups of patients, concerning the menstrual period, was not statistically significant (p >0.05) Gynecol Surg (2016) 13:451–456 455

Percentage of pregnancy Findings from this study confirm that the pregnancy rate is higher when using laparoscopic cytoreductive surgery com- 18 to 24 months bined with gestrinone than gestrinone only in the treatment of C infertility caused by adenomyosis. Also, recurrence rate is less B 12 to 18 months in group A, which constituted of women who receive A gestrinone after laparoscopic cytoreductive surgery than in 6 to 12 months the two other groups. This is similar to a study done by Zhonget al. who found that it is better to combine video 0102030405060 hysteroscopy-assisted gestrinone capsules for treatment of Fig 1 Comparison of pregnancy rate in the three groups of patients after adenomyosis, because of their higher significant clinical effect treatment. Pregnancy rate after treatment in group A was higher than in and low relapse rate. But it is important to notice that in this the group B; the difference was not statistically significant (p =0.695) study, the rate of relapse was proportional to the time of treat- ment: When the time of treatment is longer, the rate of relapse They found that surgical-medical treatment provided more is also high. definitely effective symptom control than surgery alone dur- ing 2-year follow-up period. As to reproductive outcomes, Limitations there was no statistically significant difference in either clini- cal pregnancy rate or successful delivery rate, which is differ- This study has some limitations. ent with our findings [34]. It might be because on one hand, The study was limited first by its sampling methodology. we use gestrinone instead of Gn RH-a; on the other hand, all The sampling method is a convenient sampling method. So our patients had infertility problems caused by adenomyosis. the results of this study, drawn from a non-random sample, In our study, it still needs to verify whether gestrinone treat- cannot avoid a bias; the division in the different groups was ment, used in the management of adenomyoma women with done on patient preferences (convenient sample). Another infertility, increased the preterm labor rate or not. limitation is about the retrospective character of the study. In 1997, Anibal et al. performed a prospective study with a Data were collected in a Bbackward way^ so the results have longitudinal follow-up of 4-year duration (minimum) for each to be interpreted carefully. Further research is needed and an patient. Twenty-five cases of endometriosis were treated with accurate classification system is necessary when discussing gestrinone (as a drug of choice or associated with other local adenomyosis. surgical treatment) during 6 months. The total or partial re- sponse to pain was induced with treatment in 19 of the 20 cases (95 %) of abdominal pain as the clinical symptom, and post-treatment pregnancies were induced in 3 of the 9 cases of Conclusions infertility (33.3 %). Gestrinone is presented as a drug with an efficacy comparable to other pharmacological agents currently In conclusion, this study found the following: available in the medical treatment of endometriosis [35]. So 1. we conducted this study to compare laparoscopic The effectiveness of laparoscopic cytoreductive surgery, cytoreductive surgery plus gestrinone with surgery alone or regardless of gestrinone treatment, in the management of drug therapy alone efficacy. women with symptomatic uterine adenomyosis. However, surgical-medical treatment provided more ef- 80 fective symptom control compared with surgery alone. 70 Surgical-curative effect was better than medication alone. 2. 60 Surgical-medical treatment can increase pregnancy rate in the patients with fertility requirements. 50 3. Short-term have fewer side effects; along 40 12 months a er with the extension of the time, the side effects of medica- 30 24 months a er tion increased. 20 10 Authors’ contributions Protocol/project development by W. Z. Tao and G. M. Mutangala. Data collection or management by W. Z. Ying, 0 W. X. Hai, F. Z. Hui, and W. Xiao Yan. Data analysis by W. Z. Ying and group A Group B group C A. K. Kasangye. Manuscript writing/editing by L. Y. Ping, Z. Y. Chun, Fig. 2 Recurrence rate in the patients after treatment. Twelve months and G. M. Mutangala. Translation from Chinese to English by G. M. after treatment, the recurrence rate was high in group C and 24 months Mutangala and A. K. Kasangye. after treatment; the recurrence rate was also high in group C; the difference in the three groups was statistically significant (p <0.05) Compliance with ethical standards 456 Gynecol Surg (2016) 13:451–456

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