{"paper_id":"18f8b654-471b-418a-9737-00a963585c43","body_text":"DOI: https://doi.org/10.53350/pjmhs221611020 \nORIGINAL ARTICLE \n \n1020   P J M H S  Vol. 16, No.01, JAN  2022 \nA Randomized Control Trial of Combined Surgical and Hormonal Therapy \nof Endometriosis \n \nMADHU BALA1, HUMAIRA TAHIR2, PARAS SOOMRO3, SAFIA MAQSOOD4, NADIA NAWAZ5, PARIGUL BALOCH6 \n1Assistant Professor Gynaecology and Obstetrics, Muhammad Medical and Dental College Ratanabad Mirpurkhas Pakistan \n2Gynaecologist  and Assistant professor Obstetrics/Gynaecology, Social Security Landhi Hospital Karachi Pakistan \n3Women Medical officer Gynaecology and Obstetrics, Sindh Gov ernment CDF Hospital , Bilawal Medical College for Boys Jamshoro \nPakistan \n4Professor Gynaecology and Obstetrics, Ghulam Muhammad Mahar Medical College Sukkur Pakistan \n5Gynaecologist Gynaecology and Obstetrics, Bahria International Hospital Karachi Pakistan \n6Consultant Gynaecology and Obstetrics, Sandeman Provincial Hospital Quetta Pakistan \nCorresponding author: Madhu Bala, Email: dr.madiluck@gmail.com  \n \nABSTRACT \nAim: To evaluate the three therapy strategies including surgical therapy, hormonal therapy, and combined \ntreatment for the management of endometriosis  \nStudy design: A multicentric randomized control trial \nPlace and Duration:  This study was conducted in 6  diff erent hospitals of Pakistan,  Muhammad Medical and \nDental College Ratanabad Mirpurkhas, Social Security Landhi Hospital Karachi, Sindh Government CDF Hospital \n, Bilawal Medical College for Boys Jamshoro, Ghulam Muhammad Mahar Medical College Sukkur,  Bahri a \nInternational Hospital Karachi, Sandeman Provincial Hospital Quetta Pakistan  Pakistan from June 2020 to June \n2021.  \nMethodology: The study included 360 participants with genital endometriosis. The age of the patients ranged \nfrom 18 years to 45 years. Al l the patients did not have any previous surgical intervention. The patients were \nrandomly treated with one of the three treatments. A laparoscopic evaluation was done after three months of \nhormonal and combined therapy. Re-evaluation of surgically treated patients was done after 5 to 6 months. Stage \nof endometriosis, recurrence of symptoms, and the rate of pregnancy were noted in the re-evaluation phase of the \nstudy.  \nResults: The overall cure rate of all types of endometriosis was 56.11% after every regim en of treatment. The \ncure rate after treatment from combined therapy was 60%. Those treated exclusively by hormone therapy showed \na cure rate of 54.17%. A total of 54.17% of patients were cured exclusively by surgical treatment. The rate of \nrecurrence was lowest in the patients given combined therapy. Dyspareunia and dysmenorrhea were significantly \nreduced. The overall rate of pregnancy was 53% to 64%. The rate of pregnancy was not different among all the \ngroups.   \nConclusion: After giving hormonal therapy, surgical treatment, and combined treatment, it has been noticed that \nrecurrence was lowest in the combined medical and surgical treatment group. The rate of pregnancy had also got \nbetter after all the means of treatment. The highest rate of cure was achieved by combined therapy.  \nKeywords: Endometriosis, laparoscopy, hormone therapy, combined treatment, infertility, recurrence \n \nINTRODUCTION \nEndometriosis is thought to be the second most intricate \nbenign genital disease found in women followed by uterine \nmyoma. It can be described as the presence of endometrial \nglands and endometrial stroma at an ectopic location, \noutside the epithelial lining of the cavum uteri. Common \nsymptoms of endometriosis experienced by females \nsuffering from endometriosis are dysmenorrh ea, chronic \npelvic pain, deep dyspareunia, subfertility, chronic fatigue, \nlower back pain, and dysfunctional uterine bleeding. The \npatient can also experience other symptoms such as \nbloating, rectal bleeding, constipation, dyschezia, \nhematuria, and diarrhea [1].  \n About 50% of teenagers and overall 32% of women of \nreproductive age that undergo operative intervention due or \ndysmenorrhea and chronic pelvic pain are diagnosed with \nendometriosis. A total of 9% to 50% of women who are \noperated for endometriosis had presented with infertility. \nHowever, the overall prevalence of endometriosis is \nindefinite due to diversity and non -specificity in its signs \nand symptoms [2]. An average time interval that has been \nnoticed between the onset of symptoms and diagnosis in  \ncase of endometriosis is almost seven years. The average \nage at which this condition is diagnosed is between 20 to \n40 years. In the case of secondary infertility, the frequency \nincreases as the time since the last delivery increases [3]. \nCausal treatment for endometriosis is not available due to a \nlack of data on the pathogenesis of the disease. However, \nthe options which can be used for the treatment of \nendometriosis are analgesia, expectant management, \nsurgical intervention, hormonal therapy, and combine d \ntherapy. The growth of endometriosis is triggered by \nestrogen, hence, several medical therapies can be given \n[4]. \n The primary strategies of the treatment of \nendometriosis that have been administered were \ngestagens and then danazol was used later along w ith an \nanalog of gonadotropin -releasing hormone (GnRH). Now, \nthis therapy has been upgraded by the addition of \nprogesterone. GnRH has several adverse effects such as \nvasomotor symptoms, mood swings, and bone \ndemineralization. They are prevented by estradio l [5]. \nFurther research on the inhibition of the interaction of \nmediators that are involved in the maintenance of \nvascularization, cell proliferation, and inflammatory \n\nM. Bala, H. Tahir, P. Soomro et al \n \nP J M H S  Vol. 16, No.01, JAN  2022   1021 \nprocesses, is under focus. The mediators which are of \ngreat interest in this regard are selective cyclooxygenase-2 \ninhibitors (e.g., rofecoxib and celecoxib) and aromatase \ninhibitors (e.g., exemestan, anastrozole, and letrozole) [6]. \n Endometriosis is capable of disrupting the anatomy of \nthe reproductive organs of a female. Hence, surgical \ntreatment has great significance. In the advanced stages of \nthe disease, organ damage can lead to subfertility, fibrosis, \nadhesions, and extreme pain. These consequences \ndemand surgical intervention. Laparoscopic intervention \ncan prevent an early diagnosis a nd delay the progression \nof the symptoms. Disadvantages and risk factors of \nlaparoscopic intervention are organ damage, post -\noperative complications, and the formation of adhesions \n[7]. The recurrence rate of endometriosis is 20 to 40% after \n5 years of tre atment. Oral contraceptive pills, progesterone \nintrauterine device (IUD), or any other suppressive \nhormonal therapy has shown a reduction in the rate of \nrecurrence and suppression of the pain associated with \nendometriosis [8].  \n The combined surgical and hormonal therapy involves \ndiagnostic laparoscopy that includes removal of \nendometrial foci and a six months endocrine hormonal \ntherapy. The surgery also comprises residue foci, organ \nreconstruction, and adhesiolysis [9]. The objective of the \npresent study w as the determination of the most effective \ntype of endometriosis therapy.  \n \nMETHODOLOGY \nThis was a multicentric randomized controlled trial included \na total of 360 participants who had been diagnosed with \nendometriosis. Permission was taken from the ethical \nreview committee of the institute. The range of age of the \npatients was from 18 years to 45 years. The patien ts were \nrandomly allocated into three groups of treatment. The \npresent study included medical therapy, surgical therapy, \ncombined therapy, and a second -look operation. Written \ninformed consent was taken from all the patients after a \ndescription of the mode of treatment.  \n The groups were allocated with 120 patients in each \ngroup. First of all, the symptoms of the patients were \nanalyzed. The patients were examined through a \npelviscopy. A total of 330 out of 360 patients had come \nback for a second -look laparo scopy. The remaining 30 \npatients did not return for the laparoscopy. Those patients \nwho had undergone surgery for endometriosis and had \nbeen treated for the disease previously by hormonal \ntherapy were not included in the study. The diagnosis of \nendometriosis was made based on laparoscopy and the \nrating was done according to the Endoscopic \nEndometriosis Classification (EEC). This system has been \nintroduced by Liselotte Mettler and Kurt Semm [10]. \n A tissue sample from the ectopic endometrium was \nobtained fro m the patients who had a diagnostic \nhysteroscopy. The samples were also taken during the \nlaparoscopic treatment given for endometriomas. Cryostat \nsections were prepared and hematoxylin -eosin stains were \ngiven. The histopathological evaluation confirmed the  \norigin, proliferation, and cyst wall of endometriosis.  \n The Group 1 (n=120) patients underwent laparoscopy \nfor the diagnosis and hormonal therapy was given with \n3.75mg leuprorelin acetate. The hormone was injected \nsubcutaneously every month for three con secutive months. \nThe drug is a GnRH agonist. Group 2 (n=120) underwent \nlaparoscopy for the treatment of endometriosis. No \nhormonal therapy or any medical therapy was provided to \nthese patients. The surgery comprised of removal of \nadhesions, excision of the  endometriosis foci, and \ncorrection of the normal anatomy of the reproductive \norgans. Those patients who had complained of infertility \nwere checked for tubal patency and they were also given \nchromopertubation on the second -look laparoscopy. The \nGroup 3 (n= 120) patients underwent surgical laparoscopy \nand they were given hormonal therapy after the surgery. \nThe hormonal therapy was the same that was given to the \nparticipants of Group 1 and for the same period of time.  \n The second -look laparoscopy was done in Group 1 \nand Group 3 after 1 to 2 months of the treatment. In Group \n2, the follow -up laparoscopy was performed 5 to 6 months \nfollowed by the surgical treatment. The patients were called \nfor regular follow -up visits fo r 1 year to regularly monitor \nthem for the recurrence of the symptoms and disease. \nThose patients that were trying to conceive, were called for \na follow -up visit for two years. The data were analyzed \nusing IBM SPSS version 26. \n \nRESULT \nThe treatment had imp roved the EEC stage of all three \ngroups. The rate of cure was higher in Group 3 as \ncompared to Group 1 and Group 2. Table 1 shows the \nimprovement in the stage in all three groups. The down -\nstaging of the endometriosis was confirmed through \nlaparoscopy on t he follow-up visit. To evaluate the rate of \nrecurrence, the patients were monitored through regular \nfollow-up visits. Their symptoms were recorded and \nanalyzed for one year. This was done to analyze the effect \nof all three treatments on the rate of recurre nce. The data \nfor all the groups was not significantly different. The results \nare given in Table 2 \n \nTable 1: Improvement of the stage of endometriosis \nVariable  EEC Stage  \nNumber (Percentage) \n0 1 2 3 \nGroup 1 \n(Hormone \ntherapy)  \nN=120 \nBefore \ntherapy \n0 48 (40) 46 \n(38.33) \n26 \n(21.67) \nAfter \ntherapy \n65 \n(54.\n17) \n38 \n(31.67) \n11 \n(9.17) \n6 (5) \nGroup 2 \n(Surgery) \nN=120 \nBefore \ntherapy \n0 60 (50) 38 \n(31.67) \n22 \n(18.33) \nAfter \ntherapy \n65 \n(54.\n17) \n16 \n(13.33) \n28 \n(23.33) \n11 \n(91.7) \nGroup 3 \n(combined \ntherapy) \nN=120 \nBefore \ntherapy \n0 63 \n(52.5) \n29 \n(24.17) \n28 \n(23.33) \nAfter \ntherapy \n72 \n(60) \n22 \n(18.33) \n20 \n(16.67) \n6 (5) \n \n Though recurrence of symptoms was seen in all the \ngroups, it can still be seen that the symptoms had improved \nsignificantly. The greatest efficacy was seen in the \ncombined treatment group. The overall recurrence rate was \nalso lesser in the combined treatme nt group. The third \nmeasure was the rate of pregnancy. The patients that were \n\nA Randomized Control Trial of Combined Surgical and Hormonal Therapy of Endometriosis \n \n1022   P J M H S  Vol. 16, No.01, JAN  2022 \ninterested in conceiving were monitored for 2 years. The \npregnancy rate was 53% to 64% in all the treatment \ngroups. A comparison of the rate of pregnancy is given in \ntable 3. The rate of pregnancy after an exclusive treatment \nwith surgery was 53% and it is comparatively less than \nGroup 1 and Group 3. In the framework of the present \nstudy, it has been observed that the most successful \nregimen of treatment is hormonal therapy combin ed with \nsurgical treatment. The combined treatment tended to have \nan increased cure rate, decreased recurrence of the \nsymptoms, and improved pregnancy rate.  \n \nTable 2: Recurrence of symptoms within one year of the treatment \nVariable Recurrence symptoms n (%) \nDysmeno\nrrhea \nDyspareun\nia \nAbdomi\nnal pain  \np-value before symptoms 0.600 0.060 0.050 \np-value after symptoms 0.050 0.007 0.280 \nGroup 1 \n(Hormone \ntherapy)  \nN=120 \nBefore \ntherapy \n72 (60) 67 (55.83) 58 \n(48.33) \nAfter \ntherapy \n34 \n(28.33) \n26 (21.67) 31 \n(25.83) \nGroup 2 \n(Surgery) \nN=120 \nBefore \ntherapy \n68 \n(56.67) \n60 (50) 50 \n(41.67) \nAfter \ntherapy \n24 (20) 18 (15) 29 \n(24.17) \nGroup 3 \n(combined \ntherapy) \nN=120 \nBefore \ntherapy \n65 \n(54.17) \n61 (50.83) 50 \n(41.67) \nAfter \ntherapy \n19 \n(15.83) \n10 (8.33) 20 \n(16.67) \n \nTable 3: A comparison of the rate of pregnancy in all the treatment \ngroups \nVariables Pregnanci\nes  \nLive \nBirths  \nExtra-\nuterine \npregnanci\nes  \nAbortions \nP-value 0.250 0.284 0.654 0.954 \nGroup 1 \n(Hormone \ntherapy)  \nN=120 \n77 (64%) 66 (55%) 3 (2.5%) 10 \n(8.33%) \nGroup 2 \n(Surgery) \nN=120 \n64 (53%)  54 (45%) 1 (8.33) 11 \n(9.17%) \nGroup 3 \n(combined \ntherapy) \nN=120 \n70 \n(58.5%) \n60 (50%) 2 (1.67%) 11 \n(9.17%) \n \nDISCUSSION \nIn the present study, there were 360 patients with \nendometriosis. The ages of the patients ranged from 18 \nyears to 45 years. They were randomly allocated into three \ngroups according to the mode of the treatment given to \nthem (hormonal, surgical, and combined). The success rate \nof all the groups was evaluated. All three regimens of \ntreatment reached an overall cure rate of 56.11%. \nHowever, the rate of recurrence was lowest in the \ncombined treatment group. This group had an overall high \nefficacy in the treatment of endometriosis [10].  \n The hormonal therapy can be given before surgical \nintervention to decrease the stage and size of the \nendometriosis. This strategy also makes the surgery easier. \nNonetheless, there is no research evidence regarding the \npreoperative administration of hormonal therapy and its \nbeneficial effects in terms of ease in the surgery. Some \ntrials have reported a longer pain relief period and lesser \nrecurrence of the symptoms using hormonal therapy after \nthe surgery [11]. According  to the study of Schweppe et al, \npelviscopic treatment does not treat the active cases of \nendometriosis alone. Some combined treatment is \nnecessary for the active disease [12].  \n A high statistical difference could be seen between \nthe combined treatment gr oup and the exclusive surgical \ntreatment group. According to the study of Regidor et al, a \nsignificant improvement was observed after administration \nof triptorelin, a GnRH analog. Their study showed that 63% \nof patients had no endometriosis after the treat ment. 30% \nof them had stage 1 and only 7% were left with stage 2 of \nthe disease. No Patient was left with stage 3. They had \nused the ASF classification of endometriosis. Buserelin, \nanother GnRH analog, decreased the ASF score from 17.4 \nto 7.2 when the trea tment was combined with the surgical \nintervention [13]. These findings were consistent with the \nfindings of the present study. Although many patients had \nreported relief of symptoms by hormonal therapy, hormonal \ntherapy alone is not sufficient for enhancin g fertility, \nremoval of adhesions, and diminishing pelvic masses. \nHowever, the results of the present study show lesser \nrecurrence in the combined therapy group compared to the \nstudy of Regidor. The pregnancy rate of the present study \nwas also comparable t o their study. As the study of \nSchweppe et al, the present study also shows a lower rate \nof recurrence after administration of combined therapy [12]. \nAccording to the study of Zupi et al, the patients treated \nwith GnRH antagonists showed a significant redu ction in \nsymptoms such as dysmenorrhea, dyspareunia, and pelvic \npain. They compared this treatment with estrogen -\nprogestin pills and found GnHR antagonist a better \nregimen. They also observed a better quality of life in the \npatients using GnRH antagonists as compared to those \nusing estrogen-progestin pills [13, 14].  \n Factors that are essential for the determination of an \noptimal treatment are its symptoms, localization, age of the \npatient, duration, recurrence, and activity. The major \nchallenge of any type  of treatment is the symptoms of the \ndisease. The only combined therapy of hormone and \nsurgical intervention is capable of treating complex stages \nof endometriosis and overcoming the symptoms.  \n \nCONCLUSION \nThe major objective of the treatment of endometrio sis is \novarian downregulation which can be achieved by GnRH \nagonists. A combined treatment including hormonal therapy \nand surgical intervention is used in complex diseases. The \nthree steps of the combined therapy are surgical \nlaparoscopy, hormonal therapy for 3-6 months, and then a \nsecond-look laparoscopy. The efficacy of the combined \ntherapy is better than exclusive surgical or hormonal \ntherapy. The combined therapy has a higher cure rate, \nhigher pregnancy rate, and a lesser recurrence rate.  \nFunding source: None \nConflict of interest: None \nPermission: Permission was taken from the ethical review \ncommittee of  all institutes \n \n\nM. Bala, H. Tahir, P. Soomro et al \n \nP J M H S  Vol. 16, No.01, JAN  2022   1023 \nREFERENCES \n1. Greene AD, Lang SA, Kendziorski JA, Sroga -Rios JM, \nHerzog TJ, Burns KA. Endometriosis: where are we and \nwhere are we going?  Reproduction (Cambridge, England). \n2016 Sep; 152(3): R63. \n2. Sarria-Santamera A, Orazumbekova B, Terzic M, Issanov A, \nChaowen C, Asúnsolo -del-Barco A. Systematic review and \nmeta-analysis of incidence and prevalence of endometriosis. \nHealthcare 2021 Jan (Vol.  9, No. 1, p. 29). Multidisciplinary \nDigital Publishing Institute. \n3. Husain F, Siddiqui ZA, Siddiqui M. 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