{"paper_id":"200cfb19-03e6-409d-8624-a81341e949ab","body_text":"Endometriosis is defined as endometrial glands and stroma that occur outside of the uterine\ncavity. Evidence suggests that peritoneal microenvironment is altered by immune cells,\nextracellular matrix metalloproteinase and pro-inflammatory cytokines, creating the\nconditions for abnormal endometrial cell proliferation and survival ( 1 ,  2 ). Infertility is\nthe most important complaints in patients with endometrioma (ovarian endometriotic cyst).\nEndometriomas reduces the number of follicles and oocytes quality ( 3 - 5 ).  In\nvitro  fertilization (IVF) is considered as an effective method for treatment of\ninfertility in patients with endometrioma ( 6 ). In the presence of endometrial cyst lower\nembryo quality, lower implantation rate and higher pregnancy complications were seen\ncompared to the absence of endometrial cyst during IVF cycles ( 7 ). There are different\ntreatment options for women with ovarian endometriotic cysts before IVF, including surgical\ntreatment, medical treatment, and a combination of surgical and medical treatments and\nexpectant management among infertile women ( 8 - 12 )\nThe gonadotropin releasing hormone-agonist (GnRHagonist) is one of the medical options. Since the\nendometrioma is an estrogen-dependent disorder, GnRH\nagonist can produce a hypo-estrogenic environment by\nsuppression of the hypothalamus and improve pregnancy\nrates at IVF ( 12 ,  13 ).\nThe purpose of the present prospective study was to\ninvestigate the ovarian response and pregnancy outcomes\nafter laparoscopic cystectomy plus GnRH- agonist versus\nGnRH- agonist alone among infertile women suffering\nfrom endometrioma.\n\nObtaining the formal approvals from the Ethics\nCommittee of Tehran University of Medical Sciences,\nTehran, Iran (90-02-30-14261-40996) this prospective clinical trial study was conducted in the Shariati Hospital\nof Tehran University of Medical Sciences, Tehran, Iran.\nAlso, this study was restarted at the Iranian Registry of\nClinical Trials (IRCT201106116689N2). All participants\nsigned an informed consent before entering the study.\nAll women less than 40 years old with endometriosis\nand asymptomatic (without pain, torsion or rupture)\nendometriomal cyst (2 to 6 cm diameter) who were\ncandidate to intracytoplasmic sperm injection (ICSI) were\ninvited to this study. Who suffered of endometriomal cyst\nsmaller than 2 cm or larger than 6 cm and who have history\nof surgery for endometrioma or other ovarian cysts were\nexcluded. Also, women that their husbands suffered of\nazoospermia were omitted of this study.\nIn this prospective study, all infertile women who met\nthe inclusion criteria were randomly assigned to two\ngroups by a nurse from 2015 to 2019. This study was\nblinded for the nurse who randomized the participants and\nthe statistician who analyzed the results. Randomization\nwas done with an allocation sequence generated by block\nrandomization by the trial statistician. All participants\nsigned an informed consent before entering the study.\nDuring this period, ninety-one of the women were\nassessed. Twelve of them did not have inclusion criteria. Six\npatients did not agree to be in a group and were excluded\nfrom the study. Finally, 73 participants were divided into 2\nalmost equal groups given a block size of 40.\nEndometriosis was diagnosed in all patients previously\nby laparoscopy and sonography. Ultrasound diagnosis\nof endometrioma was present of round shaped\nhomogeneous hypoechoic tissue. All transvaginal\nultrasound examinations underwent by an expert\nphysician gynecologist. The non-surgical diagnosis of\nendometrioma with transvaginal ultrasound is a valid\nmethod ( 14 ,  15 ). The combined group (laparoscopic\ncystectomy plus GnRH-agonist) underwent the\nlaparoscopic cystectomy by a single experienced surgeon\nand the surgical technique consisted of resection of the\nendometriotic cyst wall. Then patients received 3 doses\nof Diphereline 3.75 mg (Beaufouipfen, France, IM) in 3\nconsecutive months. The GnRH-a alone group received\nthree doses of Diphereline 3.75 mg (Beaufouipfen,\nFrance, IM) during three consecutive months.\nOvarian stimulation was conducted in two groups\nby Gonal F (Serono, Switzerland, 300-450 IU daily),\nten days after the third injection of Diphereline. Seven\ndays later, Gonal F was replaced by human menopausal\ngonadotropin (hMG, Ferring, Germany, 300-450 IU daily)\nuntil the observation of 18 mm follicles in the transvaginal\nultrasound. With observation of at least two 18-mm\nfollicles, human Chorionic Gonadotropin (hCG, Ferring\nCo, Germany, 10000 IU, IM) was injected and trans-vaginal\noocyte retrieval was performed under general anesthesia\nafter 36 hours. Fertilization was performed through ICSI.\nFor blinding the study, counting the number of retrieved\noocytes; determining the quality of oocytes and embryos and\nfertilization were performed by an embryologist who was\nnot aware of the treatment groups. Transcervical embryo\ntransfer was carried-out after three days. The chemical\npregnancy was diagnosed based on the rising concentration\nof serum hCG levels. This measurement was performed\nin the Shariati hospital Laboratory service based on the\nstandard serology method 14 days after embryo transfer.\nThe clinical pregnancy was detected by observation of the\npregnancy sac in transvaginal ultrasound, two weeks later\nof the hCG level rising.\nFinally, the number of retrieved oocytes and embryos;\nquality of retrieved oocytes and embryos; fertilization\nrate, chemical and clinical pregnancy rates, abortion and\nlive birth rates were compared between two groups by a\nstatistician.\nThis study was blinded for the statistician who analyzed\nthe results. All data were analyzed by SPSS software\n(Version 25, Armonk, New York, USA). The groups were\ninitially compared on baseline variables with chi-square\ntests and independent samples t tests. Also, multiple\nlogistic regression was used to examine the variables.\nData were expressed as the mean ± standard deviation\n(mean ± SD) or percent (number). Statistical significance\nwas defined as P<0.05.\n\nThere were 79 patients who were divided into two\ngroups randomly based on Bernoulli distribution and all\nof them underwent ovulation induction ( Fig .1 ).\nStudy flowchart.\nThe demographic characteristics of two groups are\nshown in  Table 1 .\nDemographic characteristic of our study groups\nCrude and adjusted odds ratio for the association between the variables were reported as a confidence interval (CI) of 95%. Values are presented as mean ± SD. P<0.05 is defined for\nstatistical significance. BMI; Body mass index, FSH; Follicle-stimulating hormone, LH; Luteinizing Hormone, GnRH; Gonadotropin-releasing hormone, and AMH; Anti mullerian hormone.\nThe IVF outcomes of two groups are shown in  Table 2 .\nAfter laparoscopic cystectomy and receiving 3 doses\nof Diphereline, there were 16 chemical pregnancies in 33\npatients. All of chemical pregnancies lead to live births\n(n=12, 3 twins /12); there were three abortions and one\nectopic pregnancy (EP). Among 40 patients who received\n3 doses of Diphereline before ART, there were 12 chemical\npregnancies who lead to nine live births (3 twins); there\nwere two abortions and one EP. Pregnancy outcomes of\ntwo groups are compared in  Table 3 .\nBased on Table 1 Cyst size and CA125 level in combined\ngroup were higher; BMI and baseline FSH were lower\nthan another group. Therefore, two groups were adjusted\nfor BMI, Cyst diameter, FSH and CA125 levels in Table 4.\nThere was no statistically significant difference between\ntwo groups regarding the live birth rate ( Table 4 ).\nComparison of IVF outcomes in our study groups\nCrude and adjusted odds ratio for the association between the variables were reported as a\nconfidence interval (CI) of 95%. Values are presented as mean ± SD. P<0.05 is\ndefined for statistical significance. IVF;  In vitro  fertilization and\nGnRH; Gonadotropin-releasing hormone.\nPregnancy outcomes in our study groups\nValues are presented as n (%). P<0.05 is defined for statistical significance.\nCrude and adjusted OR for the association between type of intervention and live birth rate\nBMI; Body mass index, FSH; Follicle-stimulating hormone, OR; Odds ratio, CI; Confidence interval, GnRH; Gonadotropin-releasing hormone, and *; Adjusted for: BMI, Cyst diameter,\nFSH, CA125.\nNo adverse effect or harm related to the drug and/or\noperation was observed in these groups.\n\nEndometriosis is a chronic inflammatory estrogendependent disease in which the endometrial glands and\nstroma grow outside the uterus. Infertility is the most\nimportant complaints in the patients with endometrioma\n(ovarian endometriotic cyst). IVF is considered as an\neffective method for treatment of infertility in patients\nwith endometriomas ( 6 ).\nRemoval of endometriomas before IVF in infertile\nwomen is controversial. Since oocyte retrieval is difficult\nin the presence of endometrioma and because of the risk\nof follicular fluid contamination many clinicians consider\ncystectomy prior to the ART. Furthermore, bloody\ncomponent of endometriomas is an excellent cultural\nenvironment and following the puncture of the cyst during\nthe oocytes retrieving procedure, there are some risks for\ninfection and pelvic abscess formation ( 16 ).\nOn the other hand, because of pseudo cyst nature\nof endometrioma without any capsule, it invades the\novarian cortex and its resection will be accompanied with\nthe resection of natural ovarian tissues. It was shown\nthat primordial follicles were found in more than 50%\nof resected endometrial cysts ( 17 ). Additionally, the\nischemic injury resulted from the electro-coagulation\nand the related local inflammation will injure ovaries.\nThrough the evaluation of the numbers of antral follicles\nand oocytes and anti-Mullerian hormones, many studies\nhave reported ovarian reserve reduction after cystectomy\n( 18 - 20 ).\nBased on the European Society of Human Reproduction\nand Embryology (ESHRE) guideline ( 12 ), GnRH agonists\nfor a period of 3-6 months prior to treatment with ART\nis one of the medical options used for improvement of\nclinical pregnancy rates in the infertile women with\nendometriosis. Sallam et al. ( 21 ) study showed that 3-6\nmonths of treatment with GnRH agonists before the start of\nIVF associated with 4 times increase in the pregnancy rate\nof endometriosis patients. The theory for improvement of\npregnancy rates at IVF with GnRH agonist pre-treatment\nis normalization of inflammation. Postoperative medical\ntherapy with GnRH agonist can produce a hypo-estrogenic\nenvironment for treating microscopic foci which were not\nsurgically removed ( 22 ).\nIn our study, although the rates of chemical and\nclinical pregnancy and live birth rate were higher in the\ncombined group than GnRH-agonist alone group but\nthese differences were not statistically significant.\nDecleer et al. ( 23 ) divided patients with mild peritoneal\nendometriosis in the two groups. A group received\nGnRH agonist post-surgical for a 3-month period and the\nother group treated immediately after laparoscopy with\nstimulation for IVF. They detected no differences in the\nnumber of MII oocytes, embryos and pregnancy rate\nbetween their groups.\nIn the Dong et al. ( 24 ) study, 153 women underwent\nlaparoscopic cystectomy then IVF and 68 women with\nan endometriomal cyst directly received IVF procedure.\nThey found no significant difference regarding the\nnumbers of retrieved oocytes, embryos; chemical and\nclinical pregnancy rates and live birth rate, that their\nresults were consistent with our results.\nZhao et al. ( 13 ) concluded that prolonged GnRH-a\nprotocol after ovarian endometrioma cystectomy may be\nan optimal choice in patients with Diminished ovarian\nreserve.\nIn Lee’s study ( 25 ), patients with endometrioma\nwere divided into three groups (surgery, aspiration of\nendometriomas and control) before ICSI, although the\nnumbers of retrieved oocytes, were similar to our study.\nThe clinical pregnancy rate was similar in all groups.\nAlborzi et al. ( 26 ) enrolled patients with endometriosis\nin 3 groups: Letrozole group (2.5 mg/day, Femara,\nNovartis Pharma AG, Basel, Switzerland), GnRH-agonist\ngroup (Amp Diepherelin3.75 mg, Beaufour Ipsen Pharma\nParis, France) and control group. The chemical pregnancy\nrate in stages III and IV of endometriosis in the all groups\nwere similar to our GnRH-agonist alone group.\nYang et al. ( 27 ) reported that GnRH-a for six months\nafter laparoscopic surgery can improve pregnancy rate\nin endometriosis. The pregnancy rate in this group was\nsignificantly higher than laparoscopic surgery group\n(30.77% vs. 9.23%, P=0.002).\nIn the Barra et al. ( 28 ) and Laganà et al. ( 29 ) study, IVF\noutcomes improved in patients with endometriosis who\nreceived Dienogest (progestin) for 3 months.\nIn the present study, the rates of chemical and clinical\npregnancy and live birth were higher in the combined\ngroup than GnRH-agonist alone group but these\ndifferences were not statistically significant.\nOur study had some limitations that should be\nmentioned. The sample size of this study was relatively\nsmall. Therefore, further randomized controlled trials are\nrequired to confirm the results of this study.\n\nThis study suggests that in the infertile women with\nendometriomal cyst Laparoscopic cystectomy followed\nby receiving GnRH-agonist prior to treatment with\nassisted reproductive technologies (ART) improve the\nrates of chemical and clinical pregnancy and live birth.","source_license":"CC0","license_restricted":false}