{"paper_id":"38999644-f75d-446f-822d-2dfdef4708a7","body_text":"Polycystic ovary syndrome (PCOS) was initially\nreported by Stein and Leventhal ( 1 ) in modern medical\ntexts when they described seven women who suffered\nfrom amenorrhea, hirsutism, and enlarged ovaries that\ncontained several cysts. This syndrome is now considered\nto be a common, heterogeneous, and hereditary disorder\nwhich can affect women of reproductive age. The\nprevalence of PCOS may vary based on the applied\ndiagnostic criteria ( 2 ,  3 ). The highest rate of PCOS has\nbeen reported at 52% among West Asian women having\nmigrated to England ( 4 ); in other references, this figure\nhas been reported as 2-26% ( 3 ). Infertility involves 40%\nof the cases affected by PCOS ( 5 ).\nClomiphene citrate is the first treatment option for\ninducing ovulation in these women ( 6 - 8 ); however,\ndrug resistance has been observed in around 20% of\nsuch cases ( 8 ). Clomiphene resistance is defined as\nthree cycles of ovulation failure or six cycles without\npregnancy ( 9 ). One of the alternatives used among\nclomiphene-resistant women is laparoscopic ovarian\ndrilling (LOD); particularly, in cases which the patient\nhas other surgical indications or when she is unable to attend the frequent visits required for treatment with\ngonadotropins ( 10 ).\nHistorically, the surgical treatment of infertile PCOS\nwomen reported by Stein and Leventhal ( 1 ) in 1935\nwas ovarian wedge resection via laparotomy, and it\nshowed promising results. However, three decades later,\nthis method was abandoned due to the risk of pelvic\nadhesions following surgery and has been replaced by\novulation-inducing medications such as clomiphene and\ngonadotropins ( 11 ). In 1984, the surgical treatment of\ninfertile PCOS women improved remarkably with the\nintroduction of LOD that had an ovulation success rate\nof 92% and pregnancy success rate of 80% ( 12 ). LOD,\nas a less harmful and less-invasive method compared to\novarian wedge resection, uses electrocautery (diathermy)\nor laser beam and has played a significant role in the\ntreatment of infertile PCOS women ( 11 ).\nThe beneficial effects of this method seem to be related\nto the destruction of the androgen generating stroma,\nwhich results in reduced production of androgens in\nthe ovary and its reduced concentration in the blood\ncirculation. Clomiphene citrate-resistant women may\nrespond better to medical therapy after this type of\nsurgery. Sensitivity to exogenic gonadotropins also\nincrease in such cases ( 13 ).\nSeveral studies have evaluated ovarian cauterization.\nIn the initial studies, it was hypothesized that a higher\nenergy level would result in a more efficient procedure.\nSubsequently, lower temperatures with a fixed\nnumber of drilled points, regardless of the ovary’s\nsize or unilateral ovarian cautery have been reported\nwith the intent to reduce a possible risk of ovarian\natrophy and adnexal adhesions. With such fixed doses\nof temperature, the optimal amount of ovulation may\nnot be achieved or the clinical manifestations of the\ndisease may persist in individuals with enlarged ovaries\n( 14 ). Armar et al. ( 15 ) reported the first descriptive\nresearch on ovarian drilling with 4 drills at a dose of\n640 joules per ovary; this method was later widely\naccepted and used in various studies. Many authors\nsubsequently examined and compared the effects and\nconsequences of changes in the number of ovarian\ndrills or the appropriate thermal dose based on the\novarian size during laparoscopic ovarian cauterization\n( 14 - 22 ). However, in some studies, the relationship\nbetween the number of ovarian drills and adnexal\nadhesion was not confirmed ( 23 ). Nevertheless, the\noptimal amount of electrosurgical energy required\nduring LOD to achieve the maximal fertility outcome\nwithout causing any risk to the follicles and ovaries\nhas not been established ( 24 ).\nWe designed this study because of the inadequate\nnumber of studies in this area (particularly in Iran) and\nby taking into consideration the influence of genetic,\nregional and nutritional factors on PCOS. We sought\nto compare the effect of ovarian cauterization between\nthe standard and dose-adjusted (based on the ovarian\nvolume) methods in Iranian women with infertile\nclomiphene-resistant PCOS.\n\nThis randomized clinical trial was conducted in the\nGynaecology Department of Imam Reza Hospital,\nMashhad, Iran from 2016 to 2017. All infertile clomipheneresistant PCOS women who visited the Gynaecology\nDepartment enrolled in this study. The sample size\nof this study was calculated at 30 women according to\nthe following formula and by taking into consideration\ninformation from a previously published study ( 14 ), with\nan alfa error=0.05, beta error=0.8, P1=0.6, and P2=0.9.\nThe achieved power of this study was 37% based on the\nantral follicle count (AFC).\n\nAt study initiation, the study protocol was fully\ndescribed to each patient and they were free to withdraw\nfrom the study at any time. Their data was regarded as\nconfidential. All patients signed a written informed\nconsent to participate in the study. The Ethics Committee\nof Mashhad University of Medical Sciences approved\nthis study (IR.MUMS.fm.REC.1395.335). The study\nwas registered in the Iranian Registry for Clinical Trials\n(IRCT20171210037820N1).\nThe inclusion criteria were: all women aged 18 to 35\nyears, not pregnant despite two years without contraception,\ndiagnosed with PCOS based on the Rotterdam criteria,\nhaving ruled out other reasons of infertility except\nfor ovulation disorder (normal sperm analysis of the\nspouse, normal uterine tubes in hysterosalpingography or\nlaparoscopy), clomiphene-resistant, and provided consent\nto participate in this study.\nExclusion criteria were: withdrawal during the study,\npatients lost to follow-up, presence of any other pathology\nduring laparoscopy (e.g., endometriosis or adhesion)\nsuggestive of other aetiologies for infertility.\nInitially, we recorded the patients’ demographic\ncharacteristics and paraclinical data by means of an\ninterview and the patient’s records. We divided the patients\ninto two groups according to a table of random number\ngenerator with equal sizes of groups: standard method\n(group A) and ovarian cautery based on the ovarian\nvolume or the dose-adjusted method (group B). One\nradiologist performed the transvaginal ultrasonography\n(TVS) for group B patients by using a Honda sonography\ndevice (Honda Electronics, Japan) to measure ovarian\nvolume. This volume was measured on the basis of a\ncubic centimetre and at three perpendiculars.\nA gynaecology laparoscopist performed each\nlaparoscopy via an Olympus laparoscopic machine\n(Olympus Europa SE & Co., Germany) in the\ngynaecology theatre of Imam Reza Hospital with patients\nunder general anaesthesia and in the lithotomy position.\nAbdominal entry was done by the closed technique and via a Veress needle. Only patients who had any history of\nabdominal surgery had an open laparoscopic procedure. A\ntriple puncture laparoscopy was performed with 3 trocars.\nThe abdominal and pelvic environment, and the patency\nof the tubes were examined. Patients with adhesions,\nendometriosis, or any pathology in the pelvic area were\nexcluded from the study.\nNext, the ovarian cautery was performed. The uteroovarian ligament was caught with an Atraumatic\nGrasper (Aesculape Inc., USA) and the ovary was\nseparated from the intestines. Afterwards, the ovarian\ncautery was carried out with a 4-millimetre monopolar\nneedle electrode (with a straight needle) and with a\nVallylab generator that had a voltage of 30 (in both\ngroups) as follows: using the CUT energy, a puncture\nwith the depth of 4 millimetres was initially created\non the ovarian capsule and then the coagulation button\nwas activated. After the cautery of each ovary and\nbefore releasing the utero-ovarian ligament, the ovary\nwas rinsed with cold normal saline serum to prevent\nany adhesion or injury to the adjacent viscera. The\nligament was then released and examined with regards\nto the possibility of mechanical injury.\nIn group B (on the basis of ovarian volume), the\nmeasurement of energy was based on the following model\n( 15 ,  16 ,  18 ,  25 ) that used 640, 450, 600, and 800 joules for\neach ovary (mean: 625 joules) and ovarian volume means\nof 8 and 10 cm 3 \n. The dose of 60 joules was chosen for\neach cubic centimetre of the ovarian mass. The ovarian\nmass was multiplied by 60 joules. In order to achieve\nthe correct time, we multiplied the ovarian volume by\n2 and measured the number and time of each puncture\nas follows: Energy=Power (voltage)×Time (number of\npunctures×time of each puncture) and by taking into\naccount that the generator’s energy for all individuals was\n30 joules.\nIn group A, based on the size of the ovary, we created\neither 4 drills of 5 s or 5 drills of 4 s with a voltage of\n30 in order to achieve an energy of 600 joules per ovary\n(4×5×30=600).\nThe patients were followed for six months from the\nfirst menstrual cycle after the operation. Hormonal\nlevels of anti-Müllerian hormone (AMH), testosterone,\ndehydroepiandrosterone sulphate (DHEAS), and\nprogesterone were obtained on the third day of the first\nmenstrual cycle after the operation and the progesterone\nlevel was measured at the mid-luteal phase of the same\ncycle. All tests were performed in the same laboratory and\nwithout charge.\nTVS was also performed from the sixth day of the first\nmenstrual cycle after the operation, every three days up\nto the 16 th  day or until the observation of a dominant\nfollicle. Ovulation was confirmed by the observation\nof an 18 mm dominant follicle or pregnancy. TVS was\nperformed by the same radiologist as before the LOD. In\nthe event of anovulation, subsequent sonographies were\nnot performed. Cycle regularity and the occurrence of\npregnancy were examined after six months.\nPatients who did not menstruate until a month after\novarian cautery (menstrual cycle over 35 days) were\nadministered 100 mg of intramuscular micronized\nprogesterone to re-establish the menstrual cycle, and the\ninvestigations were performed though most of these cases\nhad no ovulation.\n\nWe performed SPSS software (version 16)\nanalyses of te raw data. If the quantitative variables\nwere normally distributed, we used the t test and\npaired t test; for non-normally distributed data, the\ncorresponding non-parametrical tests were used.\nThe chi-square test was used to examine qualitative\nvariables. Repeated measure ANOVA was performed\nto assess the interaction and overall effect of before/\nafter assessments in the two groups. The significance\nlevel was set at P<0.05.\n\nIn this study, 60 infertile clomiphene-resistant PCOS\nwomen received LOD by two methods: standard and\ndose-adjusted on the basis of the ovarian volume. The\ndemographic, clinical and sonographic characteristics\ndid not differ between the two study groups ( Table 1 ,  Fig.1\nComparison of demographic, clinical, and sonographic data of infertile clomiphene-resistant PCOS women between the two treatment groups\nData represented as mean ± SD or frequency (%) as appropriate. PCOS; Polycystic ovary syndrome, AMH; Anti-Müllerian hormone, AFC; Antral follicle count, and DHEAS; Dehydroepiandrosterone sulphate.\nFlowchart.\nMean numbers of points and cautery time per ovary in the dose-dependent group\nData are presented as mean ± SD.\nTable 3 shows a comparison of the mean AFC and\nserum levels of AMH, testosterone, and DHEAS between\nthe two groups, before and after the operation.\nTable 4 displays the mean changes in the AFC and\nserum levels of AMH, testosterone, and DHEAS before\nand after the operation in each of the studied groups.\nRepeated measure ANOVA revealed that there was no\ninteraction, nor any difference between the two study\ngroups in terms of AFC (P=0.14), AMH (P=0.71),\ntestosterone (P=0.67), and DHEAS (P=0.12).\nThe number of antral follicles before the operation\nwas not significantly different between the two\ngroups (independent t test, P=0.43). The same result\nwas obtained after the operation (P=0.10). Intra-group\ncomparisons showed that the decrease in the number\nof antral follicles was significant in the standard\ntreatment group (paired t test, P=0.02); however, we\ndid not observe any difference in the dose-adjusted\ngroup (P=0.24).\nBefore the intervention, the two groups were matched\nin terms of AMH level (independent t test, P=0.73).\nWe observed the same result after the intervention\n(Mann-Whitney test, P=0.94). In the intra-group\ncomparison, there was a significant decrease in the\nAMH level in the dose-adjusted group (paired t test,\nP=0.04); however, this difference was not observed in\nthe standard treatment group (paired t test, P=0.17).\nBefore the intervention, the testosterone level was\nsimilar in the two groups (independent t test, P=0.91).\nThe same result was obtained after the intervention\n(P=0.46). However, the decrease in testosterone\nlevel in the standard treatment group was meaningful\n(paired t test, P=0.02), but this difference was not\nobserved in the dose-adjusted group (paired t test,\nP=0.14).\nComparison of the hormone profile and AFC between the study groups\nAFC; Antral follicle count, AMH; Anti-Müllerian hormone, and DHEAS; Dehydroepiandrosterone sulphate. Data represented as mean ± SD.\nA comparison of the changes in the hormone profile and AFC before and after the operation in the two groups\nAFC; Antral follicle count, AMH; Anti-Müllerian hormone, and DHEAS; Dehydroepiandrosterone sulphate. Data represented as mean ± SD.\nIn addition, both at study initiation and study termination,\nthe level of DHEAS did not significantly differ between\nthe two studied groups (independent t test, P=0.16 at\nstudy initiation, P=0.12 at study termination). In the intragroup comparisons, the level of DHEAS decrease was\nnot significant in either group (paired t test, P=0.16 in the\nstandard group and P=0.08 in the dose-adjusted group).\nThe status of cycle regularity and the occurrence of\novulation and pregnancy among patients were examined\nfrom the first post-surgical cycle up to six months. The\nobtained results are presented in Table 5.\nThere were regular menstrual cycles reported in 25\n(83.3%) patients in the standard treatment group and 21\n(70%) patients in the dose-adjusted group. Accordingly,\nthere was no statistically significant difference observed\nbetween the two groups (chi-square test, P=0.22).\nOvulation occurred in 26 (86.7%) patients in the\nstandard group and in 21 (70%) patients from the doseadjusted group, which was not statistically significant\n(chi-square test, P=0.11).\nFinally, 11 (36.7%) patients in the standard group and\n8 (26.7%) patients in the dose-adjusted group became\npregnant during 6 months, which indicated no meaningful\ndifference between the two groups (chi-square test, P=0.40).\nIntragroup comparisons on cycle regularity indicated a\nsignificant increase after the operation compared to before\nthe operation in the standard treatment (30 vs. 83.3%) and\ndose-adjusted (26.7 vs. 70%, P<0.001) groups.\nNo case of premature ovarian failure was observed in\nour study population. Cycle regularity was experienced in\n9 (30%) patients in the standard group before the operation\nand in 25 (83.3%) patients after the operation. In the dosedependent group 8 (26.7%) patients had cycle regularity\nbefore the operation and 21 (70%) had cycle regularity\nafter the operation. This was a significant change in both\ngroups (P<0.001).\nA comparison of cycle regularity, ovulation, and pregnancy between the study groups\nData represented as frequency (%).\nWe measured progesterone levels in both groups in\nthe first postoperative menstrual cycle. There was no\nsignificant difference between the two groups (P=0.11).\nHowever, the mean progesterone level in patients with\n(12.44 ± 2.20) and without ovulation (2.93 ± 0.20) was\nsignificantly different (P<0.001). No case of early ovarian\nfailure was observed in the studied subjects.\n\nThe results of our study indicated no difference in the\nnumber of antral follicles after the operation in both\ngroups. However, the decrease in the number of antral\nfollicles was significant in the standard treatment group.\nSuch results corresponded to those reported by Nasr et al.\n( 26 ) who observed a meaningful decrease in the number\nof antral follicles in the ovarian cautery group that had\na fixed dose. However, no decrease in the numbers of\nfollicles and the ovarian volume was observed in the\novarian cautery performed with a Harmonic scalpel\ngroup. The authors believe that the decrease in the\nnumber of antral follicles or the ovarian volume is caused\nby the adjacent thermal destruction created by the use of\nelectrocautery. The creation of one puncture destroys the\novarian tissue as deep as 4 mL; thus if 4 punctures are\nmade in each ovary, 3.2 mL of the ovarian tissue will be\ndestroyed. The Harmonic scalpel minimizes the amount\nof ovarian tissue destruction (0.50 mL), which is about\n1/8 of the destruction done by the electrocautery. Salem\net al. ( 27 ) have considered the decrease in the number\nof follicles as the undesired consequence of LOD. They\nindicated that the amount of AMH and numbers of antral\nfollicles were reliable indicators of the ovarian reserve.\nTheir measurement in clomiphene-resistant PCOS women\nwithout ovulation could be a useful indicator to assess the\ntreatment outcome of LOD. In our study, the dependency\nof the energy used by the cautery to the ovarian volume\nmight have led to the selection of a more appropriate\namount of energy for the ovarian cautery, and therefore\ncaused less damage to the ovarian tissue.\nAMH is one of the new predictive indicators of ovarian\nreserve ( 28 ). This hormone can be used as a substitute\nfor determining the age of ovaries because it is related\nto the number of initial antral follicles, which can reflect\nthe number of residually stored follicles ( 29 ). The\ncurrent study findings indicated a decrease in the AMH,\ntestosterone, and DHEAS levels in both the standard and\ndose-adjusted groups. The decrease in the amount of\nAMH in the dose-adjusted group and the decrease in the\namount of testosterone in the standard treatment group\nwere statistically significant. These findings did not fully\ncorrespond to the results of similar studies. This could\nbe due to the difference in study design, sample size,\nor genetic and regional differences among the studied\npatients. Sunj et al. ( 30 ) had a vast inclusion criteria that\nincluded variables such as weight, acceptable hormonal\nrange, infertility period, etc. in selection of their study\npopulation. This could result in decreased generalizability\nof the achieved results. In their study, only women with\nan infertility period of fewer than 3 years participated\nin the research, while the mean infertility period in our\nstudy was 4.7 years. Therefore, one of the reasons for\nthe heterogeneity of the results might be the difference in\npatient selection due to differences in the inclusion criteria.\nThe results of another study on the changes in AMH,\ntestosterone, and free androgen index by unilateral (doseadjusted) and bilateral (fixed dose) ovarian diathermy\nrevealed a significant decrease in AMH, testosterone,\nand LH levels in both treatment groups. Amer et al. ( 31 ) and Elmashad ( 32 ) also reported significant decreases in\nAMH levels following LOD. However, Farzadi et al. ( 33 )\nreported no such relationship. The meaningful decreases\nin serum levels of FSH, LH, AMH, testosterone, and free\nandrogen index following LOD were also reported in the\nstudy by Salem et al. ( 27 ).\nGiven that the increase in androgens in PCOS is the\nresult of the insulin’s ability to increase the secretion of\nandrogens in ovarian theca cells, the remarkable decrease\nin the level of androgens after drilling among patients who\nreceive cauterization with a volume dependent dose might\nbe justified by the hypothesized destruction of androgen\ngenerating stromal cells. It is believed that the effects of\nLOD on androgen levels are influenced by the amount of\nenergy entrapped by the ovaries and, for this reason, low\ndoses may be less successful ( 13 ).\nBoth groups had a nonsignficant decrease in DHEAS\nlevels. A review of previous literature has revealed\nthat the existing data on DHEAS are ambiguous. LOD\nseems to have a minimal effect on adrenal function, even\namong women affected by hyperinsulinemia, and the\nimprovement of hyperandrogenism is probably secondary\nto the decrease in LH concentration and reduced androgen\nproduction by the ovarian stroma ( 34 ).\nIn our study, the regularity of menstrual cycles\nincreased from 30 to 83.3% in the standard treatment\ngroup. The regularity of menstrual cycles in the doseadjusted group increased from 26.7 to 70%. This was\na significant increase in both groups. The intra-group\nchanges were different compared to the Zakherah et al.\n( 14 ) study. In their study, the cycle’s regularity was higher\nin the dose-adjusted cautery group (87.9%) compared to\nthe fixed-dose cautry group (75.4%); however, similar to\nour study, its effect on the regulation of the cycles was\nsignificant.\nIn a study by Nasr et al. ( 26 ), the occurrence of regular\ncycles after LOD was similar in both groups (92.8%) and\nhigher than our study results. Takeuchi et al. ( 35 ) reported\nthat a regular menstrual pattern was established in 94%\nof the patients and the rate of oligomenorrhea decreased\nto 6%. Felemban et al. ( 16 ) observed that the occurrence\nof regular cycles was 80.4% and oligomenorrhea was\n19.6% in patients after ovarian cautery. However, Salem\net al. ( 27 ) reported that among 37 clomiphene-resistant\nPCOS patients, the cycles regularization was 16.22%\nthree months after the ovarian cautery and 54.06% after\nsix months. Some authors believe that such differences\ncould be due to the different definitions used for the\ndiagnosis of PCOS or the differences in the study\npopulations ( 26 ).\nIn our study, ovulation occurred in 86.7% of patients\nin the standard treatment group and 70% of those in the\ndose-adjusted group; 36.7% of patients in the standard\ntreatment group and 26.7% in the dose-adjusted group\nbecame pregnant. The findings of our study contradicted\nthose reported by Zakherah et al. ( 14 ). In the latter study,\nthe rate of ovulation (81.8 vs. 62.2%) and pregnancy\n(51.7 vs. 36.8%) in the volume-dependent ovarian cautery\ngroup was significantly higher than the fixed thermal\ndose group. The authors concluded that the adjusted\nthermal dose on the basis of ovarian volume (60 joules/\ncm<sup>3</sup>) in LOD resulted in improved fertility consequences\nin comparison to the fixed thermal dose (600 joules per\novary) among clomiphene-resistant PCOS patients.\nThe difference between the results of this study and our\nresearch might be due to the differences in sample size or\nracial and regional characteristics. As with our study, the\nmeasurement of the ovarian volume was not done in the\nstandard treatment group. Possibly, the ovarian volume\nof these patients was more or identical to the patients of\nthe dose-adjusted group; therefore, the same intervention\nmight have been done for the patients in both groups.\nIn a study by Salem et al. ( 27 ), 4 (10.81%) pregnancies\noccurred after three months and 18 (48.65%) after six\nmonths, which were less than our study. They mentioned\nvarious reasons for the low rate of pregnancy occurrence\namong their study patients, which included the existence\nof subtle aetiologies such as hyperprolactinemia, minor\nanatomical problems, and male reasons such as varicocele.\nHe also mentioned inadequate drilling to induce optimal\nchanges in fertility parameters.\nRamezani et al. ( 36 ) examined the cumulative effect\nof pregnancy after cauterization of polycystic ovaries in\nclomiphene-resistant patients at Imam Khomeini Hospital\nin Karaj, Iran, with the following pregnancy rates after\nsurgery: 14.7% (6 months), 36.8% (12 months), 58.8% (18\nmonths), and 76.6% (24 months). However, in this study,\nthe fixed dose method was used for ovarian cauterization in\nall patients. Although the rate of pregnancy after 6 months\n(14.7%) was less than the pregnancy rate achieved in our\nstudy (26.7% for the dose-adjusted group and 36.7% for\nthe standard group), the rate of pregnancy after 12 months\nwas very close to that of our standard treatment group\nafter 6 months.\nOur study had certain limitations; the small sample\nsize which led to a low power, decreased cooperation of\npatients for the ultrasound study and the postoperative lab\ntests, as well as the impossibility of performing TVS in all\nsubjects due to limited facilities in this center.\n\nThe results of this study indicated a significant decrease\nin antral follicles and testosterone in the standard treatment\ngroup in comparison to the dose-adjusted group along with\na significant decrease in AMH level in the dose-adjusted\ngroup. The changes in DHEAS were insignificant in both\ngroups.\nCycle regulation, and the occurrence of ovulation\nand pregnancy showed that both methods were\nefficient; however, there were no statistically significant\ndifferences. In terms of the effects of ovarian cautery on\nthese variables, neither of the two methods was superior.\nIt is possible that the small number of samples examined\nand the differences in the sample selection method or\nthe racial and regional differences might have led to\nthe difference in the results of our study with previous\nresearches. Therefore, conducting similar regional studies\nwith a larger sample sizes are highly recommended.","source_license":"CC-BY-4.0","license_restricted":false}