{"paper_id":"22c09fb7-89ed-45cf-9d71-c37008c35118","body_text":"Review began\n 11/10/2022 \nReview ended\n 11/16/2022 \nPublished\n 11/21/2022\n© Copyright \n2022\nGök et al. This is an open access article\ndistributed under the terms of the Creative\nCommons Attribution License CC-BY 4.0.,\nwhich permits unrestricted use, distribution,\nand reproduction in any medium, provided\nthe original author and source are credited.\nEffects of Levonorgestrel-Releasing Intrauterine\nDevice Therapy on Ovarian Reserve in\nMenorrhagia\nSoner Gök \n \n, \nErkan Alataş \n1.\n Obstetrics and Gynecology, Pamukkale University, Denizli, TUR\nCorresponding author: \nSoner Gök, \nsonerrgok@hotmail.com\nAbstract\nObjective\nThis study aimed to investigate the effects of levonorgestrel-releasing intrauterine device (LNG-IUD)\ntreatment on ovarian reserve in women of reproductive age diagnosed with menorrhagia.\nMethods\nThis was a prospective controlled trial involving 50 women with menorrhagia and a control group\ncomprising age-matched 50 healthy women. Women who satisfied the LNG group criteria underwent an\nendometrial pipelle biopsy and LNG-IUD insertion. Ovarian reserve tests were performed prior to and six\nmonths after LNG-IUD insertion in the LNG group cases.\nResults\nFollicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), anti-Müllerian hormone\n(AMH), endometrial thickness (ET), total antral follicle count (AFC), and mean ovarian volume values before\nLNG-IUD insertion did not differ between the LNG and control groups. When the final measurements were\ncompared, FSH, AMH, total AFC, and average ovarian volume increased (p=0.05, 0.046, 0.022, and 0.022,\nrespectively), E2 and ET decreased (p=0.034 and 0.001, respectively) in the LNG group, while LH did not\ndiffer significantly between the groups (p=0.71).\nConclusion\nWe observed that LNG-IUD use effectively improves fertility capacity. In this study, LNG-IUD use in\nreproductive-age women diagnosed with menorrhagia decreased E2 levels, did not change LH levels, and\nincreased FSH, AFC, and AMH levels.\nCategories:\n Obstetrics/Gynecology\nKeywords:\n therapy, ovarian reserve, menorrhagia, levonorgestrel-releasing intrauterine device, anti-müllerian\nhormone\nIntroduction\nMenorrhagia, also called heavy menstrual bleeding, is defined as excessive menstrual bleeding (≥80 mL) that\nimpairs a woman’s physical, social, and emotional quality of life. It may occur alone or in combination with\nother symptoms \n[1]\n. Menorrhagia causes iron deficiency anemia in 60-70% of cases, and some of these\nwomen have to go undergo surgery within five years \n[2]\n. For women of reproductive age, menorrhagia is\namong the most common reasons for visiting a gynecology clinic \n[3]\n. Despite the widespread use of oral\nprogesterone in the treatment of menorrhagia for two decades, patient compliance has been limited due to\nthe reluctance of many women to take oral drugs for prolonged periods as well as their side effects \n[4]\n.\nOne of the most significant discoveries in gynecology in recent years is the levonorgestrel-releasing\nintrauterine device (LNG-IUD). This plastic T-shaped device's vertical stem contains 52 mg of levonorgestrel\nin it, which is released daily for five years at a dose of 20 \nμ\ngr. The daily dose of levonorgestrel causes\ndecidualization of the endometrial stroma, atrophy of the endometrial glands, a surface papillary pattern,\nand a stromal inflammatory infiltrate \n[5]\n. Although it was originally produced as a contraceptive device, it is\nnow widely used as menorrhagia and hormone replacement therapy \n[6,7]\n. However, there is a paucity of\nstudies on the effects of LNG-IUD, which is increasingly used in women of reproductive age due to\nmenorrhagia, on the ovarian reserve of these patients. \nOvarian reserve measures the number and quality of oocytes capable of folliculogenesis and steroidogenesis\nwithin the ovarian tissue \n[8]\n. Anti-Müllerian hormone (AMH) and antral follicle count (AFC), which are\nsubstitutes for the actual ovarian reserve, are the two most frequently used markers of ovarian reserve \n[9,10]\n.\n1\n1\n \n Open Access Original\nArticle\n \nDOI:\n 10.7759/cureus.31721\nHow to cite this article\nGök S, Alataş E (November 21, 2022) Effects of Levonorgestrel-Releasing Intrauterine Device Therapy on Ovarian Reserve in Menorrhagia.\nCureus 14(11): e31721. \nDOI 10.7759/cureus.31721\n\nBased on histological findings, AMH and AFC reflect the size of the primordial follicle pool \n[9]\n and correlate\nwith the natural timing of menopause \n[11,12]\n. Serum levels of follicle-stimulating hormone (FSH) and\nluteinizing hormone (LH), which are gonadotropic hormones that govern the menstrual cycle, also provide\ninformation about ovarian reserve \n[13,14]\n. AFC, together with ovarian volume measurement and Doppler\novarian blood flow indices, are critical measures of ovarian reserve. Ovarian volume is also a good ovarian\nreserve marker \n[15]\n.\nIn this context, the main purpose of our study was to determine whether the LNG-IUD, which is increasingly\nused in the treatment of menorrhagia in women of reproductive age, has an effect on the ovarian reserve of\nthese patients and to compare it with a healthy control group.\nMaterials And Methods\nInstitutional review board approval\nThis case-controlled prospective study was conducted between November 2020 and November 2021 in\naccordance with the principles of the Declaration of Helsinki. All participants provided written and informed\nconsent prior to participating in the study. Ethical approval was obtained from the Pamukkale University\nClinical Research Ethics Committee (13.10.2020: 19).\nStudy participants and design\nA total of 158 Turkish women of reproductive who were consecutively admitted to the department of\ngynecology at the study center were deemed eligible for the study. Among those, eight women with pelvic\npathologies (cervical and/or endometrial polyp, myoma, mass or cyst in the ovary), five women\nwith systemic diseases, three women who had acute infections, six women who regularly used combination\noral contraceptive (COC), three women who used anticoagulants, two women who had endometrial\npremalignant lesions detected on the endometrial pipelle biopsy, 19 women without regular menstrual\ncycles at the six-month follow-up after LNG-IUD insertion, four women who did not attend the follow-up\nexamination after six cycles, and five women who refused to participate were excluded. A total of 50 women\nwho had regular menstrual cycles (occurring in 21-35 days) and who experienced heavy menstrual bleeding\n(menorrhagia) were assigned to the LNG group. A total of 50 women who had regular menstrual cycles\n(occurring in 21-35 days) without menorrhagia or any known medical disease were assigned to the control\ngroup.\nThe participants were instructed to complete a guided self-assessment questionnaire that documented their\ndemographic features and clinical characteristics about menstruation. Height and weight were measured,\nand body mass index (BMI, in kg/m\n2\n) was calculated.\nStudy plan and interventions\nAn endometrial pipelle biopsy was performed in women who presented with menorrhagia. Women with\npremalignant or malignant pathology on the biopsy were excluded from the study, while non-premalignant\nor non-malignant cases were called for control on the third to the fifth day of the cycle. Venous blood\nsamples were obtained after a 12-hour fast on the third to the fifth day of the cycle. Serum FSH, LH, E2, and\nAMH levels, and hemoglobin and hematocrit levels were evaluated in the blood samples. All transvaginal\nUSGs were conducted by the same investigator in all instances on the day of the blood sampling.\nEndometrial thickness (ET), AFC, and volume of both ovaries were assessed using transvaginal USG. For ET,\ndouble-wall measurements were performed at the thickest point in the longitudinal segment. To compute\nthe follicle sizes, the average of the measurements of the diameters in three planes was calculated, and the\nfollicles with a diameter of 2-10 mm were considered antral. Ovarian volumes were determined using the\nformula D1 × D2 × D3 × 0.52 after measuring the diameters in three vertical planes for each ovary. LNG-IUD\nwas inserted into the endometrial cavity on the sixth to 10th day of the cycle in all cases in the LNG group.\nAfter six cycles (approximately six months), serum FSH, LH, E2, and AMH levels, and hemoglobin and\nhematocrit levels were re-evaluated after a 12-hour fast on the third to the fifth day of the menstrual cycle,\nand a transvaginal USG was performed again by the same investigator. ET, AFC, and both ovarian volume\nmeasurements of cases in which an LNG-IUD was detected in the endometrial cavity on transvaginal USG\nwere repeated, and all values were recorded.\nVenous blood samples were taken from healthy volunteer women in the control group on the third to the\nfifth day of the cycle after a 12-hour fast. Serum levels of FSH, LH, E2, and AMH, and hemoglobin and\nhematocrit levels were evaluated. The same investigator performed transvaginal USG in all cases on the day\nthe serum samples were collected. Transvaginal USG was used to determine the ET, AFC, and volume of both\novaries. As in the LNG group, after six cycles (approximately six months), serum FSH, LH, E2, and AMH\nlevels, and hemoglobin and hematocrit levels were re-evaluated after a 12-hour fast on the third to the fifth\nday of the menstrual cycle, and the transvaginal USG was repeated by the same investigator. All\nmeasurements of ET, AFC, and both ovarian volumes were repeated on the transvaginal USG, and all values\nwere recorded. Since the control group consisted of healthy women without menorrhagia, no endometrial\nbiopsy was performed and LNG-IUD was not inserted.\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n2\n of \n8\n\nStatistical analysis\nAll variables were analyzed descriptively. The mean, standard deviation (SD), and median were used to\nexpress descriptive statistics for numerical variables, while number and percentage were used to express\ncategorical variables. SPSS Statistics for Windows version 25.0 (IBM Corp., Armonk, NY) was used to conduct\nthe statistical analyses. The Kolmogorov-Smirnov test was used to determine whether the data were\nnormally distributed. Student’s t-test was used to compare features that were normally distributed in two\nindependent groups, and the Mann-Whitney U test was used to examine features that were not normally\ndistributed in two independent groups. The Friedman test and the corrected Shapiro-Wilk test were used to\ninvestigate characteristics that did not exhibit a normal distribution on repeated occasions. Repeated\nmeasurements were compared between the control and study groups using the two-way analysis of variance\n(ANOVA).\nResults\nThere were no statistically significant intergroup differences in demographic characteristics such as age,\nBMI, parity, or gravidity (p=0.870, 0.343, 0.790, and 0.896, respectively) (Table \n1\n). While there was no\nsignificant intergroup difference in menstrual cycle length (p=0.532), menstrual cycle duration and\nmenstrual bleeding were significantly higher in the LNG group (p<0.001) (Table \n1\n).\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n3\n of \n8\n\nVariables\nControl group (n=50), mean ± SD\nLNG group (n=50), mean ± SD\nP-value\nAge (year)\n35.96 ± 1.7\n36.10 ± 1.8\n0.870\nBody mass index (kg/m\n2\n)\n26.78 ± 2.6\n27.53 ± 2.5\n0.343\nParity\n2.30 ± 0.70\n1.96 ± 0.78\n0.790\nGravida\n2.50 ± 0.83\n2.22 ± 0.89\n0.896\nMenstrual cycle length (days)\n27.88 ± 1.95\n28.12 ± 1.87\n0.532\nMenstrual cycle duration (days)\n5.10 ± 0.91\n6.26 ± 0.94\n<0.001*\nMenstrual bleeding (pads/day)\n5.14 ± 0.90\n8.48 ± 1.1\n<0.001*\nHgb (g/dl)\nFirst level\n12.64 ± 0.84\n11.18 ± 0.96\n<0.001*\nFinal level\n12.44 ± 0.94\n12.83 ± 0.85\n0.035*\nHtc (%)\nFirst level\n37.59 ± 2.70\n33.41 ± 2.98\n<0.001*\nFinal level\n37.13 ± 2.96\n38.30 ± 2.79\n0.042*\nFSH (mIU/ml)\nFirst level\n7.46 ± 1.40\n7.82 ± 1.29\n0.422\nFinal level\n7.64 ± 1.50\n8.34 ± 1.66\n0.05*\nLH (mIU/ml)\nFirst level\n3.70 ± 1.15\n3.98 ± 1.04\n0.234\nFinal level\n3.64 ± 1.19\n3.82 ± 1.22\n0.710\nE2 (ng/L)\nFirst level\n44.96 ± 11.31\n44.52 ± 12.37\n0.150\nFinal level\n46.18 ± 8.89\n41.28 ± 12.42\n0.034*\nAMH (ng/ml)\nFirst level\n3.02 ± 3.25\n3.25 ± 1.60\n0.439\nFinal level\n2.99 ± 3.64\n3.64 ± 1.86\n0.046*\nEndometrial thickness (mm)\nFirst measure\n7.44 ± 1.98\n8.02 ± 2.05\n0.226\nFinal measure\n7.32 ± 1.38\n5.06 ± 1.20\n<0.001*\nTotal AFC\nFirst measure\n8.86 ± 1.64\n9.02 ± 1.64\n0.208\nFinal measure\n8.78 ± 9.54\n9.54 ± 1.83\n0.022*\nAverage ovarian volume (mm\n3\n)\nFirst measure\n5.93 ± 6.20\n6.20 ± 1.28\n0.208\nFinal measure\n6.01 ± 6.56\n6.56 ± 1.29\n0.022*\nTABLE\n 1: Comparison of demographic, reproductive, and sonographic characteristics between\ncontrol and LNG groups\n*Statistically significant at p<0.05\nSD: standard deviation; Hgb: hemoglobin; Htc: hematocrit; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: estradiol; AMH: anti-Müllerian\nhormone; AFC: antral follicle count\nWhile the first levels of hemoglobin and hematocrit were significantly higher in the control group (p<0.001),\nthe final levels were found to be significantly higher in the LNG group (p=0.035 and 0.042, respectively)\n(Table \n1\n). There were no significant intergroup differences in the first measurements of FSH, LH, E2, AMH,\nET, total AFC, or average ovarian volume (p=0.422, 0.234, 0.150, 0.439, 0.226, 0.208, and 0.208, respectively)\n(Table \n1\n). When the final measurements were compared, FSH, AMH, total AFC, and average ovarian volume\nincreased (p=0.05, 0.046, 0.022, and 0.022, respectively) and E2 and ET decreased (p=0.034 and 0.001,\nrespectively) in the LNG group, while LH did not differ significantly between the groups (p=0.71) (Table \n1\n).\nThe Wilcoxon signed-rank test was used to determine the differences between the first and final\nmeasurements (Table \n2\n). There were no statistically significant differences between the first and final\nmeasurements in the control group (p>0.05) (Table \n2\n). When the first and final measurements in the LNG\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n4\n of \n8\n\ngroup were compared, FSH, AMH, total AFC, and average ovarian volume increased (p=0.012, 0.001, 0.002,\nand 0.001, respectively), LH did not change (p=0.408), and E2 and ET decreased (p=0.001 and 0.001,\nrespectively) (Table \n2\n).\nVariables\nFirst value, mean ± SD\nFinal value, mean ± SD\nP-value\nFSH (mIU/ml)\nLNGG\n7.82 ± 1.29\n8.34 ± 1.66\n0.012*\nCG\n7.46 ± 1.40\n7.64 ± 1.51\n0.353\nLH (mIU/ml)\nLNGG\n3.98 ± 1.04\n3.82 ± 1.22\n0.408\nCG\n3.70 ± 1.15\n3.64 ± 1.19\n0.787\nE2 (ng/L)\nLNGG\n44.52 ± 12.37\n41.28 ± 12.42\n<0.001*\nCG\n44.96 ± 11.31\n46.18 ± 11.79\n0.146\nAMH (ng/ml)\nLNGG\n3.25 ± 1.60\n3.64 ± 1.86\n<0.001*\nCG\n3.02 ± 1.61\n2.99 ± 1.67\n0.409\nEndometrial thickness (mm)\nLNGG\n8.02 ± 2.05\n5.06 ± 1.20\n<0.001*\nCG\n7.44 ± 1.98\n7.32 ± 1.38\n0.532\nTotal AFC\nLNGG\n9.02 ± 1.64\n9.54 ± 1.83\n0.002*\nCG\n8.86 ± 1.64\n8.78 ± 1.69\n0.511\nAverage ovarian volume\nLNGG\n6.20 ± 1.28\n6.56 ± 1.29\n<0.001*\nCG\n5.93 ± 1.12\n6.01 ± 1.28\n0.232\nTABLE\n 2: Comparison between the first and final values of FSH, LH, E2, AMH, and sonographic\ncharacteristics\n*Statistically significant at p<0.05\nSD: standard deviation; LNGG: levonorgestrel group; CG: control group; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: estradiol; AMH:\nanti-Müllerian hormone; AFC: antral follicle count\nDiscussion\nMenorrhagia is seen in a significant proportion of gynecology patients and affects their physical, social, and\nemotional well-being. In recent years, LNG-IUD, which has been used in the treatment of menorrhagia, has\nbecome an alternative to hysterectomy because of its effectiveness in women with excessive menstrual\nbleeding \n[7]\n. Progestins are substances that act in a variety of ways on progesterone receptors, including\nanovulation, a relatively hypoestrogenic state, decreased FSH and LH secretion, and amenorrhea that\nprevents menorrhagia. Moreover, they have antiestrogenic effects, causing endometrial\npseudodecidualization, inhibiting inflammatory response, provoking apoptosis of endometriotic cells,\nreducing oxidative stress, inhibiting angiogenesis, and suppressing the expression of matrix\nmetalloproteinases \n[16,17]\n. LNG-IUD can lead to reduced endometrial cell proliferation and increased\napoptosis, which also causes endometrial glandular atrophy and decidual transformation of the stroma. A\n70-90% decrease in menstrual blood loss is seen after the first year of use. Indeed, studies have shown that\nLNG-IUD is an effective treatment option for heavy menstrual bleeding \n[18,19]\n. LNG-IUD provides an\nopportunity for patients with menorrhagia to preserve their reproductive function and eliminate their\nsurgical risks and costs \n[20]\n. We also used LNG-IUD as the menorrhagia treatment method in our study, and\nwe found a significant increase in hemoglobin and hematocrit parameters in the sixth month of LNG-IUD\ntreatment.\nOur study investigated the effects of the LNG-IUD on the ovarian reserve of women with menorrhagia of\nreproductive age. To that end, we evaluated FSH, LH, E2, AMH, ET, total AFC, and average ovarian volume\nvalues prior to and six months after LNG-IUD insertion. While many studies have examined the effect of\nLNG-IUD on uterine bleeding in the literature, very few have investigated its effects on ovarian reserve.\nStudies on the effects of LNG-IUD on ovarian function generally compare contraceptive methods \n[21,22]\n.\nMenorrhagia is generally a leading reason for women of reproductive age to consult a gynecologist. The\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n5\n of \n8\n\ndemographic characteristics of the patients in the LNG group were as follows - mean age: 36.1 years; BMI:\n27.5 kg/m\n2\n; and parity: 1.96. There was no statistically significant intergroup difference in demographic\ncharacteristics. This result shows that the groups had similar demographic features, and the comparative\nanalyses were consistent.\nAMH is a dimeric glycoprotein that is secreted from the granulosa cells surrounding the preantral and antral\nfollicles \n[23]\n. In addition to its functional role in the ovary, AMH affects the number of preantral follicles\nthat make up the oocyte pool, making serum AMH level a marker of ovarian reserve \n[24]\n. According to some\nauthors, gonadotropins, particularly FSH, prevent the production of serum AMH. On the other hand, the\nstimulating effect of FSH on AMH expression in normal and polycystic ovaries has been described \n[25]\n. This\ncontroversial point could be reconciled by recent findings that E2 inhibits AMH expression mediated via\nestrogen receptor ß \n[26]\n. In small antral follicles, FSH could directly stimulate AMH, but by increasing E2\nproduction in larger follicles, FSH may inhibit AMH expression through the negative feedback of E2 \n[26]\n. A\nstudy by Landersoe et al. \n[21]\n that compared AMH and AFC among contraceptive users noted approximately\n20% higher levels of AMH and AFC among LNG-IUS users than among combination oral contraceptive (COC)\nusers, but there was no significant difference between COC users and progestin-only pill or contraceptive\nvaginal ring users. They also noted that in fully adjusted models, AMH levels were 17.1% lower among\nwomen using LNG-IUS.\nHariton et al. \n[22]\n compared AMH among contraceptive users and women not on contraceptives and found\nthat AMH levels were 7% lower in women with hormonal IUD, 15% lower in those taking the progestin-only\npill, 22% lower in vaginal ring users, 23% lower in implant users, and 24% lower in those taking COC. They\nalso noted that the AMH level in women using copper IUDs was not significantly different from that in\nwomen not using contraceptives. In the current study, we found a decrease in E2, an increase in FSH and\nAMH, and no change in LH at six months after versus prior to LNG-IUD insertion in the setting of\nmenorrhagia. We obtained the same results in the comparison of six-month values between cases and\ncontrols. Our results contrast with those of the above studies among contraceptive users. We hypothesized\nthat this may be due to the suppression of E2 production by low-dose progestins secreted from the LNG-IUD,\nwhich may have caused a temporary increase in FSH secretion at the beginning, resulting in an increase in\nAMH secretion in the early period.\nAFC, an ultrasonographic ovarian reserve evaluation method, is the ovarian reserve test with the highest\npredictive value for predicting ovarian response with or without AMH \n[27]\n. Therefore, here we evaluated the\nAFC and mean ovarian volumes in all cases. According to the results of our study, there was a significant\nincrease in AFC and mean ovarian volume six months after vs. prior to LNG-IUD insertion.\nThe potent ethinylestradiol component of COC and the contraceptive vaginal ring, in conjunction with a\nhigh progestin dose, significantly suppresses the hypothalamus-pituitary to produce the contraceptive\neffects. This leads to decreased secretion of FSH and blocking of the LH surge, which results in the inhibition\nof E2 production, follicular growth, and ovulation \n[28]\n. LNG-IUD usually causes amenorrhoea by inhibiting\nendometrial growth and causing an atrophic endometrium \n[5,29]\n. Ovulation inhibition by LNG-IUD use\nappears partial and dose-dependent \n[29]\n. In addition, amenorrhoea may occur despite ovulation because of\nan atrophic endometrium \n[29]\n. This leads to thinning of the functional layer of the endometrium. The\nthinning of the ET observed in our investigation was similar to the results of previous studies \n[30]\n.\nThe following study limitations were identified: (1) this was a single-center study, (2) a group with irregular\nmenstrual cycles after LNG-IUD insertion was not included, (3) cases with leiomyoma, endometrioma, and\npolycystic ovary syndrome (PCOS) were not evaluated (only primary menorrhagia was evaluated), and (4)\ncases were evaluated after only six months.\nConclusions\nWe observed that LNG-IUD use effectively improves fertility capacity. In this study, LNG-IUD use in\nreproductive-age women diagnosed with menorrhagia decreased E2 levels, did not change LH levels, and\nincreased FSH, AFC, and AMH levels. We believe that these effects on ovarian reserve may be the systemic\nreflection of the effects of short-term intrauterine progestin administration on the endometrium, and/or the\nelimination of the stress caused by anemia due to increased hemoglobin and hematocrit parameters. Based\non the treatment outcomes reported here, women with menorrhagia of reproductive age should be able to\nmake a well-informed decision about the effect of treatment on fertility. Further studies are required to\nconfirm our findings.\nAdditional Information\nDisclosures\nHuman subjects:\n Consent was obtained or waived by all participants in this study. Pamukkale University\nClinical Research Ethics Committee issued approval 13.10.2020: 19. \nAnimal subjects:\n All authors have\nconfirmed that this study did not involve animal subjects or tissue. \nConflicts of interest:\n In compliance\nwith the ICMJE uniform disclosure form, all authors declare the following: \nPayment/services info:\n All\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n6\n of \n8\n\nauthors have declared that no financial support was received from any organization for the submitted work.\nFinancial relationships:\n All authors have declared that they have no financial relationships at present or\nwithin the previous three years with any organizations that might have an interest in the submitted work.\nOther relationships:\n All authors have declared that there are no other relationships or activities that could\nappear to have influenced the submitted work.\nReferences\n1\n. \nMatthews ML: \nAbnormal uterine bleeding in reproductive-aged women\n. 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Cochrane Database Syst Rev. 2020, 9:CD012658. \n10.1002/14651858.CD012658.pub2\n2022 Gök et al. Cureus 14(11): e31721. DOI 10.7759/cureus.31721\n8\n of \n8","source_license":"CC0","license_restricted":false}