{"paper_id":"f5765427-506c-4c80-b847-99be6b396918","body_text":"www.ogscience.org 329\nOriginal Article\nObstet Gynecol Sci 2019;62(5):329-334\nhttps://doi.org/10.5468/ogs.2019.62.5.329\npISSN 2287-8572 · eISSN 2287-8580\nIntroduction\nPrimary dysmenorrhea is defined as menstrual pain associ -\nated with ovulatory cycles and resulting from myometrial \ncontraction in the absence of a pelvic disease that may cause \nabdominal pain. Traditionally, the activity of prostaglandin, a \nvasoconstrictor that causes ischemic pain in the uterus, is re\n-\ngarded as the cause of primary dysmenorrhea [1]. Although \nprimary dysmenorrhea is common, it is frequently under-\ndiagnosed and under-treated [2]. Identification of the risk \nfactors of primary dysmenorrhea may be useful for classifying  \nPolycystic ovarian morphology is associated with \nprimary dysmenorrhea in young Korean women\nJee Young Jeong\n1,2\n, Min Kyoung Kim\n4\n, Inha Lee\n1,2\n, Jisun Yun\n1,2\n, Young Bin Won\n1,2\n, Bo Hyon Yun\n1,2\n,  \nSeok Kyo Seo\n1,2\n, SiHyun Cho\n2,3\n, Young Sik Choi\n1,2\n, Byung Seok Lee\n1,2\n1\nDepartment of Obstetrics and Gynecology, Severance Hospital, \n2\nInstitute of Women’s Life Medical Science, \n3\nDepartment of Obstetrics and \nGynecology, Gangnam Severance Hospital, Yonsei University College of Medicine; \n4\nFertility Center of CHA Gangnam Medical Center, CHA University \nSchool of Medicine, Seoul, Korea\nObjective\nThis study was aimed at identifying a correlation between polycystic ovarian morphology (PCOM) and the severity of \nprimary dysmenorrhea in young Korean women.\nMethods\nA total of 592 patients who visited a tertiary hospital from March 2008 to March 2015 for dysmenorrhea were \nexamined. After excluding those with secondary causes of menstrual pain (for example, myoma, adenomyosis, \nendometriosis, and pelvic inflammatory disease), 361 women were recruited and retrospectively analyzed. Severe \ndysmenorrhea was defined as a visual analog scale (VAS) score ≥6.\nResults\nThe mean patient age was 23.0±4.0 years, the average menstrual cycle length was 34.4±23.7 days, and the average \npain intensity was VAS 6.7±0.1 at baseline. PCOM was assessed by ultrasound in 54 women (15%). Patients with severe \nmenstrual pain were more likely to have irregular menstrual cycles (P=0.03) and heavy menstrual flow (P=0.01) than \nthose with mild menstrual pain. After adjusting for weight, height, menstrual cycle interval, and menstrual flow in the \nlogistic regression analysis, PCOM (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.05–4.97; P=0.04) and heavy \nmenstrual flow (OR, 1.85; 95% CI, 1.05–3.28; P=0.04) were found to be significant independent factors influencing \npain.\nConclusion\nOur study shows that PCOM may have a correlation with the severity of primary dysmenorrhea. Since PCOM may play \na role in the development of menstrual pain, patients with PCOM should be under active surveillance with resources \nfor prompt pain management readily available. It may also be necessary to further investigate the molecular \nmechanisms of pain development in primary dysmenorrhea.\nKeywords: Dysmenorrhea; Menstruation disturbances; Polycystic ovary syndrome\nReceived: 2018.08.26.   Revised: 2018.11.03.   Accepted: 2018.11.08.\nCorresponding author: Bo Hyon Yun\nDepartment of Obstetrics and Gynecology, Severance Hospital, \nY onsei University College of Medicine, 50 Y onsei-ro, Seodaemun-\ngu, Seoul 03722, Korea\nE-mail: garfieldzz@yuhs.ac\nhttps://orcid.org/0000-0001-5703-797X\nArticles published in Obstet Gynecol Sci are open-access, distributed under the terms of \nthe Creative Commons Attribution Non-Commercial License (http://creativecommons.\norg/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, \nand reproduction in any medium, provided the original work is properly cited.\nCopyright © 2019 Korean Society of Obstetrics and Gynecology \n\nwww.ogscience.org330\nVol. 62, No. 5, 2019\nwomen into groups that need active surveillance or prompt \npain management.\nPolycystic ovarian morphology (PCOM), one of the diagnos-\ntic criteria for polycystic ovary syndrome (PCOS), is defined \nas the presence of >12 antral follicles 2–9 mm in diameter or \nan ovarian volume >10 mL [3]. The inclusion of PCOM in the \ndiagnostic criteria for PCOS is controversial because the same \nmorphology is found in 16–25% of asymptomatic women [4]. \nIn a small study, the prevalence of PCOM was reported to be \n35–50% in healthy adolescent girls who were neither diag\n-\nnosed with nor treated for PCOS 2–4 years after menarche \n[5-7]. The inclusion of PCOM to the PCOS spectrum is a topic \nof debate because ovulatory women with isolated PCOM \nfrequently do not show clinical or biochemical evidence of \nandrogen excess [8]. The clinical significance of PCOM is \nunclear. To date, PCOM is considered a pre-PCOS state, a \nnormal morphological variant in adolescence, and a possible \ncomplication in high responders to controlled ovarian hyper-\nstimulation [9]. \nThe purpose of our study was to identify factors that may \nhave a correlation with the severity of primary dysmenor -\nrhea, and to investigate the relationship between PCOM and \nprimary dysmenorrhea.\nMaterials and methods\n1. Study population\nA comparative study was conducted using a retrospective \nchart review of a total of 592 young, postmenarcheal Korean \nwomen aged <30 years old, who visited Severance Hospital, \nYonsei University College of Medicine, between March 2008 \nand March 2015 with dysmenorrhea as their chief complaint. \nAfter initial evaluation, 231 women were excluded for other \npossible causes of dysmenorrhea (Fig. 1). The initial evalua\n-\ntion included history taking, pelvic examination, and imaging \nstudies with either pelvic sonography (Accuvix V20 Prestige, \nMedison Co., Seoul, Korea) or abdominopelvic computed \ntomography. On their initial visit and using questionnaires, \nthe patients provided information on their menstrual history \nwhich included cycle regularity and duration, quantity of \nmenstruation, pain onset, any predictable patterns such as \npain development timing and duration, any accompanying \nsymptoms such as back pain, vomiting, diarrhea, or inter\n-\nmenstrual bleeding. Patients diagnosed with pelvic masses \nsuch as myoma and adnexal cyst, endometrial pathologies \nlike polyp or submucosal myoma, endometriosis, and adeno-\nmyosis on imaging and patients with suspected symptoms \nof pelvic pathology were excluded from the analysis. Patients \nwho, in the 3 months prior to their hospital visit, had taken \nhormonal agents such as oral contraceptives or progestin \nwere also excluded. Finally, a total of 361 women with pri -\nmary dysmenorrhea were recruited for the study [10]. \n2. Variables and measurements\nBaseline physical examinations included measurements of \nheight (cm), weight (kg), and body mass index (BMI, kg/m\n2\n). \nThe pain intensity of dysmenorrhea was quantified using a \nvisual analog scale (VAS) with scores from 0 to 10. Severe \ndysmenorrhea was defined as a VAS score ≥6. Irregular \nmenstruation was defined in traditional terms as a cycle in\n-\nterval >35 days or <21 days. Menstrual flow was classified as \nscanty, moderate, or heavy and PCOM was defined accord\n-\ning to the Rotterdam criteria [3]. Sonography was performed \naccording to menstrual cycle; in the early follicular phase \nfor patients with regular periods or with a dominant follicle \nor corpus luteum on ultrasound scan, and regardless of the \novulation cycle for patients with irregular periods of over \n \n90 days or amenorrhea. In patients with sonographic evi -\ndence of ovarian cyst, the criteria for PCOM was applied \nusing the 2–9 mm antral follicle count only. Smoking status \nwas regarded as positive for current smokers only. The medi\n-\ncations administered for menstrual pain relief after consulta-\nFig. 1. Flow chart of the participant inclusion in the study.\nTotal 592 postmenarcheal women\n<30 years old\n361 women were included\nExcluded:\nAdnexal cyst 38\nEndometriosis 77\nAdenomyosis 46\nMyoma 34\nCongenital anomaly 5\nEndometrial pathology 22\nHormonal agents use 14\n\nwww.ogscience.org 331\nJee Young Jeong, et al. PCOM and primary dysmenorrhea\ntion were classified as none (no medication use), nonsteroidal \nanti-inflammatory drugs, and combined oral contraceptives, \nand information on the use of pain relief medications of dif -\nferent groups was considered.\n3. Statistical analyses\nData are presented as mean±standard deviation for continu-\nous variables and as numbers and percentages for categori -\ncal variables. The baseline characteristics between the mild \nand severe dysmenorrhea groups were compared using a \n2-sample t-test for continuous variables and the χ\n2\n test for \ncategorical variables. Logistic regression analyses were per -\nformed to identify factors that are associated with severe \nprimary dysmenorrhea. Logistic models were built based on \nthe model’s goodness-of-fit and the multicollinearity of the \nfactors. Previously known factors for primary dysmenorrhea \nwith a P -value <0.1 in the univariate analysis were included \nin the logistic model. Data were analyzed using IBM SPSS ver. \n23.0 (IBM Corp., Armonk, NY, USA). A P -value <0.05 was \nconsidered statistically significant.\nResults\nA total of 361 patients with primary dysmenorrhea were \nincluded in the analyses. Their baseline characteristics \nare shown in Table 1. The mean age of the patients was \n23.0±4.0 years, the mean menstrual cycle duration was \n34.4±23.7 days, and the mean pain intensity measured on the \nVAS scale was 6.7±0.1. The mean BMI was 20.7±3.0 kg/cm\n2\n, \nwhich was within the normal range. Of the 361 patients, \n155 (42.9%) reported having mild dysmenorrhea (VAS ≤5) \nand 206 (57.1%) reported having severe dysmenorrhea (VAS \n≥6). Pelvic ultrasound examination of a total of 54 women \n(15%) showed PCOM. Baseline characteristics such as BMI \nand menstrual cycle duration were similar between women \nwith mild dysmenorrhea and those with severe dysmenor\n-\nrhea (Table 2). However, the proportion of women who had \nirregular menstrual cycles was significantly higher in the \nsevere dysmenorrhea group ( P=0.03). Furthermore, women \nwith severe pain reported heavier menstrual flow than those \nwith mild pain (P =0.02). The proportion of women with \nPCOM was also significantly higher in the severe dysmenor\n-\nrhea group than in the mild dysmenorrhea group (P =0.03). \nA statistically significant difference in medication use for \npain relief was observed between the 2 groups, with a \nhigher frequency of combined oral contraceptive use in the \nsevere dysmenorrhea group than in the mild dysmenorrhea \ngroup (P =0.04). Table 3 shows the adjustment model for \nwomen with severe primary dysmenorrhea. After adjusting \nfor weight, height, menstrual cycle duration, and menstrual \nflow, PCOM showed a significantly increased odds ratio (OR) \nfor severe dysmenorrhea (VAS score ≥6; OR, 2.26; 95% con\n-\nfidence interval [CI], 1.05–4.97; P =0.04). Heavy menstrual \nflow was also associated with severe dysmenorrhea (OR, 1.85; \n95% CI, 1.05–3.28; P=0.04).\nDiscussion\nIn this study, we investigated the factors associated with \nsevere pain in patients with primary dysmenorrhea. Of fore -\nTable 1. Baseline characteristics of patients with primary dysmen-\norrhea\nVariables Values\nAge (yr) 23.0±4.0\nWeight (kg) 54.1±8.4\nHeight (cm) 161.7±5.3\nBody mass index (kg/cm\n2\n) 20.7±3.0\nMenstrual cycle duration (day) 34.4±23.7\nPain intensity (VAS) 6.7±0.1\nMenstrual flow  \nScanty 24 (6.6)\nModerate 232 (64.3)\nHeavy 86 (23.8)\nDysmenorrhea \nMild (VAS ≤5) 155 (42.9)\nSevere (VAS ≥6) 206 (57.1) \nPCOM 54 (15)\nCurrent smoker 9 (3.2)\nPain medication\nNone 125 (34.6)\nNSAID 102 (28.3)\nCOC 134 (37.1) \nData are presented as mean±standard deviation for continuous vari-\nables and as number (%) for categorical variables. \nSD, standard deviation; VAS, visual analog scale; PCOM, polycystic \novarian morphology; NSAID, nonsteroidal anti-inflammatory drug; \nCOC, combined oral contraceptive. \n\nwww.ogscience.org332\nVol. 62, No. 5, 2019\nmost importance was our aim to ascertain the clinical sig -\nnificance of PCOM beyond its potential status as a pre-PCOS \nstate. The results revealed that PCOM and heavy menstrual \nflow may be associated with severe primary dysmenorrhea in \nyoung Korean women.\nOur study, like a previous one, showed that the factors \nassociated with primary dysmenorrhea include a history of \nheavy menstrual flow and irregular menstrual cycles [11]. \nHowever, our study is the first to reveal a strong correlation \nbetween PCOM and primary dysmenorrhea. The clinical \nsignificance of PCOM remains unclear, especially in young \nwomen. Previous studies posited that PCOM is a pre-PCOS \nstate [12] or a prognostic factor in endometrial cancer for \npatients treated with progestin [13]. Another study described \nthe correlation between PCOM and endometriosis [14]; how\n-\never, only a few other similar studies have been conducted.\nIt is thought that the pain of primary dysmenorrhea may \nbe due to increased prostaglandin levels, which causes in -\ncreased myometrial and uterine blood vessel contractions, \nthereby producing a relative ischemic uterine state [15]. The \nTable 2. Comparison of the mild and severe dysmenorrhea groups\nVariables Mild (n=155) Severe (n=206) P-value \nAge (yr) 23.1±4.1 22.9±4.0 0.55\nWeight (kg) 53±7.8 54.9±8.8 0.05\nHeight (cm) 160.8±5.2 162.4±5.3 0.01\nBody mass index (kg/cm\n2\n) 20.5±3.0 20.8±3.0 0.43\nMenstrual cycle duration (day) 33.7±28.7 35.0±18.7 0.61\nIrregular period 42 (27.5) 76 (38.8) 0.03\nMenstrual flow 0.02\nScanty+moderate 121 (81.2) 135 (69.9)\nHeavy 28 (18.8) 58 (30.1)\nPCOM 16 (10.3) 38 (18.4) 0.03\nCurrent smoker 6 (4.8) 3 (2) 0.18\nPain medication 0.04\nNone 61 (39.4) 64 (31.1)\nNSAID 48 (31) 54 (26.2)\nCOC 46 (29.7) 88 (42.7)  \nData are presented as mean±standard deviation for continuous variables and as number (%) for categorical variables. P-values were obtained \nusing analysis of variance and 2-sample t-test for continuous variables, and the chi-square test for categorical variables.\nPCOM, polycystic ovarian morphology; NSAID, nonsteroidal anti-inflammatory drug; COC, combined oral contraceptive.\nTable 3. Adjusted odds ratios of variables for severe primary dysmenorrhea \nVariables Unadjusted OR (95% CI) P-value Adjusted OR (95% CI) P-value \nWeight 1.03 (1.0–1.06) 0.05 1.02 (0.98–1.05) 0.38\nHeight 1.06 (1.01–1.11) 0.01 1.04 (0.99–1.10) 0.11\nMenstrual flow \nScanty+moderate 1 1\nHeavy 1.86 (1.11–3.1) 0.02 1.85 (1.05–3.28) 0.04\nPCOM 1.97 (1.05–3.67) 0.03 2.26 (1.05–4.97) 0.04\nMenstrual cycle duration 1.0 (0.99–1.01) 0.62 1.0 (0.99–1.01) 0.72\nP-values were obtained using simple and multiple logistic regression analyses. The analyses were adjusted for weight (kg), height (cm), men-\nstrual cycle duration (days), menstrual flow (reference: scanty+moderate), and PCOM (reference: no PCOM).\nOR, odds ratio; CI, confidence interval; PCOM, polycystic ovarian morphology.\n\nwww.ogscience.org 333\nJee Young Jeong, et al. PCOM and primary dysmenorrhea\npain of primary dysmenorrhea is also known to be associated \nwith sensitization of pain fibers. Peripheral factors and cen -\ntral factors, such as brain-derived neurotrophic factor, were \nsuggested as key factors in the central sensitization of pain in \nwomen with primary dysmenorrhea [16]. One possible expla\n-\nnation for the correlation between PCOM and primary dys -\nmenorrhea may be uterine endothelial dysfunction. Increased \nserum levels of asymmetric dimethylarginine (ADMA), which \nis established as a strong marker of endothelial dysfunction \nin atherosclerosis, has been reported in patients with primary \ndysmenorrhea [17]. Regarding pain, it has been posited that \narginine metabolism is 1 of the key mechanisms of pain de -\nvelopment in patients with sickle cell disease, a hemoglobin-\nopathy with pain as a disease hallmark. Arginine is thought \nto play a key role in multiple metabolic processes, particularly \nwith its contribution to endothelial dysfunction and vessel \nocclusion in sickle cell disease [18]. The same ADMA study \ngroup later demonstrated a positive correlation between \nserum ADMA and serum anti-Mullerian hormone (AMH) in \nyoung women with primary dysmenorrhea. They suggested \nthat ADMA, like AMH, may be used as an ovarian reserve \nmarker [19]. However, it is unclear how serum ADMA and \nAMH are connected in the larger context of PCOM, except \nthat they share the same bone morphogenetic protein path\n-\nway for signal transduction. The correlation between PCOM \nand serum AMH is well known, even though the patients in \na few of the studies only had PCOM but not PCOS [20]. \nThe relationship between heavy menstruation and pain as \nan inflammatory response caused by increased prostaglandin \nsynthesis is well established. The serum levels of prosta\n-\nglandins, specifically prostaglandin E2 [21] or F2a [22], are \nhigher in women with heavy menstrual bleeding (HMB) as \nshown by data compiled over 30 years. Nonsteroidal anti-\ninflammatory drugs (NSAIDs) help reduce HMB by inhibiting \ncyclo-oxygenase, thereby reducing prostaglandin production \n[21,23]. Increased prostaglandin level is a common finding \nin dysmenorrhea and HMB. The strong correlation between \nheavy menstrual flow and severe dysmenorrhea shown by \nour study may be explained by increased prostaglandin level. \nOur study reports the unique finding that PCOM is strongly \nassociated with the severity of pain in women with primary \ndysmenorrhea; however, its retrospective nature is a limita\n-\ntion. It is possible that pain was caused by undiagnosed \nsecondary causes such as endometriosis since we did not \nroutinely perform diagnostic laparoscopy. Our study is also \nlimited by the fact that primary dysmenorrhea is a clinical \ndiagnosis made on the basis of menstrual symptoms and by \nexcluding pelvic pathologies that may cause pain. \nIn conclusion, PCOM and heavy menstrual flow may posi\n-\ntively correlate with the severity of pain in young women \nwith primary dysmenorrhea. Since PCOM may play a role \nin the development of menstrual pain, patients with PCOM \nshould be under active surveillance with resources for prompt \npain management readily available. It may also be necessary \nto further investigate the molecular mechanisms of pain de -\nvelopment in primary dysmenorrhea.\nConflict of interest \nNo potential conflict of interest relevant to this article was \nreported.\nEthical approval\nThe study was approved by the Institutional Review Board of \nSeverance Hospital, Yonsei University College of Medicine (IRB \nNo. 4-2015-0873) and performed in accordance with the \nprinciples of the Declaration of Helsinki. Written informed \nconsents were obtained.\nReferences\n  1.  Iacovides S, Avidon I, Baker FC. What we know about \nprimary dysmenorrhea today: a critical review. Hum Re\n-\nprod Update 2015;21:762-78.\n  2.  Campbell MA, McGrath PJ. 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