{"paper_id":"9525ab78-9088-484e-b3e2-170762f0a98f","body_text":"81\nYonago Acta medica 2013;56:81–84 Review Article:  Special Contribution\nDysmenorrhea and Endometriosis in Young Women\nTasuku Harada\nDivision of Reproductive-Perinatal Medicine and Gynecologic Oncology, Department of Surgery, School of Medicine, Tottori University \nFaculty of Medicine, Yonago 683-8504, Japan\nABSTRACT\nDysmenorrhea is defined as symptoms associated with \nmenstruation, such as abdominal pain, cramping and \nlumbago, that interfere with daily activity. Primary dys\n-\nmenorrhea refers to menstrual pain without underlying \npathology, whereas secondary dysmenorrhea is menstru\n-\nal pain associated with underlying pathology. Endome-\ntriosis, one of the main causes of secondary dysmenor-\nrhea, induces dysmenorrhea, pelvic pain and infertility, \nresulting in marked reduction of quality of life during \nreproductive age. This review article is a comprehensive \noverview of dysmenorrhea and endometriosis in young \nwomen. \n \nKey words    adolescent; infertility; laparoscopic sur -\ngery; oral contraceptive; prostaglandin \n \n \nDysmenorrhea is defined as pathological symptoms asso\n-\nciated with menstruation, marked by abdominal cramp-\ning and pain during the menstrual period that interfere \nwith daily activity. Associated general symptoms, such \nas nausea, vomiting, lumbago, diarrhea, and headache, \nare also common. Dysmennorhea is categorized into two \ntypes, primary and secondary. Primary dysmenorrhea \nrefers to menstrual pain without underlying pathology, \nwhereas secondary dysmenorrhea refers to painful men\n-\nstruation associated with underlying pathology (Table 1). \n One study, conducted with the support of the Japan \nMinistry of Health and Welfare, revealed that menstrual \npain requiring pain medication occurs in 33% of men\n-\nstruating Japanese women. In 6% of women, pain medi-\ncations were ineffective and bedrest was needed. The \nstudy results suggest that 1/3 of women who menstruate \nmay require medical intervention.\n1 Ikeda et al., reporting \nthe results of a questionnaire survey of menstrual pain \namong high school students, revealed that 90.8% of stu\n-\ndents experienced menstrual pain and that pain affected \nthe daily activities of 51.8%. The incidence of menstrual \npain increased in 3rd grade students (17–18 years old) \ncompared with 1st and 2nd grade.\n2\n The most common cause of secondary dysmenorrhea \nis endometriosis. Endometriosis is an estrogen-dependent \ninflammatory disease characterized by ectopic growth of \nendometrial stroma and glands affecting 5% to 15% of \nCorresponding author: Tasuku Harada MD, PhD\ntasuku@med.tottori-u.ac.jp\nReceived 2013  September 20\nAccepted 2013  September 20  \nAbbreviations: GnRH, gonadotropin-releasing hormone; LEP, \nlow dose estrogen-progestin; MRI, magnetic resonance imaging; \nNSAID, nonsteroidal anti-inflammatory drug; OC, oral contracep\n-\ntive; PG, prostaglandin\nwomen of reproductive age.3 The main clinical features \nare dysmennorhea, chronic pelvic pain and infertility. \nEndometriosis is a chronic and recurrent disease that ad-\nversely affects quality of life in reproductive age women. \n Sampson’s implantation theory, which describes \nintraperitoneal menstrual reflux leading to spillage of \nendometrial cells into the peritoneal cavity and the result\n-\ning development of endometrial lesions, is currently the \nprevailing explanation of the pathophysiology of endo\n-\nmetriosis. Increased exposure to menstruation in terms of \nshort menstrual cycles, prolonged flow and low parity are \npossible risk factors.\n4 Therefore, retrograde menstruation \nobserved in 90% of menstruating women is considered a \nkey factor in the pathogenesis of endometriosis.\n Incidence of endometriosis is believed to be increas\n-\ning because of changes in women’s lifestyle, such as the \ntendency to marry later and have fewer children. This \nlife style change increases the number of times a woman \nmenstruates and affects the incidence of endometriosis.\n \nMECHANISM OF (PRIMARY) DYSMENORRHEA\nThe etiology of primary dysmenorrhea includes an ex-\ncess or imbalance in the amount of prostaglandins (PGs) \nsecretion from the endometrium during menstruation. \nAssociated general symptoms, such as nausea, vomiting, \nlumbago, diarrhea and headache are the sequel of influx \nof PGs and its derivatives into systemic circulation. Syn\n-\nthesis of arachidonic acids and the pathway of cyclooxy-\ngenase are activated by a decline of progesterone con -\ncentrations in the late secretory phase. PG levels in the \nendometrium of the late secretory phase increase 3 times \nhigher than those of the proliferative phase. A further \nincrease in PG levels is observed during the menstrual \nphase. PGE2 and PGF2 alpha concentrations are higher \nin the menstrual fluid of women with dysmenorrhea than \nin women with painless periods.\n5 Among PGs, PGF2a is \nconsidered the most potent causal factor of pain.\n\n82\nT. Harada\n By preventing ovulation, oral contraceptives (OCs) \nsuppress the progesterone-driven proliferation of the \nsecretory endometrium, resulting in a decrease in pros\n-\ntaglandin synthesis and volume of menstrual fluid. 6 \nConsistent with Sampson’s theory, reduced menstrual \nflow after taking OCs contributes to reduced retrograde \nmenstruation, which then impede the development of \nendometriosis. \n \nMECHANISM OF PAIN DUE TO ENDOMETRIOSIS \nConcentrations of PGs are higher in the menstrual blood \nof women with endometriosis.\n7 Bulletti et al. found that \nfrequency, amplitude and basal pressure tone of uterine \ncontractions in women with endometriosis were higher \nthan in those without.\n8 Thus, the severe dysmenorrhea \nof endometriosis patients may be the result of abnormal \nuterine contractions. \n Endometriotic lesions and adhesions may also cause \nthe deep pelvic pain associated with endometriosis. Ac\n-\ntion mechanisms of pain with endometriosis are outlined \nin Table 2. The pain of patients with endometriosis is \nthus due to both uterine contraction and endometriotic le\n-\nsions. \n \nENDOMETRIOSIS IN YOUNG WOMEN\nRetrospective studies report a diagnosis of endometriosis \nin 25% to 38% of adolescents with chronic pelvic pain.\n9 \nNonsteroidal anti-inflammatory drugs (NSAIDs) and oral \nOCs are prescribed for adolescent patients with chronic \npelvic pain. If these agents are refractory, endometriosis \nhas been diagnosed in 50% to 70% of these patients.\n10 \nThese results suggest that endometriosis should be part \nof the differential diagnosis of chronic pelvic or lower ab\n-\ndominal pain in premenarcheal and perimenarcheal girls. \n While endometriosis usually occurs in women after \nmenarche, a series of 5 premenarcheal girls (ages 8.5 \nto 13 years) were reported to have endometriosis.\n11 The \ngirls, who all had chronic pelvic pain and a negative \ngastrointestinal workup, were found to have peritoneal \nendometriotic lesions as classified by American Society \nof Reproductive Medicine. Laparoscopic resection or \ncautery of all visible lesions resulted in marked improve\n-\nment of their pelvic pain.  \n Although Sampson’s theory of retrograde menstrua\n-\ntion and implantation is believed to explain most cases \nof endometriosis, this theory clearly cannot explain \nthe cases of endometriosis in premenacheal girls who \nneither menstruate nor have retrograde reflux. A recent \nreview by Brosens et al. suggested that endometriosis \nmay develop by mechanisms other than retrograde men\n-\nstruation and implantation, such as coelomic metaplasia, \nembryonic mullerian rests, or even the persistence of \nthe forms of embryonic endometriosis recently de\n-\nscribed.12, 13 They also proposed that the phenomenon of \nuterine bleeding in neonates and concomitant retrograde \nmenstruation in the neonate might be a source of stem \ncells that develop into premenarcheal endometriosis.\n12 \nTherefore, it is suggested that premenarcheal and pos -\nsibly adolescent endometriosis develop by activation of \nresting stem cells shed at the time of neonatal retrograde \nuterine bleeding. \n \nSYMPTOMS OF ENDOMETRIOSIS IN YOUNG WOM-\nEN\nCommon symptoms in women with endometriosis in -\nclude dysmenorrhea, lower abdominal pain and dyspa-\nreunia. Almost half of women with endometriosis also \nreport their inability to become pregnant. The pain of \nendometriosis in adults is often cyclic while the present\n-\ning pelvic pain of adolescents can be either acyclic or \ncyclic. Bowel and bladder symptoms commonly occur in \nadolescents (Table 3). The Endometriosis Association’s \n1998 registry of 4,000 adult women with endometriosis \nreported that 2/3 of those responding to the survey ex\n-\nperienced their first pelvic symptoms before 20 years of \nage, 21% before 15, and 17% between 15 to 19.\n14 \n  \nTable 2. Mechanism of pain associated with endome-\ntriosis\nA  Pain due to endometriotic lesions\n 1 Peritoneal lesions induce inflammatory reactions and secrete \nprostaglandins, cytokines, histamine and kinin that cause \npain.\n 2 Deep infiltrating endometriosis destroys tissues and nerves.\n 3 Ruptured chocolate cysts may irritate peritoneum.\nB  Scar and fibrosis, secondary lesions\n 1 Scar, fibrosis, traction, and adhesion may reduce mobility of \norgans. Pain may occur during movement or ovulation.\n 2 Adhesion of bowel may cause defecation pain or dyschezia.\n 3 Retroverted uterus due to adhesion, severe adhesion of ovaries \nto Douglas pouch, and induration of sacral ligament may cause \ndyschezia.\nTable 1. Differential diagnosis of primary and second\n-\nary dysmenorrhea\n  Primary  Secondary \n dysmenorrhea  dysmenorrhea \n \n Within 3 yr More than 5 yr Onset after menarche after menarche\nAge 15–25 yr old Over 30 yr old\nAging Gradually improve Become worse\nMarriage Improve No change\nPostpartum Improve No change\nFindings of internal  Endometriosis, \n   examination Normal fibroma, etc.\nTime Menstruation  Menstruation or \n \n  other time if worse\nDuration 4–48 h 1–5 d\n\n83\nDysmenorrhea/endometriosis in the young\nDIAGNOSIS OF ENDOMETRIOSIS IN YOUNG WOM-\nEN\nVisual inspection by laparoscopy or laparotomy is the \ngold standard for diagnosing endometriosis. However, \nlaparoscopy cannot always be performed in daily practice \nin Japan. Therefore, the term, “clinical endometriosis”, is \nused when only patient history, clinical examination and \nultrasound are available to support the diagnosis. Board \ncertified gynecologists can correctly diagnose endome\n-\ntriosis in 80% of the patients without laparoscopy. \n Differential diagnosis is challenging in adolescents \nbecause there can be coexisting diseases, including \nthose of the gastrointestinal system and urinary tract, \npelvic inflammatory disease, ovarian cysts, obstructive \nanomalies and pregnancy. The presenting symptoms can \nalso vary, ranging from only dysmenorrhea, localized \nabdominal pain, dyspareunia, non-cyclic pain or combi\n-\nnations of these symptoms.   \n On examination, ovarian tumor and anomalies of \nthe genital tract must be ruled out. We perform transab\n-\ndominal ultrasound examination while the patient has \na full bladder and rule out abnormalities in the uterus \nand ovaries. We then inspect the genital area and vagina \nand do a rectal examination if necessary. Magnetic reso\n-\nnance imaging (MRI) may also help to reveal an ovarian \ntumor or anomalies. \nLAPAROSCOPIC FINDINGS IN ENDOMETRIOSIS IN \nYOUNG WOMEN\nEndometriotic lesions consist of a variety of types, in -\ncluding peritoneal implants, ovarian chocolate cysts, \nadhesions, and deep infiltrated endometriosis. Ovarian \nendometrioma is a common disease lesion occurring in \n17% to 44% of endometriosis patients.\n15 However, the \nfinding is rare among adolescents and young women. \nOne review over a 15-year period reported no endome\n-\ntriomas among the ovarian masses found in 102 infants, \nchildren and adolescents.\n16 Peritoneal endometriotic \nlesions are categorized into 3 subgroups: red, black and \nwhite. Davis et al. reported that red lesions are the pre\n-\ndominant implant type in adolescent patients. 17 They \nexamined 36 adolescent patients presenting with severe \ndysmenorrhea who were refractory to prior therapy. \nWhen compared with 46 women aged 31 to 46 years, \nsignificantly more red lesions were present in adoles\n-\ncents (Table 4). \n Demco examined endometriotic lesions using pa\n-\ntient-assisted pelvic laparoscopy to determine color and \nsize and mapped these areas for pain.\n18 Of the lesions \nthat provoked a pain response, red, vascular lesions were \nthe most painful. This finding suggests that red lesions, \nmost frequently observed in young patients with endo\n-\nmetriosis, may be the cause of their pain. \n Although, no correlation has been found between \nseverity of pain symptoms and stage of the disease or \nsite of the endometriotic lesions, laparoscopic resection \nor cautery of the lesions improve symptoms in over 80% \nof patients.\n Clear lesions are common in adolescent endome\n-\ntriosis but are often difficult to visualize and evaluate \nlaparoscopically. Peritoneal defects or windows, which \nare also diagnostic of endometriosis, are reportedly very \ncommon in adolescents. Improved visualization and \nidentification can often be obtained by increasing the \nlaparoscopic magnification.\n19 \n \nCLINICAL MANAGEMENT OF ENDOMETRIOSIS IN \nYOUNG WOMEN\nTreatment of endometriosis may be surgical or medi -\ncal. Surgical treatment, especially laparoscopic surgery, \nis the most effective method to control pain. Careful \nhistory and examination is necessary to rule out pelvic \ntumor or inflammatory disease. Young women with dys\n-\nmenorrhea should be treated initially with a combination \nof cyclic OCs and NSAIDs. In Japan, 2 cyclic OCs con\n-\ntaining low dose estrogen-progestin (LEP) are covered \nby national insurance.\n20 Side effects, such as nausea \nand atypical bleeding, usually occur during the first 3 \nmonths of therapy, and patients should be advised about \nthis. If cyclic administration is not effective, the physi\n-\ncian can recommend a continuous regimen of 3 to 4 \nmonths in which the patient takes the medication, disre\n-\ngarding any breakthrough bleeding. After laparoscopic \nsurgery for ovarian cysts, a continuous LEP regimen is \nTable 3. Symptoms of endometriosis in young women\nSymptoms Frequency\nCombination of cyclic and acyclic pain 62.5%\nAcyclic pain 28.1%\nCyclic pain 9.4%\nIntestinal pain 34.3%\nUrinary symptoms 12.5%\nIrregular menstruation 9.4%\nAbnormal discharge 6.3% \n  Data source: Laufer et al., 1997.10 \nTable 4. Red peritoneal lesions in young patients with \nendometriosis\n  Age Patients with \n Number Mean [SD] red lesions\nYoung patients 36 16.6 [1.4] 86%\nLAVH 8 37.4  [3.4] 20%\nLAVH, laparoscopically assisted vaginal hysterectomy. \nData source: Davis et al., 1993.17 \n\n84\nT. Harada\nmore effective for pain and results in fewer recurring le-\nsions after surgery for ovarian chocolate cysts.21 \n If pain persists with medical management, imaging, \nincluding ultrasound and MRI, may be ordered to evalu-\nate endometriosis. Laparoscopy, the gold standard for \ndiagnosis, and laparoscopic excision of the lesions are \nusually effective for patients with severe pain symptoms. \n Gonadotropin-releasing hormone (GnRH) agonist \ntherapy is widely used for adult patients, but it is not rec\n-\nommended as a first choice for young women because \nthe drug causes significant reduction in bone mineral \ndensity. A new progestin, dienogest, has been available \nin Japan since 2008\n22 and can be used for management \nof pain associated with endometriosis in young women. \nDienogest has fewer side effects due to hypoestrogen \nand can be used for more than 1 year in adult patients. \nData are not available for GnRH agonist and dienogest \nin an adolescent population. These agents may be intro\n-\nduced after establishing the diagnosis of endometriosis \nby laparoscopy.\nIn summary, LEP and laparoscopic surgery are treat\n-\nments of choice for young patients with endometriosis. \nEndometriosis is a difficult disease to manage due to its \nchronic and recurrent nature. Long-term management, \nwith special attention to preservation of ovarian function, \nis highly important in treating young women with endo\n-\nmetriosis. \nThe authors declare no conflict of interest.\nREFERENCES\n 1 Taketani Y, Tsutsumi O, Terakawa N, Hoshiai H. (MHLW \nGrants System, Tokyo, Japan). [2000 General report for the \nprevention, diagnosis and treatment of endometriosis in the \naspect of reproductive health] [Internet]. Tokyo: Ministry of \nHealth, Labour and Welfare (Japan); [date unknown] - . [up\n-\ndated 2005 May 9; cited 2013 Jun 30]; [about 2 p.] Report No.: \n200000351A. Japanese. Available from: http://mhlw-grants.\nniph.go.jp.\n 2 Ikeda T, Suzuki Y, Maeda T, Harada T. Analysis of dysmenor-\nrhea-associated factors and relaxation methods in highschool \nstudents. Bosei Eisei. 2011;52:129-38. Japanese with English \nabstract.\n 3 Bulun SE. Endometriosis. N Engl J Med. 2009;360:268-279. \nPMID: 19144942.\n 4 Eskenazi B, Warner ML. Epidemiology of endometriosis. Ob\n-\nstet Gynecol Clin North Am.1997;24:235-58. PMID: 9163765.\n 5 Rees MC. Heavy painful periods. Balliere’s Clin Obstet Gy-\nnacol. 1989;3:341-56. PMID: 2692924.\n 6 Crosignani P, Olive D, Bergvist A, Luciano A. Advances in \nthe management of endometriosis: an update for clinicians. \nHum Reprod Update. 2006;12:179-89. PMID: 16280355.\n 7 Karck U, Reister F, Schäfer W, Zahrandnik HP, Breckwoldt \nM. PGE2 and PGF2 alpha release by human peritoneal mac\n-\nrophages in endometriosis. Prostaglandins. 1996;51:49-60. \nPMID: 8900443.\n 8 Bulletti C, De Ziegler D, Polli V, Del ferro E, Palini S, \nFlamigni C. Characteristics of uterine contractility during \nmenses in women with mild to moderate endometriosis. Fer\n-\ntile Steril. 2002;77:1156-61. PMID: 12057721.\n 9 Kontoravdis A, Hassan E, Hassiakos D, Botsis D, Kontoravdis \nN, Creatsas G. Laparoscopic evaluation and management of \nchronic pelvic pain during adolescence. Clin Exp Obstet Gy\n-\nnecol. 1999;26:76-7. PMID: 10459441.\n10 Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prev-\nalence of endometriosis in adolescent women with chronic \npelvic pain not responding to conventional therapy. J Pediatr \nAdolesc Gynecol. 1997:10:199-202. PMID: 9391902.\n11 Marsh EE, Laufer MD. Endometriosis in premenarcheal girls \nwho do not have an associated obstructive anomaly. Fertile \nSteril. 2005;83:758-60. PMID: 15749511.\n12 Brosens I, Puttemans P, Benagiano G. Endometriosis: a life \ncycle approach? Am J Obstet Gynecol. 2013;209:307-16. \nPMID: 23500453.\n13 Signorile PG, Baldi F, Bussani R, D’ Armiento M, De Falco M, \nBaldi A. Ectopic endometrium in human fetuses is a common \nevent and sustains the theory of mullerianosis in the pathogen\n-\nesis of endometriosis, a disease that predisposes to cancer. J \nExp Clin Cancer Res. 2009;28:49. PMID: 19358700.\n14 Ballweg ML. Big picture of endometriosis helps provide guid-\nance on approach to teens: comparative historical data show \nendo starting younger, is more severe. J Pediatr Adolesc Gy\n-\nnecol. 2003;16:S21-6. PMID: 12742183.\n15 Busacca M, Vignali M. Ovarian endometriosis: from patho-\ngenesis to surgical treatment. Curr Opin Obstet Gynecol. \n2003;15:321-6. PMID: 12858105.\n16 Cass DL, Hawkins E, Brandt ML, Chintagumpala M, Bloss \nRS, Milewicz AL, et al. Surgery for ovarian masses in infants, \nchildren, and adolescents: 102 consecutive patients treated \nin a 15-year period. J Pediatr Surg. 2001:36:693-9. PMID: \n11329568.\n17 Davis GD, Thillet E, Lindemann J. Clinical characteristics of \nadolescent endometriosis. J Adolesc Health. 1993;14:362-8. \nPMID: 8399247.\n18 Demco L. Mapping the source and character of pain due to \nendometriosis by patient-assisted laparoscopy. J Am Assoc \nGynecol Laparosc. 1998;5:241-5. PMID: 9668144.\n19 Laufer MR. Current approaches to optimizing the treatment \nof endometriosis in adolescents. Gynecol Obstete Invest. \n2008;66 (suppl 1):19-27. PMID: 18936548.\n20 Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa \nN. Low-dose oral contaceptive pill for dysmenorrhea as\n-\nsociated with endometriosis: a placebo-controlled, double-\nblind, randomized trial. Fertile Steril. 2008:90:1583-8. PMID: \n18164001.\n21 Seracchioli R, Mabrouk M, Manuzzi L, Vicenzi C, Frascà C, \nElmakky A, et al. Post-operative use of oral contraceptive pills \nfor prevention of anatomical relapse or symptom recurrence \nafter conservative surgery for endometriosis. Hum Reprod. \n2009;24:2729-35. PMID: 19625310.\n22 Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, \nHagino H, et al. Dienogest is as effective as intranasal buse\n-\nrelin acetate for the relief of pain symptoms associated with \nendometriosis: a randomized, double-blind, multicenter, con-\ntrolled trial. Fertile Steril. 2009:91:675-81. PMID: 18653184.","source_license":"CC0","license_restricted":false}