{"paper_id":"3db22eb6-88a9-432c-9a30-e8886e51f9e3","body_text":"416      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\nABSTRACT\nIntroduction: Abnormal uterine bleeding is one of the most common health dis-\norders in women of reproductive age. In addition, it represents a significant public \nhealth problem. The aim of this paper is to present the modern classification, as \nwell as the basis for diagnosis and treatment of abnormal uterine bleeding.\nMethods: This paper presents data from publications selected from the MED -\nLINE database using a combination of keywords: “menstrual bleeding” , “abnor -\nmal uterine bleeding” , “PALM-COEIN classification” , “leiomyoma” , “endometrial \npolyp” , “adenomyosis” , “gynecological malignancies” , “coagulopathy” , “diagnos-\ntics of abnormal uterine bleeding” , and “treatment of abnormal uterine bleed -\ning”. The collected data from the selected studies were used and presented in \nthis review paper.\nConclusion: In order to achieve a unique classification of abnormal uterine \nbleeding, a classification was adopted under the name/acronym PALM-COEIN. \nThe causes listed in the first part of the acronym (PALM) have a pathological/\nanatomical cause in the reproductive organs that can be diagnosed using imag -\ning techniques and/or histopathological examination. The causes listed in the \nsecond part of the acronym (COEIN) represent a group of dysfunctional disorders \nand they cannot be diagnosed using imaging techniques. \nKey words: bleeding, uterus, menstrual cycle\nSAŽETAK\nUvod: Patološko krvarenje iz materice predstavlja jedan od najčešćih poreme -\nćaja zdravlja kod žena u reproduktivnom periodu. Uz to, predstavlja i značajan \njavno-zdravstveni problem. Cilj ovog rada je da se prikaže savremena podela, kao \ni osnovi dijagnostike i lečenja patoloških krvarenja iz materice.\nMetode: U radu su prikazani podaci iz radova selektovanih pretraživanjem MED -\nLINE baze korišćenjem kombinacije ključnih reči: “menstrual bleeding”, “abnormal \nuterine bleeding”, “PALM-COEIN classification”, “leiomyoma”, “endometrial polyp”, \n“adenomyosis”, “gynecological malignancies”, “coagulopathy”, “diagnostics of ab -\nnormal uterine bleeding”, i “treatment of abnormal uterine bleeding”. Podaci priku-\npljeni iz odabranih radova upotrebljeni su i predstavljeni u ovom radu. \nZaključak: U cilju postizanja jedinstvene klasifikacije poremećaja menstrual -\nnog ciklusa, usvojena je klasifikacija ovih poremećaja koja se naziva akronimom \nPALM-COEIN. Uzroci nabrojani u prvom delu akronima  (PALM) imaju patološ -\nko-anatomski supstrat na nivou genitalnih organa koji se može dijagnostikovati \nprimenom imidžing metoda i/ili histopatološkim pregledom. Uzroci nabrojani u \ndrugom delu akronima ( COEIN) uključuju difsunkcionalne poremećaje i ne mogu \nse dijagnostikovati primenom imidžing metoda. \nKljučne reči: krvarenje, materica, menstrualni ciklus\nPrimljeno • Received: November 18, 2021;   Revidirano • Revised: November 28, 2021;   Prihvaćeno • Accepted: December 06, 2021;   Online first: December 13, 2021.\nDOI: 10.5937/smclk2-34990\nAutor za korespondenciju: \nRadmila Sparić \nKlinika za ginekologiju i akušerstvo, Univerzitetski klinički centar Srbije\nVišegradska 26, 11000 Beograd, Srbija\nElektronska adresa:  radmila@rcub.bg.ac.rs\nCorresponding author: \nRadmila Sparić \nClinic for Gynecology and Obstetrics, University Clinical Center of Serbia\n26 Višegradska Street, 11000 Belgrade, Serbia\nE-mail: radmila@rcub.bg.ac.rs\nRadmila Sparić1,2, Đina Tomašević 3 , Mladen Anđić 1, Svetlana Spremović Rađenović 1,2\n1  Klinika za ginekologiju i akušerstvo, Univerzitetski klinički centar \nSrbije, Beograd, Srbija\n2  Medicinski fakultet, Univerzitet u Beogradu, Beograd, Srbija\n3 Opšta bolnica „Čačak“ , Čačak, Srbija\n1  Clinic for Gynecology and Obstetrics, University Clinical Center of \nSerbia, Belgrade, Serbia\n2  Faculty of Medicine, University of Belgrade, Belgrade, Serbia.\n3  General Hospital Čačak, Čačak, Serbia.\nABNORMAL UTERINE BLEEDING IN WOMEN OF REPRODUCTIVE AGE \nPATOLOŠKO KRVARENJE IZ MATERICE KOD \nŽENA U REPRODUKTIVNOM PERIODU\nre Vie W artic Le pre GLedni rad\n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      417\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nINTRODUCTION\nAbnormal uterine bleeding (AUB) is any bleeding that \ndeviates from the normal cycle/frequency, length, and \nquantity of menstrual bleeding, and represents one of \nthe most frequent health problems in women in the \nreproductive period [1,2]. Also, it is a significant public \nhealth issue. According to data from literature, the prev-\nalence of this type of bleeding ranges from 3 to 30% [3].\nAccurate knowledge of the physiology of menstru-\nal bleeding is a prerequisite for establishing a timely \ndiagnosis and administering appropriate treatment for \nabnormal uterine bleeding. A normal menstrual cycle \nis defined as regular cyclical bleeding, which occurs ev-\nery 28 days, on average, and lasts from 4 to 7 days, with \nan average blood loss of around 35 ml ( Table 1). This \ncycle is the result of a complex interaction between the \nhypothalamus, the anterior pituitary lobe, the ovaries, \nand the endometrium. At each of these levels, hor -\nmones are secreted, which enable or inhibit the release \nof hormones at other levels. Less than 1.0% of women \nhave regular menstrual cycles that are shorter than 21 \ndays or longer than 35 days [4]. \nVariations in the duration and intensity of menstru-\nal bleeding are common at the beginning and at the \nend of the reproductive period - in adolescence and be-\nfore menopause. The frequency of anovulatory cycles \nis the highest before 20 years of age and after 40 years \nof age. During 12 to 18 months after menarche, men-\nstrual cycles are irregular, due to the immaturity of the \nhypothalamic-pituitary-ovarian axis. Several years after \nmenarche, the length of the luteal phase of the cycle \nbecomes relatively constant (13 to 15 days). During the \nperiod of 5 to 7 years following menarche, menstrual \ncycles become regular, and their length and duration \ndo not significantly change during the reproductive \nperiod, although, over the years, the length of the men-\nstrual cycle gradually shortens. During the period of 8 \nto 10 years before menopause, the frequency of ovula-\ntory cycles gradually decreases [1-4].\nIf the function of the hypothalamic-pituitary-ovar -\nian axis is disrupted, and/or if a structural abnormality \nof the uterus occurs (myomas, polyps, adenomyosis, \nmalignancy), or if there is a disorder in blood coagu-\nlation (coagulopathies, iatrogenic causes), the normal \nmenstrual cycle is disrupted and abnormal uterine \nbleeding occurs [5].\nAbnormal uterine bleeding has a significant im-\npact on physical and mental health, as well as on the \nemotional, sexual, and professional aspects of wom-\nen’s lives, as they diminish their quality of life. Also, this \nissue generates significant economic costs. It has been \nestimated that direct medical costs for the treatment \nof abnormal uterine bleeding in the United States of \nUVOD\nPatološko krvarenje iz materice (engl. abnormal uterine \nbleeding -AUB) predstavlja svako krvarenje koje odstu-\npa od normalne cikličnosti/učestalosti, dužine trajanja \ni obima menstrualnog krvarenja, i predstavlja jedan od \nnajčešćih poremećaja zdravlja kod žena u reproduk -\ntivnom periodu [1,2]. Uz to, predstavlja i značajan jav -\nno-zdravstveni problem. Prema podacima iz literature, \nprevalencija ovih krvarenja iznosi 3 do 30% [3].\nPrecizno poznavanje osnova fiziologije menstrual-\nnog ciklusa je uslov za postavljanje pravovremene di-\njagnoze i sprovođenje adekvatnog lečenja patološkog \nkrvarenja iz materice. Normalan menstrualni ciklus se \ndefiniše kao regularno ciklično krvarenje, koje se javlja \nna prosečno 28 dana, traje 4 do 7 dana, uz prosečan gu-\nbitak krvi od oko 35 ml (Tabela 1). Ovaj ciklus je rezultat \nsložene interakcije između hipotalamusa, prednjeg re -\nžnja hipofize, jajnika, i endometrijuma. Na svakom od \novih nivoa stvaraju se hormoni, koji omogućavaju ili \nsprečavaju oslobađanje hormona na drugim nivoima. \nManje od 1,0% žena imaju regularne menstruacione \ncikluse koji traju kraće od 21 i duže od 35 dana [4]. \nVarijacije u dužini trajanja i intenzitetu menstrualnog \nkrvarenja su uobičajene na početku i kraju reproduktiv-\nnog perioda - tokom adolescencije i pre nastupanja me-\nnopauze. Učestalost anovulatornih ciklusa je najveća pre \n20-te godine života i posle 40-te godine života. Tokom 12 \ndo 18 meseci nakon menarhe, menstruacioni ciklusi su \niregularni, usled nezrelosti hipotalamo-hipofizno-ovarijal-\nne osovine. Nekoliko godina nakon menarhe, dužina lu-\ntealne faze ciklusa postaje relativno konstantna (13 do 15 \ndana). Tokom 5 do 7 godina nakon menarhe, menstruaci-\noni ciklusi postaju regularni i njihova dužina i trajanje se ne \nmenjaju značajno tokom reproduktivnog perioda, iako se \nsa godinama dužina trajanja menstruacionih ciklusa po-\nlako smanjuje. Tokom perioda od 8 do 10 godina pre me-\nnopauze, učestalost ovulatornih ciklusa se smanjuje [1 - 4].\nUkoliko dođe do poremećaja funkcije hipotala-\nmo-hipofizne osovine i/ili strukturalnog poremećaja \nmaterice (miomi, polipi, adenomioza, malignitet), ili \nporemećaja u koagulaciji krvi (koagulopatije, jatrogeni \nuzroci), remeti se normalan menstrualni ciklus i nastaje \npatološko krvarenje [5].\nTabela 1. Karakteristike normalnog menstrualnog krvarenja\nTable 1. Characteristics of normal menstrual bleeding\nInterval između ciklusa / Interval between cycles 28 (21 - 35) dana / days\nDužina trajanja krvarenja / Duration of bleeding 4 - 7 dana / days\nObim krvarenja / Bleeding volume 35 (20 - 80) ml\n\nSparić  R. i sar.\n418      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nAmerica amount to roughly 1 billion dollars per year, \nwhile indirect costs, stemming from absence from \nwork and decrease in social and life activity, amount to \napproximately 12 billion dollars annually [6]. \nThe aim of this paper is to present the current clas-\nsification, as well as the bases of diagnosis and treat -\nment of abnormal uterine bleeding. \nMETHODS\nThis paper presents data from publications selected \nfrom the PubMed database using a combination of \nkeywords: “menstrual bleeding” , “abnormal uterine \nbleeding” , “PALM-COEIN classification” , “leiomyoma” , \n“endometrial polyp” , “adenomyosis” , “gynecological \nmalignancies” , “coagulopathy” , “diagnostics of abnor-\nmal uterine bleeding” , and “treatment of abnormal \nuterine bleeding” . The database search and the meth-\nod of publication selection and inclusion into this \nstudy are presented in Figure 1. \nPatološka krvarenja iz materice imaju značajan uti-\ncaj na fizičko i mentalno zdravlje, kao i na emotivni, \nseksualni i profesionalni aspekt života žena, smanjujući \ni njihov kvalitet života. Takođe, ova krvarenja uzrokuju \nznačajne materijalne troškove. Procenjeno je da direk-\ntni troškovi njihovog lečenja u Sjedinjenim Američkim \nDržavama iznose oko jednu milijardu dolara godišnje, \ndok indirektni troškovi koji proističu iz izostanka sa \nposla, smanjenja društvene i životne aktivnosti iznose \noko 12 milijardi dolara godišnje [6]. \nCilj ovog rada je da se prikaže savremena podela, \nkao i osnovi dijagnostike i lečenja patoloških krvarenja \niz materice. \nMETODE\nU radu su prikazani podaci iz radova selektovanih pre -\ntraživanjem PubMed baze korišćenjem kombinacije \nključnih reči: “menstrual bleeding”,  “abnormal uterine \nbleeding”,  “PALM-COEIN classification”,  “leiomyoma”,  “en-\nSlika 1. PRISMA dijagram pretraživanja i odabira publikacija Figure 1. PRISMA diagram of the publications search and selection\nPretraživanje naučnih radova i publikacija / Research papers and publications search\nPretraživanje  / Research\nRadovi pronađeni u bazi podataka /  \nPapers found in the database\n(n = 5.669)\nUključivanje / Inclusion \nRadovi isključeni pre daljeg pretraživanja /  \nPapers excluded before further search \n– Radovi označeni kao neodgovarajući putem alata za pretraživanje  /  \nPapers marked as not suitable with the aid of the search tool \n(n = 5.243 )\n– Radovi označeni kao neodgovarajući iz drugih razloga   /  \nPapers marked as not suitable for other reasons\n(n = 268)\nPretraženi radovi /  \nPapers searched\n(n = 158)\nIsključeni radovi /  \nPapers excluded\n(n = 31)\nRadovi koji su detaljno pretraženi i razmotreni za uključivanje /  \nPapers searched in detail and considered for inclusion\n(n = 127)\nPretraženi radovi /  \nPapers meeting the inclusion criteria\n(n = 31)\nUključeni radovi/  \nPapers included\n(n = 31)\n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      419\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nCurrent nomenclature of menstrual cycle disor-\nders and abnormal uterine bleeding (FIGO 2011)\nFor the purpose of achieving a uniform classification \nof menstrual cycle disorders, in 2011, the Internation-\nal Federation of Gynecology and Obstetrics (FIGO) in-\ntroduced a classification of these disorders under the \nname PALM-COEIN [1-3]. This acronym denotes indi-\nvidual causes of abnormal uterine bleeding. The caus-\nes listed in the first part of the acronym (PALM) have a \npathological/anatomical cause in the reproductive or -\ngans that can be diagnosed using imaging techniques \nand/or histopathological examination [1,2,4,7]. The \ncauses listed in the second part of the acronym (COEIN) \nrepresent a group of dysfunctional disorders and they \ncannot be diagnosed using imaging techniques [1-4]. \nEndometrial polyp \nA polyp is a lesion which is formed as the result of lo -\ncalized endometrial tissue growth. It is composed of \nglands, stroma, and blood vessels, and is covered with \nepithelium. It is most commonly encountered in women \nin the reproductive period, and the frequency of the oc-\ncurrence of polyps increases with age. It is believed that \nestrogens play a key role in their formation [8 ]. Abnor-\nmal uterine bleeding, caused by polyps, is manifested as \nintermenstrual bleeding, hypermenorrhea, metrorrha-\ngia or postmenopausal bleeding, and may also be linked \nto dysmenorrhea. However, just like myomas, polyps are \nmost commonly asymptomatic [8,9]. They are frequent \nin infertile patients and those treated with tamoxifen. \nMost of the endometrial polyps are benign, although, \nin postmenopause, in 1.5 to 4.5% of the cases, they are \nmalignant [8,9]. Polyps smaller than 1 cm may sponta-\nneously regress. They are diagnosed by ultrasound or \nwith hysteroscopy. Polyps are treated by surgical-hys-\nteroscopic resection or by explorative curettage [9]. \nAdenomyosis \nAdenomyosis is characterized by the presence of en-\ndometrial tissue (glands and stroma) in the myometri-\num. The presence of ectopic endometrial tissue leads \nto hypertrophy of the surrounding myometrium, caus-\ning diffuse enlargement of the uterus. It occurs focally \nor diffusely in the uterus, and its greatest frequency is \nin women in their forties. The most significant factor for \nthe occurrence of adenomyosis is multiparity, but it is \nbelieved that all factors contributing to the penetration \nof endometrial glands and the stroma through the basal \nlayer of the endometrium, influence the development of \nendometriosis (curettage of the uterine cavity, cesarean \nsection, miscarriage). Bleeding caused by adenomyosis \noccurs as the result of uterine contractility impairment. It \ndometrial polyp”,  “adenomyosis”,  “gynecological mali-\ngnancies”,  “coagulopathy”,  “diagnostics of abnormal ute-\nrine bleeding” , i “treatment of abnormal uterine bleeding”.  \nPretraživanje baze podataka, način odabira i uključiva-\nnja publikacija u ovaj rad prikazani su u Grafikonu 1. \nSavremena nomenklatura poremećaja menstru-\nalnog ciklusa i patoloških krvarenja iz materice \n(FIGO 2011)\nU cilju postizanja jedinstvene klasifikacije patoloških \nkrvarenja iz materice, Međunarodna federacija gineko-\nloga i akušera (engl. International Federation of Gyneco-\nlogy and Obstetrics - FIGO) je, 2011. godine, uvela klasi-\nfikaciju ovih poremećaja pod nazivom PALM-COEIN [1-\n3]. Sam akronim označava pojedine uzroke patološkog \nkrvarenja iz materice. Uzroci nabrojani u prvom delu \nakronima (PALM) imaju patološko-anatomski supstrat \nna nivou genitalnih organa koji se može dijagnostiko -\nvati primenom imidžing metoda i/ili histopatološkim \npregledom [1,2,4,7]. Uzroci nabrojani u grupi COEIN \nuključuju difsunkcionalne poremećaje i ne mogu se di-\njagnostikovati primenom imidžing metoda [1-4]. \nEndometrijalni polip\nPolip predstavlja promenu nastalu usled lokalizovanog \nrasta tkiva endometrijuma, sastavljenu od žlezda, stro -\nme i krvnih sudova, i pokrivenu epitelom. Najčešće se \nsreće kod žena u reproduktivnom periodu, a učestalost \npolipa se povećava sa godinama. Smatra se da estrogeni \nigraju ključnu ulogu u njihovom nastanku [8]. Patološko \nkrvarenje uzrokovano polipima se manifestuje kao in-\ntermenstrualno krvarenje, hipermenoreja, metroragija \nili postmenopauzalno krvarenje, a može biti povezano \ni sa dismenorejom. Ipak, kao i miomi, polipi su najčešće \nasimptomatski [8,9]. Česti su kod infertilnih pacijentki-\nnja i onih koje primaju tamoksifen. Najveći broj polipa \nendometrijuma su benigni, mada su u postmenopauzi \nu 1,5 do 4,5% slučajeva maligni [8,9]. Polipi manji od 1 \ncm mogu spontano regredirati. Dijagnostikuju se ultra-\nzvukom ili histeroskopski. Polipi se leče hirurški-histero-\nskopskom resekcijom ili eksplorativnom kiretažom [9]. \nAdenomioza\nAdenomiozu karakteriše prisustvo tkiva endometrijuma \n(žlezda i strome) u miometrijumu. Prisustvo ektopičnog \nendometrijalnog tkiva dovodi do hipertrofije okolnog \nmiometrijuma, uzrokujući difuzno uvećanje materice. \nJavlja se fokalno ili difuzno u materici, a najveću uče -\nstalost ima u petoj deceniji života. Najznačajniji faktor \nza nastanak adenomioze je multiparitet, ali se smatra \nda svi faktori koji doprinose penetraciji endometrijalnih \nžlezda i strome kroz bazalni sloj endometrijuma, utiču \nna nastanak endometrioze (kiretaža materične šupljine, \n\nSparić  R. i sar.\n420      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\ncarski rez, spontani pobačaj). Krvarenje uzrokovano \nadenomiozom nastaje kao posledica poremećaja kon-\ntraktilnosti materice. Najčešće se manifestuje menora-\ngijom i obično je povezano sa izraženom dismenore -\njom [10]. Adenomioza se dijagnostikuje ultrazvukom i \nnuklearnom magnetnom rezonancom. Definitivna dija-\ngnoza se postavlja histopatološkim pregledom. Medi-\nkamentno lečenje uključuje primenu progesteronskih \npreparata, agonista gonadotropin-oslobađajućeg hor -\nmona (engl. gonadotropin-releasing hormone - GnRH) i \ninhibitora aromataze. Fokalna ognjišta adenomioze se \nmogu lečiti hirurškom resekcijom. Kod žena koje nisu \nzainteresovane za reprodukciju, lečenje je moguće \nsprovesti embolizacijom materičnih arterija [11]. \nLeiomiom\nLeiomiomi, miomi ili fibromi su benigni tumori pore -\nklom od mišićnih ćelija miometrijuma. Predstavljaju \nnajčešće benigne tumore ženskih reproduktivnih or -\ngana. Klinička slika varira od potpunog odsustva su-\nbjektivnih tegoba do brojnih simptoma, koji mogu \nimati značajan uticaj na zdravlje žene. Manje od 50,0% \nmioma su simptomatski, a najčešći simptom je pato -\nloško krvarenje iz materice [7,12–15]. Mogu biti poje -\ndinačni ili multipli, a u oko 97,0% slučajeva su lokalizo-\nvani u telu materice. U odnosu na anatomske slojeve \nzida materice ovi tumori se dele na submukozne, in-\ntramuralne, subserozne, i intraligamentarne (miomi \nlokalizovani između listova širokih materičnih veza). \nNa Slici 2 prikazana je FIGO podela mioma na osnovu \nSlika 2. Tipovi mioma po FIGO klasifikaciji Figure 2. Types of myomas according to the FIGO classification\nmost commonly manifests as menorrhagia and is usually \nconnected to marked dysmenorrhea [10]. Adenomyosis \nis diagnosed with ultrasound and nuclear magnetic res-\nonance imaging. Definitive diagnosis is established by \nhistopathological examination. Medicamentous treat -\nment includes the application of progesterone-based \nmedicaments, gonadotropin-releasing hormone (GnRH) \nagonists, and aromatase inhibitors. Focal areas of adeno-\nmyosis can be treated with surgical resection. In women \nnot interested in reproduction, it is possible to perform \ntreatment by embolizing uterine arteries [11]. \nLeiomyomas \nLeiomyomas, myomas or fibromas are benign tumors \noriginating from muscular cells of the myometrium. \nThey are the most common benign tumors of female re-\nproductive organs. The clinical presentation varies from \ncomplete absence of subjective complaints to numer -\nous symptoms, which may significantly affect the wom-\nan’s health. Less than 50.0% are symptomatic, and the \nmost frequent symptom is abnormal uterine bleeding \n[7,12–15]. They can be solitary or multiple, and in around \n97.0% of the cases, they are localized in the body of the \nuterus. In relation to the anatomical layers of the uterine \nwall, these tumors are classified as submucosal, intramu-\nral, subserosal, and intraligamentous (myomas localized \nbetween the leaves of the broad uterine ligaments). \nFigure 2 shows the FIGO classification of myomas based \non localization [1-3]. The nomenclature of myomas, by \ntype, based on this classification is presented in Table 2. \n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      421\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nlokalizacije [1-3]. Nomenklatura mioma po tipovima na \nosnovu ove podele prikazana je u Tabeli 2.\nMehanizmi kojima miomi utiču na pojavu patološ-\nkih krvarenja iz materice su različiti, a u velikoj meri za-\nvise i od njihove veličine, broja i lokalizacije. Kod žena \nsa patološkim krvarenjem iz materice, najčešće se di-\njagnostikuju intrakavitarni (miomi u šupljini materice), \nsubmukozni miomi i veliki intramuralni miomi [16]. Ovi \nmiomi povećavaju ukupnu površinu šupljine materice \nprekrivenu endometrijumom, dovode do iregularne \ndeskvamacije endometrijuma i iregularnih kontrak -\ncija materice, izazivajući iregularna i obilna materična \nkrvarenja [17]. Pored toga, novija saznanja ukazuju na \nznačaj neoangiogeneze, povišenih nivoa vazoaktivnih \nsupstanci i faktora rasta, kao i koagulacionih promena, \nkoji zajednički utiču na pojavu patoloških krvarenja \nkod žena sa miomima [18]. Lečenje mioma je medi-\nkamentno (kombinovana oralna kontracepcija, GnRH  \nagonisti i antagonisti) ili hirurško (miomektomija, histe-\nrektomija), u zavisnosti od karakteristika mioma, godi-\nna starosti i pariteta pacijentkinje [19]. Kod žena koje \nnisu zainteresovane za reprodukciju, lečenje je moguće \nsprovesti embolizacijom materičnih arterija [20]. \nMalignitet i hiperplazija\nMaligne bolesti ženskih reproduktivnih organa koje \nmogu uzrokovati krvarenje uključuju oboljenja vulve, \nvagine, grlića materice, endometrijuma, tela materice, \njajnika i jajovoda. Najčešći uzroci patoloških krvarenja \nsu maligniteti materice. \nKarcinom grlića materice se manifestuje kontak -\ntnim, intermenstrualnim ili potpuno acikličnim krvare -\nnjem, te je isključivanje ovog oboljenja značajan deo \nThe mechanisms through which myomas affect the \noccurrence of abnormal uterine bleeding vary and de-\npend, to a great extent, on the size of the myomas, their \nnumber, and localization. In women with abnormal \nuterine bleeding, the following myomas are most com-\nmonly diagnosed: intracavitary (myomas in the uterine \ncavity), submucosal, and large intramural myomas [16]. \nThese myomas enlarge the overall surface of the uter -\nine cavity covered with endometrium, lead to irregular \ndesquamation of the endometrium and to irregular \ncontractions of the uterus, thereby causing irregular \nand profuse uterine bleeding [17]. Also, recent discov -\neries indicate the significance of neoangiogenesis, ele-\nvated levels of vasoactive substances and growth fac -\ntors, and of coagulation changes, which together affect \nthe occurrence of abnormal bleeding in women with \nmyomas [18]. Treatment of myomas is medicamentous \n(combined oral contraceptives, GnRH agonists and an-\ntagonists) or surgical (myomectomy, hysterectomy), \ndepending on the characteristics of the myomas and \non the age and parity of the patient [19]. In women \nnot interested in reproduction, it is possible to perform \ntreatment by embolizing uterine arteries [20]. \nMalignancy and hyperplasia \nMalignant diseases of female reproductive organs that \nmay cause bleeding include malignancies affecting \nthe vulva, the vagina, the cervix, the endometrium, the \nuterine body, the ovaries and the oviducts The most \ncommon causes of abnormal uterine bleeding are \nuterine malignancies. \nCervical carcinoma manifests as contact, intermen-\nstrual or completely acyclic bleeding, which is why it \nTabela 1. Karakteristike normalnog menstrualnog krvarenja Table 1. Characteristics of normal menstrual bleeding\nSM - submukozni / \nSM - submucosal\n0 Intrakavitarni miomi na peteljci / Intracavitary pedunculated myomas\n1 <0% intramuralni / <50% intramural\n2 ≥50% intramuralni / ≥50% intramural\nO - ostali/  \nO - other\n3 U kontaktu sa endometrijumom, 100% intramuralni / In contact with the endometrium, 100% intramural\n4 Intramuralni / Intramural\n5 Subserozni ≥50% intramuralni / Subserosal ≥50% intramural\n6 Subserozni <50% intramuralni / Subserosal <50% intramural\n7 Subserozni na peteljci / Pedunculated subserosal\n8 Drugi (cervikalni, intraligamentarni, parazitni)i / Other (cervical, intraligamentous, parasitic)\nHibridni leiomiomi (u kontaktu \nkako sa endometrijumom, tako \ni sa serozom materice)/ Hybrid \nleiomyomas (in contact both \nwith the endometrium and with \nthe uterine serosa)\nObeležavaju se sa dva broja odvojena crtom (-). Prvi broj označava odnos mioma sa endometrijumom, a drugi odnos mioma sa \nserozom materice. / They are marked with two numbers separated by a hyphen (-). The first number marks the relation between the \nmyoma and the endometrium, while the other one designates the relation between the myoma and the uterine serosa.\nNa primer, miom 2-5 je submukozni i subserozni, pri čemu je manje od 50% volumena mioma u odnosu sa endometrijumom i \nperitonealnom šupljinom. / For example, a myoma marked 2-5 is submucosal and subserosal, with less than 50% of the myoma \nvolume in contact with the endometrium and the peritoneal cavity. \n\nSparić  R. i sar.\n422      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nis important to rule out this disease, as a part of the \nprocess of diagnosing the cause of abnormal uterine \nbleeding [21]. Abnormal bleeding can be caused by \ndifferent endometrial disorders, such as cystic and ad-\nenomatous hyperplasia, endometrial intraepithelial \nneoplasia (EIN), and endometrial carcinoma [4,22]. The \nmost frequent symptom of endometrial carcinoma is \nabnormal uterine bleeding. Although it most frequent-\nly occurs in women in their sixties, in around 15.0% of \nthe cases it is encountered in premenopausal women, \nand in 3.0% to 5.0% of the cases in women younger \nthan 40 years. Uterine sarcomas usually occur in old-\ner women in menopause, and they clinically manifest \nas abnormal uterine bleeding and progressive en-\nlargement of the uterus. Ovarian estrogen producing \ntumors (most commonly granulosa cell tumors) may \nmanifest as abnormal uterine bleeding [2-4,23].\nCoagulopathy \nAbnormal uterine bleeding may be the first clini-\ncal manifestation of hematological diseases. Around \n13.0% of women with profuse menstrual bleeding \nhave some form of coagulation disorder, of which the \nmost common one is von Willebrand’s disease [24]. \nCoagulopathy represents one of the most frequent \ncauses of menorrhagia [25]. Diseases leading to plate -\nlet deficiency, which can be the cause of abnormal \nuterine bleeding, include leukemia, severe forms of \nsepsis, and idiopathic thrombocytopenic purpura. He -\nmophilia A and B are X-related recessive deficiencies \nof coagulation factor VIII and coagulation factor IX \n[24-26]. Women who are carriers of this disease have \ndecreased levels of factor VIII and factor IX, which may \nmanifest as menorrhagia. Less frequently, hereditary \ncoagulopathies that include a disorder in other coag-\nulation factors (V, VII, X, XI and XIII) may manifest as \nmenorrhagia. Disorders of liver function in alcoholism, \nas well as chronic liver diseases, may result in a coagu-\nlation factor production disorder and the occurrence \nof abnormal bleeding [24]. \nAround 5.0% to 20.0% of adolescent young women \nwho experience abnormal uterine bleeding have some \nform of coagulopathy. This is why coagulation status \ntesting is especially significant in women of this age [25]. \nDetailed analysis of the coagulation status pres-\nents an indispensable part of the diagnostic protocol \nin women with abnormal uterine bleeding, and the \ntreatment is hematological [24,25].\nOvulatory dysfunction \nOne of the causes of abnormal uterine bleeding, which \noccurs in the period after menarche and in perimeno -\npause, is ovulatory dysfunction. It develops as the result \npostupka dijagnostike uzroka patoloških krvarenja iz \nmaterice [21]. Patološko krvarenje može biti uzrokova-\nno različitim poremećajima endometrijuma, kao što su \ncistična i adenomatozna hiperplazija, endometrijalna \nintraepitelna neoplazija (EIN) i karcinom endometri-\njuma [4,22]. Najčešći simptom karcinoma endometri-\njuma je patološko krvarenje iz materice. Iako se najče -\nšće javlja tokom sedme decenije života, u oko 15,0% \nslučajeva se sreće kod premenopauzalih žena, a u oko \n3,0% do 5,0% slučajeva kod žena mlađih od 40 godina. \nSarkomi materice se obično javljaju kod starijih žena u \nmenopauzi, a klinički se manifestuju patološkim krva-\nrenjem iz materice i progresivnim uvećanjem materice. \nTumori jajnika koji produkuju estrogen (najčešće gra-\nnuloza-ćelijski tumori) mogu se manifestovati patološ-\nkim krvarenjem iz materice [2-4,23].\nKoagulopatija \nPatološko krvarenje iz materice može biti prva klinič -\nka manifestacija hematoloških oboljenja. Oko 13,0% \nžena sa obilnim menstrualnim krvarenjem ima neki ko -\nagulacioni poremećaj, od kojih je najzastupljenija von \nVilebrandova bolest [24]. Koagulopatija predstavlja \njedan od najčešćih uzroka menoragije [25]. Oboljenja \nkoja dovode do deficita trombocita, a mogu biti i uzrok \npatoloških krvarenja iz materice, uključuju leukemi-\nju, teške oblike sepse, idiopatsku trombocitopenijsku \npurpuru. Hemofilija A i B su X-vezani recesivni deficiti \nfaktora koagulacije VIII i faktora koagulacije IX [24-26]. \nŽene koje su prenosioci ovih bolesti imaju snižene \nnivoe faktora VIII i faktora IX, što se može manifesto -\nvati menoragijom. Ređe, nasledne koagulopatije koje \nuključuju poremećaj ostalih faktora koagulacije (V, VII, \nX, XI i XIII), mogu se manifestovati menoragijom. Pore-\nmećaji funkcije jetre kod alkoholizma, kao i njena hro -\nnična oboljenja mogu imati za posledicu poremećaj \nprodukcije faktora koagulacije i nastanak patološkog \nkrvarenja [24]. \nOko 5,0% do 20,0% adolescentkinja kod kojih se \npojavi patološko krvarenje iz materice imaju neku koa-\ngulopatiju. Zbog toga je ispitivanje koagulacinog statu-\nsa naročito značajno kod žena ovog životnog doba [25]. \nDetaljno ispitivanje koagulacionog statusa pred-\nstavlja neizostavni deo dijagnostičkog protokola kod \nžena sa patološkim krvarenjima iz materice, a lečenje \nje hematološko [24,25].\nOvulatorna disfunkcija\nJedan od uzroka patoloških krvarenja, koja se javljaju \nu periodu nakon menarhe i u perimenopauzi, jeste \novulatorna disfunkcija. Nastaje kao posledica poreme -\nćaja funkcije hipotalamo-hipofizno-ovarijalne osovine, \nsa kontinuiranom produkcijom estrogena i izostankom \n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      423\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nof a disturbance in the functioning of the hypothalam-\nic-pituitary-ovarian axis, with continuous production \nof estrogen and absence of ovulation, corpus luteum \nformation and progesterone secretion in the ovaries. \nEstrogen stimulation leads to continuous proliferation \nof the endometrium, which, at some point, due to in-\nsufficient vascularization, necrotizes. As the result of \nthis disorder, so-called breakthrough bleeding occurs. \nSuch anovulatory bleeding is most frequent during the \nfirst few years after menarche and in perimenopause. In \nadolescence, the cause of anovulation is the immaturi-\nty of the hypothalamic-pituitary-gonadal axis and the \nabsence of positive feedback by estradiol, which causes \npeak LH (luteinizing hormone). In perimenopause, the \ncause of this type of bleeding is ovarian insufficiency. \nEspecially profuse bleeding occurs after a prolonged \nperiod of endometrial exposure to estrogens, which is \nusually found in adolescent young women after men-\narche, patients with polycystic ovary (PCO) syndrome, \nobese, and perimenopausal women [4,26].\nOvulatory dysfunction can manifest as amenor -\nrhea, while anovulatory bleeding may manifest as ol-\nigomenorrhea, intermenstrual bleeding or hypermen-\norrhea. In women with regular menstrual cycles, ovula-\ntion is absent in 20.0% of the cases. \nThe most common cause of anovulatory bleeding \nduring the reproductive period in women is the poly -\ncystic ovary syndrome (PCOS). A disturbance of the hy-\npothalamic-pituitary function is a less common cause. \nAdditionally, other hormonal disbalances may be ac -\ncompanied by anovulatory bleeding, such as diseases \nof the thyroid gland (hypothyroidism, hyperthyroid-\nism), diseases of the adrenal glands, and diabetes mel-\nlitus [27,28]. Hyperprolactinemia and elevated levels of \ncortisol (Cushing’s syndrome) can also lead to anovu-\nlation. Less frequently, the causes can be eating disor -\nders (anorexia, bulimia), chronic disease, alcoholism, \ndrug abuse, and stress [4,27,28].\nIatrogenic causes \nAbnormal uterine bleeding resulting from iatrogenic \ncauses is the consequence of taking medication, most \ncommonly oral contraceptives, selective modulators \nof estrogen receptors, GnRH agonists and antagonists, \ndigitalis, and anticonvulsants. Drugs cause abnormal \nbleeding, either by disrupting the function of the hy -\npothalamic-pituitary-gonadal axis or by causing fluc -\ntuations in the levels of circulating hormones. \nHyperprolactinemia may be the result of the effect \nof antipsychotics acting as dopamine antagonists at \nthe level of the central nervous system (risperidone) \n[4,29]. This type of abnormal bleeding may occur in \npatients who use combined hormonal contraception \novulacije, formiranja žutog tela i sekrecije progestrona \nu jajniku. Estrogena stimulacija dovodi do kontinuira-\nne proliferacije endometrijuma, koji u nekom trenutku, \nusled nedovoljne vaskularizacije, podleže nekrozi. Kao \nposledica ovog poremećaja nastaje tzv. probojno krva-\nrenje. Ovakva anovulatorna krvarenja su najčešća to -\nkom prvih nekoliko godina nakon menarhe i u perime-\nnopauzi. U adolescenciji, uzrok anovulacija je nezrelost \nhipotalamo-hipofizno-gonadne osovine i izostanak \npozitivne povratne sprege estradiola, koja uzrokuje \npik LH-a (luteinizirajućeg hormona). U perimenopauzi, \nuzrok ove vrste krvarenja je ovarijalna insuficijencija. \nNaročito obilna krvarenja se javljaju nakon prolongira-\nnog perioda ekspozicije endometrijuma estrogenima, \nšto se obično sreće kod adolescentkinja nakon menar-\nhe, pacijentkinja sa PCO (engl. polycystic ovary) sindro-\nmom, gojaznih, kao i perimenopauzalnih žena [4,26].\nOvulatorna disfunkcija se može manifestovati i \namenorejom, a anovulatorna krvarenja oligomenore -\njom, intermenstrualnim krvarenjem ili hipermenore -\njom. Kod žena koje imaju regularne menstrualne ciklu-\nse u 20,0% slučajeva izostaje ovulacija.\nNajčešći uzrok anovulatornih krvarenja tokom re -\nproduktivnog perioda žene je sindrom policističnih \njajnika (engl. polycystic ovary syndrome - PCOS). Ređi \nuzrok je poremećaj hipotalamo-hipofizne funkcije. Uz \nto, i drugi hormonski poremećaji mogu biti praćeni \nanovulatornim krvarenjem, kao što su oboljenja tiro -\nidne žlezde (hipotireoidizam, hipertireoidizam), nad-\nbubrežne žlezde i diabetes mellitus [27,28]. Hiperpro -\nlaktinemija i povišene vrednosti kortizola (Kušingov \nsindrom) takođe mogu dovesti do anovulacije. Ređe, \nuzroci su poremećaji ishrane (anoreksija, bulimija), \nhronične bolesti, alkoholizam, zloupotreba droga, kao \ni stres [4,27,28].\nJatrogeni uzroci\nJatrogeno nastala patološka krvarenja iz materice na-\nstaju kao posledica uzimanja medikamenata, najčešće \noralnih kontraceptiva, selektivnih modulatora estroge-\nnih receptora, GnRH agonista i antagonista, digitalisa \ni antikonvulziva. Lekovi izazivaju patološka krvarenja, \nbilo remeteći funkciju hipotalamo-hipofizno-gonadne \nosovine, bilo izazivajući fluktuacije cirkulišućih nivoa \nhormona. \nHiperprolaktinemija može biti posledica dejstva \nantipsihotika koji deluju kao dopaminski antagoni-\nsti na nivou centralnog nervnog sistema (risperidon) \n[4,29]. Patološka krvarenja ove vrste se mogu javiti \nkod korisnica kombinovane hormonske kontracepcije \n(flasteri, vaginalni prstenovi, pilula), ali i kod korisnica \nintrauterinih kontraceptivnih uložaka. Probojna krva-\nrenja su česta tokom prva tri meseca upotrebe oralnih \n\nSparić  R. i sar.\n424      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\n(patches, vaginal rings, contraceptive pills), but also \nin women using intrauterine contraceptive implants. \nBreakthrough bleeding is common in the first months \nof using oral hormone contraceptives and occur in \n30.0% to 40.0% of the women using them. This type \nof bleeding is most commonly encountered in women \nusing oral contraceptive pills and hormonal substitu-\ntion in perimenopause [30]. Most bleeding manifests \nas menorrhagia.\nIt is important to note that all bleeding in patients \nusing hormonal contraceptives is not caused by hor -\nmonal factors. The results of recent studies have shown \nthat patients using oral contraceptives and experienc -\ning abnormal uterine bleeding also have a high preva-\nlence of Chlamydia trachomatis infection, which causes \nbleeding in these women. Screening for sexually trans-\nmitted diseases should be considered in patients with \nabnormal uterine bleeding who use hormonal contra-\nceptives [30]. \nEndometrial causes \nBleeding occurring in the absence of pathological \nchanges to the endometrium fall under this category \nand was earlier referred to as ‘ovulatory dysfunctional \nbleeding’ . Abnormal uterine bleeding may be a man-\nifestation of the disruption in the endometrial repair \nmechanism. In these patients, elevated levels of vaso -\ndilatory substances (prostacyclin I2 and prostaglandin \nE2) are present, as well as decreased levels of vasocon-\nstrictory substances (endothelin-1 and prostaglandin \n2α). These disorders may be primary and secondary, \ncaused by inflammation or infection of the endometri-\num [4]. Menorrhagia may be the first sign of endome -\ntritis in women, in sexually transmitted diseases. Ab -\nnormal uterine bleeding is frequent in cases of subclin-\nical infection caused by Chlamydia trachomatis. Oth-\ner causes include a decrease in the level of estrogen \nduring treatment with antibiotics and anticonvulsants \n[29,31]. Also, this group of disorders includes bleeding \noccurring during steroid hormone treatment, such as, \nfor example, breakthrough bleeding. \nEndometrial causes of abnormal uterine bleeding \nin women in the reproductive period are diagnosed \nonly after excluding other pathological processes and \nconfirming the existence of normal ovulations. \nUnclassified causes \nTypes of abnormal uterine bleeding not covered by the \nabove-mentioned causes fall under this category, such \nas bleeding caused by a foreign body (tampon, pessa-\nry) or trauma. Other causes of bleeding from this group \nare chronic endometritis and arteriovenous malforma-\ntions [4].\nhormonskih kontraceptiva i javljaju se kod 30,0% do \n40,0% korisnica. Ova vrsta krvarenja najčešće se sreće \nkod korisnica oralnih kontraceptivnih pilula i hormon-\nske supstitucije u perimenopauzi [30]. Većina krvarenja \nse manifestuje menoragijom.\nVažno je ukazati na to da sva krvarenja kod paci-\njentkinja koje koriste hormonsku kontracepciju nisu \nposledica hormonskih faktora. Rezultati novih istraži-\nvanja ukazuju na to da pacijentkinje koje koriste oralne \nkontraceptive i imaju patološka krvarenja imaju visoku \nprevalenciju infekcije Chlamydia-om trachomatis, koja \nuzrokuje pojavu krvarenja kod ovih pacijentkinja. Skri-\nning na polno prenosive bolesti treba razmotriti kod \npacijentkinja koje imaju patološka krvarenja i koriste \nhormonsku kontracepciju [30]. \nEndometrijalni uzroci\nU ovu kategoriju se svrstavaju krvarenja u odsustvu \npatoloških promena endometrijuma, ranije naziva-\nna „ovulatorna disfunkcionalna krvarenja“ . Patološka \nkrvarenja iz materice mogu biti manifestacija pore -\nmećaja mehanizama reparacije endometrijuma. Kod \novih pacijentkinja prisutni su povišeni nivoi vazodila-\ntatornih supstanci (prostaciklin I2 i prostaglandin E2) i \nsniženi nivoi vazokontriktornih supstanci (endotelin-1 \ni prostaglandin 2α). Ovi poremećaji mogu biti primarni \ni sekundarni, uzrokovani inflamacijom ili infekcijom en-\ndometrijuma [4]. Menoragija može biti prvi znak endo -\nmetritisa kod žena, kod seksualno prenosivih bolesti. \nPatološka krvarenja iz materice česta su u slučajevima \nsubkliničke infekcije uzrokovane Chlamydia-om trac-\nhomatis. Ostali uzroci uključuju smanjenje nivoa estro-\ngena tokom terapije antibioticima i antikonvulzivima \n[29,31]. Takođe, u ovu grupu poremećaja spadaju krva-\nrenja koja se javljaju tokom terapije steroidnim hormo-\nnima, kao što je, na primer, probojno krvarenje.\nEndometrijalni uzroci patoloških krvarenja iz mate-\nrice kod žena u reproduktivnom periodu se dijagnosti-\nkuju tek nakon isključivanja ostalih patoloških procesa \ni potvrde postojanja normalnih ovulacija. \nNeklasifikovani uzroci\nU ovu grupu patoloških krvarenja se ubrajaju krvarenja \nkoja nisu obuhvaćena prethodno opisanim uzrocima, \nkao što su krvarenja uzrokovana stranim telom (tam-\npon, pesar) ili traumom. Ostali uzroci krvarenja iz ove \ngrupe su hronični endometritis i arterio-venske malfor-\nmacije [4].\nDijagnoza patoloških krvarenja iz materice\nPre sprovođenja bilo koje dijagnostičke procedure ne -\nophodno je isključiti postojanje neprepoznate trudnoće \nodređivanjem nivoa β-HCG-a u serumu pacijentkinje. \n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      425\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nDiagnosis of abnormal uterine bleeding \nBefore carrying out any diagnostic procedure it is nec-\nessary to exclude the existence of an unrecognized \npregnancy by determining the β-HCG level in the se -\nrum of the patient. \nThe diagnostic protocol depends on anamnestic \ndata and the clinical finding, as well as on the age and \nparity of the patient. At the same time the presence \nof possible risk factors for the existence of endome -\ntrial hyperplasia and malignancy must also be taken \ninto consideration. In all cases of contact bleeding, it \nis necessary to perform colposcopy as well as cervical \ncytology by Pap smear, and, if necessary, additional di-\nagnostics, for the purpose of excluding the existence \nof cervical carcinoma. \nThe first step in the diagnostics is taking a detailed \npersonal and family medical history (length, cyclicity, \nand volume of menstrual bleeding; occurrence of bruis-\nes on the skin; nosebleeds; bleeding of gums; postpar-\ntum bleeding or bleeding after surgical procedures; \ndrugs that the patient is on – hormonal medicaments, \nanticoagulants, antipsychotics, antidepressants; exis-\ntence of accompanying signs and symptoms – change \nin body weight, physical activity, premenstrual syn-\ndrome, dysmenorrhea, dyspareunia, galactorrhea, hir -\nsutism, acne). Although subjective, information on the \nuse of tampons or menstrual pads during menstrua-\ntion may offer an estimation on the volume of bleed-\ning. Information on the change of tampons or pads \nmore often than once in every three hours, as well as \nthe use of more than 20 menstrual pads during one \nmenstrual cycle, the need for changing pads or tam-\npons during the night, discharging clots larger than 2.5 \ncm, bleeding lasting longer than 7 days, indicate pro -\nfuse abnormal uterine bleeding. \nClinical examination enables evaluation of patho -\nlogical changes in the cervix, uterus, and adnexa. It \nprimarily confirms whether there is irregular uterine \nbleeding. \nThe next step is ultrasound examination of the less-\ner pelvis, i.e., the evaluation of the uterus, the thickness \nof the endometrium, and the ovaries. Endometrial pol-\nyps and submucosal myomas can also be diagnosed \nwith this examination. In case of unclear findings, \nsonohysterography or hysteroscopy is performed, and, \nif necessary, fractional explorative curettage. In some \ncases, especially in adolescent patients and patients \nwith an intact hymen, a nuclear magnetic resonance \nimaging examination is performed. \nIf these examinations exclude the existence of \npathological changes in the endometrium, the myo -\nmetrium, and ovaries, it is necessary to examine \nthe ovulatory function, as well as to test for other \nDijagnostički protokol zavisi od anamnestičkih \npodataka i kliničkog nalaza, kao i od godina starosti, \npariteta, pri čemu se mora imati u vidu i eventualno \nprisustvo faktora rizika za postojanje endometrijalne \nhiperplazije i maligniteta. U svim slučajevima kontak -\ntnog krvarenja, neophodno je uraditi i kolposkopski i \ncitološki pregled po metodi Papanikolau, a po potrebi i \ndopunsku dijagnostiku, u cilju isključivanja postojanja \nkarcinoma grlića materice.\nPrvi korak u dijagnostici jeste uzimanje detaljne \nlične i porodične anamneze (dužina trajanja, ciklič -\nnost i obim menstrualnog krvarenja; pojava modrica \npo koži; krvarenja iz nosa; krvarenja desni; krvarenje \nposle porođaja ili operativnih zahvata; uzimanje leko -\nva - hormonski preparati, antikoagulansi, antipsihotici, \nantidepresivi; postojanje pratećih znakova i simptoma \n- promena telesne težine, fizička aktivnost, premenstru-\nalni sindrom, dismenoreja, dispareunija, galaktoreja, hi-\nrzutizam, akne). Iako subjektivan, podatak o upotrebi \ntampona, odnosno uložaka tokom ciklusa, može pružiti \nprocenu obima krvarenja. Podatak o promeni tampo -\nna, odnosno uložaka češće od jednom na tri sata, kao i \nupotreba više od 20 tokom jednog ciklusa, potreba za \npromenom tampona ili uložaka tokom noći, izbacivanje \nugrušaka većih od 2,5 cm, te krvarenje duže od 7 dana, \nukazuju na obilno patološko krvarenje iz materice. \nKlinički pregled omogućava evaluaciju patoloških \npromena grlića materice, uterusa i adneksa. Njime se \nprvenstveno potvrđuje da li se radi o iregularnom kr -\nvarenju iz materice. \nNakon toga se izvodi ultrazvučni pregled male kar-\nlice, odnosno evaluacija materice, debljine endome -\ntrijuma i ovarijuma. Ovim pregledom se takođe mogu \ndijagnostikovati endometrijalni polipi i submukozni \nmiomi. U slučaju nejasnih nalaza, radi se sonohistero -\ngrafija ili histeroskopija, a po potrebi i frakcionirana ek-\nsplorativna kiretaža. U nekim slučajevima, naročito kod \nadolescentkinja i pacijentkinja sa intaktnim himenom, \nradi se pregled nuklearnom magnetnom rezonancom.\nUkoliko se ovim pregledima isključi postojanje pato-\nloških promena endometrijuma, miometrijuma i jajnika, \nneophodno je ispitivanje ovulatorne funkcije, kao i po-\nstojanja drugih endokrinopatija i koagulacionih poreme-\nćaja, kao i mikrobiološko ispitivanje (cervikalni i vaginalni \nbakteriološki bris, brisevi na Chlamydia-u trachomatis, \nUreaplasma-u urealyticum, Mycoplasma-u hominis). \nOdređivanjem serumskog progesterona između \n22. i 24. dana ciklusa kod žena sa ciklusom na 28 dana, \nmože se dokumentovati postojanje ovulacije, a vred-\nnosti veće od 3 ng/ml ukazuju na postojanje ovulacije. \nKod žena starijih od 40 godina, neophodno je uraditi \ndijagnostičku kiretažu u cilju isključivanja karcinoma \nendometrijuma [1,2,4,5].\n\nSparić  R. i sar.\n426      Decembar 2021.  |  Volumen 2 / Broj 4  |  SrpSki  medicinSki  čaSopiS  LekarSke  komore\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\nendocrinopathies and coagulation disorders, and to \nperform microbiological testing (cervical and vaginal \nbacterial culture swabs, swabs for Chlamydia tracho -\nmatis, Ureaplasma urealyticum, Mycoplasma hominis). \nEstablishing the level of serum progesterone be -\ntween day 22 and day 24 of the menstrual cycle in \nwomen whose cycle is 28 days, can facilitate the doc -\numenting of the existence of ovulation, with values \nabove 3 ng/ml indicating the existence of ovulation. \nIn women above the age of 40 years, it is necessary to \nperform diagnostic curettage for the purpose of ex -\ncluding endometrial carcinoma [1,2,4,5].\nTreatment of abnormal uterine bleeding \nThe most important step in treating abnormal uterine \nbleeding is the diagnosis of the cause of the bleeding. \nThe therapy is expectative, medicamentous, and sur -\ngical. Expectative therapy is advised in case of break -\nthrough bleeding occurring in the first three months of \nusing oral contraceptives. Polyp treatment is surgical, \nand the method of choice is hysteroscopic polypecto -\nmy. Myomas can be treated with medication as well as \nsurgically (myomectomy, hysterectomy, blood vessel \nembolization, GnRH analogs). Malignant diseases are \ntreated according to oncological protocols, depending \non the localization of the primary tumor, the histolog-\nical type, and the FIGO stage of the disease. In women \nin their reproductive period who experience anovula-\ntory bleeding, it is recommended to apply combined \noral contraceptives or intrauterine devices with levo -\nnorgestrel. In cases of anovulatory bleeding in older \nwomen not interested in reproduction, performing \nendometrial ablation or a hysterectomy is an option. \nSurgical treatment is performed in patients in whom \nmedicamentous treatment did not provide the desired \nresults [1,4,5].\nConflict of interest: None declared.\nLečenje patoloških krvarenja iz materice\nNajvažniji korak u lečenju patološkog krvarenja je di-\njagnostika uzroka krvarenja. Terapija je ekspektativna, \nmedikamentna i hirurška. Ekspektativna terapija se \nsavetuje u slučaju pojave probojnih krvarenja, tokom \nprva tri meseca korišćenja oralnih kontraceptiva. Leče-\nnje polipa je hirurško, a metoda izbora je histeroskop -\nska polipektomija. Miomi se mogu lečiti medikamen-\ntno i hirurški (miomektomija, histerektomija, emboli-\nzacija krvnih sudova, GnRH analozi). Maligne bolesti se \nleče u skladu sa onkološkim protokolima, u zavisnosti \nod lokalizacije primarnog tumora, histološkog tipa i \nFIGO stadijuma bolesti. Kod žena u reproduktivnom \nperiodu sa anovulatornim krvarenjima, savetuje se pri-\nmena kombinovanih oralnih kontraceptiva ili intraute-\nrinih uložaka sa levonorgestrelom. U slučaju anovula-\ntornih krvarenja kod žena starije životne dobi, koje \nnisu zainteresovane za rađanje, dolazi u obzir ablacija \nendometrijuma i histerektomija. Hirurško lečenje se \nprimenjuje kod pacijentkinja kod kojih medikamentno \nlečenje nije dalo željene rezultate [1,4,5].\nSukob interesa: Nije prijavljen. \nLITERATURA / REFERENCES\n1. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Gro -\nup. The FIGO classification of causes of abnormal uterine bleeding in the \nreproductive years. Fertil Steril. 2011 Jun;95(7):2204-8, 2208.e1-3. doi: \n10.1016/j.fertnstert.2011.03.079.\n2. Spremović-Rađenović S, Stefanović A, Kadija S, Jeremić K, Sparić R. Classifi -\ncation and the diagnostics of abnormal uterine bleeding in nongravid wo -\nmen of reproductive age: The PALM-COEIN classification system adopted \nby the International Federation of Gynecology and Obstetrics. Vojnosanit \nPregl. 2016 Dec;73(12):1154-9. doi: 10.2298/VSP160709289S.\n3. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. \nThe two FIGO systems for normal and abnormal uterine bleeding symptoms \nand classification of causes of abnormal uterine bleeding in the reproducti -\nve years: 2018 revisions. Int J Gynaecol Obstet. 2018 Dec;143(3):393-408. \ndoi: 10.1002/ijgo.12666.\n4. Marnach ML, Laughlin-Tommaso SK. Evaluation and Management of \nAbnormal Uterine Bleeding. Mayo Clin Proc. 2019 Feb;94(2):326-35. doi: \n10.1016/j.mayocp.2018.12.012.\n5. Munro MG. Practical aspects of the two FIGO systems for management of \nabnormal uterine bleeding in the reproductive years. Best Pract Res Clin \nObstet Gynaecol. 2017 Apr;40:3-22. doi: 10.1016/j.bpobgyn.2016.09.011.\n6. Liu Z, Doan QV, Blumenthal P , Dubois RW. A systematic review evaluating \nhealth-related quality of life, work impairment, and health-care costs \nand utilization in abnormal uterine bleeding. Value Health. 2007 May-\nJun;10(3):183-94. doi: 10.1111/j.1524-4733.2007.00168.x.\n7. Sparic R, Mirkovic L, Malvasi A, Tinelli A. Epidemiology of Uterine Myo -\nmas: A Review. Int J Fertil Steril. 2016 Jan-Mar;9(4):424-35. doi: 10.22074/\nijfs.2015.4599.\n8. Nijkang NP , Anderson L, Markham R, Manconi F. Endometrial polyps: \nPathogenesis, sequelae and treatment. SAGE Open Med. 2019 May \n2;7:2050312119848247. doi: 10.1177/2050312119848247.\n9. Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J. Diagnosis and \nmanagement of endometrial polyps: a critical review of the literatu -\nre. J Minim Invasive Gynecol. 2011 Sep-Oct;18(5):569-81. doi: 10.1016/j.\njmig.2011.05.018.\n10. Leyendecker G, Kunz G, Herbertz M, Beil D, Huppert P , Mall G, et al. Uterine \nperistaltic activity and the development of endometriosis. Ann N Y Acad \nSci. 2004 Dec;1034:338-55. doi: 10.1196/annals.1335.036.\n11. de Bruijn AM, Smink M, Lohle PNM, Huirne JAF , Twisk JWR, Wong C, et al. \nUterine Artery Embolization for the Treatment of Adenomyosis: A Systema-\ntic Review and Meta-Analysis. J Vasc Interv Radiol. 2017 Dec;28(12):1629-\n42.e1. doi: 10.1016/j.jvir.2017.07.034.\n12. Laughlin SK, Stewart EA. Uterine leiomyomas: individualizing the approach \nto a heterogeneous condition. Obstet Gynecol. 2011 Feb;117(2 Pt 1):396-\n403. doi: 10.1097/AOG.0b013e31820780e3.\n\nSparić R. et al.\nSerbian  JournaL  of  the  m edicaL  c hamber   |  Volume 2 / No. 4  |  December 2021.      427\npatološko  krvarenje  iz  materice  kod  žena  u  reproduktivnom  periodu\nabnormal  uterine  bleeding  in  women  of  reproductive  age\n13. Sparić R. [Uterine myomas in pregnancy, childbirth and puerperium]. \nSrp Arh Celok Lek. 2014 Jan-Feb;142(1-2):118-24. Serbian. doi: 10.2298/\nsarh1402118s.\n14. Tinelli A, Vinciguerra M, Malvasi A, Andjić M, Babović I, Sparić R. Uterine \nFibroids and Diet. Int J Environ Res Public Health. 2021 Jan 25;18(3):1066. \ndoi: 10.3390/ijerph18031066.\n15. Divakar H. Asymptomatic uterine fibroids. Best Pract Res Clin Obstet Gynae-\ncol. 2008 Aug;22(4):643-54. doi: 10.1016/j.bpobgyn.2008.01.007. \n16. Tinelli A, Sparic R, Kadija S, Babovic I, Tinelli R, Mynbaev OA, et al. Myomas: \nanatomy and related issues. Minerva Ginecol. 2016 Jun;68(3):261-73.\n17. Sparic R, Terzic M, Malvasi A, Tinelli A. Uterine fibroids - clinical presen -\ntation and complications. Acta Chir Iugosl 2014;61:41–8. doi: 10.2298/\nACI1403041S.\n18. Sparic R, Nejkovic L, Mutavdzic D, Malvasi A, Tinelli A. Conservative surgical \ntreatment of uterine fibroids. Acta Chir Iugosl 2014;61:11–6. doi: 10.2298/\nACI1404011S.\n19. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract \nRes Clin Obstet Gynaecol. 2008 Aug;22(4):615-26. doi: 10.1016/j.bpo -\nbgyn.2008.01.008.\n20. Manyonda I, Belli AM, Lumsden MA, Moss J, McKinnon W, Middleton LJ, \net al.; FEMME Collaborative Group. Uterine-Artery Embolization or Myome -\nctomy for Uterine Fibroids. N Engl J Med. 2020 Jul 30;383(5):440-51. doi: \n10.1056/NEJMoa1914735.\n21. See AT, Havenga S. Outcomes of women with postcoital bleeding. Int J \nGynaecol Obstet. 2013 Jan;120(1):88-9. doi: 10.1016/j.ijgo.2012.07.017.\n22. Doraiswami S, Johnson T, Rao S, Rajkumar A, Vijayaraghavan J, Panicker \nVK. Study of endometrial pathology in abnormal uterine bleeding. J Obstet \nGynaecol India. 2011 Aug;61(4):426-30. doi: 10.1007/s13224-011-0047-2.\n23. Haidopoulos D, Simou M, Akrivos N, Rodolakis A, Vlachos G, Fotiou S, et \nal. Risk factors in women 40 years of age and younger with endometrial \ncarcinoma. Acta Obstet Gynecol Scand. 2010 Oct;89(10):1326-30. doi: \n10.3109/00016349.2010.515666.\n24. James AH, Manco-Johnson MJ, Yawn BP , Dietrich JE, Nichols WL. Von Wille-\nbrand disease: key points from the 2008 National Heart, Lung, and Blood \nInstitute guidelines. Obstet Gynecol. 2009 Sep;114(3):674-8. doi: 10.1097/\nAOG.0b013e3181b191ea.\n25. Deligeoroglou E, Karountzos V. Abnormal Uterine Bleeding including co -\nagulopathies and other menstrual disorders. Best Pract Res Clin Obstet \nGynaecol. 2018 Apr;48:51-61. doi: 10.1016/j.bpobgyn.2017.08.016.\n26. Elmaoğulları S, Aycan Z. Abnormal Uterine Bleeding in Adolescents. J Clin \nRes Pediatr Endocrinol. 2018 Jul 31;10(3):191-7 . doi: 10.4274/jcrpe.0014.\n27. Thakur M, Maharjan M, Tuladhar H, Dwa Y, Bhandari S, Maskey S, et al. \nThyroid Dysfunction in Patients with Abnormal Uterine Bleeding in a Ter -\ntiary Care Hospital: A Descriptive Cross-sectional Study. JNMA J Nepal Med \nAssoc. 2020 May 30;58(225):333-7 . doi: 10.31729/jnma.5033.\n28. Delitala AP , Capobianco G, Delitala G, Cherchi PL, Dessole S. Polycystic ovary \nsyndrome, adipose tissue and metabolic syndrome. Arch Gynecol Obstet. \n2017 Sep;296(3):405-19. doi: 10.1007/s00404-017-4429-2.\n29. Joffe H, Hayes FJ. Menstrual cycle dysfunction associated with neurologic \nand psychiatric disorders: their treatment in adolescents. Ann N Y Acad Sci. \n2008;1135:219-29. doi: 10.1196/annals.1429.030.\n30. McCarthy KJ, Gollub EL, Ralph L, van de Wijgert J, Jones HE. Hormonal \nContraceptives and the Acquisition of Sexually Transmitted Infections: An \nUpdated Systematic Review. Sex Transm Dis. 2019 May;46(5):290-6. doi: \n10.1097 /OLQ.0000000000000975.\n31. Parkash V, Fadare O, Tornos C, McCluggage WG. Committee Opinion No. 631: \nEndometrial Intraepithelial Neoplasia. Obstet Gynecol. 2015 Oct;126(4):897 . \ndoi: 10.1097 /AOG.0000000000001071.","source_license":"CC0","license_restricted":false}