Abnormal uterine bleeding in women of reproductive age

Introduction: Abnormal uterine bleeding is one of the most common health dis- orders in women of reproductive age. In addition, it represents a significant public health problem. The aim of this paper is to present the modern classification, as well as the basis for diagnosis and treatment of abnormal uterine bleeding.

This paper presents data from publications selected from the MED - LINE database using a combination of keywords: “menstrual bleeding” , “abnor - mal uterine bleeding” , “PALM-COEIN classification” , “leiomyoma” , “endometrial polyp” , “adenomyosis” , “gynecological malignancies” , “coagulopathy” , “diagnos- tics of abnormal uterine bleeding” , and “treatment of abnormal uterine bleed - ing”. The collected data from the selected studies were used and presented in this review paper.

In order to achieve a unique classification of abnormal uterine bleeding, a classification was adopted under the name/acronym PALM-COEIN. The causes listed in the first part of the acronym (PALM) have a pathological/ anatomical cause in the reproductive organs that can be diagnosed using imag - ing techniques and/or histopathological examination. The causes listed in the second part of the acronym (COEIN) represent a group of dysfunctional disorders and they cannot be diagnosed using imaging techniques. Key words: bleeding, uterus, menstrual cycle SAŽETAK Uvod: Patološko krvarenje iz materice predstavlja jedan od najčešćih poreme - ćaja zdravlja kod žena u reproduktivnom periodu. Uz to, predstavlja i značajan javno-zdravstveni problem. Cilj ovog rada je da se prikaže savremena podela, kao i osnovi dijagnostike i lečenja patoloških krvarenja iz materice. Metode: U radu su prikazani podaci iz radova selektovanih pretraživanjem MED - LINE baze korišćenjem kombinacije ključnih reči: “menstrual bleeding”, “abnormal uterine bleeding”, “PALM-COEIN classification”, “leiomyoma”, “endometrial polyp”, “adenomyosis”, “gynecological malignancies”, “coagulopathy”, “diagnostics of ab - normal uterine bleeding”, i “treatment of abnormal uterine bleeding”. Podaci priku- pljeni iz odabranih radova upotrebljeni su i predstavljeni u ovom radu. Zaključak: U cilju postizanja jedinstvene klasifikacije poremećaja menstrual - nog ciklusa, usvojena je klasifikacija ovih poremećaja koja se naziva akronimom PALM-COEIN. Uzroci nabrojani u prvom delu akronima (PALM) imaju patološ - ko-anatomski supstrat na nivou genitalnih organa koji se može dijagnostikovati primenom imidžing metoda i/ili histopatološkim pregledom. Uzroci nabrojani u drugom delu akronima ( COEIN) uključuju difsunkcionalne poremećaje i ne mogu se dijagnostikovati primenom imidžing metoda. Ključne reči: krvarenje, materica, menstrualni ciklus Primljeno • Received: November 18, 2021; Revidirano • Revised: November 28, 2021; Prihvaćeno • Accepted: December 06, 2021; Online first: December 13, 2021. DOI: 10.5937/smclk2-34990 Autor za korespondenciju: Radmila Sparić Klinika za ginekologiju i akušerstvo, Univerzitetski klinički centar Srbije Višegradska 26, 11000 Beograd, Srbija Elektronska adresa: [email protected] Corresponding author: Radmila Sparić Clinic for Gynecology and Obstetrics, University Clinical Center of Serbia 26 Višegradska Street, 11000 Belgrade, Serbia E-mail: [email protected] Radmila Sparić1,2, Đina Tomašević 3 , Mladen Anđić 1, Svetlana Spremović Rađenović 1,2 1 Klinika za ginekologiju i akušerstvo, Univerzitetski klinički centar Srbije, Beograd, Srbija 2 Medicinski fakultet, Univerzitet u Beogradu, Beograd, Srbija 3 Opšta bolnica „Čačak“ , Čačak, Srbija 1 Clinic for Gynecology and Obstetrics, University Clinical Center of Serbia, Belgrade, Serbia 2 Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 3 General Hospital Čačak, Čačak, Serbia. ABNORMAL UTERINE BLEEDING IN WOMEN OF REPRODUCTIVE AGE PATOLOŠKO KRVARENJE IZ MATERICE KOD ŽENA U REPRODUKTIVNOM PERIODU re Vie W artic Le pre GLedni rad Sparić R. et al. Serbian JournaL of the m edicaL c hamber | Volume 2 / No. 4 | December 2021. 417 patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age

Abnormal uterine bleeding (AUB) is any bleeding that deviates from the normal cycle/frequency, length, and quantity of menstrual bleeding, and represents one of the most frequent health problems in women in the reproductive period [1,2]. Also, it is a significant public health issue. According to data from literature, the prev- alence of this type of bleeding ranges from 3 to 30% [3]. Accurate knowledge of the physiology of menstru- al bleeding is a prerequisite for establishing a timely diagnosis and administering appropriate treatment for abnormal uterine bleeding. A normal menstrual cycle is defined as regular cyclical bleeding, which occurs ev- ery 28 days, on average, and lasts from 4 to 7 days, with an average blood loss of around 35 ml ( Table 1). This cycle is the result of a complex interaction between the hypothalamus, the anterior pituitary lobe, the ovaries, and the endometrium. At each of these levels, hor - mones are secreted, which enable or inhibit the release of hormones at other levels. Less than 1.0% of women have regular menstrual cycles that are shorter than 21 days or longer than 35 days [4]. Variations in the duration and intensity of menstru- al bleeding are common at the beginning and at the end of the reproductive period - in adolescence and be- fore menopause. The frequency of anovulatory cycles is the highest before 20 years of age and after 40 years of age. During 12 to 18 months after menarche, men- strual cycles are irregular, due to the immaturity of the hypothalamic-pituitary-ovarian axis. Several years after menarche, the length of the luteal phase of the cycle becomes relatively constant (13 to 15 days). During the period of 5 to 7 years following menarche, menstrual cycles become regular, and their length and duration do not significantly change during the reproductive period, although, over the years, the length of the men- strual cycle gradually shortens. During the period of 8 to 10 years before menopause, the frequency of ovula- tory cycles gradually decreases [1-4]. If the function of the hypothalamic-pituitary-ovar - ian axis is disrupted, and/or if a structural abnormality of the uterus occurs (myomas, polyps, adenomyosis, malignancy), or if there is a disorder in blood coagu- lation (coagulopathies, iatrogenic causes), the normal menstrual cycle is disrupted and abnormal uterine bleeding occurs [5]. Abnormal uterine bleeding has a significant im- pact on physical and mental health, as well as on the emotional, sexual, and professional aspects of wom- en’s lives, as they diminish their quality of life. Also, this issue generates significant economic costs. It has been estimated that direct medical costs for the treatment of abnormal uterine bleeding in the United States of UVOD Patološko krvarenje iz materice (engl. abnormal uterine bleeding -AUB) predstavlja svako krvarenje koje odstu- pa od normalne cikličnosti/učestalosti, dužine trajanja i obima menstrualnog krvarenja, i predstavlja jedan od najčešćih poremećaja zdravlja kod žena u reproduk - tivnom periodu [1,2]. Uz to, predstavlja i značajan jav - no-zdravstveni problem. Prema podacima iz literature, prevalencija ovih krvarenja iznosi 3 do 30% [3]. Precizno poznavanje osnova fiziologije menstrual- nog ciklusa je uslov za postavljanje pravovremene di- jagnoze i sprovođenje adekvatnog lečenja patološkog krvarenja iz materice. Normalan menstrualni ciklus se definiše kao regularno ciklično krvarenje, koje se javlja na prosečno 28 dana, traje 4 do 7 dana, uz prosečan gu- bitak krvi od oko 35 ml (Tabela 1). Ovaj ciklus je rezultat složene interakcije između hipotalamusa, prednjeg re - žnja hipofize, jajnika, i endometrijuma. Na svakom od ovih nivoa stvaraju se hormoni, koji omogućavaju ili sprečavaju oslobađanje hormona na drugim nivoima. Manje od 1,0% žena imaju regularne menstruacione cikluse koji traju kraće od 21 i duže od 35 dana [4]. Varijacije u dužini trajanja i intenzitetu menstrualnog krvarenja su uobičajene na početku i kraju reproduktiv- nog perioda - tokom adolescencije i pre nastupanja me- nopauze. Učestalost anovulatornih ciklusa je najveća pre 20-te godine života i posle 40-te godine života. Tokom 12 do 18 meseci nakon menarhe, menstruacioni ciklusi su iregularni, usled nezrelosti hipotalamo-hipofizno-ovarijal- ne osovine. Nekoliko godina nakon menarhe, dužina lu- tealne faze ciklusa postaje relativno konstantna (13 do 15 dana). Tokom 5 do 7 godina nakon menarhe, menstruaci- oni ciklusi postaju regularni i njihova dužina i trajanje se ne menjaju značajno tokom reproduktivnog perioda, iako se sa godinama dužina trajanja menstruacionih ciklusa po- lako smanjuje. Tokom perioda od 8 do 10 godina pre me- nopauze, učestalost ovulatornih ciklusa se smanjuje [1 - 4]. Ukoliko dođe do poremećaja funkcije hipotala- mo-hipofizne osovine i/ili strukturalnog poremećaja materice (miomi, polipi, adenomioza, malignitet), ili poremećaja u koagulaciji krvi (koagulopatije, jatrogeni uzroci), remeti se normalan menstrualni ciklus i nastaje patološko krvarenje [5]. Tabela 1. Karakteristike normalnog menstrualnog krvarenja Table 1. Characteristics of normal menstrual bleeding Interval između ciklusa / Interval between cycles 28 (21 - 35) dana / days Dužina trajanja krvarenja / Duration of bleeding 4 - 7 dana / days Obim krvarenja / Bleeding volume 35 (20 - 80) ml Sparić R. i sar. 418 Decembar 2021. | Volumen 2 / Broj 4 | SrpSki medicinSki čaSopiS LekarSke komore patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age America amount to roughly 1 billion dollars per year, while indirect costs, stemming from absence from work and decrease in social and life activity, amount to approximately 12 billion dollars annually [6]. The aim of this paper is to present the current clas- sification, as well as the bases of diagnosis and treat - ment of abnormal uterine bleeding.

This paper presents data from publications selected from the PubMed database using a combination of

“menstrual bleeding” , “abnormal uterine bleeding” , “PALM-COEIN classification” , “leiomyoma” , “endometrial polyp” , “adenomyosis” , “gynecological malignancies” , “coagulopathy” , “diagnostics of abnor- mal uterine bleeding” , and “treatment of abnormal uterine bleeding” . The database search and the meth- od of publication selection and inclusion into this study are presented in Figure 1. Patološka krvarenja iz materice imaju značajan uti- caj na fizičko i mentalno zdravlje, kao i na emotivni, seksualni i profesionalni aspekt života žena, smanjujući i njihov kvalitet života. Takođe, ova krvarenja uzrokuju značajne materijalne troškove. Procenjeno je da direk- tni troškovi njihovog lečenja u Sjedinjenim Američkim Državama iznose oko jednu milijardu dolara godišnje, dok indirektni troškovi koji proističu iz izostanka sa posla, smanjenja društvene i životne aktivnosti iznose oko 12 milijardi dolara godišnje [6]. Cilj ovog rada je da se prikaže savremena podela, kao i osnovi dijagnostike i lečenja patoloških krvarenja iz materice. METODE U radu su prikazani podaci iz radova selektovanih pre - traživanjem PubMed baze korišćenjem kombinacije ključnih reči: “menstrual bleeding”, “abnormal uterine bleeding”, “PALM-COEIN classification”, “leiomyoma”, “en- Slika 1. PRISMA dijagram pretraživanja i odabira publikacija Figure 1. PRISMA diagram of the publications search and selection Pretraživanje naučnih radova i publikacija / Research papers and publications search Pretraživanje / Research Radovi pronađeni u bazi podataka / Papers found in the database (n = 5.669) Uključivanje / Inclusion Radovi isključeni pre daljeg pretraživanja / Papers excluded before further search – Radovi označeni kao neodgovarajući putem alata za pretraživanje / Papers marked as not suitable with the aid of the search tool (n = 5.243 ) – Radovi označeni kao neodgovarajući iz drugih razloga / Papers marked as not suitable for other reasons (n = 268) Pretraženi radovi / Papers searched (n = 158) Isključeni radovi / Papers excluded (n = 31) Radovi koji su detaljno pretraženi i razmotreni za uključivanje / Papers searched in detail and considered for inclusion (n = 127) Pretraženi radovi / Papers meeting the inclusion criteria (n = 31) Uključeni radovi/ Papers included (n = 31) Sparić R. et al. Serbian JournaL of the m edicaL c hamber | Volume 2 / No. 4 | December 2021. 419 patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age Current nomenclature of menstrual cycle disor- ders and abnormal uterine bleeding (FIGO 2011) For the purpose of achieving a uniform classification of menstrual cycle disorders, in 2011, the Internation- al Federation of Gynecology and Obstetrics (FIGO) in- troduced a classification of these disorders under the name PALM-COEIN [1-3]. This acronym denotes indi- vidual causes of abnormal uterine bleeding. The caus- es listed in the first part of the acronym (PALM) have a pathological/anatomical cause in the reproductive or - gans that can be diagnosed using imaging techniques and/or histopathological examination [1,2,4,7]. The causes listed in the second part of the acronym (COEIN) represent a group of dysfunctional disorders and they cannot be diagnosed using imaging techniques [1-4]. Endometrial polyp A polyp is a lesion which is formed as the result of lo - calized endometrial tissue growth. It is composed of glands, stroma, and blood vessels, and is covered with epithelium. It is most commonly encountered in women in the reproductive period, and the frequency of the oc- currence of polyps increases with age. It is believed that estrogens play a key role in their formation [8 ]. Abnor- mal uterine bleeding, caused by polyps, is manifested as intermenstrual bleeding, hypermenorrhea, metrorrha- gia or postmenopausal bleeding, and may also be linked to dysmenorrhea. However, just like myomas, polyps are most commonly asymptomatic [8,9]. They are frequent in infertile patients and those treated with tamoxifen. Most of the endometrial polyps are benign, although, in postmenopause, in 1.5 to 4.5% of the cases, they are malignant [8,9]. Polyps smaller than 1 cm may sponta- neously regress. They are diagnosed by ultrasound or with hysteroscopy. Polyps are treated by surgical-hys- teroscopic resection or by explorative curettage [9]. Adenomyosis Adenomyosis is characterized by the presence of en- dometrial tissue (glands and stroma) in the myometri- um. The presence of ectopic endometrial tissue leads to hypertrophy of the surrounding myometrium, caus- ing diffuse enlargement of the uterus. It occurs focally or diffusely in the uterus, and its greatest frequency is in women in their forties. The most significant factor for the occurrence of adenomyosis is multiparity, but it is believed that all factors contributing to the penetration of endometrial glands and the stroma through the basal layer of the endometrium, influence the development of endometriosis (curettage of the uterine cavity, cesarean section, miscarriage). Bleeding caused by adenomyosis occurs as the result of uterine contractility impairment. It dometrial polyp”, “adenomyosis”, “gynecological mali- gnancies”, “coagulopathy”, “diagnostics of abnormal ute- rine bleeding” , i “treatment of abnormal uterine bleeding”. Pretraživanje baze podataka, način odabira i uključiva- nja publikacija u ovaj rad prikazani su u Grafikonu 1. Savremena nomenklatura poremećaja menstru- alnog ciklusa i patoloških krvarenja iz materice (FIGO 2011) U cilju postizanja jedinstvene klasifikacije patoloških krvarenja iz materice, Međunarodna federacija gineko- loga i akušera (engl. International Federation of Gyneco- logy and Obstetrics - FIGO) je, 2011. godine, uvela klasi- fikaciju ovih poremećaja pod nazivom PALM-COEIN [1- 3]. Sam akronim označava pojedine uzroke patološkog krvarenja iz materice. Uzroci nabrojani u prvom delu akronima (PALM) imaju patološko-anatomski supstrat na nivou genitalnih organa koji se može dijagnostiko - vati primenom imidžing metoda i/ili histopatološkim pregledom [1,2,4,7]. Uzroci nabrojani u grupi COEIN uključuju difsunkcionalne poremećaje i ne mogu se di- jagnostikovati primenom imidžing metoda [1-4]. Endometrijalni polip Polip predstavlja promenu nastalu usled lokalizovanog rasta tkiva endometrijuma, sastavljenu od žlezda, stro - me i krvnih sudova, i pokrivenu epitelom. Najčešće se sreće kod žena u reproduktivnom periodu, a učestalost polipa se povećava sa godinama. Smatra se da estrogeni igraju ključnu ulogu u njihovom nastanku [8]. Patološko krvarenje uzrokovano polipima se manifestuje kao in- termenstrualno krvarenje, hipermenoreja, metroragija ili postmenopauzalno krvarenje, a može biti povezano i sa dismenorejom. Ipak, kao i miomi, polipi su najčešće asimptomatski [8,9]. Česti su kod infertilnih pacijentki- nja i onih koje primaju tamoksifen. Najveći broj polipa endometrijuma su benigni, mada su u postmenopauzi u 1,5 do 4,5% slučajeva maligni [8,9]. Polipi manji od 1 cm mogu spontano regredirati. Dijagnostikuju se ultra- zvukom ili histeroskopski. Polipi se leče hirurški-histero- skopskom resekcijom ili eksplorativnom kiretažom [9]. Adenomioza Adenomiozu karakteriše prisustvo tkiva endometrijuma (žlezda i strome) u miometrijumu. Prisustvo ektopičnog endometrijalnog tkiva dovodi do hipertrofije okolnog miometrijuma, uzrokujući difuzno uvećanje materice. Javlja se fokalno ili difuzno u materici, a najveću uče - stalost ima u petoj deceniji života. Najznačajniji faktor za nastanak adenomioze je multiparitet, ali se smatra da svi faktori koji doprinose penetraciji endometrijalnih žlezda i strome kroz bazalni sloj endometrijuma, utiču na nastanak endometrioze (kiretaža materične šupljine, Sparić R. i sar. 420 Decembar 2021. | Volumen 2 / Broj 4 | SrpSki medicinSki čaSopiS LekarSke komore patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age carski rez, spontani pobačaj). Krvarenje uzrokovano adenomiozom nastaje kao posledica poremećaja kon- traktilnosti materice. Najčešće se manifestuje menora- gijom i obično je povezano sa izraženom dismenore - jom [10]. Adenomioza se dijagnostikuje ultrazvukom i nuklearnom magnetnom rezonancom. Definitivna dija- gnoza se postavlja histopatološkim pregledom. Medi- kamentno lečenje uključuje primenu progesteronskih preparata, agonista gonadotropin-oslobađajućeg hor - mona (engl. gonadotropin-releasing hormone - GnRH) i inhibitora aromataze. Fokalna ognjišta adenomioze se mogu lečiti hirurškom resekcijom. Kod žena koje nisu zainteresovane za reprodukciju, lečenje je moguće sprovesti embolizacijom materičnih arterija [11]. Leiomiom Leiomiomi, miomi ili fibromi su benigni tumori pore - klom od mišićnih ćelija miometrijuma. Predstavljaju najčešće benigne tumore ženskih reproduktivnih or - gana. Klinička slika varira od potpunog odsustva su- bjektivnih tegoba do brojnih simptoma, koji mogu imati značajan uticaj na zdravlje žene. Manje od 50,0% mioma su simptomatski, a najčešći simptom je pato - loško krvarenje iz materice [7,12–15]. Mogu biti poje - dinačni ili multipli, a u oko 97,0% slučajeva su lokalizo- vani u telu materice. U odnosu na anatomske slojeve zida materice ovi tumori se dele na submukozne, in- tramuralne, subserozne, i intraligamentarne (miomi lokalizovani između listova širokih materičnih veza). Na Slici 2 prikazana je FIGO podela mioma na osnovu Slika 2. Tipovi mioma po FIGO klasifikaciji Figure 2. Types of myomas according to the FIGO classification most commonly manifests as menorrhagia and is usually connected to marked dysmenorrhea [10]. Adenomyosis is diagnosed with ultrasound and nuclear magnetic res- onance imaging. Definitive diagnosis is established by histopathological examination. Medicamentous treat - ment includes the application of progesterone-based medicaments, gonadotropin-releasing hormone (GnRH) agonists, and aromatase inhibitors. Focal areas of adeno- myosis can be treated with surgical resection. In women not interested in reproduction, it is possible to perform treatment by embolizing uterine arteries [11]. Leiomyomas Leiomyomas, myomas or fibromas are benign tumors originating from muscular cells of the myometrium. They are the most common benign tumors of female re- productive organs. The clinical presentation varies from complete absence of subjective complaints to numer - ous symptoms, which may significantly affect the wom- an’s health. Less than 50.0% are symptomatic, and the most frequent symptom is abnormal uterine bleeding [7,12–15]. They can be solitary or multiple, and in around 97.0% of the cases, they are localized in the body of the uterus. In relation to the anatomical layers of the uterine wall, these tumors are classified as submucosal, intramu- ral, subserosal, and intraligamentous (myomas localized between the leaves of the broad uterine ligaments). Figure 2 shows the FIGO classification of myomas based on localization [1-3]. The nomenclature of myomas, by type, based on this classification is presented in Table 2. Sparić R. et al. Serbian JournaL of the m edicaL c hamber | Volume 2 / No. 4 | December 2021. 421 patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age lokalizacije [1-3]. Nomenklatura mioma po tipovima na osnovu ove podele prikazana je u Tabeli 2. Mehanizmi kojima miomi utiču na pojavu patološ- kih krvarenja iz materice su različiti, a u velikoj meri za- vise i od njihove veličine, broja i lokalizacije. Kod žena sa patološkim krvarenjem iz materice, najčešće se di- jagnostikuju intrakavitarni (miomi u šupljini materice), submukozni miomi i veliki intramuralni miomi [16]. Ovi miomi povećavaju ukupnu površinu šupljine materice prekrivenu endometrijumom, dovode do iregularne deskvamacije endometrijuma i iregularnih kontrak - cija materice, izazivajući iregularna i obilna materična krvarenja [17]. Pored toga, novija saznanja ukazuju na značaj neoangiogeneze, povišenih nivoa vazoaktivnih supstanci i faktora rasta, kao i koagulacionih promena, koji zajednički utiču na pojavu patoloških krvarenja kod žena sa miomima [18]. Lečenje mioma je medi- kamentno (kombinovana oralna kontracepcija, GnRH agonisti i antagonisti) ili hirurško (miomektomija, histe- rektomija), u zavisnosti od karakteristika mioma, godi- na starosti i pariteta pacijentkinje [19]. Kod žena koje nisu zainteresovane za reprodukciju, lečenje je moguće sprovesti embolizacijom materičnih arterija [20]. Malignitet i hiperplazija Maligne bolesti ženskih reproduktivnih organa koje mogu uzrokovati krvarenje uključuju oboljenja vulve, vagine, grlića materice, endometrijuma, tela materice, jajnika i jajovoda. Najčešći uzroci patoloških krvarenja su maligniteti materice. Karcinom grlića materice se manifestuje kontak - tnim, intermenstrualnim ili potpuno acikličnim krvare - njem, te je isključivanje ovog oboljenja značajan deo The mechanisms through which myomas affect the occurrence of abnormal uterine bleeding vary and de- pend, to a great extent, on the size of the myomas, their number, and localization. In women with abnormal uterine bleeding, the following myomas are most com- monly diagnosed: intracavitary (myomas in the uterine cavity), submucosal, and large intramural myomas [16]. These myomas enlarge the overall surface of the uter - ine cavity covered with endometrium, lead to irregular desquamation of the endometrium and to irregular contractions of the uterus, thereby causing irregular and profuse uterine bleeding [17]. Also, recent discov - eries indicate the significance of neoangiogenesis, ele- vated levels of vasoactive substances and growth fac - tors, and of coagulation changes, which together affect the occurrence of abnormal bleeding in women with myomas [18]. Treatment of myomas is medicamentous (combined oral contraceptives, GnRH agonists and an- tagonists) or surgical (myomectomy, hysterectomy), depending on the characteristics of the myomas and on the age and parity of the patient [19]. In women not interested in reproduction, it is possible to perform treatment by embolizing uterine arteries [20]. Malignancy and hyperplasia Malignant diseases of female reproductive organs that may cause bleeding include malignancies affecting the vulva, the vagina, the cervix, the endometrium, the uterine body, the ovaries and the oviducts The most common causes of abnormal uterine bleeding are uterine malignancies. Cervical carcinoma manifests as contact, intermen- strual or completely acyclic bleeding, which is why it Tabela 1. Karakteristike normalnog menstrualnog krvarenja Table 1. Characteristics of normal menstrual bleeding SM - submukozni / SM - submucosal 0 Intrakavitarni miomi na peteljci / Intracavitary pedunculated myomas 1 <0% intramuralni / <50% intramural 2 ≥50% intramuralni / ≥50% intramural O - ostali/ O - other 3 U kontaktu sa endometrijumom, 100% intramuralni / In contact with the endometrium, 100% intramural 4 Intramuralni / Intramural 5 Subserozni ≥50% intramuralni / Subserosal ≥50% intramural 6 Subserozni <50% intramuralni / Subserosal <50% intramural 7 Subserozni na peteljci / Pedunculated subserosal 8 Drugi (cervikalni, intraligamentarni, parazitni)i / Other (cervical, intraligamentous, parasitic) Hibridni leiomiomi (u kontaktu kako sa endometrijumom, tako i sa serozom materice)/ Hybrid leiomyomas (in contact both with the endometrium and with the uterine serosa) Obeležavaju se sa dva broja odvojena crtom (-). Prvi broj označava odnos mioma sa endometrijumom, a drugi odnos mioma sa serozom materice. / They are marked with two numbers separated by a hyphen (-). The first number marks the relation between the myoma and the endometrium, while the other one designates the relation between the myoma and the uterine serosa. Na primer, miom 2-5 je submukozni i subserozni, pri čemu je manje od 50% volumena mioma u odnosu sa endometrijumom i peritonealnom šupljinom. / For example, a myoma marked 2-5 is submucosal and subserosal, with less than 50% of the myoma volume in contact with the endometrium and the peritoneal cavity. Sparić R. i sar. 422 Decembar 2021. | Volumen 2 / Broj 4 | SrpSki medicinSki čaSopiS LekarSke komore patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age is important to rule out this disease, as a part of the process of diagnosing the cause of abnormal uterine bleeding [21]. Abnormal bleeding can be caused by different endometrial disorders, such as cystic and ad- enomatous hyperplasia, endometrial intraepithelial neoplasia (EIN), and endometrial carcinoma [4,22]. The most frequent symptom of endometrial carcinoma is abnormal uterine bleeding. Although it most frequent- ly occurs in women in their sixties, in around 15.0% of the cases it is encountered in premenopausal women, and in 3.0% to 5.0% of the cases in women younger than 40 years. Uterine sarcomas usually occur in old- er women in menopause, and they clinically manifest as abnormal uterine bleeding and progressive en- largement of the uterus. Ovarian estrogen producing tumors (most commonly granulosa cell tumors) may manifest as abnormal uterine bleeding [2-4,23]. Coagulopathy Abnormal uterine bleeding may be the first clini- cal manifestation of hematological diseases. Around 13.0% of women with profuse menstrual bleeding have some form of coagulation disorder, of which the most common one is von Willebrand’s disease [24]. Coagulopathy represents one of the most frequent causes of menorrhagia [25]. Diseases leading to plate - let deficiency, which can be the cause of abnormal uterine bleeding, include leukemia, severe forms of sepsis, and idiopathic thrombocytopenic purpura. He - mophilia A and B are X-related recessive deficiencies of coagulation factor VIII and coagulation factor IX [24-26]. Women who are carriers of this disease have decreased levels of factor VIII and factor IX, which may manifest as menorrhagia. Less frequently, hereditary coagulopathies that include a disorder in other coag- ulation factors (V, VII, X, XI and XIII) may manifest as menorrhagia. Disorders of liver function in alcoholism, as well as chronic liver diseases, may result in a coagu- lation factor production disorder and the occurrence of abnormal bleeding [24]. Around 5.0% to 20.0% of adolescent young women who experience abnormal uterine bleeding have some form of coagulopathy. This is why coagulation status testing is especially significant in women of this age [25]. Detailed analysis of the coagulation status pres- ents an indispensable part of the diagnostic protocol in women with abnormal uterine bleeding, and the treatment is hematological [24,25]. Ovulatory dysfunction One of the causes of abnormal uterine bleeding, which occurs in the period after menarche and in perimeno - pause, is ovulatory dysfunction. It develops as the result postupka dijagnostike uzroka patoloških krvarenja iz materice [21]. Patološko krvarenje može biti uzrokova- no različitim poremećajima endometrijuma, kao što su cistična i adenomatozna hiperplazija, endometrijalna intraepitelna neoplazija (EIN) i karcinom endometri- juma [4,22]. Najčešći simptom karcinoma endometri- juma je patološko krvarenje iz materice. Iako se najče - šće javlja tokom sedme decenije života, u oko 15,0% slučajeva se sreće kod premenopauzalih žena, a u oko 3,0% do 5,0% slučajeva kod žena mlađih od 40 godina. Sarkomi materice se obično javljaju kod starijih žena u menopauzi, a klinički se manifestuju patološkim krva- renjem iz materice i progresivnim uvećanjem materice. Tumori jajnika koji produkuju estrogen (najčešće gra- nuloza-ćelijski tumori) mogu se manifestovati patološ- kim krvarenjem iz materice [2-4,23]. Koagulopatija Patološko krvarenje iz materice može biti prva klinič - ka manifestacija hematoloških oboljenja. Oko 13,0% žena sa obilnim menstrualnim krvarenjem ima neki ko - agulacioni poremećaj, od kojih je najzastupljenija von Vilebrandova bolest [24]. Koagulopatija predstavlja jedan od najčešćih uzroka menoragije [25]. Oboljenja koja dovode do deficita trombocita, a mogu biti i uzrok patoloških krvarenja iz materice, uključuju leukemi- ju, teške oblike sepse, idiopatsku trombocitopenijsku purpuru. Hemofilija A i B su X-vezani recesivni deficiti faktora koagulacije VIII i faktora koagulacije IX [24-26]. Žene koje su prenosioci ovih bolesti imaju snižene nivoe faktora VIII i faktora IX, što se može manifesto - vati menoragijom. Ređe, nasledne koagulopatije koje uključuju poremećaj ostalih faktora koagulacije (V, VII, X, XI i XIII), mogu se manifestovati menoragijom. Pore- mećaji funkcije jetre kod alkoholizma, kao i njena hro - nična oboljenja mogu imati za posledicu poremećaj produkcije faktora koagulacije i nastanak patološkog krvarenja [24]. Oko 5,0% do 20,0% adolescentkinja kod kojih se pojavi patološko krvarenje iz materice imaju neku koa- gulopatiju. Zbog toga je ispitivanje koagulacinog statu- sa naročito značajno kod žena ovog životnog doba [25]. Detaljno ispitivanje koagulacionog statusa pred- stavlja neizostavni deo dijagnostičkog protokola kod žena sa patološkim krvarenjima iz materice, a lečenje je hematološko [24,25]. Ovulatorna disfunkcija Jedan od uzroka patoloških krvarenja, koja se javljaju u periodu nakon menarhe i u perimenopauzi, jeste ovulatorna disfunkcija. Nastaje kao posledica poreme - ćaja funkcije hipotalamo-hipofizno-ovarijalne osovine, sa kontinuiranom produkcijom estrogena i izostankom Sparić R. et al. Serbian JournaL of the m edicaL c hamber | Volume 2 / No. 4 | December 2021. 423 patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age of a disturbance in the functioning of the hypothalam- ic-pituitary-ovarian axis, with continuous production of estrogen and absence of ovulation, corpus luteum formation and progesterone secretion in the ovaries. Estrogen stimulation leads to continuous proliferation of the endometrium, which, at some point, due to in- sufficient vascularization, necrotizes. As the result of this disorder, so-called breakthrough bleeding occurs. Such anovulatory bleeding is most frequent during the first few years after menarche and in perimenopause. In adolescence, the cause of anovulation is the immaturi- ty of the hypothalamic-pituitary-gonadal axis and the absence of positive feedback by estradiol, which causes peak LH (luteinizing hormone). In perimenopause, the cause of this type of bleeding is ovarian insufficiency. Especially profuse bleeding occurs after a prolonged period of endometrial exposure to estrogens, which is usually found in adolescent young women after men- arche, patients with polycystic ovary (PCO) syndrome, obese, and perimenopausal women [4,26]. Ovulatory dysfunction can manifest as amenor - rhea, while anovulatory bleeding may manifest as ol- igomenorrhea, intermenstrual bleeding or hypermen- orrhea. In women with regular menstrual cycles, ovula- tion is absent in 20.0% of the cases. The most common cause of anovulatory bleeding during the reproductive period in women is the poly - cystic ovary syndrome (PCOS). A disturbance of the hy- pothalamic-pituitary function is a less common cause. Additionally, other hormonal disbalances may be ac - companied by anovulatory bleeding, such as diseases of the thyroid gland (hypothyroidism, hyperthyroid- ism), diseases of the adrenal glands, and diabetes mel- litus [27,28]. Hyperprolactinemia and elevated levels of cortisol (Cushing’s syndrome) can also lead to anovu- lation. Less frequently, the causes can be eating disor - ders (anorexia, bulimia), chronic disease, alcoholism, drug abuse, and stress [4,27,28]. Iatrogenic causes Abnormal uterine bleeding resulting from iatrogenic causes is the consequence of taking medication, most commonly oral contraceptives, selective modulators of estrogen receptors, GnRH agonists and antagonists, digitalis, and anticonvulsants. Drugs cause abnormal bleeding, either by disrupting the function of the hy - pothalamic-pituitary-gonadal axis or by causing fluc - tuations in the levels of circulating hormones. Hyperprolactinemia may be the result of the effect of antipsychotics acting as dopamine antagonists at the level of the central nervous system (risperidone) [4,29]. This type of abnormal bleeding may occur in patients who use combined hormonal contraception ovulacije, formiranja žutog tela i sekrecije progestrona u jajniku. Estrogena stimulacija dovodi do kontinuira- ne proliferacije endometrijuma, koji u nekom trenutku, usled nedovoljne vaskularizacije, podleže nekrozi. Kao posledica ovog poremećaja nastaje tzv. probojno krva- renje. Ovakva anovulatorna krvarenja su najčešća to - kom prvih nekoliko godina nakon menarhe i u perime- nopauzi. U adolescenciji, uzrok anovulacija je nezrelost hipotalamo-hipofizno-gonadne osovine i izostanak pozitivne povratne sprege estradiola, koja uzrokuje pik LH-a (luteinizirajućeg hormona). U perimenopauzi, uzrok ove vrste krvarenja je ovarijalna insuficijencija. Naročito obilna krvarenja se javljaju nakon prolongira- nog perioda ekspozicije endometrijuma estrogenima, što se obično sreće kod adolescentkinja nakon menar- he, pacijentkinja sa PCO (engl. polycystic ovary) sindro- mom, gojaznih, kao i perimenopauzalnih žena [4,26]. Ovulatorna disfunkcija se može manifestovati i amenorejom, a anovulatorna krvarenja oligomenore - jom, intermenstrualnim krvarenjem ili hipermenore - jom. Kod žena koje imaju regularne menstrualne ciklu- se u 20,0% slučajeva izostaje ovulacija. Najčešći uzrok anovulatornih krvarenja tokom re - produktivnog perioda žene je sindrom policističnih jajnika (engl. polycystic ovary syndrome - PCOS). Ređi uzrok je poremećaj hipotalamo-hipofizne funkcije. Uz to, i drugi hormonski poremećaji mogu biti praćeni anovulatornim krvarenjem, kao što su oboljenja tiro - idne žlezde (hipotireoidizam, hipertireoidizam), nad- bubrežne žlezde i diabetes mellitus [27,28]. Hiperpro - laktinemija i povišene vrednosti kortizola (Kušingov sindrom) takođe mogu dovesti do anovulacije. Ređe, uzroci su poremećaji ishrane (anoreksija, bulimija), hronične bolesti, alkoholizam, zloupotreba droga, kao i stres [4,27,28]. Jatrogeni uzroci Jatrogeno nastala patološka krvarenja iz materice na- staju kao posledica uzimanja medikamenata, najčešće oralnih kontraceptiva, selektivnih modulatora estroge- nih receptora, GnRH agonista i antagonista, digitalisa i antikonvulziva. Lekovi izazivaju patološka krvarenja, bilo remeteći funkciju hipotalamo-hipofizno-gonadne osovine, bilo izazivajući fluktuacije cirkulišućih nivoa hormona. Hiperprolaktinemija može biti posledica dejstva antipsihotika koji deluju kao dopaminski antagoni- sti na nivou centralnog nervnog sistema (risperidon) [4,29]. Patološka krvarenja ove vrste se mogu javiti kod korisnica kombinovane hormonske kontracepcije (flasteri, vaginalni prstenovi, pilula), ali i kod korisnica intrauterinih kontraceptivnih uložaka. Probojna krva- renja su česta tokom prva tri meseca upotrebe oralnih Sparić R. i sar. 424 Decembar 2021. | Volumen 2 / Broj 4 | SrpSki medicinSki čaSopiS LekarSke komore patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age (patches, vaginal rings, contraceptive pills), but also in women using intrauterine contraceptive implants. Breakthrough bleeding is common in the first months of using oral hormone contraceptives and occur in 30.0% to 40.0% of the women using them. This type of bleeding is most commonly encountered in women using oral contraceptive pills and hormonal substitu- tion in perimenopause [30]. Most bleeding manifests as menorrhagia. It is important to note that all bleeding in patients using hormonal contraceptives is not caused by hor - monal factors. The results of recent studies have shown that patients using oral contraceptives and experienc - ing abnormal uterine bleeding also have a high preva- lence of Chlamydia trachomatis infection, which causes bleeding in these women. Screening for sexually trans- mitted diseases should be considered in patients with abnormal uterine bleeding who use hormonal contra- ceptives [30]. Endometrial causes Bleeding occurring in the absence of pathological changes to the endometrium fall under this category and was earlier referred to as ‘ovulatory dysfunctional bleeding’ . Abnormal uterine bleeding may be a man- ifestation of the disruption in the endometrial repair mechanism. In these patients, elevated levels of vaso - dilatory substances (prostacyclin I2 and prostaglandin E2) are present, as well as decreased levels of vasocon- strictory substances (endothelin-1 and prostaglandin 2α). These disorders may be primary and secondary, caused by inflammation or infection of the endometri- um [4]. Menorrhagia may be the first sign of endome - tritis in women, in sexually transmitted diseases. Ab - normal uterine bleeding is frequent in cases of subclin- ical infection caused by Chlamydia trachomatis. Oth- er causes include a decrease in the level of estrogen during treatment with antibiotics and anticonvulsants [29,31]. Also, this group of disorders includes bleeding occurring during steroid hormone treatment, such as, for example, breakthrough bleeding. Endometrial causes of abnormal uterine bleeding in women in the reproductive period are diagnosed only after excluding other pathological processes and confirming the existence of normal ovulations. Unclassified causes Types of abnormal uterine bleeding not covered by the above-mentioned causes fall under this category, such as bleeding caused by a foreign body (tampon, pessa- ry) or trauma. Other causes of bleeding from this group are chronic endometritis and arteriovenous malforma- tions [4]. hormonskih kontraceptiva i javljaju se kod 30,0% do 40,0% korisnica. Ova vrsta krvarenja najčešće se sreće kod korisnica oralnih kontraceptivnih pilula i hormon- ske supstitucije u perimenopauzi [30]. Većina krvarenja se manifestuje menoragijom. Važno je ukazati na to da sva krvarenja kod paci- jentkinja koje koriste hormonsku kontracepciju nisu posledica hormonskih faktora. Rezultati novih istraži- vanja ukazuju na to da pacijentkinje koje koriste oralne kontraceptive i imaju patološka krvarenja imaju visoku prevalenciju infekcije Chlamydia-om trachomatis, koja uzrokuje pojavu krvarenja kod ovih pacijentkinja. Skri- ning na polno prenosive bolesti treba razmotriti kod pacijentkinja koje imaju patološka krvarenja i koriste hormonsku kontracepciju [30]. Endometrijalni uzroci U ovu kategoriju se svrstavaju krvarenja u odsustvu patoloških promena endometrijuma, ranije naziva- na „ovulatorna disfunkcionalna krvarenja“ . Patološka krvarenja iz materice mogu biti manifestacija pore - mećaja mehanizama reparacije endometrijuma. Kod ovih pacijentkinja prisutni su povišeni nivoi vazodila- tatornih supstanci (prostaciklin I2 i prostaglandin E2) i sniženi nivoi vazokontriktornih supstanci (endotelin-1 i prostaglandin 2α). Ovi poremećaji mogu biti primarni i sekundarni, uzrokovani inflamacijom ili infekcijom en- dometrijuma [4]. Menoragija može biti prvi znak endo - metritisa kod žena, kod seksualno prenosivih bolesti. Patološka krvarenja iz materice česta su u slučajevima subkliničke infekcije uzrokovane Chlamydia-om trac- homatis. Ostali uzroci uključuju smanjenje nivoa estro- gena tokom terapije antibioticima i antikonvulzivima [29,31]. Takođe, u ovu grupu poremećaja spadaju krva- renja koja se javljaju tokom terapije steroidnim hormo- nima, kao što je, na primer, probojno krvarenje. Endometrijalni uzroci patoloških krvarenja iz mate- rice kod žena u reproduktivnom periodu se dijagnosti- kuju tek nakon isključivanja ostalih patoloških procesa i potvrde postojanja normalnih ovulacija. Neklasifikovani uzroci U ovu grupu patoloških krvarenja se ubrajaju krvarenja koja nisu obuhvaćena prethodno opisanim uzrocima, kao što su krvarenja uzrokovana stranim telom (tam- pon, pesar) ili traumom. Ostali uzroci krvarenja iz ove grupe su hronični endometritis i arterio-venske malfor- macije [4]. Dijagnoza patoloških krvarenja iz materice Pre sprovođenja bilo koje dijagnostičke procedure ne - ophodno je isključiti postojanje neprepoznate trudnoće određivanjem nivoa β-HCG-a u serumu pacijentkinje. Sparić R. et al. Serbian JournaL of the m edicaL c hamber | Volume 2 / No. 4 | December 2021. 425 patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age Diagnosis of abnormal uterine bleeding Before carrying out any diagnostic procedure it is nec- essary to exclude the existence of an unrecognized pregnancy by determining the β-HCG level in the se - rum of the patient. The diagnostic protocol depends on anamnestic data and the clinical finding, as well as on the age and parity of the patient. At the same time the presence of possible risk factors for the existence of endome - trial hyperplasia and malignancy must also be taken into consideration. In all cases of contact bleeding, it is necessary to perform colposcopy as well as cervical cytology by Pap smear, and, if necessary, additional di- agnostics, for the purpose of excluding the existence of cervical carcinoma. The first step in the diagnostics is taking a detailed personal and family medical history (length, cyclicity, and volume of menstrual bleeding; occurrence of bruis- es on the skin; nosebleeds; bleeding of gums; postpar- tum bleeding or bleeding after surgical procedures; drugs that the patient is on – hormonal medicaments, anticoagulants, antipsychotics, antidepressants; exis- tence of accompanying signs and symptoms – change in body weight, physical activity, premenstrual syn- drome, dysmenorrhea, dyspareunia, galactorrhea, hir - sutism, acne). Although subjective, information on the use of tampons or menstrual pads during menstrua- tion may offer an estimation on the volume of bleed- ing. Information on the change of tampons or pads more often than once in every three hours, as well as the use of more than 20 menstrual pads during one menstrual cycle, the need for changing pads or tam- pons during the night, discharging clots larger than 2.5 cm, bleeding lasting longer than 7 days, indicate pro - fuse abnormal uterine bleeding. Clinical examination enables evaluation of patho - logical changes in the cervix, uterus, and adnexa. It primarily confirms whether there is irregular uterine bleeding. The next step is ultrasound examination of the less- er pelvis, i.e., the evaluation of the uterus, the thickness of the endometrium, and the ovaries. Endometrial pol- yps and submucosal myomas can also be diagnosed with this examination. In case of unclear findings, sonohysterography or hysteroscopy is performed, and, if necessary, fractional explorative curettage. In some cases, especially in adolescent patients and patients with an intact hymen, a nuclear magnetic resonance imaging examination is performed. If these examinations exclude the existence of pathological changes in the endometrium, the myo - metrium, and ovaries, it is necessary to examine the ovulatory function, as well as to test for other Dijagnostički protokol zavisi od anamnestičkih podataka i kliničkog nalaza, kao i od godina starosti, pariteta, pri čemu se mora imati u vidu i eventualno prisustvo faktora rizika za postojanje endometrijalne hiperplazije i maligniteta. U svim slučajevima kontak - tnog krvarenja, neophodno je uraditi i kolposkopski i citološki pregled po metodi Papanikolau, a po potrebi i dopunsku dijagnostiku, u cilju isključivanja postojanja karcinoma grlića materice. Prvi korak u dijagnostici jeste uzimanje detaljne lične i porodične anamneze (dužina trajanja, ciklič - nost i obim menstrualnog krvarenja; pojava modrica po koži; krvarenja iz nosa; krvarenja desni; krvarenje posle porođaja ili operativnih zahvata; uzimanje leko - va - hormonski preparati, antikoagulansi, antipsihotici, antidepresivi; postojanje pratećih znakova i simptoma - promena telesne težine, fizička aktivnost, premenstru- alni sindrom, dismenoreja, dispareunija, galaktoreja, hi- rzutizam, akne). Iako subjektivan, podatak o upotrebi tampona, odnosno uložaka tokom ciklusa, može pružiti procenu obima krvarenja. Podatak o promeni tampo - na, odnosno uložaka češće od jednom na tri sata, kao i upotreba više od 20 tokom jednog ciklusa, potreba za promenom tampona ili uložaka tokom noći, izbacivanje ugrušaka većih od 2,5 cm, te krvarenje duže od 7 dana, ukazuju na obilno patološko krvarenje iz materice. Klinički pregled omogućava evaluaciju patoloških promena grlića materice, uterusa i adneksa. Njime se prvenstveno potvrđuje da li se radi o iregularnom kr - varenju iz materice. Nakon toga se izvodi ultrazvučni pregled male kar- lice, odnosno evaluacija materice, debljine endome - trijuma i ovarijuma. Ovim pregledom se takođe mogu dijagnostikovati endometrijalni polipi i submukozni miomi. U slučaju nejasnih nalaza, radi se sonohistero - grafija ili histeroskopija, a po potrebi i frakcionirana ek- splorativna kiretaža. U nekim slučajevima, naročito kod adolescentkinja i pacijentkinja sa intaktnim himenom, radi se pregled nuklearnom magnetnom rezonancom. Ukoliko se ovim pregledima isključi postojanje pato- loških promena endometrijuma, miometrijuma i jajnika, neophodno je ispitivanje ovulatorne funkcije, kao i po- stojanja drugih endokrinopatija i koagulacionih poreme- ćaja, kao i mikrobiološko ispitivanje (cervikalni i vaginalni bakteriološki bris, brisevi na Chlamydia-u trachomatis, Ureaplasma-u urealyticum, Mycoplasma-u hominis). Određivanjem serumskog progesterona između 22. i 24. dana ciklusa kod žena sa ciklusom na 28 dana, može se dokumentovati postojanje ovulacije, a vred- nosti veće od 3 ng/ml ukazuju na postojanje ovulacije. Kod žena starijih od 40 godina, neophodno je uraditi dijagnostičku kiretažu u cilju isključivanja karcinoma endometrijuma [1,2,4,5]. Sparić R. i sar. 426 Decembar 2021. | Volumen 2 / Broj 4 | SrpSki medicinSki čaSopiS LekarSke komore patološko krvarenje iz materice kod žena u reproduktivnom periodu abnormal uterine bleeding in women of reproductive age endocrinopathies and coagulation disorders, and to perform microbiological testing (cervical and vaginal bacterial culture swabs, swabs for Chlamydia tracho - matis, Ureaplasma urealyticum, Mycoplasma hominis). Establishing the level of serum progesterone be - tween day 22 and day 24 of the menstrual cycle in women whose cycle is 28 days, can facilitate the doc - umenting of the existence of ovulation, with values above 3 ng/ml indicating the existence of ovulation. In women above the age of 40 years, it is necessary to perform diagnostic curettage for the purpose of ex - cluding endometrial carcinoma [1,2,4,5]. Treatment of abnormal uterine bleeding The most important step in treating abnormal uterine bleeding is the diagnosis of the cause of the bleeding. The therapy is expectative, medicamentous, and sur - gical. Expectative therapy is advised in case of break - through bleeding occurring in the first three months of using oral contraceptives. Polyp treatment is surgical, and the method of choice is hysteroscopic polypecto - my. Myomas can be treated with medication as well as surgically (myomectomy, hysterectomy, blood vessel embolization, GnRH analogs). Malignant diseases are treated according to oncological protocols, depending on the localization of the primary tumor, the histolog- ical type, and the FIGO stage of the disease. In women in their reproductive period who experience anovula- tory bleeding, it is recommended to apply combined oral contraceptives or intrauterine devices with levo - norgestrel. In cases of anovulatory bleeding in older women not interested in reproduction, performing endometrial ablation or a hysterectomy is an option. Surgical treatment is performed in patients in whom medicamentous treatment did not provide the desired

[1,4,5]. Conflict of interest: None declared. Lečenje patoloških krvarenja iz materice Najvažniji korak u lečenju patološkog krvarenja je di- jagnostika uzroka krvarenja. Terapija je ekspektativna, medikamentna i hirurška. Ekspektativna terapija se savetuje u slučaju pojave probojnih krvarenja, tokom prva tri meseca korišćenja oralnih kontraceptiva. Leče- nje polipa je hirurško, a metoda izbora je histeroskop - ska polipektomija. Miomi se mogu lečiti medikamen- tno i hirurški (miomektomija, histerektomija, emboli- zacija krvnih sudova, GnRH analozi). Maligne bolesti se leče u skladu sa onkološkim protokolima, u zavisnosti od lokalizacije primarnog tumora, histološkog tipa i FIGO stadijuma bolesti. Kod žena u reproduktivnom periodu sa anovulatornim krvarenjima, savetuje se pri- mena kombinovanih oralnih kontraceptiva ili intraute- rinih uložaka sa levonorgestrelom. 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