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Review article

Abnormal uterine bleeding in women of reproductive age

Radmila Sparić1,2, Đina Tomašević3, Mladen Anđić1, Svetlana Spremović Rađenović1,2
  • Clinic for Gynecology and Obstetrics, University Clinical Center of Serbia, Belgrade, Serbia
  • Faculty of Medicine, University of Belgrade, Belgrade, Serbia
  • General Hospital Čačak, Čačak, Serbia.

ABSTRACT

Introduction: Abnormal uterine bleeding is one of the most common health disorders 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.

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

Conclusion: 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 imaging 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.


INTRODUCTION

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 prevalence of this type of bleeding ranges from 3 to 30% [3].

Accurate knowledge of the physiology of menstrual 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 every 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, hormones 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].

Table 1. Characteristics of normal menstrual bleeding

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Variations in the duration and intensity of menstrual bleeding are common at the beginning and at the end of the reproductive period - in adolescence and before 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, menstrual 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 menstrual cycle gradually shortens. During the period of 8 to 10 years before menopause, the frequency of ovulatory cycles gradually decreases [1],[2],[3],[4].

If the function of the hypothalamic-pituitary-ovarian 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 coagulation (coagulopathies, iatrogenic causes), the normal menstrual cycle is disrupted and abnormal uterine bleeding occurs [5].

Abnormal uterine bleeding has a significant impact on physical and mental health, as well as on the emotional, sexual, and professional aspects of women’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 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 classification, as well as the bases of diagnosis and treatment of abnormal uterine bleeding.

METHODS

This paper presents data from publications selected from the PubMed database using a combination of keywords: “menstrual bleeding”, “abnormal uterine bleeding”, “PALM-COEIN classification”, “leiomyoma”, “endometrial polyp”, “adenomyosis”, “gynecological malignancies”, “coagulopathy”, “diagnostics of abnormal uterine bleeding”, and “treatment of abnormal uterine bleeding”. The database search and the method of publication selection and inclusion into this study are presented in Figure 1.

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Figure 1. PRISMA diagram of the publications search and selection

Current nomenclature of menstrual cycle disorders and abnormal uterine bleeding (FIGO 2011)

For the purpose of achieving a uniform classification of menstrual cycle disorders, in 2011, the International Federation of Gynecology and Obstetrics (FIGO) introduced a classification of these disorders under the name PALM-COEIN [1],[2],[3]. This acronym denotes individual causes of abnormal uterine bleeding. 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 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],[2],[3],[4].

Endometrial polyp

A polyp is a lesion which is formed as the result of localized 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 occurrence of polyps increases with age. It is believed that estrogens play a key role in their formation [8]. Abnormal uterine bleeding, caused by polyps, is manifested as intermenstrual bleeding, hypermenorrhea, metrorrhagia 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 spontaneously regress. They are diagnosed by ultrasound or with hysteroscopy. Polyps are treated by surgical-hysteroscopic resection or by explorative curettage [9].

Adenomyosis

Adenomyosis is characterized by the presence of endometrial tissue (glands and stroma) in the myometrium. The presence of ectopic endometrial tissue leads to hypertrophy of the surrounding myometrium, causing 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 most commonly manifests as menorrhagia and is usually connected to marked dysmenorrhea [10]. Adenomyosis is diagnosed with ultrasound and nuclear magnetic resonance imaging. Definitive diagnosis is established by histopathological examination. Medicamentous treatment includes the application of progesterone-based medicaments, gonadotropin-releasing hormone (GnRH) agonists, and aromatase inhibitors. Focal areas of adenomyosis 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 reproductive organs. The clinical presentation varies from complete absence of subjective complaints to numerous symptoms, which may significantly affect the woman’s health. Less than 50.0% are symptomatic, and the most frequent symptom is abnormal uterine bleeding [7],[12],[13],[14],[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, intramural, 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],[2],[3]. The nomenclature of myomas, by type, based on this classification is presented in Table 2.

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Figure 2. Types of myomas according to the FIGO classification

Table 2. 

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The mechanisms through which myomas affect the occurrence of abnormal uterine bleeding vary and depend, 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 commonly diagnosed: intracavitary (myomas in the uterine cavity), submucosal, and large intramural myomas [16]. These myomas enlarge the overall surface of the uterine 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 discoveries indicate the significance of neoangiogenesis, elevated levels of vasoactive substances and growth factors, 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 antagonists) 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, intermenstrual or completely acyclic bleeding, which is why it 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 adenomatous hyperplasia, endometrial intraepithelial neoplasia (EIN), and endometrial carcinoma [4],[22]. The most frequent symptom of endometrial carcinoma is abnormal uterine bleeding. Although it most frequently 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 older women in menopause, and they clinically manifest as abnormal uterine bleeding and progressive enlargement of the uterus. Ovarian estrogen producing tumors (most commonly granulosa cell tumors) may manifest as abnormal uterine bleeding [2],[3],[4],[23].

Coagulopathy

Abnormal uterine bleeding may be the first clinical 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 platelet deficiency, which can be the cause of abnormal uterine bleeding, include leukemia, severe forms of sepsis, and idiopathic thrombocytopenic purpura. Hemophilia A and B are X-related recessive deficiencies of coagulation factor VIII and coagulation factor IX [24],[25],[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 coagulation 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 coagulation 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 presents 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 perimenopause, is ovulatory dysfunction. It develops as the result of a disturbance in the functioning of the hypothalamic-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 insufficient 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 immaturity 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 menarche, patients with polycystic ovary (PCO) syndrome, obese, and perimenopausal women [4],[26].

Ovulatory dysfunction can manifest as amenorrhea, while anovulatory bleeding may manifest as oligomenorrhea, intermenstrual bleeding or hypermenorrhea. In women with regular menstrual cycles, ovulation is absent in 20.0% of the cases.

The most common cause of anovulatory bleeding during the reproductive period in women is the polycystic ovary syndrome (PCOS). A disturbance of the hypothalamic-pituitary function is a less common cause. Additionally, other hormonal disbalances may be accompanied by anovulatory bleeding, such as diseases of the thyroid gland (hypothyroidism, hyperthyroidism), diseases of the adrenal glands, and diabetes mellitus [27],[28]. Hyperprolactinemia and elevated levels of cortisol (Cushing’s syndrome) can also lead to anovulation. Less frequently, the causes can be eating disorders (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 hypothalamic-pituitary-gonadal axis or by causing fluctuations 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 (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 substitution 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 hormonal factors. The results of recent studies have shown that patients using oral contraceptives and experiencing abnormal uterine bleeding also have a high prevalence of Chlamydia trachomatis infection, which causes bleeding in these women. Screening for sexually transmitted diseases should be considered in patients with abnormal uterine bleeding who use hormonal contraceptives [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 manifestation of the disruption in the endometrial repair mechanism. In these patients, elevated levels of vasodilatory substances (prostacyclin I2 and prostaglandin E2) are present, as well as decreased levels of vasoconstrictory substances (endothelin-1 and prostaglandin 2α). These disorders may be primary and secondary, caused by inflammation or infection of the endometrium [4]. Menorrhagia may be the first sign of endometritis in women, in sexually transmitted diseases. Abnormal uterine bleeding is frequent in cases of subclinical infection caused by Chlamydia trachomatis. Other 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, pessary) or trauma. Other causes of bleeding from this group are chronic endometritis and arteriovenous malformations [4].

Diagnosis of abnormal uterine bleeding

Before carrying out any diagnostic procedure it is necessary to exclude the existence of an unrecognized pregnancy by determining the β-HCG level in the serum 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 endometrial 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 diagnostics, 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 bruises on the skin; nosebleeds; bleeding of gums; postpartum bleeding or bleeding after surgical procedures; drugs that the patient is on – hormonal medicaments, anticoagulants, antipsychotics, antidepressants; existence of accompanying signs and symptoms – change in body weight, physical activity, premenstrual syndrome, dysmenorrhea, dyspareunia, galactorrhea, hirsutism, acne). Although subjective, information on the use of tampons or menstrual pads during menstruation may offer an estimation on the volume of bleeding. 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 tampons during the night, discharging clots larger than 2.5 cm, bleeding lasting longer than 7 days, indicate profuse abnormal uterine bleeding.

Clinical examination enables evaluation of pathological changes in the cervix, uterus, and adnexa. It primarily confirms whether there is irregular uterine bleeding.

The next step is ultrasound examination of the lesser pelvis, i.e., the evaluation of the uterus, the thickness of the endometrium, and the ovaries. Endometrial polyps 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 myometrium, and ovaries, it is necessary to examine the ovulatory function, as well as to test for other endocrinopathies and coagulation disorders, and to perform microbiological testing (cervical and vaginal bacterial culture swabs, swabs for Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis).

Establishing the level of serum progesterone between day 22 and day 24 of the menstrual cycle in women whose cycle is 28 days, can facilitate the documenting 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 excluding 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 surgical. Expectative therapy is advised in case of breakthrough bleeding occurring in the first three months of using oral contraceptives. Polyp treatment is surgical, and the method of choice is hysteroscopic polypectomy. 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 histological type, and the FIGO stage of the disease. In women in their reproductive period who experience anovulatory bleeding, it is recommended to apply combined oral contraceptives or intrauterine devices with levonorgestrel. 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 results [1],[4],[5].

 

  • Conflict of interest:
    None declared.

Informations

Volume 2 No 4

December 2021

Pages 416-427
  • Keywords:
    bleeding, uterus, menstrual cycle
  • Received:
    18 November 2021
  • Revised:
    28 November 2021
  • Accepted:
    06 December 2021
  • Online first:
    13 December 2021
  • DOI:
  • Cite this article:
    Sparić R, Tomašević Đ, Anđić M, Spremović-Rađenović S. Abnormal uterine bleeding in women of reproductive age. Serbian Journal of the Medical Chamber. 2021;2(4):416-27. doi: 10.5937/smclk2-34990
Corresponding author

Radmila Sparić
Clinic for Gynecology and Obstetrics, University Clinical Center of Serbia
26 Višegradska Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


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REFERENCES

1. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011 Jun;95(7):2204-8, 2208.e1-3. doi: 10.1016/j.fertnstert.2011.03.079.[CROSSREF]

2. Spremović-Rađenović S, Stefanović A, Kadija S, Jeremić K, Sparić R. Classification and the diagnostics of abnormal uterine bleeding in nongravid women of reproductive age: The PALM-COEIN classification system adopted by the International Federation of Gynecology and Obstetrics. Vojnosanit Pregl. 2016 Dec;73(12):1154-9. doi: 10.2298/VSP160709289S.[CROSSREF]

3. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet. 2018 Dec;143(3):393-408. doi: 10.1002/ijgo.12666.[CROSSREF]

4. Marnach ML, Laughlin-Tommaso SK. Evaluation and Management of Abnormal Uterine Bleeding. Mayo Clin Proc. 2019 Feb;94(2):326-35. doi: 10.1016/j.mayocp.2018.12.012.[CROSSREF]

5. Munro MG. Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years. Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:3-22. doi: 10.1016/j.bpobgyn.2016.09.011.[CROSSREF]

6. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health. 2007 MayJun;10(3):183-94. doi: 10.1111/j.1524-4733.2007.00168.x.[CROSSREF]

7. Sparic R, Mirkovic L, Malvasi A, Tinelli A. Epidemiology of Uterine Myomas: A Review. Int J Fertil Steril. 2016 Jan-Mar;9(4):424-35. doi: 10.22074/ ijfs.2015.4599.[CROSSREF]

8. Nijkang NP, Anderson L, Markham R, Manconi F. Endometrial polyps: Pathogenesis, sequelae and treatment. SAGE Open Med. 2019 May 2;7:2050312119848247. doi: 10.1177/2050312119848247.[CROSSREF]

9. Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol. 2011 Sep-Oct;18(5):569-81. doi: 10.1016/j. jmig.2011.05.018.[CROSSREF]

10. Leyendecker G, Kunz G, Herbertz M, Beil D, Huppert P, Mall G, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004 Dec;1034:338-55. doi: 10.1196/annals.1335.036.[CROSSREF]

11. de Bruijn AM, Smink M, Lohle PNM, Huirne JAF, Twisk JWR, Wong C, et al. Uterine Artery Embolization for the Treatment of Adenomyosis: A Systematic Review and Meta-Analysis. J Vasc Interv Radiol. 2017 Dec;28(12):1629- 42.e1. doi: 10.1016/j.jvir.2017.07.034.[CROSSREF]

12. Laughlin SK, Stewart EA. Uterine leiomyomas: individualizing the approach to a heterogeneous condition. Obstet Gynecol. 2011 Feb;117(2 Pt 1):396- 403. doi: 10.1097/AOG.0b013e31820780e3.[CROSSREF]

13. Sparić R. [Uterine myomas in pregnancy, childbirth and puerperium]. Srp Arh Celok Lek. 2014 Jan-Feb;142(1-2):118-24. Serbian. doi: 10.2298/ sarh1402118s.[CROSSREF]

14. Tinelli A, Vinciguerra M, Malvasi A, Andjić M, Babović I, Sparić R. Uterine Fibroids and Diet. Int J Environ Res Public Health. 2021 Jan 25;18(3):1066. doi: 10.3390/ijerph18031066.[CROSSREF]

15. Divakar H. Asymptomatic uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):643-54. doi: 10.1016/j.bpobgyn.2008.01.007.[CROSSREF]

16. Tinelli A, Sparic R, Kadija S, Babovic I, Tinelli R, Mynbaev OA, et al. Myomas: anatomy and related issues. Minerva Ginecol. 2016 Jun;68(3):261-73.[HTTP]

17. Sparic R, Terzic M, Malvasi A, Tinelli A. Uterine fibroids - clinical presentation and complications. Acta Chir Iugosl 2014;61:41–8. doi: 10.2298/ ACI1403041S.[HTTP]

18. Sparic R, Nejkovic L, Mutavdzic D, Malvasi A, Tinelli A. Conservative surgical treatment of uterine fibroids. Acta Chir Iugosl 2014;61:11–6. doi: 10.2298/ ACI1404011S.[HTTP]

19. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):615-26. doi: 10.1016/j.bpobgyn.2008.01.008.[CROSSREF]

20. Manyonda I, Belli AM, Lumsden MA, Moss J, McKinnon W, Middleton LJ, et al.; FEMME Collaborative Group. Uterine-Artery Embolization or Myomectomy for Uterine Fibroids. N Engl J Med. 2020 Jul 30;383(5):440-51. doi: 10.1056/NEJMoa1914735.[CROSSREF]

21. See AT, Havenga S. Outcomes of women with postcoital bleeding. Int J Gynaecol Obstet. 2013 Jan;120(1):88-9. doi: 10.1016/j.ijgo.2012.07.017.[CROSSREF]

22. Doraiswami S, Johnson T, Rao S, Rajkumar A, Vijayaraghavan J, Panicker VK. Study of endometrial pathology in abnormal uterine bleeding. J Obstet Gynaecol India. 2011 Aug;61(4):426-30. doi: 10.1007/s13224-011-0047-2.[CROSSREF]

23. Haidopoulos D, Simou M, Akrivos N, Rodolakis A, Vlachos G, Fotiou S, et al. Risk factors in women 40 years of age and younger with endometrial carcinoma. Acta Obstet Gynecol Scand. 2010 Oct;89(10):1326-30. doi: 10.3109/00016349.2010.515666.[CROSSREF]

24. James AH, Manco-Johnson MJ, Yawn BP, Dietrich JE, Nichols WL. Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol. 2009 Sep;114(3):674-8. doi: 10.1097/ AOG.0b013e3181b191ea.[CROSSREF]

25. Deligeoroglou E, Karountzos V. Abnormal Uterine Bleeding including coagulopathies and other menstrual disorders. Best Pract Res Clin Obstet Gynaecol. 2018 Apr;48:51-61. doi: 10.1016/j.bpobgyn.2017.08.016.[CROSSREF]

26. Elmaoğulları S, Aycan Z. Abnormal Uterine Bleeding in Adolescents. J Clin Res Pediatr Endocrinol. 2018 Jul 31;10(3):191-7. doi: 10.4274/jcrpe.0014.[CROSSREF]

27. Thakur M, Maharjan M, Tuladhar H, Dwa Y, Bhandari S, Maskey S, et al. Thyroid Dysfunction in Patients with Abnormal Uterine Bleeding in a Tertiary Care Hospital: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc. 2020 May 30;58(225):333-7. doi: 10.31729/jnma.5033.[CROSSREF]

28. Delitala AP, Capobianco G, Delitala G, Cherchi PL, Dessole S. Polycystic ovary syndrome, adipose tissue and metabolic syndrome. Arch Gynecol Obstet. 2017 Sep;296(3):405-19. doi: 10.1007/s00404-017-4429-2.[CROSSREF]

29. Joffe H, Hayes FJ. Menstrual cycle dysfunction associated with neurologic and psychiatric disorders: their treatment in adolescents. Ann N Y Acad Sci. 2008;1135:219-29. doi: 10.1196/annals.1429.030.[CROSSREF]

30. McCarthy KJ, Gollub EL, Ralph L, van de Wijgert J, Jones HE. Hormonal Contraceptives and the Acquisition of Sexually Transmitted Infections: An Updated Systematic Review. Sex Transm Dis. 2019 May;46(5):290-6. doi: 10.1097/OLQ.0000000000000975.[CROSSREF]

31. Parkash V, Fadare O, Tornos C, McCluggage WG. Committee Opinion No. 631: Endometrial Intraepithelial Neoplasia. Obstet Gynecol. 2015 Oct;126(4):897. doi: 10.1097/AOG.0000000000001071.[CROSSREF]

1. Munro MG, Critchley HO, Fraser IS; FIGO Menstrual Disorders Working Group. The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertil Steril. 2011 Jun;95(7):2204-8, 2208.e1-3. doi: 10.1016/j.fertnstert.2011.03.079.[CROSSREF]

2. Spremović-Rađenović S, Stefanović A, Kadija S, Jeremić K, Sparić R. Classification and the diagnostics of abnormal uterine bleeding in nongravid women of reproductive age: The PALM-COEIN classification system adopted by the International Federation of Gynecology and Obstetrics. Vojnosanit Pregl. 2016 Dec;73(12):1154-9. doi: 10.2298/VSP160709289S.[CROSSREF]

3. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet. 2018 Dec;143(3):393-408. doi: 10.1002/ijgo.12666.[CROSSREF]

4. Marnach ML, Laughlin-Tommaso SK. Evaluation and Management of Abnormal Uterine Bleeding. Mayo Clin Proc. 2019 Feb;94(2):326-35. doi: 10.1016/j.mayocp.2018.12.012.[CROSSREF]

5. Munro MG. Practical aspects of the two FIGO systems for management of abnormal uterine bleeding in the reproductive years. Best Pract Res Clin Obstet Gynaecol. 2017 Apr;40:3-22. doi: 10.1016/j.bpobgyn.2016.09.011.[CROSSREF]

6. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health. 2007 MayJun;10(3):183-94. doi: 10.1111/j.1524-4733.2007.00168.x.[CROSSREF]

7. Sparic R, Mirkovic L, Malvasi A, Tinelli A. Epidemiology of Uterine Myomas: A Review. Int J Fertil Steril. 2016 Jan-Mar;9(4):424-35. doi: 10.22074/ ijfs.2015.4599.[CROSSREF]

8. Nijkang NP, Anderson L, Markham R, Manconi F. Endometrial polyps: Pathogenesis, sequelae and treatment. SAGE Open Med. 2019 May 2;7:2050312119848247. doi: 10.1177/2050312119848247.[CROSSREF]

9. Salim S, Won H, Nesbitt-Hawes E, Campbell N, Abbott J. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol. 2011 Sep-Oct;18(5):569-81. doi: 10.1016/j. jmig.2011.05.018.[CROSSREF]

10. Leyendecker G, Kunz G, Herbertz M, Beil D, Huppert P, Mall G, et al. Uterine peristaltic activity and the development of endometriosis. Ann N Y Acad Sci. 2004 Dec;1034:338-55. doi: 10.1196/annals.1335.036.[CROSSREF]

11. de Bruijn AM, Smink M, Lohle PNM, Huirne JAF, Twisk JWR, Wong C, et al. Uterine Artery Embolization for the Treatment of Adenomyosis: A Systematic Review and Meta-Analysis. J Vasc Interv Radiol. 2017 Dec;28(12):1629- 42.e1. doi: 10.1016/j.jvir.2017.07.034.[CROSSREF]

12. Laughlin SK, Stewart EA. Uterine leiomyomas: individualizing the approach to a heterogeneous condition. Obstet Gynecol. 2011 Feb;117(2 Pt 1):396- 403. doi: 10.1097/AOG.0b013e31820780e3.[CROSSREF]

13. Sparić R. [Uterine myomas in pregnancy, childbirth and puerperium]. Srp Arh Celok Lek. 2014 Jan-Feb;142(1-2):118-24. Serbian. doi: 10.2298/ sarh1402118s.[CROSSREF]

14. Tinelli A, Vinciguerra M, Malvasi A, Andjić M, Babović I, Sparić R. Uterine Fibroids and Diet. Int J Environ Res Public Health. 2021 Jan 25;18(3):1066. doi: 10.3390/ijerph18031066.[CROSSREF]

15. Divakar H. Asymptomatic uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):643-54. doi: 10.1016/j.bpobgyn.2008.01.007.[CROSSREF]

16. Tinelli A, Sparic R, Kadija S, Babovic I, Tinelli R, Mynbaev OA, et al. Myomas: anatomy and related issues. Minerva Ginecol. 2016 Jun;68(3):261-73.[HTTP]

17. Sparic R, Terzic M, Malvasi A, Tinelli A. Uterine fibroids - clinical presentation and complications. Acta Chir Iugosl 2014;61:41–8. doi: 10.2298/ ACI1403041S.[HTTP]

18. Sparic R, Nejkovic L, Mutavdzic D, Malvasi A, Tinelli A. Conservative surgical treatment of uterine fibroids. Acta Chir Iugosl 2014;61:11–6. doi: 10.2298/ ACI1404011S.[HTTP]

19. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):615-26. doi: 10.1016/j.bpobgyn.2008.01.008.[CROSSREF]

20. Manyonda I, Belli AM, Lumsden MA, Moss J, McKinnon W, Middleton LJ, et al.; FEMME Collaborative Group. Uterine-Artery Embolization or Myomectomy for Uterine Fibroids. N Engl J Med. 2020 Jul 30;383(5):440-51. doi: 10.1056/NEJMoa1914735.[CROSSREF]

21. See AT, Havenga S. Outcomes of women with postcoital bleeding. Int J Gynaecol Obstet. 2013 Jan;120(1):88-9. doi: 10.1016/j.ijgo.2012.07.017.[CROSSREF]

22. Doraiswami S, Johnson T, Rao S, Rajkumar A, Vijayaraghavan J, Panicker VK. Study of endometrial pathology in abnormal uterine bleeding. J Obstet Gynaecol India. 2011 Aug;61(4):426-30. doi: 10.1007/s13224-011-0047-2.[CROSSREF]

23. Haidopoulos D, Simou M, Akrivos N, Rodolakis A, Vlachos G, Fotiou S, et al. Risk factors in women 40 years of age and younger with endometrial carcinoma. Acta Obstet Gynecol Scand. 2010 Oct;89(10):1326-30. doi: 10.3109/00016349.2010.515666.[CROSSREF]

24. James AH, Manco-Johnson MJ, Yawn BP, Dietrich JE, Nichols WL. Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol. 2009 Sep;114(3):674-8. doi: 10.1097/ AOG.0b013e3181b191ea.[CROSSREF]

25. Deligeoroglou E, Karountzos V. Abnormal Uterine Bleeding including coagulopathies and other menstrual disorders. Best Pract Res Clin Obstet Gynaecol. 2018 Apr;48:51-61. doi: 10.1016/j.bpobgyn.2017.08.016.[CROSSREF]

26. Elmaoğulları S, Aycan Z. Abnormal Uterine Bleeding in Adolescents. J Clin Res Pediatr Endocrinol. 2018 Jul 31;10(3):191-7. doi: 10.4274/jcrpe.0014.[CROSSREF]

27. Thakur M, Maharjan M, Tuladhar H, Dwa Y, Bhandari S, Maskey S, et al. Thyroid Dysfunction in Patients with Abnormal Uterine Bleeding in a Tertiary Care Hospital: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc. 2020 May 30;58(225):333-7. doi: 10.31729/jnma.5033.[CROSSREF]

28. Delitala AP, Capobianco G, Delitala G, Cherchi PL, Dessole S. Polycystic ovary syndrome, adipose tissue and metabolic syndrome. Arch Gynecol Obstet. 2017 Sep;296(3):405-19. doi: 10.1007/s00404-017-4429-2.[CROSSREF]

29. Joffe H, Hayes FJ. Menstrual cycle dysfunction associated with neurologic and psychiatric disorders: their treatment in adolescents. Ann N Y Acad Sci. 2008;1135:219-29. doi: 10.1196/annals.1429.030.[CROSSREF]

30. McCarthy KJ, Gollub EL, Ralph L, van de Wijgert J, Jones HE. Hormonal Contraceptives and the Acquisition of Sexually Transmitted Infections: An Updated Systematic Review. Sex Transm Dis. 2019 May;46(5):290-6. doi: 10.1097/OLQ.0000000000000975.[CROSSREF]

31. Parkash V, Fadare O, Tornos C, McCluggage WG. Committee Opinion No. 631: Endometrial Intraepithelial Neoplasia. Obstet Gynecol. 2015 Oct;126(4):897. doi: 10.1097/AOG.0000000000001071.[CROSSREF]


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