{"paper_id":"606e54ff-5b9c-4ca9-85f7-070e481f370e","body_text":"Gynecological Endocrinology\nISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: www.tandfonline.com/journals/igye20\nUnmet needs in abnormal uterine bleeding due to\novulatory dysfunction\nTommaso Simoncini, Hisham Arab, Nataliia Pedachenko, Qinjie Tian,\nFernando Pineda, Balamba Puranam, Rubina Sohail & Maria Celeste Osorio\nWender\nTo cite this article: Tommaso Simoncini, Hisham Arab, Nataliia Pedachenko, Qinjie Tian,\nFernando Pineda, Balamba Puranam, Rubina Sohail & Maria Celeste Osorio Wender (2024)\nUnmet needs in abnormal uterine bleeding due to ovulatory dysfunction, Gynecological\nEndocrinology, 40:1, 2362244, DOI: 10.1080/09513590.2024.2362244\nTo link to this article:  https://doi.org/10.1080/09513590.2024.2362244\n© 2024 The Author(s). Published by Informa\nUK Limited, trading as Taylor & Francis\nGroup\nView supplementary material \nPublished online: 30 Jun 2024.\n Submit your article to this journal \nArticle views: 3257\n View related articles \nView Crossmark data\n Citing articles: 2 View citing articles \nFull Terms & Conditions of access and use can be found at\nhttps://www.tandfonline.com/action/journalInformation?journalCode=igye20\n\nReview AR ticle\nGynecoloGical endocrinoloGy\n2024, Vol. 40, no . 1, 2362244\nUnmet needs in abnormal uterine bleeding due to ovulatory dysfunction\ntommaso Simoncini a, Hisham Arab b, Nataliia Pedachenko c , Qinjie t iand, Fernando Pineda e, Balamba \nPuranamf, Rubina Sohail g and Maria c eleste Osorio wenderh \nadepartment of clinical and experimental Medicine, University of Pisa, Pisa, italy; bobstetrics and Gynecology department, dr. a rab Medical c enter, \nJeddah, Saudi a rabia; cobstetrics, Gynecology and Perinatology d epartment, Shupyk national Healthcare University of Ukraine, Kyiv, Ukraine; \nddepartment of obstetrics and Gynecology, Peking Union Medical c ollege Hospital, chinese a cademy of Medical Sciences, Beijing, china; eGynecology, \nobstetrics and Urology, Higher School of Medicine of the national Polytechnic i nstitute, Mexico c ity, Mexico; fobstetrics and Gynecology d epartment, \nShalini Hospital, Barkatpura, i ndia; gdepartment of obstetrics and Gynecology, Services i nstitute of Medical Sciences, lahore, Pakistan; hobstetrics \nand Gynaecology d epartment, Universidade Federal do r io Grande do Sul, Porto a legre, Brazil\nABSTRACT\nOvulatory disorders are a common cause of abnormal uterine bleeding in women of reproductive age. t he \ninternational Federation of Gynecology and Obstetrics currently offers a causal classification system for \novulatory disorders but does not provide clear management recommendations. t here remains regional \ndisparity in treatment practices, often influenced by institutional and insurance regulations as well as cultural \nand religious practices. A panel of experts evaluated current gaps in ovulatory disorder management \nguidelines and discussed potential strategies for addressing these unmet needs. Key gaps included a lack in \nconsensus about the effectiveness of combined estrogen and progestogen versus progestogen alone, a \npaucity of evidence regarding the relative effectiveness of distinct hormonal molecules, a lack of data \nregarding optimal treatment duration, and limited guidance on optimal sequencing of treatment. \nRecommendations included development of a sequential treatment-line approach and development of a \nclinical guide addressing treatment scenarios common to all countries, which can then be adapted to local \npractices. it was also agreed that current guidelines do not address the unique clinical challenges of certain \npatient groups. t he panel discussed how the complexity and variety of patient groups made the development \nof one single disease management algorithm unlikely; however, a simplified, decision-point hierarchy could \npotentially help direct therapeutic choices. Overall, the panel highlighted that greater advocacy for a tailored \napproach to the treatment of ovulatory disorders, including wider consideration of non-estrogen therapies, \ncould help to improve care for people living with abnormal uterine bleeding due to ovarian dysfunction.\nIntroduction\nAbnormal uterine bleeding (AUB) is associated with a significant \nburden [ 1,2]. Around 1 in 3 women will be affected by AUB at \nsome point in their lives; however, estimates of prevalence vary \nwidely according to how bleeding was measured [ 3–5], and geo -\ngraphic differences in prevalence are evident [ 4,6–8]. Women  \nwith AUB frequently live with a poor quality of life [ 2, 3], report-\ning pain and discomfort, a limited ability to perform daily activi -\nties, and negative consequences for women’s social lives [ 2,9,10]  \nas well as academic performance in those of school age [ 11]. AUB \nis also associated with a considerable economic burden; there are \nmajor direct costs associated with procedures such as hysterectomy \nor endometrial ablation and further indirect costs owing to lost \nproductivity [3,12].\nCategorization of abnormal uterine bleeding\nChronic non-gestational AUB during the reproductive years is \ndefined as bleeding from the uterine corpus that is abnormal in \nduration, volume, frequency, and/or regularity, and has been pres -\nent for the majority of the preceding 6 months [4]. Acute AUB is \ncharacterized by an episode of heavy bleeding which is of suffi -\ncient quantity to require immediate intervention to minimize or \nprevent further blood loss; this may occur in the presence or \nabsence of existing chronic AUB [ 4]. The International Federation \nof Gynecology and Obstetrics (FIGO) further subclassifies AUB \nby underlying etiology: Polyp; Adenomyosis; Leiomyoma; \nMalignancy and hyperplasia; Coagulopathy; Ovulatory dysfunc -\ntion; Endometrial disorders; Iatrogenic; and Not otherwise classi -\nfied (PALM-COEIN) [ 4]. A common contributor to AUB in \nwomen of reproductive age is ovulatory dysfunction, often asso -\nciated with endocrinopathies and episodic or chronic disruption \nof the hypothalamic-pituitary-ovarian axis [ 13]. The FIGO classi -\nfication system includes AUB-O subcategories of Type I: \nHypothalamic; Type II: Pituitary; Type III: Ovarian; and Type IV: \nPolycystic ovarian syndrome [ 13]. Despite this international clas -\nsification system for causes of AUB-O, local guidelines rarely or \nonly briefly discuss management in terms of the FIGO patient \ncategories and there remains disparity in treatment practices for \n© 2024 The a uthor(s). Published by i nforma UK limited, trading as Taylor & Francis Group\nCONTACT Tommaso Simoncini  tommaso.simoncini@unipi.it  d epartment of clinical and experimental Medicine, University of Pisa, Via r oma, 67, Pisa, 56126, i taly\n Supplemental data for this article can be accessed online at https://doi.org/10.1080/09513590.2024.2362244.\nhttps://doi.org/10.1080/09513590.2024.2362244\nThis is an o pen a ccess article distributed under the terms of the c reative c ommons a ttribution license ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri -\nbution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the a ccepted Manuscript in \na repository by the author(s) or with their consent.\nARTICLE HISTORY\nr eceived 3 March 2024\na ccepted 27 May 2024\nPublished online 30 May \n2024\nKEYWORDS\na bnormal uterine bleeding; \naUB-o; ovulatory disorders; \novulatory dysfunction; \nmanagement guidelines; \nunmet needs\n\n2 t . SiMONciNi et Al.\nabnormal uterine bleeding due to ovulatory dysfunction (AUB-O) \nin different regions of the world. Against this background, a \npanel of experts, the Global boaRd for Addressing Current unmet \nneeds in mEnstrual disorders (GRACE), was convened to evalu -\nate current gaps in AUB-O management and treatment guidelines \nwith a focus on particular patient groups and to discuss potential \nstrategies that may address these unmet needs.\nHarmony and divergence in the management of \nabnormal bleeding due to ovulatory dysfunction\nHormonal treatments provide the mainstay of medical manage -\nment for AUB-O [ 14]. For example, the combined oral contra -\nceptive (COC) pill, which contains estrogen and a progestogen, \ncan help regulate and reduce uterine bleeding [ 15]. However, \nthere remains a paucity of evidence and no consensus about \nwhether combined estrogen and progestogen or progestogen \nalone is most effective for AUB-O [ 14,16]. Other options include \ngonadotropin-releasing hormone (GnRH) analogs (which induce \nprofound estrogen suppression) [1,15], the progestogen-containing \nintrauterine device (IUD), and antifibrinolytics [ 1,17]. While \nmany guidelines discuss the effectiveness of therapeutic classes, \nrecommendations on optimal sequencing of treatment are lim -\nited to advising medical management before surgical intervention.\nBased on their local knowledge and expertise ( Supplementary \nMaterial), the GRACE panel discussed the variation in treatment \napproaches seen in different countries. In Ukraine, mandatory \nguidelines state that first-line treatment for chronic AUB-O in \nwomen who need contraception is either a COC or an IUD, while \ncyclical progestogen regimens are offered as second-line treat -\nments, especially in patients who have contraindications to estro -\ngen and/or are trying to conceive [ 18]. An advisory resolution in \n2021 identified cyclical oral progestogen regimens (on cycle days \n11–25) as an effective second-line hormonal treatment method for \ncertain patient groups, with a favorable safety profile [ 19]. In con -\ntrast, clinicians in Mexico commonly prefer to initiate therapy \nwith non-hormonal treatments and then use cyclical progestogens \nor the COCs as second- or third-line treatments, respectively. The \npanel described that, in Pakistan, erratic use of treatments for \nmenorrhagia may result in increased likelihood of irregular vagi -\nnal bleeding. In Brazil, clinicians use anti-inflammatory drugs or \nhormonal treatments, depending on the patient’s main symptoms \nand whether they have any contraindications to hormonal treat -\nment; however, panel members noted that symptom-based \napproaches, i.e. antifibrinolytics for bleeding control [ 20] and \nnon-steroidal anti-inflammatory drugs for analgesia, will not \naddress bleeding irregularity [ 15, 21–23].\nIn general, panel members highlighted the variable availability \nof treatment options due to differing institutional and insurance \nregulations and emphasized the importance of highlighting mul -\ntiple treatment options within guidelines/recommendations, along \nwith including guidance on key treatment parameters such as \nefficacy. In addition, the panel noted that cultural and religious \npractices may also influence treatment decisions. For example, a \ndesire for regular and predictable bleeding in India and Pakistan \namong Muslim and Hindu women who are exempt from prayers \nwhile menstruating means that treatments which control abnor -\nmal blood loss and manage pain but maintain regular bleeding \npatterns may be preferred. Some patients may request short-term \ntreatment to delay menstruation or manage unexpected bleeding, \nto enable participation in religious activities such as pilgrimage.\nCultural perceptions of what constitutes abnormal bleeding \nwere also highlighted as potentially influencing how likely \npatients are to present with AUB and which treatments they pre -\nfer. In Mexico, dysmenorrhea and irregular menstrual bleeding \nare widely accepted, so patients with AUB may be less likely to \nconsult a doctor. Similarly, many women in India, Pakistan, and \nEurope expect heavy bleeding during perimenopause, so may not \nseek help for AUB during the perimenopausal years. Some \nwomen in India believe that they will gain weight if their men -\nstrual blood loss is reduced, so are hesitant to accept treatment \nthat could cause amenorrhea or oligomenorrhea. Patients in \nChina may also be reluctant to accept treatment that could cause \namenorrhea, due to a perception that heavy menstrual bleeding \nindicates fertility and is necessary for excreting toxins. As a \nresult, unless there is severe anemia, progestogens may be a \nmore favorable option than COCs for these patients.\nUnmet needs in guidelines for abnormal bleeding due \nto ovulatory dysfunction\nThe GRACE panel identified multiple challenges and gaps in \nknowledge that have resulted in certain unmet needs within cur -\nrent treatment guidelines for AUB-O ( Table 1). In particular, the \npanel noted that greater clarification around treatment strategies is \nneeded. FIGO provides a classification system for women with \nAUB and AUB-O, but they provide no treatment recommenda -\ntions [ 4,13]. The American College of Obstetricians and \nGynecologists (ACOG) have published guidelines for the manage -\nment of AUB associated with ovulatory dysfunction; however, \nthese pre-date the 2022 FIGO AUB-O subclassification system and \ninstead present management guidance in terms of patient age [ 14].\nRecommendations for a sequential treatment-line approach \nwould be welcomed but are complicated by the lack of a clear evi -\ndence base for optimal treatment duration, including long-term effi-\ncacy and safety data. Furthermore, guidelines do not consider the \ninterclass differences in drug profiles noted in the literature [ 24].\nThe panel noted that the regional variations in patient percep -\ntions of normal bleeding, access to healthcare, and treatment \navailability present challenges for well-defined global guidelines \n[25]. They emphasized the importance of being aware of such \nregional differences when developing guidelines but suggested it \nmay still be possible to develop a clinical guide that addresses \ntreatment scenarios common to all countries, which could improve \nglobal utility or be more readily adapted to local practices.\nUnmet needs in patient populations\nThe GRACE panel agreed that specific patient populations are \nbeing underserved by current treatment recommendations, which \ncould benefit from updated guidance for adolescents, women of \nlate reproductive age, women seeking pregnancy (including those \nwith chronic endometriosis), and women with contraindications \nfor estrogen.\nManagement guidelines do not currently address the unique \nclinical challenges associated with adolescence. Although there is \nTable 1. c urrent needs not addressed by treatment guidelines for a UB-o.\nUnmet need\nTreatment recommendations for specific patient populations\ndifferentiation between interclass differences in drug safety profiles\nr ecommendations for a sequential treatment-line approach\ndistinction between and recommendations for the management of different \nbleeding patterns, e.g. acute, chronic, and irregular bleeding\na clinical guide for treatment in scenarios common to all countries\naUB-o, abnormal uterine bleeding due to ovulatory dysfunction.\n\nGyNec Ol OGic Al eNdOcRiNOl OGy 3\nsome evidence that COCs can cause depleted bone mass acqui -\nsition [26–28], COCs are recommended in adolescents with AUB \n[14]; however, recommendations are needed for alternative treat -\nments. In girls with chronic AUB, a panelist suggested prioritiz -\ning therapies that contribute to a biphasic menstrual cycle \nwithout suppressing the hypothalamus-pituitary-ovarian axis, \nsuch as cyclic progestogens [ 18]. The necessity for further guid -\nance on how to address social and behavioral factors in adoles -\ncents was also highlighted. For example, some parents disapprove \nof the use of contraceptives, which limits therapeutic options. \nAdditionally, adolescents may be reluctant to seek medical atten -\ntion, sometimes presenting late or displaying poor treatment \nadherence or noncompliance. These challenges should be consid -\nered when developing guidelines and treatment pathways.\nIn women of late reproductive age, disparities in treatment \nrequirements exist. For example, panelists highlighted that high \ndoses of OCs are not recommended in perimenopausal women \nwith AUB-O to avoid risk of venous thromboembolism; however, \nsome women may benefit from COCs to facilitate menstrual reg -\nularity, contraception, and smooth onset of menopause without \nvasomotor symptoms.\nFor women seeking pregnancy, or those with contraindications \nfor estrogen such as a history of thrombosis, COCs are not a viable \ntreatment option. Panel members highlighted the need for clear \ntreatment algorithms to reduce blood loss, improve iron deficien -\ncies, and simultaneously support luteal phase, particularly in women \nwith AUB-O or chronic endometriosis who are trying to conceive. \nThe panel offered a cyclic progestogen regimen, which does not \nblock ovulation, as a suggestion for this population. They also noted \nthat, when managing patients with contraindications for estrogen, \nclinicians often use empiric treatment, and off-label therapies are \ncurrently used to treat heavy bleeding and irregular cycles in some \nregions. In a lot of cases, women may benefit from non-estrogen \ntherapies; however, members of the panel acknowledged that wider \nconsideration of and more specific guidance on potential alterna -\ntives including cyclical progestogens, IUDs [14], GnRH analogs [ 1], \nselective hormone receptor modulators, or non-anti-gonadotropic \noptions, is currently lacking, contributing to non-standardized treat-\nment strategies. Overall, greater advocacy for a tailored approach to \nAUB-O treatment could help influence the development of global \nguidelines to improve care for these unique populations.\nStrategies to address unmet needs in abnormal \nbleeding due to ovulatory dysfunction\nWhen considering potential strategies to address unmet needs in \nAUB-O ( Table 2 ), the GRACE panel acknowledged that the \ncomplexity and variety in requirements based on different patient \npopulations may preclude the development of a single algorithm \nto manage AUB-O. Although some similar challenges exist world -\nwide, country-specific adaptation should consider regulatory drug \nstatus, local perceptions, and cultural preferences. Adolescent, \npregnancy-seeking, and perimenopausal life stages require distinct \ntreatment pathways, and an up-to-date, age-based treatment \nguideline may be appropriate. However, there are multiple patient \nprofiles that would need to branch from a general algorithm, tak -\ning into consideration factors such as mental health, body mass \nindex, medical history, cardiovascular risk (including thromboem -\nbolic risk), smoking, autoimmune disease, socioeconomic status, \nand patient preference. Although sequential ranking of multiple \npatient factors may not be appropriate, a simplified decision-point \nhierarchy reflecting age, reproductive need, and contraindications \nmay help stratify therapeutic choices. The panel also noted that, \ngiven the underlying etiologies of AUB-O, multidisciplinary input \nwould aid the development of potential treatment algorithms.\nConclusions\nA gap in well-defined global treatment recommendations for \nwomen with AUB-O is preventing standardized, evidence-based \nclinical practice. Certain patient populations are currently being \nunderserved and wider consideration of options is needed for \nwomen who do not require contraception or are unable or \nunwilling to use COCs. The global AUB-O community must \nwork together to deliver guideline strategies that will improve the \nlives of people living with AUB-O across all regions of the world.\nAcknowledgments\nEditorial assistance was provided by Nicole Jones, BSc, on behalf of Alpharmaxim \nHealthcare Communications.\nDisclosure statement\nTS reports consulting fees from Abbott, Applied Medical, Astellas, Gedeon \nRichter and Johnson & Johnson, and speaker’s honoraria from Abbott, Applied \nMedical, Gedeon Richter, Intuitive Surgical, Shionogi and Theramex. HA, NP , \nQT, FP , BP , RS and MCOW report they have no competing interests to declare.\nFunding\nEditorial assistance for this manuscript was funded by Abbott Established \nPharmaceuticals.\nTable 2. Key features and challenges of any potential new treatment algorithm for a UB-o.\nKey feature challenge\nSingle treatment algorithm c omplex and multifaceted nature of a UB-o excludes development of a single algorithm; the variety of patient \nprofiles would make a single algorithm a complex and inadequate solution\nGeneral algorithm for regional adaptation Some similar challenges exist worldwide, but country-specific adaptation should consider regulatory drug status, \nlocal perceptions, and cultural preferences\na ge-based treatment guideline a dolescent, pregnancy-seeking and perimenopausal ages require distinct treatment decisions based on needs, and \nan age-based treatment guideline would be a useful starting point\nc onsideration of multiple patient profiles Multiple branches would be needed, to address the needs of multiple patient populations. a ge, mental health, BMi, \nmetabolic and medical history, high cardiovascular risk (including thromboembolic risk), smoking, autoimmune \ndisease, socioeconomic status, and patient preference are examples of required considerations\nMultidisciplinary involvement endocrinology expertise would be appropriate in special cases, e.g. thyroid disorder\nVascular expertise may be needed to check for arteriovenous malformation of the uterus in adolescents,  \ne.g. diagnosis of malformations using the d oppler effect via ultrasound and angiographic examination (uterine \nartery embolization is performed as a specific treatment for this pathology)\nHematological examinations to screen for clotting or bleeding disorders, especially in adolescents\naUB-o, abnormal uterine bleeding due to ovulatory dysfunction; BMi, body mass index.\n\n4 t . SiMONciNi et Al.\nORCID\nNataliia Pedachenko  http://orcid.org/0000-0002-0821-2943\nMaria Celeste Osorio Wender  http://orcid.org/0000-0001-9085-4605\nReferences\n [ 1] Singh S, Best C, Dunn S, et  al. No. 292-Abnormal uterine bleeding in \npre-menopausal women. J Obstet Gynaecol Can. 2018;40(5):1–5.\n [ 2] The Federation of Obstetric & Gynecological Societies of India. \nManagement guidelines of abnormal uterine bleeding in reproductive pe-\nriod. 2016. https://www.fogsi.org/wp-content/uploads/2016/06/AUB-FOGS\nI-GCPR-Summary-of-recommendations.pdf. Accessed 5 October 2023\n [ 3] Liu Z, Doan QV , Blumenthal P , et  al. A systematic review evaluating \nhealth-related quality of life, work impairment, and health-care costs \nand utilization in abnormal uterine bleeding. Value Health. \n2007;10(3):183–194. doi: 10.1111/j.1524-4733.2007.00168.x.\n [ 4] Munro MG, Critchley HOD, Fraser IS. FIGO menstrual disorders commit-\ntee. The two FIGO systems for normal and abnormal uterine bleeding symp-\ntoms and classification of causes of abnormal uterine bleeding in the repro-\nductive years: 2018 revisions. Int J Gynaecol Obstet. 2018;143(3):393–408.\n [ 5] Davis E, Sparzak PB. Abnormal uterine bleeding. In: StatPearls. \nTreasure Island, FL: StatPearls Publishing; 2022. https://www.ncbi.nlm.\nnih.gov/pubmed/30422508\n [ 6] Madhab Boruah A, Jaiswal P , Chinda M, et  al. Real-world safety and \neffectiveness analysis of norethisterone in the management of abnormal \nuterine bleeding. J South Asian Fed Obst Gynaecol. 2022;14(3):313–\n316. doi: 10.5005/jp-journals-10006-2048.\n [ 7] Kitahara Y , Hiraike O, Ishikawa H, et  al. National survey of abnormal \nuterine bleeding according to the FIGO classification in Japan. J Obstet \nGynaecol Res. 2023;49(1):321–330.\n [ 8] Rezende GP , Y ela Gomes DA, Benetti-Pinto CL. Prevalence of abnor -\nmal uterine bleeding in Brazilian women: association between \nself-perception and objective parameters. PLoS One. 2023;18(3):e0282605. \ndoi: 10.1371/journal.pone.0282605.\n [ 9] Odongo E, Byamugisha J, Ajeani J, et  al. Prevalence and effects of \nmenstrual disorders on quality of life of female undergraduate students \nin Makerere University College of health sciences, a cross sectional \nsurvey. BMC Womens Health. 2023;23(1):152.\n [10] Schoep ME, Nieboer TE, van der Zanden M, et  al. The impact of \nmenstrual symptoms on everyday life: a survey among 42,879 women. \nAm J Obstet Gynecol. 2019;220(6):569.e1–569.e7.\n [11] Vakilian K, Gholami R, Ghare-shiran SY , et  al. The relationship between \ntest anxiety and the incidence and type of menstrual disorders in the case \nof students of university of medical sciences: a longitudinal study. Int Arch \nNurs Health Care. 2016;2(5):058. doi: 10.23937/2469-5823/1510058.\n [12] Bonafede MM, Miller JD, Lukes A, et  al. Comparison of direct and in -\ndirect costs of abnormal uterine bleeding treatment with global endome -\ntrial ablation and hysterectomy. J Comp Eff Res. 2015;4(2):115–122.\n [13] Munro MG, Balen AH, Cho S, et  al. The FIGO ovulatory disorders \nclassification system. Int J Gynaecol Obstet. 2022;159(1):1–20.\n [14] The American College of Obstetricians and Gynecologists. Management of \nabnormal uterine bleeding associated with ovulatory dysfunction. July 2013. \nhttps://www.acog.org/clinical/clinical-guidance/practice-bulletin/\narticles/2013/07/management-of-abnormal-uterine-bleeding-a\nssociated-with-ovulatory-dysfunction. Accessed 5 October 2023\n [15] Maybin JA, Critchley HO. Medical management of heavy menstrual \nbleeding. Womens Health (Lond). 2016;12(1):27–34. doi: 10.2217/\nwhe.15.100.\n [16] Hickey M, Higham JM, Fraser I. Progestogens with or without oestrogen \nfor irregular uterine bleeding associated with anovulation. Cochrane \nDatabase Syst Rev. 2012;2012(9):CD001895. doi: 10.1002/14651858.\nCD001895.pub3.\n [17] Bryant-Smith AC, Lethaby A, Farquhar C, et  al. Antifibrinolytics for \nheavy menstrual bleeding. Cochrane Database Syst Rev. 2018;4(4):  \nCD000249. doi: 10.1002/14651858.CD000249.pub2.\n [18] Державний Експертний Центр МО3 України. Аномальні маткові \nкровотечі [Abnormal uterine bleeding]. 29 November 2019.  https://\nwww.dec.gov.ua/wp-content/uploads/2019/11/2016_353_ykpmd_amk.\npdf. Accessed 5 October 2023\n [19] Ukrainian Expert Forum on Abnormal Uterine Bleeding. Resolution of the \n1st Ukrainian expert forum on abnormal uterine bleeding. Reproductive \nEndocrinology. 2021;62(62):64–74. doi: 10.18370/2309-4117.2021.62.64-74.\n [20] The American College of Obstetricians and Gynecologists. ACOG \ncommittee opinion no. 557: management of acute abnormal uterine \nbleeding in nonpregnant reproductive-aged women. Obstet Gynecol. \n2013;121(4):891–896. doi: 10.1097/01.AOG.0000428646.67925.9a.\n [21] Deligeoroglou E, Karountzos V , Creatsas G. Abnormal uterine bleeding \nand dysfunctional uterine bleeding in pediatric and adolescent gyne -\ncology. Gynecol Endocrinol. 2013;29(1):74–78. doi: 10.3109/09513590. \n2012.705384.\n [22] Elmaoğulları S, Aycan Z. Abnormal uterine bleeding in adolescents. J \nClin Res Pediatr Endocrinol. 2018;10(3):191–197. doi: 10.4274/jcrpe. \n0014.\n [23] Luiro K, Holopainen E. Heavy menstrual bleeding in adolescent: nor -\nmal or a sign of an underlying disease? Semin Reprod Med. 2022;40(1–\n02):23–31. doi: 10.1055/s-0041-1739309.\n [24] Stanczyk FZ, Hapgood JP , Winer S, et  al. Progestogens used in post -\nmenopausal hormone therapy: differences in their pharmacological \nproperties, intracellular actions, and clinical effects. Endocr Rev. \n2013;34(2):171–208. doi: 10.1210/er.2012-1008.\n [25] Kanagasabai PS, Filoche S, Grainger R, et  al. Interventions to improve \naccess to care for abnormal uterine bleeding: a systematic scoping re -\nview. Int J Gynaecol Obstet. 2023;160(1):38–48.\n [26] Caldeirão TD, Orsolini LR, da Silva CC, et  al. Effect of two combina -\ntions of low-dose oral contraceptives on adolescent bone mass: a clin -\nical trial with 2 years follow-up. Medicine (Baltimore). 2022;101(37):  \ne30680. doi: 10.1097/MD.0000000000030680.\n [27] Golden NH. Bones and birth control in adolescent girls. J Pediatr \nAdolesc Gynecol. 2020;33(3):249–254. doi: 10.1016/j.jpag.2020.01.003.\n [28] Orsolini LR, Goldberg TBL, Caldeirão TD, et  al. Bone impact after two \nyears of low-dose oral contraceptive use during adolescence. PLoS \nOne. 2023;18(6):e0285885. doi: 10.1371/journal.pone.0285885.","source_license":"CC0","license_restricted":false}