Unmet needs in abnormal uterine bleeding due to ovulatory dysfunction

Ovulatory disorders are a common cause of abnormal uterine bleeding in women of reproductive age. t he international Federation of Gynecology and Obstetrics currently offers a causal classification system for ovulatory disorders but does not provide clear management recommendations. t here remains regional disparity in treatment practices, often influenced by institutional and insurance regulations as well as cultural and religious practices. A panel of experts evaluated current gaps in ovulatory disorder management guidelines and discussed potential strategies for addressing these unmet needs. Key gaps included a lack in consensus about the effectiveness of combined estrogen and progestogen versus progestogen alone, a paucity of evidence regarding the relative effectiveness of distinct hormonal molecules, a lack of data regarding optimal treatment duration, and limited guidance on optimal sequencing of treatment. Recommendations included development of a sequential treatment-line approach and development of a clinical guide addressing treatment scenarios common to all countries, which can then be adapted to local practices. it was also agreed that current guidelines do not address the unique clinical challenges of certain patient groups. t he panel discussed how the complexity and variety of patient groups made the development of one single disease management algorithm unlikely; however, a simplified, decision-point hierarchy could potentially help direct therapeutic choices. Overall, the panel highlighted that greater advocacy for a tailored approach to the treatment of ovulatory disorders, including wider consideration of non-estrogen therapies, could help to improve care for people living with abnormal uterine bleeding due to ovarian dysfunction.

Abnormal uterine bleeding (AUB) is associated with a significant burden [ 1,2]. Around 1 in 3 women will be affected by AUB at some point in their lives; however, estimates of prevalence vary widely according to how bleeding was measured [ 3–5], and geo - graphic differences in prevalence are evident [ 4,6–8]. Women with AUB frequently live with a poor quality of life [ 2, 3], report- ing pain and discomfort, a limited ability to perform daily activi - ties, and negative consequences for women’s social lives [ 2,9,10] as well as academic performance in those of school age [ 11]. AUB is also associated with a considerable economic burden; there are major direct costs associated with procedures such as hysterectomy or endometrial ablation and further indirect costs owing to lost productivity [3,12]. Categorization of abnormal uterine bleeding Chronic non-gestational AUB during the reproductive years is defined as bleeding from the uterine corpus that is abnormal in duration, volume, frequency, and/or regularity, and has been pres - ent for the majority of the preceding 6 months [4]. Acute AUB is characterized by an episode of heavy bleeding which is of suffi - cient quantity to require immediate intervention to minimize or prevent further blood loss; this may occur in the presence or absence of existing chronic AUB [ 4]. The International Federation of Gynecology and Obstetrics (FIGO) further subclassifies AUB by underlying etiology: Polyp; Adenomyosis; Leiomyoma; Malignancy and hyperplasia; Coagulopathy; Ovulatory dysfunc - tion; Endometrial disorders; Iatrogenic; and Not otherwise classi - fied (PALM-COEIN) [ 4]. A common contributor to AUB in women of reproductive age is ovulatory dysfunction, often asso - ciated with endocrinopathies and episodic or chronic disruption of the hypothalamic-pituitary-ovarian axis [ 13]. The FIGO classi - fication system includes AUB-O subcategories of Type I: Hypothalamic; Type II: Pituitary; Type III: Ovarian; and Type IV: Polycystic ovarian syndrome [ 13]. Despite this international clas - sification system for causes of AUB-O, local guidelines rarely or only briefly discuss management in terms of the FIGO patient categories and there remains disparity in treatment practices for © 2024 The a uthor(s). Published by i nforma UK limited, trading as Taylor & Francis Group CONTACT Tommaso Simoncini [email protected] d epartment of clinical and experimental Medicine, University of Pisa, Via r oma, 67, Pisa, 56126, i taly Supplemental data for this article can be accessed online at https://doi.org/10.1080/09513590.2024.2362244. https://doi.org/10.1080/09513590.2024.2362244 This 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 - bution, 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 a repository by the author(s) or with their consent. ARTICLE HISTORY r eceived 3 March 2024 a ccepted 27 May 2024 Published online 30 May 2024

a bnormal uterine bleeding; aUB-o; ovulatory disorders; ovulatory dysfunction; management guidelines; unmet needs 2 t . SiMONciNi et Al. abnormal uterine bleeding due to ovulatory dysfunction (AUB-O) in different regions of the world. Against this background, a panel of experts, the Global boaRd for Addressing Current unmet needs in mEnstrual disorders (GRACE), was convened to evalu - ate current gaps in AUB-O management and treatment guidelines with a focus on particular patient groups and to discuss potential strategies that may address these unmet needs. Harmony and divergence in the management of abnormal bleeding due to ovulatory dysfunction Hormonal treatments provide the mainstay of medical manage - ment for AUB-O [ 14]. For example, the combined oral contra - ceptive (COC) pill, which contains estrogen and a progestogen, can help regulate and reduce uterine bleeding [ 15]. However, there remains a paucity of evidence and no consensus about whether combined estrogen and progestogen or progestogen alone is most effective for AUB-O [ 14,16]. Other options include gonadotropin-releasing hormone (GnRH) analogs (which induce profound estrogen suppression) [1,15], the progestogen-containing intrauterine device (IUD), and antifibrinolytics [ 1,17]. While many guidelines discuss the effectiveness of therapeutic classes, recommendations on optimal sequencing of treatment are lim - ited to advising medical management before surgical intervention. Based on their local knowledge and expertise ( Supplementary Material), the GRACE panel discussed the variation in treatment approaches seen in different countries. In Ukraine, mandatory guidelines state that first-line treatment for chronic AUB-O in women who need contraception is either a COC or an IUD, while cyclical progestogen regimens are offered as second-line treat - ments, especially in patients who have contraindications to estro - gen and/or are trying to conceive [ 18]. An advisory resolution in 2021 identified cyclical oral progestogen regimens (on cycle days 11–25) as an effective second-line hormonal treatment method for certain patient groups, with a favorable safety profile [ 19]. In con - trast, clinicians in Mexico commonly prefer to initiate therapy with non-hormonal treatments and then use cyclical progestogens or the COCs as second- or third-line treatments, respectively. The panel described that, in Pakistan, erratic use of treatments for menorrhagia may result in increased likelihood of irregular vagi - nal bleeding. In Brazil, clinicians use anti-inflammatory drugs or hormonal treatments, depending on the patient’s main symptoms and whether they have any contraindications to hormonal treat - ment; however, panel members noted that symptom-based approaches, i.e. antifibrinolytics for bleeding control [ 20] and non-steroidal anti-inflammatory drugs for analgesia, will not address bleeding irregularity [ 15, 21–23]. In general, panel members highlighted the variable availability of treatment options due to differing institutional and insurance regulations and emphasized the importance of highlighting mul - tiple treatment options within guidelines/recommendations, along with including guidance on key treatment parameters such as efficacy. In addition, the panel noted that cultural and religious practices may also influence treatment decisions. For example, a desire for regular and predictable bleeding in India and Pakistan among Muslim and Hindu women who are exempt from prayers while menstruating means that treatments which control abnor - mal blood loss and manage pain but maintain regular bleeding patterns may be preferred. Some patients may request short-term treatment to delay menstruation or manage unexpected bleeding, to enable participation in religious activities such as pilgrimage. Cultural perceptions of what constitutes abnormal bleeding were also highlighted as potentially influencing how likely patients are to present with AUB and which treatments they pre - fer. In Mexico, dysmenorrhea and irregular menstrual bleeding are widely accepted, so patients with AUB may be less likely to consult a doctor. Similarly, many women in India, Pakistan, and Europe expect heavy bleeding during perimenopause, so may not seek help for AUB during the perimenopausal years. Some women in India believe that they will gain weight if their men - strual blood loss is reduced, so are hesitant to accept treatment that could cause amenorrhea or oligomenorrhea. Patients in China may also be reluctant to accept treatment that could cause amenorrhea, due to a perception that heavy menstrual bleeding indicates fertility and is necessary for excreting toxins. As a result, unless there is severe anemia, progestogens may be a more favorable option than COCs for these patients. Unmet needs in guidelines for abnormal bleeding due to ovulatory dysfunction The GRACE panel identified multiple challenges and gaps in knowledge that have resulted in certain unmet needs within cur - rent treatment guidelines for AUB-O ( Table 1). In particular, the panel noted that greater clarification around treatment strategies is needed. FIGO provides a classification system for women with AUB and AUB-O, but they provide no treatment recommenda - tions [ 4,13]. The American College of Obstetricians and Gynecologists (ACOG) have published guidelines for the manage - ment of AUB associated with ovulatory dysfunction; however, these pre-date the 2022 FIGO AUB-O subclassification system and instead present management guidance in terms of patient age [ 14]. Recommendations for a sequential treatment-line approach would be welcomed but are complicated by the lack of a clear evi - dence base for optimal treatment duration, including long-term effi- cacy and safety data. Furthermore, guidelines do not consider the interclass differences in drug profiles noted in the literature [ 24]. The panel noted that the regional variations in patient percep - tions of normal bleeding, access to healthcare, and treatment availability present challenges for well-defined global guidelines [25]. They emphasized the importance of being aware of such regional differences when developing guidelines but suggested it may still be possible to develop a clinical guide that addresses treatment scenarios common to all countries, which could improve global utility or be more readily adapted to local practices. Unmet needs in patient populations The GRACE panel agreed that specific patient populations are being underserved by current treatment recommendations, which could benefit from updated guidance for adolescents, women of late reproductive age, women seeking pregnancy (including those with chronic endometriosis), and women with contraindications for estrogen. Management guidelines do not currently address the unique clinical challenges associated with adolescence. Although there is Table 1. c urrent needs not addressed by treatment guidelines for a UB-o. Unmet need Treatment recommendations for specific patient populations differentiation between interclass differences in drug safety profiles r ecommendations for a sequential treatment-line approach distinction between and recommendations for the management of different bleeding patterns, e.g. acute, chronic, and irregular bleeding a clinical guide for treatment in scenarios common to all countries aUB-o, abnormal uterine bleeding due to ovulatory dysfunction. GyNec Ol OGic Al eNdOcRiNOl OGy 3 some evidence that COCs can cause depleted bone mass acqui - sition [26–28], COCs are recommended in adolescents with AUB [14]; however, recommendations are needed for alternative treat - ments. In girls with chronic AUB, a panelist suggested prioritiz - ing therapies that contribute to a biphasic menstrual cycle without suppressing the hypothalamus-pituitary-ovarian axis, such as cyclic progestogens [ 18]. The necessity for further guid - ance on how to address social and behavioral factors in adoles - cents was also highlighted. For example, some parents disapprove of the use of contraceptives, which limits therapeutic options. Additionally, adolescents may be reluctant to seek medical atten - tion, sometimes presenting late or displaying poor treatment adherence or noncompliance. These challenges should be consid - ered when developing guidelines and treatment pathways. In women of late reproductive age, disparities in treatment requirements exist. For example, panelists highlighted that high doses of OCs are not recommended in perimenopausal women with AUB-O to avoid risk of venous thromboembolism; however, some women may benefit from COCs to facilitate menstrual reg - ularity, contraception, and smooth onset of menopause without vasomotor symptoms. For women seeking pregnancy, or those with contraindications for estrogen such as a history of thrombosis, COCs are not a viable treatment option. Panel members highlighted the need for clear treatment algorithms to reduce blood loss, improve iron deficien - cies, and simultaneously support luteal phase, particularly in women with AUB-O or chronic endometriosis who are trying to conceive. The panel offered a cyclic progestogen regimen, which does not block ovulation, as a suggestion for this population. They also noted that, when managing patients with contraindications for estrogen, clinicians often use empiric treatment, and off-label therapies are currently used to treat heavy bleeding and irregular cycles in some regions. In a lot of cases, women may benefit from non-estrogen therapies; however, members of the panel acknowledged that wider consideration of and more specific guidance on potential alterna - tives including cyclical progestogens, IUDs [14], GnRH analogs [ 1], selective hormone receptor modulators, or non-anti-gonadotropic options, is currently lacking, contributing to non-standardized treat- ment strategies. Overall, greater advocacy for a tailored approach to AUB-O treatment could help influence the development of global guidelines to improve care for these unique populations. Strategies to address unmet needs in abnormal bleeding due to ovulatory dysfunction When considering potential strategies to address unmet needs in AUB-O ( Table 2 ), the GRACE panel acknowledged that the complexity and variety in requirements based on different patient populations may preclude the development of a single algorithm to manage AUB-O. Although some similar challenges exist world - wide, country-specific adaptation should consider regulatory drug status, local perceptions, and cultural preferences. Adolescent, pregnancy-seeking, and perimenopausal life stages require distinct treatment pathways, and an up-to-date, age-based treatment guideline may be appropriate. However, there are multiple patient profiles that would need to branch from a general algorithm, tak - ing into consideration factors such as mental health, body mass index, medical history, cardiovascular risk (including thromboem - bolic risk), smoking, autoimmune disease, socioeconomic status, and patient preference. Although sequential ranking of multiple patient factors may not be appropriate, a simplified decision-point hierarchy reflecting age, reproductive need, and contraindications may help stratify therapeutic choices. The panel also noted that, given the underlying etiologies of AUB-O, multidisciplinary input would aid the development of potential treatment algorithms.

A gap in well-defined global treatment recommendations for women with AUB-O is preventing standardized, evidence-based clinical practice. Certain patient populations are currently being underserved and wider consideration of options is needed for women who do not require contraception or are unable or unwilling to use COCs. The global AUB-O community must work together to deliver guideline strategies that will improve the lives of people living with AUB-O across all regions of the world. Acknowledgments Editorial assistance was provided by Nicole Jones, BSc, on behalf of Alpharmaxim Healthcare Communications. Disclosure statement TS reports consulting fees from Abbott, Applied Medical, Astellas, Gedeon Richter and Johnson & Johnson, and speaker’s honoraria from Abbott, Applied Medical, Gedeon Richter, Intuitive Surgical, Shionogi and Theramex. HA, NP , QT, FP , BP , RS and MCOW report they have no competing interests to declare. Funding Editorial assistance for this manuscript was funded by Abbott Established Pharmaceuticals. Table 2. Key features and challenges of any potential new treatment algorithm for a UB-o. Key feature challenge Single treatment algorithm c omplex and multifaceted nature of a UB-o excludes development of a single algorithm; the variety of patient profiles would make a single algorithm a complex and inadequate solution General algorithm for regional adaptation Some similar challenges exist worldwide, but country-specific adaptation should consider regulatory drug status, local perceptions, and cultural preferences a ge-based treatment guideline a dolescent, pregnancy-seeking and perimenopausal ages require distinct treatment decisions based on needs, and an age-based treatment guideline would be a useful starting point c onsideration of multiple patient profiles Multiple branches would be needed, to address the needs of multiple patient populations. a ge, mental health, BMi, metabolic and medical history, high cardiovascular risk (including thromboembolic risk), smoking, autoimmune disease, socioeconomic status, and patient preference are examples of required considerations Multidisciplinary involvement endocrinology expertise would be appropriate in special cases, e.g. thyroid disorder Vascular expertise may be needed to check for arteriovenous malformation of the uterus in adolescents, e.g. diagnosis of malformations using the d oppler effect via ultrasound and angiographic examination (uterine artery embolization is performed as a specific treatment for this pathology) Hematological examinations to screen for clotting or bleeding disorders, especially in adolescents aUB-o, abnormal uterine bleeding due to ovulatory dysfunction; BMi, body mass index. 4 t . SiMONciNi et Al. ORCID Nataliia Pedachenko http://orcid.org/0000-0002-0821-2943 Maria Celeste Osorio Wender http://orcid.org/0000-0001-9085-4605

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