Scholarly article on topic 'Medical treatment for heavy menstrual bleeding'

Medical treatment for heavy menstrual bleeding Academic research paper on "Clinical medicine"

CC BY-NC-ND
0
0
Share paper
OECD Field of science
Keywords
{antifibrinolytics / "heavy menstrual bleeding" / HMB / "levonorgestrel-releasing intrauterine system" / "medical treatment"}

Abstract of research paper on Clinical medicine, author of scientific article — Yi-Jen Chen, Yiu-Tai Li, Ben-Shian Huang, Ming-Shyen Yen, Bor-Ching Sheu, et al.

Abstract Heavy menstrual bleeding, or menorrhagia, is subjectively defined as a “complaint of a large amount of bleeding during menstrual cycles that occurs over several consecutive cycles” and is objectively defined as menstrual blood loss of more than 80 mL per cycle that is associated with an anemia status (defined as a hemoglobin level of <10 g/dL). During their reproductive age, more than 30% of women will complain of or experience a heavy amount of bleeding, which leads to a debilitating health outcome, including significantly reduced health-related quality of life, and a considerable economic burden on the health care system. Although surgical treatment might be the most important definite treatment, especially hysterectomy for those women who have finished bearing children, the uterus is still regarded as the regulator and controller of important physiological functions, a sexual organ, a source of energy and vitality, and a maintainer of youth and attractiveness. This has resulted in a modern trend in which women may reconsider the possibility of organ preservation. For women who wish to retain the uterus, medical treatment may be one of the best alternatives. In this review, recent trends in the management of women with heavy menstrual bleeding are discussed.

Academic research paper on topic "Medical treatment for heavy menstrual bleeding"

Contents lists available at ScienceDirect

Taiwanese Journal of Obstetrics & Gynecology

journal homepage: www.tjog-online.com

Review Article

Medical treatment for heavy menstrual bleeding

Yiu-Tai Li

; c, 1

Yi-Jen Chen a b1 Bor-Ching Sheu e, Song-Nan Chow e, Peng-Hui Wang Gynecology Systematic Review Groupg

Ben-Shian Huang a, d, Ming-Shyen Yen a, d,

a, bf *, the Taiwan Association of

CrossMark

a Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan b Division of Gynecology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan c Department of Obstetrics and Gynecology, Kuo General Hospital, Tainan, Taiwan d Department of Obstetrics and Gynecology, National Yang-Ming University Hospital, Ilan, Taiwan

e Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan f Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

g Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan

ARTICLE INFO

ABSTRACT

Article history: Accepted 4 August 2015

Keywords: antifibrinolytics heavy menstrual bleeding HMB

levonorgestrel-releasing intrauterine system

medical treatment

Heavy menstrual bleeding, or menorrhagia, is subjectively defined as a "complaint of a large amount of bleeding during menstrual cycles that occurs over several consecutive cycles" and is objectively defined as menstrual blood loss of more than 80 mL per cycle that is associated with an anemia status (defined as a hemoglobin level of <10 g/dL). During their reproductive age, more than 30% of women will complain of or experience a heavy amount of bleeding, which leads to a debilitating health outcome, including significantly reduced health-related quality of life, and a considerable economic burden on the health care system. Although surgical treatment might be the most important definite treatment, especially hysterectomy for those women who have finished bearing children, the uterus is still regarded as the regulator and controller of important physiological functions, a sexual organ, a source of energy and vitality, and a maintainer of youth and attractiveness. This has resulted in a modern trend in which women may reconsider the possibility of organ preservation. For women who wish to retain the uterus, medical treatment may be one of the best alternatives. In this review, recent trends in the management of women with heavy menstrual bleeding are discussed.

Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All

rights reserved.

Introduction

Heavy menstrual bleeding (HMB), defined as a blood loss of more than 80 mL per cycle and often accompanied with anemia, is a major reason for gynecologic consultations around the world. Women with HMB experience a diminished quality of life and a loss of work productivity, and face high expenses for medical services [1]. Various terms have been used to describe HMB, including menometrorrhagia, metrorrhagia, menorrhagia, and polymenor-rhea. The confusing and inconsistently applied nomenclature and the lack of standardized methods for investigation and categorization of the various potential etiologies make it difficult to

* Corresponding author. Division of Gynecology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, 201, Section 2, Shih-Pai Road, Taipei, Taiwan.

E-mail addresses: phwang@vghtpe.gov.tw, phwang@ym.edu.tw (P.-H. Wang). 1 Both these authors contributed equally to this article.

compare studies performed by different investigators or research groups. Therefore, a universally accepted system of nomenclature and classification seems to be a necessary step in the evolution of collaborative research and evidence-based application of results to clinical practice [1]. In addition, an accurate diagnosis based on a universally accepted system of nomenclature and classification might offer a better understanding of the pathophysiology of HMB, which would help physicians make better decisions regarding the management of women with this condition. After an effective treatment, good control of the patient's symptoms and signs will improve her quality of life [2—4].

To clearly demonstrate HMB, the Menstrual Disorders Working Group of the International Federation of Gynecology and Obstetrics (FIGO) has proposed abandoning the use of one common term, "dysfunctional uterine bleeding" [5]. There are nine main categories, arranged according to the acronym PALM—COEIN (polyp, adenomyosis, leiomyomas, malignancy, hyperplasia—coagulopathy,

http://dx.doi.org/10.1016/j.tjog.2015.08.001

1028-4559/Copyright © 2015, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved.

Figure 1. PALM—COEIN (polyp, adenomyosis, leiomyomas, malignancy, hyperplasia- coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic causes and not-yet-classified entities) system for heavy menstrual bleeding.

ovulatory dysfunction, endometrial disorders, iatrogenic causes and not-yet-classified entities) (Figure 1). The PALM categories include polyp, adenomyosis, leiomyomas, and malignancy and hyperplasia [5]. In general, the components of PALM are structural etiologies, which can be measured visually because they can be evaluated by clinical examination, imaging techniques, or histopathology [6]. It is difficult to define a COEIN status by imaging or histopathology, since COEIN is related to nonstructural entities [6], including coagulopathy, ovulatory dysfunction [7], endometrial disorders by exclusion of other identifiable abnormalities in women of reproductive age;, iatrogenic causes, such as insertion of an intrauterine system [8] or medicine directly impacting the endometrium [9], interfering with blood coagulation mechanisms (warfarin, heparin, and low-molecular-weight heparin) [10], and influencing the systemic control of ovulation, and not-yet-classified entities, including chronic endometritis [11], arteriovenous malformation [12], myo-metrial hypertrophy, and possible future entities.

The primary classification system reflects only the presence (1) or absence (0) [5,6], and cannot totally show the severity of diseases. Therefore, a secondary classification system may be needed in some subgroups. For example, leiomyomas involving the endo-metrial cavity [submucosal (SM)] need to be distinguished from others (O) because SM lesions are most likely to contribute to the genesis of HMB [5]. Tertiary subclassification of leiomyoma types requires the clinicians to determine the relationship between the leiomyomas and the endometrium, myometrium, and serosa [13]. SM types are 0 (pedunculated intracavitary), 1 (<50% intramural), and 2 (>50% intramural), and the others are 3 (contracts endometrium, 100% intramural), 4 (intramural), 5 (subserosal >50% intramural), 6 (subserosal <50% intramural), 7 (subserosal pedun-culated), and 8 (includes cervical or parasitic and other lesions not related to the myometrium) [14].

The PALM—COEIN system not only allows clinicians and researchers to identify and classify women with HMB in a systematic manner, but also provides reliable information for research

purposes and for epidemiological and prevalence studies in different settings [15]. This classification is useful for patient-tailored therapy, especially for differential stages of women's reproductive years and for different patterns of HMB [15]. It is important to keep in mind that many of these causes of HMB can be asymptomatic, and that HMB itself might be the first symptom or the only symptom presented by patients [16,17].

Strategy to evaluate women with HMB

Measuring menstrual blood loss accurately is impractical because of the complexity of the techniques [15]. Therefore, HMB could be defined as "excess menstrual blood loss interfering with women's physical, emotional, social and material quality of life." HMB can occur alone or in combination with other symptoms. Normal limits of menstruation in women include: (1) a menstrual period frequency ranging from 24 days to 38 days; (2) duration of blood flow ranging from 4 days to 8 days; and (3) the volume of monthly blood flow ranging from 5 mL to 80 mL [6]. The cause of HMB can be clearly separated from structural and nonstructural problems. Therefore, all women with HMB should be treated in as diligent and comprehensive a fashion as is practicable, given the clinical situation and the available resources [5]. That is to say, we need to establish necessary parameters to achieve an accurate diagnosis and treatment for women with HMB (Figure 2).

Clinicians should perform a careful evaluation of a woman of reproductive age with HMB, to ensure that the bleeding is not related to an undiagnosed pregnancy and is emanating from the cervical os, rather than from another location [5]. The bleeding should be confirmed, in the absence of any other identifiable source [18]. In addition, a structured history, including the age of the woman, regularity of menstrual cycles and accompanying menstruation problems (for example, dysmenorrhea), beginning and frequency of HMB, symptoms or signs of a tendency to bleed, bruises, epistaxis, and a family history, should be taken and

Figure 2. Algorithm for evaluation of women with heavy menstrual bleeding. HMB = heavy menstrual bleeding.

evaluated. Specialists, such as hematologists, should be consulted, if coagulopathy problems, which occur in approximately 13% of women with HMB, cannot be totally excluded [14].

Basic technologies for investigation of different causes include transvaginal ultrasound (and/or transabdominal ultrasound), tissue biopsy, histology, and diagnostic hysteroscopy. Transvaginal ultrasound might be one of the most convenient, economical, and useful image modalities to evaluate women with HMB. Adequate quality to display myometrial and endometrial features clearly is important for ideal imaging by transvaginal ultrasound. Endometrial sampling should be considered in women over a certain age, usually 45 years, and with a family history of genetic disorders, such as hereditary nonpolyposis colorectal cancer syndrome [19], since the possibility of endometrial cancer should be excluded [20], even though ovulation disorders are also frequently noted in women during the menopausal transition. To detect adenomyosis, its variance (adenomyoma), or submucosal myoma more accurately, magnetic resonance imaging may be needed, although it is not practical at the present time [21—23].

Medical treatment

In women with definite causes of HMB, therapeutic choices should be based on the PALM—COEIN system. For polyps, surgical removal is highly recommended, especially the use of minimally invasive procedures, such as hysteroscopy [24,25]. For certain types of leiomyomas, for example, SM leiomyomas, surgical removal is frequently required, although medical treatment can work in some cases. Hysteroscopic resection, by either a one- or two-step procedure, or after preoperative hormonal therapy, including gonadotropin-releasing hormone agonist (GnRH agonist) and/or ulipristal acetate (one of the selective progesterone receptor modulators—SPRMs) [26—28], has been well accepted as the treatment of choice [29,30]. Endometrial lesions should be managed based on the pathological findings. Precancer lesions, including endometrial hyperplasia with and/or without atypia, or

some early-stage and well-differentiated (Grade 1) endometrioid-type endometrial cancers, could be managed conservatively. These conservative treatments include high-dose progestin and/or other hormonal therapies [20,31]. However, conservative medical treatment for women with endometrial precancer or endometrioid cancer is not totally free of risk. The following criteria or considerations should be carefully evaluated: (1) the potential oncologic risk should be assessed, since the persistent, progressive rate of cancer is 15—25%; (2) a good candidate for conservative treatment should be younger than 40 years, should have a need to give birth, and have an ability to give birth; (3) the disease should be limited to 2009 FIGO IA and this diagnosis should be confirmed by gynecologic—pathologic experts; (4) the treated women should have good compliance and not have any contraindication to high-dose progestins; (5) the women should be informed that the initial response rate of the drugs ranges from 50% to 70%; (6) these conservative treatments often include hormones, such as medroxyprogesterone, megestrol, and levonorgestrel-releasing intrauterine system (LNG-IUS) ± GnRH agonist; (7) the hormone dosage should be administered adequately, and the frequently used medication includes 200—800 mg medroxyprogesterone and 80—320 mg megestrol; (8) the women should have excellent compliance and adequate surveillance, which should occur every 2—6 months; (9) after conservative medical treatment, these women have only a 30—40% chance of a successful reproductive outcome; and (10) these patients need counseling by well-trained team workers [31,32].

Coagulation problems and endocrinopathy could be managed based on their definite causes. Iatrogenic causes could be managed by removal of the iatrogenic factors and modification of dosage use. Other important causes of HMB include not-yet-classified entities, such as chronic endometritis, especially chlamydial infection [33], arteriovenous malformation, myometrial hypertrophy, and possible future entities. Some of these not-yet-classified entities could be managed by antibiotics and embolization [34].

Women with uterine leiomyoma and/or adenomyosis can be managed with medical treatment. Our previous studies reviewed

this extensively [35—38]. Some medications, including SPRMs, gestrinone, danazol, progestins, oral pills, LNG-IUS, and GnRH agonist are discussed.

Among these medications, SPRMs, including ulipristal acetate, mifepristone, asoprisnil, lonaprisan, telapristone acetate, PRA-910, ZK 136799, and onapristone, inhibit endometrial proliferation or suppress leiomyoma and/or adenomyotic lesions, resulting in inhibition of prostaglandin production and shrinkage of leiomyoma and/or adenomyotic lesions, and endometrial atrophy, suggesting that these beneficial effects of SPRMs treatment may reflect changes in the endometrial morphology and/or the absence of bleeding [39]. A recent head-to-head comparison study showed that ulipristal acetate (one of the SPRMs) was superior to placebo and not inferior to leuprolide acetate (one of the GnRH agonists) for the control of HMB. More than 90% of women treated with ulipristal acetate had a clinically significant decrease in bleeding, and approximately three-fourths became amenorrheic [39]. The SPRMs might be promising agents in the management of uterine fibroid-related HMB; however, a potential safety issue for the endometrium is still concerned [40].

Evidence regarding the use of oral pills as treatment for women with symptomatic fibroids is very scarce and of low quality; therefore, a recent systematic review questioned the real efficacy of oral pills in women with symptomatic uterine fibroids [41].

LNG-IUS has been found to be more effective than oral medication as a treatment for HMB [42,43]. In addition, LNG-IUS is associated with a greater reduction in HMB and improved quality of life, and appears to be more acceptable in long-term treatment, but is associated with more minor adverse effects compared to oral therapy [41]. Therefore, some physicians have recommended that LNG-IUS should be used as a first-line medical therapy for HMB in women not seeking pregnancy [42].

The 2011 report of the Agency for Healthcare Research and Quality on comparative management of uterine fibroids showed that, despite the prevalence and possible complications of uterine fibroids, few published studies examining the effectiveness of treatment strategies exist [44]. Few therapies are approved by the Food and Drug Administration for fibroids; leuprolide acetate, a GnRH agonist approved in 1995 for preoperative treatment of fibroids, is a gold-standard drug in the management of women with uterine fibroid- and/or adenomyosis-related symptoms or signs. However, leuprolide acetate, with much more profound suppression of estradiol levels, significantly more hot flashes, and more substantial effects on markers of bone turnover, had a relatively poor side-effect profile in women during their reproductive age.

Therefore, the add-back therapy of GnRH administration is often suggested.

In women without definite organic lesions, such as those related to endometrial, uterine, or endocrine and hematologically abnormal causes, HMB remains poorly understood and poses a major challenge to developing novel, efficient therapies for HMB [15]. The ultimate goal of any form of treatment is to reduce the amount of menstrual blood. Medical treatment has always been considered the first-line treatment for women with HMB, as a means of achieving the goal of uterine preservation [45,46]. Conservative uterine-sparing surgery or hysterectomy tends to follow failed or ineffective medical treatment.

Matteson et al [1] conducted a systematic review that included 26 published articles, and found that a significant reduction of blood loss in women with HMB presumed secondary to endome-trial dysfunction was achieved with a 71 —95% reduction in the use of LNG-IUS, a 35—70% reduction in the use of combined oral pills, an 87% reduction in the use of an extended cycle of oral progestins (>21 days), a 26—54% reduction in the use of antifibrinolytics (tranexamic acid), and a 10—52% reduction in the use of nonsteroidal anti-inflammatory drugs (NSAlDs) [1]. However, luteal-phase progestins should be used only in special cases, since nearly all the abovementioned therapeutic strategies, including LNG-IUS (a reduction of 71 % compared with 22%, p < 0.001), NSAlDs (a reduction of 67% compared with 52%, in a small sample-size comparison, n = 32), and antifibrinolytics (a reduction of 45% compared with 20%, p < 0.001), were all superior to luteal-phase progestin treatment, with a reduction of 20—67% [1]. In addition, antifibrinolytics were superior to NSAlDs (a reduction of 54% compared with 10%, p < 0.001) for reduction of HMB. LNG-IUS was superior to combined oral pills (a reduction of 83% compared with 68%, p = 0.002) and NSAlDs (a reduction of 95% compared with 23%, p < 0.001) [1].

The cost of medications can be referenced from Table 1. Anti-fibrinolytics, such as 250-mg tranexamic acid, cost US$0.1/tab, are prescribed as two tabs three times per day and are often used to cover the whole menstrual period. NSAlDs, such as 200 mg mefe-namic acid or naproxen, are US$0.1—1/tab, often prescribed as one tab twice or three times per day, and often used during attacks of HMB. Medroxyprogesterone (5 mg) is US$0.1/tab; however, it often requires 20—40 mg/day. ln addition, extended use is preferred; suggesting that use for more than 14 days or continuous use without more than 7 missed days might have a good therapeutic effect. The monthly expense of oral pills is US$10—30. LNG-IUS costs US$100—200 per set; however, the effectiveness is

Table 1

Summary of the useful medications for women with heavy menstrual bleeding.

Drugs Cost a Opinion and effects compared with placebo

Antifibrinolytics 2.5 Well tolerated, fewer side effects, a definite therapeutic value (26—54% reduction)

(tranexamix acid)

NSAlDs 1—2 Gl and renal effects, allergy, a definite therapeutic value (10—52% reduction)

Progestins 10—15 lrregular bleeding, nausea/vomiting, mood swings, hot flush, increased body weight, a definite therapeutic value in extended use

(87% reduction)

Gestrinone 80 Seborrhea, hypertrichosis, increased body weight, the risk of metabolic syndrome such as unfavorable effects on serum

cholesterol lipoprotein distribution, a definite therapeutic value (50—70% reduction)

Danazol 40—100 Seborrhea, hypertrichosis, increased body weight, and the risk of metabolic syndrome such as unfavorable effects on serum

cholesterol lipoprotein distribution (50—70% reduction)

OC 10—20 lrregular bleeding, hypercoagulation status, nausea/vomiting, headache, a definite therapeutic value (35—70% reduction)

LNG-lUS 3—4 lrregular bleeding, abdominal pain, a definite therapeutic value (71—95% reduction)

GnRH-a 120—200 Frequent and intolerable hypoestrogenic side effects, including vasomotor syndrome, genital atrophy, mood instability, a

negative impact on bone health, and also a possible bad influence on cardiovascular health; a definite therapeutic value (reduction of >95%)

GI = gastrointestinal; GnRH-a = gonadotropin-releasing hormone agonist; LNG-IUS = levonorgestrel-releasing intrauterine system; NSAlDs = nonsteroidal anti-inflammatory drugs; OC = oral contraceptives or oral pills. a Cost: US dollars per cycle.

maintained for 5 years. The final medication is GnRH agonist, which is the most expensive (US$150/month), and many women with HMB taking GnRH agonist might be compromised by severe menopause-related problems, as shown above. Therefore, GnRH agonist is seldom considered as the first-line treatment in the management of women with HMB; it is often used for special indications, such as long-term suppression of in vitro fertilization and embryo transfer, and pre- and postoperative adjuvant therapy.

Comments

Based on the above evidence, the Taiwan Society of Gynecology Systematic Review Group has developed clinical practice suggestions for medical treatment of HMB, which include the following: (1) clinicians should use the FIGO PALM—COEIN system to perform a structured history review and physical examination to detect organic and/or nonorganic lesions that can be reversed by definite treatment; (2) no definite cause-related HMB can be managed using a step-by-step strategy, based on cost effectiveness and patients' preference (low cost, more convenience, few adverse events, and high compliance); (3) in the situation of B status, two agents could be used as a choice, including that LNG-IUS is preferred for women with HMB needing contraception; the use of two tabs of tranexamic acid three times per day is often preferred to cover the whole menstrual period for any woman without an organic-related HMB; and (4) patient-tailored therapy should always be considered.

Conflicts of interest

The authors have no conflicts of interest relevant to this article.

Acknowledgments

The work was supported by grants from the Ministry of Science and Technology, Executive Yuan (MOST 103-2314-B-010-043-MY3), and Taipei Veterans General Hospital (V102C-141; V103C-112; V104C-095; V102E4-003; and V103E4-003). The funders had no role in study design, data collection and analysis, and decision to publish or preparation of the manuscript. No additional external funding was received for this study. We thank the Medical Science & Technology Building of Taipei Veterans General Hospital for providing experimental space and facilities.

End note

The Taiwan Association of Gynecology Systematic Review group includes the following members

Drs Hsiang-Tai Chao, Kuo-Chang Wen, Chi-Hong Ho, Hsiao-Wen Tsai, Yen-Hou Chang, Yi-Wen Chang, Chi-Yao Chen, and Huann-Cheng Horng, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.

Drs Ruey-Jian Chen, Yih-Ron Lien, Men-Luh Yen, Wen-Chun Chang, Ting-Chen Chang, and Chii-Hou Chen, Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan. Dr Man-Jung Hung, Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan. Dr Kuan-Hao Tsui, Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Drs Jah-Yao Liu, and Mu-Hsien Yu, Department of Obstetrics and Gynecology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.

Dr Tze-Ho Chen, Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan. Dr Tang-Yuan Chu, Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.

Drs Wei-Chun Chang, Wu-Chou Lin, and Yao-Ching Hung, Department of Obstetrics and Gynecology, China Medical University Hospital and China Medical University, Taichung, Taiwan. Drs Hsu-Dong Sun, Wen-Yih Wu, and Sheng-Mou Hsiao, Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.

Drs Yeou-Lih Wang, Tze-Chien Chen, and Jian-Pei Huang, Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan.

Drs Jeng-Hsiu Hung, and Kuo-Hu Chen, Department of Obstetrics and Gynecology, Taipei Buddhist Tzu Chi General Hospital, Taipei, Taiwan.

Drs Fa-Kung Lee, and Tsung-Hsuan Lai, Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan. Dr Po-Hui Wang, Department of Obstetrics and Gynecology, Chung-Shang General Hospital and Chung-Shang Medical University, Taichung, Taiwan.

Dr Ching-Hui Chen, Department of Obstetrics and Gynecology, Taipei Medical University Hospital and Taipei Medical University, Taipei, Taiwan.

Dr Meng-Hsing Wu, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital and National Cheng Kung University, Tainan, Taiwan.

Drs Chin-Jung Wang, Tzu-Hao Wang, and Ting-Chang Chang, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, and Chang Gung University, Taoyuan, Taiwan. Dr Ching-Hung Hsieh, Department of Obstetrics and Gynecol-ogy, Clinic of Fu Jen Catholic University, New Taipei City, Taiwan. Dr Kok-Min Seow, Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

References

[1] Matteson KA, Rahn DD, Wheeler 2nd TL, Casiano E, Siddiqui NY, Harvie HS, et al. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol 2013;121:632—43.

[2] Lee WL, Liu WM, Fuh JL, Tsai YC, Shih CC, Wang PH. Use of uterine vessel occlusion in the management of uterine myomas: two different approaches. Fertil Steril 2010;94:1875—81.

[3] Wang PH, Liu WM, Fuh JL, Chao HT, Yuan CC, Chao KC. Symptomatic myoma treated with laparoscopic uterine vessel occlusion and subsequent immediate myomectomy—which is the optimal surgical approach? Fertil Steril 2009;92: 762—9.

[4] Wang PH, Liu WM, Fuh JL, Chao HT, Yuan CC, Chao KC. Comparison of ultra-mini-laparotomy for myomectomy through midline vertical incision or modified Pfannenstiel incision—A prospective short-term follow-up. Fertil Steril 2009;91:1945—50.

[5] Munro MG, Critchley HO, Broder MS, Fraser IS, FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet 2011;113:3—13.

[6] Fraser IS, Critchley HO, Broder MS, Munro MG. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Sem Reprod Med 2011;29:383—90.

[7] Juan CC, Chen KH, Wang PH, Hwang JL, Seow KM. Endocannabinoid system activation may be associated with insulin resistance in women with polycystic ovary syndrome. Fertil Steril 2015;104:200—6.

[8] Lin LT, Tsui KH, Cheng JT, Yen MS, Li YT, Wang PH. Rapid presentation of endometrial carcinoma after removal of an intrauterine device. Taiwan J Obstet Gynecol 2014;53:267—9.

[9] Li YT, Lee WL, Wang PH. Difficult intrauterine device insertion. Hum Reprod 2011;26:2912—4.

[10] Su WH, Lee FK, Wang PH. Recurrent pregnancy loss and thrombophilia in PCOS women. J Chin Med Assoc 2013;76:243—4.

[11] Su WH, Ho TY, Tsou TS, Lee WL, Wang KC, Yu YY, et al. Development of a chip-based multiplexed immunoassay using liposomal nanovesicles and its

application in the detection of pathogens causing female lower genital tract infections. Taiwan J Obstet Gynecol 2013;52:25-32.

[12] Koo FH, Chao ST, Wang PH, Wang HI, Shen SH, Chen CY, et al. Delayed postpartum hemorrhage secondary to idiopathic rupture of right uterine artery: a case report and literature review. Taiwan J Obstet Gynecol 2014;53: 276-8.

[13] Horng HC, Wen KC, Su WH, Chen CS, Wang PH. Review of myomectomy. Taiwan J Obstet Gynecol 2012;51:7-11.

[14] Sharma JB, Yadav M. New ground breaking International Federation of Gynecology and Obstetrics's classification of abnormal uterine bleeding: optimizing management of patients. J Midlife Health 2013;4:42-5.

[15] Bahamondes L, Ali M. Recent advances in managing and understanding menstrual disorders. F1000Prime Rep 2015;7:33.

[16] Chang WH, Wang KC, Lee NR, Huang N, Su WH, Chao HT, et al. Reproductive performance of severely symptomatic women who wanted preservation of the uterus and underwent combined surgical-medical treatment for uterine adenomyoma. Taiwan J Obstet Gynecol 2013;52:39-45.

[17] Wang KC, Chang WH, Liu WM, Yen YK, Huang N, Wang PH. Short-term advantages of laparoscopic uterine vessel occlusion in the management of women with symptomatic myoma. Taiwan J Obstet Gynecol 2012;51: 539-44.

[18] Lee WL, Wang PH. Major postpartum hemorrhage as an initial presentation of acute myeloid leukemia. Int J Gynaecol Obstet 1999;66:173-4.

[19] Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, et al. Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colo-rectal cancer syndrome. Obstet Gynecol 2005;105:569-74.

[20] Lee WL, Yen MS, Chao KC, Yuan CC, Ng HT, Chao HT, et al. Hormone therapy for patients with advanced or recurrent endometrial cancer. J Chin Med Assoc 2014;77:221-6.

[21] Wang PH, Su WH, Sheu BC, Liu WM. Adenomyosis and its variance: adeno-myoma and female fertility. Taiwan J Obstet Gynecol 2009;48:232-8.

[22] Wang PH, Fuh JL, Chao HT, Liu WM, Cheng MH, Chao KC. Is the surgical approach beneficial to subfertile women with symptomatic extensive adenomyosis? J Obstet Gynaecol Res 2009;35:495-502.

[23] Wang PH, Liu WM, Fuh JL, Cheng MH, Chao HT. Comparison of surgery alone and combined surgical-medical treatment in the management of symptomatic uterine adenomyoma. Fertil Steril 2009;92:876-85.

[24] Yang JH, Chen MJ, Chen CD, Chen SU, Ho HN, Yang YS. Optimal waiting period for subsequent fertility treatment after various hysteroscopic surgeries. Fertil Steril 2013;99:2092-6. e3.

[25] Tsui KH, Lin LT, Cheng JT, Teng SW, Wang PH. Comprehensive treatment for infertile women with severe Asherman syndrome. Taiwan J Obstet Gynecol 2014;53:372-5.

[26] Lin B, Akiba Y, Iwata Y. One-step hysteroscopic removal of sinking submucous myoma in two infertile patients. Fertil Steril 2000;74:1035-8.

[27] Lin YH, Chou YY, Huang LW, Seow KM, Hwang JL. An adenomyomatous polyp presenting as a large hypervascular tumor and its response to a gonadotropin-releasing hormone agonist. Taiwan J Obstet Gynecol 2013;52:129-30.

[28] Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med 2012;366:409-20.

[29] Wen KC, Sung PL, Lee WL, Li YT, Su WH, Wang PH. Myomectomy for uterine myomas through ultramini-laparotomy. J Obstet Gynaecol Res 2011;37: 383-92.

[30] Yen CF, Lee CL, Wang CJ, Soong YK, Arici A. Successful pregnancies in women with diffuse uterine leiomyomatosis after hysteroscopic management. Fertil Steril 2007;88:1667-73.

[31] Lee WL, Lee FK, Su WH, Tsui KH, Kuo CD, Hsieh SL, et al. Hormone therapy for younger patients with endometrial cancer. Taiwan J Obstet Gynecol 2012;51: 495-505.

[32] Yen MS, Ng HT, Wang PH. Is more radical more effective? Taiwan J Obstet Gynecol 2013;52:463-4.

[33] Su WH, Tsou TS, Chen CS, Ho TY, Lee WL, Yu YY, et al. Diagnosis of Chlamydia infection in women. Taiwan J Obstet Gynecol 2011;50:261-7.

[34] Kim M, Ko J, Lee C. Pelvic actinomycosis with abundant ascites, pleural effusion, and lymphadenopathy diagnosed with endometrial biopsy and treated with medication only. Taiwan J Obstet Gynecol 2014;53:588-91.

[35] Tsui KH, Lee WL, Chen CY, Chen YJ, Sheu BC, Yen MS, et al. Medical treatment for adenomyosis and/or adenomyoma. Taiwan J Obstet Gynecol 2014;53: 459-65.

[36] Wang PH, Lee WL, Cheng MH, Yen MS, Chao KC, Chao HT. Use of a gonado-tropin-releasing hormone agonist to manage perimenopausal women with symptomatic uterine myomas. Taiwan J Obstet Gynecol 2009;48:133-7.

[37] Cheng MH, Wang PH. Uterine myoma: a condition amendable to medical therapy? Expert Opinion Emerging Drugs 2008;13:119-33.

[38] Cheng MH, Chao HT, Wang PH. Medical treatment for uterine myomas. Taiwan J Obstet Gynecol 2008;47:18-23.

[39] Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Bará F, et al. PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366:421-32.

[40] Stewart EA. Uterine fibroids and evidence-based medicine—not an oxymoron. N Engl J Med 2012;366:471-3.

[41] Moroni RM, Martins WP, Dias SV, Vieira CS, Ferriani RA, Nastri CO, et al. Combined oral contraceptive for treatment of women with uterine fibroids and abnormal uterine bleeding: a systematic review. Gynecol Obstet Invest 2015;79:145-52.

[42] Bitzer J, Heikinheimo O, Nelson AL, Calaf-Alsina J, Fraser IS. Medical management of heavy menstrual bleeding: a comprehensive review of the literature. Obstet Gynecol Surv 2015;70:115-30.

[43] Lethaby A, Hussain M, RishworthJR, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev 2015;4. CD002126.

[44] Hartmann KE, Jerome RN, Lindgren ML, Potter SA, Shields TC, Surawicz TS, et al. Primary care management of abnormal uterine bleeding [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Mar. Report No.: 13-EHC025-EF.

[45] Horng HC, Chen CH, Chen CY, Tsui KH, Liu WM, Wang PH, et al. Uterine-sparing surgery for adenomyosis and/or adenomyoma. Taiwan J Obstet Gynecol 2014;53:3-7.

[46] Liu WM, Chen CH, Chiu LH, Tzeng CR. Long-term follow-up of severely symptomatic women with adenomyoma treated with combination therapy. Taiwan J Obstet Gynecol 2013;52:85-9.