Endometrial Cancer -Pregnancy -Uterine Or Cervical Polyps Complications -Uterine Leiomyomata -Trauma Risk Factors for Endometrial Cancer (RR = Rela�Ve Risk)

Home , Gestonorone caproate, Norgestrienone, Tanaproget

Endocrine causes Infections

-Cushing’s disease -Chlamidia -Immature hypothalamic- -Gonorrhea pituitary axis -PID -Hyperprolactinemia -Hypothyroidism Medications -Menopause -Obesity -Hormonal agents -PCOD -Low dose OCs CAUSES OF AUB -Premature ovarian failure -IUD (differential -NSAIDs analysis Structural lesions -POP (“mini pill”} and diagnosis) -Tamoxifen -Adenomyosis -Warfarin -Coagulopathies -Condyloma accuminata Pregnancy -Dysplastic or malignant lesions of cervix or vagina -Ectopic pregnancy -Endometriosis -Incomplete abortion -Endometrial cancer -Pregnancy -Uterine or cervical polyps complications -Uterine leiomyomata -Trauma Risk factors for endometrial cancer (RR = relave risk)

Age - 75% of cases occur aer menopause RR (age > 60 years) = 5.2 with peak incidence in the late 60s. Obesity - especially upper body fat. This may RR= 3 to 10 be secondary to increased estrogen producon and bioavailability. Polycysc ovary disease. RR = 5.2 Unopposed exogenous estrogen. RR = 2 to 14 When progesns are added (oral contracepves RR= 0.5 to 1 or with replacement therapy), relave risk is less than for the general populaon. Diabetes (all types grouped). Personal or family history of ovarian or breast RR = 2 to 2.8 cancer. Women who are overweight and have had breast cancer are at even greater risk. Nulliparity. RR = 1.3 Late menopause. RR entering menopause aer age 52 = 2.5 Tamoxifen therapy - Use for greater than one year is an independent risk factor. RR = 7.5 Basic FIGO classiﬁcaon system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproducve age

Polyp Coagulopathy Adenomyosis Ovulatory dysfunction Leiomyoma (submucosal or other) Endometrial Malignancy & hyperplasia Iatrogenic Not yet classified

Progesterone Dydrogesterone Tanaproget

17-OH-progesterone 19-norprogesterone derivated derivated

PREGNANES NOR-PREGNANES - Hydroxyprogesterone - Nomegestrol acetate ESTRANES GONANES caproate - Demegestone -Lynestrenol -Norgestrel - Hydroxyprogesterone - Promegestone -Levonorgestrel -Desogestrel heptanoate - Nestorone -Norethisterone -Gestodene - Gestonorone caproate - Trimegestone -Norethisterone -Norgestimate - Chlormadinone acetate acetate - Medrogestone -Ethinodiol diacetate - Medroxyprogesterone -Norgestrienone acetate -Dienogest - Cyproterone acetate Drospirenone

Hysterectomy remains the most absolutely curative treatment for DUB. Elective hysterectomy has a mortality rate of six per 10,000 operations. One randomized study found that hysterectomy was associated with more morbidity and much longer healing times than endometrial ablation. 12 hysterectomy was associated with more Fortunately,morbidity a and recent much study longer found thathealing sexual times functioning improved overall after hysterectomy than endometrial ablation with an increase in sexual activity and a decrease in problems with sexual functioning. 34 It still remains a popular method of treating DUB, especially in industrialized countries.

1. Neese RE. Abnormal vaginal bleeding in perimenopausal women. Am Fam Physician 1989; 40:185-92. 2. Bayer SR, DeCherney AH. Clinical manifestaons and treatment of dysfunconal uterine bleeding. JAMA 1993; 269:1823-8. 3. Baughan DM. Changes in the management of paents with dysfunconal uterine bleeding. Fam Pract Recerﬁcaon 1993; 15:68-78. 4. Prior JC, Ho Yuen B, Clement P, Bowie L, Thomas J. Reversible luteal phase changes and inferlity associated with marathon training. Lancet 1982; 2:269-70. Endometrial biopsy (EMB) is the most commonly used diagnosc test for DUB. It provides an adequate sample for diagnosis of endometrial problems in 90% to 100% of cases,1,2 but may fail to detect polyps and leiomyomas. It is indicated in all women with DUB who are 35 years of age or older, since their risk of developing malignancy is much higher. Any woman with amenorrhea for one year or longer who experiences uterine bleeding also should have an EMB. The slim endometrial Endometrial biopsy may fail to detect polyps sucon currees (Pipelleand ) produce samples comparable to older, leiomyomas. more traumac methods but with less pain.3

1. Goldschmit R, Katz Z, Blickstein I, Caspi B, Dgani R. The accuracy of endometrial Pipelle sampling with and without sonographic measurement of endometrial thickness. Obstet Gynecol 1993; 82:727-30. 2. Stovall TG, Ling FW, Morgan PL. A prospecve randomized comparison of the Pipelle endometrial sampling device with the Novak curee. Am J Obstet Gynecol 1991; 165:1287-9. 3. Johnson CA. Making sense of dysfunconal uterine bleeding. Am Fam Physician 1991; 44:149-57 Management of Acute Abnormal Uterine Bleeding in Nonpregnant Reproducve-Aged Women Inial evaluaon of the paent with acute abnormal uterine bleeding should include a prompt assessment for signs of hypovolemia and potenal hemodynamic instability. The eologies of acute abnormal uterine bleeding should be classiﬁed using the PALM–COEIN system. Medical management : Opons include intravenous conjugated equine estrogen, mul-dose regimens of combined oral contracepves or oral progesns, and tranexamic acid. Decisions should be based on the paent’s medical history and contraindicaons to therapies. Surgical management should be considered for paents who are not clinically stable, are not suitable for medical management, or have failed to respond appropriately to medical management. The choice of surgical management should be based on the paent’s underlying medical condions, underlying pathology, and desire for future ferlity. Once the acute bleeding episode has been controlled, transioning the paent to long-term maintenance therapy is recommended.

Management of acute abnormal uterine bleeding in nonpregnant reproducve-aged women. Commiee Opinion No. 557. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:891–6. Management of Acute Abnormal Uterine Bleeding in Nonpregnant Reproducve-Aged Women

Acute AUB refers to an episode of heavy bleeding that, in the opinion of the clinician, is of suﬃcient quanty to require immediate intervenon to prevent further blood loss.

Acute AUB may occur spontaneously or within the context of chronic AUB (abnormal uterine bleeding present for most of the previous 6 months).

The general process for evaluang paents who present with acute AUB can be approached in three stages:

1) assessing rapidly the clinical picture to determine paent acuity, 2) determining most likely eology of the bleeding, and 3) choosing the most appropriate treatment for the paent.

Once the acute episode of bleeding has been controlled, mulple treatment opons are available for long-term treatment of chronic AUB. Effecve medical therapies include the levonorgestrel intrauterine system, OCs (monthly or extended cycles), progesn therapy (oral or intramuscular), tranexamic acid, and nonsteroidal an-inflammatory drugs (6). If a paent is receiving IV conjugated equine estrogen, the health care provider should add progesn or transion to OCs. Unopposed estrogen should not be used as long-term treatment for chronic AUB. Paents with known or suspected bleeding disorders may respond to the hormonal and nonhormonal management opons listed earlier in this secon. Consultaon with a hematologist is recommended Effecve medical therapies include: for these paents, especially if bleeding is difficult to control or the gynecologist is unfamiliar with the other opons for medical management. the levonorgestrel intrauterine system, Desmopressin may help treat acute AUB in paents with von Willebrand disease if the paent is known to respond to that agent. It may be administered by OCs (monthly or extended cycles), intranasal inhalaon, intravenously, or subcutaneously. This agent must be used with cauon because of the risks of fluid retenon and hyponatremia and should not be administered to paents with progesn therapy (oral or intramuscular), tranexamic massive hemorrhage who are receiving IV fluid resuscitaon because of issues with fluid overload (15). acid, Recombinant factor VIII and von Willebrand factor also are available and may be required to control severe hemorrhage (5). Other factor deficiencies may need factor-specific replacement. and nonsteroidal an-inflammatory drugs Paents with bleeding disorders or platelet funcon abnormalies should avoid nonsteroidal aninflammatory drugs because of their effect on platelet aggregaon and their interacon with drugs that might affect liver funcon and the producon of clong factors (17).

Management of acute abnormal uterine bleeding in nonpregnant reproducve-aged women. Commiee Opinion No. 557. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:891–6.

ABNORMAL UTERINE BLEEDINGS - CONCENSUS

BRIJUNI 2015 2015 USA

Conclusions and Recommendaons Based on the available evidence and expert opinion, the American College of Obstetricians and Gynecologists’ Commiee on Gynecologic Pracce makes the following conclusions and recommendaons:

The eologies of acute AUB should be classiﬁed based on the PALM–COEIN system: Polyp, Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfuncon, Endometrial, Iatrogenic, and Not otherwise classiﬁed. Medical management should be the inial treatment for most paents, if clinically appropriate. Opons include IV conjugated equine estrogen, mul-dose regimens of OCs or oral progesns, and tranexamic acid. Decisions should be based on the paent’s medical history and contraindicaons to therapies. The need for surgical treatment is based on the clinical stability of the paent, the severity of bleeding, contraindicaons to medical management, the paent’s lack of response to medical management, and the underlying medical condion of the paent. The choice of surgical modality should be based on the aforemenoned factors plus the paent’s desire for future ferlity. Once the acute bleeding episode has been controlled, transioning the paent to long-term maintenance therapy is recommended. 2015 USA Conclusions and Recommendaons Based on the The need for surgical treatment is based on the clinical stability of the paent, the severity of bleeding, contraindicaons to medical management, the paent’s lack of response to medical management, and the underlying. medical condion of the paent available evidence and expert opinion, the American College of Obstetricians and Gynecologists’ Commiee on Gynecologic Pracce makes the following conclusions and recommendaons:

Table 1. Laboratory Tesng for the Evaluaon of Paents With Acute Abnormal Uterine Bleeding Laboratory Evaluaon Speciﬁc Laboratory Tests Inial laboratory tesng • Complete blood count • Blood type and cross match • Pregnancy test Inial laboratory evaluaon for disorders of hemostasis • Paral thromboplasn me • Prothrombin me • Acvated paral thromboplasn me • Fibrinogen Inial tesng for von Willebrand disease* • von Willebrand factor angen† • Ristocen cofactor assay† • Factor VIII† Other laboratory tests to consider • Thyroid-smulang hormone • Serum iron, total iron binding capacity, and ferrin • Liver funcon tests • Chlamydia trachomas

*Adult women who receive posive results for risk of bleeding disorders or who have abnormal inial laboratory test results for disorders of hemostasis should undergo tesng for von Willebrand disease. Adolescents with heavy menses since menarche who present with acute abnormal uterine bleeding also should undergo tesng for von Willebrand disease. †Consultaon with a hematologist can aid in interpreng these test results. If any of these markers are abnormally low, a hematologist should be consulted. Data from James AH, Kouides PA, Abdul-Kadir R, Dietrich JE, Edlund M, Federici AB, et al. Evaluaon and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an internaonal expert panel. Eur J Obstet Gynecol Reprod Biol 2011;158:124–34; Naonal Heart, Lung, and Blood Instute. The diagnosis, evaluaon, and management of von Willebrand disease. NIH Publicaon No. 08-5832. Bethesda (MD): NHLBI; 2007. Available at hp://www.nhlbi.nih.gov/guidelines/vwd/vwd.pdf. Retrieved December 5, 2012; and Diagnosis of abnormal uterine bleeding in reproducve-aged women. Pracce Bullen No. 128. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:197–206. CANADA 2015

Conclusions: Abnormal Uterine Bleeding Is A Common And Somemes Debilitang Condion In Women Of Reproducve age.Standardizaon Of Related terminology, A Systemac Approach To Diagnosis And invesgaon, And A step- wise Approach To intervenonI Necessary .Treatment Commencing With Medical Therapeuc Modalies Followed By The Least Invasive Surgical Modalies Achieving Results Sasfactory To The Paent Is The Ulmate Goal Of All Therapeuc intervenons CANADA Abnormal Uterine Bleeding in Pre-Menopausal Women 2015

Recommendaons 8. Summary Statements Endometrial biopsy should be considered in 6. bleeding women over age 40 or in those with Once malignancy and significant pelvic pathology bleeding not responsive to medical therapy, as have been ruled out, medical treatment is an well as in younger women with risk factors from effecve first line therapeuc opon for abnormal endometrial cancer. (II-2A) uterine bleeding. (I) 9. 7. Office endometrial biopsy should replace dilaon Medical treatment tailored to the individual and uterine cureage as the inial assessment of woman’s therapeuc goals, desire for contracepon, the endometrium for these women. (II-2A) underlying medical condions, and tolerance 10. of side effects will encourage compliance and Focal lesions of the endometrium that require maximize the likelihood of treatment success. biopsy should be managed through hysteroscopy- guided evaluaon. CANADA Recommendaons Abnormal Uterine Bleeding in 11. 2015 Pre-Menopausal Women Non-hormonal opons such as non-steroidal an- inflammatory drugs and anfibrinolycs can be used effecvely to treat heavy menstrual bleeding that is mainly cyclic or predictable in ming. (I-A) 12. Combined oral contracepve pills, depot medroxyprogesterone acetate, and levonorgestrel- releasing intrauterine systems significantly reduce menstrual bleeding and should be used to treat women with abnormal uterine bleeding who desire effecve contracepon. (I-A) 13. Cyclic luteal-phase progesns do not effecvely reduce blood loss and therefore should not be used as a specific treatment for heavy menstrual bleeding. (I-E) 14. Danazol and gonadotropin-releasing hormone agonists will effecvely reduce menstrual bleeding, and may be used for scenarios in which other medical or surgical treatments have failed or are contraindicated. (I-C). 15. Paents receiving a gonadotropin-releasing hormone agonist for longer than 6 months should be prescribed add-back hormone therapy, if not already iniated with gonadotropin-releasing hormone agonist commencement. (I-A) UK Abnormal Uterine Bleeding in 2015 Pre-Menopausal Women

Conclusions Women who have problemac irregular or heavy cyclic menstrual bleeding have a number of treatment opons available that are supported by systemac review of the research literature. These include high strength of evidence that COCs can improve menstrual regularity for women with irregular bleeding paerns. Meormin is supported by moderate strength of evidence for improving cycle regularity especially among women with PCOS. This provides both a contracepve and a noncontracepve opon for irregular menses. Other intervenons like progestogens are associated with stascally and clinically meaningful improvements from baseline paerns, however the overall evidence is insufficient from well-designed, larger studies with ability to directly compare treatment arms rather than only pre-post measures within groups. Mulple intervenons for heavy cyclic bleeding are supported by evidence that they reduce MBL. These include strong evidence that COCs are effecve and moderate strength of evidence that the LNG-IUS, NSAIDs, and TXA reduce bleeding relave to baseline, decrease total volume of bleeding when comparisons are made across treatment groups, and when measured, decrease days of bleeding per cycle. In direct comparisons, LNG-IUS is superior to NSAIDs. TXA is superior to NSAIDs and TXA combined with an NSAID was superior to TXA alone. Results from COC and NSAID comparisons suggest comparable effecveness. Not all women will benefit from these intervenons. Across agents data are sparse to evaluate long-term improvements and risk of harms. Limitaons include a predominance of small, short trials lacking standard terminology and diagnosc criteria for idenfying and including women with AUB. Tools for collecng outcome data are crude (collecon of sanitary products) and may contribute to a high rate of arion. Biologic outcomes, like measured blood loss and hemoglobin or hematocrit levels, may neglect the importance of paent-reported outcomes that assess whether symptoms are considered resolved by women themselves. Nevertheless, the variety of effecve opons suggests many women can achieve symptom relief and have available choices that address both symptoms and contracepve or ferlity desires, as well as potenally improving other symptoms like menstrual cramping. ITALIA AUB 2015 Italia

. Conclusione

Un gruppo internazionale di clinici-ricercatori con vasta esperienza di AUB ha trovato un accordo consensuale su un sistema di classificazione che facilita gli studi mulcentrici su epidemiologia, eziologia e terapia delle donne con sanguinamento uterino anomalo acuto o cronico. Il sistema dovrebbe dare impulso anche alla realizzazione di meta-analisi di trials clinici ben disegna e adeguatamente riporta. Si riconosce che il sistema necessita di periodici aggiornamen e, al bisogno, di una sostanziale revisione, al passo con l’evoluzione delle conoscenze e della tecnologia e la crescente disponibilità di opzioni diagnosche nelle diverse aree geografiche. Pertanto, raccomandiamo una revisione sistemaca del sistema, programmata a cadenza regolare, da parte di un comitato permanente di un’organizzazione internazionale come la FIGO, che ha già approvato l’istuzione di uno specifico Gruppo di Lavoro sui Disordini Mestruali. Editori e comita editoriali delle riviste scienfiche sono invita a richiedere che nei manoscri sull’AUB le sezioni “materiali”, “metodi” e quelle di presentazione e discussione dei risulta siano elaborate tenendo conto del sistema di classificazione proposto. Conflio di interesse MMG, CHOD e FIS sono sta consulen, hanno tenuto conferenze e ricevuto compensi da Bayer Schering Pharma, che ha in parte finanziato questa iniziava (come segnalato nelle pubblicazioni di maggior rilievo). Numerose altre organizzazioni e società hanno contribuito, direamente o indireamente, allo sviluppo del progeo. Anche ques contribu sono esplicitamente segnala nelle pubblicazioni di maggior rilievo. L’intero progeo è stato approvato dalla FIGO e dal suo Gruppo di Lavoro sui Disordini Mestruali. (Traduzione di Alessandro Maturo, “Sapienza” Università di Roma) F AUB 2015 France – the land of progesns !

Caractérisques du traitement progestaf

Pour chaque paent élaborer un plan individuel de prise de certains médicaments. Gynécologue de surveillance obligatoire considérée, et, si nécessaire – et un endocrinologue. W DUB 2015 Overall New ground breaking Internaonal Federaon of Gynecology and Obstetrics's classiﬁcaon of abnormal uterine bleeding: Opmizing management of paents

There is considerable worldwide confusion in the use of terminologies and definions around the symptom of abnormal uterine bleeding (AUB), and these are increasingly leading to difficules in seng up mulnaonal clinical trials and in interpreng the results of studies undertaken in single centers. In November 2010, the Internaonal Federaon of Gynecology and Obstetrics formally accepted a new classificaon system for causes of AUB in the reproducve years. The system, based on the acronym polyps, adenomyosis, leiomyoma, malignancy and hyperplasia – coagulopathy, ovulatory disorders, endometrial causes, iatrogenic, not classified was developed in response to concerns about the design and interpretaon of basic science and clinical invesgaon that relates to the problem of AUB. W AUB 2015 Overall New ground breaking Internaonal Federaon of Gynecology and Obstetrics's classificaon of abnormal uterine bleeding: Opmizing management of paents

The PALM group The PALM categories refer to discrete (structural) enes that can be measured visually with imaging techniques, such as sonography and/or histopathology tesng. The “polyp” category lends itself to the development of a sub-classificaon for clinical or invesgave use based on a combinaon of variables, including polyp dimension, locaon, number, and morphologic and histologic features. The “leiomyoma” category is subdivided into paents with at least 1 submucosalmyoma and those with myomas that do not affect the endometrial cavity. Within the “malignancy and hyperplasia” group, it was proposed that malignant or premalignant lesions, such as atypical endometrial hyperplasia, endometrial carcinoma, and leiomyosarcoma, be categorized as such within the major category, but further described with use of exisng World Health Organizaon and FIGO classificaon and staging systems. The COEIN group In contrast to the PALM group, the COEIN group includes non-structural enes that are not defined on imaging or histopathology tesng. The “iatrogenic” category refers to AUB associated with the use of exogenous gonadal steroids, intrauterine systems or devices, or other systemic or local agents. AUB 2015 Overall

Praccal ps Dysfunconal uterine bleeding is a diagnosis of exclusion: other condions such as uterine fibroids, endometrial polyps, and systemic diseases must be excluded by appropriate invesgaons Tranexamic acid and mefenamic acid are among the most effecve first line drugs for treang menorrhagia Women needing contracepon have a choice of combined oral contracepve, levonorgestrel releasing intrauterine system, or long acng progestogens Only 2% of endometrial carcinomas occur before age 40. Nulliparity, diabetes, obesity, and polycysc ovary syndrome are risk factors Postmenstrual scans are oen useful; the endometrium should be at its thinnest then, and polyps and cysc areas are more noceable