Abnormal Uterin BleedingOn Behalf of Cihat Unlu, MD

M. Faruk Kose, MDAcıbadem University, School of Medicine,

Dept of Ob&Gyn, Dept of Gynecologic Oncology

mfarukkose@outlook.com

Abnormal Uterine Bleeding

AUB is a common problem, affecting 14% of women during their reproductive years and impairing their quality of life by creating significant physical, emotional, sexual, social and financial burdens

Bradley L, AJOG 2016

‘‘Normal’’ Limits for Menstrual Parameters

Fraser IS, Semin Reprod Med 2011

Clinical Dimensions of Menstruation and

Menstrual Cycle

Descriptive Terms Normal Limits

Menstruation and menstrual cycle (5–95th percentiles)Frequency of menses (days) Frequent <24

Normal 24–38Infrequent >38

Regularity of menses, cycle to cycleVariation over 12 months (days) Absent No bleeding

Regular Variation_2–20 daysIrregular Variation >20 days

Duration of flow (days) Prolonged >8.0Normal 4.5–8.0Shortened <4.5

Volume of monthly blood loss (mL) Heavy >80Normal 5–80Light <5

Abnormal Uterine Bleeding Terminology

• Menorrhagia (all usages, including ‘‘essential menorrhagia,’’ ‘‘idiopathicmenorrhagia,’’ ‘‘primary menorrhagia,’’ ‘‘functional menorrhagia,’’ ‘‘ovulatory or anovulatory menorrhagia’’)

• Metrorrhagia

• Hypermenorrhea

• Hypomenorrhea

• Menometrorrhagia

• Polymenorrhea

• Polymenorrhagia

• Epimenorrhea

• Epimenorrhagia

• Metropathica hemorrhagica

• Uterine hemorrhage

• Dysfunctional uterine bleeding

• Functional uterine bleeding

Abnormal Uterine Bleeding HistoricalClassification

Organic

• Reproductive organ diseases (Myoma, polyps, carcinoma, cervical erosions etc.)

• Systematic diseases (Disorders of hemostasis, endocrinopathies, liver failure)

• Trauma

• Pharmacologic (Hormonal contraception, antipsychotics)

Dysfunctional uterine bleeding

Guidelines Review: Medical Treatment

US Canada UK France Finland

Diagnosis/symptomcovered

AUB and DUB

Menorrhagia from AUB

Heavy menstrual bleeding

Pre-menopausal

AUB

Menorrhagia

Differentiate ovulatoryvs. anovulatory

+

Medical treatment

Indication (generally first line unlesscontraindicated/ patient choice or preservedfertilty not desired)

+ + + + +

HormonalCOCs

+ + Second line Third line‡ +

Progestogens, oral/injected + + Third line Fourth line‡ Only in short-term

Progestogens, local (LNG-IUS) + + First line* First line‡ +

Progestogens, luteal phase Not recommended Not recommended Not recommended

Non-hormonal NSAIDs

+ + Second line† Fourth line‡

Antifibrinolytics + + Second line† Second line‡§ +

FIGO Classification for Causes of AUB

• Abnormal Uterine Bleeding (AUB) was not restricted to just menstrual bleeding that was abnormally heavy, but also included bleeding that was abnormal in timing

• The terms “menorrhagia” and “dysfunctional uterine bleeding (DUB)” should be discarded

• Abnormalities of bleeding associated with pathology of the lower reproductive tract that could be defined as "abnormal reproductive tract bleeding" but which were not within the domain of AUB would not be included in the classification system

FIGO Classification for Causes of AUB

Instead of “menorrhagia”

• “Heavy menstrual bleeding (HMB)” should replace for the symptom of excess menstrual bleeding

Instead of “DUB”

• “Coagulopathy”

• “Endometrial dysfunction”

• “Ovulatory disorders”

Types of AUB

• Chronic AUB be defined as bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing, and has been present for themajority of the past 6 months• Chronic AUB would not, in the opinion of the clinician, require immediate

intervention

• By contrast, acute AUB was defined as an episode of heavy bleedingthat, in the opinion of the clinician, is of sufficient quantity to requireimmediate intervention to prevent further blood loss

• Intermenstrual bleeding (IMB) occurs between clearly defined cyclicand predictable menses. Such bleeding may occur at random times or may manifest in a predictable fashion at the same day in each cycle• This designation is designed to replace the word “metrorrhagia”

Workup

•Duration of flow

•Measurement of hemoglobin and/or hematocrit

•Evaluation of the uterus for myomas by ultrasound

•Assessment of the endometrial cavity by any method

•Assessment for coagulopathies• Systemic disorders of hemostasis (coagulopathies) should

be screened for using a structured history

Heavy Menstrual Bleeding

Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss (MBL) >80 mL per cycle, that interferes with a woman's physical, emotional, social wellbeing and quality of life

Studies using this method indicate that maximum normal menstrual blood flow is 60–80 mL, with a mean of 30 mL

The proportion of women with haemoglobin less than 12 g/dL and low ferritin levels were only significantly increased in the group with MBL >120 mL

Assessment of HMB

• The alkaline-haematin method is perhaps the most accurate method for quantification of MBL

• Pictorial blood assessment chart (PBAC) is a semi objectivemethod that takes into account the number of towels and tampons used, the degree to which individual items are soiled, and the passage of clots and flooding

• The menstrual cup (Mooncup®) is an alternative to usingsanitary towels and tampons

Pictorial Blood Assessment Chart

Pictorial Blood Assessment Chart

•From this information a score is ascertained, and a score >100 has a sensitivity and specificity of >80% for HMB (menstrual blood loss of 80 mL or more with the alkaline-haematin method)

FIGO Classification for Causes of AUB

PALM

• Polyp

• Adenomyosis

• Leiomyoma• Submucosal

• Other

• Malignancy&Hyperplasia

COEIN

• Coagulopathy

• Ovulatory dysfunction

• Endometrial

• Iatrogenic

• Not yet classified

Munro MG, Int J Gynaecol Obstet 2011

Polyp (AUB-P)

Polyps are categorized as being either present or absent

As defined by one or a combination of

• Ultrasound (Saline infusion sonography preferred)

• Hysteroscopic imaging with or without histopathology

Endometrial Assessment

•Ultrasonography

•Saline infusion sonography

•Hysteroscopy

•Endometrial biopsi•Outpatient•D&C

Assessment of AUB-A

• As yet, there is no consensus regarding the best imaging feature or combination thereof for the non-surgical diagnosis of adenomyosis

• Pooled sensitivity and specificity for TVUS 2D for the diagnosis of adenomyosis for all combined imaging characteristics was 83.8% and 63.9%, respectively

• Doppler showed a high sensitivity and specificity (95.6% and 93.4%) for the differentiation between adenomyosis and myomas

• These features include:• Myometrial heterogeneity• Asymmetric thickening of myometrium• Endometrial cysts• Linear striations• An ill-defined endometrial edges

Leiomyoma (AUB-L)

SM-SubMucosal 0 Pedunculated intracavitary

1 <50% intramural

2 ≥50% intramural

O-Other 3 Contacts endometrium; 100% intramural

4 Intramural

5 Subserosal ≥50% intramural

6 Subserosal <50% intramural

7 Subserosal pedunculated

8 Other (specify e.g. cervical, parasitic)

Hybrid leiomyomas(Impact bothendometrium andserosa)

Two numbers are listed seperated by a hyphon. By convention, the first refers to the relationship withthe endometrium while the second refers to the relationship to the serosa. One example below

2-5 Submucosal and subserosal, each with less than half thediameter in the endometrial and peritoneal cavities,respectively

Coagulopathy (AUB-C)

Up to 20% of women with HMB have an underlying inherited bleeding disorder

HMB since menarche and a family history are predictive of an inherited bleeding disorder

The most common inherited bleeding disorder resulting in HMB is von Willebrand Disease (vWD) which occurs in upto 1% of the population

Disorders of Hemostasis (Coagulopathy)

Ovulatory Dysfunction (AUB-O)

• Absence of predictable cyclic progesterone production from thecorpus luteum every 22–35 days, but in later reproductive years many relate to unusual “disturbed” ovulations, which have been labeled as “luteal out-of-phase” events

• Disorders of ovulation may present as a spectrum of menstrual abnormalities• Amenorrhea

• Extremely light and infrequent bleeding

• Episodes of unpredictable and extreme HMB

• Endocrinopathies (e.g. polycystic ovary syndrome, hypothyroidism, hyperprolactinemia, mental stress, obesity, anorexia, weight loss, or extreme exercise such as that associated with elite athletic training)

Endometrial (AUB-E)

• High-quality evidence has demonstrated deficiencies in local production of vasoconstrictors such as endothelin-1 and prostaglandin F2α, and/or accelerated lysis of endometrial clot because of excessive production of plasminogen activator, in addition to increased local production of substances that promote vasodilation, such as prostaglandin E2 and prostacyclin

• Despite this evidence, some of which has been available for more than 2 decades, tests measuring such abnormalities are notcurrently available to clinicians

• As a result of these issues, and for the present version of theclassification system, the diagnosis of endometrial disorders shouldprobably be determined by exclusion of other identifiable abnormalities in women of reproductive age who seem to have normal ovulatory function

Iatrogenic (AUB-I)

• Unscheduled endometrial bleeding that occurs during the use of gonadal steroid therapy is termed “breakthrough bleeding (BTB)”and is the major component of the AUB-I classification

• Systemically administered single-agent or combination gonadalsteroids—including estrogens, progestins, and androgens

• Tricyclic antidepressants (e.g. amitriptyline and nortriptyline) andphenothiazines belong to a group of drugs that impact dopaminemetabolism by reducing serotonin uptake

• HMB is a relatively common consequence of the use ofanticoagulant drugs such as warfarin, heparin, and low molecularweight heparin

Not yet classified (AUB-N)

•This has not been demonstrated conclusivelybecause these entities—such as chronic endometritis, arteriovenous malformations, and myometrial hypertrophy—have been poorly defined, inadequately examined, or both

Notation (One Positive Category)

• From the top• At least one submucosal

leiomyoma (LSM)

• Adenomyosis (A)

• Focal and/or diffuse; endometrial polyps (P)

• Absence of any abnormality, leaving endometrial causes (E) as a diagnosis of exclusion

In all cases, the presence or absence of each criterion is noted using “0” if absent, “1” if present, and “?” if not yet assessed

Notation (More than One Positive Category)

• From the top:• Submucosal leiomyoma and

atypical endometrialhyperplasia(M)

• As diagnosed by endometrialsampling; endometrial polyps and adenomyosis

• Endometrial polyps and subserosal leiomyoma (LO)

• Adenomyosis, subserosalleiomyoma and coagulopathy (C), as determined by positivescreening test and subsequent biochemical confirmation of vonWillebrand disease

Conclusion

A multinational group of clinician–investigators with broad experience in the investigation of AUB has agreed on a system of classification to facilitate multi-institutional investigation into theepidemiology, etiology, and treatment of women with acute and chronic AUB

Treatment Modalities

Progestins

•Cyclic luteal-phase administration of progestinremained a widely used but little-researchedtreatment strategy for HMB for several decades

•Scientific studies comparing luteal 10-14 days/mowith NSAIDs, tranexamic acid, or LNG-IUS haverevealed that luteal-phase progestin has minimal orno effect on the bleeding and is no longerconsidered a valid treatment option for HMB

Menstrual Cycle

Progestins

• Extended ( cycle days 5-26) use of progestin with 2.5-10 mg MPA, 2,5-5 mg of NETA, micronised P 200-400 mg daily

• Three months of extended use of NETA reduced themeasured blood loss (MBL) by 87% among women withdocumented HMB

• Satisfaction with the extended NETA treatment was poor, and only few women (i.e., 22%) chose to continue thetreatment

• IM or SC injection of high dose (DMPA 150 mg) can induceamenorrhoea in up to 50% of women after 1 year

• 3900 women, 57.3% experienced abnormal bleeding at 12 months

Irvine, BrJ ObG 1998; Abu Hashim H, Contrception 2012; Bradley LD, Am J Obstet Gynecol 2016

Progesterone Only Contraceptives

•The progesterone only pill (POP) taken continuouslywithout a break is usually associated with irregularand unpredictable MBL, therefore not usuallyconsidered a treatment for HMB

•Desogestrel containing POP may induceamenorrhoea in up to 20% of women, and may be considered an effective treatment for women in whom the COC pill is contraindicated

LNG-IUS (Mirena®)

Was approved by the FDA in October 2009 for the treatment of HMB in women who also require contraception

It remains effective as a contraceptive and treatment for AUB for as long as 5 years

Reduction in menstrual blood loss of 86% after 3 months and 97% at 12 months of use in the treatment of HMB

Mansour D, Best Pract Res Clin Obstet Gynaecol. 2007; Kaunitz AM, 2009

Mirena®

The LNG-IUS is superior to luteal phase oral MPA; norethindrone for 21 days; oral progestin (norethisterone in extended use); DMPA; combination OCs; and mefenamic acid

Hemoglobin and serum ferritin levels are significantly improved after insertion of an LNG-IUS in women with iron deficiency anemia

Treatment Failure

Mamdouh M, Contraception 2011

Treatment failure• LNG-IUS %11• COC %32

Ethinylestradiol-Containing Preparations

The use of combined oral contraceptives (COCs)

reduces uterine bleeding in healthy women by

approximately 40% during 6 months of use

Mechanism:

• The downregulation of endometrial estrogen receptors resulting in atrophic glandular endometrium because of prolonged progestin exposure of the endometrium

Estradiol Valerate/Dienogest (Qlairista®)

• Is the only combination OC that was approved by theUS Food and Drug Administration (FDA) for thetreatment of HMB (March 2012)• Two placebo-controlled trials assessed efficacy of

E2V/DNG in 269 women with HMB for 7 menstrualcycles•A pooled analysis reported a significant reduction in

median MBL by the end of treatment relative tobaseline (88% in the E2V/DNG treatment group versus24% in placebo)•Withdrawal bleeding was absent in approximately 20%

of the women with the use of estradiol valerate- anddienogest-containing COC

Fraser IS, Eur J Contracept Reprod Health Care 2011; Jensen JT, Obstet Gynecol 2011; Westhoff C, Obstet Gynecol 2012

• 26 aktif tablet - östrojen azaltıcı, progestojen arttırıcı

Östradiol valerat 2 mg3 mg

1 mg Plasebo

2 mgDienogest 3 mg

1

2 gün yalnızca

E2V

5 gün E2V 2 mg ve DNG 2 mg

2 gün plasebo hormonsuz

2 gün yalnızca

E2V

2 5 63 7 84 9 10 11 12 15 1613 17 1814 19 20 21 22 25 2623 27 2824

17 gün E2V 2 mg/ DNG 3 mg

Qlairista®

MBL According to the Cycles

Fraser IS, Contraception 2012

Comparition of Treatment Modalities

Calaf J, Eur J Obstet Gynecol Reprod Biol 2015

Tranexamic Acid (Transamine®)

Transamine®

•Oral tranexamic acid is FDA approved for the treatment of ovulatory AUB; an

•IV formulation is approved for use in hemophilia

Transamine®

• In the systematic review of 12 studies involving 690 women, the reduction in MBL ranged from 34% to56% in those treated with 3-4 g tranexamic acid for5 days

•However, it does not reduce the duration of menses or regulate the cycle

•Thromboembolic events have not been reported in treatment studies

Leminen H, Int J Womens Health 2012

Others

•NSAID• Thromboxane A2 increases (Ferenczy A 2003)

• Reduces MBL up to %50

•GNRH ANALOG

•DESMOPRESSIN

•SPRM• Ulipristal actate-licensed for fibroids

National Guidelines

AUBNo contrindication for medical treatment*

Oral Hormonal Therapy

Nonacceptable

Transamine®

NSAID

Acceptable

Qlairista® **

Other COCsOral Progestins (5-25)

LNG IUS (Mirena®)

*Pregnancy desiring, no PALM

**Qlairista; FDA approved only this COC

Effects on MBL in HMB with VariousTreatments

Indirect comparison of studies of treatments for reduction in MBL

(all studies assessed MBL using the alkaline hematin method)

*Data are presented at 6 months; ‡Data are presented at 12 months; **Data are from a pooled analysis of 2 studiesFigure adapted from references 1–8COC: Combined oral contraceptive; TXA: Tranexamic acid

% r

ed

ucti

on

of

MB

L (

aft

er

6 t

o 1

2

mo

nth

s o

f tr

ea

tme

nt)

60

80

40

20

100

0

LNG-IUS

*

‡xx *

x *

*

x ‡

x *

*

*

*

**

Sayed GH, Int J Gynecol Obstet 2011; Tang GW, Contraception 1995; Xiao B, Fertil Steril 2003; Reid PC, BJOG 2005; Shabaan MM,Contraception 2011; Milsom I, AJOG 1991; Fraser IS, Eur J Contracept Reprod Health Care 2011; Lukes AS, Obstet Gynecol 2010

Thank You for Your Attention!