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Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Abnormal Uterine Bleeding: Conflict of Interest Disclosure From Terminology to Treatment Anita L. Nelson, MD

Grants/ Bayer, Merck, Pfizer, Teva Research Anita L. Nelson, MD Honoraria/ Harbor-UCLA Medical Center Bayer, Merck, Teva Speakers Bureau

Consultant/ Agile, Bayer, Advisory Board Merck, Teva, Watson Contraceptive Technology Washington DC – April 17-20, 2013

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 2

Learning Objectives Normal

At the end of this presentation, the participants  Interval: 24-38 days will be able to  Duration: 4.5-8 days  State the terminology used to describe abnormal uterine bleeding.  Blood loss: 5-80 cc  Describe the evaluation needed for women with chronic excessive bleeding.  Develop a treatment plan for acute heavy bleeding and for chronic menstrual blood loss which reflects their individual desire for fertility.

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 3 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 4

New Terminology and Menstrual Bleeding Terminology

Classification System for Clinical Dimensions Descriptive Normal Limits Abnormal Uterine Bleeding Terms (5th to 95th percentiles)  New terms to replace older, imprecise terms Frequency of menses Frequent <24  Bleeding described in 4 dimensions: Normal 24-38 Infrequent >38  Frequency, duration, volume and variability Absent --  English words (heavy, prolonged, infrequent) Regularity of menses, Regular Variation ± 2-20 replace Greek and Latin terms (menorrhagia) cycle-to-cycle days variation over Irregular Variation > 20 Fraser IS, et al. Curr Opin Obstet Gynecol. 2007;19:591-5. 12 months days Woolcock JG, et al. Fertil Steril. 2008;90;2269-80. Fraser IS, et al. Semin Reprod Med. 2011;29:383-90. Fraser IS, et al. Fertil Steril. 2007;87(3):466-76. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 5 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 6

1 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Menstrual Bleeding Terminology PALM-COEIN Classification Clinical Dimensions Descriptive Normal Limits Terms (5th to 95th percentiles)

Duration of flow Prolonged >8.0 Normal 4.5-8.0 Shortened <4.5 Volume of monthly Heavy >80 blood loss Normal 5-80 Light <5

Fraser IS, et al. Fertil Steril. 2007;87(3):466-76. Adapted from the Munro. Fertil Steril. 2011;95:2204. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 7 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 8

PALM-COEIN PALM-COEIN Cases

 AUB-P Polyps  AUB-A  AUB P0 A1 L1→sm M0 C0 O0 E0 I0 N0

 AUB-L SM/O (location)  AUB P1 A0 L0 M0 C0 O0 E0 I1 N0

 WHO/FIGO subclassification AUB-M Malignancy  AUB P0 A0 L1→0 M1 C0 O1 E0 I0 N0  AUB-C Coagulopathy  AUB P0 A1 L1→sm M0 C1 O0 E0 I0 N0  AUB-O Ovulatory dysfunction  AUB-E Endometrial causes  AUB-I Iatrogenic  AUB-N Not yet classified Garza-Cavazos A, et al. Female Patient. 2012;37(8):27-36. Garza-Cavazos A, et al. Female Patient. 2012;37(8):27-36. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 9 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 10

Coding for AUB Coding for AUB

 626 Disorders of and other  626.4 Irregular menstrual cycle, irregular abnormal bleeding from female bleeding, , genital tract irregular periods  626.0 (primary)(secondary)  626.5 bleeding, regular  626.1 Scanty of infrequent menstruation, ,  626.6 Metrorrhagia, bleeding unrelated to  626.2 Excessive or frequent menstruation, menstrual cycle, irregular heavy periods, menorrhagia, intermenstrual bleeding , polymenorrhea  626.8 Dysfunctional or functional uterine hemorrhage Graza-Cavazos A, et al. Female Patient. 2012;37:27-36. Graza-Cavazos A, et al. Female Patient. 2012;37:27-36. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 11 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 12

2 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Secondary Amenorrhea Secondary Amenorrhea Special Issues

 Amenorrhea in a reproductive woman  status determines concerns

 ≥ 3-6 months in a previously normally  Estrogen deficiency  osteoporosis, menstruating woman menopausal issues

OR  Estrogen unopposed  endometrial  < 9 months or 2 times usual interval carcinoma

ASRM. Fertil Steril. 2006;86(5 Suppl):S148-55 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 13 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 14

Common Causes of Chronic Diseases Secondary Amenorrhea Causing Amenorrhea Category Frequency Low or normal FSH: weight loss/anorexia; 66%  Uncontrolled  Hepatic failure non-specific hypothalamic; chronic juvenile diabetes  Adrenal insufficiency including PCOS; ; Cushing’s syndrome; pituitary tumor, empty sella,  End-stage renal  Cushing’s syndrome Sheehan syndrome disease Gonadal failure: high FSH 12%  Sarcoidosis  AIDS 46 XX; abnormal karyotype  Acromegaly High 23%  Malabsorption Anatomic: Asherman syndrome 7%  Craniopharyngiomas  Malignancy Hyperandrogenic states: 2%  dysfunction ovarian tumor; non-classic CAH; undiagnosed  Androgen excess  Obesity ASRM. Fertil Steril. 2006;86(5 Suppl):S148-55 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 15 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 16

Medications Causing Amenorrhea Secondary Amenorrhea Differential Diagnosis  DMPA, LNG IUS, extended-cycle OCs  Pregnancy  Chemotherapeutic agents  Anesthetics, including cocaine  Endocrine disorder

 Psychoactive drugs: phenothiazines, tricyclic  Thyroid dysfunction: TRH increases PRO antidepressants, opiates, chlordiazepoxide, amphetamines, diazepams, haloperidol, fluphenazine,  Diabetes mellitus: slowed clearance of chlorpromazine, SSRIs estrogen

 Antihypertensives: α-methyldopa, reserpine, verapamil  Androgen excess: adrenal or ovarian origin  Dopamine receptor agonists: metoclopramide  Obesity: excess estrogen  Antiemetics: sulpiride, promazine, perphenazine  Others: cimetidine, cyproheptadine, protease inhibitors

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3 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Menstrual Cycle Workup of Secondary Amenorrhea

 History: recent surgical procedures, weight changes, medications, other health problems, radiation therapy, chemotherapy  Family history: autosomal disorders associated with ovarian failure, endocrinopathy  Physical exam: galactorrhea, obstruction, hirsutism, virilization, acromegaly  Lab tests: pregnancy test, FSH, TSH, prolactin

 Other tests if indicated: androgens

ASRM. Fertil Steril. 2006;86(5 Suppl):S148-55 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 19 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 20

A Treatment Course of Progestin Progestin Challenge Test Limitations  High false positive rate: no withdrawal bleed  Up to 20% of women with estrogen have no withdrawal bleeding  Androgen excess states common  High false negative rate: withdrawal bleeding  Up to 40% of women with amenorrhea from  Stress, weight loss, exercise or hyperprolactinemia  Up to 50% of women with amenorrhea from  ovarian failure

ASRM. Fertil Steril. 2006;86(5 Suppl):S148-55 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 21 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 22

Ovary Evaluation Work-up of Secondary Amenorrhea Evaluation

 High FSH =  If FSH and LH elevated and E2 low, consider probable ovarian ovarian failure or (rarely) insensitive ovary failure syndrome

 Low FSH = pituitary  Repeat tests to confirm if early is or hypothalamic suspected

etiology  Perform karyotype if patient < 30

 Rule out autoimmune disease if patient < 35  Common sites affected include thyroid, adrenal, parathyroid, pancreas

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4 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Work-up of Secondary Amenorrhea High Prolactin

 If gonadotrophins level or low (FSH and LH <5 IU/L) and no response to progestin  Persistent hyperprolactinemia without challenge, evaluate pituitary and hypothalamus primary hypothyroidism or medication, evaluate with MRI of pituitary  If androgen elevated or high normal  If levels in tumor range, order radiographic  Pituitary tumor found in 50-60% studies to localize tumor  Other CNS lesions  High normal testosterone consistent with PCOS or medications  Congenital aqueductal stenosis  Elevated DHEAS, consider adrenal  Adenomas- ACTH, GH hyperfunction  Empty sella syndrome

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CAT Scan or MRI Hypothalamic Amenorrhea

 Hypothalamic amenorrhea is a diagnosis of Tumor involving exclusion with the pituitary  Low-normal gonadotrophins gland  Normal PRO  Normal imaging of pituitary  No withdrawal bleeding  Most common cause of amenorrhea, often associated with stress, eating disorders, weight loss?, diabetes??  72% of women had spontaneous return of menses within 6 years

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 27 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 28

Secondary Amenorrhea Secondary Amenorrhea Athletic Triad Treatments: Target the Cause Long-Term Consequences  Correct thyroid or prolactin dysfunctions

 Reduced bone mass: particularly harmful in  Provide progestin protection for young adolescents, who should be until normalizes accumulating bone mineralization  Estrogen deficient conditions  Lipid changes: amenorrheic athletes  Provide estrogen and progestin demonstrate increased potential for lipid  Unopposed estrogen conditions peroxidation after exercise  Provide progestin cyclically or suppression  : exercise moderation/cessation and correct diet usually prompt return of ovulation

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5 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Heavy Menstrual Bleeding (HMB)  30% of women consider their bleeding excessive1  Common gynecologic problem in reproductive aged women  80% of women treated for HMB have no anatomical pathology2  9-14% of healthy women  12% of all GYN referrals in U.K. are for HMB  Accounts for over 20% of outpatient clinic visits  60% of women referred to GYN get hysterectomies3  Women with self reported excessive bleeding  50% of done for HMB  45% more likely to use health services  1/3 have anatomically normal uteri4  38% less likely to be working 1. Prentice A. BMJ 1999;319:343-5. 2. Clark. BJOG 1995;102:611-20.  $1,697 in lost annual wages 3. Coulter A. BJOG. 1991;98:789-96. 4. Gath A. BJ Psych. 1982;140:335-40. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 31 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 32

Heavy Menstrual Bleeding Basis for Traditional Definitions

 476 Swedish women in 1960s with measured  Also results in deficiency , social menstrual losses

discomfort, reduced productivity, decreased  No impaired iron function seen in women with < 60 quality of life mL loss  Calculations based on typical Swedish diet of the  Commonly associated with leiomyoma and day, ≤ 63 mL malignancy th  Of the 183 healthy women, 90 percentile was 76  However, 50-80% of women with mL loss 1 menorrhagia have no uterine pathology  More recently, no difference in ferritin levels seen in 50-79 mL vs 80-119 mL 1. Lethaby A, et al. Cochrane Database Syst Rev.  > 120 mL losses associated with lower ferritin levels 2000;(2):CD001016.

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 33 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 34

Heavy Uterine Bleeding: Measurement of Blood Loss

Definition  Current standard of estimating blood loss is  Deviations from textbook definitions of normal modified alkaline hematin extraction cycles  Not reproducible in practice  Deviations from an individual’s own established patterns of normal cycles  Pad counts not accurate  Adverse impact on quality of life  Different pad absorbencies Menstrual bleeding is heavy  Patient factors when it is heavy to the woman:  Pictorial blood loss assessment chart Objective definitions are irrelevant for an individual who (PBAC) score used in research, but is inconvenienced, discontent, or made anxious by the limitations noted perception of an excessively heavy menstrual flow. Fraser IS, et al. Obstet Gynecol. 2001;98(5 Pt 1):806-14. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 35 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 36

6 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Blood Loss by Age Heavy Bleeding: Reality vs Perception

 77 healthy women aged 21-55, 2 consecutive cycles with colormetric measurement of hbg Perception of Anovulatory Median menstrual Reproductive Stage N Cycles Blood Loss bleeding Mid reproductive 21 2 30 mL Late reproductive 17 0 33 mL Early transition 16 1 55.7 Late transition 23 9 68.9

 Highest blood losses seen in late menopausal Actual Menstrual Blood Loss Per Cycle transition with ovulatory cycle and high E2 levels Hale GE, et al. Obstet Gynecol. 2010;115(2):245-56. Hallberg L, et al. Acta Obstet Gynecol Scand. 1966;45:320. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 37 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 38

HMB Assessment Etiologies of Self-Reported Survey Abnormal Uterine Bleeding

 Postal survey of 7,121 women (40-54 years)  Organic gynecologic diseases  Baseline, 6, 12, 18, 24 months  Systemic diseases  64% response rate  Blood dyscrasia  2,051 naturally menstruating women selected  Medications  2/3’s reported HMB in previous 6 months

 > 20% resolved in next 6 months  Trauma/foreign body  50% of those recurred  Anovulatory bleeding  1/3 without HMB at baseline

 30% will develop in next 2 years Shapley M, et al. BJOG. 2012;119(5):545-53. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 39 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 40

OB-GYN Diseases Systemic Diseases Causing Bleeding

 Pregnancy and pregnancy complications.  Thyroid disorders  Infections:  Liver cirrhosis or active hepatitis  Cervical (post-coital bleeding)  Adrenal hyperplasia  Uterine and (spotting)  Renal failure  Neoplasia  Hypersplenism  Benign (polyps, leiomyoma)

 Malignant:  Cervical (post coital)  Endometrial (intermenstrual bleeding)

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 41 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 42

7 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Menorrhagia Screening Tool Utility of Screening Tool for Bleeding Disorders And Other Measures Q1. How many days did your period usually last, from the time bleeding began until it completely stopped? Screening Sensi- Speci- Q2. How often did you experience a sensation of “flooding” or “gushing” during your period? Tool tivity ficity PPV NPV Q3. During your period did you ever have bleeding where you would bleed through a or napkin in ≤2 hours? Only 89 16 72 37 Q4. Have you ever been treated for anemia? Q5. Has anyone in your family ever been diagnosed with a bleeding disorder? With PBAC 95 6 72 33 Q6. Have you ever had a tooth extracted or had dental surgery? > 185 Q6a. Did you have problem with bleeding after tooth extraction or dental surgery? Q7. Have you ever had surgery other than dental surgery? With ferritin 93 11 72 39 Q7a. Did you have bleeding problem after surgery? ≤ 20 ng/mL Q8. Have you ever been pregnant? Q8a. Have you ever had bleeding problem after delivery or after a miscarriage? Philipp CS, et al. Am J Obstet Gynecol. 2011;204(3):e1-7. Philipp CS, et al. Am J Obstet Gynecol. 2011;204(3):e1-7. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 43 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 44

Disorders of Hemostasis in Common Bleeding Disorders Women With Heavy Bleeding

(VWF) deficiencies 

function defects  Type I (mild) – decrease in quantity

 Platelet aggregation defects  Type III (severe) – decrease in quantity  Decreased to ristocetin  Type II – qualitative defects  Decreased to epinephrine  Platelet function disorders  Platelet release defects: ATP  Defects in platelet function  Thrombocytopenia disorders (ITP)  Disorders of fibrinolysis  Disorders of Philipp CS, et al. Obstet Gynecol. 2005;105:61-6. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 45 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 46

Prevalence of Bleeding Disorders Hemostatic Abnormalities in Women with Heavy Bleeding  Women without heavy menstrual bleeding (HMB)  0.6%-1.3% von Willebrand Disease  115 women with physician-diagnosed  1% platelet function disorders menorrhagia  Women with HMB (PBAC > 100)  217 women ages 18-50  47% had hemostatic abnormality % Hemostatic Abnormalities  Platelet aggregation: 44% Platelet Coag  von Willebrand factor: 7% ≥ 1 function Low factor abnormality deficit VWF deficiency  Coagulation factors: 5% Population 71 55 5 5 Caucasian 66 50 Black 91 81 Philipp CS, et al. Obstet Gynecol. 2005;105:61-6. Philipp CS, et al. Am J Obstet Gynecol. 2011;204(3):e1-7. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 47 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 48

8 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Excessive Bleeding in Teens Medications That Increase Blood Loss

 Platelet disorders affect 1-3% of the US population  Steroid hormones  64 teens with platelet disorders   25% menorrhagia only Digitalis  85% primary menorrhagia  Dilantin  16% menorrhagia + another symptom   Storage pool defects were a cause of platelet function disorder in 63%  Tranquilizers  Aspirin like disorder affected 29%  IUD (usually copper or plastic)  11/19 treated successfully with single agent medications  9/11 oral contraceptives Boshert S. OB GYN News. 2008;11:19. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 49 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 50

Normal Controls of Abnormalities in Anovulatory Menstrual Bleeding Women with HMB

 Normal controls in ovulation:  PGE2 produces vasodilation  Production of both PGE2 and PGF2x increase in  PGF2 induces vasoconstriction

 Thromboxane promotes platelet aggregation  PGF2x > PGE2  PGF2x binds to receptors in spiral arteries in late  Prostacyclin inhibits platelet aggregation secretory phase  Causes vasoconstriction  Normally, both PGE2 and PFG2 increase,  Anovulatory cycle: abnormalities but PGF2/PGE2 ratio increases near  No increase in production PGF menses 2x  PGF2x/PGE2 lower  Less vasoconstriction, heavier and/or prolonged flow

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 51 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 52

Abnormalities in Ovulatory Women Abnormal Bleeding In Older Women with HMB  Menstrual flow  Perimenopausal women   Higher levels PGE2 and PGF2x Define terms clearly (normal cyclic changes  PGE2 > PGF2x versus intermenstrual bleeding versus heavy  Endometrium and bleeding)  Anovulatory bleeding is most common cause  Higher release of PGE2 and prostacyclin  Myometrium  2-3% of perimenopausal women with abnormal bleeding have malignancy  Elevated PGE2 receptors  Endometrium  Postmenopausal women  Prostacyclin/thromboxane higher  Malignancy is most common cause of  Fibrinolytic activity higher (plasminogen activators) unstimulated postmenopausal bleeding Rees MC, et al. BJOG. 1985;92(11):1164-8. Rees MC, et al. BJOG. 1984;91(7):662-6.  30-45% of women with bleeding have Smith SK, et al. BJOG. 1981;88(4):434-42. malignancy Adelantado JM, et al. BJOG. 1988;95(2):162-5. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 53 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 54

9 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Heavy Bleeding Work-Up: Goals Heavy Bleeding Work-Up: History

 Menstrual history  Establish whether heavy bleeding is due to a  Determine regular or irregular treatable organic disorder  Medication and medical history  Determine whether bleeding is ovulatory or  Identify any current medications that may anovulatory affect menstrual cycle or risk of excess  Assess burden of symptoms as well as menstrual bleeding patient expectations from therapy  Sexual history

 Determine method, desire and potential for pregnancy, risk for sexually transmitted diseases

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 55 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 56

Laboratory Evaluation of Imaging Studies Heavy Uterine Bleeding

 Pregnancy test  Pelvic ultrasound  CBC, and if patient anemic, TIBC, Fe, ferritin and other appropriate tests to evaluate  Indicated if pelvic mass suspected (ovarian  Screen for blood dyscrasia (if indicated by personal or uterine) or family history)  May identify submucous or intramural fibroids  Thyroid function tests (if clinically suspected)  Does not rule out endometrial pathology  Cervical cytology (if not done recently)  Saline Infusion Sonography (SIS)  Screen for cervical infections, (if indicated)  Liver function tests (if alcohol or substance abuse  May identify endometrial polyps or or other risk factors) submucous fibroids  Endometrial evaluation, (if bleeding suspicious)

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 57 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 58

Saline Infusion Sonography (SIS) Saline Infusion Sonography – Polyps Sonohysterography

 Transvaginal ultrasound—real time  Introduce small tubing into endometrial cavity, inflate self-retaining balloon above internal os and infuse 5-15 cc normal saline  Able to better detect:

 Polyps u Submucous fibroids

 Synechia u Uterine malformations  Sensitivity similar to office

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10 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

SIS vs. Hysteroscopy Indications For Endometrial Sampling Diagnosis of Intracavitary Lesions  Abnormal bleeding in:  Age > 35  89 premenopausal women  Unopposed estrogen stimulation:  TVS first normal < 15mm, and homogeneous  Nulliparity or prolonged reproductive years echodense midline  Polycystic ovary syndrome, infrequent menses Lesion Detected Outpatient SIS HS Pathology  Feminizing ovarian tumors Polyp 27 30 32 34  Obesity Submucosal fibroid 3 4 4 4  3-fold increase if, 21-50 lb excess  10 fold increase if > 50 lb excess Endo hyperplasia 17 9 9 7  Diabetes Endo carcinoma 7 5 5 2  Tamoxifen Other 35 41 40 42  Hereditary nonpolyposis colorectal Soquktas S, et al. Eur J Obstet Gynecol Reprod Biol. 2012;161(1):66-70. (HNPCC) Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 61 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 62

Endometrial Aspiration Heavy Menstrual Bleeding: Factors Influencing Therapies

 Age of patient  Severity of symptoms  Presence of associated pelvic pathology  Fertility plans

 NOTE: Most therapies recommended are off-label

 The only drugs that are FDA-approved for the treatments of heavy bleeding are cyclic MPA, LNG-

IUS, , E2V/DNG oral contraceptive

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Severe Acute Excessive Bleeding: Published Prospective Studies Medical Therapies Appropriate Number of If Patient Stable Subjects Treated Intravenous conjugated equine estrogen1 17 Combined birth control pill (Norgestrel 0.5 mg  9 + 9 Initial therapy + EE 50mcg) PO QID x 2-4d very slow taper2,3  Transitional therapy (days 2-7) MPA 60-120 mg PO x 1d + 20 mg PO x 4d 4 24  Follow-up (days 7-21) MPA 20 mg PO TID x 7d + 20 mg daily x 21d5 20 Combined birth control pill (35 mg EE/1 mg 20 NETA) PO TID x 1d + T tab PO x 21d6

1. DeVore GR, et al. Obstet Gynecol. 1982;59:285-91. 2. Foss GL. J Reprod Fertil. 1969;18(1):59-66. 3. Rau 4. DeVore GR, et al. Obstet Gynecol. 1982;59:285-91. 5. Aksu F et al. Aust N Z J Obstet Gynaecol. 1997;37:228-31.

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 65 Anita L.6. Nelson,Munroe MD MG, et al. Obstet Gynecol. 2006;108(4):924-29. HMB 2013- 04-17 CT WDC 66

11 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

High Dose Progestin Treatments for Complimentary Therapies Acute Uterine Bleeding (n=40) in Acute Setting MPA 20mg given orally 3 times a day for 7 days, then once daily for 21 days  Antiemetics to reduce nausea and vomiting vs associated with high-dose hormonal therapy 35 mcg EE/1 mg NETA given orally 3 times a day for 7 days, then 20 mcg EE/1 mg NETA once daily for 21 days  Especially helpful in therapies using estrogen MPA COC  NSAIDs to reduce acute bleeding; can be No surgery 100% 95% used in conjunction with hormonal therapy Cessation of bleeding 76% 88%  Iron supplements, if anemic Days to Cessation 3 3  Menstrual calendars Patient satisfaction (0-4)* 3 3  * 0 = unsatisfied Re-evaluate in appropriate intervals Munroe MG, et al: Obstetrics & Gynecology.2006;108(4):924-29. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 67 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 68

Evaluation of Severe Acute or Medical Treatment For Mild-To-Moderate Unresponsive Uterine Bleeding and Non-Acute, Severe Bleeding and Longer-Term Therapy to  Endometrial sampling Prevent Recurrence of All Forms of  Usually fractional curettage--D&C Heavy Bleeding  Provides temporary arrest of bleeding and pathologic material for diagnosis  Mild-to moderate (HGB > 10 g/dL)  Hysteroscopy and directed endometrial biopsy  Severe (HGB < 10 g/dL)  Helpful if bleeding persists or returns after  Hormonal interventions to suppress ovulation diagnostic D&C and endometrial thickness  25% of women with unexplained bleeding after D&C can have cause identified with  Hormonal methods to prevent endometrial hysteroscopy thickening and uncoordinated sloughing

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Chronic Heavy Menstrual Bleeding: Chronic Heavy Menstrual Bleeding: Medical Therapies Medical Therapies

 Prostaglandin normalization: NSAIDs  Coordinate endometrial sloughing

 Inhibiting cyclooxygenase  Combined hormonal contraceptives

 Converts arachidonic acid to prostaglandin  Progestin 7-12 days each cycle  Binding to prostaglandin receptors  Suppress endometrium  Metaanalysis shows no one NSAID  DMPA, continuous progestin, extended-cycle superior to another COCs, vaginal rings  Decrease fibrinolysis  GnRH,

-releasing IUS Lethabie A, et al. Cochrane Database Syst Rev. 2009;CD000400 Lethabie A, et al. Cochrane Review 2009;CD000400. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 71 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 72

12 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Nonsteroidal Anti-Inflammatory Drugs NSAID Regimens (NSAIDs) to Correct Relative  Prostaglandin Overproduction by  500 mg TID first 4-5 days of menses  500 mg TID from 4-5 days prior to menses to cessation Inhibiting Prostaglandin Synthetase  500 mg initially; 200 mg QID for 3-5 days  Naproxen  500 mg at onset and 3-5 hours later; 500 mg BID for 5  Effects: reduce menstrual blood loss by 20- days 50% in women with anovulatory cycling  500 mg in AM and 250 in PM for two days; 250 mg BID for 7 days  Administration: first 3 days of menses for  500 mg; 250 mg QID for 4 days long term control  550 mg; 275 mg QID for 5 days  Ibuprofen  May be used in conjunction with hormonal  800 mg TID for 5 days (Norplant trial) therapy in acute setting Lethabie A, et al. Cochrane Review 2009;CD000400. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 73 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 74

Antifibrinolytics Tranexamic Acid Approved in US  Dose: 650 mg 2 tabs orally 3 times daily for up to 5 days during menses  Plasminogen activators are a group of enzymes that cause fibrinolysis  In placebo controlled trials, 38% greater reduction in blood loss  Increased levels of plasminogen activators  Adverse events: headache, sinus pain, found in endometria of women with heavy muscle and joint pain, anemia, fatigue menstrual bleeding  Might raise risk of thrombosis  Plasminogen activator inhibitors  Women who use ( agents) block enzymes should use tranexamic acid only for strong  Tranexamic acid medical indications for which benefits outweigh risks Lethabie A, et al. Cochrane Review 2009;CD000400. FDA Announcement, Nov. 13, 2009. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 75 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 76

Tranexamic Acid and Ferritin Levels Pooled Subanalysis Patients with Low Hemoglobin or Ferritin

 Tranexamic acid 650 mg TT orally tabs TID up to 5 days  Baseline and mean change from baseline of hemoglobin and (3.9g/d) ferritin levels among patients with low hemoglobin (< 12g/dL) or Reduction in Blood Loss ferritin (< 19 ng/mL) at baseline with tranexamic acid Variable (mL) Baseline Cycle 1 Cycle 3 Cycle 6 Age < 30 40 Hemoglobin (n = 191) Age 30-45 60-65 Patients, n 191 186 170 146 Age ≥ 45 80 Hemoglobin, g/dL 10.76 + 0.37 + 0.71 0.96 p value vs. baseline ─ < 0.001 < 0.001 < 0.001 Fibroids vs. non 75 vs. 60 Ferritin (n = 233) BMI < 25 75 Patients, n 233 ──+179 BMI 25-29 65 Ferritin, ng/mL 6.11 ──+ 3.19 BMI ≥ 30 65 p value vs. baseline ───< 0.001 Butler JB. OB-GYN News. 2012:12-13. Muse K, et al. J Wp,ems Jea;tj. 2012;21(7):756-61. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 77 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 78

13 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Combined Hormonal Contraceptives E2V/DNG: Average Reduction in To Prevent Endometrial Thickening Blood Loss* And Uncoordinated Sloughing

 Oral contraceptive pills or vaginal contraceptive ring

 Conventional monthly cycling

 Extended cycles

• In women who entered the study with symptoms specific  Transdermal patches to HMB • Among patients with HMB, MBL was statistically significantly reduced in the  Conventional monthly cycling group treated with Natazia® compared with placebo (p<0.0001 in 2 clinical studies)

Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 79 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 80

Extended Cycle OC Trial: Scheduled Extended Cycle OC Trial: Scheduled Withdrawal Bleeding/Spotting Days Withdrawal Bleeding/Spotting Days

30 30

25 25

Median Number of 20 Median Number of 20 Scheduled Scheduled Withdrawal 15 36 Withdrawal 15 36 Bleeding Days Bleeding Days 10 10 Per Year Per Year 5 10 5 10 0 0 Seasonale® Nordette® Seasonale® Nordette® Anderson FD, et al. Contraception. 2003;68:89-96. Anderson FD, et al. Contraception. 2003;68:89-96. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 81 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 82

Extended Cycle OC Trial: Median Days Cumulative Amenorrhea of Unscheduled Bleeding/Spotting with Extended OC

12

10

8 12 6

4 Days per Cycle per Days 66 2 4

0 Days: 1–84 92–175 183–266 274–357 Cycle: 1 2 3 4 Data on file, Wyeth Pharmaceuticals Inc. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 83 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 84

14 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Progestin Methods to Prevent Bleeding Patterns In DMPA Users Endometrial Thickening and

Uncoordinated Sloughing 100% 90%  MPA 10 mg orally daily for 12 days on cycle 80% 11-30 70% days 15-26 (FDA-approved) 60% 8-10 50% 1-7  MPA 5 mg orally daily 40% 0 30%  Norethindrone 5 mg orally cycle days 19-26 20% 10%  Progestin only pills 0% 3 9 15 21 27 33 39 45 54 60 66  DMPA 150 mg IM every 11-13 weeks Month  Levonorgestrel-releasing IUS Schwallie PC, Assenzo JR. Fertil Steril. 1973;24:331. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 85 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 86

Levonorgestrel Intrauterine Heavy Bleeding Therapy: LNG-IUS System (LNG IUS)  Advantages  Long-term efficacy  Effective: ~20% of patients amenorrheic at 1 year  Highly effective contraception Steroid  Delivery of progestin locally to endometrium reservoir  70 – 90% reduction in blood loss at 1 year  Disadvantages Levonorgestrel  Requires insertion 20 mcg/day  Upfront initial cost Milsom I, et al. Am J Obstet Gynecol. 1991;164(3):879-83. Crosignani PG, et al. Obstet Gynecol. 1997;90(2):257-63. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 87 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 88

Heavy Bleeding Therapy: Bleeding Reduction with LNG-IUS LNG IUS vs NSAID and Tranexamic Acid

400

300

200

100

0 36 12 Menstrual blood loss (mL) blood Menstrual Before treatment Months of use

Andersson and Rybo. Br J Obstet Gynaecol. 1990;97:690. Milsom I, et al. Am J Obstet Gynecol. 1991;164(3):879-83. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 89 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 90

15 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

LNG-IUS vs. Cyclic Provera LNG-IUS vs. OCs

160 0 140 –10 P (baseline vs. end study) 120 –20 <0.001 –30 P between groups = 0.002 100 –40 80 Mirena® –50 LNG-IUS OC 60 MPA –60 –70 40 –68 Median MBL (mL) Median MBL –80 20 Score Baseline PBAC –90 –83 Percentage Change from Percentage Change 0 End Study Baseline 3 Month 6 Month Bayer HealthCare Pharmaceuticals Data on file. Endrikat, et al. J Obstet Gynaecol Can. 2009;31(4):340-7. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 91 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 92

Newer Meta-Analysis: Patient Dissatisfaction with LGN-IUS vs Ablation for HMB Heavy Menstrual Bleeding  No apparent difference between rates of treatment Treatments at 12 Months failures

 21.2% vs 17.9% % of Women P Value vs. Dissatisfied  Both methods had similar improvements in quality of life LNG IUS 17% 0.07 st  Complications rates higher with ablation 1 generation 13% <0.001

 Uterine perforation: 1/1000 vs 3-25/1000 ablation nd  Ablation requires provision of additional long term 2 generation 11% 0.006 effective contraceptive method ablation

 Post ablation placentation problem Hysterectomy 5% -- Kaunitz AM, et al. AJOG. 2009;113(5):1104-16b. Middleton LJ, et al. BMJ. 2010;341:c3929. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 93 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 94

LNG IUS as LNG IUS Versus Hysterectomy: Alternative to Hysterectomy Outcomes and Costs

 236 women age 35-49 with heavy bleeding Women Canceling  Randomized to hysterectomy versus LNG-IUS Hysterectomy  5-year follow-up

 No difference in Health-related Quality Of Life

 42% of LNG-IUS users underwent hysterectomy

Discounted Indirect and Direct Costs LNG-IUS $2817 95% CI ($2222-3530) Hysterectomy $4660 95% CI ($4014-5180)

Lahteenmaki, et al. BMJ. 1998;316:1122-6. Hurskainen G, et al. JAMA. 2004;291:1456-63. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 95 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 96

16 Nelson: Abnormal Uterine Bleeding: From Terminology to Treatment

Evolving Perceptions Summary of Menstruation  Menstrual bleeding disorders are common  Up to 20% of women experience debilitating  Menstruation is not physiologically necessary symptoms of heaving bleeding at some point in in women without cyclic endometrial menstrual history1 proliferation  Heavy menstrual bleeding may signal systemic  In women burdened by menstrual cycles, disorders, coagulopathies, disease of long-term hormonal suppression of ovulation reproductive disorders2 is feasible and safe  The cause of most heavy menstrual bleeding is  Hormonal therapies are effective for benign and symptoms are often effectively regulating, reducing, eliminating, or even managed with hormonal therapies3 timing menstrual cycles 1. Long C, et al. Obstet Gynecol Clin N Am. 1990;17:343-59. 2. Speroff L, Fritz M. Clinical Gynecological Endocrinology and Infertility, 8th ed. 2010. 3. Shaw R. Br J Obstet Gynaecol. 1994;101(Suppl 1);15-8. Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 97 Anita L. Nelson, MD HMB 2013- 04-17 CT WDC 98

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