ABNORMAL UTERINE BLEEDING

Leslie Ablard, M.D.

Quiz

1. True or False Most women would say periods are

AWESOME!! FALSE

2. True or False ABNORMAL periods are even more

AWESOME!!! FALSE

Definitions

Normal menstrual cycle Interval: 28 +/- 7 days (21-35 days) Can change from cycle to cycle Length </= 7 days Flow: Avg blood loss: 35ml (20-60ml)

Menorrhagia Prolonged – more than 7 days or Heavy – greater than 80ml/day CYCLIC menstruation Aka “hypermenorrhea”

Definitions

Menometrorrhagia Prolonged or heavy with breakthrough

bleeding

Polymenorrhea Bleeding occuring at intervals <21 days

Oligomenorrhea Intervals between bleeding episodes vary

from 35 days to 6 months

Definitions

Amenorrhea (Secondary) No menses for 6 months or more

It’s Common!

Estimated 10 million women in the US Over 2 million seen each year for

menstrual abnormalities 1/3 of gyn visits Most common cause of emergency gyn

hospital admission Most common reason for hysterectomy Commonly mismanaged!!!

Etiology

Pregnancy Hormonal Imbalance (hypothal/pit/ovary) Hemostatic Disorders (systemic vs local) Reproductive Tract Pathology Iatrogenic

Pregnancy

Ectopic Spontaneous/Incomplete Abortion Gestational Trophoblastic Disease “Normal Pregnancy”

DON’T FORGET THE PREGNANCY TEST (you will look stupid)

Hormonal

Anovulation/Oligo-ovulation PCOS/Obesity

20% PCOS have normal BMI Menarcheal/Perimenarcheal- immature HPA

Fully active in fetal life, suppressed in childhood, and then reactivated

Perimenopausal insensitive ovarian follicles

Hormonal

Anovulation/Oligo-ovulation Thyroid/Prolactin disorder

TRH induced increases in Prolactin- inhibits pulsatile GnRH

Hypothalamic Disorders Anorexia, exercise induced, gonadotropin

deficiency, POF Drugs- hypothalamic depressants, steroids,

herbs Anti-dopaminergic meds- take away inhibitory

dopamine on prolaction- inhibits pulsatile GnRH

Systemic Hemostatic Disorders Inherited disorders

Von Willebrand disease Hemophilias

Acquired disorders ITP/TTP Liver Disease Leukemia

Iatrogenic Anticoagulants ASA/NSAIDS

Iatrogenic Causes

Medications Hormonal Non-hormonal

Procedures D&C

Devices Copper IUD (Paraguard) Levonogestrel IUD (Mirena)

Reproductive Tract Disorders Uterine Lesions

Endometrial polyps Submucosal polyps Endometritis Adenomyosis Hyperplasia or cancer

Anovulation or Oligo-Ovulation Pathophysiology

In a reproductive age patient who is not having regular menses, must determine if 1. Progesterone Deficient 2. Estrogen and Progesterone Deficient

Anovulation or Oligo-Ovulation Patholophysiology

LACK OF PROGESTERONE Estrogen production with lack of

progesterone leads to unopposed estrogen stimulation of the endometrium

Can result in irregular shedding of the endometrium resulting in unscheduled/heavy bleeding

Potential for development of endometrial hyperplasia or cancer.

Anovulation or Oligo-ovulation

Pathophysiology: lack of ESTROGEN and PROGESTERONE

Lack of estrogen AND progestin in reproductive age women can lead to osteoprorosis, increased risk for heart disease, and reduced quality of life

Examples: anorexia nervosa, athletic amenorrhea, premature ovarian failure

Anovulation or Oligo-Ovulation Progestin Challenge

Purpose: Assess endogenous estrogen status of the patient Is there estrogen present

From peripheral conversion (estrone) Or Ovaries

Types: Medroxyprogesterone acetate (Provera, MPA) 10mg

for 10-12 days Progesterone in oil 100-150mg IM Norethindrone acetate (agestin, NETA) 5mg for 10-

12 days

Endometrial Cancer

Most common gynecologic malignancy: est 40,100 cases/ 7,470 deaths in 2008

Most patients between ages of 50-59 25% prior to menopause 5% before age 40 75% stage 1 disease

Endometrial Cancer- Preventable Estrogen Excess!!!!

Perimenopausal with estrogen excess PCOS Obesity Postmenopausal with continued estrogen

production from ovary/peripheral conversion of androstendione to estrone

TREAT WITH PROGESTINS OR PROGESTIN DOMINANT FORMULATIONS (OCs)

Rembember………

Many perimenopausal patients are PROGESTRONE deficient, NOT estrogen deficient!!!

Management

Medical management of Profuse Bleeding Very few published randomized trials Estrogen only Progestin only Estrogen + Progestin

Management

Use of IV Premarin in tx of DUB a double blind randomized controlled study

Only randomized trial assessing IV estrogen in tx of acute bleeding

34 randomized to IV placebo solution vs IV conjugated equine estrogen (premarin) 25mg IV q 4 hrs

At 5 hrs, bleeding stopped in 72% in CEE group vs 38% in placebo group (p= 0.021)

DeVore et al: Obstet Gynecol 1982; 59: 286-91

Management

High dose MPA for tx of DUB in 24 Adolescents

Hospitalized for excessive uterine bleeding Given 60-120mg MPA on day one, followed

by 20mg/day x 10 days All stopped bleeding within 4 days

Aust N Z Obstet Gynaecol 1997; 37: 228-31

Management

Oral MPA and Combination OCs for Acute Uterine Bleeding

Presented with acute uterine bleeding requiring emergent medical or surgical intervention

40 subjects randomized to a 7 day treatment of MPA 20mg TID OCPs (1mg NTE/35 mcg EE) TID

Doses reduced to once a day for the next 3 weeks

Management

Patient characteristics: avg age 43, BMI 30, mean hgb 8.0

Only one patient required surgical intervention (D&C for acute bleeding in OCP group)

Median # days to cessation of bleeding: 3 days in both groups

Cessasion of bleeding by 2 week visit in 76% in MPA and 88% in OCP group

Management

Mean satisfaction scores were similar Would use medication again for bleeding

if necessary 81% in MPA group 69% in OCP group

Median scores for bloating/cramping/nausea did not differ

Munro et al Obstet Gynecol 2006; 108: 924-9

Management

Progestins High dose MPA 20mg TID High dose NTE 5mg TID

Estrogen + Progestins (OCPs)

Anovulatory bleeding

PROGESTINS!!!!! Progestins alone Combination OCPs Depo Provera (MPA) Clomiphine Citrate (Clomid) or other

ovulation inducing medication if pregnancy desired

Anovulatory Bleeding

Cyclic Progestins MPA 10mg NTE 5mg

Patient instructed to take for 14 days every month. Can decrease interval over time

Anovulatory Bleeding

Cyclic Progestins Warn the patient that bleeding may be

heavy initially but will decrease over time Explain reason for treatment: prevention of

episodic irregular/heavy bleeding and CANCER

Can modify timing of progestin therapy around activities/ events for convenience

Anovulatory Bleeding

OCPs If no bleeding in over a month, consider

progestin withdrawl (NETA 5mg x 12 days) before initiating OCPs to shed thickened endometrium (began OCPs on day 3 of bleeding)

Also effective in treating associated problems (acne, hirsutism)

Anovulatory Bleeding

DMPA (Depo Provera) Menstrual changes occur in almost all users Most experience unpredictable bleeding

patterns in the first few months of use ¼ will discontinue in the 1st yr for irregular

bleeding With continued use, frequency and length

of bleeding episodes decreases with most becoming amenorrheic over time ¼ will not resume regular menses for up to 1 yr

Ovulatory Hypermenorrhea

Uterine bleeding controlled by prostaglandins

Abnormal prostaglandin levels in the endometrium can lead to excessive bleeding Decrease in prostaglandin F2alpha

(vasoconstrictor) and thromboxane (platelet aggregator)

Increase in prostaglandin E2 (vasodilator) and prostacyclin (platelet inhibitor)

Ovulatory Bleeding

NSAIDs OCPs Oral Progestins DMPA Danazol GnRH (Lupron) Anti-fibrinolytic agents Progestin IUD (Mirena)

Ovulatory Bleeding

NSAIDs Several studies show reduction in blood loss Less effective than other medical modalities

Ibuprofen 800mg 3-4 x day Naproxen sodium 550mg 3 x day Mefenamic acid 500mg 3 x day Meclofenamate 100mg 3 x day

Beginning day prior to or first day of menses for 3-5 days

Ovulatory Bleeding

Continuous OCP use (no 7 day break) should be considered as many will have unacceptable withdrawl bleeding if given 21/7

If breakthrough bleeding on continuous OCPs, stop 3 days and then restart (3 day 90% effective in resolving BTB)

Sulak et al Am J Obstet Gynecol 2006; 195: 935-41

Ovulatory Bleeding

Oral Progestins MPA 10-20mg/day or NETA 5-15mg/day Higher doses/longer intervals of cyclic

progestins Required for tx of menorrhagia as compared to

anovulatory bleeding NETA 5mg BID x 21 days starting cyle day #7

Continuous Progestins Without a break NETA 5mg daily starting on day 3 of cycle, don’t take a

break unless breakthrough bleeding, stop 3 days and restart or give in 24/4 fashion for predictable bleeding each month.

Ovulatory Bleeding

DMPA (Depo Provera) Dose 150-250mg IM every 2-3 months Disadvantage- high incidence of irregular

bleeding

Ovulatory Bleeding

GnRH agonists (Lupron) MOA: inhibits ovulation and ovarian steroid

productions, inducing amenorrhea Dose: 3.75mg IM every month or 11.25mg IM

every 3 months Often benefits short term for induction of

amenorrhea and to correct severe anemia Consider simultaneous norethendrone 5mg/d

Disadvantage to long term use Expense Hypoestrogenic state- need for add back for

prevention of side effects

Ovulatory Bleeding

Antifibrinolytics (Tranexamic Acid- Lysteda)

Approved by the FDA in the US in 2009 for tx of heavy menstrual bleeding

Commonly used throughout the world (OTC in some countries)

Effective in reducing menstrual blood loss (50%)

Concern about thromboembolic events has not been substantiated in recent studies

Ovulatory Bleeding

Progestin IUD (mirena) Effective in reducing mean blood loss Approved by FDA for treatment of heavy

menstrual bleeding october 2009 80-90% report reduction in blood loss after

6 months, approx 30% amenorrheic

DUB and Fibroids

NSAIDs Combination OCPs Oral progestins DMPA Dnazol GnRH agonists Antifibrinolytic agents Medicated IUDs Selective Progesterone Receptor Modulators Antiprogestational agents Aromatase inhibitors

Procedures/Surgery

Endometrial Ablation Hysteroscopic resection/ablation Non-hysteroscopic ablation

Uterine Artery Embolization Hysterectomy

Key Points

Many patients are progesterone deficient Most endometrial cancer is preventable Anovulatory bleeding is easy to treat with

low dose cyclic progestins Ovulatory bleeding can be difficult to treat

(high dose progestins) unless patients can take continuous OCPs or use Mirena

If acute, profuse bleeding, consider high dose progestin therapy

Conclusions

Most DUB can be medically managed- today we have more options

Endometrial ablation/resection offers an alternative to hysterectomy

Most endometrial cancer is preventable- must identify those at risk and TREAT!!! (biopsy first)

THANK YOU