Abnormal uterine bleeding in - PowerPoint Presentation

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Abnormal uterine bleeding in reproductive-aged women : medical management

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Slide3

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(AUB) is a common clinical problem, affecting up to

14% of women during their reproductive years and impairing their

quality of life by creating

significant

physical

, emotional, sexual, social,

and financial burdens

.Prevalence:20 million office visits/year25% of visits to gynecologists

Abnormal uterine bleeding

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Perception of menstrual bleeding

Actual Menstrual Blood Loss Per Cycle

Hallberg

, L et al,

G. Acta Obstet Gynecol Scand

1966;45:320-51.

Menorrhagia

: Perception vs. Reality

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The normal interval is 21 to 35 days

. The normal duration of bleeding

is 1 to 7 days

.

The amount should be less than

1 pad or tampon per 3-hour period

with

cycle-to-cycle variation over 12 months of 2 to 20 days.The duration of the follicular phase is highly variable, ranging from 10.3 to 16.3 days

, whereas the

luteal phase remains fairly constant at

amean

of 14.13 days .Cycle length varies most during the years immediately succeeding menarche (age <20 years) and during the perimenopausal transition (age >40 years) because these age ranges have the highest prevalence of anovulatory cycles. Vaginal Bleeding

…What’s Normal?

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Severe acute bleeding: Bleeding that requires more than one pad/tampon per hour or vital signs indicating hypovolemia.

Irregular bleeding:

Includes

metrorrhagia

,

menometrorrhagia

,

oligomenorrhea, prolonged bleeding, intermenstrual bleeding, or other irregular pattern. Menorrhagia: Heavy but regular cyclic bleeding plus 7 days of bleeding or clots or iron deficiency anemia.

Prolonged bleeding 12 days should be considered irregular regardless of cyclic pattern.

Vaginal Bleeding

…

What’s abnormal

?

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Vaginal Bleeding

Fifty percent

of the endometrial

lining is

shed during the

first 24 hours

of

menstrual flow.

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Vaginal Bleeding

Vasoconstriction

of

the denuded

spiral arterioles

in the basal

layer of the endometrium (and, potentially, the radial arteries in the surface of the myometrium) brings about the end of menses.

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Vaginal Bleeding

Endothelins

and prostaglandins

are

highly concentrated

in the

endometrium and are responsible for the intense vasoconstriction of the spiral arterioles that leads to the cessation

of bleeding.

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The cause of AUB in ovulatory women with AUB is the dysregulation of the hemostatic and vasoconstrictive

capabilities of the endometrial lining.

There is

a rise

in the

total prostaglandin (PG

) production

, with a significant increase in PGE2 (promoting vasodilation) as well as a rise PGF2 (an inhibitor of platelet

aggregation)

receptors.

Vaginal Bleeding

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Focused assessment of abnormal uterine

bleeding :

History

1

.

Bleeding pattern

Quantity, frequency of changing pads or tampons, presence of clots, timing during menstrual cycle, impact on quality of life

2.

Symptoms of anemia

Headache, palpitations, shortness of breath, dizziness, fatigue,

pica

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Focused assessment of abnormal uterine

bleeding :

History

3

. Sexual and reproductive history

Use of contraception, sexually transmitted infections, cervical screening, possibility of pregnancy, desire for future pregnancy, known infertility

4. Associated symptoms

Fever, chills, increasing abdominal girth, pelvic pressure or pain, bowel or bladder dysfunction, vaginal discharge or odor

5.

Symptoms associated with a systemic cause for AUB

Overweight, obesity, PCOS, hypothyroidism, hyperprolactinemia, hypothalamic or adrenal disorder

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Focused assessment of abnormal uterine

bleeding :

History

6

. Chronic medical illness

Inherited bleeding disorders (coagulopathy, blood

dyscrasias

, platelet functional disorders), systemic lupus erythematosus or other

connective tissue

diseases, liver disease, renal disease, cardiovascular disease

7. Medications

Hormonal contraceptives, anticoagulants, SSRIs, antipsychotics, tamoxifen, herbals (eg, ginseng)8. Family historyCoagulation or thromboembolic disorders, hormone-sensitive cancers

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Vital signs: blood pressure, pulse, orthostatics as clinically indicated, weight, BMI

Neck: thyroid examination

Abdomen:

tenderness, distension,

striae

, palpable mass, hepatomegaly

Skin:

pallor, bruising, petechia, signs of hirsutism (male hair pattern distribution, acanthotis nigricans) Pelvic examination/inspection: vulva, vagina, cervix, anus, and urethra

Bimanual examination of uterus and adnexal structures

Rectal examination

if bleeding from rectum suspected or risk of concomitant pathology

Testing: Papanicolaou smear, cervical cultures if risk for sexually transmitted infectionPhysical examination

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Laboratory

Beta

hCG

Complete blood count with

platelets

Other

laboratory testing as clinically indicated

TSH Free testosterone Prolactin PTT/PT/fibrinogen or thrombin time or von Willebrand diagnostic panel Imaging

TVS or SIS

Office endometrial sampling (as clinically indicated)

Office hysteroscopy (as clinically indicated)

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Women who should undergo evaluation for endometrial hyperplasia or endometrial cancer

Abnormal uterine bleeding

•

Postmenopausal women

– Any uterine bleeding, regardless of volume (including spotting or staining). Further evaluation of a sonographic finding of an endometrial thickness >4 mm (even if the patient has no uterine bleeding).

•

Age 45 years to menopause

– Any abnormal uterine bleeding, including intermenstrual bleeding in women who are ovulatory. Abnormal uterine bleeding in any woman that is frequent (interval between the onset of bleeding episodes is less than 21 days), heavy (total volume of >80 mL), or prolonged (longer than seven days).

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Younger than 45 years – Abnormal uterine bleeding that is persistent, occurs in the setting of a history of unopposed estrogen exposure (obesity, chronic anovulation) or failed medical management of the bleeding

, or in women at high risk of endometrial cancer (

eg

, tamoxifen therapy, Lynch syndrome, Cowden syndrome

).

• In addition, endometrial neoplasia should be suspected in premenopausal women who are

anovulatory

and have prolonged periods of amenorrhea (six or more months). Cervical cytology results• Presence of atypical glandular cells (AGC)-endometrial. • Presence of AGC-all subcategories other than endometrial – If ≥35-years-old OR at risk for endometrial cancer (risk factors or symptoms). • Presence of benign-appearing endometrial cells in women ≥40 years of age who also have abnormal uterine bleeding or risk factors for endometrial cancer.

Other indications

• Monitoring of women with endometrial pathology (

eg

, endometrial hyperplasia). • Screening in women at high risk of endometrial cancer (eg, Lynch syndrome).

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Munro MG, et al, FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age, Int J Gynecol Obstet (2011)

Structural

Non-Structural

FIGO System for AUB, 2011

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Causes Immature HPO axis, PCOS

, obesity, inherited bleeding disorder

Management

Acute AUB

:

parenteral estrogen

HMB:

1. Low-dose combination hormonal contraceptive (20-35 mg ethinyl estradiol)2. Weight

loss

Medical treatment of

AUB based

on age groupsAge groups :13-18 y

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Causes PCOS, obesity, premalignant

or malignant endometrial pathology (if risk factors are present)

Management

Acute

AUB

:

1. Parenteral estrogen

2. Multidose oral progestinsHMB:1. Cyclic or continuous low-dose combined hormonal contraceptive2.

Progestins

including LNG-IUS

3. Weight loss

Medical treatment of AUB based on age groupsAge groups :19-39 y

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Causes Intermittent anovulation

, premalignant or malignant endometrial pathology

Management

Acute

AUB

:

Multidose

progestin-only regimenHMB:1. Cyclic progestin therapy2. LNG-IUS3. Cyclic combined hormone therapy4. Weight loss

Medical treatment of

AUB based

on age groups

Age groups :40 y to menopause

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Hormonal therapies

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Dienogest/estradiol valerate (

Natazia) is

the only combination OC that

was approved

by the US Food and

Drug Administration

(FDA) for the

treatment of HMB (March 2012). Hormonal therapies

Estrogen and progestin

contraceptives

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Hormonal therapies

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RegimenAcute: monophasic pill 35

mg estradiol 3 times daily

for 1

week

, then daily dosing

for 3

wks

HMB: cyclic oral contraceptive pills, extended or continuous monophasic oral contraceptive pill, transdermal patch or vaginal ring

Efficacy

High

Combined contraceptives

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Combined contraceptives

Contraindications

Pregnant

,

smoking

(aged35

years and

15 cigarettes/d),

history of

malabsorptive

bariatric surgery,multiple risk factors for arterial cardiovascular disease (ie, older age, smoking, diabetes, and hypertension), hypertension (systolic 160 mm Hg or diastolic 100 mm Hg)active or previous venous or arterial thromboembolic disease,known thrombogenic mutations,current or past ischemic

heart disease, stroke, Complicated valvular heart disease,SLE with vascular disease, nephritis, or antiphospholipid antibodies,headaches with aura, current or past history of breast cancer, diabetic nephropathy, retinopathy, neuropathy, or diabetes for > 20 y,liver cirrhosis, or tumor

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Side effectsSpotting,

nausea,headache,

Breast tenderness

,

breakthrough bleeding,

VTE,

stroke,

MIContraceptionYes

Combined contraceptives

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Intravenous (IV) conjugated equine estrogens (CEE) were approved by the FDA in November 2009 for the treatment

of acute AUB

.

High-dose

estrogen

quickly treats

acute AUB

by:causing rapid growth of the endometrial epithelium and stroma;stimulating vasospasm of uterine arteries;

promoting

platelet

aggregation

and capillary clotting; increasing fibrinogen, factor V and factor XI;increasing the production of both estrogen and progesterone receptors.Parenteral estrogen

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Parenteral administration of CEE led to the cessation of uterine bleeding in 72% of patients

, compared with 38%who received placebo,

even with the

presence of uterine pathology such

as polyps

, hyperplasia, and endometritis

.

In hemodynamically unstable women with acute AUB, a 25 mg dose of IV CEE can be administered every 4-6

hours

for up

to 24 hours, followed by

progesterone alone or a combination OC for 10-14 days. Patients should receive CEE for no longer than 24 hours before transitioning to OCs to reduce the duration of exposure to unopposed estrogen.

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Regimen

Acute: 25 mg IV every 4-6 h for 24 h

Efficacy

High

Contraindications

Pregnant,

active or previous venous or arterial thromboembolic disease,

breast cancerUse with caution in obese women

Conjugated equine estrogen

Side effects

Spotting, nausea,

headache, breasttenderness,breakthrough bleeding,VTE, stroke, MIContraceptionNo

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Ovulatory status determines the regimen for oral progestin use.

For example, in women with ovulatory

AUB

,

oral MPA (

2.5-10 mg

daily), norethindrone (2.5-5 mg daily), megestrol acetate (40-320 mg daily),

or micronized

progesterone (

200-400 mg daily)

taken cyclically (starting on menstrual day 5 for 21 days) or continuously provides cycle control and reduction of menstrual blood loss. The use of a luteal-phase progestin alone has not proved to be successful in the treatment of ovulatory HMB.Oral

progestins

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In women with anovulatory bleeding, a cyclic progestin (

ie, MPA, norethindrone

, or

norethisterone

), given

for

12-14

days each month, leads to regulation of the menstrual cycle in 50% of women. In patients presenting with acute

AUB

, a

multidose

progestin (ie, MPA 20 mg 3 times daily for 1 week, followed by daily dosing for 3 weeks) can significantly reduce menstrual blood loss.Oral progestins

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RegimenAcute: MPA 20 mg 3

times a day for 7 days

HMB

:

oral MPA (

2.5-10

mg

), norethindrone (2.5-5 mg),megestrol acetate (40-320 mg), or micronized progesterone (200-400

mg

)

Without

ovulatory dysfunction, take 1 tablet daily starting day 5 for 21 d With ovulatory dysfunction, take 1 tablet daily for 2 wks every 4 wksEfficacyHighOral

progestins

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ContraindicationsPregnant,

history of malabsorptive

bariatric

surgery

,

liver disease

or tumor, breast cancer, current or past ischemic heart diseaseSide effectsIrregular bleeding

Contraception

No

Oral

progestins

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Progestational agents are an ideal alternative for women who have a contraindication to

estrogen.

Progestogen-only formulations

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stabilizing endometrial fragility;

inhibiting the growth of the endometrium by

triggering apoptosis

;

inhibiting angiogenesis

;

stimulating the conversion of estradiol to the less active estrone. prevents ovulation and ovarian steroidogenesis

,

interrupting

the production of

estrogen receptors and the estrogen-dependent stimulation of the endometrium, leading to an atrophic endometrium.Progesterone quickly treats AUB by

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Regimen

HMB: intrauterine placement every 5 y, releases 20 mg/d

Contraindications

Pregnant

,

unexplained

abnormal vaginal bleeding, untreated cervical or uterine cancer, large or distorted cavity should sound to a depth of 6 -10

cm

,

breast cancer, cervix or uterus abnormalities, Pelvic inflammatory disease within 3 mo,STI such as chlamydia or gonorrhea within 3 mo, liver disease or tumorLNG-IUSSide effects

Irregular bleeding and spotting, cramping,breast tenderness, Mood changes, acne, nausea,decreased libido

Contraceptionyes

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RegimenHMB: 150 mg IM injection

every 12 wks

Efficacy

:

Low

Contraindications

Pregnant,

multiple risk factors for arterial cardiovascular disease (ie, older age, smoking, diabetes, and hypertension), current or past ischemic heart disease,

stroke,

hypertension with vascular

disease,CAD, CVD, current or previous history of breast cancer, Liver disease or tumoraDMPA

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Side effectsDecreased bone

mineral density, irregular (

reversible) bleeding,

weight gain,

amenorrhea

,

bloating

, breast tenderness, and fluid retentionContraceptionyes

DMPA

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Danazol is a synthetic steroid ethisterone

Danazol

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RegimenHMB:

100-400 mg orally daily (in divided doses)

Efficacy :

Low

Contraindications

Pregnant,

unexplained vaginal bleeding, impaired hepatic, renal, or cardiac function

Side

effects

Weight gain

, acne,androgenic effectsContraceptionNoDanazol

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GnRH

agonists

Atrophy

and amenorrhea usually occur among premenopausal women within

3-4 weeks

of the drug’s administration.

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RegimenHMB: 3.75 mg IM monthly or 11.25

mg IM every 3 mo

Efficacy

: High

Contraindications

: Pregnant

Side effects

Hot flashes, sweating, and vaginal dryness (effects minimized with add-back

therapy

with estrogen

and

progestins),trabecular bone loss with use for longer than 6 mo (reversible)ContraceptionNoLeuprolide acetate

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Nonhormonal

therapies

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Because prostaglandin E2 and prostaglandin F2 are highly concentrated

at the menstrual endometrium in women with HMB

,

treatment

with an

NSAID increases

thromboxane A2

, thereby increasing platelet aggregationNSAID may reduce blood loss by as much as 40%.

Nonsteroidal

anti inflammatory

drugs (NSAIDs)

PGFPGE2

TXA2 vasoconstriction and platelet aggregation vasodilation and prevents platelet aggregation

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Regimen

HMB: Meclomen: 100 mg 3 times daily

Ibuprofen 600-800 mg

every 6-8

h,

Efficacy

: Moderate

ContraindicationsPregnant, gastrointestinal bleeding,inflammatory bowel disease,

Severe asthma,

use after CABG procedure,

renal disease, CVD, CHFSide effectsGastrointestinal adverse effects (bleeding, ulceration, and perforation), worsening of

asthma, effect on platelet functionContraceptionnoNSAIDs

Slide48

Endometrial plasminogen activators

and

L

ocal

fibrinolytic activity

Slide49

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

; an IV formulation is approved for use in hemophilia

.

This

medication works

by

competitively

blocking plasminogen binding sites, preventing plasma formation, fibrin degradation

,

and

clot degradation.

Tranexamic acid

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Regimen

Acute: 1.3 g orally every 8 h for 5 d (indicated in

ovulatory

women

with

excessive menstrual

bleeding)

Efficacy : HighContraindicationsCurrent or past thromboembolic disease,

acquired

impaired

color vision

(cannot be used with combined oral contraceptives)Side effectsHeadachesnausea,vomiting,

diarrhea,muscle pain,dysmenorrheaContraceptionNoTranexamic acid

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This drug, a synthetic analog of vasopressin, promotes the release of

von Willebrand

factor

from endothelial

cell storage

sites

.

It is used to treat patients with bleeding disorders, notably, von Willebrand’s disease, during episodes of acute AUB.

It should be utilized

only when

all other hormonal and nonhormonal therapies have failed. Collaboration with a hematologist is strongly encouraged before treatment of AUB with desmopressin.Desmopressin

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It is important to select medical therapy by fully assessing the patient’s medical history, age, desire

for fertility, and risk factors.

The

ultimate goal

in the management of AUB

is:

to identify the cause and prevent recurrence,to create a long-term clinical plan, to prevent and treat anemia,to treat

underlying systemic or

anatomic causes

,

to decrease unnecessary surgical intervention, to improve a woman’s quality of life.Conclusion

Slide53

Thanks for your attention

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AVB: Presentation-based Management

History and physical examination

Rule out pregnancy

Determine bleeding pattern

Severe acute bleeding

Irregular bleeding

Menorrhagia

Contraceptive method (oral contraceptive pill (OCP), depo-medroxyprogesterone, IUD)

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Orthostatic hypotension ? Hemoglobin <10 g/dL

?

Profuse bleeding ?

Severe acute bleeding (not pregnant)

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Orthostatic hypotension or hemoglobin <10 g/dL or profuse bleeding.

Admit to the hospital. Premarin

25 mg IV q4 hours × 24 hours

+

25 mg of promethazine PO or IM or per rectum every 4 to 6 hours

as needed for nausea.

Dilation and curettage (D&C) if no response

after 1 to 2 doses of Premarin. Transfuse if hemoglobin <7.5 g/dL.

Severe acute bleeding (not pregnant)

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Orthostatic hypotension or hemoglobin <10 g/dL or profuse bleeding.

Simultaneous with IV Premarin, start

LoOvral

, 1 active pill QID × 4d, TID × 3d, BID × 2d, QD × 3 weeks, then one week off, then cycle for at least 3 months.

If OCP contraindicated,

cycle 10 mg of Provera for 14 days, off 14 days, on 14 days, and so on for at least 3 months.

Obtain TVUS, TSH, complete blood cell count (CBC), platelet count, prothrombin time, activated partial thromboplastin time, and platelet function analysis.

Start oral iron.

Severe acute bleeding (not pregnant)

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No orthostatic hypotension, hemoglobin ≥10 g/dL, bleeding not profuse.

Outpatient management: 2.5 mg of

Premarin

PO QID plus 25 mg of promethazine PO or IM or per rectum every 4 to 6 hours

as needed for nausea.

D&C if no response after 2 to 4 doses of

Premarin or sooner if bleeding >1 pad/hour.

Severe acute bleeding (not pregnant)

Slide60

No orthostatic hypotension, hemoglobin ≥10 g/dL, bleeding not profuse.

After acute bleeding start LoOvral, 1 active pill QID × 4d, TID × 3d, BID × 2d, QD × 3 weeks, then 1 week off, then cycle for at least 3 months.

If OCP contraindicated, cycle 10 mg of Provera for 14 days, off 14 days, on 14 days, and so on for at least 3 months.

Obtain TVUS, TSH, CBC, platelet count, prothrombin time, activated partial thromboplastin time, and platelet function analysis.

Start oral iron.

Severe acute bleeding (not pregnant)

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TSH. Prolactin if oligomenorrhea.If more than age 35 or prolonged unopposed estrogen, obtain endometrial biopsy and consider TVUS.

Consider as a cause endometritis (tender uterus), medications (phenytoin, antipsychotics, tricyclic antidepressants, corticosteroids), advanced systemic disease, or polycystic ovary syndrome.

Irregular bleeding in

nonpregnant

patient

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If the patient does not want to achieve pregnancy, start oral contraceptive (eg, Necon 1/35) and cycle at least 3 months

. If the oral contraceptive is contraindicated, start 10 mg of Provera QD for 14 days, off 14 days, on 14 days, and so on for at least 3 months

.

If abnormal bleeding persists, offer higher dose oral contraceptive (

eg

,

Demulen 1/50) or higher dose Provera (20 mg, 30 mg, 40 mg, 60 mg, 80 mg). If abnormal bleeding persists, consider TVUS and endometrial biopsy. Contraindications to oral contraceptives include history of thromboembolic event or stroke, estrogen-dependent tumor, active liver disease, pregnancy, hypertriglyceridemia, smoking more than 15 cigarettes per day when age is ≥35.

Irregular bleeding in

nonpregnant

patient

Slide63

TSH. Hemoglobin. Consider platelet function analysis. Consider TVUS if abnormal uterus on pelvic examination.Cycle oral contraceptive (eg,

Necon 1/35).

If oral contraceptive contraindicated, 10 mg of Provera QD x 14 days, off 14 days, on 14 days, and so on for at least 3 months.

Other

options include nonsteroidal

antiinflammatory

drugs (eg, 400 mg of ibuprofen TID for 4 days, staring day 1 of menses) or no treatment. If response inadequate, obtain TVUS to identify polyps, myomas, endometrial hyperplasia, adenomyosis.

Menorrhagia in

nonpregnant

patient

Slide64

Breakthrough bleeding. If breakthrough bleeding occurs during the first 3 months, encourage continued use

. If breakthrough bleeding occurs after 3 months of use or patient requests intervention sooner, test for chlamydia and gonorrhea, ask about compliance, consider changing to higher estrogen pill (

eg

,

Necon

1/35,

Demulen

1/35, Demulen 1/50, LoOvral). If more than age 35, obtain endometrial biopsy. Amenorrhea. Rule out pregnancy.

Consider higher estrogen pill (

eg

, Necon 1/35, Demulen 1/35, Demulen 1/50, LoOvral). Or may continue same pill because endometrial hyperplasia should not develop on oral contraceptives. Oral contraceptive pill-associated bleeding

Slide65

Amenorrhea. Advise that amenorrhea or scant bleeding is expected.If unacceptable irregular bleeding and patient more than age 35 or otherwise at risk for endometrial carcinoma, do endometrial biopsy.

If less than age 35 and not otherwise at high risk for endometrial carcinoma and first 4 to 6 months of use, can encourage continued use or substitute oral contraceptive, or temporarily increase frequency of injections (

eg

, every 2 months).

If less than age 35 and not otherwise at high risk for endometrial carcinoma and after first 4 to 6 months of use, offer 1.25 mg of

Premarin

QD for 7 days.

Can repeat Premarin course if abnormal bleeding recurs. Consider other methods of contraception if bleeding persists.

Depo-medroxyprogesterone

or progesterone-only pill-associated bleeding

Slide66

Uterus tender; 100 mg of doxycycline BID for 10 days. Consider removal.First 4 to 6 months of use. Encourage continued use. Can offer NSAID (eg, 400 mg of ibuprofen TID for 4 days, starting day 1 of menses).

After 4 to 6 months of use, consider oral contraceptive for one cycle or, if copper IUD, 10 mg of Provera QD for 7 days. If unacceptable bleeding persists, consider removal.

IUD-associated bleeding

Slide67

Thanks for your attention