Abnormal Uterine

Bleeding Menopause

FEU-NRMF Medical Foundation, Department of Obstetrics and Gynecology Gynecology: Abnormal Uterine Bleeding, School Year 2009-2010

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Learning Objectives
1 2

Characterize normal menstrual flow. Describe the hemostatic mechanism in normal menstrual flow. Recognize the different forms of AUB given cases. Enumerate the different organic cause of AUB Diagnose ovulatory and anovulatory DUB Elaborate on the appropriate management of DUB

3 4 5 6 7

Rationalize the use of surgical therapy in DUB

FEU-NRMF Medical Foundation, Department of Obstetrics and Gynecology Gynecology: Abnormal Uterine Bleeding, School Year 2009-2010

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Clinical guidelines for normal menstruation

Normal values 28 7 days 4 (up to 7) days Menstrual blood 35 ( 55 to 60) loss ml Average iron loss 16 mg per menses Cycle length Duration of flow

March CM, Brenner PF. In Lobo RA, et al, eds. Mishells Textbook of Infertility, Contraception, and Reproductive Endocrinology, ed 4, Blackwell Science, 1997

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Normal Hemostatic Mechanism in menstruation

1 2 3 4 5 Localized vasoconstriction PGF2 in the basalis layer Platelet adhesion Thromboxane Formation of a platelet plug Functional endometrium Reinforcement of the plug Removal of coagulated material Fibrin Fibrinolysis

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Normal Hemostatic Mechanism in menstruation

Normal ovulatory women Women with DUB (Ovulatory and anovulatory) Endometrial PGF2/PGE2 ratio steadily increasing from midcycle to menses. Alterations in prostaglandin synthesis and release occur in women with both anovulatory and ovulatory DUB. Why these changes occur and their exact causal relation with menorrhagia have not yet been determined. 1 Low levels of PGF2 2 decreased PGF2/PGE2 ratio

Women with ANOVULATORY DUB

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

What are the role of hormones?

Estrogens Estradiol stimulates synthesis of prostaglandins from arachidonic acid by cyclic endoperoxides, thus, PGE2 are normal because estrogen is normal. Progesterone necessary to increase levels of arachidonic acid, the precursor of PGF2. With the absence of progesterone in anovulatory cycles, PGF2 lower. Decreased levels of PGF2 could cause heavier or more prolonged bleeding.

Progestogens

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

In women with OVULATORY DUB, menorrhagia is associated with:

1 2 3 4 5 reduced uterine synthesis of PGF2 increase in synthesis of PGE2 and prostacyclin increase in PGE receptor in the myometrium decreased thromboxane in the endometrium greater amount of phospholipase C in the endometrium

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

FORMS of Abnormal Uterine Bleeding:

Infrequent episodes

Frequent intervals
Excessive Flow Prolonged duration Intermenstrual bleeding

Amenorrhea Oligomenorrhea Metrorrhagia Polymenorrhea Menorrhagia Menorrhagia Menometrorrhagia

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

State the two major types of abnormal uterine bleeding.

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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Two Types of ABNORMAL UTERINE BLEEDING

Abnormal uterine Any form of bleeding that is irregular in amount, duration, or timing, and not bleeding (AUB)
related to regular menstrual bleeding

Dysfunctional uterine bleeding (DUB)

Subset of AUB
Irregular bleeding in the absence of organic pathology (genital or extragenital) To diagnose DUB, all other forms of AUB must be ruled out

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Discuss AUB as to: a. Organic cause b. Dysfunctional causes

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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ORGANIC CAUSES of AUB:

Systemic Diseases
Blood coagulation
Von Willebrands Disease Platelet deficiency Prothrombin deficiency

Leukemia
ITP Severe sepsis Hypersplenism

Hypothyroidism Hyperthyroidsm Cirrhosis

Menorraghia
Oligomenorrhea, amenorrhea

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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ORGANIC CAUSES of AUB:

Reproductive tract Diseases
Complications of pregnancy
Abortion Ectopic gestation Retained products of conception

Placental polyp
Trophoblastic disease Leiomyomata uteri Polyps Adenomyosis and endometriosis Endometritis, salpingitis, cervicitis Traumatic lesions Foreign body Cervix, endometrium, tube, ovary, vagina, vulva Precancer: endometrial hyperplasia

Benign pelvic lesions

Malignant pelvic lesions

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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ORGANIC CAUSES of AUB:

Iatrogenic Causes
Oral and injectable steroids
Contraception HRT Dysmenorrhea

Hirsutism/acne
endometriosis

Tranquilizers and psychotropic drugs

Digitalis Dilantin LNG-IUS

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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DIAGNOSIS OF AUB:
1 2 3 Thorough history. Indirect assessment of MBL. Hemoglobin concentration,
serum iron levels, and serum ferritin levels.

Other laboratory tests if necessary: a hCG determination

b c d
e f g

TSH and Prolactin Screening for coagulation defects Document ovulation: Serum progesterone, endometrial biopsy Pelvic sonography Investigate endometrial cavity: Hysteroscopy or SIS Dilatation and curettage
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AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

After organic, systemic, and iatrogenic causes for the AUB are ruled out, the diagnosis of DUB can be made
AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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Two Types of DYSFUNCTIONAL UTERINE BLEEDING

Anovulatory Ovulatory

Predominant cause of DUB in the postmenarcheal and premenopausal years

90% of cases
Ovulatory DUB occurs most commonly after the adolescent years and before the perimenopausal years. 10% of ovulatory women

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Anovulatory DUB: Pathogenesis

Premenarcheal girls Premenopausal women
Estradiol rise not followed by LH surge Indicates absence of positive feedback due to HPO immaturity. Lessened capacity to secrete estradiol leads to abnormal LH surge Indicates defect in follicular maturation (dysfolliculogenesis)

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Anovulatory DUB: Pathogenesis

Anovulation is key pathophysiologic mechanism
No corpus luteum No progesterone Continous estradiol production Continuous endometrial proliferation Endometrium outgrows its supply Necrosis Disorganized sloughing Excessive uterine bleeding

March CM, Brenner PF. In Lobo Ra, et al, eds. Mishells Textbook of Infertility, Contraception, and Reproductive Endocrinology, ed 4, Blackwell Science, 1997
AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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What is the appropriate management for patients presenting with AUB?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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MANAGEMENT of ABNORMAL UTERINE BLEEDING

Organic cause Endocrine/ Dysfunctional cause Identify and treat Medical therapy
Estrogens Progestogens NSAIDs Anti-fibrinolytic

COCs
LNG-IUS GnRH analog

Ergot
Danazol

Surgical management

Dilatation and curettage Endometrial ablation Hysterectomy

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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DUB: Summary of Approach to patient

Treat Acute bleeding episode
High dose estrogens Combined Oral contraceptives High dose progestogens Adolescent: cyclic progestin Reproductive age: COCs or Clomiphene Citrate Perimenopausal: Low dose COCs Progestins

Prevent Recurrence Anovulatory (Long-term Management) Ovulatory

LNG-IUS
NSAIDs Antifibrinolytic agents Ergot

Androgenic Steroid (Danazol)

GnRH analogs

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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ASSIGNED READING: Discuss the following medical therapeutic options in AUB:

a. b. c. d. e. f. g. Estrogen Progestins NSAIDs Anti-fibrinolytic agents Ergot alkaloids Androgenic steroids (Danazol) GnRH agonist

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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ESTROGENS for DUB

Rationale
Estrogen in pharmacologic dose causes rapid growth (healing) of endometrium

To stop acute bleeding Followed by

CEE (conjugated equine estrogens) oral 10-20 mg/d in divided doses or CEE IV 25 mg every 2-4 h for 24 h CEE oral 10 mg/d for 21-25 days and Progestins for last 7-10 days or CEE oral in decreasing dose for 3 weeks and Progestins for last 7-10 days
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AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Can I use it for long-term treatment?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Is IV estrogen better than Oral?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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Will the thickness of the endometrium affect patient response to estrogen?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Is high dose estrogen SAFE for all women to stop acute bleeding?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Combined oral contraceptives for DUB

Combined OCs
Use OCs with 50 g ethinylestradiol per tablet

To stop acute bleeding For longterm treatment

OC 4 tabs/d continued for 5-7 days tapered to 1 tab/d over 21 days OC 1 tab/d for 21 days, rest 7 days, for 3 cycles or longer

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Combined oral contraceptives for DUB

Regimen for LOW dose monophasic COC

Day
1-2 3-4 5-19 20-25 26

Frequency 1 tab 4x a day 1 tab 3x a day One tab daily Expect menses Start COC at standard dosage

Tomasso Falcone, William Hurd, Clinical Reproductive Medicine and Surgery, Mosby, Philadelphia, 2007

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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PROGESTINS for DUB

Rationale
Stimulate arachidonic acid formation and increase PGF2/PGE ratio Stop / limits endometrial growth post-ovulation Organize the enodometrium to allow universal sloughing Reverses of hyperplasia
Stimulates 17OHSD & sulfotransferase (converts estradiol to estrone) Estrogen receptor replenishment inhibition Suppresses estrogen-mediated transcription of oncogenes (Anti-mitotic, anti-growth)
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Molecular mode of action: Anti-estrogen

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

Is it more effective than estrogen?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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PROGESTINS for DUB

Acute Bleeding For long-term treatment
Not effective for acute bleeding Warranted for long-term treatment MAINSTAY for opposing the effects of estrogen in anovulatory women
Progestin therapy does not interfere with the normal resumption of ovulatory cycles.

Adverse effects

Fatigue, mood changes, weight gain, lipid changes

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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PROGESTINS for Anovulatory DUB

Progestogens
Norethisterone 5 mg
Medroxyprogesterone acetate

Brand name Dose

10 mg BID day 11 25 of cycle

Dydrogesterone 10 mg Duphaston

Primolut N
Provera

5 15 mg/d on day 1625

10 mg/d for first 10 days each month

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Adolescent anovulatory patient: Ideal model for progestogen use Additional diagnostic tests necessary

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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For women who wants to be pregnant, clomiphene citrate is the most ideal agent.

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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For peri-menopausal women especially those who needs contraception. How about those with no sexual partner?
Abnormal histologic findings should be ruled out

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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PROGESTINS for Ovulatory DUB

Progestogens
Norethisterone 5 mg Medroxyprogesterone acetate

Brand name Dose

10 mg BID day 5 25 of cycle

Dydrogesterone 10 mg Duphaston

Primolut N Provera

5 15 mg/d on day 5-25

5-10 mg TID days 5-25 month

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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NSAIDs for DUB

Non-Steroidal AntiInflammatory Drugs:
Mode of Action NOT CLEAR

Prostaglandin synthase inhibitors

inhibit the biosynthesis of cyclic endoperoxides endoperoxides convert arachidonic acid to prostaglandins

Block the action of prostaglandins by interfering directly at their receptor sites

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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NSAIDs for DUB

DOSE:
Continued only for 3 days

Mefenamic acid 500 mg TID Ibuprufen 400 mg TID

Meclofenamate 100 mg TID sodium Naproxen sodium Loading dose: 550mg then 275 mg q 6 hours

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Anti-fibrinolytic agents for DUB

Potent inhibitors of fibrinolysis
Epsilon-aminocaproic

Epsilon-aminocaproic acid (EACA) 18 g/d for 3 days, then 12, 9, 6, and 3 g/d on successive days

Tranexamic acid

Tranexamic acid (AMCA) 6 g/d for 3 days, then 4, 3, 2, and 1 g/d on successive days

PAMBA (paraaminomethylbenzoic acid)

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Anti-fibrinolytic agents for DUB

Potent inhibitors of fibrinolysis
Epsilon-aminocaproic

Reduce menstrual blood loss in ovulatory patients by 50% Best combined with OCs or progestins There has been a reluctance to prescribe tranexamic acid due to possible side effects of the drugs such as an increased risk of thrombogenic disease (deep venous thrombosis). Side effect: nausea, dizziness, diarrhea, headaches, abdominal pain, allergic manifestations

Tranexamic acid

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Ergot Androgenic steroids for DUB

DANAZOL
Doses of 200-400 mg/d given for 12 weeks Reduced menstrual blood loss from >200 ml to <25 ml over 12 weeks More effective than mefenamic acid

Adverse androgenic effects, weight gain, acne

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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GnRH agonists for DUB

Rationale Dosage
Induce medical menopause Depot preparations (Zoladex, Lupron)
IM every 28 days for 3-6 months

Use limited by expense and side effects

Reserved for heavy bleeders unresponsive to other medical therapy and desirous of future fertility Add-back hormone replacement therapy to prevent bone loss with prolonged therapy

Effects

Menstrual blood loss reduced from 100-200 ml to 0-30 ml per cycle

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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Describe the following surgical procedures in the management of AUB. Give the indications and complications of each procedure.
a. b. c. d. Dilatation and Curettage Endometrial Ablation Hysteroscopy Hysterectomy

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

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AUB: Surgical Management

Dilatarion and curettage Endometrial Ablation
Acute bleeding resulting in hypovolemia. Older women (usually older than 35) who are at higher risk of having endometrial neoplasia. Women with severe menorrhagia who have medical contraindications against performing a hysterectomy Women with ovulatory DUB who do not wish to take medications.
Electrosurgical ablation (loop, roller ball or bar) Laser ablation (Nd:YAG) Microwave endometrial ablation (MEA) Thermal balloon therapy (Cavaterm, Thermachoice) Bipolar vaporization (Versapoint) Cryosurgical ablation (First Option Uterine System) Photodynamic therapy (PDT)

Hysterectomy

Should only be used to treat persistent ovulatory DUB after all medical therapy has failed
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AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009

For this patient, what is the most appropriate surgical management?

AUB/DUB, FEU-NRMF Department of Obstetrics and Gynecology, 2009
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