ABNORMAL UTERINE BLEEDING

Cruz, Rivera, Tai, Veloso

Menorrhagia - menses lasting longer than 7 days or exceeding 80 mL of blood loss

Metrorrhagia - intermenstrual bleeding.

menometrorrhagia. hypomenorrhea - diminished flow or

shortening of menses Oligomenorrhea - interval longer

than 35 days (normal 28 days ± 7 days)

• withdrawal bleeding refers to the predictable bleeding that often results from abrupt progestin cessation.

• Assessment: lack of correlation between patient perception of blood loss and objective measurement

• passing clots more than 1.1 inches in diameter and changing pads more frequently than every 3 hours

FIGO CLASSIFICATION SYSTEM FOR CAUSES OF ABNORMAL UTERINE BLEEDING IN NONGRAVID WOMEN OF REPRODUCTIVE AGE

P- Polyps

Endometrial and endocervical epithelial proliferations comprise a

variable vascular, glandular, and fibromuscular and connective tissue

often asymptomatic, but generally accepted that at least some contribute to the genesis of AUB

A- Adenomyosis

presence of endometrial tissue within the uterine wall (myometrium)

Relationship unclear

L- Leiomyoma

Benign fibromuscular tumors of the myometrium

submucosal lesions are the most likely to contribute to the genesis of AUB

M- Malignancy

Endometrial carcinoma is the most common invasive cancer of the female genital tract

Risks: obesity, diabetes, hypertension, infertility, unopposed estrogen stimulation

C- Coagulopathy

Coagulation disorders von Willebrand's disease prothrombin deficiency

Platelet deficiency leukemia, severe sepsis, idiopathic

thrombocytopenic purpura, and hypersplenism, can also cause excessive bleeding.

O – Ovulatory dysfunction

Unpredictable timing of bleeding and variable amount of flow

O - Ovulatory

absence of predictable cyclic progesterone production from the corpus luteum every 22–35 days

later reproductive years: “luteal out-of-phase” events

O - Ovulatory

Endocrinopathies polycystic ovary syndrome,

hypothyroidism, hyperprolactinemia, mental stress, obesity, anorexia, weight loss, or extreme exercise such as that associated with elite, athletic training).

E - Endometrial

predictable and cyclic menstrual bleeding, and particularly when no other definable causes are identified

E - Endometrial

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

increased local production of prostaglandin E2 and prostacyclin (vasodilators)

E - Endometrial

deficiencies in the molecular mechanisms of endometrial repair secondary to: endometrial inflammation or infection; abnormalities in the local inflammatory

response; or aberrations in endometrial vasculogenesis.

I - Iatrogenic

Gonadal steroid therapy breakthrough bleeding (BTB)

Systemically administered single-agent or combination gonadal steroids impact the control of ovarian

steroidogenesis via effects on the hypothalamus, pituitary, and/or ovary itself, and also exert a direct effect on the endometrium.

I - Iatrogenic

Poor compliance Use of anticonvulsants and

antibiotics Cigarette smoking

I - Iatrogenic

Tricyclic antidepressants and phenothiazines

Use of anticoagulant drugs (e.g. warfarin, heparin and LMW heparin)

N – Not yet classified

Chronic endometritis Arteriovenous malformations Myometrial Hypertrophy

Management

TO CUT OR NOT TO CUT?

Medical Treatment

Estrogen Progestogen NSAIDs Anti-fibrinolytics agents Danazol Gonadotropin-releasing hormone

(GnRH) agonists

Estrogen

Used for acute management of AUB Causes rapid endometrial growth

Preferred if endometrial lining is <5mm Oral Conjugated Equine Estrogen

(CEE) 10 mg/day, administered in 4 divided

doses May also promote platelet adhesiveness

(Livio et.al)

Estrogen

IV Estrogen Several hours needed to induce mitotic

activity (DeVore, et.al) No great advantage to oral estrogen

Estrogen and Progestin

Estrogen + progestin (high dose) after bleeding has stopped Most acute heavy bleeding episodes is

due to anovulation Progestin addition: Medroxyprogesterone

acetate (MPS) 10mg OD Estrogen and Progestin are given for 7-

10 days then stopped

Estrogen and Progestin

OCPs that contain estrogen and progestin Four tablets of an oral contraceptive

containing 50 μg of estrogen q 24 h in divided doses

Not as effective as high doses of CEE

Progestogen

Slows down endometrial growth by organizing and supporting endometrial tissue Organized slough to basalis layer stops

bleeding quickly Stimulates arachidonic acid formation

in endometrium Opposes effects of anovulation Menometrorrhagia – MPA 10mg/day

for 10 days monthly

Progesterone-releasing IUD

needs to be reinserted annually rapid diffusion of progesterone through

polysiloxone Levonorgestrol-releasing intrauterine

system (LNG-IUS) duration of action: more than 5 years Increases hemoglobin Decreases dysmenorrhea Reduces blood loss secondary to fibroids and

adenomyosis Good alternative to hysterectomy

NSAIDs

Ideal for decreased endometrial bleeding Stop prostaglandin pathway Allow thromboxane formation (for

platelet aggregation) NSAIDs blocks

Thromboxane formation Prostaglandin pathway

More effective in ovulating women

Curretage

If bleeding does not cease within 24 hours consider curretage

Invasive and fast For volume-depleted and anemic

patients Thick endometrium ( >10-12 mm) Anatomic problem

Antifibrinolytic Agents

Examples: ε-Aminocaproic acid (EACA), tranexamic acid (AMCA), and para-aminomethylbenzoic acid (PAMBA)

Study by Nilsson and Rybo significant reduction in blood loss after

treatment with EACA, AMCA, and oral contraceptives, and use of each of these agents resulted in about a 50% reduction in MBL

greatest reduction in blood loss with antifibrinolytic therapy occurred in women who exhibited the greatest MBL

Antifibrinolytic Agents

Preston et al AMCA reduced MBL by 45%, but there

was a 20% increase with norethindrone side effects (in decreasing order of

frequency): nausea, dizziness, diarrhea, headaches, abdominal pain, and allergic manifestations

*much more common with EACA than with AMCA

Antifibrinolytic Agents

Produce a reduction in blood loss Can be used by ovulating women with

menorrhagia Best combined with other agents like oral

contraceptives for greater effect Use limited by side effects

Mostly GI Minimized by reducing dose and use to first 3

days of bleeding Contraindications: Renal failure and

pregnancy

Antifibrinolytic Agents

Ergot – Not recommended Rarely effective High incidence of side effects: nausea,

vertigo, abdominal cramps Nilsson and Rybo no reduction in blood

loss among 82 women with menorrhagia who were treated with methylergobase immaleate

Androgenic Steroids (Danazol) MBL markedly reduced in studies

from more than 200 mL to less than 25 mL with increased interval between bleeding episodes

Most common side effects: weight gain and acne (Reduction of dosage from 400 to 200 mg daily decreased the side effects but did not alter the reduction in blood loss)

Androgenic Steroids (Danazol) Dockeray et al Danazol was more

effective in reducing MBL, 60% compared with 20% for mefenamic acid but side effects were more severe with Danazol and occurred in 75% of patients

Appears to be more effective than placebo, progestogens, oral contraceptives and NSAIDs. However, side effects were 7x greater as compared to NSAIDS and 4x more when compared with progestogens

Expensive with moderate side effects

GnRH Agonists

Possible to inhibit ovarian steroid production with GnRH agonists (not based on any large scale studies)

Due to expense and side effects, use for menorrhagia caused by ovulatory DUB limited to women with severe MBL who fail to respond to other methods of medical management and wish to retain their childbearing capacity

Will help prevent bone loss if used with an estrogen and/or progestin (add-back therapy)

Dilatation and Curettage

Can be diagnostic and is therapeutic for immediate management of severe bleeding

Markedly excessive uterine bleeding with possible hypovolemia quickest way to stop acute bleeding (Treatment of choice for hypovolemia from DUB)

Preferred to stop acute bleeding in women older than 35 (higher incidence of pathologic findings)

D&C

Rarely curative for DUB Temporary cure for chronic

anovulation removes hyperplastic endometrium but has no effect on underlying pathology

Not useful for ovulating women with menorrhagia * Nilsson and Rybo No difference or an in increase in MBL 1 month S/P D&C

D&C

Indications: Acute bleeding that results in

hypovolemia Older women (Higher risk for

endometrial neoplasia)

Otherwise: Medical therapy after ruling out organic disease via endometrial biopsy, sonohysteroscopy or diagnostic hysteroscopy

Endometrial Ablation

Laser photovaporization of the endometrium for menorrhagia Minimum endometrial regeneration Causes varying degrees of uterine

contraction, scarring and adhesion formation but complications are minor and uncommon

Erian 56% amenorrhea, 38% reduced menses, 7% no reduction requiring 2nd treatment with good response

Cochrane database preoperative GnRH agonists or danazol is beneficial

Endometrial Ablation

Laser photovaporization Nd-YAG laser (expensive) Electrocautery by urologic resectoscope

through a hysteroscope (Transcervical resection)

Magos et al 30% amenorrhea, 90% improvement in 1 treatment group

Endometrial Ablation

Thermal destruction via electrocautery through a ball-end electrode attached to a urologic resectoscope Larger contact area, better fit into cornual

area and easier contact with tissue as compared to loop electrode

Outpatient procedure with general anesthesia Preop endometrial suppresion with at least 1

month danazol, GnRH analogues or progestin Paskowitz 60% decreased bleeding Easier to learn and equipment less expensive

Endometrial Ablation

Thermal balloon Does not require pretreatment regimens

or hysteroscopy training Local anesthesia

Meyer et al Thermal balloon and rollerball – 80% return to normal bleeding

Endometrial ablation

VestaBlate new balloon device with a silicone inflatable electrode carrier

Hydrotherablator heated free fluid system Does not allow passage of fluid into fallopian

tubes May be used with endometrial distortions

including fibroids 35% amenorrhea, 87% decreased blood flow

Novasure 3D bipolar device and generator with suction

Endometrial ablation

Microwave, Cryoablation, Photodynamic therapy

Becoming more popular for women with menorrhagia without uterine lesions who are unresponsive to medical therapy

Alternative to hysterectomy (Less cost, mortality, days in hospital)

For women contraindicated for hysterectomy or those with ovulatory DUB who don’t want to take medication

Not for those who want to maintain their reproductive capacity

Endometrial ablation

Complications: fluid overload, uterine hemorrhage, uterine perforation, thermal damage to adjacent organs, and hematometria When ablation extends too deep,

opening up uterine vessels and exposing adjacent tissues to thermal injury

Endometrial ablation

Should be restricted to women with heavy MBL in the absence of organic distress

Should destroy all of the endometrium but only the superficial myometrium to reduce posttreatment problems

Suggested that the surgeon should perform 15 supervised procedures before being credentialed

Hysterectomy

Decision should be made on an individual basis

For women with other indications for hysterectomy like leiomyomas or uterine prolapse

Only for persistent ovulatory DUB after all medical therapy has failed and with excessive amount of MBL by direct measurement or that causes abnormally low serum ferritin

Hysterectomy

Levonorgestrel releasing IUD (LNG-IUS) may be beneficial when hysterectomy/ablation are being considered

Uterine artery embolization not effective unless fibroids cause excessive bleeding

Approach to Treatment

Depends on acute and chronic needs or short-term and long-term therapy

Acute bleeding

Requires immediate cessation Pharmacologic doses of estrogen or curettage

(the latter to be used more liberally in older women with risk factors or in those who are hemodynamically compromised)

* not dependent on whether the patient is anovulatory or ovulatory• Estrogen will be temporarily helpful, even if

there are abnormal anatomic findings, such as fibroids

• If pathology is suspected Curettage preferable

Acute bleeding

After the acute episode, it is imperative to know if the patient is bleeding from an anovulatory or ovulatory “dysfunctional” state

Majority of women: Anovulatory

Less significant bleeding

*Warrants treatment, but not necessitating the immediate cessation of blood loss High doses of progestogen alone

may be used (Popular practice but no good supporting data)

For Adolescents

10 mg of MPA for 10 days each month for at least 3 months should be prescribed with careful observation

Additional diagnostic studies to detect possible defects in the coagulation process, particularly if bleeding is severe

For women of reproductive age Long-term therapy depends on

whether she requires contraception, induction of ovulation, or treatment of DUB alone

DUB alone oral contraceptive or MPA can be administered, monthly for at least 6 months, whereas oral contraceptives and clomiphene citrate are used for the other indications

For the perimenopausal

*Have lower amounts of circulating estrogen Use of cyclic progestogen alone is

frequently not curative Abnormal bleeding is best treated by low-

dose oral contraceptives The cyclic use of CE (0.625–1.25 mg)

given for 25 days, with 10 mg of MPA or another progestogen + CE from days 15 to 25 can also be used after ruling out abnormal endometrial histologic findings

Ovulatory women with menorrhagia

A challenge to treat chronically No anatomic abnormalities need

long term therapy to reduce MBL NSAIDs, progestins, oral contraceptives,

danazol, and GnRH analogues are all useful

Combination of two or more of these agents is often required to obviate the need for endometrial ablation or hysterectomy