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Cruz, Rivera, Tai, Veloso. ABNORMAL UTERINE BLEEDING. 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

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ABNORMAL UTERINE BLEEDING

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Cruz, Rivera, Tai, Veloso

ABNORMAL UTERINE BLEEDING


  • 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 - intervallonger 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 nongravidwomen 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 (Livioet.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-aminomethylbenzoicacid (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 methylergobaseimmaleate


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 mefenamicacid but side effects were more severe with Danazoland 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 GnRHagonists (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 hemodynamicallycompromised)

    * not dependent on whether the patient is anovulatoryor ovulatory

  • Estrogenwill 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


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