ABNORMAL UTERINE BLEEDING An overview

Mochammad Anwar Division of Reproductive Endocrinology Department of Obstetrics and Gynecology Faculty of Medicine Gadjah mada University

The nature of abnormal uterine bleeding (AUB)

The perception of menstrual bleeding varies considerebly among individual women. What is normal for one woman can be abnormal for another. The duration of menstruation also varies greatly, with an average of 5 days and the heaviest loss usually on the first 2 days. Studies designed to quantity menstrual blood loss (MBL) have demonstrated considerable inacuracy in subjective assessment of volume and womens recall of menstrual events.
(Wesley et al, 2004,: Abnormal Uterine bleeding. Am Fam Physician)

Problems in AUB
Menstrual disorders were the one of the commonest reason of women visit to physician offices for gynecologic condition. Furthermore , a reported of 25 percent of gynecologic surgeries involve abnormal uterine bleeing. Menstrual dysfunction is an important cause of ill health women.

Causes of abnormal uterine bleeding Systemic diseases Stress, exercise and nutrition Organic gynecologic pathology Medications Dysfunctional uterine bleeding (DUB)

ABNORMAL UTERINE BLEEDING

Dysfunction NON-Organic pathology Organic pathology

Systemic disease
Willebrand disease Platelet disorders Anticoagulation Hypothyroidism Hyperthyroidsm SLE Chronic lever failure

Pelvic pathology
Uterine leiomyoma Adenomyosis Endometrial polyp endometrial hyperplasia Adenocarcinoma Benign and malignant cervical disease

An-ovulatory
A primary disorder of the hypothalamic-pituitary ovarian axis

Ovulatory
A primary endometrial disorder of the molecular mechanisms

Von Willebrand disease

Is a bleeding disorder which will effect bloods abilility to clots. Low level (type-1) of certain protein (von willebrand factor/VWF) or the protein doesnt work the way it should be (type-2) or have no VWF factor (type-3). VWF also carries clotting factor VIII. It occurs in about 1 out of every 100 to 1000 people, and affects both males and females.

Blood discrasia
Idiopathic thrombocytopenic purpura (ITP)

Menorrhagie or hypermenorrhagie
Petechiae Echymosis Gastrointestinal bleeding

Thyroid disease
Although the reason is not understood, women are at a higher risk of most types of thyroid disease than men

Thyroid disease may be the cause, rather than the result of menstrual abnormalities.
(The New York Thyroid Disease Centre, 2002)

HYPOTHYROIDISM

Primary

Secondary

Tertiary Hypothalamic

disease Hashimotos thyroiditis

Thyroid

Lack stimulation by TSH

Emotional

dysfunction

conflicts

Impaired estrogen metabolism

Menstrual irregularities

HYPERTHYROIDISM

Autoimmune origin

Graves disease

Non Autoimmune origin Toxic nodular goitre or toxic adenoma

Menstrual disturbances and impaired fertility

IT IS IMPORTANT TO EXCLUDE MAJOR SERIOUS /SYSTEMIC DISEASES WHEN PRESENTED WITH AN ABNORMALITY OF THE MENSTRUAL CYCLE
(Neil Buddicom, 1989)

THE NORMAL MENSTRUAL CYCLES IS DETERMINED BY A COMPLEX INTERACTION BETWEEN REPRODUCTIVE ENDOCRINE ORGANs

HYPOTHALAMUS ANTERIOR PITUITARY GLAND OVARY ENDOMETRIUM

But the main regulation is intra-ovarian

Ovarian hormone control of the endometrium

Ovary
Follicle
Estradiol

Corpus luteum
Estradiol Progesterone

PROLIFERATIVE ENDOMETRIUM Matrix matalloproteinases (MMPs) EXPRESSED

SECRETORY ENDOMETRIUM Matrix matalloproteinases (MMPs) NOT EXPRESSED

MMPs appear to be an important role for endometrial remodeling

Matrix metaloproteinases (MMP)

MMP are a family a proteolytic enzymes that degrade components of the extra-cellular matrix and basement membrane.
Collagenases Gellatines Stromelysins

degrade interstitial and basement membrane collagens

further digest collagens,

attack fibronectine, laminin, and glycoprotein.

The key substance of the fibrinolytic system

Plasminogen
Plasminogen activator

Plasmin
Plasminogen activator inhibitor

TGF-

Overall, progesterone inhibits endometrial metalloproteinase expression, an action mediated by transforming growth factor (TGF-). TIMP

Metaloproteinase family:
Collagenases Gelatinases Stromelysins

The role of progesteron

Matrix degradation

BASIC LOCAL MECHANISMS OF MENSTRUATION

1. Changes in vascular tone of the spiral arterioles (prostaglandins). 2. Alterations of lysosomal function 3. Changes in the mechanisms of haemostasis in the uterus. 4. Regeneration of endometrium.

1. Changes in vascular tone of the spiral arterioles (prostaglandins).

Endometrial remodeling

The arterioles undergo episodic vasoconstriction and relaxation leading to endometrial ischaemia and reperfusion damage, contributing to local release of cytokines. ( Under the influence of PGF2 and Endothelin-1)

Thromboxan (platelet activation) Prostacyclin (potent anti-coagulators)

2. Alterations of lysosomal
function

Endometrial lysosomes
Endometrial lysosomes can be particularly sensitive to falling progesterone levels.

Release hydrolytic enzymes prior to the onset of menstruation, which contribute to tissue breakdown, the further release of PGs and subsequent remodeling of the tissue.

3. Changes in the mechanisms of haemostasis in the uterus.

Hemostasis prevents blood loss from damage vessels

Step -1 : Vasoconstriction, caused by vasoconstrictive paracrines released by the endothelium.
Step-2 :Temporary blockage of a break

by platelet plug

Step-3 : Blood coagulation or formation a clot

that seals the hole untill tissues are repaired.

Damage to wall of blood vessel

Collagen exposed Tissue factor exposed
Coagulation cascade

Step1 : Vasoconstriction

Platelet adhere and release platelet factors

Platelets aggregate into loose platelet plug

Thrombine formation Converts fibrinogen to fibrin

Step 2: Temporary hemostasis

Step 3 : Reinforce platelet plug (clot)

Cell growth and tissue repair

Fibrin slowly dissolved by plasmin Clot dissolves

Intact blood vessel wall

The Megakaryocytes is a bone marrow cell responsible for the production of blood thrombocytes (platelet), which is necessary for normal blood clotting.
Cytoplasm contains mitochondria, smooth endoplasmic reticulum, and many granules filled with clotting proteins and cytokins.

Platelet factor 3 (PF3) + Other factors in cloting cascade

secretes
Thrombin-induced fibrin generation is an essential part of normal blood clotting, and is stimulated in endometrium by tissue factor.

Platelet agregation

+ Enhances

Enhances

+
+

Prothrombine

Activation

Thrombine
Stimulates conversion

Activates

+
Factor XIII

+ Fibrinogen

Fibrin (loose meshwork)

Fibrin (stabilized meshwork)

Roles of Thrombin in Haemostasis

Fibrin-platelet plugs appear within the superficial vessels but not in the surrounding tissue , because of the highly active fibrinolytic mechanisms in endometrium.

PLATELET PLUG FORMATION

AUB may involve any disturbance of regularity, frequency, duration or volume of menstrual flow.
MENSTRUAL DISTURBANCES

The duration of menstrual cycle Oligomenorrhea Polymenorrhea Amenorrhea Metrorrhagia

The amount of menstrual flow Hypomenorrhea Hypermenorrhea Menorrhagia Menometrorrhagia

Oligomenorrhea

The often scanty menstrual flows occur at interval 36-90 days. Longer menstrual intervals (> 90 days) are considered to fall within the amenorrheal range. It is usually the result of hypothalamic dysfunction which is very often based upon emotional conflicts. The therapy of choice is to regulate the cycle.

POLYMENORHEA

Hypo-luteotropic Inadequate LH stimulation of the corpus luteum

Hyper-luteotropic Defective steroid biosynthesis in the corpus luteum

Inadequate progesteron production Deficient secretory preparation of endometrium The fertilized ovum is unable to implant

Polimenorrhea can be treated by the cyclic administration of an estrogen-gestagen preparation.

Hypermenorrhea

Hypermenorrhea is characterized by excessive menstrual flow with coagula, because the fibrinolytic enzymes released from the endometrium are no longer adequat to keep all the menstrual blood from clotting. Hypermenorrhea is usually the result of organic changes which interfere with hemostasis.

Hypomenorrhea

Hypomenorrhea is the term applied to scanty mentrual flow lasting only 1-2 days, and sometimes only a few hours. Hypomenorrhea is usually caused by endocrine disturbances.

Menorrhagia is the term applied to menstrual flows lasting more than 7 but less than 14 days.

ALGORITHM FOR THE MANAGEMENT OF ABNORMAL UTERINE BLEEDING Office endometrial biopsy

Abnormal

Unsatisfactory

Negative

Appropriate management

Low risk

High risk

Symptom (+) Repeated biopsi

Symptom (-) Follow

Transvaginal USG (+) (-) Follow

D&C or hysteroscopy

ENDOMETRIUM EVALUATION

Endometrial sampling

Vaginal ultrasonography

Hysteroscopy

Office endometrial biopsy. Dilatation and curettage Endocervical curretage

The endometrial stripe Is less than 5 mm thick, the risk of endometrial hyperplasia or cancer is extremely small

Allows identification of of endometrial polyps and submucosal leiomyomas

Hormonal management for Abnormal Uterine Bleeding

Oral progestins

Synthetic progestines (NET, MPA) Natural (micronized) progesterone

Levonorgestrel IUS Mirena Progesterone IUD (no longer marketed) Oral contraceptives Hormone replacement therapy Danazol GnRH analogues

Intrauterine progestins

Combinned estrogen and progestogen

Other

RAMEET H, SINGH,MD,MPH andPAUL BLUMENTHAL, MD,MPH Clin. Obstet . Gynecol, Volume 48, Number 2, 337-352, 2005

Non-steroidal anti-inflammatory drugS (NSAIDs)

Endometrial PGs are elevated in women with heavy menstrual bleeding. NSAIDs inhibit cyclo-oxygenase, reduce endometrial prostaglandins level and improve dysmenorrhea in up to 70%. Therapy should start at the first day of menses and be continued for five days or until cessation of menstruation.

Tranexamic acid
(Cyclokkapron Transamin)

It is an antifibrinolytic that competetively inhibit the activation of plasminogen to plasmin, a molecule responsible for degradation of fibrin. Fibrin is the basic frame work for the formation of a blood clot in hemostatsis. It has roughly 8 times the antifibrinolytic activity of an older analogue, eaminoacrapoic acid.

Progestines and estrogens

Progestines may be useful for women with irregular and an-ovulatory cycles when given for 12 to 14 days of each month. Progesterone impregnated intrauterine devices (IUDs) have been reported to reduce menstrual bleeding Mirena (IUS). The reduction of menstrual blood loss with combined OC is probably the result of induced endometrial atrophy.

Danazol

Danazol, a synthetic steroid with mild androgenic properties, inhibits steroidogenesis in the ovary and has a profound effect on endometrial tissue, reducing menstrual blood loss by up to 80 percent. The most common complaints was weight gain of two to six pound in 60 percent of pasient. The recommended treatmen is 100 to 200 mg daily for three months.

GONADOTROPHIN AGONISTS

GnRH-a induced a reversible hypo estrogenic state, and effective in reducing blood loss in perimenopausal women, but are limited by their side effects, including hot flahes and reduction of bone density.

summaries

Abnormal uterine bleeding is a common but complicated clinical presentation,since the perception of menstrual bleeding varies greatly amongst individual women. In women of child-bearing age, abnormal uterine bleeding includes any change in menstrualperiod frequency or duration, or amount of flow, as well as bleeding between cycles. In those who are at low risk for endometrial cancer may be assessed initially by transvaginal ultrasonography, but for those of high risk, the initial evaluation includes endometrial biopsy, saline-infusion sonography (SIS) or hysteroscopy.

ABNORMAL UTERINE BLEEDING

NON-ORNGANIC PATHOLOGY Blood vessels : Microcirculation, thrombocytopenia, primary coagulation disorder, blood vessel rupture Hormone therapy HRT and hormonal contraception Systemic disease Hypo and Hyperthyroid, hyperprolactinemia, Cushing syndrome

ORGANIC PATHOLOGY

DYSFUNCTION

Pathology of cervix, uterine, tube and ovary :

Anovulatory cycle 90%

ovulatory cycle 10%

Pregnancy, Erosion, Laceration, infection, Tumor, carcinoma

Hypothalamic Hypophysis Ovary Endometrial Function