Blok16 Endocrinology of Uterine Bleeding Disorder - DJ.ppt

8/14/2019 Blok16 Endocrinology of Uterine Bleeding Disorder - DJ.ppt

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ENDOCRINOLOGY OF UTERINE

BLEEDING DISORDERS

Djaswadi Dasuki


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Ovarian Physiology

Oocyte Maturation

Follicle Development

The Effect of LH on Theca Cells

The Effect of FSH on Granulosa Cells

Follicular Microenvironment

Inhibin

Follicle-Regulatory ProteinProstaglandins

Melatonin

Steroids, Gonadotropins, anda Prolactin

INTRODUCTION


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THECA INTERNA

Diagram of two-cell-two-gonadotropin concept of follicle estrogen production. (From

Erickson. Reproduced with permission)


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Menstrual Period Characteristics

Normal Abnormal

Duration 4-6 days Less than 2 or more than 7 days

Vulume 30 ml More than 80 ml

Interval 24-35 days


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Table Abnormal Menses - Terminology

Term Interval Duration Amount

Menorrhagia Regular Prolonged excessive

Metrorrhagia Irregular . Prolonged Normal

Menometrorrhagia Irregular Prolonged iixecssive

Hypermenorrhea Regular Normal Excessive

Hypomenorrhea Regular Normal or less Less

Oligomenorrhea Infrequent or irregulai Variable Scanty

Amenorrhea Absent Nomenses for 90 d Absent


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Dysfunctional Uterine

Bleeding


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Introduction

Dysfunctional uterine bleeding describes thespectrum of abnormal menstrual bleeding patterns thatmay occur in anovulatory women who have no medicalillness or pelvic pathology

The first is to reserve the the abnormalities ofendometrial growth and development that result fromchronic anovulation and predispose to excessive andprolonged menstrual flow. The second goal of treatmentis to induce or restore cyclic predictable menses of

normal volume and duration.


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Basically, menstruation was envisioned asischemic necrosis of the endometrium caused by

vasocon - striction of the spriral arterioles in thebasal layer, triggered by withdrawal of estrogenand progesterone.

Similarly, the end of menses was explained

by longer and more intense waves ofvasocontriction, combined with coagulationmechanisms activated by vascular stasis andendometrial collapse, aided by rapidreepithelialization mediated by estrogen derivedfrom the emerging new follicular cohort.


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Instead of vascular events, the central themeof the new model of the initiation of menstruationis an enzymatic autodigestion of the functionallayer of the endometrium with its subsurface

capillary plexus, possibly extending to the spiralarteriolar system in the basal layer. The classicconcept of the mechanisms that end normalmenstruation is essentially unchanged;

coagulation mechanisms, local vasoconstriction,and reepithelialization all contribute tohemostasis in the menstrual endometrium withvascular events playing the key role.

The Etiopathogenesis


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The enzymatic degradation ofendometrium triggered by estrogen-progesterone withdrawal involves anumber of different but interrelatedmechanisms including the release ofintracellular lysosomal enzymes,proteases from infiltrating inflammatory

cells, and the actions of matrixrhetalloproteinases.


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Matrix metalloproteinases are a family

a proteolytic enzymes that degrade

components of the extracellular matrix and

basement membrane. The

metalloproteinases include collagenasesthat degrade insterstitial and basement

membrane collagens, gelatinases that

further digest collagens, and stromelysinsthat attack fibronectin, laminin, and

glycoproteins.


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Overall, progesterone inhibits endometrial

metalloproteinase expression, an actionmediated by transforming growth factor (TFG)-.Progesterone withdrawal has the opposite effectincreased metalloproteinase secretion and

activation, followed by dissolution of theextracellular matrix. Local modulators(predominantly cytokines) derived fromendometrial epithelial, stromal, and endothelial

cells and natural tissue inhibitors of matrixmetalloproteinases that bind the active form ofthe enzymes also play an important role in theirregulation.


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To some extent, the amount of menstrualbleeding is controlled by the local balancebetween fibrinolysis and clotting. Endometrial

stromal cell tissue factor and plasminogenactivator inhibitor (PAI)-1 promote clotting andhelp to balance fibrinolytic processes.

Endothelins are potent long-activating

vasoconstrictors of vascular smooth muscleproduced by endometrial glandular, stromal, andendothelial cells. Menstrual endometriumcontains high concentrations of endothelins andprostaglandins which together cause intense

vasocontriction in the spiral arterioles. TheMyometrial contractions associated withmenstrual events very likely reflect the actions ofprostaglandin.


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Matrix metalloproteinases present in the

menstrual endometrium and other proteases

may be important mediators of the release andactivation of growth factors needed for

endometrial repair. Vascular endothelial growth

factor (VEGF) is in important promoter of

endometrial mitosis and can be induced by

tumor necrosis factor (TNF)-, TGF-, and

insulin-like growth factor-1. Experimental

evidence derived from model systems suggeststhat activins and other members of the TGF-

superfamily may also play a role.


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There are two basic reasons why normal

menstrual bleeding is self-limited

1. In response to a simultaneous estrogen-progesterone withdrawal, endometrialshedding is universal

2. In response to cyclic sequentialestrogen-progesterone stimulation,growth and development of theendometrial epithelium, stoma, andmicrovasculature are structurally stableand random breakdown is avoided.


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Although all standard oral contraceptive

pill regimens contain pharmacologic

quantities of both estrogen and progestin,

the progestin component is always thedominant hormone and the net effect of

oral contraceptives on the endometrium is

profoundly progestational


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The weight of available evidence from

histologic and molecular studies indicates that

anovulatory bleeding results from an increaseddensity of abnormal vessels having a fragile

structure prone to focal rupture, followed by

release of lysosomal proteolytic enzymes from

surrounding epithelial and stromal cells andmigratory leukocytes and macrophages. Once

initiated, the process is further aggravated by

local release of prostaglandins, with greater

sensitivity to those that vasodilate (PGE2) than

to those that vasoconstrict (PGR2)


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In summary, biopsy is unnecessarywhen the endometrial thickness is less

than 5 mm, that biopsy is indicated when

the clinical history suggests long-termunopposed estrogen exposure even when

endometrial thickness is grater than 12

mm even when clinical suspicion ofdisease is low.


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In anovulatory women with metrorrhagia orpolymenorrhea, progestin treatment for 14 days

can induce stabilizing predecidual changes in

vascular and fragile endometrium and, after

withdrawal, achieve a socalled medicalcurettage Thereafter, standard cyclic progestin

treatment or an estrogen-progestin

contraceptive may be offered for longer term

management. Failed progestin treatmentrequires further diagnostic evaluation.

The Treatment


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That the term endometrial hyperplasiashould be used to describe lesions without

atypia and prefer the term endometrial

intraepithelial neoplasia should be used todescribe lesions that exhibit nuclear atypia

in the cells that line the endometrial glands

(enlargement, rounding, and

pleomorphism, aneuploidy)


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These is little question that prostaglandins (PG)

have important action on the endometrialvasculature and in endometrial hemostasis. Theconcentrations of PGE2 and PGF2increaseprogressively in human endrometrium during the

menstrual cycle and are found in highconcentrations in menstrual endometrium.Neosteroidal anti inflammatory drugs (NSAIDs)inhibit PG synthesis and decrease menstrual bloodloss. NSAIDs may also alter the balance between

thromboxane A2(a vasoconstrictor and promoter ofplatelet aggregation) and prostacyclin (PGI2); avasodilator and inhibitor of platelet aggregation)


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Gonadotropin-Releasing Hormone

Agonists. The treatment with agonadotropin-releasing hormone agonist

(GnRHa) can achieve short-term relif from

aa bleeding problem and has been used

effectively as a preoperative adjunct in

women awaiting conservative

(myomectomy, endometrial ablation) or

definitive surgery (hysterectomy) forabnormal bleeding.


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Blok16 Endocrinology of Uterine Bleeding Disorder - DJ.ppt