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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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THANK YOU