ENDOCRINOLOGY OF UTERINE BLEEDING DISORDERS

Djaswadi Dasuki

INTRODUCTION 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 Protein Prostaglandins Melatonin Steroids, Gonadotropins, anda Prolactin
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THECA INTERNA

Diagram of two-cell-two-gonadotropin concept of follicle estrogen production. (From Erickson. Reproduced with permission) 3

Menstrual Period Characteristics

Normal
Duration 4-6 days

Abnormal
Less than 2 or more than 7 days

Vulume
Interval

30 ml
24-35 days

More than 80 ml

Table Abnormal Menses - Terminology

Term Menorrhagia Metrorrhagia Menometrorrhagia Hypermenorrhea Hypomenorrhea

Interval Regular Irregular Irregular Regular Regular

Duration Prolonged . Prolonged Prolonged Normal Normal or less

Amount excessive Normal iixecssive Excessive Less

Oligomenorrhea
Amenorrhea

Infrequent or irregulai
Absent

Variable
Nomenses for 90 d

Scanty
Absent
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Dysfunctional Uterine Bleeding

Introduction
Dysfunctional uterine bleeding describes the spectrum of abnormal menstrual bleeding patterns that may occur in anovulatory women who have no medical illness or pelvic pathology The first is to reserve the the abnormalities of endometrial growth and development that result from chronic anovulation and predispose to excessive and prolonged menstrual flow. The second goal of treatment is to induce or restore cyclic predictable menses of normal volume and duration.

Basically, menstruation was envisioned as ischemic necrosis of the endometrium caused by vasocon - striction of the spriral arterioles in the basal layer, triggered by withdrawal of estrogen and progesterone. Similarly, the end of menses was explained by longer and more intense waves of vasocontriction, combined with coagulation mechanisms activated by vascular stasis and endometrial collapse, aided by rapid reepithelialization mediated by estrogen derived from the emerging new follicular cohort.

The Etiopathogenesis
Instead of vascular events, the central theme of the new model of the initiation of menstruation is an enzymatic autodigestion of the functional layer of the endometrium with its subsurface capillary plexus, possibly extending to the spiral arteriolar system in the basal layer. The classic concept of the mechanisms that end normal menstruation is essentially unchanged; coagulation mechanisms, local vasoconstriction, and reepithelialization all contribute to hemostasis in the menstrual endometrium with vascular events playing the key role.
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The enzymatic degradation of endometrium triggered by estrogenprogesterone withdrawal involves a number of different but interrelated mechanisms including the release of intracellular lysosomal enzymes, proteases from infiltrating inflammatory cells, and the actions of matrix rhetalloproteinases.
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The inflammatory infiltrate (including neutrophils, eosinophils, and macrophages or monocytes) is drawn by chemoattractive molecules (chemokines) synthesized by endormetrial cells, some of which are downregulated by progesterone (interleukin 8;IL-8). When activated, the leukocytes produce a wide assortment of regulatory molecules including cytokines, chemokines, and a range of enzymes that contribute to degradation of the extracellular matrix, directly or indirectly via activation of other proteases.
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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 collagenases that degrade insterstitial and basement membrane collagens, gelatinases that further digest collagens, and stromelysins that attack fibronectin, laminin, and glycoproteins.
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Overall, progesterone inhibits endometrial metalloproteinase expression, an action mediated by transforming growth factor (TFG)-. Progesterone withdrawal has the opposite effect increased metalloproteinase secretion and activation, followed by dissolution of the extracellular matrix. Local modulators (predominantly cytokines) derived from endometrial epithelial, stromal, and endothelial cells and natural tissue inhibitors of matrix metalloproteinases that bind the active form of the enzymes also play an important role in their regulation.
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To some extent, the amount of menstrual bleeding is controlled by the local balance between fibrinolysis and clotting. Endometrial stromal cell tissue factor and plasminogen activator inhibitor (PAI)-1 promote clotting and help to balance fibrinolytic processes. Endothelins are potent long-activating vasoconstrictors of vascular smooth muscle produced by endometrial glandular, stromal, and endothelial cells. Menstrual endometrium contains high concentrations of endothelins and prostaglandins which together cause intense vasocontriction in the spiral arterioles. The Myometrial contractions associated with menstrual events very likely reflect the actions of prostaglandin.
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Matrix metalloproteinases present in the menstrual endometrium and other proteases may be important mediators of the release and activation 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 suggests that 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 estrogenprogesterone withdrawal, endometrial shedding is universal 2. In response to cyclic sequential estrogen-progesterone stimulation, growth and development of the endometrial epithelium, stoma, and microvasculature are structurally stable and 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 the dominant 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 increased density of abnormal vessels having a fragile structure prone to focal rupture, followed by release of lysosomal proteolytic enzymes from surrounding epithelial and stromal cells and migratory 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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Endometrial hyperplasia and cancer are more commonly detected in older than in younger women, but duration of exposure to unopposed estrogen stimulation is the more critical risk factor. In women with abnormal bleeding and no recent exposure to exonegous progestational agents, a secretory endometrium provides reliable evidence of recent ovulation and signals the need to search for an anatomical cause.
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In summary, biopsy is unnecessary when the endometrial thickness is less than 5 mm, that biopsy is indicated when the clinical history suggests long-term unopposed estrogen exposure even when endometrial thickness is grater than 12 mm even when clinical suspicion of disease is low.
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The Treatment
In anovulatory women with metrorrhagia or polymenorrhea, progestin treatment for 14 days can induce stabilizing predecidual changes in vascular and fragile endometrium and, after withdrawal, achieve a socalled medical curettage Thereafter, standard cyclic progestin treatment or an estrogen-progestin contraceptive may be offered for longer term management. Failed progestin treatment requires further diagnostic evaluation.
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That the term endometrial hyperplasia should be used to describe lesions without atypia and prefer the term endometrial intraepithelial neoplasia should be used to describe 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 endometrial vasculature and in endometrial hemostasis. The concentrations of PGE2 and PGF2 increase progressively in human endrometrium during the menstrual cycle and are found in high concentrations in menstrual endometrium. Neosteroidal anti inflammatory drugs (NSAIDs) inhibit PG synthesis and decrease menstrual blood loss. NSAIDs may also alter the balance between thromboxane A2 (a vasoconstrictor and promoter of platelet aggregation) and prostacyclin (PGI2); a vasodilator and inhibitor of platelet aggregation)
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Gonadotropin-Releasing Hormone Agonists. The treatment with a gonadotropin-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) for abnormal bleeding.
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THANK YOU

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