Pathophysiology of

Dysfunctional Uterine Bleeding

Julianto Witjaksono

Reproductive Immuno-Endocrinology Division

Department of Obstetrics and Gynaecology
Faculty of Medicine, University of Indonesia
Harapan Kita, Children & Maternity Hospital
Jakarta
2003
 Types of Uterine Bleeding
Normal menstrual bleeding

Timing: There is no standard definition of "normal" menstrual cycles, but in

general, normal cycles are those in which the first day of each bleeding episode
occurs every 28 days +/- 7 days, lasting 4-5 days +/- 4-5 days. So, a woman
with 1-2 days of bleeding every 35 days is normal, as is one with 10 day-long
cycles every 26 days. Slight changes in menstrual cyclicity have no
significance, and most patients can be reassured about such changes. In
practice, patients with AUB/ irregular cycles are usually markedly irregular
(menses every 3-4 months, or very erratic).

Flow : "Normal" menstrual blood loss is the equivalent of 30-60 mL of blood,

and over 80 is considered excessive. Clinically, it is usually impossible to
objectively measure blood loss from the history, and the patient's impression is
frequently misleading.
 Types of Uterine Bleeding
Uterine bleeding due to an organic cause

Complications of Benign pelvic Medications/iatrogenic

pregnancy pathology Intrauterine device
Intrauterine pregnancy Cervical polyp Hormones (oral contraceptives,
Ectopic pregnancy Endometrial polyp estrogen, progesterone)
Spontaneous abortion Leiomyoma Anovulatory cycles
Gestational trophoblastic Adenomyosis Hypothyroidism
disease Hyperprolactinemia
Placenta previa Cushing's disease
Malignant neoplasm Polycystic ovarian syndrome
Systemic disease Cervical Adrenal dysfunction/tumor
Endometrial Stress (emotional, excessive
Hepatic disease
Ovarian exercise)
Renal disease
Coagulopathy
Thrombocytopenia Trauma Infection
von Willebrand's disease Laceration Cervicitis
Leukemia abrasion Endometritis
Foreign body
Physiology of normal
menstrual cycle
Primate menstrual cycle
Day 0
menstruation- sloughing
off of endometrium (lining
of the uterus)
Previous Corpus luteum
disintegrating - no
implantation of fertilized
ovum, release of
hypothalamus from
negative feedback.
Hypothalamus produces
more GnRH, triggers
release of FSH and LH.
Follicle stimulated by
FSH, begins to grow and
produce estrogen.
Primate menstrual cycle -
Follicular Phase

Day 10-12
Increasing estrogen
levels of growing
follicle provide
positive feedback to
hypothalamus.
Day 12 -14
Increased activation of
hypothalamus leads to
a surge of LH and
FSH from anterior
pituitary.
Surge of FSH triggers
maturation of
developing follicle - it
ruptures and releases
the egg.
Increased estrogens
lead to buildup of
endometrium.
Primate menstrual cycle
Luteal Phase Days 14 - 28 Luteal
Phase
After release of ovum, follicle
develops into corpus luteum
Corpus luteum secretes
progesterone and some
estrogen.
High levels of progesterone has
negative feedback effect on the
hypothalamus - decreased
secretion of FSH and LH.
Inhibin, released from follicle
at ovulation, also inhibits FSH
release.
Progesterone also stimulates
buildup of endometrium.
In absence of implantation,
corpus luteum degenerates.
Progesterone and estrogen
levels fall, triggering
menstruation again.
Functional anatomy of Endometrium is a multilayered mucosa
the endometrium specialized for implantation and support of
pregnancy. A single, continuous layer of
epithelial cells lines the surface of the
stroma and penetrates the stroma with deep
invaginations almost all the way down to
the myometrium-endometrium junction.
The entire thickness of the endometrium is
penetrated by the spiral arteries and their
capillaries. Spiral arteries originate from
the radial branches of arcuate arteries,
which in turn arise from uterine arteries.
The superficial layer (functionalis) is shed
during menstruation, whereas the
permanent bottom layer (basalis) gives rise
to the regeneration of endometrium after
each menstruation. The striking changes in
the spiral arteries (coiling, stasis,
vasodilatation followed by intense
vasoconstriction) are consistently observed
before the onset of every menstruation
episode.
Cyclic changes in thickness and morphology of endometrium and
the relation of these changes to those of the ovarian cycle.
Noyes RW, Hertig
AT, Rock J
Dating the
endometrial
biopsy.
Fertil Steril 1950;1:325
Nidation Window
From basic to clinic
Uterine receptivity & endometrial thickness

Poor prognosis of hyper-echogenicity on the day of hCG

Fanchin et al. Fertil Steril 2000;74:274-81
Four basic mechanisms of menstruation
Changes in vascular tone of the spiral
arterioles
Changes in the mechanisms of haemostasis
in the uterus
Alterations in lysosomal function
Regeneration of endometrium
1 Basic mechanisms of menstruation
Changes in vascular tone of the spiral arterioles

Menstruation is preceeded by intense vasoconstriction of

the spiral arterioles as a consequent of endometrial
regression and an increased coiling of the spiral arteriole
(Markee, 1940)
Ischaemia induced by intense vasoconstriction of 4 to 24
hours will be augmented by increased release of free
oxygen radicals produced by tissue (endometrial)
desquamation
 Basic mechanisms of menstruation
2 Changes in the mechanisms of haemostasis in the uterus

Platelet fibrin plug formation is grossly deficient in

endometrium
Ruptured spiral arterioles do form platelet fibrin thrombi
in the early phases of menstruation, but these retained
within the vessels and do not form plug formation
At the end of the 24th hours of menses bleeding, the
endometrium is principally devoid of this plug formation
The rapid formation of fibrin plugs and their degradation
play a part of the control of menstrual bleeding
3 Basic mechanisms of menstruation
Alterations in lysosomal function

Lysosomes are assumed to contain a series of hydrolytic

enzymes activities involved with the maintenance of
prostaglandin synthesis
Increased lysosomes enzymes has been correlated to
progesterone withdrawal, therefore endometrial lysosomal
enzymes activity increased in ovulatory DUB (Christiaens et
al, 1982)
Enhanced activity also observed in menorrhagia women
using IUD, but lower in progestore-IUD (Wang et al, 1994)
Basic mechanisms of n
Prostaglandins and endometrial function
Balancing of prostacyclyn and thromboxane
PGI is a potent anticoagulators involve in the mechanism of platelet
activation
Imbalance of ratio PGI to TBX is demonstrated in menorrhagia,
whenever elevated PGI results in reduced formation of fibrin
platelet plugs
The source of PG :
PGI is derived from endothelial cells
TBX is released by activated platelets
4 Basic mechanisms of menstruation
Regeneration of endometrium

The endometrium undergoes regeneration almost from

the beginning of menstruation
By the end of 24 hours of menstruation, the outer two-
thirds of the endometrium layer of endometrium has
been lost, the basal layer consists of tufts of epithelial
cells extruding up from the basal glands, and a raw
surface consisting of endothelial and mesenchymal
cells of the stroma
By the 5th day of menstruation, the endometrium has
undergone profound regeneration of epithelial and
stromal cells
Basic mechanisms of menstruation
Regeneration of endometrium

There is little evidence in vitro to confirm the role of

direct estradiol potency as a mitogen in either breast
or endometrial epithelial cells
Endometrial proliferation is directed by polipeptide
growth factors (EGF, TGF-/, CSF-1, ect) which is
regulated by steroid and PG hormones
Basic mechanisms of menstruation
Most questionable on physiology of menstruation

Do the continuation of vasoconstriction is responsible for

control of the blood loss ?
Whether the platelet fibrin plug formation or other local
haemostatic factors are involved in the subsequent control
of menstrual bleeding ?
What degree the rapidly of the angiogenic stimulus to
vascular regeneration is involved in the control of
menstrual loss ?
Critical epithelial effects of estrogen (e.g., deoxyribonucleic
acid [DNA] synthesis, proliferation, and gene expression) are
mediated primarily by estrogen receptor (ER) in stromal cells
in a paracrine manner in the endometrium.
The antiestrogenic effects of progesterone on epithelial cells (e.g.,
decreased proliferation and enhanced differentiation) are mediated
primarily by progesterone receptors (PRs) in stromal cells in a
paracrine manner in the endometrium. DNA, deoxyribonucleic
acid; ER, estrogen receptor .
Abnormal & Dysfunctional
Uterine Bleeding
 Abnormal Uterine Bleeding
Amenorrhea : Lack of menstrual bleeding
Hypomenorrhea : Regular uterine bleeding that is decreased in amount
Oligomenorrhea : Infrequent, irregular episodes of bleeding usually with
intervals of more than 40 days
Polymenorrhea : Frequent but regular episodes of bleeding, usually with
intervals of 21 days or less
Menorrhagia : Bleeding excessive in both amount and
(Hypermenorrhea) duration of flow, occurring at
regular intervals
Metrorrhagia : Bleeding (usually not excessive) occurring at irregular
intervals
Metrometrorrhagia : Bleeding, usually excessive and prolonged occurring
at frequent and irregular intervals
 Types of Uterine Bleeding

Normal menstrual bleeding

Bleeding not exceeding 5 days in an ovulatory cycle

Abnormal uterine bleeding

Organic cause
Non-organic cause (DUB)
Ovulatory cycle
Anovulatory cycle
 Dysfunctional Uterine Bleeding

DEFINITION

Dysfunctional uterine bleeding (DUB) is heavy or irregular

menstrual bleeding that is not caused by an underlying anatomical
abnormality, such as a fibroid, lesion,infection, tumor, systemic
coagulation disorders or pregnancy.

DUB is the most common type of abnormal uterine bleeding.

DUB originally due to any abnormalities of reproductive
endocrinology of ovarian function
DUB is defined in reproductive age, not in menopausal age
 Types of Uterine Bleeding
Uterine bleeding due to an organic cause

Complications of Benign pelvic Medications/iatrogenic

pregnancy pathology Intrauterine device
Intrauterine pregnancy Cervical polyp Hormones (oral contraceptives,
Ectopic pregnancy Endometrial polyp estrogen, progesterone)
Spontaneous abortion Leiomyoma Anovulatory cycles
Gestational trophoblastic Adenomyosis Hypothyroidism
disease Hyperprolactinemia
Placenta previa Cushing's disease
Malignant neoplasm Polycystic ovarian syndrome
Systemic disease Cervical Adrenal dysfunction/tumor
Endometrial Stress (emotional, excessive
Hepatic disease
Ovarian exercise)
Renal disease
Coagulopathy
Thrombocytopenia Trauma Infection
von Willebrand's disease Laceration Cervicitis
Leukemia abrasion Endometritis
Foreign body
 Dysfunctional Uterine Bleeding

OVULATORY CYCLE

Most common after the adolescent years and before the

perimenopausal years, to as many as 10 % of ovulatory women.
Menstrual irregularity associated with corpus luteum defects or
midcycle staining is considered as subgroup of DUB, but anovulatory
DUB is most widely accepted form of DUB.
 Dysfunctional Uterine Bleeding

OVULATORY CYCLE

Regular cycle length

Presence of premenstrual symptoms
Dysmenorrhea
Breast tenderness
Change in cervical mucus
Mittleschmertz
Biphasic temperature curve
Positive result from use of luteinizing-hormone predictor kit
 Dysfunctional Uterine Bleeding

OVULATORY CYCLE

Unpredictable cycle length

Unpredictable bleeding pattern
Frequent spotting
Infrequent heavy bleeding
Monophasic temperature curve
Basic mechanisms of menstruation
Ovulatory DUB : Endometrial appearances
Increased lysosomal enzymes activity
Decreased MMP (Rodgers et al 1994; Salamonsen, 1996)
whish is responsible for decreasing of neutral
endopeptidase
Attenuated of endothelins leading for prevention of
vasoconstriction (Marsh, 1996)
Endometrial leucocytes (granulated lymphocytes, T-
lymphocytes, macrophages, PMNL, other migratory
leucocytes) in increased in excessive MBL
including ovulatory DUB or associated to copper
IUD usage (Song et al, 1996; Sheppard, 1997)
 Dysfunctional Uterine Bleeding

ANOVULATORY CYCLE
Any disruption to the cyclic release of GnRH, FSH, LH can result in
anovulation.
Due to immaturity of the HPO axis in postmenarche, & decreased
sensitivity of the ovary to gonadotropin stimulation in perimenopausal
women.
Most anovulatory DUB is due to estrogen withdrawal or estrogen
breakthrough bleeding
Iatrogenic anovulatory is secondary to widely side effect (12-24%) of
progestogen long-acting contraceptive use and 2-7% due to oral
contraceptive pills usage
 Dysfunctional Uterine Bleeding

ANOVULATORY CYCLE
Disordered proliferative endometrium
(proliferative endometrium during the secretory
phase) to hyperplasia

Histopathology appearance
Various form of proliferative endometrium
Hyperplasia (simple or complex)
Atypical
 Types of Uterine Bleeding
Hyperplasia to Carcinoma

Microscopically, the well differentiated tumors (upper left) appear as glands with the
morphologic feature of normal endometrial glands. The glands are densely packed with
little intervening stroma or may exhibit a cribriform appearance. The poorly differentiated
tumors (upper right) appear as sheets and rarely form glandular structures. Some tumors
may form papillary structures (lower left), or may consist of clear cells (lower right).
 Endocrine abnormality in
Dysfunctional Uterine Bleeding

Event Phase Change Endometrial Menstrual pattern

histology
Ovulation Shortened follicular Normal endometrium Polimenorrhea,
phase menorrhagia
Ovulation Long follicular phase Normal endometrium Oligomenorrhea,
menorrhagia
Luteal phase defect Shortened luteal Defficient secretory/out- Pre-menstrual spotting,
phase phase dating endometrium menorrhagia
Persistent corpus luteal Long luteal phase Well development Prolonged cycle
secretory endometrium
Anovulation (small foll) Short cycles Defficient proliverative Polimenoorhea,
endometrium menorrhagia
Anovulation (PCO) Prolonged cycle Proliverative/hyperplasia Oligomenorrhea,
metropathia hemorrhagica
Pathogenesis of
Dysfunctional Uterine Bleeding
 Dysfunctional Uterine Bleeding

OVULATORY CYCLE

Inadequate proliferative phase

Disparity between the endometrial phase and date of menstrual cycle

Inadequate secretory phase (luteal phase defect)

Disparity between the endometrial phase and date of menstrual cycle

Irregular shedding
Lag in shedding of secretory endometrium leading to bleeding over 7 days
Basic mechanisms of menstruation
Ovulatory DUB : Endometrial appearances
A shifting in the ratio of endometrial vasoconstricting
PGF2a to vasodilatory PGE2 (Smith et al., 1982)
Increase total endometrial concentration of prostaglandin
(Cameron et al., 1987)
Increased capacity for myometrial generation of
prostacyclin (PGI2), which is a potent inhibitor platelet
aggregation (Smith et al, 1981)
Successful treatment of ovulatory DUB with PG
synthetase inhibitors leads to a reduction in endometrial
concentration of PGF2a & PGE2, and also inhibits the
binding of PGE to its receptor (Fraser, 1993; Rees et al., 1998)
Basic mechanisms of menstruation
Ovulatory DUB : Endometrial vasculature & haemostasis
Normal menstrual bleeding arises predominantly
from the spiral arterioles, under the control of
ovarian steroid hormones (Markee, 1940)
Bleeding resources were arteriolar, small veins in
the deep endometrium and inner myometrium
(Hourihan et al., 1989; Fraser & Peek, 1992)
Increased endometrial blood flow compared with
normal women (Fraser et al, 1987)
Increase in endometrial fibrinolysis (Rybo, 1966) and
tissue plasminogen activator (Kasonde & Bonnar, 1976)
 Types of Uterine Bleeding
ANOVULATORY CYCLE

Thick endometrium
Crowded glands with little stroma
Fragile endometrium
Hypervascular endometrium
Spontaneous bleeding

In absence of a controlled progesterone withdrawal there is:

No vasoconstriction
No tight coiling of spiral vessels
No orderly collapse to induce stasis
Bleeding is long and heavy
Basic mechanisms of menstruation
An-ovulatory DUB : Endometrial appearances
Major changes are seen in endometrial morphology in
women with simple hyperplasia as a consequense of
excessive and unopposed ovarian estradiol secretion
(Schroder, 1954)
Endometrial blood flow rates are variable but tend to be
higher than normal (Fraser et al., 1987)
Incerase endometrial nitric oxide (endothelium derived
relaxing factor) stimulated by estrogen
In proliferative endometrium, arachidonic acid
availability is reduced and overall PG production is
impaired (Smith et al., 1982)
Basic mechanisms of menstruation
Break-through bleeding in progestogen contraceptive use

No particular histological pattern appears to correlate

with the occurance of BTB (Witjaksono et al, 1996)
Increased endometrial microvascular density as
consequences of angiogenesis effect of progestogen
(Rogers et al., 1999)
Increased of endometrial VEGF is correlated to
anbormal vascular morphology and function (Peek et al,
1995; Smith, 1996)
 Future comparison of clinical appearance of
various dysfunctional uterine bleeding to break-through bleeding

Events Ovulatory Anovulatory Break-through

DUB DUB Bleeding
Cycle bleeding Regular Irregular Irregular
pattern
Pattern of diary Normal Prolonged Prolonged
menstrual loss
Measured menstrual Heavy Heavy Reduced
blood loss
Hormone Normal menstrual High unopposed Continous progestogen
environment cycle estrogen exposure, varying estradiol
Association with Yes Usually Sometimes
hormonal withdrawal
Endometrial blood Follicular phase Variable increase Unknown
flow increase

Fraser et al, 1996; Witjaksono et al., 1996

Future comparison of endometrial appearance of
various dysfunctional uterine bleeding to break-through bleeding
Ovulatory Anovulatory Break-through
Events
DUB DUB Bleeding
Endothelium-derived ? Normal ? Increased Unknown
relaxin factor
Vasoconstrictors - Decreased ? Decreased Variable
endothelins
Endometrial Unknown Unknown Increased
Vascular endothelial Unknown Unknown Increased
growth factor
Lysosomal enzymes Some increase Unknown Subtle changes
Matrix Unknown Unknown Unknown
metalloproteinases
Fibrinolytic activity Increased ? Increased ? Supressed
Endometrial repair Normal ? Abnormal ? Abnormal
mechanisms
 Ovulatory Anovulatory Break-through
Events
DUB DUB Bleeding
Origin of bleeding Arteriolar Venous/capilary Capilary/venous
Endometrial Normal Proliferative or Suppressed secretion or
histology hyperplastic atrophy
Cytoskeleton Unknown Unknown Minor changes
Steroid receptor Unknown Unknown Complex
changes
Endometrial ? Normal, minor Decrease arterioles, Decrease arterioles,
vascularchanges of small increase distored, thin- increase endothelial
veins walled vessel structures, increase thin-
morphology
walled superficial dilated
vessels
Vascular fragility Normal Increased Increased
Vascular basement Unknown Unknown ? Unknown
membrane
Endothelial ? Normal Unknown ? Decreased
intercellular junction
Leucocytes Increased Unknown Increase in EGL
Prostaglandins Increased PGE2 Decreased PGE2 & Increased PG epoxides,
& PGI2 PGI2 decreased other PG
Pathogenesis Dysfunctional Uterine Bleeding
Fall in estrogen and progesterone

Activated Incerased Suppressed Activated Increased migratory

lysosome MMP NEP PLA2 Leucocytes

Endothelin PGF2a/PGE2 eGL, T-lymphs,

Macrophages, PMNL
Hydrolytic
enzymes
Activation
Vasocontriction multiple factors

Ischemia Cytokines release

EDRF Hydrolytic & oxydative
Free oxygen enzyme
Growth factors
Reperfusion Radicals Other molecules
(interaction, adhesive)
Tissue damage
Edema
Vascular damage
Bleeding
Defective haemostasis
Tissue shedding Tissue healing
VEGF Estradiol bFGF
Angiotensin
PGE2
Endothelin
Tissue remodelling
Angiogenesis
Strategy Management of
Dysfunctional Uterine Bleeding
based on the pathogenesis findings
Selective Estrogen Receptor Modulators
Estrogen Ligand
Receptor E / SERM / ERD

/ AF 1 & 2 Coregulatory Proteins

Estrogen Receptor Gene

Ligand Complex Transcription

DNA Estrogen Tissue Response

Response element Agonistic & or
Antagonistic
Mechanism of Tissue Response