Januari 17, 2010
Dear Doctor,
Could you please advise me on treatment for my
bothersome menstrual bleeding.
I’m 46 years of age and mother of 3 children.
I hardly can keep up my job as a teacher due to the
prolonged bleeds and a lack of energy after a period.
Yours sincerely,
Mrs Jones
© PHMvdW 2010
Dysfunctional Uterine Bleeding
Peter van de Weijer MD PHD
CCO Paramaribo
Januari 24th 2010
Dysfunctional Uterine Bleeding
describes
the spectrum of abnormal menstrual bleeding patterns
that occur in women secondary after
anovulation or oligo- ovulation
and
where no pelvic pathology or medical illness is present.
Speroff L. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins
© PHMvdW 2010
Januari 17, 2010
Dear Doctor,
Could you please advise me on treatment for my
bothersome menstrual bleeding.
I’m 46 years of age and mother of 3 children.
I hardly can keep up my job as a teacher due to the
prolonged bleeds and a lack of energy after a period.
Yours sincerely,
Mrs Jones
Cycle problem ?
Bleeding problem ?
© PHMvdW 2010
Features of the menstrual cycle
Cycle length
1
Length of the
1
follicular
variation
© PHMvdW 2010
+
luteal phase
consistent
P5-P95 =
24 - 35 days
28 days = 15%
Features of the menstrual cycle
Cycle length
regularity
1
© PHMvdW 2010
1
1
Features of the menstrual cycle
regularity
© PHMvdW 2010
Features of the menstrual cycle
regularity
Sex-steroid hormones
Oestrogen
Progesterone
Endometrium
Proliferative
© PHMvdW 2010
Secretory
Features of the menstrual cycle
regularity
Sex-steroid hormones
Features of the menstrual cycle
regularity
Endometrium
© PHMvdW 2010
Features of the menstrual cycle
Cycle length
regularity
1
1
1
Variation
24 - 35 days
Irregular > 20%
© PHMvdW 2010
Features of the menstrual cycle
Treloar AE et al.
Variation of the human menstrual cycle through reproductive life.
Int J Fert 1967;12:77-126
34 years of
observation
25.825 person years
250.000 cycles
© PHMvdW 2010
Features of the menstrual cycle
Interval between succeeding menstruations
days
age
© PHMvdW 2010
Treloar AE et al. Variation of the human menstrual cycle through reproductive life. Int J Fert 1967;12:77-126
Features of the menstrual cycle
Bleeding
regularity
length
© PHMvdW 2010
Features of the menstrual cycle
Bleeding
regularity
length
Duration
4 – 6 days
Volume
30 ml
250.000 cycles
© PHMvdW 2010
v
o
l
u
m
e
duration
bleeding
How does menstrual bleeding occur ?
regularity
length
v
o
l
u
m
e
duration
bleeding
© PHMvdW 2010
How does menstrual bleeding occur ?
Classical Concept
Sex-steroid hormones
Histology Endometrium
Vascular integrity
© PHMvdW 2010
Corpus luteum deficiency
Oestrogen
Progesterone
Proliferative
Secretory
Bleeding
Bleeding Mechanisms in the Endometrium
Vascular integrity
© PHMvdW 2010
Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
Bleeding Mechanisms in the Endometrium
The capillaries in the endometrium have only one thick cell layer
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
The capillaries in the endometrium have only one thick cell layer
Tunica intima: a single layer of simple squamous endothelial
cells glued by a polysaccharide extracellular matrix, surrounded
by a thin layer of subendothelial connective tissue interlaced
with a number of circularly arranged elastic bands called the
Cell to cell
Adhesion
internal elastic lamina
endothelial
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Collagenase
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Pro-collagenase
Collagenase
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
Matrix Metallo Proteinase
> 25 enzymes able to degrade
all components of ECM
MMP’s
1-2-3-9
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Pro-collagenase
Collagenase
Vascular integrity
© PHMvdW 2010
Bleeding Mechanisms in the Endometrium
Progesteron
Pro MMP’s
MMP’s
Proteolytic cleavage by
Plasmin / Gelatinase
1-2-3-9
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Pro-collagenase
Collagenase
Vascular integrity
© PHMvdW 2010
Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001
Bleeding Mechanisms in the Endometrium
Progesteron
Pro MMP’s
MMP’s
Proteolytic cleavage by
Plasmin / Gelatinase
1-2-3-9
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Pro-collagenase
Collagenase
Vascular integrity
© PHMvdW 2010
Cornet PB et al. Regulation of MMP-9 and activation by ovarian steroids. J Clin Metab 2005; 90 : 1001
Bleeding Mechanisms in the Endometrium
© PHMvdW 2010
Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
Bleeding Mechanisms in the Endometrium
Ischemia
Progesterone withdrawal
PGF 2α
Free Oxygen Radicals
Pro MMP’s
MMP’s
Proteolytic cleavage by
Plasmin / Gelatinase
IL-1
1-2-3-9
Extra Cellular Matrix
Degradation
Cell to cell
Adhesion
endothelial
Pro-collagenase
Collagenase
Vascular integrity
© PHMvdW 2010
Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005
How does menstrual bleeding stop ?
© PHMvdW 2010
How does menstrual bleeding stop ?
vasoconstriction
© PHMvdW 2010
PG
How does menstrual bleeding stop ?
Prostaglandine
Synthetase
Thromboxane A2
Prostacyclin
Promotes
Aggregation
Inhibits
Aggregation
Vasoconstriction
© PHMvdW 2010
Platelets
Vasodilatation
How does menstrual bleeding stop ?
vasoconstriction
PG
Clotting mechanisms
© PHMvdW 2010
Thrombin
How does menstrual bleeding stop ?
Fibrinogen
Fibrin
Fibrin degradation
Plasmin
Thrombin
© PHMvdW 2010
Plasminogen
How does menstrual bleeding stop ?
vasoconstriction
PG
Clotting mechanisms
Estrogen action
© PHMvdW 2010
Thrombin
Features of the menstrual cycle
Bleeding
regularity
length
Duration
4 – 6 days
Volume
30 ml
250.000 cycles
© PHMvdW 2010
v
o
l
u
m
e
duration
bleeding
Features of the menstrual cycle
Accompanying features
regularity
length
© PHMvdW 2010
duration
v
o
l
u
m
e
Features of the menstrual cycle
Accompanying features
regularity
length
Dysmenorrhea
Prevalence 45-72%
menarche + 3 yrs
Severity:duration/flow
Analgetics
© PHMvdW 2010
39% y
Dysmenorrhea
duration
v
o
l
u
m
e
Features of the menstrual cycle
Accompanying features
regularity
length
PMS
Cycle related problems 40%
Prevalence PMS
2-10 %
SSRI / GnRH analogue
Analgetics
© PHMvdW 2010
39% y
Dysmenorrhea
duration
PMS
v
o
l
u
m
e
Features of the menstrual cycle
regularity
length
24-35 days
duration
v
o
l
u
m
e
4-6 days
30 ml
Dysmenorrhea
PMS
bleeding
© PHMvdW 2010
Changes in Cycle Pattern (climacteric)
Dear Doctor,
Could you please advise me on treatment for my
Interval between succeeding menstruations
bothersome irregular menstrual bleeding.
I’m 46 years of age
days
age
© PHMvdW 2010
endocrinology
Changes in Cycle Pattern (climacteric)
3 effects
Oestrogen levels
Progesteron levels
Endometrial growth
Freeman EW et al. Fertil Steril 2005;83:383-92
© PHMvdW 2010
endocrinology
Changes in Cycle Pattern (climacteric)
Freeman EW et al. Fertil Steril 2005;83:383-92
© PHMvdW 2010
endocrinology
I. Oestrogen levels
Freeman EW et al. Fertil Steril 2005;83:383-92
© PHMvdW 2010
endocrinology
I. Oestrogen levels
Oestrogen levels are sustained
Freeman EW et al. Fertil Steril 2005;83:383-92
© PHMvdW 2010
Progesteron
Interval between succeeding menstruations
Anovulation
days
age
© PHMvdW 2010
Oestrogen surplus
Anovulation
Progesterone deficiency
ADD
Progestagen
1
© PHMvdW 2010
15
Days of cycle
21
day 14 -28
28
How does progestagen work ?
© PHMvdW 2010
Effect on the Endometrium
© PHMvdW 2008
Progestogen Actions on the Endometrium
Progesteron
Stops the oestrogen-induced
growth of the endometrium
© PHMvdW 2010
Progestogen Actions on the Endometrium
Progesteron
Suppression of Bcl-2 expression
Apoptosis
Induces apoptosis of endometrial cells
© PHMvdW 2010
Progestogen Actions on the Endometrium
Bcl-2
Apoptosis
Progesteron
+
Synthesis of 17ß-hydroxysteroid
dehydrogenase sulfotransferase
E2
ES
Promotes synthesis of 17B-HDS which converts E2 into ES
© PHMvdW 2010
estradiol metabolism
estradiol
0,15
0,05
0,85
0,014
estrone sulphate
0,54
estrone
0,21
•
0,85 = 85% of estradiol is converted into Estrone sulphate
•
Estrone sulphate is a non active estrogen
•
Enzymes involved are: 17ß-hydroxysteroid dehydrogenase,
sulfotransferase en sulfatase
•
Activity of these enzymes shows large inter individual variation
© PHMvdW 2010
Progestogen Actions on the Endometrium
Bcl-2
Apoptosis
Progesteron
+
Synthesis of 17ß-hydroxysteroid
dehydrogenase sulfotransferase
E2
ES
TAF-1DNA bindingLigand Binding TAF-2
domain
domain
Estrogen Receptor
Suppresses
DNA synthesis through interference with the
ligand binding domain
© PHMvdW 2010
How does progestagen work ?
Stops the oestrogen-induced growth of the endometrium
Induces apoptosis of endometrial cells
Promotes synthesis of 17B-HDS which converts E2 into ES
Suppresses DNA synthesis through interference with the
ligand binding domain
© PHMvdW 2010
How to treat anovulatory bleeding problems ?
Acute Heavy Bloodloss
Chronic Menorrhagia
© PHMvdW 2010
Acute Heavy Bloodloss
High dose Progestagens
( Norethisteron 5 mg 2-3dd 1 / 10 days)
or 4 tabs OC during 5 days
or tranexamic acid 1-1.5 g tds
or ( curettage )
© PHMvdW 2010
Acute Heavy Bloodloss
High dose Progestagens
than
Regulate Cycle for at least 3 months
© PHMvdW 2010
Acute Heavy Bloodloss
Dydrogesteron 10 mg
MPA 10 mg
Lynestrenol 5 mg
Norethisteron 5 mg
Medrogeston 5 mg
P
P normal dose
day 15-28 cycle
10 days
High dose
M
© PHMvdW 2010
OAC during 3 months
M
M
M
Speroff L. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins
How to treat menstrual bleeding problems ?
Acute Heavy Bloodloss
Chronic Menorrhagia
© PHMvdW 2010
How to treat menstrual bleeding problems ?
If cycle and bleeding problems are present
first correct cycle
Progestagens
OCC
Ultrasound
If bleeding problems still persist
Progestagen
day Hysteroscopy
14 -28
exclude anatomical / systemic
pathology
Lab examination
1
Oral contraceptive
If bleeding problems still persist
treat bleeding problems
1
15
Days of cycle
© PHMvdW 2010
21
PGSI
Antifibrinolytics
Surgery28
How to treat menstrual bleeding problems ?
If cycle and bleeding problems are present
first correct cycle
Progestagens
OCC
If bleeding problems still persist
exclude anatomical / systemic pathology
Ultrasound
Hysteroscopy
Lab examination
If bleeding problems still persist
treat bleeding problems
PGSI
Antifibrinolytics
Surgery
© PHMvdW 2010
How to treat menstrual bleeding problems ?
If cycle and bleeding problems are present
first correct cycle
Progestagens
OCC
If bleeding problems still persist
exclude anatomical / systemic pathology
Ultrasound
Hysteroscopy
Lab examination
If bleeding problems still persist
treat bleeding problems
PGSI
Antifibrinolytics
Progestagens
Surgery
© PHMvdW 2010
How to treat menstrual bleeding problems ?
vasoconstriction
© PHMvdW 2010
PG Synthetase
inhibitors
Prostaglandine
Synthetase
PG Synthetase
inhibitors
Thromboxane A2
Prostacyclin
Promotes
Aggregation
Inhibits
Aggregation
Vasoconstriction
© PHMvdW 2010
Platelets
Vasodilatation
Endometrium & Bleeding
PG Synthetase
inhibitors
PGSI : Prostaglandin Synthetase
Inhibitors
Prostacyclin
Thromboxane A2
naproxen 500 mg bd
ibuprofen 400 mg tds
Inhibits
diclofenac 50 mg tds
Promotes
Reduction
in blood loss (%)
Aggregation
Platelets
Aggregation
Prog. Oral seq
Prog. Oral cont
Prog. IUD
Anti-Fibrinolytic
Vasoconstriction
Vasodilatation
Oral Contraceptive
GnRH analoque
Prostaglandine SI
Danazol
0
©PHMvdW
PHMvdW2010
2005
©
20
40
60
80
100
How to treat menstrual bleeding problems ?
vasoconstriction
Clotting mechanism
© PHMvdW 2010
PG Synthetase
inhibitors
Antifibrinolytics
How to treat menstrual bleeding problems ?
Fibrinogen
Fibrin
Fibrin degradation
Plasmin
Antifibrinolytics
Thrombin
Clotting
© PHMvdW 2010
Plasminogen
How to treat menstrual bleeding problems ?
Antifibrinolytic drugs
tranexamic acid 1-1.5 g tds
Reduction in blood loss (%)
Prog. Oral seq
Prog. Oral cont
Antifibrinolytics
Prog. IUD
Anti-Fibrinolytic
Oral Contraceptive
GnRH analoque
Prostaglandine SI
Danazol
0
© PHMvdW 2010
20
40
60
80
100
How to treat menstrual bleeding problems ?
vasoconstriction
Inactive endometrium
Clotting mechanism
© PHMvdW 2010
PG Synthetase
inhibitors
Progestagen
Antifibrinolytics
How to treat Dysfunctional Uterine Bleeding ?
Progestagen
Reduction in blood loss (%)
© PHMvdW 2010
Prog. Oral seq
Prog. Oral cont
Prog. IUD
Anti-Fibrinolytic
Oral Contraceptive
GnRH analoque
Prostaglandine SI
Danazol
0
20
40
60
Progestagen oral continuous
80
Progestagen IUD
100
GnRH analoques
Danazol
OC
Progestagen oral sequential
1
© PHMvdW 2010
3
15
Days of cycle
21
28
How to treat menstrual bleeding problems ?
If cycle and bleeding problems are present
first correct cycle
Progestagens
OCC
If bleeding problems still persist
exclude anatomical / systemic pathology
Ultrasound
Hysteroscopy
Lab examination
If bleeding problems still persist
treat bleeding problems
PGSI
Antifibrinolytics
Progestagens
Surgery
© PHMvdW 2010
Health care for Women
© PHMvdW 2010