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Dysfunctional Uterine
Bleeding (DUB)
功能失调性子宫出血
Definition
Dysfunctional uterine bleeding (DUB):
Abnormal uterine bleeding with no
demonstrable organic causes.
• A diagnosis of exclusion
Epidemiology
• About 10% of the outpatients
• Common at the extremes of reproductive
life, but can occur at reproductive age:
50% at near menopause
20% in adolescents
30% at reproductive age
Key Learning Points
• Clinical classification and features of DUB
• Principles of treatment and methods
• Etiology and mechanism of DUB
• Common diagnostic methods and key points
in making the differential diagnosis
Normal menstrual cycle
A brief review
• Menstrual cycle
• Endometrial cycle
• Ovarian cycle
• Hypothalamic-pituitary-ovarian axis
Ovarian /Endometrial cycles
The normal menstrual cycle
• Menstruation is triggered by a sudden decrease in
progesterone and estrogen secretions.
• After menstruation, the increased secretion of estrogen
causes cellular growth and the regeneration of the
endometrium.
• After ovulation, the secretion of progesterone stops the
growth of the endometrium, turning the proliferative
phase into the secretory phase.
• If conception does not occur, the corpus luteum (黄体)
regresses causing declines in estrogen and progesterone
production, thus the next menstruating begins.
Classification
• Anovulatory bleeding (无排卵性DUB)
DUB that occurs without ovulation
• Ovulatory bleeding (排卵性DUB)
DUB that involves ovulation
Anovulatory bleeding
Etiology
• About 85% of all DUB
• In adolescents
Immaturity of the hypothalamic-pituitary-ovarian axis.
Especially, low response of hypothalamus and pituitary
gland to positive feedback from estrogen.
• In transitional period to menopause
(premenopausal/premenopausal)
Low response of the remaining follicles to gonadotropins.
• Women of reproductive age
Stress, fear, etc. interferes with ovulation
Pathophysiology
1. Patterns of bleeding
• Withdrawal bleeding
Decrease in estrogen
• Breakthrough bleeding
Low level of estrogen
High level of estrogen
2. Mechanism of the bleeding
Lack of progesterone causes defects in the selflimiting mechanism of menstruation
1) Friability of tissue
Lack of stromal support.
2) Incomplete shedding of endometrium
Not enough stimulation for epithelial regeneration.
(Complete loss of tissue is an effective stimulant
for epithelial regeneration.)
3) Abnormal structure and function of blood
vessels
Lack of spiralization of the arteries.
4) Abnormal production of vascular factors
PGE2, PGI2  causing dilation of blood vessels.
(Proliferative endometrium produces PGE2)
5) Abnormal coagulation and Fibrinolysis
Defects in TF and PAI-I
3. Pathologic changes of
endometrium
1) Hyperplasia endometrium
•
Simple hyperplasia
•
Complex hyperplasia
•
Atypical hyperplasia
2) Proliferative phase of endometrium
3) Atrophic endometrium
Proliferative phase and simple hyperplasia
Complex hyperplasia
Atypical hyperplasis and carcinoma in situ
Clinical Manifestation
Loss of regularity and self-limiting mechanism.
Bleeding may be long and heavy leading to
anemia and shock.
Diagnosis
DUB is a diagnosis of exclusion, so exhaustive
measures should be used to rule out organic
causes.
• Medical history
• Physical examination
• Laboratory tests
• Imaging tests
Medical history
Anovulatory DUB may show various patterns of
bleeding.
1. Menorrhagia (月经过多):
Prolonged (>7 days) or excessive (>80 ml) bleeding
that occurs at regular intervals
2. Polymenorrhea (月经频发):
Frequent, regular periods that occur less than every 21
days
Medical history
3. Metrorrhagia (子宫不规则出血):
Bleeding of various amounts that occurs at
irregular but frequent intervals
4. Menometrorrhagia(子宫不规则过多出血) :
Frequent, excessive, and prolonged bleeding that
occurs at irregular intervals
Medical history
• Contraceptive methods
• Liver diseases
• Hematopathy (血液病)
血小板减少
(甲状腺高功或低功)
Physical Examination
• Systemic diseases
• Reproductive tract
Laboratory and Imaging Tests
•
•
Blood coagulation tests
Assays for thyroid hormone and
prolactin
• A complete blood count
• A pregnancy test
• Ultrasound
Laboratory and Imaging Tests
•
Basal body temperature
• Cervical mucus
• Levels of female hormones tests
Patterns of cervical mucus
Laboratory and Imaging Tests
•
A Diagnostic D & C (dilatation and curettage)
Purpose:
Diagnosis and hemostasis (止血)
Indications:
Perimenopausal women at first visit or in whom
hormone therapy has failed.
Unmarried woman, when the bleeding is
intractable or a malignancy is suspected.
Laboratory and Imaging Tests
Hysteroscopy
•Endometrial polyp
•Submucous myoma
•Endometrial cancer
Differential diagnosis
•
Pregnancy and its related diseases
Ectopic pregnancy, abortion, gestational
trophoblastic diseases, poor uterine involution,
retention of placenta components
•
Diseases of the reproductive tract
Tumors: cancers, polyp, myoma
Inflammation: endometritis
Differential diagnosis
•
Systemic disorders
Hemorrhagic diseases, hyper-/hypothyroidism,
liver or kidney diseases
• Drug or IUD induced uterine bleeding
ERT(雌激素替代疗法),
oral contraceptives (避孕药)
Treatment
Principle of treatment
Depends on the age and clinical findings of the patients
For younger patients (adolescents and women of
reproductive age):
1. Hemostasis (止血)
2. Regulating bleeding cycle (调节周期)
3. Induction of natural ovulatory cycles (诱发自身排卵
周期)
Treatment
Principle of treatment
For perimenopausal women:
1. Hemostasis (止血)
2. Regulating bleeding cycle (调节周期)
3. (1) Reducing bleeding (usu. by accelerating the
arrival of menopause) (减少出血)
(2) Preventing cancer (预防癌变)
Treatment
Principle of treatment
• Correction of anemia
• If medical treatment fails, diagnostic D&C
or ablationof the endometrium or
hysterectomy has to be considered.
Treatment
1. Hemostasis
2. Regulating bleeding cycle
3. Promoting ovulation
Preventing cancer
Treatment
Hemostasis
1. Combination therapy
1) Progestin-dominate oral contraceptives
a) For adolescents with mild condition: cyclic
use starting from 1st day of menstruation
for 21 days
b) For profuse bleeding: 3 tablets/day, reduce
1/3 at 3 day interval till 1 tablet/day, for 20
days
Treatment
Hemostasis
2) Triple sex hormone injection
Components:
Estradiol benzoate (苯丙酸雌二醇) 1.25mg
Progesterone (黄体酮) 12.5mg
Testosterone propionate (丙酸睾丸酮) 25mg
In 1 ml
Usage:
2-3 times/day, reduce doses till 1 injection/day
for 20 days
Treatment
Hemostasis
2. Estrogens
Mechanism:
Promoting coagulation and endometrial regeneration
Indications:
Adolescents with low estrogen level and thin
endometrium
Contra-indications:
Hypercoagulability and a history of
thrombotic diseases (血栓性疾病)
Treatment
Hemostasis
Drug used:
(1) Conjugated estrogens /Premarin (结合雌激素/ 孕马
雌酮) (倍美力): 2.5mg, 4 times/day, reduce at 3 day
interval till 1.25mg/day for 20 days
(2) Diethylstilbestrol (DES) /Stilboestrol (己烯雌酚/乙
菧酚): 1mg, 4 times/day, reduce at 3 day interval till
1mg/day for 20 days
Medroxyprogesterone acetate (甲羟孕酮) (10mg/day) is
added for the last 7-10 days
Treatment
Hemostasis
Progestogens
Mechanism:
a) Stabilizing membrane of the lysosome.
b) Restoring the self-limiting mechanism.
c) Drug curretage
Indications:
For patients with some level of estrogens.
Treatment
Drugs used:
Hemostasis
1) If the bleeding is profuse, high does of progestogens
with subsequent reduction.
Norethisterone (炔诺酮/妇康片):5mg, oral, 3 times/day
reduce at 3 day interval till 2.5-5mg/day for 20 days
2) If the bleeding is a prolonged one and in small
amount, injection of progesterone/progestins (黄体酮/
孕酮), 20mg/day for 5 days.
Note: If the endometrium is thick, extending the use of
progestogen may decrease thickness of endometrium.
Treatment
Hemostasis
Adjuvant drugs
① Coagulants
Reptilase (立止血针剂)
② Antifibrinolytics (抗纤溶药物)
Aminomethylbenzoic acid (PAMBA)(氨甲苯酸/止血芳酸)，
Epsilon aminocaproic acid (EACA)(氨基己酸)，
Transamic acid (氨甲环酸/止血环酸/凝血酸)
③ Traditional Chinese medicine
云南白药，痛血康胶囊
Hemostasis
(3) Surgery
① D&C
② Hysterectomy
③ Endometrial ablation (with a hysteroscope)
Treatment
1. Hemostasis
2. Regulating bleeding cycle
3. Promoting ovulation
Preventing cancer
Regulating Bleeding Cycle
Purposes: Restoring ovarian function
Preventing endometrial cancer
Methods:
①Sequential therapy with E and P (artificial cycle)
② Combination therapy with E and P
③ Progestogen
Regulating Bleeding Cycle
①Sequential therapy with E and P (artificial cycle)
(雌、孕激素序贯疗法/人工周期)
For adolescents/reproductive age women with
low estrogen level
Withdrawal
bleeding
d1
P
E
d5
d16
d25
①Sequential therapy with E and P (artificial cycle)
(雌、孕激素序贯疗法/人工周期)
E: (1 ) Conjugated estrogens (结合雌激素/孕马雌酮)
Premarin (倍美力)
Usage: oral, 1.25mg/day
(2) DES (己烯雌酚)
Usage：oral, 2mg/day
P: Medroxyprogesterone (安宫黄体酮)
usage: 10mg/day
Regulating Bleeding Cycle
② Combination therapy with E and P
For patients at reproductive age who are
having relatively higher level of estrogen,
thick endometrium, and heavy withdrawal
bleeding or perimenopausal women.
E+P: contraceptive pills
Withdrawal
bleeding
d1
P
E
d5
d25
Regulating Bleeding Cycle
③ Progestogen for the second half cycle
For women near menopause
P: progesterone 20 mg/day, 5 days
Medroxyprogesterone 10mg/day, 10 days
Withdrawal
bleeding
d1
P
d16
d25
Treatment
1. Hemostasis
2. Regulating bleeding cycle
3. Promoting ovulation
Promoting ovulation
• Spontaneous ovulation usually occurs after the
sequential or combined therapy.
• For those that have failed the therapy,
ovulation inducing method may be tried.
• Methods:
1) Clomiphene citrate (氯米芬, CC) 50mg/day,
for 5 days starting from day 5.
Promoting ovulation
2) Human chorionic gonadotropin
(绒促性素, HCG)
3) Human menopausal gonadotropin
(尿促性素, HMG)
4) Gonadotropin releasing hormone agonist
(促性腺激素释放激素激动剂, GnRHa)
Ovulatory bleeding
排卵性月经失调
• Luteal phase defect, LPD
(黄体功能不全)
• Irregular shedding of endometrium
(子宫内膜不规则脱落)
Luteal phase defect
Low production of progesterone leading to
shortening of the luteal phase (<11 days)
• Causes
1. Dysplasia (发育不良) of ovarian follicles
2. Insufficiency of the LH peak
3. Defects in the lower LH impulse after LH peak
• Pathophysiology
Endometrium not well differentiated (secretory).
• Clinical manifestation
1. Polymenorrhea
2. Short high temperature phase in BBT
3. Infertility or loss of early pregnancy
• Diagnosis
1. Diphase in BBT, but high temperature phase
is short ( < 11 days)
2. Biopsy of the endometrium shows late
development of the secretory phase
(≥ 2 days)
• Treatment
1. Stimulating follicular development
CC 50mg/day or Premarin 0.625mg
for 5 days from 5th day
2. Enhancing the LH peak
HCG 5,000 or 10,000IU when the follicles are
mature
3. Stimulating luteal function
HCG for 5 days during luteal phase
4. Replacement therapy
Progesterone 10mg for 10-14 days in luteal phase
5. Bromocriptine for associated hyperprolactinemia
2.5-5mg/day
Irregular shedding of endometrium
Prolongation of the luteal regression process leading
to slow or incomplete shedding of the endometrium
• Pathophysiology
Incomplete regression of the corpus luteum.
Existence of secretory endometrium on day 5-6.
• Clinical manifestation
Length of menstrual cycle is normal, but
menstruation period is prolonged.
• Diagnosis
1. Diphase in BBT, but slow returning to the
lower temperature phase.
2. Endometrial biopsy at day 5 of the
menstrual cycle shows presence of
secretory endometrium.
Diagnosis
• Treatment
1) Progestogens
(progesterone 10mg or medroxyprogesterone
10mg)beginning from post ovulatory day 12 or
10 14 days before the next menses
2) HCG to stimulate luteal function
Notes on treatment
The treatment should be individualized.
• B-ultrasound
• Endometrial biopsy
• D&C
• Intrauterine progestogen-releasing system
Brief Summary
Anovulatory DUB
Susceptible population
Pathophysiology
Endometrium
Clinical features
Diagnosis
1) Diagnostic D and C
2) BBT
Treatment
Adolescents and premenopausal women
No ovulation, no progesterone
Hyperplasia, proliferative, atrophic
Irregular bleeding
Premenstrual or 6h within menses
Monophase
For adolescents: hemostasis,
regulating the cycle,
inducing ovulatory cycle
For premenopausal women:
reducing bleeding
preventing cancer
Luteal phase Defect
Susceptible population
Pathophysiology
Endometrium
Clinical features
Diagnosis
1) Diagnostic D and C
2) BBT
Treatment
Women at reproductive age
Production of P is insufficent
Secretion is not sufficient
Polymenorrhea, infertility, miscarriage
Insufficient secretion
Diphase, but short duration
Stimulating follicle growth (CC)
Enhancing LH peak and luteal function
(HCG)
Replacement of luteal function
(progesterone)
Irregular shedding of endometrium
Susceptible population Women at reproductive age
Pathophysiology
Late regression of corpus luteum, late
shedding of endometrium
Endometrium
Mixed endometrium on day 5-6
Clinical features
Menstrual cycle is normal, but
menstruation is prolonged.
Diagnosis
1) Diagnostic D and C Secretory endometrium on day 5-6
2) BBT
Diphase, but slow decline of BT
Treatment
Stimulating luteal function (HCG, P)
End
Treatment
after ruling out "organic" causes of bleeding
the first line treatment for DUB is hormonal
2. the objective of hormones is to promote
universal, synchronous endometrial
bleeding, structural stability and vasomotor
rhythmicity. This can be accomplished with
either progestin or oral contraceptive
therapy
3. progestins work by excreting a powerful
anti-estrogen effect (i.e. antimitotic and
antigrowth effect on endometrium)
1.
Acute bleeding - Emergency:
i.
ii.
1.
Stabilize.
- IV fluids +/- transfusion
- appropriate exam and investigations
Conjugated estrogens (e.g. Premarin) 25 mg
IVq4h until bleeding stops or for 12-24 hours.
Coincidentally start low dose monophasic BCP
(e.g. Minovral) one tablet po qid x 2 days, then
one. tablet po tid x 2 days, then one tablet po
bid x 2 days, then one tablet po OD x 2 weeks,
then allow withdrawal bleeding. On day 5 of
withdrawal bleeding start low dose monophasic
BCP cyclically for 3-6 months .