Normal Menstrual Physiology

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BLOODY HELL
Abnormal Uterine Bleeding
(AUB)
Dr. Christiane Kuntz
MD CCFP FCFP
Annual Scientific Assembly
Nov. 29, 2013
Faculty/Presenter Disclosure
• Faculty: Dr. Christiane Kuntz
• Program: 51st Annual Scientific Assembly
• Relationships with commercial interests:
–
–
–
–
Grants/Research Support: none
Speakers Bureau/Honoraria: see next slides
Consulting Fees: none
Other: none
Disclosure of Commercial
Support
• This program has received no financial support through any
commercial organization.
• This program has received no in-kind support from any
commercial organization.
• Potential for conflict(s) of interest:
– Bayer/Berlex are makers of Mirena which will be discussed in this
session; the company has provided unrestricted educational
grants to fund the Benign Uterine Conditions project sponsored by
the OCFP.
Mitigating Potential Bias
• The speaker has no direct involvement with
Bayer/Berlex in terms of financial support; the OCFP
administers the BUC program through an
unrestricted educational grant.
Abnormal Uterine Bleeding
Objectives
Define AUB in pre-, peri- and postmenopausal women
 Explore the etiology and pathophysiology
of AUB
 Review assessment tools
 Discuss treatment options
 Apply learning pearls through clinical
cases

Normal Menstrual Physiology
average cycle 28-35 d, with approximately
14-21 d in follicular phase and 14 d in
luteal phase (relatively constant)
 relatively little cycle variability ages 20-40
 cycle varies 5-7 y after menarche and for
10 y before menopause
 cycle often shortens as women approach
menopause

Normal Menstrual Physiology
follicular phase begins with the onset of
menstrual flow and ends on the day
before the luteinizing hormone (LH) surge
 luteal phase begins on the day of the LH
surge and ends at the onset of the next
menstrual period

Hormonal Changes during
Normal Menstrual Cycle

Normal Menstrual Physiology
Abbreviations
Estradiol (E)
 Progesterone (P)
 Gonadotropin-releasing hormone (GnRH)
 Follicle-stimulating hormone (FSH)
 Luteinizing hormone (LH)
 Transvaginal Ultrasound (TVUS)

Normal Menstrual Physiology


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Early follicular phase:
low E & P levels
release from the negative feedback effects of E,
P, and probably luteal phase inhibin A results in
late follicular phase increase in GnRH pulse
frequency and subsequent increase in FSH
 small increase in FSH secretion appears to be
required for the recruitment of the subsequent
group of developing follicles, one of which will
become dominant and ultimately ovulatory
follicle during that cycle
 rapid increase in LH pulse frequency at this time
Normal Menstrual Physiology

Early follicular phase:
TVUS has demonstrated that ovary is quiescent
except for occasionally visible resolving corpus
luteum from the previous cycle
 The endometrium is relatively indistinct during
menses and then becomes a thin line once
menses is complete
 normal to see small follicles of 3 to 8 mm in
diameter at this time

Normal Menstrual Physiology

Mid-follicular phase:
Increase in FSH secretion causes follicle growth
and E production
 Ovarian follicle granulosa cells hypertrophy and
divide, producing increasing E via FSH
stimulation of aromatase and then inhibin A
 Increase in E production feeds back negatively
on the hypothalamus and pituitary, resulting in
suppression of mean serum FSH and LH
concentrations as well as the LH pulse amplitude

Normal Menstrual Physiology

Mid-follicular phase:
In comparison, the GnRH pulse generator
speeds up slightly to a mean LH pulse
frequency of about one per hour (vs. one
per 90 minutes in early follicular phase)
 GnRH stimulation is presumably due to
release of negative feedback effects of P
from the previous luteal phase

Normal Menstrual Physiology

Mid-follicular phase:
Within about 7 d from the onset of
menses, several 9 to 10 mm antral follicles
are visible on TVUS
 increasing E results in thickening
endometrium, with increase in number of
glands and development of "triple stripe"
pattern on TVUS

Normal Menstrual Physiology


Late follicular phase:
E and inhibin A levels increase daily during the
week before ovulation due to release from the
growing follicle
 Serum FSH and LH concentrations decrease at
this time due to negative feedback effects of E
 As dominant follicle selected and grows, FSH
induces LH receptors in the ovary and increases
ovarian secretion of intrauterine growth factors
such as insulin-like growth factor-I (IGF-I)
 Endometrium thickens further
Normal Menstrual Physiology


Mid-cycle surge and ovulation:
E continues to rise until peak approximately 1 d
before ovulation
 Mid-cycle surge represents a switch from
negative feedback control of LH secretion by
ovarian hormones (such as E & P) to sudden
positive feedback effect, resulting in 10X
increase in LH and smaller rise in FSH
 other ovarian factors contribute to the LH surge
besides E & P (poorly understood)
Normal Menstrual Physiology
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Ovulation:
LH surge initiates substantial changes in the ovary
Oocyte in dominant follicle completes its first meiotic
division
Local secretion of plasminogen activator and other
cytokines required for ovulation increased
Oocyte is released from the follicle at the surface of the
ovary approximately 36 hours after LH surge
Oocyte travels down fallopian tube to the uterine cavity
Close relation of follicular rupture and oocyte release to
the LH surge and as a result, measurements of serum or
urine LH can be used to estimate the time of ovulation in
women
Normal Menstrual Physiology

Ovulation:

Even before oocyte released, granulosa cells surrounding
it begin to luteinize and produce progesterone
Progesterone acts rapidly to slow pulse generator so that
LH pulses become less frequent by the termination of
surge
Gradually increasing serum P has a profound impact on
the endometrial lining initiating cessation of mitoses and
"organization" of the glands
Change can be detected on US relatively soon after
ovulation: the "triple stripe" image is lost and the EE
becomes more uniformly bright



Normal Menstrual Physiology

Mid- to late luteal phase:
Rising P concentrations leads to progressive slowing of
LH pulses down to one pulse every four hours
 Pulses of P occur soon after these slow LH pulses
 As a result, there can be significant excursions in serum
P concentrations during the luteal phase
 Inhibin A is also produced by the corpus luteum, and
serum concentrations of inhibin A peak in the mid-luteal
phase
 Inhibin B secretion is virtually absent and serum leptins
are highest during luteal phase

Normal Menstrual Physiology

Late luteal phase:
Gradual decrease in LH secretion results in
gradual fall in P & E production by the corpus
luteum in absence of a fertilized oocyte
 If oocyte becomes fertilized, it implants in the
endometrium several days after ovulation
 early embryo begins to make chorionic
gonadotropin, which maintains the corpus
luteum and P production

Normal Menstrual Physiology



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Late luteal phase:
decline in E & P release from resolving corpus luteum
results sequentially in loss of endometrial blood supply,
endometrial sloughing, and onset of menses about 14
days after the LH surge
Menses is relatively imprecise marker of hormonal
events in the menstrual cycle, since there is considerable
inter-individual variability in relationship between the
onset of endometrial sloughing and fall in serum
hormone concentrations during luteal phase
In response to falling corpus luteum steroid production,
the hypothalamic-pituitary axis is released from negative
feedback and FSH levels rise, thereby beginning next
cycle.
Abnormal Uterine Bleeding
Premenopausal Women
Definition
Any variation from the normal menstrual cycle,
including changes in regularity and frequency of
menses, in duration of flow, or in amount of
blood loss
 Subdivided based on volume of menstruation,
regularity, frequency, duration, chronicity, and
timing related to reproductive status
 Bleeding not related to menses may be further
characterized as well

Abnormal Uterine Bleeding
Premenopausal Women
Categories

Ovulatory AUB


usually regular
often associated with premenstrual symptoms and
dysmenorrhea

Anovulatory AUB

more common near menarche and the perimenopause
often irregular, heavy, and prolonged flow
more likely to be associated with endometrial
hyperplasia and cancer


Abnormal Genital Bleeding
Premenopausal Women
Differential Diagnosis
Anatomic categorisation:
 Uterus – pregnancy, menorrhagia,

anovulatory – periods of transition in
reproductive life including adolescence
and perimenopause; PCO, endocrine,
other; fibroid, polyp, adenomyosis,
structural abnormalities; Ca; FB; infections
like endometritis/PID; bleeding disorders;
meds; ruptured ovarian cyst
Abnormal Genital Bleeding
Premenopausal Women
Differential Diagnosis


Anatomic categorisation contd.:
Cervix – polyps, cervicitis, ectropian, Ca, pelvic
floor laxity
 Vagina – vaginitis, trauma, Ca, fistulas, benign
neoplasms, cysts, radiation changes, FB, atrophy
 Vulva – infection, benign growths, Ca, trauma
 ***Neighbouring structures – bowel, urethra,
bladder, systemic disease involving skin in
region eg. Crohn’s, lichen sclerosis
Abnormal Genital Bleeding
Premenopausal Women
Differential Diagnosis



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In adolescent within the first 1.5-2 years following
menarche, the AUB may be caused by an immature HPO
axis***
Other Endocrine Causes:
PCOS, CAH, hyperprolactinemia, Cushings, thyroid
dysfunction, pituitary tumors
Meds: see list
Infections: vulva, vagina, cervix etc.
Bleeding disorders
Systemic disorders eg. DM, renal failure, SLE, Ca
Structural lesions eg. fibroids, polyps
Other Causes: FB, trauma
Abnormal Uterine Bleeding
Premenopausal Women
History





Systemic: SOB, dizziness – consider anemia; Sx of
hypothyroidism, hyperprolactinemia, coagulation
disorders, polycystic ovary syndrome, adrenal or
hypothalamic disorders
GU Sx: vaginal discharge, change in odor, pelvic
pain/pressure
Sexual Hx: contraception, pregnancy risk, STDs,
cervical screening
Reproductive Hx: family planning, infertility
Social Hx: impact on QOL including sexual function
Medications causing AUB




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Anticoagulants
Antidepressants (selective serotonin reuptake
inhibitors and tricyclics)
Hormonal contraceptives
Tamoxifen
Antipsychotics (first generation and risperidone)
Corticosteroids
Herbs: ginseng, chasteberry, danshen
Abnormal Uterine Bleeding
Premenopausal Women
History
PMH: hormonally dependent tumours,
thromboembolic disease, or cardiovascular
problems – affects Rx choices
 FH: inherited coagulation disorders,
PCOS, endometrial or colon cancer

Abnormal Uterine Bleeding
Premenopausal Women
Physical Exam
Vital signs
Weight/BMI
Thyroid exam
Skin exam (pallor, bruising, striae, hirsutism, petechiae)
Abdominal exam (mass, hepatosplenomegaly)
GU: inspection: vulva, vagina, cervix, anus, and urethra;
Bimanual examination of uterus and adnexal structures;
Pap smear, cervical cultures if risk for sexually
transmitted infection
 Rectal examination if bleeding from rectum suspected or
risk of concomitant pathology

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
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Investigations:

CBC
Pregnancy test (urine or serum) if any chance of
pregnancy
TSH if there is other evidence of thyroid disease
Coagulopathy tests if FH of coagulopathy or if
woman has had AUB since menarche
FSH – measure twice 1 month apart; irregular
bleeding could herald POI (my suggestion)




AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Imaging:
Transvaginal US (TVUS) is first line
 Saline infusion sonogram (SIS) and
diagnostic hysteroscopy to be used for Dx
of intrauterine abnormalities such as
submucosal fibroids or polyps or
abnormally structured uterus

AUB Management
Premenopausal Women

TVUS endometrial thickness in premenopausal woman:
Follicular phase: as thin as 4 mm
 Luteal phase: up to 16 mm

AUB Management
Premenopausal Women
SOGC Guidelines May 2013


Imaging:
MRI rarely used to assess the endometrium in
patients who have menorrhagia
 may be helpful to map exact location of fibroids
in planning surgery and prior to therapeutic
embolization for fibroids
 may also be useful in assessing the
endometrium when transvaginal ultrasound or
instrumentation of the uterus (i.e. congenital
anomalies) cannot be performed.
FIBROIDS

Benign smooth muscle tumors of uterus
 If asymptomatic do not require treatment
 Symptoms: pain/pressure, bowel and bladder
dysfunction, AUB/anemia & infertility
 Physical exam and ultrasound
 Must SAMPLE ENDOMETRIUM if AUB and
risk factors for cancer present.
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Tissue sampling:

Endometrial biopsy (Bx) should be
considered in bleeding women over age
40 or in those with bleeding not
responsive to medical therapy, as well as
in younger women with risk factors for
endometrial cancer.
AUB Management
Risk Factors for Endometrial Ca
Fam. Hx endometrial or colon Ca (HNPCC)
 Age > 40
 Diabetes type II
 PCOS/Anovulatory cycles
 Obesity (BMI > 30 kg/m2)
 Nulliparity
 Tamoxifen

AUB Management
Pre-menopausal Women

Indications:
 Pre-menopausal
 Any
persistent change in menstrual cycle, frequency,
duration, or flow
 Breakthrough bleeding
average age for women with endometrial
cancer is 61 years, but 5% to 30% of cases occur
in premenopausal women (SOGC May 2013)
 ***The
AUB Management
Endometrial Biopsy

Purpose is to evaluate the endometrial lining for:
 Cancer
 Pre-cancerous tissue (hyperplasia)
 Normal endometrial growth


Infertility: luteal phase defect
Small tube inserted through the os

Office procedure
AUB Management
Endometrial Biopsy

Sensitivity to detect abnormalities 81-96 %
 Comparable
to D&C; may be better
 Less reliable than hysteroscopy

Adequate sample obtained > 85%
 OHIP billing: Z770 & E542
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Tissue sampling:
Office endometrial Bx should replace D&C
as initial assessment of endometrium
 Focal lesions of endometrium requiring Bx
should be managed through hysteroscopyguided evaluation

AUB Management
Interpreting Endometrial Biopsy

Normal
 Symptoms resolve→follow
 Symptoms persist→TVUS
 Unable to perform/inadequate sample
 Repeat
 TVUS
AUB Management
Interpreting Endometrial Biopsy

Hyperplasia without atypia
 Provera 10mg od/ Prometrium 200 mg po/pv for
30 days or cyclic 12-14 days x 3- 6 months
 Repeat biopsy 3- 6 months
 Hyperplasia with atypia, cancer→refer
AUB Management
Medications for AUB

NSAIDS
 Tranexamic acid (Cyklokapron)
 OCP (combined)
 Mirena
 Progestins (oral, IM)
 GNrH agonist
 Danazol
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:

Non-hormonal options such as NSAIDs
and antifibrinolytics (tranexamic acid or
Cyklokapron) can be used effectively to
treat heavy menstrual bleeding that is
mainly cyclic or predictable in timing
AUB Management
Medications for AUB

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Cyclokapron:
Synthetic derivative of lysine (amino acid)
Antifibrinolytic effect through reversible blockade
on production of plasminogen
Coagulation/dysmenorrhea not affected
s/e: nausea, leg cramps in 30%
Dose: 2-3 tabs (500 mg) tid prn - start Rx at
onset of bleeding for heaviest days
Cost: $1/tab generic; $1.50 trade name
**Calendar BMJ 1970;24:214-6
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:

Combined oral contraceptive pills, depot
medroxyprogesterone acetate, and
levonorgestrel-releasing intrauterine
systems significantly reduce menstrual
bleeding and should be used to treat
women with abnormal uterine bleeding
who desire effective contraception
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:

****In premenopausal women who have
regular periods, cyclic luteal-phase
progestins do not effectively reduce blood
loss and therefore should not be used as a
specific treatment for heavy menstrual
bleeding
AUB Management
Medications for AUB

Danazol:

Synthetic steroid with mild androgenic properties
Inhibits steroid production in the ovary
80% reduction in menstrual blood loss
20% of patients develop amenorrhea; 70 % of
women develop oligomenorrhea
s/e – none in 50%; 20% report minor concerns
like weight gain 2-6 lbs.
Dose: 100-200 mg od for three months

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
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AUB Management
Medications for AUB

GnRH agonists:
induce reversible hypoestrogenic state –
like “temporary menopause”
 Decrease fibroids and uterine volume by
40-60% (reverses within months of
stopping Rx) which decreases blood flow
 s/e: hot flashes; decreased bone density
 **Friedman Obs Gyne 1991;77:720-5.

AUB Management
Medications for AUB

GnRH agonists:
Leuprolide (Lupron) depot given IM 7.5
mg q monthly or 11.25 mg q 3 months for
6-12 months – duration of Rx based on
individual woman
 Add back therapy – progestin +/- estradiol
transdermal preferred – patch/gel

AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:
Danazol and gonadotropin-releasing hormone
(GnRH) agonists to be used when other medical
or surgical treatments have failed or are
contraindicated
 women receiving GnRH agonist for longer than 6
months should be prescribed add-back hormone
therapy if not already initiated with GnRH
agonist commencement

AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:

Progestin intrauterine system (ie. Mirena)
has outcomes similar to endometrial
ablation for women with heavy menstrual
bleeding and thus may be considered prior
to surgical intervention
Progestin Intrauterine System
(Mirena)

Indication initially: contraception
 Also used for:
 AUB
 Endometriosis
 Fibroids
 Endometrial Hyperplasia
Progestin Intrauterine System
(Mirena)

Breakthrough bleeding up to 6 months
 followed

by amenorrhea in 70 % by one year
Mild cramps upon insertion
 Possible progesterone side effects from
systemic absorption in first few weeks
 Expulsion, perforation rate (1/1000)
Progestin Intrauterine System
(Mirena)

T-shaped device which releases 20 ug/day of
levonorgestrel locally in the uterine cavity
 Inserted in the office, similar to regular IUD
 Lasts 5 years
 $400 + script fee ($11.99 at SDM Sept. 2013)
 Device covered on ODB
 OHIP billing: G378 & E430
Progestin Intrauterine System
(Mirena)

Insert early in cycle (days 4-8) to reduce
spotting/bleeding
 Consider priming with OCP x 1-2 months if
severe menorrhagia
 Warn patient about potential side-effects to
improve compliance
 Ovulation will continue normally in most ♀
Progestin Intrauterine System
(Mirena)

Immediately effective as contraceptive, and
immediately reversible
 May get free replacement if dropped, expulsed,
or causing pain
 No need to remove if endometritis; treat with
Mirena in-situ
 May do PAP, SIS, and endo biopsy with
Mirena in-situ
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:

With the exception of NSAIDs, same
medical agents used to treat heavy
menstrual bleeding among women with
normal coagulation can effectively be used
in the setting of inherited bleeding
disorders
AUB Management
Premenopausal Women
SOGC Guidelines May 2013

Treatment:
Acute heavy menstrual bleeding should be
managed promptly and systematically to
minimize patient morbidity and the need
for blood transfusion using high-dose
estrogen and tranexamic acid
 Consider possible bleeding disorder in
recently menarchal adolescents

AUB Management
Premenopausal Women
Surgery

D&C: out of favor; bleeding decreased for
a couple of months after procedure and
then returns to pre-treatment levels
 Endometrial ablation: usual outcome
markedly decreased menstrual flow rather
than amenorrhea

Hysterectomy
AUB Management
Premenopausal Women
Surgery

Endometrial Ablation:
surgical destruction of the endometrium
 Resectoscopic ablation performed under
hysteroscopic guidance, using resectoscopic
instruments to ablate or resect the endometrium
 Non-resectoscopic ablation performed with a
disposable device which is inserted into the
uterine cavity and delivers energy to uniformly
destroy the uterine lining

AUB Management
Premenopausal Women
Surgery

Endometrial Ablation:
Designed for women who have completed
their families
 Contraception still required for those who
are sexually active
 Pre-op: biopsy needed to rule out Ca and
hyperplasia
 Post-op: cramping and vaginal discharge

AUB Management
Premenopausal Women
Surgery

Endometrial Ablation:
Presence of submucosal fibroids make
procedure less effective; may need to be
removed prior to ablation
 Endometrial preparation using GnRH
agonists recommended prior to ablation
(using either resectoscope or nonresectoscope procedure)

AUB Management
Premenopausal Women
Surgery

Resectoscope vs. Non-resectoscope
endometrial ablation:
Equal efficacy and patient satisfaction
 Resectoscopic ablation - regional or
general anesthesia
 Non-resectoscopic uses local, regional, or
general anesthesia

AUB Management
Premenopausal Women
Surgery

Resectoscopic endometrial ablation
Cons: more frequent use of general anesthesia,
longer duration, increased risk of surgical
complications like fluid overload
 Pros: less costly per procedure; optimal for
women with acute flexion or version of the
uterus that does not allow a non-resectoscopic
ablation device to reach the uterine fundus;
better for women undergoing repeat procedure

AUB Management
Premenopausal Women
Surgery

Hysterectomy (minimally invasive):

option in women who desire definitive
therapy and who are willing to accept the
risk of perioperative complications
AUB Management
Premenopausal Women
Surgery

Endometrial ablation vs. hysterectomy:
ablation less costly, lower complication
rates of bleeding and infection (sexual
effects?), less recovery time post-op
 At 2 yrs. post-op patient satisfaction
favored hysterectomy (79 vs. 71%) but at
4 yrs. basically the same

Abnormal Uterine Bleeding
Postmenopausal Women (PMW)
Postmenopausal bleeding (PMB) refers to
any uterine bleeding in a menopausal
woman (other than that expected with
progestin withdrawal in cyclic combined
postmenopausal hormone therapy)
 Unexpected vaginal bleeding in PMW must
be investigated

Abnormal Uterine Bleeding
Postmenopausal Women (PMW)
Vaginal bleeding occurs in 4-11% of PMW
 In PMW with vaginal bleeding, the risk of
uterine Ca is 7.3% if the endometrial
thickness or echo (EE) is >5 mm and
<0.07% if EE is thin < or = 5 mm**
 As age increases the risk for endometrial
Ca for each EE measurement increases
 **Smith-Bridman Ultrasound Obstet
Gynecol 2004;24(5):558

Causes of AUB
Postmenopausal Women

Atrophy**
 Endometrial Polyp
 Endometrial Hyperplasia
 Endometrial Cancer
 Hormonal effect
 Cervical Cancer
 Other
Source: Karlsson et al 1995
59%
12%
10%
10%
7%
<1%
2%
AUB Management
Endometrial Biopsy

Indications in PMW:
 Vaginal
bleeding > 12 months after last period
 Bleeding
> 6-12 months after initiating HT
AUB Management
PMW

If AUB occurs, evaluate endometrium and
uterine cavity as well as the genital tract and
external genitalia


Either endometrial Bx, TVUS or both can be done to
initially assess the endometrium
Can base choice of first investigation upon patient
preference, physician comfort with procedure, US
availability
Abnormal Uterine Bleeding
Postmenopausal Women (PMW)

If TVUS done as initial investigation,
endometrial cancer can reasonably be
excluded in postmenopausal women with
a thin (<5 mm), homogeneous
endometrium.
AUB Management
Endometrial Biopsy

Endometrial tissue sampling required if:

Endometrial thickness > 4 mm

Endometrium heterogeneous or irregular in
thickness within various areas of the cavity

Endometrium not adequately examined

PMW bleeds persistently
AUB Management
PMW
Once endometrial Ca excluded no need for
further treatment of bleeding
 Endometrial ablation not recommended
for PMW – can be difficult to assess for Ca
after procedure

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