Dysfunctional Uterine Bleeding

Objectives
Become familiar with the normal menstrual cycle and the pathophysiology of
DUB.
Understand options for evaluation of DUB.
Develop an understanding of treatment options for DUB.
Introduction
Dysfunctional uterine bleeding (DUB) is defined as abnormal uterine bleeding caused by
a hormonal mechanism. Any alteration of the normal menstrual cycle mechanisms can
lead to steady-state estrogen roduction and DUB.
!he "ormal #enstrual $ycle
%&'
!he events of the menstrual cycle are sho(n in )igure %. !he first day of a tyical cycle
(day l) corresonds to the first day of menses. !he menstrual phase usually lasts * days
and involves the disintegration and sloughing of the functionalis layer of the
endometrium. +rostaglandins are involved in regulation of menses& (ith rostaglandin
)'-alha causing myometrial contractions and vasoconstriction& and rostaglandin ,'
causing vasodilitation and muscle rela-ation.
%

!he proliferative (follicular) phase e-tends from day . to day %* of the tyical cycle. It
is mar/ed by endometral roliferation brought on by estrogen stimulation. !he estrogen
is roduced by the develoing ovarian follicles under the influence of follicle stimulating
hormone ()01). !here is mar/ed cellular roliferation of the endometrium and an
increase in the length and convolutedness of the siral arteries. ,ndometrial glands
develo and contain some glycogen. !his hase ends as estrogen roduction ea/s (must
be greater than '22 g3ml for more than '* hours)& triggering the )01 and luteini4ing
hormone (51) surge.
%
6uture of the ovarian follicle follo(s& (ith release of the ovum
(ovulation).
!he secretory (luteal) phase is mar/ed by roduction of rogesterone and less otent
estrogens by the corus luteum.
'
It e-tends from day %. to day '7 of the tyical cycle.
!he functionalis layer of the endometrium increases in thic/ness& and the stroma becomes
edematous. !he glands become tortuous (ith dilated lumens and stored glycogen. If
regnancy occurs& the lacenta roduces human chorionic gonadotroin (1$8) to relace
rogesterone& and the endometrium (and regnancy) is maintained.
If regnancy does not occur& the estrogen and rogesterone feed bac/ to the
hyothalamus& and )01 and 51 roduction falls. !he siral arteries become coiled and
have decreased blood flo(. At the end of this eriod& they alternately contract and rela-&
causing disintegration of the functionalis layer and menses.


!erms
%-*
"ormal menstruation - regular cyclic uterine blood flo( lasting ' to 9 days (ith
an interval of '% to :. days and a tyical blood loss of '2 to 92 ml.
#enorrhaga - rolonged or e-cessive uterine bleeding occurring at regular
intervals.
#etrorrhaga - uterine bleeding occurring at irregular and more fre;uent than
normal intervals.
#enometrorrhagia - rolonged or e-cessive uterine bleeding occurring at
irregular and more fre;uent than normal intervals (the ' above combined.)
Intermenstrual bleeding - (commonly called <sotting<) uterine bleeding of
variable amounts occurring bet(een regular menstrual eriods.
+olymenorrhea - uterine bleeding occurring at regular intervals of less than '%
days.
Oligomenorrhea - uterine bleeding occurring at intervals of :. days to si- months.
Amenorrhea - no uterine bleeding for 9 months or longer.
+athohysiology
DUB is most common near the beginning and end of a (oman=s reroductive life& but
may occur at any time. In the first %7 months after menarche& the immature
hyothalamin-ituitary a-is may fail to resond to estrogen and rogesterone& resulting in
anovulation.
'&:
In obese (omen& the non-ovarian endogenous estrogen roduction may
uset the normal menstrual cycle.
.
As menoause aroaches& decreases in hormone
levels or in resonsiveness to hormones also may lead to anovulatory DUB. +otential
causes of vaginal bleeding are sho(n in !able %.

Table 1. Causes of dysfunctional uterine bleeding.
ndocrine
$ushing=s disease
immature hyothalamin-ituitary
a-is
hyerrolacinemia
hyothyroidism
menoause
obesity
olycystic ovary disease
remature ovarian failure
!tuctural lesions
adenomyosis
coaguloathies
condyloma acuminata
dyslastic or malignant lesion of the
cervi- or vagina
endometiosis
endometrial cancer
"nfections
chlamydia
gonorrhea
+ID
#edications
hormonal agents
lo(-dose oral contracetive ills
(O$+s)
nonrogestin-containing IUDs
nonsteroidal anti-inflammatory drugs
("0AID0)
"orlant 0ystem
rogestin-only contracetive (the <mini
ill<)
tamo-ifen
(arfarin
uterine or cervical olys
uterine leiomyomata
trauma
$regnancy
ectoic regnancy
incomlete abortion
regnancy comlications

#ost cases of DUB are caused by anovulatory cycles that result in high steady-state
estrogen (ith no rogesterone.
l&.&9
!he continuous estrogen stimulation causes continuous
develoment of the functionalis layer until estrogen feedbac/ roduces a slo( dro in
)01. ,ventually& the blood suly is outgro(n and arts of the endometrium slough.
,strogen& ho(ever& romotes healing of the endometrium so some arts are al(ays
healing as others slough& resulting in menometrorrhagia.
'&:

A luteal hase deficiency also may result in DUB. It is characteri4ed by a shortened luteal
hase from insufficient rogesterone roduction or effect.
9&>
!he insufficient rogesterone
stimulation may be coe-istent (ith high& lo(& or normal estrogen levels and often (ill
result in similar roblems in anovulatory cycles. !his roblem& along (ith the loss of 51
surge& may be esecially rominent in amenorrheic athletes.
9-7

Another mechanism of DUB& esecially in atients (ho are *2 years old and older& is
diminishing number and ;uality of ovarian follicles. )ollicles continue to develo but do
not roduce enough estrogen in resonse to )01 to trigger ovulation. ,strogen continues
to be roduced& (hich usually results in late cycle estrogen brea/through bleeding.
%&'

Imroer balance of estrogen and rogesterone may result in DUB. It may result in lo(
estrogen states from lo(-dose oral contracetive ills (O$+s)& resulting in insufficient
build u of stable endometrial lining& (ith resultant rolonged light bleeding.
:-?
DUB can
also be caused by high rogestin activity oral contracetive ills.
:
!hese atients (ill
often need a higher level of estrogen or a lo(er activity rogestin.
?
Bleeding irregularities
are very common (ith the "orlant 0ystem& deo-medro-yrogesterone injection& and
the <mini ill&< (hich is often the reason these contracetives are discontinued.
%2&%%

"onrogestin-containing IUDs also may cause DUB.
*
"onsteroidal anti-inflammatory
drugs ("0AID0) or sulemental estrogen as described belo( may hel (ith this side-
effect.
,ndocrine disorders also may cause DUB. 1yerrolactinemia inhibits roduction and
release of gonadotroin-releasing hormone. +olycystic ovary disease often resents as
anovulatory cycles resulting in DUB.
.
1yothyroidism& hyerthyroidism& and $ushing=s
disease can be associated (ith DUB.
*&%'
)inally& remature ovarian failure may be a factor
in atients (ho resent (ith DUB.
.

+ostcoital bleeding usually indicates a structural lesion of the cervi- or vagina.
%
Infectious
etiologies such as chlamydia and gonorrhea must be e-cluded or treated. Uterine or
cervical olys also may be a source of bleeding.
*
Dyslastic or malignant lesion of the
cervical or vaginal eithelium may cause irregular or ostcoital bleeding.
'&*

An enlarged uterus may be caused by adenomyosis& uterine fibroids& endometriosis& or
regnancy.
'&*&%:
0ubmucosal myomas and endometrial olys are associated (ith DUB in
both remenoausal and ostmenoausal (omen.
%:
,ctoic regnancy and regnancy
comlications also must be ruled out. A high inde- of susicion for the ossibility of
regnancy must be maintained.
'&*
,ndometrial cancer should be e-cluded& esecially in
older and high-ris/ atients (ith this symtom.
%&'&*

,ndometrial $ancer
One of the most imortant goals in (or/-u of DUB is to rule out endometrial cancer&
esecially in older (omen. Develoment of endometrial cancer is related to estrogen
stimulation and endometrial hyerlasia. 6is/ factors are sho(n in !able '. 0ymtoms
include ostmenoausal bleeding& (hich is usually considered endometrial cancer until
roven other(ise.
%*
Bleeding revalence may be as high as %3: of cases& and the resence
of uterine myomas should "O! delay aroriate (or/-u. Other symtoms may include
metrorrhagia& lo(er abdominal ain or ressure& and (rarely) bac/ ain or lo(er
e-tremity edema secondary to metastasis.
$linical findings most commonly are a normal e-am of vagina& uterus& and cervi-&
although advanced disease may be associated (ith enlarged uterus or elvic mass.
$ervical and vaginal metastasis can cause cervical stenosis& yometra& or a
mucosanguineous vaginal discharge. 6egional metastasis may resent as a bladder or
rectal mass.

Table %. &is' factors for endometrial cancer.
*%-*>
(&& ( relative ris')
Age - >.@ of cases occur after menoause
(ith ea/ incidence in the late 92s.
Obesity - esecially uer body fat. !his
may
be secondary to increased estrogen
roduction and bioavailability.
+olycystic ovary disease.
Unoosed e-ogenous estrogen.
Ahen rogestins are added (oral
contracetives
or (ith relacement theray)& relative ris/ is
less
than for the general oulation.
66 (age B 92 years) C ..'

66C : to %2


66 C ..'
66 C ' to %*
66C 2.. to %


66 C ' to '.7


Diabetes (all tyes groued).
+ersonal or family history of ovarian or
breast
cancer. Aomen (ho are over(eight and
have
had breast cancer are at even greater ris/.
"ulliarity.
5ate menoause.
!amo-ifen theray - Use for greater than
one
year is an indeendent ris/ factor.


66 C %.:
66 (entering menoause after age .') C '..
66 C >..
,valuation
,valuation of DUB emhasi4es establishing the cause and ruling out endometrial cancer.
A tyical algorithm ()igure ') begins (ith a thorough history. Imortant factors to
document include atient=s age& last menstrual eriod& last normal menstrual eriod&
amounts and duration of bleeding& ostcoital bleeding& medications (esecially hormonal
agents& "0AID0& or (arfarin)& history of any endocrine abnormalities& symtoms of
regnancy& symtoms of coaguloathies& contracetive history& and history of trauma.
8eneral hysical e-amination should focus on symtoms of endocrinoathies& including
olycystic ovary disease (including obesity and hyerandrogenism)& hyerrolactinemia&
and hyothyroidism.
'
+elvic e-amination is unnecessary in oligomenorrheic atients (ho
are not se-ually active and are (ithin %7 months of menarche.
:
Other(ise& gynecologic
e-amination includes insection of the vagina and cervi- for hysical lesions (olys&
leiomyomata& tears& malignancy& or incomlete abortion) or infection. !he si4e& shae&
osition& and firmness of the uterus should be e-amined. "ote any signs of e-cessive
blood loss.
Basal temerature charting may assist in determining (hen and (hether ovulation occurs&
if the atient (ill cooerate (ith testing. !he atient may ta/e her temerature any time
during the day as long as she is consistent from day to day. A rise in basal temerature of
2.:
D
$ to 2.9
D
$ is indicative of ovulation. !his determination may also be made using
serum rogesterone determination in the luteal hase& (ith a level greater than : mg3m5
indicating ovulation has occurred.
'



Table ). *aboratory tests to consider for DUB. Testing should be
individuali+ed based on each patiet,s history and physical findings.
Test "ndication (to rule out)
urine regnancy test
$B$
+!3+!!
+a smearE
)01
liver function tests
!01
rolactin level
D1,A0
regnancy
anemia
coagulathy (esecially in adolescents
cervical cancer
B *2IU35 suggests ovarian failure
liver disease
thyroid disease
ituitary adenoma ((ith breast
discharge)
olycystic ovary disease
E if there is no evidence of infection and it is indicated

Diagnostic !ests
ndometrial biopsy (#B) is the most commonly used diagnostic test for DUB (ages
%> -%?). It rovides an ade;uate samle for diagnosis of endometrial roblems in ?2@ to
%22@ of cases&
%.&%9
but may fail to detect olys and leiomyomas.
%>
It is indicated in all
(omen (ith DUB (ho are :. years of age or older& since their ris/ of develoing
malignancy is much higher.
'&:
Any (oman (ith amenorrhea for one year or longer (ho
e-eriences uterine bleeding also should have an ,#B.
'
!he ne(er slim endometrial
suction currettes (+ielle) roduce samles comarable to older& more traumatic methods
but (ith less ain.
%&:&%.&%9&%7
0amling should be erformed late in the cycle if ossible& so it
can be determined if ovulation has ta/en lace.
:

Uterine ultrasound& esecially transvaginal ultrasonography (!F-U0)& can give
information about susected structural roblems including fibroid tumors.
'&%>&%?
It is
classically indicated (hen hysical e-am indicates anatomic gynecologic abnormalities&
esecially of the ovaries (here other methods rovide oor information.
%?
!he
endometrial strie assessment on !F-U0 can rovide information about the ovulatory
stage of the endometrium that has a ?:@ correlation (ith hystological diagnosis.
%?
An
endometrial thic/ness measurement of less than * to > mm is rarely associated (ith
cancer& and endometrial samling may not be necessary in such atients.
%>& '2& '%

Dilatation and curettage (DG$) allo(s more e-tensive samling of the uterine cavity
and has the advantage of being both diagnostic and theraeutic. It may be the treatment
of choice (hen bleeding is severe or necessitates blood transfusions.
'
It has a higher
sensitivity than endometrial biosy& esecially (ith smaller in-situ lesions. It is often
used (hen ,#B is inade;uate& the cervical os is stenotic& or DUB treatment fails.
%& :& %7

Ahen DG$ is combined (ith endometrial biosy& the detection rate aroaches %22@.
)ractional DG$ is usually not used in teenagers& because they rarely have endometrial
cancer and the rocedure may damage the cervi- or uterus.
.
It is currently re;uired for
the staging of occult cancer.
%*& ''

-ysteroscopy can be used in lace of DG$ for most indications& and allo(s for direct
visuali4ation of the endometrial cavity (ith directed biosy. 1ysteroscoy is more
sensitive than fractional DG$& esecially at diagnosing olys and submucosal
leiomyomas& but it may miss endometritis.
':& '*
Ahen combined (ith ,#B& it has almost
%22@ accuracy in diagnosing endometrial dyslasia and cancer. '* It may eventually
become re;uired for staging of occult cancer. 5i/e ,#B& it often can be erformed in the
office setting and may be used for treatment of DUB (see belo(.)
'*

!reatment
!here are medical& surgical& and combined methods of treating DUB. !he choice of
aroach deends on the cause& severity of bleeding& atient=s fertility status& need for
contracetion& and treatment otions available at the care site. A tyical algorithm for the
treatment of mild to moderate DUB is sho(n in )igure :.
$ases of acute& heavy& uncontrolled bleeding should be treated (ith intravenous
estrogen& '.mg every * hours& to a ma-imum of : doses or until bleeding stos (!able
*.)
'.
.ral con/ugated estrogen also may be given in divided doses u to %2mg er day&
although this regimen often causes nausea and vomiting. In less severe cases& conjugated
estrogens at doses of '.. to .mg er day stos the bleeding over '* to *7 hours.
6egardless of (hich regimen is used& it should be follo(ed by conjugated estrogen at
%.'. to '..mg lus %2mg of medro-yrogesterone er day for about %2 days. Aithdra(al
bleeding should then occur as all drugs are (ithdra(n.
:
In ostmenoausal (omen&
continuous estrogen theray (ith conjugated estrogens (2.9'. - %.'.mg) lus cyclic
medro-yrogesterone (%2 mg ) for %2 - %* days of each month may be continued.
:
!his
regimen (or/s best in atients (ith atrohic eithelium.
%



Table 0. #edical Therapies for DUB.
%&'&:&%'&'?
Therapy Comments
#edro-yrogesterone (+rovera)
%2 mg
+O3day for %2 to %' days
Deo-medro-yrogesterone %.2
mg
I# every : months
+rogesterone in oil %22 - '22 mg
I#
+rogestine-only oral
contracetives ills
Oral contracetive illls u to Hid
for . to > days or until bleeding
stos

Intravenous estrogen '. mg H*
hrs-- ma-imum of : doses or until
bleeding stos
Oral conjugated estrogen
(+remarin) divided doses u to %2
mg3day

Oral conjugated estrogen
(+remarin) '.. to . mg3day

$onjugated estrogen %.'.
mg3day
$onjugated estrogens 2.9'. to
%.'. mg
H day lus cyclic
medro-yrogesterone %2 mg for
%2 to %* days each month
Aor/s (ell to correct midcycle sotting and (hen
the ,#B demonstrates roliferative endometrium.
Also rovides contracetion.



Also rovides contracetion.
)or acute moderately heavy bleeding. !he rest of the
ills may then be ta/en H day until the ac/ is
comleted& follo(ed by an additional ' months of
O$+s.
)or acute& heavy& uncontrolled bleeding.

)or acute& heavy& uncontrolled bleeding. Often causes
nausea and vomiting. 0hould be follo(ed by conjugated
estrogen % .'. to '.. mg lus %2 mg of
medro-yrogesterone er day for about %2 days.
)or less severe bleeding. Often causes nausea and
vomiting. 0hould be follo(ed by conjugated estrogen
%.'. to '.. mg lus %2 mg of medro-ygesterone er day
for abouth %2 days.
Used for DUB and atients (ith lo(-dose O$+s (ith
midcycle sotting.
Used in treatment of eri- or ostmenoausal (omen.
#ainly used for chronic DUB. 8ood for atients (ho
desire regnancy.


,ffective for long-term use. #uch e-erience (ith
long-term use for other roblems. Aatch for 8I and
$lomihene citrate ($lomid&
0erohene)
+rogesterone-containing IUD
"0AID0 "aro-en ("arosyn)
.22 mg BiD& menfenamic acid
(+onstel) .22 mg !iD&
ethamsylate .22 mg HiD
Dana4ol (Danocrine) '22 to 722
mg3day
for : to 9 months
8n61 agonists goserelin acetate
(Iolade-)& :.9 mg 0H every '7
daysJ leurolide
acetate (5uron) or nafarelin
acetate (0yneral)
renal side-effects.
Androgenic side-effects limit use. Acts as anti-estrogen
and revents ovulation.
+rimarily used to thin the endometrium rior to surgery.
Used (hen hormonal methods have failed or are
containdicated. #ay cause oseoriis the chrnoic use&
DUB (ill also recur in u %2 %2Kof (omen treants
In cases of moderately heavy DUB& oral contraceptive pills (.C$s) may be given u to
four times a day for . to > days or until bleeding stos.
'& :
!he rest of the ills may then
be ta/en once a day until the ac/ is finished and (ithdra(al bleeding occurs. In
anovulatory atients& this is follo(ed by an additional ' months of O$+s as usually
rescribed. !his regimen (ill stabili4e the eithelium& slough e-cessive build-u& and
rovide contracetion. O$+s may also be started initially at one ill every day in milder
cases of DUB.
' - *& >
If the atient is already on O$+s and e-eriencing DUB& a change to
a higher estrogen activity O+$ is indicated.
:

#edro1yprogesterone ($rovera) at %2mg +O er day for %2 to %' days has traditionally
been one of the most common methods used to control DUB. !his <medical curettage<
(or/s (ell to correct midcycle sotting and (hen the ,#B demonstrates roliferative
endometruim.
% - :
Deo-medro-yrogesterone (%.2mg) or rogesterone in oil (%22 -
'22mg) may be given intramuscularly to achieve similar effects.
'& :
!he rogestin-only
contracetive ills also (or/ (ell and& li/e deo-+rovera& have the added benefit of
roviding contracetion.
:
Breast tenderness and mood s(ings are ossible side-effects
of theray. !hese regimens (or/ esecially (ell (ith chronic or milder acute DUB.
+rogestin-containing IUDs& together (ith oral or transdermal estrogen& may control DUB
in ostmenoausal atients.
'9& '>

2onsteroidal anti3inflammatory drugs ("0AID0) can decrease DUB& robably through
inihibition of rostaglandin synthesis.
'>
"aro-en ("arosyn) .22mg t(ice daily&
mefenamic acid (+onstel) .22mg three times daily& or ethamsylate .22mg four times a
day has been sho(n to decrease menstrual flo(.
'7 - :2
Once bleeding is controlled&
"0AID0 need only be used during menstruation.
'>
!hese drugs are safe for long-term
usage& and the long-term effects are (ell studied. Asirin does not aear to be effective.
*

!he androgenic synthetic steroid dana+ol (Danocrine)& (hich is traditionally used to
treat endometriosis& can be used to treat DUB. 0imilarly& the 8n61 agonists goserelin
acetate (4olade15) leuprolide acetate (*upron5) or nafarelin acetate (!yneral) induce
a hyogonadotroic state (hich stos dysfunctional bleeding.
'>& '7& :%
!hey all roduce
hyogonadism and induce ammenorrhea. Because of their side effects& these drugs are
used (hen hormonal methods have failed or are contraindicated. !hese agents are
rimarily used to thin the endometrium rior to surgical intervention.
*& %'& :% - :*
6esearch
involving estrogen and rogesterone <add bac/< theray may rovide a means of
overcoming the long- and short-term side-effects.
'>& :%& :.& :9
DUB (ill recur in u to .2@
of (omen treated.
Dilatation and curettage (DG$) may ameliorate DUB& as (ell as diagnose otential
dyslasia or malignancy. It is sometimes avoided in adolescents because of concerns
about ossible infertility. 6eeated rocedures may result in intrauterine adhesions.
%'

2eodymium6yttrium3aluminum3garnet (2d6789) laser endometrial ablation is a
ne(er method of surgically treating the endometrium. It has a success rate of
aro-imately 7.@ and is more effective in atents over the age of :. years.
:>
Amenorrhea may occur in '?@ of atients. !here is some concern that cancers could be
missed& since no tissue is available for athologic study.
:>
+ossible ris/s include fluid
overload& endometritis& and uterine erforation. :> 5aser e;uiment is e-ensive and
re;uires secial safety recautions.
*

-ysteroscopic transcervical resection of the endometrium (TC&) ma/es use of an
electrocautery loo or ball to remove or coagulate the endometrium to sto DUB. It may
reduce the need for hysterectomy by u to ?2@&
'?& :7& :?
and has been sho(n to have a
lo(er overall rocedure cost (including retreatment costs and eventual hysterectomies)
than immediate hysterectomy for more severe DUB.
::
!he goal is to ablate the
endometrium and encourage endometrial adhesions resulting in hyo- or amenorrhea.
!he hysteroscoe is considerably less e-ensive to buy and maintain than the laser but
carries the ris/s of fluid overload& endometritis& and uterine erforation.
'*& :*& '?& :7
!he
otential fluid overload roblem can be alleviated by the use of carbon-dio-ide gas or
De-tran >2 solution to distend the uterus.
'*
1ysteroscoy is most effective in (omen
(ho are over the age of :.& and ostmenoausal 16! may be safely started or continued
in atients after endometrial ablation.
'?& :?
!here have been : reorted cases of
adenocarcinoma diagnosed after endometrial ablation for DUB.
*2& *%

!he enometrium may also be hysteroscoically ablated via the insertion of a thermal
uterine balloon. !he system consists of a control system attached to a %9cm by .mm
catheter (ith a late- balloon on the end that houses a heating element. A sterile
.@de-trose solution is instilled until the ressure reaches bet(een %92 and %72mm1g.
!he solution is heated to 7> degrees $. for 7 minutes and then the device is removed.
!he treatment has been fount to be as efficatious as roller-ball ablation (ith less
comlications.
*%a

-ysterectomy remains the most absolutely curative treatment for DUB. ,lective
hysterectomy has a mortality rate of si- er %2&222 oerations. One randomi4ed study
found that hysterectomy (as associated (ith more morbidity and much longer healing
times than endometrial ablation.
%'
)ortunately& a recent study found that se-ual
functioning imroved overall after hysterectomy (ith an increase in se-ual activity abd a
decrease in roblems (ith se-ual functioning.
*7
It still remains a oular method of
treating DUB& esecially in industriali4ed countries.
6eferences
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?'.
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udated 73:232.
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