18th Expert Committee on the Selection and Use of Essential Medicines

(21 to 25 March 2011)

Section 18: Hormones, other endocrine medicines and contraceptives
Section 18.7: Progestogens -- Norethisterone (Possible deletion)

Norethisterone for hormone replacement therapy and dysfunctional

uterine bleeding

Nameoftheorganizationpreparingtheapplication
SchoolofMedicine,UniversityofSplit,oltanska2,21000Split,Croatia
1.NovakRibicicKristijana
2.SambunjakDario
3.PehlicMarina
4.StipicIvica
5.StrinicTomislav
Acknowledgment

WethankAnaUtrobicicforherassisstanceinconductingliteraturesearchandobtainingtheneeded
articles.

1.

2.

3.

4.

5.

NovakRibicicKristijana,MD,Residentdoctor,DepartmentofObstetricsandGynecology,University
HospitalSplit,Spinciceva1,21000Split
SambunjakDario,MD,PhD,Director,CroatianBranchoftheItalianCochraneCentre,SeniorEditorof
CroatianMedicalJournal,SchoolofMedicine,UniversityofSplit,Soltanska2,21000Split
PehlicMarina,MD,Researchfellow,DepartmentofMedicalBiology,SchoolofMedicine,Universityof
Split,Soltanska2,21000Split,CROATIA
IvicaStipic,MD,Residentdoctor,DepartmentofObstetricsandGynecology,UniversityHospitalSplit,
Spinciceva1,Split,SchoolofMedicine,UniversityofSplit,Soltanska2,21000Split
ProfessorTomislavStrinic,MD,PhD,SpecialistinObstetricsandGynecology,DepartmentofObstetrics
andGynecology,UniversityHospitalSplit,Spinciceva1,Split,SchoolofMedicine,UniversityofSplit,
Soltanska2,21000Split

Theaimofthisreviewistoevaluatetheefficacyofnorethisteroneusageinperoraldoseof5mgfor
hormonalreplacementtherapyanddysfunctionaluterinebleedingbysearchingallpublishedpapers
andreports.
NorethisteroneiscurrentlylistedontheWHOModelListofEssentialMedicinesasamedicineused
forcontraception,dysfunctionaluterinebleedingandhormonalreplacementtherapy.
Introduction
Norethisterone(norethindrone)isasyntheticgestagendevelopedfromtestosterone.Inthelate
1930sitwasdiscoveredthattheetinilesubstanceonthetestosteronemoleculeleadstowardsthe
developmentoforallyactiveethisteronepreparation.Norethisterone,thatkepttheoralpotentiality
ofitspreviousforms,wascreatedbymovingthe19Catomefrometistheronein1951,butitalmost
completely changed the hormone's characteristics; a gestagenic preparation was made out of an
androgenic substance. Since then, all gestagenic preparations developed from testosterone have
beencalledderivatesof19norethisterone,19nordenotingthelackof19Catome.Norethisterone
anditsderivates(norethinodrel,norethisteroneacetate,ethinodioldiacetateandlinestrol)havethe
same metabolic effect, considering the fact that after metabolization in gastrointestinal tract and
liver, all derivates transform into the outcoming substance norethisterone. Besides its connection
with progesterone receptors, norethisterone has the affinity of linking to both, estrogenic and
androgenicreceptors.
Indicationsforuse
1) Treatmentofmenstrualdisorders,includingsecondaryamenorrheaanddysfunctional
uterinebleeding(DUB)causedbyhormonalimbalanceintheabsenceoforganicpathology.
2) Premenstrualtension
3) Dysmenorrhea
4) Treatmentofendometriosis
5) Hormonereplacementtherapy(HRT)
continuouscombinedregimens,
sequentialcombinedregimens.
Progestinsareusedtoopposetheeffectsofestrogenontheendometriuminmenopausal
womenwhotakeestrogensforHRT.
6) Contraception(aloneorincombinationwithestrogens).
(Source:NationalLibraryofMedicineNationalInstitutesofHealth(wwwtoxnet.nlm.nih.gov))
ContraindicationsandPrecautions
1) Thrombophlebitis,thromboembolicdisorders,cerebralapoplexy,orahistoryofthese
conditions,
2) Undiagnosedvaginalbleeding,
3) Knownsensitivitytothedrugoranyingredientsintheformulation,
4) Markedlyimpairedliverfunctionorliverdisease,
5) CarcinomaofbreastNorethisteroneshoudnotbeusedinpatientswithbenignormalignant
changesintissueswhichrespondtosexhormones.

6) Conditionsthatmightbeaggravatedbyfluidretention(asthma,seizuredisorders,migraine,
cardiacorrenaldysfunction),
7) Mentaldepressionorahystoryofthesecondition.
(Source:NationalLibraryofMedicineNationalInstitutesofHealth(wwwtoxnet.nlm.nih.gov))
Adverseeffects
1) menstrualirregularity,changesinmenstrualflow,amenorrhea,breakthroughbleeding,
spotting(IrregularbleedingorspottingiscommoninthefirstyearofcontinuousE+PHRTbut
followingthefirstyearoftreatment,bleedingandspottingbecomemorecommoninsequential
E+Pregimens.AlargeproportionofwomentakingcontinuousE+PHRTbecomeamenorrhoeic
afterayearoftherapywhilstwithdrawalbleedingcontinuesforwomentakingsequential
regimens.)
2) fluidretention,edema,weightgain,
3) nausea,
4) breasttenderness,
5) headache,
6) mentaldepression.
(Source:NationalLibraryofMedicineNationalInstitutesofHealth(wwwtoxnet.nlm.nih.gov))
Formulationanddosageregimens
Tablet:5mg
Oilysolution:200mg/mlin1mlampoule
Atlowdose(1mgaday)itcanbeuseincombinationwithoestrogenseitherasacontraceptiveor
inhormonereplacementtherapy.Athigherdose(5mgdaily)itcanbeusedfortreatmentof
menorrhagia.Norethisteroneisnotavailableinaoralformulationgreaterthan5mg.[1]
Summaryofavailableefficacydata
Identificationofclinicalevidence
Medline(1950toSeptemberWeek12010),CochraneDatabaseofSystematicReviews,andCochrane
CentralRegisterofControlledTrials(3rdQuarter2010)weresearchedtoidentifyallpublished
papersandreportsevaluatingtheeffectivenessofnorethisteroneindoseof5mginhormone
replacementtherapy(HRT),anditseffectivenessfortreatmentofdysfunctionaluterinebleeding
(DUB)(Figures14).
SearchStrategyfornorethisteroneandHRT

1expHormoneReplacementTherapy/
2hormonereplacement.mp.
3estrogenreplacement.mp.
3

4oestrogenreplacement.mp.
51or2or3or4
6Norethindrone/
7(norethisteroneornoretisterone).mp.[mp=title,originaltitle,abstract,nameofsubstanceword,
subjectheadingword,uniqueidentifier]
86or7
95and8
10randomizedcontrolledtrial.pt.
11controlledclinicaltrial.pt.
12random$.ab.
13placebo.ab.
14drugtherapy.fs.
15trial.ab.
16groups.ab.
1710or11or12or13or14or15or16
18expanimals/nothumans.sh.
1917not18
209and19

Search Strategy for norethisterone and DUB

-------------------------------------------------------------------------------1

Norethindrone/

norethisterone.mp.

1 or 2

exp Uterine Hemorrhage/

5 (uter$ adj5 h?emorrhage$).mp. [mp=title, original title, abstract, name of substance word, subject
heading word, unique identifier]
6 (uter$ adj5 bleed$).mp. [mp=title, original title, abstract, name of substance word, subject heading
word, unique identifier]
7 (irregular adj5 (period$ or menstrua$ or bleed$ or blood loss)).mp. [mp=title, original title, abstract,
name of substance word, subject heading word, unique identifier]

8 (dysfunction$ adj5 uter$ bleed$).mp. [mp=title, original title, abstract, name of substance word, subject
heading word, unique identifier]
9 DUB.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique
identifier]
10

4 or 5 or 6 or 7 or 8 or 9

11

3 and 10

12

randomized controlled trial.pt.

13

controlled clinical trial.pt.

14

random$.ab.

15

placebo.ab.

16

drug therapy.fs.

17

trial.ab.

18

groups.ab.

19

12 or 13 or 14 or 15 or 16 or 17 or 18

20

exp animals/ not humans.sh.

21

19 not 20

22

11 and 21

ThestudiesinlanguagesotherthanEnglishwereexcluded.
Titlesandabstractsofretrievedpaperswerereviewed.Studieswereincludedforreviewiftheywere
systematicreviews(SRs),randomizedcontrolledtrials(RCTs)orcontrolledclinicaltrials(CCTs).The
citationlistsofincludedstudiesweresearchedtoidentifyanyadditionalstudies.Studiesinwhich
norethisteronewasusedasapartofcombinationofmedicinesforHRTwereincludedforreview,
becausenorethisteroneisindicatedforuseincombinationwithothermedicinesforthemanagment
ofmenopausalsymptoms.
Fromtheliteratureobtained,datarelevantforevaluationofnorethisteroneeffectivenesswas
extractedandtabulated(Tables14).

Identification

Figure1.Flowdiagramforidentificationofsystematicreviewsevaluatingtheeffectivenessof
norethisterone(NET)forthemanagementofhormonereplacementtherapy(HRT)

Recordsidentifiedthrough
Medline
(n=17)

Additionalrecordsidentified
throughCDSR
(n=15)

Screening

Recordsafterduplicatesremoved
(n=15)

Eligibility

Fulltextarticlesassessed
foreligibility
(n=4)

Included

Recordsscreened
(n=15)

Studiesincludedintabular
presentationofsystematic
reviews
(n=1)

Recordsexcluded
(n=11)
Thetitlesandabstractsofthese
SRdidnotindicatethattheyare
evaluatingtheeffectivenessof
NETforthemanagmentofHRT

Fulltextarticlesexcluded
(n=3)
ThedoseofNETintheseSRs
wasdifferentfromour
assignment(5mg)

Identification

Figure2.Flowdiagramforidentificationofclinicaltrialsevaluatingtheeffectivenessof
norethisterone(NET)forthemanagementofhormonereplacementtherapy(HRT)

RecordsidentifiedthroughMedline
(n=463)

RecordsidentifiedthroughCCRCT
(n=399)

Screening

Recordsafterduplicatesremoved
(n=460)

Eligibility

Fulltextarticlesassessed
foreligibility
(n=6)

Included

Recordsscreened
(n=460)

Studiesincludedintabular
presentationofclinical
trials
(n=3)

Recordsexcluded
(n=454)
Otherdosearereviewedin
thesearticles

Fulltextarticlesexcluded
(n=3)
Inthesetrialstherewereno
assessmentofeffectiveness
ofNET

Identification

Figure3.Flowdiagramforidentificationofsystematicreviewsevaluatingtheeffectivenessof
norethisterone(NET)forthemanagementofdysfunctionaluterinebleeding(DUB)

Recordsidentifiedthrough
Medline
(n=10)

RecordsidentifiedthroughCDSR
(n=20)

Screening

Recordsafterduplicatesremoved
(n=20)
Recordsexcluded
(n=11)

Recordsscreened
(n=20)

Eligibility

Fulltextarticlesassessed
foreligibility
(n=11)

Thetitlesandabstractsofthese
SRsdidnotindicatethatthey
areevaluatingtheeffectiveness
ofNETforthemanagmentof
DUB

Fulltextarticlesexcluded
(n=3)
Othertreatmentandindications
arereviewedinthesearticles

Included

Studiesincludedintabular
presentationofsystematic
reviews
(n=8)

Identification

Figure4.Flowdiagramforidentificationofclinicaltrialsevaluatingtheeffectivenessof
norethisterone(NET)forthemanagementofdysfunctionaluterinebleeding(DUB)

Recordsidentifiedthrough
Medline
(n=190)

RecordsidentifiedthroughCCRCT
(n=103)

Screening

Recordsafterduplicatesremoved
(n=152)

Recordsscreened
(n=152)

Eligibility

Fulltextarticlesassessed
foreligibility
(n=16)

Recordsexcluded
(n=136)
Otherindicationsare
reviewedinthesearticles

Fulltextarticlesexcluded
(n=6)
Otherdosesarereviewedin
thesearticles

Included

Studiesincludedintabular
presentationofclinical
trials
(n=10)


Summaryofcomparativeeffectivenessindifferentclinicalsettings
Usenorethisteronasprogestogeninhormonereplacementtherapy(HRT)
Menopausemeansthecessationofmenstruationandtypicallyoccursinwomenagedbetween45
and55yearswithameanageofabout51years.Womenaresaidtobepostmenopausalwhen
menstruationhasceasedfor6to12monthsandbloodserumlevelsoffolliclestimulatinghormone
(FSH)increasetoatleast49IU/L.Thedeclineincirculatingestrogenaroundthetimeofthe
menopausecaninducesymptomsthataffectthewellbeingandhealthofwomen,hotflushes,
insomnia,decliningbonemass,nightsweats,mooddisturbancesandvaginaldrynesshaveallbeen
reported.Aslifeexpectancyandtheproportionofolderadultsinthepopulationincreases,therehas
beenanincreasedfocusontheeffectsofageing.Estrogentherapyhasbeenutilisedforthe
treatmentofmanyofthemenopausalsymptoms,particularyhotflushesandvaginaldryness.HRT
mayconsistofeitherunopposedestrogenoracombinationofestrogenandprogesteron.Thereisa
numberofdifferentprogestogensusedinHRT,whichcanbeclassifiedaccordingtotheirstructure
and/orbioactivity.TheprimaryreasonforaddingaprogestogentoHRTistoprotectthe
endometriumagainsthyperplasia.Endometrialhyperplasiaisregardedasaprecursorofendometrial
cancerbutprogressionisdependentonthetypeofhyperplasia.Theriskofhyperplasiaand/or
carcinomaappearstoincreasewithhigherdosesandincreaseddurationofunopposedestrogen
treatment.Addingaprogesterontoestrogentherapysignificantlyreducestheriskofhyperplasia[2],
butcanresultinpremenstrualsymptomswhichareproblematicforsomewomen.Thesesymptoms
andincreasedbleedingandspottingareoftengivenasareasonnottocontinueHRT.Anadditional
concernisthattheadditionofprogesterontoestrogenalsoappearstoincreasetheriskof
cardiovasculardiseaseandbreastcancer.
Asmensionedbefore,progestinsareusedinhormonereplacementtherapytocounteractestrogen
inducedproliferationoftheendometrium.[2]Asidefromtheirlocalaction,progestinsactatdifferent
bodysitesincludingthecentralnervoussystem(CSN).IntheCNSprogestinsmayinfluencedifferent
functionsamongwhichtheregulationofbodytemperatureandmood.Whiletheeffectonbody
temperaturemayhavemetabolicimplications,theeffectonmood,particularlyifnegative,canbe
invalidatingandinducenonacceptanceorwithdrawalfromhormonereplacementtherapy[3,4,5].

IncombinedHT,progestogencanbetakeneithercontinuously(everyday)orsequentially(afew
daysforeachmonthorlessfrequently).Itappearsthatcontinuoustherapymaybemoreprotective
thansequentialtherapyinthelongtermpreventionofendometrialhyperplasia[2].

HRTisaneffectivetreatmentforwomenwithmenopausalsymptomsofhotflushes,nightswears
andvaginaldrynessandthedurationoftherapyshoudbedecidedforindividualwomenbasedonan
assessmentofbothbenefits,intermsofmenopausalsymptommanagmentandharmsoftherapy,
suchasvenousthromboembolism.ThedurationoftreatmentwithHRTshoudbereviewedbya
womanwithherdoctor,becauseformostwomenhotflushesresolvewithinayearofonsetofthe
menopause.Aboutonethirdofwomenwillcontinuetohavevasomotorsymptomsforupto5years
andsomewomenforevenlonger.[2]

10

Table1.Systematicreviewsandmetaanalysisevaluatingtheeffectivenessof5mgnorethisterone
inhormonereplacementtherapy(HRT)
No.
01.

Article;Searchstrategy

Selectioncriteria;Outcomes

Conclusions;Comment

Zweifel(1997)[3]

Assessmenttheeffectivenessof
HRTonmenopausaldepressed
mood.
Themostcommonlyused
measuresweretheBeck
DepressionInventory(BDI),the
HamiltonRatingScalefor
Depression,andtheMultiple
AffectAdjectiveChecklist.
The most commonly used
measures were the Beck
Depression Inventory
(BDI), the Hamilton Rating Scale
for Depression, and the Multiple
Affect Adjective
Checklist.The most commonly
used measures were the Beck
Depression Inventory
(BDI), the Hamilton Rating Scale
for Depression, and the Multiple
Affect Adjective
Checklist.

HRTappearedtobeeffectivein
reducingdepressedmoodamong
menopausalwomen.
Theoveralleffectsize(ES)for
HRTwas0.68.Thisindicatedthat
theaveragetreatmentpatient
hadlowerlevelsofdepressed
moodthan76%ofthecontrol
patients.
1)estrogensignificantlyreduced
depressedmood(ES=0.69);
2)progesteron(norethisterone)
alone,andincombinationwith
estrogen,wasassociatedwith
smallerreductionsindepressed
mood(ES=0.39,ES=0.45,
respectively);
3)androgenaloneandin
combinationwithestrogenwas
associatedwithgreater
reductionsindepressedmood
(ES=1.37;ES=0.90,respectively).

PsychologicalAbstracts(from
1974to1995)andMEDLINE
(from1966to1995)were
searched.26RCTswere
included.
Thereisjust2RCTs(Magos,
1986[5];Montgomery,
1987[6])whichused
norethisterone,5mg7
days/moincombinationwith
implantofestrogen50
mg/day.

11

Table2.Clinicaltrialsevaluatingtheeffectivenessof5mgnorethisteroneinhormonereplacement
therapy(HRT)
No.

Article;StudyType;StudyDesign

1.

Investigationtheeffectsonbodytemperature,
anxietyanddepressionoffourdifferent
Onehundredtwentypostmenopausalwomen progestinsallassociatedwiththesame
estrogeniccompound.
oncontinuoushormonalreplacementtherapy
AllprogestinsexceptDYDincreased(P<0.0001)
withtransdermalestradiol(50gperday)
associated,for10daysevery28days,withfour BBTby0.30.5C.Anxietywasdecreasedby
DYD(2.3+1.1;P<0.01)andMPA(1.5+0.5;P
differentprogestins:dydrogesterone
<0.01),butnotbyNMGorNETA.Depressiondid
(DYD;10mgperday;n=20),
notsignificantlyincreaseduringprogestinsand
medroxyprogesteroneacetete(MPA;10mgper
actuallydecreasedduringMPA(3.0+0.7;
day;n=20),nomegestrolacetate(NMG;5mg
P<0.01).OnlytheeffectofDYDonanxiety
perday;n=20)ornorethisteroneacetate
andthatofMPAondepressionweresignificant
(NETA;10mgperday;n=20).
Other40women,10foreachtreatmentgroup, versusthecontrolgroup(P<0.05).
wereusedascontrolsandweremonitoredfor
asinglecycleof28daysduringthe
administrationoftransdermalestradiolplus
placebo.
AssessmenttheinfluenceofNETonmoodand
Magos(1986)[5]
behaviour.
RCT
Therewerewidespreadadvarseeffectswhich
58postmenopausalhysterectomizedwomen
weredoserelated.Significantchangesinfive
weretreatedwithsubcutaneusestradioland
testosteronimplants.NET(2,5mgor5mg)was symptoms(painbaselinevsNETp<0.02,
givenfor7daysandaplacebofortwoperiodof concentrationBvsNETp<0.0001,behavioural
changeBvsNETp<0.02,waterretentionBvs
7days.
NETp<0.0001andnegativeaffectBvsNET
p<0.001)werefoundwith5mg/dayoftheNET.
ThedoseofNETshouldbetheminimumto
achievethedesiredtherapeuticeffect.
Alltheestrogentestedshowedsimilarefficacyin
Volpe(1986)[7]
themanagmentofclimactericsymptoms.As
RCT
regardstheavailableprogesteroncompounds,it
113postmenopausalwomenwithclimacteric
wouldseemthatCPAissaferthanNET,sinceit
symptoms.Theywererandomlyallocatedto
sevengroupsof127subjectswhoreceivedfor doesnotantagonisethebeneficialeffectsof
estrogenonHDLlevels.WhenNETwascombined
6monthsthefollowingtherapies:
witheitherEVorCEtherewasadecreaseinHDL
1)conjugatedestrogen(CE)0,625mg/dayfor
cholesterol(p<0,05and0,01respectively)anda
21days+NET5mg/dayfromday12today21
simultaneusincreasetryglicerides(p<0,05),while
2)CE+cyproteroneacetate(CPA)12,5
NET+CEdecreasedserumcholesterol(p<0,05).
mg/dayfromday1today10
3)estradiolvalerate(EV)2mg/dayfor21days+
NET
4)EV+CPA
5)estradiol24mg/day
6)tibolone2,5mg/day
7)placebo.

2.

3.

Findings;Conclusion

Cagnacci(2004)[4]
RCT

Onlythreestudiesoutofthe460reviewedregardingtheeffectivenessofnorethisteroneinHRTmet
theinclusioncriteria(Table2).The5mgdoseofnorethisteroneinHRTisrarelymentioned.After
searchingthereferencesweconcludedthefollowing:hormonereplecementtherapymaybeusedto
managethemenopausalsymptoms,butitiscurrentlyrecommendedtobegivenatthelowest
12

effectivedoseandregularyreviewedbywomenandtheirdoctor.Incaseofwomenwithanintact
uterususingHRTcomprisingestrogenandprogestogenitisdesirabletominimisetheriskof
endometrialhyperplasiawhichcandevelopintoendometrialcancer.[2]Theuseoflowdoseestrogen
plusprogestogen(1mgnorethisteroneacetateor1.5mgmedroxyprogesteronacetate)takendaily
(continuously)appearssafefortheendometrium.Forwomenwithinoneyearofmenopauselow
doseestrogencombinedsequentiallywith10daysofprogestogen(1mgnorethisteroneacetate)per
monthappearssafefortheendometrium[2].
LowdoseHRThaslesssideeffects,andwomenmostlycontinuewithHRT.Only2%ofthepatients
giveupfromHRTafterthefirstyearusage.[2]ThelowdoseHRThasthesameeffectonvasomotor
symptoms,urogenitalatrophy,cardiovasculardiseases,osteoporosisandCNS,aswellas
conventionaltreatment.NEThasanindividualeffectonthebone,andthereforeemphasizes
preventiveestrogeninfluence.ThatdataisofgreatimportancewhenconsideringlowdoseHRT
usageforwomenwithosteoporosis[4].
Theprogesteronerecommendedformenopausalwomenreceivinglongtermestrogenreplacement
therapyisoftenassociatedwithsideeffectswhichlimittheacceptabilityofcombinedtreatment[5].
Peroraldoseof5mgnorethisteroneinHRTcausesthesideeffectsthatprevailovertheadvantages
ofHRTinpostmenopausalwomen.Therefore,itisrecommendedthatnorethisteronein5mgdose
forHRTshouldnotbeusedanymore.
Norethisteroneinthetreatmentofdysfunctionaluterinebleeding(DUB)
ThediagnosisofDUBismadebytheexclusionoforganicdiseaseasacauseoftheabnormalmenses;
theconditionaccountsforabout80%ofcasesofmenorrhagia.Ofthese,over80%willhaveno
abnormalityofthehypothalamopituitaryovarianaxis,anditislikelythatthedisorderistheresultof
localendometrialfactors.Thereappearstobenotonlyapreponderanceofvasodilatory
prostaglandinsintheendometriumofwomenwithmenorrhagia,butalsoanexcessiveincreasein
fibrinolyticactivitywithintheuterinecavity.Onceadiagnosishasbeenreachedwiththeaidof
history,examination,haematologicalandendocrineinvestigations,anddilatationandcurettage
whenappropriate,medicaltreatmentistheusualfirstlineapproach.Nonsteroidalanti
inflammatorydrugssuchasmefenamicacid,orantifibrinolyticagentssuchastranexamicorepsilon
aminocaproicacids,willreducebloodlossbybetween25and50%[8].Nonsteroidalanti
inflammatorydrugsreduceprostaglandinlevelswhichareelevatedinwomenwithexcessive
menstrualbleedingandalsomayhaveabeneficialeffectondysmenorrhea.Medicationswhich
suppressovarianfunction,suchasdanazolorgonadotrophinreleasinghormoneanalogues,are
highlyeffectiveinlessening,orinhibiting,menstrualloss,butattheexpenseofsideeffectsand
conveniencerespectively.Thecombinedcontraceptivepillmayreducebloodlossby50%butisnot
appropriateforolderwomen.Cyclicalgestagenssuchasnorethisteronehavebeenwidelyemployed,
particularlyforthetreatmentofanovulatorycycles,buttheirplaceinthemanagementofovulatory
DUBislessclear[8].
Thehistologicalassessmentofendometrialmorphologyconstitutesavitaladjuncttohormonal
therapyincasesofdysfunctionalbleeding.Inaconsiderablenumberofpatientsthereisaneedfor
progesteronetreatmentbecauseofrepeatanovulatorycycles.Prolongedstimulationbyeither
endogenousorexogenousestrogensresultsinendometrialhyperplasiainsomepremenopausaland
13

postmenopausalwomen.Itisstillnotknownwhyonlysomewomenexhibitthisabnormalresponse.
Thepossiblefactorsinvolvedincludedisorderedestrogenmetabolism,reducedplasmalevelsofsex
hormonebindingglobulin(SHBG)andincreasedsensitivityoftheendometriumtoestrogen
stimulation[9].
Theintrauterinecoildevicewasoriginallydevelopedasacontraceptivebuttheadditionofuterine
relaxinghormones,progestogens,tothesedevicesresultedinalargereductioninmenstrualblood
loss.Ifmedicaltreatmentfailshysterectomyshouldbeconsidered,thoughlessinvasivesurgical
methodsofendometrialablationarebeingdeveloped.Finally,itshouldberememberedthatinthe
absenceofassociatedsignsorsymptomsofirondeficiencyanaemia,heavymenstrualbleedingisa
subjectivecomplaintandupto50%ofwomendescribingmenorrhagiawillhaveameasuredmonthly
bloodlosswithinnormallimits[8].

14

Table3.Systematicreviewsevaluatingtheeffectivenessof5mgnorethisteroneforthemanagment
ofdysfunctionaluterinebledding(DUB)
No.
1.

Article;Searchstrategy
Coulter(1995)[10]
MEDLINEandEMBASEwere
searched.
31studieswereincluded.
Unclearwhenliterature
searchwasconducted.

2.

Lethaby(2008)[11]
CochraneMenstrual
DisordersandSubfertility
GroupTrialregister
(searchedApril2007),
MEDLINE(1966toApril
2007)andEMBASE(1985to
April2007)weresearched.
SevenRCTswereincluded.

Selectioncriteria;Outcomes

Conclusions;Comment

Womenwithmenorrhagia.
Comparisoneffectsof
aminocaproicacid(3g),danazol
(200mg),diclofenac(50mg),
ethamsylate(500mg),
flurbiprofen(100mg),ibuprofen
(600,1200and1600mg),
meclofenamatesodium(100mg),
mefenamicacid(500mg),
naproxen(5,250,500,750and
1250mg),norethisterone(5mg),
oralcontraceptive(lowdose),
tranexamicacid(1,12and24g),
intrauterinedevices(IUDs)and
hormonereleasingIUDs.
Outcomeswerereductionin
menstrualbloodloss(MBL).

Theinterventionsproducedthe
followingpercentagereductionsin
menstrualbloodloss:
Hormonereleasingcoil58.6(95%
CI:56.7,60.6);danazol49.7(95%
CI:47.9,51.6);tranexamicacid
46.7(95%CI:45.0,46.7);
mefenamicacid29.0(95%CI:
27.9,30.2);diclofenac26.9(95%
CI:23.2,30.6);naproxen26.4(95%
CI:24.6,28.3);ibuprofen16.2
(95%CI:13.6,18.7);ethamsylate
13.1(95%CI:10.9,15.3)and
norethisterone3.6(95%CI:6.1,
1.1).
Whereastheleasteffectivedrug,
norethisterone,isthemost
frequentlyprescribed(to38%of
patients).Thiscomparisonshowed
thathormonereleasingcoils,
danazolandtranexamicacidlead
tosignificantreductionin
menstrualbloodloss.
Comparisonsoforalprogestogen NETadministeredfromday15or
19today26ofthecycleofferno
therapyversusplaceboorother
advantageoverothermedical
medicaltreatmensinwomenof
therapiessuchasdanazol,
reproductiveyearswithregular
tranexamicacid,nonsteroidal
heavyperiods.Progestogens
antiinflammatorydrugs(NSAIDs)
weretakeneitherduringluteal
phase(days15or19to26)orfor andtheprogesteronereleasing
alongercourseof21days.
IUSinthetreatmentof
Norethisterone(NET)wasthe
menorrhagia.
onlytypeoforalprogestogenthat MBL:
wasassessed.
NETvs.NSAIDseffectsize22.97[
NETtakenforthelongercourse
0.62,46.57],NETvs.danazol55.63
comparedonlywithprogesteron [14.73,96.54],
NETvs.tranexamicacid111.0
releasingIUS.
Outcomes:menstrualbloodloss [43.54,178.46],NETvs.IUS51.0
[18.38,83.62].
(MBL).
NETfor21daysresultsin

significantreductioninbloodloss
althoughwomenfoundthe
treatmentlessacceptablethan
intrauterinelevonorgestrel.
NETfor21daysvs.IUS:
medianMBLafter3monthsof
NET:20mls
medianMBLafter3monthsof
LNGIUS.6mls,p=0.033

15

3.

Lethaby(2007)[12]
CochraneMenstrual
Disorders&Subfertility
Grouptrialsregister
(searchedApril2007),the
CochraneCentral
RegisterofControlledTrials
(CENTRAL)(TheCochrane
Library,Issue1,2007),
MEDLINE(1966toApril
2007),EMBASE(1985
toApril2007),CINAHL(1982
toApril2007),Current
Contents(1993toApril
2007)weresearched.
SeventeenRCTswere
included,butjusttwoRCTs
comparedNSAIDSvsNET.

4.

Hickey(2007)[13]
CochraneMenstrual
DisordersandSubfertility
GroupTrialsRegister
(searched4May2007),
CochraneCentralRegisterof
ControlledTrials,MEDLINE
(1966tomay2007),
EMBASE(1985toMay
2007),CINAHL(1982toMay
2007),BiologicalAbstracts
(1969toMay2007),Current
Contents(1980to2007)
weresearched.
2RCTswereincluded.

5.

Lethaby(2005)[14]
TheCochraneLibrary,
MEDLINE(1966to2005)
andEMBASE(1980to2005)
weresearched.
9RCTswereincluded.

6.

Lethaby(2000)[15]
CochraneMenstrual
Disorders&Subfertility
Grouptrialsregister
(searched6April2004),the

Interventions:
Mefenamicacid500mg3times
dailyondays1to5ofmenses,
n=17.
Control:Norethisterone5mg2
timesdailyoncycledays1926,
n=15.
Durationover2cycles.MBL
(alkalinehaematinmethod).
Outcomes:
MBL(alkalinehaematinmethod)
Numberofdaysbleeding.
Adverseevents.
Patientcompliance.

MBL:
NSAIDSvsNEToddsratio22.97,
95%CI[46.57,0.62]
Durationofbleeding:
Oddsratio0.41,95%CI[0.95,
0.13].
Totaladverseevents:
Oddsratio0.54,95%CI[0.13,
2.26].
Thereisnosignificant
differenceinefficacybetween
NSAIDsandothermedical
treatmentssuchasoralluteal
progestogen.

Determinationtheeffectiveness
andacceptabilityofprogestogens
aloneandestrogensand
progestogensincombinationin
themanagementofDUB.
Theroleofprogestogensin
anovulatoryDUBwasfoundin
twotrials.
Assessmenteffectivenessoftwo
typesofprogestogens(3x5mg
NETfor14daysfromday12to25
and3x10mg
medroxyprogesteronacetate
(MPA)for14daysfromday12to
25).

Thereisnotenoughevidenceto
showtheeffectofprogestogens
aloneorincombinationwith
estrogensforDUB.

AsignificantreductioninMBL
fromapreatreatmentmeanof
13140mLto8031mLduringthe
firsttreatmentcycle,and6414
mLinthesecondcycle.The
durationofbleedingwasalso
reducedfollovingtreatment,from
ameanof8.52.4daysbefore
treatmentto6.21.7daysinthe
firsttreatmentcycle,and5.51.1
daysinthesecond.Noobvious
differencewasobservedbetween
thetwoprogestogens.

Determinationtheeffectiveness
andacceptabilityofprogesterone
orprogesteronereleasing
intrauterinedevicesinachievinga
reductioninheavymenstrual
bleeding.Thelevonorgestrel
releasingintrauterinedevice(LNG
IUS)hasbeencomparedtooral
cyclicalnorethisterone
administredondays5to26of
themenstrualcycle.
Theoutcomewasreductionin
MBL,satisfactionand
acceptability.

TheLNGIUSismoreeffectivethan
cyclicalnorethisterone.
MBLmedian6mlvsmedian20ml.
Agraterproportionofwomen
wereamenorrhoeicafterthree
monthsoftreatmentwithLNGIUS
whencomparedwiththeNET
(32%vs0%).
Ratesofsatisfactionwith
treatmentdidnotdifferbetween
groups.Asignificantlygreater
proportionofwomenintheLNG
IUSgroupwerewillingtocontinue
withtreatmentwhencompared
withtheNET(77%vs22%).
Inallgroupsoftreatments,there
wasasignificantreductionin
menstrualbloodloss(WMD73.0,
95%CI123.4to22.6;WMD
111.0,95%CI178.5to43.5;and

Determinationtheeffectiveness
ofantifibrinolyticsinachievinga
reductioninheavymenstrual
bleeding.Antifibrinolyticswere
comparedtothreeothermedical

16

CochraneCentralRegisterof therapies:mefenamicacid,
ControlledTrials,MEDLINE
norethisteroneadministeredin
(1966toApril2004),
thelutealphaseandethamsylate.
EMBASE(1985toApril
2004)weresearched.
Fifteentrialswereincluded.

7.

Beaumont(2009)[16]
MenstrualDisordersand
SubfertilityGroups
SpecialisedRegister(April
2007),Cochrane
ControlledTrialsRegister
(CochraneLibrary,Issue2,
2007),MEDLINE(1966to
April2007),EMBASE(1980
toApril2007,CINAHL(1982
toApril2007)were
searched.
NineRCTs,with353women
withwereincluded.

8.

Wellington(2003)[17]
Medicalliteraturepublished
inanylanguagesince1980
to2003identifiedusing
MEDLINEandEMBASE.

Womenwithheavymenstrual
bleeding.
ComparisonDanazolwithother
medical(nonsurgical)therapy,
includedNET,forheavy
menstrualbleedinginwomenof
reproductiveagewithregular
HMB.
Outcomewasmenstrualblood
loss(MBL).

Womenwithidiopathic
menorrhagia(excludedorganic
ethyology).
Comparasiontranexamicacid
withothermedicaltherapy,
includedNET.
OutcomewasMBL.

WMD100,95%CI143.9to56.1
respectively).
Therewerenosignificant
differencesinthefrequencyof
reportedsideeffectswith
tranexamicacidwhencompared
toorallutealphaseprogestogens
(RR0.4,95%CI0.1to1.2).Change
inthequalityoflifemeasures,
floodingandleakageandsexlife,
weresignificantlyimprovedinthe
tranexamicacidgroupwhen
comparedtotheNET.
Antifibrinolytictherapycausesa
greaterreductioninmenstrual
bleedingwhencomparedto
NSAIDS,NETorethamsylate).This
treatmentisnotassociatedwith
anincreaseinsideeffects
comparedwithNSAIDS,NETor
ethamsylate.
Danazolappearstobemore
effectivethanplacebo,
progestogensNET5mg(OR
35.60;95%CI102.20,31.00),
NSAIDsandtheoral
contraceptivesatreducingMBL,
butconfidenceintervalswere
wide.TreatmentwithDanazol
causedmoreadverseevents
thanNSAIDs(OR7.0;95%CI1.7to
28.2)andprogestogens
(OR4.05,95%CI1.6to10.2).
Mostdatawerenotinaform
suitableformetaanalysis,andthe
resultsarebasedonasmall
numberoftrials,allofwhichare
underpowered.
Tranexamicacid,24.5g/dayfor4
7days,wassignificantlymore
effectiveatreducingMBLthanthe
oralNSAIDSmefenamicacid,1,5
g/day(p<0.05),theoral
haemostaticagentetamsylate,
2g/dayfor5days(p<0.001),and
progesteronnorethisteron2x5
mg/dayadministredorallyfor7
daysduringthelutealphase
(p<0.0001).MeanMBLincreased
by20%inrecipientofNET,
comparedwithreductionof45%
intranexamicacidrecipiens.
Tranexamicacidwassignificantly
lesseffectivethanlevonorgestrel
releasing(20g/day)IUD(p<0.01).

17

Table4.Clinicaltrialsevaluatingtheeffectivenessof5mgnorethisteroneforthemanagmentof
dysfunctionaluterinebleeding(DUB)
No.

Article;StudyType;StudyDesign

Findings;Conclusion

1.

Franke(2006)[18]

Toassesstheeffectsofaddingcombined
estradiol/norethisteroneacetatetherapy(CENT)
togoserelinacetate(GA)treatmentof
dysfunctionaluterinebleeding(DUB)in
perimenopausalwomen. Abdominalpain,number
ofbleedingdaysandendometrialthickness
decreasedinbothgroups,thebetweengroup
differenceindecreasenotbeingstatistically
significant.BMDdecreasedsignificantlyinthe
GA/placebogroup(4.1%)comparedwiththe
GA/CENTgroup(0.3%).
AddingCENTtoGAtreatmentforDUBin
perimenopausalwomeninitiallypreventedBMD
lossandimprovedclimactericcomplaints,while
havingnonegativeimpactonvaginalbleeding.
Prolongedtreatmentdidnotresultinalasting
preventionofboneloss.
Assessingreductionofmenstrualbloodloss(MBL).
Inbothgroups,MBLdecreasedsignificantlyfrom
baselineto12months(P<0.001).MBLdecreased
significantlymoreintheLNGIUSgroup(median
from228to13,meanpercentchange83%)
comparedwith2.group(medianfrom290to72;
meanpercentchange68%)(P=0.002)after12
months.IntheLNGIUSgroup,80%ofsubjects
hadtreatmentsuccesscomparedwith36.8%in2.
group(P<0.009).
Tocomparetheefficacyandacceptabilityofthe
LNGIUDandNETfortreatmentofidiopathic
menorrhagia.Themainoutcomemeasurewasthe
changeinobjectivelyassessedmenstrualblood
lossafterthreemonthsoftreatment.
Whenmenstrualbloodlossatthreemonthswas
expressedasapercentageofthecontrol,
thelevonorgestrelintrauterinesystemreduced
menstrualbloodlossby94%(medianreduction
103ml;range70to733ml),andoral
norethisteroneby87%(medianreduction95ml;
range56to212ml).Afterthreecyclesof
treatment76%ofthewomeninthelevonorgestrel
intrauterinesystemgroupwishedtocontinuewith
thetreatment,comparedwithonly22%ofthe
norethisteronegroup.
Boththelevonorgestrelintrauterinesystemand
oralnorethisteroneinthisregimenprovidedan
effectivetreatmentformenorrhagiaintermsof
reducingmenstrualbloodlosstowithinnormal
limits.Thelevonorgestrelintrauterinesystemwas
associatedwithhigherratesofsatisfactionand
continuationwithtreatment,andthusoffersan
effectivealternativetocurrentlyavailablemedical

DoubleblindRCT
PerimenopausalwomenwithDUB(N=31)for6
months
1.groupreceivedgoserelinacetate(GA)+placebo
2.groupreceivedgoserelinacetate(GA)+CENT
(combinedE2+NETA)for6months
Followedby18monthsofGA/CENTforall.

2.

Endrikat(2009)[19]
RCT
Healthywomenover30yearsofagesuffering
fromidiopathicmenorrhagia(n=39).
1.grouptreatedwithlevonorgestrelreleasing
intrauterinesystem(LNGIUS)N=20
2.grouptreatedwithoralcontraceptives(20g
ethinylestradiol+1mgNETA)(n=19).
Thetreatedperiodwas12months.

3.

Irvine(1998)[20]
Randomisedcomparativeparallelgroupstudy
44womenwithheavyregularperiodsanda
measuredMBL80ml.
1.grouphadaLNGIUDinsertedwithinthefirst
sevendaysofmenses(n=22),
2.groupreceivedNET,3x5mgdaily,fromday5
today26ofthecycleforthreecycles(n=22).

18

andsurgicaltreatmentsformenorrhagia.

4.

Cameron(1990)[21]
RCT
Womenwithmenorrhagia(MBL80mlper
cycle).
1.groupreceivedmefenamicacid,500mgthree
timesdailyduringmenses(n=17),
2.groupreceivednorethisterone,2x5mgdailyon
days1926ofthecycle(n=15),
Fortwoadditionalcycles.

5.

Bonduelle(1991)[22]
RCT
Womenwithdysfunctionaluterinebleeding
1.groupreceivednorethisterone,5mg
threetimesadayfromday19to26(n=14)
2.groupreceiveddanazol,200mgdaily(n=10).

6.

Preston(1995)[23]
DoubleblindRCT
Womenwithovulatorymenorrhagia
1.groupreceivedNET,5mgtwiceadayondays
19to26(n=21),
2.groupreceivedtranexamicacid(TA)(1gfour
timesdailyondays1to4)(n=25)
Fortwocycles.

MBLwasassessed.
ThemedianMBLwasreducedfrom123ml(range
86237)to81ml(22193)(p<0.001)andfrom109
ml(81236)to92ml(43189)(p<0.002)with
mefenamicacidandNET,respectively.
Apartfromadecreaseinthemediannumberof
daysofbleeding,from7(58)to5(38)inthose
womentreatedwithmefenamicacid,noother
differenceswereseenbetweenthegroups.
ConclusionisthatmefenamicacidandNETwere
similaryeffectiveinreducingthedegreeofMBLin
womenwithprovedmenorrhagia,butthat52and
67%ofthewomen,respectively,remained
menorrhagicafter2monthsoftreatment.
ComparationtheefficacyNETvs.danazolfor
treatmentofDUB.
Bleedingintensityscoresweresignificantlylower
withdanazolthanwithnorethisteroneforthe
thirdmenses.Thisscorewasalsosignificantly
improvedwithdanazol,butnotwith
northisterone,bythe2ndand3rdmensesin
comparisonwithbaseline(P<0.02)aswerethe
numberofpads/tamponsused(P<0.05).Some
reductioninthesymptomsofbackacheand
abdominalpainaccompaniedbothtreatments
althoughbetweentreatmentcomparisonswere
notsignificant.
Comparasiontheefficacyandsafetyoftranexamic
acidandNET.
Outcome:MBLwasmeasured.
TAreducedmeanMBLby45%,from175mlto97
ml(95%CIforthedifferenceinMBL52to108,
p 0.0001),NETincreasedmeanMBLby20%from
173mlto208ml(95%CIforthedifferenceinMBL
64to2,p=0.26).
14women(56%)whoreceivedTAachieveda
meanMBLoflessthan80mlpercycleduring
treatment,butonlytwo(9.5%)whoreceivedNET
achievedthismeanMBL.
Therewerenoseriusadverseeventsreportedfor
eitherdrug.

19

7.

Higham(1993)[24]
SingleblindRCT
57womenwithbaselinemeanMBL80ml/cycle
1.groupreceiveddanazol,200mg/day(n=19)for
threecycles,
2.groupreceiveddanazol,200mg/dayforone
cycle,100mg/dayforonecycle,and50mg/day
foronecycle(n=19),
3.groupreceivednorethisterone,5mgthree
timesdailyondays19through26ofthecyclefor
threeconsecutivecycles(n=19).

8.

Cameron(1987)[25]
RCT
30womenwithmenorrhagia
1.receiveddanazol,200mgdaily(n=6),
2.groupreceivedmefenamicacid,500mgthree
timesdailyduringmenses(n=8),
3.groupreceivednorethisterone,5mgtwice
dailyfromday1525ofthecycle(n=8),
4.groupwastreatedwithprogesteron
impregnatedcoilwichreleasing65g
progesteronedaily(n=8).

9.

Saarikoshi(1990)[9]
RCT
80womenwithdysfunctionaluterinebleeding.
Theendometrial(hyperplastic)morphology
indicatedaneedforprogesteronetherapy.
1.groupreceivednorethisterone,5mgthree
timesdailyfrom15today24(n=40,meanage
was45years),
2.groupreceivednaturalmicronized
progesterone(NMP),100mgthreetimesdailyin
thesametime(n=40,meanagewas47years).
Thedurationoftreatmentwas6months.

Comparationtheefficacyoftherecommended
doseofdanazol,areduceddosedanazolregimen,
andnorethisteroneinthetreatmentof
menorrhagia.
ThefinalMBLontreatmentwassignificantlyless
forthosepatientswhoreceivedbothdanazol
regimenscomparedwiththosewhoreceivedNET
(p=0.017forreducingdosedanazolvsNetand
p=0.043for200mgofdanazolvsNET).
Significantlymorerecepientsof200mgofdanazol
thanofNETsubjectivelyratedtheirtreatmentto
bemoderatelyorhighlyeffective(p=0.033).Both
danazoltreatmentregimenswereassociatedwith
ahigherincidenceofadverseeventsthanwasNET
therapy.
Assessmenttheeffectsoffourmedicaltreatment
onMBLandendometrialprostaglandin(PG)
concentrationinwomenwithmenorrhagia.
Endometrialbiopseswereobtainedinthemid
lutealphasebeforeandaftertreatmentand
assayedforPGcontentusingradioimmunoassay.
TreatmentwithNEThadnoeffectoneitherMBL
ortheconcentrationofPGsintheendometrium.
MBLwassignificantlyreducedaftertreatment
withmefenamicacid(p=0,05,n=6)andthe
progesteroncoil(p<0,05,n=6)andwasreducedin
4casestreatedwithdanazolinwhomendometrial
biopseswereavailable.Althoughttherewasno
consistentchangeinendometrialPG
concentrationsineitherthemefenamicacidor
danazolgroups,thelowerMBLafterinsertionof
thecoilwasassociatedwithareduced
endometrialcontentofPGs(p=0,05).
TheeffectsofNETandNMPonhystological,
hormonalandlipidparametersweredetermined
andthecarryovereffectofeachdrugwasalso
investigated.
ThesequentialadministrationofNETsignificantly
decreasethelevelsofE2(p<0,001),SHBG
(p<0,001),FSHandLH(p<0.01).Theonlychange
inducedbyNMPwasasignificantincreaseinthe
serumP(progestogene)level(p<0.001).
Thehystologicaldiagnosis,beforetreatment,in
halfofthecaseswascysticglandularhyperplasia.
Thispatterndisappearedinallcasesafter6cycles
intheNETgroup.Aproliferativeendometrium
wasseenslightlymoreoftenintheNMPgroup.
ThelongtermeffectsofNETandNMPwerevery
week.Threemonthsaftercessationoftherapya
regularsecretoryendometriumwasfoundinonly
25%ofthepatientsasopposedtoahyperplastic
orproliferativeendometriumin34%.
Withbothprogestogensonlyaslightdecreasein
totalcholesterolwasseenafter6monthsof
treatment(p<0,05).TheHDLcholesteroland
triglyceridelevelsdecreasedsignificantlyinthe
NETgroup(p<0,001and<0,02)respectively,but

20

nosuchchangewasseenintheNMPgroup.The
slightdecreaseinphospholipidswasalsoobserved
duringthethirdcycleintheNETgroup(p<0,05).

10.

Fraser(1990)[26]
RCT
AnovulatorywomenwithDUB(n=6)
1.groupreceivednorethisterone(NET),5mg3
timesdaily(n=3),
2.groupreceivedmedroxyprogesteroneacetate
(MPA),10mg3timesdaily(n=3).
Bothgroupsreceiveddrugsfor14days,fromday
12today25.
OvulatorywomenwithDUB(n=10)
1.groupreceivedNET,5mg3timesdaily(n=5),
2.groupreceivedMPA,10mg3timesdaily(n=5).
Bothgroupsreceiveddrugsfor21days,fromday
5today25.

Outcomes(MBLanddurationofmenstrual
bleeding)weremeasuredimmediatlybefore
treatmentandduringthefirst2cyclesof
treatment.

Anovulatorypatients
MBLbeforetreatmentwas131ml,andduration
ofMBwas8,5days.Duringthefirstcycleof
treatmentMBLfellto80ml,duration6,2days;
withafutherfallto64ml,duration5,5days,inthe
secondcycle(pairedttest,t=4,638,p<0,005;
t=4,025,p<0,01,respectivelyforfirstandsecond
treatmentcycles).Therewasnoobvious
differencebetweenthe2progestogens,andmuch
largernumberswouldberequiredforstatistical
comparison.
Ovulatorypatients
MBLbeforetreatmentwas112ml,andduration
ofMBwas6,1days.Duringthefirstcycleof
treatmentMBLfellto76ml,duration5,2days.
Therewasafuthersmallerfallto71ml,duration
5,0days,duringthesecondcycle.MBLduring
treatmentwashighlysignificantlyreduced
comparedwithcontrol(pairedttest;t=4,651;
p<0,001).DurationofMBwasslightlyand
significantlyreduced(pairedt=3,498;p=0,007).
Therewasnoobviousdifferencebetweenthe2
progestogens.
Conclusion:Theseregimensareeffectiveformsof
managmentformostwomenwithovulatoryor
anovulatoryDUB.

Norethisteronevs.levonorgestrelintrauterinesystem
BoththeLNGIUSandoralnorethisterone(5mgthreetimesdaily,fromday5today26)providedan
effectivetreatmentformenorrhagiaintermsofreducingmenstrualbloodlosstowithinnormal
limits.TheLNGIUSwasassociatedwithhigherratesofsatisfactionandcontinuationwithtreatment,
andthusoffersaneffectivealternativetosurgicaltreatmentsformenorrhagia(hysterectomyand
endometrialablation).[10,14,20]
Norethisteronevs.danazol
Danazol(bothregimens,100mgdailyand200mgdaily)wassignificantlymoreeffectivethan
norethisteroneinreducingtheexcessivemenstrualbloodlossofwomenwithdysfunctionaluterine
bleeding.Significantlymorerecipientsof200mgofdanazolthanofnorethisteronesubjectivelyrated
theirtreatmenttobemoderatelyorhighlyeffective.Bothdanazoltreatmentregimenswere
associatedwithahigherincidenceofadverseeventsthanwasnorethisteronetherapy.[10,16,
22,24,25]
Norethisteronevs.tranexamicacid
Tranexamicacid(antifibrinolytictherapy)causesagreaterreductioninmenstrualbloodlosswhen
comparedtonorethisterone.Thistreatmentisnotassociatedwithanincreaseinsideeffects
comparedwithnorethisterone.Therehasbeenareluctancetoprescribetranexamicaciddueto
21

possiblesideeffectssuchasanincreasedriskofthromboembolicdisease.Therearenodata
availablewithinRCTswhichrecordthefrequencyofthromboembolicevents.Changeinthequalityof
lifemeasuresweresignificantlyimprovedinthetranexamicacidgroupwhencomparedtothe
norethisteronegroup.[10,15,23]
Norethisteronevs.NSAIDs
Themefenamicacidandnorethisterone,twoofthemostcommondrugtreatmensformenorrhagia,
arebotheffectiveinreducingbloodlossinwomenwithDUB.Therewasnoevidenceofadifference
betweentheindividualNSAIDs(naproxenandmefenamicacid)inreducingmenstrualbloodloss.The
mefenamicacid(500mgthreetimesdaily)andnorethisteroneweresimilarlyeffectiveinreducing
thedegreeofmenstrualbloodloss.NSAIDsarelesseffectivethaneithertranexamicacid,danazolor
LNGIUS.[10,12,19]
Conclusion:
Norethisteroneisahormonethatsuppressesendometrialgrowthandactivity.NETmayoffersome
helpinreducingheavymenstrualbleedingbutisnotaseffectiveasothertherapies.
NETistakenbymontheitherduringdays15or16today26ofthemenstrualcycle(shortcourse)or
fromday5today26(longcourse).However,itisconsideredunacceptableforlongtermuseby
manywomenduetotheprevalenceofsideeffectssuchasbreasttenderness,bloating,headaches
andtheymayalsoprecipitatebreakthroughbleeding.
Norethisteronecanbeusedalone,orwithoestrogen,totreatmentanovulatorydysfunctionaluterine
bleeding.Thereisnotenoughevidencetoshowtheeffectofnorethisteroneincombinationwith
estrogensforDUB.[13]
ManyreviewedstudiesfoundthatNETsignificantlyreducedMBL,butwaslesseffectivethan
danazol,tranexamicacid,NSAID,andtheprogesteronereleasingintrauterinesystem(IUS).A
decisionanalysiscomparingtheefficacy,sideeffectsandconsumeracceptabilityofthesetreatments
rankedtheminordershownabove,withtheLNGIUScomingtop.Surgerymaybeindicatedfor
womenwhohavecompletedchildbearingandforwhommedicaltreatmentisineffectiveor
intolerable.
Althoughitisnotthefirstchoice,peroraldoseof5mgnorethisteroneisaneffectiveformof
managmentformostwomenwithovulatoryoranovulatorydysfunctionaluterinebleeding.
Thereforenorethisterone,indoseof5mg,canberecomendedfortreatmentofdysfunctional
uterinebleeding.
Riskofbiasassessment

RiskofbiasintheincludedclinicalstudieswasassessedbyusingTheCochraneCollaboration'sriskof
biastool,whichaddressesthefollowingdomains:sequencegeneration,allocationsequence
concealment,blinding,incompleteoutcomedata,selectiveoutcomereportingandotherissues(Figs.
58).Informationextractedfromeachreportfortheriskofbiastoolispresentedinthe
accopmanyingExcelspreadsheet,alongwithajudgementoflow,highorunclearriskofbias,as
describedinChapter8oftheCochraneHandbookforSystematicReviewsofInterventions(Higgins
JPT,GreenS(editors).CochraneHandbookforSystematicReviewsofInterventionsversion5.0.2
22

(updatedSeptember2009).TheCochraneCollaboration,2009.Availablefrom:www.cochrane
handbook.org.).IntheExcelspreadsheet,yesdesignatesalowriskofbias,andnodesignatesa
highriskofbias.

Generationofallocationsequence
Hormonereplacementtherapy
Intwostudies[4,7]patientswererandomlyassignedtostudyarms,withoutfurtherexplanationof
themethodofrandomization.Inonestudytherewasnorandomizationprocedure[5].

Dysfunctionaluterinebleeding
Majorityofstudies(7of10)simplyreportedthatsubjectswererandomlyallocatedtostudyarms,
withoutprovidinganydetailhowtherandomizationsequencewasgenerated,sotheriskofbiasin
thesecaseswasjudgedunclear.Twostudiesadequatelyreportedthatrandomizationwasdoneby
computergeneratednumbers[20,23],andinonestudytherewasnomentionofrandomization,so
theriskofbiaswasjudgedtobehigh[26].

Concealmentofallocationsequence
Hormonereplacementtherapy
Twostudiesreportednoattempttoconceltheallocationsequence[4,7],andtherewasno
randomizationinthethirdstudy[5].

Dysfunctionaluterinebleeding
Majorityofstudies(7of10)didnotreportanyattempttoconcealtheallocationsequence,sothe
riskofbiasinthesestudieswasjudgedunclear.Twostudiesadequatelyreportedthatthesequence
wasplacedinopaque,sealed,consecutivelynumberedenvelopes[20,23],andinonestudythere
wasnorandomizationandthereforenoallocationsequenceconcealment[26].

Blinding
Hormonereplacementtherapy
Innoneoftheincludedstudiestheblindingprocedurewasadequatelydescribed.Twostudieswere
reportedlydoubleblinded[4,5],andoneofthemstatedthatplacebotabletwasindenticalto
treatment[5].Inonestudy[7],pathologistwhoassessedendometrialbiopsywasunawareofthe
treatmentgiven,buttheblindingforthepatientreportedoutcomeswasnotdone,asgroupshad
differenttherapeuticregimesandnoattempttomaskthetreatmentwasattempted.

Dysfunctionaluterinebleeding
Adequatedoubleblinding,withtheuseofplacebotabletsidenticalwiththetreatment,wasreported
inonlytwostudies[18,23].Threeopenlabelstudies[19,20,22]andtwostudiesthatreportedno
attemptofblinding[21,26]werejudgedtohaveahighriskofbiasintermsofblinding.Threestudies
hadanunclearriskofbiasintwoofthemitwasnotclearwhoperformedtheassessmentand
whetherthesepersonswereblinded[9,25],andthethirdonewasdescribedassingleblind,butwith
nodetailsonhowtheresearchers/assessorswereblinded[24].Inonestudytherewereno
researcherassessedoutcomes[22],andinanotherstudytherewerenopatientreportedoutcomes
[9].

Incompleteoutcomedata
Hormonereplacementtherapy
Twostudieswerejudgedtobeunderahighriskofbiasregardingincompleteoutcomedataduetoa
highandpoorlyexplainedattrition[5,7].Inthethirdstudy[4],theriskofbiaswaslow,asthe
attritionwasrelativelysmallandequallydistributedamongthestudygroups.

Dysfunctionaluterinebleeding
23

Riskofbiasregardingincompleteoutcomedatawasjudgedhighinfourstudies[9,19,22,25]duetoa
relativelyhighrateofattrition.Infourstudiesthisriskofbiaswasunclearintwoofthemattrition
wasrelativelyhigh,butintentiontotreatanalysiswasperformed[20,24],andinanothertwo
attritionwasnotclearlyreportedorexplained[18,23].Intwostudiestheriskofbiasregarding
incompleteoutcomedatawaslow,asattritionwassmallandunlikelytohaveaffectedtheresults
[21,26].

Selectiveoutcomereporting
Wedidnotattempttofindprotocolsfortheincludedstudies,butwecomparedtheoutcomesstated
inthemethodssectionwiththeonesreportedintheresultssection.

Hormonereplacementtherapy
Alloutcomesstatedinthemethodssectionreportedintheresultssectionofallincludedstudies.

Dysfunctionaluterinebleeding
Anadequatematchbetweenoutcomesstatedinthemethodssectionandtheonesreportedinthe
resultssectionwasfoundin9of10studies,whichwerethusjudgedtobeunderalowriskofbias
withregardtoselectiveoutcomereporting.Theriskofbiaswasunclearinonlyonestudywhichdid
reportresultsforalloutcomesmentionedinthemethodssection,butnotfully[18].

Otherpotentialthreatstovalidity
Hormonereplacementtherapy
Otherpotentialthreatstovaliditywerejudgedunclearinallthreeincludedstudies,astherewasno
assessmentofcompliance,andnofinancialsupportorconflictofinterestweredeclared.

Dysfunctionaluterinebleeding
Attempttoassessthecompliancetotreatmentregimentwasreportedinonlyonestudy[23],which
alsohadadeclaredfinancialsupport(thoughfromunclearsource).Thiswastheonlystudythatwas
judgedtohavealowriskofbiasintermsofotherpotentialthreatstovalidity.Threestudieswere
judgedtohaveanunclearriskofbias[9,22,25],astheydidnotattempttoassessthecomplianceand
theirfinancialsupportwaseithernotdeclared,ornonindustryrelated.Theremainingsixstudies
werejudgedtohaveahighriskofbias[18,19,20,21,24,26],astheydidnotattempttoassessthe
compliance,theirfinancialsupportwaseitherindustryrelatedorundeclared,andtheyallhavea
smallnumberofparticipants,whichwaslikelytoaffecttheprecisionoftheirestimates.

24

Figure5.Riskofbiassummaryforhormonereplecementtherapy:reviewauthors'judgementsabout
eachriskofbiasitemforeachincludedstudy.

Figure6.Riskofbiasgraphforhormonereplecementtherapy:reviewauthors'judgementsabout
eachriskofbiasitemforeachincludedstudy.

25

Figure7.Riskofbiassummaryfordysfunctionaluterinebleedingoutcome:reviewauthors'
judgementsabouteachriskofbiasitemforeachincludedstudy.

26

Figure8.Riskofbiasgraphfordysfunctionaluterinebleedingoutcome:reviewauthors'judgements
abouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.

27

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