- Email: [email protected]
S13 Combination continuous therapy-what is the optimal (MPA) dose? Structure of the study
Sll
S12 EVALUATION ULTRASOUND
OF THE ENDOMETR~UM BY THE VIEW FROM THE SCREEN
W Hiineai,
LIVIAL ~IBOLONE) AND THE SPECIFIC ENDOMETR~AL RESPONSE - THE VIEW FROM RECENT CLINICAL STUDIES
Departmentof Obstetricsand Gynaecology, University of Bern, HJT Coelinph Bmnink, Bern, Switzerland ScientificDevelopmentGroup,NV Organon,Oss,TheNetherlands. With the increasing useof HRT in pos~enopau~lwomen,a simple Livial (tibolone)is a steroidwith a mixed ho~on~ profile with an noninvasiveoutpatienttechniqueto assess the endometrialstatusis estrogeniceffect on climacteric symptomsand bone without required. Transvaginal ultrasound(TUS) is a well accepteddiagnostic stimulationof the endometrium.One of the major advantagesof tool in the clinicalgynaecological setting. Wepreviouslydemonstrated Livial comparedto conventionalHRT is the lower incidenceof that in non-pregnant womenthepredicitivevalueof TUSwas7 I. 1%for vaginal bleedingwith concomitanthigher compliance. This was endometrial malignancy and95.6%for benigndisease with a sensitivity confirmedin a recent study showingsignificantly lower bleeding of 82.1%anda specificityof 92.I %. incidences combinedwith lowerdrop-outrateswith Livial thanwith In a recentprospectiverandomizedstudy in 105HRT usersand 35 continuouscombinedE$NETA replacementtherapy. In other well untreatedcontrols,endometriawere evaluatedby TUS and biopsy. controlled randomizedstudies,bleedingevents with Livial occur Endometrialthicknesscorrelatedwell with biopsyfindings. After 12 about 10% more frequently than in placebousers. Most vaginal months,if endometrial thicknesswas<5 mm,the biopsysamplewas bleedingwith Livial occursin the first 3 monthsof use. An early either inactive/atrophic or insufftcientfor histopathological diagnosis. menopause, a short interval betweenmenopauseand the start of However,after 24 monthsthe optimalcut-off point appeared to be ~4 treatmentand remainingendocrineovarian activity are correlated mm. Whether the aged changeover time in cut-off point for with bleedingduring Liviai use. Long term treatmentwith Livial endometriai thicknessin HRT usersbearsclinicalrelevanceshouldbe resultsin atrophic progestagendominatedendometriumin most investigated in huurestudies.TUS of the endometrium reliablypredicts users. This remarkablecombinationof an estrogeniceffect on the histologicalpicture in HRT users. Using 4-5 mm endometrial climacteric complaintsand bone without concurrent stimulatory thicknessas cut-off point, more than 6575% of biopsiescould be effect on the endometriumcan be explainedby local conversionof avoided. Liviaf by endometrialtissueinto its A4 metabolite,which hasbeen In the samestudywe showed that after24 months,endometrial thickness shownto have progestagenic activity. This metabolicpathway is wasincreased with both oralandtmnsdermal sequential HRT. whereas possibly due to the presence of 313-OH steroid with tibolonethechangein endometrial thickness wasnot differentfrom deh!,drogenase/isomerase in the endometrium. The in vitro data untreated controls,All threeHRT regimens weresafewith respectto the supporting this explanation became available after clinical endometrium.With sequential HRT the expectedprogestogen induced documentation of low vaginal bleedingrateswith the product and secretorystate was observed,whereasendometrialhistologywith areanotherexampleof serendipityin the searchanddevelopmentof tibolone treatment closely mimicked the natural atrophic newandinnovativeph~maceuticalcompounds. postmenopausal state.
s13 COMBINATION CONTINUOUS THERAPY - WHAT IS THE OPTIMAL (MPA) DOSE? STRUCTURE OF THE STUDY
s14 EFFICACY
OF OGENlPROVERA
REGIMENS
RJ Briber
MenopauseCentre. Royal North ShoreHospital, Sydney for The Department of Clinical Endocrinology, Westmead Hospital OgenProveraStudyGroup Westmead NSW 2145 womenwereenrolledin a 9 centrerandomised Thisstudyuseda continuous oestrone sulphate/MPAregimenin patients 568postmenopausal over a two year period. Patientswere recruitedthroughcentresin parallel study to receive one of three continuous regimensof acetate(MPA 2.5, 5.0 or IOmg Australiaandwererandomlyallocated to treatment with 1.25mgoestrone micronisedmedroxyprogesterone daily) together with 1.25mg oestrone sulphatedaily for 24 months. suiphateandeither2.5, 5.0 or IO.Omgof MPA. Eachadvent group had~p~ximately equalnumbersof patientswho hadeithernot used The numberof patientsexperiencinghot flushesdiminishedfrom 80 HRTpreviouslyor whohadcompleted a sixweekwashoutperiodbefore % at enrollmentto 20 % at 3 months. After 24 monthsthe commencing the study. Inclusioncriteriaincludedhealthywomenwith percentageexperiencinghot flushesrangedfrom 3 % (1OmgMPA) morethanoneyearandlessthan5 yearsamenorrhoea, with menopausal to 9.2 % (2.5mgMPA). symptoms requiringtherapy,an intact uterusanda serumFSHgreater 55-60%of womenexperiencedmild to moderateand lo- 12%severe than40.0I.U./l . Patientswereseeneverythreemonthsfor two years.A moodswingsat screening(meanintensity l.l- 1.2). This diminished full clinica ex~ination whichincludedm~urementof weight,height, to 16.90/o,10.6% and 22.4% in the 2.5, 5 and 1Omggroups bloodpressure andvaginalpH wascompleted prior to commencement,respectively(meanintensity0.2-0.3). Vaginal drynesswasreported after 12and24 months.Patientsmaintained a menstrual diary aswell a by 70%at screeningreducingto 10%at 3 months.Mild to moderate recordof dietarycalciumintake. Theywereencouraged to maintaina lethargywasreducedfrom 50-60%at screeningto 9% at 6 months. libido wasreportedby 70-75% at screening.At month3 calciumintakeof 1.5gm/dayby supplementation if necessary.Patients Decreased only 7-1 I % reportedseverely decreasedlibido. Improvement who neededan increaseddoseof oestrogento control menopausal s~ptoms were dis~ntinuedfrom the study. Blood sampleswere continuedfor the durationof the study with 76-82 % reportingno in libidoat 24 months. collectedfor measurement of total cholesterol,triglycerides,HDL decrease In summary, all treatmentgroups were comparable. A shift in cholesterol, LDL cholesterol andanti-thrombin III at the initialvisit then after3, 6, 12and24months.Endometrial biopsysamples wereobtained severity of symptomsfrom screeningoccurred as the study Most womenreportedalleviationof all four menopausal usingthePipelleaspirator priorto commencing treatment thenafter3, 12, progressed. symptom groups asthe treatmentprogressed. and24 months.Bonedensitywasmeasured by dualX raymachinery at 0, 12and24 months.Efficacyof thetreatmentwasassessed by bleeding patterns and patient compliance, endometrial histoIogy, lipid changes andbonedensitychanges.
S12 EVALUATION ULTRASOUND
OF THE ENDOMETR~UM BY THE VIEW FROM THE SCREEN
W Hiineai,
LIVIAL ~IBOLONE) AND THE SPECIFIC ENDOMETR~AL RESPONSE - THE VIEW FROM RECENT CLINICAL STUDIES
Departmentof Obstetricsand Gynaecology, University of Bern, HJT Coelinph Bmnink, Bern, Switzerland ScientificDevelopmentGroup,NV Organon,Oss,TheNetherlands. With the increasing useof HRT in pos~enopau~lwomen,a simple Livial (tibolone)is a steroidwith a mixed ho~on~ profile with an noninvasiveoutpatienttechniqueto assess the endometrialstatusis estrogeniceffect on climacteric symptomsand bone without required. Transvaginal ultrasound(TUS) is a well accepteddiagnostic stimulationof the endometrium.One of the major advantagesof tool in the clinicalgynaecological setting. Wepreviouslydemonstrated Livial comparedto conventionalHRT is the lower incidenceof that in non-pregnant womenthepredicitivevalueof TUSwas7 I. 1%for vaginal bleedingwith concomitanthigher compliance. This was endometrial malignancy and95.6%for benigndisease with a sensitivity confirmedin a recent study showingsignificantly lower bleeding of 82.1%anda specificityof 92.I %. incidences combinedwith lowerdrop-outrateswith Livial thanwith In a recentprospectiverandomizedstudy in 105HRT usersand 35 continuouscombinedE$NETA replacementtherapy. In other well untreatedcontrols,endometriawere evaluatedby TUS and biopsy. controlled randomizedstudies,bleedingevents with Livial occur Endometrialthicknesscorrelatedwell with biopsyfindings. After 12 about 10% more frequently than in placebousers. Most vaginal months,if endometrial thicknesswas<5 mm,the biopsysamplewas bleedingwith Livial occursin the first 3 monthsof use. An early either inactive/atrophic or insufftcientfor histopathological diagnosis. menopause, a short interval betweenmenopauseand the start of However,after 24 monthsthe optimalcut-off point appeared to be ~4 treatmentand remainingendocrineovarian activity are correlated mm. Whether the aged changeover time in cut-off point for with bleedingduring Liviai use. Long term treatmentwith Livial endometriai thicknessin HRT usersbearsclinicalrelevanceshouldbe resultsin atrophic progestagendominatedendometriumin most investigated in huurestudies.TUS of the endometrium reliablypredicts users. This remarkablecombinationof an estrogeniceffect on the histologicalpicture in HRT users. Using 4-5 mm endometrial climacteric complaintsand bone without concurrent stimulatory thicknessas cut-off point, more than 6575% of biopsiescould be effect on the endometriumcan be explainedby local conversionof avoided. Liviaf by endometrialtissueinto its A4 metabolite,which hasbeen In the samestudywe showed that after24 months,endometrial thickness shownto have progestagenic activity. This metabolicpathway is wasincreased with both oralandtmnsdermal sequential HRT. whereas possibly due to the presence of 313-OH steroid with tibolonethechangein endometrial thickness wasnot differentfrom deh!,drogenase/isomerase in the endometrium. The in vitro data untreated controls,All threeHRT regimens weresafewith respectto the supporting this explanation became available after clinical endometrium.With sequential HRT the expectedprogestogen induced documentation of low vaginal bleedingrateswith the product and secretorystate was observed,whereasendometrialhistologywith areanotherexampleof serendipityin the searchanddevelopmentof tibolone treatment closely mimicked the natural atrophic newandinnovativeph~maceuticalcompounds. postmenopausal state.
s13 COMBINATION CONTINUOUS THERAPY - WHAT IS THE OPTIMAL (MPA) DOSE? STRUCTURE OF THE STUDY
s14 EFFICACY
OF OGENlPROVERA
REGIMENS
RJ Briber
MenopauseCentre. Royal North ShoreHospital, Sydney for The Department of Clinical Endocrinology, Westmead Hospital OgenProveraStudyGroup Westmead NSW 2145 womenwereenrolledin a 9 centrerandomised Thisstudyuseda continuous oestrone sulphate/MPAregimenin patients 568postmenopausal over a two year period. Patientswere recruitedthroughcentresin parallel study to receive one of three continuous regimensof acetate(MPA 2.5, 5.0 or IOmg Australiaandwererandomlyallocated to treatment with 1.25mgoestrone micronisedmedroxyprogesterone daily) together with 1.25mg oestrone sulphatedaily for 24 months. suiphateandeither2.5, 5.0 or IO.Omgof MPA. Eachadvent group had~p~ximately equalnumbersof patientswho hadeithernot used The numberof patientsexperiencinghot flushesdiminishedfrom 80 HRTpreviouslyor whohadcompleted a sixweekwashoutperiodbefore % at enrollmentto 20 % at 3 months. After 24 monthsthe commencing the study. Inclusioncriteriaincludedhealthywomenwith percentageexperiencinghot flushesrangedfrom 3 % (1OmgMPA) morethanoneyearandlessthan5 yearsamenorrhoea, with menopausal to 9.2 % (2.5mgMPA). symptoms requiringtherapy,an intact uterusanda serumFSHgreater 55-60%of womenexperiencedmild to moderateand lo- 12%severe than40.0I.U./l . Patientswereseeneverythreemonthsfor two years.A moodswingsat screening(meanintensity l.l- 1.2). This diminished full clinica ex~ination whichincludedm~urementof weight,height, to 16.90/o,10.6% and 22.4% in the 2.5, 5 and 1Omggroups bloodpressure andvaginalpH wascompleted prior to commencement,respectively(meanintensity0.2-0.3). Vaginal drynesswasreported after 12and24 months.Patientsmaintained a menstrual diary aswell a by 70%at screeningreducingto 10%at 3 months.Mild to moderate recordof dietarycalciumintake. Theywereencouraged to maintaina lethargywasreducedfrom 50-60%at screeningto 9% at 6 months. libido wasreportedby 70-75% at screening.At month3 calciumintakeof 1.5gm/dayby supplementation if necessary.Patients Decreased only 7-1 I % reportedseverely decreasedlibido. Improvement who neededan increaseddoseof oestrogento control menopausal s~ptoms were dis~ntinuedfrom the study. Blood sampleswere continuedfor the durationof the study with 76-82 % reportingno in libidoat 24 months. collectedfor measurement of total cholesterol,triglycerides,HDL decrease In summary, all treatmentgroups were comparable. A shift in cholesterol, LDL cholesterol andanti-thrombin III at the initialvisit then after3, 6, 12and24months.Endometrial biopsysamples wereobtained severity of symptomsfrom screeningoccurred as the study Most womenreportedalleviationof all four menopausal usingthePipelleaspirator priorto commencing treatment thenafter3, 12, progressed. symptom groups asthe treatmentprogressed. and24 months.Bonedensitywasmeasured by dualX raymachinery at 0, 12and24 months.Efficacyof thetreatmentwasassessed by bleeding patterns and patient compliance, endometrial histoIogy, lipid changes andbonedensitychanges.