- Email: [email protected]
Efficacy and safety of a combination of 2 mg estradiol valerate plus 2 mg dienogest in postmenopausal women
WEDNESDAY,
FC3.05
SEPTEMBER
EFFECTS
6
OF HRT
FC3.05.01 ENDOMETRIAL HYPERPLASIA WITH TIBOLONE (LIVIALB) L. M. Albernaz, E. Souza, Dept. OBIGYN, Hospital Materno Infantil de Goilnia, Goi$nia, Brazil. Objectives: To question the endometrial security after long term Tibolone use. Study Methods: Case report of 3 cases of endometrial hyperplasia during Tibolone medication. Results: The first placebo controlled trials suggested almost an endometrial protection, showing no stimulation and bleeding not greater than placebo. Most studies had only one year follow-up and there are very few described cases of Tibolone associated hyperplasia, until now. We describe 3 cases of private office, that developed endometrial hyperplasia, tow of them with focal atipias, after on year or more of Tibolone. The patients were 2 54 years old, more than 1 year menopause, weren’t obese, had normal exams, except for a type II controlled diabetes and had 5 5 mm endometrium before and HRT (Hormone Replacement Therapy). Case 1 had only one month of combined estrogen during HRT, and two of them had used oral or local estrogen before Tibolone, but all had endometrium less than 6 mm and stayed amenorrheic for more than 1 year before bleeding and hyperplasy diagnosed by transvaginal sonography, hysteroscopy and biopsy. Conclusion: We need more studies with long-term follow-up and Tibolone interaction to confirm it is safe to the endometrium. Until then, doctors must control endometrial stimulation with Tibolone like any other HRT.
FC3.05.02 SUBCUTANEOUS EXTRADIOL IMPLANT AS A REGIMEN FOR HRT IN MENOPAUSAL ESTROGEN DEFICIENCY S. Suhonencl), L. Anttila(2), R. Punnonen(3), E. Varila (3), I. Rauramo (4), T. Salmi(2) (1) Dept OBIGYN, Helsinki City Maternity Hospital, Helsinki, Finland. (2) Turku University Central Hospital, Turku, Finland. (3) Tampere University Hospital, Tampere, Finland. (4) Leiras Oy, Helsinki, Finland Objectives: To investigate the efficacy and safety of the subcutaneous estradiol implant (EJ treatment for menopausal estrogen deficiency. Study Methods: This was an open, non-comparative, multi-center study in 37 peri- and 61 postmenopausal women. Two implants, each containing 70 mg E,, were inserted at study entry under local anesthesia in the subjects’ upper arm and the treatment was used for 24 months. Oral MPA (10mg) for 10 days/month was used to oppose endometrial stimulation. S-E, concentrations were measured and the relief of climacteric symptoms was evaluated by using Kupperman index. Results: The treatment compliance was high: 85 (86.7%) out of 98 subjects completed the 24 months follow-up. The steady state E, concentration (192.0 pmoV1) was reached in 7 days remaining at an acceptable level for up to 24 months. Relief of menopausal symptoms was successful: the median Kupperman index declined from entry to three months by 64% and 80% and to 24 months by 100% and 90% in the peri- and postmenopausal groups. The most common adverse events were headache and breast tenderness. 10 out of 13 discontinuations were due to adverse events. Conclusions: Subcutaneous E, implant is an effective and safe long-term treatment method for HRT in menopausal estrogen deficiency. Patient compliance is high since daily or weekly administration is not needed.
FC3.05.03 EFFICACY AND SAFETY OF A COMBINATION OF 2 MG ESTRADIOL VALERATE PLUS 2 MG DIENOGEST IN POSTMENOPAUSAL WOMEN T. Graser (l), T. Romer (2), F. Walter (l), M. Oettel(l) Medical Research Dept. Jenapharm GmbH & Go. KG, Germany Jena and Clinic OBIGYN, University of Cologne, Germany. Objectives: To evaluate the efficacy, safety and tolerability of continuous combined hormone replacement therapy (HRT) with 132 valerate plus 2 mg dienogest).
23
Study Methods: In an open, multinational, multicenter, non-controlled phase III study, 1501 women aged 52-65 years with postmenopausal symptoms were treated with Klimodien’ for 12 treatment cycles (48 weeks), with assessments of efficacy, safety, tolerability (adverse events) at 8, 24 and 48 weeks. Efficacy was assessed using the Kupperman Index. Safety assessment included transvaginal sonography, endometrial biopsy, mammography, physical and gynecological examination, vital signs, prothrombotic factors and routine laboratory safety parameters. Results: Kupperman Index improved with increasing duration of treatment, accompanied by improvement of self-reported well being. Individual climacteric symptoms, such as hot flushes and pychonervous disorders, also improved. The most pronounced improvement was seen in HRT-naive patients. The incidence of breakthrough bleeding declined over time, resulting in complete amenorrhea in 86.2% of the patients after 12 cycles of treatment. Furthermore, total and LDL cholesterol levels decreased and HDL cholesterol levels increased. Decreases in alkaline phosphatase, pyridinoline, and desoxypyridinoline demonstrated that dienogest did not affect the inhibitory action of extradiol on bone resorption. Endometrial thickness remained almost constant and the incidence of serious endometrial findings was similar to that of untreated women. Conclusions: Continuous combined substitution with Klimodien” is effective, safe and well tolerated in postmenopausal women. The hybrid progestin dienogest does not abolish the estrogen benefits of Klimodien’.
FC3.05.04 WHAT IS COMING AFTER HORMONE REPLACEMENT IN WOMEN AND MEN? CONSIDERATIONS FROM THE ENDOCRINOLOGIC AND PHARMACOLOGIC POINTS OF VIEW REGARDING HORMONE DISPLACEMENT M. Oettel (l), W. Elger (l), M. Obendorf(l), V. Patchev (l), U. Schumacher (l), B. Winkelmann (2) (1) Dept. Research and Development, Jenapharm GmbH & Co. KG, Jena, Germany. (2) Herzzentrum Ludwigshafen Medizinische Klinik B, Ludwigshafen, Germany. The near future of hormone replacement in women is strongly influenced by the development of selective estrogen receptor modulators, estrogen sulfamates, and selective progesterone receptor modulators. New developments for hormone replacement in men refer to tissue specific androgens (selective androgen receptor modulators) and non-feminizing estrogens. A new approach could be hormone displacement. On the basis of our own epidemiologic data the age-related reductions of the secretion of estrogens, androgens, DHEAS and their clinical consequences will be discussed. The secretion of cortisol and progesterone (at least in men) is not age related. Therefore, a relative hypercortisolism and a progesterone/testosterone imbalance occurs. The potential therapeutic value of selective antiglucocorticoids will be presented as well as the different approaches to the modulation of non-classical progesterone action.
FC3.05.05 COMPARATIVE BIOAVAILABILITY OF TWO TRANSDERMAL DEVICES OF 17-P. (ESTRADIOL TD760 AND OESCLIM’SO) IN POST-MENOPAUSAL VOLUNTEERS D. Deurez (l), G. Blanchot (l), A. Renoux (2), D. Chassard (2) (1) Institut de Recherche Pierre Fabre, Boulogne, France. (2) Groupe CEPHAC-ASTER, Paris, France. Objective: To compare the pharmacokinetic profiles and the relative bioavailability of estradiol and estrone after a 2-week application of TD760 applied once weekly versus Oesclim”50 applied twice weekly. Study Methods: Single center, open labelled, randomized, two 14 day period cross-over study in 36 healthy post-menopausal women with FSH 2 40 IU/I and plasma estradiol < 45 pgiml. A wash-out period of one week was observed between the two treatment periods. Blood samples were collected for each treatment period before patch application (TO) and every 12124 hours from D8 to D15 as well as 1, 2, 4 and 12 hours after last patch removal on D15. Plasma estradiol (E2) and estrone (El) were assayed by GCIMS. C,, T,,, Cmln,AUC168~336h, C,,, mF and E2/El
FC3.05
SEPTEMBER
EFFECTS
6
OF HRT
FC3.05.01 ENDOMETRIAL HYPERPLASIA WITH TIBOLONE (LIVIALB) L. M. Albernaz, E. Souza, Dept. OBIGYN, Hospital Materno Infantil de Goilnia, Goi$nia, Brazil. Objectives: To question the endometrial security after long term Tibolone use. Study Methods: Case report of 3 cases of endometrial hyperplasia during Tibolone medication. Results: The first placebo controlled trials suggested almost an endometrial protection, showing no stimulation and bleeding not greater than placebo. Most studies had only one year follow-up and there are very few described cases of Tibolone associated hyperplasia, until now. We describe 3 cases of private office, that developed endometrial hyperplasia, tow of them with focal atipias, after on year or more of Tibolone. The patients were 2 54 years old, more than 1 year menopause, weren’t obese, had normal exams, except for a type II controlled diabetes and had 5 5 mm endometrium before and HRT (Hormone Replacement Therapy). Case 1 had only one month of combined estrogen during HRT, and two of them had used oral or local estrogen before Tibolone, but all had endometrium less than 6 mm and stayed amenorrheic for more than 1 year before bleeding and hyperplasy diagnosed by transvaginal sonography, hysteroscopy and biopsy. Conclusion: We need more studies with long-term follow-up and Tibolone interaction to confirm it is safe to the endometrium. Until then, doctors must control endometrial stimulation with Tibolone like any other HRT.
FC3.05.02 SUBCUTANEOUS EXTRADIOL IMPLANT AS A REGIMEN FOR HRT IN MENOPAUSAL ESTROGEN DEFICIENCY S. Suhonencl), L. Anttila(2), R. Punnonen(3), E. Varila (3), I. Rauramo (4), T. Salmi(2) (1) Dept OBIGYN, Helsinki City Maternity Hospital, Helsinki, Finland. (2) Turku University Central Hospital, Turku, Finland. (3) Tampere University Hospital, Tampere, Finland. (4) Leiras Oy, Helsinki, Finland Objectives: To investigate the efficacy and safety of the subcutaneous estradiol implant (EJ treatment for menopausal estrogen deficiency. Study Methods: This was an open, non-comparative, multi-center study in 37 peri- and 61 postmenopausal women. Two implants, each containing 70 mg E,, were inserted at study entry under local anesthesia in the subjects’ upper arm and the treatment was used for 24 months. Oral MPA (10mg) for 10 days/month was used to oppose endometrial stimulation. S-E, concentrations were measured and the relief of climacteric symptoms was evaluated by using Kupperman index. Results: The treatment compliance was high: 85 (86.7%) out of 98 subjects completed the 24 months follow-up. The steady state E, concentration (192.0 pmoV1) was reached in 7 days remaining at an acceptable level for up to 24 months. Relief of menopausal symptoms was successful: the median Kupperman index declined from entry to three months by 64% and 80% and to 24 months by 100% and 90% in the peri- and postmenopausal groups. The most common adverse events were headache and breast tenderness. 10 out of 13 discontinuations were due to adverse events. Conclusions: Subcutaneous E, implant is an effective and safe long-term treatment method for HRT in menopausal estrogen deficiency. Patient compliance is high since daily or weekly administration is not needed.
FC3.05.03 EFFICACY AND SAFETY OF A COMBINATION OF 2 MG ESTRADIOL VALERATE PLUS 2 MG DIENOGEST IN POSTMENOPAUSAL WOMEN T. Graser (l), T. Romer (2), F. Walter (l), M. Oettel(l) Medical Research Dept. Jenapharm GmbH & Go. KG, Germany Jena and Clinic OBIGYN, University of Cologne, Germany. Objectives: To evaluate the efficacy, safety and tolerability of continuous combined hormone replacement therapy (HRT) with 132 valerate plus 2 mg dienogest).
23
Study Methods: In an open, multinational, multicenter, non-controlled phase III study, 1501 women aged 52-65 years with postmenopausal symptoms were treated with Klimodien’ for 12 treatment cycles (48 weeks), with assessments of efficacy, safety, tolerability (adverse events) at 8, 24 and 48 weeks. Efficacy was assessed using the Kupperman Index. Safety assessment included transvaginal sonography, endometrial biopsy, mammography, physical and gynecological examination, vital signs, prothrombotic factors and routine laboratory safety parameters. Results: Kupperman Index improved with increasing duration of treatment, accompanied by improvement of self-reported well being. Individual climacteric symptoms, such as hot flushes and pychonervous disorders, also improved. The most pronounced improvement was seen in HRT-naive patients. The incidence of breakthrough bleeding declined over time, resulting in complete amenorrhea in 86.2% of the patients after 12 cycles of treatment. Furthermore, total and LDL cholesterol levels decreased and HDL cholesterol levels increased. Decreases in alkaline phosphatase, pyridinoline, and desoxypyridinoline demonstrated that dienogest did not affect the inhibitory action of extradiol on bone resorption. Endometrial thickness remained almost constant and the incidence of serious endometrial findings was similar to that of untreated women. Conclusions: Continuous combined substitution with Klimodien” is effective, safe and well tolerated in postmenopausal women. The hybrid progestin dienogest does not abolish the estrogen benefits of Klimodien’.
FC3.05.04 WHAT IS COMING AFTER HORMONE REPLACEMENT IN WOMEN AND MEN? CONSIDERATIONS FROM THE ENDOCRINOLOGIC AND PHARMACOLOGIC POINTS OF VIEW REGARDING HORMONE DISPLACEMENT M. Oettel (l), W. Elger (l), M. Obendorf(l), V. Patchev (l), U. Schumacher (l), B. Winkelmann (2) (1) Dept. Research and Development, Jenapharm GmbH & Co. KG, Jena, Germany. (2) Herzzentrum Ludwigshafen Medizinische Klinik B, Ludwigshafen, Germany. The near future of hormone replacement in women is strongly influenced by the development of selective estrogen receptor modulators, estrogen sulfamates, and selective progesterone receptor modulators. New developments for hormone replacement in men refer to tissue specific androgens (selective androgen receptor modulators) and non-feminizing estrogens. A new approach could be hormone displacement. On the basis of our own epidemiologic data the age-related reductions of the secretion of estrogens, androgens, DHEAS and their clinical consequences will be discussed. The secretion of cortisol and progesterone (at least in men) is not age related. Therefore, a relative hypercortisolism and a progesterone/testosterone imbalance occurs. The potential therapeutic value of selective antiglucocorticoids will be presented as well as the different approaches to the modulation of non-classical progesterone action.
FC3.05.05 COMPARATIVE BIOAVAILABILITY OF TWO TRANSDERMAL DEVICES OF 17-P. (ESTRADIOL TD760 AND OESCLIM’SO) IN POST-MENOPAUSAL VOLUNTEERS D. Deurez (l), G. Blanchot (l), A. Renoux (2), D. Chassard (2) (1) Institut de Recherche Pierre Fabre, Boulogne, France. (2) Groupe CEPHAC-ASTER, Paris, France. Objective: To compare the pharmacokinetic profiles and the relative bioavailability of estradiol and estrone after a 2-week application of TD760 applied once weekly versus Oesclim”50 applied twice weekly. Study Methods: Single center, open labelled, randomized, two 14 day period cross-over study in 36 healthy post-menopausal women with FSH 2 40 IU/I and plasma estradiol < 45 pgiml. A wash-out period of one week was observed between the two treatment periods. Blood samples were collected for each treatment period before patch application (TO) and every 12124 hours from D8 to D15 as well as 1, 2, 4 and 12 hours after last patch removal on D15. Plasma estradiol (E2) and estrone (El) were assayed by GCIMS. C,, T,,, Cmln,AUC168~336h, C,,, mF and E2/El