Muturitas, 15 (1992) 195-198 Elsevier Scientific Publishers Ireland Ltd.
195
MAT 00703
A transdermal regimen for continuous combined hormone replacement therapy in the menopause Paul J. Keller, Elsa Hotz and Bruno Imthurn Department of Obstetrics and Gynecology, University Hospital, Zurich (Switzerland) (Received April 21, 1992; revision received July 20, 1992; accepted August 20, 1992)
Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efftciently relieved and the Kupperman score drop ped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no signiticant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDLZ-, HDW-cholesterol, LDL-cholesterol and apolipoproteins Al and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.
Key words: menopause; hormone replacement therapy; combined transdermal therapeutic systems
Introduction The benefit of oestrogen replacement therapy in postmenopausal women is undisputed; however, the mode of application remains a matter of controversy. Transdermal therapeutic systems, which avoid the hepatic first-pass effect and maintain steady near-physiological blood hormone levels are thought to be particularly suited for this purpose. Since any hormone substitution in the menopause must be continued for long time in order to prevent osteoporosis and arterial disease, patient compliance is of great importance [ 1,2]. It is often seriously impeded when a conventional oestradiol releasing patch is used in conjunction with cyclical oral progestogens to protect against endometrial hyperplasia and cancer, which leads to monthly bleeds in non-hysterectomized women and to other undesirable psychological and symptomatic effects. For these reasons it seemed worthwhile to use a newly-developed transdermal system delivering oestrogen and progestogen, Correspondence to: P.J. Keller, Department of Obstetrics and Gynecology, University Hospital, CH-8091 Zurich, Switzerland. 0378-5122/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
196
which was originally designed for sequential use 131, in a continuous manner. A similar regimen has been successfully adopted for oral hormone replacement therapy, particularly in the late postmenopause [4-61. The objectives of this pilot study were to assess the efficacy for acute menopausal symptoms, the incidence of breakthrough bleedings and the nature of any changes in serum lipid profiles on therapy.
Materials and Methods Fifteen healthy women aged between 49 and 60 years, who were in the natural menopause for 3-7 (mean 5.2) years and who had not been taking hormones for at least 3 months previously were treated for 6 months with a combined transdermal therapeutic system releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day (Estragest, Ciba-Geigy Ltd., Basle, Switzerland). The patches, which had an active area of 10 cm2 were applied to the lower abdominal wall or to the buttocks and they were changed twice a week. Four patients left the study after 3-5 months for personal, not treatment-related reasons and 1 due to side-effects. Vasomotor and psychic complaints, which were scored according to Kupperman [9], frequency, severity and duration of vaginal bleeds and side effects were recorded monthly. Before treatment and after 3 and 6 months of therapy blood samples were taken for hormone and serum lipid assays. FSH, LH and 17&oestradiol were determined by means of commercially available radioimmunoassays (Sorin Biomedica, respectively Amerlex, Amersham). Cholesterol, HDL-, HDL2-, HDL3- and LDL cholesterol were enzymatically measured (CHOD-PAP, Boehringer, Mannheim, Germany) using a Hitachi, 337, respectively Cobas Fara analyzer. Triglycerides were estimated by means of the GPO-PAP method (Boehringer, Mannheim, Germany; Hitachi 737). Apolipoprotein Al and B values were assessed by laser nephelometry (Behring, Marburg, Germany). Endometrial biopsies were performed with a Novak curette before and at the end of the study. Mean and standard error of the mean (S.E.M.) of the lipid and hormone values before and during treatment were calculated by conventional methods, differences among the results were tested by analysis of variance.
Rl?sUlts The therapeutic efficacy of the continuous combined transdermal regimen in alleviating vasomotor and psychic complaints was very good, the mean menopausal score as defined by Kupperman [7] dropped from 27.6 to 6.6 and 5.0 after 3 and 6 months treatment (P < 0.01). In seven patients one or more spotting episodes were observed, mainly within the first 3 months (Table I). Only one woman experienced mild breakthrough bleedings in the fifth and ninth week of the combined transderma1 therapy. No adverse systemic effects were noted, however, two patients had minor skin reactions, one discontinued the treatment because of local irritation and itching. The mean baseline FSH values decreased from 58.9 to 30.1 after 6 months of continuous combined therapy (P < 0.05). The mean oestradiol levels on treatment was 168 pmol/l comparable to those of the early proliferative phase of fertile women.
197 TABLE I NUMBER OF WOMEN WITH SPOTTING AND BREAKTHROUGH BLEEDING DURING TRANSDERMAL CONTINUOUS COMBINED HORMONE REPLACEMENT THERAPY (N = 10) Month of treatment
Bleeding Spotting
1
2
3
4
5
6
0 5
1 7
1 4
0 2
0 1
0 0
The results of the lipid study are summarized in Table II. Neither the total cholesterol, triglyceride, HDL-, HDL2- and HDL3- cholesterol values and their ratios nor the apolipoprotein Al and B levels were significantly altered (P > 0.05), but there was a slight reduction of the LDL-cholesterol from 3.31 to 2.75 mmol/l (P < 0.05). In 6 patients the endometrial biopsies yielded none or inadequate material for histological assessment, while the specimens from the other four showed atrophy or
TABLE II PLASMA LIPIDS IN POSTMENOPAUSAL WOMEN BEFORE AND DURING CONTINUOUS COMBINED TRANSDERMAL HORMONE REPLACEMENT THERAPY (N= 10) MEAN VALUES (S.E.M.) Months
Total cholesterol @now Triglycerides mnow HDL cholesterol (mmow HDL-2 cholesterol @mom) HDL-3 cholesterol bmow LDL cholesterol @mow Apolipoprotein Al (8/1) Apolipoprotein B (g/l) LDL/HDL ratio
0
3
6
6.24 (0.16)
5.45 (0.17)
5.97 (0.21)
1.29 (0.17)
1.33 (0.39)
1.21 (0.16)
1.58 (0.15)
1.37 (0.11)
1.40 (0.16)
0.40 (0.08)
0.29 (0.09)
0.31 (0.06)
1.28 (0.11)
0.99 (0.15)
1.33 (0.17)
3.31 (0.33)
3.06 (0.40)
2.75 (0.40)
1.60 (0.10)
1.58 (0.14)
1.77 (0.07)
1.08 (0.10)
0.96 (0.10)
1.01 (0.07)
2.09
2.23
1.96
198
slight proliferation with progestin effect, but no hyperplastic features after 6 months of continuous combined treatment.
very
Discussion The evaluation of these preliminary findings shows that combined transdermal therapeutic systems releasing both oestrogens and progestogens in low amounts might be successfully used for continuous hormone replacement therapy in the menopause. The fear of frequent bleedings, which have been reported with some of the continuous combined oral regimens [8] seems not to be justified, if the method is not used in the early postmenopause, i.e. within the first 3-5 years. The lipid profiles compared favourably with those observed with unopposed percutaneous oestrogen or with combined oral therapy [9,10]. Admittedly there was no significant increase in HDL- or HDL2- cholesterol and in apolipoprotein Al which is presumed to be antiatherogenic, however, this protective effect has been qualified by recent studies suggesting a direct rather than a lipid-mediated action of oestrogens on the arterial wall [ 1I]. Our preliminary data suggest that this combined regimen might further improve the acceptability of long-term transdermal hormone replacement therapy in the menopause, although more extensive studies are needed. References 1 Wren BG, Brown L: Compliance with hormonal replacement therapy. Maturitas 1990; 13: 17-21. 2 Keller PJ: Compliance of oral and transdennal estrogen replacement therapy. In: von Schoultx B ed. Cardiovascular effects of hormone replacement therapy. Copenhagen: Gladsaxe-Soeborg, 1991; 63-67. 3 Whitehead MI, Fraser D, Schenkel L, Crook D, Stevenson JC: Transdermal administration of oestrogen/progestagen hormone replacement therapy. Lancet 1990, 335: 310-312. 4 Mattson LA, Cullberg G, Samsioe G: Evaluation of continuous oestrogen-progestogen regimen for climacteric complaints. Maturitas 1982; 4: 95-102. 5 Staland B: Continuous treatment with natural oestrogens and progesterones: A method to avoid endometrial stimulation. Maturitas 1981; 3: 145-156. 6 Weinstein L: Efficacy of a continuous estrogen-progestin regimen in the menopausal patient. Obstet Gynecol 1987; 69: 929-932. I Kupperman HS, Wetchler BB, Blatt MHG: Contemporary therapy of the menopausal syndrome. J Am Med Assoc 1959; 171: 1627-37. 8 Clisham PR, de Ziegler D, Lozano K, Judd HL: Comparison of continuous versus sequential estrogen and progestin therapy in postmenopausal women. Obstet Gynecol 1991; 77: 241-246. 9 Jenson J, Riis BJ, Strom V, Christiansen C: Continuous oestrogen-progestogen and serum lipoproteins in postmenopausal women. Br J Obstet Gynaecol 1987; 94: 132-135. 10 Cano A, Femandes H, Serrano S, Mahiques P: Effect of continuous oestradiol-medroxyprogesterone administration on plasma lipids and lipoproteins. Maturitas 1991; 13: 35-42. 11 Clarkson TB, Shively CA, Morgan TM, Karrtnik DR, Adams MR, Kaplan JR: Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol 1990; 75: 217-222.
195
MAT 00703
A transdermal regimen for continuous combined hormone replacement therapy in the menopause Paul J. Keller, Elsa Hotz and Bruno Imthurn Department of Obstetrics and Gynecology, University Hospital, Zurich (Switzerland) (Received April 21, 1992; revision received July 20, 1992; accepted August 20, 1992)
Transdermal systems for oestrogen therapy in the menopause have become very popular. The compliance, however, is impeded by the cyclic addition of oral progestins which leads to monthly withdrawal bleeds. In this pilot study a skin patch releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day, which was originally designed for sequential therapy, was used in a continuous manner. Results were quite favourable. Menopausal complaints were efftciently relieved and the Kupperman score drop ped from 27.6 to 5.0. Out of 10 women, 1 had mild breakthrough bleeding, and 7 patients recorded one or several spotting episodes, mainly within the first 3 treatment months. No endometrial hyperplasia was observed and there was no signiticant change in plasma lipids, i.e. cholesterol, triglycerides, HDL-, HDLZ-, HDW-cholesterol, LDL-cholesterol and apolipoproteins Al and B. The regimen might be a useful alternative to oral continuous combined replacement therapy.
Key words: menopause; hormone replacement therapy; combined transdermal therapeutic systems
Introduction The benefit of oestrogen replacement therapy in postmenopausal women is undisputed; however, the mode of application remains a matter of controversy. Transdermal therapeutic systems, which avoid the hepatic first-pass effect and maintain steady near-physiological blood hormone levels are thought to be particularly suited for this purpose. Since any hormone substitution in the menopause must be continued for long time in order to prevent osteoporosis and arterial disease, patient compliance is of great importance [ 1,2]. It is often seriously impeded when a conventional oestradiol releasing patch is used in conjunction with cyclical oral progestogens to protect against endometrial hyperplasia and cancer, which leads to monthly bleeds in non-hysterectomized women and to other undesirable psychological and symptomatic effects. For these reasons it seemed worthwhile to use a newly-developed transdermal system delivering oestrogen and progestogen, Correspondence to: P.J. Keller, Department of Obstetrics and Gynecology, University Hospital, CH-8091 Zurich, Switzerland. 0378-5122/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
196
which was originally designed for sequential use 131, in a continuous manner. A similar regimen has been successfully adopted for oral hormone replacement therapy, particularly in the late postmenopause [4-61. The objectives of this pilot study were to assess the efficacy for acute menopausal symptoms, the incidence of breakthrough bleedings and the nature of any changes in serum lipid profiles on therapy.
Materials and Methods Fifteen healthy women aged between 49 and 60 years, who were in the natural menopause for 3-7 (mean 5.2) years and who had not been taking hormones for at least 3 months previously were treated for 6 months with a combined transdermal therapeutic system releasing 0.05 mg oestradiol and 0.25 mg norethisterone acetate per day (Estragest, Ciba-Geigy Ltd., Basle, Switzerland). The patches, which had an active area of 10 cm2 were applied to the lower abdominal wall or to the buttocks and they were changed twice a week. Four patients left the study after 3-5 months for personal, not treatment-related reasons and 1 due to side-effects. Vasomotor and psychic complaints, which were scored according to Kupperman [9], frequency, severity and duration of vaginal bleeds and side effects were recorded monthly. Before treatment and after 3 and 6 months of therapy blood samples were taken for hormone and serum lipid assays. FSH, LH and 17&oestradiol were determined by means of commercially available radioimmunoassays (Sorin Biomedica, respectively Amerlex, Amersham). Cholesterol, HDL-, HDL2-, HDL3- and LDL cholesterol were enzymatically measured (CHOD-PAP, Boehringer, Mannheim, Germany) using a Hitachi, 337, respectively Cobas Fara analyzer. Triglycerides were estimated by means of the GPO-PAP method (Boehringer, Mannheim, Germany; Hitachi 737). Apolipoprotein Al and B values were assessed by laser nephelometry (Behring, Marburg, Germany). Endometrial biopsies were performed with a Novak curette before and at the end of the study. Mean and standard error of the mean (S.E.M.) of the lipid and hormone values before and during treatment were calculated by conventional methods, differences among the results were tested by analysis of variance.
Rl?sUlts The therapeutic efficacy of the continuous combined transdermal regimen in alleviating vasomotor and psychic complaints was very good, the mean menopausal score as defined by Kupperman [7] dropped from 27.6 to 6.6 and 5.0 after 3 and 6 months treatment (P < 0.01). In seven patients one or more spotting episodes were observed, mainly within the first 3 months (Table I). Only one woman experienced mild breakthrough bleedings in the fifth and ninth week of the combined transderma1 therapy. No adverse systemic effects were noted, however, two patients had minor skin reactions, one discontinued the treatment because of local irritation and itching. The mean baseline FSH values decreased from 58.9 to 30.1 after 6 months of continuous combined therapy (P < 0.05). The mean oestradiol levels on treatment was 168 pmol/l comparable to those of the early proliferative phase of fertile women.
197 TABLE I NUMBER OF WOMEN WITH SPOTTING AND BREAKTHROUGH BLEEDING DURING TRANSDERMAL CONTINUOUS COMBINED HORMONE REPLACEMENT THERAPY (N = 10) Month of treatment
Bleeding Spotting
1
2
3
4
5
6
0 5
1 7
1 4
0 2
0 1
0 0
The results of the lipid study are summarized in Table II. Neither the total cholesterol, triglyceride, HDL-, HDL2- and HDL3- cholesterol values and their ratios nor the apolipoprotein Al and B levels were significantly altered (P > 0.05), but there was a slight reduction of the LDL-cholesterol from 3.31 to 2.75 mmol/l (P < 0.05). In 6 patients the endometrial biopsies yielded none or inadequate material for histological assessment, while the specimens from the other four showed atrophy or
TABLE II PLASMA LIPIDS IN POSTMENOPAUSAL WOMEN BEFORE AND DURING CONTINUOUS COMBINED TRANSDERMAL HORMONE REPLACEMENT THERAPY (N= 10) MEAN VALUES (S.E.M.) Months
Total cholesterol @now Triglycerides mnow HDL cholesterol (mmow HDL-2 cholesterol @mom) HDL-3 cholesterol bmow LDL cholesterol @mow Apolipoprotein Al (8/1) Apolipoprotein B (g/l) LDL/HDL ratio
0
3
6
6.24 (0.16)
5.45 (0.17)
5.97 (0.21)
1.29 (0.17)
1.33 (0.39)
1.21 (0.16)
1.58 (0.15)
1.37 (0.11)
1.40 (0.16)
0.40 (0.08)
0.29 (0.09)
0.31 (0.06)
1.28 (0.11)
0.99 (0.15)
1.33 (0.17)
3.31 (0.33)
3.06 (0.40)
2.75 (0.40)
1.60 (0.10)
1.58 (0.14)
1.77 (0.07)
1.08 (0.10)
0.96 (0.10)
1.01 (0.07)
2.09
2.23
1.96
198
slight proliferation with progestin effect, but no hyperplastic features after 6 months of continuous combined treatment.
very
Discussion The evaluation of these preliminary findings shows that combined transdermal therapeutic systems releasing both oestrogens and progestogens in low amounts might be successfully used for continuous hormone replacement therapy in the menopause. The fear of frequent bleedings, which have been reported with some of the continuous combined oral regimens [8] seems not to be justified, if the method is not used in the early postmenopause, i.e. within the first 3-5 years. The lipid profiles compared favourably with those observed with unopposed percutaneous oestrogen or with combined oral therapy [9,10]. Admittedly there was no significant increase in HDL- or HDL2- cholesterol and in apolipoprotein Al which is presumed to be antiatherogenic, however, this protective effect has been qualified by recent studies suggesting a direct rather than a lipid-mediated action of oestrogens on the arterial wall [ 1I]. Our preliminary data suggest that this combined regimen might further improve the acceptability of long-term transdermal hormone replacement therapy in the menopause, although more extensive studies are needed. References 1 Wren BG, Brown L: Compliance with hormonal replacement therapy. Maturitas 1990; 13: 17-21. 2 Keller PJ: Compliance of oral and transdennal estrogen replacement therapy. In: von Schoultx B ed. Cardiovascular effects of hormone replacement therapy. Copenhagen: Gladsaxe-Soeborg, 1991; 63-67. 3 Whitehead MI, Fraser D, Schenkel L, Crook D, Stevenson JC: Transdermal administration of oestrogen/progestagen hormone replacement therapy. Lancet 1990, 335: 310-312. 4 Mattson LA, Cullberg G, Samsioe G: Evaluation of continuous oestrogen-progestogen regimen for climacteric complaints. Maturitas 1982; 4: 95-102. 5 Staland B: Continuous treatment with natural oestrogens and progesterones: A method to avoid endometrial stimulation. Maturitas 1981; 3: 145-156. 6 Weinstein L: Efficacy of a continuous estrogen-progestin regimen in the menopausal patient. Obstet Gynecol 1987; 69: 929-932. I Kupperman HS, Wetchler BB, Blatt MHG: Contemporary therapy of the menopausal syndrome. J Am Med Assoc 1959; 171: 1627-37. 8 Clisham PR, de Ziegler D, Lozano K, Judd HL: Comparison of continuous versus sequential estrogen and progestin therapy in postmenopausal women. Obstet Gynecol 1991; 77: 241-246. 9 Jenson J, Riis BJ, Strom V, Christiansen C: Continuous oestrogen-progestogen and serum lipoproteins in postmenopausal women. Br J Obstet Gynaecol 1987; 94: 132-135. 10 Cano A, Femandes H, Serrano S, Mahiques P: Effect of continuous oestradiol-medroxyprogesterone administration on plasma lipids and lipoproteins. Maturitas 1991; 13: 35-42. 11 Clarkson TB, Shively CA, Morgan TM, Karrtnik DR, Adams MR, Kaplan JR: Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys. Obstet Gynecol 1990; 75: 217-222.
