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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg, Sweden; and the Department of Pathology, University of Basle and Novartis Pharma AG, Basle, Switzerland.
Address reprint requests to: Lars A. Mattsson, MD, PhD, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, East, S-416 85 Göteborg, Sweden
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Abstract |
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Methods: This was a randomized, open, parallel-group trial during 1 year in 441 postmenopausal women who received either a 10-cm2 patch of 0.025 mg estradiol (E2) and 0.125 mg norethisterone acetate, a 20-cm2 patch of 0.05 mg E2 and 0.25 mg norethisterone acetate twice weekly, or tablets of 2 mg E2 and 1 mg norethisterone acetate once daily. The efficacy variables were frequency of endometrial hyperplasia after 1 year of treatment, number of bleeding and spotting days from the fourth to sixth treatment months, relief of climacteric symptoms, and tolerability.
Results: The frequency of endometrial hyperplasia was no more than 2% after 1 year of treatment in all groups. One case of simple hyperplasia was detected among the women treated with 10-cm2 patches and two among those treated with oral HRT. From the fourth to sixth treatment months, amenorrhea occurred in 73%, 47%, and 66% of the women in the 10-cm2, 20-cm2, and oral HRT groups, respectively. The 10-cm2 patches and oral treatment were associated with fewer bleeding days than were the 20-cm2 patches (P < .001). During the last 3 months of the treatment year, amenorrhea was found in 100 subjects (86%) for 10-cm2 patches, 61 (65%) for 20-cm2 patches, and in 85 (79%) for oral HRT. All treatments alleviated the climacteric symptoms to a comparable extent.
Conclusion: In postmenopausal women, 10-cm2 patches relieved climacteric symptoms and prevented endometrial hyperplasia at least as effectively as oral HRT. Amenorrhea was induced early in a high percentage of women using 10-cm2 patches and oral HRT, and these therapies seemed to be convenient, effective, and safe for estrogen deficiency symptoms in postmenopausal women.
Estrogen replacement therapy effectively alleviates vasomotor symptoms and considerably reduces overall mortality from cardiovascular diseases.1,2 However, it has been reported that adverse effects of higher estrogen doses may be problematic in older women.3 Lower doses than those commonly prescribed, such as transdermal administration of 20–25 µg estradiol (E2) per 24 hours and 1 mg E2 orally per day, relieved climacteric symptoms and prevented bone loss.4,5
Hormone replacement therapy (HRT) given cyclically or sequentially is often accompanied by recurrence of uterine bleeding in postmenopausal women with intact uteri. These withdrawal bleeding episodes are unacceptable to a majority of women and may reduce compliance with HRT.6 Continuous, combined regimens were developed to reduce bleeding disturbances.7,8 Most studies7–9 of continuous, combined regimens have shown that bleeding episodes occur early in therapy and gradually decrease with treatment duration. Oral formulations of continuous, combined regimens have been available for many years. Transdermal administration of HRT might offer an advantage because it obviates the first liver passage, minimizing the synthesis of several unwanted hepatic proteins and triglycerides.10,11
The objective of the present study was to compare two doses of a new continuous, combined transdermal treatment (Estragest 10 cm2 and 20 cm2; Novartis Pharma AG, Basle, Switzerland) with a commercially available oral combination (Kliogest; Novo Nordisk, Bagsvaerd, Denmark). The preparations were compared for efficacy in preventing endometrial hyperplasia and for rates of amenorrhea, frequency of climacteric symptoms, and tolerability.
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Methods |
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This study was an open, parallel-group, comparative trial with active control and balanced randomization with a treatment duration of 1 year. The study could not be masked because of the different drug administration routes and different patch sizes. It was a multicenter study conducted in 49 centers in Sweden and Germany. During a washout period of at least 5 weeks, the women received medroxyprogesterone acetate 10 mg/day for 14 days to induce endometrial shedding before starting the study treatment. Eligible women were randomly allocated by computer to one of three groups of equal number and were given a 10-cm2 patch (daily delivery of 0.025 mg E2 and 0.125 mg norethisterone acetate), a 20-cm2 patch (daily delivery of 0.05 mg E2 and 0.25 mg norethisterone acetate), or a daily oral dose of 2 mg E2 and 1 mg norethisterone acetate. All treatments were given continuously for 13 cycles of 4 weeks. Patches were applied twice weekly and tablets were given daily.
Women were assessed at baseline and at 12, 24, 36, and 52 weeks of treatment. Climacteric symptoms were assessed at each visit using the Women’s Health Questionnaire, which consisted of 24 questions that allowed four different answers, ranked from 1 to 4, assessing symptoms such as hot flashes and insomnia.12 Daily bleeding diaries were collected from the women at each visit. Severity of bleeding was classified as spotting, normal bleeding, or heavy bleeding. At each visit, weight, blood pressure (BP), climacteric symptoms, breast tenderness, adhesion, local tolerability of patches, and any adverse experiences were recorded. General and gynecologic examinations, cervical smears, transvaginal ultrasonography, and mammography were done at baseline and at the final visit. Endometrial biopsies were done at baseline if the endometrial thickness was greater than 5 mm, but should be taken in all women whose cervical canals were not too narrow for sampling at the end of the study. The endometrial biopsy specimens obtained were evaluated according to recognized standards by a peer pathologist who was masked to the treatment.13
At the end of the study, we made an overall assessment of therapeutic efficacy and tolerability based on a four-point scale. In case of premature discontinuations, all final-visit assessments were done at the time of discontinuation. Primary efficacy variables were the frequency of endometrial hyperplasia after 1 year of treatment and the number of bleeding and spotting days during months 4–6 of treatment. Secondary variables were evaluation of climacteric symptoms at 12, 24, and 36 weeks. The criteria for tolerability and safety included details of adverse experiences, body weight, BP, and the investigators’ overall assessment of tolerability.
A sample of 150 women per group was considered sufficient to detect clinically relevant differences between groups in bleeding patterns and climacteric symptoms, based on an incidence of endometrial hyperplasia of 2% for effective combined HRT and a frequency of hyperplasia of 10% for unopposed estrogen treatment. The dropout rate was expected to be one-third. We calculated that 100 evaluated women per group were needed to show an increased frequency of endometrial hyperplasia in each treatment group, with a power of 95% and an 
level of 5% for within-group comparison. A two-sided binomial test at the 5% significance level was done to determine whether the frequency of hyperplasia within specific treatment groups was 10% (which was used as an external standard). For the analysis of differences in bleeding patterns (bleeding and spotting days) between the groups in months 4–6, the odds ratio (OR) was analyzed using a continuation ratio model for eight categories corresponding to ranges in the numbers of bleeding and spotting days. We calculated two-sided 95% confidence interval (CI) for the OR of the 10-cm2 patch and 20-cm2 patch versus oral HRT.
Two subject data sets were analyzed. The intent-to-treat data set for efficacy and safety analyses included all subjects with at least one post-treatment measurement. Missing values were not replaced. The number of subjects differed per time point, depending on the number of premature discontinuations. The acceptable-subject data set included women who received treatment for at least six cycles, or a total of 348 women. All randomized subjects were included in the safety analysis, which was descriptive.
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). The 1-year trial was completed by 328 subjects (75%). Premature discontinuation occurred most frequently in the 20-cm2 patch group (49 subjects, 33%), followed by the oral-treatment group (36 subjects, 25%), and was least frequent in the 10-cm2 patch group (28 subjects, 19%). No cases of endometrial hyperplasia were detected in these women.
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The frequency of endometrial hyperplasia is shown in Table 2. Three cases of simple hyperplasia but no complex hyperplasias were observed. One case of cervical or endometrial carcinoma was found in the 10-cm2 patch group, although the origin could not be determined.
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Amenorrhea was reported more frequently among women in the 10-cm2 patch group than in the other groups, which was consistent for all time periods (Figure 1). The 20-cm2 patch group had the lowest rate of amenorrhea. For all three groups, there was a tendency toward fewer bleeding days with longer duration of therapy. During the first 3 months of therapy, 64% of women in the 10-cm2 patch group reported amenorrhea, compared with 35% in the 20-cm2 patch group and 45% in the oral group. During the last 3 months of treatment, the corresponding figures were 86%, 65%, and 79%. Amenorrhea over the year was registered in 60% of women who used the 10-cm2 patch, compared with 36% for oral treatment and 28% for the 20-cm2 patch. In this respect, the women in the 10-cm2 patch group differed from the women in the other treatment groups (P < .05).
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), confirmed by pairwise comparisons of treatment groups by analysis of covariance after 9 months of treatment (P > .4).
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Discussion |
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The majority of women in all three treatment groups had fewer than 6 days of bleeding or spotting during the 3 months between the fourth and sixth treatment cycles. Most women were amenorrheic after three treatment cycles. The rate of amenorrhea increased with increasing duration of therapy, which is consistent with previous observations for orally administered, continuous, combined HRT.7,8,18 A long-term study showed that further bleeding was uncommon once amenorrhea was achieved.5 It has been proposed that amenorrhea rates in some other studies may have been biased because of dropouts due to bleeding. The bleeding results in the current study should be reliable for the 10-cm2 patch and the oral-treatment groups because very few women in these groups discontinued participation because of bleeding disturbances. The higher dropout rate due to bleeding among the 20-cm2 patch users may overestimate amenorrhea frequency for that group. The 20-cm2 patch was associated with too much bleeding to be well accepted by women. Despite equal ratios between estrogen and progestogen components in the patches, the formulation with the higher dosage did not control for bleeding as well as the lower dosage, which probably induced less endometrial stimulation, leading to fewer bleeding disturbances.
Regardless of the doses of E2 given, subjective symptoms of estrogen deficiency were relieved, as measured by the Women’s Health Questionnaire. There was an overall improvement in hot flashes, insomnia, and joint or limb pain. No reports have been found showing that a low dose of continuous, transdermal E2 alleviates climacteric complaints as effectively as 2 mg of daily E2 given orally. However, lower doses of orally administered estrogens than those commonly prescribed were reported to control climacteric complaints of moderate severity.4 A low dose of estrogen may be preferable in elderly women because of poor compliance due to side effects such as bleeding and breast tenderness.16 All preparations alleviated climacteric symptoms and did not induce an unacceptable rate of endometrial hyperplasia. Transdermal application of a low dose of combined estrogen-progestogen may be an alternative treatment for elderly women requesting HRT. However, long-term data are needed to show whether low-dose estrogen prevents bone loss and cardiovascular disease.
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Footnotes |
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Received July 16, 1998. Received in revised form December 14, 1998. Accepted January 13, 1999.
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2. Cauley JA, Seeley DG, Browner WS, Ensrud K, Kuller LH, Lipschutz RC, et al. Estrogen replacement therapy and mortality among older women. Arch Intern Med 1997;157:2181–7.[Abstract]
3. Grey AB, Cundy TF, Reid IR. Continuous combined oestrogen/progestin therapy is well tolerated and increases bone density at the hip and spine in post-menopausal osteoporosis. Clin Endocrinol (Oxf) 1994;40:671–7.[Medline]
4. Stadberg E, Mattsson LA, Uvebrant M. 17 betaestradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy. Maturitas 1996;23:31–9.[Medline]
5. Evans SF, Davie MW. Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post-menopausal ages. Clin Endocrinol (Oxf) 1996;44: 79–84.[Medline]
6. Stadberg E, Mattsson LA, Milsom I. Women’s attitudes and knowledge about the climacteric period and its treatment. A Swedish population-based study. Maturitas 1997;27:109–16.[Medline]
7. Mattsson LA, Cullberg G, Samsioe G. Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints. Maturitas 1982;4:95–102.[Medline]
8. Marslew U, Riis BJ, Christiansen C. Bleeding patterns during continuous combined estrogen-progestogen therapy. Am J Obstet Gynecol 1991;164:1163–8.[Medline]
9. Bewtra C, Kable WT, Gallagher JC. Endometrial histology and bleeding patterns in menopausal women treated with estrogen and continuous or cyclic progestin. J Reprod Med 1988;33:205–8.[Medline]
10. Cheang A, Sitruk-Ware R, Utian WH. A risk-benefit appraisal of transdermal estradiol therapy. Drug Saf 1993;9:365–79.[Medline]
11. Mattsson LÅ, Samsioe G, von Schoultz B, Uvebrant M, Wiklund I. Transdermally administered oestradiol combined with oral medroxyprogesterone acetate: The effects on lipoprotein metabolism in postmenopausal women. Br J Obstet Gynaecol 1993; 100:450–3.[Medline]
12. Wiklund I, Karlberg J, Lindgren R, Sandin K, Mattsson L-A. A Swedish version of the women’s health questionnaire. A measure of postmenopausal complaints. Acta Obstet Gynecol Scand 1993; 72:648–55.[Medline]
13. Mazur HT, Kurman RJ. Diagnosis of endometrial biopsies and curettings. New York: Springer, 1994.
14. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994;170:1213–23.[Medline]
15. Archer DF, McIntyre-Seltman K, Wilborn WW Jr, Dowling EA, Cone F, Creasy GW, et al. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 1991;165:317–22.[Medline]
16. Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong SJ. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol 1991;78:195–9.
17. Magos AL, Brincat M, Studd JW, Wardle P, Schlesinger P, O’Dowd T. Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol 1985;65:496–9.[Medline]
18. Sporrong T, Hellgren M, Samsioe G, Mattsson LA. Comparison of four continuously administered progestogen plus oestradiol combinations for climacteric complaints. Br J Obstet Gynaecol 1988;5: 1042–8.
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