Transdermal administration of continuous-combined hormone replacement therapy (HRT) may be advantageous because it circumvents first-pass hepatic metabolism and the synthesis of several unwanted hepatic proteins and triglycerides. Mattsson and colleagues compared the efficacy of two transdermal continuous-combined formulations with that of oral therapy in alleviating menopausal symptoms without producing vaginal bleeding or endometrial hyperplasia.
The randomized, parallel-group study included 441 healthy postmenopausal women who requested HRT because of moderate vasomotor symptoms. None of them had had a menstrual period for at least two years. An endometrial thickness of less than 5 mm was documented on vaginal ultrasound examination.
Three HRT regimens were evaluated: a 10-cm2 patch that delivered a daily dose of 0.025 mg of estradiol and 0.125 mg of norethisterone acetate (147 patients), a 20-cm2 patch that delivered a daily dose of 0.05 mg of estra-diol and 0.25 mg of norethisterone acetate (150 patients), and oral tablets of 2 mg of estradiol and 1 mg norethisterone acetate daily (144 patients). The study could not be blinded because of the differences in delivery systems. HRT was provided for 13 cycles, each of four weeks. Assessment of symptom control and vaginal bleeding was conducted every 12 weeks during the initial 36 weeks of the study and then after one year of therapy. Physical examination, cervical smears, transvaginal ultrasonography and mammography were performed at the first and last visits.
During the first three months of therapy, amenorrhea was reported by 64 percent of the women who were treated with the 10-cm2 patch, by 35 percent of those who received the 20-cm2 patch and by 45 percent of those who received the tablets. In the final three months, the corresponding rates of no bleeding were 86 percent, 65 percent, and 79 percent, respectively. Amenorrhea over the year occurred in 60 percent of the women who used the 10-cm2 patch, in 28 percent of those who used the 20-cm2 patch and in 36 percent of those who received oral therapy.
Endometrial hyperplasia was documented in one of the 147 women treated with the 10-cm2 patch, in none of the 150 women treated with the 20-cm2 patch and in two of the 144 women who received oral therapy.
Patients in all three groups reported improvement in menopausal symptoms, with no significant differences in symptom relief noted among the three groups. At baseline, the percentage of women experiencing hot flashes was 59.3 percent, 55.5 percent and 56.5 percent in the 10-cm2 patch, 20-cm2 patch and oral therapy groups, respectively. In contrast, after 36 weeks of therapy, hot flashes were reported in 8.4 percent, 3.7 percent and 5.2 percent of the 10-cm2 patch, 20-cm2 patch and oral therapy groups, respectively. Similarly, by 36 weeks the percentage of women reporting sleep disturbances dropped to 17.8 percent and 21.5 percent in the 10-cm2 and 20-cm2 patch groups and to 18.3 percent in the oral therapy group. At baseline, sleep disturbances were reported by 38.3 percent, 46.3 percent and 44.1 percent of the women in these three groups, respectively.
The overall therapeutic effect was assessed as very good or good in 92 percent of the group using the 10-cm2 patch, in 86 percent of the 20-cm2 group and in 96 percent of the oral therapy group. Although patch adherence was not reported to be a problem, local reactions were reported by 23 percent of those using the 10-cm2 patch and by 34 percent of those using the 20-cm2 patch.
The authors conclude that all three continuous-combined regimens relieve menopausal symptoms and are not associated with unacceptable rates of endometrial hyperplasia after one year of therapy. Long-term studies are needed to show whether low-dose HRT prevents bone density loss and cardiovascular disease.