Estrogen replacement therapy reduces bone loss, alleviates vasomotor symptoms and may decrease mortality from cardiovascular causes in postmenopausal women. However, cyclic hormone replacement therapy frequently induces a recurrence of uterine bleeding in women with an intact uterus. This withdrawal bleeding leads to a significant decrease in patient compliance. Continuous combined hormone replacement regimens have been developed that significantly reduce the incidence of bleeding, particularly with extended duration of therapy. The majority of these regimens are based on oral formulations, but recently transdermal continuous combined hormone replacement products have been developed. By avoiding the first-pass metabolism, this dosage route should eliminate the hepatic synthesis of several proteins and triglycerides. A study conducted by Mattsson and colleagues compared the efficacy of two dosages of a transdermal formulation with an available oral combination in terms of incidence of amenorrhea, frequency of climacteric symptoms, prevention of endometrial hyperplasia and subjective tolerability.

The study included 441 healthy post-menopausal women with an intact uterus who requested hormone replacement therapy for moderate vasomotor symptoms. The women were randomized into three treatment groups and were given (1) a 10-cm² patch (daily delivery of 0.025 mg estradiol and 0.125 mg norethisterone acetate); (2) a 20-cm² patch (daily delivery of 0.05 mg estradiol and 0.25 mg norethisterone acetate); or (3) a daily oral dose of 2 mg estradiol and 1 mg norethisterone acetate. All treatments were given for a total of 13 continuous cycles of four weeks' duration. 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 for climacteric symptoms, bleeding frequency and tolerability. The initial and final visits also included general physical and gynecologic examinations, cervical smears, transvaginal ultrasonography and mammography.

Results indicate that the majority of women in all groups were amenorrheic after three treatment cycles, with the rate of amenorrhea increasing with duration of therapy. Amenorrhea was reported more frequently among women in the 10-cm² patch group than in the other groups. The incidence of hot flushes, insomnia, and joint or limb pain were decreased equivalently in all three treatment groups. The frequency of endometrial hyperplasia after one year of treatment was less than 2 percent with all three regimens, a rate that is lower than the prevalence of hyperplasia in postmenopausal women without hormone replacement therapy. Of the 441 women participating in the study, 327 reported adverse experiences. The lowest frequency of adverse experiences was in the 10-cm² patch group. The most frequent adverse experiences reported were mastalgia and bleeding. Applicationsite reactions to the patch were reported by 23 percent of women using the 10-cm² patch and 34 percent of women using the 20-cm² patch.

The authors concluded that transdermal application of a low dosage of combined estrogen-progestogen may be a good alternative in women requesting hormone replacement therapy, because all preparations studied alleviated climacteric symptoms and did not induce endometrial hyperplasia. Because the low-dose transdermal application had the lowest reported incidence of adverse effects, it seems that this dosage would be preferable for relief of symptoms. However, this study did not evaluate whether low-dose transdermal estrogen is effective in preventing the bone loss and cardiovascular disease associated with menopause; a long-term study will be necessary to obtain that information.