Results from many epidemiologic studies have shown that unopposed estrogen therapy is associated with a dose-dependent increased risk of endometrial hyperplasia and increases the risk of endometrial cancer in women with intact uteri. Although the addition of progesterone to the therapy reduces these risks, the appropriate dosage and mode of administration, and the extent of risk have not been determined. Kurman and colleagues identified the lowest continuous dosage of norethindrone acetate combined with 1 mg of 17β-estradiol (E2) that would reduce the incidence of endometrial hyperplasia and compared the continuous-combination regimen with unopposed E2 therapy.
|Patient characteristics||E2, 1 mg (%)||E2, 1 mg + NETA, 0.1 mg (%)||E2, 1 mg + NETA, 0.25 mg (%)||E2, 1 mg + NETA, 0.5 mg (%)|
|Number of patients randomized||296||294||291||295|
|Number of available biopsies||247||249||251||241|
|Number normal||189 (76.5)||246 (98.8)||250 (99.6)||240 (99.6)|
|Number with disordered proliferative phase||21 (8.5)||1 (0.4)||0 (0.0)||0 (0.0)|
|Number with endometrial hyperplasia||36 (14.6)||2 (0.8)||1 (0.4)||1 (0.4)|
|Simple without atypia||30 (12.2)||1 (0.4)||0 (0.0)||1 (0.4)|
|Complex without atypia||4 (1.6)||0 (0.0)||0 (0.0)||0 (0.0)|
|Simple with atypia||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|Complex with atypia||2 (0.8)||1 (0.4)||1 (0.4)||0 (0.0)|
|Number with carcinoma||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|Number with other conditions||1 (0.4)*||0 (0.0)||0 (0.0)||0 (0.0)|
A double-masked, randomized, parallel, controlled study was conducted in 40 centers in the United States. Healthy women volunteers were accepted for the study if they were at least one year postmenopausal, had an intact uterus without endometrial abnormalities and had serum E2 levels less than 25 pg per mL (92 pmol per L). Exclusion criteria included history of a hormone-dependent tumor, thromboembolic disorders, hypertension, myocardial infarction or stroke. Women who smoked (one pack or more per day) or were more than 30 percent above ideal body weight, and those with endometrial hyperplasia demonstrated on endometrial biopsy or ultrasonography were also excluded. Participants were randomly assigned to one of four groups: 1 mg of unopposed E2 or 1 mg of continuous-combined E2 and 0.1, 0.25 or 0.5 mg of norethindrone acetate. They were instructed to take a single tablet once daily for 12 months. Endometrial biopsies were performed at baseline, at screening visits and after 12 months of treatment or at the time of withdrawal.
Of the 1,176 women enrolled, 925 completed 12 months of treatment, and histologic evaluations of 988 women were conducted at the end of the study. No endometrial cancers were detected during the study. Results of the end-of-study histologic evaluation are provided in the accompanying table. A significant reduction in the 12-month incidence of endometrial hyperplasia was observed in the women receiving continuous-combined E2-norethindrone acetate treatment compared with those in the unopposed E2 treatment group (less than 1 percent versus 14.6 percent, respectively). Although the continuous-combined regimens appear to adequately protect the endometrium, the bleeding profile associated with each of the treatment regimens differed significantly. The dosage of E2-norethindrone acetate of 0.5 mg resulted in the lowest incidence of bleeding.
The authors conclude that continuous norethindrone acetate combined with 1 mg of E2 negates the risk of endometrial hyperplasia for at least the first 12 months of treatment. Because treatment with continuous-combined regimens is meant to achieve or maintain amenorrhea, physicians should consider the dosage of progestogen in terms of endometrial protection and bleeding profile.