Long-term compliance with postmenopausal hormone replacement therapy (HRT) is poor despite its many health benefits. Recurrent vaginal bleeding is the major cause for discontinuation of HRT. Although studies have established strategies to minimize vaginal bleeding during HRT using conjugated equine estrogens and medroxyprogesterone acetate, little is known about bleeding profiles associated with other forms of estrogen and progesterone. Archer and colleagues studied bleeding associated with estradiol and norethindrone acetate (NETA) in various dosages.

They studied female volunteers more than 45 years of age who had an intact uterus and gave a history of at least one year since last menstruation. Exclusions included recent use of reproductive hormones, endometrial hyperplasia, hormone-dependent cancer, abnormal vaginal bleeding, hypertension, obesity or any contraindication to hormone use. Smoking of more than one pack per day was not permitted. Over 1,000 women were randomly assigned to four treatment groups. All patients received 1 mg daily of estradiol. In one group, this therapy was unopposed. The other three groups received estradiol and NETA in dosages of 0.1 mg, 0.25 mg or 0.5 mg. During the 12-month follow-up period, the women recorded all vaginal bleeding and any signs or symptoms attributed to the medication.

The four groups were comparable at the beginning of the study. More than 70 percent of women in each group completed the study. The rate of discontinuation in the unopposed estradiol group (28.4 percent) was significantly higher than the rate in women taking combination therapy. The lowest rates of discontinuation (16.8 and 19.4 percent) occurred in women taking 0.25 and 0.1 mg of NETA, respectively. Discontinuation attributed to bleeding was reported by 10.5 percent of women taking unopposed estradiol, 5.4 percent of those taking 0.1 mg NETA, 4.5 percent in the group taking 0.25 mg NETA and 1.7 percent of women taking 0.5 mg NETA. After one year, no bleeding or spotting was reported by 75, 79, 84 and 90 percent of women receiving the unopposed estradiol, NETA-0.1 mg, NETA-0.25 mg and NETA-0.5 mg, respectively. The percentage of months without bleeding or spotting increased over time in all groups taking combination therapy but decreased in women taking unopposed estradiol.

The authors conclude that continuous combined HRT using 1 mg estradiol and NETA is associated with low rates of vaginal bleeding and high rates of compliance. Over time, the lowest rates of vaginal bleeding were associated with the higher dosages of NETA.