Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Endometrium Study Group.
OBJECTIVE
To investigate the incidence of uterine bleeding during 12 months of treatment with 17beta-estradiol (E2) 1 mg, unopposed or in combination with three doses of norethindrone acetate.


METHODS
This study was a prospective, double-masked, randomized, multicenter trial. A total of 1176 healthy postmenopausal women age 45 years and older without evidence of endometrial abnormalities were randomly assigned to receive either unopposed E2 1 mg, or continuous-combined formulations of E2 1 mg and norethindrone acetate 0.1 mg, 0.25 mg, or 0.5 mg. Any spotting or bleeding episodes during the treatment period were recorded in a daily diary and reported by weekly telephone calls.


RESULTS
The incidence of bleeding was low in the combination groups, even during the initial 3 months of treatment (24-28%), after which it decreased with increasing doses of norethindrone acetate. Conversely, the incidence of bleeding increased over time with unopposed E2 1 mg. After the initial 3 months, the incidence of bleeding among the combination groups was lowest in the norethindrone acetate 0.5 mg group. Among women initiating therapy close to menopause, fewer reported bleeding with norethindrone acetate 0.5 mg than with the other combination groups. There was a significantly (P<.05) lower discontinuation rate due to bleeding in the norethindrone acetate 0.5 mg group compared with all other treatment groups.


CONCLUSIONS
Continuous-combined formulations of E2 1 mg with norethindrone acetate 0.1, 0.25, or 0.5 mg are associated with a low incidence of uterine bleeding. After the initial 3 months of treatment, bleeding profiles improved with increasing doses of norethindrone acetate.
Archer
D F
DF
Clinical Research Center, Eastern Virginia Medical School, Norfolk, 23507, USA.
Dorin
M H
MH
Heine
W
W
Nanavati
N
N
Arce
J C
JC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D004958:Estradiol / Q000009:adverse effects*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009640:Norethindrone / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077563:Norethindrone Acetate; D017698:Postmenopause; D011446:Prospective Studies; D014592:Uterine Hemorrhage / Q000139:chemically induced / Q000453:epidemiology*
D004958:Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone