Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone.
OBJECTIVE
The aim of this study was to compare the incidence of women presenting irregular bleeding episodes following 9 months of treatment with a low dose continuous combined hormone replacement therapy consisting of estradiol (E(2)) and norethisterone acetate (NETA) versus a sequential hormone replacement therapy consisting of conjugated equine estrogens (CEE) and medrogestone (MG). Secondary aims were to establish the relationship between menopausal age and the occurrence of irregular bleeding for both therapies and to assess the efficacy of both therapies in alleviating menopausal symptoms.


METHODS
This was a stratified and randomised, open label study conducted with late peri and postmenopausal women at 35 sites in Austria and Germany. A total of 446 women were randomly allocated into two cohorts based on time since last bleeding and then stratified to either a low dose continuous combined therapy consisting of 1 mg E(2) and 0.5 mg NETA for 28 days or a sequential therapy consisting of 0.625 mg CEE for 28 days and 5 mg MG for the final 14 days. Bleeding and menopausal complaints were continuously assessed. Treatments were administered for 9 lunar months.


RESULTS
The incidence rate of women presenting irregular bleeding episodes including spotting during cycle 9 was 12.2% with 1mgE(2)/0.5mgNETA and 25.8% with 0.625mgCEE/5mgMG (P = 0.0014). In the group of postmenopausal women (time since last bleeding > or = 12 months) the incidence of irregular bleeding during cycle 9 was 11.0% for 1mgE(2)/0.5mgNETA and 25.0% for 0.625mgCEE/5mgMG). In the group of late perimenopausal women (time since last bleeding 6-11 months) the incidence of irregular bleeding was similar for both treatments at cycle 3, but markedly less in patients with 1mgE(2)/0.5mgNETA at cycle 6 and 9, being significantly different compared to patients with 0.625mgCEE/5mgMG at cycle 6 (P < 0.05). The cumulative rate of amenorrhea (no bleeding or spotting) achieved with 1mgE(2)/0.5mgNETA was 89% for the postmenopausal women and 83.7% for the late perimenopausal women. Both treatments relieved menopausal complaints equally effective.


CONCLUSIONS
Regarding the occurrence of irregular bleeding, the low dose continuous combined therapy was superior to the sequential therapy (0.625mgCEE/5mgMG). The low dose continuous combined E(2)/NETA regimen is also suitable for late perimenopausal women since more than 80% of the women had no bleeding or spotting after 9 months of treatment.
von Holst
Thomas
T
Ruprecht-Karls-Universität Heidelberg, Universitäts-Frauenklinik, Vossstrasse 9, 69115 Heidelberg, Germany. thomas_van_holst@med.uni-heidelberg.de
Lang
Eva
E
Winkler
Ulrich
U
Keil
Dieter
D
D000328:Adult; D000368:Aged; D001317:Austria; D015331:Cohort Studies; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005858:Germany; D019584:Hot Flashes / Q000188:drug therapy; D006801:Humans; D008524:Medrogestone / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008593:Menopause; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077563:Norethindrone Acetate; D011446:Prospective Studies; D016896:Treatment Outcome; D014592:Uterine Hemorrhage / Q000139:chemically induced* / Q000473:pathology
D004966:Estrogens, Conjugated (USP); D008524:Medrogestone; D004958:Estradiol; D000077563:Norethindrone Acetate; D009640:Norethindrone