Combined versus sequential hormonal replacement therapy: a double-blind, placebo-controlled study on quality of life-related outcome measures.

BACKGROUND: To compare combined and sequential hormonal replacement therapies to each other as well as placebo in patients suffering from the postmenopausal syndrome. Clinical outcomes were measured concerning both the specific postmenopausal symptoms (using the Kupperman scale) and health or well-being dimensions (using subscales of the General Health Questionnaire and specific depression and anxiety scales). METHODS: A prospective randomized double-blind study over 12 months of 105 normal early postmenopausal women in the setting of a general hospital. RESULTS: Both hormone replacement therapies were superior to placebo on the Kupperman scale (sweating, hot flushing, myalgia and vertigo). The psychic symptoms on the Kupperman scale were psychometrically invalid. However, psychic symptoms as measured by the Beck Depression Inventory and the General Health Questionnaire were significantly improved by the hormonal replacement therapies. No differences were observed when combined therapy was compared to sequential therapy. CONCLUSION: One-year treatment with hormonal replacement therapy is superior to placebo in measuring the somatic and psychic symptoms of the menopausal syndrome. No differences were found in this respect between combined and sequential replacement therapy.

Continuous combined and sequential estradiol and norethindrone acetate treatment of postmenopausal women: effect of plasma lipoproteins in a two-year placebo-controlled trial.

OBJECTIVE: Our purpose was to examine the effects of postmenopausal estrogen therapy supplemented with progestogen on plasma lipoprotein levels. STUDY DESIGN: One hundred thirteen women were randomized to receive either placebo or a combination of 17 beta-estradiol and norethindrone acetate administered continuously (Kliogest) or sequentially (Trisequens). Plasma lipoprotein levels were measured at baseline and after 2 years of treatment and compared by analysis of variance. RESULTS: Hormone therapy lowered plasma cholesterol levels (p < 0.001) and low-density lipoprotein cholesterol (Kiogest, p < 0.001; Trisequens, p < 0.01), whereas high-density lipoprotein cholesterol levels were unchanged (Trisequens) or reduced (Kliogest, p < 0.01), primarily because of a decrease in the high-density lipoprotein-2 subfraction (p < 0.05). Low-density lipoprotein/high-density lipoprotein cholesterol ratios remained unchanged. CONCLUSIONS: Although hormonal replacement therapy with estradiol combined with norethindrone acetate eliminated the increase in high-density lipoprotein cholesterol levels observed with estrogen monotherapy, the reductions in low-density lipoprotein cholesterol concentrations still suggest reduced cardiovascular risk, according to the National Cholesterol Education Program and to recent observations indicating that risk is not necessarily inversely proportional to high-density lipoprotein cholesterol levels.

Magnitude and pattern of skeletal response to long term continuous and cyclic sequential oestrogen/progestin treatment.

OBJECTIVE: To investigate the magnitude and pattern of the changes in bone mass during five years of continuous and cyclic sequential oestrogen/progestin treatment. DESIGN: Prospective study of normal, early postmenopausal women, initially a double-blind, placebo controlled trial, subsequently an open, controlled investigation. SETTING: Clinical physiology unit of a general hospital. SUBJECTS: Sixty-eight normal, early postmenopausal women. RESULTS: 1. Continuous treatment resulted in significantly higher lumbar spine bone density than did sequential treatment (P < 0.001). Lumbar spine bone density was 19% and 15%, respectively, above that of untreated women after three years and onwards, and 10% and 6%, respectively, above the initial value; 2. Both regimens induced a more pronounced rise in lumbar spine bone density than in forearm bone mineral content (P < 0.001); 3. The spontaneous decline (without treatment) in lumbar spine bone density and forearm bone mineral content averaged 1.86% and 1.90% per year, respectively. 4. There was a significant bone loss from the lumbar spine during the last year of active treatment (P < 0.001). This would suggest that lumbar spine bone density rises to a certain level and subsequently declines. However, neither data pooled before computation nor data processed individually for each patient over five years allowed for any definite conclusions regarding the pattern of the long term skeletal response to combined oestrogen/progestin treatment. CONCLUSION: Five years treatment with oestradiol/norethisterone resulted in a substantial gain in bone mass. The highest values were found in the axial skeleton with daily administration of 2 mg oestradiol and 1 mg norethisterone. It is likely that bone mass after an absolute rise begins to decline after about four years of treatment.

A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment.

A total of 151 postmenopausal women were randomly allocated to 3 groups for treatment with hormone replacement therapy. One group received combined therapy (2 mg oestradiol (E2) and 1 mg norethisterone acetate (NETA) daily), the second group was placed on sequential therapy (2 mg E2 for 12 days, 2 mgE2 and 1 mg NETA for 10 days and 1 mg E2 for 6 days), while the third was given placebo. Treatment was administered over 24 cycles of 28 days. The two active treatments were equally effective in relieving climacteric symptoms. In the combined therapy group, 62% of the women experienced spotting and/or breakthrough bleeding during the first 3 cycles; thereafter this proportion decreased to between 3 and 18% in each of the following three-cycle periods. Sixty-four percent (64%) of these women had no more bleeding after the first 3 cycles. Endometrial atrophy was detected in 93% of the women in this group after 24 cycles of therapy. Bleeding irregularities occurred during the first 3 cycles in 27% of the patients treated with sequential therapy and in 21% of those receiving placebo. In the subsequent 3-cycle periods these figures fell to below 10% in the 2 groups. In all 3 groups weight remained stable but blood pressure increased equally in the actively treated groups and the placebo group. The levels of follicle-stimulating hormone (FSH), sex-hormone-binding globulin (SHBG) and the free fraction of E2 in serum were significantly lower in the combined therapy group than in the sequential therapy group. The higher level of free E2 in the latter group may have been caused by a decrease in metabolism associated with the increased SHBG concentration. It was concluded that combined treatment with E2 and NETA might provide an alternative to sequential treatment in postmenopausal women willing to tolerate the initial high risk of breakthrough bleeding/spotting in order to avoid subsequent regular bleeding. In the subgroup of women in whom bleeding irregularities continue, sequential treatment should be considered.

Reversal of postmenopausal vertebral bone loss by oestrogen and progestogen: a double blind placebo controlled study.

Because of uncertainty about the place of hormones in the treatment of postmenopausal bone loss vertebral and forearm bone loss was measured by absorptiometry in early postmenopausal women before and after continuous or sequential treatment with combined oestrogen and progestogen in a double blind placebo controlled trial. Treatment with hormones significantly reversed the vertebral bone loss. The net gain in vertebral bone density amounted to 6.4% a year with continuous supplementation and 5.4% a year with sequential supplementation; the net gain in forearm bone density was lower (3.6% with continuous and 3.7% with sequential supplementation). Before a policy of supplementation with hormones can be recommended to all postmenopausal women with the aim of reducing the incidence of vertebral crush fractures further studies with different doses and combinations of hormones, administered over several years, are needed.