Efficacy of a selective COX-2 inhibitor for controlling irregular uterine bleeding in DMPA users. Long-interval treatment regimen with a desogestrel-containing oral contraceptive. A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial. Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate. Oestrogen treatment for increased bleeding in Norplant users: preliminary results. Extended regimens of the contraceptive vaginal ring: a randomized trial. Bleeding patterns after immediate vs. conventional oral contraceptive initiation: a randomized, controlled trial. Menstrual reduction with extended use of combination oral contraceptive pills: randomized controlled trial.
This double-blind, placebo-controlled study was conducted to evaluate the efficacy of valdecoxib and placebo for controlling irregular uterine bleeding in depot-medroxyprogesterone acetate (DMPA) users.
                A total of 51 DMPA users were enrolled. All subjects in the study had abnormal bleeding and were randomly divided into two groups. One group totaling 22 received valdecoxib, 40 mg, once a day for 5 days, and placebos were given to another 24 in the same manner; 5 subjects dropped out from the study. Analysis of the number of treatment days required for stopping the bleeding episode, percentage of women whose bleeding was stopped in 7 days, total number of bleeding-free days and length of the bleeding-free interval after the initial treatment was determined in the first and the fourth weeks.
                The percentage of the subjects whose bleeding was stopped during the first week after the initial treatment and the mean value of the bleeding-free days during the 28 days of the follow-up period were significantly higher in the valdecoxib group than in the placebo group (77.3% vs. 33.3%, p<.01; and 17.8 days vs. 11.5 days, p<.05, respectively). The mean duration of treatment days required for stopping the bleeding episode in the valdecoxib-treated group was 1.7 days, and the mean duration of the bleeding-free interval in valdecoxib-treated group was 18.6 days.
                Valdecoxib was more effective than placebo in the short-term control of irregular bleeding in DMPA users. The mechanism of nonsteroidal anti-inflammatory drugs (NSAIDs) for the reduction of endometrial bleeding is likely from COX-2 inhibition. A randomized multicenter study was performed in order to investigate the acceptance of a low-dose OC (30 micrograms of ethinyloestradiol and 150 micrograms of desogestrel), using a 9 weeks on and 1 week off schedule (prolonged regimen, n = 198), compared to a traditional 3 weeks on, 1 week off schedule (standard regimen, n = 96). Haemoglobin and blood pressure remained the same in both groups during the study. No significant differences were found in body weight changes between the two groups. There was significantly more breakthrough bleeding and spotting in the group with prolonged regimen than in the group with standard regimen, but both breakthrough bleeding and spotting decreased during the trial. Irregular bleeding was significantly less in women who were already using OC, compared to "new starters." No serious side effects occurred. Significantly more women stopped the trial because of bleeding problems in the group with prolonged regimen, while there were significantly more women who stopped the trial because of headache in the group with standard regimen. After completing 12 months, or after premature withdrawal from the study, each women completed a questionnaire. Sixty-three per cent of the women preferred the studied alternative and twenty-six per cent preferred the traditional OC. 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. To compare bleeding profiles of a traditional 28-day oral contraceptive pill cycle with continuous administration.
                After a 28-day run-in cycle, women were randomized to either 28-day cycles (21 active pills and a pill-free week) or continuous use of the same 20 microg ethinyl estradiol/100 microg levonorgestrel formulation for 12 study cycles (336 days). The number of bleeding and spotting days were measured by daily diary. A subset underwent cycle 1 (n = 16), and nine (n = 14) pelvic ultrasound and endometrial histology sampling. Blood pressure, weight, hemoglobin, and adverse events were measured at revisit. The sample size with 80% power to detect a 67% reduction in bleeding days required 27 subjects in each arm.
                Of the 79 subjects randomized, 28 (70%) of the 28-day cycle and 32 (82%) of the continuous-use subjects completed the entire study (P =.6). With continuous use, 49%, 68%, and 88% of women reported no bleeding during cycles 2, 6, and 12, respectively. Amenorrhea or infrequent bleeding was present in 68% of continuous users during cycles 1-3 and increased to 88% during cycles 10-12. Spotting during cycle days 1-21 increased initially with continuous use but reduced over time, and by 9 months was less than the spotting reported by cyclic users. Adverse events, blood pressure, weight, and hemoglobin findings were similar between groups.
                Extension of the 28-day oral contraceptive cycle to continuous use with a low-estrogen dose combination oral birth control pill resulted in significantly fewer bleeding days. This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms.
                The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study.
                All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group.
                All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern. A clinical study was conducted to assess the effects of oestrogen in controlling increased endometrial bleeding problems in the first year of Norplant use. Three treatment groups were studied: (i) 50 micrograms ethinyl oestradiol (EE); (ii) a combined pill containing 30 micrograms EE and 150 micrograms levonorgestrel (LNG); and (iii) placebo. Based on menstrual diary records, women with prolonged, frequent or irregular bleeding, as defined by World Health Organization criteria, were randomly allocated to one treatment for 21 days. A first endometrial biopsy was taken before commencing treatment and a second biopsy at either day 14 or 21 of treatment. Following treatment, all subjects kept a menstrual diary card for 90 days. In this preliminary study, 48 subjects had completed the full 90 day post-treatment record. Within 21 days of EE treatment, the number of bleeding/spotting days was reduced significantly (P < 0.02). In the 90 days following treatment, the administration of EE and EE + LNG significantly decreased the number of bleeding/spotting days (P < 0.05). There was no reduction in the number of bleeding/spotting episodes in the EE and EE + LNG groups, but the length of each bleeding/spotting episode was significantly shorter (P < 0.05). Histopathological findings of endometrium on day 0 revealed consistent progestogenic effects, and there was no apparent change in response by day 14 or 21 of EE or EE + LNG treatment. The results of this study confirm the clinical effectiveness of EE and EE + LNG for the treatment of irregular, frequent and prolonged bleeding in Norplant users. To compare the bleeding patterns and tolerability of 3 different extended ring regimens with those of the standard 28-day cycle with 21 days of contraceptive vaginal ring use followed by 7 ring-free days.
                Following a run-in 28-day ring cycle, women were randomized to 1 of 4 regimens: monthly (28-day cycle), every other month (49-day cycle), every third month (91-day cycle), or continuous (364-day cycle). Treatment duration was 1 year. Daily bleeding diary, interval visit questionnaire, and examination data were collected.
                A total of 561 women were enrolled, 429 were subsequently randomized, and 289 (67.4%) women completed the entire year. All schedules were well tolerated and acceptable to women, but study completion rates were higher for the shorter cycles. Bleeding days were reduced with postponement of the withdrawal bleeding (ring-free) week, but spotting days increased. For example, women using the continuous or 364-day ring cycle reported a median of zero bleeding days but 10-12 days of spotting during the first 3 months of extended use. Unscheduled bleeding during ring use was the lowest with the traditional 28-day cycle. Adverse events, blood pressure, body weight, and laboratory findings were comparable over the 4 treatment groups.
                The combination vaginal contraceptive ring can be used for extended cycles to alter the bleeding schedule. Women willing to tolerate some spotting might choose the longer extensions to have fewer menstrual periods.
                I. To compare bleeding patterns after immediate vs. conventional oral contraceptive (OC) initiation.
                Randomized controlled trial.
                University-based clinic.
                One hundred thirteen women initiating combination OCs.
                Participants received a 4-month supply of a monophasic 35-microg ethinyl E(2) (EE) OC and a bleeding diary, were randomized to immediate or conventional OC start, underwent monthly telephone follow-up, and after 90 days returned the diary and completed an exit interview.
                Total number of bleeding-spotting days, using the World Health Organization 90-day reference period method. Comparisons were made by trial assignment (immediate vs. conventional) and cycle day of OC initiation (day 8+ vs. days 1-7).
                There was no significant difference in the number of bleeding-spotting days (mean difference: -0.5 days; 95% CI: -3.4 to 2.3) or any other bleeding parameter between the immediate and conventional starters, or days 1-7 and day 8+ starters.
                Immediate start of OCs does not induce bleeding patterns different from conventional starting regimens. Concern about adverse bleeding patterns should not be considered a justification for instructing women to wait until menses before starting OCs. To compare a traditional 28-day cycle to an extended 49-day cycle of the 30 microg ethinyl estradiol (E2)/300 microg norgestrel monophasic birth control pill regimen.
                Ninety subjects randomized to either 28-day cycles with 21 active pills or 49-day cycles with 42 active pills for a prospective open label trial over four 84-day reference periods or trimesters. Bleeding, pill taking, and symptom diaries were completed. The sample size with 80% power to detect a 40% reduction in bleeding days required 24 subjects in each arm.
                Of the 90 women, 24 subjects (54.5%) on the 28-day cycle and 29 (63%) on the 49-day cycle completed the entire study (P =.41). There were no statistically significant differences between the two groups in demographics or continuation rates. There was a significant reduction in bleeding days in the experimental arm beginning in the first trimester (28-day = 10.9, 49-day = 6.4 mean days of bleeding, P <.001) and continuing to the fourth trimester (28-day = 11.3, 49-day = 5.8 mean days, P =.005). The number of spotting days was similar between both schedules in the first trimester (28-day = 4.8, 49-day = 3.7 mean days, P =.24) and continued into the fourth trimester (28-day = 3.4, 49-day = 2.9 mean days, P =.30). Annual expenditure for hygiene products was significantly less for extended use subjects (28-day = $41.45, 49-day = $17.54 spent, P <.001).
                Extension of the 28-day oral contraceptive (OC) cycle to a 49-day cycle resulted in fewer bleeding days and no increase in mean spotting days or bleeding episodes.
Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect.