Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations. The FemHRT Study Investigators

OBJECTIVE: To determine the effect of continuous combined treatment with norethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spotting, or bleeding and/or spotting in postmenopausal women. METHODS: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 microg ethinyl E2, 0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 microg ethinyl E2, 1 mg norethindrone acetate/5 microg ethinyl E2, or 1 mg norethindrone acetate/10 microg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting.Results: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 microg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 microg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1.Conclusion: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.     

Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy

OBJECTIVE: The purpose of this study was to compare the effects on vaginal bleeding patterns of continuous combined hormone replacement therapy with norethindrone acetate and ethinyl estradiol versus conjugated equine estrogens and medroxyprogesterone acetate. STUDY DESIGN: Three hundred fifty-seven postmenopausal women were selected randomly (in a blinded manner) to 12 months of treatment with 1 mg norethindrone acetate/5 microg ethinyl estradiol, placebo, or open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (conjugated equine estrogens/medroxyprogesterone acetate [CEE/MPA]; Prempro). The incidence and duration of vaginal bleeding were assessed throughout the study. Statistical analyses used Cochran-Mantel-Haenszel methodology and analysis of variance. RESULTS: At 3 months, 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy reduced the incidence of bleeding (12% vs 23%; P <.029) and bleeding and/or spotting (22% vs 44%; P <.001), compared with conjugated equine estrogens/medroxyprogesterone acetate therapy. The mean duration of bleeding and bleeding and/or spotting were also reduced with 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy versus conjugated equine estrogens/medroxyprogesterone acetate (P =.004 and P <.001, respectively). The incidence of cumulative amenorrhea at every monthly interval was significantly better with 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy versus conjugated equine estrogens/medroxyprogesterone acetate therapy (P <.05). Associated adverse event (ie, headache, breast pain) incidence rates were similar in the 2 active treatment groups. CONCLUSION: The 1 mg norethindrone acetate/5 microg ethinyl estradiol therapy provides significantly better control of vaginal bleeding than conjugated equine estrogens/medroxyprogesterone acetate therapy at all time points investigated in this 12-month study.     

Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding

Objective: To compare the effects of frequently used two different regimens of combined continuous hormone replacement therapy; 0.625 mg conjugated equine estrogen (CEE) + 2.5 mg medroxyprogesterone acetate (MPA) and 1 mg 17β estradiol (E2) + 0.5 mg norethindrone acetate (NETA), on endometrial histopathology and postmenopausal uterine bleeding. Materials and methods: Two hundred and forty-six outpatient subjects aged 41–57 years were enrolled in the study conducted at the menopause clinic between November 2003 and November 2004. One hundred and thirty-nine patients were assigned to receive 0.625 mg conjugated equine estrogen + 2.5 mg medroxyprogesterone acetate (CEE/MPA), whereas 107 patients were to receive 17β estradiol + 0.5 mg norethindrone acetate (E2/NETA). Inclusion criteria of the study were: normal values of endometrial thickness at basal evaluation, women with intact uterus, at least 12 months of amenorrhea, normal vaginal smear, bilateral mammography and biochemical blood parameters. All women were questioned every 3 months for vaginal bleeding/spotting. Endometrial sampling was performed by Pipelle catheter in the 12th month of therapy. Results: For the first 3 months, vaginal bleeding/spotting rate for the CEE/MPA group was 38.7%, whereas it was higher (45%) in the E2/NETA group. For the second 3-month period, vaginal bleeding/spotting frequencies were 41.1 and 37.8%, respectively. In the third 3-month period 30.6 and 29.6%, and in the fourth 3-month period, 18.5 and 12.5% of the patients reported vaginal bleeding or spotting. None of the results of endometrial sampling have shown findings of cancer histopathology. Conclusion: Compared to CEE/MPA regimen, E2/NETA therapy has not shown more favorable effects on postmenopausal bleeding abnormalities. Irregular endometrial proliferation was seen more with the E2/NETA regimen.     

Uterine bleeding pattern during low dosage Noretisterone acetate and 17-b-Estradiol treatment in postmenopausal patients

BACKGROUND: Recent years have been characterized by progressive optimization of postmenopausal hormonal replacement therapy. More physiological therapeutic protocols have been, in fact, proposed to control the possible symptomatology and to prevent the associated risks, with estro-progestinic compounds characterized by lower effective dosages and suitable for the single patient need. However this therapy is not widely accepted by the women from our country for the fears and the inconvenience raised around such side effects as abnormal uterine bleeding and spotting. Aim: to obtain a good compliance and clinical benefits a continuous administration protocol of the hormonal replacement therapy, alternatively to the sequential one has been proposed. METHODS: Our research group has been observing a sample of 42 patients for 12 months, taking oral 17-b-estradiol 1 mg/noretisterone 0.5 mg in continuous administration. All of them were aged from 42 to 63 years and had been in symptomatic menopause for at least 3 months. The characteristics, the onset and the trend of vaginal bleeding were registered in appropriate monthly diaries. Endometrial thickness was evaluated by transvaginal sonography before starting the administration, not exceeding 4 mm in all the women considered. RESULTS: The incidence of bleeding (calculated as a percent of women who experienced a vaginal bleeding for al least a day during a menstrual cycle) was from 26% to 32% in the 1st trimester, reducing during the following months. At 6 months of therapy only 5% of women reported evident vaginal bleeding; at 12 months 90% of women complained with absence of bleeding or spotting. At 12 months no women showed an endometrial thickness over 6 mm. CONCLUSIONS: This observational study suggests that the majority of treated patients proved to be positively responsive to the treatment and that the 17-b-estradiol 1 mg/noretisterone 0.5 mg association reduces the incidence of bleeding and spotting with a sufficient endometrial protection from hyperplasia.     

A randomized,double-blind,placebo-controlled,multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone

OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.     

Endometrial response to a cyclic regimen of percutaneous 17beta-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension.

Endometrial response to natural estradiol and low-dose vaginal progesterone replacement therapy was evaluated in 20 postmenopausal women with chronic, mild-to-moderate hypertension. A cyclic hormone replacement therapy (HRT) regimen was used (21/28 days) with percutaneous estradiol (1.5 mg/day) and vaginal micronized progesterone (100 mg/day). Menopausal symptoms decreased and estradiol concentrations increased substantially and remained in the physiological range throughout treatment. Serum gonadotropin concentrations decreased significantly (p < 0.001, Friedman's ANOVA). Bone mineral density increased by 2.1% (p = 0.029) only at the lumbar spine. Endometrial thickness remained unchanged. Breakthrough bleeding or spotting occurred in 18% of cycles in the first 3 months of HRT, 30% in months 4-9 and 22% in months 10-12. Withdrawal bleeding occurred in 40% of cycles in the first 3 months and decreased to 25% in months 10-12. At month 12, there were 11 women with amenorrhea due to endometrial atrophy. Nine women had active endometria (proliferative or secretory) and thus reported vaginal bleeding. No severe bleeding, hyperplasia, or carcinoma was found. Vaginal bleeding was tolerated, and no subject withdrew from the study. Results suggest that this regimen confers endometrial protection and is well tolerated, and can therefore safely be used for at least 1 year by postmenopausal women with hypertension and menopausal symptoms.     

Endometrial response to a cyclic regimen of percutaneous 17β-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension

Endometrial response to natural estradiol and low-dose vaginal progesterone replacement therapy was evaluated in 20 postmenopausal women with chronic ,mild-to-moderate hypertension. A cyclic hormone replacement therapy (HRT) regimen was used (21/28 days) with percutaneous estradiol (1.5 mg/day) and vaginal micronized progesterone (100 mg/day). Menopausal symptoms decreased and estradiol concentrations increased substantially and remained in the physiological range throughout treatment. Serum gonadotropin concentrations decreased significantly (p < 0.001 ,Friedman's ANOVA). Bone mineral density increased by 2.1% (p = 0.029) only at the lumbar spine. Endometrial thickness remained unchanged. Breakthrough bleeding or spotting occurred in 18% of cycles in the first 3 months of HRT ,30% in months 4-9 and 22% in months 10-12. Withdrawal bleeding occurred in 40% of cycles in the first 3 months and decreased to 25% in months 10-12. At month 12 ,there were 11 women with amenorrhea due to endometrial atrophy. Nine women had active endometria (proliferative or secretory) and thus reported vaginal bleeding. No severe bleeding ,hyperplasia ,or carcinoma was found. Vaginal bleeding was tolerated ,and no subject withdrew from the study. Results suggest that this regimen confers endometrial protection and is well tolerated ,and can therefore safely be used for at least 1 year by postmenopausal women with hypertension and menopausal symptoms.     

Efficacy of a continuous estrogen-progestin regimen in the menopausal patient

The major concern with the use of unopposed estrogen is its neoplastic effect on the endometrium. Progestins used to oppose the estrogen may be associated with vaginal bleeding and reversal of estrogen's protective changes in serum lipoprotein concentrations. A study was performed in which all postmenopausal women received conjugated equine estrogen for days 1-28; with group I receiving 2.5 mg medroxyprogesterone acetate for days 1-28, group II receiving 5 mg medroxyprogesterone acetate for days 1-28, and group III receiving 5 mg medroxyprogesterone acetate for days 17-28. Pre- and postdrug evaluations of the endometrium revealed atrophic changes after therapy with continuous combined estrogen-progestin. Pre- and poststudy evaluation of serum lipoprotein concentrations demonstrated significant declines in cholesterol and low-density lipoprotein cholesterol within groups I and III, and no change in group II. All patients kept a weekly diary recording any vaginal bleeding or change in vasomotor symptoms. The results suggest that a continuous regimen of 0.625 mg conjugated equine estrogen with 2.5 mg medroxyprogesterone acetate is beneficial as a primary hormonal replacement therapy for the postmenopausal patient.     

Five years with continuous combined oestrogen/progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern

OBJECTIVE--To study the effect of long-term continuous combined oestrogen/progestogen therapy on calcium metabolism, lipoproteins, and bleeding pattern in early postmenopausal women. DESIGN--A prospective, open, controlled study. After initial examinations, control examinations were performed every three months for the first two years and every year for the following three (two) years, with determinations of bone mass, serum lipoproteins, and bleeding pattern. SETTING--Out-patient research clinic at The Department of Clinical Chemistry, Glostrup Hospital, Denmark. PARTICIPANTS--Eighteen healthy women between 6 months and 3 years after a natural menopause, entered in a trial of continuous long-term hormone replacement therapy and a comparison group of 19 age-matched untreated women. INTERVENTION--The treated group received 2 mg of 17 beta-oestradiol combined with 1 mg of norethisterone acetate orally each day continuously for 5 years with a 3 month therapy-free interval after the first 2 years. The women were investigated before treatment, then every 3 months for the first 2 years and every year for the next 3 years for determinations of bone mass, serum lipoproteins and bleeding patterns. The comparison group was followed-up in parallel for the first 4 years. Forearm bone mass was measured with single photon absorptiometry. Blood and urine samples were taken in the morning after an overnight fast and tobacco abstinence. MAIN OUTCOME MEASURES--The effects of hormone therapy on bone mineral content in the forearm, on serum and urine indices of calcium metabolism, on serum levels of total, high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, and bleeding pattern. RESULTS--Bone mineral content in the forearm was stable during the 5 years of treatment, whereas it declined significantly averaging 10% after 4 years in the comparison group. The biochemical estimates of bone turnover decreased to premenopausal level in the hormone group, whereas they remained at a high level in the comparison group. In the hormone group total cholesterol and LDL-C decreased by 20% whereas HDL-C was virtually unchanged. The treatment was associated with minor irregular bleeding in nine women during the first 6 months of treatment, after which no bleeding was experienced. CONCLUSION--Continuous combined oestrogen/progestogen therapy can keep early postmenopausal women free of bleeding episodes for a period of 5 years, after the first 6 months in which spotting occurs in 25%. The therapy prevented bone loss completely. The changes in serum lipoproteins were concordant with a lipid profile associated with a decreased risk of coronary heart disease.     

Effects of low-dose continuous combined conjugated estrogens and medroxyprogesterone acetate on menopausal symptoms, body weight, bone density, and metabolism in postmenopausal women.

OBJECTIVE: The purpose of this study was to determine the effects of a low dose of conjugated equine estrogens and medroxyprogesterone acetate plus calcium supplementation on bone density, metabolism, body weight, and symptoms in young postmenopausal women. STUDY DESIGN: Sixty postmenopausal women, aged 45 to 56 years, were randomized in an open-label, 2-year trial that compared treatment with low-dose continuous combined hormone replacement therapy that contained 0.3 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate plus 1000 mg of calcium per day or treatment with 1000 mg of calcium per day alone. Menopausal symptoms were evaluated for the first 12 weeks of the study; bleeding profiles, bone mineral density, bone turnover, and body weight were assessed for 24 months. RESULTS: After 24 months, we evaluated 15 subjects in the control group (with a 50% drop-out rate) and 23 patients (with a 23% drop-out rate) in the low-dose continuous combined hormone replacement therapy group. Low-dose continuous combined hormone replacement therapy was effective in reducing menopausal clinical symptoms and provided a favorable bleeding profile and minimal side effects. In comparison with basal values, bone mineral density significantly (P <.05) increased by 2.72% +/- 0.3% in the low-dose continuous combined hormone replacement therapy group and decreased by 7.9% +/- 0.8% (P <.05) in the control group after 24 months, with parallel changes in bone metabolism marker action. In the control group, body mass index significantly (P <.05) increased from baseline value with a weight gain of 3%; in the low-dose continuous combined hormone replacement therapy group, the body mass index did not change after 24 months of treatment, and the 1.3% gain in body weight was not significant. CONCLUSION: Low-dose continuous combined hormone replacement therapy can alleviate subjective symptoms and minimize body transformations that are associated with early menopause and provide an effective protection against the activation of bone turnover and osteoporosis.     

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. CONCLUSION: 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.     

Continuous, combined hormone replacement: randomized comparison of transdermal and oral preparations.

OBJECTIVE: To compare two new transdermal, continuous, combined formulations and an oral regimen of hormone replacement therapy (HRT) with respect to endometrial hyperplasia, bleeding patterns, and climacteric symptoms in postmenopausal women. METHODS: This was a randomized, open, parallel-group trial during 1 year in 441 postmenopausal women who received either a 10-cm2 patch of 0.025 mg estradiol (E2) and 0.125 mg norethisterone acetate, a 20-cm2 patch of 0.05 mg E2 and 0.25 mg norethisterone acetate twice weekly, or tablets of 2 mg E2 and 1 mg norethisterone acetate once daily. The efficacy variables were frequency of endometrial hyperplasia after 1 year of treatment, number of bleeding and spotting days from the fourth to sixth treatment months, relief of climacteric symptoms, and tolerability. RESULTS: The frequency of endometrial hyperplasia was no more than 2% after 1 year of treatment in all groups. One case of simple hyperplasia was detected among the women treated with 10-cm2 patches and two among those treated with oral HRT. From the fourth to sixth treatment months, amenorrhea occurred in 73%, 47%, and 66% of the women in the 10-cm2, 20-cm2, and oral HRT groups, respectively. The 10-cm2 patches and oral treatment were associated with fewer bleeding days than were the 20-cm2 patches (P<.001). During the last 3 months of the treatment year, amenorrhea was found in 100 subjects (86%) for 10-cm2 patches, 61 (65%) for 20-cm2 patches, and in 85 (79%) for oral HRT. All treatments alleviated the climacteric symptoms to a comparable extent. CONCLUSION: In postmenopausal women, 10-cm2 patches relieved climacteric symptoms and prevented endometrial hyperplasia at least as effectively as oral HRT. Amenorrhea was induced early in a high percentage of women using 10-cm2 patches and oral HRT, and these therapies seemed to be convenient, effective, and safe for estrogen deficiency symptoms in postmenopausal women.     

A randomized trial of oral contraceptive and hormone replacement therapy on bone mineral density and coronary heart disease risk factors in postmenopausal women

OBJECTIVE: To identify the effects of oral contraceptive (OC) and hormone replacement therapy (HRT) on bone mineral density and coronary heart disease risk factors in postmenopausal women. METHODS: Eighty healthy postmenopausal women were randomly assigned to a cyclic regimen of OC containing 30 microg of ethinyl estradiol and 150 microg of desogestrel or HRT containing 0.625 mg of conjugated equine estrogens 21 days per cycle and 5 mg of medrogestone 10 days per cycle for 12 months. Bone mineral density of lumbar spine and hip, biochemical markers of bone turnover, lipid-lipoprotein profiles, coagulation profiles, fasting plasma glucose, and blood pressure were evaluated. RESULTS: Both regimens caused significant increase in bone mineral density of lumbar spine, trochanter, intertrochanteric region, total hip, and Ward triangle. Only OC therapy was associated with a significant increase in femoral neck bone mineral density (mean score +/- standard error 2.5% +/- 0.7%, P < .01). Biochemical markers of bone turnover, total cholesterol, and low-density lipoprotein cholesterol decreased significantly in both groups. Posttreatment levels of those bone markers and lipid-lipoprotein were significantly lower after OC therapy than HRT. Fasting plasma glucose and systolic blood pressure decreased significantly in both groups; however, only the OC group showed a significant decrease in diastolic blood pressure. CONCLUSION: Both OC and HRT increased bone mineral density of lumbar spine and hip, but OC suppressed bone turnover more than HRT. Both methods favorably affected lipid-lipoprotein metabolism, fasting plasma glucose, and blood pressure during the 12 months of treatment.     

Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial

OBJECTIVE: To compare bleeding profiles of a traditional 28-day oral contraceptive pill cycle with continuous administration. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Italian multicenter study for the verification of the efficacy and tolerability of short-term substitution hormone therapy using conjugated estrogens and progestagens administered orally in the postmenopausal a period]

Three hundred and sixty-three postmenopausal women received 6 months of cyclic hormone replacement therapy with conjugated estrogens in differing doses (0.625 mg and 1.25 mg) associated in a sequential pattern lasting 12 days with progestagens (medroxyprogesterone acetate or medrogestone) in 16 italian health centres. The results of the multicentre study confirm the efficacy of this conjugated estrogen-progestogen regimen in resolving climacteric syndrome, offering cardiovascular protection and vaginal trophic effect and preventing postmenopausal osteoporosis, as well as confirming its tolerability in relation to blood pressure, body weight, breast, endometrium, blood coagulation and hepato-renal function.     

Bone density effects of continuous estrone sulfate and varying doses of medroxyprogesterone acetate. Ogen/Provera Study Group.

OBJECTIVE: To establish the optimum oral daily dose of medroxyprogesterone acetate with estrone sulfate for 2 years to maintain bone density. METHODS: A multicenter, double-blind study involved 568 postmenopausal women given estrone sulfate, 1.25 mg, and randomized to receive 2.5, 5, or 10 mg of medroxyprogesterone acetate. Bone density analyses of the lumbar spine and femoral neck were done at baseline and 12 and 24 months. RESULTS: There was a significant increase from baseline to 24 months in mean lumbar spine (4.0% +/- 0.27%) and femoral neck (3.2% +/- 0.28%) bone density, with no significant differences between the treatment groups. Factors most influencing bone density changes were baseline bone density and treatment duration. Significant increases were seen in the spine over 2 years; in the hip, those occurred in the first 12 months only. In both sites, lower baseline bone density resulted in greater increases. In the spine only, no previous hormone replacement therapy, higher body mass index, more than 2 years postmenopause, and nonsmoking resulted in greater gains. Once those covariates and center-to-center variations were corrected for, in the spine, the 10-mg group had smaller increases than the other groups. Changes were unrelated to age, parity, calcium, and alcohol intakes in either site. CONCLUSION: Daily estrone sulfate, 1.25 mg, with 2.5, 5, or 10 mg medroxyprogesterone acetate was effective for preventing bone loss in postmenopausal women.     

Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60

OBJECTIVE: To assess the uterine effects of 3 years of therapy with raloxifene in healthy, postmenopausal women under age 60. METHODS: Integrated data from two identically designed, randomized, double-masked, placebo-controlled clinical trials were analyzed. Nine hundred sixty-nine healthy women with uteri (ages 45 through 60, 2 to 8 years postmenopausal) were assigned randomly to raloxifene 30, 60, or 150 mg per day, or an identical placebo for 3 years. Endometrial thickness was evaluated with transvaginal ultrasonography every 6 months for 2 years and again after 3 years. Further uterine evaluation, including endometrial sampling if necessary, was initiated for vaginal bleeding or findings of endometrial thickness greater than 5 mm. RESULTS: Endometrial thickness was unchanged by raloxifene and not significantly different from placebo at any time. One hundred seventy-two women had at least one episode of endometrial thickness greater than 5 mm or vaginal bleeding distributed equally among all groups. A total of 102 (10.5%) women underwent endometrial sampling at least once: 15 (1.5%) for vaginal bleeding, 78 (8.0%) for endometrial thickness greater than 5 mm, and nine (0.9%) for other reasons. There were no significant treatment differences in the proportion of women sampled, in the clinical findings, or in the histologic diagnoses. CONCLUSION: Raloxifene given to healthy postmenopausal women at doses from 30 to 150 mg per day does not stimulate uterine growth and does not cause vaginal bleeding, spotting, or discharge through 3 years of therapy. Thus, any bleeding during therapy should be deemed unexpected and prompt a clinical evaluation.     

A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy.

OBJECTIVE: To investigate endometrial histology, bleeding, and the effects of replacing the levonorgestrel intrauterine system (LNG IUS, Mirena/Levonova, Leiras Oy, Turku, Finland) after 5 years of combined use with estrogen. DESIGN: Prospective cohort study. SETTING: Private outpatient clinic. PATIENT(S): Forty postmenopausal women started hormone replacement therapy with LNG IUS and either a patch (50 microg/24 h) or oral (2 mg) estradiol valerate protocol. Thirty-nine completed 12 months of treatment. Twenty-nine of them had used LNG IUS with continuous estradiol replacement therapy for 5 years. Seven of them volunteered to a 3-month treatment-free period before reinsertion; 22 opted for immediate reinsertion. INTERVENTION(S): Endometrial sampling for histology, endometrial thickness, and location of the LNG IUS by ultrasound at removal and after washout. The women completed bleeding diaries from 3 months prior to removal to 3 months after reinsertion. MAIN OUTCOME MEASURE(S): Endometrial histology was evaluated and estrogen and progestin effects were also investigated. Endometrial thickness was measured. Bleeding was examined based on bleeding diaries. The investigator and the women evaluated the insertion, removal, and reinsertion of the LNG IUS. RESULT(S): At 6 and 12 months endometrial histology was nonproliferative. At removal, all endometria were suppressed and a strong progestin effect was seen. The thickest endometrium was 3.6 mm. After washout, all seven endometria were atrophic. Before the IUS was replaced, 26 women were amenorrheic, whereas three had minor spotting. After replacement 5 women had no bleeding and an additional 10 women had only spotting. The bleeding or spotting discontinued within 18 days. The insertion of LNG IUS was characterized as easy by the investigator and it was well tolerated by the women. Cervical dilatation and/or paracervical blockade was used in 10 insertions. CONCLUSION(S): Intrauterine levonorgestrel effectively protects against endometrial hyperplasia. In most women it induces amenorrhea, which is only temporarily affected by replacement of the LNG IUS.     

Continuous oral contraceptives: are bleeding patterns dependent on the hormones given?

OBJECTIVE: To estimate whether progestin type or estrogen dose influences bleeding patterns, adverse effects, or satisfaction with combined oral contraceptives dosed continuously. METHODS: This was a randomized, double blind, 4-arm active treatment study. Subjects received either 100 microg levonorgestrel/20 microg ethinyl estradiol (E2) (20LNG group), 100 microg levonorgestrel/30 microg ethinyl E2 (30LNG group), 1,000 microg norethindrone acetate/20 microg ethinyl E2 (20NETA group), or 1,000 microg norethindrone acetate/30 microg ethinyl E2 (30NETA group) for 180 days. Subjects logged bleeding events and adverse effects on a daily menstrual calendar. An exit survey measured satisfaction with bleeding patterns. RESULTS: One hundred thirty-nine women were enrolled. Patients in the 20NETA and 30NETA arms had significantly more days of amenorrhea than the 30LNG arm in the second 90 days (P < .008). The 30LNG group reported more spotting days than the 20NETA group over the entire study period (P < .008) and the 30NETA group for the second 90 days (P < .008). Only a small number of bleeding days were reported with no differences between groups. No differences in adverse effects between groups were found. Women in the 30LNG arm reported lower levels of satisfaction with their bleeding patterns than the other groups (30LNG compared with 20NETA, P = .01; 30LNG compared with 30NETA, P = .001). CONCLUSION: The addition of 10 microg of ethinyl E2 to a 20 microg ethinyl E2 pill containing levonorgestrel or norethindrone acetate did not improve bleeding patterns. During continuous dosing, the use of oral contraceptives containing 1,000 microg norethindrone acetate resulted in more days of amenorrhea and fewer days of spotting than preparations containing 100 microg levonorgestrel. LEVEL OF EVIDENCE: I.     

Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with 17beta-estradiol and norethindrone acetate

OBJECTIVE: We studied bleeding patterns in postmenopausal women who were using 2 types of continuous combination regimens. STUDY DESIGN: A prospective, double-blind, randomized study of 208 postmenopausal women treated with conjugated estrogen, 0.625 mg, and medroxyprogesterone acetate, 5 mg, or with 17beta-estradiol, 2 mg, and norethindrone acetate, 1 mg. RESULTS: The mean number of bleeding days decreased during the first 4 months of treatment (P <.002) but not thereafter. The number of bleeding days was fewer (P <.002) and the time until amenorrhea was shorter (P <.02) in patients receiving conjugated estrogen and medroxyprogesterone acetate than in patients receiving 17beta-estradiol and norethindrone acetate. The odds ratio for progression to amenorrhea with the use of conjugated estrogen and medroxyprogesterone acetate was 1.58, in comparison with the use of 17beta-estradiol and norethindrone acetate. A thick endometrium at the start of treatment resulted in more bleeding days than were found for a thin endometrium (P <.03). Body mass index, age, and blood pressure had no predictive value for bleeding problems. CONCLUSIONS: Treatment with continuous combined conjugated estrogen and medroxyprogesterone acetate resulted in fewer bleeding problems than did treatment with 17beta-estradiol and norethindrone acetate. Endometrial thickness may help to predict the chance of achieving amenorrhea during early hormone replacement therapy.