Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate

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1 FERTILITY AND STERILITY VOL. 75, NO. 6, JUNE 2001 Copyright 2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate Wulf H. Utian, M.D., Ph.D., a Donna Shoupe, M.D., b Gloria Bachmann, M.D., c Joanne V. Pinkerton, M.D., d and James H. Pickar, M.D. e Case Western Reserve University, Cleveland, Ohio; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, New Brunswick, New Jersey; University of Virginia Health Sciences Center, Charlottesville, Virginia; and Wyeth-Ayerst Research, Philadelphia, Pennsylvania Received November 14, 2000; revised and accepted January 16, Supported by Wyeth- Ayerst Research, Philadelphia, Pennslvania. Reprint requests: Wulf H. Utian, M.D., Ph.D., Executive Director, The North American Menopause Society, 5900 Landerbrook Drive, Suite 195, Mayfield Heights, Ohio (FAX: ; utian@menopause.org). a Department of Obstetrics and Gynecology, Case Western Reserve University. b Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California. c Department of Obstetrics and Gynecology, UMDNJ Robert Wood Johnson Medical School. d Department of Obstetrics and Gynecology, University of Virginia Health Sciences Center. e Wyeth-Ayerst Research /01/$20.00 PII S (01) Objective: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. Design: A randomized, double-blind, placebo-controlled trial (the Women s Health, Osteoporosis, Progestin, Estrogen study). Setting: Study centers across the United States. Patient(s): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n 241 at baseline). Intervention(s): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. Main Outcome Measure(s): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. Result(s): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. Conclusion(s): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses. (Fertil Steril 2001;75: by American Society for Reproductive Medicine.) Key Words: Conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), lower doses, vasomotor symptoms, Women s HOPE study, hormone replacement therapy (HRT), vaginal maturation index (VMI), vaginal atrophy, postmenopausal women, menopause The effectiveness of hormone replacement therapy (HRT) for relief of vasomotor symptoms and vaginal atrophy in postmenopausal women with an intact uterus is well established (1 3). In the United States, the most commonly prescribed estrogen for HRT is oral-conjugated equine estrogens (CEE) at a dosage of mg/d (4, 5). Medroxyprogesterone acetate (MPA) is the most commonly used progestin for HRT in the United States (4), with typical dosages varying from 2.5 to 5 mg/d when taken daily, and 5 to 10 mg/d for 10 to 14 days of a cycle when administered sequentially (5). Clinical research has confirmed that each of these recommended MPA dosages provides endometrial protection (6). Despite the proven benefits of HRT, beliefs about side effects and concerns about safety hinder acceptance of HRT among patients (7). Women commonly identify irregular or withdrawal bleeding, breast tenderness, and fears about developing breast cancer as obstacles to starting or continuing HRT (8 10). In studies 1065

2 TABLE 1 Women s HOPE study exclusion criteria. History or active presence of cerebro- or cardiovascular disease Gallbladder disease Known or suspected estrogen-dependent neoplasia Endocrine disorders, except for controlled thyroid disease Known hypersensitivity to estrogens or progestins Use of any estrogen-, progestin-, or androgen-containing medication within 8 weeks (12 weeks for the substudy) of the prestudy screening Endometrial hyperplasia or an abnormal Papanicolaou smear Liver function test results 1.5 times the upper limit of normal Smoking more than 15 cigarettes per day Use of an IUD within the last 3 months Chronic renal or hepatic disease Neuro-ocular disorders History of malignancy other than basal cell carcinoma of the skin Thromboembolic disorders Use of medications known to affect vasomotor symptoms within 2 weeks of the prestudy screening Fasting levels of glucose 6.94 mmol/l (125 mg/dl), total cholesterol 7.77 mmol/l (300 mg/dl), or triglycerides 3.39 mmol/l (300 mg/dl) Sitting blood pressure 160 mm Hg systolic or 90 mm Hg diastolic, or use of more than two antihypertensive agents Malabsorption disorders Known alcohol or drug abuse Evidence of malignant changes on the prestudy mammogram using lower dosages of estrogens, patients reported reductions in bleeding and other side effects (11 13). Lower doses of hormones may also help allay patients concerns about the safety of using HRT (14). Anticipation that lower-dose HRT might enhance utilization and continuation of hormone therapy in postmenopausal women has increased interest in the efficacy and side-effect profiles of lower hormone doses. Numerous small studies of short duration have found lower doses of various estrogens to be effective in reducing the number and severity of hot flushes, the effect being almost as great as that seen with the most commonly prescribed HRT doses (12, 15 18). Nilsson and Heimer (19) reported significant improvement in symptoms of urogenital atrophy in women administered 12.5 g/d of 17 -estradiol transdermally. These promising results point to the need for larger-scale studies of longer duration to more firmly establish the efficacy of lower dosages of estrogen for alleviating vasomotor symptoms and vaginal atrophy. Examining the efficacy of lower doses of CEE, the most widely used estrogen for HRT, is particularly important. Research is also needed to explore whether lower progestin doses are effective in preventing uterine hyperplasia. This paper is the first in a series of reports from the Women s Health, Osteoporosis, Progestin, Estrogen (Women s HOPE) study, a 2-year clinical trial of the safety and efficacy of lower-dose regimens of CEE and MPA in postmenopausal women. The lower CEE dosages used in the Women s HOPE study were 0.3 and 0.45 mg/d. MPA dosages were either 1.5 or 2.5 mg/d, which provided the opportunity to examine differing ratios of CEE/MPA as well as lower hormone doses. The design of the Women s HOPE study included a 1-year basic study focused on menopausal symptoms, endometrial histology, and bleeding profiles, and a 2-year substudy that examined bone density and turnover, serum lipoproteins, and carbohydrate metabolism. This paper reports results from the first year of the study on the efficacy of three lower dosage combinations of CEE and MPA for relieving vasomotor symptoms and vaginal atrophy. Other outcomes evaluated in year 1 included endometrial histology (20), bleeding profiles (21), and plasma lipoproteins, coagulation parameters, and carbohydrate metabolism (22). Data from the 2-year substudy will be used to assess the efficacy of lower doses of CEE and MPA to prevent postmenopausal osteoporosis and maintain an acceptable metabolic profile. MATERIALS AND METHODS Healthy, postmenopausal women aged 40 to 65 years were recruited for this randomized, double-blind, placebocontrolled study. Safety and efficacy variables were assessed in 2,673 patients. All procedures were approved by the institutional review board at each of the 57 Women s HOPE study sites. Each patient provided her informed consent before enrollment. The complete list of investigators is presented in the Appendix. Women were eligible if they had an intact uterus, no menses within the last year ( 4 years from their last menses if included in the metabolic and bone substudy), FSH levels of 30 IU/L and 17 -estradiol levels of 184 pmol/l (50 pg/ml), and were within 20% of normal body weight range. Exclusion criteria included known hypersensitivity to estrogens or progestins, use of medication containing estrogens, progestins, or androgens within 8 weeks (within 12 weeks for the substudy), or use of concomitant drugs known to affect vasomotor symptoms within 2 weeks of the prestudy screening. Table 1 contains the complete list of exclusion criteria. Screening and assessment methods employed in the Women s HOPE study are summarized in Table 2. This paper reports the results related to vasomotor symptom relief and changes in vaginal maturation index (VMI) Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

3 TABLE 2 Summary of procedures and methods used in the Women s HOPE study. Segment Prestudy On therapy Study procedures Month Visit 1 2 a Cycle b 19 b 22 b 26 b History X Physical examination X X X X X Vital signs X X X X X X X X X Papanicolaou smear X X X X X Laboratory safety screen X X X X X FSH, 17 -estradiol X Mammography X c X X Endometrial biopsy X X d X d X d X d Daily diary X X X X TSH & Lp(a) phenotype b X Lipids and coagulation b X e X e X X X X Carbohydrates b X X X X X Bone markers b,f X X X X X Bone mineral density b X g X g X X X X h X h Treatment daily X X Dispense medication X X X X X X X X FSH follicle-stimulating hormone; TSH thyroid-stimulating hormone (thyrotropin); Lp lipoprotein. a After a minimum 8-week washout period (12 weeks for osteoporosis and metabolic substudy group) for prior estrogen, progestin, or androgen therapy (if required). b For osteoporosis and metabolic substudy a subgroup of 768 patients at designated investigational sites. c Previous mammogram within 6 months was acceptable. d Performed on cycle days e To be performed approximately 7 14 days apart but not to exceed 3 weeks. Second coagulation specimen was analyzed only if the first specimen was unsuitable for analysis. f Serum osteocalcin and urinary calcium, creatinine, and N-telopeptide. g To be performed approximately 7 14 days apart but not to exceed 3 weeks. The two lumbar spine scans must have differed by less than 5%; otherwise, a third lumbar spine scan was performed before randomization. h To be performed approximately 14 days apart but not more than 3 weeks apart. All eligible women had initial screenings that included a complete medical history (including last natural menstrual period and obstetric history) and a complete physical examination to ensure that inclusion/exclusion criteria were met. The initial screening also included pelvic examination, Papanicolaou smear with VMI, endometrial biopsy, breast examination and mammogram (unless results from a previous mammogram within the last 6 mo were provided), urinalysis, fasting blood drawn by venipuncture for hematologic and blood chemistry tests, and determinations of serum FSH and 17 -estradiol. Patients maintained a daily diary card for at least 7 days before study entry to record any bleeding episodes and hot flushes. Patients used assigned weights to indicate severity of each hot flush. The assigned weights were as follows: 1 mild (a fleeting warm sensation, no sweating; does not disrupt activity), 2 moderate (a warm sensation with sweating; does not disrupt activity), or 3 severe (a hot sensation with sweating; disrupts activity). After the prestudy screenings, women accepted into the study were assigned to one of eight treatment groups: CEE at mg/d (CEE 0.625), CEE at mg/d and MPA at 2.5 mg/d (CEE 0.625/MPA 2.5), CEE at 0.45 mg/d (CEE 0.45), CEE at 0.45 mg/d and MPA at 2.5 mg/d (CEE 0.45/MPA 2.5), CEE at 0.45 mg/d and MPA at 1.5 mg/d (CEE 0.45/ MPA 1.5), CEE at 0.3 mg/d (CEE 0.3), CEE at 0.3 mg and MPA at 1.5 mg/d (CEE 0.3/MPA 1.5), or placebo. Randomization was determined by a computer-generated table; block randomization was used to ensure a balanced allocation of patients into the eight treatment regimens. Patients were instructed to take two tablets (CEE or matching placebo and CEE/MPA or matching placebo) once daily in a doubleblind, double-dummy fashion. Two tablets were necessary because the tablet containing CEE alone was slightly smaller than that containing CEE/MPA. Medications consisted of enough for 14 cycles (an extra cycle to allow for lost medication). All women in the study received calcium carbonate supplements (600 mg elemental calcium/tablet; Caltrate, Whitehall-Robins, Madison, NJ) and were instructed to take one tablet daily. Medication codes were provided to the FERTILITY & STERILITY 1067

4 investigators in individually sealed and numbered envelopes that could be opened in the event of an emergency. Safety and Efficacy Parameters Year 1 study visits were scheduled during cycles 3, 6, 9, and 13 for all patients. At each study visit, weight was recorded, blood pressure and pulse were determined, and study medication, calcium supplements, and diary cards were provided. Women were instructed to record the dates they took study medication, as well as any dates they missed medication, on a daily diary card, which they returned to the investigator at their next visit. The diary cards were also used to record the number and severity of vasomotor symptoms (i.e., hot flushes) and bleeding or spotting information. At the cycle 6 and cycle 13 visits, physical examinations were performed that included a Papanicolaou smear with VMI, endometrial biopsy, and routine laboratory tests (hematologic, blood chemistry, urinalysis). Mammograms were obtained during the cycle 13 visit. Specimen collection, processing, and shipping for the laboratory tests done at prescreening, cycle 6, and cycle 13 were coordinated by the Core Laboratory for Clinical Studies (CLCS) of Washington University (St. Louis, MO). A general chemistry safety panel analysis containing 16 components was performed in the CLCS on refrigerated serum using the Hitachi 917 analyzer (Roche Diagnostics, Indianapolis, IN). Dipstick urinalysis for ph, blood, protein, and ketones was performed on refrigerated urine using the CHEMSTRIP Urine Analyzer (Roche Diagnostics). A complete blood count was performed in the Hematology Laboratory of Washington University using the MAXM analyzer (Beckman Coulter, Inc., Fullerton, CA). If the white blood count was abnormal, a reflex five-part automated differential was performed. The serum concentration of estradiol was determined at Endocrine Sciences (Calabasas Hills, CA) by radioimmunoassay after extraction and column chromatography (23). The intra-assay coefficient of variation (CV) for estradiol was 4%; the interassay CV was 7%. The serum concentration of FSH was determined in the CLCS using the IMx analyzer (Abbott Laboratories, Abbott Park, IL). The intra-assay CV for FSH was 6.2%; the interassay CV was 14%. Evaluation of the Papanicolaou smear with VMI was performed at Empire Laboratories (Garden Grove, CA) and reported using the Revised Bethesda System (24). Safety was monitored by means of physical examination, gynecologic examination, and laboratory determinations. Any patient who developed endometrial hyperplasia was terminated from the study and given the appropriate treatment. Signs and symptoms reported by patients, as well as reports of adverse events, were also used to assess safety. All adverse events were recorded in the adverse event record. Treatment-emergent adverse events (TEAEs) were adverse events not present at baseline or events present at baseline that worsened during treatment. Statistical Analyses All tests were two-sided, and statistical significance was set a priori at P.05. Baseline characteristics (means SD) were compared among groups using a one-way analysis of variance procedure or 2 test for categorical variables such as race. A 2 test was used to compare the number of patients who discontinued medication in each group, both overall and for specific reasons. Vasomotor symptoms were analyzed as the frequency and severity of hot flushes as recorded on patient daily diary cards. The mean daily number of hot flushes was calculated as the sum of the number of hot flushes on each day or number of days for which data were available. To assess severity of hot flushes, a daily severity score, which used the weights assigned to mild, moderate, and severe hot flushes, was calculated as [(number of mild flushes 1) (number of moderate flushes 2) (number of severe flushes 3)] divided by the total number of hot flushes on that day. The average daily severity of hot flushes was calculated as the sum of the daily severity scores, divided by the number of days for which data were available. Vasomotor symptoms were analyzed in an efficacyevaluable patient population that included all patients randomly assigned who recorded taking study medication and who had at least 7 moderate-to-severe baseline hot flushes recorded on each of the last 7 days of screening, or at least 50 total hot flushes on the last 7 days combined. Relief of vasomotor symptoms was analyzed by week (for weeks 1 through 12) and by cycle (for 13 cycles). Data excluded from vasomotor symptom analyses included patients with fewer than 5 days of baseline data (excluded data represented 1% of cycles and weeks), cycles with fewer than 20 days of data (excluded data represented approximately 2% of cycles), and weeks with fewer than 5 days of data (excluded data represented 1% of weeks). Changes from baseline in the number and severity of hot flushes were assessed within treatment groups by using paired t-tests. Comparisons to placebo were performed using an analysis of covariance procedure with baseline as a covariate. The mean daily number and severity of hot flushes were compared among treatment groups for each week and for each cycle using an analysis of covariance, with treatment as a factor in the model and baseline as the covariate. The least significant difference procedure was used for pairwise comparisons. At each of the three dose levels of CEE, the CEE and CEE/MPA groups were compared with placebo. These comparisons were performed in descending order, beginning with the highest dose of CEE (0.625 mg) or CEE/MPA (CEE 0.625/MPA 2.5) and proceeding to the next lower dose only if statistical significance at the 0.05 level was found. No adjustment to alpha level for multiple comparisons was necessary because of the sequential manner of testing that was performed for a limited number of pairwise comparisons Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

5 TABLE 3 Baseline characteristics of patients in the Women s HOPE study by treatment group. Characteristic CEE (n 348) CEE 0.625/ MPA 2.5 (n 331) CEE 0.45 (n 338) CEE 0.45/ MPA 2.5 (n 340) CEE 0.45/ MPA 1.5 (n 331) CEE 0.3 (n 326) CEE 0.3/ MPA 1.5 (n 327) Placebo (n 332) Total (n 2,673) Age (y) Height (cm) Weight (kg) BMI (kg/m 2 ) Age at menopause (y) Years since menopause (y) Parity (n) Note: All doses are milligrams per day. Values are means SD. CEE conjugated equine estrogens; MPA medroxyprogesterone acetate; BMI body mass index. P.05 for all between group comparisons. Vaginal atrophy was assessed by VMI, which was reported as the proportion of vaginal superficial cells, relative to the number of parabasal and intermediate cells, in a lateral vaginal wall smear. VMI data were analyzed within groups by the change from baseline using the Wilcoxon matchedpairs signed-rank test and among groups using Wilcoxon s rank-sum test. VMI analyses were done in an intent-to-treat population that included all patients randomly assigned in the study who recorded taking study medication. RESULTS Description of Sample Baseline characteristics for patients in the Women s HOPE study are reported in Table 3. All variables were similar among the eight treatment groups. The women were predominantly Caucasian (88%), with African American or black (6%), Hispanic (4%), Asian (2%), Native American ( 1%), and Arabic ( 1%) women accounting for the remaining identified ethnic groups. Discontinuation Rates A total of 521 patients (19%) withdrew from the study, and there was a statistically significant difference in overall dropout rate among the groups (P.001). The highest dropout rates, which included women with endometrial hyperplasia, occurred in the CEE group (30%) and the placebo group (23%). Dropout rates ranged from 14% to 19% for the remaining groups, which included all of the combined CEE/MPA dosages. Adverse events were the most common reason for discontinuation (8%, n 221), and there were significant differences among groups in the rates of adverse events (P.001). The CEE group had the highest rate of dropouts due to adverse events (18%, n 61). Rates in all other groups ranged from 4% to 9%. Discontinuation rates due to lack of efficacy also differed among groups (P.001) and were highest in the placebo group (8%, n 27). Discontinuation due to lack of efficacy was no higher than 2% in the active treatment groups. Treatment Compliance Treatment groups were comparable with respect to noncompliance, with no evidence of a dose response relationship. Patients in the CEE group reported the highest percentage of cycles in which at least one tablet was missed (27%), whereas the placebo group missed tablets in 26% of cycles. The rate ranged from 22% to 25% in the other groups. Population Evaluable for Vasomotor Symptoms Table 4 presents baseline characteristics for the efficacyevaluable population that was evaluated for vasomotor symptoms. At baseline, this population included 241 patients. Within each treatment group, the number of patients included in analyses ranged from 25 to 34 during weeks 1 through 12 and from 17 to 34 during cycles 1 through 13. In general, treatment groups were similar at baseline. The only statistically significant difference among groups was ethnicity. Overall, the women were predominantly Caucasian (84%), with African American or black (9%), Hispanic (5%), Asian ( 1%), Native American ( 1%), and Arabic ( 1%) women accounting for the remaining identified ethnic groups. Percentages across treatment groups varied, with the highest percentages of African American or black patients in the CEE 0.3 and CEE 0.45/ MPA 1.5 groups (20% and 17%, respectively) and the lowest percentage in the CEE 0.3/MPA 1.5 group (3%). The percentage of Hispanic patients in each group ranged from 3% in the CEE 0.45/MPA 1.5 and CEE 0.3/MPA 1.5 groups to 13% in the CEE 0.45 group. FERTILITY & STERILITY 1069

6 TABLE 4 Baseline characteristics of patients in the vasomotor symptom efficacy-evaluable population. Characteristic CEE (n 27) CEE 0.625/ MPA 2.5 (n 34) CEE 0.45 (n 32) CEE 0.45/ MPA 2.5 (n 28) CEE 0.45/ MPA 1.5 (n 29) CEE 0.3 (n 30) CEE 0.3/ MPA 1.5 (n 33) Placebo (n 28) Total (n 241) Age (y) Height (cm) Weight (kg) BMI (kg/m 2 ) Age at menopause (y) Years since menopause (y) Parity (n) Note: All doses are milligrams per day. Values are means SD. CEE conjugated equine estrogens; MPA medroxyprogesterone acetate; BMI body mass index. P.05 for all between group comparisons. Mean Daily Number of Hot Flushes Figure 1A shows the mean daily number of hot flushes for weeks 1 through 12 for the CEE alone and placebo groups. Figure 1B shows these results for the CEE/MPA and placebo groups. All groups, including placebo, experienced a statistically significant decrease from baseline in mean number of hot flushes (P.01). This effect was seen in the first week in all active treatment groups, except the CEE 0.3/MPA 1.5 group. This group experienced a significant decrease from baseline (P.001) by the end of the second week. By the second or third week of treatment, the mean daily number of hot flushes in each of the CEE and CEE/MPA groups was significantly lower than the mean daily number of hot flushes in the placebo group (P.001). Thus, all of the active FIGURE 1 Mean daily number of hot flushes by week are shown for the eight treatment groups. (A), The placebo and the CEE alone groups. (B), The placebo and the CEE/MPA groups. Data are adjusted for baseline. All values for mean number of hot flushes (unadjusted) were significantly less than baseline (P.05), except CEE 0.3/MPA 1.5 at week 1. *Difference from placebo was significant (P.05) from weeks 2 through 12. Difference from placebo was significant (P.05) from weeks 3 through 12. Difference between CEE 0.45 and CEE 0.45/MPA 2.5 was significant (P.05) at weeks 3, 4, 5 and 9. Difference between CEE and CEE 0.45 was significant (P.05) from weeks 2 through 12. Difference between CEE and CEE 0.3 was significant (P.05) at weeks 4, 5, 6, 9, 10, and Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

7 FIGURE 2 Mean daily number of hot flushes by cycle are shown for the eight treatment groups. (A), The placebo and the CEE alone groups. (B), The placebo and the CEE/MPA groups. Data are adjusted for baseline. All values for mean number of hot flushes (unadjusted) were significantly less than baseline (P.05) in all groups. *Difference from placebo was significant (P.05) for all cycles. Difference from placebo was significant (P.05) for all cycles except cycle 1. Difference from placebo was significant (P.05) for all cycles except cycle 6. Difference between CEE and CEE 0.45 was significant (P.05) at cycles 1 through 3 and 9 through 13. Difference between CEE and CEE 0.3 was significant (P.05) at cycles 3, 5, and 6. Difference between CEE 0.45 and CEE 0.45/MPA 2.5 was significant (P.05) at cycles 2 and 3. #Difference between CEE 0.3 and CEE 0.3/MPA 1.5 was significant (P.05) at cycle 5. treatments examined in this study provided significant symptom relief within the first few weeks of use. Figure 1B also shows that the reduction in number of hot flushes was comparable in all CEE/MPA groups. No significant differences in the mean daily number of hot flushes were observed between the CEE 0.625/2.5 group and any of the three lower-dosage CEE/MPA groups (CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3/MPA 1.5). At weeks 3 to 5 and week 9, the CEE 0.45/MPA 2.5 group had a significantly lower mean daily number of hot flushes than the CEE 0.45 group (P.05). The mean daily number of hot flushes in the CEE group was lower than the mean daily number in the CEE 0.45 and CEE 0.3 groups at weeks 2 through 12 and weeks 4 to 6, 9, 10, and 12, respectively (P.05). Figure 2 shows the mean daily number of hot flushes for cycles 1 through 13 in the CEE alone, CEE/MPA, and placebo groups. At all time points, all groups including placebo experienced a significant decrease from baseline in mean number of hot flushes (P.001). By cycle 1, in all active treatment groups except CEE 0.45, the mean daily number of hot flushes was significantly lower than the mean daily number of hot flushes reported in the placebo group (P.05). By cycle 2, the mean daily number of hot flushes in the CEE 0.45 group was significantly lower than placebo (P.001). At cycle 6, the mean daily number of hot flushes in the CEE 0.3 group was not significantly different from placebo (P.085). However, the mean daily number of hot flushes for the CEE 0.3 group was significantly lower than the mean observed in the placebo group at all other cycles (i.e., 1 5 and 7 13). The mean daily number of hot flushes in the lower-dosage CEE/MPA groups (CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3/MPA 1.5) was not significantly different from the mean number in the CEE 0.625/MPA 2.5 group at any cycle (Fig. 2B). At cycles 2 and 3, treatment with CEE 0.45/MPA 2.5 was significantly better than CEE 0.45 at reducing the number of hot flushes (P.05). Significant differences in the mean daily number of hot flushes were detected between the CEE and CEE 0.45 groups at cycles 1 3 and 9 13 (P.05) and between CEE and CEE 0.3 at cycles 3, 5, and6(p.05). Mean Daily Severity of Hot Flushes Figure 3 shows the mean daily severity of hot flushes for weeks 1 through 12. There were significant decreases from baseline in mean daily severity of hot flushes in all CEE and CEE/MPA groups by the second week (P.001) and in the placebo group by the third week (P.05). The effect in all active treatment groups was maintained through week 12. By the third week, all CEE and CEE/MPA groups showed a FERTILITY & STERILITY 1071

8 FIGURE 3 Mean daily severity of hot flushes by week for the eight treatment groups. (A), The placebo and the CEE alone groups. (B), The placebo and the CEE/MPA groups. Data are adjusted for baseline. All values for mean severity of hot flushes (unadjusted) were significantly less than baseline (P.05), except CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5 at weeks 1 and 2, and placebo at weeks 1, 2, and 4. *Difference from placebo was significant (P.05) from weeks 2 through 12. Difference from placebo was significant (P.05) from weeks 3 through 12. Difference between CEE and MPA 0.45 was significant (P.05) at weeks 3 through 5 and 8 through 12. Difference between CEE 0.45 and CEE 0.45/MPA 2.5 was significant (P.05) at week 5 and weeks 8 through 12. Difference between CEE and CEE 0.3 was significant (P.05) at weeks 4 through 7 and 9 through 12. Difference between CEE 0.625/MPA 2.5 and CEE 0.3/MPA 1.5 was significant (P.05) at weeks 4 and 9. #Difference between CEE 0.45/MPA 2.5 and CEE 0.3/MPA 1.5 was significant (P.05) at weeks 4 through 6 and weeks 8 and 9. significantly lower mean daily severity of hot flushes compared with placebo (P.05). Mean daily severity of hot flushes in the CEE 0.45/MPA 2.5 and CEE 0.45/MPA 1.5 groups were not significantly different from the CEE 0.625/MPA 2.5 group at any time point (Fig. 3B). Mean daily severity of hot flushes was significantly lower in the CEE 0.625/MPA 2.5 group, compared with CEE 0.3/MPA 1.5, at weeks 4 and 9. Treatment with CEE 0.45/MPA 2.5 showed a significantly greater reduction in the mean daily severity of hot flushes compared with CEE 0.45 at week 5 and weeks 8 12 (P.05). The mean daily severity of hot flushes was significantly lower in the CEE group compared with in the CEE 0.45 and CEE 0.3 groups, respectively, at weeks 3 5 and 8 12 and at weeks 4 7 and 9 12 (P.05). Figure 4 shows the mean daily severity of hot flushes for cycles 1 through 13. By the first cycle, all groups, including placebo, showed a significant decrease from baseline in the mean daily severity of hot flushes (P.05). This effect was maintained through cycle 13. In addition, at all time points, the mean daily severity of hot flushes was lower in all the active treatment groups, compared with placebo (P.05). No differences were observed at any cycle in the mean daily severity of hot flushes in the CEE 0.625/MPA 2.5 group, compared with each of the lower-dosage CEE/MPA groups (CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3/ MPA 1.5; Fig. 4B). Treatment with CEE 0.45/MPA 2.5 resulted in a significantly greater reduction in the mean daily severity of hot flushes than treatment with CEE 0.45 at cycles 2, 3, 5, and 9. Treatment with CEE 0.3/MPA 1.5 resulted in significantly lower mean daily severity of hot flushes than treatment with CEE 0.3 at cycles 4 through 7 and 9 through 13 (P.05). The mean daily severity of hot flushes was significantly lower at all cycles in the CEE group, compared with the CEE 0.45 group (P.05). By cycle 2, mean severity in the CEE group was significantly lower than in the CEE 0.3 group, and this difference continued through cycle 13 (P.05). Effects on VMI Figure 5 shows the distributions and median values for the changes from baseline in VMI for superficial cells at cycle 13. Median changes from baseline at cycle 6 (data not shown) were identical to those for cycle 13 in all groups except CEE 0.45 (median 15.0 at cycle 6; median 12.5 at cycle 13). The percentage of superficial cells was increased significantly from baseline at cycles 6 and 13 in all CEE and CEE/MPA groups (P.001), but not in placebo. These changes from baseline in the active treatment groups were 1072 Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

9 FIGURE 4 Mean daily severity of hot flushes by cycle for the eight treatment groups. (A), The placebo and the CEE alone groups. (B), The placebo and the CEE/MPA groups. Data are adjusted for baseline. All values for mean severity of hot flushes (unadjusted) were significantly less than baseline (P.05) for all cycles. *Difference from placebo was significant (P.05) from cycles 1 through 13. Difference between CEE and CEE 0.45 was significant (P.05) at all cycles. Difference between CEE and CEE 0.3 was significant (P.05) from cycles 2 through 13. Difference between CEE 0.45 and CEE 0.45/MPA 2.5 was significant (P.05) at cycles 2, 3, 5, and 9. Difference between CEE 0.3 and CEE 0.3/MPA 1.5 was significant (P.05) at cycles 4 through 7 and 9 through 13. Difference between CEE 0.45/MPA 2.5 and CEE 0.3/MPA 1.5 was significant (P.05) at cycle 2. significantly different from placebo at cycles 6 and 13 (P.001). Changes from baseline at cycles 6 and 13 were significantly greater in the CEE group compared with in the CEE 0.625/MPA 2.5 group (P.05), the CEE 0.45 group (P.05), and the CEE 0.3 group (P.001). No differences in median changes in VMI were detected between the CEE 0.45 group and the CEE 0.45/MPA 2.5 or CEE 0.45/MPA 1.5 groups. Similarly, no significant difference was detected between CEE 0.3 and CEE 0.3/MPA 1.5. Treatment-Emergent Adverse Events The most commonly reported TEAEs for which statistically significant differences (P.05) were seen among treatment groups were leg cramps, breast enlargement, breast pain, dysmenorrhea, vaginal hemorrhage (e.g., vaginal bleeding, intermittent vaginal bleeding, excessive or heavy vaginal bleeding), vaginal moniliasis, and vaginitis. Of these, breast pain was most commonly reported (15% of patients). More patients in the CEE/MPA than CEE groups reported this TEAE (26% in CEE 0.625/MPA 2.5, 19% in CEE 0.45/MPA 2.5, 21% in CEE 0.45/MPA 1.5, and 13% in CEE 0.3/MPA 1.5). The percentage of patients reporting breast pain in the remaining groups ranged from 7% in the CEE 0.3 group to 12% in the CEE 0.45 group. Vaginal hemorrhage was most common in the CEE (14%) and CEE 0.625/MPA 2.5 (6%) groups and was least common in the placebo (0%), CEE 0.3/MPA 1.5 (2%), and CEE 0.3 (2%) groups. Breast enlargement and vaginal moniliasis were most common in the CEE 0.625/MPA 2.5 group (5% and 8%, respectively). Leg cramps were most common in the CEE 0.625/MPA 2.5 and CEE 0.45 groups (7% of patients in each group). Dysmenorrhea and vaginitis were most commonly reported in the CEE 0.45/MPA 1.5 (6%) and CEE (7%) groups. DISCUSSION The results of this study showed that lower-dosage combinations of CEE and CEE/MPA were effective in decreasing the number and severity of hot flushes and in improving vaginal atrophy in generally healthy, postmenopausal women. By week 3, the reported number and severity of hot flushes were significantly reduced from baseline and from placebo in all active treatment groups, including the lowerdosage CEE/MPA groups. In general, the lower-dosage combinations, especially CEE 0.45/MPA 1.5 and CEE 0.3/ MPA 1.5, were as effective for symptom relief as the most commonly prescribed dosage combination of CEE and MPA. These findings are consistent with the results of previous studies that examined the efficacy of lower estrogen dosages FERTILITY & STERILITY 1073

10 FIGURE 5 Box and whisker plots of median change from baseline in VMI for superficial cells (%) at cycle 13. For each treatment group, the box shows the distance between the 75th and 25th percentiles, with the median marked as a line, and the whiskers show the maximum (top) and minimum (bottom) values. *Significantly different from CEE 0.625, P.001. Significantly different from CEE 0.625, P.05. Significantly different from CEE 0.3/MPA 1.5, P.05. for relief of vasomotor symptoms (12, 15 18) and urogenital atrophy (19). The results reported here are especially relevant because they confirm the effectiveness of lower doses of CEE and MPA, the most widely prescribed hormones for HRT, in the context of a large clinical trial that examined efficacy over the course of an entire year. Others (25) have shown improvements in bone mineral density with lower doses of unopposed estrogens taken in combination with supplemental calcium, without significant increases in rates of endometrial hyperplasia. The endometrial safety and bone mineral density results from this trial will be reported separately (20); however, on preliminary examination, the lowerdose CEE/MPA combinations appear effective in preventing endometrial hyperplasia. The bone density results are expected at the conclusion of study year 2. The findings from this trial also provide preliminary evidence for a therapeutic role for MPA beyond endometrial protection when lower dosages of CEE are used. Although not consistent across all weeks or cycles, trends in statistically significant differences between active treatment groups suggest that lower doses of CEE combined with MPA may be better than equivalent lower doses of unopposed CEE for vasomotor symptom relief. In previous research, Schiff and colleagues (26) documented the usefulness of MPA alone for treatment of hot flushes. However, studies with the most common dosages of CEE have reported no additional effect of MPA on vasomotor symptom relief (1). The discrepancy in these results may be due to a threshold effect of CEE, in which MPA enhances the efficacy of CEE in relieving vasomotor symptoms when CEE doses are lower than mg/d. The preliminary results from this study and from other investigations point to the need for research specifically designed to examine the ability of MPA to enhance effectiveness of lower CEE doses. Improvement in the percentage of vaginal superficial cells as measured by VMI also was significant after treatment with lower dosages of CEE and CEE/MPA. Not surprisingly, the greatest improvement in VMI was seen in the group receiving the highest dose of unopposed estrogen. Lower doses of estrogen and administration of MPA with CEE resulted in improvements of lesser magnitude, but the clinical significance of the difference in effect is unknown. The relationship between VMI and severity of symptoms such as vaginal dryness, dyspareunia, and postcoital bleeding appears to be highly individualized (27, 28), and it is not clear how much improvement in VMI is necessary for symptom improvement in most women. Further investigation of the 1074 Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

11 clinical significance of VMI improvement with low-dosage HRT is warranted. In summary, the Women s HOPE trial demonstrated the efficacy of CEE 0.45 combined with either 1.5 or 2.5 mg of MPA per day and of CEE 0.3/MPA 1.5 for vasomotor symptom relief and improvement in VMI in postmenopausal women. Confirmation of the efficacy of these lower doses of estrogen and progestin expands the number of options for women considering HRT. Lower doses of CEE and CEE/ MPA appear to be as effective as the most commonly prescribed doses and should be considered as initial treatment options for a majority of women. These lower-dose combinations may allow more patients to obtain the proven preventive benefits of long-term HRT. Acknowledgments: We thank Dr. Thomas G. Cole, Director of the Core Laboratory for Clinical Studies, Washington University School of Medicine, St. Louis, MO, and his assistants for analyses of blood and urine specimens. We appreciate the statistical assistance provided by Michelle Lucas, M.S., and the editorial assistance provided by Bernadette Janas, Ph.D. References 1. Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92: Kronenberg F. Hot flashes: phenomenology, quality of life, and search for treatment options. Exp Gerontol 1994;29: Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Metaanalysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol 1998;92: Wysowski DK, Golden L, Burke L. Use of menopausal estrogens and medroxyprogesterone in the United States, Obstet Gynecol 1995;85: Sobel NB. Progestins in preventive hormone therapy. Including pharmacology of the new progestins, desogestrel, norgestimate, and gestodene: are there advantages? Obstet Gynecol Clin North Am 1994;21: Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994;170: Coope J, Marsh J. Can we improve compliance with long-term HRT? Maturitas 1992;15: Hammond CB. Women s concerns with hormone replacement therapy compliance issues. Fertil Steril 1994;62(suppl 2):157S 60S. 9. Utian WH, Schiff I. NAMS-Gallup survey on women s knowledge, information sources, and attitudes to menopause and hormone replacement therapy. Menopause 1994;1: Ryan PJ, Harrison R, Blake GM, Fogelman I. Compliance with hormone replacement therapy (HRT) after screening for post menopausal osteoporosis. Br J Obstet Gynaecol 1992;99: Selby PL, Peacock M. Dose dependent response of symptoms, pituitary, and bone to transdermal oestrogen in postmenopausal women. Br Med J (Clin Res Ed) 1986;293: Utian WH, Burry KA, Archer DF, Gallagher JC, Esclim Study Group, Boyett RL, et al. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. Am J Obstet Gynecol 1999;181: Mizunuma H, Okano H, Soda M, Kagami I, Miyamoto S, Tokizawa T, et al. Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2-year prospective study. Maturitas 1997;27: Ettinger B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause 1999;6: Speroff L, Whitcomb RW, Kempfert NJ, Boyd RA, Paulissen JB, Rowan JP. Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms. Obstet Gynecol 1996;88: Notelovitz M, Lenihan JP Jr, McDermott M, Kerber IJ, Nanavati N, Arce J-C. Initial 17 -estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000;95: Gordon SF, Thonpson KA, Ruoff GE, Imig JR, Lane PJ, Schwenker CE, et al. Efficacy and safety of a seven-day, transdermal estradiol drug-delivery system: comparison with conjugated estrogens and placebo. Int J Fertil 1995;40: de Aloysio D, Rovati LC, Giamcovelli G, Setnikar I, Bottiglioni F. Efficacy on climacteric symptoms and safety of low dose estradiol transdermal matrix patches. A randomized, double-blind placebo-controlled study. Drug Res 2000;50: Nilsson KE, Heimer GM. Ultra-low-dose transdermal estrogen therapy in postmenopausal urogenital estrogen deficiency a placebo-controlled study. Menopause 1994;1: Pickar JH, Yeh I-T, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;76(1). In press. 21. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75: Lobo RA, Bush T, Carr BR, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001;76(1). In press. 23. Wu C-H, Lundy LE. Radioimmunoassay of plasma estrogens. Steroids 1971;18: National Cancer Institute Workshop. The revised Bethesda system for reporting cervical/vaginal cytologic diagnoses: report of the 1991 Bethesda workshop. Acta Cytol 1992;36: Genant HK, Lucas J, Weiss S, Akin M, Emkey R, McNancy-Flint H, et al. Low-dose esterified estrogen therapy. Effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med 1997;157: Schiff I. The effects of progestins on vasomotor flushes. J Reprod Med 1982;27(Suppl): Redmond GP. Hormones and sexual function. Int J Fertil Wom Med 1999;44: Stone SC, Mickal A, Rye PH. Postmenopausal symptomatology, maturation index, and plasma estrogen levels. Obstet Gynecol 1975;45: FERTILITY & STERILITY 1075

12 APPENDIX David F. Archer, MD The Jones Institute for Reproductive Medicine 601 Colley Avenue Room 142 Norfolk, VA Gloria Bachmann, MD University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Clinical Academic Building 125 Paterson Street New Brunswick, NJ Katherine Bass, MD Co-principal investigator with Trudy Bush, PhD, MHS Johns Hopkins Bayview Medical Center 4940 Eastern Avenue Baltimore, MD Michelle Battistini, MD Penn Health for Women Penn Medicine at Radnor 250 King of Prussia Road Radnor, PA Trudy Bush, PhD, MHS Co-principal investigator with Katherine Bass, MD The Johns Hopkins Women s Research Core 2330 West Joppa Road, Suite 170 Lutherville, MD John Calkins, MD Replaced Julia Ann Chapman, MD, who replaced Valerie Montgomery-Rice, MD University of Kansas Medical Center 3901 Rainbow Boulevard Building 3C Wescoe Kansas City, KS Basic and substudy Bruce R. Carr, MD University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard Room J6-114 Dallas, TX Linda Carson, MD Mayo Memorial Building 420 Delaware Street, SE Box 395 Minneapolis, MN Charles H. Chestnut, III, MD Co-principal investigator with Thomas Olsen, MD Deaconess Research Institute 1500 Poly Drive, Suite 103B Billings, MT Women s HOPE Study Investigators Christine L. Cook, MD Alliant Medical Pavilion Women s Health and Research Center M East Broadway Louisville, KY Bryan D. Cowan, MD University of Mississippi Medical Center 2500 North State Street Jackson, MS Yusoff Dawood, MD University of Texas Medical School at Houston and Reproductive Sciences 6431 Fannin, Suite Houston, TX Maxine Dorin, MD University of New Mexico Hospital ACC Lomas Boulevard NE Albuquerque, NM Daniel Dumesic, MD Mayo Clinic Charleton Building, CH-4A 200 First Street, SW Rochester, MN Esther Eisenberg, MD Vanderbilt University Medical Center Center for Fertility and Reproductive Research Nashville, TN Cynthia Evans, MD Stoneridge Obstetrics and Gynecology 4053 West Dublin Granville Road Dublin, OH Gregory T. Fossum, MD Thomas Jefferson University Hospital Benjamin Franklin House 834 Chestnut Street, Suite 400 Philadelphia, PA Donald L. Fylstra, MD Replaced William J. Butler, MD, who replaced Charles C. Tsai, MD Medical University of South Carolina 171 Ashley Avenue Charleston, SC J. Christopher Gallagher, MD Creighton University Medical School Bone Metabolism Unit 601 North 30th Street, Suite 6718 Omaha, NE Utian et al. Lower HRT doses and vasomotor symptoms Vol. 75, No. 6, June 2001

13 APPENDIX J. Timothy Harrington, MD University of Wisconsin Medical School Jackson Foundation/Physicians Plus 20 South Park Street, Suite 455 Madison, WI Bryan Hecht, MD Aultman Hospital th Street, SW Canton, OH M. Wayne Heine, MD University of Arizona Health Sciences Center 1501 North Campbell Avenue, Room 8330 Tucson, AZ Women s HOPE Study Investigators James Liu, MD Reproductive Medical Research Holmes Hospital Bethesda and Eden Avenue Room 2220, ML0457 Cincinnati, OH Rogerio A. Lobo, MD Columbia-Presbyterian Medical Center 622 West 168th Street Room 1630 East New York, NY Steve N. London, MD Center for Fertility and Reproductive Health 2401 Greenwood Road Shreveport, LA Howard D. Homesley, MD Gynecologic Oncology of Middle Tennessee 2021 Church Street Nashville, TN Ralph Kazer, MD Northwestern University Northwestern Medical Faculty Foundation 680 North Lakeshore Drive, Suite 806 Chicago, IL Bruce Kessel, MD Patients transferred to Brian Walsh, MD Beth Israel Hospital 330 Brookline Avenue, DA 881 Boston, MA Michael Kleerekoper, MD Co-principal investigator with Kamran S. Moghissi, MD Center for Osteoporosis Research Northwestern Highway Southfield, MI Carolyn Kubik, MD Replaced Joel S. Krasnow, MD Magee Women s Hospital 300 Halket Street Clinical Research Center, Room 4330 Pittsburgh, PA Vivian Lewis, MD University of Rochester Medical Center Strong Obstetrics and Gynecology Specialty Care Center 601 Elmwood Avenue Ambulatory Center, 5th Floor Rochester, NY Paul Manganiello, MD Dartmouth-Hitchcock Medical Center One Medical Center Drive Lebanon, NH Nicholas Mezitis, MD St. Luke s Roosevelt Hospital Center Division of Endocrinology, Diabetes, and Nutrition 111 Amsterdam Avenue WH-1006 New York, NY Kamran S. Moghissi, MD Co-principal investigator with Michael Kleerekoper, MD University Center for Women s Medicine Hutzel-Warren Professional Building Ryan Road, Suite 320 Warren, MI Kenneth N. Muse, MD University of Kentucky 800 Rose Street Room C-359 Lexington, KY Thomas Olson, MD Co-principal investigator with Charles H. Chestnut, III, MD Replaced Janet Dietrich, MD Deaconess Research Institute Deaconess Billings Clinic Research Division 1500 Poly Drive, Suite 103B Billings, MT JoAnne Pinkerton, MD The Women s Place Midlife Health 2955 Ivy Road, Suite 104 Charlottesville, VA FERTILITY & STERILITY 1077