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Comparison of two continuous combined estrogen progestogen regimens in postmenopausal women: a randomized trial*†
Menopause FERTILITY AND STERILITY® Copyright
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1996 American Society for Reproductive Medicine
Vol. 66, No.6, December 1996 Printed on acid-free paper in U. S. A.
Comparison of two continuous combined estrogen progestogen regimens in postmenopausal women: a randomized trial*t
Youssef AinMelk, M.D.:!: Departement d'obstetrique et de gynecologie, Faculte de Medecine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
Objective: To compare two different continuous regimens of estrogens: conjugated estrogens or estrone sulfate with medroxyprogesterone acetate (MPA). To evaluate the impact of these two regimens on bleeding pattern, endometrial histology, lipid metabolism, and climacteric symptoms. Design: Prospective, open label, single center, randomized trial. Setting: The menopause clinic, Centre Universitaire de Sante de l'Estrie, Universite de Sherbrooke, Quebec, Canada. Patient(s): Fifty-nine postmenopausal women seeking treatment for symptomatic menopause. Intervention(s): Patients were randomized to two groups. Both groups received 2.5 mg/d MPA plus 0.625 mg/d conjugated estrogens (group A: 31 patients) or 0.625 mg/d estrone sulfate (group B: 28 patients). Lipid metabolism, endometrial biopsies, and endometrial thickness (measured by vaginal ultrasound) were determined at 52 and 104 weeks. Result(s): Six women (10%) withdrew from the study (irregular bleeding and side effects). Fifty-three patients completed the study. Amenorrhea was produced in 92.6% and 96.1% by 52 weeks, and 100% by 104 weeks for groups A and B, respectively. Endometrial atrophy was observed by histology in 92.4% by 52 weeks and in 100% by 104 weeks in both groups. The correlation between an endometrial thickness (vaginal ultrasound) of :=;4 mm and histologic diagnosis of endometrial atrophy was found in 41 of 53 patients. In both groups the climacteric symptoms were improved and the lipid profile showed a beneficial effect. Conclusion(s): No significant difference was found between the two continuous regimens. Amenorrhea and atrophic endometrium occurred in 92.4% after 52 weeks of treatment. A favorable change in lipid metabolism even with the addition ofMPA to estrogens was noted. Irregular bleeding was reduced and the long-term compliance with the continuous regimen was high (90%). Fertil Steril® 1996;66:962-8 Key Words: Menopause, hormonal replacement therapy, continuous combined estrogan-progestogen, Premarin, Ogen
Women can expect to live one third oftheir lives in postmenopause. Estrogens or hormonal replacement therapy (HRT) is prescribed increasingly to relieve
Received October 31, 1995; revised and accepted July 10, 1996.
* Presented at the 41st Annual Meeting of The Canadian Fertility and Andrology Society, Montebello, Quebec, Canada, September 21 to 23, 1995. t Supported in part, by limited financial aid, from Dpjohn Company of Canada, Don Mills, Ontario, Canada. :I: Reprint requests: Youssef AinMelk, M.D., Centre Dniversitaire de Sante de l'Estrie (CDSE), 3001, 12e Avenue North, Sherbrooke, Quebec, Canada, J1H 5N4 (FAX: 819-820-6434). 962
AinMelk Comparison of two HRT regimens
climacteric symptoms (1), vasomotor symptoms, and vaginal atrophy, in addition to preventing osteoporosis and lowering the risk of cardiovascular disease during the postmenopausal period (2). Despite these numerous known benefits, only 15% to 20% of North American women are receiving HRT (3). One of the reasons for the infrequent use ofHRT is the very low compliance that characterizes HRT. It is suggested that only 30% of patients are compliant with HRT. The reasons for this low compliance rate are multiple: withdrawal bleeding, fear of cancer (breast and endometrium), premenstrual syndrome-like symptoms, and other side effects (weight Fertility and Sterility®
gain, breast tenderness, edema, and bloating) (4). Also, estrogen replacement alone increases the risk of endometrial hyperplasia and endometrial cancer (5). By adding a cyclic progestogen to estrogen replacement therapy, the risk of endometrial disease can be reduced significantly (5). Most of the problems of the low compliance with HRT are related to the cyclic addition of the progestin (4). In an effort to increase the compliance and the patient acceptance of HRT, a continuous daily combined estrogen and progestogen replacement regimen was introduced. By using the continuous combined regimen, the withdrawal bleeding is eliminated, endometrial atrophy and amenorrhea is produced, and the premenstrual-like symptoms may be reduced or avoided (6-12). The purpose of this study was to evaluate two oral continuous combined regimens ofHRT, a conjugated estrogen with medroxyprogesterone acetate (MPA), and an estrone sulfate with MPA during a 104-week period. We have compared the effects of these two regimens on bleeding patterns, endometrial histology, endometrial thickness measured by vaginal ultrasound (US), lipid metabolism, blood pressure, and climacteric symptoms over 104 weeks. MATERIALS AND METHODS
In a prospective, open label, randomized study, 59 healthy postmenopausal women aged between 46 and 56 years were recruited from the menopause clinic at the "Centre universitaire de sante de l'Estrie" (Universite de Sherbrooke). This investigation was approved by the Research Ethics Committee. All women had been menopausal for ~ 1 year before the initial screening and had an intact uterus. All were normotensive with vasomotor symptoms but no chronic illness. None of the women had ever used any HRT (estrogen or progestogen) before starting the study. Endometrial biopsy was performed on 48 patients (81.4%) at the initial visit, and only patients with normal histology were included in the study. The biopsies were performed by means of either the pipelle endometrial suction curette (Prodimed, Neuilly-en-Thelle, France) or the Wallach endocell endometrial sampler (Wallach Surgical Devices Inc. Milford, CT). A mammogram, complete blood count, and fasting (12-hour) blood sample for the lipid profile (cholesterol, low-density lipoproteins [LDL] , highdensity lipoproteins [HDL], and triglycerides) were obtained as a baseline. After initial evaluation, the patients were assigned randomly to one of two treatment groups by means of a random number table. Group A (31 patients) received continuous daily doses of 2.5 mg MPA (Provera; Upjohn Company of Canada, Don Vol. 66, No.6, December 1996
Mills, Ontario, Canada) with 0.625 mg/d of conjugated estrogen (Premarin; Wyeth-Ayerst Canada Inc., Montreal, Quebec, Canada). Group B (28 patients) received continuously daily dose of 2.5 mg MPA (Provera) with 0.625 mg/d of estrone sulfate (Ogen; Upjohn Company of Canada). Each patient was followed for 104 weeks. All patients were given diary cards to record daily any vaginal bleeding or spotting, vasomotor symptoms, side effects, or missed tablets. Patients were asked to continue therapy even if vaginal bleeding occurred. Review was done every 13 weeks (diary evaluation, side effects, climacteric symptoms, and bleeding patterns). At 52 and 104 weeks, a physical and pelvic examination was done, the weight and blood pressure were recorded, mammogram, fasting lipid profile, Papanicolaou smear, endometrial biopsy, and vaginal US to evaluate the endometrial thickness were performed. By introducing the probe of the vaginal US machine in the posterior fornix of the vagina, the uterus could be inspected at close range. The sonography was obtained with a 5-0 MHz frequency vaginal probe (Advanced Technology Laboratories [ATLD. Endometrial thickness was measured including both endometrial layers at the thickest part in the longitudinal plane of the uterus. Amenorrhea was defined as the absence of bleeding or spotting in the previous 13 weeks. Irregular bleeding was defined as any bleeding or spotting that occurred at any time during therapy. The results were tabulated and analyzed by unpaired t-tests for demographic data. Analysis ofvariance was used to compare the two treatment regimens, and the Dunnett two-tailed test was used to analyze the results between the baseline and 52- or 104-week values, with significance regarded at the 0.05 level. RESULTS
Fifty-nine postmenopausal women were enrolled in the study. Only data from the 53 patients (90%) who completed the 104 weeks of the trial (27 patients in group A and 26 patients in group B) were evaluated. The drop out from the study was 10%. In group A, four patients dropped out (6.7%): two for irregular bleeding and two others for mastalgia, bloating, and nausea. In group B, two patients dropped out for irregular bleeding (3.3%). The demographics of the study population are shown in Table 1 (prestudy). There were no statistically significant differences between the two groups in any demographic characteristic. The incidence of amenorrhea during weeks 13, 26, 39, 52, and 104 (numbers and percentages of amenAinMelk Comparison of two HRT regimens
963
Table 3 Lipid Profile*
Table 1 Demographic of the Study Population* Group At (n = 27)
Attribute Age (y)
Age at menopause (y) Years since menopause Blood pressure Systolic Diastolic Weight (kg)
* Values are means
Group B:j: (n
=
26)
53.1 ± 1.9 (47 to 56) 50.4 ± 1.7 (45 to 53) 2.8 ± 1.0 (1 to 6)
53.0 ± 2.0 (46 to 56) 50.0 ± 1.5 (46 to 52) 3.0 ± 1.0 (1 to 5)
129.1 ± 6.1 70.9 ± 4.4 62.5 ± 2.3 (58 to 67.2)
128.3 ± 5.9 70.7 ± 5.8 62.1 ± 2.2 (58 to 67)
± SD with ranges in parentheses.
t Group A, 0.625 mg of conjugated estrogens daily + 2.5 mg MPA daily. :j: Group B, 0.625 mg of estrone sulfate daily + 2.5 mg MPA daily.
orrhea) are reported in Table 2. Amenorrhea was produced in 92.6% and 96.1% by 52 weeks and 100% by 104 weeks for groups A and B, respectively. The percentage of amenorrhea tended to increase during the course of treatment in both groups but without any significant differences between the two groups. The amenorrhea was achieved more rapidly in patients who have had their menopause ~3 years before starting the treatment. Irregular bleeding (bleeding or spotting) decreased with time, from 55.5% and 50.0% at 13 weeks to 7.4 and 3.8% at 52 weeks, to complete absence of bleeding at 104 weeks for groups A and B, respectively. Differences between the two groups were not significant. The baseline values for lipid profile were similar and within the normal range, without significant differences between the two groups. All results were the mean changes from the baseline (Table 3). The results were in mg/dL (conversion factor to SI unit, 0.02586 for cholesterol, LDL, and HDL cholesterol, and 0.01129 for the triglycerides). Total cholesterol levels decreased 4% from the baseline (P < 0.05) at 52 weeks in both groups and 6% and 5% (P < 0.05) at 104 weeks in groups A and B, respectively. This was statistically significant, but
Table 2 Patients With Amenorrhea* Time of treatment
Group At Premarin (n = 27)
Group B* Ogen (n = 26)
wk
13 26 39 52 104
12127 (44.4) 16/27 23/27 25/27 27/27
(59.3) (85.2) (92.6) (100)
13/26 17/26 23/26 25/26 26/26
(50.0) (65.3) (88.5) (96.1) (100)
* Values in parentheses are percentages. t Group A, 0.625 mg of conjugated estrogens daily + 2.5 mg MPA daily. * Group B, 0.625 mg of estrone sulfate daily + 2.5 mg MPA daily.
964
AinMelk Comparison of two HRT regimens
Lipid
Baseline
52 weeks
104 weeks
mg/dL
Total cholesterolt 186.2 ± 12.0 Group A* 180.0 ± 14.3 Group BII LDL cholesterolt Group A 110.1 ± 15.6 109.5 ± 12.2 Group B HDL cholesterol 49.8 ± 8.8 Group A Group B 50.6 ± 9.3 Triglycerides** 141.7 ± 38.3 Group A Group B 142.8 ± 48.6
178.9 ± 11.5§ 176.3 ± 10.8§ 172.8 ± 13.4§ 170.6 ± 13.4§ 100.0 ± 14.6§ 98.9 ± 10.7§
96.7 ± 13.7§ 95.9 ± 10.6§
52.7 ± 53.9 ±
9.4~ 9.8~
53.9 ± 54.8 ±
9.5~ 9.9~
156.2 ± 160.1 ±
42.3~ 54.3~
161.2 ± 164.4 ±
44.0~ 55.9~
* Values are means ± SD (change from baseline). t Conversion factor to SI unit, 0.02586. * Group A, 0.625 mg conjugated sulfate daily + 2.5 mg MPA daily. §P < 0.05. ~ Not significant. II Group B, 0.625 mg estrone sulfate daily + 2.5 mg MPA daily. ** Conversion factor to SI unit, 0.01129.
there were no significant differences between the two groups. In comparison with baseline, serum LDL cholesterollevels decreased significantly (P < 0.05) in both groups at 52 and 104 weeks (10% and 12% for group A and 9% to 12% for group B). No significant differences between the two regimens were noted. High-density lipoprotein cholesterol levels increased by 6% and 8% (not significant) in both groups when the baseline was compared with the 52- and 104-week levels. There were no significant differences between the two regimens. When compared with the baseline, total triglyceride levels increased by 10% and 14% (not significant) for group A and by 12% and 15% (not significant) for group B at 52 and 104 weeks. No significant differences were noted between the two groups. Endometrial biopsies were performed after 52 and 104 weeks of continuous therapy in all 53 patients. We defined inactive endometrium as either atrophic or insufficient material for diagnosis. Of the 27 endometrial biopsies performed at 52 weeks in group A, 24 (89.0%) showed inactive endometrium, 1 showed (4.0%) secretory endometrium (minimal), and 2 showed (7.0%) proliferative endometrium. At 104 weeks, all 27 endometrial biopsies (100%) revealed inactive endometrium. Of the 26 endometrial biopsies performed on group B, 25 (96.0%) showed inactive endometrium and 1 showed (4.0%) secretory endometrium at 52 weeks. At 104 weeks, all 26 endometrial biopsies (100%) revealed inactive endometrium. There were no cases of abnormal endometrial histology (hyperplasia or carcinoma) during the 104 Fertility and Sterility®
Table 4 Relationship Between Endometrial Histology and Bleeding Pattern* Endometrial histology (52 wk)
Endometrial histology (104 wk)
Bleeding pattern
Inactive endometriumt
Secretory
Proliferative
Inactive endometrium
Secretory
Proliferative
Amenorrhea Irregular bleeding
48/53* 1153
1/53 1/53
0/53 2/53
53/53 0/53
0/53 0/53
0/53 0/53
* The data for the two regimens have been combined because of similar histologic results.
t Inactive endometrium, atrophic or insufficient material for diagnosis. * Number of patients.
weeks of continuous therapy. Both regimens (conjugated estrogens and estrone sulfate) produced similar histologic results. The data for the two regimens have been combined in Table 4, to show the relationship between endometrial histology and bleeding patterns at 52 and 104 weeks. Detailed information on the endometrium was obtained by the use of transvaginal sonography. Taking into consideration previous studies (13-15) and the fact that the postmenopausal endometrium is most often atrophic, we set the cutoff limit of thickness of the endometrium at :::;;4 mm (as measured by vaginal US) as indicative of atrophic endometrium (end-effect of continuous combined regimens). At 52 weeks, the endometrial thickness was similar in both groups. The results have been combined in Figure 1. Of the 53 patients, 44 had endometrial thickness of :::;;4 mm measured by US. Among these 44, histologic examination had indicated that 22 had insufficient tissue for diagnosis, 19 had atropic endometrium, 2 had minimal secretory endometrium, and 1 had proliferative endometrium. The remaining nine patients had endometrial thickness
> 4 mm. On biopsy, eight had an atrophic endometrium and one had a proliferative endometrium. At 104 weeks, the endometrial thickness by transvaginal sonography was :::;;4 mm in 52 of 53 patients, and in 1 patient it was 5 mm (all biopsies showed inactive endometrium). The mean initial weight of the patients was 62.5 ± 2.3 kg (mean ± SD) and 62.1 ± 2.2 kg and the final weights were 63.4 ± 2.6 kg and 63.6 ± 2.3 kg after 104 weeks under therapy, for groups A and B, respectively, with no statistical differences between the groups or between initial and final weights. Systolic blood pressure increased from the initial value of 129.1 ± 6.1 to 130.5 ± 5.0 at 104 weeks for group A and from 128.3 ± 5.9 to 129.9 ± 5.6 at 104 weeks for group B. This increase was not statistically significant in either group, and no differences were noted between the two treatment groups. Diastolic blood pressure increased from the initial value of 70.9 ± 4.4 to 72.7 ± 3.7 at 104 weeks for group A and from 70.7 ± 5.8 to 71.9 ± 7.1 at 104 weeks for group B. No significant difference occurred in either group or between the two treatment groups. All patients in both groups noted an improvement of their climacteric symptoms and vaginal atrophy. No serious side effects occurred. Two patients stopped the treatment because of excessive mastalgia, bloating, and nausea, and four stopped treatment because of irregular bleeding.
11 10
'=="
Je.
H
i
;; ·c 11 E
=
l
9
•
8
•••
•
7
•
6
•••
5 4 J 1
•••••••• •••••••• ••••• In.uftIc\ent for dlagoosls
••••••• ••••••••
••
•
•••• Atrophic
Minimal
Proliferative
S....etory elfect
Figure 1 Relationship between endometrial thickness in millimeters measured by transvaginal US and the histologic diagnosis of the endometrium at 52 weeks. The data for the two regimens have been combined (similar sonographic results in 53 patients). Vol. 66, No.6, December 1996
DISCUSSION
The current study was designed to establish the efficacy and acceptability of two combined continuous estrogens (conjugated estrogens and estrone sulfate) and progestogen (MPA) regimens and to evaluate the differences between those two regimens after 104 weeks of therapy (24 months). The duration of treatment in other studies on the combined continuous regimen varied between 3 and 36 months (6,12, 16, 17). Most of them were for 12 months, and the majority compared the continuous regimen to a sequential HRT. One of the major reasons invoked by postmenoAinMelk Comparison of two HRT regimens
965
;
. pausal women to discontinue HRT is withdrawal or irregular bleeding. In this study, amenorrhea was achieved by 93.0% and 96.0% of women at 52 weeks in group A and B, respectively, and in 100% at 104 weeks in both groups, without any significant differences between the two groups. These results agree with the findings of others (8-12). Mter a variable interval of irregular bleeding, our data demonstrated a marked decrease in this irregular bleeding in those women who completed 104 weeks oftherapy, from 55.5% and 50.5% at 13 seeks of therapy to 7.4% and 3.8% at 52 weeks, and total amenorrhea at 104 weeks for groups A and B, respectively, without any significant differences between the treatment groups. As others (6, 12) have, we found that amenorrhea was harder to achieve rapidly in perimenopausal women. The problems, the frequency of irregular bleeding and amenorrhea, seemed to be related mainly to the dosage of progestogen (7, 16, 18). Magos et al. (7), by increasing the progestogen dose, in women who experienced bleeding episodes, the percentage of women who became amenorrheic increased to 95.1% after 1 year of continuous therapy. He suggested that the ratio of the two hormones needed to be adjusted individually according to response. Archer et al. (16) and Spaulding (18) observed lower rates of irregular bleeding and higher degrees of amenorrhea, by increasing the dosage of MPA from 2.5 to 5 mg/d. Luciano et al. (11) found no difference in amenorrhea rates with varying doses ofprogestogens. Weinstein et al. (8) noted no difference in bleeding patterns between 2.5 and 5.0 mg. In the present study, the dose of progestogen was not altered (2.5 mg/d) even if irregular bleeding persisted. Our data demonstrate that almost all women became amenorrheic at 52 weeks, at the same frequency or incidence as in other studies in which dpses of progestogens were adjusted during therapy (7, 16, 18). We obtained the same results without increasing the side effects related to the higher doses of progestogen, reducing the beneficial effects of HRT on the lipid profile, or increasing the dropout rate. All the endometrial biopsies showed atrophic en
AinMelk Comparison of two HRT regimens
et al. (20) reported two cases of adenocarcinoma of the endometrium, after long-term therapy with combined continuous regimen in patients with late breakthrough bleeding after a period of established amenorrhea. In the patients with irregular bleeding, the endometrial biopsies showed one atrophic, one secretory, and two proliferative endometrium at 52 weeks of therapy (Table 4). This is in discordance with others. Mattson et al. (10) reported that, irrespective ofuterine bleeding, the endometrium does not show proliferative or secretory changes even after 3 months of continuous combined therapy, using 1 mg of norethisterone daily. Magos et al. (7) reported that biopsy after 6 months of continuous treatment showed complete suppression of endometrial formation even in those patients who had breakthrough bleeding in the previous 3 months. Questions can be raised about the endometrial surveillance during the continuous regimen therapy: What are the indications and the role of endometrial biopsy? When to do it? And to whom? Based on the present study (presence of proliferative endometrium at 52 weeks), the incidence of < 1% of endometrial hyperplasia after 1 year of therapy (19), the two reported cases of endometrial adenocarcinoma (20) after a long-term continuous therapy, and the absence oflong-term studies on the effects on the endometrium, it is suggested that endometrial biopsy is indicated after the first year of continuous therapy if irregular bleeding persists, in cases of bleeding refractory to increased dosage of progestogen, and in patients with irregular bleeding after a period of established amenorrhea while receiving continuous therapy, and when the endometrial thickness is >4 mm, measured by transvaginal sonography. An endometrial biopsy can be done with hysteroscopy to eliminate organic lesions (18). In the current study, an improvement in the lipid profile with beneficial effects has be~n noted. Significant decreases were observed in total cholesterol and LDL cholesterol in both groups at 52 and 104 weeks compared with the baseline. No statistically significant differences were observed between the two treatment groups. Increases in HDL cholesterol and total triglycerides were noted, but these increases did not reach significance between the initial and final measures or between the two groups. All these changes should be beneficial for protection against cardiovascular disease, even if this contribution is only partial (21,22). These results agree with others (8, 9, 11, 18, 23) and support the idea that continuous MPA does not negate the beneficial effects of HRT on lipid metabolism. The climacteric symptoms and the hot flushes diminished significantly in both groups with few side Fertility and Sterility®
>
effects, such as premenstrual-like symptoms. This probably was related to the low doses of progestogen, which do not prevent the beneficial effect of estrogen on the climacteric symptoms. Mean body weight and systolic and diastolic blood pressure did not change significantly during the 104 weeks of the study, in either of the groups, and even between the two groups, as reported by others (8, 9, 12). The compliance and the satisfaction of patients were very high. The dropout rate was 10%. All 53 patients who completed the study accepted continuation of the same regimen beyond 104 weeks. Transvaginal sonography is an acceptable technique and used widely to monitor the endometrium in postmenopausal women (14, 15). One of the purposes of this study was to compare endometrial assessment by sonography with histology obtained by endometrial biopsy and to determine if this technique can replace endometrial biopsy as a diagnostic method. Nasri et al. (14) and others (15, 24) demonstrated that the ability of transvaginal sonography to predict endometrial atrophy or low estrogen stimulation is pertinent. They suggested that an endometrial thickness of ::;;4 mm by sonography is not associated with endometrial abnormalities, and there is a strong correlation between this thickness of ::;;4 mm and atrophic or hypoplastic endometrium. Dorum et al. (13) mentioned that the discrepancy between sonography and histology was estimated at 8% to 9%. She found 3 cases of endometrial malignancy out of 54 patients with an endometrial thickness of <5 mm as measured by US. She concluded that the endovaginal US evaluation of endometrial thickness was not sensitive enough to detect cancer of the endometrium and could not replace histologic evaluation of endometrial tissue. In the present study, we found that histology demonstrated an atrophic endometrium in 41 of 44 patients in whom the endometrial thickness was ::;;4 mm and in 8 of 9 patients in whom the endometrial thickness was >4 mm (5 to 9 mm). Even with this discrepancy between sonography and histology, we suggest the use of transvaginal sonography to measure endometrial thickness as an indicator of hormonal effect on the endometrium. If the endometrial thickness is ::;;4 mm, there is no need for endometrial sampling. If this measurement is 2':5 mm, then an endometrial biopsy is suggested, as in the nine patients mentioned above. Using the HDL levels for power analysis, the 104week change in HDL levels within each group averages 4.1 : :': : 0.7 mg/dL for group A and 4.2 : :': : 0.6 mg/ dL for group B. An increase of 1 mg/dL in HDL levels in considered clinically relevant and was associated with a reduction in heart disease risk in women Vol. 66, No.6, December 1996
(Barrett-Connor) (25), and a power analysis for paired continuous data (Lachin) was computed, using the Barrett-Connor value for the smallest group size (26 in group B versus 27 in group A). The computed value (1-,8) is 0.9967. This study was strengthened by the fact that it is a prospective, randomized trial that extended over a 104-week period, with a positive impact on lipid profile and with a very low dropout rate. In conclusion, no significant differences were noted between the two therapeutic regimens (conjugated estrogens and estrone sulfate) concerning the effectiveness in relieving vasomotor symptoms, the incidence of irregular bleeding and amenorrhea, endometrial histology (atrophy), endometrial thickness by US, the favorable changes in lipid profile, and the effect on weight and blood pressure. Both combined continuous regimens are appropriate options for postmenopausal women by reducing the hormonal side effects, resolving the vasomotor and other climacteric symptoms, reducing the uterine bleeding, and increasing amenorrhea by an atrophic endometrium, which is protected from development of a neoplastic process. Favorable changes and beneficial effects on the lipid profile were produced. Long-term compliance with HRT in postmenopausal women is feasible once uterine bleeding is eliminated (dropout 10% only) with a continuous combined estrogen and progestogen regimen. Acknowledgments. We thank these companies for their gifts of the following medications: Provera (Upjohn Company of Canada, Don Mills, Ontario, Canada; Premarin (Wyeth-Ayerst Canada Inc., Montreal, Quebec, Canada); and Ogen (Upjohn Company of Canada). We also thank Raymond Gagner, M.D., from the Department of Obstetrics and Gynecology, University ofSherbrooke, for his advice and for reviewing this manuscript. REFERENCES 1. Ferguson KJ, Hoegh C, Johnson S. Estrogjln replacement therapy: a survey of women's knowledge and attitudes. Arch Intern Med 1989; 149:133-6. 2. Grady D, Rubin SM, Pettiti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117:101637. 3. Cauley JA, Cummings SR, Black DM, Marcioli SR, Seeley DG. Prevalence and determinants of estrogen replacement therapy in elderly women. Am J Obstet Gynecol 1990;163: 1338-44. 4. Hahn RG. Compliance considerations with estrogen replacement: withdrawal bleeding and other factors. Am J Obstet Gynecol 1989; 161:1854-8. 5. Harlap S. The benefits and risks of hormone replacement therapy: an epidemiologic overview. Am J Obstet Gynecol 1992; 166:1986-92. 6. Staland B. Continuous treatment with a combination of estrogen and gestagen-a way of avoiding endometrial stimulation. Acta Obstet Gynecol Scand Suppl 1985; 130:29-35.
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7. Magos AL, Brincat M, Studd JWW, Wardle P, Schlesinger P, O'Dowd O. Amenorrhea and endometrial atrophy with continuous oral estrogen and progesterone therapy in postmenopausal women. Obstet Gynecol 1985;65:496-9. 8. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162:133-42. 9. Marslew U, Riis BJ, Christiansen C. Bleeding patterns during continuous combined estrogen progestogen therapy. Am J Obstet Gynecol 1991; 164:1163-8. 10. Mattson La, Callberg G, Samsioe G. Evaluation of a continuous estrogen-progestogen regimen for climacteric patients. Maturitas 1982;4:95-102. 11. Luciano AA, De Souza MJ, Roy MP, Schoenfeld MJ, Nulsen JC, Halvorson CV. Evaluation of low-dose estrogen and progestin therapy in postmenopausal women. A double-blind, prospective study of sequential versus continuous therapy. J Reprod Med 1993;38:207-14. 12. MacLennan AH, MacLennan A, Wenzel S, Chambers HM, Eckert K. Continuous low-dose estrogen and progestogen hormone replacement therapy: a randomized trial. Med J Aust 1993; 159:102-6. 13. Dorum A, Kristensen Gb, Langebrekke A, Somes T, Skarr O. Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding. Acta Obstet Gynecol Scand 1993;72:116-9. 14. Nasri MN, Shepherd JH, Setchell ME, Lowe DG, Chard T. The role of vaginal scan in measurement of endometrial thickness in postmenopausal women. Br J Obstet Gynaecol 1991; 98:470-5. 15. Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong S-J. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol1991;78:195-9. 16. Archer DF, Pickar JH, Bottiglioni F. For the menopause
968
AinMelk Comparison of two HRT regimens
17. 18.
19.
20.
21.
22.
23.
24.
25.
study group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83:686-92. The postmenopausal estrogen/progestin intervention trial. JAMA 1995;273:199-208. Spaulding CB. Endometrial ablation for refractory postmenopausal bleeding with continuous hormone replacement therapy. Fertil Steril 1994;62:1181-5. Woodruff DJ, Pickar JH. For the menopause study group. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994; 170:1213-23. Leather AT, Savvas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet GynecoI1991;78:1008-10. Bush TL. Non-contraceptive estrogen use and risk of cardiovascular disease: an overview and critique of the literature. In: Korenman SG, editor. The menopause: biological and clinical consequences of ovarian failure; evolution and management. Norwell (MA): Serono Symposia, 1990:211-24. March MS, Whithead MI. The practicalities of hormone replacement. Baillieres Clin Endocrinol Metab 1993;7:183202. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonon E. For the menopause study group metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 1994;84:987-95. Castello-Branco C, Puerto B, Duran M, Gratacos E, Torne A, Fortuny A, et al. Transvaginal sonography of the endometrium in postmenopausal women: monitoring the effect of hormone replacement therapy. Maturitas 1994; 19:59-65. Barrett-Connor E. Heart disease in women. Fertil Steril 1994;2 Suppl 62:127S-32S.
Fertility and Sterility®
«-)
1996 American Society for Reproductive Medicine
Vol. 66, No.6, December 1996 Printed on acid-free paper in U. S. A.
Comparison of two continuous combined estrogen progestogen regimens in postmenopausal women: a randomized trial*t
Youssef AinMelk, M.D.:!: Departement d'obstetrique et de gynecologie, Faculte de Medecine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
Objective: To compare two different continuous regimens of estrogens: conjugated estrogens or estrone sulfate with medroxyprogesterone acetate (MPA). To evaluate the impact of these two regimens on bleeding pattern, endometrial histology, lipid metabolism, and climacteric symptoms. Design: Prospective, open label, single center, randomized trial. Setting: The menopause clinic, Centre Universitaire de Sante de l'Estrie, Universite de Sherbrooke, Quebec, Canada. Patient(s): Fifty-nine postmenopausal women seeking treatment for symptomatic menopause. Intervention(s): Patients were randomized to two groups. Both groups received 2.5 mg/d MPA plus 0.625 mg/d conjugated estrogens (group A: 31 patients) or 0.625 mg/d estrone sulfate (group B: 28 patients). Lipid metabolism, endometrial biopsies, and endometrial thickness (measured by vaginal ultrasound) were determined at 52 and 104 weeks. Result(s): Six women (10%) withdrew from the study (irregular bleeding and side effects). Fifty-three patients completed the study. Amenorrhea was produced in 92.6% and 96.1% by 52 weeks, and 100% by 104 weeks for groups A and B, respectively. Endometrial atrophy was observed by histology in 92.4% by 52 weeks and in 100% by 104 weeks in both groups. The correlation between an endometrial thickness (vaginal ultrasound) of :=;4 mm and histologic diagnosis of endometrial atrophy was found in 41 of 53 patients. In both groups the climacteric symptoms were improved and the lipid profile showed a beneficial effect. Conclusion(s): No significant difference was found between the two continuous regimens. Amenorrhea and atrophic endometrium occurred in 92.4% after 52 weeks of treatment. A favorable change in lipid metabolism even with the addition ofMPA to estrogens was noted. Irregular bleeding was reduced and the long-term compliance with the continuous regimen was high (90%). Fertil Steril® 1996;66:962-8 Key Words: Menopause, hormonal replacement therapy, continuous combined estrogan-progestogen, Premarin, Ogen
Women can expect to live one third oftheir lives in postmenopause. Estrogens or hormonal replacement therapy (HRT) is prescribed increasingly to relieve
Received October 31, 1995; revised and accepted July 10, 1996.
* Presented at the 41st Annual Meeting of The Canadian Fertility and Andrology Society, Montebello, Quebec, Canada, September 21 to 23, 1995. t Supported in part, by limited financial aid, from Dpjohn Company of Canada, Don Mills, Ontario, Canada. :I: Reprint requests: Youssef AinMelk, M.D., Centre Dniversitaire de Sante de l'Estrie (CDSE), 3001, 12e Avenue North, Sherbrooke, Quebec, Canada, J1H 5N4 (FAX: 819-820-6434). 962
AinMelk Comparison of two HRT regimens
climacteric symptoms (1), vasomotor symptoms, and vaginal atrophy, in addition to preventing osteoporosis and lowering the risk of cardiovascular disease during the postmenopausal period (2). Despite these numerous known benefits, only 15% to 20% of North American women are receiving HRT (3). One of the reasons for the infrequent use ofHRT is the very low compliance that characterizes HRT. It is suggested that only 30% of patients are compliant with HRT. The reasons for this low compliance rate are multiple: withdrawal bleeding, fear of cancer (breast and endometrium), premenstrual syndrome-like symptoms, and other side effects (weight Fertility and Sterility®
gain, breast tenderness, edema, and bloating) (4). Also, estrogen replacement alone increases the risk of endometrial hyperplasia and endometrial cancer (5). By adding a cyclic progestogen to estrogen replacement therapy, the risk of endometrial disease can be reduced significantly (5). Most of the problems of the low compliance with HRT are related to the cyclic addition of the progestin (4). In an effort to increase the compliance and the patient acceptance of HRT, a continuous daily combined estrogen and progestogen replacement regimen was introduced. By using the continuous combined regimen, the withdrawal bleeding is eliminated, endometrial atrophy and amenorrhea is produced, and the premenstrual-like symptoms may be reduced or avoided (6-12). The purpose of this study was to evaluate two oral continuous combined regimens ofHRT, a conjugated estrogen with medroxyprogesterone acetate (MPA), and an estrone sulfate with MPA during a 104-week period. We have compared the effects of these two regimens on bleeding patterns, endometrial histology, endometrial thickness measured by vaginal ultrasound (US), lipid metabolism, blood pressure, and climacteric symptoms over 104 weeks. MATERIALS AND METHODS
In a prospective, open label, randomized study, 59 healthy postmenopausal women aged between 46 and 56 years were recruited from the menopause clinic at the "Centre universitaire de sante de l'Estrie" (Universite de Sherbrooke). This investigation was approved by the Research Ethics Committee. All women had been menopausal for ~ 1 year before the initial screening and had an intact uterus. All were normotensive with vasomotor symptoms but no chronic illness. None of the women had ever used any HRT (estrogen or progestogen) before starting the study. Endometrial biopsy was performed on 48 patients (81.4%) at the initial visit, and only patients with normal histology were included in the study. The biopsies were performed by means of either the pipelle endometrial suction curette (Prodimed, Neuilly-en-Thelle, France) or the Wallach endocell endometrial sampler (Wallach Surgical Devices Inc. Milford, CT). A mammogram, complete blood count, and fasting (12-hour) blood sample for the lipid profile (cholesterol, low-density lipoproteins [LDL] , highdensity lipoproteins [HDL], and triglycerides) were obtained as a baseline. After initial evaluation, the patients were assigned randomly to one of two treatment groups by means of a random number table. Group A (31 patients) received continuous daily doses of 2.5 mg MPA (Provera; Upjohn Company of Canada, Don Vol. 66, No.6, December 1996
Mills, Ontario, Canada) with 0.625 mg/d of conjugated estrogen (Premarin; Wyeth-Ayerst Canada Inc., Montreal, Quebec, Canada). Group B (28 patients) received continuously daily dose of 2.5 mg MPA (Provera) with 0.625 mg/d of estrone sulfate (Ogen; Upjohn Company of Canada). Each patient was followed for 104 weeks. All patients were given diary cards to record daily any vaginal bleeding or spotting, vasomotor symptoms, side effects, or missed tablets. Patients were asked to continue therapy even if vaginal bleeding occurred. Review was done every 13 weeks (diary evaluation, side effects, climacteric symptoms, and bleeding patterns). At 52 and 104 weeks, a physical and pelvic examination was done, the weight and blood pressure were recorded, mammogram, fasting lipid profile, Papanicolaou smear, endometrial biopsy, and vaginal US to evaluate the endometrial thickness were performed. By introducing the probe of the vaginal US machine in the posterior fornix of the vagina, the uterus could be inspected at close range. The sonography was obtained with a 5-0 MHz frequency vaginal probe (Advanced Technology Laboratories [ATLD. Endometrial thickness was measured including both endometrial layers at the thickest part in the longitudinal plane of the uterus. Amenorrhea was defined as the absence of bleeding or spotting in the previous 13 weeks. Irregular bleeding was defined as any bleeding or spotting that occurred at any time during therapy. The results were tabulated and analyzed by unpaired t-tests for demographic data. Analysis ofvariance was used to compare the two treatment regimens, and the Dunnett two-tailed test was used to analyze the results between the baseline and 52- or 104-week values, with significance regarded at the 0.05 level. RESULTS
Fifty-nine postmenopausal women were enrolled in the study. Only data from the 53 patients (90%) who completed the 104 weeks of the trial (27 patients in group A and 26 patients in group B) were evaluated. The drop out from the study was 10%. In group A, four patients dropped out (6.7%): two for irregular bleeding and two others for mastalgia, bloating, and nausea. In group B, two patients dropped out for irregular bleeding (3.3%). The demographics of the study population are shown in Table 1 (prestudy). There were no statistically significant differences between the two groups in any demographic characteristic. The incidence of amenorrhea during weeks 13, 26, 39, 52, and 104 (numbers and percentages of amenAinMelk Comparison of two HRT regimens
963
Table 3 Lipid Profile*
Table 1 Demographic of the Study Population* Group At (n = 27)
Attribute Age (y)
Age at menopause (y) Years since menopause Blood pressure Systolic Diastolic Weight (kg)
* Values are means
Group B:j: (n
=
26)
53.1 ± 1.9 (47 to 56) 50.4 ± 1.7 (45 to 53) 2.8 ± 1.0 (1 to 6)
53.0 ± 2.0 (46 to 56) 50.0 ± 1.5 (46 to 52) 3.0 ± 1.0 (1 to 5)
129.1 ± 6.1 70.9 ± 4.4 62.5 ± 2.3 (58 to 67.2)
128.3 ± 5.9 70.7 ± 5.8 62.1 ± 2.2 (58 to 67)
± SD with ranges in parentheses.
t Group A, 0.625 mg of conjugated estrogens daily + 2.5 mg MPA daily. :j: Group B, 0.625 mg of estrone sulfate daily + 2.5 mg MPA daily.
orrhea) are reported in Table 2. Amenorrhea was produced in 92.6% and 96.1% by 52 weeks and 100% by 104 weeks for groups A and B, respectively. The percentage of amenorrhea tended to increase during the course of treatment in both groups but without any significant differences between the two groups. The amenorrhea was achieved more rapidly in patients who have had their menopause ~3 years before starting the treatment. Irregular bleeding (bleeding or spotting) decreased with time, from 55.5% and 50.0% at 13 weeks to 7.4 and 3.8% at 52 weeks, to complete absence of bleeding at 104 weeks for groups A and B, respectively. Differences between the two groups were not significant. The baseline values for lipid profile were similar and within the normal range, without significant differences between the two groups. All results were the mean changes from the baseline (Table 3). The results were in mg/dL (conversion factor to SI unit, 0.02586 for cholesterol, LDL, and HDL cholesterol, and 0.01129 for the triglycerides). Total cholesterol levels decreased 4% from the baseline (P < 0.05) at 52 weeks in both groups and 6% and 5% (P < 0.05) at 104 weeks in groups A and B, respectively. This was statistically significant, but
Table 2 Patients With Amenorrhea* Time of treatment
Group At Premarin (n = 27)
Group B* Ogen (n = 26)
wk
13 26 39 52 104
12127 (44.4) 16/27 23/27 25/27 27/27
(59.3) (85.2) (92.6) (100)
13/26 17/26 23/26 25/26 26/26
(50.0) (65.3) (88.5) (96.1) (100)
* Values in parentheses are percentages. t Group A, 0.625 mg of conjugated estrogens daily + 2.5 mg MPA daily. * Group B, 0.625 mg of estrone sulfate daily + 2.5 mg MPA daily.
964
AinMelk Comparison of two HRT regimens
Lipid
Baseline
52 weeks
104 weeks
mg/dL
Total cholesterolt 186.2 ± 12.0 Group A* 180.0 ± 14.3 Group BII LDL cholesterolt Group A 110.1 ± 15.6 109.5 ± 12.2 Group B HDL cholesterol 49.8 ± 8.8 Group A Group B 50.6 ± 9.3 Triglycerides** 141.7 ± 38.3 Group A Group B 142.8 ± 48.6
178.9 ± 11.5§ 176.3 ± 10.8§ 172.8 ± 13.4§ 170.6 ± 13.4§ 100.0 ± 14.6§ 98.9 ± 10.7§
96.7 ± 13.7§ 95.9 ± 10.6§
52.7 ± 53.9 ±
9.4~ 9.8~
53.9 ± 54.8 ±
9.5~ 9.9~
156.2 ± 160.1 ±
42.3~ 54.3~
161.2 ± 164.4 ±
44.0~ 55.9~
* Values are means ± SD (change from baseline). t Conversion factor to SI unit, 0.02586. * Group A, 0.625 mg conjugated sulfate daily + 2.5 mg MPA daily. §P < 0.05. ~ Not significant. II Group B, 0.625 mg estrone sulfate daily + 2.5 mg MPA daily. ** Conversion factor to SI unit, 0.01129.
there were no significant differences between the two groups. In comparison with baseline, serum LDL cholesterollevels decreased significantly (P < 0.05) in both groups at 52 and 104 weeks (10% and 12% for group A and 9% to 12% for group B). No significant differences between the two regimens were noted. High-density lipoprotein cholesterol levels increased by 6% and 8% (not significant) in both groups when the baseline was compared with the 52- and 104-week levels. There were no significant differences between the two regimens. When compared with the baseline, total triglyceride levels increased by 10% and 14% (not significant) for group A and by 12% and 15% (not significant) for group B at 52 and 104 weeks. No significant differences were noted between the two groups. Endometrial biopsies were performed after 52 and 104 weeks of continuous therapy in all 53 patients. We defined inactive endometrium as either atrophic or insufficient material for diagnosis. Of the 27 endometrial biopsies performed at 52 weeks in group A, 24 (89.0%) showed inactive endometrium, 1 showed (4.0%) secretory endometrium (minimal), and 2 showed (7.0%) proliferative endometrium. At 104 weeks, all 27 endometrial biopsies (100%) revealed inactive endometrium. Of the 26 endometrial biopsies performed on group B, 25 (96.0%) showed inactive endometrium and 1 showed (4.0%) secretory endometrium at 52 weeks. At 104 weeks, all 26 endometrial biopsies (100%) revealed inactive endometrium. There were no cases of abnormal endometrial histology (hyperplasia or carcinoma) during the 104 Fertility and Sterility®
Table 4 Relationship Between Endometrial Histology and Bleeding Pattern* Endometrial histology (52 wk)
Endometrial histology (104 wk)
Bleeding pattern
Inactive endometriumt
Secretory
Proliferative
Inactive endometrium
Secretory
Proliferative
Amenorrhea Irregular bleeding
48/53* 1153
1/53 1/53
0/53 2/53
53/53 0/53
0/53 0/53
0/53 0/53
* The data for the two regimens have been combined because of similar histologic results.
t Inactive endometrium, atrophic or insufficient material for diagnosis. * Number of patients.
weeks of continuous therapy. Both regimens (conjugated estrogens and estrone sulfate) produced similar histologic results. The data for the two regimens have been combined in Table 4, to show the relationship between endometrial histology and bleeding patterns at 52 and 104 weeks. Detailed information on the endometrium was obtained by the use of transvaginal sonography. Taking into consideration previous studies (13-15) and the fact that the postmenopausal endometrium is most often atrophic, we set the cutoff limit of thickness of the endometrium at :::;;4 mm (as measured by vaginal US) as indicative of atrophic endometrium (end-effect of continuous combined regimens). At 52 weeks, the endometrial thickness was similar in both groups. The results have been combined in Figure 1. Of the 53 patients, 44 had endometrial thickness of :::;;4 mm measured by US. Among these 44, histologic examination had indicated that 22 had insufficient tissue for diagnosis, 19 had atropic endometrium, 2 had minimal secretory endometrium, and 1 had proliferative endometrium. The remaining nine patients had endometrial thickness
> 4 mm. On biopsy, eight had an atrophic endometrium and one had a proliferative endometrium. At 104 weeks, the endometrial thickness by transvaginal sonography was :::;;4 mm in 52 of 53 patients, and in 1 patient it was 5 mm (all biopsies showed inactive endometrium). The mean initial weight of the patients was 62.5 ± 2.3 kg (mean ± SD) and 62.1 ± 2.2 kg and the final weights were 63.4 ± 2.6 kg and 63.6 ± 2.3 kg after 104 weeks under therapy, for groups A and B, respectively, with no statistical differences between the groups or between initial and final weights. Systolic blood pressure increased from the initial value of 129.1 ± 6.1 to 130.5 ± 5.0 at 104 weeks for group A and from 128.3 ± 5.9 to 129.9 ± 5.6 at 104 weeks for group B. This increase was not statistically significant in either group, and no differences were noted between the two treatment groups. Diastolic blood pressure increased from the initial value of 70.9 ± 4.4 to 72.7 ± 3.7 at 104 weeks for group A and from 70.7 ± 5.8 to 71.9 ± 7.1 at 104 weeks for group B. No significant difference occurred in either group or between the two treatment groups. All patients in both groups noted an improvement of their climacteric symptoms and vaginal atrophy. No serious side effects occurred. Two patients stopped the treatment because of excessive mastalgia, bloating, and nausea, and four stopped treatment because of irregular bleeding.
11 10
'=="
Je.
H
i
;; ·c 11 E
=
l
9
•
8
•••
•
7
•
6
•••
5 4 J 1
•••••••• •••••••• ••••• In.uftIc\ent for dlagoosls
••••••• ••••••••
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•
•••• Atrophic
Minimal
Proliferative
S....etory elfect
Figure 1 Relationship between endometrial thickness in millimeters measured by transvaginal US and the histologic diagnosis of the endometrium at 52 weeks. The data for the two regimens have been combined (similar sonographic results in 53 patients). Vol. 66, No.6, December 1996
DISCUSSION
The current study was designed to establish the efficacy and acceptability of two combined continuous estrogens (conjugated estrogens and estrone sulfate) and progestogen (MPA) regimens and to evaluate the differences between those two regimens after 104 weeks of therapy (24 months). The duration of treatment in other studies on the combined continuous regimen varied between 3 and 36 months (6,12, 16, 17). Most of them were for 12 months, and the majority compared the continuous regimen to a sequential HRT. One of the major reasons invoked by postmenoAinMelk Comparison of two HRT regimens
965
;
. pausal women to discontinue HRT is withdrawal or irregular bleeding. In this study, amenorrhea was achieved by 93.0% and 96.0% of women at 52 weeks in group A and B, respectively, and in 100% at 104 weeks in both groups, without any significant differences between the two groups. These results agree with the findings of others (8-12). Mter a variable interval of irregular bleeding, our data demonstrated a marked decrease in this irregular bleeding in those women who completed 104 weeks oftherapy, from 55.5% and 50.5% at 13 seeks of therapy to 7.4% and 3.8% at 52 weeks, and total amenorrhea at 104 weeks for groups A and B, respectively, without any significant differences between the treatment groups. As others (6, 12) have, we found that amenorrhea was harder to achieve rapidly in perimenopausal women. The problems, the frequency of irregular bleeding and amenorrhea, seemed to be related mainly to the dosage of progestogen (7, 16, 18). Magos et al. (7), by increasing the progestogen dose, in women who experienced bleeding episodes, the percentage of women who became amenorrheic increased to 95.1% after 1 year of continuous therapy. He suggested that the ratio of the two hormones needed to be adjusted individually according to response. Archer et al. (16) and Spaulding (18) observed lower rates of irregular bleeding and higher degrees of amenorrhea, by increasing the dosage of MPA from 2.5 to 5 mg/d. Luciano et al. (11) found no difference in amenorrhea rates with varying doses ofprogestogens. Weinstein et al. (8) noted no difference in bleeding patterns between 2.5 and 5.0 mg. In the present study, the dose of progestogen was not altered (2.5 mg/d) even if irregular bleeding persisted. Our data demonstrate that almost all women became amenorrheic at 52 weeks, at the same frequency or incidence as in other studies in which dpses of progestogens were adjusted during therapy (7, 16, 18). We obtained the same results without increasing the side effects related to the higher doses of progestogen, reducing the beneficial effects of HRT on the lipid profile, or increasing the dropout rate. All the endometrial biopsies showed atrophic en
AinMelk Comparison of two HRT regimens
et al. (20) reported two cases of adenocarcinoma of the endometrium, after long-term therapy with combined continuous regimen in patients with late breakthrough bleeding after a period of established amenorrhea. In the patients with irregular bleeding, the endometrial biopsies showed one atrophic, one secretory, and two proliferative endometrium at 52 weeks of therapy (Table 4). This is in discordance with others. Mattson et al. (10) reported that, irrespective ofuterine bleeding, the endometrium does not show proliferative or secretory changes even after 3 months of continuous combined therapy, using 1 mg of norethisterone daily. Magos et al. (7) reported that biopsy after 6 months of continuous treatment showed complete suppression of endometrial formation even in those patients who had breakthrough bleeding in the previous 3 months. Questions can be raised about the endometrial surveillance during the continuous regimen therapy: What are the indications and the role of endometrial biopsy? When to do it? And to whom? Based on the present study (presence of proliferative endometrium at 52 weeks), the incidence of < 1% of endometrial hyperplasia after 1 year of therapy (19), the two reported cases of endometrial adenocarcinoma (20) after a long-term continuous therapy, and the absence oflong-term studies on the effects on the endometrium, it is suggested that endometrial biopsy is indicated after the first year of continuous therapy if irregular bleeding persists, in cases of bleeding refractory to increased dosage of progestogen, and in patients with irregular bleeding after a period of established amenorrhea while receiving continuous therapy, and when the endometrial thickness is >4 mm, measured by transvaginal sonography. An endometrial biopsy can be done with hysteroscopy to eliminate organic lesions (18). In the current study, an improvement in the lipid profile with beneficial effects has be~n noted. Significant decreases were observed in total cholesterol and LDL cholesterol in both groups at 52 and 104 weeks compared with the baseline. No statistically significant differences were observed between the two treatment groups. Increases in HDL cholesterol and total triglycerides were noted, but these increases did not reach significance between the initial and final measures or between the two groups. All these changes should be beneficial for protection against cardiovascular disease, even if this contribution is only partial (21,22). These results agree with others (8, 9, 11, 18, 23) and support the idea that continuous MPA does not negate the beneficial effects of HRT on lipid metabolism. The climacteric symptoms and the hot flushes diminished significantly in both groups with few side Fertility and Sterility®
>
effects, such as premenstrual-like symptoms. This probably was related to the low doses of progestogen, which do not prevent the beneficial effect of estrogen on the climacteric symptoms. Mean body weight and systolic and diastolic blood pressure did not change significantly during the 104 weeks of the study, in either of the groups, and even between the two groups, as reported by others (8, 9, 12). The compliance and the satisfaction of patients were very high. The dropout rate was 10%. All 53 patients who completed the study accepted continuation of the same regimen beyond 104 weeks. Transvaginal sonography is an acceptable technique and used widely to monitor the endometrium in postmenopausal women (14, 15). One of the purposes of this study was to compare endometrial assessment by sonography with histology obtained by endometrial biopsy and to determine if this technique can replace endometrial biopsy as a diagnostic method. Nasri et al. (14) and others (15, 24) demonstrated that the ability of transvaginal sonography to predict endometrial atrophy or low estrogen stimulation is pertinent. They suggested that an endometrial thickness of ::;;4 mm by sonography is not associated with endometrial abnormalities, and there is a strong correlation between this thickness of ::;;4 mm and atrophic or hypoplastic endometrium. Dorum et al. (13) mentioned that the discrepancy between sonography and histology was estimated at 8% to 9%. She found 3 cases of endometrial malignancy out of 54 patients with an endometrial thickness of <5 mm as measured by US. She concluded that the endovaginal US evaluation of endometrial thickness was not sensitive enough to detect cancer of the endometrium and could not replace histologic evaluation of endometrial tissue. In the present study, we found that histology demonstrated an atrophic endometrium in 41 of 44 patients in whom the endometrial thickness was ::;;4 mm and in 8 of 9 patients in whom the endometrial thickness was >4 mm (5 to 9 mm). Even with this discrepancy between sonography and histology, we suggest the use of transvaginal sonography to measure endometrial thickness as an indicator of hormonal effect on the endometrium. If the endometrial thickness is ::;;4 mm, there is no need for endometrial sampling. If this measurement is 2':5 mm, then an endometrial biopsy is suggested, as in the nine patients mentioned above. Using the HDL levels for power analysis, the 104week change in HDL levels within each group averages 4.1 : :': : 0.7 mg/dL for group A and 4.2 : :': : 0.6 mg/ dL for group B. An increase of 1 mg/dL in HDL levels in considered clinically relevant and was associated with a reduction in heart disease risk in women Vol. 66, No.6, December 1996
(Barrett-Connor) (25), and a power analysis for paired continuous data (Lachin) was computed, using the Barrett-Connor value for the smallest group size (26 in group B versus 27 in group A). The computed value (1-,8) is 0.9967. This study was strengthened by the fact that it is a prospective, randomized trial that extended over a 104-week period, with a positive impact on lipid profile and with a very low dropout rate. In conclusion, no significant differences were noted between the two therapeutic regimens (conjugated estrogens and estrone sulfate) concerning the effectiveness in relieving vasomotor symptoms, the incidence of irregular bleeding and amenorrhea, endometrial histology (atrophy), endometrial thickness by US, the favorable changes in lipid profile, and the effect on weight and blood pressure. Both combined continuous regimens are appropriate options for postmenopausal women by reducing the hormonal side effects, resolving the vasomotor and other climacteric symptoms, reducing the uterine bleeding, and increasing amenorrhea by an atrophic endometrium, which is protected from development of a neoplastic process. Favorable changes and beneficial effects on the lipid profile were produced. Long-term compliance with HRT in postmenopausal women is feasible once uterine bleeding is eliminated (dropout 10% only) with a continuous combined estrogen and progestogen regimen. Acknowledgments. We thank these companies for their gifts of the following medications: Provera (Upjohn Company of Canada, Don Mills, Ontario, Canada; Premarin (Wyeth-Ayerst Canada Inc., Montreal, Quebec, Canada); and Ogen (Upjohn Company of Canada). We also thank Raymond Gagner, M.D., from the Department of Obstetrics and Gynecology, University ofSherbrooke, for his advice and for reviewing this manuscript. REFERENCES 1. Ferguson KJ, Hoegh C, Johnson S. Estrogjln replacement therapy: a survey of women's knowledge and attitudes. Arch Intern Med 1989; 149:133-6. 2. Grady D, Rubin SM, Pettiti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117:101637. 3. Cauley JA, Cummings SR, Black DM, Marcioli SR, Seeley DG. Prevalence and determinants of estrogen replacement therapy in elderly women. Am J Obstet Gynecol 1990;163: 1338-44. 4. Hahn RG. Compliance considerations with estrogen replacement: withdrawal bleeding and other factors. Am J Obstet Gynecol 1989; 161:1854-8. 5. Harlap S. The benefits and risks of hormone replacement therapy: an epidemiologic overview. Am J Obstet Gynecol 1992; 166:1986-92. 6. Staland B. Continuous treatment with a combination of estrogen and gestagen-a way of avoiding endometrial stimulation. Acta Obstet Gynecol Scand Suppl 1985; 130:29-35.
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7. Magos AL, Brincat M, Studd JWW, Wardle P, Schlesinger P, O'Dowd O. Amenorrhea and endometrial atrophy with continuous oral estrogen and progesterone therapy in postmenopausal women. Obstet Gynecol 1985;65:496-9. 8. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162:133-42. 9. Marslew U, Riis BJ, Christiansen C. Bleeding patterns during continuous combined estrogen progestogen therapy. Am J Obstet Gynecol 1991; 164:1163-8. 10. Mattson La, Callberg G, Samsioe G. Evaluation of a continuous estrogen-progestogen regimen for climacteric patients. Maturitas 1982;4:95-102. 11. Luciano AA, De Souza MJ, Roy MP, Schoenfeld MJ, Nulsen JC, Halvorson CV. Evaluation of low-dose estrogen and progestin therapy in postmenopausal women. A double-blind, prospective study of sequential versus continuous therapy. J Reprod Med 1993;38:207-14. 12. MacLennan AH, MacLennan A, Wenzel S, Chambers HM, Eckert K. Continuous low-dose estrogen and progestogen hormone replacement therapy: a randomized trial. Med J Aust 1993; 159:102-6. 13. Dorum A, Kristensen Gb, Langebrekke A, Somes T, Skarr O. Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding. Acta Obstet Gynecol Scand 1993;72:116-9. 14. Nasri MN, Shepherd JH, Setchell ME, Lowe DG, Chard T. The role of vaginal scan in measurement of endometrial thickness in postmenopausal women. Br J Obstet Gynaecol 1991; 98:470-5. 15. Varner RE, Sparks JM, Cameron CD, Roberts LL, Soong S-J. Transvaginal sonography of the endometrium in postmenopausal women. Obstet Gynecol1991;78:195-9. 16. Archer DF, Pickar JH, Bottiglioni F. For the menopause
968
AinMelk Comparison of two HRT regimens
17. 18.
19.
20.
21.
22.
23.
24.
25.
study group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994; 83:686-92. The postmenopausal estrogen/progestin intervention trial. JAMA 1995;273:199-208. Spaulding CB. Endometrial ablation for refractory postmenopausal bleeding with continuous hormone replacement therapy. Fertil Steril 1994;62:1181-5. Woodruff DJ, Pickar JH. For the menopause study group. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994; 170:1213-23. Leather AT, Savvas M, Studd JWW. Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet GynecoI1991;78:1008-10. Bush TL. Non-contraceptive estrogen use and risk of cardiovascular disease: an overview and critique of the literature. In: Korenman SG, editor. The menopause: biological and clinical consequences of ovarian failure; evolution and management. Norwell (MA): Serono Symposia, 1990:211-24. March MS, Whithead MI. The practicalities of hormone replacement. Baillieres Clin Endocrinol Metab 1993;7:183202. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonon E. For the menopause study group metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 1994;84:987-95. Castello-Branco C, Puerto B, Duran M, Gratacos E, Torne A, Fortuny A, et al. Transvaginal sonography of the endometrium in postmenopausal women: monitoring the effect of hormone replacement therapy. Maturitas 1994; 19:59-65. Barrett-Connor E. Heart disease in women. Fertil Steril 1994;2 Suppl 62:127S-32S.
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