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ORIGINAL RESEARCH |
From the Menopause Research Unit, Department of Obstetrics and Gynaecology, University of Leicester, Leicester; and Novartis Pharmaceuticals, Camberley, Surrey, United Kingdom.
Address reprint requests to: Farook Al-Azzawi, MA, PhD, FRCOG Department of Obstetrics and Gynaecology University of Leicester Leicester Royal Infirmary Robert Kilpatrick Clinical Sciences Building Leicester, LE2 7LX United Kingdom E-mail: fa2{at}leicester.ac.uk
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Abstract |
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Methods: In a multicenter, randomized, open-label study, 235 postmenopausal women received one of the above-mentioned treatments. Fasting lipoproteins were measured at baseline and at 3, 6, and 12 months. At each visit, participants completed Greene climacteric questionnaires and recorded any bleeding episodes. Data are presented as mean ± standard deviation if normally distributed, median and interquartile range if non-normally distributed, or as frequency count. For menopausal symptoms and diary card data, the differences were tested by Wilcoxon rank-sum test.
Results: One hundred sixteen women received continuous combined HRT and 119 women received tibolone; 72 and 76 women, respectively, completed 12 months of therapy. Both treatments effectively relieved vasomotor symptoms and reduced serum total cholesterol. Continuous combined HRT, but not tibolone, significantly reduced low-density lipoprotein levels. Both treatments reduced high-density lipoprotein levels, but the effect was more profound with tibolone. The initial bleeding score was higher for women taking continuous combined HRT; however, by the end of the study, the percentages of amenorrheal women were comparable. Endometrial histology was similar for both treatments at the end of the study, although two cases of proliferative endometrium were found in the tibolone group.
Conclusion: Estradiol valerate–norethisterone continuous combined HRT controls symptoms and is associated with a safe lipid profile.
It is estimated that 9% of women aged 40–64 years are prescribed hormone replacement therapy (HRT)1; however, no more than 50–60% of women who start HRT will take it beyond 1 year.2 One of the main causes of noncompliance with HRT in peri- and postmenopausal women is withdrawal bleeding, particularly if it is irregular or heavy. Cyclic regimens carry a 50% chance of such bleeding.3 Continuous combined HRT has been suggested as an alternative to improve compliance because it is associated with a lower frequency of bleeding.4 Such regimens prevent bleeding because progestogen maintains the endometrium in the thin and atrophic state, which is seen on hysteroscopic examination and confirmed by histologic assessment.5
Changes in lipoprotein profile account for 30–50% of the cardioprotective effect of oral estrogen. Norethisterone, an androgenic progestogen widely used in HRT, commonly prescribed at a dose of 1 mg/day, reverses the beneficial effect of postmenopausal estrogen treatment on high-density lipoprotein (HDL).6 Tibolone is a gonadomimetic synthetic steroid, currently used as a hormone supplement for postmenopausal women to protect against bone loss and relieve vasomotor symptoms, which has the added advantage of causing bleeding in only a minority of cases.7
We investigated the effect of a new HRT, containing 0.7 mg/day norethisterone, on menopausal symptoms, lipoprotein profile, coagulation factors, and bleeding patterns in postmenopausal women over a 12-month period in a randomized study, compared with an established amenorrheal regimen, tibolone.8
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Materials and Methods |
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Climacteric symptoms were assessed at each visit according to the Greene menopausal symptoms scale,9 which distinguishes three main groups of symptoms: vasomotor, somatic, and psychological. Symptoms were scored as 0 = not at all, 1 = mild, 2 = moderate, and 3 = severe. All women were given menstrual diaries in which they recorded and scored any bleeding episodes: 0 = no bleeding, 1 = spotting, 2 = slight, 3 = moderate, and 4 = heavy bleeding. These diaries were collected every 3 months. The total bleeding score was calculated by multiplying the bleeding score by the number of days in which bleeding was recorded. Endometrial sampling was performed at screening and at the end of the study.
Venous blood samples were collected at enrollment and at 3, 6, and 12 months for measurement of lipoproteins, apoproteins, fibrinogen, and factor VIIc. Samples were collected after 12 hours of fasting, without use of a tourniquet. Total cholesterol and triglyceride levels were measured enzymatically. We isolated HDL using heparin manganese, and its cholesterol content was measured enzymatically. Low-density lipoprotein (LDL) levels were calculated. The coefficient of variation for cholesterol was less than 1%, for HDL less than 5%, and for triglycerides less than 2%. Apoproteins AI and B were measured by immunoturbidimetric assay (Ryan Diagnostics, Espoo, Finland; coefficient of variation = 5% for both assays). Lipoprotein(a) was measured by enzyme-linked immunosorbent assay of its apoprotein A–specific component (Innogenics, Antwerp, Belgium; coefficient of variation = 3–5%).
Plasma fibrinogen was measured by determining the clotting time after the addition of excess thrombin to the test plasma (Organon Teknika, Turnhout, Belgium). Factor VIIc levels were determined by the degree of correction of the prothrombin time after the addition of test plasma to factor VII–deficient substrate (Manchester Comparative Thromboplastin Reagents, Manchester, UK). The inter- and intra-batch precisions (coefficients of variation) were 1% and 3.6%, respectively.
The study population was calculated to obtain 150 evaluable patients, 75 in each group, sufficient to detect a 13% difference in LDL between the groups with a power of 80%. The size of the difference was deemed clinically relevant by a consensus of all the investigators. The data collected during the trial actually achieved a mean fall of 10.5% standard deviation (SD), 16.13 for the continuous combined HRT group, and an increase of 0.4% (SD 17.9) in the tibolone group, with an overall SD of 17.86. Using the methods described by Machin and Campbell10 for comparing two means, a sample size of 46 patients per group is required to show a significant two-sided test with 
= 0.05 and a power of 80%. A total of 15 centers (two large and 13 small centers) recruited 235 patients over 9 months. The protocol did not specify testing for between-center variation; therefore, this was not assessed. All the laboratory measurements were done centrally.
Randomization codes were generated using a randomization-schedule generator in the SAS statistical package (SAS Institute Inc., Cary, NC) using the SAS Macro facility.
Data that were not distributed normally were summarized by median and interquartile ranges. Mean and 95% confidence intervals were used for normally distributed data, and frequency count was used for categoric or ordinal data. Continuous data were tested for normality by assessing the normal probability plots and using the Shapiro-Wilk statistic. All patients who were randomized to treatment, who received at least one dose of the study drugs, and who provided baseline and at least one postbaseline evaluation were included in the analysis. Missing values were replaced by the last observation carried forward, which is standard practice for the analysis of phase III clinical trials because it gives a conservative view of the data. For laboratory characteristics and menopausal symptoms, the significance of group differences in the percentage change in values at months 6 and 12 compared with those at baseline was tested by Wilcoxon rank-sum test, using the SAS statistical package (version 6.11). Differences in diary-card data and laboratory data between the groups were tested using Wilcoxon rank-sum test, which was also used for continuous variables that were not normally distributed. Fisher’s exact test was used for categoric variables. The number of patients subject to analysis in the groups varied because of the intention-to-treat analysis and depending on the number of available blood samples and completed diaries.
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Results |
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One hundred forty-eight women completed the study, 72 who received HRT and 76 who took tibolone. Forty-four women taking HRT and 43 taking tibolone did not complete the study (Table 1
). There were no significant differences between treatments in total scores for any of the symptom categories. Symptoms tended to improve in all domains for both groups. However, only vasomotor symptoms showed a significant change from baseline values. At the start of this study, only six continuous combined HRT and nine tibolone patients were without vasomotor symptoms, whereas by month 3, 67 HRT patients and 58 tibolone patients were free of such symptoms (data not shown). There was a statistically significant drop in the severity of vasomotor symptoms in both groups of treatments (P < .001); however, there was no significant difference between the groups (analysis of variance).
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. Percentage changes in individual lipoproteins and apoproteins are presented in Table 3. There was a statistically significant reduction in total cholesterol by both treatments at 3, 6, and 12 months (P < .001) from a median baseline of 241.9 mg/100 mL and 238.0 mg/100 mL in the continuous combined HRT and tibolone groups, respectively, to 214.8 mg/100 mL and 216.7 mg/100 mL, respectively, at the end of the study. There was a statistically significant reduction in HDL in both groups from a baseline median of 63.9 mg/100 mL and 65.8 mg/100 mL in the HRT and tibolone groups, respectively, to 54.2 mg/100 mL and 46.4 mg/100 mL at the end of the study (P < .001). The reduction was constant throughout the study, but was more pronounced in the tibolone group at 3, 6, and 12 months (P < .001). In contrast, LDL was significantly suppressed throughout the study only by continuous combined HRT (P < .001). The median baseline was 154.8 mg/100 mL, decreasing to 133.1 mg/100 mL at 12 months. Both regimens reduced serum triglyceride levels, which dropped from a median baseline of 99.6 mg/100 mL and 88.5 mg/100 mL in the continuous combined HRT and tibolone groups, respectively, to 92.9 mg/100 mL and 70.8 mg/100 mL, respectively, at 3 months. This trend was maintained until the end of the study. The reduction induced by tibolone, but not continuous combined HRT, was statistically significant at 3, 6, and 12 months (P < .001).
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There was a reduction in lipoprotein(a) levels by both treatments, from baseline medians of 17.0 mg/100 mL and 21.0 mg/100 mL in the HRT and tibolone groups, respectively, to 11.0 mg/100 mL and 13.0 mg/100 mL, respectively, at the end of the study, but the change was not statistically significant. Apoprotein AI was significantly reduced by both treatments (P < .001), but this reduction was more pronounced in the tibolone group (P < .001). The drop started at 3 months from a median baseline of 1.40 mg/100 mL and 1.35 mg/100 mL in the HRT and tibolone groups, respectively, to 1.28 mg/100 mL and 1.04 mg/100 mL, which was maintained throughout the study. For apoprotein B, both regimens resulted in a statistically significant reduction from a median baseline of 1.08 mg/100 mL and 1.07 mg/100 mL in the HRT and tibolone groups, respectively, to 0.96 mg/100 mL and 0.98 mg/100 mL at 3 months. This change was maintained at 6 and 12 months (P < .001) for the HRT group but only to month 6 for the tibolone group (P < .001).
There was a consistent drop in factor VIIc, which was statistically significant only in the tibolone group at 6 months (P < .040); at 12 months, however, there was a nonsignificant rise. There were no significant changes in fibrinogen level induced by either treatment at 6 or 12 months (data not shown).
Of the 148 women who completed 12 months of therapy, only 121 had complete diaries suitable for analysis (continuous combined HRT = 61, tibolone = 60). There was no statistically significant difference between the groups for the number of bleeding episodes experienced over the total 12 months of treatment (P < .113, Fisher’s exact test). In the first month of therapy, the total bleeding score for women taking continuous combined HRT (mean 6.77, range 0–50) was significantly higher than for women treated by tibolone (mean 1.1, range 0–23). However, the total bleeding score of women taking HRT fell progressively during the study, and the mean total bleeding scores at month 6 were 1.6 (range 0–27) for the HRT group and 2.11 (range 0–45) for the tibolone group. At month 12, the total bleeding scores were 1.96 (range 0–33) for HRT and 0.86 (range 0–16) for tibolone (Figure 1). There were no statistically significant differences between the treatments at any of these later times.
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In the present study, norethisterone appeared to exert a substantial lowering effect on triglycerides, despite a lower dose of norethisterone (0.7 mg/day) compared with other studies.16 These results are in agreement with our findings,22 but other authors have reported no change.4 Stratification of baseline lipid data according to levels of total cholesterol, HDL, or LDL cholesterol did not affect the final analysis. The effect of estrogen in the continuous combined group was uniform on lipids regardless of the baseline data.
Apoprotein AI is found mainly in HDL cholesterol, whereas apoprotein B is associated with LDL. Apoprotein B has been directly associated with cardiovascular disease,18 while apoprotein AI is inversely related to cardiovascular disease19; lipoprotein(a) is an independent risk factor for premature arteriosclerosis and ischemic heart disease.20 Both treatments resulted in a drop in apoprotein B and lipoprotein(a), and although these changes appear favorable, the reduction in HDL and apoprotein AI might point toward an increased risk of ischemic heart disease.
The potentially unfavorable effects of lipids are probably due to the androgenic effects of norethisterone and tibolone. These effects on lipids could have been avoided by a further reduction of norethisterone, because it has been shown that doses as small as 0.5 mg are associated with an atrophic endometrium.21
Fibrinogen and factor VIIc levels increase after menopause, which might contribute to the increase in ischemic heart disease associated with menopause. Fibrinogen was reduced after sequential HRT.22 It is difficult to draw any conclusions about the effects of treatment on factor VIIc and fibrinogen because the only significant effect was the decrease in factor VIIc at 6 months by tibolone, which was not maintained at 12 months.
Our data show that continuous combined HRT is associated with a higher incidence of bleeding, particularly in the first month of therapy. This improved with continuation of therapy, and over a 1-year period the total bleeding scores in the two regimens were comparable. This evolution of bleeding patterns is not unexpected with estrogen-containing preparations and should be weighted against the cardiovascular benefits accrued by the daily use of 2 mg of estradiol. Less than 10% of the women who received the new continuous combined HRT discontinued the medication because of bleeding.
The regimens resulted in similar proportions of atrophic and secretory endometrium at the end of the study, but this did not show any association with a history of bleeding. The continuous administration of norethisterone along with estrogen down-regulates the estrogen receptor, resulting in an atrophic endometrium, whereas tibolone, with its combined progestogenic and weak estrogenic characteristics, induces an atrophic endometrium. The finding of two proliferative endometrial samples in the tibolone group, one at the end of 6 months, when the patient was withdrawn from the study, and the other at the end of the study, but none in the HRT group, is interesting and confirms our previous report on women who presented with bleeding while taking tibolone.23 Although it is reassuring that histology confirmed the benign nature of the endometrium in both groups, the reason for bleeding on these regimens warrants further investigation into the mechanism(s) of bleeding and its relation to endometrial morphology induced by sex-steroid therapy.
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Footnotes |
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This clinical study was supported by Novartis Pharmaceuticals. Tracey Mason is an employee of Novartis Pharmaceuticals.
Received February 6, 1998. Received in revised form August 3, 1998. Accepted August 13, 1998.
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References |
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2. Wren BG, Brown L. Compliance with hormonal replacement therapy. Maturitas 1991;13:17–21.[Medline]
3. Habiba MH, Bell SC, Abrams K, Al-Azzawi F. Endometrial responses to hormone replacement therapy: The bleeding pattern. Hum Reprod 1996;11:503–8.
4. Christiansen C, Riis BJ. Five years with continuous combined oestrogen/progestogen therapy. Effects on calcium metabolism, lipoproteins, and bleeding pattern. Br J Obstet Gynaecol 1990;97: 1087–92.[Medline]
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9. Greene JG. A factor analytic study of climacteric symptoms. J Psychosom Res 1976;20:425–30.[Medline]
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12. Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and lipid concentration as risk factors for transient ischaemic attacks and minor ischaemic strokes. BMJ 1991;303:605–9.
13. Austin M. Plasma triglycerides as a risk factor for coronary heart disease: The epidemiological evidence and beyond. Am J Epidemiol 1989;129:249–59.
14. Gordon T, Castelli W, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. Am J Med 1977;62:707–14.[Medline]
15. Lipid Research Clinics Program. The Lipid Research Clinics coronary, primary prevention trial results, II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365–74.[Abstract]
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17. Milner MH, Sinnott MM, Cooke TM, Kelly A, McGill T, Harrison RF. A 2-year study of lipid and lipoprotein changes in postmenopausal women with tibolone and estrogen-progestin. Obstet Gynecol 1996;87:593–9.[Abstract]
18. Contois JH, McNamara JR, Lammi-Keefe CJ, Wilson PW, Massov T, Schaefer EJ. Reference intervals for plasma apolipoprotein B determined with a standardized commercial immunoturbidimetric assay. Results from the Framingham Offspring Study. Clin Chem 1996;42:515–23.
19. Contois J, McNamara JR, Lammi-Keefe C, Wilson PW, Massov T, Schaefer EJ. Reference intervals for plasma apolipoprotein A-1 determined with a standardised commercial immunoturbidimetric assay. Results from the Framingham Offspring Study. Clin Chem 1996;42:507–14.
20. Scanu AM. Lipoprotein (a): A genetic risk factor for premature coronary heart disease. JAMA 1992;267:3326–9.[Abstract]
21. Sporrong T, Hellgren M, Samsioe G, Mattsson LA. Comparison of four continuously administered progestogen plus oestradiol combinations for climacteric complaints. Br J Obstet Gynaecol 1988;95: 1042–8.[Medline]
22. Habiba M, Akkad A, Al-Azzawi F. Effect of a new cyclical sequential postmenopausal HRT on lipoprotein, apoprotein and thrombophilia profile. Eur J Obstet Gynecol Reprod Biol 1995;62: 89–94.[Medline]
23. Habiba M, Ramsay J, Akkad A, Hart DM, Al-Azzawi F. Immunohistochemical and hysteroscopic assessment of postmenopausal women with uterine bleeding whilst taking tibolone. Eur J Obstet Gynecol Reprod Biol 1996;66:45–9.[Medline]
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