© 1996 American Heart Association, Inc.
Articles |
Hormone Replacement Therapy Lowers Plasma Lp(a) Concentrations
Comparison of Cyclic Transdermal and Continuous Estrogen-Progestin Regimens
the Department of Medicine, University of Helsinki, Helsinki (M.-R.T., S.L.); the Department of Obstetrics and Gynecology, Central Hospital of Jyvaskyla, Jyvaskyla (J.P.); Gyne-Praxis, Jyva-skyla (T.P., H.L.); Central Hospital of Northern Carelia, Joensuu; Iisalmi District Hospital, Iisalmi (M.B.); and the National Public Health Institute, Helsinki (J.K., C.E.), Finland.
Correspondence to Prof Marja-Riitta Taskinen, MD, Department of Medicine, University of Helsinki, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
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Abstract |
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To study the responses of serum lipoproteins, apoproteins (apo's), and lipoprotein(a) (Lp[a]) to two frequently used hormone replacement therapies (HRTs), 120 postmenopausal women were randomly allocated to receive either transdermal therapy consisting of 28-day cycles with patches that delivered 17ß-estradiol (50 µg/d) combined with cyclic oral medroxyprogesterone acetate (10 mg/d for 12 days per cycle) or continuous oral 17ß-estradiol (2 mg/d) together with norethisterone acetate (1 mg/d) for 12 months. Blood samples were taken before and at 6 and 12 months of HRT. Concentrations of serum total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol decreased by 14% (P<.001), 17% (P<.001), and 9% (P<.001) in the oral HRT group. Respective changes were 5.7% (P<.001), 4.8% (P<.05), and 4.7% (NS) in the transdermal group. Serum triglycerides remained unchanged in the oral group but decreased by 15.7% (P<.001) in the transdermal group. We observed only trivial changes in serum apo B levels. The changes in apo A-I levels paralleled those of HDL cholesterol in the oral HRT group. The concentration of serum Lp(a) decreased by 31% (P<.001) and 16% (P<.001) in the two groups. The combination of progestin and transdermal estrogen was not associated with any further change of Lp(a). The decrement in Lp(a) during therapy was positively associated with baseline Lp(a) levels in both groups (r=.96, P<.001 and r=.88, P<.001). Thus, both HRT regimens were highly effective in lowering elevated Lp(a) levels in postmenopausal women. The divergent responses of LDL and HDL cholesterol in the two HRT groups may influence the potential cardioprotective effects of the two HRT regimens. Prospective trials are needed to define the long-term effects with respect to coronary heart disease risk.
Key Words: hormone replacement therapy • lipoprotein(a) • postmenopause • LDL cholesterol • HDL cholesterol
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Introduction |
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The incidence of CVD in women increases markedly after menopause and becomes the major cause of death in this group.1 2 3 Recent substantial evidence has suggested that estrogen replacement therapy can reduce both CHD morbidity and mortality in postmenopausal women.4 5 6 7 The beneficial effects of unopposed estrogen replacement therapy on CVD have been related to the well-established antiatherogenic changes in lipid profile induced by estrogens. However, the decrease in LDL cholesterol and the increase in HDL cholesterol can explain only 35% to 50% of the observed reduction in CHD risk.8 Combination therapy is based on the fact that addition of progestin protects the endometrium and helps to avoid the risk of endometrial hyperplasia.9 To eliminate the monthly bleeding induced by cyclic combination therapy, continuous administration of both estradiol and progestin has been introduced.10 11 Unfortunately the combination of progestin and estrogen tends to offset the increase in HDL induced by estrogens. This observation has initiated concern that progestins negate the potential cardioprotective effects of estrogen use. However, the effect of progestins is highly variable and depends on their androgenicity and dose. Recent data suggest that the lowering of HDL cholesterol by currently used low-dose progestin regimens are more innocuous than previously reported.7 12 13 14 This issue is important with respect to CHD risk, since HDL level is a strong independent predictor of CHD death in women.15
Lp(a) is a lipoprotein that resembles LDL. The protein moiety consists of apo B-100 linked to a unique glycoprotein, apo(a).16 17 Substantial evidence indicates that a high concentration of plasma Lp(a) is an independent risk factor for CVD, but some studies have failed to find any relation.16 17 18 19 20 The current concept is that elevation of the LDL level is required for a raised Lp(a) level to be a CHD risk factor.20 Much of the genetically defined variability in plasma Lp(a) levels seems to be determined by the size of the apo(a) isoform.21 22 Lp(a) concentrations appear to be relatively resistant to modifications by environmental factors, and at present there is no effective therapy available to lower high Lp(a) levels.23 24 The observation that Lp(a) levels increase after menopause25 26 raised immediate interest in the possible effects of HRT on Lp(a) levels. Both estrogens and progestins have been reported to lower Lp(a) levels.7 13 27 28 Recent data from relatively small trials have shown that cyclic combination therapy also lowers Lp(a) levels.13 29 30 31 However, whether this effect is caused by estrogen, progestin, or both remains uncertain.
The purpose of the present study was to compare the responses of serum lipids and apoproteins, Lp(a) in particular, to two frequently used HRT regimens: transdermal estrogen (17ß-estradiol, 50 µg/d) combined with cyclic oral progestin (MPA, 10 mg/d for 12 days per cycle) versus continuous oral estrogen and progestin (17ß-estradiol 2 mg/d plus NETA 1 mg/d). These regimens were selected for comparison because of their popularity in clinical practice.
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Methods |
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The study cohort consisted of 120 healthy postmenopausal women with climacteric symptoms from four outpatient gynecological clinics (Department of Obstetrics and Gynecology, Central Hospital of Jyvaskyla, Jyvaskyla; Gyne-Praxis, Jyvaskyla; Central Hospital of Northern Carelia, Joensuu; and Iisalmi District Hospital, Iisalmi, Finland). The women were recruited by newspaper advertisements and by interview of former clinic patients.
Menopause was defined as amenorrhea for >6 months or age >52 years and an FSH level >30 IU/L. The women were eligible for entry into the study if they were <60 years old and had a body mass index <30 kg/m2, a serum cholesterol level <7.0 mmol/L, and a serum triglyceride level <2.3 mmol/L. These cutoff values for lipids represent the mean+1SD for 60-year-old white women who are not taking sex hormones.32 We excluded women who had diabetes; a current medication regimen that might influence lipid metabolism; hypertension (systolic blood pressure >170 mm Hg and/or diastolic blood pressure >100 mm Hg) if uncontrolled with stable ß-blocker therapy, angiotensin-converting enzyme inhibitors, or calcium channel blockers; known thyroid, liver, or kidney disease or other endocrinopathies; known or suspected estrogen-dependent neoplasia; and known or past history of breast cancer, deep venous thrombosis, or other thromboembolic disorders. Altogether, 72 women had previously used HRT and they were eligible after a 3-month withdrawal period. Gynecological examination and endometrial biopsy were performed for each patient before HRT was initiated. If a woman had not had mammography during the previous 2 years this procedure was also performed. Written voluntary consent was obtained from each subject. The study protocol was reviewed and approved by the Ethics Committees of the four local hospitals.
Study Protocol
Entry into the study was preceded by a 3-month washout period that included a screening visit for lipid measurements between -6 and -4 weeks before the baseline visit. Concentrations of serum cholesterol and triglycerides averaged 6.06±0.71 and 1.30±0.60 mmol/L, respectively, in the oral treatment group and 6.11±0.72 and 1.14±0.57 mmol/L, respectively, in the transdermal treatment group. During the screening visit the subjects received dietary counseling (American Heart Association Step I diet: 30% fat, 55% carbohydrate, and 15% protein)33 and were instructed to follow their usual pattern of exercise. The subjects were randomly allocated to receive either transdermal or oral HRT therapy for 12 months. Transdermal therapy consisted of 28-day cycles with patches delivering 50 µg/d 17ß-estradiol (Estraderm) combined with 10 mg/d oral MPA (Provera) for 12 days per cycle. The patches were changed twice a week. Oral therapy consisted of 2 mg/d continuous 17ß-estradiol and 1 mg/d NETA (Kliogest). Compliance was monitored by control of the medication packages at each visit. A total of 8 women discontinued participation in the study. Four women discontinued HRT because of irregular bleeding and 1 woman because of elevated liver enzyme levels at entry. One woman dropped out because thiazide treatment was initiated for hypertension and 1 because of protocol violation.
The women attended the clinics at 3, 6, and 12 months. At each visit physical and gynecological examinations including palpation of the breasts were performed and side effects recorded. Each participant kept a daily record of possible vaginal bleeding. Blood pressure and weight were recorded at each visit. Fasting blood samples for measurements of serum lipids, lipoproteins, and apoproteins were taken at baseline and again at 6 and 12 months. At 6 months blood samples were taken at the end of the combined phase. The 12-month blood samples were taken at the end of both the estrogen phase (days 14 to 16) and the combined phase in the transdermal treatment group and at analogous time points in the oral treatment group.
Laboratory Analyses
All blood samples were collected in the morning after a 12-hour fast. Serum was isolated immediately by centrifugation at 3000 rpm for 10 minutes at 4°C and stored frozen at -20°C or at -70°C (for Lp[a] analyses). All analyses were performed within 3 months of blood sampling. Serum triglyceride and cholesterol levels were determined with an automated Cobas Mira analyzer (Hoffman–La Roche) using enzymatic methods. The concentration of HDL cholesterol was measured by the phosphotungstic acid–MgCl2 precipitation method in a commercially available kit (Hoffman–La Roche).34 LDL cholesterol values were calculated from the Friedewald equation.35 Serum apo A-I, A-II, and B concentrations were determined by immunoturbidimetric methods in commercially available kits (No. 726478 and 726486, Boehringer Mannheim; and Orion Diagnostica). The interassay coefficients of variation for apo A-I, A-II, and B were 3.6%, 2.1%, and 5.9%, respectively. Lp(a) concentrations in serum were determined by using the Pharmacia Apolipoprotein(a) RIA assay system. This assay is a solid-phase, two-site immunoradiometric assay with two monoclonal antibodies directed toward different epitopes of apo(a).36 The interassay coefficient of variation was 4.9%. Serum concentration of FSH was measured by fluoroimmunometric assay37 and serum estradiol levels by radioimmunoassay.38 Serum SHBG level was measured by using a fluoroimmunoassay kit (AutoDELFIA SHBG Kit, Wallac Oy).39
Statistical Analyses
Analysis of the data distribution was performed with BMDP statistical software (University of California at Berkeley). Data that were not normally distributed were logarithmically transformed before statistical analyses were done. Data were expressed as mean±SD. Lp(a) data were expressed as the median and range. The significance of changes between groups was evaluated by ANOVA (programs 4D and 7D). Comparisons between different groups were performed by ANOVA (program 4D) and Wilcoxon's signed rank test (BMDP program 3S). The 
2 test was used to compare categorized measures as appropriate. Standard regression coefficients were calculated.
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Results |
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The groups had similar ages and body mass index values at entry (Table 1
). There were no differences in baseline FSH levels between the two groups. During HRT estradiol levels were similar in the two groups at 12 months (0.27±0.17 versus 0.22±0.14 nmol/L). Serum SHBG levels increased significantly in the oral HRT group but remained unchanged in the transdermal group. The baseline concentrations of serum lipids, apoproteins, and Lp(a) were closely comparable in the two groups (Table 2).
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Effects of HRT on Serum Lipids
Serum cholesterol levels decreased more in the oral HRT than in the transdermal HRT group after both 6 (11.7% versus 5.7%, P<.001) and 12 (14.0% versus 5.7%, P<.001) months of therapy. Likewise the LDL cholesterol concentration decreased more in the oral HRT group than in the transdermal HRT group at both 6 (16.5% versus 8.2%, P<.05) and 12 (17.1% versus 4.8%, P<.01) months. Consequently at both 6 and 12 months concentrations of both serum total and LDL cholesterol were significantly lower in the oral HRT group than in the transdermal HRT group (Table 2
). Neither serum total nor LDL cholesterol values showed differences during the 17ß-estradiol–only phase and 17ß-estradiol–plus-MPA phase. Decrements in LDL cholesterol values were positively related to baseline levels in both the transdermal HRT group (r=.37, P<.05) and the oral HRT group (r=.53, P<.001).
Serum triglyceride concentrations did not change during the 12 months of therapy in the oral HRT group. In the transdermal HRT group concentrations of serum triglycerides at the end of the combined phases were significantly lower at both 6 and 12 months than at baseline. HDL cholesterol levels decreased in the oral HRT group, being 3.9% (P<.05) and 9.0% (P<.001) lower at 6 and 12 months, respectively, than at baseline. Transdermal HRT caused a minor increase in HDL cholesterol at 6 months (+3.6% change). At 12 months, however, HDL cholesterol levels did not differ from pretreatment values after either the 17ß-estradiol–only phase or the 17ß-estradiol–plus-MPA phase. We observed a slight but significant decrease in HDL cholesterol levels when MPA was added to 17ß-estradiol in the transdermal HRT group (Table 2). In the oral HRT group HDL cholesterol levels were lower at 6 and 12 months than in the transdermal HRT group (1.52±0.39 versus 1.75±0.52, P<.05 and 1.42±0.38 versus 1.61±0.48, P<.05).
The total to HDL cholesterol ratio decreased slightly in both groups at 6 months (4.01±1.34 versus 3.62±1.16, P<.001 and 3.91±1.38 versus 3.48±1.16, P<.01), but this effect waned at 12 months, with ratios that were comparable with baseline values. After 6 months of treatment the LDL-HDL cholesterol ratio had decreased in both groups. In the oral HRT group the LDL-HDL ratio was and remained significantly lower at 12 months than at baseline. In contrast in the transdermal HRT group the LDL-HDL ratio did not differ from baseline values after 12 months of therapy (2.51±1.18 versus 2.43±1.10).
Effects of HRT on Apoprotein Levels
In both treatment groups the response of apo B was much less than expected on the basis of the decrease in LDL cholesterol values (Table 2). In fact we observed only trivial variation in apo B levels. In the oral HRT group the apo A-I concentration decreased by 5.8% at 6 months and by 4.5% at 12 months. In the oral HRT group there were no changes in apoA-II levels. In the transdermal HRT group both apo A-I and apo A-II levels were lower at 6 and 12 months than at baseline. Similar to the findings for HDL cholesterol we observed a significant cyclic variation in apo A-I levels at 12 months (Table 2).
Effects of HRT on Lp(a)
At baseline median values and ranges of Lp(a) were comparable in the two groups. After 6 months of treatment Lp(a) concentrations had decreased markedly in both groups and remained so for another 6 months. In the transdermal HRT group Lp(a) levels were similar during both the 17ß-estradiol–only and the 17ß-estradiol–plus-MPA phases. In both groups the change in Lp(a) level at 12 months was positively correlated with the baseline serum Lp(a) concentration (r=.96, P<.001 and r=.88, P<.001; Fig 1), indicating that the higher the baseline value, the larger the decrement in Lp(a). Since a threshold effect for CHD risk has been proposed for Lp(a), we next categorized our subjects into subgroups according to baseline serum Lp(a) levels. The distribution of subjects with high Lp(a) levels was similar in the two treatment groups (Fig 2). The median Lp(a) concentration decreased more in subjects who had a high baseline Lp(a) value (Fig 2). The decrement in Lp(a) values in women with initially higher Lp(a) levels was greater in the oral HRT than in the transdermal HRT group (Fig 2). There were no significant differences in pretreatment or posttreatment LDL levels in these subgroups. At baseline the overall cumulative distribution of Lp(a) values was similar in the two groups (Fig 3). We observed a significant shift toward lower values in the frequency distribution of Lp(a) values during both oral and transdermal treatments (Fig 3). We found no correlations between changes in estrogen levels and Lp(a) in the two groups at 12 months (r=.163 versus r=.065).
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) and hatched (
) columns indicate the percent changes in oral and transdermal HRT groups, respectively.
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Discussion |
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The novel finding of the present study is that in postmenopausal women, both transdermal estrogen combined with cyclic progestin and continuous oral estrogen-progestin regimens drastically lowered Lp(a) concentrations after 6 months of therapy and that this effect persisted for the remaining 6 months of therapy. Our data are consistent with recent evidence that female sex hormones influence Lp(a) metabolism.7 23 40 The obvious question is whether estrogen or progestins are responsible for this beneficial action. Data from previous studies indicate that conjugated estrogen lowers Lp(a) levels.13 28 41 Recently Kim et al31 reported that in postmenopausal women, a decrease in Lp(a) levels during 2 months of estrogen-only or combination therapy (estrogen and cyclic progestin [MPA 10 or 5 mg/d]) was of similar magnitude and averaged 20%. Nabulsi et al13 also observed that the lowering of Lp(a) levels in current users of either estrogen or estrogen and progestin was of similar magnitude. In addition, lowering of Lp(a) levels has been observed in two other studies of estrogen and cyclic HRT regimens.29 30 Since the catabolic rate of Lp(a) is slow, averaging 0.287 pool/d, no changes in Lp(a) concentration can be expected to occur during short-term cyclic progestin administration.42 So far the lowering of Lp(a) by sex hormones has been reported only after oral administration.7 23 40 41 We observed that a significant reduction in Lp(a) levels also occurred during transdermal delivery of estrogen alone and that cyclic progestin did not influence this response. However, reductions in Lp(a) values were slightly less than those observed during oral HRT regimens, particularly in women with initially high Lp(a) levels. Overall the available data envisage the concept that estrogen is the element mainly responsible for causing reductions in Lp(a) levels during HRT regimens and progestins do not negate this effect. This tenet does not exclude the possibility that continuous administration of high doses of progestins and androgens can also lower Lp(a) levels, as suggested in a preliminary report.27 Our data suggest that lowering Lp(a) levels by either of the two HRT regimens can be effective in postmenopausal women with high Lp(a) levels.
What are the mechanisms whereby HRT regimens lower Lp(a) levels? Since Lp(a) binds to the LDL receptor, it has been proposed that one mechanism could be estrogen-induced enhanced uptake of Lp(a) by the LDL receptor.28 43 However, data from kinetic studies in homozygous and heterozygous familial hypercholesterolemia patients indicate that the LDL receptor is not required for normal catabolism of Lp(a).42 44 In fact the kinetic data support the concept that the variation in plasma Lp(a) levels due to both heritable factors, ie, apo(a) phenotype and other factors, are mainly caused by differences in Lp(a) production rate in the liver.45 46 Therefore, it is highly likely that the lowering of Lp(a) levels during the two HRT regimens can be explained by a reduction in Lp(a) production by estrogens in the liver. However, regulation of the synthesis, processing, and secretion of Lp(a) is still poorly understood.47
As previously reported for a subgroup of this cohort,48 the responses of LDL cholesterol to the two different HRT regimens were clearly divergent. In the transdermal group the lowering of LDL cholesterol was trivial, averaging only 6%, whereas LDL cholesterol was reduced by 17% in the group given estrogen together with continuous progestin. In fact the LDL cholesterol concentration was 15% higher in the transdermal group than in the oral group after 12 months of therapy. Strong evidence indicates that estrogens lower LDL cholesterol by upregulating LDL receptors in the liver, resulting in enhanced LDL catabolism.49 The effects of progestins on LDL kinetics are less clear, and progestins may increase or have no effect on LDL catabolism.49 However, in most studies the lowering of LDL cholesterol by estrogens appears to be affected minimally or not at all by addition of progestin.14 50 51 The fact that we had different progestin preparations in the two groups could be a potential confounding factor. However, it has been shown that 1 mg NETA is equivalent to 10 mg MPA with respect to effects on lipoproteins as well as endometrial protection.52
Recently Walsh et al53 reported that transdermal estrogen had no effect on LDL catabolism and consequently on LDL levels. Consistently we observed only a trivial lowering of LDL cholesterol in the transdermal group. Likewise, previous studies have reported that the response of LDL cholesterol is much smaller or insignificant during transdermal compared with oral HRT.54 55 56 The difference in LDL response occurred despite similar estradiol levels in the present study. However, we may have failed to measure peak estradiol levels in the oral HRT group because of the sampling schedule and direct exposure of the liver to estrogen via the portal circulation. This notion is supported by the significant increase in SHBG levels in the oral HRT group. Thus, differences in hepatic exposure to estrogen may well explain the divergent response of LDL cholesterol between the two groups. This may also explain the difference in Lp(a) response if we assume that estrogen also lowers Lp(a) levels.
Comparison of the two HRT regimens revealed divergent actions not only in LDL but also in HDL metabolism. Although there was some fluctuation in HDL cholesterol values, we observed no significant changes in HDL cholesterol in the transdermal group over 12 months. The changes in apoA-I were trivial, but apoA-II levels fell significantly, suggesting a decrease in the number of LpA-I/A-II particles. In most previous studies HDL cholesterol levels also remained unchanged during transdermal treatment.55 57 In contrast Tufecki et al56 and Crook et al50 reported an increase in HDL cholesterol during transdermal estrogen-progestin replacement therapy. Recently Walsh et al58 reported that the increases in HDL cholesterol and apoA-I due to oral estrogen resulted entirely from the increased production of apoA-I, which is synthesized mainly in the liver. Thus, lack of direct hepatic exposure during transdermal estrogen delivery explains why the effects on HDL kinetics or plasma concentration are different from those observed during oral estrogen administration.58
Continuous therapy with 17ß-estradiol and NETA (1 mg/d) was associated with a significant 10% reduction in HDL cholesterol after 12 months. However, the concurrent change in apo A-I was only 
5% and apo A-II levels remained unchanged. Likewise, Jensen et al,59 using a similar estrogen-progestin combination, reported a 10% reduction in HDL cholesterol during 1-year therapy. In a 5-year study this same HRT regimen was not associated with any changes in HDL cholesterol compared with levels in untreated women.60 It has been proposed that the unfavorable effect of progestins on HDL cholesterol may wane with time.61 Detailed results on responses and specific properties of HDL subclasses during the two HRT regimens will be discussed separately in a later communication (M. Tilly-Kiesi et al, unpublished data, 1996).
In the context of CHD risk, lowering of the HDL cholesterol level, particularly in postmenopausal women with initially low HDL levels, may partly counteract the benefits produced by lowering LDL cholesterol and Lp(a) levels during continuous estrogen-progestin regimen. A critical issue with respect to overall CHD risk will be whether these two HRT regimens can improve vascular function like oral estrogen alone does.62 Finally the long-term effects and mechanisms of different HRT regimens with respect to CHD risk and other CHD risk factors should be evaluated in prospective trials.
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Acknowledgments |
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This study was supported by grants from the Finnish Foundation for Cardiovascular Research, the Finnish Academy (Helsinki, Finland), and Novo Nordisk A/S (Copenhagen, Denmark). We express our sincere gratitude for the assistance of Airi Pyorala and Anja Luotola in the recruitment and care of the subjects. We also appreciate the skillful laboratory work by Sirkka-Liisa Runeberg, Ritva Marjanen, Leena Lehikoinen, Marjatta Karnasaari, Aila Koponen, and Anneli Sokka.
Received July 10, 1995;
revision received March 13, 1996;
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