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(Circulation. 1998;97:979-986.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Effect of Postmenopausal Hormone Therapy on Lipoprotein(a) Concentration

Mark A. Espeland, PhD; Santica M. Marcovina, PhD, ScD; Valery Miller, MD; Peter D. Wood, DSc; Carol Wasilauskas, MS; Roger Sherwin, MB; BChir; Helmut Schrott, MD; Trudy L. Bush, PhD; ; for the PEPI Investigators

From the Section on Biostatistics, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC (M.A.E, C.W.); the Department of Medicine, University of Washington, Northwest Lipid Research Laboratories, Seattle (S.M.M); George Washington University Lipid Research Clinic, Washington, DC (V.M.); the Center for Research in Disease Prevention, Stanford University, Palo Alto, Calif (P.D.W.); the Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore (T.L.B., R.S.); and the Lipid Research Clinic, University of Iowa, Iowa City (H.S.).

Correspondence to Mark A. Espeland, PhD, Section on Biostatistics, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1063. E-mail mespelan{at}rc.phs.bgsm.edu

	Abstract

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Background—Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy.

Methods and Results—The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n=366), 12 months (n=354), and 36 months (n=342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use.

Conclusions—Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

Key Words: lipids • lipoproteins • hormones • cardiovascular diseases • risk factors

	Introduction

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Increased concentrations of plasma Lp(a) appear to be associated with higher prevalence and risk of cardiovascular disease, independent of associations of other lipids/lipoproteins and risk factors.^{1 2 3 4 5} Lp(a) concentration has been reported to be stable and influenced little by diet, physical activity, and most drugs other than niacin, including lipid-lowering drugs, and so may serve as one important index of cardiovascular disease risk.

One intervention that has been repeatedly shown to decrease Lp(a) levels has been postmenopausal hormone therapy. Cross-sectional⁶ and relatively small, short-term longitudinal studies^{7 8 9 10 11 12 13 14 15 16} indicate that hormone therapy reduces Lp(a) concentrations by 10% to 50% and that its impact may be influenced by the type of estrogen, its dose, and the route of administration. Given the strong evidence that postmenopausal hormone therapy decreases the risk of cardiovascular disease and may increase life expectancy,^{17 18 19 20} it seems reasonable to assume that its impact on Lp(a) may be one mechanism that accounts for some of these health benefits.^{6 21 22} To clarify this role from a clinical standpoint, better understanding of the consistency and long-term impact of hormone therapy on Lp(a) is needed.

The PEPI study²³ provides the largest randomized, placebo-controlled, clinical trial to ascertain the long-term impact of hormone therapy on Lp(a) concentration. PEPI has reported previously that (1) estrogen therapy results in increased levels of HDL-C and lower levels of LDL-C and (2) inclusion of progesterone in therapeutic regimens may moderate but not eliminate the effect on HDL-C and has little impact on LDL-C.²⁴ This report extends these analyses to Lp(a) concentrations and examines the impact of hormone therapy on Lp(a) within the context of its impact on other lipoprotein concentrations. Women in PEPI were followed for 3 years, which allows for the first comprehensive examination of the consistency of the effects of hormone therapy across this time span. Importantly, PEPI also provides an opportunity to characterize the impact of hormone therapy across a diverse cohort and to examine the consistency of effects across subgroups defined by traditional clinical and demographic measures.

	Methods

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Detailed descriptions of the PEPI study design, recruitment practices, methods, and baseline characteristics appear elsewhere.^{23 25 26 27} Briefly, PEPI was a 3-year, placebo-controlled, randomized clinical trial to assess the relative impact of four hormone therapy regimens and placebo on a number of cardiovascular risk factors, including lipoprotein concentrations. One estrogen (CEE at 0.625 mg daily) and three progestin regimens (cyclic MPA at 10 mg days 1 through 12; continuous MPA at 2.5 mg daily; and cyclic MP at 200 mg days 1 through 12) defined five treatment arms: (1) placebo (placebo CEE, placebo MPA daily, placebo MP days 1 through 12); (2) CEE only (CEE, placebo MPA daily, and placebo MP days 1 through 12); (3) CEE+MPAcyc (CEE, MPA days 1 through 12, placebo MPA days 13 through 28, and placebo MP days 1 through 12); (4) CEE+MPAcont (CEE, MPA daily, placebo MP days 1 through 12); and (5) CEE+MPcyc (CEE, placebo MPA daily, MP days 1 through 12). Seven clinical centers participated in the PEPI program; however, only three of these sites conducted more extensive laboratory assessments that included Lp(a) measurement. These clinical centers (George Washington University Medical Center, University of California at Los Angeles, and Stanford University) randomized 366 women across the five treatment groups: placebo (n=72), CEE only (n=74), CEE+MPAcyc (n=73), CEE+MPAcont (n=74), and CEE+MPcyc (n=73). The experience of these 366 women (42% of the total randomized PEPI cohort) is summarized in this report.

Key exclusion criteria included (1) natural menopause before age 44 years or <1 year or >10 years before time of enrollment, (2) hysterectomy within 2 months, (3) body mass index 40 kg/m², and (4) a medical history (eg, stroke, endometrial cancer) that might contraindicate use of postmenopausal hormone therapy or curtail follow-up. All women were ambulatory and provided written informed consent.

Fasting morning blood for assessing Lp(a) concentrations was obtained from participants at baseline and 12 and 36 months after randomization. At these times, a panel of lipoprotein chemistries was performed, including total cholesterol, HDL-C, LDL-C, triglycerides, VLDL-C, apo-A1, and apo-B. Plasma fibrinogen levels were also measured at these times. One month before randomization, an abbreviated panel of lipoprotein measures was obtained (total cholesterol, triglycerides, HDL-C, LDL-C, VLDL-C, apo-A1, and apo-B); for these analytes, the baseline value used in analyses is the average of these two measures.

Northwest Lipid Research Laboratory, University of Washington, Seattle, served as the central laboratory for PEPI lipid, lipoprotein, and apolipoprotein analyses. Cholesterol and triglycerides were determined enzymatically on the Abbot Spectrum Autoanalyzer. Total HDL-C, HDL₂-C, and HDL₃-C separations were performed by a chemical precipitation technique, as previously reported,^{28 29} and the resultant supernatants were analyzed enzymatically for cholesterol concentration. Determination of HDL-C and LDL-C was performed by the Lipid Research Clinic Beta Quantification procedure.³⁰ Apo-A1 and apo-B were measured on the Behring Nephelometer System with in-house prepared calibrator and quality control materials with values assigned against the WHO-IFCC International Reference Preparation for apo-A1 and apo-B.^{31 32} Lp(a) concentration was measured by a direct binding double monoclonal antibody–based enzyme-linked immunoassay (ELISA).³³ The capture monoclonal antibody (a-6) is directed to an epitope present in apo(a) kringle 4 (K4) type 2 and the detection antibody (a-40) is directed to an epitope present in apo(a) K4 type 9. Because K4 type 9 is present in only one copy per apo(a) molecule, this immunoassay is insensitive to apo(a) isoform size heterogeneity. Lp(a) concentrations were expressed in nmol/L. Fresh-frozen sera from five individuals representing a broad range of Lp(a) concentrations were used as quality controls for the ELISA. Detailed evaluations of the assay, including the analytical performance, have been previously reported.³³

Fibrinogen was assayed at a central laboratory (University of Vermont) by the Dade method, based on the clotting time of fasting citrated plasma using excess thrombin.³⁴ Height and weight were measured at baseline with a standard stadiometer while participants were wearing light clothing and no shoes. Body mass index was calculated as the ratio of height in centimeters to the square of weight in kilograms. Cigarette smoking (current/former/never), current alcohol intake (drinks per day), and history of hormone use (ever/never) data were collected by standardized self-report questionnaires.

Statistical Analysis
PEPI follow-up was nearly complete-97% and 93% of the cohort providing Lp(a) data at baseline attended 12- and 36-month examinations. Results were analyzed for the entire cohort according to participant's random treatment assignment and for the 317 women who took 80% of their assigned medications during the 6 months before their 12-month visit and the 272 women who met this adherence criterion at 36 months on the basis of pill counts. This "current adherers only" analysis included the following percentages of the attenders for each treatment assignment at 12 and 36 months: 86%/76% (placebo), 82%/61% (CEE only), 94%/89% (CEE+MPAcyc), 93%/87% (CEE+MPAcont), and 93%/85% (CEE+MPcyc).

The distribution of Lp(a) concentrations was skewed with relatively more low values, as noted previously for predominantly Caucasian cohorts.^{3 4} Because of this, analyses were conducted on log-transformed Lp(a) data; means and standard deviations were transformed back into their raw units for reporting using the delta method.³⁵ Mean changes were summarized in terms of percentages. Similar approaches were used for other right-skewed measures (triglycerides and fibrinogen). Mean changes from baseline of log-transformed Lp(a) were computed for the two scheduled data collection visits. Comparisons of changes involved two-sided hypothesis tests based on Laird-Ware models³⁶ for repeated measures assessed with Wald tests.^{37 38} Each comparison included all postrandomization changes in log[Lp(a)]; linear models were fitted in which the two stratification factors in the PEPI randomization (clinical center and hysterectomy status) were included as covariates. Contrasts within these models were used to assess separately the effect of each active treatment relative to placebo and the consistency of these treatment effects across time and to develop estimates of mean relative effects. Bonferroni adjustments were used to control overall type I error for the pairwise comparisons of treatment arms.

Pearson correlation coefficients were used to portray associations between changes in Lp(a) and changes in other lipoprotein measures. The consistency of changes in Lp(a) across subgroups defined by baseline characteristics and lipoprotein measures was assessed using Laird-Ware models for repeated measures in which interactions between these subgroups and treatment effects were explicitly parameterized.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Baseline Characteristics
The baseline characteristics of the entire PEPI cohort (n=875) have been detailed elsewhere.²⁷ The subset of 366 women described in this report had a similar overall profile. These women averaged 55.8±4.2 years (mean±SD); 27% had a prior hysterectomy and 56% reported prior use of postmenopausal hormone therapy; 6% were African-American and 4% were Hispanic; 13% were current smokers; and 26% reported alcohol intake of one or more drinks per day.

Lp(a) Concentrations
Table 1 describes the Lp(a) concentrations at baseline and across time for the five randomized cohorts. At baseline, differences in mean levels of Lp(a) concentrations were minor (P=.61), as expected from randomization. Concentrations of Lp(a) were fairly stable across time among women assigned to placebo; however, differences associated with active hormone therapy were evident for each of the other four arms.

View this table: [in this window] [in a new window]   Table 1. Descriptive Statistics for Lp(a) Values by Treatment Assignment: All Randomized Participants Regardless of Adherence

Table 2 portrays the covariate-adjusted mean relative differences from placebo at 12 and 36 months after randomization for each of the four active treatment groups resulting from these models. Mean relative treatment effects are listed for the entire cohort and for the subsets of the cohort who met the criteria for current adherence. Means for the adherers are portrayed graphically in the Figure. At 12 months, assignment to CEE-only therapy was associated with a 24.0±5.7% mean drop in Lp(a) concentrations relative to placebo. At 36 months, this mean drop was 17.1±6.4%. Overall, these treatment effects were highly statistically significant (P=.002); the apparent diminishment of effect from 12 to 36 months was also statistically significant (P=.02). For the subset of current adherers, medication was similarly associated with average decreases in Lp(a) (P=.0009). The estimated relative treatment effects were 25.8±6.1% and 20.4±7.0% at 12 and 36 months and were not significantly different (P=.26).

View this table: [in this window] [in a new window]   Table 2. Estimated Treatment Effects on Lp(a) Concentration for Each Active Therapy Versus Placebo and Results From Statistical Inference

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean changes in Lp(a) concentrations from baseline among adherers to active hormone regimens (relative to adherers to placebo) at 12 and 36 months after randomization.

Women assigned to each of the three combination regimens had statistically significant mean decreases of Lp(a) concentrations compared with placebo. The treatment effects for the two CEE+MPA regimens were similar at 12 and 36 months. The relative treatment effect of the CEE+MP regimen may have increased from 12 to 36 months (P=.03 for current adherers only). Overall, however, no significant differences (P>.10) were apparent between each combination regimen and CEE only and among the combination regimens.

Table 3 summarizes the magnitude of the relative treatment effects of active therapy (all four regimens combined) versus placebo for each of the PEPI lipoprotein measures in this cohort. These mean levels were computed in the same manner as in Table 2. Also included in Table 3 are baseline mean levels of these measures for the subsets of current adherent women (women who were adherent at either follow-up examination contributed to the baseline average for adherers only). Hormone therapy was strongly associated with mean reductions in Lp(a), LDL-C, and total cholesterol concentrations and with increases in HDL-C, HDL₂-C, HDL₃-C, triglycerides, and apo-A1. In terms of mean percentages, the largest impact of hormone therapy was on triglycerides and Lp(a). Differences in the estimated treatment effects for all participants and for current adherers only were minor. Treatment effects were fairly stable across the 12- and 36-month visits for Lp(a), HDL₂-C, LDL-C, VLDL-C, total cholesterol, triglycerides, apo-B, and fibrinogen. The treatment effect for HDL appeared to wane with time among all participants, but this trend was less pronounced and not statistically significant for current adherers. Treatment effects for HDL₃-C and apo-A1 appeared to decrease with time among both current adherers and nonadherers.

View this table: [in this window] [in a new window]   Table 3. Estimated Treatment Effects for Active Therapy Versus Placebo for Each Lipoprotein Component and Fibrinogen

Relationships Between Lp(a) and Other Lipoproteins
Table 4 lists the correlations between Lp(a) and other lipoproteins at baseline. Lp(a) had fairly strong positive associations with LDL-C (r=.22; P<.0001), total cholesterol (r=.13; P=.0002), and apo-B (r=.12; P=.0005). It had more modest negative relationships with HDL₃-C (r=-.07; P=.03) and HDL-C (r=-.07; P=.05). Positive associations with fibrinogen (r=.06; P=.06) and negative associations with apo-A1 (r=-.06; P=.07) and VLDL-C (r=-.06; P=.09) were of borderline statistical significance.

View this table: [in this window] [in a new window]   Table 4. Among Adherers, Pearson Correlations of Baseline Levels of Lp(a) With Baseline Levels of Other Lipoprotein Concentrations; Changes in Lp(a) From Baseline at 12 and 36 Months With Changes in Other Lipoprotein Concentrations at These Times for Women Assigned to Active Therapy; and Changes in Lp(a) From Baseline at 12 and 36 Months With Changes in Other Lipoprotein Concentrations at These Times for Women Assigned to Placebo Therapy

Also included in Table 4 are correlations between changes from baseline in Lp(a) and changes in each other lipoprotein. These are presented separately for adherent women assigned to active therapy (and therefore are presumed to portray predominately changes attributable to hormones) and for adherent women assigned to placebo (and therefore are presumed to portray changes attributable to other causes). At 12 months, changes in Lp(a) attributable to hormone therapy were most strongly linked to changes in LDL-C (r=.30; P<.0001), total cholesterol (r=.26; P<.0001), apo-B (r=.22; P=.0005), and fibrinogen (r=.18; P=.003). Each of these relationships remained statistically significant at 36 months; however, each appeared to be slightly less pronounced at this later time. Among the smaller cohort of women assigned to placebo, several marginally significant relationships were found between changes in Lp(a) concentrations and changes in other lipoproteins: at 12 months, fibrinogen (r=.26; P=.05); and at 36 months, total cholesterol (r=.28; P=.05), apo-B (r=.27; P=.05), and LDL-C (r=.24; P=.09).

Consistency of Hormone Effects Across Baseline Lipoprotein Levels
Table 5 examines the consistency of hormone effects on Lp(a) across women grouped by baseline lipoprotein concentrations. Listed are comparisons based on baseline levels of Lp(a). Also included are comparisons with several factors which, based on Table 4, appeared to have related hormone-induced changes: HDL-C, LDL-C, total cholesterol, apo-B, and fibrinogen. Women were grouped into quartiles according to the baseline levels of each of these factors. The mean relative treatment effect of hormone therapy (for adherers) was tabulated for each of these subgroups of women, and results of ANCOVA to assess the consistency of these relative treatment effects across these quartiles is presented. None of the analyses had a significant association between its baseline level and the hormone effect on Lp(a). The strongest association was with baseline Lp(a): Relative treatment effects appeared to be slightly stronger for women with lower levels of Lp(a) at baseline (P=.14). Similar analyses were performed to assess the consistency of relative treatment effects of hormone therapy on Lp(a) across subgroups defined at baseline by age, body mass index, hysterectomy status, prior hormone use, reported alcohol intake, race/ethnicity, and smoking status. No significant departures from consistency were observed.

View this table: [in this window] [in a new window]   Table 5. Estimated Relative Treatment Effects of Hormone Therapy (All Active Arms Combined Averaged Across 12 and 36 Months) for Subgroups Defined by Quartiles of Baseline Lipid Concentrations and Fibrinogen Concentration: Current Adherers Only

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Hormone therapy with CEE resulted in sustained decreases in Lp(a) concentrations among PEPI women. At 36 months, these ranged from 20% to 29% among adherers and from 17% to 26% among all women regardless of adherence. These results were in the range reported by smaller longitudinal studies of 0.625 mg/d CEE,^{7 8 10 14} with the exception of one that resulted in little observed effect.¹⁶ Of the potential beneficial effects of CEE on lipids and lipoproteins measured in PEPI, its impact on a percentage basis was most pronounced for Lp(a). Among adherers, the 25% average reduction in Lp(a) observed at 36 months markedly exceeded the 5% average increase in HDL-C, the 13% average drop in LDL-C, and the 6% average drop in total cholesterol.

Concomitant progestin therapy with MPA or MP had little impact on the overall magnitude of CEE effect on Lp(a). This finding is also consistent with reports for these and other progestins.^{6 16} It suggests that recommendations for concomitant progestin therapy prescribed to women with an intact uterus may not diminish any Lp(a)-mediated impact on cardiovascular disease risk.^{20 24 39}

The treatment effects of hormone therapy on Lp(a) were fairly consistent at 1 and 3 years for women who adhered to their medication. One possible exception may be for women taking micronized progesterone; in PEPI, these women had a 25.7% mean relative treatment-related reduction in Lp(a) at 36 months compared with 16.4% mean reduction at 12 months, a difference that reached nominal statistical significance (P=.03). However, given the large number of comparisons we examined in this report, this finding may be a product of chance. Overall, PEPI's primary finding is that these impacts were long term. This is in contrast to two previous studies^{8 40} that reported treatment effects waned within 1 year.

PEPI confirms that hormone therapy has a broad-scale and sustained impact on lipid metabolism. As recorded in Table 3, hormone therapy was associated with statistically significant alterations in HDL-C, HDL₂-C, HDL₃-C, LDL-C, total cholesterol, triglycerides, apo-A1, and apo-B, besides changes in Lp(a). At baseline, Lp(a) was most highly correlated with LDL-C, total cholesterol, and apo-B concentrations. In PEPI, the reductions of Lp(a) across 1 and 3 years among women adhering to medication were most closely associated with reductions in LDL-C, total cholesterol, apo-B, and fibrinogen, and to increases in HDL-C and HDL₂-C. None of these relationships reached statistical significance at both time points for women taking placebo medications, although the sample size of this cohort was smaller. The magnitudes of the correlations, however, were modest, as might be expected from a complex physiological system that is affected by a number of factors, and may have been diminished by measurement error.

The large PEPI cohort provided a more powerful characterization of associations between changes in Lp(a) and other lipids/lipoproteins than prior smaller studies. For example, whereas Lobo, et al⁷ reported nonsignificant relationships between changes in Lp(a) and both LDL-C and HDL-C but significant negative relationships between changes in Lp(a) and both triglycerides and VLDL-C, Sacks, et al¹⁰ reported that changes in Lp(a) were not significantly correlated with changes in apo-B or LDL-C. PEPI suggests that some of the differences among prior studies may be attributable to random variation.

PEPI indicates that some correlations may change with time. For example, the relationship of changes in Lp(a) and LDL-C that were attributable to hormone therapy were stronger at 12 months than at 36 months. This is consistent with Soma et al,⁹ who reported that short-term relationships between changes in Lp(a) and other lipid/lipoproteins differ at 6 versus 12 months. In their study of 51 participants, of which approximately half were assigned to 1.25 mg/d CEE (with 10 mg/d cyclic MPA), Lp(a) changes were more strongly correlated with changes in total cholesterol and LDL-C at 12 months than at 6 months. This may result from the accrued influence of other mediating factors or perhaps different time courses of treatment effects on these two analyses.

The impact of hormone therapy on Lp(a) was largely independent of baseline lipoprotein profiles. PEPI found a slight but not significant trend for the percent impact of hormone therapy on Lp(a) to be less for women with higher concentrations of Lp(a) at baseline, which is consistent with reports from two other studies.^{7 10} No significant differences in treatment effects were found across subgroups defined by age, body mass, hysterectomy status, prior hormone use, reported alcohol intake, ethnicity, or smoking status. The consistency of the attributable effects indicates that hormones have a direct impact on lipid/lipoprotein metabolism that is not typically or strongly mediated by external factors. It also suggests that the lipid-related benefits of hormone therapy may be broadly expressed across populations.

Several recent studies strengthen evidence that Lp(a) is a substantial risk factor for women younger than 65 years of age. Orth-Gomer et al⁵ found that median Lp(a) was 38% higher in cases compared with control subjects. The prospective Stanford Five-City Project found Lp(a) concentrations were 34% higher in female cases than in control subjects.⁴¹ The prospective Framingham Study found that elevated Lp(a) was an independent risk factor for cardiovascular disease for women (mean age, 45 years).⁴² Because there are no data as to whether reduction of Lp(a) leads to a reduced risk for cardiovascular disease, we cannot quantify the potential risk reduction attributable to CEE therapy.

In summary, PEPI indicated that 0.625 mg/d CEE therapy, with or without progestational agents, leads to long-term stable average decreases in Lp(a) concentrations of 20% to 30% for women who adhere to its prescription. These 3-year changes had modest but statistically significant correlations with concomitant changes in HDL-C, HDL₂-C, LDL-C, total cholesterol, apo-B, and fibrinogen. The treatment effect on Lp(a) was not significantly influenced by baseline levels of lipids and was consistent across clinical subgroups. These findings also indicate that postmenopausal hormone therapy produces consistent changes in a number of plasma lipoproteins and apolipoproteins that with the exception of increased triglycerides are associated with reduced risk of coronary heart disease in women. PEPI data support the hypothesis that Lp(a) is one of the mechanisms through which postmenopausal hormone therapy may convey health benefits.

	Selected Abbreviations and Acronyms

 

apo = apolipoprotein C = cholesterol (HDL-C, LDL-C, VLDL-C) CEE = conjugated equine estrogens Lp(a) = lipoprotein(a) MP = micronized progesterone MPA = medroxyprogesterone acetate PEPI = Postmenopausal Estrogen/Progestin Interventions study

	Acknowledgments

 
The PEPI trial was supported by cooperative agreement research grants (U01-HL-40154, U01-HL-40185, U01-HL-40195, U01-HL-40205, U01-HL-40207, U01-HL-40231, U01-HL-40232 and U01-HL-40273) from the National Heart, Lung, and Blood Institute; the National Institute of Child Health and Human Development; and the National Institutes of Arthritis and Musculoskeletal Diseases. The National Packaged medications and placebos for PEPI were provided by Wyeth-Ayerst Research, Schering-Plough Research Institute, and the Upjohn Co.

Received August 5, 1997; revision received October 24, 1997; accepted October 30, 1997.

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