Journal of Cardiovascular Pharmacology:
Differential Effect of Hormone Therapy and Tibolone on Lipids, Lipoproteins, and the Atherogenic Index of Plasma
Christodoulakos, George E. MD*; Lambrinoudaki, Irene V. MD*; Economou, Emmanuel V. PhD†; Papadias, Constantinos MD*; Panoulis, Constantinos P. MD*; Kouskouni, Evangelia E. MD†; Vlachou, Sofia A. MD*; Creatsas, George C. MD, FACS*
*Second Department of Obstetrics and Gynecology, University of Athens, Aretaieio Hospital, Athens, Greece
†Hormonal and Biochemical Laboratory, University of Athens, Aretaieio Hospital, Athens, Greece
Reprints: Lecturer Irene Lambrinoudaki, 27 Themistokleous St, GR-14578, Dionysos, Athens, Greece (e-mail: email@example.com)
Received for publication October 7, 2005; accepted February 28, 2006
The aim of our study was to assess the effect of various regimens and doses of hormone therapy and tibolone on the Atherogenic Index of Plasma (AIP). A total of 519 postmenopausal women attending our menopause clinic were studied in a prospective design. Women with climacteric symptoms were randomly assigned to receive 1 of the following regimens: tibolone 2.5 mg, conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA), 17β-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), or 17β-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA). Serum parameters were assessed at baseline and after 6 months and included total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The AIP was assessed as the log (triglycerides [mmol/L]/HDL-C [mmol/L]). CEE/MPA treatment associated with lower mean LDL-C but higher mean triglyceride levels (−15.5 mg/dL±3.6, P=0.0001; 12.6 mg/dL±4.8, P=0.01). Furthermore, CEE/MPA treatment resulted in higher AIP levels (0.073±0.021, P=0.001). On the contrary, both E2/NETA regimens and tibolone associated with lower mean triglyceride and HDL-C levels (E2/NETA, triglycerides: −9.8 mg/dL±5.0, P=0.049; HDL-C: −4.9 mg/dL±1.8, P=0.01, low E2/NETA triglycerides: −12.5 mg/dL±4.1, P=0.003; HDL-C: −4.7 mg/dL±1.3, P=0.001; tibolone, triglycerides: −21.9 mg/dL±2.7, P=0.0001; HDL-C: −12.7 mg/dL±1.1, P=0.0001). None of the 3 regimens had any effect on AIP. The effect of a particular regimen of hormone therapy on the lipid-lipoprotein profile differs depending on the parameter assessed. The use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.
In postmenopausal women estrogen deficiency has both metabolic and vascular consequences which increase the risk for cardiovascular disease (CVD). CVD is the leading cause of mortality among postmenopausal women. CVD is influenced by a cluster of factors, the balance of which determines the incidence of the disease.1–3
Following menopause, the beneficial effect of endogenous estrogens on lipid metabolism is lost4 and a proatherogenic lipid-lipoprotein profile is established, which includes an increase in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and lipoprotein (a) [Lp(a)] and a minor decrease in high density lipoprotein cholesterol (HDL-C).4–7 This proatherogenic lipid profile has been considered as contributing to the postmenopausal increase in CVD risk.8 Observational studies have repeatedly reported that hormone therapy (HT) decreased significantly the risk for coronary artery disease (CAD).3,9 This has been partly attributed to the HT-induced beneficial changes on the lipid-lipoprotein profile.10 However, the clinical trials Heart and Estrogen/Progestin Replacement Study (HERS),11 Estrogen Replacement and Atherosclerosis Study,12 and Women's Health Initiative (WHI)13 have failed to corroborate the results of the observational studies. Although in all 3 studies, HT associated with a significant decrease in LDL-C and an increase in HDL-C, the HERS and WHI reported a significant increase in early coronary events, whereas the ERA concluded that HT did not slow the progression of atherosclerosis. Even though the effect of HT on the vascular wall and endothelium is more important in modulating the risk for CVD compared to lipid-lipoproteins, the role of the latter should not be underestimated.14–17 HT preparations combine different estrogens and progestins. Estrogen therapy has a more favorable effect on the lipid profile compared with estrogen-progestin.18 However, in nonhysterectomized women, the addition of the progestin aims in preventing endometrial proliferation.19 The type of progestin, the dose, the mode (continuous, sequential) and the route of administration may enhance, attenuate or even abolish the estrogen induced effect on lipids-lipoproteins.5,6,20,21 Tibolone, an alternative HT regimen, is a synthetic steroid that expresses via its 3α and 3β hydroxymetabolites and the Δ4 isomer a variable affinity for the estrogen, progesterone, and androgen receptor and has a differential effect on the lipid profile compared to HT, with a lesser stimulatory effect on the endometrium and the breast.22–27
Although the concentrations of LDL-C continue to hold a principal role in the association of lipids to CAD, the atherogenic potential of a high TG:HDL-C molar ratio is now recognized by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III.28 The Atherogenic Index of Plasma (AIP), defined as the logarithm of the ratio TG:HDL-C has been proposed recently as a marker of the atherogenic potential of plasma. AIP's significance as a marker is based on the following facts: that it is found increased in cohorts at high risk for CAD; that it is positively correlated with the fractional esterification rate of HDL-C (FERHDL), which is perhaps the most dependable marker for the atherogenic capacity of the lipid-lipoprotein profile; and that it is inversely correlated to LDL-C particle size.29,30 Because the estimation of FERHDL requires chromatography, which is a laborious and often imprecise method, and given the strong correlation between FERHDL and AIP, this index may be used as an alternative marker of plasma atherogenicity.30
The purpose of this study was to evaluate the effect on the lipid-lipoprotein profile and the AIP of different HT regimens and tibolone in postmenopausal women and to evaluate AIP as a global marker of the impact of lipid-lipoprotein modulation induced by hormone therapy on the cardiovascular system.
MATERIALS AND METHODS
A total of 892 postmenopausal women ages 43 to 61 years were included in the study. Subjects were recruited between September 2001 and April 2005 from the Menopause Clinic of the Second Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital. Patients were menopausal for at least 1 year. Women who were past users of HT, tibolone, or raloxifene were not included in the study unless they had been off therapy for at least 6 months.
Before commencing therapy, patients had a gynecological and biochemical evaluation that included bimanual examination, PAP smear and transvaginal sonography, breast examination and mammography, thyroid–liver–renal function, as well as blood coagulation tests and bone densitometry. Criteria for inclusion in the study were an endometrial thickness ≤5 mm, follicle-stimulating hormone (FSH) >20 mIU/mL, serum estradiol <50 pg/mL, the absence of a history of gynecological malignancy, ischemic heart disease, thromboembolism, diabetes mellitus, nontreated thyroid dysfunction, and the intake of lipid-lowering or antihypertensive medication.
The decision to treat was based on the presence of climacteric symptoms. Women were randomly assigned to 1 of the following regimens: tibolone 2.5 mg (Livial, Organon, Oss, the Netherlands); conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, Premelle 5, Wyeth-Ayerst Laboratory, Philadelphia); 17β-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, Kliogest, Novo-Nordisk, Copenhagen, Denmark); or 17β-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, Activelle, Novo-Nordisk, Copenhagen, Denmark). Women without climacteric complaints or women not willing to receive hormone therapy served as controls. All of the subjects signed an informed consent and Institutional Review Board approval was obtained by the Ethics Committee of Aretaieion Hospital.
The study period was 6 months. This is the maximum time allowed for hormone therapy to take effect on clinical symptoms. Blood pressure, weight, and height were recorded in the morning in light clothing and body mass index (BMI) was computed at each visit. Fasting blood samples were drawn at 9:00 AM for the determination of lipid-lipoproteins. Samples were immediately centrifuged and serum was stored at −30°C until assayed.
Serum TC, HDL-C, and TG were assessed enzymatically by an autoanalyzer (COBAS-MIRA, Roche Diagnostics Limited, Lewes, UK). LDL-C was estimated as described by Friedewald [(LDL-C=TC−TG/5−HDL-C)].31 Apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) were determined by an immunoturbimetric assay (ABX Diagnostics BP7290-34187 Monpellier, France). AIP was computed by the following equation: log [TG (mmol/L)/HDL-C (mmol/L)].29
Statistical analysis was performed by SPSS Version 8.0 (SPSS, Chicago, IL). Baseline characteristics were compared between therapy groups by analysis of variance (ANOVA) for continuous variable and by χ2 for categorical variables. Baseline and follow-up lipid-lipoprotein mean levels were compared across the same therapy group by paired t-test. Percentage changes of lipid parameters between groups were assessed by ANOVA. Statistical significance was set at the 0.05 level.
From the 892 women originally enrolled in the study, 519 completed the 6-month study period and were entered in the statistical analysis. Baseline demographic characteristics according to treatment assignment are presented in Table 1. No differences with respect to age, menopausal age, BMI, or serum estradiol were detected. Women in the low E2/NETA group tended to smoke less and exercise more, but this difference failed to reach statistical significance.
Pearson correlation coefficients between baseline serum lipids and age, years since menopause, BMI, and serum steroids and insulin are presented in Table 2. AIP exhibited a positive correlation with age, whereas menopausal age did not correlate with any of the lipid parameters. Furthermore, BMI and serum insulin had a strong positive correlation with AIP. Regarding serum hormones, FSH correlated negatively, whereas testosterone and Free Androgen Index correlated positively with AIP.
Baseline and 6-month mean values of lipid, apolipoprotein, and AIP levels are presented in Table 3. Although no differences between baseline and 6-month assessments were detected in the control group, CEE/MPA users had lower total cholesterol, LDL-C, and higher TG and AIP at the end of the study. The increase in AIP was statistically significantly different compared with the control group (Fig. 1). Tibolone use associated with lower total cholesterol, HDL-C and TG levels, whereas no effect was detected on AIP. Both E2/NETA regimens associated with lower TC, LDL-C, TG, and HDL-C, whereas no effect on AIP was detected.
Although endothelial and vascular wall factors are now accepted as mainly responsible in defining the incidence of CVD among postmenopausal women, a prominent role is still attributed to the lipid-lipoprotein metabolism as a factor involved early in the genesis of arterial disease.32
Experimental, observational, and clinical studies have established, albeit with minor differences, that HT results in an overall antiatherogenic lipid-lipoprotein profile. Oral HT decreases TC, LDL-C, and Lp(a) and increases HDL-C and TG, the latter being the only “dark spot” of the treatment.3,9,33–40 The HT regimens investigated in these studies exhibited a variable effect on lipid-lipoproteins. All regimens decreased TC significantly and this is in accordance with results of previous studies.18,24,37,41–43 Only CEE/MPA and E2/NETA decreased LDL-C significantly. Loh et al42 and Ylikorkala et al41 have reported a greater decrease in TC and LDL-C under E2/NETA. Low E2/NETA had no significant effect on LDL-C, and this may implicate the low estrogen dose as the causative factor. Administering a similar regimen, Loh et al42 also reported a nonsignificant decrease in LDL-C and suggested a dose-related effect. We found that CEE/MPA had no effect on HDL-C and this may be caused by an antagonist effect of MPA on the estrogen-induced increase of HDL-C. This finding contrasts our previous observation37 and the results of large observational studies40 and clinical trials.11,13 Furthermore, Peeyananjarassri and Baber have reported that even low (0.3 mg) CEE/MPA increased HDL-C significantly.44
Progestins do not express a class effect. Progestins even of the same origin may have different metabolic and vascular effects depending on their affinity for the estrogen, progesterone, and androgen receptors.19 Depending on its androgenic potency, a progestin may modulate the metabolic effects of estrogen.20,21,35,36,40,41,45 In this study, the androgenic NETA, both 1 and 0.5 mg, not only abolished the effect of estrogen on HDL-C but even contributed to a significant decrease. A marginal decrease under E2/NETA was also reported in our previous study37 and that of Ylikorkala et al,41 whereas the Post-menopausal Estrogen/Progestin Interventions (PEPI) trial40 showed that the favorable lipid-lipoprotein effects induced by CEE were attenuated less by micronized progesterone as compared with MPA.
The complexity of the lipid-lipoprotein factor and the difficulty in obtaining a clear evaluation on the net effect of this factor on the cardiovascular system becomes evident when considering TG. In our study, CEE/MPA associated with an unwanted statistical significant increase in TG. As yet there is no consensus regarding the effect of estrogen dose. Mercuro et al46 and Lobo et al47 have reported similar magnitudes of TG increase among CEE 0.625 mg and 0.3 mg, whereas Sanada et al48 and Wakatsuki et al49 have associated 0.3 mg with a lower TG increase. Nonandrogenic progestins associate with a minor attenuation of the estrogen-induced effect on HDL-C, but tend to maintain high TG levels. Androgenic progestins invariably tend to counteract the estrogen-associated increase in TG, the extend of which depends on their potency.21 Al-Azzawi et al21 have reported that E2/NETA, in contrast to E2/trimegestone, left TG unchanged. Shang et al,36 however, reported no difference in TG levels between MPA and dydrogesterone. In our study, both E2/NETA and low E2/NETA decreased TG levels significantly. The discrepant effect between MPA and E2/NETA and low E2/NETA may suggest the difference in androgenic potency as a causative factor.
Tibolone expresses a particular effect on the lipid-lipoprotein profile. Tibolone has a less favorable effect on TC and LDL-C compared to HT.6,50,51 Similar to previous reports37,52 we found that tibolone significantly decreases TC, but this is probably attributable to the significant decrease in HDL-C.22,23,37,53 As previously reported,4,22,37 we found that tibolone had no effect on LDL-C. Nevertheless, both an increase as well as a decrease has been reported.52,53 It appears that regarding HDL-C and TG, tibolone has an effect analogous to that of E2/NETA and low E2/NETA. Consistent with the findings of other investigators,22,23,37,51,53 we found that tibolone decreased significantly HDL-C and this may be related to the action of Δ4-isomer. The androgenicity of this isomer contributed to a significant TG decrease, both in the present study as well as in previous ones,23,24,37,50,51,53 with the exception of the study by von Eckardstein et al,22 which failed to confirm this decrease. The significant decrease in TG may be in accord with the suggestion that under tibolone LDL particles may be larger, less dense, and theoretically less atherogenic.54
D'Agostino et al55 refer to the multifactorial etiology of CVD. The lipid-lipoprotein factor is made up of various interrelated parameters, which are differently modulated by the steroid components and their relative estrogenic, progestogenic, and androgenic potencies and the dose and route of administration of the HT regimens as well as by the synthetic steroid tibolone.6 The atherogenic impact of the lipid-lipoprotein factor has been valued variably by different investigators. Jacobs et al56 considers HDL-C to be the most important predictor for CAD risk. The NCEP Adult Treatment Panel III28 identifies LDL-C as the primary target of cholesterol-lowering therapy. TGs have acquired prominence among lipid profile parameters, and their concentration is now considered an independent risk predictor for CAD, particularly among postmenopausal women.30,55,57 Hypertriglyceridemia both by itself and through interaction with other atherogenic metabolic changes increases CAD risk.58,59 Among oral HT users, the estrogen-induced increase in TG is attributed to an increase in hepatic synthesis of VLDL triglycerides and could partly account for the increase in CAD risk.60 TGs are regulators of lipoprotein interactions and are associated with the diameter and density of LDL particles; in essence TG increase reflects the presence of the highly atherogenic VLDL and small dense LDL.29,30,35,58
Although we have a fair understanding of the effect of each individual regimen on each parameter of the lipid profile, the overall impact on CVD prevention is still unclear. The value of a complex unified marker that can determine the net effect cannot be underestimated. AIP is an index that attempts to evaluate this net effect of changes induced on the lipid profile by therapeutic regimens. In essence, it reflects the balance between harmful and cardioprotective lipid-lipoproteins and monitors the efficacy of the therapy administered.29 Gaziano et al61 have reported that the ratio of TG:HDL-C is a strong predictor of myocardial infarction. Tan et al29 have compared the log TG:HDL-C to the TG:HDL-C ratio and have found that the P values for AIP were lower than those of TG:HDL-C ratio.
In our study we found that the AIP increases linearly with age and furthermore that it is positively related to the BMI as well as fasting serum insulin, 2 well-established risk factors for CVD. We found AIP to be positively correlated to the levels of testosterone and free androgen index and negatively to FSH levels. Of the treatment regimens CEE/MPA doubled AIP. Although CEE/MPA associated with a statistically significant decrease in TC and LDL-C, it had no effect on HDL-C, while it significantly increased TG. In the HERS11 and WHI13 trials the same regimen with a lesser MPA dose (2.5 mg) failed to associate with secondary or primary CAD prevention, respectively, and caused an increase in early CAD events, respectively. In this study, neither E2/NETA nor low E2/NETA influenced AIP. E2/NETA has been considered as having an apparently harmful effect on the lipid-lipoprotein profile because of the significant decrease in HDL-C. The observed lack of an effect on AIP may suggest that the concomitant significant decrease in TG negated the nonbeneficial effect on HDL-C.
Although there is as yet no evidence that tibolone is associated with increased risk of cardiovascular events,51,52 its effect on the lipid profile has raised reservations as to the association of this drug with cardiovascular health. Animal studies have suggested that tibolone may have mechanisms of cardioprotection independent of its effect on plasma lipids.62 It has recently been demonstrated, however, that tibolone therapy is associated with increased progression of carotid intima-media thickness in healthy postmenopausal women.63 In our study, tibolone had no effect on AIP, suggesting that the ability of its potent androgenic Δ4-isomer to significantly decrease TG may have neutralized the adverse effect on HDL-C and lack of an effect on LDL-C.
The WHI trial has inevitably shifted clinical interest to HT regimens of different estrogen-progestin combinations administered by different routes and in lower doses. Randomized controlled trials will help further clarify the efficacy and safety of such estrogen-progestin regimens. However, the use of unified markers such as AIP will be helpful in evaluating the overall effect of lipid-lipoprotein modulation on the cardiovascular system. This index does not negate the importance of LDL-C as a cardiovascular risk parameter. In fact, the concurrent assessment of the therapy effect on both LDL-C and AIP may be more dependable in evaluating the cardiovascular impact of a given regimen.
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© 2006 Lippincott Williams & Wilkins, Inc.
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