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
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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