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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 11 3543-3547
Copyright © 1997 by The Endocrine Society

Original Studies

Oral 17ß-Estradiol Continuously Combined with Dydrogesterone Lowers Serum Lipoprotein(a) Concentrations in Healthy Postmenopausal Women1

V. Mijatovic, P. Kenemans, J. C. Netelenbos, E. R. A. Peters-Muller, G. J. van Kamp, G. A. Voetberg, P. H. M. van de Weijer and M. J. van der Mooren

Departments of Obstetrics and Gynecology (V.M., P.K., E.R.A.P.-M., G.A.V., P.H.M.v.d.W., M.J.v.d.M.), Endocrinology (J.C.N.), and Clinical Chemistry (G.J.v.K.), Project Ageing Women and the Institute for Cardiovascular Research-Vrije Universiteit, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Prof. Dr. P. Kenemans, University Hospital, Vrije Universiteit, Department of Obstetrics and Gynecology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. Serum Lp(a) concentrations increase after menopause, and postmenopausal estrogen replacement appears to decrease Lp(a) levels. In a randomized, double blind study, we examined the effects of 6-month treatment with daily 17ß-estradiol (E2; 2 mg, orally) continuously combined with one of four dosages [2.5 mg (n = 41), 5 mg (n = 38), 10 mg (n = 38), and 15 mg (n = 20)] of dydrogesterone on fasting serum Lp(a) concentrations in 137 healthy postmenopausal women.

At baseline, no significant differences were noted among the four treatment groups. During the study period of 6 months the median serum Lp(a) concentration decreased significantly from 128 mg/L (range, 5–1660) to 110 mg/L (range, 1–1530) in the total population, corresponding to a reduction of 13% (P < 0.001). The percent changes in serum Lp(a) correlated positively with the percent changes in serum E2 at 3 as well as 6 months of therapy (r = 0.38; P < 0.001 and r = 0.35; P < 0.001, respectively). A dose response of dydrogesterone on serum Lp(a) was not found. In addition, serum lipids and (apo)lipoproteins improved significantly in all four treatment groups.

In conclusion, oral E2 continuously combined with dydrogesterone has beneficial effects on the lipid and lipoprotein profile and is effective in lowering Lp(a) concentrations in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A GROWING body of evidence indicates that lipoprotein(a) [Lp(a)] represents an important independent risk factor for atherosclerotic cardiovascular disease in both men and women (1, 2, 3, 4, 5, 6). Lp(a) is a highly atherogenic lipoprotein particle that structurally resembles low density lipoprotein (LDL). However, in contrast to LDL, in Lp(a) the protein moiety consisting of apoprotein B-100 is covalently linked to an additional apoprotein, Apo(a) (7, 8). Lp(a) may cross the arterial endothelium and accumulate at the intimal level, where it contributes in the formation of atherosclerotic plaque (9, 10). In addition, Lp(a) is of particular interest because of the molecular similarity of Apo(a) to plasminogen. In vitro Lp(a) appears to compete for the binding of plasminogen in the fibrinolytic cascade (11). Thus, Lp(a) may have both thrombogenic and atherogenic potentials.

A number of observations suggest a possible role for sex hormones in modulating Lp(a) concentrations. Serum levels of Lp(a) increase after natural and surgical menopause (12, 13), suggesting that these alterations in Lp(a) concentrations may be due either directly or indirectly to estrogen deficiency resulting from the loss of ovarian function. In addition, Lp(a) concentrations are significantly higher in women between 50–59 yr of age than in men of the corresponding age group (14).

Although Lp(a) levels are to some degree lowered by niacin and neomycin (15), they are not appreciably reduced by most conventional pharmacological and dietary therapies for hyperlipidemia (16). On the other hand, several recent reports suggest that postmenopausal hormone replacement therapy (HRT) improves the lipid profile not only by reducing LDL cholesterol serum levels and increasing high density lipoprotein (HDL) cholesterol serum levels, but also by lowering serum Lp(a) concentrations (17, 18, 19, 20, 21). Decreases in LDL cholesterol levels and increases in HDL cholesterol levels do not explain all the apparent cardioprotective effects of HRT in postmenopausal women. A part of the remaining protection could result from decreased Lp(a) concentrations, although many other HRT-induced changes, via various mechanisms, could play a role (22).

It is now generally accepted and strongly recommended to add a progestogen to postmenopausal estrogen supplementation in nonhysterectomized women to ensure endometrial safety. An alternative form of combination hormone therapy is the continuous combined HRT regimen. In this regimen, continuously combined use of estrogen with progestogen in the long run causes endometrial atrophy with the advantage of avoiding monthly withdrawal bleeding (23). Because the addition of some progestogens may partially negate the beneficial effects of estrogen on lipid and lipoprotein profile (24), there is a need for a combined HRT regimen that maintains the beneficial lipoprotein profile typical of estrogen monotherapy. Dydrogesterone is a C-21 progestogen with a chemical structure very closely related to that of natural progesterone. Data from a relatively small study show that cyclically administered dydrogesterone in a combined HRT regimen does not oppose the favorable effects on Lp(a) induced by estradiol (17). However, as far as we know there are no published data concerning the effects of dydrogesterone in a continuous combined HRT regimen on Lp(a). In the present paper we analyze possible effects of various clinically relevant dosages of dydrogesterone on serum Lp(a) concentrations when administered continuously combined with oral micronized 17ß-estradiol (E2) to healthy postmenopausal women in a randomized, double blind study.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

In the Department of Obstetrics and Gynecology out-patient clinic, healthy postmenopausal women were included in this study, which was previously described in more detail (25).

The participants were randomly allocated to one of four treatment groups. The subjects received daily oral treatment consisting of 2 mg micronized E2 (Zumenon) continuously combined with 2.5, 5, 10, or 15 mg dydrogesterone (Duphaston) for a study period of 6 months (Solvay-Duphar, Weesp, The Netherlands). Blood was obtained before commencement of the study, after 3 months of therapy, and at completion of treatment. Each blood sample was collected in the morning after a 12-h fast. Blood was drawn from an antecubital vein with minimal stasis. Compliance was assessed by control of the medication packages and diary cards at each visit.

Laboratory analyses

Venous blood samples were placed into plain tubes and allowed to clot for 1–2 h. Serum was then separated by centrifugation at 3000 x g for 10 min, frozen, and stored at -70 C in sealed polypropylene vials. Serum Lp(a) concentrations were determined using a commercially available enzyme-linked immunoassay (Innotest, Innogenetics, Zwijndrecht, Belgium). The intra- and interassay coefficients of variation for this ELISA were 3.6% and 4.5%, respectively. In this assay configuration, no measurable cross-reactivity was found with plasminogen or LDL up to a concentration of 500 mg/dL. Assays of lipids and (apo)lipoproteins have been described previously (25). Serum E2 concentrations were determined by a double antibody RIA (Sorin Biomedica, Saluggia, Italy) after extraction with diethyl ether to eliminate possible cross-reactivity with estrogen conjugates (26). The lower limit of detection was 18 pmol/L. FSH concentrations were measured in serum by an immunometric (luminescence) assay (Amerlite, Amersham, UK).

Statistical analyses

Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS/PC+ 4.0). Data are expressed as the mean ± SD when appropriate. Lp(a) and triglyceride data are expressed as the median and range. Statistical analyses of all measured parameters for between-group differences at baseline and at 3 and 6 months of therapy were performed by means of one-way ANOVA and the Kruskal-Wallis test. The {chi}2 test was used to compare categorized measures when appropriate. Student’s paired t test and Wilcoxon matched pairs, signed ranks test were used for within-group comparison of the outcome of parameters at baseline with those at 3 and 6 months.

Mean or median percentages of change in concentrations (conc.) of a given parameter were computed on individual values as follows: (conc.3 or 6 months - conc.baseline/conc.baseline) x 100%. Correlations with Lp(a) and triglycerides were assessed using Spearman’s rank coefficients. For assessment of correlations between parameters with a normal distribution, Pearson coefficients were calculated. Statistical significance was inferred when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
After screening, 194 healthy postmenopausal women with a mean age of 51.6 ± 5.0 yr were included in the study. Twenty-one women did not complete the study due to several reasons reported previously (25). Eight women were excluded from analysis due to treatment with lipid-lowering drugs during the study period. Another 28 women were excluded from analysis because of insufficient serum and/or technical reasons. Thus, the results presented here relate to the data of 137 women randomly allocated to 1 of the 4 treatment groups.

Descriptive characteristics (Table 1Go) as well as baseline concentrations of serum Lp(a) (Table 2Go) and serum lipids and (apo)lipoproteins (Table 3Go) were not significantly different among the 4 treatment groups. Furthermore, at baseline there were no significant differences in the descriptive characteristics between the 137 women reported here and the 57 women excluded from analysis (data not shown). In 13 subjects, serum E2 concentrations at baseline were below the detection limit (Table 1Go). The serum E2 values were equally distributed over all groups.


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  		Table 1. Baseline characteristics of the four treatment groups receiving oral micronised E2 (2 mg daily) continuously combined with four different doses of dydrogesterone (2.5, 5, 10, and 15 mg, respectively)

 

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  		Table 2. Serum concentrations of Lp(a) (milligrams per L) in the four HRT groups receiving different dosages of dyrogesterone (2.5, 5, 10, and 15 mg) during the 6-month study period

 

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  		Table 3. Serum concentrations of lipids and (apo)lipoproteins in the total subject population (n = 137) during the 6-month study period

 
Lp(a)

Serum Lp(a) concentrations showed the typical highly skewed distribution (skewness, 2.04; kurtosis, 3.57) among the total subject population before treatment (Table 2Go). During the study period the median serum Lp(a) concentration decreased significantly from 128 mg/L at baseline to 112 mg/L (at 3 months) to 110 mg/L at 6 months in the total subject population. The mean reduction in Lp(a) between pretreatment and 6 months was 13.0%. At both 3 months and 6 months of therapy, serum Lp(a) concentrations as well as their changes vs. baseline were not significantly different among the 4 treatment groups. The differences in serum Lp(a) concentrations before and after treatment [{Delta} Lp(a) values] were related to their baseline levels. In the total study population, the {Delta} Lp(a) values at 6 months of hormone therapy negatively correlated with the baseline serum Lp(a) levels (r = -0.65; P < 0.001; Fig. 1Go), indicating that the greatest Lp(a) reduction was obtained in the women with the highest baseline levels.



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  		Figure 1. Differences in serum Lp(a) concentrations before and after treatment ({Delta} Lp(a) values) were related to their baseline levels. In the total study population, the delta Lp(a) values at six months of hormone therapy negatively correlated with the baseline serum Lp(a) levels (r = -0.65, P < 0.001), indicating that the greatest Lp(a) reduction was obtained in the women with the highest baseline levels.

 
As cardiovascular risk has been associated with serum concentrations of Lp(a) greater than 250–300 mg/L (27), we divided the study population into two subgroups classified according to a baseline serum Lp(a) lower (n = 98) or higher (n = 39) than 250 mg/L. Although the reductions in serum Lp(a) concentrations vs. baseline were larger in the women who had elevated pretreatment Lp(a) values (>250 mg/L) than in women with normal baseline Lp(a) values (<=250 mg/L) at both 3 and 6 months of treatment, this difference between absolute changes was not statistically significant (P = 0.055 and P = 0.078, respectively). There was a positive correlation between the concentrations of Lp(a) and LDL cholesterol both before and at the end of the study (r = 0.21; P < 0.05 and r = 0.18; P < 0.05, respectively; n = 137). Likewise, the absolute changes in Lp(a) concentration after 6 months of treatment correlated with the absolute change in LDL cholesterol concentration (r = 0.18; P < 0.05; n = 137). At baseline as well as during treatment, serum Lp(a) levels showed no significant correlation with serum E2 concentrations. However, the percent changes in serum Lp(a) correlated positively with the percent changes in serum E2 at 3 as well as 6 months of therapy (r = 0.38; P < 0.001 and r = 0.35; P < 0.001, respectively; n = 124).

Serum lipids and (apo)lipoproteins

Table 3Go gives the changes in serum lipids and (apo)lipoprotein profile in the total subject population (n = 137) after 3 and 6 months of continuously combined HRT. As previously reported (25), no dydrogesterone dose-dependent effects were demonstrable.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Lp(a) is a focus of research interest because of the epidemiological association of its elevation in serum with clinical (1, 2, 3, 4, 5, 6) as well as preclinical cardiovascular disease (28). The highly skewed distribution of Lp(a) together with the wide range of serum concentrations found have been explained by variations in the Apo(a) gene locus on the long arm of chromosome 6 adjacent to the plasminogen gene (7, 29). Therefore, Lp(a) concentrations seem to be determined by genetic inheritance. However, nongenetic factors, including age, gender, and menopausal status, appear to be closely associated with Lp(a) levels (12, 13, 14).

Our data support the concept that exogenous female sex hormones favorably influence Lp(a) metabolism. We observed a mean reduction of 13% in serum Lp(a) concentrations in postmenopausal women after 6 months of treatment with oral continuous combined HRT. The reduction found is consistent with previous reports on Lp(a) lowering in postmenopausal users of HRT (17, 21, 30, 31, 32). However, it should be noted that in studies using androgenic progestogens, a greater reduction in Lp(a) has been found (33, 34, 35).

Earlier, Van der Mooren et al. (17) reported beneficial alterations in Lp(a) levels and lipid profile during sequential E2/dydrogesterone therapy in postmenopausal women, with no differences in Lp(a) or other serum lipoprotein levels between the E2-only phase and the combined E2-dydrogesterone phase, suggesting that dydrogesterone is a metabolically inert progestogen. In addition, Gelfand et al. (36) recently reported a more pronounced improvement in lipid profile when oral conjugated estrogens were sequentially combined with dydrogesterone compared to the effect of medroxyprogesterone acetate. This confirms the neutral effects of dydrogesterone on lipid metabolism. In the present study, the different doses of dydrogesterone did not show any significantly different effect on Lp(a), although the decrease in median Lp(a) concentration in the group with the unrealistically high dose of 15 mg dydrogesterone was smaller than those with the other, more common doses. Changes in the concentration of Lp(a) during treatment correlated negatively with the baseline concentrations of Lp(a). This result confirms that lowering Lp(a) concentrations by HRT can be effective precisely in those women who have elevated Lp(a) pretreatment values (17, 18, 19). In most epidemiological studies that indicated Lp(a) as an independent risk factor for cardiovascular disease atherogenesis has been associated with plasma Lp(a) concentrations greater than 250–300 mg/L (27), cut-off levels that are indicative, but not unequivocally established. Normolipidemic subjects with Lp(a) concentrations above these levels (~20–30% of individuals in a normal population) (27) have a risk for myocardial infarction approximately twice that of subjects with normal levels (37). Recently, Taskinen et al. (19), demonstrated that after 12 months of oral continuous combined E2 and norethisterone acetate therapy, plasma Lp(a) concentrations decreased more in postmenopausal women with high pretreatment Lp(a) values (>300 mg/L) than in women with normal pretreatment Lp(a) values. In our study population, baseline Lp(a) concentrations above 250 mg/L were observed in 28% of the participants. There was no significant difference between the Lp(a)-lowering effect in women with baseline Lp(a) concentrations above 250 mg/L and women with baseline Lp(a) concentrations in the normal range (<=250 mg/L) during the study period, although there was a trend toward a larger reduction in Lp(a) concentrations in women with elevated baseline Lp(a) values (>250 mg/L). When using a threshold for Lp(a) of 300 mg/L, this difference in reduction disappeared completely (data not shown).

The exact mechanisms responsible for the regulation of serum Lp(a) concentrations are complex and only partially understood. Because of the structural resemblance between Lp(a) and LDL, much attention has been given to investigating the role of the hepatic LDL receptor in Lp(a) catabolism. Snyder et al. (38) showed that Lp(a) does bind to the LDL receptor, but that the LDL receptor-mediated degradation of Lp(a) by human hepatocytes is slower than that of LDL. As estrogens lower LDL cholesterol by up-regulating the expression of LDL receptors in the liver in vitro (39), it is possible that increased LDL receptor-mediated catabolism (40) is accountable in part for the estrogen-induced reduction in Lp(a) concentrations. The significant correlations found between Lp(a) and LDL cholesterol in our study would support the above-described mechanism. As evidence was recently given for Lp(a) concentrations being controlled more by hepatic synthesis than by catabolism (41), a possible alternative mechanism is that estrogens stimulate the synthesis and secretion of VLDL in the liver (42). Increased synthesis of VLDL requires Apo B-100, thus making it less available for the assembly of Lp(a).

Changes in the concentrations of the other lipids and (apo)lipoproteins during treatment were favorable and without any dose response of dydrogesterone. In contrast to previous studies (19, 30) that reported reductions in HDL cholesterol during oral continuous combined HRT, we found a significant increase in HDL cholesterol (mean change of 11%) during treatment. This outcome is important with respect to cardioprotection, as low levels of HDL cholesterol have been found to increase a woman’s risk of developing an accelerated form of atherosclerotic cardiovascular disease (43). The inconsistency in the HRT-induced effect on HDL cholesterol levels, as described above, appears to be due to differences in progestional agents applied (norethisterone acetate and desogestrel vs. dydrogesterone), considering that continuous E2 therapy was used in all three studies.

In summary, oral E2 continuously combined with varying dosages of dydrogesterone lowers the concentration of serum Lp(a) in postmenopausal women. The observed favorable changes in Lp(a), lipids and (apo)lipoproteins could be related to the effect of both E2 and dydrogesterone, although it is unlikely that dydrogesterone has any demonstrable effect on lipid profile (36). According to current concepts, reduction of total cholesterol, LDL cholesterol, and Lp(a) in addition to a rise in HDL cholesterol decrease cardiovascular disease risk. Therefore, oral E2 and dydrogesterone can indeed be recommended for use in a continuous combined HRT regimen.


   Acknowledgments
 
We thank Dr. C. Popp-Snijders (Department of Clinical Chemistry, Endocrine Laboratory) for advice, Mrs. A. Kok-Verspuy (Department of Clinical Chemistry, Immunochemistry Laboratory) for excellent technical assistance with the Lp(a) determinations, and Dr. A. A. Verstraeten (Department of Obstetrics and Gynecology) for statistical consultation.


   Footnotes
 
1 This work was supported by Solvay Duphar bv (Weesp, The Netherlands) and Grant 96–18 from the Biocare Foundation. Back

Received May 14, 1997.

Revised July 23, 1997.

Accepted July 28, 1997.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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