Effects of three combined oral contraceptive preparations containing desogestrel plus ethinyl estradiol on lipid metabolism in comparison with two levonorgestrel preparations Helenius J. Kloosterboer, PhD, and Hans Rekers, MD Oss, The Netherlands The effects of three different desogestrel-containing combined oral contraceptive preparations on lipid metabolism were compared with those of two levonorgestrel preparations. The following preparations were studied: (1) monophasic desogestrel (150/30), (2) monophasic desogestrel (150/20, containing 20 fLg of ethinyl estradiol instead of 30 fLg of ethinyl estradiol, (3) biphasic desogestrel, (4) monophasic levonorgestrel (150/30), and (5) triphasic levonorgestrel. The effects of these preparations were assessed on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol, and the ratio of apolipoprotein A-I to apolipoprotein B after 3 months of treatment, and the percentage changes with regard to pretreatment were calculated. The monophasic desogestrel (150/30) and biphasic desogestrel preparations induced higher high-density lipoprotein cholesterol and apolipoprotein A-I levels than did their levonorgestrel-containing counterparts. Low-density lipoprotein Cholesterol levels were increased in monophasic levonorgestrel and clearly decreased in the lowest ethinyl estradiol-containing monophasic desogestrel (150/20) and biphasic desogestrel preparations. Apolipoprotein B increased in all preparations. The antiatherogenic indexes (ratios of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B were higher for monophasic desogestrel (150/30) and biphasic desogestrel than for comparable levonorgestrel-containing preparations. The differences seen between the desogestrel and levonorgestrel preparations can best be explained by the lower intrinsic androgenicity of 3-keto-desogestrel (active metabolite of desogestrel) than that of levonorgestrel. (AM J OBSTET GVNECOL 1990;163:370-3.)
Key words: Desogestrel, lipid metabolism, oral contraceptives
The two constituents of combined oral contraceptives have counteracting effects on various lipid parameters. Ethinyl estradiol increases triglycerides, highdensity lipoprotein cholesterol, and its major apolipoprotein, whereas low-density lipoprotein cholesterol is decreased. Progestogens, especially those derived from nortestosterone, have opposite effects on these parameters. Larsson-Cohn et al. l showed that for levonorgestrel-containing preparations, the ratio ethinyl estradiol to levonorgestrel determines the final effect on various lipid parameters. In 1981 an oral contraceptive preparation containing the new progestogen, desogestrel (150 ILg), in combination with 30 ILg of ethinyl estradiol, was introduced. In comparative studies 2. 3 it appeared that this oral contraceptive preparation induces a higher high-density lipoprotein cholesterol level than a similar combination of levonorgestrel and ethinyl estradiol. This difference is attributed to the less intrinsic androgenicity of 3-ketoFrom the Organon Scientific Development Group 055. Reprint requests: H.I Kloosterboer, PhD, Organon Int. B. V., P. O. Box 20,5340 BH 055, The Netherlands.
610/18221
370
Table I. Composition and regimen of the oral contraceptive preparations used in the present study Regimen
Preparation Biphasic desogestrel Monophasic desogestrel (150/30) Monophasic de sogestrel (150/20) Monophasic levonorgestrel Triphasic levonorgestrel
7 days 14 days 21 days
25 fLg DSG 125 fLg DSG ISO ILg DSG
+ + +
40 fLg EE 30 fLg EE 30 fLg EE
21 days
150 fLg DSG
+
20 fLg EE
21 days
150 fLg LNG
+
30 fLg EE
6 days
50 fLG LNG
+
30 fLg EE
5 days 10 days
75 fLg LNG 125 fLg LNG
+ +
40 fLg EE 30 fLg EE
DSG, Desogestrel; LNG, levonorgestrel; EE, ethinyl estradiol.
desogestrel (the active metabolite of desogestrel) compared with that of levonorgestreJ.4 Another oral contraceptive preparation containing 150 ILg of the progestogen, desogestrel, in combination with only 20 ILg of ethinyl estradiol, was marketed in 1988. Furthermore, a biphasic preparation containing approximately
Desogestrel and lipid metabolism
Volume 163 Number 1, Part 2
HDl-cholesterol (prec.) alter 3 cycles
371
Apo A-I after 3 cycles
.6.%
.6.%
20
30
20
10
i i~jljijiji
+ 10
20
. . . .: . : . : . : . .
:1.:1....::...:i::. .
..1:... ::.. :·.. :.:.. :·... :::: ...... ::...
O;-~--~~--~~~~~~~~~~--
lNG+EE
lNG+EE
DSG+EE
DSGtEE
150/30
TRI
150/20
150/30
DSG+EE Bl
Fig. 1. Percentage change in high-density lipoprotein cholesterol (precipitation method) during treatment with the various combinations of oral contraceptives studied. Open bars are levonorgestrel preparations and dotted bars desogestrel preparations (see Table I for composition and intake regimen of the preparations). HDL, High-density lipoprotein; LNG, levonorgestrel; EE, ethinyl estradiol; DSG, desogestrel.
30% less desogestrel than that in the monophasic preparations is in development. In past years several wellcontrolled studies were performed with these preparations, in which levonorgestrel preparations were used as reference to assess the effects on lipid metabolism. In this article we give a survey of our findings to see whether we can observe certain trends in effects on lipid metabolism in relation to the composition of the various preparations. We discuss the effects of the three desogestrel-containing preparations on some important lipid parameters (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, and the ratios high-density lipoprotein cholesterol to low-density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B) in comparison with those of monophasic and triphasic levonorgestrel preparations. Material and methods
All women participating in the various studies were in good general health and without contraindications for oral contraceptives. They were 20 to 36 years of age with regular menstrual cycles and had no hormonal treatment 2 months before the start of the study. During the study, they did not receive any medication and were not allowed to change their life-style with respect to alcohol consumption, exercise, and smoking. Table I shows the composition of the oral contraceptives used and the intake regimen given. Blood samples were taken after overnight fasting be-
10
20
lNGtEE
lNGtEE
150/30
TRI
DSGtEE
DSGtEE
150/20
150/30
DSG+EE BI
Fig. 2. Percentage change in apolipoprotein A-I (apo A-I) during treatment with the various combinations of oral contraceptives studied (see Fig. I for explanation about bars and abbreviations).
LDl-cholesterol (grad.) alter 3 cycles .6.%
20
10
+
20
lNG+EE
150/30
lNGtEE
TRI
DSGtEE
150/20
DSG+EE
150/30
DSGtEE BI
Fig. 3. Percentage change in low-density lipoprotein cholesterol (isolated by gradient centrifugation) during treatment with the various oral contraceptive combinations studied (see Fig. I for explanation about bars and abbreviations). LDL, lowdensity lipoprotein.
fore the start of treatment and in the third treatment cycle on one of the last 3 days of tablet intake. Blood was collected in tubes containing ethylenediaminetetraacetic acid as anticoagulant and plasma was prepared according to a routine laboratory procedure. Serum was also prepared. All lipid assessments were carried out as previously described. 5
372
Kloosterboer and Rekers
July 1990 Am J Obstet Gynecol
HDl-chol. (grad.) after 3 cycles LDl-chol.
Apo A-I after 3 cycles Apo B
20
10
20
10
lNG+EE 150/30
lNG+EE TRI
DSGHE 150/20
DSG+EE 150/30
DSG+EE BI
Fig. 4. Percentage change in the calculated ratio of highdensity lipoprotein cholesterol to low-density lipoprotein cholesterol (both isolated by gradient centrifugation) with the various oral contraceptive combinations (see Fig. 1 for explanation about bars and abbreviations).
20
lNG+EE 150/30
lNGHE TRI
DSGHE 150/20
DSG+EE 150/30
DSGHE BI
Fig. 5. Percentage change in the calculated ratio of apolipoprotein A-I (apo A-I) to apolipoprotein B (apo B) with the various oral contraceptive combinations studied (see Fig. 1 for explanation about bars and abbreviations).
Table II. RBAs of levonorgestrel and 3-keto-desogestrel for the progesterone and androgen receptors in intact MCF-7 cells and their selectivity indexes (ratio RBA progesterone receptor to that of androgen receptor)
3-keto-desogestrel Levonorgestrel
Progesterone receptor (Org 2058 = 100%)
Androgen receptor (DHT = 100%)
260 135
6.5 15.3
Selectivity index
40
8.8
From Kloosterboer et al. Contraception 1988;38:325-32, with permission of Butterworth Publishers.
Results
The effects of the various preparations on highdensity lipoprotein cholesterol are illustrated in Fig. l. A clear decrease in high-density lipoprotein cholesterol is observed with monophasic levonorgestrel. A reduction in the amount of levonorgestrel of approximately 30% as in triphasic levonorgestrel gives a smaller decrease in high-density lipoprotein cholesterol. The use of desogestrel as progestogen in two monophasic preparations gives a slight increase in high-density lipoprotein. Reducing the amount of desogestrel as in the biphasic preparation shows a further increase in highdensity lipoprotein cholesterol. The apolipoprotein A-I levels increase for all preparations studied as seen in Fig. 2. We measured total apolipoprotein A-I levels in these studies, and because a small contribution of apolipoprotein A-I may be derived from serum fractions other than high-density lipoprotein, no decrease was observed for any of the preparations studied. Most likely the contribution to apolipoprotein A-I of these fractions is more or less similar for the various prep-
arations, since the same trend is seen for apolipoprotein A-I as for high-density lipoprotein cholesterol. The changes in low-density lipoprotein cholesterol are seen in Fig. 3. An increase in this atherogenic parameter is found for monophasic levonorgestrel, whereas no change is observed for the monophasic desogestrel (150/30) preparation. Surprisingly, the other monophasic desogestrel (150/20) shows a decrease. The increase in low-density lipoprotein cholesterol is less pronounced for triphasic levonorgestrel than for monophasic levonorgestrel, but its desogestrelcontaining counterpart shows a clear decrease. The apolipoprotein B levels measured in serum were increased for all preparations and did not show the trend found for low-density lipoprotein cholesterol (results not shown). The antiatherogenic indexes, ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol, and ratio of apolipoprotein A-I to apolipoprotein B were calculated, because various investigators believe that these parameters are the best indicators of cardiovascular risk. Both parameters
Desogestrel and lipid metabolism
Volume 163 Number 1, Part 2
(Figs. 4 and 5) give the same pattern: a clear decrease in values for monophasic levonorgestrel, whereas the values for biphasic desogestrel show a profound increase.
Comment The best explanation for the difference in effects on high-density lipoprotein between desogestrel preparations and comparable levonorgestrel preparations can be found in the lower intrinsic androgenicity of 3keto-desogestrel compared with that of levonorgestrel. Table II4 shows the relative binding affinities for the progesterone and androgen receptors of the two progestogens. The calculated selectivity index for 3-ketodesogestrel is far higher than that of levonorgestrel. Kuusi et al. 6 showed that the two progestogens, desogestrel and levonorgestrel, have a different effect on hepatic lipase. This enzyme is involved in the catabolism of HDL2 and it is stimulated by levonorgestrel. Consequently, lower high-density lipoprotein cholesterol and apolipoprotein A-I, the major apolipoprotein of high-density lipoprotein, will be found for the levonorgestrel preparations compared with the desogestrel preparations. The difference in intrinsic androgenicity of the two progestogens is likely to be responsible for the difference in effect on low-density lipoprotein cholesterol. Reducing the dose of levonorgestrel as in the triphasic preparation diminishes the effects on lipid metabolism, whereas lowering the dose of desogestrel as in the biphasic preparation further improves the effects on lipid metabolism. Thus both the type and dose of the progestogen are important for the final effect on lipid metabolism. The lower androgenicity of 3-keto-desogestrel makes
373
it possible to reduce the amount of ethinyl estradiol to 20 fLg without substantially impairing the lipid profile. Castelli7 showed that high levels of high-density lipoprotein and low low-density lipoprotein decrease the risk of coronary heart disease in women. In light of these observations, it can be concluded that oral contraceptive preparations with a good lipid profile (high high-density lipoprotein and low lowdensity lipoprotein) have an advantage. Therefore the better antiatherogenic indexes found with the desogestrel prepartions compared with those for the levonorgestrel preparations can be considered beneficial. REFERENCES 1. Larsson-Cohn U, Fahraeus L, Wallentin L, Zador G. Lipoprotein changes may be minimized by proper composition of a combined oral contraceptive. Fer Steril 1981; 35: 172-9. 2. Van der Vange N, Kloosterboer Hj, Haspels AA. Effects of seven low-dose combined oral contraceptives on high density lipoprotein subfractions. Br j Obstet Gynecol 1987;94:559-67. ~. Samsioe G. Comparative effects of the oral contraceptive combinations 0.150 mg desogestrel + 0.030 mg ethinylestradiol and 0.150 mg levonorgestrel + 0.030 mg ethinylestradiol on lipid and lipoprotein metabolism in healthy female volunteers. Contraception 1982;25:487-503. 4. Kloosterboer Hl, Vonk-NoordegraafCA, Turpijn EW. Selectivity on progesterone and androgen receptor binding of progestogens used in oral contraceptives. Contraception 1988;38:325-32. 5. Kloosterboer Hj, Van Wayjen RGA, Van der Ende A. Comparative effects of monophasic desogestrel plus ethinyloestradiol and triphasic levonorgestrel plus ethinyloestradiol on lipid metabolism. Contraception 1986;34:135-44. 6. Kuusi T, Nikkilii EA, Tikkanen Mj, Sipinen S. Effects of two progestins with different androgenic properties on hepatic endothelial lipase and high density lipoprotein. Atherosclerosis 1985;54:251-62. 7. Castelli WP. Cardiovascular disease in women. AM 1 OBSTET GYNECOL 1988;158:1553-60.
Key words: Desogestrel, lipid metabolism, oral contraceptives
The two constituents of combined oral contraceptives have counteracting effects on various lipid parameters. Ethinyl estradiol increases triglycerides, highdensity lipoprotein cholesterol, and its major apolipoprotein, whereas low-density lipoprotein cholesterol is decreased. Progestogens, especially those derived from nortestosterone, have opposite effects on these parameters. Larsson-Cohn et al. l showed that for levonorgestrel-containing preparations, the ratio ethinyl estradiol to levonorgestrel determines the final effect on various lipid parameters. In 1981 an oral contraceptive preparation containing the new progestogen, desogestrel (150 ILg), in combination with 30 ILg of ethinyl estradiol, was introduced. In comparative studies 2. 3 it appeared that this oral contraceptive preparation induces a higher high-density lipoprotein cholesterol level than a similar combination of levonorgestrel and ethinyl estradiol. This difference is attributed to the less intrinsic androgenicity of 3-ketoFrom the Organon Scientific Development Group 055. Reprint requests: H.I Kloosterboer, PhD, Organon Int. B. V., P. O. Box 20,5340 BH 055, The Netherlands.
610/18221
370
Table I. Composition and regimen of the oral contraceptive preparations used in the present study Regimen
Preparation Biphasic desogestrel Monophasic desogestrel (150/30) Monophasic de sogestrel (150/20) Monophasic levonorgestrel Triphasic levonorgestrel
7 days 14 days 21 days
25 fLg DSG 125 fLg DSG ISO ILg DSG
+ + +
40 fLg EE 30 fLg EE 30 fLg EE
21 days
150 fLg DSG
+
20 fLg EE
21 days
150 fLg LNG
+
30 fLg EE
6 days
50 fLG LNG
+
30 fLg EE
5 days 10 days
75 fLg LNG 125 fLg LNG
+ +
40 fLg EE 30 fLg EE
DSG, Desogestrel; LNG, levonorgestrel; EE, ethinyl estradiol.
desogestrel (the active metabolite of desogestrel) compared with that of levonorgestreJ.4 Another oral contraceptive preparation containing 150 ILg of the progestogen, desogestrel, in combination with only 20 ILg of ethinyl estradiol, was marketed in 1988. Furthermore, a biphasic preparation containing approximately
Desogestrel and lipid metabolism
Volume 163 Number 1, Part 2
HDl-cholesterol (prec.) alter 3 cycles
371
Apo A-I after 3 cycles
.6.%
.6.%
20
30
20
10
i i~jljijiji
+ 10
20
. . . .: . : . : . : . .
:1.:1....::...:i::. .
..1:... ::.. :·.. :.:.. :·... :::: ...... ::...
O;-~--~~--~~~~~~~~~~--
lNG+EE
lNG+EE
DSG+EE
DSGtEE
150/30
TRI
150/20
150/30
DSG+EE Bl
Fig. 1. Percentage change in high-density lipoprotein cholesterol (precipitation method) during treatment with the various combinations of oral contraceptives studied. Open bars are levonorgestrel preparations and dotted bars desogestrel preparations (see Table I for composition and intake regimen of the preparations). HDL, High-density lipoprotein; LNG, levonorgestrel; EE, ethinyl estradiol; DSG, desogestrel.
30% less desogestrel than that in the monophasic preparations is in development. In past years several wellcontrolled studies were performed with these preparations, in which levonorgestrel preparations were used as reference to assess the effects on lipid metabolism. In this article we give a survey of our findings to see whether we can observe certain trends in effects on lipid metabolism in relation to the composition of the various preparations. We discuss the effects of the three desogestrel-containing preparations on some important lipid parameters (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, and the ratios high-density lipoprotein cholesterol to low-density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B) in comparison with those of monophasic and triphasic levonorgestrel preparations. Material and methods
All women participating in the various studies were in good general health and without contraindications for oral contraceptives. They were 20 to 36 years of age with regular menstrual cycles and had no hormonal treatment 2 months before the start of the study. During the study, they did not receive any medication and were not allowed to change their life-style with respect to alcohol consumption, exercise, and smoking. Table I shows the composition of the oral contraceptives used and the intake regimen given. Blood samples were taken after overnight fasting be-
10
20
lNGtEE
lNGtEE
150/30
TRI
DSGtEE
DSGtEE
150/20
150/30
DSG+EE BI
Fig. 2. Percentage change in apolipoprotein A-I (apo A-I) during treatment with the various combinations of oral contraceptives studied (see Fig. I for explanation about bars and abbreviations).
LDl-cholesterol (grad.) alter 3 cycles .6.%
20
10
+
20
lNG+EE
150/30
lNGtEE
TRI
DSGtEE
150/20
DSG+EE
150/30
DSGtEE BI
Fig. 3. Percentage change in low-density lipoprotein cholesterol (isolated by gradient centrifugation) during treatment with the various oral contraceptive combinations studied (see Fig. I for explanation about bars and abbreviations). LDL, lowdensity lipoprotein.
fore the start of treatment and in the third treatment cycle on one of the last 3 days of tablet intake. Blood was collected in tubes containing ethylenediaminetetraacetic acid as anticoagulant and plasma was prepared according to a routine laboratory procedure. Serum was also prepared. All lipid assessments were carried out as previously described. 5
372
Kloosterboer and Rekers
July 1990 Am J Obstet Gynecol
HDl-chol. (grad.) after 3 cycles LDl-chol.
Apo A-I after 3 cycles Apo B
20
10
20
10
lNG+EE 150/30
lNG+EE TRI
DSGHE 150/20
DSG+EE 150/30
DSG+EE BI
Fig. 4. Percentage change in the calculated ratio of highdensity lipoprotein cholesterol to low-density lipoprotein cholesterol (both isolated by gradient centrifugation) with the various oral contraceptive combinations (see Fig. 1 for explanation about bars and abbreviations).
20
lNG+EE 150/30
lNGHE TRI
DSGHE 150/20
DSG+EE 150/30
DSGHE BI
Fig. 5. Percentage change in the calculated ratio of apolipoprotein A-I (apo A-I) to apolipoprotein B (apo B) with the various oral contraceptive combinations studied (see Fig. 1 for explanation about bars and abbreviations).
Table II. RBAs of levonorgestrel and 3-keto-desogestrel for the progesterone and androgen receptors in intact MCF-7 cells and their selectivity indexes (ratio RBA progesterone receptor to that of androgen receptor)
3-keto-desogestrel Levonorgestrel
Progesterone receptor (Org 2058 = 100%)
Androgen receptor (DHT = 100%)
260 135
6.5 15.3
Selectivity index
40
8.8
From Kloosterboer et al. Contraception 1988;38:325-32, with permission of Butterworth Publishers.
Results
The effects of the various preparations on highdensity lipoprotein cholesterol are illustrated in Fig. l. A clear decrease in high-density lipoprotein cholesterol is observed with monophasic levonorgestrel. A reduction in the amount of levonorgestrel of approximately 30% as in triphasic levonorgestrel gives a smaller decrease in high-density lipoprotein cholesterol. The use of desogestrel as progestogen in two monophasic preparations gives a slight increase in high-density lipoprotein. Reducing the amount of desogestrel as in the biphasic preparation shows a further increase in highdensity lipoprotein cholesterol. The apolipoprotein A-I levels increase for all preparations studied as seen in Fig. 2. We measured total apolipoprotein A-I levels in these studies, and because a small contribution of apolipoprotein A-I may be derived from serum fractions other than high-density lipoprotein, no decrease was observed for any of the preparations studied. Most likely the contribution to apolipoprotein A-I of these fractions is more or less similar for the various prep-
arations, since the same trend is seen for apolipoprotein A-I as for high-density lipoprotein cholesterol. The changes in low-density lipoprotein cholesterol are seen in Fig. 3. An increase in this atherogenic parameter is found for monophasic levonorgestrel, whereas no change is observed for the monophasic desogestrel (150/30) preparation. Surprisingly, the other monophasic desogestrel (150/20) shows a decrease. The increase in low-density lipoprotein cholesterol is less pronounced for triphasic levonorgestrel than for monophasic levonorgestrel, but its desogestrelcontaining counterpart shows a clear decrease. The apolipoprotein B levels measured in serum were increased for all preparations and did not show the trend found for low-density lipoprotein cholesterol (results not shown). The antiatherogenic indexes, ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol, and ratio of apolipoprotein A-I to apolipoprotein B were calculated, because various investigators believe that these parameters are the best indicators of cardiovascular risk. Both parameters
Desogestrel and lipid metabolism
Volume 163 Number 1, Part 2
(Figs. 4 and 5) give the same pattern: a clear decrease in values for monophasic levonorgestrel, whereas the values for biphasic desogestrel show a profound increase.
Comment The best explanation for the difference in effects on high-density lipoprotein between desogestrel preparations and comparable levonorgestrel preparations can be found in the lower intrinsic androgenicity of 3keto-desogestrel compared with that of levonorgestrel. Table II4 shows the relative binding affinities for the progesterone and androgen receptors of the two progestogens. The calculated selectivity index for 3-ketodesogestrel is far higher than that of levonorgestrel. Kuusi et al. 6 showed that the two progestogens, desogestrel and levonorgestrel, have a different effect on hepatic lipase. This enzyme is involved in the catabolism of HDL2 and it is stimulated by levonorgestrel. Consequently, lower high-density lipoprotein cholesterol and apolipoprotein A-I, the major apolipoprotein of high-density lipoprotein, will be found for the levonorgestrel preparations compared with the desogestrel preparations. The difference in intrinsic androgenicity of the two progestogens is likely to be responsible for the difference in effect on low-density lipoprotein cholesterol. Reducing the dose of levonorgestrel as in the triphasic preparation diminishes the effects on lipid metabolism, whereas lowering the dose of desogestrel as in the biphasic preparation further improves the effects on lipid metabolism. Thus both the type and dose of the progestogen are important for the final effect on lipid metabolism. The lower androgenicity of 3-keto-desogestrel makes
373
it possible to reduce the amount of ethinyl estradiol to 20 fLg without substantially impairing the lipid profile. Castelli7 showed that high levels of high-density lipoprotein and low low-density lipoprotein decrease the risk of coronary heart disease in women. In light of these observations, it can be concluded that oral contraceptive preparations with a good lipid profile (high high-density lipoprotein and low lowdensity lipoprotein) have an advantage. Therefore the better antiatherogenic indexes found with the desogestrel prepartions compared with those for the levonorgestrel preparations can be considered beneficial. REFERENCES 1. Larsson-Cohn U, Fahraeus L, Wallentin L, Zador G. Lipoprotein changes may be minimized by proper composition of a combined oral contraceptive. Fer Steril 1981; 35: 172-9. 2. Van der Vange N, Kloosterboer Hj, Haspels AA. Effects of seven low-dose combined oral contraceptives on high density lipoprotein subfractions. Br j Obstet Gynecol 1987;94:559-67. ~. Samsioe G. Comparative effects of the oral contraceptive combinations 0.150 mg desogestrel + 0.030 mg ethinylestradiol and 0.150 mg levonorgestrel + 0.030 mg ethinylestradiol on lipid and lipoprotein metabolism in healthy female volunteers. Contraception 1982;25:487-503. 4. Kloosterboer Hl, Vonk-NoordegraafCA, Turpijn EW. Selectivity on progesterone and androgen receptor binding of progestogens used in oral contraceptives. Contraception 1988;38:325-32. 5. Kloosterboer Hj, Van Wayjen RGA, Van der Ende A. Comparative effects of monophasic desogestrel plus ethinyloestradiol and triphasic levonorgestrel plus ethinyloestradiol on lipid metabolism. Contraception 1986;34:135-44. 6. Kuusi T, Nikkilii EA, Tikkanen Mj, Sipinen S. Effects of two progestins with different androgenic properties on hepatic endothelial lipase and high density lipoprotein. Atherosclerosis 1985;54:251-62. 7. Castelli WP. Cardiovascular disease in women. AM 1 OBSTET GYNECOL 1988;158:1553-60.
