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Effects of estrogens and progestogens on lipid metabolism
Effects of estrogens and progestogens on lipid metabolism PETER OSTER LE!\ORE ARAB :\1ARTI:"J KOHLMEIER RUBINO MORDASINI BER:\1 HARD SCHELLENBERG GCJ'\THER SCHLIERF Bern, Swit:nland, and Heidelbng, West Germany Because the incidence of venous thromboembolism, coronary heart disease, and stroke is increased in users of oral contraceptives (OCs), the possible causal metabolic side effects of OCs have been widely investigated. In this article we present epidemiologic data associated with OC use. Total plasma triglycerides and cholesterol levels were elevated in OC users while high-density lipoprotein cholesterol levels were lowered. Another section discusses some hormone-dependent physiologic and pathophysiologic aspects of lipid metabolism. Finally, we report on the isolated influence of estrogens and progestogens and their interrelation, including some recent findings about the effects of different progestogens on lipoproteins. (AM. J. OBSTET. GYNECOL. 142: 773, 1982.)
are carried in the plasma in the form of lipoproteins. These lipoproteins consist of triglycerides, cholesterol, phospholipids, and a protein component, the so-called apoproteins. They can be separated by ultracentrifugation according to their densitv, resulting in three major classes oflipoproteins: very low-density lipoproteins (VLDLs), including chylomicrons, low-density lipoproteins (LDLs), and highdensity lipoproteins ( HDLs). The LDL fraction carries bv far the largest amount of cholesterol and apoprotein B and is the atherogenic fraction; HDLs (composition: 50'7c apoprotein A and 20'7c cholesterol) and especiallv HDL cholesterol were shown in epidemiologic studies to be antiatherogenic. 1 In the VLDL fraction most triglycerides are transported. The atherogenic potency of triglycerides was recently much debated.~ Two European studies, however, showed triglycerides to be a risk factor for coronary heart disease (CHD)Y· ~
\VATER -11'\ S 0 L l' B L E Ll PI D S
From the University of Bern, Switurland, and the University of Heidelberg, West Germany. Supported by Bundesministerium fur jugend, Familie und Gusundheit. Reprint requests: Peter Oster, University of Bern, Tiefenauspital, T1e{enoustr. 112, CH-3004, Switurland. 0002-9378/82/060773+03$00.30/0 © 1982 The C. V. Mosby Co.
Results and comment
When the lipoproteins are separated b) lipid electrophoresis, the fractions are named pre-{:l- ( \'LDL), {3- (LDL), and a-lipoproteins ( HDL). (Corresponding ultracentrifugation classes are shown in parentheses.) Epidemiologic data: "The Heidelberg study." In a health and nutrition survey of 800 women ages 20 to ~0 years from Heidelberg, \Vest Germam·, fasting blood values, 24-hour urine values, blood pressure readings, fat biopsies, and data on nutritional and medication intakes were recorded." Comparisons were made between current users of oral contracepti\·es (0Cs). former users, and those who had never used "the pill." The signil1cance was calculated with nonparametric tests by means of a S.P.S.S.7 .2. computer program on the university's IBM 370-168 by comparing current users and nonusers. Table I shows lipid, lipoprotein, and apoprotein B le\·els. Significant differences were found for total plasma triglycerides and cholesterol (elevated with OC) and HDL cholesterol (lower with OC). Interestingly, the LDL and {:l-lipoprotein cholesterol levels were not signif1cantly different, whereas the apolipoprotein B level was higher in current OC users (P < 0.0000). The explanation for this phenomenon 773
77 4
Oster et al. A"'
.f.
Manh 15. lt)H~ Ohster. ( ;, neml.
Table I. Plasma lipids and lipoproteins with oral contraceptives 5 120
Subject categories*
-
-:c -f Q.
-
c
100
90
n <5
~
6-8
9-10
I
Cholesterol Triglycerides Phospholipids HDL cholesterol LDL cholesterol a-Lipoprotein cholesterol (3- Lipoprotein cholesterol Pre-(3-lipoprotein cholesterol Apolipoprotein B
110
I ll 0
Lipid!lipoproteim in rngldl
>10
years
I
II
I
lfl
fit
IH4.8 105.4 251 52.1 125.2 58.5 135.5 9.8
180.ti 80.5 234 56.1 120.8 65.4 128.7 8.5
177.8 79.7 231:) 55.2 122.1 t) 1.3 130.5 7.8
0.0028 0.0000 0.0000 (),()()06 :\S 0.055 0.0845 0.0000
97.2
87.0
H6.6
0.0000
*I, Current OC users; II, former OC users; III, no use of OCs. t Significance.
Fig. l. Apolipoprotein B (Apo B) and duration of oral con-
traceptive use in years. could be (aside from increased variation of LDL cholesterol for unknown reasons) either an apoprotein B-enriched LDL fraction in OC users or, in the presence of significant pre-,8-cholesterol differences (TaJle I), an increase of apoprotein B in the pre-,8 or \'LDL fraction. The latter possibility would be consistent with the finding of a decreased postheparin lipolnic acti,·ity.'; To exclude the possibly confounding variable of smoking. the HDL cholesterol values were anahLed separately (Table II); OC users always had lower HDL cholesterol values irrespective of smoking habits. The temporal aspect of the lipid changes is interesting. with a continuous rise of apoprotein B with longer OC use (Fig. 1). A similar continuous rise of blood pressure over at least 5 years has been reported.' Some "natural" hormonal changes and lipid metabolism. In childhood, girls have usually somewhat higher plasma levels for triglycerides and cholesterol. reHecting higher levels of VLDL and LDL. This finding is reversed during puberty, so that after early adulthood men have higher levels for VLDL and LDL as well as lower levels of HDL. 8 In premenopausal women a l0'7c to 25% cyclic suppression of total plasma cholesterol. LDL cholesterol. and LDL apoprotein B occurs during the luteal phase. while HDL cholesterol increases slightly during the second half of the menstrual cycle. 9 In postmenopausal women the lipid and lipoprotein values change in the direction of increased atherogenicity (e.g., LDL cholesterol rises, HDL cholesterol falls) and toward male values. During the sixth decade of life, women develop even higher LDL cholesterol levels than men.H' In pregnancy, total plasma triglycerides and choles-
Table II. HDL cholesterol (in milligrams per deciliter) with smoking and OC use
With OC Without OC
54 57
1-15 Cigarettes/day
>15 Cigarettes/day
52 54
48 51
terol are elevated because of an increase in all lipoprotein classes, including HDL; the LDL and HDL fraction' are relatively enriched in triglycerides. The increase of total apoprotein B is caused by higher VLDLapoprotein B levels. 11 As parity is not related to CHD, 10 the lipid abnormalities of pregnancy are apparently of minor importance. Azoospermic and oligospermic young men demonstrated high plasma triglycerides and low HDL cholesterol values. 12 A correlation could be establi'shed between plasma testosterone and HDL cholesterol (positive) and triglvcerides (negati\'e). Effects of exogenous estrogens and progestogens on lipid metabolism. Exogenous estrogen leads to an increase of triglycerides and HDL cholesterol and a decrease of LDL cholestero!Y· 1" The triglycerides might increase significanth' in susceptible individuals and even cause acute pancreatitis. The LDL and HDL changes seem htvorable with respect to the atherogenic risk. In the coronary drug project, however, the group of male patients treated with estrogen (2.5 and 5 mg) to lower blood lipids was withdrawn from the study beft)re the end of the trial because of excess mortality from cardiovascular causes. 1,;, 17 On the other hand, menopausal estrogen therapy might be associated with a lower risk of CHD. 1 " Exogenous progestogens decrease HDL cholesterol
Volume 142 Number 6, Part 2
and increase LDL cholesterol.''l Like exogenous androgens, some progestogens lower the plasma triglyceride level because of an increased triglyceride clearance.';
Estrogen and progestogen effects on lipid metabolism
775
and hypertension with the progestogen content of the pill were noted. 22 • 2'l There are differences between effects of exogenous
Altogether, the effects of progestogens on lipid metabolism depend on their androgenic, antiestrogenic,
and endogenous gonadal hormones in men and women (premenopausal and postmenopausal) and be-
and estrogenic properties,'a. '"and some progestogens,
tween single or combined treatment with estrogens and
such as medroxyprogesterone, have lesser effects on HDL cholesterol than others.'"· ~o Similar differences
progestogens. Beneficial effects on some lipoproteins can possibly be elicited with certain progestogens; however, the authors feel that the significance of a change,
among progestogens have been noted in their effects on blood pressure."' The epidemiologic experience with users of OCs showed an association between the estrogen content of the pill and venous thromboembolism; therefore, the estrogen close was lowered. Now, in the low-estrogen OC, significant positive correlations of arterial disease
especially concerning HDL cholesterol and the HDL molecule, has to be the subject of further studies. 24 Postmenopausal women might profit from estrogen therapy. If they have not undergone hysterectomy, this can best be done cyclically and combined with a progestogen in the last 7 to 13 days of the cycle.~:.
REFERENCES 1. Miller, N. E.: The evidence for the antiatherogenicity of high densitv lipoprotein in man, Lipids 13:914, 1978. 2. Hulley, S. B., Rosenman, R. H., Bawol, R. D., et al.: Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease, N. Engl. J. Med. 302:1383, 1980. 3. Carlson, L. A., Bottiger, L. E., and Ahfeld, P. E.: Risk factors for myocardial infarction in the Stockholm Prospective Study, Acta Med. Scand. 206:351, 1979. 4. Pelkonen, R., Nikkila, E. A., Koskinen, S., et al.: Association of serum lipids and obesity with cardiovascular mortality, Br. Med.J. 2:1185, 1977. 5. Arab, L., Schellenberg, B., and Schlierf, G.: Ernahrung und Gesundheit-Eine Untersuchung beijungen Frauen und Mannern in Heidelberg. Infusionstherapie und Klin, Basel, 1981, S. Karger. 6. Glueck, C. J .. and Fallat, R.: Gonadal hormones and triglycerides, Proc. R. Soc. Med. 67:667, 1974. 7. Weir, R. J., Briggs, E., Mack, A., et al.: Blood pressure in women taking oral contraceptives, Br. Med. J. 1:533, 19H. 8. Christensen, B., Glueck, C., Kwiterowich, P., et a!.: Plasma cholesterol and triglyceride distributions in 13665 children and adolescents: The prevalence study of the Lipid Research Clinics Program, Pediatr. Res. 14:194, 19HO.
9. Kim, H. J ., and Kalkhoff, R. K.: Changes in lipoprotein composition during the menstrual cycle, Metabolism 28: 663, 1979. 10. Rifkind, B. M., Tamir, 1., Heiss, G., et al.: Distribution of high density and other lipoproteins in selected LRC prevalence study populations: A brief survey, Lipids 14:105, 1979. 11. Hillman, L., Schonfeld, G., Miller, J. P., et al.: Apolipoproteins in human pregnancy, Metabolism 24:943, 1975. 12. Mendoza, S. G., Osuna, A., Zerpa, A., et al.: Hypertriglyceridemia and hypoalphalipoproteinemia in azoospermic and oligospermic young men: Relationships of endogenous testosterone to triglyceride and high density lipoprotein cholesterol metabolism, Metabolism 30:481, 1981.
13. Bradley, D. D., Wingerd, j.. Petitti, D. B., et al.: Serum high-density-lipoprotein cholesterol in women using oral contraceptives, estrogens and progestins, N. Engl. J. Med. 299:17, 1978. 14. Tikkanen, M.J., and Nikkila, E. A.: Menopausal estrogen therapy, serum lipoproteins, and ischemic heart disease, Lancet 1: 1319, 1981 . 15. Molitch, M. E., Oill, P., and Odeu, W. D.: Massive hvperlipemia during estrogen therapy,]. A.M. A. 227:522, 1974. 16. The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease,]. A.M. A. 231:360, 1975. 17. Carlson, L.A., and Roessner, S.: Results of the coronary drug project-an interpretation, Atherosclerosis 22:317, 1975. 18. Ross, R. K .. Paganini-Hill, A., Mack, T. M., et al.: Menopausal estrogen therapy and protection from death from ischemic heart disease. Lancet 1:858, 1981. 19. Hirvonen, E., Maelkoenen, M., and Manninen, V.: Effects of different progestogens on lipoproteins during postmenopausal replacement therapv, N. Engl. J. Med. 304:560, 1981. 20. Silferstolpe, G., Gustafson, A., Samsioe, G., et al.: Lipid metabolic studies in oophorectomized women. Effects of three different progestogens, Acta Obstet. Gynecol. Scand. (Suppl.) 88:89, 1979. 2l. Dalen, J. E., and Hickler, R. B.: Oral contraceptives and cardiovascular disease, Am. Heart J. 101:626, 1981. 22. Anonymous: Triphasic oral contraceptives, Lancet 1: 1191, 1981. 23. Bottiger, L. E., Boman, G .. Eklund, G., et al.: Oral contraceptives and thromboembolic disease: Effects of lowering estrogen content, Lancet 1: 1096, 1980. 24. Oster, P., Schlierf, G., Heuck, C. C., et al.: Diet and high density lipoproteins, Lipids 16:93, 1981. 25. A Statement by the British Gynecological Cancer Group: Estrogen replacement and endometrial cancer, Lancet 1:1356. 1981.
are carried in the plasma in the form of lipoproteins. These lipoproteins consist of triglycerides, cholesterol, phospholipids, and a protein component, the so-called apoproteins. They can be separated by ultracentrifugation according to their densitv, resulting in three major classes oflipoproteins: very low-density lipoproteins (VLDLs), including chylomicrons, low-density lipoproteins (LDLs), and highdensity lipoproteins ( HDLs). The LDL fraction carries bv far the largest amount of cholesterol and apoprotein B and is the atherogenic fraction; HDLs (composition: 50'7c apoprotein A and 20'7c cholesterol) and especiallv HDL cholesterol were shown in epidemiologic studies to be antiatherogenic. 1 In the VLDL fraction most triglycerides are transported. The atherogenic potency of triglycerides was recently much debated.~ Two European studies, however, showed triglycerides to be a risk factor for coronary heart disease (CHD)Y· ~
\VATER -11'\ S 0 L l' B L E Ll PI D S
From the University of Bern, Switurland, and the University of Heidelberg, West Germany. Supported by Bundesministerium fur jugend, Familie und Gusundheit. Reprint requests: Peter Oster, University of Bern, Tiefenauspital, T1e{enoustr. 112, CH-3004, Switurland. 0002-9378/82/060773+03$00.30/0 © 1982 The C. V. Mosby Co.
Results and comment
When the lipoproteins are separated b) lipid electrophoresis, the fractions are named pre-{:l- ( \'LDL), {3- (LDL), and a-lipoproteins ( HDL). (Corresponding ultracentrifugation classes are shown in parentheses.) Epidemiologic data: "The Heidelberg study." In a health and nutrition survey of 800 women ages 20 to ~0 years from Heidelberg, \Vest Germam·, fasting blood values, 24-hour urine values, blood pressure readings, fat biopsies, and data on nutritional and medication intakes were recorded." Comparisons were made between current users of oral contracepti\·es (0Cs). former users, and those who had never used "the pill." The signil1cance was calculated with nonparametric tests by means of a S.P.S.S.7 .2. computer program on the university's IBM 370-168 by comparing current users and nonusers. Table I shows lipid, lipoprotein, and apoprotein B le\·els. Significant differences were found for total plasma triglycerides and cholesterol (elevated with OC) and HDL cholesterol (lower with OC). Interestingly, the LDL and {:l-lipoprotein cholesterol levels were not signif1cantly different, whereas the apolipoprotein B level was higher in current OC users (P < 0.0000). The explanation for this phenomenon 773
77 4
Oster et al. A"'
.f.
Manh 15. lt)H~ Ohster. ( ;, neml.
Table I. Plasma lipids and lipoproteins with oral contraceptives 5 120
Subject categories*
-
-:c -f Q.
-
c
100
90
n <5
~
6-8
9-10
I
Cholesterol Triglycerides Phospholipids HDL cholesterol LDL cholesterol a-Lipoprotein cholesterol (3- Lipoprotein cholesterol Pre-(3-lipoprotein cholesterol Apolipoprotein B
110
I ll 0
Lipid!lipoproteim in rngldl
>10
years
I
II
I
lfl
fit
IH4.8 105.4 251 52.1 125.2 58.5 135.5 9.8
180.ti 80.5 234 56.1 120.8 65.4 128.7 8.5
177.8 79.7 231:) 55.2 122.1 t) 1.3 130.5 7.8
0.0028 0.0000 0.0000 (),()()06 :\S 0.055 0.0845 0.0000
97.2
87.0
H6.6
0.0000
*I, Current OC users; II, former OC users; III, no use of OCs. t Significance.
Fig. l. Apolipoprotein B (Apo B) and duration of oral con-
traceptive use in years. could be (aside from increased variation of LDL cholesterol for unknown reasons) either an apoprotein B-enriched LDL fraction in OC users or, in the presence of significant pre-,8-cholesterol differences (TaJle I), an increase of apoprotein B in the pre-,8 or \'LDL fraction. The latter possibility would be consistent with the finding of a decreased postheparin lipolnic acti,·ity.'; To exclude the possibly confounding variable of smoking. the HDL cholesterol values were anahLed separately (Table II); OC users always had lower HDL cholesterol values irrespective of smoking habits. The temporal aspect of the lipid changes is interesting. with a continuous rise of apoprotein B with longer OC use (Fig. 1). A similar continuous rise of blood pressure over at least 5 years has been reported.' Some "natural" hormonal changes and lipid metabolism. In childhood, girls have usually somewhat higher plasma levels for triglycerides and cholesterol. reHecting higher levels of VLDL and LDL. This finding is reversed during puberty, so that after early adulthood men have higher levels for VLDL and LDL as well as lower levels of HDL. 8 In premenopausal women a l0'7c to 25% cyclic suppression of total plasma cholesterol. LDL cholesterol. and LDL apoprotein B occurs during the luteal phase. while HDL cholesterol increases slightly during the second half of the menstrual cycle. 9 In postmenopausal women the lipid and lipoprotein values change in the direction of increased atherogenicity (e.g., LDL cholesterol rises, HDL cholesterol falls) and toward male values. During the sixth decade of life, women develop even higher LDL cholesterol levels than men.H' In pregnancy, total plasma triglycerides and choles-
Table II. HDL cholesterol (in milligrams per deciliter) with smoking and OC use
With OC Without OC
54 57
1-15 Cigarettes/day
>15 Cigarettes/day
52 54
48 51
terol are elevated because of an increase in all lipoprotein classes, including HDL; the LDL and HDL fraction' are relatively enriched in triglycerides. The increase of total apoprotein B is caused by higher VLDLapoprotein B levels. 11 As parity is not related to CHD, 10 the lipid abnormalities of pregnancy are apparently of minor importance. Azoospermic and oligospermic young men demonstrated high plasma triglycerides and low HDL cholesterol values. 12 A correlation could be establi'shed between plasma testosterone and HDL cholesterol (positive) and triglvcerides (negati\'e). Effects of exogenous estrogens and progestogens on lipid metabolism. Exogenous estrogen leads to an increase of triglycerides and HDL cholesterol and a decrease of LDL cholestero!Y· 1" The triglycerides might increase significanth' in susceptible individuals and even cause acute pancreatitis. The LDL and HDL changes seem htvorable with respect to the atherogenic risk. In the coronary drug project, however, the group of male patients treated with estrogen (2.5 and 5 mg) to lower blood lipids was withdrawn from the study beft)re the end of the trial because of excess mortality from cardiovascular causes. 1,;, 17 On the other hand, menopausal estrogen therapy might be associated with a lower risk of CHD. 1 " Exogenous progestogens decrease HDL cholesterol
Volume 142 Number 6, Part 2
and increase LDL cholesterol.''l Like exogenous androgens, some progestogens lower the plasma triglyceride level because of an increased triglyceride clearance.';
Estrogen and progestogen effects on lipid metabolism
775
and hypertension with the progestogen content of the pill were noted. 22 • 2'l There are differences between effects of exogenous
Altogether, the effects of progestogens on lipid metabolism depend on their androgenic, antiestrogenic,
and endogenous gonadal hormones in men and women (premenopausal and postmenopausal) and be-
and estrogenic properties,'a. '"and some progestogens,
tween single or combined treatment with estrogens and
such as medroxyprogesterone, have lesser effects on HDL cholesterol than others.'"· ~o Similar differences
progestogens. Beneficial effects on some lipoproteins can possibly be elicited with certain progestogens; however, the authors feel that the significance of a change,
among progestogens have been noted in their effects on blood pressure."' The epidemiologic experience with users of OCs showed an association between the estrogen content of the pill and venous thromboembolism; therefore, the estrogen close was lowered. Now, in the low-estrogen OC, significant positive correlations of arterial disease
especially concerning HDL cholesterol and the HDL molecule, has to be the subject of further studies. 24 Postmenopausal women might profit from estrogen therapy. If they have not undergone hysterectomy, this can best be done cyclically and combined with a progestogen in the last 7 to 13 days of the cycle.~:.
REFERENCES 1. Miller, N. E.: The evidence for the antiatherogenicity of high densitv lipoprotein in man, Lipids 13:914, 1978. 2. Hulley, S. B., Rosenman, R. H., Bawol, R. D., et al.: Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease, N. Engl. J. Med. 302:1383, 1980. 3. Carlson, L. A., Bottiger, L. E., and Ahfeld, P. E.: Risk factors for myocardial infarction in the Stockholm Prospective Study, Acta Med. Scand. 206:351, 1979. 4. Pelkonen, R., Nikkila, E. A., Koskinen, S., et al.: Association of serum lipids and obesity with cardiovascular mortality, Br. Med.J. 2:1185, 1977. 5. Arab, L., Schellenberg, B., and Schlierf, G.: Ernahrung und Gesundheit-Eine Untersuchung beijungen Frauen und Mannern in Heidelberg. Infusionstherapie und Klin, Basel, 1981, S. Karger. 6. Glueck, C. J .. and Fallat, R.: Gonadal hormones and triglycerides, Proc. R. Soc. Med. 67:667, 1974. 7. Weir, R. J., Briggs, E., Mack, A., et al.: Blood pressure in women taking oral contraceptives, Br. Med. J. 1:533, 19H. 8. Christensen, B., Glueck, C., Kwiterowich, P., et a!.: Plasma cholesterol and triglyceride distributions in 13665 children and adolescents: The prevalence study of the Lipid Research Clinics Program, Pediatr. Res. 14:194, 19HO.
9. Kim, H. J ., and Kalkhoff, R. K.: Changes in lipoprotein composition during the menstrual cycle, Metabolism 28: 663, 1979. 10. Rifkind, B. M., Tamir, 1., Heiss, G., et al.: Distribution of high density and other lipoproteins in selected LRC prevalence study populations: A brief survey, Lipids 14:105, 1979. 11. Hillman, L., Schonfeld, G., Miller, J. P., et al.: Apolipoproteins in human pregnancy, Metabolism 24:943, 1975. 12. Mendoza, S. G., Osuna, A., Zerpa, A., et al.: Hypertriglyceridemia and hypoalphalipoproteinemia in azoospermic and oligospermic young men: Relationships of endogenous testosterone to triglyceride and high density lipoprotein cholesterol metabolism, Metabolism 30:481, 1981.
13. Bradley, D. D., Wingerd, j.. Petitti, D. B., et al.: Serum high-density-lipoprotein cholesterol in women using oral contraceptives, estrogens and progestins, N. Engl. J. Med. 299:17, 1978. 14. Tikkanen, M.J., and Nikkila, E. A.: Menopausal estrogen therapy, serum lipoproteins, and ischemic heart disease, Lancet 1: 1319, 1981 . 15. Molitch, M. E., Oill, P., and Odeu, W. D.: Massive hvperlipemia during estrogen therapy,]. A.M. A. 227:522, 1974. 16. The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease,]. A.M. A. 231:360, 1975. 17. Carlson, L.A., and Roessner, S.: Results of the coronary drug project-an interpretation, Atherosclerosis 22:317, 1975. 18. Ross, R. K .. Paganini-Hill, A., Mack, T. M., et al.: Menopausal estrogen therapy and protection from death from ischemic heart disease. Lancet 1:858, 1981. 19. Hirvonen, E., Maelkoenen, M., and Manninen, V.: Effects of different progestogens on lipoproteins during postmenopausal replacement therapv, N. Engl. J. Med. 304:560, 1981. 20. Silferstolpe, G., Gustafson, A., Samsioe, G., et al.: Lipid metabolic studies in oophorectomized women. Effects of three different progestogens, Acta Obstet. Gynecol. Scand. (Suppl.) 88:89, 1979. 2l. Dalen, J. E., and Hickler, R. B.: Oral contraceptives and cardiovascular disease, Am. Heart J. 101:626, 1981. 22. Anonymous: Triphasic oral contraceptives, Lancet 1: 1191, 1981. 23. Bottiger, L. E., Boman, G .. Eklund, G., et al.: Oral contraceptives and thromboembolic disease: Effects of lowering estrogen content, Lancet 1: 1096, 1980. 24. Oster, P., Schlierf, G., Heuck, C. C., et al.: Diet and high density lipoproteins, Lipids 16:93, 1981. 25. A Statement by the British Gynecological Cancer Group: Estrogen replacement and endometrial cancer, Lancet 1:1356. 1981.