0021-972X/78/4 703-0596$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 3 Printed in U.S.A.
Changes of Plasma Lipid Metabolism in Males during Estrogen Treatment for Prostatic Carcinoma* Departments of Internal Medicine and Urology, Linkoping University, Linkoping, Sweden ABSTRACT. Fourteen patients with prostatic carcinoma were treated with 1.0-0.5 mg ethinyl estradiol orally daily and 160-80 mg polyestradiol phosphate im monthly. Lipid concentrations were determined in plasma and the high density lipoprotein fraction, and the plasma lecithin-cholesterol acyl transfer rate was measured before and 1 and 6 months after the start of therapy. During treatment, the concentration of total cholesterol was unchanged while there was a 60% increase of high density lipoprotein-total cholesterol. Triglyceride (TG) concentration increased 40%, indicating
H
IGH doses of estrogens are the established treatment for advanced stages of prostatic carcinoma. During recent years, this therapy has been found associated with increased cardiovascular mortality (1-4). It is well known that elevated plasma lipids are a main risk factor for the development of ischemic cardiovascular disease (5). Therefore, we have studied the concentration of lipids and high density lipoproteins (HDL) in plasma during treatment of males with high dosages of estrogen. The lecithin-cholesterol acyl transfer rate (LCAT) was determined in order to obtain information on changes of lipoprotein metabolism in plasma during the estrogen treatment. Materials and Methods
an augmented level of very low density lipoprotein concentration. The plasma lecithin-cholesterol acyl transfer rate increased 20-35%, indicating that an increased rate of production and turnover of TG, cholesteryl esters, and very low density lipoproteins probably was a main cause of the elevated TG concentration. The potential effects on the development of atherosclerosis by the plasma lipid changes during estrogen treatment are discussed. (JClin Endocrinol Metab 47: 596, 1978)
(6), five patients had T2, five patients had T3 and four patients had T4 tumors. According to the grade of malignancy, 13 patients had G2 and 1 patient had Gl. Four patients had distant metastases. Some of the men were treated for other diseases, e.g. congestive heart disease (four patients on digitalis and diuretics), diabetes mellitus (one patient on diet and sulfonylurea), and connective tissue disease (one patient on corticosteroid therapy for several years). The estrogen treatment was started with 160 mg polyestradiol phosphate (PEP) im monthly and 1.0 mg ethinyl estradiol (EE) orally daily during the first 2 months. Thereafter, they were given 80 mg PEP im monthly and 0.5 mg EE orally daily continuously. Venous blood samples were drawn after an overnight fast immediately before and 1 and 6 months after the start of the treatment. Methods
Subjects and samples
Total cholesterol (TC) was determined enzymatically (Boehringer Mannheim Test Combination Fourteen patients, aged 60-85 yr (mean, 72.3 yr), Cholesterol) and unesterified cholesterol (UC) was with cytologically proven prostatic carcinoma pardetermined by gas-liquid chromatography (7). Triticipated in the study. Using the Union International Contre Le Caucrum classification of tumors glycerides (TG) were quantified by enzymatic glycerol determination after alkaline hydrolysis (Boehringer Mannheim Test Combination Triglycerides). Received July 5, 1977. Address requests for reprints to: Dr. L. Wallentin, Phospholipids (PL) were measured by phosphorous Department of Internal Medicine, Linkoping University, determination in lipid extracts of plasma (8). The S-581 85 Linkoping, Sweden. lipid concentrations in HDL were determined in * This study was supported by the Swedish Medical Research Council (project B77-19X-04529) and the Swed- the supernatant after heparin-MnCl2 precipitation ish National Association against Heart and Chest Dis- (9). Plasma LCAT rate was measured during incubation in vitro as the esterification rate of added eases. 596
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LARS WALLENTIN AND EBERHARD VARENHORST
PLASMA LIPIDS IN ESTROGEN-TREATED MALES
597
tritiated cholesterol which was assumed to equilibrate completely with UC in plasma lipoproteins (7). Statistical calculations
v-
—r
Results The concentrations of lipids and HDL lipids and the LCAT rate in plasma before and during estrogen therapy in the group are shown in Table 1. The percentage of changes in these parameters during estrogen therapy compared to the initial determinations are illustrated in Fig. 1. The mean TC concentration was unchanged, but there was a considerable redistribution of the TC within the lipoprotein fractions. The TC concentration in the HDL fraction increased in all patients and the mean HDL-TC concentration was augmented by 60%. The TG concentration was raised in 9 patients after 1 month of treatment, and in 11 of the 14 patients after 6 months of treatment. The mean TG concentration increased by 40%. The mean UC concentration was raised by 10% based on an TABLE 1. Lipid and HDL lipid concentrations and LCAT
rates in plasma before and during estrogen therapy Months after start of treatment 1
0
6
TC (mmol
5.16 (1.43)
5.33
(1.50)
5.84
(1.49)
UC (mmol
1.63 (0.55)
1.79** (0.61)
1.78
(0.49)
TG (mmol X T1)
1.56 (1.03)
1.90*
1.96*
(0.85;
PL (mmol
2.82 (0.66)
3.41*** (0.84)
3.45** (0.70)
1.01 (0.24)
1.59*** (0.35)
1.67*** (0.43)
HDL-PL (mmol x
0.94 (0.20)
1.56* ** (0.33)
1.82*** (0.41)
LCAT rate
99.4 (20.9)
x r1) x r1)
(1.00)
X T1)
HDL-TC (mmol x 1
I" )
r1)
117.9*
(33.4)
130.5**
(27.4)
(fimol X
r 1 x h"1) Figures are mean (SD). Significance of mean differences were tested by paired t tests and are symbolized: *, P < 0.05; **, P < 0.01; ***, P < 0.001. Differences between mean TG concentrations were tested as differences between "log TG concentrations.
FIG. 1. Mean percentage of changes of concentrations of lipids and lipoprotein lipids and of the LCAT in plasma during estrogen treatment. VLDL + LDL = sum of very low and low density lipoproteins. Time in months where 0 is before treatment and 1 and 6 represent months after the start of treatment, h • H, Mean ± SE.
increase in 11 patients. The PL concentration was augmented in all patients and the mean increased by 20-25%, most of which was explained by an increase of PL in the HDL fraction. HDL-PL concentration increased in all patients and the mean HDL-PL was raised by 70-100%. The mean LCAT rate was augmented by 20-25%, based on an increased LCAT rate in 10-12 patients after 1 and 6 months of treatment, respectively. The mean LCAT rate and the mean HDL-PL concentration tended to show a further increase in the second observation at 6 months after the start of therapy based on a further increase in 9 and 11 of the 14 patients, respectively. The other parameters seemed stable after 1 month of therapy. The correlations between the LCAT rate and the lipid and HDL-lipid concentrations in plasma are shown in Table 2. Before the estrogen treatment, the LCAT rate was positively correlated to the UC concentration in plasma. The changes of the LCAT rate during the estrogen treatment were positively correlated with the changes of TG, PL, and UC concentrations in plasma. After 6 months of
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
Significances of mean differences were calculated as paired t tests. The skew distribution of TG concentration was approximately normalized by using "log TG in calculations of correlations and probabilities.
598
WALLENTIN AND VARENHORST
TABLE 2. Correlations between the LCAT rate and the lipid and HDL lipid concentrations in plasma LCAT (jumol X
r 1 x tr1)
Before
During*
0.41 0.51* 0.41 0.49 0.01 0.03
0.48 0.61* 0.63* 0.67** -0.22 0.05
treatment, the LCAT rate was positively correlated with the TG, PL, and UC concentrations in plasma. There were no correlations between the LCAT rate and the PL or TC concentration in the HDL fraction before or after 6 months of estrogen treatment. Neither were there any correlations between the changes of HDL-PL or HDL-TC concentrations and the changes of LCAT rate in plasma during the estrogen treatment. Discussion Few studies concerning the influences of estrogen treatment on plasma lipids and lipoproteins in men have been published. Most reports have concerned only the TC concentration which was found decreased by EE (10-12) but not changed by diethylstilbestrol or conjugated equine estrogens (11, 13-15). During treatment with high doses of different estrogen preparations, there were elevations of TG or very low density lipoproteins (VLDL) and HDL concentrations (13, 15, 16). In the present study, a high dose of EE and PEP was found to raise the TG concentration. Most of plasma TG are transported in the VLDL. The VLDL concentration, hence, was probably elevated. In spite of unchanged TC concentration, there was a considerable redistribution of TC within the plasma lipoprotein fractions. The HDL-TC was considerably increased and hence, TC in the other lipopro-
1978 No 3
teins decreased. As the VLDL concentration probably increased, the decrease of TC should be confined mainly to the LDL fraction. These results agree with the cited studies above and with the changes of plasma lipids and lipoproteins induced by considerably lower dosages of EE in postmenopausal women (17, 18). The reasons for the increase of TG and VLDL concentrations in plasma during estrogen treatment have been disputed. The activities of postheparin lipoprotein lipases was decreased during estrogen treatment, but the changes of lipolytic activity were not correlated to the changes of TG concentration (19). On the other hand, a positive correlation was found between the increase of TG concentration and increased rate of production and turnover of TG and VLDL during estrogen treatment (20-22). In the present study, there was a positive correlation between the changes of TG concentration and the changes of the LCAT rate. The LCAT rate has been reported to correlate positively with the rate of production and turnover of TG and cholesterol in plasma (23) and might reflect the rate of production and turnover of TG, cholesteryl esters, and VLDL in plasma (23, 24). In the present study, the LCAT rate was elevated 20-35% during EEPEP treatment which, hence, might reflect an increased rate of turnover of TG and cholesteryl esters. This interpretation agrees with the finding of increased cholesterol turnover measured with an isotope method during EE therapy in a few males (12). Thus, it seems probable that an increase of production rate of TG and VLDL particles is a main cause of the elevated TG concentration during estrogen treatment. In the HDL fraction, there was a greater elevation of PL than TC, which might indicate an increased number of HDL particles (18). Thus, the increase of HDL concentration might also be explained by the induction of protein and lipoprotein synthesis during estrogen therapy (25). However, there were no correlations between the changes in HDL-PL or HDL-TC concentrations and the changes in TG concentration or LCAT rate in plasma during the treatment.
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
After" 0.42 0.62* uc TG 0.67** PL 0.66** HDL-TC -0.24 HDL-PL -0.14 Significances of the correlation coefficients are symbolized as: *, P < 0.05; **, P < 0.01. " Correlations were calculated between the concentrations of lipids and HDL lipids and the LCAT rate in plasma before and 6 months after the start of estrogen treatment. h Correlations were calculated between the differences of concentrations of lipids and HDL lipids and the differences of LCAT rate before and after 6 months of the estrogen treatment. TC
JCE&M Vol47
PLASMA LIPIDS IN ESTROGEN-TREATED MALES
ids in pregnant and non-pregnant women with special reference to lysolecithin, Acta Med Scand 175: 443, 1964. 9. Lipid and lipoprotein analysis, Manual of Laboratory Operations, vol. 1, NIH (DHEW Publication 75-628) Bethesda, MD, 1975. 10. OLIVER, M. F., AND G. S. BOYD, Influences of reduction of serum lipids on prognosis of coronary heart disease, Lancet 2: 499, 1961. 11. MARMORSTON, J., F. J. MOORE, C. E. HOPKINS, 0. T. KUZMA,
AND J. WEINER, Clinical studies of long-term estrogen therapy in men with myocardial infarction, Proc Soc Exp Med Biol 110: 400, 1962. 12. NESTEL, P. J., E. Z. HIRSCH, AND E. A. COUZENS, The effect
of chlorophenoxyisobutyric acid and ethinyl estradiol on cholesterol turnover, J Clin Invest 44: 891, 1965. 13. SHAMANESH, M., C. H. BOLTON, R. C. L. FENELEY, AND M.
14.
15.
16. 17.
HARTOG, Metabolic effects of estrogen treatment in patients with carcinoma of prostate: a comparison of stilbestrol and conjugated equine estrogens, Br Med J 2: 512, 1973. DETRE, K. M., AND L. SHAW, Long term changes of serum cholesterol altering drugs in patients with coronary heart disease, Circulation 50: 998, 1974. SOTANIEMI, E. A., AND M. J. KONTTURI, Serum lipid levels and thromboembolic complications during estrogen therapy in prostatic carcinoma, Scand J Urol Nephrol 9: 89, 1975. BOYD, G. S., Estrogens, cholesterol and atherosclerosis, Front Horm Res 2: 74, 1973. GUSTAFSON, A., AND A. SVANBORG, Gonadal steroid effects on plasma lipoproteins and individual phospholipids, J Clin Endocrinol Metab 35: 203, 1972.
18. WALLENTIN, L., AND U. LARSSON-COHN, Metabolic and hor-
monal changes during postmenopausal estrogen replacement treatment. II. Plasma lipids, Acta Endocrinol 86: 597, 1977.
Acknowledgments We thank Miss Ylva Svensson and Mrs. Siv-Britt Fredrickson for technical assistance in the laboratory and Mrs. Marianne Andersson for secretarial assistance.
References
19. GLUECK, C. J., P. GARTSIDE, R. W. FALLAT, AND S. MENDOZA,
Effect of serum hormones on protamine inactivated and resistant postheparin plasma lipase, Metabolism 25: 625, 1976. 20. KEKKI, M., AND E. A. NIKKILA, Plasma triglyceride turnover during use of oral contraceptives, Metabolism 24: 878, 1971. 21. KIM, H. J., AND R. K. KALKHOFF, Sex steroid influence on triglyceride metabolism, J Clin Invest 56: 888, 1975. 22. GLUECK, C. J., R. W. FALLAT, AND B. SCHEEL, Effects on
1. Veterans Administration Cooperative Urological Research Group, Treatment and survival of patients with cancer of the prostate, Urol Gynecol Obstet 124: 1011, 1967. 2. Veterans Administration Cooperative Urological Research Group, Carcinoma of the prostate: treatment comparisons, J Urol 98: 516, 1967.
23.
24.
3. BLACKARD, C. E., R. P. DOE, G. T. MELLINGER, AND D. P.
4. 5.
6. 7.
8.
BYAR, Incidence of carciovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate, Cancer 26: 249, 1970. Coronary Drug Project, Initial findings leading to modification of its research protocol, JAMA 214: 1303, 1970. GLUECK, C. J., AND R. W. FALLAT, The heritable hyperlipoproteinemias and atherosclerosis, Adu Exp Med Biol. 63: 305, 1975. Union Internationale Contre Le Cancrum, TNM classification of malignant tumours, Geneva, 1974. WALLENTIN, L., AND 0. VIKROT, Evaluation of an in vitro assay of lecithin:cholesterol acyl transfer rate in plasma, Scand J Clin Lab Invest 35: 661, 1975. VIKROT, 0., Quantitative determination of plasma phospholip-
25.
26.
27. 28. 29.
estrogen compounds on triglyceride kinetics, Metabolism 24: 537, 1975. KUDCHODKAR, B. J., AND H. S. SODHI, Turnover of plasma cholesteryl esters and its relationship to other parameters of lipid metabolism in man, Eur J Clin Invest 6: 285, 1976. WALLENTIN, L., Lecithin:cholesterol acyl transfer rate in plasma and its relation to lipid and lipoprotein concentrations in primary hyperlipidemia, Atherosclerosis 26: 233, 1977. MUSA, B. U., U. S. SEAL, AND R. P. DOE, Elevation of certain plasma proteins in man following estrogen administration: a dose:response relationship, J Clin Endocrinol Metab 25: 1163, 1965. MILLER, G. J., AND N. E. MILLER, Plasma high density lipoprotein concentration and development of ischaemic heart disease, Lancet 1: 16, 1975. GLUECK, C. J., Alpha lipoprotein cholesterol, beta lipoprotein cholesterol and longevity, Artery 2: 196, 1976. NICHOLS, A. V., Human serum lipoproteins and their relationships, Adv Biol Med Phys 11: 109, 1967. CARLSSON, L. A., Lipoprotein fractionation, J Clin Pathol (SupplS) 26: 32, 1973.
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
Changes in plasma lipids are related to the risk for development of ischemic cardiovascular disease. Elevated TG (or VLDL) concentrations and/or elevated LDL concentrations increase this risk, while augmented HDL levels decrease the risk for atherosclerotic disease (5, 26, 27). Most epidemiological studies of relations between cardiovascular disease and plasma lipids concern subjects with primary hyperlipoproteinaemia. Such patients show an inverse relationship between TG (or VLDL) and HDL-TC concentration (28, 29). The net effect on the development of atherosclerotic disease of a simultaneously increased VLDL concentration and increased HDL/LDL quotient, as found during estrogen treatment in the present study, is therefore, at present, hard to evaluate. However, these changes of the plasma lipid metabolism do not necessarily increase the risk for atherosclerotic disease.
599
Vol. 47, No. 3 Printed in U.S.A.
Changes of Plasma Lipid Metabolism in Males during Estrogen Treatment for Prostatic Carcinoma* Departments of Internal Medicine and Urology, Linkoping University, Linkoping, Sweden ABSTRACT. Fourteen patients with prostatic carcinoma were treated with 1.0-0.5 mg ethinyl estradiol orally daily and 160-80 mg polyestradiol phosphate im monthly. Lipid concentrations were determined in plasma and the high density lipoprotein fraction, and the plasma lecithin-cholesterol acyl transfer rate was measured before and 1 and 6 months after the start of therapy. During treatment, the concentration of total cholesterol was unchanged while there was a 60% increase of high density lipoprotein-total cholesterol. Triglyceride (TG) concentration increased 40%, indicating
H
IGH doses of estrogens are the established treatment for advanced stages of prostatic carcinoma. During recent years, this therapy has been found associated with increased cardiovascular mortality (1-4). It is well known that elevated plasma lipids are a main risk factor for the development of ischemic cardiovascular disease (5). Therefore, we have studied the concentration of lipids and high density lipoproteins (HDL) in plasma during treatment of males with high dosages of estrogen. The lecithin-cholesterol acyl transfer rate (LCAT) was determined in order to obtain information on changes of lipoprotein metabolism in plasma during the estrogen treatment. Materials and Methods
an augmented level of very low density lipoprotein concentration. The plasma lecithin-cholesterol acyl transfer rate increased 20-35%, indicating that an increased rate of production and turnover of TG, cholesteryl esters, and very low density lipoproteins probably was a main cause of the elevated TG concentration. The potential effects on the development of atherosclerosis by the plasma lipid changes during estrogen treatment are discussed. (JClin Endocrinol Metab 47: 596, 1978)
(6), five patients had T2, five patients had T3 and four patients had T4 tumors. According to the grade of malignancy, 13 patients had G2 and 1 patient had Gl. Four patients had distant metastases. Some of the men were treated for other diseases, e.g. congestive heart disease (four patients on digitalis and diuretics), diabetes mellitus (one patient on diet and sulfonylurea), and connective tissue disease (one patient on corticosteroid therapy for several years). The estrogen treatment was started with 160 mg polyestradiol phosphate (PEP) im monthly and 1.0 mg ethinyl estradiol (EE) orally daily during the first 2 months. Thereafter, they were given 80 mg PEP im monthly and 0.5 mg EE orally daily continuously. Venous blood samples were drawn after an overnight fast immediately before and 1 and 6 months after the start of the treatment. Methods
Subjects and samples
Total cholesterol (TC) was determined enzymatically (Boehringer Mannheim Test Combination Fourteen patients, aged 60-85 yr (mean, 72.3 yr), Cholesterol) and unesterified cholesterol (UC) was with cytologically proven prostatic carcinoma pardetermined by gas-liquid chromatography (7). Triticipated in the study. Using the Union International Contre Le Caucrum classification of tumors glycerides (TG) were quantified by enzymatic glycerol determination after alkaline hydrolysis (Boehringer Mannheim Test Combination Triglycerides). Received July 5, 1977. Address requests for reprints to: Dr. L. Wallentin, Phospholipids (PL) were measured by phosphorous Department of Internal Medicine, Linkoping University, determination in lipid extracts of plasma (8). The S-581 85 Linkoping, Sweden. lipid concentrations in HDL were determined in * This study was supported by the Swedish Medical Research Council (project B77-19X-04529) and the Swed- the supernatant after heparin-MnCl2 precipitation ish National Association against Heart and Chest Dis- (9). Plasma LCAT rate was measured during incubation in vitro as the esterification rate of added eases. 596
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
LARS WALLENTIN AND EBERHARD VARENHORST
PLASMA LIPIDS IN ESTROGEN-TREATED MALES
597
tritiated cholesterol which was assumed to equilibrate completely with UC in plasma lipoproteins (7). Statistical calculations
v-
—r
Results The concentrations of lipids and HDL lipids and the LCAT rate in plasma before and during estrogen therapy in the group are shown in Table 1. The percentage of changes in these parameters during estrogen therapy compared to the initial determinations are illustrated in Fig. 1. The mean TC concentration was unchanged, but there was a considerable redistribution of the TC within the lipoprotein fractions. The TC concentration in the HDL fraction increased in all patients and the mean HDL-TC concentration was augmented by 60%. The TG concentration was raised in 9 patients after 1 month of treatment, and in 11 of the 14 patients after 6 months of treatment. The mean TG concentration increased by 40%. The mean UC concentration was raised by 10% based on an TABLE 1. Lipid and HDL lipid concentrations and LCAT
rates in plasma before and during estrogen therapy Months after start of treatment 1
0
6
TC (mmol
5.16 (1.43)
5.33
(1.50)
5.84
(1.49)
UC (mmol
1.63 (0.55)
1.79** (0.61)
1.78
(0.49)
TG (mmol X T1)
1.56 (1.03)
1.90*
1.96*
(0.85;
PL (mmol
2.82 (0.66)
3.41*** (0.84)
3.45** (0.70)
1.01 (0.24)
1.59*** (0.35)
1.67*** (0.43)
HDL-PL (mmol x
0.94 (0.20)
1.56* ** (0.33)
1.82*** (0.41)
LCAT rate
99.4 (20.9)
x r1) x r1)
(1.00)
X T1)
HDL-TC (mmol x 1
I" )
r1)
117.9*
(33.4)
130.5**
(27.4)
(fimol X
r 1 x h"1) Figures are mean (SD). Significance of mean differences were tested by paired t tests and are symbolized: *, P < 0.05; **, P < 0.01; ***, P < 0.001. Differences between mean TG concentrations were tested as differences between "log TG concentrations.
FIG. 1. Mean percentage of changes of concentrations of lipids and lipoprotein lipids and of the LCAT in plasma during estrogen treatment. VLDL + LDL = sum of very low and low density lipoproteins. Time in months where 0 is before treatment and 1 and 6 represent months after the start of treatment, h • H, Mean ± SE.
increase in 11 patients. The PL concentration was augmented in all patients and the mean increased by 20-25%, most of which was explained by an increase of PL in the HDL fraction. HDL-PL concentration increased in all patients and the mean HDL-PL was raised by 70-100%. The mean LCAT rate was augmented by 20-25%, based on an increased LCAT rate in 10-12 patients after 1 and 6 months of treatment, respectively. The mean LCAT rate and the mean HDL-PL concentration tended to show a further increase in the second observation at 6 months after the start of therapy based on a further increase in 9 and 11 of the 14 patients, respectively. The other parameters seemed stable after 1 month of therapy. The correlations between the LCAT rate and the lipid and HDL-lipid concentrations in plasma are shown in Table 2. Before the estrogen treatment, the LCAT rate was positively correlated to the UC concentration in plasma. The changes of the LCAT rate during the estrogen treatment were positively correlated with the changes of TG, PL, and UC concentrations in plasma. After 6 months of
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
Significances of mean differences were calculated as paired t tests. The skew distribution of TG concentration was approximately normalized by using "log TG in calculations of correlations and probabilities.
598
WALLENTIN AND VARENHORST
TABLE 2. Correlations between the LCAT rate and the lipid and HDL lipid concentrations in plasma LCAT (jumol X
r 1 x tr1)
Before
During*
0.41 0.51* 0.41 0.49 0.01 0.03
0.48 0.61* 0.63* 0.67** -0.22 0.05
treatment, the LCAT rate was positively correlated with the TG, PL, and UC concentrations in plasma. There were no correlations between the LCAT rate and the PL or TC concentration in the HDL fraction before or after 6 months of estrogen treatment. Neither were there any correlations between the changes of HDL-PL or HDL-TC concentrations and the changes of LCAT rate in plasma during the estrogen treatment. Discussion Few studies concerning the influences of estrogen treatment on plasma lipids and lipoproteins in men have been published. Most reports have concerned only the TC concentration which was found decreased by EE (10-12) but not changed by diethylstilbestrol or conjugated equine estrogens (11, 13-15). During treatment with high doses of different estrogen preparations, there were elevations of TG or very low density lipoproteins (VLDL) and HDL concentrations (13, 15, 16). In the present study, a high dose of EE and PEP was found to raise the TG concentration. Most of plasma TG are transported in the VLDL. The VLDL concentration, hence, was probably elevated. In spite of unchanged TC concentration, there was a considerable redistribution of TC within the plasma lipoprotein fractions. The HDL-TC was considerably increased and hence, TC in the other lipopro-
1978 No 3
teins decreased. As the VLDL concentration probably increased, the decrease of TC should be confined mainly to the LDL fraction. These results agree with the cited studies above and with the changes of plasma lipids and lipoproteins induced by considerably lower dosages of EE in postmenopausal women (17, 18). The reasons for the increase of TG and VLDL concentrations in plasma during estrogen treatment have been disputed. The activities of postheparin lipoprotein lipases was decreased during estrogen treatment, but the changes of lipolytic activity were not correlated to the changes of TG concentration (19). On the other hand, a positive correlation was found between the increase of TG concentration and increased rate of production and turnover of TG and VLDL during estrogen treatment (20-22). In the present study, there was a positive correlation between the changes of TG concentration and the changes of the LCAT rate. The LCAT rate has been reported to correlate positively with the rate of production and turnover of TG and cholesterol in plasma (23) and might reflect the rate of production and turnover of TG, cholesteryl esters, and VLDL in plasma (23, 24). In the present study, the LCAT rate was elevated 20-35% during EEPEP treatment which, hence, might reflect an increased rate of turnover of TG and cholesteryl esters. This interpretation agrees with the finding of increased cholesterol turnover measured with an isotope method during EE therapy in a few males (12). Thus, it seems probable that an increase of production rate of TG and VLDL particles is a main cause of the elevated TG concentration during estrogen treatment. In the HDL fraction, there was a greater elevation of PL than TC, which might indicate an increased number of HDL particles (18). Thus, the increase of HDL concentration might also be explained by the induction of protein and lipoprotein synthesis during estrogen therapy (25). However, there were no correlations between the changes in HDL-PL or HDL-TC concentrations and the changes in TG concentration or LCAT rate in plasma during the treatment.
Downloaded from https://academic.oup.com/jcem/article-abstract/47/3/596/2678828 by University of Edinburgh user on 16 January 2019
After" 0.42 0.62* uc TG 0.67** PL 0.66** HDL-TC -0.24 HDL-PL -0.14 Significances of the correlation coefficients are symbolized as: *, P < 0.05; **, P < 0.01. " Correlations were calculated between the concentrations of lipids and HDL lipids and the LCAT rate in plasma before and 6 months after the start of estrogen treatment. h Correlations were calculated between the differences of concentrations of lipids and HDL lipids and the differences of LCAT rate before and after 6 months of the estrogen treatment. TC
JCE&M Vol47
PLASMA LIPIDS IN ESTROGEN-TREATED MALES
ids in pregnant and non-pregnant women with special reference to lysolecithin, Acta Med Scand 175: 443, 1964. 9. Lipid and lipoprotein analysis, Manual of Laboratory Operations, vol. 1, NIH (DHEW Publication 75-628) Bethesda, MD, 1975. 10. OLIVER, M. F., AND G. S. BOYD, Influences of reduction of serum lipids on prognosis of coronary heart disease, Lancet 2: 499, 1961. 11. MARMORSTON, J., F. J. MOORE, C. E. HOPKINS, 0. T. KUZMA,
AND J. WEINER, Clinical studies of long-term estrogen therapy in men with myocardial infarction, Proc Soc Exp Med Biol 110: 400, 1962. 12. NESTEL, P. J., E. Z. HIRSCH, AND E. A. COUZENS, The effect
of chlorophenoxyisobutyric acid and ethinyl estradiol on cholesterol turnover, J Clin Invest 44: 891, 1965. 13. SHAMANESH, M., C. H. BOLTON, R. C. L. FENELEY, AND M.
14.
15.
16. 17.
HARTOG, Metabolic effects of estrogen treatment in patients with carcinoma of prostate: a comparison of stilbestrol and conjugated equine estrogens, Br Med J 2: 512, 1973. DETRE, K. M., AND L. SHAW, Long term changes of serum cholesterol altering drugs in patients with coronary heart disease, Circulation 50: 998, 1974. SOTANIEMI, E. A., AND M. J. KONTTURI, Serum lipid levels and thromboembolic complications during estrogen therapy in prostatic carcinoma, Scand J Urol Nephrol 9: 89, 1975. BOYD, G. S., Estrogens, cholesterol and atherosclerosis, Front Horm Res 2: 74, 1973. GUSTAFSON, A., AND A. SVANBORG, Gonadal steroid effects on plasma lipoproteins and individual phospholipids, J Clin Endocrinol Metab 35: 203, 1972.
18. WALLENTIN, L., AND U. LARSSON-COHN, Metabolic and hor-
monal changes during postmenopausal estrogen replacement treatment. II. Plasma lipids, Acta Endocrinol 86: 597, 1977.
Acknowledgments We thank Miss Ylva Svensson and Mrs. Siv-Britt Fredrickson for technical assistance in the laboratory and Mrs. Marianne Andersson for secretarial assistance.
References
19. GLUECK, C. J., P. GARTSIDE, R. W. FALLAT, AND S. MENDOZA,
Effect of serum hormones on protamine inactivated and resistant postheparin plasma lipase, Metabolism 25: 625, 1976. 20. KEKKI, M., AND E. A. NIKKILA, Plasma triglyceride turnover during use of oral contraceptives, Metabolism 24: 878, 1971. 21. KIM, H. J., AND R. K. KALKHOFF, Sex steroid influence on triglyceride metabolism, J Clin Invest 56: 888, 1975. 22. GLUECK, C. J., R. W. FALLAT, AND B. SCHEEL, Effects on
1. Veterans Administration Cooperative Urological Research Group, Treatment and survival of patients with cancer of the prostate, Urol Gynecol Obstet 124: 1011, 1967. 2. Veterans Administration Cooperative Urological Research Group, Carcinoma of the prostate: treatment comparisons, J Urol 98: 516, 1967.
23.
24.
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Changes in plasma lipids are related to the risk for development of ischemic cardiovascular disease. Elevated TG (or VLDL) concentrations and/or elevated LDL concentrations increase this risk, while augmented HDL levels decrease the risk for atherosclerotic disease (5, 26, 27). Most epidemiological studies of relations between cardiovascular disease and plasma lipids concern subjects with primary hyperlipoproteinaemia. Such patients show an inverse relationship between TG (or VLDL) and HDL-TC concentration (28, 29). The net effect on the development of atherosclerotic disease of a simultaneously increased VLDL concentration and increased HDL/LDL quotient, as found during estrogen treatment in the present study, is therefore, at present, hard to evaluate. However, these changes of the plasma lipid metabolism do not necessarily increase the risk for atherosclerotic disease.
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