Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma

Increase in Plasma High-Density Androgen Blockage Sital Moorjani,

Andri

DuPont,

Lipoprotein Concentration Following in Men With Prostatic Carcinoma

Complete

Fernand Labrie, Paul-J. Lupien, Daniel Brun, Claude Gag&

Michel Gig&e,

and Alain Bklanger

There is evidence that endogenous estrogens have a positive effect on plasma high density lipoprotein (HDL) concentration, whereas the relation between HDL and male sex hormones is unclear, since both positive and negative effects have been reported. This study examined the effects of LHRH agonist in combination with an antiandrogen on plasma lipids and lipoproteins in 17 elderly men with prostatic carcinoma. Subjects were examined prior to and after therapy at 4-week intervals up to 16 weeks. Prior to therapy, their lipid and lipoprotein profiles were not significantly different from a control group composed of individuals of similar age and living in the same community area. Following therapy plasma levels of testosterone and dihydrotestosterone ware markedly decreased (above 90%) and their residual activity neutralized through effective use of an antiandrogen. Plasma estradiol decreased between 65% and 65% and the concantration of cortisol was unaffected. The very low density lipoprotein (VLDL) apo-B decreased and low density lipoprotein (LDL) apo-B increased: thus, no change was observed in the total plasma apo-B levels. Total plasma cholesterol increased by 6% (baseline v peak values, mg/dL, mean + SEM; 219 f 9 Y 233 f 9, P -C 0.05) due to a significant rise in HDL cholesterol concentration (45.5 f 2.8 Y 56.5 ? 3.6, P < 0.01). Both VLDL and LDL cholesterol levels remained unchanged. The mean elevation of 21% in HDL cholesterol was accompanied by a significant rise in HDL apo-A concentration (161 + 6 Y 193 f 10, P < 0.01). thus suggesting an increase in HDL mass and/or particle number. The opposite changes in the concentration of apo-B in the VLDL and LDL fractions, together with a corresponding increase in HDL concentration, ara suggestive of stimulation in VLDL hydrolysis. The favorable effect of this antihormonal therapy on plasma lipoprotein profile is indicated by decrease in the atherogenic index ratios. Finally, the data suggests that suppression of endogenous androgens in men increases HDL concentration and hence, it may be concluded that the low levels of HDL in men (relative to women) might be the result of the metabolic actions of androgens. Q 1987 by Grune & Stratton, Inc.

EX DIFFERENCES in the manifestation of cardiovascular diseases are well-recognized and also there is indirect evidence supporting the hypothesis that endogenous estrogen levels are protective. Thus, at every age cardiovascular risk is lower in women than in men, and furthermore, women without functioning ovaries have an increased risk of disease.‘*2 On the other hand, there are important primary differences in the plasma lipoprotein profile that differ considerably between sexes.3 Women in general have higher levels of high density lipoprotein (HDL) and lower concentrations of low density lipoprotein (LDL).334 It is believed that metabolic basis for these differences in the lipoprotein profile are related to sex steroids. Our knowledge on the role of sex steroids in lipoprotein metabolism is mainly derived from the use of estrogenic and androgenic compounds administered at pharmacologic doses. It is generally agreed that estrogens or estrogenic analogues increase the plasma levels of very low density lipoproteins (VLDL), HDL, and triglycerides.596 In contrast, exogenous androgenic-anabolic steroids produce severe depression of HDL levels and either an increase or a decrease in LDL concentration.‘” Regarding the role of endogenous sex hormones in lipoprotein metabolism in males, attention

S

From the Lipid Research Center, MRC Group in Molecular Endocrinology, Lava1 University Hospital Center, and the Departments of Biochemistry, Physiology and Medicine, Faculty of Medicine. Lava1 University, Quebec. Address reprint requests to Lipid Research Center, Le Centre Hospitalier de I’UniversitC Laval. 2705 Boulevard Laurier. Quebec, Canada, Gl V 4G2. 0 1987 by Grune & Stratton, Inc. 00264495/87/3603-0007$03.00/O

244

has been drawn in many studies on the influence of testosterone and estrogen on the levels of plasma lipoproteins, but the results are contradictory.‘“‘4 The development of long-acting gonadotropin releasing hormone agonists has provided opportunity to manipulate endogenous sex steroid levels in humans.” In recent studies, complete androgen blockage has been described as an approach in the management of prostatic cance?’ using the LHRH agonist to obtain medical castration levels of testosterone and an antiandrogen to neutralize the tumor stimulation by androgens of adrenocortical origin. The use of this combination antihormonal therapy has permitted us to evaluate the possible role of endogenous androgens in determining plasma lipoprotein concentrations. MATERIALS Patients,

AND METHODS

Controls, and Samples

Seventeen patients, aged 56 to 84 years (average age 68 year), with cytologically proven prostatic adenocarcinoma (stage C or ~),I’.18 participated in the study. All men were previously untreated (eight in Stage C and nine in stage D) and gave their informed written consent after approval of study by the Lava1 University Hospital Center’s Ethics Committee. The mean body mass of the group was 110% of the ideal body weight (range, 83% to 139%). Four patients (24%) had a previous history of ischemic heart disease and one had an episode of cerebrovascular disease. The mean + SD systolic and the diastolic blood pressure of the group was 142 + 11 and 82 + 12 mm Hg, respectively; only one patient suffered from arterial hypertension and was being treated with diuretics. One patient was diabetic, and none was suffering from thyroid, hepatic, or renal dysfunction. All medication was kept unchanged during the study. All patients were staying outside of the hospital and consumed their habitual diet. A record of personal lifestyles was kept throughout the study: five patients were physically inactive, eight (47%)

Metabolism, Vol36,

No 3

(March), 1987: pp 244-250

HDL DURING ANDROGEN

BLOCKAGE

lived a normal routine life, whereas four patients indulged in regular leisure physical activity. Nine patients (53%) were nonsmokers; of the remainder, six patients smoked less and two smoked more than 20 cigarettes per day, respectively. Only one patient had a history of regular alcohol consumption. For comparison of plasma lipids, lipoproteins, and apolipoprotein levels in prostate cancer patients, control subjects were randomly selected from an ongoing cardiovascular risk factor prevalence study in menI living in the same community area. Serum steroid levels in the elderly controls of similar age (57-81 years, average age 72) were measured in subjects living in the veterans hostel attached to medical center. Complete clinical, biochemical, and radiologic evaluation of the patients was performed prior to the treatment. W’ Patients received combination therapy with LHRH agonist (HOE 766, Buserelin) and antiandrogen (RU 23908, Anandron) at daily doses of 500 pg subcutaneously and 100 mg orally twice a day, respectively, as previously described.‘6,” Morning blood samples were taken after at least 12 hours of fasting, immediately before and then every 4 weeks after the start of treatment. Blood was collected from an anticubital vein in evacuated tubes containing ethylenediaminetetracetate (final concentration, I mg/mL) while the patient was in the reclining position. Plasma was separated by low speed centrifugation (1,000 x g for ten minutes) and stored at 4 OC in the presence of thimerosal (0.15 mg/mL, final concentration) before lipoprotein analyses were performed.

Laboratory Methods Plasma testosterone, dihydrotestosterone, 17-@-estradiol, and cortisol levels were measured by double-antibody radioimmunoassay as already described.‘6,*o Plasma VLDL fraction was isolated by ultracentrifugation using a 50.3 rotor (Beckman Instruments Inc, Palo Alto, Calif) at a density of 1.006 g/mL as described by Have1 et aL2’ The top fraction containing VLDL was recovered by tube slicing. Heparin and manganese chloride**~” were added to the infranatant, (density of more than 1.006 g/mL and containing both LDL and HDL) to precipitate apo-B containing LDL, leaving the HDL in solution. The concentration of LDL was obtained by differences from the values of cholesterol in the infranatant, measured before and after the precipitation step. The cholesterol and triglycerides in plasma and lipoprotein fractions were quantified on an AutoAnalyser II (Technicon Instruments Corp, Tarrytown, NY) using 2propanol extracts treated with zeolite mixture as described by Rush et alZ4 The mean recovery of cholesterol in the lipoprotein fractions averaged 95% and ranged from 92% to 102%. The precision of lipid determinations has been previously reported.2s Total phospholipid? were measured in plasma and in the supernatant obtained after the precipitation step. The electroimmunoassay of Laurel?’ was used to quantitate apolipoproteins. Total apo-B concentration was measured in plasma whereas the density fraction (d > 1.006 g/mL) was used to quantitate LDL apo-B levels. The concentration of apo-B in the VLDL fraction was obtained by difference. The apo-A levels were measured in the density fraction with d > 1.006 g/mL. Monospecific rabbit antisera of the same batch obtained from Behringwerke AG (Marburg) were used throughout the study. The specificity of the antisera was tested by radial double immunodiffusion against albumin. fibrinogen VLDL. LDL, and HDL preparations, A-I and A-II. Antiserum A was found to react only against HDL, A-I, and A-II. Electrophoresis was performed on a water-cooled electrophoresis cell model 1415 (Bio-Rad, Richmond, Calif) for 16 hours, using a standard barbital electrophoresis buffer (pH 8.6). The concentrations of apolipoproteins were calculated by comparison of peak heights of sample and standard rockets. The serum standards were lyophilized in small aliquots and stored at -80 OC. These sera were

standardized by electroimmunoassay using purified LDL and HDL quantitated by the method of Lowry et alz8 with albumin as standard and a correction for LDL protein due to higher color yield.29 The standard curves were established by relating protein content to rocket heights measured by microcomparator or millimeter graph paper. Subsequent studies have shown that apo A-I concentration measured by the same method represents 63% of the total apo-A in the plasma of elderly men, a value that is similar to 65% reported by Curry et al.” Significance of the mean differences between controls and patients with prostate cancer were analyzed by Student’s t-test. Differences from baseline levels during treatment were tested for significance by using paired nonparametric tests.” Regression analyses were carried out according to the method of least squares.

RESULTS

The clinical features and lifestyles of patients in the study shows that five (29%) of the 17 patients suffered from cardiovascular or vascular diseases, one had mild hypertension, and one was diabetic. All patients consumed their normal diet throughout the study. Nonsmokers represented 53% at the time of study and only two patients smoked more than 20 cigarettes per day. Table 1 details the concentration of plasma lipids, lipoproteins, and apolipoproteins and shows that there are no significant differences between patients with prostate cancer and the free living control subjects of similar age and also living in the same region. Also shown in Table 1 is comparative data on lipids, lipoproteins, and apolipoproteins in prostate cancer patients classified into stage C (localized to glands) or D (local and distant metastasis) of the disease, and again there are no significant differences in the untreated patients. The serum steroid levels in men with prostate cancer were similar to controls as shown in Table 2. Also shown in Table 2 are changes in the concentration of various serum steroids during the 16 weeks of treatment. The testosterone levels decreased remarkably by 88% at the fourth week of treatment and then ranged between 5% to 7% of the baseline value. Similarly, the concentration of dihydrotestosterone diminished by 84% to 91% during the treatment. On the other hand, concentration of plasma estradiol decreased

Table 1. Mean Plasma Concentration Apolipoproteins

in Untreated

of Lipids, Lipoproteins,

Men With Prostate

and

Cancer and in

Control Subjects Prostate Cancer Controls

N

Age (vr) Cholesterol Triglycerides VLDL-Cholesterol LDL-Cholesterol HDL-Cholesterol

stageC’

62 66.8

8

i 4.6

213 i 5 158 t 9 21.0

i

1.7

149 + 5 42.3

stage Dt

k 1.6

71.9

-+ 2.2

215 +_8

9 65.2

+ 2.2

222 t 10

138 ” 10

150 + 12

15.9 + 1.6

19.4 + 1.9

155 f 7 44.5

+- 2.7

157 t9 46.4

+ 3.2

Apo-B

110 * 4

118 t 5

117 t 6

APO-A

188 * 7

186 t 7

203 + 9

Values are given as mg/dL (mean k SEM). *Localized to the glands. tLocal and distant metastasis.

246

MOORJANI ET AL

Table 2.

Plasma Steroid Levels in Controls (n = 151 and Men With Prostate

Cancer (n = 17) Before and During Antihormonal

Treatment

With LHRH Agonist and Antiandrogen

4.41

t 0.72

5.82

+ 0.79

0.67

0.29

f O.ll*

0.39

+ 0.04

0.45

+ 0.08

0.07

0.04

k 0.01* (16)

17-@-Estradiol (pg/mL) Cortisol (ng/mL)

18.1 + 2.5 18Ok

23.3

11

+ 3.4

181 f 12

0.35

+ 0.06* * 0.01

3.4 + 0.8*

(35)

(15) 179 + 16

180 f 12

l

0.05

k 0.01 (11)

5.1 k 0.8* (22) 184 + 8 (102)

(99)

(99)

0.41

+ 0.07s

0.07

(7) * 0.01

(6)

(9)

8.2 r 2.2’

16ti

c 0.04,

(5)

(12) Dihydrotestosterone (ng/mL)

12wk

6wk

4wk

Baseline

COfWOlS

Testosterone (ng/mL)

l

l

(16) 7.9 k 0.9’ (34) 185 + 12 (102)

Values are mean + SEM. Values in parentheses refer to the % of the mean baseline values. lP-c 0.001.

between 65% and 85% and the cortisol levels did not vary by more than 2% of the baseline value. The effects of combination treatment on plasma levels of lipids and apo-B are shown in Table 3. Plasma phospholipids and apo-B levels were stable and did not vary more than 3% of the baseline value. Triglyceride concentration decreased initially at 4 and 6 weeks (but not significantly) and then stabilized within 6% of the baseline value. Plasma cholesterol concentration did not change during the first 8 weeks and then increased by 5% to 6% and attained significance only at 16 weeks of treatment. The data on various lipoprotein fractions is shown in Table 4. The concentration of cholesterol in the VLDL and LDL fractions did not vary to a great extent throughout the treatment period. The concentration of triglycerides in the VLDL showed parallel changes to total triglyceride levels, but the data is not significantly different from the baseline value. However, the apo-B levels decreased significantly in the VLDL fraction at all measured intervals and increased in the LDL fraction significantly during the 12 and 16 weeks of treatment. The regression analysis showed that the opposite changes in apo-B concentrations in the VLDL and LDL fractions are not correlated (r = .19, NS). The concentrations of both cholesterol and apo-A increased significantly in the HDL fraction at all measured intervals during the treatment. The HDL phospholipids also increased, but the data is not significant. The relationships between cholesterol, Table 3.

The Effect of Combined Treatment

apo-B, LDL, and HDL are expressed as ratios (also regarded as atherogenic indices) in Table 5. All the ratios except for LDL apo-B/HDL apo-A decreased significantly by 15% to 20%, both at 4 and 8 weeks of treatment. Thereafter, the ratios still remained lower than the baseline values, but the differences were not statistically significant. Since HDL is the most affected variable during complete androgen blockage, its relationship to other parameters known to influence its concentration were analyzed. The baseline triglycerides were not correlated to the concentration of HDL cholesterol, as one would expect. However, upon treatment this negative correlation coefficient increased from -0.19 to -0.41 but did not attain statistical significance probably due to a small number of patients. The concentration of HDL apo-A was strongly correlated to HDL cholesterol (I = .62, P < 0.01) as it was expected; moreover, this relationship was further strengthened after complete androgen blockage (r = .72, P -c 0.001). There was no correlation between HDL cholesterol and the pretreatment levels of testosterone and estradiol, as well as the ratio of the testosterone to estradiol (r = .36, -.07, and .29, respectively).

DISCUSSION

Among the many risk factors for coronary heart disease (CHD), male sex is one of the most important unmodifiable

With LHRH Agonist and an Antiandrogen With Prostate

on the Levels of Plasma Lipids and APO-B in Men

Cancer Rx

Baseline Cholesterol

4wk

8wk

12wk

16wk

219 + 9

223 + 9

221+9

230 + 9

233 -t 9’

Triglycerides

144 + 11

(102) 125 k 8

(101) 125 + 9

(105) 136 k 13

(106) 138 + 10

Phospholipids

223 + 8

(87) 216 + 9

(87) 219 k 10

(94) 227 f 10

(96) 225 r 10

APO-B

118 k 6

(97) 120 k 8

(98) 115 +6

(102) 119 k 7

(101) 121 k 7

(101)

(103)

(102) Values are given as mean + SEM mg/dL (n = 17). Values in parentheses refer to the % of the mean baseline value. lP c 0.05.

(98)

HDL DURING ANDROGEN

Table 4.

247

BLOCKAGE

The Effects of Combined Treatment With LHRH Agonist and an Antiandrogen on the Levels of Plasma Lipoproteins and Apolipoproteins in Men With Prostate Cancer Rx

Baseline

12wk

16wk

19.1 + 2.2

19.2 + 2.2

8 wk

4wk

VLDL 15.1 i

17.8 + 1.8

Cholesterol

1.5’

15.5 ? 1.8

(83) 77.4

Triglycerides

69.2 ? 6.1

r 8.3

70.3

(88)

80.6

+ 6.1

13.1 f 1.9t

(63)

168)

152 r 8

150 t 6

(97)

(96)

79.2

? 8.7

+ 7.9

(104)

(103)

12.4 + 1.8t

14.2 * 2.4’

(90)

12.4 k 1.9t

19.4 + 1.7

APO-B

(106)

(106)

(89)

(74)

(63)

LDL 156 i 8

Cholesterol

98 + 5

APO-B

158?

(103) 108 t 6* (110)

(109)

(105)

(104)

161 ? 6

107 t 6*

103 r 5

102 ? 6

7

(101)

HDL 56.5 r 3.6t

45.5 k 2.8

Cholesterol

55.1

(124) 90 i 5

Phospholipids

701 + 5 (112)

161 + 6

APO-A

186 + lot

54.0

r 3.9t

54.2

? 3.9t

(117)

(117)

93 + 6

96 i- 7

96 & 7

(103)

(107)

(1071 182+8t

193 + lot

184 + 9’

(115)

+ 4.1 t

(120)

(113)

(120)

(114)

Values are given as mg/dL (mean i SEM) (n = 17). Values in parentheses refer to the % of the mean baseline value. *P < 0.05. tP < 0.01.

risk factors. Among young American white adults men are tenfold more likely to develop acute myocardial infarction than are women’ and these sex differences are persistent, even in heterozygous familial hypercholestero1emia.32 It is believed that endogenous estrogens that have a direct affect on HDL cholesterol (negatively correlated to CHD) concentration4 are responsible for these differences. Testosterone is also known to influence plasma lipids and lipoproteins, but how the male sex hormone affects the metabolism of lipoproteins is not completely understood. Several studies have reported that the administration of synthetic androgenic compounds at pharmacologic doses diminish the plasma concentration of VLDL and HDL, whereas their effect on LDL, seems to be less consistent.7-9*33 In contrast, many epidemiologic and case-control studies have demonstrated that endogenous testosterone has a beneficial effect on plasma lipoproteins as shown by a positive correlation between plasma testosterone and HDL cholesterol levels. ‘“~‘2~34 However, these later findings have been contra-

dieted by certain reports,35336which have instead shown a negative correlation between plasma testosterone and HDL concentration. In more recent studies,‘3,36 it has been suggested that other hormonal variables such as estradiol may further modify the effects of endogenous testosterone on HDL metabolism and also that of other lipoproteins.37v38 The data from this study reveals that acute and effective lowering of plasma androgen levels, and testosterone in particular, results in a marked and stable increase in the concentration of HDL. The levels of both cholesterol and apo-A increased in the HDL fraction, the HDL phospholipid also increased but did not attain statistical significance. Together, the results are suggestive that increase in HDL concentration is due to an increase in the number of HDL particles and that possibly in the HDL, subfraction as suggested recently by Golberg et a1.39 Based on modest elevations in total cholesterol and serum apo-B levels in normal volunteers, these same authors also suggested that the concentration of LDL may also have increased. Direct

Table 5. Changes in the Ratios of Total and LDL Cholesterol to HDL Cholesterol and APO-B to APO-A in Men With Prostate Cancer Before and During Antihormonal Treatment With LHRH Agonist and Antiandrogen Rx Ratio

Baseline

4wk

6wk

12wk

16wk

4.1 + 0.2$ 2.8 ? 0.2$

4.4 * 0.2

4.6 * 0.3

Cholesterol/HDL cholesterol

5.1 + 0.3

4.0 + 0.2’

LDL cholestarol/HDL cholesterol

3.6 & 0.3

2.8 + 0.2’

3.1 * 0.2

3.2 ? 0.2

Plasma apo-B/HDL apo-A

0.73

c 0.04

0.65

* 0.04t

0.63

-c 0.03t

0.62

* 0.04

0.66

LDL apo-B/HDL apo-A

0.61

* 0.03

0.55

f 0.04

0.56

+ 0.02

0.55

i 0.03

0.59 ? 0.04 __-

Values are mean + SEM (n = 17)

lP< 0.001. tP < 0.05. $P < 0.02.

* 0.04

248

MCXIRJANI ET AL

measurement of LDL fraction in this study shows that the LDL cholesterol levels did not change; however, the LDL apo-B increased significantly, thereby indicating protein enrichment of LDL particles. In fact, our results also demonstrate that a modest increase in the total cholesterol in not due to LDL cholesterol increase, but is entirely accounted by considerable rise in HDL cholesterol. Also in contrast to previous findings, a lack of increase in the plasma apo-B levels, in spite of significant increase in LDL apo-B, is explained by a compensatory decrease in VLDL apo-B levels. These differences may be partly due to younger age of subjects as well as shorter duration (7 weeks) of the previous study.39 Another major difference in the present protocol is that in addition to administration of LHRH agonist which produces testoterone deficiency, and also reduced dihydrotestosterone levels by more than 80%, residual androgenic activity was effectively neutralized by the concomitant use of an antiandrogen as reported previously.‘* Thus, a complete neutralization of androgen activity was achieved”*” instead of a partial withdrawal. There is sufficient evidence that exogenous androgens in adults7-9 as well as changes in endogenous testosterone levels both result in a reduction of during puberty in boys 35,36p38; plasma HDL concentration. Conversely, in some epidemiologic and case-control studies, both positive and negative correlations have been observed between endogenous testosterone and HDL concentrations.‘“” The rise in HDL concentration during complete androgen blockage in this study does not lend support to observations on positive relationships between testosterone and HDL. Other studies have suggested that a positive association in men is not causal but related to estradiol levels36,37and to its interaction with testosterone. For example, a high estradiol/testosterone ratio in men would lead to a reduction in HDL cholesterol and apo-A concentration. If such was the case, then in the present study, one would expect a decrease in HDL concentration. Conversely, the data shows an increase in HDL, in spite of complete inhibition of testosterone and only a partial reduction in estradiol. It is postulated that the changes in HDL may even by of greater magnitude if estradiol concentration is not affected. On the basis of the above discussion it is proposed that endogenous androgens mainly contribute to low levels of HDL in men. No differences in HDL cholesterol levels were also found in men with a high estradiol/ testosterone ratio as compared to those in normal men.40 Thus, testosterone is mainly responsible for low HDL levels in men, and the possible role of endogenous estradiol in men requires further verification. Higher triglycerides and lower HDL levels in men as compared to women with normal ovarian function are suggestive that sex hormones may also be involved in the metabolism of VLDL. Dynamic changes in plasma lipoproteins occur during sexual maturation38*4’; girls have higher

VLDL cholesterol and similar levels of HDL cholesterol in comparison to boys before sex maturation. During adolescence, there is a pronounced decrease in HDL in boys and furthermore, unlike girls, they continue to show an increase in VLDL cholesterol. These observations strongly imply the important role of sex hormones in lipoprotein metabolism. Plasma triglycerides decreased initially in the present study; however, the concentration approached the baseline value during the later part of the treatment. Changes in VLDL cholesterol and triglycerides were not statistically significant; nevertheless, some decrease was noted and it followed a similar pattern to triglycerides. On the other hand, apo-B was depressed between 26% and 37% in the VLDL fraction and increased conversely in the LDL. These results suggest that lipoprotein lipase or hepatic lipase may be more active during the complete suppression of androgens. An increase in the concentration of HDL is also consistent with this hypothesis. In this respect, the treatment procedure provides a pharmacologic model to study further the interrelationships between triglyceride lipase activities and lipoprotein metabolism. The plasma lipids and apolipoproteins in men with prostate cancer are not different from that in the controls of similar age. Furthermore, lipoprotein levels are not influenced by the advanced stage (C v D) of the disease. Another objective of the study was to evaluate any adverse effects of combined antihormonal therapy on the levels of plasma lipoproteins, as it is noticed with the conventional estrogen therapy. The results indicate that complete suppression of androgens has a beneficiary effect, such as an increase in the concentration of HDL cholesterol and a decrease in the atherogenic risk, as indicated by favorable changes in the ratios of cholesterol/HDL cholesterol, LDL cholesterol/ HDL cholesterol, and the plasma apo-B/HDL apo-A. Changes were less remarkable for LDL apo-B/HDL apo-A ratio. Previous hormonal therapy of prostate cancer with estrogens has proven more efficacious in retarding the progression of cancer, as compared to orchiectomy, but it is also associated with an increased incidence of cardiovascular complications’8~42*43and raised plasma lipid levels.” The present combined antihormonal approach” has a significantly higher rate of remission than other conventional treatments. Whether the beneficiary effects on plasma lipoproteins will also result in a better prognosis for cardiovascular disease, especially in young patients, remains to be shown by appropriate long-term studies. ACKNOWLEDGMENT The authors gratefully acknowledge the outstanding work of Suzanne Croft for obtaining blood samples and clinical data. We would also like to thank the staff of Lipid Research Center for their valuable technical assistance and Doris Moreau, who prepared the manuscript.

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BLOCKAGE

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