Obstetrics & Gynecology Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Obstetrics & Gynecology 2000;96:521-528
© 2000 by The American College of Obstetricians and Gynecologists
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by KURABAYASHI, T.
Right arrow Articles by TANAKA, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by KURABAYASHI, T.
Right arrow Articles by TANAKA, K.

ORIGINAL RESEARCH

Eicosapentaenoic Acid Effect on Hyperlipidemia in Menopausal Japanese Women

TAKUMI KURABAYASHI, MD, MASAHIKO OKADA, MD and KENICHI TANAKA, MD FOR THE NIIGATA EPADEL STUDY GROUP

From the Department of Obstetrics and Gynecology and the Department of Laboratory Medicine, Niigata University School of Medicine, Niigata, Japan.

Address reprint requests to: Kenichi Tanaka, MD Department of Obstetrics and Gynecology Niigata University School of Medicine 1-757 Asahimachi-dori, Niigata-city Niigata 951-8510 Japan


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To assess the efficacy and safety of eicosapentaenoic acid for the treatment of hyperlipidemia in symptomatic menopausal Japanese women.

Methods: We performed a prospective observational 48-week study in hyperlipidemic menopausal women. We randomly assigned 141 women, whose levels of serum total cholesterol were 220 to 280 mg/dL or whose serum triglycerides were 150 to 400 mg/dL at baseline to groups treated with estriol (E3) 2 mg daily (control group, n = 72) or ethyl icosapentate 1800 mg daily and E3 2 mg (eicosapentaenoic acid group, n = 69).

Results: Serum levels of total cholesterol decreased significantly from 249.4 to 238.6 mg/dL (-4.3%, P = .003) in the control group and from 252.3 to 234.0 mg/dL (-7.3%, P = .001) in the study group at week 48 in the women whose total cholesterol was not less than 220 mg/dL at baseline. Serum levels of triglycerides decreased significantly from 194.5 to 141.5 mg/dL (-27.2%, P = .001) in the study group but increased slightly from 192.9 to 207.4 mg/dL (+7.5%) in the control group at week 48 in the women whose level of triglycerides was not less than 150 mg/dL. There were significant differences between these two groups at weeks 12, 24, and 48. Serum levels of total cholesterol and triglycerides were significantly decreased at week 48 in the study group regardless of whether the women were obese. There were no severe adverse effects.

Conclusion: Combination therapy with eicosapentaenoic acid and E3 was effective and safe for menopausal women with hypertriglyceridemia.

Heart disease is the leading cause of death in women in the United States, followed by malignant neoplasms, cerebrovascular disease, and traffic accidents. Japanese women might follow a similar trend in the future. During the reproductive years, women are protected from coronary heart disease. The levels of total cholesterol and low-density lipoprotein (LDL) cholesterol are lower in premenopausal women than in men, although they gradually increase with age and after menopause they increase rapidly.1–3 Prospective studies have documented a strong association between total cholesterol and coronary heart disease in women; however, the risk of coronary heart disease in women occurs at higher total cholesterol levels compared with men.4 Hypertriglyceridemia is also an important risk factor for coronary heart disease,5,6 because it is associated with hypercoagulability.7–9 It is known that estrogen improves not only menopausal symptoms but also hyperlipidemia by increasing high-density lipoprotein (HDL) cholesterol and decreasing LDL cholesterol.10–14 Most, but not all, epidemiologic studies show decreased incidence of coronary heart disease of about 40–50% in postmenopausal women taking estrogen compared with those who did not,15–18 although estrogen increased serum triglycerides.19

Epidemiologic studies involving Greenland Eskimos found that fish oils rich in eicosapentaenoic acid have a variety of beneficial effects that protect against atherosclerotic disease.20–24 The effect of eicosapentaenoic acid on plasma lipoprotein has been studied because lipoprotein abnormalities have important effects on the pathogenesis of atherosclerosis.25–27 A recent study showed that combination therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors plus eicosapentaenoic acid was effective for patients with hyperlipidemia.28 The addition of eicosapentaenoic acid might attenuate an estrogen-induced increase in triglycerides.

The present prospective observational study was undertaken to assess the efficacy and safety of combining eicosapentaenoic acid and estriol (E3) versus a control group treated with E3 alone in the treatment of symptomatic menopausal Japanese women with hyperlipidemia.


   Materials and Methods
Top
Abstract
 Materials and Methods
Results
 Discussion
 References
 
We studied 141 women, 23 premenopausal and 118 postmenopausal, who had menopausal symptoms and hyperlipidemia, 46 to 62 years of age, between June 1996 and March 1999, at 33 health institutions in Niigata, Japan. Hyperlipidemia was defined as a serum total cholesterol concentration of 220–280 mg/dL or a serum triglyceride concentration of 150–400 mg/dL. Women with severe hyperlipidemia (serum total cholesterol greater than 280 mg/dL or serum triglycerides greater than 400 mg/dL) were considered to have a high risk of coronary heart disease if assigned to the control group, so we set an upper limit of hyperlipidemia in this study. We excluded women who had a bleeding tendency, estrogen-dependent tumors, venous thrombosis, pulmonary embolism, or history of these diseases, women who had familial hypercholesterolemia, or women who were judged by a physician to be unsuitable for this study. We also excluded women who had been treated with conjugated estrogen or estradiol (E2) within the previous 6 months. Eligible women were informed of the study protocol at the time of diagnosis of hyperlipidemia. They were randomly allocated to the control group (n = 72) or the eicosapentaenoic acid group (n = 69) by using opaque sealed envelopes. Envelopes containing cards indicating the study allocation were prepared by administrative staff not directly involved in subject care, using computer-generated random numbers with randomization. In the control group, 72 patients received estriol (E3) 2 mg/day for 48 weeks. In the eicosapentaenoic acid group, 69 patients received ethyl icosapentate (EPADEL capsules; Mochida Pharmaceuticals Co. Ltd, Tokyo, Japan) 1800 mg/day and E3 2 mg/day for 48 weeks. EPADEL capsules contain over 96.5% eicosapentaenoic acid ethyl ester and 0.2% vitamin E. Informed consent was obtained from all patients before the start of the study. Because the average body mass index (BMI) for Japanese women is 22, we defined obesity as a BMI of 24 or greater, ie, about 10% excess. All patients enrolled in the study who received a least one dose of the medication were included in the safety analyses. Patients who completed at least 12 weeks of treatment were included in the efficacy analyses.

Blood samples for laboratory tests were collected after overnight fasting at baseline and at the end of weeks 12, 24, and 48. Serum concentrations of total cholesterol, triglycerides, and HDL cholesterol were quantified enzymatically. Apolipoproteins (A-I, A-II, B, and E) were measured by turbidimetric immunoassay. Lipoprotein(a) was measured by latex agglutination, and remnant lipoprotein cholesterol was measured by the immunoabsorption method. Low-density lipoprotein cholesterol was calculated using the formula of Friedewald et al.29 Atherosclerotic index was defined as apolipoprotein B/apolipoprotein A-I.30 According to the decision criteria defined by the Niigata Epadel Study Group, improvement occurred if the total cholesterol level decreased by more than 10% at the end of week 48 in women whose level of total cholesterol was not less than 220 mg/dL at baseline or if triglycerides decreased by more than 20% in women whose triglycerides were not less than 150 mg/dL at baseline, because the mean percentage change in total cholesterol and triglycerides has been found to be 9% (6–11%) and 32% (16–48%), respectively, in some Japanese studies.27,28,31,32 Cervical and endometrial smears were examined at baseline and at week 48. Endometrial biopsy or measurement of endometrial thickness by transvaginal ultrasonography was added in cases of genital bleeding. Other laboratory tests (hematologic tests, serum chemistry, and urinalysis) were done at the same time points during the study.

We estimated the statistical power of this study. Given the fixed 48-week follow-up, we planned to enroll 140 subjects, which would provide 80% power with .05 two-sided tests to detect differences in most comparisons. Because the incidence of adverse effects was 3.7% for eicosapentaenoic acid and 4.2% for E3 according to available drug information, the power of this study was considered to be adequate for determining some of the adverse effects.

All data were expressed as the mean ± standard deviation (SD). All data management and statistical analyses were performed with Stat View 4.0 (Abacus Concepts, Berkeley, CA). The significance of differences between the two groups was determined using Student unpaired t test and that of differences in changes over time was determined by one-way repeated-measures analysis of variance. The statistical significance of intergroup differences was evaluated by two-way factorial analysis of variance followed by Fisher least significant difference method for multiple comparisons. Differences in some background characteristics of the patients and the improvement rate between the two groups were analyzed using Fisher exact test. Differences with a P value below .05 were considered statistically significant.


   Results
Top
Abstract
 Materials and Methods
 Results
Discussion
 References
 
There were no significant differences in clinical background of the women allocated to the two groups (Table 1Go). The proportion of patients who took all medication prescribed was 87.5% in the control group and 88.8% in the eicosapentaenoic acid group at week 12, 84.7% and 81.2% at week 24, and 75.0% and 68.1% at week 48, respectively. The changes in serum levels of total cholesterol, triglycerides, HDL, and LDL cholesterol from baseline to week 48 for premenopausal and postmenopausal women were -4.8% versus -2.6%, 13.4% versus 8.2%, -1.7% versus 3.9%, and -9.2% versus -6.6% in the control group, and -4.9% versus -5.9%, -7.6% versus -11.8%, -0.1% versus 0.1%, and -5.7% versus -6.2% in the eicosapentaenoic acid group, respectively. These changes were not significantly different between premenopausal and postmenopausal women in the two groups. The following data for premenopausal and postmenopausal women were than analyzed together.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical Backgrounds of Women in the Control and Eicosapentaenoic Acid Groups
 
The changes in serum levels of total cholesterol, triglycerides, and HDL and LDL cholesterol from baseline to week 48 are shown in Table 2Go. Serum total cholesterol levels decreased significantly from 249.4 to 238.6 mg/dL (-4.3%, P = .003) in the control group and from 252.3 to 234.0 mg/dL (-7.3%, P = .001) in the eicosapentaenoic acid group at the end of week 48 in the women whose level of total cholesterol was not less than 220 mg/dL at baseline. There was no statistically significant difference between these two groups from baseline to week 48 (Figure 1Go). Serum triglycerides levels decreased significantly from 194.5 to 141.5 mg/dL (-27.2%, P = .001) in the eicosapentaenoic acid group but increased slightly from 192.9 to 207.4 mg/dL (+7.5%, P = .29) in the control group at week 48 in the women whose level of triglycerides was not less than 150 mg/dL at baseline. There was a statistically significant difference between these two groups at weeks 12, 24, and 48 (P = .009, .001, and .004, respectively) (Figure 2Go). Although the proportion of cases showing improvement in total cholesterol levels was 25.0% (14 of 56) in the control group and 38.5% (20 of 52) in the eicosapentaenoic acid group, there was no significant difference between the two groups. The proportion of cases showing improvement of triglycerides levels was 10% (two of 20) and 55% (11 of 20), respectively (P = .003). High-density lipoprotein cholesterol levels remained almost unchanged. Low-density lipoprotein cholesterol levels in both groups were significantly lower at weeks 12, 24, and 48, and the percentage change in LDL cholesterol was -8.3% (P = .001) in the control group and -8.1% (P = .02) in the eicosapentaenoic acid at week 48, but there was no significant difference between the two groups.


View this table:
[in this window]
[in a new window]
  		Table 2. Change in Serum Levels of Total Cholesterol, Triglycerides, High-Density Lipoprotein Cholesterol, and Low-Density Lipoprotein Cholesterol
 


View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. Changes in serum total cholesterol levels from baseline to week 48 in the control and eicosapentaenoic acid groups in women whose level of total cholesterol was not less than 220 mg/dL at baseline. EPA = eicosapentaenoic acid. Data are mean ± standard deviation. Numbers in parentheses indicate number of samples. *P < .05. ***P < .005 (versus baseline as calculated by Student paired t test).

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 2. Changes in serum triglycerides levels from baseline to week 48 in the control and eicosapentaenoic acid groups in women whose level of triglycerides was not less than 150 mg/dL at baseline. Abbreviations as in Figure 1Go. Data are mean ± standard deviation. Numbers in parentheses indicate number of samples. ***P < .005 (versus baseline as calculated by Student paired t test). ¶¶P < .01. ¶¶¶P < .005 (intergroup differences were assessed by Student unpaired t test).

 
The changes in serum levels of apolipoproteins from baseline to week 48 are shown in Table 3Go. The apolipoprotein A-II level in the eicosapentaenoic acid group significantly decreased from baseline to week 48, and there were significant differences between the two groups at weeks 12 and 24. The apolipoprotein B level in the eicosapentaenoic acid group was significantly lower at week 48 compared with the baseline level, but there was no significant difference between the groups. The atherosclerotic index of the eicosapentaenoic acid group decreased significantly from baseline to week 48. In the eicosapentaenoic acid group, the level of lipoprotein(a) significantly decreased from baseline to week 48. The difference in remnant lipoprotein cholesterol was not statistically significant.


View this table:
[in this window]
[in a new window]
  		Table 3. Changes in Serum Levels of Apolipoprotein, Lipoprotein(a), and Remnant Lipoprotein
 
The changes in triglycerides and HDL cholesterol were different between obese and nonobese women (Table 4Go). In obese women, the serum triglycerides level was significantly higher and serum HDL cholesterol was significantly lower than those of nonobese women at baseline and week 48. In the eicosapentaenoic acid group, serum total cholesterol and triglycerides were significantly lower at week 48 regardless of whether women were obese. Serum LDL cholesterol was significantly lower at week 48 in nonobese women. In the control group, the serum triglycerides level was slightly higher at week 48 in obese women, and serum LDL cholesterol was significantly lower at week 48 regardless of whether women were obese.


View this table:
[in this window]
[in a new window]
  		Table 4. Change in Serum Levels of Total Cholesterol, Triglycerides, High-Density Lipoprotein Cholesterol, and Low-Density Lipoprotein Cholesterol Between Obese and Nonobese Subgroups
 
There were no adverse effects of treatment as indicated by the results of hematologic tests, serum biochemistry, and urinalysis. There were no abnormal findings in the endometrial smears at any determination point. Five women, four in the control group and one in the study group, had genital bleeding, but there was no abnormality in endometrial biopsy findings or in measurements of endometrial thickness by transvaginal ultrasonography. Two women in the control group had low-grade squamous intraepithelial lesions as found by examination of a cervical smear at week 48. The cervical biopsies of these two women showed mild dysplasia. Five women had side effects, two in the control group, and three in the eicosapentaenoic acid group. In the control group, one woman had epigastric discomfort and mild liver dysfunction and the other complained of headache. In the eicosapentaenoic acid group, two women had increased serum creatinine phosphokinase levels, and the third had epistaxis. This latter patient withdrew from the study at week 28, but the other four continued to receive treatment until week 48.


   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
We prospectively studied the effects of eicosapentaenoic acid on lipid metabolism in hyperlipidemic women with menopausal symptoms. The postmenopausal hypoestrogen state could cause osteopenia and hyperlipidemia, which is associated with coronary heart disease and brain embolism. The most important finding of this study was that combination therapy with eicosapentaenoic acid and E3 significantly decreased the serum triglycerides level compared with E3 alone. Eicosapentaenoic acid has an inhibitory effect on hepatic triglycerides syntheses and secretion and has a stimulatory effect on lipoprotein degradation, resulting in reduced particle size. Eicosapentaenoic acid also has an inhibitory effect on intestinal cholesterol absorption and hepatic cholesterol biosynthesis, as well as an enhancing effect on hepatic biliary secretion as shown in rodent studies.33,34 Although eicosapentaenoic acid might be useful for perimenopausal hyperlipidemic women, it is questionable whether all these mechanisms actually apply in humans. This study also showed that eicosapentaenoic acid decreased the atherosclerotic index. Eicosapentaenoic acid also has been shown to have an antithrombotic effect,32 which is essential for controlling coronary heart disease by lowering serum total cholesterol and triglycerides and through its antithrombotic action.

Treatment with E3 alone resulted in a 3.7% decrease in serum total cholesterol levels, which was considered a weak effect compared with that of conjugated estrogen, but it resulted in an 8.8% increase in serum triglyceride levels. Estrogen causes a decrease in serum total cholesterol and LDL cholesterol and an increase in HDL cholesterol resulting from increased hepatic LDL-receptor activity and suppressed hepatic triglyceride lipase activity; it also causes an increase in triglycerides resulting from suppression of lipoprotein lipase.19 Estriol therapy for hyperlipidemic menopausal women was effective not only for menopausal symptoms but also for alterations in lipid metabolism, so combination therapy with eicosapentaenoic acid and E3 might prevent hypertriglyceridemia caused by hormone replacement therapy.

In this study, E3 alone caused a 10.8% increase in serum triglycerides in obese women at week 48 and a 3.7% increase in nonobese women. Combination therapy with E3 and eicosapentaenoic acid resulted in a significant decrease (about 11%) in serum triglycerides in both obese and nonobese women. In general, levels of triglycerides can be increased because of obesity, smoking, or lack of exercise. Central fat distribution in women is positively correlated with increases in the level of total cholesterol, triglycerides, and LDL cholesterol and negatively correlated with HDL cholesterol levels.35 The atherogenic lipid profile associated with abdominal adiposity is at least partly mediated through the interplay of insulin and estrogen.36 Weight loss also can decrease elevated levels of triglycerides to normal.

In some trials, postmenopausal women treated with oral E3 showed improvement of menopausal symptoms, urogenital symptoms, and bone loss.37–39 Estriol is a low-potency estrogen with considerably weaker endometrial proliferation-inducing effects than estradiol and conjugated estrogens.40,41 Estriol therapy is associated with less frequent genital bleeding and might not require concomitant use of progestins. According to the results of some prospective cohort studies, women treated with oral E3 showed no increase in the relative risk of endometrial cancer.42–44 Therefore we used E3 alone without progestins in this study. Subjects whose endometrial cytology and histology were examined showed neither abnormalities nor hyperplasia in this study. However, Weiderpass et al45 found in 1999 that oral E3 at a dose of 1–2 mg daily increased the relative risk of endometrial cancer and endometrial atypical hyperplasia. We should monitor the endometrium during such treatment and consider whether to add progestins when we use E3 in future.

There was a case of epistaxis in the eicosapentaenoic acid group, which might have resulted from the antithrombotic effect of eicosapentaenoic acid. No serious adverse effects were observed in this study.

Combination therapy with eicosapentaenoic acid and E3 resulted in marked improvement of lipid metabolism, especially of hypertriglyceridemia, in women with or without obesity, although E3 alone did not show a sufficient effect. In the future, it will be necessary to analyze the effects of eicosapentaenoic acid in preventing coronary heart disease in a larger number of subjects treated for a longer period.


   Footnotes
 
The clinical investigators comprising the Niigata Epadel Study Group are: Akira Honda, MD, Tetsuro Yahata, MD, Masatoshi Tomita, MD, Hiroshi Matsushita, MD, Takashi Miida, MD, Minoru Nakamura, MD, Norihito Sudo, MD, Kouichi Tanaka, MD, Kiyoshi Yamada, MD, Ichiro Yamazaki, MD, Masahiro Yasuda, MD, Masaaki Takahashi, MD, Takeshi Takahashi, MD, Michihito Endo, MD, Takeshi Hirohashi, MD, Masami Kato, MD, Isao Hataya, MD, Naoki Motani, MD, Susumu Abe, MD, Hiroshi Watanabe, MD, Shigeru Arai, MD, Hideo Yuzawa, MD, Susumu Ozaki, MD, Shiro Ishii, MD, Kunio Tanaka, MD, Toshio Nishiyama, MD, Masaharu Hirokawa, MD, Akira Tohyama, MD, Takao Terashima, MD, Yasuo Adachi, MD, Akiteru Tokunaga, MD, Yoshiya Tojo, MD, Takaaki Suzuki, MD, Yoshiki Kazama, MD, Norio Nishimura, MD, Yuuetsu Sudo, MD, Toshihiro Maruhashi, MD, Akira Goto, MD, Akira Higuchi, MD, Ayako Sasaki, MD, Yusuke Minagawa, MD, Kazushige Suzuki, MD, Miwako Ishii, MD, Toru Yanase, MD, Takashi Fujimaki, MD, Shigeko Takagi, MD, Masaki Tamura, MD, Tetsuo Tomita, MD, and Syuji Honda, MD.

This research was supported by an educational grant from Mochida Pharmaceutical Co., Ltd., Tokyo, Japan.

PII S0029-7844(00)00988-1

Received January 10, 2000. Received in revised form April 21, 2000. Accepted May 3, 2000.


   References
Top
Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989;321:641–6.[Abstract]

2. Campos H, McNamara JR, Wilson PW, Ordovas JM, Schaefer EJ. Differences in low density lipoprotein subfractions and apolipoproteins in premenopausal and postmenopausal women. J Clin Endocrinol Metab 1988;67:30–5.[Abstract]

3. Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993;98:83–90.[Medline]

4. Brunner D, Weisbort J, Meshulam N, Schwartz S, Gross J, Saltz-Rennert H, et al. Relation of serum total cholesterol and high-density lipoprotein cholesterol percentage to the incidence of definite coronary events: Twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary Artery Disease Study. Am J Cardiol 1987;59:1271–6.[Medline]

5. Castelli WP. The triglycerides issue: A view from Framingham. Am Heart J 1986;112:432–7.[Medline]

6. Bass KM, Newschaffer CJ, Klag MJ, Bush TL. Plasma lipoprotein levels as predictors of cardiovascular deaths in women. Arch Intern Med 1993;153:2209–16.[Abstract]

7. Simpson HC, Mann JI, Meade TW, Chakrabarti R, Stirling Y, Woolf L. Hypertriglyceridaemia and hypercoagulability. Lancet 1983;1: 786–90.[Medline]

8. Miller GJ, Martin JC, Webster J, Wilkes H, Miller NE, Wilkinson WH, et al. Association between dietary fat intake and plasma factor VII coagulant activity—A predictor of cardiovascular mortality. Atherosclerosis 1986;60:269–77.[Medline]

9. Oseroff A, Krishnamurti C, Hassett A, Tang D, Alving B. Plasminogen activator and plasminogen activator inhibitor activities in men with coronary artery disease. J Lab Clin Med 1989;113:88–93.[Medline]

10. Lobo EA. Effect of hormone replacement on lipids and lipoproteins in postmenopausal women. J Clin Endocrinol Metab 1991;73:925–30.[Medline]

11. Muesing RA, Miller VT, LaRosa JC, Stoy DB, Phillips EA. Effect of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution. J Clin Endocrinol Metab 1992;75:1250–4.[Abstract]

12. Granfone A, Campos H, McNamara JR, Schaefer MM, Lamon-Fava S, Ordovas JM, et al. Effect of estrogen replacement on plasma lipoproteins and apoproteins in postmenopausal, dyslipidemic women. Metabolism 1992;41:1193–8.[Medline]

13. Whitcroft SI, Crook D, Marsh MS, Ellerington MC, Whitehead MI, Stevenson JC. Long-term effects of oral and transdermal hormone replacement therapies on serum lipid and lipoprotein concentrations. Obstet Gynecol 1994;84:222–6.[Abstract/Free Full Text]

14. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: A long-term cohort study. Am J Med 1994;97:66–77.[Medline]

15. Hulley S, Grady D, Bush T, Furberg C, Herrington DB, Vittinghoff E, for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–13.[Abstract/Free Full Text]

16. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. N Engl J Med 1985;313:1038–43.[Abstract]

17. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199–208.[Abstract]

18. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and risk of cardiovascular disease. N Engl J Med 1996;335:453–61.[Abstract/Free Full Text]

19. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196–204.[Abstract]

20. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic west-coast Eskimos. Lancet 1971;1:1143–5.[Medline]

21. Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975;28:958–66.[Abstract/Free Full Text]

22. Needleman P, Minkes M, Raz A. Thromboxanes: Selective biosynthesis and distinct biological properties. Science 1976;193:163–5.[Abstract/Free Full Text]

23. Dyerberg J, Bang HO, Stoffersen E. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet 1978;2:117–9.[Medline]

24. Needleman P, Raz A, Minkes MS, Ferrendelli JA, Sprecher H. Triene prostaglandins: Prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Natl Acad Sci U S A 1979;76:944–8.[Abstract/Free Full Text]

25. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: A critical review. J Lipid Res 1989;30:785–807.[Abstract]

26. Gries A, Malle E, Wurm H, Kostner GM. Influence of dietary fish oils on plasma Lp(a) levels. Thromb Res 1990;58:667–8.[Medline]

27. Nozaki S, Matsuzawa Y, Hirano K, Sakai N, Kubo M, Tarui S. Effects of purified eicosapentaenoic acid ethyl ester on plasma lipoproteins in primary hypercholesterolemia. Int J Vitam Nutr Res 1992;62:256–60.[Medline]

28. Nakamura N, Hamazaki T, Ohta M, Okuda K, Urakaze M, Sawazaki S, et al. Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res 1999;29:22–5.[Medline]

29. Friedewald WT, Levy RI, Fredrick DS. Estimation of the concentration of low density lipoprotein in plasma without use of a preparative ultracentrifuge. Clin Chem 1972;18:449–56.[Abstract]

30. Vaisanen S, Gavert J, Julkunen A, Voutilainen E, Penttila I. Correlation between the ratio of serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with that of serum apolipoprotein B and A-I. Int J Clin Lab Res 1993;23:160–4.[Medline]

31. Shiozaki K, Kambayashi J, Kawasaki T, Uemura Y, Sakon M, Shiba E, et al. The long-term effect of eicosapentaenoic acid on serum levels of lipoprotein (a) and lipids in patients with vascular disease. J Atheroscler Thromb 1996;2:107–9.[Medline]

32. Hayashi K, Ohtani H, Kurushima H, Nomura E, Koide K, Kunita T, et al. Decreases in plasma lipid content and thrombotic activity by ethyl icosapentate purified from fish oils. Curr Ther Res 1995;56:24–31.

33. Mizuguchi K, Yano T, Ishibashi M, Masada A, Mizota M, Saito Y. Ethyl all-cis-5,8,11,14,17-icosapentaenoate modifies the biochemical properties of rat very low-density lipoprotein. Eur J Pharmacol 1993;235:221–7.[Medline]

34. Mizuguchi K, Yano T, Tanaka Y, Ishibashi M, Masada A, Mizota M, et al. Mechanism of the lipid-lowering effect of ethyl all-cis-5,8,11,14,17-icosapentaenoate. Eur J Pharmacol 1993;231:121–7.[Medline]

35. Haarbo J, Hassager C, Riis BJ, Christiansen C. Relation of body fat distribution to serum lipids and lipoproteins in elderly women. Atherosclerosis 1989;80:57–62.[Medline]

36. Soler JT, Folsom AR, Kaye SA, Prineas RJ. Associations of abdominal adiposity, fasting insulin, sex hormone binding globulin, and estrogen with lipids and lipoproteins in post-menopausal women. Atherosclerosis 1989;79:21–7.[Medline]

37. Esposito G. Estriol: A weak estrogen or a different hormone? Gynecol Endocrinol 1991;5:131–53.[Medline]

38. Molander U, Milsom I, Ekelund P, Mellström D, Eriksson O. Effect of oral oestriol on vaginal flora and cytology and urogenital symptoms in the post-menopause. Maturitas 1990;12:113–20.[Medline]

39. Minaguchi H, Uemura T, Shirasu K, Sato A, Tsukikawa S, Ibuki Y, et al. Effect of estriol on bone loss in postmenopausal Japanese women: A multicenter prospective open study. J Obstet Gynaecol Res 1996;22:259–65.[Medline]

40. Tzingounis VA, Aksu MF, Greenblatt RB. Estriol in the management of the menopause. JAMA 1978;239:1638–41.[Abstract]

41. Hauser HP, Staemmler HJ. Histological investigations into the effect of oestriol succinate on the corpus uteri in postmenopausal women. Arzneimittelforschung 1973;23:558–62.[Medline]

42. Salmi T. Endometrial carcinoma risk factors, with special reference to the use of estrogens. Acta Endocrinol (Copenh) 1980;233(Suppl): 37–43.

43. Persson I, Adami HO, Bergkvist L, Lindgren A, Pettersson B, Hoover R, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: Results of a prospective study. BMJ 1989;298:147–51.

44. Schairer C, Adami HO, Hoover R, Persson I. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology 1997;8:59–65.[Medline]

45. Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergström R, et al. Low-potency oestrogen and risk of endometrial cancer: A case-control study. Lancet 1999;353:1824–8.[Medline]





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by KURABAYASHI, T.
Right arrow Articles by TANAKA, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by KURABAYASHI, T.
Right arrow Articles by TANAKA, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS