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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1383-1387.)
© 1996 American Heart Association, Inc.

Articles

The Association of Hyperestrogenemia With Coronary Thrombosis in Men

Gerald B. Phillips; Bruce H. Pinkernell; Tian-Yi Jing

the Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's–Roosevelt Hospital Center, New York, NY.

Correspondence to Dr Gerald B. Phillips, Roosevelt Hospital, 1000 Tenth Ave, New York, NY 10019.

	Abstract

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Both hyperestrogenemia and hypotestosteronemia have been reported in association with myocardial infarction (MI) in men. It was previously observed that the serum testosterone concentration correlated negatively with the degree of coronary artery disease (CAD) in men who had never had a known MI. The present study investigated the relationship of sex hormone levels to the thrombotic component of MI by comparing these levels in 18 men who had had an MI (ie, thrombosis) and 50 men with no history of MI (ie, no thrombosis) whose degree of CAD was in the same range. The mean degree of CAD, age, and body mass index in these two groups was not significantly different. The mean serum estradiol level in the men who had had an MI (38.5±8.8 pg/mL) was higher (P=.002) than the level in the men who had not had an MI (31.9±7.1 pg/mL). The mean levels of testosterone, free testosterone, sex hormone–binding globulin, insulin, dehydroepiandrosterone sulfate, cholesterol, HDL cholesterol, and systolic and diastolic blood pressure did not differ significantly. Estradiol was the only variable measured that showed a significant relationship to MI (P<.003 by multivariate logistic regression). These findings suggest that hyperestrogenemia may be related to the thrombosis of MI.

Key Words: estradiol • estrogen • testosterone • myocardial infarction • coronary thrombosis

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Most laboratories studying sex hormone levels in men with MI, either acutely or months to years later, have reported either hyperestrogenemia, hypotestosteronemia, or both.¹ In a recent study, we observed a strong negative correlation between the testosterone level and degree of CAD in 55 men who had never had a known MI.¹ This finding supported a role for hypotestosteronemia in the development of CAD. The estradiol level, even though it also appears to be related to MI, did not correlate with the degree of CAD.¹ Since the patients in that study had never had a known coronary thrombosis, it was hypothesized that hyperestrogenemia may be related to the thrombosis of MI rather than to the CAD, especially since estrogen administration to men has been reported to provoke thrombosis.² The present study investigated the relationship of sex hormones and risk factors for MI to the thrombosis. To do this, the levels of sex hormones and risk factors for MI in men who had had an MI (ie, thrombosis) were compared with those in men whose degree of CAD was in the same range but who had never had a known MI (ie, no thrombosis).

	Methods

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One hundred male patients referred to the cardiac catheterization laboratory of Roosevelt Hospital for diagnostic coronary angiography were studied. The patients were consecutive except for the exclusion of patients who had either an MI within 2 months of catheterization, an MI that was non–Q wave, or a major medical disorder other than coronary heart disease. Patients were not excluded for hypertension or non–insulin-dependent diabetes mellitus. Eighty-two patients had never had an MI diagnosed. Eighteen patients had had an MI at a mean of 5.9 years before sampling; in one patient the MI occurred 2 months, in four patients 6 to 14 months, and in 13 patients 2 or more years before sampling.

Coronary Angiography and Analytical Methods
Coronary angiography was performed via the femoral artery by using preformed catheters, and angiograms were taken by using the Judkins technique³ with multiple views. One of the authors (Dr Pinkernell) visually estimated the maximum percent reduction in luminal diameter of the main left, left anterior descending, left circumflex, and right coronary artery in each patient without knowledge of the laboratory results. The mean of these four values was used as the estimate of the degree of CAD for each patient in the statistical analyses.

Blood samples were obtained through the needle inserted into the femoral artery for angiography before heparin administration. All samples were taken before noon with the patient fasting. All measurements were performed on serum that had been stored airtight at -20°C. Hormones were measured by using radioimmunoassay. Estradiol and testosterone were measured¹ on serum stored <7 months. Materials for the radioimmunoassay of estradiol were obtained from ICN Biomedicals, Inc, and those for testosterone, FT, insulin, and DHEAS were from Diagnostic Products Corp. Materials for the immunoradiometric assay of SHBG were from Farmos Diagnostica. The interassay means and coefficients of variation for the quality control samples for estradiol were 23.2 pg/mL±6.9% and 62.0 pg/mL±4.0%, and for testosterone, 3.75 ng/mL±5.3% and 6.46 ng/mL±6.7%, respectively. Total cholesterol was measured enzymatically, as was the cholesterol in the supernatant after phosphotungstic acid precipitation of serum in the measurement of HDL-C (DMA, Inc).

Statistical Analysis
Student's t test was used to test the difference in the mean levels of variables between patients with and without MI and to calculate the possible effect of drug intake or smoking on sex hormone levels. Multivariate logistic regression analysis was performed to determine the relationship between MI and the variables measured; forward stepwise selection with the likelihood-ratio test was used to remove variables from the model. The Mantel-Haenszel ² was calculated to test whether MI was related to smoking history. These as well as calculations of means, SDs, and outliers (using box plots) were performed by using SPSS programs on a Macintosh SE/30 computer. A probability value of less than .05 was considered significant.

	Results

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The mean serum estradiol level was higher (P=.005) in the 18 men with MI (38.5±8.8 pg/mL) than in the 82 men without MI (32.2±8.4 pg/mL). The mean degree of CAD was also higher (P<.02) in the men with MI (49.3±17.9%) than in those without MI (36.2±29.6%). None of the other variables measured, including age, BMI, testosterone, FT, SHBG, insulin, DHEAS, cholesterol, HDL-C, SBP, and DBP, showed a significant difference between the two groups. Because of a possible confounding effect of the difference in degree of CAD between the groups on the relationship of estradiol to MI, the variables were compared in the men with MI to those of the 50 patients without MI whose degree of CAD was in the same range (20% to 85%) (Table 1). Neither the mean age, BMI, nor degree of CAD differed significantly between the latter two groups. The mean estradiol level was higher (P=.002) in the patients who had had an MI, but the mean levels of testosterone, FT, SHBG, insulin, DHEAS, cholesterol, HDL-C, SBP, and DBP did not differ significantly between the two groups. A scatterplot comparing the estradiol levels of these two groups of patients is shown in the Figure. The highest estradiol value in the MI group was found to be an outlier. Excluding this outlier, the mean estradiol level in the MI group was 37.2±7.2 pg/mL, but the difference between the two groups was still significant (P<.009); none of the differences in means of the other variables compared in Table 1 became significant when the outlier was removed from the calculations. When the MI group was divided according to the degree of CAD, the 9 patients with the greater degree of CAD had a lower (P=.03) estradiol level than the 9 patients with the lesser degree of CAD.

View this table: [in this window] [in a new window]   Table 1. Comparison of Levels of Variables in Men With a Similar Degree of CAD With and Without Past MI

View larger version (11K): [in this window] [in a new window]   Figure 1. Scatterplot compares estradiol values, means (), and 95% confidence intervals (bars) of 18 patients with previous MI and 50 patients with the same range of CAD values without a known MI.

Table 2 shows a multivariate logistic regression analysis in patients with and without MI using MI as the dependent variable and estradiol, testosterone, age, BMI, and degree of CAD as independent variables entered into the model. In this model, only estradiol was significantly related to MI. When the outlier was excluded, the relationship remained significant both in Group 1 (P<.01) and Group 2 (P<.02).

View this table: [in this window] [in a new window]   Table 2. Multivariate Logistic Regression Analysis in Men With and Without Past MI

Because the 100 patients were taking an average of 3.1 drugs each, a drug effect may have accounted for the difference in estradiol levels found. In fact, the 18 patients who had had an MI were taking an average of 4.5 drugs each, while the 50 patients without MI whose degree of CAD was in the same range were taking an average of 3.0 drugs each. Thus, the possible effect of drugs on sex hormone levels was tested for any class of drugs consumed by more than 5 of the 68 patients in these two groups. To exclude a confounding effect of MI, the sex hormone levels of patients on or off a class of drugs were compared in the 82 patients without MI. Neither the testosterone nor FT level was significantly different with any of the drugs. The results for estradiol are shown in Table 3. The only drug showing a significant difference was digoxin (the only digitalis drug used); the estradiol level was higher in the patients on digoxin. However, when the 6 patients (2 with MI and 4 of the 50 patients without MI) taking digoxin were excluded, the estradiol level was still higher in the patients with MI (P=.002).

View this table: [in this window] [in a new window]   Table 3. Effects of Drug Intake on Estradiol Levels in 82 Men With No Known MI

To investigate further the relationship of the variables measured to MI in the 18 patients with MI and the 50 patients without MI, a multivariate logistic regression analysis using forward stepwise selection with the likelihood-ratio test was performed. The dependent variable entered into the model was MI; the independent variables were age, BMI, CAD, estradiol, FT, insulin, cholesterol, SBP, smoking, indicators of medication (consisting of each of the nine drugs listed in Table 3), and the interaction term digoxinxestradiol. The only variable to show a significant relationship to MI, including or excluding the estradiol outlier, was estradiol. For the null hypothesis including the outlier, P was <.003; excluding the outlier from the group of 18, P was <.01.

To determine whether the difference in estradiol levels between the 18 patients with MI and 50 patients without MI could be attributed to a difference in smoking history between the two groups, the patients were classified into the categories of current smoker, past smoker, and nonsmoker. Comparing nonsmokers with current and/or past smokers in the 82 patients without MI showed no significant difference in the mean levels of estradiol. Using the Mantel-Haenszel ² test, smoking and MI were unrelated (P=.34).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
MI is usually the result of two main processes, CAD and thrombosis.^{4 5} Each process may have its own etiological factors. We have observed¹ a negative correlation of the serum testosterone level both with the degree of CAD and with hemostatic risk factors for MI in 55 men without a known coronary thrombosis. This finding suggests that hypotestosteronemia may underlie both CAD and thrombosis. The serum estradiol level in that study¹ did not correlate with the degree of CAD or with the hemostatic risk factors measured. That hyperestrogenemia may not underlie CAD in men is supported by observations that estrogen administration does not lead to CAD.^{6 7 8} However, the association of hyperestrogenemia with MI in men suggests that hyperestrogenemia may play a role in the development of MI in men.¹ Thus, since estrogen administration to men has been reported to lead to MI and venous thrombosis,² it was hypothesized that hyperestrogenemia in men may relate to MI by underlying the thrombosis.¹ Although correlations between estradiol and the hemostatic factors measured have not been observed in men,^{1 9 10} the relationship between estrogen and hemostasis is complex,^{11 12 13} and estradiol might provoke thrombosis through a different mechanism. Of interest is that hyperestrogenemia has also been implicated in coronary spasm¹⁴ and ventricular arrhythmias,¹⁵ factors that may accompany coronary thrombus formation.^{16 17}

To test the hypothesis that hyperestrogenemia may relate to the thrombosis of MI, the present study was performed on 100 men undergoing diagnostic coronary angiography. The 18 men with known past MI had a higher mean estradiol level (P=.005) than the 82 men without known MI. But the patients with MI also had a higher degree of CAD (P<.02). To determine the relationship of the variables measured to the thrombosis, the 18 patients with MI were compared with the 50 of the 82 patients without MI whose degree of CAD was in the same range; these two groups showed no significant difference in mean degree of CAD, nor in age or BMI, factors that may influence the sex hormone levels.^{18 19} The only variable measured, including testosterone and risk factors for MI, that was significantly different between the 18 patients with MI and the 50 patients without MI was estradiol, which was higher in the patients with MI (P=.002). A multivariate logistic regression test also showed estradiol as the only variable measured that showed a significant relationship to MI (P<.003). Thus, the findings in the present study support the hypothesis that hyperestrogenemia may underlie the thrombosis of MI. Similarly, Small et al⁹ have observed in a group of men undergoing coronary angiography that hyperestrogenemia was associated with MI rather than CAD (as determined by the number of stenosed coronary vessels).

Drug intake and smoking history were evaluated as possible confounding factors. Although most of the patients were taking multiple drugs, the only significant drug-hormone relationship found was a higher estradiol level in the patients on digoxin, an observation previously reported.^{20 21} However, when the patients on digoxin were excluded, the significance of the difference in estradiol levels between the patients with and without known MI did not change. Nor could the difference be attributed to a difference in smoking history.

When the 18 patients with MI were divided into two equal groups according to their degree of CAD, the group with the higher degree of CAD had a significantly lower mean estradiol level than the group with the lower degree of CAD. This observation suggests that a lower estradiol level may delay thrombosis until a greater degree of CAD is present.

If hyperestrogenemia underlies the thrombosis and hypotestosteronemia underlies the CAD and thrombosis of MI, the possibility arises that either hormonal alteration by itself may provoke MI. A complicating factor is the positive correlation between estradiol and testosterone levels,²² a correlation that may result from testosterone being the major precursor for estradiol in men.²³ Thus, a low testosterone level might mitigate an increase in the estradiol level. These relationships may explain at least in part why few studies have found both a low testosterone and high estradiol level in men with MI. In the 15 studies that measured both estradiol and testosterone levels and reported an abnormal testosterone and/or estradiol level in men who had had an MI at least 4 months previously, only four found both high estradiol and low testosterone levels.¹ None of the studies reported a low estradiol or high testosterone level.

An association between hyperestrogenemia and coronary thrombosis does not by itself mean cause and effect. Moreover, if the association found is cause and effect, the results of the present study could be explained by the hyperestrogenemia being a result of the MI. In support of this explanation is the failure thus far to find an association between hyperestrogenemia and MI in prospective studies.¹ However, possible reasons for this failure are the technical difficulties of measuring the miniscule concentrations of serum estradiol in men,^{22 24} a decrease in estradiol values during serum storage,²⁵ and interventions between samplings that affect the estradiol level.²⁵

It appears more likely that hyperestrogenemia precedes MI in men for the following reasons: (1) the association of hyperestrogenemia with diabetes, hypertension, hypercholesterolemia, smoking, and obesity, which are major risk factors for MI, in men who had not had an MI,²⁶ (2) evidence for feminization preceding the MI,²⁷ (3) the induction of MI by the administration of estrogens,² (4) the presence of hyperestrogenemia long after the MI (a mean time of 5.9 years in the present study and 10.8 years in a previous study²⁸ ), and (5) the unlikelihood that hyperestrogenemia is a result of a change in lifestyle after MI, because the changes in lifestyle usually recommended after MI, ie, change to a low-fat, high–complex carbohydrate, high-fiber diet, weight reduction, cessation of smoking, and exercise, have all been reported to decrease the estradiol level in men.^{29 30 31 32 33}

Seemingly against the hypothesis that hyperestrogenemia underlies the thrombosis of MI in men is the infrequency of MI in premenopausal women and evidence that estrogen administration to postmenopausal women prevents MI.³³ It is possible, however, that estradiol and testosterone may have certain different effects in women than in men²⁴ ; the limited data available suggest that estradiol may act similarly in women to testosterone in men and vice versa.²⁴ For example, testosterone has been reported to correlate negatively in men^{26 34} and positively in women²⁴ with risk factors for MI. Estrogens have been implicated in MI in men³⁵ and androgens in women.^{36 37} Moreover, although an administered hormone may not have the same effect as the endogenous hormone, testosterone administration to men^{38 39} and estrogen administration to postmenopausal women⁴⁰ appear to decrease risk factors for MI. Postmenopausal women administered estrogen have also been reported to show decreased CAD,³³ whereas in our previous study in men we found the testosterone level to correlate inversely with the degree of CAD.¹ Estrogen administration to women and testosterone administration to men also appear to protect against osteoporosis,^{41 42} to decrease BMI in women⁴⁰ and visceral adiposity in men,³⁸ and to increase the feeling of well-being.^{38 39 43} Thus, findings of the effects of a sex hormone in women may not be applicable to men and vice versa. Why the same hormone may act differently in men and women, if confirmed, is not evident, but it is a possibility that deserves further investigation.

	Selected Abbreviations and Acronyms

 

BMI = body mass index CAD = coronary artery disease DBP = diastolic blood pressure DHEAS = dehydroepiandrosterone sulfate FT = free testosterone HDL-C = HDL cholesterol MI = myocardial infarction SBP = systolic blood pressure SHBG = sex-hormone binding globulin

	Acknowledgments

 
This study was supported in part by the Myron C. Patterson, MD, Fund. We are also grateful to the staff of the cardiac catheterization laboratory for their excellent assistance.

Received December 18, 1995; revision received April 15, 1996;

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Phillips GB, Pinkernell BH, Jing TY. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb. 1994;14:701-706.[Abstract/Free Full Text]

2. The Coronary Drug Project. JAMA. 1970;214:1303-1313.[Abstract/Free Full Text]

3. Judkins MP. Selective coronary arteriography, I: a percutaneous transfemoral technic. Radiology. 1967;89:815-824.[Medline] [Order article via Infotrieve]

4. Blumgart HL, Schlesinger MJ, Davis D. Studies on the relation of the clinical manifestations of angina pectoris, coronary thrombosis, and myocardial infarction to the pathologic findings. Am Heart J. 1940;19:1-91.

5. DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897-902.[Abstract]

6. Rivin AU, Dimitroff SP. The incidence and severity of atherosclerosis in estrogen-treated males, and in females with a hypoestrogenic or a hyperestrogenic state. Circulation. 1954;9:533-539.[Medline] [Order article via Infotrieve]

7. London WT, Rosenberg SE, Draper JW, Almy TP. The effect of estrogens on atherosclerosis. Ann Intern Med. 1961;55:63-69.

8. Fortin CJ, Klein T, Messmore HL, O'Connell JB. Myocardial infarction and severe thromboembolic complications as seen in an estrogen-dependent transsexual. Arch Intern Med. 1984;144:1082-1083.[Abstract/Free Full Text]

9. Small M, Lowe GDO, Beastall GH, Beattie JM, McEachern M, Hutton I, Lorimer AR, Forbes CD. Serum oestradiol and ischaemic heart disease: relationship with myocardial infarction but not coronary atheroma or haemostasis. Q J Med. 1985;223:775-782.

10. Yang XC, Jing TY, Resnick LM, Phillips GB. Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men. Arterioscler Thromb. 1993;13:467-471.[Abstract/Free Full Text]

11. Ogston D. The Physiology of Hemostasis. Cambridge, Mass: Harvard University Press; 1983.

12. Wessler S. Estrogen-associated thromboembolism. Ann Epidemiol. 1992;2:439-443.[Medline] [Order article via Infotrieve]

13. Lobo RA. Estrogen and the risk of coagulopathy. Am J Med. 1992;92:283-285.[Medline] [Order article via Infotrieve]

14. Jaffe MD. Effect of oestrogens on postexercise electrocardiogram. Brit Heart J. 1977;38:1299-1303.[Abstract/Free Full Text]

15. Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE. Serum estrogen levels in men with acute myocardial infarction. Am J Med. 1982;73:872-880.[Medline] [Order article via Infotrieve]

16. Maseri A, L'Abbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi O, Biagini A, Distante A, Pesola A. Coronary vasospasm as a possible cause of myocardial infarction. N Engl J Med. 1978;299:1271-1277.[Abstract]

17. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310:1137-1140.[Abstract]

18. Pirke KM, Doerr P. Age related changes and interrelationships between plasma testosterone, oestradiol, and testosterone-binding globulin in normal adult males. Acta Endocrinol. 1973;74:792-800.

19. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48:633-638.[Abstract/Free Full Text]

20. Stoffer SS, Hynes KM, Jiana N, Ryan RJ. Digoxin and abnormal serum hormone levels. JAMA. 1973;225:1643-1644.[Abstract/Free Full Text]

21. Tappler B, Katz M. Pituitary-gonadal dysfunction in low-output cardiac failure. Clin Endocrinol. 1979;10:219-226.[Medline] [Order article via Infotrieve]

22. Phillips GB. The variability of the serum estradiol level in men: effect of stress (college examinations), cigarette smoking, and coffee drinking on the serum sex hormone and other hormone levels. Steroids. 1992;57:135-141.[Medline] [Order article via Infotrieve]

23. Longcope C, Kato T, Horton R. Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest. 1969;48:2191-2201.

24. Phillips GB. Relationship of serum sex hormones to coronary heart disease. Steroids. 1993;58:286-290,554-555.[Medline] [Order article via Infotrieve]

25. Phillips GB, Yano K, Stemmermann GN. Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program: pitfalls in prospective studies on sex hormones. J Clin Epidemiol. 1988;41:1151-1156.[Medline] [Order article via Infotrieve]

26. Phillips GB. Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity. Metabolism. 1993;42:116-120.[Medline] [Order article via Infotrieve]

27. Phillips GB. Evidence for hyperoestrogenaemia as a risk factor for myocardial infarction in men. Lancet. 1976;2:14-18.[Medline] [Order article via Infotrieve]

28. Phillips GB, Castelli WP, Abbott RD, McNamara PM. Association of hyperestrogenemia and coronary heart disease in men in the Framingham cohort. Am J Med. 1983;74:863-869.[Medline] [Order article via Infotrieve]

29. Rosenthal MB, Barnard J, Rose DP, Inkeles S, Hall J, Pritikin N. Effects of a high-complex-carbohydrate, low-fat, low-cholesterol diet on levels of serum lipids and estradiol. Am J Med. 1985;78:23-27.

30. Stanik S, Dornfeld LP, Maxwell MH, Viosca SP, Korenman SG. The effect of weight loss on reproductive hormones in obese men. J Clin Endocrinol Metab. 1981;53:828-832.[Abstract/Free Full Text]

31. Lindholm J, Winkel P, Brodthagen U, Gyntelberg F. Coronary risk factors and plasma sex hormones. Am J Med. 1982;73:648-651.[Medline] [Order article via Infotrieve]

32. Mendoza SG, Carasco H, Zerpa A, Briceno Y, Rodriguez F, Speirs J, Glueck CJ. Effect of physical training on lipids, lipoproteins, apolipoproteins, lipases, and endogenous sex hormones in men with premature myocardial infarction. Metabolism. 1991;40:368-377.[Medline] [Order article via Infotrieve]

33. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47-63.[Medline] [Order article via Infotrieve]

34. Phillips GB. Relationship between serum sex hormones and glucose, insulin, and lipid abnormalities in men with myocardial infarction. Proc Natl Acad Sci U S A. 1977;74:1729-1733.[Abstract/Free Full Text]

35. Phillips GB. Sex hormones, risk factors and cardiovascular disease. Am J Med. 1978;65:7-11.[Medline] [Order article via Infotrieve]

36. ffrench-Constant CK, Spengel FA, Thompson GR. Hyperlipidaemia and premature coronary artery disease associated with sex-change in a female. Postgrad Med J. 1985;61:61-63.[Abstract/Free Full Text]

37. Wild RA, Grubb B, Hartz A, Van Nort JJ, Bachman W, Bartholomew M. Clinical signs of androgen excess as risk factors for coronary artery disease. Fertil Steril. 1990;54:255-259.[Medline] [Order article via Infotrieve]

38. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes. 1992;16:991-997.

39. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992;75:1092-1098.[Abstract]

40. Barrett-Connor E, Wingard DL, Criqui MH. Postmenopausal estrogen use and heart disease risk factors in the 1980s. JAMA. 1989;261:2095-2100.[Abstract/Free Full Text]

41. Lindsay R. Estrogens, bone mass, and osteoporotic fracture. Am J Med. 1991;91:10S-13S.

42. Horowitz M, Wishart JM, O'Loughlin PD, Morris HA, Need AG, Nordin BEC. Osteoporosis and Klinefelter's syndrome. Clin Endocrinol. 1992;26:113-118.

43. Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obstet Gynecol. 1991;78:991-995.[Medline] [Order article via Infotrieve]

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