Gerald B. Phillips

The association of hypotestosteronemia with coronary artery disease in men.

Hyperestrogenemia and hypotestosteronemia have been observed in association with myocardial infarction (MI) and its risk factors. To determine whether these abnormalities may be prospective for MI, estradiol and testosterone, as well as risk factors for MI, were measured in 55 men undergoing angiography who had not previously had an MI. Testosterone (r = -.36, P = .008) and free testosterone (r = -.49, P < .001) correlated negatively with the degree of coronary artery disease after controlling for age and body mass index. When the patient group was successively reduced to a final study group of 34 men by excluding the patients with other major disorders, the testosterone and free testosterone correlations persisted (r = -.43, P < .02 and r = -.62, P < .001, respectively). Neither estradiol nor the risk factors, except for high-density lipoprotein cholesterol, correlated with the degree of coronary artery disease in the final group. Testosterone correlated negatively with the risk factors fibrinogen, plasminogen activator inhibitor-1, and insulin and positively with high-density lipoprotein cholesterol. The correlations found in this study between testosterone and the degree of coronary artery disease and between testosterone and other risk factors for MI raise the possibility that in men hypotestosteronemia may be a risk factor for coronary atherosclerosis.

Relationship Between Serum Sex Hormones and Coronary Artery Disease in Postmenopausal Women

Although sex hormones appear to be importantly involved in the development of coronary heart disease, apparently no study has yet reported an alteration in an endogenous sex hormone level in relation to coronary heart disease in women. In an attempt to determine whether any sex hormone abnormality might be a factor in the development of myocardial infarction in women, estradiol and testosterone, as well as sex hormone-binding globulin, insulin, dehydroepiandrosterone sulfate, and risk factors for myocardial infarction, were measured in relation to the degree of coronary artery disease (CAD) in 60 postmenopausal women undergoing coronary angiography. In a multiple-regression analysis with the degree of CAD as the dependent variable and free testosterone (FT), estradiol, age, body mass index, systolic blood pressure, cholesterol, smoking, and insulin as independent variables in the model, only FT (P < .008) and cholesterol (P = .01) were significantly related to the degree of CAD, both positively. To exclude a possible confounding effect due to prior myocardial infarction, the multiple-regression analysis was repeated for the subgroup of 49 patients remaining after excluding the 11 patients who had ever had a myocardial infarction; again only FT (P < .04) and cholesterol (P = .05) were significantly related to the degree of CAD. Neither total testosterone in place of FT nor HDL cholesterol in place of total cholesterol in the model was significantly related to CAD. Sex hormone-binding globulin and dehydroepiandrosterone sulfate, added individually to the model, showed no significant relationship to CAD. These results raise the possibility that in women an elevated FT level may be a risk factor for coronary atherosclerosis.

Association of hyperestrogenemia and coronary heart disease in men in the Framingham cohort

The serum levels of estradiol and testosterone as well as established risk factors for coronary heart disease were estimated in 61 men (mean age 70.0 +/- 6.4 [SD] years) with coronary heart disease and in 61 matched control subjects enrolled in the Framingham Heart Study. The mean serum estradiol level was significantly higher in the subjects with coronary disease (p = 0.011). This difference in estradiol level increased with the exclusion of subjects older than 75 years (p less than 0.001). The mean serum testosterone level was not significantly different. None of the established risk factors for coronary heart disease was different between subjects with coronary disease and control subjects except blood glucose level, which was higher in the subjects with coronary disease (p = 0.025). We conclude that hyperestrogenemia is an important correlate of coronary heart disease in men.

Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity

It has been hypothesized that an alteration in the sex hormone milieu may underlie coronary heart disease (CHD) and its risk factors. Leading to this hypothesis and important to it was the observation that serum testosterone level correlated negatively and the estradiol to testosterone ratio (E/T) correlated positively with serum insulin and glucose levels in non-obese men. As a test of the validity of this observation, the present study was conducted to investigate these correlations in men with obesity. Obesity in men is associated with hyperestrogenemia, hypotestosteronemia, hyperinsulinemia, hyperglycemia, and CHD. To determine whether the relationships between sex hormone levels and insulin and glucose levels found in non-obese men also occur in obese men independent of obesity, fasting levels of these substances, as well as free testosterone (FT) and sex-hormone-binding globulin (SHBG), were measured in 55 obese men aged 21 to 70. Correlation coefficients of sex hormones with other risk factors for CHD, ie, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), blood pressure, and waist to hip circumference ratio (W/H), were also calculated. As found previously, testosterone level correlated negatively with insulin (r = -.31, P = .01) and glucose (r = -.23, P < .05) levels and the insulin to glucose ratio ([I/G] r = -.26, P < .05), and E/T correlated positively with insulin (r = .41, P = .001) and glucose (r = .24, P < .05) levels and I/G (r = .37, P < .005). The above correlations were controlled for body mass index (BMI) and age.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension.

Objective and design: It has been hypothesized that risk factors for coronary heart disease in men are linked and that the underlying factor linking them may be an alteration in the sex hormone milieu. As a test of this hypothesis, sex hormones and fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), hemostatic factors recently shown to be risk factors for myocardial infarction, were measured in men with hypertension and in healthy control subjects. Results: The fasting serum testosterone and free testosterone levels were decreased and the plasma factor VII and PAI-1 levels increased in the men with hypertension. Conclusion: These findings are consistent with the stated hypothesis.

Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men.

The present study was carried out to explore the possible relation of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and factor VII levels to other risk factors for coronary heart disease (CHD) and to serum sex hormone levels. The study group comprised 48 apparently healthy men. To avoid the confounding factor of obesity, correlations were determined in the 30 men in this group with a body mass index (BMI) < 26.4, after controlling for age. PAI-1 correlated with testosterone, estradiol/testosterone, and free testosterone/testosterone (FT/T), and fibrinogen correlated with FT/T. All three hemostatic factors correlated with glucose and with the ratio of cholesterol/high density lipoprotein cholesterol, while PAI-1 correlated with diastolic blood pressure. To test the effect of obesity, correlations were determined in the entire group of 48 men, which included 18 subjects with a BMI > 26.4. All three hemostatic factors correlated with BMI in this group after controlling for age; however, on controlling for testosterone, only PAI-1 correlated with BMI. Fibrinogen correlated with age in both groups after controlling for testosterone or BMI. These correlations support the hypothesis that PAI-1, fibrinogen, and factor VII are related to other risk factors for CHD and that an alteration in the sex hormone milieu may be the underlying factor linking them.

Does Insulin Resistance, Visceral Adiposity, or a Sex Hormone Alteration Underlie the Metabolic Syndrome? Studies in Women

Insulin resistance, obesity, and a sex hormone alteration have each been suggested as the underlying link for the constellation of risk factors for myocardial infarction (MI) commonly referred to as the metabolic syndrome or the insulin resistance syndrome. In an attempt to identify in women which of these variables is the most likely link, insulin, adiposity variables, sex hormones, and risk factors for MI were measured and their relationships analyzed statistically in 58 premenopausal and 20 postmenopausal healthy women. On controlling for age, visceral adipose tissue (VAT) correlated more strongly with risk factors for MI, insulin, and free testosterone (FT) than did total adipose tissue or subcutaneous adipose tissue. VAT, therefore, was used as the adiposity variable for further data analysis. Waist circumference was a better surrogate of VAT than was waist-hip ratio, which was a poor surrogate of VAT. VAT correlated positively with insulin, FT, triglyceride, and glucose, and negatively with high-density lipoprotein and sex hormone-binding globulin. On controlling for age, FT and insulin correlated with risk factors for MI and with each other, but on controlling for age and VAT, all of their correlations lost statistical significance except for FT-triglyceride and FT-insulin in the postmenopausal women. In conclusion, VAT accumulation in women, independently of other measures of adiposity, may largely explain the correlations of insulin, obesity, and sex hormones with risk factors for MI and may be the immediate underlying factor that links risk factors for MI to form the metabolic syndrome. Insulin resistance, which has been generally accepted to be the underlying factor, may be a component of the syndrome rather than its underlying link. We hypothesize that in women FT may effect preferential VAT accumulation and induce insulin resistance directly, as well as via VAT accumulation, so that a sex hormone alteration may underlie VAT accumulation and thus ultimately underlie the metabolic syndrome (with insulin resistance as a component).

The Association of Hyperestrogenemia With Coronary Thrombosis in Men

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, HDI, 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.

Evidence for hyperestrogenemia as the link between diabetes mellitus and myocardial infarction

The previous findings of hyperestrogenemia in men with myocardial infarction and of a correlation between the ratio of serum estradiol to testosterone and the glucose-insulin-lipid defect have led to the hypothesis that hyperestrogenemia may be responsible for the increased incidence of atherosclerosis and its complications in patients with diabetes. The hypothesis predicts that the mean serum level of estradiol and the ratio of serum estradiol to testosterone are elevated in patients with diabetes. To test this hypothesis, the serum levels of estradiol and testosterone were measured in 21 nonobese men with diabetes and in 19 apparently healthy men of similar age and weight. A higher mean serum estradiol level (p less than 0.001) and estradiol-to-testosterone ratio (p less than 0.005) were observed in the patients with diabetes, whereas the mean serum testosterone level was not significantly different. The findings are consistent with the hypothesis.

The phospholipid and fatty acid composition of platelets in patients with primary defects of platelet function

Platelet phospholipid and fatty acid composition was determined in nine normal subjects and in 11 patients with primary defects in platelet function. Two of the patients had thrombasthenia (Glanzmann) and nine had various types of abnormalities in platelet aggregation and platelet factor 3 availability attributed to impairment of the platelet release reaction. The values observed for platelet lipids in the normal subjects were similar to those reported by others. Four of the patients with a disturbance in the platelet release reaction were in the same family and showed the same abnormal pattern of platelet lipid composition. Phospholipid analysis showed a decrease in the relative amount of phosphatidyl ethanolamine (PE) and an increase in lecithin. Abnormalities in fatty acids consisted of an increase in the relative amounts of 18∶1ω9, 20∶0 and 20∶1ω9 and a decrease in the 22∶4ω6+24∶1 fraction. Similar changes in PE and 18∶1ω9 were also observed in another patient with a similar defect in platelet function. In this patient the relative amount of platelet sphingomyelin was also increased. The platelet lipid composition in the other six patients and in one normal subject given aspirin was essentially normal.