Sex Hormones, Risk Factors and Cardiovascular Disease
GERALD 6. PHILLIPS, M.D. New York, New York
The solution to the problem of coronary heart disease is prevention. Yet, despite the enormous research effort that has been invested in this disorder, no effective means of prevention has been established. Research in this field has been devoted largely to studies of lipids and lipoproteins. As a result, much has been learned about lipids and lipoproteins, but their relationship to the development of coronary heart disease remains enigmatic. In the past decade, it has become clear that abnormality in glucose tolerance and abnormality in insulin response to glucose administration each has a high incidence in patients with coronary heart disease similar to that of hyperlipidemia and that most patients with coronary heart disease have an abnormality in either glucose tolerance, insulin response, serum lipid level or some combination of these [ 11. That this same high incidence of these abnormalities occurs in patients with angina [I] * and with coronary artery disease [I] without myocardial infarction indicates that these abnormalities are not a result of myocardial infarction. Thus, if one could find a mechanism for these abnormalities, one might have the solution to coronary heart disease. In a recent study of young men who had had a myocardial infarction, the chance observation of signs of feminization in several of these patients was made [z]. This finding was surprising inasmuch as the marked male prevalence of this disorder in this age group had incriminated “masculinity” as a major factor. Because of the evidence for feminization, the concentrations of serum sex hormones were measured in these patients. The mean serum concentrations of estradiol and estrone were found to be increased whereas the mean serum concentrations of testosterone and dihydrotestosterone were not significantly different from those of the control subjects. The incidence of hyperestrogenemia in the patients with myocardial infarction in this study, moreover, was similar to the respective incidences of the glucose abnormality, insulin abnormality and hyperlipidemia reported in such patients by others [ I]. Further analysis of the data revealed that the areas under the glucase (glucose area) and insulin (insulin area) curves in the glucose tolerance test correlated highly significantly with the ratio of the concentrations in serum of &radio1 to testosterone (E:T) [ 1,3]. A correlation, of course, does not mean a cause and effect relationship, but the high degree of these correlations supported this possibility. l
l
l
From the Department of Medicine, Columbia University College of Physicians and Surgeons, Roosevelt HosDital. New York. New York. Requests for rep&ts.should be addressed to Dr. Gerald 8. Phillips, Department of Medicine, Columbia University College of Physicians and Surgeon’s,Roosevelt Hospttal. New York, New York 10019. Manuscript accepted February 23, 1978.
l
The asterisk signifies that appropriate references are contained in [ 11,
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who had a myocardial infarction and hyperestrogenemia had the lowest E:T of the patients and control subjects, and had a normal glucose tolerance and insulin response with serum cholesterol and triglyceride concentrations of 130 and 67 mg/dl, respectively. Two other patients had serum cholesterol concentrations of 135 and 157 mg/dl and triglyceride concentrations of 63 and 60 mg/dl, respectively. The glucose-insulin defect when glucose intolerance is present appears to be the mild diabetes commonly associated with coronary heart disease. If this defect is secondary to an increase in E:T, an alteration in the sex hormone milieu may be the long-sought link between mild diabetes and coronary heart disease. A high incidence of the glucose-insulin defect reported in patients with hypertension [20] raises the possibility that an increase in E:T and hyperestrogenemia may be operative in this disorder as well. Hypertension has been precipitated in women by the administration of estrogens [21]. That the overt forms of diabetes, hypercholesterolemia and hypertension also appear to be associated with myocardial infarction suggests that these disorders may also be associated with hyperestrogenemia and may thus result, in certain instances, from an interaction of an altered sex hormone milieu with the appropriate genetic substrate. For example, the increase in E or E:T with aging in men [22] may be a factor in the expression of maturity-onset diabetes. On the other hand, the overt forms of these disorders may be based on mechanisms different from those of the mild forms. This possibility would support the popular hypothesis that these disorders themselves contribute to the development of myocardial infarction. Abnormality in glucose tolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia and hypertension, all risk factors for myocardial infarction, are also associated with obesity [23]. Mortality from cardiovascular disease is higher in those over 25 per cent above average weight and appears to decrease with weight reduction [24]. Of further interest is that these risk factors decrease with weight reduction [23,25]. All these risk factors in the obese, therefore, may be secondary to a common abnormality imposed by obesity, and the studies described [l] suggest that this abnormality is an increase in E:T. A strong correlation has been reported between body weight and the rate of estrone production in postmenopausal women [ 261. These observations suggest, therefore, that obesity may induce these risk factors through an increase in E:T. The tendency to weight gain with contraceptive medication [ 271 and pregnancy [ 281, and the increase in adiposity with aging in men [29], conditions associated with an increase in serum estrogen concentration, also raise the possibility that increased E or E:T might lead to
Circumstantial evidence, moreover, suggests that the increased E:T, or a closely related hormonal alteration, was the “cause” of the increased glucose and insulin responses. For example, an increased incidence of a similar glucose and insulin response has been observed in women receiving contraceptive medication [4], a finding which suggests that hormonal alterations can give rise to this response. Furthermore, a high incidence of abnormal glucose tolerance with increased insulin response has also been observed in men with cirrhosis of the liver [5] and with Klinefelter’s syndrome [6], disorders associated with increases in E:T [7,8], as well as in patients with other hypogonadal syndromes such as Werner’s syndrome [9], myotonic dystrophy [lo] and Turner’s syndrome [ 111, disorders in which the serum sex hormone patterns have not yet been defined except for a decrease in plasma testosterone concentration in men with myotonic dystrophy [ 121. The degree of the glucose-insulin defect in this study correlated in turn with the serum cholesterol and triglyceride levels [ 11. A correlation between insulin area and triglyceride concentration, had been reported previously in patients with [ 13,14L] and without [ 151 coronary heart disease. Thus, the glucose, insulin and lipid abnormalities appeared to be’part of the same defect (glucose-insulin-lipid defect) and its mechanism an increase in E:T. If this is so, the observation that most patients with coronary heart disease have this defect suggests that an alteration inthe sex hormone milieu may be the major predisposing factor for myocardial infarction in men. That a high,incidence of abnormality in glucose tolerance, of hyperinsulinemia, when measured, and of hyperlipidemia has been reported not only in patients with myocardial infarctlon [l] and stroke [ 161, but also in patients with angina [l] , coronary artery disease [l] and peripheral vascular disease [ 14,16,17], suggests that this alteration in the sex hormone milieu may not merely be a factor in provoking thrombosis but may be the major predisposing factor for the atherosclerotic process itself. Myocardial infarction in this study correlated with the serum estradiol concentration (E) whereas the glucose-insulin-lipid defect correlated with E:T. The increase in E:T that tends to accombany hyperestrogenemia [l] could explain the association between the glucose-insulin-lipid defect and myocardial infarction. That a high serum estrogen concentration predisposes to myocardial infarction is supported by the finding that the administration of estrogen to men [ 181 or women [ 191 increases the incidence of myocardial infarction. If the correlation with E is confirmed, then hyperestrogenemia by itself may lead to myocardial infarction and the glucose-insulin-lipid defect may not be required or even contribute to the development of myocardial infarction. For example, one of the patients in this series l
l
l
8
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obesity without increasing food intake. Thus, two types of obesity may be hypothesized, one secondary to overeating with consequent increase in E:T, and the other secondary to an increase in E or E:T. The combination of these two factors might make it more difficult for the patient who has become obese to reduce. It is possible, therefore, that obesity is a cause as well as a result of this hormonal alteration. An increase in E or E:T could also play a part in the development of the fluid retention with concomitant hemodynamic changes [30], gallstones [31] and possibly the osteoarthritis 1321 associated with obesity. Of particular interest is the fact that these same factors, i.e., glucose intolerance, insulin response, serum cholesterol and triglyceride concentrations, blood pressure and tendency to obesity, increase with age, as does the incidence of myocardial infarction and the level of E and E:T in men [l] . The intriguing possibility arises that this changing pattern of sex hormones with aging is the basis for these as well as other manifestations of aging and may play an important part in the development of disorders such as gallstones, osteoarthritis and sexual hypofunction. Reports of depression [27] and psychosis [33] after contraceptive medication and of improvement in involutional melancholia after testosterone administration [34] suggest that E or E:T may be a factor in the development of emotional disturbances as well. An increase in E:T, therefore, may be the culprit in the pudgy, middle-aged man with mild diabetes, hyperlipidemia and hypertension who appears to be prone to myocardial infarction. In the presence of the appropriate genetic substrate, this hormonal alteration might give rise to the more overt forms of these disorders. Thus, a similar constellation of abnormalities, i.e., glucose intolerance, hyperinsulinemia, hyperlipidemia and hypertension, has been found in association with myocardial infarction, obesity and aging. Of interest is that this constellation has also been observed in other clinical states that are associated with an alteration of the sex hormone milieu, such as in women receiving contraceptive medication, in pregnancy and in hypogonadal disturbances such as Werner’s syndrome [9] and Turner’s syndrome [43]. In the latter two syndromes, premature atherosclerosis and aging have also been described [9,43]. Another hormonal disorder in which an increased incidence of glucose intolerance, hypertension, hypercholesterolemia and obesity has been reported is Cushing’s syndrome [35]. Hyperinsulinemia has also been described [36]. Patients with Cushing’s syndrome appear to be particularly susceptible to atherosclerosis 1351. That this high incidence of glucose intolerance, hypertension and hypercholesterolemia has not been reproduced by corticosteroid administration suggests that these manifestations are l
DISEASE-PHILLIPS
not secondary to hypercortisolism alone [37,38]. The possibility arises that an increase in E:T in this disorder, perhaps acting in concert with cortisol [39], may explain this discrepancy. The adrenal gland appears to be a major source, although indirectly, of plasma estrone [26], and ACTH administration leads to an increase in plasma estrone concentration in normal men [40]. Although plasma estrogen levels have not been reported in patients with Cushing’s syndrome, the plasma testosterone level has been found to be low in men with this disorder [ 4 1,421. The concurrence of the same abnormalities, i.e., glucose intolerance, hyperinsulinemia, hyperlipidemia and hypertension, in these different clinical states as well as in myocardial infarction, obesity and aging provides further evidence that these abnormalities are related and may be on the basis of a common defect. The evidence discussed suggests that this defect is an increase in E:T or a closely related alteration. The sharp increase in the incidence of myocardial infarction after the menopause raises the possibility that a change in the sex hormone milieu might also be the major predisposing factor in women. The marked difference in the incidence of myocardial infarction between premenopausal women and men of the same age had prompted the notion that estrogens protected against myocardial infarction. The observation that the administration of estrogens to men “feminized” the plasma lipid pattern led to the use of these substances in an attempt to prevent myocardial infarction [44]. Although little, if any, data to support such a protective action are available, evidence to the contrary has been reported both in men [ 181 and women [ 191, namely, that estrogen administration increases the likelihood of myocardial infarction. Hormones other than estrogens also differ in plasma concentration between premenopausal women and men, and between premenopa&al and postmenopausal women [45-471, and can be invoked as possible factors in the protection of premenopausal women against the high plasma estrogen concentration and myocardial infarction. One such hormone is progesterone which, like estradiol, has a considerably higher concentration in the plasma of premenopausal women than of men and drops precipitously at menopause to levels similar to those in men [45,47]. Progesterone, in addition, has been shown to have antiestrogen effects [48]. Thus, postmenopausal women, like men, may be more vulnerable to the effects of estrogen than are premenopausal women. The main source of estrogen in postmenopausal women [49], and a major source in men [ 261, appears to be the conversion of plasma androstenedione to estrone. The reported increase in the efficiency of this conversion with age in women and men [50] supports the possibility that an increase in serum es-
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trogen concentration is the major predisposing factor for myocardial infarction in women as well as in men. If hyperestrogenemia is a factor in the development of myocardial infarction, then a means of lowering the serum estrogen level should be a useful preventive measure. It is possible that elimination of remediable factors, such as smoking, obesity and insufficient exercise, could lower the serum estrogenlevel. Another possibility is that a reduction in serum estrogen concentration could be achieved by an alteration in diet, other than through weight loss in the obese. Should a change in these factors not be effective, serum estrogen levels can be lowered by the administration of hormones, although the ideal way to do this is not yet
clear. One way is to administer a testosterone analogue [51] that is not transformed into an estrogenic substance. Use of a hormone to counteract the effect of estrogens, such as progesterone [48], is also a possibility. Of interest are reports of the effectiveness of testosterone propionate in reversing angina [52] and intermittent claudication [53]. If an alteration in the sex hormone milieu is indeed the major predisposing factor in coronary and, perhaps, in cerebral and peripheral vascular disease, and an important factor in other disorders discussed, then prevention of these cardiovascular diseases and possibly certain of the other disorders may soon be attainable.
REFERENCES 1.
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Phillips GB: Relationship between serum sex hormones and glucose, insulin, and lipid abnormalities in men with myocardial infarction. Proc Natl Acad Sci 74: 1729, 1977. Phillips GB: Evidence for hyperestrogenaemia as a risk factor for myocardial infarction in men. Lancet 2: 14, 1976. Phillips GB: Sex hormones and atherosclerosis (letter). Lancet 2: 511, 1977. Spellacy WN, Buhi WC, Spellacy CE. et al.: Glucose, insulin, and growth hormone studies in long-term users of oral contraceptives. Am J Obstet Gynecol 106: 173. 1970. Megyesi C, Samols E, Marks V: Glucose tolerance and diabetes in chronic liver disease. Lancet 2: 1051, 1967. Nielsen J, Johansen K, Yde H: Frequency of diabetes mellitus in patients with Klinefelter’s syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J Clin Endocrinol Metab 29: 1062, 1969. Chopra IJ, Tulchinsky D, Greenway FL: Estrogen-androgen imbalance in hepatic cirrhosis. Studies in 13 male patients. Ann Intern Med 79: 198, 1973. Ruder HJ, Loriaux DL, Sherins HJ, et al.: Leydig cell function in men with disorders of spermatogenesis. J Clin Endocrinol Metab 38: 244, 1974. Epstein CJ, Martin GM, Schultz AL, et al.: Werner’s syndrome. Medicine (Baltimore) 45: 177, 1966. Huff .TA, Horton ES, Lebovitz HE: Abnormal insulin secretion in myotonic dystrophy. N Engl J Med 277: 837, 1967. Nielsen J, Johansen K, Yde H: The frequency of diabetes mellitus in patients with Turner’s syndrome and pure gonadal dysgenesis. Acta Endocrinol62: 251, 1969. Harper P, Penny R, Foley TP Jr, et al.: Gonadal functiin in males with myotonic dystrophy. J Clin Endocrinol Metab 35: 852, 1972. Tzagournis M, Chiles R, Ryan JM, et al.: Interrelationships of hyperinsulinism and hypertriglyceridemia in young patients with coronary heart-disease. Circulation 38: 1156, 1968. Sorge F, Schwartzkopff W, Neuhaus GA: lnsulln response to oral glucose in patients with a previous myocardial infarction .and in patients with peripheral vascular disease. Diabetes 25: 586, 1976. Olefsky JM, Farquhar JW, Reaven GM: Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med 57: 551, 1974. Schrade W, Boehle E, Biegler R: Humoral changes in arteriosclerosis. Lancet 2: 1409. 1960. Sloan JM, MacKay JS, Sheridan B: Glucose tolerance and
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insulin response in atherosclerosis. Br Med J 4: 586, 1970. The Coronary Drug Project. JAMA 214: 1303, 1970. Mann JI, Vessey MP, Thorogood M, et al.: Myocardial infarction in young women with special reference to oral contraceptive practice. Br Med J 2: 241, 1976. Welborn TA, Breckenridge A, Rubinsteln AH, et al.: Serum insulin in essential hypertension and in peripheral vascular disease. Lancet 1: 1336, 1966. Crane MG, Harris JJ, Winsor W: Hypertension, oral contraceptive agents and conjugated estrogens. Ann Intern Med 74: 13, 1971. Pirke KM, Doerr P: Age related changes and interrelationships between plasma testosterone, oestradiol, and testosterone-binding globulin in ncnnal adult males. Acta Endocrinol 74: 792, 1973. Ashley FW Jr, Kannel WB: Relation of weight change to changes in atherogenic traits. The Framingham study. J Chronic Dis 27: 103, 1974. Hutchinson JJ: Clinical implications of an extensive actuarial study of build and blood pressure. Ann Intern Med 54: 90, 1961. Olefsky J, Reaven GM, Farquhar JW: Effects of weight reduction on obesity. Studies on lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects. J Clin Invest 53: 64. 1974. Siiteri PK. MacDonald PC Role of extragrandular estrogen in human endocrinology. Handbook of Physiology, sect 7, Endocrinology, vol. 2, (Greep RO, Astwood EB, eds), Washington, D.C., American Physiological Society, 1973, p 615. Nilsson A, Almgren PE: Psychiatric symptoms during the postpartum period as related to use of oral contraceptives. Br Med J 2: 453,1968. Taggart NR, Holliday RM, Billewicz .WZ. et al.: Changes in skinfolds during pregnancy. Br J Nutrition 21: 439, 1967. Meneely GR, Heyssel RM, Ball COT, et al.: Analysis of factors affecting body composition determined.from potassium content in 915 normal subjects. Ann NY Acad Sci 110: 271, 1963. Drenick EJ, Carlson HE, Robertson GL, et al.: The role of vasopressin and prolactin in abnormal salt and water metabolism of obese patients before and after fasting and during refeeding. Metabolism 26: 309, 1977. The Coronary Drug Project Research Group. Gallbladder diseassas a side effect of drugs influencing lipid metabo-
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lism. N Engl J bled 296: 1185, 1977. Kellgren JH, Lawrence JS: Dsteo-arthrosis and disk degeneration in an urban population. Ann Rheum Dis 17: 388,
44.
1958. 33.
Daly RJ, Kane FJ Jr, Ewing JA: Psychosis associated with the use of a sequential oral contraceptive. Lancet 2: 444,
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Danziger L, Schroeder HT, Unger AA: Androgen therapy for involutional melancholia. Arch Neurol Physchiat 51: 457, 1944. Plotz CM, Knowlton Al, Ragan C: The natural history of Cushing’s syndrome. Am J Med 13: 597, 1952. Klink D, Estrich D: Plasma insulin concentration in Cushing’s syndrome and thyrotoxicosis (abstract). Clin Res 12: 354, 1964. Christy NP: latrogenic Cushing’s syndrome. The Human Adrenal Cortex, Edited by (Christy NP, ed) New York, Harper & Row, 1971, p 395. Bloom B, Pierce FT Jr: Relationship of ACTH and cortisone to serum lipoproteins and atherosclerosis in humans. Metabolism 1: 155, 1952. Nelson DH. Tanney H, Mestman G. et al.: Potentiation of the biologic effect of administered cortisol by estrogen treatment. J Clin Endocrinol Metab 23: 261, 1963. Doerr P, Pirke KM: Regulation of plasma oestrogens in normal adult males. Acta Endocrinol 78: 531, 1975. Smals AGH, Kloppenborg PWC, Benraad ThJ: Plasma testosterone profiles in Cushing’s syndrome. J Clin Endocrinol Metab 45: 240, 1977. Luton J, Thiebolt P, Vafcke J. et al.: Reversible gonadotropin deficiency in male Cushing’s disease. J Clin Endocrinol Metab 45: 488, 1977. Engel E, Forbes AP: Cytogenetic and clinical findings in 48 patients with congenitally defective or absent ovaries.
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Medicine (Baltimore) 44: 135, 1965. Russ EM, Eder HA, Barr DP: Influence of gonadal hormones on protein-lipid relationships in human plasma. Am J Med 19: 4, 1955. Abraham GE, Hopper K, Tulchinsky D, et al.: Simultaneous measurement of plasma progesterone, 17-hydroxyprogesterone and estradiol- 17B by radioimmunoassay. Anal Letters 4: 325, 1971. Coyotupa J, Parlow AF, Abraham GE: Simultaneous radioimmunoassay of plasma testosterone and dihydrotestosterone. Anal Letters 5: 329, 1972. Abraham GE, Maroulis GB: Effect of exogenous estrogen on serum pregnenolone, cortisol, and androgens in postmenopausal women. Obstet Gynecol45: 271, 1975. Hsueh AJW, Peck EJ Jr, Clark JH: Control of estrogen receptor levels by progesterone. Endocrinology 98: 438, 1976. Grodin JM, Siiteri PK, MacDonald PC: Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 36: 207, 1973. Hemsell DC, Grodin JM. Brenner PF, et al.: Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab 38: 476, 1974. Doerr P, Pirke KM: Regulation of plasma oestrogens in normal adult males. I. Response of oestradiol, oestrone, and testosterone to HCG and fluoxymesterone administration. Acta Endocrinol 75: 617, 1974. Lesser MA: Testosterone propionate therapy in one hundred cases of angina pectoris. J Clin Endocrinol Metab 6: 549, 1946. Edwards EA. Hamilton JB. Duntley SQ: Testosterone propionate as a therapeutic agent in patients with organic disease of the peripheral vessels. N Engl J Med 220: 865, 1939.
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Volume 85
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GERALD 6. PHILLIPS, M.D. New York, New York
The solution to the problem of coronary heart disease is prevention. Yet, despite the enormous research effort that has been invested in this disorder, no effective means of prevention has been established. Research in this field has been devoted largely to studies of lipids and lipoproteins. As a result, much has been learned about lipids and lipoproteins, but their relationship to the development of coronary heart disease remains enigmatic. In the past decade, it has become clear that abnormality in glucose tolerance and abnormality in insulin response to glucose administration each has a high incidence in patients with coronary heart disease similar to that of hyperlipidemia and that most patients with coronary heart disease have an abnormality in either glucose tolerance, insulin response, serum lipid level or some combination of these [ 11. That this same high incidence of these abnormalities occurs in patients with angina [I] * and with coronary artery disease [I] without myocardial infarction indicates that these abnormalities are not a result of myocardial infarction. Thus, if one could find a mechanism for these abnormalities, one might have the solution to coronary heart disease. In a recent study of young men who had had a myocardial infarction, the chance observation of signs of feminization in several of these patients was made [z]. This finding was surprising inasmuch as the marked male prevalence of this disorder in this age group had incriminated “masculinity” as a major factor. Because of the evidence for feminization, the concentrations of serum sex hormones were measured in these patients. The mean serum concentrations of estradiol and estrone were found to be increased whereas the mean serum concentrations of testosterone and dihydrotestosterone were not significantly different from those of the control subjects. The incidence of hyperestrogenemia in the patients with myocardial infarction in this study, moreover, was similar to the respective incidences of the glucose abnormality, insulin abnormality and hyperlipidemia reported in such patients by others [ I]. Further analysis of the data revealed that the areas under the glucase (glucose area) and insulin (insulin area) curves in the glucose tolerance test correlated highly significantly with the ratio of the concentrations in serum of &radio1 to testosterone (E:T) [ 1,3]. A correlation, of course, does not mean a cause and effect relationship, but the high degree of these correlations supported this possibility. l
l
l
From the Department of Medicine, Columbia University College of Physicians and Surgeons, Roosevelt HosDital. New York. New York. Requests for rep&ts.should be addressed to Dr. Gerald 8. Phillips, Department of Medicine, Columbia University College of Physicians and Surgeon’s,Roosevelt Hospttal. New York, New York 10019. Manuscript accepted February 23, 1978.
l
The asterisk signifies that appropriate references are contained in [ 11,
July 1978
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Volume 65
7
SEX HORMONES, RISK FACTORS AND CARDIOVASCULAR
DISEASE-PHILLIPS
who had a myocardial infarction and hyperestrogenemia had the lowest E:T of the patients and control subjects, and had a normal glucose tolerance and insulin response with serum cholesterol and triglyceride concentrations of 130 and 67 mg/dl, respectively. Two other patients had serum cholesterol concentrations of 135 and 157 mg/dl and triglyceride concentrations of 63 and 60 mg/dl, respectively. The glucose-insulin defect when glucose intolerance is present appears to be the mild diabetes commonly associated with coronary heart disease. If this defect is secondary to an increase in E:T, an alteration in the sex hormone milieu may be the long-sought link between mild diabetes and coronary heart disease. A high incidence of the glucose-insulin defect reported in patients with hypertension [20] raises the possibility that an increase in E:T and hyperestrogenemia may be operative in this disorder as well. Hypertension has been precipitated in women by the administration of estrogens [21]. That the overt forms of diabetes, hypercholesterolemia and hypertension also appear to be associated with myocardial infarction suggests that these disorders may also be associated with hyperestrogenemia and may thus result, in certain instances, from an interaction of an altered sex hormone milieu with the appropriate genetic substrate. For example, the increase in E or E:T with aging in men [22] may be a factor in the expression of maturity-onset diabetes. On the other hand, the overt forms of these disorders may be based on mechanisms different from those of the mild forms. This possibility would support the popular hypothesis that these disorders themselves contribute to the development of myocardial infarction. Abnormality in glucose tolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia and hypertension, all risk factors for myocardial infarction, are also associated with obesity [23]. Mortality from cardiovascular disease is higher in those over 25 per cent above average weight and appears to decrease with weight reduction [24]. Of further interest is that these risk factors decrease with weight reduction [23,25]. All these risk factors in the obese, therefore, may be secondary to a common abnormality imposed by obesity, and the studies described [l] suggest that this abnormality is an increase in E:T. A strong correlation has been reported between body weight and the rate of estrone production in postmenopausal women [ 261. These observations suggest, therefore, that obesity may induce these risk factors through an increase in E:T. The tendency to weight gain with contraceptive medication [ 271 and pregnancy [ 281, and the increase in adiposity with aging in men [29], conditions associated with an increase in serum estrogen concentration, also raise the possibility that increased E or E:T might lead to
Circumstantial evidence, moreover, suggests that the increased E:T, or a closely related hormonal alteration, was the “cause” of the increased glucose and insulin responses. For example, an increased incidence of a similar glucose and insulin response has been observed in women receiving contraceptive medication [4], a finding which suggests that hormonal alterations can give rise to this response. Furthermore, a high incidence of abnormal glucose tolerance with increased insulin response has also been observed in men with cirrhosis of the liver [5] and with Klinefelter’s syndrome [6], disorders associated with increases in E:T [7,8], as well as in patients with other hypogonadal syndromes such as Werner’s syndrome [9], myotonic dystrophy [lo] and Turner’s syndrome [ 111, disorders in which the serum sex hormone patterns have not yet been defined except for a decrease in plasma testosterone concentration in men with myotonic dystrophy [ 121. The degree of the glucose-insulin defect in this study correlated in turn with the serum cholesterol and triglyceride levels [ 11. A correlation between insulin area and triglyceride concentration, had been reported previously in patients with [ 13,14L] and without [ 151 coronary heart disease. Thus, the glucose, insulin and lipid abnormalities appeared to be’part of the same defect (glucose-insulin-lipid defect) and its mechanism an increase in E:T. If this is so, the observation that most patients with coronary heart disease have this defect suggests that an alteration inthe sex hormone milieu may be the major predisposing factor for myocardial infarction in men. That a high,incidence of abnormality in glucose tolerance, of hyperinsulinemia, when measured, and of hyperlipidemia has been reported not only in patients with myocardial infarctlon [l] and stroke [ 161, but also in patients with angina [l] , coronary artery disease [l] and peripheral vascular disease [ 14,16,17], suggests that this alteration in the sex hormone milieu may not merely be a factor in provoking thrombosis but may be the major predisposing factor for the atherosclerotic process itself. Myocardial infarction in this study correlated with the serum estradiol concentration (E) whereas the glucose-insulin-lipid defect correlated with E:T. The increase in E:T that tends to accombany hyperestrogenemia [l] could explain the association between the glucose-insulin-lipid defect and myocardial infarction. That a high serum estrogen concentration predisposes to myocardial infarction is supported by the finding that the administration of estrogen to men [ 181 or women [ 191 increases the incidence of myocardial infarction. If the correlation with E is confirmed, then hyperestrogenemia by itself may lead to myocardial infarction and the glucose-insulin-lipid defect may not be required or even contribute to the development of myocardial infarction. For example, one of the patients in this series l
l
l
8
July 1978
The American
Journal
of Mediclne
Volume
85
SEX HORMONES, RISK FACTORS AND CARDIOVASCULAR
obesity without increasing food intake. Thus, two types of obesity may be hypothesized, one secondary to overeating with consequent increase in E:T, and the other secondary to an increase in E or E:T. The combination of these two factors might make it more difficult for the patient who has become obese to reduce. It is possible, therefore, that obesity is a cause as well as a result of this hormonal alteration. An increase in E or E:T could also play a part in the development of the fluid retention with concomitant hemodynamic changes [30], gallstones [31] and possibly the osteoarthritis 1321 associated with obesity. Of particular interest is the fact that these same factors, i.e., glucose intolerance, insulin response, serum cholesterol and triglyceride concentrations, blood pressure and tendency to obesity, increase with age, as does the incidence of myocardial infarction and the level of E and E:T in men [l] . The intriguing possibility arises that this changing pattern of sex hormones with aging is the basis for these as well as other manifestations of aging and may play an important part in the development of disorders such as gallstones, osteoarthritis and sexual hypofunction. Reports of depression [27] and psychosis [33] after contraceptive medication and of improvement in involutional melancholia after testosterone administration [34] suggest that E or E:T may be a factor in the development of emotional disturbances as well. An increase in E:T, therefore, may be the culprit in the pudgy, middle-aged man with mild diabetes, hyperlipidemia and hypertension who appears to be prone to myocardial infarction. In the presence of the appropriate genetic substrate, this hormonal alteration might give rise to the more overt forms of these disorders. Thus, a similar constellation of abnormalities, i.e., glucose intolerance, hyperinsulinemia, hyperlipidemia and hypertension, has been found in association with myocardial infarction, obesity and aging. Of interest is that this constellation has also been observed in other clinical states that are associated with an alteration of the sex hormone milieu, such as in women receiving contraceptive medication, in pregnancy and in hypogonadal disturbances such as Werner’s syndrome [9] and Turner’s syndrome [43]. In the latter two syndromes, premature atherosclerosis and aging have also been described [9,43]. Another hormonal disorder in which an increased incidence of glucose intolerance, hypertension, hypercholesterolemia and obesity has been reported is Cushing’s syndrome [35]. Hyperinsulinemia has also been described [36]. Patients with Cushing’s syndrome appear to be particularly susceptible to atherosclerosis 1351. That this high incidence of glucose intolerance, hypertension and hypercholesterolemia has not been reproduced by corticosteroid administration suggests that these manifestations are l
DISEASE-PHILLIPS
not secondary to hypercortisolism alone [37,38]. The possibility arises that an increase in E:T in this disorder, perhaps acting in concert with cortisol [39], may explain this discrepancy. The adrenal gland appears to be a major source, although indirectly, of plasma estrone [26], and ACTH administration leads to an increase in plasma estrone concentration in normal men [40]. Although plasma estrogen levels have not been reported in patients with Cushing’s syndrome, the plasma testosterone level has been found to be low in men with this disorder [ 4 1,421. The concurrence of the same abnormalities, i.e., glucose intolerance, hyperinsulinemia, hyperlipidemia and hypertension, in these different clinical states as well as in myocardial infarction, obesity and aging provides further evidence that these abnormalities are related and may be on the basis of a common defect. The evidence discussed suggests that this defect is an increase in E:T or a closely related alteration. The sharp increase in the incidence of myocardial infarction after the menopause raises the possibility that a change in the sex hormone milieu might also be the major predisposing factor in women. The marked difference in the incidence of myocardial infarction between premenopausal women and men of the same age had prompted the notion that estrogens protected against myocardial infarction. The observation that the administration of estrogens to men “feminized” the plasma lipid pattern led to the use of these substances in an attempt to prevent myocardial infarction [44]. Although little, if any, data to support such a protective action are available, evidence to the contrary has been reported both in men [ 181 and women [ 191, namely, that estrogen administration increases the likelihood of myocardial infarction. Hormones other than estrogens also differ in plasma concentration between premenopausal women and men, and between premenopa&al and postmenopausal women [45-471, and can be invoked as possible factors in the protection of premenopausal women against the high plasma estrogen concentration and myocardial infarction. One such hormone is progesterone which, like estradiol, has a considerably higher concentration in the plasma of premenopausal women than of men and drops precipitously at menopause to levels similar to those in men [45,47]. Progesterone, in addition, has been shown to have antiestrogen effects [48]. Thus, postmenopausal women, like men, may be more vulnerable to the effects of estrogen than are premenopausal women. The main source of estrogen in postmenopausal women [49], and a major source in men [ 261, appears to be the conversion of plasma androstenedione to estrone. The reported increase in the efficiency of this conversion with age in women and men [50] supports the possibility that an increase in serum es-
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SEX HORMONES, RISK FACTORS AND CARDIOVASCULAR DISEASE-PHILLIPS
trogen concentration is the major predisposing factor for myocardial infarction in women as well as in men. If hyperestrogenemia is a factor in the development of myocardial infarction, then a means of lowering the serum estrogen level should be a useful preventive measure. It is possible that elimination of remediable factors, such as smoking, obesity and insufficient exercise, could lower the serum estrogenlevel. Another possibility is that a reduction in serum estrogen concentration could be achieved by an alteration in diet, other than through weight loss in the obese. Should a change in these factors not be effective, serum estrogen levels can be lowered by the administration of hormones, although the ideal way to do this is not yet
clear. One way is to administer a testosterone analogue [51] that is not transformed into an estrogenic substance. Use of a hormone to counteract the effect of estrogens, such as progesterone [48], is also a possibility. Of interest are reports of the effectiveness of testosterone propionate in reversing angina [52] and intermittent claudication [53]. If an alteration in the sex hormone milieu is indeed the major predisposing factor in coronary and, perhaps, in cerebral and peripheral vascular disease, and an important factor in other disorders discussed, then prevention of these cardiovascular diseases and possibly certain of the other disorders may soon be attainable.
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Medicine (Baltimore) 44: 135, 1965. Russ EM, Eder HA, Barr DP: Influence of gonadal hormones on protein-lipid relationships in human plasma. Am J Med 19: 4, 1955. Abraham GE, Hopper K, Tulchinsky D, et al.: Simultaneous measurement of plasma progesterone, 17-hydroxyprogesterone and estradiol- 17B by radioimmunoassay. Anal Letters 4: 325, 1971. Coyotupa J, Parlow AF, Abraham GE: Simultaneous radioimmunoassay of plasma testosterone and dihydrotestosterone. Anal Letters 5: 329, 1972. Abraham GE, Maroulis GB: Effect of exogenous estrogen on serum pregnenolone, cortisol, and androgens in postmenopausal women. Obstet Gynecol45: 271, 1975. Hsueh AJW, Peck EJ Jr, Clark JH: Control of estrogen receptor levels by progesterone. Endocrinology 98: 438, 1976. Grodin JM, Siiteri PK, MacDonald PC: Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 36: 207, 1973. Hemsell DC, Grodin JM. Brenner PF, et al.: Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age. J Clin Endocrinol Metab 38: 476, 1974. Doerr P, Pirke KM: Regulation of plasma oestrogens in normal adult males. I. Response of oestradiol, oestrone, and testosterone to HCG and fluoxymesterone administration. Acta Endocrinol 75: 617, 1974. Lesser MA: Testosterone propionate therapy in one hundred cases of angina pectoris. J Clin Endocrinol Metab 6: 549, 1946. Edwards EA. Hamilton JB. Duntley SQ: Testosterone propionate as a therapeutic agent in patients with organic disease of the peripheral vessels. N Engl J Med 220: 865, 1939.
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