Is Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The
                          Estrogen-Androgen Pa...
0021-972X/05/$15.00/0                                                                 The Journal of Clinical Endocrinolog...
Phillips • Sex Hormones and Cardiovascular Disease                               J Clin Endocrinol Metab, May 2005, 90(5):...
2710   J Clin Endocrinol Metab, May 2005, 90(5):2708 –2711                                 Phillips • Sex Hormones and Car...
Phillips • Sex Hormones and Cardiovascular Disease                                                       J Clin Endocrinol...
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  1. 1. Is Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The Estrogen-Androgen Paradox Gerald B. Phillips J. Clin. Endocrinol. Metab. 2005 90:2708-2711 originally published online Feb 1, 2005; , doi: 10.1210/jc.2004-2011 To subscribe to Journal of Clinical Endocrinology & Metabolism or any of the other journals published by The Endocrine Society please go to: Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
  2. 2. 0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(5):2708 –2711 Printed in U.S.A. Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-2011 Is Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The Estrogen- Androgen Paradox Gerald B. Phillips Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital Center, New York, New York 10019 The strikingly lower incidence of myocardial infarction (MI) have been carried out. Also puzzling is that whereas the gen- in premenopausal women than in men of the same age sug- der difference in incidence of MI would suggest that testos- gests an important role for sex hormones in the etiology of MI. terone promotes and/or estrogen prevents MI, the cross- Supporting such a role are studies, carried out mostly in men, sectional, hormone administration, and prospective studies that report abnormalities of sex hormone levels in patients have suggested that in men testosterone may prevent and with MI, correlations of sex hormone levels with degree of estrogen promote MI. These studies have thus revealed an atherosclerosis and with levels of risk factors for MI, and estrogen-androgen paradox: that endogenous sex hormones changes in the levels of risk factors with administration of sex may relate both to atherosclerotic cardiovascular disease and hormones. Studies have also reported a prospective relation- its risk factors oppositely in women and men. Recently rec- ship in men of testosterone level with progression of athero- ognized experiments of nature and their knockout mouse sclerosis, accumulation of visceral adipose tissue, and other models may present another manifestation of this estrogen- risk factors for MI. Puzzling, however, is that neither the level androgen paradox and could help resolve these apparent of testosterone nor of estrogen was found to be predictive of contradictions. (J Clin Endocrinol Metab 90: 2708 –2711, 2005) coronary events in any of the eight prospective studies that T HE DISCOVERY OF five men with deficient estrogen action (DEA)— one with estrogen resistance (1) and four with deficient estrogen synthesis (2–5), on the bases of these abnormalities appeared to improve with estrogen ad- ministration in the patients with aromatase deficiency. That one (5) of two (3, 5) aromatase-deficient patients adminis- mutations in the genes for estrogen receptor (ER ) and tered testosterone developed diabetes during its adminis- aromatase, respectively—and studies on their knockout tration suggests that the improvement in the abnormalities mouse models suggest that DEA men develop, at an early with estrogen administration could have resulted, at least in age, atherosclerosis, increased visceral adipose tissue (VAT), part, from the concomitant marked decrease in the testos- and the constellation of risk factors for myocardial infarction terone level (3–5, 29) or testosterone-to-estradiol ratio. Two (MI) (6) that has come to be known as the “metabolic syn- patients showed evidence of premature atherosclerosis. One drome.” Whereas the ER -deficient man had elevated es- of these, the ER -deficient man, a nonsmoker with a cho- tradiol levels, the four aromatase-deficient men had estradiol lesterol level of 130 mg/dl, showed at age 31 calcification of levels below the sensitivity of the methods used for mea- the left anterior descending coronary artery suggestive of surement; the testosterone levels in the five men were normal coronary artery disease (1, 30). He also showed impairment or high. The findings on these five patients support a primary of flow-mediated endothelium-dependent peripheral vaso- and prospective role for sex hormones in the development of dilation (31). A relationship of ER to coronary heart disease atherosclerotic cardiovascular disease. They also present a is further supported by reports of an association in men of paradox: the atherosclerosis, increased VAT, hyperinsulin- a polymorphism in the ER gene with MI (32, 33). The emia, and risk factors for MI in these DEA men appear to be second of these two patients, an aromatase-deficient man based on low estrogen action rather than on the low andro- with a cholesterol level of 177 mg/dl, was found by echo- gen action that has been suggested by the cross-sectional, Doppler examination at age 30 to have two “lipid plaques” hormone administration, and prospective studies on men in the carotid artery, which disappeared completely after less who have sufficient estrogen action (SEA) (7–28). than 1 yr of transdermal estradiol administration (5). The The five DEA patients exhibited similar abnormalities; DEA patients also exhibited evidence of a premature increase in abdominal girth as suggested by the published photo- First Published Online February 1, 2005 graphs of the aromatase-deficient patients (2, 4, 5, 34) and Abbreviations: ArKO, Aromatase-deficient knockout; DEA, deficient confirmed by a waist-to-hip ratio (35) of 1.02 in the one estrogen action; ER , estrogen receptor ; ERKO, ER -deficient knock- patient in whom it was measured (4). No photograph of the out; MI, myocardial infarction; SEA, sufficient estrogen action; VAT, visceral adipose tissue. ER -deficient man was published with the report (1). An JCEM is published monthly by The Endocrine Society (http://www. increase in VAT is consistent with the observation that VAT, the foremost professional society serving the en- in men appears to underlie the constellation of risk factors for docrine community. MI (22). All of the patients also had other risk factors for MI, 2708
  3. 3. Phillips • Sex Hormones and Cardiovascular Disease J Clin Endocrinol Metab, May 2005, 90(5):2708 –2711 2709 four before age 30 (1, 2, 4, 5). The receptor-deficient man had estrone with degree of atherosclerosis, but another (28) re- diabetes, hyperinsulinemia, and acanthosis nigricans (1). ported a “borderline significant” positive correlation of es- One of the aromatase-deficient men had hyperinsulinemia tradiol with progression. That the testosterone but not the (2, 29) and another had insulin resistance (4); the insulin level estradiol level showed this correlation in SEA men could in both men decreased with estrogen administration (4, 29). have been owing to a requirement that the estradiol be pro- A third aromatase-deficient man, during transdermal tes- duced by aromatization in the vessel wall to prevent ath- tosterone administration, developed diabetes with hyperin- erosclerosis. Countering this explanation is the observation sulinemia and acanthosis nigricans, all of which improved on that estradiol administration to an aromatase-deficient man switching to transdermal estradiol administration (5). Two completely reversed the evidence of atherosclerosis (5). Es- aromatase-deficient men had hypercholesterolemia (2, 3), tradiol administration to SEA men has been reported to three had hypertriglyceridemia (2– 4), and three had a low increase the incidence of MI (43), although the associated high-density lipoprotein level (3–5). Blood pressure, re- increase in incidence of venous thrombosis in this secondary ported in three of the men (1, 2, 4, 30), was 140/85 (1) and prevention trial suggests this effect may occur through the 130/64 (30) in the receptor-deficient man and 158/72 in an promotion of thrombosis rather than atherosclerosis. aromatase-deficient man (2). A similar discrepancy in estrogen and androgen action Supporting the validity of these observations in the DEA between DEA and SEA men is found with abdominal adi- patients are the findings in ER -deficient (ERKO) and aro- posity. The apparent association of abdominal adiposity with matase-deficient (ArKO) knockout mice, whose phenotypes insufficient estrogen action in the DEA men was validated in appear to be remarkably similar to the human phenotypes. the knockout mice by the preferential accumulation of intra- The ERKO and ArKO mice preferentially accumulate intra- abdominal adipose tissue, which was reversed by estrogen abdominal adipose tissue, a process that in the ArKO mice administration in the ArKO mice. In SEA men, however, a is reversed by estrogen administration (36, 37); this finding low testosterone level has been reported to be prospective suggests not only that the DEA men do indeed have in- specifically for VAT accumulation (17), and testosterone ad- creased abdominal girth, as suggested in the photographs, ministration has been reported to decrease VAT specifically but also that it is attributable to VAT accumulation. ERKO without a significant change in estradiol level (10). While (36) and ArKO (38) mice also develop glucose intolerance testosterone could exert an effect via local conversion to and insulin resistance, both of which in the ArKO mice are estradiol, administration of estrogen plus antiandrogen to improved by estrogen administration (38). The ArKO mice young, healthy, nonobese men has been reported to increase were reported to be hypercholesterolemic at 1 yr (37). The VAT (21). similarity of the human and mouse phenotypes is reinforced Additional examples of this paradox are found in the re- by the additional findings of impaired spermatogenesis (1, lationship of sex hormones to insulin and risk factors for MI. 3–5, 39 – 41), fatty liver (5, 37, 38, 42), and decreased bone The DEA men and the ERKO and ArKO mice showed evi- mineral density (1–5, 39, 42) in both. dence of insulin resistance and risk factors for MI, which Thus, data from studies on the five patients and on the improved in the aromatase-deficient men and ArKO mice ERKO and ArKO mice suggest that a sex hormone alteration with estrogen administration. Diabetes with hyperinsulin- is prospective for cardiovascular disease and its risk factors. emia developed in one (5) of the two men (3, 5) administered These data would suggest, however, that low estrogen action testosterone. In SEA men, however, the testosterone level has in men is associated with atherosclerosis, increased VAT, been found to correlate inversely and the estradiol-to-tes- hyperinsulinemia, and risk factors for MI, rather than the low tosterone ratio (E/T) positively and more strongly with the androgen action suggested by studies in SEA men. Defining insulin and glucose levels (7, 14, 22); this is opposite from the role of estrogen vs. androgen in these relationships is what was found in the DEA men, where the effective E/T complicated by the fact that androgen aromatization is the would be very low. Likewise, administration of estrogen plus source of estrogen and estrogen inhibits testosterone secre- antiandrogen to healthy men has been reported to decrease tion by inhibiting gonadotropin secretion. A comparison of insulin sensitivity (13, 21), whereas testosterone administra- these five patients and their knockout mouse models with tion has been reported to increase insulin sensitivity without SEA men and wild-type mice provides examples of the ap- a significant change in the estradiol level (10). Administra- parent paradoxical actions of estrogen and androgen. tion of a nonaromatizable androgen to normal men increased That both the ER- -deficient man, with a high estrogen insulin sensitivity (9) and glucose disposal (15), whereas level, and an aromatase-deficient man, with an undetected administration of the aromatizable testosterone enanthate estradiol level, had evidence of premature atherosclerosis did not— even though the estradiol level was increased by would suggest that estrogen action through the ER pre- the aromatizable and not by the nonaromatizable androgen vents atherosclerosis in men. But in SEA men, the estradiol (15). A high incidence of mild diabetes has been reported in level has not been found to correlate significantly with the men with Klinefelter’s syndrome (44), a sex chromosome degree of atherosclerosis of the coronary (12) or carotid artery abnormality resulting in a low testosterone level and asso- (20), whereas the testosterone level showed an inverse cor- ciated with a normal or high estradiol level. A low testos- relation with the degree of atherosclerosis of the coronary terone level in SEA men has been reported to be prospective artery (12), carotid artery (20, 23, 24), and aorta (19). The for diabetes (16, 18, 27) and the metabolic syndrome (27); the testosterone level has also been found to correlate inversely estradiol level, measured in two of these studies, was not with the progression of carotid artery atherosclerosis (28). predictive (16, 18). One of these studies (20) did report an inverse correlation of Thus, men with a primary deficiency of estrogen action
  4. 4. 2710 J Clin Endocrinol Metab, May 2005, 90(5):2708 –2711 Phillips • Sex Hormones and Cardiovascular Disease based on mutations of either of two genes, and a normal or Acknowledgments high testosterone level, appear to develop atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI, Received October 12, 2004. Accepted January 26, 2005. which appear to be reversed by estrogen administration and Address all correspondence and requests for reprints to: Dr. Gerald B. Phillips, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, may be exacerbated by testosterone administration. But the New York, New York 10019. E-mail: findings in SEA men suggest paradoxically that these ab- normalities are associated with a low testosterone and a References normal or high estrogen level and are reversed by androgen 1. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams administration and may be exacerbated by estrogen admin- TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation istration. With regard to these abnormalities, then, the sex in the estrogen-receptor gene in a man. N Engl J Med 331:1056 –1061 2. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K 1995 Aromatase hormones may be acting oppositely in DEA compared with deficiency in male and female siblings caused by a novel mutation and the SEA men just as they appear to act oppositely in women physiological role of estrogens. J Clin Endocrinol Metab 80:3689 –3698 compared with SEA men (45, 46). 3. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER 1997 Effect of testosterone and estradiol in a man with Why the sex hormones appear to relate oppositely to ath- aromatase dificiency. N Engl J Med 337:91–95 erosclerosis, VAT accumulation, hyperinsulinemia, and risk 4. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, Mann K, Broecker M 2002 Impact of estrogen replacement therapy in a male with factors for MI in DEA compared with SEA men is unex- congenital aromatase deficiency caused by a novel mutation in the CYP19 plained. That the sex hormones appear to relate similarly to gene. J Clin Endocrinol Metab 87:5476 –5484 these abnormalities in DEA men compared with women 5. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, Clyne CD, Davis S, Simpson ER, Carani C 2004 Dysmetabolic syndrome in a man with raises the possibility that a female-like response pattern with a novel mutation of the aromatase gene: effects of testosterone, alendronate, regard to these abnormalities was imprinted in the DEA men and estradiol treatment. J Clin Endocrinol Metab 89:61–70 during development as a result of deficient estrogen action 6. Phillips GB 2004 The GILHT-E syndrome? Diabetes Care 27:2285–2286 7. Phillips GB 1977 Relationship between serum sex hormones and glucose, (40, 47). In contrast, the male identity and apparently normal insulin, and lipid abnormalities in men with myocardial infarction. Proc Natl genital development present in the DEA patients but absent Acad Sci USA 74:1729 –1733 8. Phillips GB 1978 Sex hormones, risk factors, and cardiovascular disease. Am J in males with complete androgen insensitivity indicates that Med 65:7–11 certain characteristics may not require estrogen or ER but 9. Friedl KE, Jones RE, Hannan Jr CJ, Plymate SR 1989 The administration of may depend on androgen acting solely through the androgen pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance. receptor. The interplay between estrogen and androgen and J Clin Endocrinol Metab 68:971–975 their receptors is complex. Evidence has been reported that 10. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, estrogen can interact with the androgen receptor and an- Bjorntorp P 1992 The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes 16:991–997 drogen with the estrogen receptor, that each hormone may 11. Phillips GB 1993 Relationship between serum sex hormones and the glucose- affect the expression of the receptor of the other hormone, insulin-lipid defect in men with obesity. Metabolism 42:116 –120 12. Phillips GB, Pinkernell BH, Jing T-Y 1994 The association of hypotestoster- that the estrogen and androgen receptors can interact di- onemia with coronary artery disease in men. Arterioscler Thromb 14:701–706 rectly, and that these interactions may be affected by other 13. Polderman KH, Gooren LJG, Asscheman H, Bakker A, Heine RJ 1994 In- factors (48 –50). Further studies on ER -deficient, aromatase- duction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265–271 deficient, and androgen receptor-deficient patients and on 14. Tchernof A, Despres J, Dupont A, Belanger A, Nadeau A, Prud’homme D, the ERKO , ERKO , ERKO , ArKO, Tfm (testicular Moorjani S, Lupien PJ, Labrie F 1995 Relation of steroid hormones to glucose feminized), and the recently produced ARKO (androgen re- tolerance and plasma insulin levels in men. Diabetes Care 18:292–299 15. Hobbs CJ, Jones RE, Plymate SR 1996 Nandrolone, a 19-nortestosterone, ceptor knockout) (51) mouse models should be helpful in enhances insulin-independent glucose uptake in normal men. J Clin Endocri- clarifying these relationships. The resolution of the paradox nol Metab 81:1582–1585 16. Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L 1996 Low levels of sex could reveal underlying mechanisms for the development of hormone-binding globulin and testosterone predict the development of non- atherosclerotic cardiovascular disease. insulin-dependent diabetes mellitus in men. Am J Epidemiol 143:889 – 897 In summary, deficient estrogen action based on mutations 17. Tsai EC, Boyko EJ, Leonetti DL, Fujimoto WY 2000 Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J of either of two genes in men with normal or high testos- Obes 24:485– 491 terone levels has been observed to result in evidence of 18. Oh J-Y, Barrett-Connor E, Wedick NM, Wingard DL 2002 Rancho Bernardo premature atherosclerosis, increased VAT, hyperinsulin- Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women. Diabetes Care 25:55– 60 emia, and risk factors for MI. These same abnormalities have 19. Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP been observed in men with sufficient estrogen action but low 2002 Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab 87:3632–3639 testosterone levels. The reason for this apparent paradox is 20. van den Beld AW, Bots ML, Janssen JAMLL, Pols HAP, Lamberts SWJ, not known. However, these abnormalities also appear to Grobbee DE 2003 Endogenous hormones and carotid atherosclerosis in elderly relate oppositely to estrogen and androgen in women com- men. Am J Epidemiol 157:25–31 21. Elbers JMH, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, pared with SEA men but similarly in women compared with Gooren LJG 2003 Effects of sex steroids on components of the insulin resistance DEA men. A possible explanation, therefore, is that the pat- syndrome in transsexual subjects. Clin Endocrinol (Oxf) 58:562–571 tern of sex hormone exposure during early development may 22. Phillips GB, Jing T-Y, Heymsfield SB 2003 Relationships in men of sex hormones, insulin, adiposity, and risk factors for myocardial infarction. Me- determine the subsequent response to sex hormones. That a tabolism 52:784 –790 primary defect that decreases either the production or uti- 23. De Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R 2003 Free testosterone plasma levels are negatively associated with the intima- lization of estrogen may result in evidence of atherosclerosis, media thickness of the common carotid artery in overweight and obese glu- increased VAT, hyperinsulinemia, and risk factors for MI cose-tolerant young adult men. Int J Obes Relat Metab Disord 27:803– 807 suggests that a sex hormone alteration may underlie these 24. Fukui M, Kitagawa Y, Nakamura N, Kadono M, Mogami S, Hirata C, Ichio N, Katsuya W, Hasegawa G, Yoshikawa T 2003 Association between serum abnormalities and that atherosclerotic cardiovascular disease testosterone concentration and carotid atherosclerosis in men with type 2 may indeed be an endocrinological disorder. diabetes. Diabetes Care 26:1869 –1873
  5. 5. Phillips • Sex Hormones and Cardiovascular Disease J Clin Endocrinol Metab, May 2005, 90(5):2708 –2711 2711 25. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen T-P, OK, Leury BJ, Robertson KM, Yao S, Simpson ER 2000 Aromatase-deficient Salonen R, Rauramaa R, Salonen JT 2003 Sex hormones, inflammation and (ARKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA the metabolic syndrome: a population-based study. Euro J Endocrinol 149: 97:12735–12740 601– 608 38. Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T, Sugiura T, 26. Phillips GB, Pinkernell BH, Jing T-Y 2004 Are major risk factors for myo- Shizuta Y 2003 Progessive development of insulin resistance phenotype in cardial infarction the major predictors of degree of coronary artery disease in male mice with complete aromatase (CYP19) deficiency. J Endocrinol 176: men? Metabolism 53:324 –329 237–246 27. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen T-P, 39. Korach KS 1994 Insights from the study of animals lacking functional estrogen Valkonen V-P, Salonen R, Salonen JT 2004 Testosterone and sex hormone- receptor. Science 266:1524 –1527 binding globulin predict the metabolic syndrome and diabetes in middle-aged 40. Couse JF, Korach KS 1999 Estrogen receptor null mice: what have we learned men. Diabetes Care 27:1036 –1041 and where will they lead us? Endocr Rev 20:358 – 417 28. Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SWJ, van der 41. Rochira V, Balestrieri A, Madeo B, Baraldi E, Faustini-Fustini M, Granata Schouw YT 2004 Endogenous sex hormones and progression of carotid ath- ARM, Carani C 2001 Congenital estrogen deficiency : in search of the estrogen erosclerosis in elderly men. Circulation 109:2074 –2079 role in human male reproduction. Mol Cell Endocrinol 178:107–115 29. Bilezikian JP, Morishima A, Bell J, Grumbach MM 1998 Increased bone mass 42. 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