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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2011
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2708-2711
Copyright © 2005 by The Endocrine Society

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

Address all correspondence and requests for reprints to: Dr. Gerald B. Phillips, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, New York 10019. E-mail: gbp1{at}columbia.edu.


   Abstract
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 Abstract
References
 
The strikingly lower incidence of myocardial infarction (MI) in premenopausal women than in men of the same age suggests an important role for sex hormones in the etiology of MI. Supporting such a role are studies, carried out mostly in men, that report abnormalities of sex hormone levels in patients with MI, correlations of sex hormone levels with degree of atherosclerosis and with levels of risk factors for MI, and changes in the levels of risk factors with administration of sex hormones. Studies have also reported a prospective relationship in men of testosterone level with progression of atherosclerosis, accumulation of visceral adipose tissue, and other risk factors for MI. Puzzling, however, is that neither the level of testosterone nor of estrogen was found to be predictive of coronary events in any of the eight prospective studies that have been carried out. Also puzzling is that whereas the gender difference in incidence of MI would suggest that testosterone promotes and/or estrogen prevents MI, the cross- sectional, hormone administration, and prospective studies have suggested that in men testosterone may prevent and estrogen promote MI. These studies have thus revealed an estrogen-androgen paradox: that endogenous sex hormones may relate both to atherosclerotic cardiovascular disease and its risk factors oppositely in women and men. Recently recognized experiments of nature and their knockout mouse models may present another manifestation of this estrogen-androgen paradox and could help resolve these apparent contradictions.

THE DISCOVERY OF five men with deficient estrogen action (DEA)—one with estrogen resistance (1) and four with deficient estrogen synthesis (2, 3, 4, 5), on the bases of mutations in the genes for estrogen receptor {alpha} (ER {alpha}) and aromatase, respectively—and studies on their knockout mouse models suggest that DEA men develop, at an early age, atherosclerosis, increased visceral adipose tissue (VAT), and the constellation of risk factors for myocardial infarction (MI) (6) that has come to be known as the "metabolic syndrome." Whereas the ER {alpha}-deficient man had elevated estradiol levels, the four aromatase-deficient men had estradiol levels below the sensitivity of the methods used for measurement; the testosterone levels in the five men were normal or high. The findings on these five patients support a primary and prospective role for sex hormones in the development of atherosclerotic cardiovascular disease. They also present a paradox: the atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI in these DEA men appear to be based on low estrogen action rather than on the low androgen action that has been suggested by the cross-sectional, hormone administration, and prospective studies on men who have sufficient estrogen action (SEA) (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28).

The five DEA patients exhibited similar abnormalities; these abnormalities appeared to improve with estrogen administration in the patients with aromatase deficiency. That one (5) of two (3, 5) aromatase-deficient patients administered testosterone developed diabetes during its administration suggests that the improvement in the abnormalities with estrogen administration could have resulted, at least in part, from the concomitant marked decrease in the testosterone level (3, 4, 5, 29) or testosterone-to-estradiol ratio. Two patients showed evidence of premature atherosclerosis. One of these, the ER {alpha}-deficient man, a nonsmoker with a cholesterol level of 130 mg/dl, showed at age 31 calcification of the left anterior descending coronary artery suggestive of coronary artery disease (1, 30). He also showed impairment of flow-mediated endothelium-dependent peripheral vasodilation (31). A relationship of ER {alpha} to coronary heart disease is further supported by reports of an association in men of a polymorphism in the ER {alpha} gene with MI (32, 33). The second of these two patients, an aromatase-deficient man with a cholesterol level of 177 mg/dl, was found by echo-Doppler examination at age 30 to have two "lipid plaques" in the carotid artery, which disappeared completely after less than 1 yr of transdermal estradiol administration (5). The DEA patients also exhibited evidence of a premature increase in abdominal girth as suggested by the published photographs of the aromatase-deficient patients (2, 4, 5, 34) and confirmed by a waist-to-hip ratio (35) of 1.02 in the one patient in whom it was measured (4). No photograph of the ER {alpha}-deficient man was published with the report (1). An increase in VAT is consistent with the observation that VAT in men appears to underlie the constellation of risk factors for MI (22). All of the patients also had other risk factors for MI, four before age 30 (1, 2, 4, 5). The receptor-deficient man had diabetes, hyperinsulinemia, and acanthosis nigricans (1). One of the aromatase-deficient men had hyperinsulinemia (2, 29) and another had insulin resistance (4); the insulin level in both men decreased with estrogen administration (4, 29). A third aromatase-deficient man, during transdermal testosterone administration, developed diabetes with hyperinsulinemia and acanthosis nigricans, all of which improved on switching to transdermal estradiol administration (5). Two aromatase-deficient men had hypercholesterolemia (2, 3), three had hypertriglyceridemia (2, 3, 4), and three had a low high-density lipoprotein level (3, 4, 5). Blood pressure, reported in three of the men (1, 2, 4, 30), was 140/85 (1) and 130/64 (30) in the receptor-deficient man and 158/72 in an aromatase-deficient man (2).

Supporting the validity of these observations in the DEA patients are the findings in ER {alpha}-deficient (ERKO) and aromatase-deficient (ArKO) knockout mice, whose phenotypes appear to be remarkably similar to the human phenotypes. The ERKO and ArKO mice preferentially accumulate intra-abdominal adipose tissue, a process that in the ArKO mice is reversed by estrogen administration (36, 37); this finding suggests not only that the DEA men do indeed have increased abdominal girth, as suggested in the photographs, but also that it is attributable to VAT accumulation. ERKO (36) and ArKO (38) mice also develop glucose intolerance and insulin resistance, both of which in the ArKO mice are improved by estrogen administration (38). The ArKO mice were reported to be hypercholesterolemic at 1 yr (37). The similarity of the human and mouse phenotypes is reinforced by the additional findings of impaired spermatogenesis (1, 3, 4, 5, 39, 40, 41), fatty liver (5, 37, 38, 42), and decreased bone mineral density (1, 2, 3, 4, 5, 39, 42) in both.

Thus, data from studies on the five patients and on the ERKO and ArKO mice suggest that a sex hormone alteration is prospective for cardiovascular disease and its risk factors. These data would suggest, however, that low estrogen action in men is associated with atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI, rather than the low androgen action suggested by studies in SEA men. Defining the role of estrogen vs. androgen in these relationships is complicated by the fact that androgen aromatization is the source of estrogen and estrogen inhibits testosterone secretion by inhibiting gonadotropin secretion. A comparison of these five patients and their knockout mouse models with SEA men and wild-type mice provides examples of the apparent paradoxical actions of estrogen and androgen.

That both the ER-{alpha}-deficient man, with a high estrogen level, and an aromatase-deficient man, with an undetected estradiol level, had evidence of premature atherosclerosis would suggest that estrogen action through the ER {alpha} prevents atherosclerosis in men. But in SEA men, the estradiol level has not been found to correlate significantly with the degree of atherosclerosis of the coronary (12) or carotid artery (20), whereas the testosterone level showed an inverse correlation with the degree of atherosclerosis of the coronary artery (12), carotid artery (20, 23, 24), and aorta (19). The testosterone level has also been found to correlate inversely with the progression of carotid artery atherosclerosis (28). One of these studies (20) did report an inverse correlation of estrone with degree of atherosclerosis, but another (28) reported a "borderline significant" positive correlation of estradiol with progression. That the testosterone but not the estradiol level showed this correlation in SEA men could have been owing to a requirement that the estradiol be produced by aromatization in the vessel wall to prevent atherosclerosis. Countering this explanation is the observation that estradiol administration to an aromatase-deficient man completely reversed the evidence of atherosclerosis (5). Estradiol administration to SEA men has been reported to increase the incidence of MI (43), although the associated increase in incidence of venous thrombosis in this secondary prevention trial suggests this effect may occur through the promotion of thrombosis rather than atherosclerosis.

A similar discrepancy in estrogen and androgen action between DEA and SEA men is found with abdominal adiposity. The apparent association of abdominal adiposity with insufficient estrogen action in the DEA men was validated in the knockout mice by the preferential accumulation of intra-abdominal adipose tissue, which was reversed by estrogen administration in the ArKO mice. In SEA men, however, a low testosterone level has been reported to be prospective specifically for VAT accumulation (17), and testosterone administration has been reported to decrease VAT specifically without a significant change in estradiol level (10). While testosterone could exert an effect via local conversion to estradiol, administration of estrogen plus antiandrogen to young, healthy, nonobese men has been reported to increase VAT (21).

Additional examples of this paradox are found in the relationship of sex hormones to insulin and risk factors for MI. The DEA men and the ERKO and ArKO mice showed evidence of insulin resistance and risk factors for MI, which improved in the aromatase-deficient men and ArKO mice with estrogen administration. Diabetes with hyperinsulinemia developed in one (5) of the two men (3, 5) administered testosterone. In SEA men, however, the testosterone level has been found to correlate inversely and the estradiol-to-testosterone ratio (E/T) positively and more strongly with the insulin and glucose levels (7, 14, 22); this is opposite from what was found in the DEA men, where the effective E/T would be very low. Likewise, administration of estrogen plus antiandrogen to healthy men has been reported to decrease insulin sensitivity (13, 21), whereas testosterone administration has been reported to increase insulin sensitivity without a significant change in the estradiol level (10). Administration of a nonaromatizable androgen to normal men increased insulin sensitivity (9) and glucose disposal (15), whereas administration of the aromatizable testosterone enanthate did not—even though the estradiol level was increased by the aromatizable and not by the nonaromatizable androgen (15). A high incidence of mild diabetes has been reported in men with Klinefelter’s syndrome (44), a sex chromosome abnormality resulting in a low testosterone level and associated with a normal or high estradiol level. A low testosterone level in SEA men has been reported to be prospective for diabetes (16, 18, 27) and the metabolic syndrome (27); the estradiol level, measured in two of these studies, was not predictive (16, 18).

Thus, men with a primary deficiency of estrogen action based on mutations of either of two genes, and a normal or high testosterone level, appear to develop atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI, which appear to be reversed by estrogen administration and may be exacerbated by testosterone administration. But the findings in SEA men suggest paradoxically that these abnormalities are associated with a low testosterone and a normal or high estrogen level and are reversed by androgen administration and may be exacerbated by estrogen administration. With regard to these abnormalities, then, the sex hormones may be acting oppositely in DEA compared with SEA men just as they appear to act oppositely in women compared with SEA men (45, 46).

Why the sex hormones appear to relate oppositely to atherosclerosis, VAT accumulation, hyperinsulinemia, and risk factors for MI in DEA compared with SEA men is unexplained. That the sex hormones appear to relate similarly to these abnormalities in DEA men compared with women raises the possibility that a female-like response pattern with regard to these abnormalities was imprinted in the DEA men during development as a result of deficient estrogen action (40, 47). In contrast, the male identity and apparently normal genital development present in the DEA patients but absent in males with complete androgen insensitivity indicates that certain characteristics may not require estrogen or ER {alpha} but may depend on androgen acting solely through the androgen receptor. The interplay between estrogen and androgen and their receptors is complex. Evidence has been reported that estrogen can interact with the androgen receptor and androgen with the estrogen receptor, that each hormone may affect the expression of the receptor of the other hormone, that the estrogen and androgen receptors can interact directly, and that these interactions may be affected by other factors (48, 49, 50). Further studies on ER {alpha}-deficient, aromatase-deficient, and androgen receptor-deficient patients and on the ERKO {alpha}, ERKO ß, ERKO {alpha}ß, ArKO, Tfm (testicular feminized), and the recently produced ARKO (androgen receptor knockout) (51) mouse models should be helpful in clarifying these relationships. The resolution of the paradox could reveal underlying mechanisms for the development of atherosclerotic cardiovascular disease.

In summary, deficient estrogen action based on mutations of either of two genes in men with normal or high testosterone levels has been observed to result in evidence of premature atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI. These same abnormalities have been observed in men with sufficient estrogen action but low testosterone levels. The reason for this apparent paradox is not known. However, these abnormalities also appear to relate oppositely to estrogen and androgen in women compared with SEA men but similarly in women compared with DEA men. A possible explanation, therefore, is that the pattern of sex hormone exposure during early development may determine the subsequent response to sex hormones. That a primary defect that decreases either the production or utilization of estrogen may result in evidence of atherosclerosis, increased VAT, hyperinsulinemia, and risk factors for MI suggests that a sex hormone alteration may underlie these abnormalities and that atherosclerotic cardiovascular disease may indeed be an endocrinological disorder.


   Footnotes
 
First Published Online February 1, 2005

Abbreviations: ArKO, Aromatase-deficient knockout; DEA, deficient estrogen action; ER {alpha}, estrogen receptor {alpha}; ERKO, ER {alpha}-deficient knockout; MI, myocardial infarction; SEA, sufficient estrogen action; VAT, visceral adipose tissue.

Received October 12, 2004.

Accepted January 26, 2005.


   References
Top
 Abstract
 References
 

  1. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061[Abstract/Free Full Text]
  2. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689–3698[Abstract]
  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 aromatase dificiency. N Engl J Med 337:91–95[Free Full Text]
  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 congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab 87:5476–5484[Abstract/Free Full Text]
  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 a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab 89:61–70[Abstract/Free Full Text]
  6. Phillips GB 2004 The GILHT-E syndrome? Diabetes Care 27:2285–2286[Free Full Text]
  7. Phillips GB 1977 Relationship between serum sex hormones and glucose, insulin, and lipid abnormalities in men with myocardial infarction. Proc Natl Acad Sci USA 74:1729–1733[Abstract/Free Full Text]
  8. Phillips GB 1978 Sex hormones, risk factors, and cardiovascular disease. Am J Med 65:7–11[CrossRef][Medline]
  9. Friedl KE, Jones RE, Hannan Jr CJ, Plymate SR 1989 The administration of pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance. J Clin Endocrinol Metab 68:971–975[Abstract/Free Full Text]
  10. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P 1992 The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes 16:991–997
  11. Phillips GB 1993 Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity. Metabolism 42:116–120[CrossRef][Medline]
  12. Phillips GB, Pinkernell BH, Jing T-Y 1994 The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 14:701–706[Abstract/Free Full Text]
  13. Polderman KH, Gooren LJG, Asscheman H, Bakker A, Heine RJ 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265–271[Abstract]
  14. Tchernof A, Despres J, Dupont A, Belanger A, Nadeau A, Prud’homme D, Moorjani S, Lupien PJ, Labrie F 1995 Relation of steroid hormones to glucose tolerance and plasma insulin levels in men. Diabetes Care 18:292–299[Abstract]
  15. Hobbs CJ, Jones RE, Plymate SR 1996 Nandrolone, a 19-nortestosterone, enhances insulin-independent glucose uptake in normal men. J Clin Endocrinol Metab 81:1582–1585[Abstract]
  16. Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L 1996 Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. Am J Epidemiol 143:889–897[Abstract/Free Full Text]
  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 Obes 24:485–491
  18. Oh J-Y, Barrett-Connor E, Wedick NM, Wingard DL 2002 Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women. Diabetes Care 25:55–60[Abstract/Free Full Text]
  19. Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP 2002 Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab 87:3632–3639[Abstract/Free Full Text]
  20. van den Beld AW, Bots ML, Janssen JAMLL, Pols HAP, Lamberts SWJ, Grobbee DE 2003 Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol 157:25–31[Abstract/Free Full Text]
  21. Elbers JMH, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJG 2003 Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol (Oxf) 58:562–571[CrossRef][Medline]
  22. Phillips GB, Jing T-Y, Heymsfield SB 2003 Relationships in men of sex hormones, insulin, adiposity, and risk factors for myocardial infarction. Metabolism 52:784–790[CrossRef][Medline]
  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-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord 27:803–807[CrossRef][Medline]
  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 testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care 26:1869–1873[Abstract/Free Full Text]
  25. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen T-P, Salonen R, Rauramaa R, Salonen JT 2003 Sex hormones, inflammation and the metabolic syndrome: a population-based study. Euro J Endocrinol 149:601–608[Abstract]
  26. Phillips GB, Pinkernell BH, Jing T-Y 2004 Are major risk factors for myocardial infarction the major predictors of degree of coronary artery disease in men? Metabolism 53:324–329[CrossRef][Medline]
  27. Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen T-P, Valkonen V-P, Salonen R, Salonen JT 2004 Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 27:1036–1041[Abstract/Free Full Text]
  28. Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SWJ, van der Schouw YT 2004 Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 109:2074–2079[Abstract/Free Full Text]
  29. Bilezikian JP, Morishima A, Bell J, Grumbach MM 1998 Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603[Free Full Text]
  30. Sudhir K, Chou TM, Chatterjee K, Smith EP, Williams TC, Kane JP, Malloy MJ, Korach KS, Rubanyi GM 1997 Premature coronary artery disease associated with a disruptive mutation in the estrogen receptor gene in a man. Circulation 96:3774–3777[Abstract/Free Full Text]
  31. Sudhir K, Chou TM, Messina LM, Hutchison SJ, Korach KS, Chatterjee K, Rubanyi GM 1997 Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene. Lancet 349:1146–1147[CrossRef][Medline]
  32. Lehtimaki T, Kunnas TA, Mattila KM, Perola M, Penttila A, Koivula T, Karhunen PJ 2002 Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study. J Mol Med 80:176–180[CrossRef][Medline]
  33. Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, Levy D 2003 Association between estrogen receptor {alpha} gene variation and cardiovascular disease. JAMA 290:2263–2270[Abstract/Free Full Text]
  34. Faustini-Fustini M, Rochira V, Carani C 1999 Oestrogen deficiency in men: where are we today? Eur J Endocrinol 140:111–129[CrossRef][Medline]
  35. Seidell JC, Cigolini M, Deslypere J-P, Charzewska J, Ellsinger B-M, Cruz A 1991 Body fat distribution in relation to physical activity and smoking habits in 38-year-old European men. The European fat distribution study. Am J Epidemiol 133:257–265[Abstract/Free Full Text]
  36. Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS 2000 Increased adipose tissue in male and female estrogen receptor-{alpha} knockout mice. Proc Natl Acad Sci USA 97:12729–12734[Abstract/Free Full Text]
  37. Jones MEE, Thorburn AW, Britt KL, Hewitt KN, Wreford NG, Proietto J, Oz OK, Leury BJ, Robertson KM, Yao S, Simpson ER 2000 Aromatase-deficient (ARKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 97:12735–12740[Abstract/Free Full Text]
  38. Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T, Sugiura T, Shizuta Y 2003 Progessive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol 176:237–246[Abstract]
  39. Korach KS 1994 Insights from the study of animals lacking functional estrogen receptor. Science 266:1524–1527[Abstract/Free Full Text]
  40. Couse JF, Korach KS 1999 Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20:358–417[Abstract/Free Full Text]
  41. Rochira V, Balestrieri A, Madeo B, Baraldi E, Faustini-Fustini M, Granata ARM, Carani C 2001 Congenital estrogen deficiency: in search of the estrogen role in human male reproduction. Mol Cell Endocrinol 178:107–115[CrossRef][Medline]
  42. Murata Y, Robertson KM, Jones ME, Simpson ER 2002 Effect of estrogen deficiency in the male: the ARKO mouse model. Mol Cell Endocrinol 193:7–12[CrossRef][Medline]
  43. The Coronary Drug Project 1970 The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA 214:1303–1313[Abstract/Free Full Text]
  44. Nielsen J, Johansen K, Yde H 1969 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 29:1062–1073[Abstract/Free Full Text]
  45. Phillips GB 1993 Relationship of serum sex hormones to coronary heart disease. Steroids 58:286–290, 554–555[CrossRef][Medline]
  46. Phillips GB, Pinkernell BH, Jing T-Y 1997 Relationship between serum sex hormones and coronary artery disease in postmenopausal women. Arterioscler Thromb Vasc Biol 17:695–701[Abstract/Free Full Text]
  47. Simerly RB, Zee MC, Pendleton JW, Lubahn DB, Korach KS 1997 Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. Proc Natl Acad Sci USA 94:14077–14082[Abstract/Free Full Text]
  48. Kreitmann B, Bayard F 1979 Androgen interaction with the oestrogen receptor in human tissues. J Steroid Biochem 11:1589–1595[CrossRef][Medline]
  49. Yeh S, Miyamoto H, Shima H, Chang C 1998 From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci USA 95:5527–5532[Abstract/Free Full Text]
  50. Panet-Raymond V, Gottlieb B, Beitel LK, Pinsky L, Trifiro MA 2000 Interactions between androgen and estrogen receptors and the effects on their transactivational properties. Mol Cell Endocrinol 167:139–150[CrossRef][Medline]
  51. Matsumoto T, Takeyama K, Sato T, Kato S 2003 Androgen receptor functions from reverse genetic models. J Steroid Biochem Mol Biol 85:95–99[CrossRef][Medline]



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