J. Clin. Endocrinol. Metab. 2005 90:2708-2711 originally published online Feb 1, 2005; , doi: 10.1210/jc.2004-2011  

Gerald B. Phillips  

Estrogen-Androgen ParadoxIs Atherosclerotic Cardiovascular Disease an Endocrinological Disorder? The

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Is Atherosclerotic Cardiovascular Disease anEndocrinological 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)in premenopausal women than in men of the same age sug-gests 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 patientswith MI, correlations of sex hormone levels with degree ofatherosclerosis and with levels of risk factors for MI, andchanges in the levels of risk factors with administration of sexhormones. Studies have also reported a prospective relation-ship in men of testosterone level with progression of athero-sclerosis, accumulation of visceral adipose tissue, and otherrisk factors for MI. Puzzling, however, is that neither the levelof testosterone nor of estrogen was found to be predictive ofcoronary events in any of the eight prospective studies that

have been carried out. Also puzzling is that whereas the gen-der difference in incidence of MI would suggest that testos-terone promotes and/or estrogen prevents MI, the cross-sectional, hormone administration, and prospective studieshave suggested that in men testosterone may prevent andestrogen promote MI. These studies have thus revealed anestrogen-androgen paradox: that endogenous sex hormonesmay relate both to atherosclerotic cardiovascular disease andits risk factors oppositely in women and men. Recently rec-ognized experiments of nature and their knockout mousemodels may present another manifestation of this estrogen-androgen paradox and could help resolve these apparentcontradictions. (J Clin Endocrinol Metab 90: 2708–2711, 2005)

THE DISCOVERY OF five men with deficient estrogenaction (DEA)—one with estrogen resistance (1) and

four with deficient estrogen synthesis (2–5), on the bases ofmutations in the genes for estrogen receptor � (ER �) andaromatase, respectively—and studies on their knockoutmouse models suggest that DEA men develop, at an earlyage, 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 syn-drome.” Whereas the ER �-deficient man had elevated es-tradiol levels, the four aromatase-deficient men had estradiollevels below the sensitivity of the methods used for mea-surement; the testosterone levels in the five men were normalor high. The findings on these five patients support a primaryand prospective role for sex hormones in the development ofatherosclerotic cardiovascular disease. They also present aparadox: the atherosclerosis, increased VAT, hyperinsulin-emia, and risk factors for MI in these DEA men appear to bebased on low estrogen action rather than on the low andro-gen action that has been suggested by the cross-sectional,hormone administration, and prospective studies on menwho have sufficient estrogen action (SEA) (7–28).

The five DEA patients exhibited similar abnormalities;

these abnormalities appeared to improve with estrogen ad-ministration in the patients with aromatase deficiency. Thatone (5) of two (3, 5) aromatase-deficient patients adminis-tered testosterone developed diabetes during its adminis-tration suggests that the improvement in the abnormalitieswith estrogen administration could have resulted, at least inpart, from the concomitant marked decrease in the testos-terone level (3–5, 29) or testosterone-to-estradiol ratio. Twopatients showed evidence of premature atherosclerosis. Oneof these, the ER �-deficient man, a nonsmoker with a cho-lesterol level of 130 mg/dl, showed at age 31 calcification ofthe left anterior descending coronary artery suggestive ofcoronary artery disease (1, 30). He also showed impairmentof flow-mediated endothelium-dependent peripheral vaso-dilation (31). A relationship of ER � to coronary heart diseaseis further supported by reports of an association in men ofa polymorphism in the ER � gene with MI (32, 33). Thesecond of these two patients, an aromatase-deficient manwith 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 lessthan 1 yr of transdermal estradiol administration (5). TheDEA patients also exhibited evidence of a premature increasein abdominal girth as suggested by the published photo-graphs of the aromatase-deficient patients (2, 4, 5, 34) andconfirmed by a waist-to-hip ratio (35) of 1.02 in the onepatient in whom it was measured (4). No photograph of theER �-deficient man was published with the report (1). Anincrease in VAT is consistent with the observation that VATin men appears to underlie the constellation of risk factors forMI (22). All of the patients also had other risk factors for MI,

First Published Online February 1, 2005Abbreviations: ArKO, Aromatase-deficient knockout; DEA, deficient

estrogen action; ER �, estrogen receptor �; ERKO, ER �-deficient knock-out; MI, myocardial infarction; SEA, sufficient estrogen action; VAT,visceral adipose tissue.JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the en-docrine community.

0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(5):2708–2711Printed in U.S.A. Copyright © 2005 by The Endocrine Society

doi: 10.1210/jc.2004-2011

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four before age 30 (1, 2, 4, 5). The receptor-deficient man haddiabetes, hyperinsulinemia, and acanthosis nigricans (1).One of the aromatase-deficient men had hyperinsulinemia(2, 29) and another had insulin resistance (4); the insulin levelin both men decreased with estrogen administration (4, 29).A third aromatase-deficient man, during transdermal tes-tosterone administration, developed diabetes with hyperin-sulinemia and acanthosis nigricans, all of which improved onswitching to transdermal estradiol administration (5). Twoaromatase-deficient men had hypercholesterolemia (2, 3),three had hypertriglyceridemia (2–4), and three had a lowhigh-density lipoprotein level (3–5). Blood pressure, re-ported in three of the men (1, 2, 4, 30), was 140/85 (1) and130/64 (30) in the receptor-deficient man and 158/72 in anaromatase-deficient man (2).

Supporting the validity of these observations in the DEApatients are the findings in ER �-deficient (ERKO) and aro-matase-deficient (ArKO) knockout mice, whose phenotypesappear 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 miceis reversed by estrogen administration (36, 37); this findingsuggests not only that the DEA men do indeed have in-creased 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 intoleranceand insulin resistance, both of which in the ArKO mice areimproved by estrogen administration (38). The ArKO micewere reported to be hypercholesterolemic at 1 yr (37). Thesimilarity of the human and mouse phenotypes is reinforcedby the additional findings of impaired spermatogenesis (1,3–5, 39–41), fatty liver (5, 37, 38, 42), and decreased bonemineral density (1–5, 39, 42) in both.

Thus, data from studies on the five patients and on theERKO and ArKO mice suggest that a sex hormone alterationis prospective for cardiovascular disease and its risk factors.These data would suggest, however, that low estrogen actionin men is associated with atherosclerosis, increased VAT,hyperinsulinemia, and risk factors for MI, rather than the lowandrogen action suggested by studies in SEA men. Definingthe role of estrogen vs. androgen in these relationships iscomplicated by the fact that androgen aromatization is thesource of estrogen and estrogen inhibits testosterone secre-tion by inhibiting gonadotropin secretion. A comparison ofthese five patients and their knockout mouse models withSEA men and wild-type mice provides examples of the ap-parent paradoxical actions of estrogen and androgen.

That both the ER-�-deficient man, with a high estrogenlevel, and an aromatase-deficient man, with an undetectedestradiol level, had evidence of premature atherosclerosiswould suggest that estrogen action through the ER � pre-vents atherosclerosis in men. But in SEA men, the estradiollevel has not been found to correlate significantly with thedegree of atherosclerosis of the coronary (12) or carotid artery(20), whereas the testosterone level showed an inverse cor-relation with the degree of atherosclerosis of the coronaryartery (12), carotid artery (20, 23, 24), and aorta (19). Thetestosterone level has also been found to correlate inverselywith 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) re-ported a “borderline significant” positive correlation of es-tradiol with progression. That the testosterone but not theestradiol level showed this correlation in SEA men couldhave been owing to a requirement that the estradiol be pro-duced by aromatization in the vessel wall to prevent ath-erosclerosis. Countering this explanation is the observationthat estradiol administration to an aromatase-deficient mancompletely reversed the evidence of atherosclerosis (5). Es-tradiol administration to SEA men has been reported toincrease the incidence of MI (43), although the associatedincrease in incidence of venous thrombosis in this secondaryprevention trial suggests this effect may occur through thepromotion of thrombosis rather than atherosclerosis.

A similar discrepancy in estrogen and androgen actionbetween DEA and SEA men is found with abdominal adi-posity. The apparent association of abdominal adiposity withinsufficient estrogen action in the DEA men was validated inthe knockout mice by the preferential accumulation of intra-abdominal adipose tissue, which was reversed by estrogenadministration in the ArKO mice. In SEA men, however, alow testosterone level has been reported to be prospectivespecifically for VAT accumulation (17), and testosterone ad-ministration has been reported to decrease VAT specificallywithout a significant change in estradiol level (10). Whiletestosterone could exert an effect via local conversion toestradiol, administration of estrogen plus antiandrogen toyoung, healthy, nonobese men has been reported to increaseVAT (21).

Additional examples of this paradox are found in the re-lationship of sex hormones to insulin and risk factors for MI.The DEA men and the ERKO and ArKO mice showed evi-dence of insulin resistance and risk factors for MI, whichimproved in the aromatase-deficient men and ArKO micewith estrogen administration. Diabetes with hyperinsulin-emia developed in one (5) of the two men (3, 5) administeredtestosterone. In SEA men, however, the testosterone level hasbeen found to correlate inversely and the estradiol-to-tes-tosterone ratio (E/T) positively and more strongly with theinsulin and glucose levels (7, 14, 22); this is opposite fromwhat was found in the DEA men, where the effective E/Twould be very low. Likewise, administration of estrogen plusantiandrogen to healthy men has been reported to decreaseinsulin sensitivity (13, 21), whereas testosterone administra-tion has been reported to increase insulin sensitivity withouta significant change in the estradiol level (10). Administra-tion of a nonaromatizable androgen to normal men increasedinsulin sensitivity (9) and glucose disposal (15), whereasadministration of the aromatizable testosterone enanthatedid not—even though the estradiol level was increased bythe aromatizable and not by the nonaromatizable androgen(15). A high incidence of mild diabetes has been reported inmen with Klinefelter’s syndrome (44), a sex chromosomeabnormality resulting in a low testosterone level and asso-ciated with a normal or high estradiol level. A low testos-terone level in SEA men has been reported to be prospectivefor diabetes (16, 18, 27) and the metabolic syndrome (27); theestradiol level, measured in two of these studies, was notpredictive (16, 18).

Thus, men with a primary deficiency of estrogen action

Phillips • Sex Hormones and Cardiovascular Disease J Clin Endocrinol Metab, May 2005, 90(5):2708–2711 2709

based on mutations of either of two genes, and a normal orhigh testosterone level, appear to develop atherosclerosis,increased VAT, hyperinsulinemia, and risk factors for MI,which appear to be reversed by estrogen administration andmay be exacerbated by testosterone administration. But thefindings in SEA men suggest paradoxically that these ab-normalities are associated with a low testosterone and anormal or high estrogen level and are reversed by androgenadministration and may be exacerbated by estrogen admin-istration. With regard to these abnormalities, then, the sexhormones may be acting oppositely in DEA compared withSEA men just as they appear to act oppositely in womencompared with SEA men (45, 46).

Why the sex hormones appear to relate oppositely to ath-erosclerosis, VAT accumulation, hyperinsulinemia, and riskfactors for MI in DEA compared with SEA men is unex-plained. That the sex hormones appear to relate similarly tothese abnormalities in DEA men compared with womenraises the possibility that a female-like response pattern withregard to these abnormalities was imprinted in the DEA menduring development as a result of deficient estrogen action(40, 47). In contrast, the male identity and apparently normalgenital development present in the DEA patients but absentin males with complete androgen insensitivity indicates thatcertain characteristics may not require estrogen or ER � butmay depend on androgen acting solely through the androgenreceptor. The interplay between estrogen and androgen andtheir receptors is complex. Evidence has been reported thatestrogen can interact with the androgen receptor and an-drogen with the estrogen receptor, that each hormone mayaffect the expression of the receptor of the other hormone,that the estrogen and androgen receptors can interact di-rectly, and that these interactions may be affected by otherfactors (48–50). Further studies on ER �-deficient, aromatase-deficient, and androgen receptor-deficient patients and onthe ERKO �, ERKO �, ERKO ��, ArKO, Tfm (testicularfeminized), and the recently produced ARKO (androgen re-ceptor knockout) (51) mouse models should be helpful inclarifying these relationships. The resolution of the paradoxcould reveal underlying mechanisms for the development ofatherosclerotic cardiovascular disease.

In summary, deficient estrogen action based on mutationsof either of two genes in men with normal or high testos-terone levels has been observed to result in evidence ofpremature atherosclerosis, increased VAT, hyperinsulin-emia, and risk factors for MI. These same abnormalities havebeen observed in men with sufficient estrogen action but lowtestosterone levels. The reason for this apparent paradox isnot known. However, these abnormalities also appear torelate oppositely to estrogen and androgen in women com-pared with SEA men but similarly in women compared withDEA men. A possible explanation, therefore, is that the pat-tern of sex hormone exposure during early development maydetermine the subsequent response to sex hormones. That aprimary defect that decreases either the production or uti-lization of estrogen may result in evidence of atherosclerosis,increased VAT, hyperinsulinemia, and risk factors for MIsuggests that a sex hormone alteration may underlie theseabnormalities and that atherosclerotic cardiovascular diseasemay indeed be an endocrinological disorder.

Acknowledgments

Received October 12, 2004. Accepted January 26, 2005.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@columbia.edu.

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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.

Phillips • Sex Hormones and Cardiovascular Disease J Clin Endocrinol Metab, May 2005, 90(5):2708–2711 2711