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The Role of Sex Steroids and Sex Steroid Metabolites in Atherosclerotic Disease

The overall aim of our research is to elucidate the importance of local and circulating sex steroids and sex steroid metabolites for atherogenesis, using both experimental and clinical approaches.

Atherosclerosis is a complex process which involves several different cell types, and progressive cellular changes develop silently for decades before the acute manifestation of cardiovascular disease. Key steps of the atherosclerotic process include hypercholesterolemia and the retention of low-density lipoprotein (LDL) particles in the vascular wall, oxidative modification of LDL, activation of endothelial cells, adhesion and migration of leukocytes, differentiation of monocytes into macrophages and lipid uptake of macrophages. Activation of macrophages and T-cells results in inflammation within the atherosclerotic lesion and contributes, as does the proliferation of vascular smooth muscle cells, to the formation of an atherosclerotic plaque.

Contradictory results on the role of sex steroids in atherosclerotic disease

The age-related development of atherosclerosis occurs approximately 10 years earlier in men than in women and, in accordance, men are significantly more affected by cardiovascular disease early in life. This difference prevails even after the adjustment for traditional vascular risk factors. The male preponderance in cardiovascular disease often has been ascribed to the protective effects of endogenous estrogens in premenopausal women. Numerous studies reporting beneficial effects of estradiol, the major endogenous estrogen, on e.g. serum lipids and experimental atherosclerosis support this assumption. Recent results from the Women’s Health Initiative showed that oral hormone replacement therapy may increase the risk for cardiovascular disease in postmenopausal women, thus challenging the “estrogen protection hypothesis”. In line with these results, we recently showed that circulating estradiol is an independent predictor of the progression of carotid atherosclerosis in middle-aged men (1) and that high serum levels of estradiol, but low levels of testosterone, associate with lower extremity atherosclerotic disease in elderly men (2). As estrogens, androgens are reported to modulate atherogenesis in both a beneficial and a deleterious manner.

Sex-specific effects of sex steroids on atherosclerosis have been suggested and the effect of sex steroids may also depend upon the extent of atherosclerotic disease at the time therapy is initiated. However, little attention has been focused on the complexity of the sex hormone system, which potentially may underlie some of these contradictory results regarding cardiovascular effects of sex steroids.

Sex steroid metabolism and “intracrinology”

An important finding within the field of sex steroid physiology is that a large proportion of sex steroids in both males and females are synthesized locally in peripheral target tissues from circulating, inactive precursors (Fig. 1). The term “intracrinology” has been coined to focus the attention on this important principle, where sex steroid action is exerted in the same cells in which the synthesis takes place. The precursors C19 androgens are derived from the adrenal cortex and circulate at high concentrations, together with the sex steroids from the gonads (mainly testosterone in men and estradiol in premenopausal women). The local metabolism of sex steroids gives rise to metabolites that bind to the androgen and estrogen receptors as well as a large number of other metabolites which may exert effects through yet unidentified pathways. Many of the sex steroid metabolites that are synthesized in this fashion, i.e. outside the classical endocrine organs, can be measured in the circulation.

The synthesis and metabolism of sex steroids take place in cell types relevant to atherogenesis, such as endothelial cells, vascular smooth muscle cells, and macrophages. However, little is known about the possible importance of local or circulating sex steroid metabolites in cardiovascular disease processes.

The estradiol metabolite 2-methoxyestradiol and atherosclerosis

Hydroxylation (catalyzed by CYP450 enzymes, Fig. 2) and subsequent methylation (catalyzed by catechol-O-methyltransferase (COMT)) to methoxyestradiols provide an important pathway for the metabolism of estradiol. Enzymes necessary for the metabolism of estradiol to methoxyestradiols, of which 2-methoxyestradiol is the most important, are expressed in vascular cells. Furthermore, 2-methoxyestradiol circulates at measurable levels in humans. During the last decade much interest has focused on 2-methoxyestradiol, which is a potent inhibitor of cell proliferation, tumor growth, and angiogenesis currently being evaluated in Phase II clinical trials as treatment of solid tumors. Although 2-methoxyestradiol’s mechanism of action requires further clarification, it appears to be independent of the classical estrogen receptors.



2-methoxyestradiol has been shown inhibit the oxidation of low density lipoprotein (LDL) and the proliferation of vascular smooth muscle cells. We recently showed that 2-methoxyestradiol reduces atherosclerotic lesion formation in female mice deficient in apolipoprotein E (ApoE-/- mice), a well-established mouse model of atherosclerosis (3). This is the first study showing that a sex steroid metabolite can modulate atherogenesis.

Although most experimental studies that showed anti-atherogenic effects of estrogens employed estradiol, two large clinical trials conducted on hormone replacement therapy in postmenopausal women used conjugated equine estrogens (CEE) as the estrogen component. These trials unexpectedly demonstrated adverse cardiovascular effects of treatment, raising skepticism about whether the “correct” estrogen compound was used. CEE contain >10 estrogens extracted from horse urine, and their exact composition remains undetermined. However, CEE contain very small amounts of estradiol, thus generating little or no estradiol metabolites. Our results on anti-atherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity suggest that future trials should use estradiol rather than other estrogens.

Concluding remarks

Despite a wealth of data indicating that sex steroids are important modulators of cardiovascular disease, many of the contradictory results on sex steroids and atherosclerotic disease are left unexplained. Increased knowledge about the role of sex steroid metabolites in the development of atherosclerosis may shed light over some of these contradictory results and may contribute to elucidate the background to the gender difference in cardiovascular disease.


Åsa Tivesten

SU/Sahlgrenska , 413 45 Göteborg


031-342 29 13

Sidansvarig: Karin Allander|Sidan uppdaterades: 2010-09-28

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