Why Do the Clinical Sequelae of Estrogen Deficiency Affect Women More than Men?a

Evan Simpson

Prince Henry’s Institute of Medical Research, and The Victorian Breast Cancer Research Consortium Monash Medical Centre Clayton, Victoria 3168, Australia Susan Davis Jean Hailes Foundation Research Unit Clayton, Victoria 3168, Australia

There has been recent focus in the Editorials of this Journal on the long-term sequelae of the decline in estrogens at menopause, particularly in relationship to the pattern of cardiovascular disease in women vs. men and the effects of exogenous estrogen therapy (1, 2). Certainly there is compelling observational epidemiological and in vivo and in vitro mechanistic data to support the cardioprotective effects of postmenopausal estrogen replacement (3), even with concomitant progestin therapy (4). However a distinct relationship between menopause and the increased incidence of cardiovascular disease in women beyond the sixth decade has not been demonstrated (5), whereas cardiovascular disease in women is clearly related to other factors such as age (5), obesity (6, 7) and smoking (7). Furthermore, the differing incidences and patterns of the considered consequences of estrogen deficiency (coronary heart disease, osteoporosis, and dementia) between men and women cannot be explained by gender differences in circulating estrogen levels alone. Men have low plasma estradiol levels throughout their adult years, yet have a much lower incidence of osteoporosis and dementia compared with women. We know that men need estrogen to prevent bone loss (8, 9). Therefore the obvious conclusion is that local tissue levels of estrogen rather than circulating levels are what count in terms of bone preservation, and perhaps this extends to vascular function and the central nervous system.

Aromatase, which converts androgens to estrogens, is expressed in adipose tissue (10), vascular endothelium and smooth muscle (11, 12), bone (13, 14, 15), and the brain (16, 17, 18). Unlike the ovaries, these extragonadal tissues lack the capacity to synthesize C19 steroids, hence the ability of these tissues to generate adequate local estrogen resides in the availability of circulating C19 precursors. Testosterone (T) in women declines with increasing age such that women in their 40’s have only half the level of total and free T compared with women in their 20’s (19). In contrast, the decline in T with advancing years in men is small, and the levels of T in the circulation of men are at least an order of magnitude greater than in postmenopausal women (10–30 vs. 0.5–1.5 nmol/L). Because these circulating levels of T in the male are similar to the Km of aromatase (20–30 nmol/L), it is likely that circulating T can be converted efficiently in extragonadal sites to give rise to local concentrations of estradiol sufficient to transactivate both estrogen receptors ({alpha} and ß) (KD ~ 1 nmol/L). Androgens have been shown to have beneficial effects on vascular function, namely that intracoronary T administration induces coronary artery vasodilation and increases coronary artery blood flow in male and female dogs in vivo (20) and enhances endothelial-dependent vasorelaxation in men (21). Furthermore, these effects may be secondary to local aromatization of T to estradiol within the vascular tissue. This warrants further investigation.

We propose that a major physiological role for androgens in both men and women is as a general circulating precursor pool for local tissue estrogen production, such that the necessary high levels of estrogen required by target tissues (bone, brain, vascular endothelium) can be achieved without total body exposure to excess estrogen. We also suggest that the age-related decline in androgens in women (and hence estrogen precursor decline) contributes significantly to the pathogenesis of what have been traditionally viewed as diseases of estrogen deficiency, and that the relatively high levels of circulating androgen levels in men partly protect them from osteoporosis and dementia by providing adequate concentrations of estrogen precursor at extragonadal sites of aromatase expression.

Currently, there is considerable interest in the use of T as a component of hormone replacement therapy (HRT) for postmenopausal women, but its use is mostly limited to those women who complain of loss of sexual interest and libido. However, the present discussion suggests a broader role for the use of T in HRT, namely as a circulating precursor for local synthesis of estrogen in target tissues, where the latter acts in an autocrine and paracrine fashion.

Footnotes

Address correspondence to: Evan R. Simpson, Prince Henry’s Institute of Medical Research, Monash Medical Center, P.O. Box 5152, 246 Clayton Road, Level 4, Block E, Clayton, Australia 3168.

Received December 8, 1997.

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