There is a significant difference in the cardiovascular disease (CVD) risk between men and women (1). Epidemiological studies have shown that the risk of atherosclerotic disease is low in premenopausal women and increases dramatically after menopause (1). The basis of differences in CVD risk has been attributed to declining levels of estrogens in women (2). In this issue, Schreckenberg et al.(3) provide new insights into the mechanism of action of estrogens on heart tissue, showing that PTHrP is a crucial downstream mediator. The significance of their findings in the context of hormone replacement therapy (HRT) use is discussed below. After the onset of menopause, levels of estrogens slowly ebb to equilibrate with those of age-matched men. Because of the disparity in CVD rates before and after menopause, estrogens in general were long touted as agents capable of preventing CVD (4). This claim was substantiated by numerous case-controlled and laboratory studies in the 1980s and 1990s (5); these studies demonstrated that estrogens could reduce CVD risk via a variety of mechanisms, including producing more favorable lipid profiles, causing vascular dilatation, and augmenting endothelial repair after damage (4). The composition of HRT, with conjugated estrogens, combined with progestin for those women with a uterus, is eloquently reviewed by Blaustein (2); because of its beneficial effects on the heart, the use of HRT moved from being a symptomatic treatment for peri-and postmenopausal vasomotor symptoms to a general therapy for the prevention of all menopausal-related pathology (6). The logic for using HRT as a preventative treatment was based on the aforementioned evidence for its protective effect on the cardiovascular system as well as copious studies dating back to the 1960s showing that estrogen deficiency has a causal role in postmenopausal osteoporosis (7). The mechanism whereby estradiol-17ßprevented osteoporosis was shown to involve augmenting osteoblast survival and decreasing pro-osteoclastic signals (8). The beneficial effects of HRT were challenged in 2002 with the publication of two studies not only showing a lack of benefit for HRT on CVD but also suggesting the HRT could worsen CVD and lead to strokes and deep venous thrombi (7). One study in particular, the Women’s Health Initiative (WHI)(7), was widely publicized, with the New York Times commenting on the “Women’s

Health Initiative findings of increased risks of heart disease, breast cancer, strokes and gallbladder disease”(9). These publications had a substantial negative impact on HRT use and left clinicians and patients confused as to the role of HRT (9). Several hypotheses were rapidly put forward to explicate the negative results of HRT on CVD risk and in turn justify its use in certain patient segments. One was the timing hypothesis, which asserted that the crucial timing of action for estrogens needed to happen before the deficiency-induced changes in the vasculature have irreversibly manifested themselves (10, 11). Secondary analyses of major studies have shown that there is indeed some truth to this hypothesis and that starting HRT during the late perimenopausal period or early postmenopausal period leads to mild decreases in CVD risk (12). However, the effect is not generalizable to the whole cardiovascular system, because there is still a significantly increased risk of stroke regardless of the timing of HRT initiation (12). Another hypothesis was that the action of estrogens alone is cardioprotective and that when combined with progestin, which is known to have detrimental effects on the vasculature, the progestin blocked estrogens …