br Effects of estrogen on vascular function Atherosclerosis
Effects of estrogen on vascular function Atherosclerosis is a chronic inflammatory condition of the vascular wall (Figure 1) that can be converted to an acute clinical event by the induction of plaque rupture or erosion, leading to thrombosis . This perpetuating process is characterized by phases of initiation (endothelial dysfunction, fatty streaks), progression (atherosclerotic lesions with or without calcification and narrowing of the lumen) and, finally, complicated lesions (vulnerable atherosclerotic plaques leading to thrombosis) 4, 58. A growing body of evidence suggests that the spectrum of the effects of hormone therapy on vascular pathophysiology is complex; the effects of estrogen on the evolution of the atherosclerotic process appear to depend largely on the state of vascular pathology  (detailed explanation is provided in Table 2, Table 3 and Figure 2, Figure 3). In relatively healthy vessels (i.e. with no or early signs of atherosclerosis), estrogen appears to prevent the development and progression of atherosclerotic lesions  (Table 2, Figure 2). Estrogen has been shown extensively to be protective in the 7ACC1 by exerting total cholesterol- and LDL-cholesterol lowering , antioxidant , and vasodilating effects . Estrogen also has a direct atheroprotective effect via the transcriptional regulation of endothelial NO synthase and the induction of NO release . This improves endothelial function, increases vasodilation and inhibits the response of blood vessels to injury. Furthermore, estrogen downregulates several proinflammatory molecules that mediate the early stages of atherosclerosis 64, 65, 66. Of note, the necessary addition of progestogens to prevent endometrial cancer in women with an intact uterus does not appear to negate the beneficial cardiovascular effects of estrogens . By contrast, in the presence of established atherosclerotic lesions, estrogen fails to inhibit the progression of atherosclerosis, and might even trigger cardiovascular events 64, 68, 69 (Table 3, Figure 3). The mechanisms responsible for this are not yet fully understood. Increased methylation of the estrogen receptor gene, resulting in reduced expression of estrogen receptors with advancing age and with atherosclerosis might partly explain the diminished response to hormone therapy in older postmenopausal women . Furthermore, it has recently been suggested that estrogen exerts a proinflammatory and prothrombotic effect in vessels with ‘vulnerable lesions’ 71, 72. Increased metalloproteinase levels, which have a role in destabilizing plaques 64, 73, and increased blood coagulability  could be other important contributors.
What is the optimal treatment for young women with premature ovarian failure? Decisions on whether and how young women with POF must be treated should not be based on studies of hormone therapy in women older than 50 years . Women with POF have severe menopausal symptoms (hot flashes, mood changes) and increased risk for osteoporosis  and cardiovascular disease . Furthermore, the majority of women who develop POF are in their mid-30s , representing a population with mostly normal arteries around the time of their diagnosis 55, 75. Experimental data support the hypothesis that, when atherosclerosis is not established, estrogen therapy might effectively prevent the development of atherosclerotic plaques 52, 53, 54. However, data from experimental studies cannot be extrapolated to humans, and prospective studies to assess the effect of hormone replacement therapy in young POF women without pre-existing atherosclerosis are lacking. Indeed, the effect of treatment on cardiovascular and overall prognosis, as well as the optimal duration of treatment in young women with POF, should be a direction for future research (Box 1). Estrogens administered in usual replacement doses do not suppress spontaneous follicular activity or ovulation  and do not prevent spontaneous conception. However, most pregnancies have occurred during or following hormone replacement . For this reason, only cyclical regimens of hormone therapy that produce regular, predictable menstrual flow patterns, mimicking the menses of age-matched women with normal ovarian function, should be used, instead of continuous combined hormone therapy that results in the absence of menses. Consequently, if these young patients miss an expected menses, they should be tested for pregnancy and instructed to discontinue the hormone therapy.