Low estrogen levels in young
Low EGTA levels in young women, irrespective of etiology, might have harmful effects on cardiovascular physiology. Indeed, a study in premenopausal women with low estrogen levels owing to hypothalamic hypogonadism showed an increased incidence of angiographic CAD in these women compared with premenopausal women with normal ovarian function . Another condition characterized by low estrogen in young women is athletic amenorrhea. Athletic amenorrhea is a form of amenorrhea that occurs in female athletes, particularly in endurance and esthetic sports. It is caused by an inhibition of the hypothalamic–pituitary–ovarian axis, leading to low gonadotropin and low estrogen levels as a result of caloric restriction, and might also be associated with eating disorders and osteoporosis, also known as ‘the female athletic triad’ . Two recent studies showed that young women with athletic amenorrhea have endothelial dysfunction 45, 46, suggesting that, despite the known beneficial effects of regular physical exercise on the cardiovascular system, estrogen deprivation caused by intense physical exercise in highly fit female athletes can lead to an increased risk for cardiovascular disease.
Cyclical hormone replacement therapy improves endothelial function in young women with premature ovarian failure Several studies have shown that hormone therapy improves endothelial function in postmenopausal women 2, 37, 47. It has also recently been demonstrated that administration of standard cyclical hormone therapy in women with POF for six months restores endothelial function . FMD increased by more than twofold (P<0.005 compared with pretreatment) and reached normal values at the end of the six-month treatment. As expected, hormone therapy also induced a favorable change in the lipid profile; this might have contributed to the improvement in endothelial function. Cyclical hormone therapy was chosen to be administered in women with POF because these women can have spontaneous pregnancies  and thus hormone therapy should produce regular, predictable menstrual flow patterns. Similarly, another recent study demonstrated that oral contraceptives improve endothelial function in young athletes with low estrogen and amenorrhea . Further research is needed to investigate whether improvement of endothelial function with hormone therapy translates into a reduction in cardiovascular events in young women with low estrogen.
Hormone therapy studies in postmenopausal women might not be applicable in young women with premature ovarian failure Prospective cohort studies suggest that hormone therapy decreases the risk of CAD in relatively young and healthy postmenopausal women 49, 50. By contrast, large, prospective, randomized trials conducted in older postmenopausal women who had undergone menopause more than a decade earlier (the average age of the women studied in these trials was 60–65 years) failed to confirm the cardioprotective role of hormone therapy 14, 15, 16, 17. A woman's age, the number of years of ovarian failure and the hormone formulation used are potential factors influencing the effects of hormone therapy on CAD. Indeed, most observational and prospective cohort studies of hormone therapy showing that it protects against CAD involved the use of estrogen given alone or in cyclical regimens in relatively young postmenopausal women, whereas most randomized studies indicating that there is no effect on CAD involved the use of continuous combined hormone therapy in older postmenopausal women . Therefore, it seems that a beneficial effect on cardiovascular disease with hormone therapy can be seen with estrogen alone or with cyclical estrogen and progestogen treatment, but not with continuous combined therapy, and in younger women with a relatively short duration of menopause. Another important factor that appears to influence the effect of estrogens on atherosclerosis is the presence of atherosclerosis per se. Experimental studies 52, 53 have indicated that effective prevention of atherosclerosis can be achieved when hormone therapy is used before atherosclerotic plaque formation. This has been demonstrated in studies with oophorectomized monkeys, which showed that estrogen treatment reduced the progression of coronary atherosclerosis only in animals without established atherosclerotic plaques , whereas it had no effect when plaques existed before the commencement of treatment . Supporting evidence has been provided by a recent experimental study in a novel ovary-intact mouse model of drug-induced ovarian senescence mimicking the human perimenopausal transition; estrogen administration before the formation of atherosclerotic lesions inhibited atherogenesis in these mice, and this effect was more pronounced when estrogen was given during the drug-induced ‘perimenopausal transition’ . Although it is not safe to draw conclusions solely from experimental studies, it is possible that hormone therapy might be beneficial in younger women before atherosclerotic plaque formation  but it might not prevent progression of atherosclerotic plaques and coronary events in older women 56, 57. Prospective studies to assess the effect of hormone replacement therapy on cardiovascular disease in young women without pre-existing atherosclerosis are needed.