Previous studies from our laboratory have shown that estrogens can protect against lipoprotein peroxidation and DNA damage. In this study, the mechanism of estradiol-17β (E2) action was investigated by comparing E2 with selective scavengers of reactive oxygen species (ROS) in terms of inhibition of 1) human low-density lipoprotein (LDL) peroxidation (measured by the diene conjugation method) and 2) DNA damage (measured by the formation of strand breaks in supercoiled OX-174 RFI DNA). In addition, the direct effect of E2 on the generation of individual ROS was also measured. By use of ROS scavengers, it was determined that lipoprotein peroxidation was predominantly due to superoxide (39%), with some contributions from hydrogen peroxide (23%) and peroxy (38%) radicals. E2 was a more effective inhibitor of peroxidation than all the ROS scavengers combined. In DNA damage, scavengers of hydrogen peroxide, hydroxyl, and superoxide radical offered significant protection (49–65%). E2 alone offered a similar degree of protection, and no additional effect was evident when it was combined with ROS scavengers. E2caused a significant reduction (37%) in the production of superoxide radical by bovine heart endothelial cells in culture but had no effect on the formation of either hydrogen peroxide or hydroxyl radicals. These studies show that 1) the protection offered by E2 in terms of lipid peroxidation could be due to its ability to inhibit generation of superoxide radical and prevent further chain propagation, and 2) in DNA damage protection, E2 mainly appears to inhibit chain propagation.

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Perimenopausal women contributed to a higher placebo response, compared with the rate of response previously reported in clinical studies of estrogen replacement in postmenopausal women. Including perimenopausal women in future vasomotor symptom trials will require study populations of sufficient size to maintain the statistical power to demonstrate a difference between therapeutic response to active or placebo treatment.

Fifty early postmenopausal women completed a double-blind, placebo-controlled study evaluating the short-term effect of a new synthetic conjugated estrogens formulation (Cenestin) on bone turnover. Subjects were randomized to either 0.625 mg/day synthetic conjugated estrogens (n = 35) or placebo (n = 15) for 3 months. Biochemical markers were evaluated at baseline (three measurements at Days -2, -1, and 0) and Days 30, 60, and 90. Bone resorption assessed by urinary NTX (-31.4%) and serum CTX (-34.2%) was significantly (p < 0.01) decreased in the estrogen-treated group compared to the placebo group within 1 month of treatment. The mean percent decreases for urinary NTX from baseline during estrogen treatment were -58.0% (p < 0.01 vs. placebo) and -34.1% (ns) after 2 and 3 months, respectively. For serum CTX, the percent changes from baseline were -17.6% (p < 0.01) and -16.9% (p < 0.01) at 2 and 3 months, respectively. As expected, the decrease of both bone formation markers (bone ALP and PINP) was delayed compared to that of bone resorption and significant (p < 0.05-0.01) only after 2 months of treatment in the estrogen-treated group compared to the placebo group. Synthetic conjugated estrogens significantly decreased bone resorption and bone formation comparable to that previously reported for estrogen treatments proven efficacious in preventing postmenopausal bone loss.

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