Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women.

OBJECTIVE: Oxidized low-density lipoprotein (LDL) seems to play an important role in the etiology of atherosclerosis. To further study this, we performed two studies: (1) we determined the ability of 10 estrogen components of the drug, conjugated equine estrogen (CEE), trans-resveratrol (t-resveratrol) and quercetin (red wine components), trolox (vitamin E analog), and probucol (a serum cholesterol-lowering drug) to delay or prevent the oxidation of plasma LDL isolated from untreated postmenopausal women, and (2) we assessed the effect of long-term (>1 year) estrogen replacement therapy and hormone replacement therapy on LDL oxidation by ex vivo methods. DESIGN: For the in vivo study, three groups of postmenopausal women were selected based on whether they were on long-term CEE therapy (group A: 0.625 mg CEE; n = 21), on combination CEE plus progestogen therapy (group B: 0.625 mg CEE + 5.0 mg medroxyprogesterone acetate, 10 days; n = 20), or not on any hormone therapy (group C; n = 37). For the in vitro study, only LDL samples obtained from group C were used. The kinetics of LDL oxidation were measured by continuously monitoring the formation of conjugated dienes followed by determination of the lag time. RESULTS: All compounds tested protected the LDL from oxidative damage. The relative antioxidant potency of estrogen components was generally greater than that of the other compounds. The minimum dose (nmoles) required to double the lag time from the control lag time of 57 ±â€Š2 min was 0.47 for 17ß-dihydroequilenin, 17α-dihydroequilenin, Δ-estrone; 0.6 to 0.7 for Δ-17ß-estradiol, equilenin, and quercetin; 0.9 for 17ß-dihydroequilin and 17α-dihydroequilin; 1.3 for equilin, estrone, 17ß-estradiol, 17α-estradiol; 1.4 for trolox; 1.9 for probucol; and 3.0 for t-resveratrol. The data from the in vivo study indicate that after long-term estrogen replacement therapy (group A) and hormone replacement therapy (group B), the LDL was significantly (p < 0.01) protected (higher lag time) against oxidation compared with the control (group C). There was no difference between groups A and B. CONCLUSIONS: The oxidation of LDL isolated from postmenopausal women is inhibited differentially by various estrogens and other antioxidants. The unique ring B unsaturated estrogen components of CEE were the most potent, and t-resveratrol, the red wine component, was the least potent. Long-term CEE or CEE + medroxyprogesterone acetate administration to postmenopausal women protects the LDL against oxidation to the same extent. These combined data support the hypothesis that some of the cardioprotective benefits associated with CEE therapy and perhaps red wine consumption may be due to the ability of their components to protect LDL against oxidative modifications.

What is the best regimen for low-risk gestational trophoblastic neoplasia? A review.

A review of published and unpublished material was performed using medical databases, bibliographies and personal contact with peer experts to determine the best treatment of low-risk gestational trophoblastic neoplasia (GTN). Thirty-nine studies contained the minimum information required for inclusion in this study. Additional reports were retrieved but could not be disaggregated with sufficient accuracy to obtain valid comparative information. Four general regimen types were identified: methotrexate with/without folinic acid rescue, actinomycin, etoposide and 5-fluorouracil. The studies were compared based on effectiveness, cost and patient preference. Effectiveness and toxicity data were abstracted from the 39 studies. Intuitive assumptions about cost and preference were made to help differentiate the regimens. The following regimens were judged to be superior based on the data available: oral methotrexate, 100 mg/m2; infusional methotrexate; and pulse actinomycin. The small sample size of these 3 regimens limited the generalizability of the conclusions, but pulse actinomycin appeared to be the best choice given the data available. There is a paucity of level 1 and 2 evidence on the best chemotherapeutic management of low-risk GTN. A biochemical or consensus-based clinical definition of persistent disease and a standardized scoring system should be developed and used by future authors. The dearth of prospective, randomized information on this disease makes determination of the best practice and the choice of a best regimen problematic.

Successful salvage of relapsed high-risk gestational trophoblastic neoplasia patients using a novel paclitaxel-containing doublet.

OBJECTIVE: To describe one institution's results with a novel 3-drug doublet, consisting of paclitaxel, etoposide and cisplatin, for salvage of relapsed high-risk gestational trophoblastic neoplasia (GTN) patients. STUDY DESIGN: Analysis of treatment results with the doublet regimen in two patients with recurrent/persistent high-risk choriocarcinoma in the Division of Gynecologic Oncology, Toronto-Sunnybrook Regional Cancer Centre, University of Toronto. Both patients had been treated previously with one or more of the doublet drugs. RESULTS: Both patients experienced complete responses, patient 1 for 13 months and patient 2 for 9. Patient 1 required surgical resection of a single focus of recurrence and was again in complete remission 27 months after completing her last course of doublet chemotherapy. Patient 2 has not relapsed since completing the treatment. CONCLUSION: The doublet regimen appears capable of producing a sustained response in patients with recurrent high-risk GTN who have previously undergone extensive chemotherapy. Further, the regimen seems to be reasonably well tolerated.

Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the prevention of coronary heart and neurodegenerative diseases in postmenopausal women.

BACKGROUND: An inverse relationship between the level of high-density lipoprotein (HDL) and coronary heart disease (CHD) has been reported. In contrast, oxidized HDL (oHDL) has been shown to induce neuronal death and may play an important role in the pathogenesis of CHD. In the present study we have investigated a: the effect of various equine estrogens on HDL oxidation, b: the inhibition of LDL oxidation by HDL and c: the effect of these estrogens on LDL oxidation in the presence of HDL. RESULTS: All 11 equine estrogens tested protected the HDL from oxidation in a concentration dependant manner. Equilenin, 17beta-dihydroequilenin, and 17alpha-dihydroequilenin (Delta6-8-estrogens) were found to be the most potent inhibitors of HDL oxidation. Some of the novel ring B unsaturated estrogens were 2.5 to 4 times more potent inhibitors of HDL oxidation than 17beta-estradiol. HDL was found to delay LDL oxidation. The protection of LDL oxidation by HDL is enhanced by the addition of estrogen, with equilenin being again more potent than 17beta-estradiol. CONCLUSIONS: Equine estrogens can differentially inhibit the oxidation of HDL with the Delta6-8-estrogens being the most potent antioxidants. The ability of estrogens to enhance HDL's antioxidant activity is to our knowledge the first report of an interaction of estrogen with HDL that results in the delay or inhibition of LDL oxidation. This may be another mechanism by which estrogens may reduce the risk of CHD and neurodegenerative diseases in healthy and younger postmenopausal women.

Pharmacokinetics of 17 beta-dihydroequilin sulfate in normal postmenopausal women under steady state conditions.

OBJECTIVE: In the present study, the constant infusion of [3H]17 beta-dihydroequilin sulfate ([3H]17 beta-EqS) was used to estimate the metabolic clearance rate (MCR) of 17 beta-dihydroequilin sulfate (17 beta-EqS) and to measure the conversion of this estrogen to equilin sulfate (EqS), equilenin sulfate (EqnS), 17 beta-dihydroequilenin sulfate (17 beta-EqnS), equilin (Eq), equilenin (Eqn), 17 beta-dihydroequilin (17 beta-Eq), and 17 beta-dihydroequilenin (17 beta-Eqn) in normal postmenopausal women. METHODS: In seven healthy postmenopausal women, infusion of [3H]17 beta-EqS was started 30 minutes after a priming dose and continued at a constant rate of 10-20 microCi/hour, for 3-6 hours. Three blood samples were taken during and at the end of infusion. From the plasma, unconjugated and sulfate-conjugated estrogens, 17 beta-EqS, EqS, EqnS, 17 beta-EqnS, Eq, Eqn, 17 beta-Eq, and 17 beta-Eqn were isolated and purified by high performance liquid chromatography. The MCR of 17 beta-EqS and the conversion ratios and transfer constants (rho) for precursor (17 beta-EqS) to products were calculated. RESULTS: The mean MCR of 17 beta-EqS was calculated to be 797 +/- 90 L/day or 506 +/- 60 L/m2 per day. The mean conversion ratio (CRPRE-PROBB) was 2.4 +/- 0.4 for EqS, 0.3 +/- 0.04 for EqnS, 0.25 +/- 0.03 for 17 beta-EqnS, 0.09 +/- 0.02 for Eq, 0.03 +/- 0.01 for Eqn, 0.08 +/- 0.02 for 17 beta-Eq, and 0.03 +/- 0.01 for 17 beta-Eqn. In both the sulfate-conjugated and unconjugated forms, the most abundant metabolite formed was Eq. Based on the previously reported MCR of EqS (170 L/m2 per day) and 17 beta-Eq (1252 L/m2 per day), the transfer constants [rho]BB were calculated to be 0.8 +/- 0.10 and 0.20 +/- 0.03, respectively. The results indicate that a large portion of 17 beta-EqS is converted to EqS and the more potent estrogen 17 beta-Eq. The ratio of rho EqS-17 beta-EqS to rho 17 beta-EqS-EqS was calculated to be 0.8 +/- 0.1 and represents the extent of C-17-oxidation and reduction and indicates that substantial amounts of 17 beta-reduced metabolites will still be present in the blood although the oxidation reaction was somewhat greater. CONCLUSION: The data indicate that, compared with the classic estrogens, the in vivo metabolism of ring B unsaturated estrogens is complex. Thus, although the amount of 17 beta-EqS originally present in the conjugated equine estrogens is small, the pharmacokinetics and pharmacodynamics of EqS, 17 beta-EqS, and the extensive interconversions between these estrogens support the hypothesis that the major in vivo activity of the EqS present in conjugated equine estrogens is expressed through its metabolism to 17 beta-EqS and 17 beta-Eq. Furthermore, the increased estrogenic activity associated with this drug may in part be due to the formation of these 17 beta-reduced metabolites.