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At least 19 recordsLinked to original sources
PubMed2003

A randomized, double-blind, placebo-controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone.

OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.

Double-Blind Method↗
PubMed1984

Enhancement of the mutagenicity of carcinogenic arylamines by ethinyl estradiol.

Ethinyl estradiol, the estrogenic component of oral contraceptives, has been shown to enhance the mutagenicity of 2-aminofluorene, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, and N-acetoxy-2-acetylaminofluorene with strain TA 98 of Salmonella typhimurium and various rat liver activating systems. The magnitude of the enhancement of mutation produced by ethinyl estradiol is dependent upon: the type of mixed-function oxidase inducer of the liver activating system; the structure and concentration of the arylamine; the concentration of ethinyl estradiol; and metabolism of ethinyl estradiol to its catechol, 2-hydroxyethinyl estradiol, by the activating system. Moxestrol, a biologically potent estrogenic derivative of ethinyl estradiol which is not metabolized effectively to its catechol by the mixed-function oxidases, does not enhance the mutagenicity of the above arylamines and related compounds. Both 2-hydroxyethinyl estradiol and 2-hydroxymoxestrol enhance the mutagenicity of 2-aminofluorene and 2-acetylaminofluorene. Neither the estrogens nor their catechols are mutagenic by themselves in this system. In the presence of ethinyl estradiol, a marked inhibition of ring hydroxylation of 2-acetylaminofluorene was demonstrated. Since ring hydroxylation is a well established detoxification pathway of arylamine and arylamide metabolism, the enhancement of mutagenicity by ethinyl estradiol may be the result of a net increase in N-hydroxylation of arylamines and arylamides.

2-Acetylaminofluorene↗
PubMed1978

Serum alkaline phosphatase elevation in female rats treated with ethinyl estradiol.

Ethinyl estradiol treatment to female rats resulted in increased levels of serum alkaline phosphatase, but was not associated with any other manifestation of toxicity such as increased serum transaminases or toxic lesions. Elevated serum alkaline phosphatase seen in rats treated with chloroform was associated with frank hepatotoxicity. Induction of hepatic drug metabolising enzymes in rats by phenobarbitone treatment did not result in raised serum alkaline phosphatase levels. Estradiol benzoate treatment to rats also did not increase serum alkaline phosphatase levels. Ethinyl estradiol also resulted in increased alkaline phosphatase content in the liver, intestine and bone. The raised intestinal alkaline phosphatase content of rats treated with phenobarbitone or estradiol benzoate was not associated with an increase in the serum levels. There was histochemical evidence of induction of canalicular alkaline phosphatase in the liver in Ethinyl Estradiol treatment. The study of the electrophoretic separation of serum alkaline phosphatase of ethinyl estradiol treated rats revealed the presence of a new fast moving fraction, similar to those seen in bile duct ligated rats. It is concluded that the serum alkaline phosphatase increase during ethinyl estradiol treatment at least in part is from the liver, due to new synthesis.

Alkaline Phosphatase↗
PubMed1986

Accelerated differentiation in seminiferous tubules of fetal mice prenatally exposed to ethinyl estradiol.

Ethinyl estradiol (EE) in olive oil (0.02, 0.2, or 2.0 mg/kg) administered to pregnant mice on days 11 to 17 of pregnancy induced abnormal differentiation of gonocytes and fetal Sertoli cells in male fetuses on day 18 of gestation. Light and electron microscopic examination of the testes showed fewer darkly stained prospermatogonia and more lightly stained prospermatogonia in the experimental than in the control fetuses. Widespread degeneration and lysis of gonocytes were seen only in the experimental mice. No spermatogonia type A could be detected. In spite of comparable mitotic rates in the Sertoli cells of the experimental and control mice and more dark Sertoli cells with well developed smooth endoplasmic reticulum (SER) in the experimental mice, one of the functions of fetal Sertoli cells was suppressed: there were fewer dark slender Sertoli cells with long processes extending to the centers of tubules and more contact areas with gonocytes, phenomena which may play a role in the migration of gonocytes towards the periphery of the tubules. More Sertoli cells were detected in the undescended than the descended testes exposed to the highest dose of EE. These morphological findings indicate that prenatal exposure to EE induces acceleration of prespermatogenesis and disturbances in the initiation of spermatogenesis and in the mechanical function of Sertoli cells.

Animals↗
PubMed1994

Growth stimulation followed by growth inhibition in livers of female rats treated with ethinyl estradiol.

Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis in female rats. A common effect shared by many non-genotoxic hepatic promoters is the stimulation of hyperplastic growth. However, studies by others with several hepatic promoters have shown that following an initial, transient increase in liver growth, continued exposure causes an inhibition in basal and/or induced growth. We have shown that EE also causes an initial, transient increase in hepatocyte proliferation (Carcinogenesis, 7, 2007-20014, 1986). The objective of the investigation reported here was to determine whether chronic EE treatment also becomes inhibitory to basal and/or induced liver growth. Female Lewis rats were treated with EE at 2.5 and 5.0 micrograms/rat/day using time-release tablets. Seven days prior to sacrifice, the rats were implanted with osmotic minipumps containing bromodeoxyuridine (BrdU) to allow the cumulative labeling of replicating hepatocytes. At sacrifice, liver tissue was fixed, sectioned and the percent labeled hepatocyte nuclei determined by immunohistochemistry. The results of these experiments revealed that, as expected, during the first 7 days of treatment, EE increased hepatocyte proliferation. However, after 28 and 42 days of EE treatment, the basal level of liver growth was dramatically inhibited. Thus, hepatocyte nuclear labeling indices, compared to controls, were reduced by 72 and 88% after 28 and 42 days of treatment respectively. An analysis of 125I-labeled EGF binding to isolated liver membranes revealed that EGF receptor levels decreased during the initial period of growth, but had returned to control levels by day 21 when replication had ceased. In another experiment, rats were treated with EE at 5.0 micrograms/rat/day for 21 days; control rats received placebo time-release tablets. At the end of that time, the rats were surgically partially hepatectomized and the level of subsequent regenerative DNA synthesis was determined using [3H]thymidine administered 2 h prior to sacrifice 24, 48, 72 and 96 h later. The results showed that EE caused an inhibition of regenerative growth. While at each time point the level of DNA synthesis in EE-treated rats was not significantly less than in corresponding controls, statistical analysis indicated that overall, EE caused a significant reduction in liver growth. The results of these studies demonstrate that chronic EE treatment leads to the appearance of a mitosuppressed state in the liver which is characterized by reduced cell turnover and decreased growth responsiveness.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Comparison of the antiatherosclerotic effect of tibolone with that of estradiol and ethinyl estradiol in cholesterol-fed, ovariectomized rabbits.

OBJECTIVE: Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The drug relieves climacteric symptoms and prevents osteoporosis but does not stimulate the endometrium. We have previously shown that in laboratory animals tibolone inhibits the atherogenesis induced by a high-cholesterol diet. Therefore, we compared the antiatherosclerotic effect of oral tibolone at different dose levels with that of oral 17beta-estradiol (E2) and ethinyl estradiol (EE). DESIGN: Atherosclerotic lesion formation (increase in vessel wall cholesterol deposition and fatty streak formation) was measured in ovariectomized rabbits after 20 weeks on an atherogenic diet (fed daily 80 g of a rabbit chow containing 0.4% cholesterol, 3.75% peanut oil, and 3.75% coconut oil) in eight groups: group 1, placebo (n = 35); group 2, control (n = 34) received normal rabbit chow; group 3, E2 group (E2 4 mg, n = 12); group 4, EE group (EE 60 microg, n = 10); and groups 5-8, tibolone (6 mg, n = 12; 2 mg, n = 13; 0.6 mg, n = 25; and 0.15 mg, n = 11, respectively). During the study, blood samples were obtained for the evaluation of plasma triglycerides, cholesterol, lipoproteins, and glutamate pyruvate transaminase. After 20 weeks, the animals were killed, and cholesterol concentration and the formation of fatty streaks in the wall of the aortic arch were evaluated. RESULTS: In the placebo group, the atherogenic diet induced a mean increase in total plasma cholesterol concentration from 1.1+/-0.1 mmol/L (control group) to 34.1+/-1.8 mmol/L (mean +/- SE). This resulted in an accumulation of cholesterol in the aortic arch from 48+/-4 (control group) to 608+/-44 nmol/mg protein and in the formation of fatty streaks (41.8+/-3.2% of the surface of the aortic arch was covered with fatty streaks). Tibolone had strong dose-dependent antiatherosclerotic effects. It reduced the accumulation of cholesterol in the aortic arch at doses of 6 to 0.15 mg by 99, 97, 87, and 57% and the formation of fatty streaks by 98, 97, 81, and 38%, respectively. E2 had only a marginal antiatherosclerotic effect, whereas EE showed an effect comparable to that of tibolone at doses of 2 to 0.6 mg. With EE, the accumulation of cholesterol in the vessel wall was reduced by 93% and the formation of fatty streaks by 73%. Mean plasma cholesterol concentrations were also reduced by tibolone (64, 70, 61, and 47%) and EE (57%). This reduction was mainly mediated via a reduction in beta-very-low-density lipoprotein cholesterol. Analysis, however, indicated that the observed antiatherosclerotic effects of tibolone and EE, at least partly, are due to a direct effect on the vessel wall and independent of the changes in plasma cholesterol. At equipotent antiatherosclerotic doses, EE showed a stronger uterotropic effect (measured as the increase in uterine weight) than tibolone. EE increased uterine weight from 0.57 g/kg body weight (BW) (control group) to 3.5 g/kg BW; tibolone at doses of 6, 2, 0.6, and 0.15 mg increased uterine weight to 2.5, 2.8, 2.2, and 1.3 g/kg BW, respectively. CONCLUSION: Tibolone can protect the arterial vessel wall against atherosclerotic lesions induced by a hypercholesterolemic diet. However, it has much less estrogenic effects on the uterus compared with EE at equipotent doses, indicating tissue selectivity for tibolone. The clinical implications of these findings require investigation.

Animals↗
PubMed1986

Estrogen induction of liver proteins and high-density lipoprotein cholesterol: comparison between estradiol valerate and ethinyl estradiol.

The effects of ethinyl estradiol and estradiol valerate were compared in 135 postmenopausal women during estrogen replacement therapy. Subfractions of high-density lipoprotein (HDL) cholesterol and its apolipoproteins and the serum levels of 2 estrogen-sensitive liver proteins were followed during 3 cycles of unopposed treatment with either ethinyl estradiol 10 or 30 micrograms or estradiol valerate 2 mg daily. Estrogen therapy induced significant and dose-dependent changes in all serum factors except HDL3 cholesterol. The effects of 10 micrograms of ethinyl estradiol upon the lipoproteins were 1.5-2.5 times greater than those of 2 mg of estradiol valerate. Sex-hormone-binding globulin and the pregnancy zone protein were the most sensitive markers for the estrogenic effect and these 2 liver-derived plasma proteins were also much more sensitive to ethinyl estradiol than to estradiol valerate. Although satisfactory therapeutic effects were achieved with both estrogens, the marked influence of ethinyl estradiol on liver protein synthesis should make estradiol valerate the first choice in clinical replacement therapy.

Adult↗
PubMed1999

A multicenter randomized comparison of cycle control and laboratory findings with oral contraceptive agents containing 100 microg levonorgestrel with 20 microg ethinyl estradiol or triphasic norethindrone with ethinyl estradiol.

OBJECTIVE: This study was undertaken to compare the effects of 2 oral contraceptive regimens on menstrual cycle control and laboratory findings. METHODS: In a multicenter randomized study 100 microg levonorgestrel with 20 microg ethinyl estradiol (Alesse or Loette) was given to 155 healthy women. A triphasic preparation of 500, 750, and 1000 microg norethindrone with 35 microg ethinyl estradiol (Ortho-Novum 7/7/7 or TriNovum) was given to 167 women for 1 to 4 cycles of treatment. RESULTS: Overall, the percentages of normal menstrual cycles and the percentages of cycles with intermenstrual and withdrawal bleeding were similar between the 2 treatment groups. In the levonorgestrel with ethinyl estradiol group, there was a statistically significantly longer latent period and a statistically significantly shorter withdrawal bleeding episode. Adverse events were similar between treatment groups, and none were serious. Most mean changes from baseline laboratory values were comparable between groups, although the mean increase in cholesterol concentration was statistically significantly lower in the levonorgestrel with ethinyl estradiol group. Changes in triglyceride and glucose concentrations were not statistically significantly different between groups. CONCLUSIONS: Levonorgestrel (100 microg) with ethinyl estradiol (20 microg) provides menstrual cycle control equivalent to that obtained with triphasic norethindrone with ethinyl estradiol (75% higher estrogen dose) with similar safety and tolerability.

Adult↗
PubMed1990

Protein binding of active ingredients and comparison of serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ethinyl estradiol (Femovan) or a combination of desogestrel/ethinyl estradiol (Marvelon) and single-dose ethinyl estradiol bioequivalence from both oral contraceptives.

Results from two clinical pharmacokinetic studies are given. The first study was an observational study in oral contraceptive users who took either a combination of gestodene and ethinyl estradiol (pill A, Femovan) or desogestrel and ethinyl estradiol (pill B, Marvelon). A total of 69 women (39 receiving pill A and 30 receiving pill B) were evaluated to determine serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels. Samples were obtained on 1 day during the tenth to twenty-first days of pill intake. All women received the respective oral contraceptive for at least 3 months. The test power was such that an 80% difference of 1 standard deviation of each target variable would have been detected (alpha = 0.05; beta = 0.1). No statistically significant differences were found in sex hormone-binding globulin, corticosteroid-binding globulin, or cortisol serum levels between both groups. Time and height of maximum ethinyl estradiol levels were identical as was the area under the curves. Ex vivo protein-binding analysis of the progestins revealed a free portion of 0.6% for gestodene and 2.5% for 3-ketodesogestrel as the active metabolite of desogestrel. Sex hormone-binding globulin-bound portions were much higher for gestodene (75.3% +/- 9.1%) than for 3-ketodesogestrel (31.6% +/- 12%). The remaining fractions were bound to albumin. In a second study, ethinyl estradiol-bioequivalence from pills A and B was investigated in 18 women in a controlled, single-dose, randomized, crossover design. The area under the ethinyl estradiol serum levels were identical up to 4 hours after pill intake between both treatments. According to the relatively low variation in data in this group of women, a 10% difference in ethinyl estradiol-availability could have been detected. Both studies indicate that the pharmacokinetics of ethinyl estradiol were independent of the concomitantly administered progestin, that is, desogestel and gestodene.

Adult↗
PubMed1990

Dissolution testing of norethindrone:ethinyl estradiol, norethindrone:mestranol, and norethindrone acetate:ethinyl estradiol combination tablets.

Dissolution of oral contraceptive combination products from six manufacturing firms was studied utilizing the rotating basket method at 100 rpm in 600 mL of 0.1 M HCl and 0.02% sodium lauryl sulfate (SLS). Most of the combination products of norethindrone (NE):ethinyl estradiol (EE) dissolved satisfactorily in water using the paddle method which was first proposed by U.S.P., whereas three of 18 tested products showed better dissolution in acidic aqueous medium containing SLS. Acidic medium with surfactant was also found to be suitable for combination products of norethindrone (NE):mestranol (ME) and norethindrone acetate (NEAc):ethinyl estradiol (EE). A modified U.S.P. assay procedure, a reversed-phase high-performance liquid chromatographic (HPLC) method with a mobile phase of acetonitrile and phosphate buffer, was used to analyze NE and EE concurrently. The NEAc and ME were analyzed separately in these combination products. The NEAc was found to hydrolyze to some extent (approximately 20% in 8 h) in acidic dissolution medium at room temperature, but less so at 4 degrees C. The NE was identified as the sole degradation product of NEAc hydrolysis and was also measured to account for the total amount of NEAc dissolved. A simple dissoluting testing method which utilizes a single dissolution medium was applicable for all oral contraceptive combination tablets surveyed.

1-Propanol↗
PubMed2002

The effect of extending the pill-free interval on follicular activity: triphasic norgestimate/35 micro g ethinyl estradiol versus monophasic levonorgestrel/20 micro g ethinyl estradiol.

This study was designed to evaluate follicular activity in women taking oral contraceptives with imposed imperfect compliance. After completing a 28-day cycle of either triphasic norgestimate/EE (NGM/EE) (Ortho Tri-Cyclen, Ortho-McNeil Pharmaceutical, Raritan, NJ) or monophasic levonorgestrel/EE (LNG/EE) (Alesse, Wyeth-Ayerst Laboratories, Philadelphia, PA), women were instructed to intentionally "miss" the first two active pills of the next pack. The first two tablets in the second treatment cycle were deliberately omitted, thereby extending the pill-free interval from 7 days to 9 days. Subjects were randomized to take NGM/EE (n = 40) or LNG/EE (n = 39) for two consecutive cycles. The mean maximum follicular diameter was significantly greater in women taking LNG/EE than in those taking NGM/EE (16.4 +/- 7.1 mm vs. 12.6 +/- 8.3 mm, p = 0.047). The LNG/EE group had significantly higher median serum estradiol concentrations compared to women taking NGM/EE on pill Days 10 [29.5 pg/mL (range: 10.0-540.0 pg/mL) vs. 2.5 pg/mL (range: 2.0-6.0 pg/mL), p < 0.001] and 14 [11.0 pg/mL (range: 2.0-416.0 pg/mL) vs. 2.0 pg/mL (range: 2.0-3.0 pg/mL), p = 0.001]. Two women in the NGM/EE group and three women in the LNG/EE group had at least one progesterone level > or =3 ng/mL; none of these women demonstrated a maximum follicular diameter >13 mm. Significantly greater follicular activity was observed after an extended pill-free interval in women taking LNG/EE compared to those taking triphasic NGM/EE. The clinical implications of these findings require further study.

Adolescent↗
PubMed1999

Clinical comparison of triphasic norgestimate/35 micrograms ethinyl estradiol and monophasic norethindrone acetate/20 micrograms ethinyl estradiol. Cycle control, lipid effects, and user satisfaction.

This six-cycle, multicenter, open-label, randomized study compared the clinical experience of two low-dose oral contraceptives (OC): a triphasic OC containing norgestimate (NGM) and 35 micrograms ethinyl estradiol (EE) (Ortho Tri-Cyclen) and a monophasic OC containing norethindrone acetate (NETA) and 20 micrograms EE (Loestrin Fe 1/20). Cycle control, lipid and androgen profiles, and user satisfaction were studied in new-start OC users (i.e., no prior use within 60 days). Breakthrough bleeding or breakthrough spotting (BTB/BTS) occurred in a significantly smaller percentage of NGM/EE users than NETA/EE users during each of six cycles (p < or = 0.002). The incidence of BTB/BTS ranged from 3.7% to 13.5% for NGM/EE users and from 23.5% to 49.7% for NETA/EE users. Significantly fewer NGM/EE users than NETA/EE users experienced absence of menses at cycles 2 through 6 (p < or = 0.003). The percentages of women having no menses at each cycle ranged from 0.9% to 4.7% for NGM/EE users and from 10.3% to 21.3% for NETA/EE users. NGM/EE users reported a significantly (p < 0.001) higher level of satisfaction with their OC at the end of six cycles than did NETA/EE users, but there was no significant difference in compliance, discontinuation rates, or adverse events between the two groups. NGM/EE produced a significantly (p < or = 0.001) greater beneficial effect on HDL-C, HDL2, and apo A-I than did NETA/EE. No statistically significant treatment differences were found for total cholesterol, LDL-C, triglycerides, or apo-B. Both OC increased sex hormone binding globulin and decreased free testosterone, but NGM/EE had a significantly greater effect (p < 0.009).

Androgens↗
PubMed2001

A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene on hemostatic variables, lipids, and carbohydrate metabolism.

In this double-blind study we compared the influence of two oral contraceptives, a 23-day regimen with 20 microg ethinyl estradiol and 75 microg gestodene (23-day 20/75) and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene (21-day 30/75), on hemostatic variables, lipids, and carbohydrate metabolism. The volunteers received the preparations daily for six 28-day cycles. Hemostatic variables and lipids were measured at baseline and after six treatment cycles. Carbohydrate metabolism was assessed by determination of the area under the curve (AUC) of carbohydrate parameters after oral glucose tolerance tests performed at baseline and after three treatment cycles. Data from 33 volunteers in each group were obtained. No significant differences between the effects of both treatments on the hemostatic system were detected. Neither the overall change of all hemostatic variables from baseline to treatment Cycle 6 [defined as primary target variable in the study] nor the change of any of the individual hemostatic parameters differed significantly between the treatment groups. Likewise, no significant nor clinically relevant differences in the effects of both treatments on the volunteers' lipid profiles were detected. The data on carbohydrate variables suggested a slightly more favorable influence of the 23-day 20/75 regimen. The increase of the glucose AUCs after three cycles tended to be stronger with the 21-day 30/75 regimen than with the 23-day 20/75 regimen. In addition, the AUCs for insulin and C-peptide were slightly reduced after three cycles with the 23-day 20/75 regimen but slightly increased with the 21-day 30/75 regimen. Both study treatments were safe and well tolerated by the volunteers as shown by the nature and frequency of adverse events, the routine laboratory examinations, and the physical and gynecological examinations. Both preparations provided adequate contraceptive reliability. The only pregnancy during treatment was attributable to intake errors. In conclusion, the prolongation of the treatment phase of an oral contraceptives with 20 microg ethinyl estradiol does not evoke more pronounced metabolic effects than a conventional 21-day regimen with 30 microg ethinyl estradiol.

Adolescent↗
PubMed1999

Increased mitochondrial superoxide production in rat liver mitochondria, rat hepatocytes, and HepG2 cells following ethinyl estradiol treatment.

Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis. Treatment of rats with EE and other hepatic promoters induces a mitosuppressed state characterized by decreased hepatocyte turnover and reduced growth responsiveness. Previously, we identified several nuclear and mitochondrial genome-encoded mitochondrial genes whose transcripts were increased during EE-induced hepatic mitosuppression in rats and in EE-treated HepG2 cells (Chen et al. Carcinogenesis, 17, 2783-2786, 1996 and Carcinogenesis, 19, 101-107, 1998). In both cultured rat hepatocytes and HepG2 cells, EE increased respiratory chain activity (reflected by increased mitochondrial superoxide production detected as increased lucigenin-derived chemiluminescence (LDCL). In this paper, we provide additional characterizations of these effects. Increased LDCL was detected in mitochondria isolated from EE-treated rats, documenting that these estrogen effects on mitochondrial function are not confined to cells in culture. EE and estradiol (E2) increased LDCL in cultured rat hepatocytes and HepG2 cells in a dose- (beginning at 0.25 microM levels) and time-dependent response. Inhibition of P450-mediated estrogen metabolism inhibited, while direct exposure to E2 catechol metabolites enhanced LDCL. Co-treatment with glutathione ester or with the specific antiestrogen, ICI 182708 inhibited LDCL. In contrast, estrogen-induced LDCL was enhanced by glutathione depletion, and by inhibition of catechol-o-methyltransferase. These results support a working hypothesis that in liver cells, increased respiratory chain activity induced by estrogen treatment requires both metabolism to catechols and an estrogen receptor-mediated signal transduction pathway.

Animals↗