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PubMed2005

Associations between aerobic fitness and estrogen metabolites in premenopausal women.

UNLABELLED: Chronic physical activity may alter estrogen metabolism, a proposed biomarker of breast cancer risk, by causing a shift toward higher 2-OHE1 and lower 16alpha-OHE1 levels. PURPOSE: To investigate the association between an objective indicator of chronic exercise, aerobic fitness, and 2-OHE1 and 16alpha-OHE1 in premenopausal women. METHODS: Women with high aerobic fitness (N=17; VO2max>or=48 mL.kg.min-1) were compared with women with average aerobic fitness (N=13; VO2max<or=40 mL.kg.min-1) in terms of 2-OHE1 and 16alpha-OHE1 profiles. Participants were healthy, regularly menstruating, Caucasian women, aged 20-42 yr, with a normal body mass index (BMI) of 18-24, not using pharmacologic contraceptives. We measured height, weight, sum of four skinfolds, and maximal aerobic fitness (VO2max), using an incremental cycle ergometer test. Urine samples were collected during the follicular and luteal phase of the menstrual cycle. RESULTS: There were no statistically significant differences between average and highly fit women for 2-OHE1, 16alpha-OHE1, or the 2:16alpha-OHE1 ratio in either the follicular or luteal phase. However, the high-fitness group showed a trend toward a higher luteal 2:16alpha-OHE1 (P=0.20). In ancillary analyses, a higher sum of skinfolds was associated with significantly higher luteal 16-OHE1 levels (r=0.39, P=0.03) and lower luteal phase 2:16 OHE ratio (r=-0.41, P=0.02). Higher BMI was associated with lower follicular phase 2-OHE1 (r=-0.37, P=0.04) and lower follicular 2:16 OHE1 ratio (r=-40, P=0.03). CONCLUSION: This exploratory study is the first to investigate the association between aerobic fitness and estrogen metabolites in premenopausal women using metabolic parameters. We observed no statistically significant association between aerobic fitness and 2-OHE1 and 16alpha-OHE1, but found that body composition was associated with 2-OHE1 and 16alpha-OHE1 levels.

Adult↗
PubMed1998

Induction of 16alpha-/2-hydroxyestrone metabolite ratios in MCF-7 cells by pesticides, carcinogens, and antiestrogens does not predict mammary carcinogens.

The effects of several pesticides, mammary carcinogens, and antiestrogens on 17beta-estradiol (E2), 16alpha- and 2-hydroxylase activities, and 16alpha-/2-hydroxyestrone (OHE1) ratios were investigated in MCF-7 cells using a radiometric assay. The mammary carcinogens 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (BaP), respectively, increased and decreased 16alpha-/2-OHE1 ratios at some concentrations. The 16alpha-/2-OHE1 metabolite ratios for 10(-5) M kepone, atrazine, p,p'-DDE, o,p'-DDE, o,p'-DDT, and beta-hexachlorocyclohexane were 1.82 +/- 0.060, 0.71 +/- 0.027, 0.66 +/- 0.030, 1.56 +/- 0.089, 1.14 +/- 0.059, and 0.69 +/- 0.052 (mean +/- standard error), respectively, and did not show any specific trend. The effects of a series of direct and indirect acting antiestrogens on 16alpha-/2-OHE1 metabolite ratios were also investigated, and the results were compound specific. Indole-3-carbinol, tamoxifen, 4'-hydroxytamoxifen, and 9-cis,retinoic acid decreased the ratio; the effects of all trans-retinoic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin were concentration dependent; the antiestrogen ICI 182,780 increased the 16alpha-/2-OHE1 metabolite ratio. The results indicate that in MCF-7 cells treated with pesticides, mammary carcinogens, and antiestrogens, there were both increased and decreased 16alpha-/2-OHE1 metabolite ratios for each class of chemicals and the assay did not predict mammary carcinogens.

Animals↗
PubMed1987

[Hypocholesterolemic effect of catechol estrogen 2-monomethyl ether].

The hypocholesterolemic effect of 2-methoxyestrone (2-MeOE1), 2-methoxyestriol (2-MeOE3) and estradiol-17 beta (E2-17 beta) was investigated in two experimental systems of normocholesterolemic and dietary hypercholesterolemic rats that had undergone oophorectomy. Each compound was subcutaneously administered for 6 consecutive days at a dose of 10 micrograms per day in the former systems and at 300 micrograms per day in the latter system, respectively. The hypocholesterolemic effect was in the following relation: 2-MeOE3 = E2 - 17 beta greater than 2-MeOE1. In the latter system, the serum total cholesterol level of individual rats in both 2-MeOE3- and E2-17 beta-administered groups returned to normal. No uterotrophic activity was exhibited by either 2-MeOE1 or 2-MeOE3, while E2-17 beta exhibited an anomalous activity. The effect of 2-MeOE1 and 2-MeOE3 on body weight was not exhibited, while E2-17 beta reduced it slightly. The results suggest that catechol estrogen 2-monomethyl ether plays an important role in lipid metabolism through estrogen receptor independent mechanisms and has a pharmacologically important effect on hyperlipidemia and atherosclerosis.

Animals↗
PubMed1994

Catechol estrogens are more potent antioxidants than estrogens for the Cu(2+)-catalyzed oxidation of low or high density lipoprotein: antioxidative effects of steroids on lipoproteins.

In order to clarify the mechanism of antiatherogenic action of several steroids such as estrogens, dehydroepiandrosterone (DHEA) and dexamethasone, we investigated the effects of various steroids on the copper (Cu2+)-catalyzed oxidation of low density lipoprotein (LDL) or high density lipoprotein (HDL) in 0.15 M NaCl by measuring thiobarbituric acid-reactive substances (TBARS). At a concentration of 10(-5) M, estrogens strongly protected against LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: estradiol (E2) (75%), estrone (E1) (35%) and estriol (E3) (30%). However, the corresponding metabolites of these estrogens, the catechol estrogens, had an even more protective effect on LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: 2-hydroxyestradiol (2-OHE2) (98%), 2-OHE1 (97%) and 2-OHE3 (96%). E2 and 2-OHE2 from 10(-7) M to 10(-5) M inhibited LDL oxidation in a dose-dependent manner, with a more marked effect for oxidation by 0.1 microM Cu2+ than by 0.5 microM Cu2+. 10(-5) M dexamethasone produced a slight (10%) but significant inhibition of LDL oxidation by 0.5 microM Cu2+. In addition, the estrogens and catechol estrogens were also effective in protecting against HDL oxidation by 0.5 microM Cu2+. Other steroids including DHEA and DHEA-sulfate had no antioxidative effects on either LDL or HDL in this system. These results indicate that estrogens and their metabolites, the catechol estrogens, exert antioxidative effects on both LDL and HDL. The catechol estrogens may be more important antioxidants than estrogens for both LDL and HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants↗
PubMed1982

Synthesis of immunogenic C-6 derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta and characterization of the corresponding antisera.

The synthesis, purification and structural confirmation of the 6-(carboxymethoxyimino) derivatives of 2-methoxyestrone and 2-methoxyestradiol-17 beta are described. These derivatives were coupled to bovine serum albumin by the mixed anhydride method, and rabbits were immunized with the product. The resulting antisera showed high affinity and specificity for 2-methoxyestrone and 2-methoxyestradiol-17 beta, respectively, with low cross reactivities to structurally related estrogens.

2-Methoxyestradiol↗
PubMed2005

A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio.

Cytochrome P450 (CYP) is a multigene family of enzymes involved in important life functions; some of these genes are inducible and are implicated in the oxidative metabolic activation and detoxification of many endogenous and exogenous compounds. CYP1B1 codes for an enzyme that catalyses the production of a 2- and 4-hydroxyl group in estrone and estradiol, while CYP1A1 catalyzes the 2-hydroxylation of estradiol in endometrium. The two genes were evaluated in a cohort of 150 subjects: African-American women had significantly lower 2-hydroxyl estrone/16-hydroxyl estrone (2-OHE1/16-OHE1) urinary metabolite ratios than Caucasian women (2.06+/-1.05 vs. 1.43+/-0.56; p=0.0002). A common polymorphism in the CYP1B1 gene (leucine to valineat codon 432) was associated with changes in urinary estrogen levels: both Caucasian and African-American women carrying the variant allele showed higher urinary metabolite ratios than women with the wild-type allele. No effect of the CYP1A1 MspI was observed. The 4-OHE1/2-OHE1 ratio was lower in subjects carrying the variant allele (Leu). The percentage change in 2-OHE1/16-OHE1 urinary ratio after indole treatment was significant in both Caucasian and African-American women carrying the wild-type CYP1B1 genotype, although it was more evident in African-Americans than in Caucasians. These results suggest that the Leu/Val CYP1B1 polymorphism may modify estradiol metabolism.

Adult↗
PubMed1981

Radioimmunoassay for 4-hydroxyoestrone in human urine.

Under the protection of ascorbic acid a 4-hydroxyoestrone-bovine serum albumin conjugate was prepared containing intact 4-hydroxyoestrone as determined by gas chromatography-mass spectrometry. Using this antigen, antibodies with high affinity and specificity for 4-hydroxyoestrone were raised in rabbits. An assay procedure for the determination of 4-hydroxyoestrone in human urine and the assessment of its reliability are described. The following urinary excretion rates were found: male children 0.29 microgram/24 h, men (less than 50 microgram/24 h, men (20-40 years) 1.6 microgram/24 h, men (less than 50 years) 1.8 microgram/24 h, women, follic, 2.0 microgram/24 h, pre-ov. 5.3 microgram/24 h, luteal 2.4 microgram/24 h, women, pregnant, first trim. 30.0 microgram/24 h, second trim. 64.0 microgram/24 h, third trim. 48.0 microgram/24 h, women, post-men. 1.5 microgram/24 h. Thus the amounts of 4-hydroxyoestrone excreted in human urine are about 1/3 to 1/10 of those of 2-hydroxyoestrone. During the menstrual cycle the excretion rates of 4-hydroxyoestrone are in the same order of magnitude as those of oestradiol and show a clear-cut pre-ovulatory peak.

Adult↗
PubMed1982

Concentrations of 2-hydroxyoestrogens in human sera measured by a heterologous immunoassay with an 125I-labelled ligand.

A heterologous immunoassay for 2-hydroxyoestrogens has been established in which antibodies raised against 2-hydroxyoestradiol-17-succinyl-BSA serve as binding protein and 2-hydroxyoestrone-17-cmo-[125I]iodohistamine as radioligand. Lipophilic serum components competing for binding sites in this system were defined as total 2-hydroxyoestrogens'. The underlying assumption of specificity was supported by the pattern of cross-reactivity evaluated with structural related steroids and o-diphenols and by the fact, that an additional chromatography of the serum extracts preceding the competing reaction had little if any effect. Sensitivity: 2.8 +/- 1 pg/tube; accuracy: Y = 0.91x + 2.2; r = 0.989; precision: 5.8% intra-assay; 6.5% inter-assay. The following concentrations (+/- standard deviation) were found in the sera of healthy subjects. Young men: 29 +/- 5 pg/ml (n = 11); women follicular phase: 32 +/- 8 pg/ml (n = 25); luteal phase: 53 +/- 13 pg/ml (n = 23); postmenopausal women: 13 +/- 4 pg/ml (n = 10); pregnant women 11th--20th week: 70 +/- 16 mg/ml (n = 64); 36th--40th week: 240 +/- 23 pg/ml (n = 40); newborn cord blood: 604 +/- 43 pg/ml (n = 48).

Adult↗
PubMed1983

Concentrations of 2-methoxyoestrogens in human serum measured by a heterologous immunoassay with an 125I-labelled ligand.

A radioimmunoassay has been developed for the measurement of 2-methoxyoestrogens in samples of human serum without chromatography after solvent extraction. Antibodies raised against 2-methoxyoestradiol-17 beta-hemi-succinyl-BSA served as binding protein and 2-methoxyoestrone-17-cmo-[125I]iodohistamine served as 125I-labelled ligand. A specific (little or no cross-reactivities to other oestrogens), sensitive (2.4 +/- 0.9 pg/tube) and precise (6.5% intra-assay; 9.1% inter-assay) assay was obtained by employing the heterologous bridge system. The following concentrations were found in serum samples of healthy subjects (median, range in parentheses): men (19-58 years): less than 10.3 (less than 10.3-35.5) pg/ml (n = 22); women follicular phase: 46 (18-63) pg/ml (n = 8); luteal phase: 70 (31-138) pg/ml (n = 8); post-menopausal women: 33 (21-76) pg/ml (n = 10); pregnant women 11th-16th week: 674 (216-1678) pg/ml (n = 46); 37th-40th week: 3768 (2035-10691) pg/ml (n = 34); newborn cord serum 1608 (575-3095) pg/ml (n = 41).

Adult↗
PubMed1983

Levels of circulating and urinary oestrogens during pregnancy in the marmoset monkey (Callithrix jacchus).

The levels of immunoreactive oestrone, oestradiol-17 beta and oestriol in plasma and urine were measured during early, mid- and late pregnancy in the marmoset monkey. In plasma, unconjugated oestrone remained less than 2% of total (conjugated plus unconjugated) oestrone throughout gestation, whereas unconjugated oestradiol-17 beta increased from 3% of the total value in early and mid-pregnancy to 35% in late pregnancy. The reversal in the unconjugated oestrone: oestradiol-17 beta concentration ratio from early (12:1) to late (0 . 15:1) pregnancy occurred despite the continuing predominance of oestrone in terms of total hormone. Total oestriol was measurable but in relatively low concentrations. Oestradiol conjugate was the predominant urinary oestrogen metabolite measured at each stage of pregnancy. The pattern of urinary oestrone and oestradiol-17 beta reflected plasma levels of total hormone, rather than unconjugated hormone, showing no further increase after mid-pregnancy. In contrast, oestriol increased throughout pregnancy and to a proportionately greater extent than oestrone or oestradiol-17 beta, but at lower absolute levels. High-pressure liquid chromatography of urine extract indicated the presence of considerable amounts of oestrogen immunoreactivity not accounted for by oestrone, oestradiol-17 beta and oestriol and with a retention time similar to that of 16 alpha-hydroxyoestrone. Gas chromatography and mass spectroscopy provided further evidence to suggest that 16 alpha-hydroxyoestrone is an abundant urinary oestrogen metabolite during pregnancy in the marmoset monkey.

Animals↗
PubMed1981

Stimulation of release of luteinizing hormone from cultured pituitary cells by 2- and 4-hydroxylated oestrogens.

We have examined the effect of the catechol oestrogens 2-hydroxyoestradiol (2-OHE2), 4-hydroxyoestradiol (4-OHE2) and 2-hydroxyoestrone (2-OHE1) and their corresponding primary oestrogens on secretion of LH and FSH by enzymatically dispersed rat anterior pituitary cells in monolayer culture. Basal LH levels in the medium were significantly higher than in control wells when cells were exposed to 10(-8) M-oestradiol-17 beta for 40 h: oestrone and all three catechol oestrogens (in the same doses) also stimulated basal LH concentrations to levels quantitatively similar to those seem after oestradiol treatment. The same effects were observed when steroids were given at 10(-9) mol/l. Oestradiol, 2-OHE2, and 4-OHE2 but not 2-OHE1 increased pituitary responsiveness to LH releasing hormone (LH-RH) (given in a range of doses from 10(-11) to 10(-6) mol/l). The responses of cells treated with 2-OHE2 and 4-OHE2 were similar, though less than the response seen after treatment with oestradiol. This contrasts with the very different oestrogenic effects of 2- and 4-OHE2 previously observed in vivo. Neither oestradiol nor the catechol oestrogens had any effect on basal or LH-RH-stimulated FSH release.

Animals↗
PubMed1982

Comparative pharmacology of oestrogens and catechol oestrogens: actions on the immature rat uterus in vivo and in vitro.

The effects of primary and catechol oestrogens on the uterus of the immature rat were compared. Because differences between the in-vivo and in-vitro oestrogenic actions of catechol oestrogens on the secretion of LH had been observed, their effects on a peripheral target organ, the uterus, were examined under similar conditions. In-vivo effects were assessed by measurement of uterine weight, induction of uterine cytoplasmic progestogen receptors, and by histological examination. In-vitro actions were determined by measurement of oestrogen-specific induced protein. It was found that the uterotrophic effects in vivo of 4-hydroxyoestradiol were indistinguishable from those of oestradiol whereas 2-hydroxyoestradiol was only weakly oestrogenic and 2-hydroxyoestrone had no effect. However, in vitro, 2-hydroxyoestradiol was as effective as 4-hydroxyoestradiol or oestradiol in stimulating synthesis of uterine induced protein, and 2-hydroxyoestrone, although less potent than oestradiol, had a significant effect. These results were consistent with the observed effects on the secretion of LH. The differences between in-vivo and in-vitro uterotrophic properties of catechol oestrogens can be explained on the basis of known pharmacokinetic factors.

Animals↗