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PubMed1981

Temporal and other effects of catechol estrogens on prolactin secretion in the rat.

Temporal alterations in plasma prolactin levels caused by the administration of 2-hydroxyestradiol and 2-hydroxyestrone (100 microgram/kg) into the right atrium of freely-moving conscious male rats were examined. The catechol estrogens were given in a single bolus via an indwelling cannula and plasma prolactin concentration was monitored by taking blood samples every 2 min. A pulsatile elevation of plasma prolactin occurred approximately 4 h after the injection of 2-hydroxyestradiol and a small increase was also observed when it was administered to rats bearing a Silastic capsule containing estradiol. 2-Hydroxyestrone had no effect in untreated male rats but produced a 5- to 6-fold elevation in plasma prolactin level 4 h after its administration to rats implanted with estradiol. It is proposed that 2-hydroxyestrone suppresses the action of estradiol on prolactin secretion from the pituitary and that the accumulated hormone is released when the concentration of this catechol estrogen falls below a critical level. A longer latent period was required to produce an elevation in plasma prolactin levels by 2-hydroxyestradiol than by estradiol.

Animals↗
PubMed2001

Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity.

Estrogen metabolism in women with SLE is weighted towards 16alpha-hydroxyestrone, an estrogenic compound that might fuel disease activity. Indole-3-carbinol (I3C) is a nutritional compound that can shift estrogen metabolism towards less estrogenic metabolites. However, the effects of I3C in women with SLE have not been studied. Open-label 1-week metabolic study of 375 mg/day I3C was carried out in women with SLE, followed by a 3-month observational period for disease activity. The primary outcome measure was the change in ratio of urinary 2:16alpha hydroxyestrone levels. Secondary measures included the SLE Disease Activity Index. Seventeen clinically premenopausal women fulfilling ACR criteria for probable/definite SLE (mean age 37.9 y, range 20-49 y, mean disease duration 4.3 y, range 0.5-15) completed the 1-week metabolic study; 12 took I3C for 3 months. The mean 2:16alpha hydroxyestrone ratio increased by 1.84 to 3.15 (P = 0.0001). Mean SLEDAI scores were 10.0 (baseline); 6.25 (3 months); and 8.8 (3 months after withdrawal; P = NS). Women with SLE can manifest a metabolic response to I3C and might benefit from its antiestrogenic effects. We did not observe any striking effects on SLE disease activity during the 3-month observational period.

Adult↗
PubMed1989

Radioimmunoassay of 2-hydroxyesterone using antisera raised against antigenic complexes obtained by convenient methods.

Antigenic complexes of 2-hydroxyestrone (2-OHE1) were obtained by Mannich reaction of 2-OHE1 and bovine serum albumin (BSA) and by coupling of 2-OHE1 1-glutathione thioether to BSA using glutaraldehyde. Antiserum raised against the antigen obtained by the Mannich reaction had high affinity (Kd = 3.8 x 10(9) M-1) and relatively high specificity; cross reactivities for estrone, 4-hydroxyestrone and 2-methoxyestrone were 2.1%, 10% and 1.5%, respectively. The other antiserum also had high affinity (4.5 x 10(9) M-1) but its cross reactivities for the above three steroids were more than 100%. Concentrations of 2-hydroxyestrone in human plasma were determined by radioimmunoassay with the more specific antiserum and Sephadex LH-20 chromatography to be less than a minimum detectable amount (less than 10 pg/ml) (men), 20.9 pg/ml (women, proliferation) and 26.0 pg/ml (women, periovulation).

Adult↗
PubMed1992

[Biological effect of estrogen metabolites in human breast cancer].

In order to investigate the estrogen metabolism in human breast cancer, the estradiol 2- and 16 alpha-hydroxylase (2-, 16 alpha-OHase) activities were determined in the microsomal fractions of human breast tissues by using reverse-phase HPLC. The effects of estrogen metabolites on the cell proliferation were also examined by employing two human breast cancer cell lines. The 2-OHase activity was detected in most cancerous and noncancerous tissues, but the value in cancerous tissues was significantly lower than that in noncancerous tissues (p less than 0.05). Patients without lymph node metastases showed relatively higher activity than those with metastases (0.05 less than p less than 0.1). The 16 alpha-OHase activity was, however, found in only 23% of cancerous tissues. Among those, the activity was present in 52% of ER positive cancerous tissues, but almost absent in ER negative ones. The growth ER positive cell line, MCF-7, was suppressed with 2-hydroxyestrone and stimulated with 16 alpha-hydroxyestrone. The cell proliferation stimulated with 16 alpha-hydroxyestrone was not inhibited by the addition of tamoxifen, a strong antagonist of estradiol. Two metabolites had no effect on the growth of ER negative cell line, MDA-MB-231. These results suggest that estrogen metabolites influence the proliferation of human breast cancer cells as the endogenous regulatory factors and should be considered for the future endocrine therapy.

Adolescent↗
PubMedDate not supplied

The characteristic binding of catechol estrogens to estrogen receptors in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors.

The binding of catechol estrogens (2-hydroxyestrone, 4-hydroxyestrone, 2-hydroxyestradiol, and 4-hydroxyestradiol) to estrogen receptors in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumor cytosols was investigated. Cytosol estrogen receptors exhibited high affinities (Ka = 1.12-1.88 X 10(8) M-1) for all catechol estrogens as well as estradiol. The receptor level of catechol estrogens (46.1-97.5 fmol/mg protein) was 1.6-3.0 times higher than that of estradiol; especially the binding of 4-hydroxyestrone to estrogen receptors was the highest of all catechol estrogens and estradiol. In judging the receptor level of more than 20 fmol/mg protein to be positive, the binding of catechol estrogens to estrogen receptors was approximately correlated with that of estradiol. The positive receptor level of catechol estrogens was found in a half of tumor cytosols which showed the negative receptor level of estradiol. These results suggested that characteristic estrogen receptors indicating high affinities for catechol estrogens might be present in rat mammary tumor cytosols.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Stopped-flow investigation of antioxidant activity of estrogens in solution.

A kinetic study of the reaction between estrogens (female hormone) and substituted phenoxyl radical has been performed, as a model for the reactions of estrogens with lipid peroxyl radical in biological systems. The rates of reaction of estrogens (estrone 1, estradiol 2, 2-methoxyestrone 3, 3-methoxyestrone 4, and 2-hydroxyestrone 5) with substituted phenoxyl radical in benzene have been determined spectrophotometrically, using stopped-flow technique. The second-order rate constants, k2, obtained are 84 M-1.s-1 for 1, 138 M-1.s-1 for 2, 520 M-1.s-1 for 3, less than 10(-4) M-1.s-1 for 4, and 2.6 X 10(5) M-1.s-1 for 5 at 25.0 degrees C. 2-Hydroxyestrone 5 was found to be 2.9-times more active than alpha-tocopherol, which has the highest antioxidant activity among natural tocopherols. The order of magnitude of k2 value (1 less than 2 less than 3 less than alpha-Toc less than 5) is in agreement with that of in vitro tests of their antioxidant activities, as measured by the inhibition of lipid peroxidation. Further, similar measurements have been performed for the reaction between the above estrogens 1-5 and tocopheroxyl 6 in benzene solution. It was found that the estrogens having an OH group at the aromatic ring have an ability to regenerate the tocopheroxyl 6 to tocopherol. Especially, the 2-hydroxyestrone 5 showed about three orders of magnitude higher reactivity than ascorbic acid.

Antioxidants↗
PubMed2000

The effects of A-ring and D-ring metabolites of estradiol on the proliferation of vascular endothelial cells.

The effects of 14 estradiol metabolites on the proliferation of cultured endothelial cells of human umbilical cord veins were examined and compared with that of their parent substance estradiol. The relationship between dosage and effect was tested over the pharmacological concentration range of 10(-8) to 10(-5) M. Estradiol showed a biphasic behaviour, in the form of stimulation at low concentrations and inhibition at the highest concentration. All 10 A-ring metabolites tested stimulated the growth of the endothelial cells at the lower concentrations. At the highest concentration, the 5 A-ring metabolites: 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol caused significant inhibitions. Except for the 2-hydroxyestradiol, methylation of these metabolites resulted in the loss of the proliferation inhibiting effect. The D-ring metabolites showed no marked effects compared to the A-ring metabolites except for 16alpha-hydroxyestrone which had an inhibiting effect from 10(-7) to 10(-5) M. Our results show that estradiol metabolites can influence the growth of vascular endothelial cells in the concentration range tested. While the antiproliferative action of 2-methoxyestradiol has been known for some time this study is the first to show the potential capacity of non-methylated metabolites of the A-ring metabolism in inhibiting endothelial proliferation. This may open up new clinical pharmacological aspects in the anti-angiogenetic treatment of tumors.

Cell Division↗
PubMedDate not supplied

Molecular characteristics of catechol estrogen quinones in reactions with deoxyribonucleosides.

Estrogens can have two roles in the induction of cancer: stimulating proliferation of cells by receptor-mediated processes, and generating electrophilic species that can covalently bind to DNA. The latter role is thought to proceed through catechol estrogen metabolites, which can be oxidized to o-quinones that bind to DNA. Four estrogen-deoxyribonucleoside adducts were synthesized by reaction of estrone 3,4-quinone (E1-3,4-Q), 17 beta-estradiol 3,4-quinone (E2-3,4-Q), or estrone 2,3-quinone (E1-2,3-Q) with deoxyguanosine (dG) or deoxyadenosine (dA) in CH3CO2H/H2O (1:1). Reaction of E1-3,4-Q or E2-3,4-Q with dG produced specifically 7-[4-hydroxyestron-1(alpha, beta)-yl]guanine (4-OHE1-1(alpha, beta)-N7Gua) or 7-[4-hydroxyestradiol-1(alpha, beta)-yl]-guanine (4-OHE2-1(alpha, beta)-N7Gua), respectively, in 40% yield, with loss of deoxyribose. These two quinones did not react with dA, deoxycytidine, or thymidine. When E1-2,3-Q was reacted with dG or dA, N2-(2-hydroxyestron-6-yl)deoxyguanosine (2-OHE1-6-N2dG, 10% yield) and N6-(2-hydroxyestron-6-yl)deoxyadenosine (2-OHE1-6-N6dA, 80% yield), respectively, were formed. These adducts provide insight into the type of DNA damage that can be caused by o-quinones of the catechol estrogens. The estrogen 3,4-quinones are expected to produce depurinating guanine adducts that are lost from DNA, generating apurinic sites, whereas the 2,3-quinones would form stable adducts that remain in DNA, unless repaired. The adducts reported here will be used as references in studies to elucidate the structure of estrogen adducts in biological systems.

Chromatography, High Pressure Liquid↗
PubMed1997

Bioreductive activation of catechol estrogen-ortho-quinones: aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity.

There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure, as may be facilitated by early menses, late menopause and long-term estrogen replacement therapy. Equilenin (1,3,5(10),6,8-estrapentaen-3-ol-17-one) or its 17-hydroxylated analogs make up 15% of the most widely prescribed estrogen replacement formulation, Premarin, and yet there is very little information on the human metabolism of these estrogens. In this study, we synthesized the catechol metabolite of equilenin, 4-hydroxyequilenin, and examined how aromatization of the B ring affects the formation and reactivity of the o-quinone (3,5-cyclohexadien-1,2-dione). 4-Hydroxyequilenin-o-quinone is much more redox-active and longer-lived than the endogenous catechol estrone-o-quinones, which suggests that the mechanism(s) of toxicity of the former could be quite different. Interestingly, the rate of reduction of the 4-hydroxyequilenin-o-quinone is increased at least 13-fold in the presence of NAD(P)H:quinone oxidoreductase (DT-diaphorase). Once NADH is consumed however, the catechol auto-oxidized rapidly to the o-quinone. NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both with the purified enzyme and with cytosol from human melanoma cells with high levels of DT-diaphorase activity. P450 reductase and rat liver microsomes also catalyzed NADPH consumption and oxygen uptake. 4-Hydroxyestrone-o-quinone was also rapidly reduced by NAD(P)H; however, this o-quinone does not auto-oxidize and once the o-quinone is reduced the reaction terminates. Including oxidative enzymes in the incubation completes the redox couple and 4-hydroxyestrone-o-quinone behaves like 4-hydroxyequilenin-o-quinone. These data suggest that reduction of estrogen-o-quinones may not result in detoxification. Instead this could represent a cytotoxic mechanism involving consumption of reducing equivalents (NADH/NADPH) as well as formation of superoxide and other reactive oxygen species leading to oxidative stress. Finally, we have compared the cytotoxicity of 4-hydroxyequilenin with that of the estrone catechols in human melanoma cells. 4-Hydroxyequilenin is 5-fold more toxic in these cells compared with 4-hydroxyestrone (ED50 = 7.8 versus 38 microM, respectively) suggesting that formation of the longer-lived redox-active 4-hydroxyequilenin-o-quinone was responsible for the cytotoxic differences. These results substantiate the conclusion that the involvement of quinoids in catechol estrogen toxicity depends on a combination of the rate of formation of the o-quinone, the lifetime of the o-quinone, and the electrophilic/redox reactivity of the quinoids.

Animals↗
PubMed1977

In vitro and in vivo studies on the metabolism of estrogens and their sulfates in guinea pigs.

Labelled estradiol-17 beta(E2) or estrone (E1), when incubated with guinea pig liver slices, is metabolized by two main pathways. Part of each substrate is converted to estrone-3-glucuronide and estradiol-3-glucuronide. A further part of each is metabolized to estradiol-3-sulfate (E23S) and estrone-3-sulfate (E13S), which are interconverted. The latter conjugate appears to be the substrate for a 16 alpha-hydroxylase forming 16 alpha-hydroxyestrone-3-sulfate (16 alpha OHE13S). This, in turn, is further sulfurylated to yield 16 alpha-hydroxyestrone-3, 16-disulfate, accompanied by estriol-3,16-disulfate. A relatively small amount of tentatively indentified '6-hydroxyestrone disulfate accompanies these other two diconjugates. The guinea pig liver system suggests itself as a useful and relatively simple model for further study of 16 alpha-hydroxylation of E13S. The use of the latter as a natural subd E23S are present in liver, kidney, blood, gallbladder bile, intestine, uterus, and placenta after injection of labelled E2 into mature male and female guinea pigs. Some evidence has been obtained for the disulfate fraction (above) in liver and bile after injection of labelled E1.

Animals↗
PubMed2004

Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Aged↗
PubMed1968

Estradiol metabolism in cirrhosis.

Abnormal estrogen metabolism has been found in cirrhosis after administration of intravenous tracers of estradiol-(3)H to 6 patients and 23 healthy controls. The major abnormalities observed involved estrogen metabolites other than the 3 "classic" ones, i.e., estrone (E1), estradiol (E2), and estriol (E3). Urinary recovery of radioactivity was regularly elevated in the patients, to an average of 71% of the dose compared to 51% in normals. This is considered to reflect the component of intrahepatic cholestasis in cirrhosis. The per cent dose recovered as urinary glucosiduronates (42%) was normal in cirrhotics in contrast to impaired glucuronidation of cortisol metabolites in this disease. E1 and E2 were present in normal amounts, and E3 was slightly elevated to 21% of the extract compared to 14% in controls. There were strikingly decreased excretion of 2-hydroxyestrone (3% compared with normal 20%) and 2-methoxyestrone (2% compared with 5%) and increased excretion of 16alpha-hydroxyestrone (12% compared with normal 6%). Thus cirrhosis, too, is characterized by the reciprocal relationship between decreased 2-hydroxylation and increased 16alpha-hydroxylation previously described in hypothyroidism and male breast cancer. However, unlike these latter, the increase of 16alpha-hydroxy metabolites was less than the decrease of 2-hydroxy metabolites. The data indicate clearcut impairment of 2-hydroxylation, suggestive impairment of 16alpha-hydroxylation, and a definite depression of the reaction 16alpha-hydroxyestrone-->estriol, the latter finding so far unique to cirrhosis. Demonstration of abnormal peripheral metabolism of estrogen in cirrhosis provides a new approach to the origin of the hyperestrogenic syndrome in this disease.

Journal Article↗
PubMed2003

Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms.

We systematically characterized the oxidative metabolites of 17beta-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17beta-estradiol 2-hydroxylation, followed by 15alpha-, 6alpha-, 4-, and 7alpha-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4-hydroxyestrone than 15alpha- or 6alpha-hydroxyestrone, with 2-hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17beta-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9-13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar metabolite, and small amounts of 16alpha- and 16beta-hydroxyestrogens were also formed. The ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone with CYP3A4 was 0.22 or 0.51, respectively. CYP3A5 had similar catalytic activity for the formation of 2- and 4- hydroxyestrogens. Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively). CYP3A4 and 3A5 also catalyzed the formation of nonpolar estrogen metabolite peaks (chromatographically less polar than estrone). CYP3A7 had a distinct catalytic activity for the 16alpha-hydroxylation of estrone, but not 17beta-estradiol. CYP4A11 had little catalytic activity for the metabolism of 17beta-estradiol and estrone. In conclusion, many human CYP isoforms are involved in the oxidative metabolism of 17beta-estradiol and estrone, with a varying degree of catalytic activity and distinct regioselectivity.

Aryl Hydrocarbon Hydroxylases↗
PubMed2004

The unusual binding properties of the third distinct teleost estrogen receptor subtype ERbetaa are accompanied by highly conserved amino acid changes in the ligand binding domain.

Three forms of estrogen receptor: ERalpha, ERbeta (ERbetab), and a second ERbeta, ERbetaa (formerly ERgamma) are present in teleost fish. All ERbetaas share amino acid changes in the ligand binding domain that may influence ligand specificity and receptor function. We compared binding specificities of the three ERs of the teleost fish, Atlantic croaker Micropogonias undulatus. Bacterially expressed Atlantic croaker (ac) ERalpha, -betab, and -betaa fusion proteins showed specific, high affinity binding to 17beta-[(3)H]estradiol, with K(d) values of 0.61 +/- 0.013, 0.40 +/- 0.006, and 0.38 +/- 0.059 nm, respectively. Rank orders of binding were: diethylstilbestrol >> ICI182780 > 4-hydroxytamoxifen > ICI164384 > estradiol >/= zearalenone > moxestrol > tamoxifen > estrone >/= 17alpha-estradiol > estriol > 2-hydroxyestrone = genistein >> RU486 for acERalpha; ICI182780 > diethylstilbestrol > 4-hydroxytamoxifen > estradiol > ICI164384 > genistein > moxestrol > tamoxifen > zearalenone = estrone > estriol = 17alpha-estradiol > 2-hydroxyestrone >> RU486 for acERbetab; and estradiol >/= diethylstilbestrol > 4-hydroxytamoxifen > ICI182780 > ICI 164384 > estriol >/= genistein > moxestrol > zearalenone > estrone > 17alpha-estradiol > RU486 >/= tamoxifen > 2-hydroxyestrone for acERbetaa. acERbetaa showed higher relative binding affinities for estradiol, estriol, and RU486 and lower relative binding affinities for synthetic estrogens and antiestrogens than previously characterized ERs. Mutation of the conserved teleost substitutions (acERbetaaPhe(396)) to the ERalpha or ERbetab counterpart shifted diethylstilbestrol and tamoxifen affinities toward those of wild-type acERalpha and acERbetab, supporting the hypothesis that the positions with conserved residue changes in teleost ERs are important to ER structure and function.

Amino Acid Sequence↗
PubMed1978

16-Hydroxylation of estrone-3-sulfate and estrone in the guinea pig in vivo.

[6,7-3H]Estrone-3-sulfate or [6,7-3H]-estrone of high specific activity was injected into adult female English Shorthair guinea pigs. Blood, liver, kidney, gall bladder bile, and urine were obtained and investigated for metabolites. Chromatographic procedures followed by enzymatic or solvolytic cleavage of conjugates and subsequent crystallization with appropriate carrier steroids revealed the pattern of metabolites formed. Injected estrone sulfate was partially hydrolyzed and reconjugated, resulting in the production of estrone and estradiol glucuronides. The main metabolites, however, were monosulfates of 16alpha-hydroxyestrone, 16-keto-17beta-estradiol, and estriol as well as disulfates of 16alpha-hydroxyestrone, estriol, and 16beta-hydroxyestrone. Particularly high amounts of these were found in urine. By far the main metabolites of injected estrone were glucuronides of estrone and estradiol, although the pattern of mono- and disulfated steroids was qualitatively similar to that found after estrone sulfate injection. It is concluded that the guinea pigs employed in the study hydroxylated estrogen in the 16alpha- and 16beta-configurations and that this activity was much more pronounced after injection of estrone sulfate than after estrone.

Animals↗
PubMed1996

Excretion of 2- and 3-monomethyl ethers of 2-hydroxyestrogens in healthy male volunteers.

The formation of catecholestrogens by 2- and 4-hydroxylation of monophenolic estrogens represents a major route of estrogen metabolism. In vitro and in vivo studies on catecholestrogens have shown that 2-hydroxylated catecholestrogens are primarily inactivated by O-methylation, while o-methylation of 4-hydroxylated estrogen is of minor importance. In the present study the in vivo production of isomeric 2- and 3-monomethyl ethers of 2-hydroxyestrogens was measured in 12 healthy omnivorous male volunteers aged 51 +/- 4 years. The sum of estrone and 17 beta-estradiol, 2-hydroxyestrogens (sum of 2-hydroxyestrone and 2-hydroxyestradiol), 4-hydroxyestrogens (sum of 4-hydroxyestrone and 4-hydroxyestradiol) and the sum of the isomeric monomethyl ethers of 2-hydroxyestrone and 2-hydroxyestradiol were measured in 24-h urinary samples. The determination included hydrolysis of steroid conjugates, separation by chromatographic steps and final quantification by radioimmunoassay. The specificity of the antibodies enabled differentiation between the isomeric monomethyl ethers. The mean urinary excretion rates were 8.8 +/- 2.9 micrograms/24 h for estrone plus estradiol, 5.2 +/- 2.4 micrograms/24 h for 2-hydroxyestrogens and 1.3 +/- 0.5 micrograms/24 h for the 4-hydroxyestrogens. The 2- and 3-monomethyl ethers of the 2-hydroxyestrogens were found in all individuals, with excretion rates of 5.8 +/- 2.6 micrograms/24 h for 2-methoxyestrogens and 3.6 +/- 1.1 micrograms/24 h for 2-hydroxyestrogen-3-methyl ethers. The findings indicated that 2-hydroxyestradiol is metabolized in vivo by 2-O-methylation and, to a lesser extent, by 3-O-methylation.

Estrogens, Catechol↗
PubMedDate not supplied

Effects of dioxin on metabolism of estrogens in waste incinerator workers.

The authors measured the concentrations of serum dioxins and urinary estrogen metabolites in 57 male waste incinerator workers to determine whether dioxin influenced the metabolism of estrogens. Concentrations of serum dioxin levels and urinary estrogen metabolites, such as estrone, 17beta-estradiol, 2-hydroxyestrone, 2-methoxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestrone, 4-hydroxyestradiol, 4-methoxyestradiol, 16-hydroxyestrone, and estriol from the workers were measured. An analysis of covariance showed that mean estriol concentrations, adjusted for confounding factors among 3 serum dioxin levels, indicated a progressive increase with increasing serum dioxin level: 1.30, 1.41, and 2.02 nmol/mol creatinine at < 30.3, 30.3-39.7, and > 39.7 pg toxicity equivalent quantity/g lipid, respectively (F = 3.56, p = .036). This study showed that dioxin acts to metabolize estrogens to 16-hydroxyestrogens rather than to 2- or 4-hydroxyestrogens.

Adult↗
PubMed2003

Endogenous estradiol metabolites stimulate the in vitro proliferation of human osteoblastic cells.

OBJECTIVES: Evidence is accumulating that estradiol metabolites are not merely waste products but may play physiologic and pathophysiologic roles. In the present study, effect of estradiol metabolites on the proliferation of human female osteoblasts was investigated for the first time and compared to effect of their parent substance 17beta-estradiol. MATERIALS AND METHODS: Osteoblasts from female hipbone were incubated with estradiol and estradiol metabolites at dosages of 10(-9), 10(-7) and 10(-5) M for 7 days. Cell proliferation was measured using a cell counter. RESULTS: Estradiol had no effect on cell proliferation at the tested concentrations. In contrast, the A-ring metabolites 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol displayed significant increases in cell proliferation, although only at high physiologic or pharmacologic dosages. Methylation ofthese metabolites completely abolished their proliferating property. For the D-ring metabolites estrone, estriol, estetrol and 16alpha-hydroxyestrone, no significant changes in cell proliferation were observed. CONCLUSION: The present results suggest that endogenous estradiol metabolites are capable of stimulating the proliferation of human female osteoblastic cells. None of the estradiol metabolites examined inhibited cell proliferation. Thus, estradiol metabolism may play a decisive role in development and maintenance of bone mass.

Cell Division↗