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PubMed1987

Metabolism of [3H]2-hydroxyestradiol by cultured porcine granulosa cells: evidence for the presence of a catechol-O-methyltransferase pathway and a direct stimulatory effect of 2-methoxyestradiol on progesterone production.

Porcine granulosa cells synthesize and respond to catecholestrogens, but the stimulatory potency of catecholestrogens on progesterone production is much less than that of estradiol (E2). Therefore, to determine if metabolism of catecholestrogens by granulosa cells could account for the reduced potency of 2-hydroxyestradiol (2-OH-E2) observed in vitro, porcine granulosa cells were cultured with [3H]2-OH-E2 and medium collected at 0, 0.5, 1, 2, 4, 6, or 12 h in the presence or absence of 1 microgram/ml 2-OH-E2, 0.5 mM L-ascorbate or 10 microM U-0521 (a specific catechol-O-methyltransferase inhibitor). Metabolism of [3H]2-OH-E2 was very rapid with only 16% of the original [3H]2-OH-E2 remaining after 4 h exposure to cells. The main metabolite comigrated with 2-methoxyestradiol (2-MeO-E2) on thin-layer chromatography. Although appreciable degradation of [3H]2-OH-E2 occurred with time in the absence of cells, formation of the O-methyl derivative was minimal. Rather, formation of polar metabolites occurred in the absence of cells. Ascorbate dramatically reduced this noncellular degradation. Ascorbate added to cell cultures had no effect on the rate of formation of O-methyl products but slowed the formation of polar compounds as well as the overall rate of degradation of [3H]2-OH-E2 by nearly 2-fold. U-0521 completely blocked the formation of O-methyl products, slowed the overall rate of degradation of [3H]2-OH-E2 by half and resulted in an increase in polar metabolites. The effects of U-0521 and ascorbate on 2-OH-E2-stimulated progesterone production in vitro was also examined. Ascorbate (0.5 mM) enhanced the effect of 2-OH-E2 (but not E2) on progesterone production by 2-fold (p less than 0.05). The addition of 10 microM U-0521 in the presence of 0.5 mM ascorbate had no effect on 1 microgram/ml 2-OH-E2-stimulated progesterone production, but it increased (p less than 0.05) the response to 4 micrograms/ml 2-OH-E2. The effects of 2-MeO-E2, 2-OH-E2, and E2 on progesterone production by cultured granulosa cells were then compared. The ED50 of E2 was 6- to 8-fold lower than that of 2-OH-E2 and 2-MeO-E2, whereas the ED50 of 2-OH-E2 was 15% lower than that of 2-MeO-E2. In the presence of ascorbate (0.5 mM), the maximal effect of E2 and 2-OH-E2 was approximately equal, whereas 2-OH-E2 was nearly 2-fold more efficacious than 2-MeO-E2.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Methoxyestradiol↗

PubMed1989

Inhibition of rat liver microsomal estrogen 2-hydroxylase by 2-methoxyestrogens.

The inhibition of estrogen 2-hydroxylase by 2-methoxyestrogens was demonstrated in screening assays and has been further investigated under initial velocity conditions. The ability of 2-methoxyestradiol and 2-methoxyestrone to block the conversion of estradiol to 2-hydroxyestradiol by male rat liver microsomal preparations was determined by measuring the release of 3H2O from [2-3H]estradiol. The apparent Kis were found to be 34.86 microM for 2-methoxyestradiol and 18.65 microM for the methoxyestrone, with the apparent Km for the substrate estradiol in these essays of 3.21 microM. Mixed inhibition studies with the methoxyestrogens and 2,4-dibromoestradiol, an effective estrogen 2-hydroxylase inhibitor, in male rat liver microsomes resulted in Dixon plots consisting of a series of parallel lines. Thus, methoxyestrogens and 2,4-dibromoestradiol are mutually exclusive inhibitors, i.e., the binding of one compound to the enzyme interferes with the binding of the other. These results indicate that the compounds are interacting at the same enzymatic site. Finally, a method utilized to measure estrogen 2-hydroxylase activity in vitro is a radioenzymatic assay involving addition of catechol o-methyltransferase (COMT) and radiolabeled S-adenosylmethionine, and the amount of catechol estrogens formed is determined by the amount of radiolabeled methoxyestrogens isolated. The results described here demonstrate inhibition of estrogen 2-hydroxylase by methoxyestrogens; however, under enzymatic conditions of low product formation, the estrogen 2-hydroxylase inhibitory effect of catechol estrogen products from the radioenzymatic assay would be insignificant. Thus, these interactions of methoxyestrogens suggest that the steroid hormonal environment be considered in the examination of estrogen 2-hydroxylase and the catechol estrogen products. off

2-Methoxyestradiol↗

PubMed1986

Carcinogenicity of catechol estrogens in Syrian hamsters.

Estradiol and other estrogens induce renal carcinoma in male Syrian hamsters. The mechanism of carcinogenesis still remains unclear. Activation of estrogens to catechol metabolites has in the past been postulated to play a role in estrogen-induced carcinogenesis. Therefore, the carcinogenic activity of catechol estrogens was investigated. After 175 days of treatment, 4-hydroxyestradiol was found to be as carcinogenic as estradiol in male Syrian hamsters (4/5 and 4/5 animals with kidney tumors, respectively). Animals treated with 2-hydroxyestradiol (0/5) or 2-methoxyestradiol (0/6) did not develop renal carcinoma. The catechol estrogens failed to be mutagenic in the Ames test (reversions of his- S. typhimurium to histidine prototrophy in the TA 100 strain). The lack of carcinogenic activity of 2-hydroxyestradiol was not due to a failure to stimulate estrogen-dependent tumor growth. Growth of H-301 cells, an estrogen-dependent hamster kidney tumor cell line, was supported in vivo by estrogens in the following order: estradiol greater than 4-hydroxyestradiol greater than 2-hydroxyestradiol. Stimulation of tumor growth by 2-methoxyestradiol was not detected. It was concluded that the carcinogenic activity of 4-hydroxyestradiol was consistent with a role of catechol metabolites in estrogen-induced carcinogenesis. However, the intrinsic carcinogenic or hormonal activity of 2-hydroxyestradiol probably can not be assessed accurately in vivo because of its rapid methylation and metabolic clearance.

Animals↗

PubMed1991

Sex hormone-binding globulin: anatomy and physiology of a new regulatory system.

Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that binds a number of circulating steroid hormones (testosterone, dihydrotestosterone and estradiol) with high affinity, thus regulating their free concentration in plasma. In addition to binding steroids, SHBG itself binds to receptor sites on plasma membranes with somewhat unusual kinetics. Both the off and on rates are quite slow. The steroid-binding and membrane-binding functions are intertwined in what is clearly an allosteric relationship. Occupation of SHBG's steroid-binding site by a steroid inhibits its ability to bind to its membrane receptor-binding site. This inhibition is not related to a steroid's biological activity. Metabolites of steroids without biological activity, e.g. 2-methoxyestradiol, actively inhibit SHBG's interaction with its membrane receptor. However, if unliganded SHBG is allowed to bind to its receptor on intact cells, and an appropriate steroid hormone then is introduced, adenylate cyclase is activated and intracellular cAMP increases. This function is specific for steroids with biological activity, 2-methoxyestradiol has no activity in this arena. These observations demonstrate a potentially important role for SHBG as a regulator of cell function. They also demonstrate an additional mode of action of steroid hormones, one that does not require that the steroid interact with a steroid receptor.

Amino Acid Sequence↗

PubMed1988

Comparative effects of androgens and catecholestrogens on progesterone production by porcine granulosa cells.

The objective of the present studies was to evaluate and compare the effects of 5 alpha-dihydrotestosterone (DHT) to those of 2-hydroxyestradiol (2-OH-E2) and 2-methoxyestradiol (2-MeO-E2) on progesterone production in cultured porcine granulosa cells. Granulosa cells were exposed to various treatments of DHT, 2-OH-E2 and 2-MeO-E2 in the absence or presence of follicle stimulating hormone (FSH) for 4 days and concentrations of progesterone in medium and cell numbers were determined. In the absence of FSH, maximally effective concentrations of DHT (1 micrograms/ml) and 2-OH-E2 (4 micrograms/ml) stimulated progesterone production (ng/10(5) cells/48 h) to 2.2 +/- 0.2- and 10.8 +/- 2.2-fold of controls (n = 4 experiments), respectively. In the presence of 200 ng/ml FSH, progesterone production stimulated by 1 micrograms/ml DHT and 4 micrograms/ml 2-OH-E2 was 5.4 +/- 1.1- and 15.5 +/- 6.0-fold of controls (n = 4 experiments), respectively. Thus, FSH appeared to enhance the response of both DHT and 2-OH-E2. The dose-response of DHT was biphasic in the presence and absence of FSH, such that progesterone production in the presence of 8 micrograms/ml DHT was similar to basal progesterone production. Concurrent treatment with saturating concentrations of 2-OH-E2 and DHT resulted in fully additive increases in progesterone production. Testosterone mimicked the effect of DHT. In comparison, concurrent treatment of saturating concentrations of 2-MeO-E2 and DHT or 2-MeO-E2 and 2-OH-E2 resulted in progesterone production that was only partially additive.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗

PubMed1989

Catecholestrogens inhibit proliferation and DNA synthesis of porcine granulosa cells in vitro: comparison with estradiol, 5 alpha-dihydrotestosterone, gonadotropins and catecholamines.

Studies were conducted to assess the role of catecholestrogens on ovarian follicular growth using cultured porcine granulosa cells. Effects of the catecholestrogens, 2-hydroxyestradiol (2-OH-E2) and 2-methoxyestradiol (2-MeO-E2) were compared to those of estradiol (E2). Treatment with saturating concentrations of 2-OH-E2 caused a significantly greater decrease in cell numbers measured after 2 days of treatment than E2 treatment. The inhibitory effect of 2-OH-E2 was time and concentration dependent, not associated with a change in the viability of cells, and was partially reversible. The potency of 2-MeO-E2 to inhibit cell numbers was similar to or greater than that of 2-OH-E2. 2-MeO-E2 had a greater inhibitory effect on DNA synthesis, as measured by [3H]thymidine incorporation into trichloroacetic acid-precipitable macromolecules, than 2-OH-E2 or E2 in the absence or presence of insulin, epidermal growth factor or platelet-derived growth factor. Concurrent treatment with epinephrine significantly enhanced the inhibitory effect of 2-OH-E2 on granulosa cell DNA synthesis. Collectively, these studies indicate that catecholestrogens are more potent inhibitors of granulosa cell replication than E2 and 5 alpha-dihydrotestosterone (DHT), and that catecholamines may modulate the antimitotic activity of 2-OH-E2. These results support the hypothesis that catecholestrogens play a role in proliferation of granulosa cells during growth of ovarian follicles.

2-Methoxyestradiol↗

PubMed1990

Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate.

The binding of human sex hormone-binding globulin (SHBG) to a human prostatic cancer cell line (LNCaP) and the results of that binding were examined. Membranes derived from LNCaP cells bound unliganded SHBG on two sets of sites whose affinities were: Ka1 = 3.1 +/- 1.6 x 10(10) M-1 and Ka2 = 8.7 +/- 4.3 x 10(6) M-1. Intact cells also bound SHBG, but even after 6 h, less than 10% of specifically bound SHBG was internalized. This observation speaks against a role for the membrane binding of SHBG in steroid transport across cell membranes. When LNCaP cells were prebound with SHBG, addition of dihydrotestosterone or estradiol resulted in a dose-dependent increase in intracellular cAMP. SHBG in the absence of steroids or dihydrotestosterone in the absence of SHBG was without effect. 2-Methoxyestradiol, a steroid metabolite without biological activity, but which binds to SHBG more tightly than does estradiol, was also without effect. These observations demonstrate a potentially important role for SHBG as a regulator of cell function. They also demonstrate an additional mode of action of steroid hormones, one that does not require that the steroid interact with a steroid receptor.

2-Methoxyestradiol↗

PubMed1992

Effects of 17 beta-estradiol metabolites on cell cycle events in MCF-7 cells.

Different cell growth effects were observed in MCF-7 cells after six daily exposures to either 17 beta-estradiol (E2), 2-hydroxyestradiol (2-OHE2), or 2-methoxyestradiol (2-MeOE2) at 10 nM levels. 2-OHE2 enhanced cell growth significantly (P < 0.05) more than did the parent compound, whereas 2-MeOE2 inhibited cell growth. To identify the estrogen-affected cellular processes involved in cell cycle progression, hydroxy urea-synchronized MCF-7 cells were studied. No effects on DNA synthesis in mid-S-phase or on mitotic indices were observed after E2 or 2-OHE2 treatment. 2-MeOE2, however, significantly (P < 0.05) inhibited DNA synthesis and mitosis. Synchronized cells were exposed for 1 h to E2, 2-OHE2, or 2-MeOE2 before cAMP levels were determined in early S-phase and mid-S-phase, as well as during mitosis. E2 and 2-OHE2 had no effect, but 2-MeOE2 caused a significant (P < 0.05) increase in cAMP concentration in early S-phase and a decrease during mitosis. Phosphorylation of S-phase proteins was also studied. [32P]Pi incorporation was significantly (P < 0.05) enhanced in many proteins in 2-MeOE2-exposed cells. Small proteins (M(r) < 25,000), as well as large proteins (M(r) > 220,000), were most prominently affected. In comparison, E2 and 2-OHE2 had little effect. We suggest that the enhanced 2-MeOE2-induced protein phosphorylation during S-phase may affect S-phase events, which subsequently causes inhibition of mitosis. Protein synthesis during G2/M transition was unexpectedly enhanced by 2-OHE2 and was not enhanced by E2. [35S]Methionine incorporation into proteins in the order of M(r) 32,000-46,000, 47,000-50,000, 58,000-67,000, and 83,000-89,000 was significantly (P < 0.05) increased. 2-MeOE2 had no effect. The results of this study indicate that 2-OHE2 may be the more potent mitogen, whereas 2-MeOE2 acts as a cytostatin.

2-Methoxyestradiol↗

PubMed1986

A male specific hepatic estrogen binding protein: characteristics and binding properties.

Mammalian liver is a sex-steroid responsive tissue in that androgen and estrogen receptors are present and mediate differential hepatic hormonal effects. Further, we and others have found a sexual dimorphism in the hepatic cytosolic content of estrogen binding proteins. In addition to the estrogen receptor, the male has a high-capacity (12.0-15.0 pmol/mg protein) estrogen binding protein (MEB) which demonstrates a moderate affinity for estradiol (Kd = 31.0-43.2 nM) if estradiol metabolizing enzymes are first precipitated with protamine sulfate. This protein exhibits a unique specificity for steroidal estrogens: 2-methoxyestriol greater than estradiol greater than estriol = 2-methoxyestradiol greater than 2-hydroxyestradiol greater than estrone greater than 2-methoxyestrone greater than estriol 3-glucuronide greater than 2-hydroxyestrone = 3-methoxyestriol greater than androstanediol greater than dihydrotestosterone greater than testosterone. Other androgens such as androstenedione and methyltrienolone, nonsteroidal estrogens such as diethylstilbestrol, and the antiestrogens tamoxifen and 4-hydroxytamoxifen do not compete for [3H]estradiol ([3H]E2) binding. MEB is a relatively small-molecular-weight protein with a Sr of 20.4 A as determined by gel filtration on Sephadex G-100. The kinetics of [3H]E2 association and dissociation at 4 degrees C are very rapid, with t1/2 values of less than 5 s. Sodium molybdate, generally used to stabilize steroid receptors, inhibits MEB-[3H]estradiol binding activity in cytosol in a time- and dose-dependent manner, an effect not observed with partially purified MEB. Magnesium chloride inhibits binding activity of the Sephadex G-100 MEB pool, an effect reversed by EDTA. Other divalent cations also inhibit binding: Mn2+ greater than Mg2+ greater than Ca2+. Furthermore, EDTA complexes of these cations slightly enhance binding relative to EDTA alone: Ca2+ EDTA greater than Mg2+ EDTA greater than Mn2+ EDTA. These results demonstrate that MEB is a unique sex-steroid binding protein, albeit of unknown function, which is distinct from hepatic steroid receptors.

Animals↗

PubMed1989

Studies on the stoichiometry of estrogen oxidation catalyzed by purified prostaglandin-H-synthase holoenzyme.

Prostaglandin-H-synthase (PHS) is a key enzyme in the biosynthesis of prostaglandins (PGs) from arachidonic acid and can oxidatively metabolize synthetic and steroidal estrogens. To investigate the relationship between estrogen cooxidation and PG synthesis, purified PHS-holoenzyme was incubated with radiolabeled arachidonic acid and various estrogens, namely diethylstilbestrol (DES), estradiol (E2), 2-hydroxyestradiol (2-OHE2), and 2-methoxyestradiol (2-MeOE2). The amount and pattern of PGs synthesized were analyzed by TLC and HPLC, estrogen metabolism was studied by HPLC. All tested compounds increased conversion of arachidonic acid to PG H2-derived prostanoids. A stoichiometric ratio between net estrogen oxidation and net PG H2 formation of approximately 2:1 for monophenolic compounds (2-MeOE2, E2) and of 1:1 for diphenolic estrogens (DES, 2-OHE2) was found, indicating that estrogens are apparently acting as electron donors for the PHS-peroxidase. In contrast, glutathione was not found to provide electrons for the reduction of PGG2 to PGH2, and rather decreased the conversion of arachidonic acid. The results of this in vitro study are discussed with respect to its implications for the in vivo situation.

Catalysis↗

PubMed1975

Metabolism of 2-3H- and 4-14C-17alpha-ethynylestradiol 3-methyl ether (mestranol) by women.

A mixture of 2-3H and 4-14C-mestranol was administered orally to five women and 2-3H-mestranol alone to one woman. Reactions involving position 2 were extensive as judged by liberation of 3H into body water (14-45% of the dose). 17alpha-Ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol, 2-methoxy-17alpha-ethynylestradiol, 2-hydroxy-17alpha-ethynylestradiol 3-methyl ether and 16geta-hydroxy-17alpha-ethynylestradiol were measured in the "glucuronide" and pH1 fractions and mestranol, D-homoestrone-17a and D-homoestradiol-17abeta were also measured in the "glucuronide" fraction frum the urine to two of the women by reverse isotope dilution. Radioactive 2-methoxyestradiol accounted for less than 0.011% of the 14C dose in the "glucuronide" fraction of one of the women, consistent with the extent of de-ethynylation previously reported (Steroids, 25, 343 (1975).

Adult↗

PubMed1979

Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormone secretion.

The biological activity of a series of natural catechol estrogens was examined under conditions of continuous administration. 2-Hydroxyestradiol (2OH-E2), 2-methoxyestradiol (2MeOE2), 4-hydroxyestrone (4OH-E1), 4-methoxyestradiol (4MeOE2), 2-hydroxyestrone (2OH-E1), and 4-methoxyestrone (4MeOE1) were delivered at the rate of 1 microgram/h from osmotic pumps implanted in ovariectomized rats. Uterine growth and plasma LH concentrations were measured 24, 48, and 72 h after implantation. Little or no uterotropic activity was exhibited by the 2-hydroxylated metabolites 2OH-E1 and 2MeOE2 at any interval, while 2OH-E2 exhibited anomalous uterotropic activity, which terminated at 48 h. The 4-hydroxylated compounds 4MeOE2, 4OH-E1, and 4MeOE1 all produced substantial and progressive uterine growth. Tonic LH secretion was suppressed by 2OH-E2, 4OH-E1, and 4MeOE1 in proportion to their uterotropic activity. 2OH-E1 was the only substance which increased plasma LH concentrations. The nuclear receptor occupancy by 2OH-E2 was substantially shorter than that of E2. Binding studies of the test and other related estrogens to the uterine cytosol estradiol receptor showed that their relative binding affinities in many instances did not correlate with their biological activities.

Animals↗

PubMed1990

Inhibition of the soluble form of testis adenylate cyclase by catechol estrogens and other catechols.

The soluble form of rat germ cell adenylate cyclase was inhibited by compounds with a catechol moiety. Among the naturally occurring catechols tested, catechol estrogens were the most potent inhibitors. Catechol estrogens at 2-6 microM inhibited enzyme activity by 50% and almost completely at 30-100 microM concentration. The inhibitory activity of catechol estrogens depends on the catechol moiety of the molecule. Catechol per se also inhibited the activity of this enzyme, 50% inhibition being achieved at about 11 microM. The two hydroxyls of the catechol moiety are essential for the inhibitory interaction with the enzyme. Thus, aromatic compounds containing only one hydroxyl group in the benzene ring, such as tyrosine, phenylephrine, estradiol, and 6 alpha-hydroxyestradiol were either completely inactive or had marginal inhibitory activity at concentrations up to 0.3-1 mM. Moreover, methylation of the hydroxyl groups of the catechol moiety of the catechol estrogens as in 2-methoxyestradiol 3-methyl ether rendered the catechol estrogens inactive. The inhibitory potency of these compounds varied greatly depending on the structure associated with the catechol ring. Thus, compounds in which catechol is associated with an aliphatic side chain, such as dopamine, L-dopa, norepinephrine, and isoproterenol, were about 11- to 34-fold less potent than catechol. On the other hand, compounds in which catechol is associated either with a hydroaromatic ring system, as in apomorphine, or with an alicyclic ring system, as in catechol estrogens, were about 2- to 5-fold more potent than catechol. The inhibitory effect of dopamine, apomorphine, and catechol estrogens was not affected by specific D-1 or D-2 antagonist, indicating that they do not act via receptors for dopamine.

Adenylyl Cyclase Inhibitors↗

PubMed1990

The control of the interaction of sex hormone-binding globulin with its receptor by steroid hormones.

Sex hormone-binding globulins (SHBG) is a plasma glycoprotein that binds certain steroids. It, in turn, binds to a specific receptor on cell membranes. This work was undertaken to investigate the role of steroids in the interaction of SHBG with its receptor. Because the probe for the interaction of SHBG with its receptor is 125I-SHBG, we first showed that 125I-SHBG binds [3H]dihydrotestosterone (DHT) at 4 degrees C and 37 degrees C with KD values similar to those published previously for pure radioinert SHBG. 125I-SHBG could be prevented from binding to its receptor by a variety of steroids whose relative inhibitory activity (dihydrotestosterone much greater than 2-methoxyestradiol greater than testosterone greater than estradiol much greater than methyltrienolone greater than cortisol) was almost identical to their relative ability to bind to SHBG. Because significant binding of [3H]DHT to the SHBG receptor could not be demonstrated, steroid inhibition of SHBG binding must be noncompetitive. If steroids bound to SHBG prevent binding to the SHBG receptor, then liganded SHBG should have a higher apparent KD for its receptor than unliganded SHBG. This is the case. The KD was 0.86 +/- 0.25 nM for the high affinity receptor site using liganded SHBG and 0.19 +/- 0.024 nM for unliganded SHBG. Thus, only liganded SHBG assumes a conformation that prohibits interaction with the SHBG receptor. However, when unliganded SHBG was prebound to its receptor, it retained its ability to bind [3H] DHT. The model that emerges from these observations is as follows. Unliganded SHBG can bind either steroids or receptor in a reversible reaction; SHBG bound to a steroid cannot bind to the receptor, but unliganded SHBG that first binds to the receptor can subsequently bind steroids.

Binding Sites↗

PubMed1986

Studies of catecholestrogen metabolism during normal pregnancy: changes of plasma catecholestrogen levels after DHA-S or E1-S injection.

So as to evaluate metabolism of catecholestrogens during pregnancy, changes in plasma unconjugated estradiol (E2), estrone (E1), 2-methoxyestradiol (2-mE2) and 2-methoxyestrone (2-mE1) concentrations were measured after a bolus injection of 40mg of estrone-sulfate (E1-S) or 100mg of dehydroepiandrosterone-sulfate (DHA-S) to normal pregnant women near term. The injection of E1-S resulted in a marked rise in plasma 2-mE1 levels followed by a rapid marked increase in the plasma E1 concentration. The injection of DHA-S produced a small increase in the plasma 2-mE2 levels in spite of a marked increase in the plasma E2 concentration. No significant correlation between E2 and 2-mE2 was found, however, significant correlations between E1 and 2-mE1, between E1 and 2-mE2 and between 2-mE2 in in both groups were demonstrated. The marked increase in 2-mE1 compared to a small increase in 2-mE2 after DHA-S injection indicates that E2 may participate in the formation of catecholestrogen via its conversion to E1 during pregnancy. These results suggest that the main route for the formation of catecholestrogen is via E2----E1----(2OHE1)----2-mE1 in normal pregnancy near term.

Biotransformation↗

PubMed1987

The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines.

In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (-)-adrenaline. Oestradiol (40 mumol/l), 2-hydroxyoestradiol (2OHE2) (20 mumol/l), and 2-methoxyoestradiol (2MeOE2) (20 mumol/l) all sensitized the rabbit aorta to contractile responses to (-)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (-)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. Oestradiol and 2OHE2 did not increase responses of the aorta to (-)-noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE3. The potentiating effect of 2OHE2 on contractile responses to (-)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mumol/l). Conversely, pretreatment of the tissue with 2OHE2 prevented the augmented aortic contraction to (-)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE2 and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mumol/l). Oestradiol and 2MeOE2 reduced the formation of both the 3H-O-methylated, 3H-deaminated and the 3H-O-methylated deaminated metabolites of 3H-(-)-adrenaline (0.15 mumol/l) during exposure of the aorta to the tritiated catecholamine.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗

PubMed1991

Effect of catechol oestrogens on extraneuronal metabolism of noradrenaline by rabbit uterine endometrium and myometrium.

The effects of 2-hydroxy and 2-methoxy oestrogens on the extraneuronal O-methylation of 3H-(-)-noradrenaline were examined in progesterone-dominated, monoamine oxidase (MAO)-inhibited, rabbit uterine tissues in vitro. Both the corticosteroid-sensitive system in myometrium and the cocaine-sensitive system in endometrium were examined. In myometrial slices preincubated with nialamide to inhibit MAO and incubated with cocaine to inhibit neuronal uptake, 3H-normetanephrine (3H-NMN) formation was inhibited in the order of potency 2-hydroxy oestrone greater than or equal to 2-hydroxy oestradiol = 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone. In myometrial slices not exposed to cocaine and nialamide, inhibition of 3H-NMN formation by both 2-hydroxy and 2-methoxy oestradiol did not affect the formation of deaminated metabolites of 3H-(-)-noradrenaline by the alternative metabolising pathway. In endometrial slices preincubated with nialamide to inhibit MAO, only 2-hydroxy oestrogens inhibited 3H-NMN formation, but they were one to two orders of magnitude less potent in this regard than in the myometrium. The uptake of 3H-(-)-noradrenaline by MAO- and COMT-inhibited myometrial slices was inhibited by 2-hydroxy and 2-methoxy oestrogens in the order of potency 2-methoxy oestradiol greater than or equal to 2-methoxy oestrone greater than or equal to 2-hydroxy oestrone greater than 2-hydroxy oestradiol. Uptake of 3H-(-)-noradrenaline by endometrial slices was not affected by either 2-hydroxy or 2-methoxy oestrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗

PubMed1991

Urinary excretion of catecholestrogens, 2-methoxy-estrogens and "classical estrogens" throughout the normal menstrual cycle.

Catecholestrogens, 2-methoxyestrogens and "classical" estrogens (estrone, estradiol, estriol) were measured simultaneously in urine samples of healthy women during the menstrual cycle. All estrogen values reach a preovulatory maximum at the time of the LH peak and show a marked increase during the luteal phase as compared to the follicular phase. Catecholestrogens and estrone seem to behave similarly supporting the assumption that catecholestrogens are predominantly metabolites of estrone. Daily measurements of urinary estrogens show large interindividual variations of 2- and 4-hydroxyestrogens as well as very differing 2-hydroxy-/2-methoxyestrogen ratios. The results obtained support the assumption, that catecholestrogens and their methylethers are excretory products with no additional regulatory functions.

2-Methoxyestradiol↗