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PubMed1983

Inhibition of phasic but not tonic pituitary secretion by 2-hydroxyoestrone in the rat: evidence of action as an oestrogen antagonist.

Rats with 4-day oestrous cycles, implanted with intracardiac catheters, were injected with 2-hydroxyoestrone at noon on pro-oestrus and their plasma LH levels monitored at frequent intervals thereafter. A dose of 100 micrograms 2-hydroxyoestrone completely abolished the preovulatory LH rise in four out of ten animals tested, showing no effect in the six others. When an injection of 10 micrograms oestradiol 1 h before the 2-hydroxyoestrone administration was given all the rats showed an absence of the preovulatory LH surge, while it remained intact in the controls treated with oestradiol only. The principal metabolite of 2-hydroxyoestrone, 2-methoxyoestrone, exhibited no influence on the pituitary gonadotrophin release. Repeated injections of 100 micrograms doses of 2-hydroxyoestrone to long-term ovariectomized rats produced no change in plasma LH and prolactin levels. In animals primed with oestradiol benzoate, 2-hydroxyoestrone given 1-2 h after the priming dose blocked the phasic release of the pituitary hormones on the afternoon of the 2 subsequent days. The LH and prolactin surges in the primed animals, however, were not affected when the catechol oestrogen was injected 2 h before their appearance. These results indicate that in the cyclic rat exogenous 2-hydroxyoestrone inhibits the preovulatory LH surge when its administration is coincident with the preovulatory oestradiol rise. In the ovariectomized rat 2-hydroxyoestrone inhibits the oestrogen-dependent priming step but does not affect either the oestrogen-independent expression of the induced surges or the tonic secretion of these pituitary hormones. These results indicate a dissociation of central and peripheral activities in this oestradiol metabolite and suggest that this catechol oestrogen functions as an oestrogen antagonist in neuroendocrine events. Since catechol oestrogens can be formed in the brain these pharmacological responses may reflect physiological mechanisms.

Animals↗
PubMed1984

Effects of acute administration of 2-hydroxylated metabolites of oestrogens on LH and prolactin secretion in male and female prepubertal rats.

The effects of catechol oestradiol and catechol oestrone on the release of LH and prolactin were investigated in immature male and female Wistar rats. In male rats both catechol oestradiol and catechol oestrone significantly increased the plasma concentration of LH, and catechol oestradiol but not catechol oestrone significantly increased the plasma concentration of prolactin and decreased the pituitary concentration of LH. The parent oestrogens, oestradiol-17 beta and oestrone, had no effect on plasma LH concentrations, but both increased significantly the plasma concentration of prolactin, and oestrone but not oestradiol-17 beta increased the pituitary concentration of LH. In immature female rats, catechol oestradiol inhibited the surge of LH and the increase in uterine weight induced by injecting pregnant mare serum gonadotrophin (PMSG). The injection of oestrone induced an increase in the plasma concentration of LH which was about nine times greater than that produced by oestradiol-17 beta. There were no significant differences in the effects of these steroids on plasma prolactin concentration. These results (i) confirm that in the immature male rat catechol oestrogens can stimulate LH release and show that catechol oestradiol can increase prolactin release, (ii) show that catechol oestradiol can inhibit the stimulatory effects of PMSG on LH release and uterine weight in the immature female rat, and (iii) demonstrate that oestrone can stimulate LH release in the immature female rat.

Animals↗
PubMed2004

Endogenous estradiol metabolism during treatment with oral contraceptives.

OBJECTIVE: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women. METHODS: Two studies were conducted, firstly comparing 2 different progestins, i.e. norethisterone and dienogest, each in combination with a constant ethinyl estradiol dosage (study A) and secondly comparing a single progestin, i.e. levonorgestrel in 2 ethinyl estradiol/progestin dosage combinations (study B). The main A- and D-ring metabolites, i.e. 2-OHE1 and 16-OHE1, were measured by enzyme immunoassay in 8-h night-urine collected before and after 3 cycles of OC administration. RESULTS: In study A, i.e. ethinyl estradiol plus dienogest or norethisterone acetate, the ratios of 16-OHE1 to 2-OHE1 before administration were 0.62 and 0.68, and after 3 months 0.31 and 0.54, respectively. The ratio after ethinyl estradiol and dienogest was significantly lower after treatment. In study B, i.e. ethinyl estradiol plus levonorgestrel (0.03 mg/0.15 mg and 0.02 mg/0.1 mg), the ratios before treatment were 0.71 and 0.75 for the higher and the lower dosages, respectively, which changed not significantly to 0.73 and 0.71 after 3 cycles. CONCLUSION: OCs containing norethisterone acetate, dienogest or levonorgestrel did not have a negative effect on estradiol metabolism, i.e. they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

Adult↗
PubMed2000

The effect of 2-methoxyoestrone-3-O-sulphamate on the growth of breast cancer cells and induced mammary tumours.

2-Methoxyoestrogens are emerging as a new class of drug that can inhibit tumour growth and angiogenesis. As sulphamoylation of oestrogens enhances their potency and bioavailability we have synthesized 2-methoxyoestrone-3-O-sulphamate (2-MeOEMATE) and compared its ability to inhibit the proliferation of breast cancer cells with that of 2-methoxyoestrone (2-MeOE1). 2-MeOEMATE (1 microM) inhibited the growth of oestrogen receptor positive MCF-7 breast cancer cells by 52% whereas 2-MeOE1 had little effect at this concentration. 2-MeOEMATE also inhibited the growth of oestrogen receptor negative MDA-MB-231 breast cancer cells. Exposure of cells to 2-MeOEMATE caused them to round up and become detached suggesting that this compound may induce cells to undergo apoptosis. Cell cycle analysis revealed that 2-MeOEMATE caused cells to arrest in the G(2)/M phase with the increase in G(2)/M arrested cells being detectable by 12 hr. Exposure of MCF-7 cells to 2 L-MeOEMATE for 24 hr followed by culture in drug-free medium for 24 hr did not reverse the arrest of cells in the G(2)/M phase. TUNEL analysis confirmed that 2-MeOEMATE induced apoptosis in a significant proportion of treated MCF-7 cells. In an in vivo study, employing nitrosomethylurea-induced mammary tumours in intact rats, 2-MeOE1 (20mg/kg/d, p.o. for 11 days) had little effect on tumour growth. In contrast, the same dose of 2-MeOEMATE resulted in the almost complete regression of 2/3 tumours over an 11-day period. We conclude that 2-MeOEMATE should have considerable therapeutic potential for the treatment of breast tumours.

Animals↗
PubMed1999

Conjugated estrogens--the natural SERMs.

Tissue selective and metabolite replacement therapy may become a new aspect in hormone replacement therapy (HRT). In addition to the naturally secreted hormones, there are also the later formed metabolites that exert a characteristic pharmacological profile. This mechanism is well known in thyroid replacement therapy, when triiodothyronine, the metabolite of thyroxine, is added to substitution therapy. The same is true for testosterone replacement therapy, when dihydrotestosterone is used for replacement. Also in menopausal HRT these aspects will gain tremendous importance. Progesterone metabolites have a strong clinical potency as neurosteroids, and estradiol metabolites are important factors in angiogenesis and angiostasis. Conjugated estrogens consist of different metabolites such as 16-hydroxy-equilin, which has no angiogenetic effect compared with 16-hydroxy-estrone. Estrone sulfate, the main component in conjugated estrogens, can be activated into estrone and 17 beta-estradiol in a tissue specific manner. This aspect will become of interest in clinical practice with HRT.

2-Methoxyestradiol↗
PubMed2000

Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest, apoptosis, and microtubule assembly in human breast cancer cells.

There is considerable interest in the potential use of estrogen derivatives for the treatment and prevention of breast cancer. We demonstrated previously that the sulfamoylated estrone derivative 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) induced G2-M cell cycle arrest and modest levels of apoptosis in breast cancer cells in vitro, whereas the parent estrone derivative, 2-methoxyestrone, did not. 2-MeOEMATE also induced breast tumor regression in vivo in intact rats. To further explore the significance of sulfamoylation on the anticancer activity of estrone derivatives and to elucidate their mechanism of action, we synthesized two additional agents, 2-ethylestrone and 2-ethylestrone-3-O-sulfamate (2EtEMATE). 2-MeOEMATE and 2-EtEMATE inhibited the growth of a panel of estrogen receptor-negative and -positive breast cancer cell lines in vitro, induced mitotic arrest and apoptosis, and suppressed the long-term clonogenic potential of MCF7 and CAL51 breast cancer cells. In each assay, the sulfamoylated estrone derivatives were >10-fold more potent than their parent compounds. The sulfamoylated estrone derivatives were also significantly more potent inhibitors of cell growth than the previously studied endogenous estradiol metabolite 2-methoxyestradiol. 2-MeOEMATE and 2-EtEMATE functioned as antimicrotubule agents and inhibited the ability of paclitaxel to promote tubulin assembly in vitro. Like other antimicrotubule agents, the sulfamoylated estrone derivatives induced BCL-2 and BCL-XL phosphorylation and increased p53 expression. 2-MeOEMATE and 2-EtEMATE are novel antimicrotubule agents that have potent anticancer activity in breast cancer cells in vitro and may be beneficial as anticancer agents in vivo.

Antineoplastic Agents↗
PubMed2001

Relationship between estradiol 16 alpha-hydroxylation and human papillomavirus infection in cervical cell transformation.

The ovarian steroid hormone estradiol and its metabolite estrone were examined in 45 normal women and 127 premenopausal women with precancerous cervical lesions. Interviews, colposcopy and cervical scrapings were performed. The mean +/- SD values for estradiol and estrone were 0.07 +/- 0.08 ng/ml and 0.06 +/- 0.02 ng/ml, respectively in normal subjects. Corresponding data in patients with cervical intraepithelial neoplasia alone or in association with human papillomavirus (HPV) infection were 0.074 +/- 0.03 ng/ml and 0.076 +/- 0.03 ng/ml or 0.080 +/- 0.03 ng/ml and 0.148 +/- 0.02 ng/ml, respectively, which revealed a significantly greater extent of estrogenic action in the latter population (p < 0.05). We considered that the presence of HPV infection probably increased 16 alpha-hydroxylation of estradiol, providing a possible link between the viral and hormonal elements, possibly having a bearing on the etiology of the disease.

Adolescent↗
PubMed2001

Determination of estradiol metabolites in human liver microsome by high performance liquid chromatography-electrochemistry detector.

AIM: To constitute a method to determine the estradiol metabolites in human liver microsome in low concentration of estradiol. METHODS: Use high performance liquid chromatography after solvent extraction, evaporation, and reconstitution to separate the metabolites and use a electrochemistry detector to detect the metabolites. RESULTS: With a mobile phase of acetic acid buffer-acetonitrile (50:50, v/v, pH 4.5) at flow rate of 1.0 mL/min and a potential of +0.7 V vs Ag/AgCl, all six composition were well separated and satisfactorily detected. There are E3, 16alpha-OHE1, 2-OHE2, E1, and two unidentified composition. The minimum detectable amount is about 100 p g on column. This method is sensitive enough to detect E1 in a substrate concentration of 1 micromol/L. CONCLUSION: The method can be used to study the metabolism mechanism of estradiol in liver microsome.

Adult↗
PubMed1990

[Effects of catecholestrogen and catecholestrogen 2-monomethyl ether on serum lipids and lipoproteins in rats].

To clarify the mechanism of action of catecholestrogen and catecholestrogen 2-monomethylether on lipid metabolism, the effects of 2-OHE1, 2-MeoE1, 2-MeoE3 and E2-17 beta on serum total cholesterol, HDL-cholesterol, triglyceride levels, beta/alpha lipoprotein ratio, body weights and uterine weights were investigated in five serial experimental systems using normochoesterolemic and dietary hypercholesterolemic female rats those were previously oophorectomized. The results obtained were as follows: 1) In a short term hormone administration experiment using normocholesterolemic rats, 2-OHE1, 2-MeoE1, and 2-MeoE3 showed a serum triglyceride reducing effect as strong as that of E2-17 beta. 2) To integrate the results of the short term hormone administration experiment in normocholesterolemic rats and the results of short term and long term hormone administration experiments in dietary hypercholesterolemic rats, the serum cholesterol reducing activity was in the following sequences; 2-MeoE3 not equal to E2-17 beta greater than 2-MeoE1 greater than 2-OHE1. Hypocholesterolemic activity of 2-MeoE3 was almost equivalent or slightly stronger than that of E2-17 beta, and 2-MeoE1 showed approximately a half of that of E2-17 beta. 3) According to the results of the short term hormone administration experiment, and the long term hormone administration experiment in dietary hypercholesterolemic rats, the serum HDL-cholesterol increasing effect was in the following relation; E2-17 beta greater than 2-MeoE3 greater than 2-MeoE1. Dose dependency was not observed in the serum HDL-cholesterol increasing effect. 4) From the results of the short term hormone administration experiment, 2-MeoE3 had an equal or stronger activity than that of E2-17 beta in serum beta/alpha lipoprotein ratio decreasing effect. 5) In experiment 4 which 2-MeoE3 and E2-17 beta were administered singly or combined with Tamoxifen to the dietary hypercholesterolemic rats, the hypocholesterolemic effect of neither hormone was inhibited by Tamoxifen. On the other hand, the uterotrophic activity of E2-17 beta was slightly, but not significantly inhibited by Tamoxifen. 6) Although E2-17 beta, 2-MeoE1 exhibited a remarkable uterotrophic activity and a slight reducing effect on body weight, neither 2-OHE1 nor 2-MeoE3 had an effect on uterine weight or body weight. Given these results, it was strongly suggested that the effects of catecholestrogen and catecholestrogen 2-monomethyl ether on serum lipids were not mediated by the estrogen receptor system but by other mechanisms of action.

Animals↗
PubMed1988

[The biotransformation of STS 267 [16 alpha-azido-3-methoxyestra-1,3,5(10)-triene-17-one]. Epimerization of a 16 alpha-azido group--a new metabolic reaction in the rat liver].

STS 267 [1; 16 alpha-azido-3-methoxy-estra-1,3,5(10)-trien-17-one] was found to have lipid shifting and fertility inhibitory effects in rats. In preclinical studies the metabolic fate of 1 was investigated in the rat. Demethylation in 3-position, reduction of the 17-carbonyl to the 17 beta-hydroxyl group, and for the first time the epimerization of the 16 alpha-azido to the 16 beta-azido group were established following perfusion of STS 267 in the isolated rat liver. From the perfusion medium 16 alpha-azido-estra-1,3,5(10)-trien-3-ol-17-one (2), 16 alpha-azido-estra-1,3,5(10)-trien-3,17 beta-diol (3), 16 beta-azido-3-methoxy-estra-1,3,5(10)-trien-3,17 beta-diol (4) and 16 beta-azido-estra-1,3,5(10)-trien-3,17 beta-diol (5) as the main metabolite were isolated by TLC and identified by comparison with authentic samples. The extent of the hepatic extraction of 1 in the rat liver was significant lower compared with mestranol.

Animals↗
PubMed1988

Identification of 16 alpha-hydroxy-estrone as a metabolite of estriol.

During a study on the uptake and retention of estrogens by uterine tissues in postmenopausal women, evidence was obtained of the presence of a metabolite of estriol, tentatively identified as 16 alpha-hydroxy-estrone (16-OHE1). In view of the recent hypothesis concerning the role of 16-OHE1 as a risk marker for breast cancer, attempts were made to establish the identity of the metabolite. After infusions with labelled estriol, radioactive material with chromatographic properties of 16-OHE1 was observed; insufficient material was obtained for micro-recrystallization. After oral administration of estriol, myometrial tissue was extracted, then purified by chromatography and the appropriate fraction was analyzed by gas chromatography-mass spectrometry, monitored at 3 specific mass units. In the women receiving estriol the presence of 16-OHE1 could be unequivocally demonstrated, the concentrations in the myometrium being 6 and 18 ng/g tissue, whereas less than 0.2 ng/g was found in an untreated patient. This identification of 16-OHE1 does not support the hypothesis about its prominent role in human breast cancer. Additional investigations will be necessary to clarify its role in the process of stimulation of estrogen-sensitive tissues under physiological conditions and after exogenous administration of estriol.

Biotransformation↗