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PubMed1977

Introduction of a 16 alpha-hydroxyl function into estrone by Streptomyces roseochromogenes.

Streptomyces roseochromogenes (NRRL B-1233) converted estrone predominantly into its 16 alpha-hydroxyl derivative. Chemical and spectroscopic (UV, IR, NMR, MS) methods were used in establishing the structure and strereochemistry of the oxidation product. The product was assigned as 16 alpha-hydroxyestrone (yield, 17%). No other oxidation product was detected in this experiment. An interrelationship between cell growth and 16 alpha-hydroxy-estrone formation was observed. Also, 16 alpha-hydroxylation of estrone was observed in resting cells. 16 alpha-Hydroxylase showed good activity at 3.7 X 10(-4)M of estrone concentration and was completely inhibited by 1.1 X 10(-3)M. These results indicate the presence of a constitutive 16 alpha-hydroxylase in the organism investigated.

Chemical Phenomena↗
PubMed1978

Responses of articular and epiphyseal cartilage zones of developing avian radii to estrone treatment and a 2-G environment.

Female chicks at 2 weeks post-hatch were maintained for 2 weeks at earth gravity or 2 G with daily injections of 0.2 or 0.4 mg estrone. Animals were sacrificed following the last injection and radii were fixed in 10% NBF, decalcified in 3% Nitric acid, doubly embedded, sectioned at 4 to 5 micrometer, and routinely processed for histological measurements of the midcoronal height and width of the cartilage zones of the proximal and distal epiphyses. Estrone treatment increased the growth in height and width of the cartilage layers of the proximal epiphyses and inhibited the growth in height of the distal epiphyseal cartilage of earth gravity chicks. Animal exposure to 2 G without estrone treatment resulted in increased width of the cartilage layers of the proximal epiphyses and inhibition of both height and width growth of the cartilage layers of the distal epiphyses. Growth in height, but not width, of the cartilage layers of both proximal and distal epiphyses was inhibited by combined estrone treatment and animal exposure to the 2 G environment.

Animals↗
PubMed1983

Estrone sulfate concentrations in plasma of normal individuals, postmenopausal women with breast cancer, and men with cirrhosis.

Estrone sulfate is quantitatively the most important estrogen in plasma. A method for its determination in human plasma is described, and the precision, accuracy, sensitivity, and specificity are defined. Free steroids were extracted from plasma with diethyl ether and steroid sulfates were isolated with use of Vlitos' reagent (methylene blue in dilute H2SO4/Na2SO4 solution). After enzymic hydrolysis, estrone was isolated by chromatography on Celite and measured by radioimmunoassay. The mean concentrations (nmol/L +/- 1 SD) of estrone sulfate were 2.51 +/- 0.90 for plasma from 13 women in follicular phase, 5.33 +/- 1.55 for 17 women in luteal phase, 0.89 +/- 0.60 for 44 postmenopausal women, and 0.96 +/- 0.43 for 24 postmenopausal women with breast cancer. Results for postmenopausal women with or without breast cancer did not differ significantly. For 13 normal men, estrone sulfate concentrations were 2.62 +/- 0.79 nmol/L, and for a group of 19 cirrhotic men the mean value was 1.43 +/- 0.95 nmol/L, significantly lower than normal.

Adult↗
PubMed1993

Inhibition of the in vivo conversion of androstenedione to estrone by the aromatase inhibitor vorozole in healthy postmenopausal women.

Vorozole is a new, potent, and highly selective nonsteroidal aromatase inhibitor, which in animal and human studies was found to be about 1000-fold more potent than aminoglutethimide. Almost all aromatase-inhibiting activity resides in the dextro-enantiomer currently undergoing clinical trials. A marked decrease in circulating estrogens was found in several studies of healthy premenopausal women and male volunteers treated with the racemate, referred to as vorozole racemate. To further evaluate the aromatase-inhibiting potency of this drug, the in vivo conversion of androstenedione to estrone was studied in 12 healthy postmenopausal women. Four h after a single oral dose of vorozole racemate, [14C]androstenedione and [3H]estrone were infused at a constant rate for 2 h. Women were randomized to receive vorozole racemate orally in one of three different doses, i.e., 1, 2.5, and 5 mg, in a double-blind protocol. Each woman acted as her own control in an identical experiment with a placebo carried out 2-4 weeks either before or after the test with vorozole racemate. In the urine, collected for 4 days after each experiment, estrogens were extracted and purified until a constant 3H/14C ratio of estrone was achieved. The percentage conversion of androstenedione to estrone in the 12 placebo experiments was 2.19 +/- 0.60% (mean +/- SD, n = 12). Following a single administration of vorozole racemate, the conversion decreased to 0.14 +/- 0.04%. The percentage inhibition was 93.0 +/- 2.5 (n = 4) following administration of 1 mg vorozole racemate; administration of 2.5 or 5 mg resulted in an inhibition percentage of 93.2 +/- 1.6 or 94.4 +/- 1.2, respectively. It is concluded that a single oral dose of 1-5 mg vorozole racemate results in an almost complete inhibition of in vivo aromatase activity.

Aged↗
PubMed1983

Ultrastructure of endometrium of postmenopausal patients on two modes of hormonal therapy: estrone sulfate with or without MPA.

The response of human postmenopausal endometrium to standard, oral doses of an estrogen alone (estrone sulfate) and to an estrogen plus a progestin (medroxyprogesterone acetate; MPA) was evaluated by scanning electron microscopy and transmission electron microscopy. Endometrial biopsies were obtained over a 4-year period from 12 patients with well-established ovarian failure. Biopsies were taken before the initiation of therapy and during each mode of hormonal treatment. The ability of estrone sulfate alone to stimulate growth of the endometrium was shown during the 1st treatment cycle when the atrophic epithelial cells transformed into tall columnar cells which synthesized and released some secretory products. Unopposed estrogen therapy led to excessive ciliation and breakthrough bleeding. Addition of MPA to the estrone sulfate regimen produced a progestational endometrium. The epithelial cells had ultrastructural features of those in normal postovulatory endometrium, including nucleolar channel systems. MPA elicited deciliation and transformation of ciliated cells into secretory cells. Stromal cells hypertrophied, the vascular endothelium thickened, and bleeding subsided. Estrogen-progestin therapy as tremendously more physiological than unopposed estrogen therapy.

Biology↗
PubMed1991

Inhibition of estrone sulfatase enzyme in human placenta and human breast carcinoma.

Estrone sulfatase is an important mechanism of local synthesis of biologically active estrogens in human breast cancer. The human placental microsome and breast carcinoma mitochondrial/microsomal estrone sulfatase activity were characterized and inhibition studies performed. The Km of the placental tissue enzyme was 6.83 microM, Vmax 0.015 nmol/min/mg, and for the breast carcinoma tissue Km was 8.91 microM and Vmax 0.022 nmol/min/mg. Danazol produced a significant inhibition of estrone sulfatase (20% with 50 microM danazol). No significant inhibition was seen in the presence of aminoglutethimide, rogletimide, tamoxifen, 4-hydroxyandrostenedione, stilboestrol, or any metabolites of danazol or tamoxifen. Studies with synthetic and naturally occurring steroids demonstrated that the presence of a sulfate group at the 3 position to be the most important factor in determining inhibition, and the most potent inhibitor was 5 alpha-androstene-3 beta,17 beta-diol-3-sulfate (Ki of 2.0 microM). The naturally occurring 3-sulfated steroids all demonstrated competitive inhibition. These studies could form the basis for the design of a potent estrone sulfatase inhibitor which would have potential therapeutic activity in the management of breast cancer.

Androgens↗
PubMed1996

Effect of nomegestrol acetate on estrone-sulfatase and 17beta-hydroxysteroid dehydrogenase activities in human breast cancer cells.

It is well recognized that estradiol (E2) is one of the most important hormones supporting the growth and evolution of breast cancer. Consequently, to block this hormone before it enters the cancer cell or in the cell itself, has been one of the main targets in recent years. In the present study we explored the effect of the progestin, nomegestrol acetate, on the estrone sulfatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone sulfate (E1S: 5 x 10(-9)M), nomegestrol acetate blocked very significantly the conversion of E1S to E2. In the MCF-7 cells, using concentrations of 5 x 10(-6)M and 5 x 10(-5) M of nomegestrol acetate, the decrease of E1S to E2 was, respectively, -43% and -77%. The values were, respectively, -60% and -71% for the T-47D cells. Using E1S at 2 x 10(-6) M and nomegestrol acetate at 10(-5) M, a direct inhibitory effect on the enzyme of -36% and -18% was obtained with the cell homogenate of the MCF-7 and T-47D cells, respectively. In another series of studies, it was observed that after 24 h incubation of a physiological concentration of estrone (E1: 5 x 10(-9)M) this estrogen is converted in a great proportion to E2. Nomegestrol acetate inhibits this transformation by -35% and -85% at 5 x 10(-7)M and 5 x 10(-5)M, respectively in T-47D cells; whereas in the MCF-7 cells the inhibitory effect is only significant, -48%, at 5 x 10(-5)M concentration of nomegestrol acetate. It is concluded that nomegestrol acetate in the hormone-dependent MCF-7 and T-47D breast cancer cells significantly inhibits the estrone sulfatase and 17beta-HSD activities which converts E1S to the biologically active estrogen estradiol. This inhibition provoked by this progestin on the enzymes involved in the biosynthesis of E2 can open new clinical possibilities in breast cancer therapy.

Breast Neoplasms↗
PubMed1996

Serum Estradiol and Estrone Levels During 3 Weeks of Alternate-Site and Same-Site Applications of a Once-A-Week Drug-in-Adhesive Transdermal Estradiol Patch.

This open-label, randomized crossover trial was conducted in healthy postmenopausal women to characterize the serum estradiol and estrone profiles from a once-a-week transdermal estradiol patch applied repeatedly to the same site or to alternate sites on the abdomen over a 3-week period. Similar mean serum estradiol and estrone profiles and circulating estradiol:estrone ratios of approximately 1.0 were observed for both patch application regimes. Repeated application to the same or alternate sites did not result in an accumulation of exogenous estradiol or in a statistically significant increase in application-site reactions. Although the once-a-week transdermal estradiol patch should be applied to alternate sites to reduce the likelihood of dermatologic reactions, accidental application site overlap should not result in an increase in serum estradiol and estrone concentrations.

Journal Article↗
PubMed1971

Inhibition by estrone of the antiviral protection and interferon elicited by interferon inducers in mice.

The susceptibility of mice to infection with MM virus is markedly increased after treatment with the sex hormone estrone. Studies were undertaken to determine if either suppression of production or interference with the action of interferon was involved in this phenomenon. The protection of mice against MM virus infection by several interferon-inducing agents was partially impeded by estrone treatment either 24 hr before or 24 hr after the administration of the inducing agent. The titers of circulating interferon induced by each of the agents were lower in estrone-pretreated animals than in untreated controls. The protection of mice by exogenous L cell interferon was blocked only when the hormone was given prior to the interferon. It is concluded that the adverse activity of estrone is related to its ability to interfere with the action of interferon.

Journal Article↗
PubMed2002

Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer.

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3 beta,17 beta-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid/estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken to date, as well as possible future development with respect to dual inhibitors of both estrone sulfatase and AR.

Antineoplastic Agents↗
PubMed1996

Lack of tumorigenicity of cholesterol epoxides and estrone-3,4-quinone in the rat mammary gland.

The purpose of this study is to test the long-standing hypothesis that endogenous agents found in human breast fluid and in plasma are potential initiators of breast cancer. Therefore, we evaluated the tumorigenicity in the mammary glands of female CD rats of cholestan-5 alpha,6 alpha-epoxy-3 beta-ol (cholesterol-alpha-epoxide), cholestan-5 beta,6 beta-epoxy-3 beta-ol (cholesterol-beta-epoxide), and 1,5(10)estradiene-3,14,17-trione (estrone-3,4-quinone). As a positive control, trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthren e (BcPDE) was used. Rats were fed a high-fat AIN-76A diet (23.5% corn oil) to mimic the Western dietary composition. Because literature data suggest that the endogenous agents tested in this study are weak electrophiles, the total doses of cholesterol epoxides (12.3 mumol/rat) and of estrone-3,4-quinone (30 mumol/rat)were 10- and 25- fold higher, respectively, than that of BcPDE (1.2 mumol/rat). Each agent was dissolved in DMSO, and one-sixth of the total dose was injected under each of six nipples on the right side. The thoracic glands of the rat were treated at 30 days of age, and those located in the inguinal area were treated on the following day. The experiment was terminated at 44 weeks after treatment. Consistent with our previous study, BcPDE was a strong mammary carcinogen. However, there were no differences between rats treated with DMSO alone or those receiving DMSO containing cholesterol-alpha-epoxide, cholesterol-beta-epoxide, or estrone-3,4-quinone. The results of this study clearly indicate, for the first time, that metabolites derived from cholesterol and estrone lack tumorigenic activity in the rat mammary gland, at least under the conditions of the present protocol.

Animals↗
PubMed2004

Trace level quantification of deuterated 17beta-estradiol and estrone in ovariectomized mouse plasma and brain using liquid chromatography/tandem mass spectrometry following dansylation reaction.

A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method coupled with dansylation was developed for the simultaneous quantification of exogenously administered deuterated 17beta-estradiol-d4 (E2-d4) and its metabolite, estrone-d4 (E1-d4), in mouse plasma and brain homogenates. The dansylation reaction was simple, fast, and sensitive, and a lower limit of quantification of 50 pg/mL was achieved by using 50 microL of mouse plasma. Interference from endogenous 17beta-estradiol and estrone in plasma and brain samples was minimized by the use of deuterated-E2 as well by utilizing ovariectomized (OVX) mice. The recovery of dansylated derivative exceeded 83% and the reaction was completed within approximately 3 min. The intra- and inter-day assay precision were better than 12.9% and assay accuracy ranged between 92-104% for E1-d4 and E2-d4 in plasma, respectively. The absorption of E2-d4 at both 1 and 3 mg/kg P.O. was rapid, reaching peak plasma concentrations (Cmax) at 5 min post-dose that was the earliest time point obtained, and were 1.1 and 13.8 ng/mL, respectively; the Cmax values for the estrone metabolite, E1-d4, were 1.1 and 43.2 ng/mL, respectively. The area-under-the-plasma-time curve (AUC(0-2 h)) values were determined to be 0.65 and 2.90 ng. h/mL for E2-d4 and 0.77 and 6.74 ng. h/mL for E1-d4, respectively, at 1 and 3 mg/kg. The mean brain-to-plasma ratio for E1-d4 and E2-d4 after P.O. administration of E2-d4 to the OVX mice at 1 and 3 mg/kg indicated that both E1-d4 and E2-d4 were present in the brain as well as in the circulation.

Animals↗
PubMed1977

Effects of increased earth gravity and estrone treatment on intact and healing avian radii.

Estrone, 0.4 mg administered daily for 7 days to developing chicks at 2 weeks post hatching, increased total mass and accelerated the rate of growth of the diaphyseal and proximal epiphyseal diameters of intact radii. Fractured radii of animals subjected to the same hormonal treatment displayed decreased bone weight but increased rate of growth of the proximal epiphyseal diameters and longer but thinner and lighter calluses. Two-week-old chicks, which had received no estrone, when exposed to a week-long 2g environment showed decreased intact bone weight and, with the exception of length of fracture callus, a reduction of all measured parameters of fractured bones. Estrone treatments of 0.4 mg administered daily to hypergravity-exposed animals over a week-long period resulted in greater length of fracture callus and increased rate of growth of the proximal epiphyseal diameter of both intact and fractured bones. The same treatments decreased weight and linear growth of fractured bones and width and weight of the fracture callus.

Animals↗
PubMed2003

Immunosensor for estrone with an equal limit of detection as common analytical methods.

Immunoanalytical methods at a very low limit of detection (LOD) and a low limit of quantification (LOQ) are becoming more and more important for environmental analysis and especially for monitoring drinking water quality. Biosensors have suitable characteristics such as efficiency in allowing very fast, sensitive, and cost-effective detection. Here we describe a fully automated immunoassay for estrone with a LOD below 0.20 ng L(-1) and a LOQ below 1.40 ng L(-1). In contrast to common analytical methods such as GC-MS or HPLC-MS, the biosensor used requires no sample pre-treatment and pre-concentration. The basis of our sensitive assay is the antibody with a high affinity constant towards estrone. The very low amount of antibody per sample results in low validation parameters (LOD, LOQ, and IC50), but this assay for estrone represents the current device-related limitation of the River Analyser (RIANA).

Automation↗
PubMed1978

Effect of obesity on conversion of plasma androstenedione to estrone in ovulatory and anovulator young women.

The purpose of this study was to evaluate the transfer constant of conversion of plasma androstenedione to estrone ([p]AE1BU) as a function of total body weight and excess body weight in ovulatory and anovulatory young adult women. Twenty-four ovulatory and 31 anovulatory women were studied; their weights ranged from 90 to 350 pounds. The [p]AE1BU among these women ranged from 0.006 to 0.048. The extent of conversion of plasma androstenedione to estrone was significantly correlated with total body weight and with excessive body weight in both ovulatory and anovulatory young women. However, the mean [p]AE1BU for the anovulatory women (0.018) was not significantly different from that of the ovulatory women (0.015). Indeed, when the [p]AE1BU values of ovulatory and anovulatory women of similar total body weight or excessive body weight were compared, no difference was found in the extent of conversion of plasma androstenedione to estrone between the two groups.

Adolescent↗
PubMed1979

Studies on the chaotropically solubilized arylsulfatase C and estrone sulfatase of sheep brain.

Arylsulfatase C (aryl-sulfate sulfohydrolase, EC 3.1.6.1) from sheep brain acetone powder was solubilized with the chaotropic agent, KSCN. Anti-chaotropes such as (NH4)2SO4 or sodium citrate significantly enhanced the activity of the solubilized enzyme indicating that hydrophobicity was an important factor influencing the enzyme activity. Dialysis or gel filtration of the solubilized enzyme resulted in a marked loss of activity. 3a dialyzable activator could reconstitute the activity in the presence of the antichaotropes. The activator was purified partially and preliminary studies indicated it to be a low molecular weight peptide. Arylsulfatase C and estrone sulfatase activities were compared in the solubilized enzyme. Estrone sulfatase activity was also increased in the presence of antichaotropes at lower concentration in comparison to arylsulfatase C. It however did not show a requirement for the dialyzable activator. Kinetic studies showed that elevation of enzyme activity by the antichaotropes and activator in the case of arylsulfatase C and by antichaotropes in the case of estrone sulfatase was due to an increase in V with a decrease in Km.

Ammonium Sulfate↗
PubMed1990

Hormonal determinants of apolipoprotein B,E receptor expression in human liver. Positive association of receptor expression with plasma estrone concentration in middle-aged/elderly women.

The relationships of the expression of hepatic low-density lipoprotein (LDL) receptors (apo B,E receptors) to several plasma hormone concentrations were examined in 15 fasted women aged 37-75 years (mean, 57 years), who were undergoing laparotomy for non-neoplastic disease. No subject had clinical or biochemical evidence of familial hypercholesterolemia, renal disease, hepatic disease, or endocrine disease. Hepatic apo B,E receptor expression was quantified in vitro as the EDTA-suppressible binding of 125I-labeled human LDL (15 micrograms protein/ml) by liver homogenate at 37 degrees C; values were 23-75 ng LDL protein/mg cell protein (mean, 47 ng/mg). Receptor expression was strongly correlated with plasma estrone concentration (rs = +0.70, P = 0.035), but was unrelated to the concentrations of testosterone, thyroxine, free triiodothyronine, cortisol, sex hormone-binding globulin (SHBG) or cortisol-binding globulin. Insulin and estradiol concentrations were mostly very low. The correlation of receptor expression with plasma total estrone concentration reflected associations with both the albumin-bound (rs = +0.78, P = 0.014) and unbound (rs = +0.80, P = 0.009) fractions, but not with the SHBG-bound fraction (rs = -0.22, P = 0.574), of this hormone. As the non-SHBG-bound fractions of gonadal steroids are considered to be the biologically active components, these results are consistent with experimental evidence that the synthesis of apo B,E receptors in hepatocytes is stimulated by estrogens, and suggest that circulating estrone may be the major hormonal determinant of receptor expression in fasted middle-aged/elderly women.

Adult↗
PubMed1979

Enzymatic determination of estradiol and estrone in plasma and urine.

Plasma and urine estradiol and estrone can be determined using the transhydrogenase function of the estradiol dehydrogenase of human placenta: in the conditions described the transhydrogenase activity which is directly related to the estrogen concentration is measured by spectrophotometry. Estrone and estradiol can be determined together or separately if estrone is previously reacted with hydrazine with a limit of sensitivity of 10 picograms in the sample. On urine samples the assay is performed directly without extraction, a simplification which makes the method highly suitable for numerous routine determinations.

Estradiol↗