estrone-sulfate and estrone-3-glucuronide

The pharmacokinetics of oral 17 beta-estradiol (E2) were evaluated: only a limited amount of information is available on the subject. Because of the first passage hepatic effect, the blood levels of estrone (E1) are greater than those of E2; similar profiles exist for oral E1 sulfate, micronized E2 and E2 valerate. However, the short-term effects of oral E2 versus E1 on hepatic parameters may vary somewhat. Peak levels of E1 and E2 are achieved four hours after the administration of 1 mg of E2 and average 200 and 40-50 pg/mL, respectively. A dose-response relationship exists for serum levels achieved after oral E2 administration. Twelve-hour values are representative of the 24-hour profile. With prolonged use, the 24-hour levels may be equally representative and serum E2 levels increase, suggesting some cumulative effects. Smoking enhances the hepatic metabolism of oral estrogen and results primarily in a lower unbound E2 level.

Topics: Administration, Oral; Dose-Response Relationship, Drug; Drug Compounding; Estradiol; Estrone; Humans; Sex Hormone-Binding Globulin; Smoking

Transfer of steroidal and nonsteroidal compounds across guinea pig amnion and chorion laeve was investigated as a function of stage of gestation, tissue orientation, steroid specificity, and molecular size. Each fetal membrane was examined at early and late stages of gestation, before and after pubic symphysis relaxation. Early amnion was impermeable to macromolecules and small charged molecules while [3H]estrone and [3H]pregnenolone were transferred, the latter depending on tissue orientation and involving conjugation at the basolateral interface. After symphysis dilation, amnion transferred all substrates tested with the exception of BSA; the molecular weight cutoff was approximately 5,000. Unlike amnion, early chorion transferred both free and conjugated steroids as well as inorganic sulfate. Transfer of estrone involved conjugation and depended on tissue orientation. Transfer of [3H]estrone-sulfate, [3H]estrone-glucuronide, and [3H]pregnenolone-sulfate was similar despite selective deconjugating activity toward estrone-sulfate. Near term, chorion was impermeable to inorganic sulfate and transfer of estrone-glucuronide depended on tissue orientation, involving deconjugation in the maternal to fetal direction. At no stage of gestation did chorion transfer macromolecules. These results suggest that the transfer of free and conjugated steroids across fetal membranes is differentially regulated by tissue, its stage of development, and direction of transfer.

Topics: Amnion; Animals; Chorion; Estrogens, Conjugated (USP); Estrone; Extraembryonic Membranes; Female; Gestational Age; Guinea Pigs; Pregnancy; Pregnenolone; Steroids

Oestrogen was measured in urine samples collected from captive females representing 7 species of New World monkey to provide an overview of the applicability of such formation in the noninvasive monitoring of ovarian function and to assess the potential applicability of such information in phylogenetic studies. Species available for study were the pygmy marmoset, common marmoset, red-bellied tamarin, cotton-top tamarin, golden lion tamarin, Goeldi's monkey and the owl monkey. Oestrone conjugates were measured in serially collected urine samples to demonstrate ovarian cyclicity. Urine samples obtained during the luteal phase were subjected to HPLC to identify immunoreactive oestrogens; oestrone and oestradiol-17 beta accounted for almost all of the immunoreactive oestrogen detected while oestriol content was negligible. Urine samples obtained during the follicular phase and luteal phase were subjected to glucuronidase hydrolysis, sulphatase hydrolysis and acid solvolysis, which revealed that the major immunoreactive oestrogen metabolite was: (1) oestradiol sulphate in the pygmy marmoset and common marmoset, (2) residual oestradiol in the red-bellied tamarin, (3) residual oestradiol and oestrone glucuronide in the cotton-top tamarin, and (4) oestrone glucuronide in the golden lion tamarin, Goeldi's monkey and owl monkey. A phylogenetic tree based on the above shifts in oestrogen excretion suggested that clawed New World monkeys are specialized and that the lineages leading to the study species split off in the following order: Goeldi's monkey, golden lion tamarin, cotton-top tamarin, red-bellied tamarin, common marmoset and pygmy marmoset.

Topics: Animals; Aotidae; Biological Evolution; Callithrix; Cercopithecidae; Estradiol; Estrogens; Estrone; Female; Menstrual Cycle; Monitoring, Physiologic; Ovary; Phylogeny; Radioimmunoassay; Reproducibility of Results; Saguinus; Sensitivity and Specificity; Species Specificity

To determine the absorption and metabolism of 17 beta-estradiol (E2) by the stomach and liver of the pig, crystalline E2 was placed in the stomach of prepubertal gilts. Blood samples were subsequently obtained from the hepatic portal and jugular veins and plasma was assayed for E2, estrone (E1), 17 beta-estradiol-glucuronide (E2G), estrone-glucuronide (E1G) and estrone-sulfate (E1S). Concentrations of E2, E1, E2G and E1S rose in the hepatic portal vein within five min and remained elevated for several hr. Concentration of E2 represented only 6% of the total estrogen detected in the hepatic portal vein during the sampling period, indicating that most of the E2 was converted or conjugated prior to entering the hepatic portal vein. The metabolism of E2 presumably occurred in the stomach mucosa because food had been withheld for 26 hr before infusion of E2. Concentrations of E2G, E1G and E1S, but not E2 and E1, rose in the jugular vein and remained elevated for several hr. The lack of a rise in E2 and E1 in the jugular vein indicates that the E2 and E1 from the hepatic portal vein were completely converted and/or removed by the liver. Most of E2 was converted to E1 and then to E1G. The infusion of bile containing normal estrogens from pregnant gilts into the duodenum of prepubertal gilts resulted in a peak of E1G and E2G in the hepatic portal and jugular veins within a few minutes. This was followed in about 180 min by a second sustained rise. The first peak was essentially abolished by extracting E1 and E2 from the bile before infusion. The second peak failed to occur in gilts given antibiotics orally to reduce gut bacteria before infusion of bile.

Topics: Absorption; Animals; Duodenum; Estradiol; Estrone; Female; Gastric Mucosa; Intestinal Absorption; Jugular Veins; Kinetics; Liver; Portal Vein; Swine

Normal AXC/SSh rat ventral prostate and clonally derived AXC/SSh rat prostate cancer cells were evaluated for ability to metabolize estrone sulfate (E1S), estrone glucuronide (E1G), or dehydroepiandrosterone sulfate (DHEAS). Both normal and malignant prostate cells converted E1S to estrone. Neither normal nor malignant prostate cells had significant ability to metabolize DHEAS to DHEA, indicating differential specificity of prostate sulfatases(s) for estrogen and androgen sulfates. Both normal and neoplastic prostate cells possess beta-glucuronidase which hydrolyzed E1G to estrone. To assess potential physiologic consequences of these enzymatic activities, we determined the effect of steroid conjugates on in vitro proliferation of selected clonal lines of AXC/SSh rat prostate cancer cells. DHEAS, 10(-6) to 10(-9) M in decade intervals, did not affect in vitro proliferation of AXC/SSh prostate cancer cells; however, 10(-5) M DHEAS decreased in vitro proliferation of these cells. Neither E1S nor E1G, 10(-5) to 10(-9) M in decade intervals, affected in vitro proliferation of AXC/SSh prostate cancer cells. These findings suggest that low residual levels of steroid conjugates, which are not removed by charcoal stripping of serum, do not affect demonstrated in vitro androgen modulation of AXC/SSh rat prostate cancer cell proliferation (Cancer Res. 46, 3775-3781, 1986).

Topics: Animals; Cell Division; Cell Line; Clone Cells; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estrogens, Conjugated (USP); Estrone; Male; Prostate; Prostatic Neoplasms; Rats

The absorption of oestrone (E1), oestrone glucuronide (E1G) and oestrone sulphate (E1S) from the small intestine of anaesthetized rats has been evaluated using the Doluisio in situ technique. Luminal disappearance of E1 was biphasic, which is consistent with a 3-compartment model; t1/2 alpha (first phase) was less than 5 min and t1/2 beta (second phase) approx 27 min for each concentration of steroid studied (trace identical to 10 nM, 1 microM and 10 microM). In contrast, luminal disappearance of E1G and E1S was monoexponential; t1/2 for E1G was 159, 229 and 299 min (trace identical to 200 nM, 10 microM and 100 microM respectively) and for E1S, 215, 174 and 192 min (trace identical to 10 nM, 10 microM and 100 microM respectively). There was a good correlation between the luminal disappearance data and recovery of steroid in bile. Adsorption of E1S was estimated from the initial rapid fall in luminal content within the first 5 min after drug administration. The study provides further evidence that E1S can be absorbed intact. Since saccharolactone only caused a reduction in E1G absorption of 32% we also conclude that part of the administered E1G was absorbed intact.

Topics: Animals; Bile; Estrone; Female; Half-Life; Intestinal Absorption; Intestine, Small; Methods; Rats; Rats, Inbred Strains

Incubation of nanomolar concentrations of [3H]estrone with ovine liver slices from adult and fetal animals demonstrated, in particular, the production of estrogen sulfates together with smaller amounts of glucuronides, even although microsomal estrogen glucuronyltransferase (GT) and sulfatase activities were high, especially in adult tissue. [3H]Estriol was conjugated almost exclusively as sulfate under the same experimental conditions. Slices of maternal and fetal kidney medulla were also strikingly active in promoting estrogen sulfate production as were slices of fetal kidney cortex. Adult kidney cortex conjugated estrogen only in the glucuronide form. These data indicate the possibility that maternal and fetal liver and kidney might contribute to the high circulating level of estrone sulfate in the pregnant sheep. Through the use of [3H]estrone and [3H]estrone sulfate as substrates, it was possible to demonstrate that adult slices of kidney medulla possessed relatively low sulfatase, considerable sulfotransferase (ST), and virtually no GT activity, whereas cortex had high sulfatase, little or no ST, and low, though demonstrable, GT activity. The ST activity of kidney high-speed supernatants was stimulated by the presence of sulfhydryl groups, whereas that in liver was not. Enzymic reduction of estrone and (or) estrone sulfate by liver and kidney slices indicated that, in the former, 17 alpha-reduction prevailed and, in the latter with the exception of the maternal medulla, 17 beta-reduction was the main pathway, particularly in the fetus.

Topics: Animals; Estriol; Estrogens, Conjugated (USP); Estrone; Female; Fetus; Glucuronosyltransferase; In Vitro Techniques; Kidney; Kidney Cortex; Kidney Medulla; Liver; Pregnancy; Sheep; Sulfatases

The biliary excretion of steroid after administration of [3H]oestrone ([3H]E1), [3H]oestrone glucuronide ([3H]E1G) and [3H]oestrone sulphate ([3H]E1S) into the hepatic portal vein of anaesthetized rats was very rapid with more than 70% of E1S and greater than 80% of E1 and E1G excreted in the first 30 min. There was a lag period in the biliary excretion of E1S, this was less apparent with E1 and absent with E1G. Biliary excretion accurately reflects the amount of steroid in the portal circulation and was therefore used as an assessment of absorption from the gastrointestinal (GI) tract. Absorption (as judged by excretion in bile) was least after administration of each steroid into the stomach. The extent of absorption correlated well with the lipophilicity of the steroids as shown by their relative partition coefficients between n-octanol and pH 6.5 phosphate-buffered saline (E1 greater than or equal to E1S greater than or equal to E1G). There was no significant difference in excretion profile when the steroids were given into the caecum (at 5 h, E1, 46.3 +/- 9.1%; E1G, 42.2 +/- 14.5%; E1S, 39.9 +/- 7.1%). The similarity, despite marked differences in physicochemical properties, suggested conjugate hydrolysis to the parent steroid. In contrast, after administration into the small intestine, excretion of E1 was very rapid and was maximal at 1 h (72.5 +/- 8.0%); E1G showed a near-linear excretion rate (1 h, 14.4 +/- 3.0%; 5 h, 80.0 +/- 11.7%), whereas in comparison E1S excretion was low (1 h, 12.1 +/- 2.4%; 5 h, 36.9 +/- 2.7%). The involvement of hydrolytic enzymes in conjugate absorption was assessed. Ampicillin pretreatment (200 mg/kg/day for 2 days) reduced the absorption of E1G from both the proximal and distal small intestine (by approximately 50%) but had no effect on the absorption of E1S. There was, therefore, evidence that quantitative absorption of E1G requires prior hydrolysis (by mammalian and/or microbial enzymes) but intact absorption of E1S from this region of the tract was implicated. Ampicillin pretreatment reduced the absorption of both conjugates (greater with E1S) from the caecum; hydrolysis clearly precedes absorption from the caecum. The above findings were supported by an in vitro study which showed that ampicillin pretreatment abolished the hydrolysis of E1S by caecal contents but only partially reduced the hydrolysis of E1G. The presence of mammalian glucuronidase enzyme may account for this difference.

Topics: Ampicillin; Animals; Bile; Cecum; Digestive System; Estrone; Female; Gastric Mucosa; Hydrolases; Hydrolysis; Intestinal Absorption; Intestine, Small; Rats; Rats, Inbred Strains

Non-invasive methods for monitoring reproductive status based on the measurement of urinary steroid conjugates were examined. Levels of urinary oestrone-3-glucuronide, oestrone-3-sulphate, oestradiol glucuronide, oestradiol sulphate and pregnanediol-3 alpha-glucuronide were determined during the ovarian cycle and pregnancy. Sequential hydrolysis showed oestradiol conjugates to be more abundant than oestrone conjugates. The levels of sulphates and glucuronides were similar in the follicular phase whereas sulphates predominated during the luteal phase and pregnancy. Although levels of oestrone-3-sulphate were two- to fourfold lower than those of oestradiol sulphate, measured after hydrolysis, the profiles throughout the cycle and pregnancy were similar. Levels of oestrone-3-sulphate, measured by direct assay, were below 1 mumol/mmol creatinine during the follicular phase, rising 3-4 days after ovulation to reach maximum values (2-8 mumol/mmol creatinine) in the mid-luteal phase. There was no consistent increase before ovulation. Levels during pregnancy rose gradually until days 70-90, after which there was no further increase (gestation length = 144 days). The pattern of pregnanediol-3 alpha-glucuronide was similar to that of oestrone-3-sulphate during the ovarian cycle but levels did not increase during pregnancy. The patterns of excretion of oestrogen and progesterone metabolites were similar to the pattern of the circulating hormones during the ovarian cycle. Circulating and urinary hormone patterns were similar for oestrogens throughout pregnancy but pregnanediol-3 alpha-glucuronide did not reflect progesterone secretion beyond day 70 of gestation.

Topics: Animals; Callitrichinae; Estradiol; Estrogens, Conjugated (USP); Estrone; Estrus; Female; Pregnancy; Pregnancy, Animal; Pregnanediol; Progesterone

Urine samples were collected daily during ten nonfertile and four fertile ovarian cycles of four adult female lion-tailed macaques (Macaca silenus). Urine was analyzed for concentrations of total immunoreactive estrogen (Et), estrone conjugates, and bioactive luteinizing hormones (LH). The estrone conjugates of selected samples were separated by high-performance liquid chromatography (HPLC) to evaluate the relative proportions of estrone glucuronide (E1 G) to estrone sulfate (E1 S) contributing to the sum total of the conjugate measured in the samples. The estrone conjugate profile was found to accurately reflect the preovulatory estrogen peak in both nonfertile and fertile cycles as well as the early pregnancy increase which was found to be statistically significant on Day + 14 postovulation (P = 0.003). Estrone conjugate levels rose in the early follicular phase from 126.00 +/- 24.07 (SEM) ng/mg creatinine to a preovulatory peak of 471.90 +/- 62.95 ng/mg creatinine. Fertile cycles exhibited a postovulatory climb to a peak of 515.00 +/- 38.00 ng/mg creatinine on Day + 19, in contrast to the secondary rise observed in nonfertile cycles that peaked at 148.11 +/- 13.80 ng/mg creatinine on Day + 10. Bioactive LH evaluations confirmed ovulation and, in the fertile cycles, reflected the subsequent elevation of chorionic gonadotropin on Day + 18. The estrone conjugate profile of fertile cycles and early pregnancy compared favorably to the Et profile: both showed the same time course and increases in estrogen excretion.

Topics: Animals; Animals, Zoo; Creatinine; Embryo Implantation; Estrogens; Estrone; Female; Luteinizing Hormone; Macaca; Ovulation; Pregnancy

One minute after instillation of 14C-estradiol-17 beta (14C-E2 17 beta) into selected sections of the gastrointestinal tract of swine, radioactive estradiol metabolites were present in blood collected from the portal and jugular veins. Ether was used to extract free but not conjugated estrogens. The percentage of plasma radioactivity that was ether extractable (EE) was low in portal plasma and even lower in jugular plasma following instillation of 14C-E2 17 beta into the stomach, ileum and colon. EE radioactivity was not detectable in either portal or jugular plasma when estradiol was instilled into the duodenum or jejunum. Therefore, estrogens were conjugated either in the lumen of the gastrointestinal tract or as they crossed the intestinal mucosa. The liver played only a minor role in conjugation of these steroids, since the estrogen metabolites present in portal plasma were very similar to those in jugular plasma, and metabolites in the urine were similar to those in plasma. The principal estrogen conjugate found in both portal and jugular plasma, regardless of the gastrointestinal section into which 14C-E2 17 beta was instilled, was estrone glucuronide. There was no uniform metabolic pattern observed in the metabolites of estradiol that remained in the lumen of each gastrointestinal section; however, many metabolic transformations occurred. We concluded that almost all estrogens absorbed were metabolized during the absorption process. The liver was active only in the metabolism of estrogens that escaped conjugation in the intestinal mucosa.

Topics: Animals; Digestive System; Estradiol; Estrone; Female; Intestinal Absorption; Jugular Veins; Liver; Portal Vein; Swine

The absorption, metabolism and clearance of oestradiol, oestrone and oestriol from the peripheral circulation were investigated in five postmenopausal women after the oral administration of Hormonin (oestradiol 600 micrograms, oestrone 1400 micrograms, oestriol 270 micrograms) daily for five consecutive days. In addition the concentrations of plasma oestrone-3-sulphate, oestrone-3-glucuronide, LH and FSH were determined in the same plasma samples. The maximum concentration of each steroid in peripheral plasma and the time intervals during which the peak occurred after ingestion of the last tablet were: -oestrone (750 to 2116 pmol/l, 0.5 to 6.0 hours), oestradiol (246 to 813 pmol/l, 1 to 8 hours), oestriol (173 to 241 pmol/l, 5 to 12 hours), oestrone-3-glucuronide (32.2 to 78.8 nmol/l, 0.5 to 3.0 hours) and oestrone-3-sulphate (21.9 to 39.0 nmol/l, 1 to 7 hours). The mean factorial increases in the concentration of each compound during the first 12 hours post-treatment over the baseline values were: -oestrone (4.1); oestradiol (4.4); oestriol (1.7); oestrone-3-sulphate (2.6) and oestrone-3-glucuronide (8.1). After treatment, the concentration of plasma oestradiol remained significantly higher than the baseline values (p less than 0.025) for 24 hours and the values for each subject were within the normal range of premenopausal women. Moreover, there was a significant reduction (p less than 0.025) in the level of circulating LH. It is concluded that the simultaneous administration of oestrone, oestradiol and oestriol, by mouth, to postmenopausal women is a good approach to maintaining an appropriate concentration of oestradiol in peripheral plasma.

Topics: Adult; Estradiol; Estriol; Estrogens; Estrone; Female; Follicle Stimulating Hormone; Glucuronates; Humans; Intestinal Absorption; Luteinizing Hormone; Menopause; Middle Aged