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Maternal serum progesterone, 17 beta-estradiol and estriol are increased in pregnancies which follow treatment with human menopausal gonadotropins: effects of multiple gestation and maternal endocrine status.

A high incidence of premature labor, incompetent cervix and fetal wastage occurs in multiple gestations which follow treatment with human menopausal gonadotropins (HMG). In order to determine the effect of treatment with HMG on hormone secretion in human pregnancy, progesterone (PROG), 17 beta-estradiol (E2), estriol (E3) and human chorionic gonadotropin (hCG) were determined by radioimmunoassay in 341 serum specimens from 229 normal singleton pregnancies and in 79 serum specimens from 20 pregnancies following induction of ovulation with HMG in women with either hypothalamic amenorrhea (HA) or the polycystic ovary syndrome (PCO). Fitting equations were found for the log transformed normal values and the residuals were obtained by subtraction of the predicted normal values from the log transformed values observed in the HMG pregnancies. In pregnancies which followed treatment with HMG, PROG and E2 were initially elevated above normal. As pregnancy progressed, the deviation from normal became proportionately less. PROG (P less than 0.025) was lower and E2 (P less than 0.025) and E3 (P less than 0.05) were higher in PCO pregnancies than in HA pregnancies. Multiple gestation produced increases in PROG (P less than 0.005), E2 (P less than 0.005) and E3 (P less than 0.001) in comparison to singleton pregnancies.

Amenorrhea↗

Reduced estriol and dehydroepiandrosterone sulphate plasma levels in methadone-addicted pregnant women.

The plasma levels of human chorionic somatomammotropin (hCS), estriol (E3), dehydroepiandrosterone sulphate (DHA-S), cortisol and the circadian changes of the two last adrenal hormones were studied in 25 pregnant methadone-addicted women (MA) and 21 pregnant drug-naive controls (C) at different periods of gestation and in 13 non-pregnant women (7 MA and 6 drug-naive). MA pregnant women showed normal plasma levels of hCS both at the second (6.9 +/- 0.1 vs. 7.2 +/- 0.1 micrograms/ml) and third (9.6 +/- 0.2 vs. 9.3 +/- 0.2) trimester, while plasma concentrations of E3 at term were lower than normal (MA: 4.4 +/- 0.8; C: 8.2 +/- 1.0 ng/ml, P less than 0.05). DHA-S plasma levels of MA pregnant women were half the normal values in three trimesters of gestation, while there were no differences in non-pregnant subjects. Circadian variations of cortisol and DHA-S plasma levels were present in both MA and C. The blunted DHA-S but normal cortisol plasma levels found in MA pregnant women indicate that opiate abuse interferes with adrenal function, mainly of the fetus. Due to the scarce availability of adrenal precursors, these data suggest that E3 measurements should not be considered as a useful index of fetal well-being in the presence of opiate addiction.

Adult↗

A rapid method for the estimation of estriol in plasma during pregnancy.

A rapid, reliable fluorimetric method for the determination of estriol (E3) in plasma is described. The method is eminently suitable for use in hospital laboratories and provides results within 5 hours of the reception of samples. It has several features not found in other methods. As little as 0.2 ml of plasma is required, all additions and aliquoting procedures are semi-automated an no special technical skill is necessary. A technician can carry out 20 determinations per day. Average recoveries of 70% are routinely achieved, and the accuracy (2.4%) and the precision (4.0%) of the method are remarkably good for an assay of this type. A spectrofluorometer of high sensitivity, counting equipment and a high temperature oven are the essential major pieces of equipment.

Estriol↗

Polyamine biosynthetic decarboxylase activities following estradiol-17 beta or estriol stimulation of the immature rat uterus.

Following a single intraperitoneal injection of 0.5 microgram estradiol-17 beta (E2) into immature female rats uterine ornithine decarboxylase (ODC) activity increased to a peak at 4 hours postinjection. It decreased to intermediate levels by 6 hours and remained elevated until returning to control levels by 18 hours. When either 0.5 microgram estriol (E3) or 0.05 microgram E2 was injected, activity increased to a 4 hour ODC peak then decreased to control levels by 10 hours. The decrease to intermediate levels of ODC activity after dosing with 0.5 microgram E2 occurred at the same time activity decreased to control levels following treatment with either 0.05 microgram E2 or 0.5 micrograms E3. S-Adenosyl methionine decarboxylase (SAMDC) activity had increased by 4 hours following an injection of 0.5 microgram E2 and remained elevated until 16 hours then decreased to control levels. An injection of 0.05 microgram E3 stimulated only a 4 hour peak after which time SAMDC decreased to control levels by 14 hours. After an injection of 5.0 microgram E2 SAMDC activity had increased by 4 hours and remained elevated for the remainder of the experiment (16 hours). Decreases in ODC activity following 4 and 10 hours may reflect a decrease in nuclear estrogen receptor levels. The ODC activity seen here following 0.5 microgram E2 injection is similar in timing to that seen in other proliferating systems and may be due to a common mechanism.

Adenosylmethionine Decarboxylase↗

Rat uterine polyamine biosynthetic decarboxylase activities following multiple injections of estradiol-17 beta and/or estriol.

A single injection of 0.5 micrograms estradiol-17 beta (E2) plus 0.5 micrograms estriol (E3) stimulated a different pattern in 22-24 day-old rat uterine ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAMDC) activities than was induced by either a single injection of 0.5 micrograms E2 or multiple injections of 0.5 micrograms E3. Differences included alterations in enzyme activity peak timing as well as activity duration. Every 3 hour injections of 0.05 micrograms E2 induced maximum uterine ODC activity at 4, 24, 32, and 40 hours, intermediate activity at 48, 64, and 72 hours as well as a small peak by 56 hours. When 0.05 micrograms E2 plus 0.05 micrograms E3 were injected simultaneously every 3 hours, the ODC activity pattern was similar except that activity fell to intermediate levels by 40 hours. It is suggested that E3 alterations of E2 induced uterine enzyme activities (when monitored at frequent intervals) could be physiological alterations in uterine growth responses due to E2-E3 hormone interactions. However, there appeared to be no differences between E2 or E2 plus E3 induction of DNA synthesis and luminal epithelial cell height and cross-sectional area or ODC and SAMDC activities when measured at 24, 48, or 72 hours.

Adenosylmethionine Decarboxylase↗

Correlation of concentrations of estriol-3-sulfate with those of potassium and sodium in human breast cyst fluid.

Estriol-3-sulfate (E3-3S) was assayed in 92 specimens of human breast cyst fluid (BCF) obtained by needle aspiration from women with fibrocystic disease. The concentrations of K+ and Na+ were determined in the same samples. The median concentration of E3-3S in the fluids from premenopausal women under 51 years of age (69 cases) was 4.4 ng/mL. Based on the K+ levels the samples were divided into two groups, above 50 mM (Type I) and below 50 mM (Type II). Correlations were made between the concentrations of the estrogen conjugate and the univalent ions. In the premenopausal women, Type I cysts were associated with above median E3-3S and Type II cysts with below median E3-3S (P less than 0.01). A K+/Na+ ratio of more than one was also related to elevated E3-3S (P less than 0.025). The BCF obtained from postmenopausal women and women older than 50 years tended to be low in E3-3S (median 1.64 ng/mL) and high in K+ but there were too few cases to permit statistical comparisons to be made. Since fibrocystic disease constitutes a risk factor for the development of breast cancer, it will be of interest to determine retrospectively whether any of the above subsets of BCF may be useful in identifying a patient at such risk.

Adult↗

Quantification of the sulfates of 16 alpha-hydroxy androgens that are possible precursors of estriol-3-sulfate in human breast cyst fluid.

The concentration of 16 alpha-hydroxydehydroepiandrosterone-3-sulfate (16 alpha-OHDHAS) was determined in 29 samples of human breast cyst fluid (BCF) and in 15 of these, androst-5-ene-3 beta,16 alpha,17 beta-triol-3-sulfate (A-TriolS) was also assayed. The median value of both was about 100 ng/mL and the ranges were from 1.4 to about 1800 ng/mL. There was a significant association in the values for the two sulfates (p less than 0.05). These concentrations are consistent with a role for 16 alpha-hydroxy androgens as possible precursors for estriol-3-sulfate. The latter is highly elevated relative to other body fluids in BCF. The androgens also correlated directly with the concentrations of K+, an indicator of apocrine proliferation of breast cysts.

Androstenols↗

Modulation of food intake by hypothalamic implants of estradiol benzoate, estrone, estriol and CI-628 in female rats.

ovariectomised rats were implanted unilaterally with cannulae aimed at the ventromedial nucleus-arcuate region of the hypothalamus. Crystalline implants of estradiol benzoate and of the antiestrogenic compound CI-628 over a 72-hour stimulation period caused significantly greater food intake reductions than did implants of cholesterol. More dorsal and lateral placements were generally ineffective in reducing food intake. Implants of estrone and estriol produced equivalent reductions in food intake and body weight to those produced by estradiol benzoate. The possible molecular mode of action is discussed.

Animals↗

Effects of estradiol-17 beta and estriol on their binding sites in the rabbit uterus.

1. Receptors for estradiol-17 beta (E2) and estriol (E3) were detected in the rabbit uterus. 2. Saturation analysis of estrogen binding sites in the cytosol showed that the dissociation constants of E2 and E3 for the high affinity binding sites were 1.8 +/- 0.5 nM and 2.3 +/- 0.3 nM, respectively, when dextran-coated charcoal was used to isolate free and bound ligands. 3. To eliminate non-specific (cross) bindings to their receptors, effects of unlabeled E2 and E3 on [3H]E3 and [3H]E2 bindings was examined. 4. [3H]E2 cytosol binding was observed to be specific for E2 and [3H]E3 cytosol binding was more specific for E3. 5. E2 priming to rabbits increased the binding sites for both E2 and E3, which was also more potent than E3 priming. 6. Moreover, the increase in E2 binding sites was greater than that in E3 binding sites. 7. These findings may suggest that there are separate binding sites for E2 and E3 in rabbit uterus and that synthesis of their binding sites is regulated by E2 but not E3.

Animals↗

Estriol binding in uterine corpus cancer and in normal uterine tissues.

1. The specific bindings of estriol (E3) and estradiol-17 beta (E2) to their specific receptors were investigated in endometrial carcinoma from 7 patients and normal tissues from their respective organs or from other patients. 2. In both cytosolic and KCl-extracted fractions from them, specific binding sites for E3 and E2 were detected, demonstrating the presence of their separate receptors in human uterus-associated tissues. 3. In certain cases (6 cases) of well-differentiated adenocarcinoma, the ratio of concentration of E3 receptor to that of E2 receptor was almost equal to or higher than in other normal tissues. 4. These findings of unique localization of E3 receptor distribution may offer new insight into identification of endometrial carcinoma more likely to respond to hormonal influence or therapy.

Adenocarcinoma↗

Formation of ethinylestradiol in postmenopausal women during continuous treatment with a combination of estradiol, estriol and norethisterone acetate.

Previous studies indicated that during treatment of postmenopausal women with preparations containing norethisterone, a small proportion of the progestogen is aromatized into ethinylestradiol. We therefore investigated the serum concentrations of estradiol, ethinylestradiol and norethisterone in 25 patients of a gynecological practice who were continuously treated for climacteric complaints with a combination of 2 mg estradiol, 1 mg estriol and 1 mg norethisterone acetate for a time period between 4 months and 6 years. Blood sampling occurred between 1 and 20 h after intake of the last tablet. The mean serum concentration of estradiol was 138 +/- 50 (53-279) pg/ml, of ethinylestradiol 18.1 +/- 13.5 (0-44) pg/ml, and of norethisterone 5.1 +/- 3.5 (0.7-11.6) ng/ml. The serum concentrations of estradiol showed a broad maximum between 1 and 14 h, and those of norethisterone a steep rise to maximum within 1-4 h after intake followed by a subsequent decline. Contrary to this, the ethinylestradiol levels were not related to the time after application indicating that the aromatization of norethisterone mainly occurs in peripheral tissue. There was no correlation between age, body mass index or duration of treatment and the ethinylestradiol levels. It is concluded that in the presence of the high estradiol concentrations the low conversion rate of norethisterone into ethinylestradiol is probably without clinical significance.

Aged↗

Mammary tumor immunoscintigraphy in rats: the use of 131I-anti-estriol 3-sulfate antibody.

The scintigraphic imaging of mammary tumors with anti-estriol 3-sulfate (E3 3-S) antibody was studied in rats. A chemical carcinogen, 7,12-dimethylbenz(a)anthracine (DMBA), induced mammary tumors in Sprague-Dawley female rats. Highly specific anti-E3 3-S antibody was prepared and radioiodinated by [131I]NaI using the chloramine-T method. At 24 h after administration of 131I-anti-E3 3-S antibody, goat anti-guinea pig immunogloblin G (IgG) was injected as the second antibody (SA) and nuclear scintigraphy was performed. Mammary tumors were clearly visualized following SA injection.

9,10-Dimethyl-1,2-benzanthracene↗

Highly specific polyclonal antisera against estriol: cross-reactivity restriction following affinity chromatography.

An immunosorbent technique was developed to attenuate cross-reactivity of a polyclonal antiserum against a 4(2) (rho-carboxyphenylazo)-1,3,5[10]-estratrien-3,16 alpha,17 beta-triol-bovine serum albumin conjugate. The chromatographic separation of antiserum through stationary phases having either rho(carboxymethyl)phenylazo-phenol or rho(carboxymethyl)-phenylazo-2-naphthol side residues reduced the antiserum avidity, while increasing the apparent antiserum affinity and decreasing the residual cross-reactivities against heterologous ligands. The highly specific antiserum obtained allowed the development of a competitive binding assay over an extended analytical range, which opens up the possibility of direct measurement of estriol from the early pregnancy to delivery. The significance of the attenuation of antiserum cross-reactions after affinity chromatography is discussed with reference to epitope-paratope interaction in the case of small endogenous molecules like estrogens.

Animals↗

Specific imaging of hormone-dependent mammary carcinoma in nude mice with [131I]-anti-estriol 3-sulfate antibody.

We tried to put the estrogen metabolite to use in tumor imaging. The antibody against estriol 3-sulfate (E3 3-S), which was one of the major metabolites of estrogen in hormone-dependent mammary carcinoma, was prepared and the tissue distribution and imaging of human breast carcinoma with anti-E3 3-S antibody (Ab) were studied in nude mice. In hormone-dependent breast carcinoma, MCF-7,-bearing nude mice, [125I] anti-E3 3-S Ab localized in tumor with the percentage injected dose/g of 9.29 +/- 3.01 (mean +/- SD). This value was significantly high compared with that in hormone-independent breast carcinoma, MDA-MB-231,-bearing nude mice. At 72 h after the administration of [125I]anti-E3 3-S Ab to MCF-7 bearing mice, tumor/blood, tumor/liver and tumor/muscle ratios were 0.49, 5.02 and 6.83, respectively. These ratios were supposed to be enough for imaging. In radioimmunoscintigraphy, a MCF-7 tumor was clearly visualized at 120 or 168 h post-injection of [131I]anti-E3 3-S Ab.

Animals↗

High maternal estriol level in pregnancy as a predictor of surgical intervention for undescended testis.

To assess whether elevated levels of estriol (E3) in pregnancy are a factor in the fetal environment associated with undescended testes, we carried out a two-part study: case-control followed by a retrospective cohort study on cryptorchid boys born in the Sapir Medical Center (Kfar Saba, Israel). We found significantly lower pregnancy urinary E3 levels in cryptorchid newborns as compared to controls; however, subgroup comparison yielded significantly higher pregnancy unconjugated E3 levels in the infants who underwent orchiopexy as compared to those who did not.

Adult↗

A function for estriol during human pregnancy--a hypothesis.

It has been hypothesized that large amounts of estriol (E3) are produced during human pregnancy to ensure a quiescent uterus during prelabour pregnancy by combining with most of the myometrial nuclear receptors, leaving an inadequate number for a stimulatory estradiol (E2) concentration. It is further hypothesized that the amount of E3 formed is controlled by the amount of E2 present. During labour this control is lost, which together with an increased E2 (plus or minus a simultaneous drop in E3) production permits labour. Two of the seven pieces of evidence offered in support of this hypothesis were carried out in the author's laboratory. These are: 1. Urinary assays by two methods, one for total estrogens and one for the fractionated classical estrogens revealed that while the ratio (formula; see text) varies from patient to patient, for any one patient it remains markedly constant, especially during the second half of pregnancy. 2. Pieces of myometrium removed at cesarean delivery and assayed for their nuclear estrogen content revealed an E3/E2 ratio of 1.7 when the cesarean was an elective one (and therefore with a quiescent uterus) but reduced to 0.65 when the cesarean was performed after labour had started. The relationship between these two pieces of evidence and five from the literature with the hypothesis are discussed.

Estradiol↗