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Comparative effect of estriol and equine conjugated estrogens on the uterus and the vagina.

Estriol has been reported to act selectively on the vagina and cervix without causing endometrial proliferations. Studies comparing this effect of estriol to that of equine conjugated estrogens after intravaginal administration have not been reported. In this study, intravaginally administered Ortho- Gynest which contains estriol, and Premarin which contains equine conjugated estrogens, were evaluated for their ability to stimulate vaginal maturation and uterine growth in rats. Approximately 15 times more conjugated estrogens than estriol was needed to induce the same degree of vaginal cornification in castrated rats. In contrast, estriol was less potent than the conjugated estrogens in causing uterine growth in immature rats after subcutaneous administration in sesame oil and in mature rats after intravaginal administration in cream preparations. In studies evaluating the vaginal irritation potential of estriol vaginal cream, the irritation exhibited by treated rabbits was found to be comparable to that of sham-treated control rabbits. Estriol was well-tolerated in an oral acute safety study in rats.

Administration, Topical↗

Comparison between oral and intramuscular dexamethasone in suppressing unconjugated estriol levels during the third trimester.

OBJECTIVES: Unconjugated estriol production depends on fetal adrenal androgen precursors. Fetal exposure to exogenous glucocorticoids results in adrenal suppression with a subsequent decrease in maternal serum unconjugated estriol levels. We compared the efficacy between oral and intramuscular dexamethasone in maternal serum unconjugated estriol suppression at 48 hours after the initial dose among women at risk for preterm delivery. STUDY DESIGN: Twenty-four gravidas at risk for preterm delivery were randomized to receive either 6 mg intramuscular or 8 mg oral dexamethasone every 12 hours for a total of 4 doses. Blood samples (9 mL) were obtained before the initial dexamethasone administration and again after the fourth dose. Serum was separated and frozen at -70 degreesC and subsequently underwent batch analysis. Unconjugated estriol levels were determined by radioimmunoassay with intra-assay and interassay coefficients of variation of 7.9% and 5.5%, respectively. All values are reported as mean +/- SD. The primary statistical analysis was a t test, with P <.05 considered significant. RESULTS: At the time of dexamethasone administration, gestational ages in both groups were similar. Predexamethasone and postdexamethasone unconjugated estriol levels were also similar between the intramuscular and oral groups (5.39 +/- 3.99 vs 1.80 +/- 2.49 ng/mL and 6.05 +/- 3.00 vs 1.61 +/- 1.03 ng/mL, respectively, P >.05). No difference in percent decrease in unconjugated estriol levels was found between the intramuscular (0.67 +/- 0.24) and oral (0.65 +/- 0.39) groups. CONCLUSION: Oral dexamethasone (8 mg) produces similar maternal serum unconjugated estriol suppression compared with intramuscular dexamethasone (6 mg) when evaluated 48 hours after administration.

Administration, Oral↗

Efficacy and safety of oral estriol for managing postmenopausal symptoms.

OBJECTIVE: to assess the therapeutic efficacy and safety of oral estriol for the treatment of climacteric symptoms in postmenopausal women. METHODS: 68 postmenopausal women with climacteric symptoms received oral estriol, 2 mg/day, daily for 12 months. We evaluated the degree of climacteric complaints with estriol therapy; serum levels of gonadotropins, estradiol (E2) and lipids; biochemical markers of bone metabolism; blood pressure; and side effects both at baseline and during treatment. Climacteric symptoms were assessed according to the menopausal index (MI), a version of the Kupperman index that had been modified for Japanese women. RESULTS: oral estriol therapy significantly reduced total MI scores. The greatest relief was noted for hot flushes, night sweats, and insomnia. Estriol treatment significantly lowered serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations but did not affect any of the other parameters (lipids, bone, liver and blood pressure) during the study period. Slightly vaginal bleeding occurred in 14.3% of those who underwent natural menopausal women. Histologic evaluation of the endometrium and ultrasound assessment of the breasts following 12 months of estriol treatment found normal results in all women. CONCLUSION: Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal Japanese women.

Administration, Oral↗

In vitro production of estriol from four steroid precursors by rabbit tissues.

The production of estriol was demonstrated in intact leukocytes and homogenates of liver, adrenals and ovaries of young adult female rabbits from 17 beta-estriol, testosterone, androst-4-ene-3,17-dione and dehydroepiandrosterone. Androst-4-ene-3,17-dione constituted the best substrate in liver and adrenals and the poorest substrate for estriol production in lymphocytes. Estriol was least readily transformed into estriol in liver and adrenals, while it proved to be the best substrate in ovaries. Phenobarbital administration to rabbits resulted in 49-fold and 23-fold increases in the transformation of androst-4-ene-3,17-dione and dehydroepiandrosterone, respectively, into estriol by lymphocytes. The results indicate that the enzymes involved in estriol biosynthesis in the various tissues respond differently to phenobarbital.

Adrenal Glands↗

The effect of betamethasone on salivary estriol.

OBJECTIVE: Study of the degree and pattern of salivary estriol suppression after administration of betamethasone. STUDY DESIGN: A total of 26 patients with singleton pregnancies (> 24 but < 35 weeks' gestation) in preterm labor with intact membranes had salivary estriol collected prior to betamethasone administration and then daily in late afternoon to evening. All patients were receiving magnesium sulfate. Five patients received a second dose of steroids 1 week after the first. Specimens were frozen and later batch analyzed. RESULTS: Betamethasone induced a mean 35.1 +/- 18.2% decrease in salivary estriol which reached its nadir in 1-6 days. By day 6, the salivary estriol in all patients remained suppressed. A second dose of betamethasone caused a further decrease in estriol. CONCLUSION: Betamethasone suppressed salivary estriol in all patients, consistent with the effect of glucocorticoids on fetal adrenal estriol precursors. The suppression persisted for at least 1 week.

Adolescent↗

Facilitated tissue expansion with topical estriol.

Tissue expansion is a helpful technique in reconstructive plastic surgery. Unfortunately, tissue expansion still needs to be improved. Twenty-four male Wistar rats were used to evaluate the effect of estriol on tissue expansion. The agents hyaluronidase, estriol, and base cream (as a control) were applied topically to separate animal groups for 5 weeks, and their effects were studied on tissue expansion. Both hyaluronidase (p < 0.05) and estriol (p < 0.001) enhanced the rate of expansion when compared with control animals. Estriol was more effective than hyaluronidase (p < 0.05). Breaking strengths were measured in the estriol and the control groups. Breaking strength was not evaluated in the hyaluronidase group because of the necrotic changes seen at the end of the fifth week. The breaking strength was higher in the control group than in the estriol group (p < 0.05). The authors suggest that topical estriol be used as an adjunctive agent to facilitate tissue expansion.

Administration, Topical↗

Estriol sensitizes rat Kupffer cells via gut-derived endotoxin.

The relationship between gender and alcohol-induced liver disease is complex; however, endotoxin is most likely involved. Recently, it was reported that estriol activated Kupffer cells by upregulation of the endotoxin receptor CD14. Therefore, the purpose of this work was to study how estriol sensitizes Kupffer cells. Rats were given estriol (20 mg/kg ip), and Kupffer cells were isolated 24 h later. After addition of lipopolysaccharide (LPS), intracellular Ca2+ concentration was measured using a microspectrofluorometer with the fluorescent indicator fura 2, and tumor necrosis factor-alpha was measured by ELISA. CD14 was evaluated by Western analysis. One-half of the rats given estriol intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by sterilization of the gut with antibiotics. A similar pattern was obtained with liver histology and serum transaminases. Translocation of horseradish peroxidase was increased about threefold in gut segments by treatment with estriol. This increase was not altered by treatment with nonabsorbable antibiotics. On the other hand, endotoxin levels were increased to 60-70 pg/ml in plasma of rats treated with estriol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells, LPS-induced increases in intracellular Ca2+ concentration, tumor necrosis factor-alpha production, and CD14 were increased, as previously reported. All these phenomena were blocked by antibiotics. Therefore, it is concluded that estriol treatment in vivo sensitizes Kupffer cells to LPS via mechanisms dependent on increases in CD14. This is most likely due to elevated portal blood endotoxin caused by increased gut permeability.

Animals↗

Radioimmunoassay of estriol-16-glucuronide.

A specific radioimmunoassay of estriol-16-glucuronide has been developed, using an antiserum obtained by immunization of rabbits against estriol-16-glucuronide-BSA. The assay does not require hydrolysis, extraction and purification, but only a dilution of the crude sample. This constitutes the main advantage of the precedure. Accuracy, precision and sensitivity of the method are similar to those reported for other radioimmunoassays of estriol. Its specificity is good for the measurement of estriol-16-glucuronide in urine and in amniotic fluid, but not in serum of pregnant women, which apparently contains material interfering with the radioimmunoassay, at dilutions of less than 1/100. A significant correlation was observed between estriol-16-glucuronide and total estriol in urine during pregnancy; however, the contribution of the glucuronide to the total increases as pregnancy progresses, rising from 50% for a total of 5 mg/24 h to 85% for a total of 50 mg/24 h. The present radioimmunoassay can be used as a quick and reliable method for the measurement of urinary estriol-16-glucuronide in high risk pregnancies.

Amniotic Fluid↗

HCS, estriol and oxytocinase in maternal serum and neonatal condition in high risk pregnancies.

In order to find a reliable index of fetal wellbeing, maternal estriol, hCS and oxytocinase levels were related with condition of the neonate. Fifty six high risk pregnancies were studied. Estriol and hCS were determined by specific radioimmunoassay and oxytocinase with a colorimetric method. The condition of the newborn was evaluated by the APGAR score. Neonates were divided into two groups, depressed (APGAR score 0-6) and vigorous (APGAR score 7-10). When the mean birthweights of both groups were statistically different, maternal estriol levels were corrected to avoid the influencing factor of newborn weight. Mean maternal estriol level corresponding to vigorous newborns was 46.73 ng/ml. This value was statistically higher than that corresponding to the group of depressed newborns, which was 26.25 ng/ml (Fig. 1). The mean birthweight of depressed infants (2,382.75 g) was statistically lower than that of the vigorous group (3,044.75 g). The corrected mean maternal estriol values of vigorous neonates (45.44 ng/ml) was different from that of depressed ones (25.14 ng/ml) (Fig. 2). When patients were divided according to maternal diseases (diabetes, vascular pathology, Rh sensitization) serum estriol levels of the mother were statistically different according to the Apgar score of the newborns. There was no significant difference between serum hCS and oxytocinase levels of mothers with depressed and vigorous newborns. Discarding fetal weight as an influencing factor in maternal hormone level, our results indicate the suitability of maternal serum estriol determinations to predict condition of the newborns in high risk pregnancies.

Aminopeptidases↗

[Effect of estriol and bone mineral density of lumbar vertebrae in elderly and postmenopausal women].

To compare the efficacy of estriol (E3) in postmenopausal and senile osteoporosis, we administered orally 1 g/day calcium lactate either alone (control groups) or with 2 mg/day estriol (estrogen groups) for 10 months to 20 postmenopausal women aged 50-65 years and to 29 elderly women aged 70-84 years, and measured their bone mineral density of the lumbar vertebrae by dual energy X-ray absorptiometry. Out of 41 subjects who completed 10 months of treatment, 8 postmenopausal women and 12 elderly women in the estrogen groups had significant (p < 0.05) increases in bone mineral density (5.59 +/- 4.79% of the respective basal values). Ten postmenopausal women and 11 elderly women in the control groups had decreases bone mineral density (-4.02 +/- 7.00% and -3.26 +/- 4.60% of the respective basal values) at the 10th month. Genital bleeding as a side effect of estriol was seen in 6 out 29 elderly subjects at this dose. Moreover, decreases in the levels of calcium, total cholesterol, and triglycerides in serum, and an increase in the level of high-density lipoprotein-cholesterol were seen only in the elderly women receiving estriol. Although a lower dosage of estriol may be recommended for elderly subjects, these observations suggest that hormone replacement therapy with estriol is effective against degenerative osteoporosis, and that low-turnover bones in elderly women are also responsive to estriol.

Aged↗

Total urinary estriol determined by "on-line" liquid chromatography with ultraviolet detection.

We report a fully automated method for the specific assessment of total estriol in urine. Acid-hydrolyzed urine is concentrated on a short reversed-phase column and prepurified with methanolic Tris buffer, the pH of the buffer increasing from 7 to 11. The anionic form of the estriol molecule is eluted with methanolic NaOH. By acidification in a mixing chamber, estriol in its neutral form is focused on the top of a second short reversed-phase column, effectively chromatographed on an analytical column, and quantified by ultraviolet absorbance at 278 nm. Losses of estriol throughout the total procedure are negligible and thus external calibration is feasible for quantification. Analytical recoveries for estriol-supplemented urines ranged from 98.3 to 105%. Replicate analyses of a urine containing 68 mumol of estriol per liter gave a CV of 2.76%. As little estriol as 2 mumol/L can be detected. Results from pregnancy urines correlated well with those of radioimmunoassay. The method is especially suited for clinical emergencies in a routine laboratory.

Autoanalysis↗

Urinary estriols in diabetic pregnancy: a reappraisal.

The clinical usefulness of serial urinary estriols was tested in 138 insulin-dependent diabetic pregnant women. No action was taken on an estriol drop if fetal well-being was demonstrated by a reactive nonstress test and/or negative contraction stress test within 24 hours. Of 3085 estriol values, a greater than or equal to 40% estriol drop, confirmed by a greater than or equal to 40% decrease in the estriol-creatine ratio, was observed in 21 tests. In only two of these tests, was fetal distress indicated by a nonstress test or contraction stress test. A significant linear correlation was demonstrated between the mean level of estriol excretion and birth weight, placental weight, and fetal abdominal circumference measured by ultrasound. Chronically low estriol excretion (less than 12 mg per 24 hours at greater than 36 weeks' gestation) related to smaller placentas but not to fetal jeopardy.

Apgar Score↗

Serial first morning estriol determinations in evaluating the high-risk obstetric patient.

Over the past decade, 24-hour urinary estriol determination has become an integral part of the evaluation and monitoring of high-risk obstetric patients for fetal well-being. This study was undertaken to assess the utility of estriol determinations obtained by simpler collection methods: serum estriol and first morning urine specimens. Serum estriol proved to be an unreliable predictor of 24-hour urine values and of estriol fluctuations. Although the correlation between first morning and 24-hour primary estriol:creatinine ratios was statistically significant (P less than .0001), any single first morning specimen value chosen at random was a poor predictor of the corresponding 24-hour specimen value. However, in the monitoring of high-risk obstetric patients, it is the significant changes with respect to time rather than the absolute estriol levels that are of interest. As the plots of first morning and 24-hour specimen values with respect to time in 8 subjects exhibit time trends of equivalent diagnostic utility, it it concluded that first morning values may be used in place of 24-hour values to monitor high-risk obstetric patients, making the process simple and quicker.

Creatinine↗

Effect of serum lipids on radioimmunoassays of unconjugated estriol in serum.

Controversy regarding the presence of a circadian rhythm in unconjugated estriol in serum during pregnancy led us to study the possibility that the observed rhythms actually are the result of partitioning of estriol into serum lipids when these increase postprandially. Addition of triglycerides to purified estriol standards significantly decreased (p less than 0.001) apparent estriol as detected by radioimmunoassay after separation on dextran-coated charcoal and significantly increased (p less than 0.001) estriol as detected by radioimmunoassay after double-antibody separation. Compensation for individual nonspecific binding of standards nullified the effect of lipids only in systems involving dextran-coated charcoal separation, incubated for 1.0 h at 37 degrees C followed by 1.0 h at 4 degrees C. In contrast to other protocols, data obtained with this system revealed no significant circadian variation in serum estriol concentrations in normal pregnant women (CV, 4.3%). Evidently, reported variations in apparent serum estriol concentration are artifactual.

Circadian Rhythm↗

Effects of estrone, estradiol, and estriol on hormone-responsive human breast cancer in long-term tissue culture.

The effects of estrone, estradiol, and estriol on MCF-7 human breast cancer are compared. In this estrogen-responsive cell line, all three estrogens are capable of inducing equivalent stimulation of amino acid and nucleoside incorporation. Estriol is capable of partially overcoming antiestrogen inhibition with Tamoxifen (lCl 46474), even when antiestrogen is present in 1000-fold excess. Antiestrogen effects are completely overcome by 100-fold less estriol. Studies of metabolism of estrogens by MCF-7 cells revealed no conversion of estriol to either estrone or estradiol. All three steroids bind to a high-affinity estrogen receptor found in these cells. The apparent dissociation constant is lower for estradiol than for estrone and estriol, but all three bind to an equal number of sites when saturating concentrations are used. Tritiated estrogens used in binding studies were shown to be radiochemically pure. We conclude that estriol can bind to estrogen receptor and stimulate human breast cancer in tissue culture. Our data do not support an antiestrogenic role for estriol in human breast cancer.

Binding, Competitive↗

Endometrial effect of oral estriol treatment in postmenopausal women.

Estriol is a weak estrogen with a claimed specific action on the epithelium in cervix uteri and vagina and with no or limited ability to induce endometrial proliferation. In a previous pharmacokinetic study we have shown elevated estriol levels for only 2-3 hours after oral administration of the drug. The present study was performed to test if estriol, when given orally in daily divided doses to postmenopausal women, has any effect on the endometrium. Twenty postmenopausal women who had no vaginal bleeding in response to lynestrenol (Orgametil 5 mgX2XV) were treated with 6 mg estriol a day (Ovesterin 2 mgX3), divided into three doses, for 2 up to 3.5 months. When lynestrenol (5 mgX2XV) was given following the estriol treatment periods, 12 women out of 20 experienced a vaginal bleeding and one reported spotting. Endometrial biopsies in ten of these women who had a bleeding were examined histologically. The endometrium was atrophic in four women, proliferative in two, slightly hyperplastic in one and showed signs of weak hormonal activity in one. Two women had secretory endometrium. It is concluded that estriol, administered in a way that gives prolonged elevation of the blood levels, is able to produce the same effect on the endometrium as other estrogens.

Administration, Oral↗

Circadian rhythms in maternal plasma cortisol and estriol concentrations at 30 to 31, 34 to 35, and 38 to 39 weeks' gestational age.

In order to examine the relationship between circadian rhythms in different steroids, cortisol and estriol were measured by radioimmunoassay in maternal venous plasma taken at 30- to 60-minute intervals over 24 hours from nine healthy women at 30 to 31, 11 at 34 to 35, and 10 at 38 to 39 weeks' gestation. Maternal cortisol was maximal at 0730 to 0830 hours and fell significantly to its lowest concentration between 1830 and 0130 hours. At 30 to 31 and 34 to 35 weeks there was a significant circadian rhythm in estriol concentrations which was inversely related to the circadian rhythm in cortisol. At 38 to 39 weeks mean estriol concentrations were significantly higher than those at 30 to 31 and 34 to 35 weeks but there was no significant circadian pattern. We concluded that there is an inverse relationship between maternal cortisol and estriol at 30 to 31 and 34 to 35 weeks, which would be consistent with a maternal effect on fetal adrenal function. The increase in mean concentration and absence of circadian rhythm in maternal plasma estriol at term might suggest an additional positive stimulus to fetal adrenal function. The existence of patterns in maternal estriol concentrations must be taken into account in the u;se of sequential measurements of this hormone during the last 10 weeks of pregnancy.

Circadian Rhythm↗

Pregnancy outcome for women with very low levels of maternal serum unconjugated estriol on second-trimester screening.

OBJECTIVE: Our purpose was to assess pregnancy outcome for women whose second-trimester triple screen results revealed very low unconjugated estriol levels. STUDY DESIGN: Of 44,146 women screened for alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol, a group of women with isolated very low unconjugated estriol levels were selected as the study group. Pregnancy outcome was obtained by contacting the referring physicians. RESULTS: During the study period 62 women had unconjugated estriol levels at or below the sensitivity of the assay. Fetal death was the most common explanation, accounting for 37.1% of cases. Six cases of early death followed uneventful prenatal visits. Eighteen women had unexplained very low unconjugated estriol levels. Of these 18, four cases of placental sulfatase deficiency were diagnosed. Sixteen of these 18 women gave birth to male infants (p = 0.03). CONCLUSION: A very low unconjugated estriol level in the second trimester is associated with increased risk for early death and placental sulfatase deficiency.

Adult↗