The effect of adding oestriol or oestriol succinate to oestradiol in the treatment of climacteric postmenopausal patients was examined in a cross-over trial. Plasma concentrations of oestrone (E1), oestradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay after collection over a day after each medication. The subjective effect of each therapy was evaluated by the patient herself. The combination of 1 mg oestriol with 2 mg oestradiol did not change the daily profiles of plasma E1, E2, LH and FSH in three out of four patients, compared with only 2 mg of oestradiol. The other combination, 8 mg of oestriol succinate with 1 mg oestradiol, similarly did not change the daily plasma profiles of oestrogens or gonadotrophins, compared with only 1 mg of oestradiol. Neither oestriol succinate changed the clinical response during the treatment of these climacteric patients.

A randomised, single-blind comparative study was carried out in 9 ovariectomized women to evaluate the kinetics of single doses of three different steroid combinations: 0.150 mg desogestrel + 2.0 mg micronized 17 beta-oestradiol, 0.150 mg desogestrel + 0.500 mg 17 beta-oestradiol cyclo-octyl acetate and 0.150 mg desogestrel + 1.0 mg 17 beta-oestradiol decanoate. Serum levels of 17 beta-oestradiol and oestrone were measured, as well as the excretion of 17 beta-oestradiol and its metabolites (oestrone and oestriol) in urine. In relation to the doses given, higher peak serum concentrations of 17 beta-oestradiol were obtained after the two fat soluble analogues, while the AUCs were similar to that after micronised 17 beta-oestradiol. However, there was more extensive conversion of the micronised 17 beta-oestradiol preparation into oestrone compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. The oestrone/17 beta-oestradiol serum concentration ratio was approximately 2.6 before tablet intake and remained essentially unchanged after intake of 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate. After micronized 17 beta-oestradiol however, there was a 2-3-fold increase in the ratio at Cmax and slower elimination of 17 beta-oestradiol from plasma, which may be due to the fact that high serum oestrone levels may serve as a reservoir, since both a metabolite and also a precursor of 17 beta-oestradiol. The urinary excretion of 17 beta-oestradiol, oestrone and oestriol was highest after oral administration of micronized 17 beta-oestradiol compared to 17 beta-oestradiol cyclo-octyl acetate and 17 beta-oestradiol decanoate.(ABSTRACT TRUNCATED AT 250 WORDS)

Ozone oxidation is proven to be an effective solution for the degradation of selected oestrogenic active substances detected in secondary wastewaters such as beta-oestradiol, oestrone, oestriol, 17-alpha-ethinyloestradiol, mestranol, daidzeine, beta-sitosterol, bisphenol A, norethisterone, 4-tert-octylphenol and 4-iso-nonylphenol, up to their limit of detection. The matrix-effect of wastewater was investigated performing ozone experiments under batch mode and continuous mode using drinking water and a wastewater issued from a local plant both spiked with the non-detected substances. The results obtained indicate that the wastewater matrix greatly affects the kinetics of ozone reaction with these substances but does not really change the related reactivity scale. The ozone dose corresponding to the full conversion of target EDCs consequently increases as their oxidation takes place competing with reactions of background pollutants represented by the COD and DOC content. However, a usual dose close to 12 mg/L was found sufficient to provide high degradation yields for all substances studied while 35% of COD was removed. This is a contribution to the numerous current works focused on technologies able to improve the quality of water discharged from wastewater treatment plants, both considering conventional parameters and emerging contaminants.

Maternal serum levels of human placental lactogen (hPL), schwangerschaftsprotein 1 (SP1), pregnancy-associated plasma protein A (PAPP-A), placental protein 5 (PP5) and total oestriol (E3) were measured serially in 35 twin pregnancies during the third trimester. Eighteen pregnancies had major complications including dysmaturity of one or both fetuses in nine, premature labour in six, and placental abruption in three. Serum levels of all five variables were higher than in singletons, this distinction being greatest for hPL and lowest for SP1 and E3. The levels of hPL, PP5 and E3 just before delivery were significantly correlated with the total birthweight, a correlation with placental weight being evident only for hPL and PP5. A significant correlation between the five biochemical variables at 33-34 weeks was only seen between hPL and PAPP-A. Protein and hormone levels in the abnormal twin pregnancies were not apparently different from those in the normal twin pregnancies. These data suggest that only hPL levels biochemically reflect this extreme of fetal and placental growth, but that neither the levels of hPL nor any of the other biochemical indices examined are altered in abnormalities in twin pregnancy.

Oestrogen concentrations (oestradiol = E2 and oestriol = E3) were determined in plasma and liver tissue of female rats before, during and after treatment with two different doses (1.2 and 12.0 mg/kg/d) of oestradiol valerate (E2-val) given in the feed over 27 days. The oral bioavailability of E2 was determined in a pharmacokinetic study in which rats received a single intramuscular administration of E2-val. The aim of the present investigation was to support the evaluation of the results of a previous 90 weeks chronic toxicity and tumorigenicity study in rats where the same dosages were administered. The bioavailability was approximately 0.5%; the systemic body burden of exogenous E2 was 1.6 fold, the endogenous E2 burden at the low, and 9 fold at the high dose. Despite these low values, distinct systemic effects were noted. At 1.2 mg/kg/d a marked decrease in food consumption and body weight gain occurred in the 27 day study as well as in the chronic study. In addition, in the latter study mortality increased from the low dose onwards and was complete at the high dose after 72 weeks. The incidence of pituitary adenoma increased. The results indicate that theoretically rats are far more sensitive towards exogenous oestradiol treatment than humans.

A cytosolic oestrogen receptor from baboon endometria was detected and partially characterized. The apparent dissociation constant for oestradiol was 1.5 x 10(-10)--4 x 10(-10) mol/l. Steroids that competed with the [3H]oestradiol binding to the receptor were oestradiol and ethynyloestradiol greater than oestriol greater than oestrone; progesterone, testosterone and corticosterone were not competitors. The [3H]oestradiol-receptor complexes migrated as a 3-3.5S peak during sucrose density-gradient centrifugation when endometrial samples were taken during either the proliferative or the secretory phase. A 7S peak was observed for samples taken at the period of ovulation. A [3H]oestradiol exchange technique was used to detect changes in the receptor concentration during the menstrual cycle. This concentration which was high during the early follicular phase fell sharply before the ovulatory peak of ovarian oestrogens. It remained at a base level during the early secretory phase and then rose during the last days of the cycle to the same concentration as that measured at the beginning of the cycle.

The maturation value (MV), cervical mucus parameters (ferning, Spinnbarkeit), oestrone (E1), oestradiol (E2), oestriol (E3), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyrotropin (TSH), growth hormone (GH), sex hormone binding globulin (SHBG), corticosteroid binding globulin (CBG) and thyroxin-binding globulin (TBG) were determined in 11 post-menopausal women presenting with vaginal atrophy prior to, and following, treatment with Ovestin vaginal cream containing 0.5 mg/day of E3 for 8 wk. In 6 of the patients E3 was measured during frequent plasma sampling on days 1, 21 and 56; in the same patients and on the same days TRH-stimulated PRL, TSH and GH levels were estimated. While the therapy induced a sharp rise in the MV, there was a moderate effect on ferning/Spinnbarkeit. Baseline E3 rose from undetectable levels to a mean value of 86.8 pmol/l at day 21. E3 levels achieved during frequent plasma sampling were higher on day 1 than on days 21 and 56 - a decline of the areas under the response curves being significant (P2-sided = 0.03). There was a slight suppression of FSH and LH. No changes in the circulating levels of E1, E2, SHBG, CBG, TBG, PRL, TSH and GH were seen. TRH-stimulated PRL, TSH and GH levels remained unaffected. Clinical effect was excellent and no untoward effects were reported.

Serum screening for fetal Down's syndrome in the second trimester is far more efficient in older mothers than in younger ones because the risk calculation is based on maternal age. In recent publications, several authors have tried to better the 'classical' test for Down's syndrome screening by creating an age-independent index. This procedure, however, requires the assumption that at least for one parameter the mean MOM or the variance is not constant in relation to maternal age, leading to a smaller overlap in younger women. This study, based on almost 3000 normal cases and 161 cases with Down's syndrome, could not demonstrate any relationship between maternal age and MOM distribution for alpha-fetoprotein, unconjugated oestriol, total human chorionic gonadotropin (hCG), and free beta hCG. We conclude that for a constant false-positive rate, the detection rate of the 'classical' test for Down's syndrome screening in younger women cannot be bettered by creating an age-independent index.

A bioavailability study was performed on ten oophorectomized women in a randomized cross-over design. The absorption of tablets containing 2 mg of micronized oestradiol and 1 mg of micronized oestriol (Estrofem) was compared to the absorption of the same micronized hormones administered in an aqueous suspension. Serum concentration values of oestradiol, oestriol and oestrone were measured by radioimmunoassay. The data obtained were analyzed both by univariate and multivariate analyses, and neither the serum concentrations at the various sample times, the maximum concentrations, the times for the maximum concentrations, nor the areas under the serum concentration curves disclosed any significant differences between the tablet and suspension administrations at the 5% level. The serum concentration values achieved by giving 2 mg of oestradiol and 1 mg of oestriol were of the same magnitude or higher than those of the normal menstrual cycle.

Maternal serum screening for Down syndrome involves biochemical tests such as alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG) and unconjugated oestriol (uE3), either alone or in combination, that have variable detection and false-positive rates. Choosing a screening protocol requires a trade-off between a desired detection rate and an acceptable false-positive rate. Selecting a screening protocol that maximizes the net benefit to society provides one approach. We have developed a general formula for calculating the per case net social benefit of a screening test and have applied it to United States data. The maximum net benefit associated with each of the various screening options currently available is estimated and the model is further applied to determine the conditions under which the addition of a new marker to an existing protocol can be justified. For each test, or combination of tests, optimal net benefits occur at different detection and false-positive rates. Net benefits are strongly and positively dependent on maternal age; high net benefits are associated with older patients and low, or even negative, net benefits with younger patients. Also, net benefits are affected by the term risk cut-off rate. For triple testing, the 1:351 Down syndrome term risk cut-off appears to provide a higher net benefit than that obtained with 1:250 or 1:300. The optimization of societal net benefit provides a powerful approach to evaluating screening strategies, but the policies used must also consider individuals' freedom in decision making at each step of the prenatal diagnosis pathway.

The metabolism of various unconjugated oestrogens [oestrone (E1), oestradiol (E2) and oestriol (E3)], in MDA-MB-468 human mammary cancer cells, a cell line characterised by the absence of oestrogen receptor has been investigated. 24 h after incubation of these cells with 5 x 10(-9) mol/l of tritiated E1, E2, or E3, 62-90% of the total radioactivity was localised in the sulphate fraction. Analysis showed that 73-90% of the sulphate fraction corresponds with the oestrogen incubated. The formation of the oestrogen sulphates is rapid and maximum values are found after 3 h incubation. Intense sulphotransferase activity was also found for testosterone, pregnenolone and dehydroepiandrosterone. Thus these cells contained high oestrogen sulphotransferase activity, suggesting that the presence of high levels of oestrogen sulphates in breast cancer can be synthesised in the tumour itself. In addition, the control of this enzymatic activity could open new possibilities in the knowledge of oestrogen responses and of therapeutic applications in breast cancer.

Diurnal changes in the concentrations of oestrone (E1) and oestradiol (E2) in maternal peripheral plasma have been measured in samples of blood taken at one hour intervals from women at 30 to 31, 34 to 35 and 38 to 39 weeks of pregnancy. There was a significant effect of time of sampling on the plasma concentration of E1 at all stages of gestation, and circadian changes in the levels of E1 were apparent at 34 to 35 and 38 to 39 weeks. Peak values were measured around 0830 to 0930 hours, and troughs occurred between 0130 and 0530 hours. Significant effects of time of sampling on the plasma concentration of E2 were found at 34 to 35 and 38 to 39 weeks of pregnancy; night-time concentrations were lower than the peak values at 0730 to 0830 hours. The relation of these changes to the circadian rhythms in the concentrations of cortisol and oestriol in maternal plasma are discussed.

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.

The subjects (N = 50) were born to mothers who had earlier participated in an extensive clinical investigation during their pregnancies. Maternal serum hormone levels were investigated from pregnancy week 20 and on to partus. Fourteen children were born small-for-gestational age (SGA) and eight pre-term appropriate-for-gestational age (AGA). Each SGA child had two control children, born to mothers with normal or high serum levels of alpha-fetoprotein (AFP) in pregnancy week 16-17. Elevated serum levels of AFP was considered to be a sign of fetal stress. All 50 children were administered the WISC-test at 10 years of age. The SGA children had lower scores than control children in Performance and Full scale scores. The pre-term SGA children had lower scores than the controls in Verbal, Performance and Full scales. That was not the case for on-time SGA and pre-term AGA children. Girls born to smoking mothers performed less well than girls of non-smoking mothers on the Verbal scale. Positive correlations of maternal serum hormone levels (oestriol, hCG, and hPL) and WISC-test scores were present for girls. For boys a single maternal hormone in pregnancy (prolactin) was correlated with WISC-test scores at 10 years of age.