Plasma Estriol Research Articles

Plasma Estrogen Levels and Aneurysmal Subarachnoid Hemorrhage in Women

ObjectivesAneurysmal subarachnoid hemorrhage is more prevalent in post-menopausal women and it has been postulated that this relationship is hormonally driven by lower circulating levels of estrogens. We examined the association between circulating plasma estrogen levels and subsequent development of aneurysmal subarachnoid hemorrhage in women. MethodsWomen from the Nurses’ Health Study with confirmed aneurysmal subarachnoid hemorrhage (n=38) were matched with controls (n=38) on age, smoking, menopausal status, and other reproductive factors. Plasma estriol, estradiol and sex hormone-binding globulin (SHBG) were measured at baseline, prior to the development of aSAH. Conditional logistic regressions were performed to assess the association between hormone levels and incident aSAH. ResultsPlasma estradiol, estriol, and SHBG were not associated with the subsequent development of aneurysmal subarachnoid hemorrhage. Women with a history of current or former smoking were associated with lower levels of circulating estriol (β = -0.35±0.12, p=0.004), and estradiol (β = -0.63±0.16, p=0.0002) levels. ConclusionsIn this study, we did not find an association between estrogen levels and incidence of aneurysmal subarachnoid hemorrhage in women.

Prospective Observational Study Evaluating Systemic Hormones and Corneal Crosslinking Effects in Keratoconus

To evaluate associations between hormone levels and corneal parameters in patients with keratoconus (KC), before and after photooxidative corneal collagen crosslinking (CXL). Prospective, observational cohort study. Twenty-eight patients with KC who were scheduled for CXL at Aarhus University Hospital in Denmark. Androgen (dehydroepiandrosterone sulfate [DHEA-S]) and estrogen (estrone and estriol) plasma levels were measured and clinical assessments were performed before CXL and 2 to 3 months post-CXL, comparing the CXL eye with the control eye from the same participant. Associations between hormone levels and maximum corneal curvature (Kmax) and minimum central corneal thickness (CCtmin) before and after CXL. Corneal collagen crosslinking was associated with a 2% reduction in Kmax values in the CXL eye, post-CXL, from baseline (median, 56.8 diopters [D]; 95% confidence interval [CI], 50.4-60.3) to the second visit (55.7 D; 95% CI, 50.4-58.8; P < 0.001). Systemic DHEA-S levels were 5 to 6 orders of magnitude higher than estriol or estrone concentrations in plasma. Importantly, estriol levels, rather than DHEA-S or estrone levels, were more closely correlated with Kmax before CXL (Spearman's r= 0.55, P= 0.01). Post-CXL Kmax and CCtmin were not associated with DHEA-S, estrone, or estriol plasma levels at the same timepoint. This study provides supporting evidence based on a KC clinical population that systemic estrogen levels may influence corneal parameters (curvature and thickness) pre-CXL. Further studies evaluating the interplay between the therapeutic benefits of CXL and systemic hormone distributions are needed to determine if perturbation of the local corneal microenvironment influences endocrine function. The authors have no proprietary or commercial interest in any materials discussed in this article.

Simultaneous Measurement of Sex Steroid Hormones in Largemouth Bass (Micropterus salmoides) Plasma by Application of Liquid Chromatography-Tandem Mass Spectrometry.

Sex steroid hormones are potential biomarkers of reproductive function in teleost fish, but their measurement continues to rely on antibody-based assays. The objective of this study was to optimize a robust and simultaneous liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measurement of eight steroid hormones (cortisol, 11-ketotestosterone, estradiol, 17α-ethynyl estradiol, estrone, estriol, progesterone and testosterone) in fish plasma. The extraction was followed by liquid-liquid extraction with tert-butyl methyl ether and time scheduled multi-reaction monitoring (sMRM) was used for quantitation of steroids. Validation of method performance using charcoal-stripped human plasma showed extraction recoveries for eight steroids ranged from 85.5 to 108.2% with matrix effects>80%. The limits of quantitation were 0.01pg/μL for testosterone, 0.05pg/μL for cortisol and progesterone, 0.1pg/μL for 11-ketotestosterone, estradiol and estrone, 0.125pg/μL for estriol and 0.25pg/μL for 17α-ethynyl estradiol. The proposed method was applied to plasma samples of largemouth bass (Micropterus salmoides) collected from contaminated (Lake Apopka) and reference sites (Wildcate Lake) in Florida. Concentrations of testosterone, cortisol, estradiol and estrone were significantly different in female fish, but plasma concentration of cortisol was only statistically different in male fish between two sites (P<0.05). This study demonstrates the application of a robust LC-MS/MS analysis for a range of sex steroid hormones representative of endocrine function in a top predator, largemouth bass.

Relations between second-trimester aneuploidy screening results and prediction of labour induction success in term pregnancies

We aimed to assess whether the second-trimester maternal serum markers could be used for the prediction of labour induction success. This prospective study enrolled women planned labour induction at term. Women were assigned to one of two groups: vaginal prostaglandin or balloon dilatation. All patients were evaluated for Bishop score, maternal serum oestriol, human chorionic gonadotropin and progesterone at the time of second-aneuploidy screening. The total successful rate for induction of labour was 63.9% in both groups. Maternal serum oestriol multiple of median (MoM) values were significantly lower among the caesarean section group compared to the vaginal delivery group (p < .001). A MoM value of 0.74 for oestriol was associated with a sensitivity of 75.9%, specificity of 41.0%, a positive predictive value of 76.6% and a negative predictive value of 58.0% for a successful induction of labour. Oestriol had a good performance in the prediction of successful induction of labour at term. IMPACT STATEMENT What is already known on this subject? Induction of labour is a common procedure undertaken whenever the benefits of prompt delivery outweigh the risks of expectant management. Previous studies have reported that a decreased progesterone/oestradiol ratio and increased maternal plasma oestriol levels are associated with successful labour. What the results of this study add? The results of this study showed that second-trimester oestriol multiple of median (MoM) value provide a significant contribution to the efforts of the prediction of successful induction of labour in term pregnancy, having a sensitivity of 69.8%, specificity of 92.4%, positive predictive value of 83.3% and negative predictive value of 82.5%. What the implications are of these findings for clinical practice and/or further research? This finding can be used as an additional method for prediction of labour induction as well as multiparity and Bishop score. This adds new valuable data to the literature which could be used for systematic reviews and for implementing guidelines and protocols on labour induction.

Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS

In this study, a novel liquid chromatography - tandem mass spectrometry method for the simultaneous determination of bisphenols (BPA, BPS, BPF, BPAF), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben) and estrogens (estrone, estradiol, estriol) in human plasma is presented. Since all analytes possess the phenolic group, dansyl chloride derivatization was applied in order to gain high sensitivity. The method was validated according to FDA guidelines, and all validation requirements were satisfactory. The lower limits of quantifications were 41.6, 54.9, 43.5 and 150.8pg/mL for BPA, BPS, BPF and BPAF; 172, 149, 171, 134 and 202pg/mL for methyl-, ethyl-, propyl-, butyl- and benzyl-paraben; 10.5, 6.7 and 9.4pg/mL for estrone, estradiol and estriol, respectively. This is the first method allowing the determination of plasma bisphenols, parabens and estrogens in one run, and also the first determination of BPF levels in human plasma. The method was used to examine the plasma levels of healthy normospermic men, where three times higher plasma levels of BPF than BPA were found.

Development and validation of LC–MS/MS method for quantification of bisphenol A and estrogens in human plasma and seminal fluid

Bisphenol A (BPA) is a widely known endocrine disruptor with estrogenic, antiestrogenic or antiandrogenic properties. BPA could interfere with estrogen metabolism as well with receptor-mediated estrogen actions. Both environmental BPA and estrogens may be traced in body fluids, of which, besides the blood plasma, the seminal fluid is of particular interest regarding their possible interactions in the testis. The method for simultaneously determining BPA and estrogens is then needed, taking into account that their concentrations in these body fluid may differ. Here the method was developed and validated for measurements of BPA, estrone (E1), estradiol (E2) and estriol (E3) in blood plasma and seminal plasma using liquid chromatography–tandem mass spectrometry. Due to the phenolic moiety of all compounds, dansyl chloride derivatization could be used. The analytical criteria of the method with respect to expected concentration of the analytes were satisfactory. The lower limits of quantifications (LLOQ) amounted to 43.5, 4.0, 12.7, 6.7pg/mL for plasma BPA, E1, E2 and E3, and 28.9, 4.9, 4.5, 3.4pg/mL for seminal BPA, E1, E2 and E3, respectively. The concentrations of individual steroids differed between body fluids. To the best of our knowledge, this is the first method that enabled the measurement of estrogens and BPA together in one run. The concentrations of E1, E2 and for the first time also of E3 in seminal plasma in normospermic men are reported.

Biochemical tests of placental function for assessment in pregnancy.

Biochemical tests of placental or feto-placental function were widely used in the 1960s and 1970s in high-risk pregnancies to try to predict, and thus try to avoid, adverse fetal outcome. To assess the effects of performing biochemical tests of placental function in high-risk, low-risk, or unselected pregnancies. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 May 2012). Controlled trials (randomized or 'quasi-randomized') that compare the use of biochemical tests of placental function in pregnancy with non-use. Trial quality was assessed and data were extracted by the review author. A single eligible trial of poor quality was identified. It involved 622 women with high-risk pregnancies who had had plasma (o)estriol estimations. Women were allocated to have their (o)estriol results revealed or concealed on the basis of hospital record number (with attendant risk of selection bias). There were no obvious differences in perinatal mortality (relative risk (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13) or planned delivery (RR 0.97, 95% CI 0.81 to 1.15) between the two groups. The available trial data do not support the use of (o)estriol estimation in high-risk pregnancies. The single small trial available does not have the power to exclude a beneficial effect but this is probably of historical interest since biochemical testing has been superseded by biophysical testing in antepartum fetal assessment.

The Effect of Fetal Maturity on the Regulation of Fetoplacental Unit through Cortisol In Nigerian Women

In this study, we examined the suppression of free plasma oestriol by cortisol in mature and immature fetuses. In group 1 where n = 8 patients in the 32nd week of pregnancy and in group II n = 8 patient in the 38th week who received 100mg cortisol intravenously between 9a.m and 2p.m. Blood samples were taken at 60 minutes intervals respectively. Free plasma oestriol was measured by RIA and total plasma cortisol by the binding method. In group I plasma cortisol increased from 559.93 + 113ng/ml to 1000.5 + 104.792ng/ml, whereas oestriol decreased from 6.33 ± 1.356ng/ml to 3.306 ± 1.433 ng/ml[P

Quantitative trace analysis of estriol in human plasma by negative ion chemical ionization gas chromatography–mass spectrometry using a deuterated internal standard

A stable isotope dilution gas chromatography–mass spectrometry (GC–MS) assay for the trace level determination of estriol in human plasma is described. Negative ion chemical ionization (NICI) MS is used for highly specific detection. The method involves derivatization of the phenolic hydroxyl to the pentafluorobenzyl ether derivative and subsequent reaction of the remaining hydroxyls with heptafluorobutyric anhydride. This derivative allows detection of the strikingly abundant phenolate ion under NICI conditions. [2,4,17β]- 2H 3-labeled estriol was used as an internal standard. For high-level measurements (>313 ng/l) plasma was directly derivatized by extractive alkylation followed by heptafluorobutylation prior to analysis. A rapid and simple sample work up procedure was elaborated for trace level determinations (>5 ng/l plasma) using solid-phase extraction on C 18 with an absolute recovery of 92.9%. For low-level measurements, the calibration curve was linear in the range of 5 to 625 ng/l ( r=0.99993). Inter-assay analytical precisions (RSDs) were 1.29, 2.30 and 2.89% at 39, 156 and 650 ng/l plasma, respectively. For high-level measurements, calibration curve linearity was observed in the range of 0.313 to 20 μg/l ( r=0.99998). Inter-assay analytical precisions (RSDs) were 5.17, 1.92, 2.57 and 2.74% at 0.313, 0.625, 2.5 and 10 μg/l plasma, respectively. Postmenopausal plasma was used for spiked plasma samples. Sensitivity and specificity of the presented method allows adequate determination of estriol in human plasma samples.

Pharmacokinetics of oestriol after repeated oral administration to dogs

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1–7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before ( C trough) and 1 h after dosing (C t=1 h ) . During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C max and t max, were determined from the plasma concentration–time curves using non-compartmental methods. The between animal variation in C max and the AUC was high. Individual values of the C max varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC 0–24 h from 789 pg·h/ml (day 1) to 5718 pg·h/ml (day 7). t max occurred within 1 h. The mean C trough value was slightly above the pre-treatment level ( 38±2 pg/ml vs. 18±5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C max and C trough did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration–time curve around 8–12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC 0–24 h was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.

Plasma progesterone, dehydroepiandrosterone sulfate and estriol levels during labor induction with a sustained-release prostaglandin E 2 vaginal insert

Plasma progesterone, dehydroepiandrosterone sulfate and estriol levels during labor induction with a sustained-release prostaglandin E 2 vaginal insert

Equine Type Estrogens Produced by a Pregnant Woman Carrying a Smith-Lemli-Opitz Syndrome Fetus

The equine-type estriols 1,3,5(10),7-estratetraene-3,16α,17β-triol (16α-hydroxy-17β-dihydroequilin) and 1,3,5(10),6,8-estrapentaene-3,16α,17β-triol (16α-hydroxy-17β-dihydroequilenin) constituted over half of the estrogens excreted by a woman carrying a Smith-Lemli-Opitz syndrome (SLOS) affected fetus. The steroids were characterized by gas chromatography-mass spectrometry (GC/MS), and mass spectra of the dehydro estriols as trimethylsilyl ethers are illustrated. SLOS is associated with 7-dehydrocholesterol (7DHC), delta 7-reductase deficiency; the enzyme catalyzing the final step in cholesterol biosynthesis. Identification of these equine estrogens show that an estrogen biosynthetic pathway parallel to normal is functional in the feto-placental unit and uses 7DHC as precursor, therefore P450scc, P450c17, and 3βHSD and P450arom are all active on 7-dehydrometabolites. Patients with affected fetuses have low plasma estriol values (probably due to deficient production of the cholesterol precursor) and this is often a warning sign which instigates further evaluation for SLOS. The estriol deficiency is not quantitatively made up by the dehydrometabolites, and the combined excretion was found to be about one-third of the mean of gestational age matched controls. The importance of these findings lies in the potential value of dehydroestriol measurement for non-invasive diagnosis of SLOS at mid-gestation. Currently diagnosis relies on imaging, since SLOS is a malformation syndrome, and measurement of 7DHC levels in amniotic fluid and chorionic villus tissue.

Corticotropin-releasing hormone and pituitary-adrenal hormones in pregnancies complicated by chronic hypertension

OBJECTIVE: We hypothesized that maternal plasma corticotropin-releasing hormone levels are elevated in chronic hypertension and that elevations modulate maternal and fetal pituitary-adrenal function. STUDY DESIGN: Venous blood samples and 24-hour urine speciemsn were obtained in normal and hypertensive pregnancies at 21 to 40 weeks of gestatin. Corticotropin-releasing hormone, corticotropin, cortisol, dehydroepiandrosterone sulfate, and total estriol levels were measured by radioimmunoassay. Mean hormone levels were compared by unpaired t test or two-way analysis of variance. RESULTS: Plasma corticotropin-releasing hormone levels were elevated early in hypertensive pregnancies but did not increase after 36 weeks. Levels of pituitary and adrenal hormones were not different in normal and hypertensive women. However, maternal plasma estriol levels were lower in hypertensive pregnancies compared with normal pregnancies. CONCLUSIONS: Fetal 16-hydroxy dehydroeplandrosterone sulfate, the major precursors to placental estriol production, has been reported to be lower than normal in hypertensive pregnancies, possibly explaining the decreased plasma estriol levels reported here. Early stimulation of placental corticotropin-releasing hormone production or section may be related to accelerated maturation of placental endocrine function in pregnancies complicated by chronic hypertension.

Changes in the concentrations of dehydroepiandrosterone sulfate and estriol in maternal plasma during pregnancy: a longitudinal study in healthy women throughout gestation and at term.

In a longitudinal study, the changes in plasma concentrations of dehydroepiandrosterone sulfate (DHAS) and total estriol (E3) were followed in 10 normal pregnant women throughout gestation at 8-10, 14-17, 21-24, 28-32, and 38 weeks as well as at the time of admission to the delivery room. The mean plasma concentration of DHAS decreased from 325 +/- 38.2 micrograms/dl in early gestation to minimum levels of 120 +/- 15.9 micrograms/dl at week 38. At delivery there was a 2-fold increase in plasma DHAS (205.3 +/- 17.7 micrograms/dl). The mean total E3 plasma concentration increased from 6.53 +/- 2.5 ng/ml at week 8-10 to 198.6 +/- 30.3 ng/ml prior to delivery. The decrease in the DHAS plasma levels is caused by the elevated metabolic clearance rate throughout pregnancy. The increasing E3 plasma levels are caused by increasing steroid production by the fetoplacental unit and reflect fetal well-being. The peak levels of DHAS and E3 as well as of other steroids of adrenal or placental origin at admission to the delivery room reflect increased maternal and fetal stress with the onset of labor. These longitudinal reference data determined by modern radioimmunoassay methodology are helpful for the prenatal diagnosis of congenital disorders with insufficient or absent fetoplacental function, and in the control of suppression of the fetal pituitary-adrenal axis during dexamethasone treatment in pregnancies with a female fetus affected with congenital adrenal hyperplasia.

A comparison of serial ultrasound measurements of fetal adrenal glands with maternal plasma and saliva oestriol and progesterone levels in normal pregnancy

SummaryThe purpose of the study was to assess the feasibility of making measurements of fetal adrenal glands using ultrasound and to determine whether there is any correlation between such measurements and maternal oestriol levels. Serial measurements of fetal adrenal and renal maximum transverse diameters, circumference and area, and maternal plasma and saliva oestriol and progesterone levels were made at 4 weekly intervals from 24 weeks to delivery in 32 normal pregnant women. There was an approximately linear increase in the fetal adrenal and renal measurements that were studied. There was no correlation between these measurements and either plasma or saliva oestriol or progesterone levels, or the saliva oestriol:progesterone ratio, at any specific gestation.

Plasma Estriol Levels after Intramuscular Injection of Estriol and Two of Its Esters&lt;sup&gt;1&lt;/sup&gt;

Twelve female volunteers from Berlin and 9 from Stockholm, all using a contraceptive pill (30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel), received an intramuscular injection of estriol (E3; 1 mg in oil) on day 5 of withdrawal bleeding. Blood samples were collected at increasing time intervals during 4 weeks. Three months later, on day 5 of their withdrawal bleeding, 6 women were given intramuscularly (in oil) estriol 3,17-dipropionate (E3-prop) and 15 women estriol 3,17-dihexanoate (E3-hex). The doses were equivalent to 5 mg of estriol, i.e. 6.94 and 8.90 mg, respectively. Blood samples were collected during a period of 9 weeks. Estriol was analyzed by radioimmunoassay in all plasma samples. The average half-life of E3 ranged from 1.5 to 5.3 h after the administration of E3. It was 12.7 h and between 187 and 221 h after the administration of E3-prop and E3-hex, respectively. The average areas under the curve (in nmol.l-1.h) of E3 were between 82.5 and 161 after the administration of E3-prop or E3-hex, and between 27.1 and 37.9 when E3 had been given. As E3 was administered in a 5-fold lower dose than the esters, the areas under curve appeared to be comparable. Thus, the total exposure to E3 seemed to be almost independent of the type of E3 derivatization, while the time and intensity of exposure were very different.

Mixed silyl ether-perfluoroacyl ester derivatives for gas chromatography/mass spectrometry of oestrogens. Application to the quantitative determination of oestriol in human plasma.

The conversion of oestrogens into mixed derivatives comprising a phenolic silyl ether and one or more alcoholic perfluoroactyl ester(s) is described. They are easily formed in quantitative yield and have excellent gas chromatographic and mass spectrometric properties, making them suitable for analysis by selected ion monitoring. Reaction mechanisms are examined which propose explanations for the experimentally observed optimal reaction conditions. The 3-t-butyldimethylsilyl ether-16 alpha 17 beta-bis(pentafluoropropionate) has been used for the quantitative determination of oestriol in plasma by gas chromatography/mass spectrometry using a stable isotope internal standard. Comparison with the pertrimethylsilyl ether of oestriol indicates higher specificity and better precision for low-level (less than 0.5 ng ml-1) estimations.

Diurnal variations in unconjugated plasma and total urinary estriol levels in late normal pregnancy.

Diurnal variations in plasma unconjugated estriol and urinary estriol were assessed in 12 pregnant women during the 3rd trimester of uncomplicated pregnancies. Commercially available 125I-labelled radioimmunoassay kits were used. The preliminary data presented here support the hypothesis that there is no circadian rhythm of unconjugated plasma estriol in normal late pregnancy. Total urinary estriol reaches a nadir during the sleep hours (24.00-6.00). A biological carrier 'stick' for estriol measurements might serve as test of choice in the monitoring of high-risk pregnancy as well as for identifying pregnancies complicated by chromosomal abnormalities (e.g., Down's syndrome).

Regulation of the fetoplacental unit. 3. Suppression of the fetoplacental unit by cortisol in relation to the maturity of the fetus

The present study investigates the suppression of free plasma oestriol by cortisol in mature and immature foetuses. 6 patients in the 32nd week of gestation and 6 patients in the 38th week received an infusion of 100 mg cortisol (Hydrocortison Hoechst) from 10 a.m. to 12 a.m. Blood specimens (5 ml) were drawn from 8 a.m. to 5 p.m. in 60 or 30 minutes intervals, respectively. Free plasma oestriol was measured by radioimmunoassay, total plasma cortisol by the protein binding method. In the 32nd week of gestation plasma oestriol rose from 501 +/- 240 ng/ml to 1035 +/- 301 ng/ml, whereas oestriol decreased from 5.2 +/- 1.0 ng/ml to 3.9 +/- 1.5 ng/ml (p less than 0.001). After an analogous rise of cortisol, oestriol levels in the 38th week were suppressed from 12.5 +/- 3.3 ng/ml to 4.0 +/- 1.6 ng/ml (p less than 0.001). The degree of oestriol suppression of 68 percent in the 38th week markedly exceeded that of the 32nd week (25%). According to these results, the hypothalamic-hypophyseal system of mature foetuses exhibits a higher sensitivity to the feed back action of cortisol than immature foetuses.

Rhythmic oscillations of plasma estriol concentrations in maternal blood during pregnancy

Journal Article Rhythmic oscillations of plasma estriol concentrations in maternal blood during pregnancy Get access V Wiesner, V Wiesner Universitäts-Frauenklinik Erlangen Search for other works by this author on: Oxford Academic Google Scholar W Jäger, W Jäger Universitäts-Frauenklinik Erlangen Search for other works by this author on: Oxford Academic Google Scholar A Bittl, A Bittl Universitäts-Frauenklinik Erlangen Search for other works by this author on: Oxford Academic Google Scholar L Wildt L Wildt Universitäts-Frauenklinik Erlangen Search for other works by this author on: Oxford Academic Google Scholar Acta Endocrinologica (Norway), Volume 117, Issue 4_Supplement, Apr 1988, Page S42, https://doi.org/10.1530/acta.0.117S042 Published: 01 April 1988