Second-trimester unconjugated oestriol (UE3) levels were measured retrospectively in maternal serum from 78 chromosomally abnormal pregnancies and 390 matched controls using a radioimmunoassay kit (Amersham AMERLEX-M) optimized for use in the second trimester. Reduced levels of UE3 were found in a group of 49 Down's syndrome pregnancies with a median UE3 level of 0.79 multiples of the median (MOM) of the controls. Four trisomy 18 pregnancies had UE3 levels less than 0.7 MOM. There was a highly significant level of correlation between alpha-fetoprotein (AFP) and UE3 levels in the controls (r = 0.25, p < 0.01), the Down's syndrome pregnancies (r = 0.44, p < 0.01), and the other chromosome abnormalities (r = 0.61, p < 0.01). When used as an additional marker to AFP and human chorionic gonadotrophin in screening for Down's syndrome, UE3 does not appear to add to the sensitivity of such screening.

The incidence of preeclampsia in a consecutive series of 642 twin pregnancies was 25.9% compared with 9.7% in singleton pregnancies (p less than 0.001); in primiparas it was 35.2% and in multiparas 20.4% (p less than 0.001). Preeclampsia in twin pregnancies was more commonly of early onset (p less than 0.001) and the maternal disease more severe as assessed by the incidences of severe hypertension (p less than 0.001), proteinuria (p less than 0.004), and eclampsia (p less than 0.01). There were 1 maternal and 12 perinatal deaths. Oestriol excretion before the emergence of preeclampsia was lower in patients with severe compared with milder preeclampsia (p less than 0.05) as was plasma glucose concentration (p less than 0.05). Mean birth and placental weights according to gestation, tended to be lower in the severe group compared with uncomplicated cases and those with milder preeclampsia, as were also the placental-fetal weight ratios. The similarity of results with those already reported for singleton pregnancy suggested a similar pathogenesis for preeclampsia in twin and singleton pregnancies.

OBJECTIVE

To study whether the degree of elevation of mid-trimester triple test markers differs in patients with early versus late onset severe pre-eclampsia.

METHODS

A retrospective study of the medical records of 102 patients with severe pre-eclampsia for whom mid-trimester triple test result data were available was made. None of these patients had fetuses with abnormal karyotype nor delivered infants with malformations. Pre-eclampsia was defined as early onset when it presented before 32 weeks' gestation. The levels of mid-trimester maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotrophin (hCG) and unconjugated oestriol (MSuE(3)) in patients with early and late onset severe pre-eclampsia were compared.

RESULTS

Twenty-five patients had early onset and 77 patients had late onset severe pre-eclampsia. The two groups did not differ significantly with regard to age, weight, parity and severity of pre-eclampsia. The mean MSAFP in patients with early onset was significantly higher than in patients with late onset severe pre-eclampsia (1.46 MoM, SE 0.12 versus 1.16 MoM, SE 0.05; p=0.01). The mean hCG in the early onset group was also significantly higher than in the late onset group (1.71 MoM, SE 0.18 versus 1.21 MoM, SE 0.07; p=0.03). Mean MSuE(3) levels in patients with early onset were significantly lower than in patients with late onset severe pre-eclampsia (0.83 MoM, SE 0.05 versus 1.02 MoM, SE 0.03; p=0.04).

CONCLUSIONS

Higher MSAFP and hCG, and lower MSuE(3), may be more significant markers of early rather than late onset severe pre-eclampsia.

Sulphation of oestrogens represents an important regulatory mechanism for these biologically active compounds. We have characterized and purified a form of rat liver sulphotransferase (ST), existing as a 32,500 Da monomer, which sulphates oestrogens, and have used this preparation to produce antibodies against oestrogen ST. The enzyme was active against oestrone, oestriol and beta-oestradiol, but not towards androgens. Using the antibody as a probe for immunoblotting, it was determined that the enzyme is expressed solely in male rats, and predominantly in the liver. Of the tissues examined, the only major extrahepatic tissue found to have any oestrogen ST was the brain (although the levels were very low), indicating that there might be a role for the sulphation of oestrogens in the brain. Examination of human liver and platelet cytosols by immunoblotting showed that the antibody recognized two major proteins of 32 and 34 kDa, which were presumed to correspond to the two principal phenol ST isoenzymes present in man.

The mitogenic response to phytohaemagglutinin of lymphocytes from women in the third trimester of pregnancy is not inhibited by progesterone, oestriol or oestradiol even at much greater than normal physiological levels. There was no difference in the response of lymphocytes from pregnant or non-pregnant women. Inhibition in the mitogenic response to phytohaemagglutinin was achieved with hydrocortisone but not at the physiological levels found in pregnancy. The results from this in vitro study would not support the view that the level of steroid hormones in pregnancy significantly affects the immunological status of the mothers.

A longitudinal investigation regarding the serum concentrations of oestradiol, oestriol and progesterone in relation to uterine activity has been performed in 80 healthy primigravid women during the course of pregnancy up to the 37th week of pregnancy. The frequency of uterine contractions was quantitatively objectivated by means of external toco-dynamometry; simultaneously the uterine activity has been recorded by the pregnant women qualitatively. It appears that there is a gradual increase of all the three mentioned hormones during the course of pregnancy. However, there is a large interindividual spread. There exists no relation between the hormonal serum levels and uterine activity (quantitatively as well as qualitatively recorded). Between these two latter there is a poor relation. It is impossible to predict the occurrence of preterm birth based on hormonal serum changes. This holds for the progesterone-oestradiol ratio.

Oestriol and progesterone concentrations were measured in samples of saliva obtained daily from six normal women during the final four weeks before the spontaneous onset of labour. Progesterone concentrations were found to plateau whereas oestriol concentrations continued to rise so that the mean ratio of saliva oestriol to progesterone increased from 0.80 to 1.43 between 29 days and one day before labour. Saliva oestriol concentrations were 15 times higher than saliva oestradiol concentrations. As saliva steroid concentrations reflect the unbound unconjugated (free) plasma steroid concentrations these data suggest that a changing ratio of oestriol to progesterone may play a part in initiating spontaneous labour in man.

Maternal serum unconjugated oestriol (uE3) was measured in 15,375 pregnancies during 2 years of second-trimester risk assessment for Down syndrome using biochemical markers. Very low levels of uE3 (< 0.1 MOM) were detected in 22 serum samples (0.14 per cent). Very low uE3 was associated with an adverse outcome in 13 pregnancies including fetal death and miscarriage (N = 11) anencephaly (N = 1), and Meckel-Gruber syndrome (N = 1). Dry scales on the skin appeared in the first year of life in four boys. From dermatological diagnosis, prenatal uE3 levels, and pedigree analysis, it is concluded that at least 5 in approximately 7500 male births in the study population are affected by steroid sulphatase deficiency, which is the biochemical defect in X-linked ichthyosis. Very low uE3 levels in the second trimester are indicative of this disease in pregnancies with normal ultrasound findings.

Serum concentrations of oestrone, oestradiol and oestriol were measured in 23 postmenopausal women, 12 with ovarian cancer and 11 with genital prolapse. Oestrone (387.6 pmol/l) and oestradiol (72.7 pmol/l) levels were higher in the cancer group than those in the control group (159.8 and 27.5 pmol/l respectively), while oestriol levels did not differ (434.5-270.8 pmol/l). The results indicate abnormal ovarian function in postmenopausal patients with ovarian cancer.

We have earlier reported on a prolonged effect of orally administered oestriol caused by its enterohepatic recycling after reabsorption from the intestine. The aim of the present study was to test if oral administration of activated charcoal could inhibit the enterohepatic recirculation of orally given oestriol. Plasma concentrations of unconjugated oestriol were measured using a specific radioimmunoassay (RIA). Twelve mg oestriol administered orally to postmenopausal women resulted in elevated plasma oestriol levels for more than 24 h. Plasma oestriol fluctuations in relation to meals were seen. When activated charcoal was given 3 h after oestriol administration, the plasma oestriol concentration declined without further fluctuations and returned to the pretreatment value within 6 h. Our data indicate that oestriol given orally undergoes enterohepatic recirculation after reabsorption from the intestine since administration of charcoal, which binds steroids, resulted in a rapidly declining oestriol level. It is concluded that the prolonged oestriol elevation, which is normally seen, is caused by enterohepatic recycling.

Growth and neurological outcome to 7 years of age were determined in 273 growth retarded infants, 341 infants from pregnancies complicated by subnormal urinary oestriol excretion and 72 control infants. By 1 year of age 80.6% of growth retarded infants were above the 10th percentile for weight. Growth continued so that after 2 years of age only 10.6% were beneath the 10th percentile. A neurological abnormality was detected in 9.5% of growth retarded infants and 8.3% of control infants (P = NS). Only 6 (2.2%) of the growth retarded infants were severely handicapped. A neurological abnormality was detected in 16.4% of infants from pregnancies with low oestriol excretion and although this incidence was higher than that of the control infants (8.3%), the difference failed to achieve statistical significance. The neurological abnormality was severe in only 7 infants (2.1%). The intelligence quotient (IQ) was the same in infants from pregnancies complicated by chronically low oestriol excretion whether hypertonic dextrose (mean IQ 103) had been administered to the mother or not (mean IQ 105). It is concluded that the pregnancy complicated by low oestriol excretion and/or fetal growth retardation should be treated with optimism.

OBJECTIVE

To study the effect of induced hypoglycaemia on serum levels of the placental hormones oestriol, human placental lactogen, placental growth hormone and progesterone in the third trimester of pregnancy.

METHODS

A prospective experimental investigation.

METHODS

High risk pregnancy unit and diabetes research unit at Karolinska Institutet Danderyd Hospital, a university hospital.

METHODS

Ten women with insulin-dependent diabetes mellitus in the third trimester of pregnancy.

METHODS

Venous blood samples were collected every 15 minutes for analyses of oestriol, progesterone, human placental lactogen and placental growth hormone, during the 150 min of a hyperinsulinaemic hypoglycaemic clamp, which maintained arterial blood-glucose level of about 2.2 mmol/l.

METHODS

Levels of analysed placental hormones during hypoglycaemia.

RESULTS

A statistically significant increase was observed in placental growth hormone during hypoglycaemia (P < 0.0001), whereas the placental hormones progesterone, human placental lactogen and oestriol did not show changes of clinical significance.

CONCLUSIONS

The increase in placental growth hormone indicates that the placenta is an endocrine organ which may take an active part in acute metabolic processes, such as here in the hormonal counterregulation of hypoglycaemia.

In order to identify possible aetiological factors in the genesis of physiological hydronephrosis in pregnancy, the degree of pelvic-calyceal dilatation in 90 asymptomatic pregnant women was correlated with levels of plasma oestradiol, progesterone, 24-hour urinary oestriol, the site of the placenta, birthweight of the fetus, and pelvic inlet measurements. A grading system based on maximum calyceal diameter was used; 90% of the patients were found to have at least mild dilatation on the right side. No correlation was demonstrated between the degree of hydronephrosis and the levels of oestradiol, progesterone and 24-hour urinary oestriol excretion. The birth-weight of the fetus and its relationship with the pelvic inlet measurements also did not correlate with the occurrence of hydronephrotic changes in the kidneys. The only significant positive finding was a higher incidence of moderate and severe hydronephrosis occurring in patients with a right-sided placenta than compared with the left (x2 = 4.77; p less than 0.05), although the sensitivity and specificity in predicting hydronephrosis from a right-sided placenta is low (53% and 66% respectively). Our results support the hypothesis of a mechanical aetiology in the genesis of pregnancy hydronephrosis, where vascular compression on the ureters may be an important contributory factor. Our study has also shown that urinary tract infection and reduction of creatinine clearance were not more common in patients with moderate or severe pelvic-calyceal dilatation.

In order to elucidate the mechanism of impaired LH secretion, 60 female patients with anorexia nervosa were investigated. A control group consisted of 14 women of the same age, examined in the follicular phase of the menstrual cycle. The serum LH, FSH, prolactin, TSH, testosterone, dihydrotestosterone, dehydroepiandrosterone, delta 4-androstenedione, oestrone, oestradiol, oestriol, progesterone, thyroxine, triiodothyronine, reverse T3 and serum sex hormone binding globulin (SHBG) concentrations were measured. The results showed a significant increase in serum dehydroepiandrosterone, testosterone, oestriol and reverse T3 concentrations. However, oestrone, oestradiol, progesterone, SHBG and triiodothyronine levels were significantly lower than those of the control group. The mean serum LH concentration in patients with anorexia nervosa before and after LRH stimulation was significantly lower than that in the control group, but FSH secretion in response to LRH was normal. All hormonal changes in anorexia nervosa disappeared after weight gain during cyproheptadine treatment. Dramatically increased dehydroepiandrosterone levels suggest that the high testosterone in women with anorexia nervosa is derived from adrenal rather than from gonadal steroids. There was no correlation between serum testosterone, dehydroepiandrosterone, oestriol and LH concentrations indicating that steroid hormone disturbances do not cause impaired LH release in anorexia nervosa.

1. The present study was undertaken in order to examine the effect of various oestrogens on tert-butyl hydroperoxide (t-BHP)-induced cell injury and changes in apical transporters in primary cultured rabbit renal proximal tubule cells. 2. Compared with control, t-BHP (0.5 mmol/L; 1 h) decreased cell viability (62%) and glutathione (GSH) content (60%) and increased lipid peroxide (LPO) formation (309%), arachidonic acid (AA) release (193%) and Ca(2+) influx (168%). 3. The protective potency of various oestrogens for these parameters is dependent on the precise oestrogenic structure, with 2-hydroxy-oestradiol-17 beta (2-OH-E(2)) and 4-OH-E(2), both catecholic oestrogens, or diethylstilbesterol (DES) being more potent than oestradiol (E(2)), oestriol or oestradiol-17 alpha, all phenolic oestrogens (P < 0.05). 4. These cytoprotective effects of oestrogens occur at concentrations above 10 micromol/L and are not dependent on classical oestrogen receptors and gene transcription and translation. In addition, various oestrogens have different preventative effects against t-BHP-induced inhibition of [(14)C]-alpha-methyl-D-glucopyranoside (alpha-MG), inorganic phosphate (Pi) and Na(+) uptake, consistent with the results of cell injury. In contrast, the potency against t-BHP-induced changes in cell viability, LPO, GSH content and transporter function of the anti-oxidants taurine and vitamin C is similar to that of phenolic oestrogens, whereas that of the iron chelators deferoxamine and phenanthroline is similar to that of catecholic oestrogens. 5. In conclusion, various oestrogens have differential cytoprotective potential against t-BHP-induced cell injury and decreases in alpha-MG, Na(+) and Pi uptake. These effects are due, in part, to both the basic chemical properties of the compounds and the maintenance of endogenous GSH or inhibition of AA release and Ca(2+) influx.

In the second trimester, oestriol is synthesized in the placenta and secreted into the maternal circulation. 16alpha-hydroxy dehydroepiandrosterone sulphate (16alpha-OH-DHEAS) is formed in the fetal liver by hydroxylation of dehydroepiandrosterone sulphate (DHEAS) and transported to the placenta where it undergoes desulphation by steroid sulphatase (STS) and aromatization to oestriol. Maternal serum levels of unconjugated oestriol (UE3) are lower in Down's syndrome pregnancies than in unaffected pregnancies in the second trimester. The underlying cause of this variation was investigated in placenta, fetal liver, maternal serum and amniotic fluid from Down's syndrome pregnancies by measuring the levels of UE3, DHEAS and STS in appropriate tissues and in corresponding samples from unaffected pregnancies. UE3 levels, expressed as multiples of the control median at the appropriate gestation (MOM), were lower in placental tissue (0.52 MOM), maternal serum (0.65 MOM) and amniotic fluid (0.61 MOM) than in unaffected pregnancies. There was a significant correlation between placental and maternal serum levels of UE3 in the Down's syndrome cases. The median STS activity in placental tissue from Down's syndrome pregnancies (1.14 MOM) was not significantly different from that of the control pregnancies (1. 01 MOM), suggesting that placental turnover of the fetal precursor DHEAS is not reduced. However, levels of DHEAS were reduced in maternal serum (0.69 MOM), placental tissue (0.54 MOM) and fetal liver (0.65 MOM) from Down's syndrome pregnancies. Thus, a diminished supply of the fetal precursor DHEAS may be the cause of the decreased placental production of UE3 in Down's syndrome pregnancies in the second trimester.

Sulfamate substitution at the C-3 position of the steroid skeleton leads to orally active prodrugs of ethinyloestradiol, oestradiol, oestrone, oestriol and probably many other natural or synthetic steroidal oestrogens. These compounds have higher systemic, but reduced hepatic, oestrogenic activity than their parent steroids. The release of the parent oestrogen results from the passage of the sulfamates in the erythrocyte compartment through the liver and the systemic hydrolysis of the sulfamate ester. Sulfamates may be used to generate natural oestrogens, oestradiol and other oestrogens for different types of oral oestrogen therapy, e.g., as oestriol for hindered oestrogen or as 17-alpha oestradiol for 'non-feminising' oestrogen. Oestradiol sulfamate J995 is currently in the initial stages of clinical testing. It has per se no oestrogen receptor affinity or oestrogenic activity in vitro, i.e., is inactive without hydrolysis. Its oral uterotropic activity in rats is approximately 100-times higher than that of oestradiol, its hepatotropic activity, however, is only 2- to 3-fold higher than oestradiol. Oral oestradiol sulfamate treatment should, therefore, reduce the hepatic side-effects seen with conventional oral hormone therapy, while at the same time lead to full stimulation of the uterus and the vagina, and suppression of gonadotropin. In the rat, orally administered oestradiol is effectively extracted from the portal vein and excreted via the bile. In contrast, oestradiol sulfamate is present in the circulation at high concentrations, up to 30% of the dose. Initially, 98% of this is found in the erythrocyte compartment and only 2% in the plasma. Significant oestradiol levels in the blood are recorded during the depletion of this pool. Pharmacokinetic and toxicological studies reveal complete excretion of the compound and its metabolites. No toxic effects have been seen in rats and cynomolgus monkeys at any dose, in spite of the compound's distinct oestrogenicity. The evaluation of genotoxicity also yielded negative results.

The prostates of 41 foetuses and neonates have been assayed for testosterone, 5 alpha-dihydrotestosterone (DHT), oestradiol and oestriol and the presence of these hormones has been demonstrated in all cases. Oestriol was found to be present in the highest concentration. A highly significant correlation was found between testosterone and DHT as well as between DHT and oestradiol. The correlation between oestriol and oestradiol was also significant. It has been pointed out that the presence of these hormones is essential for the growth and development of the prostate gland.

The influence of various oestrogens during unopposed replacement therapy on circulating androgens and cortisol was studied in 65 post-menopausal women. As dose dependent decrease in dehydroepiandrosterone sulphate (DHAS) was found. Ethinyloestradiol (0.05 mg daily) already gave a significant decrease after 1 mth of treatment. The decline following 17 beta-oestradiol (2 mg) and oestrone sulphate (2.5 mg) was less pronounced. Oestriol (6 mg daily) had no effect. Ethinyloestradiol also increased the levels of total cortisol and testosterone, probable because of serum protein induction, while 17 beta-oestradiol had no significant effect. Serum levels of androstenedione remained unchanged during therapy.

Forty patients participated in a randomized controlled trial of complete bed rest versus ambulation as desired in the management of proteinuric hypertension during pregnancy. Daily increases in serum human placental lactogen and oestriol concentrations were greater in the rested group. An especially 'at risk' group of 10 patients with both hyperuricaemia and severe fetal growth retardation was identified. Strict confinement to bed in these cases seemed to encourage the development of the premonitory symptoms of eclampsia, but was associated with a better prognosis for the fetus.

A total of 162 fallopian tubes was obtained from a sample of subjects comprising fertile women with regular ovulatory cycles, post-menopausal women taking no hormonal drugs and post-menopausal women receiving oestrogen therapy in various forms. During the menstrual cycle the highest percentage of ciliated cells was found, in all of the three tubal portions studied, around ovulation time. The epithelial height decreased significantly subsequent to ovulation. After more than 1 yr had elapsed following the menopause, the percentage of ciliated cells and epithelial height decreased significantly. Very low values were observed in women 10 yr after the menopause. In women receiving oestrogen therapy for more than 10 yr following the onset of menopause - conjugated equine oestrogens (CEE), 1.25 mg/day - the percentage of ciliated cells was significantly higher than that in subjects not receiving hormonal therapy. Similar data were obtained in the case of women taking oestriol (2 mg/day). The data presented demonstrate that oestrogen therapy influences the ciliation and height of oviductal epithelium.

Oestriol and progesterone concentrations were measured by specific radioimmunoassays in the saliva of six women on a daily basis during the last month of pregnancy, at frequent intervals during labour and daily during the puerperium. Salivary steroid concentrations are thought to reflect the circulating concentrations of the free hormone, and hence may be more biologically relevant than the total plasma concentration, or the urinary excretion of a metabolite. There was no sign of a fall in salivary oestriol or progesterone concentrations before the onset of labour. During the first and second stages, the concentrations fluctuated widely, perhaps due to alterations in uterine blood flow. After delivery of the placenta, hormone concentrations declined abruptly. Oestriol reached undetectable levels of less than 0.1 nmol/l within a day, whereas progesterone concentrations declined somewhat more slowly, approaching follicular-phase values after 2-3 days. This slower decline in the concentration of progesterone may be due to a leaching-out of the hormone from body fat stores. The absence of any prepartum progesterone withdrawal presumably explains the characteristic postpartum delay in the onset of lactogenesis.