Churg-Strauss syndrome (CSS) is a rare disease belonging to the group of necrotizing vasculitides affecting medium and small vessels, classified together with Wegener granulomatosis and microscopic polyarteritis. The literature is reviewed concerning vasculitides associated with drug use, focusing on CSS. A representative case of CSS is reported, in whom the possibility could not be excluded that oestrogen replacement therapy contributed to the onset of CSS. The case of a 56-year-old female patient is presented who had a history of allergic rhinitis and steroid-dependent asthma for years. To prevent postmenopausal complaints and further loss of bone density, she received oestrogen replacement therapy. After three months of hormone therapy, signs of CSS appeared. Oestrogen administration (1 mg norethisterone acetate, 1 mg oestriol and 2 mg oestradiol daily) was stopped. The diagnosis was confirmed by the clinical appearance, laboratory tests and tissue biopsies. The patient received corticosteroids and cyclophosphamide treatment and subsequently the eosinophil count returned to normal within two weeks and her condition improved significantly.

Hormones play a major role in the development of acne vulgaris of pubertal onset. In addition to a seborrhoeic diathesis, an imbalance of oestrogens and androgens, as well as altered enzyme metabolism in the sebaceous glands are factors frequently implicated in the aetiology of this condition. There are many reports on hormonal treatment in the literature; the therapeutic regimes and results achieved varied greatly. The present report is concerned with a discussion of the results obtained in 50 patients with acne vulgaris treated with a drug containing oestriol.

OBJECTIVE

Subjectively and objectively assess stress urinary incontinence (SUI) symptoms before and after topical oestrogen therapy.

METHODS

A prospective study was performed in 3 centres in South-Africa, Australia and the Netherlands. Postmenopausal women with SUI were treated with topical oestriol cream for 6 weeks. The primary subjective outcome was the Patient's Global Impression of Improvement (PGI-I) scale. The primary objective outcome was vaginal pH. Secondary subjective outcomes were: the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form, the Incontinence Impact Questionnaire, the Urogenital Distress Inventory (UDI-6) and the most bothersome symptom approach. Secondary objective outcome was the erect cough pad test. Compliance was scored.

RESULTS

A total of 68 women were enrolled. Half of the participants reported improvement on the PGI-I scale after treatment. Vaginal pH was significantly lower after treatment (median 5.3 (interquartile range (IQR) 4.5-6.0) vs. 5.0 (4.4-5.4), p = 0.002). Improvement on the UDI stress domain was observed (p = 0.01). No statistically significant differences were found in the other subjective outcomes. Baseline and repeat cough pad tests demonstrated a wide variation with no significant difference. Compliance was high (median 100 (IQR 83-100%)).

CONCLUSIONS

Topical oestriol cream during 6 weeks improved quality of life and vaginal pH but no other objective measures of incontinence.

Recent articles by Cuckle et al., Canick et al., and Isozaki et al. have evaluated urine beta-core fragment as a screening test for Down syndrome in second-trimester pregnancies. They found over four-fold elevation of beta-core fragment levels in Down syndrome pregnancies, and between 62 and 88 per cent detection of this trisomy at a 5 per cent false-positive rate. Urine beta-core fragment may be a superior screening test for Down syndrome pregnancies. In the present study, urinary total oestriol has been evaluated as a marker to use in combination with beta-core fragment in screening for Down syndrome pregnancies. The two markers were evaluated separately in relation to the urine creatinine concentration. To amplify screening performance, we evaluated the ratio of beta-core fragment to total oestriol levels (creatinine-independent). beta-core fragment and total oestriol levels were determined (normalized to creatinine, ng/mg creatinine) in urine samples from 480 unaffected and 12 Down syndrome pregnancies, collected consecutively at a single prenatal diagnosis centre. The median beta-core fragment level in Down syndrome cases was 4.5 MOM. Fifty-eight per cent of Down syndrome cases had beta-core fragment levels exceeding the 95th centile of unaffected pregnancies. The median total oestriol level in Down syndrome cases was 0.33 MOM. Forty-two per cent of Down syndrome cases had total oestriol levels exceeding the 95th centile of unaffected pregnancies. We investigated the ratio of the two determinants (beta-core fragment, ng/ml divided by total oestriol, ng/ml) in our sample set. The median beta-core fragment:total oestriol ratio in Down syndrome cases was 13 MOM. Seventy-five per cent of Down syndrome cases had a ratio exceeding the 95th and the 99.5th centile of unaffected pregnancies. Total oestriol complements beta-core fragment in urine screening for Down syndrome pregnancies. A test measuring the ratio of the two urine determinants may be a significant improvement over current serum methods for detecting Down syndrome.

We assessed the reproducibility of measurements of plasma hormone and binding protein levels in umbilical cord blood collected from 30 male and female babies. They were delivered as singleton births from full-term pregnancies (gestational age>>or= 37 weeks) in a cord blood donation programme. We assayed three plasma replicates from each cord blood sample at two points in time. Plasma oestradiol, unconjugated oestriol, testosterone, progesterone, prolactin, sex-hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and IGF binding protein-3 (IGFBP-3) levels were measured in duplicates in the same batch (batch 1). In addition, another set of assays was conducted for each cord blood 1 year apart in a different batch (batch 2). Means and standard deviations for each hormone and binding protein were similar in replicates assayed in batch 1 and 2. Pearson's correlation coefficients were 0.9 or higher in duplicates assayed in batch 1. The correlation coefficients were between 0.77 and 0.96 for between-batch assays. Intra-class correlation coefficients (ICC) were higher than 0.9 for assay of SHBG [95% CI 0.92, 1.0] and progesterone [95% CI 0.87, 0.97] and between 0.8 and 0.9 for assay of oestradiol, unconjugated oestriol, prolactin, IGF-1, and IGFBP-3. The lowest ICC value was found for testosterone (ICC = 0.74; [95% CI 0.56, 1.0]). These data indicate a high reproducibility of cord blood hormone measurements; minimal differences were observed between the calibrated and the original regression coefficients for the association of hormones/binding proteins with percent of CD34+ cells in mononuclear cells.

Homogenates of cerebral metastatic chorionepithelioma tissue were incubated with labelled dehydroepiandrosterone, pregnenolone or 20alpha-hydroxypregn-4-en-3-one. The metabolites of dehydroepiandrosterone which were isolated and identified were androstenedione, testosterone, oestrone, and oestradiol; no oestriol was detected. The only metabolite of pregnenolone and 20alpha-hydroxypregn-4-en-3-one isolated and identified was progesterone. No conversion of C-21 to C-19 steroids occurred in the metastatic chorionepithelioma tissue.

Six sexual steroidal hormones (progesterone, pregnenolone, testosterone, ethinyl-oestradiol, oestriol and oestrone) inhibit acetylcholine- and histamine-induced contractions of the isolated guinea-pig ileum. Different degrees of inhibitory capacity were found. High concentrations of PGE1 and F2alpha reverse some of these inhibitions. This reversal seems to be non-specific and probably related to sensitization of the ileal smooth muscle by prostaglandins. The inhibitory action of sexual steroids might be non-specific as well. But a "corticoid-like" effect cannot be excluded.

Urine and plasma oestriol, plasma progesterone, human placental lactogen, beta 1-glycoprotein and serum cystyl aminopeptidase were measured at intervals during 608 pregnancies. The predictive accuracy of low values for identification of pregnancies with low birthweight outcomes was assessed for each test at various gestations. Data were analysed to obtain 10th-90th centile values for each test from 28 weeks to delivery. Groups with values under different centile levels were compared: those under the lower centiles had higher proportions but smaller absolute numbers of low birthweight infants than those under higher centiles. No test was superior to the others at all centiles and gestations. Biochemical screening of pregnant populations to identify high-risk groups for intensive fetal monitoring has limited potential. If screening is used, the definition of high-risk groups is best achieved by practical rather than statistical criteria. If monitoring facilities are available and well accepted by patients then higher centile 'cut-offs' to define fetal risk may be used than when they are not. Combining any pair of tests with values below the 10th centile did not reduce false positive and negative predictions any more than could be achieved by movement of centiles up or down for a single test.

Samples of cord serum from 29 healthy neonates were analysed for digoxin-like immunoreactive substance (DLIS), cortisol, 17 beta-oestradiol, progesterone, dehydroepiandrosterone-sulphate (DHEAS), 17 alpha-hydroxyprogesterone (17OHP), androstenedione, oestriol and ouabain-like activity (OLA; by inhibition of Na+, K+ATPase activity). The mean serum concentration of DLIS was 0.91 (SD = 0.19) nmol/L and the mean OLA was 26.1 (SD = 11.5) nmol/L. There was no correlation between DLIS and OLA. DLIS correlated significantly with oestriol (r = 0.521), progesterone (r = 0.534) and 17OHP (r = 0.43). Stepwise multiple regression analysis showed that 17 beta-oestradiol, progesterone and androstenedione contributed to DLIS and the intercept was 0.64 (SD = 0.127). The concentrations of steroids (17 beta-oestradiol, progesterone, androstenedione) required to displace digoxin by 50% in the digoxin immunoassay and inhibit Na+,K+ATPase in the OLA assay were 10(3)-10(4)-fold higher than those found in cord serum. We conclude that the contribution of these steroids to DLIS is small and that DLIS and OLA measure different compounds.

The endocrine regulation of parturition exhibits several interspecies differences. Among the endocrine parameters considered to be the most important ones from the point of view of the regulation of parturition the concentration of oestrogens (oestradiol, oestriol and oestrone), progesterone, PGF2 alfa and its degradation product PGFM, was determined in both peripheral and uterine venous blood by RIA method in rats starting from the 15th day of pregnancy to the 3rd or 4th day following parturition. In the pregnant rat oestriol could only be detected on the day of parturition (21th day). Concentrations of oestriol and oestradiol were the highest on the day of parturition. An opposite tendency could be observed as far as progesterone concentration was concerned, i.e., the concentration decreased gradually from the 15th day of pregnancy onwards and the lowest value was reached on the day of parturition both in peripheral and uterine venous blood. PGF2 alfa and PGFM concentrations in the uterine vein increased gradually from the 15th day of pregnancy and the highest value could be detected peri partum. Our data, in accordance with those of others support the idea that the hormones investigated are involved in the process of parturition, i.e., characteristic changes of oestrogens, progesterone and prostaglandin levels ensue in the rat prior to parturition.

Serial blood samples were collected from ten patients at between 40 and 42 weeks gestation, who were having labour induced by amniotomy and intravenous oxytocin. The plasma levels of human placental lactogen and pregnancy-specific beta 1 glycoprotein showed no more than their normal late pregnancy variability during labour; oestradiol-17 beta showed a small rise in early labour followed by a fall in the second stage of labour; unconjugated oestriol and 11-hydroxycorticosteroids showed a progressive rise throughout labour and progesterone a progressive fall. The ratio of progesterone to oestradiol-17 beta fell throughout labour. The significance of these changes in our understanding of the control of placental hormone secretion and of the hormone profile of spontaneous labour is discussed.

Peripheral plasma concentrations of unconjugated oestradiol-17 beta, progesterone and total oestriol were measured in patients presenting with uncomplicated preterm labour. Control samples were obtained from normal healthy women matched for maternal age, parity and duration of pregnancy. Oestrogen concentrations were often higher and progesterone concentrations often lower in patients presenting in preterm labour, and in particular, in those presenting in advanced labour and those failing to respond to treatment with ritodrine, but the differences were not statistically significant.

Placental protein 5 (PP5), pregnancy-specific glycoprotein (SP1), pregnancy-associated alpha 2-glycoprotein (SP3) and chorionic gonadotrophin could not be demonstrated in appreciable molar quantities in the soluble fraction from microvillous plasma membrane preparations isolated from the syncytiotrophoblast of full-term human placentae. However, progesterone, total oestriol and placental lactogen may have some association with this membrane.

In order to elucidate the effects of dehydroepiandrosterone sulfate (DHAS) on softening and dilatation of the uterine cervix, changes of oestriol, 17 beta-oestradiol and progesterone levels in serum and cervix, Bishop score and collagenase activity in the cervical tissue were assessed in pregnant women before and after treatment with DHAS. 17 beta-oestradiol level in the serum and cervical tissue markedly increased after the administration of DHAS, while oestriol level remained unchanged. Serum progesterone level did not change in the majority of cases, while it decreased within several hours in patients in whom delivery was accomplished within 24 hours after the administration of DHAS. Among the factors connected with the Bishop score, effacement and consistency of the cervix were remarkably improved by DHAS administration. Total collagenase activity in the cervical tissue of patients treated with DHAS was elevated by an average of 152%. These results suggest that DHAS is potent in ripening the uterine cervix through an activation of collagenase activity induced by the enhanced conversion to 17 beta-oestradiol. Thus, DHAS administration in the late stage of pregnancy is valuable in prepartal treatment for induction of labour.

The atrial natriuretic factor (ANF) and parameters related to renal sodium handling and renal function were evaluated in 92 normotensive pregnant women at different gestational ages (1st group: 7th-13th week, 2nd group: 14th-20th week; 3rd group: 21st-27th week; 4th group: 28th-34th week; 5th group: greater than 34th week), in 15 normotensive non-pregnant women and in 15 normotensive women 6 days after spontaneous delivery at the end of a normal pregnancy. ANF did not differ significantly between the 5 groups of pregnant women while, concurrently with a further increase in plasma volume (as shown by our data) it was significantly higher in late pregnancy (3rd and 5th groups) than in the non-pregnant women. ANF in post-partum women was significantly higher than in non-pregnant and pregnant women. Only in post-partum women was ANF significantly directly related to sodium excretion. Even though ANF does not seem to play an important role in water and sodium excretion in pregnancy in comparison with other hormones such as progesterone, oestriol and aldosterone, the higher levels of ANF in late pregnancy probably represent a compensatory increase when a given threshold of plasma volume (and therefore of atrial stretch) is reached. However ANF does seem to play a more important role in the induction of diuresis and natriuresis in early puerperium.

The potency ratio of oestriol compared to oestradiol or to ethinyloestradiol depends on the experimental conditions of the test. If a sufficiently high level of oestriol is maintained in a target tissue, either by infusion or by frequent administration, this steroid is capable of eliciting a full oestrogenic effect. At the target tissue, oestriol is a short-acting rather than a weak-acting oestrogen. This explains why certain oestrogenic effects are not observed after a single administration of oestriol or after far-spaced dosings. The short retention time of oestriol in the target tissues makes the oestrogenic effects dependent on the manner of administration of the compound, in particular on the route of administration and on the frequency of dosing.

Plasma total oestriol was measured daily before and during ampicillin therapy in five pregnancy patients and in eight patients, four of whom were receiving ampicillin, for four days following delivery. Ampicillin caused a fall in plasma oestriol of 25 per cent during the first three days of treatment, thereafter the level remained stable with a lower day-to-day variability than in untreated patients. Ampicillin reduced the plasma half life of total oestriol by 60 per cent. This study illustrates how the re-entry of oestriol from the gut leads to irregular fluctuations in plasma oestriol levels and helps to keep up the plasma concentration of the steroid when inflow from the fetoplacental unit is cut off.

OBJECTIVE

Stress-related peptide and steroid hormones are involved in the pathogenesis of preterm delivery, even though their clinical usefulness as predictive markers of preterm delivery remains unclear. The present study evaluated whether mid-trimester amniotic fluid concentrations of stress-related peptides, that is corticothophin-releasing factor (CRF) and urocortin (Ucn) and feto-placental steroids (oestriol, DHEA-S and cortisol) correlated with preterm delivery.

METHODS

It is a retrospective case-control study. Healthy women (n=130) undergoing amniocentesis at mid-gestation for genetic indications, of whom 15 had a preterm delivery (cases) and 115 delivered at term (controls). CRF, urocortin, cortisol, DHEA-S and oestriol concentrations were measured by specific and sensitive immunoenzymatic assays.

RESULTS

Amniotic fluid urocortin concentrations in the cases (0.50+/-0.07 ng/ml) (M+/-SD) were significantly lower (P<0.0001) than in the control group (0.90+/-0.26 ng/ml), while CRF concentrations did not differ between the cases (1.52+/-0.39 ng/ml) and control group (1.64+/-0.68 ng/ml). Amniotic fluid cortisol (17.71+/-3.72 ng/ml vs. 17.32+/-3.17 ng/ml), DHEA-S (0.16+/-0.06 ng/ml vs. 0.17+/-0.09 ng/ml) and oestriol (4.68+/-1.95 ng/ml vs. 4.79+/-1.84 ng/ml) concentrations were similar in the two groups.

CONCLUSIONS

The low amniotic fluid concentrations of urocortin at mid-trimester may be a signal of predisposition to preterm delivery, while the unchanged CRF and steroid hormones concentrations in women delivering preterm suggest that this mechanisms are not yet activated at mid-trimester.

1. 18-Hydroxyoestrone was reduced by NaBH(4) in methanol, giving 18-hydroxyoestradiol-17alpha and 18-hydroxyoestradiol-17beta in the ratio 3:7. 2. Treatment of 18-hydroxyoestrone with a strong alkali yielded 18-noroestrone; however, the 18-hydroxyoestradiols did not undergo transformation to their respective 18-nor derivatives. 3. All the 18-hydroxylated oestrogens were stable under acid conditions. They formed Kober chromogens: the chromogenicity of 18-hydroxyoestrone was only one-third that of the 18-hydroxyoestradiols and oestriol. 4. Paper-, thin-layer- and gas-liquid-chromatographic systems for the characterization of these compounds are described. 5. An examination of the mass spectra revealed peaks characteristic of the substituted carbon atoms. Definite assignment of the 17alpha- and 17beta-hydroxyl groups of the epimeric 18-hydroxyoestrogens was possible by characteristic fragmentation of the free steroids. Further, the configuration of 18-hydroxyoestradiol-17beta was confirmed by the formation of the dimethylsildioxy derivative of the 3-methylether of the steroid. 6. Both rat and rabbit liver slices reduced 18-hydroxyoestrone to 18-hydroxyoestradiol-17beta and some other labile, polar metabolites with properties similar to 2-hydroxylated oestrogens. No formation of 18-hydroxyoestradiol-17alpha in vitro was observed. 7. The results are discussed with respect to the possible influence of the 18-hydroxyl group on reactions at C-17, as well as the reactions of 18-hydroxylated oestrogens with strong acid (Kober reactions) and alkali.