The diurnal variation of plasma oestrone (E1), oestradiol (E2), oestriol (E3), progesterone (P), cortisol (F) and dehydroepiandrosterone sulphate (DHAS) and saliva E1, E2, E3, P and F was investigated in matched plasma, and saliva samples were obtained hourly from 08.00 to 24.00 h and at 04.00, 07.00 and 08.00 h from nine pregnant women (3 at 30, 3 at 34 and 3 at 38 weeks gestation). A diurnal variation in plasma and saliva cortisol levels was found in all subjects and in plasma DHAS in 8 out of 9 subjects. No consistent diurnal variation was found at any gestation in any of the other hormones in plasma or saliva. There was a significant correlation between saliva E3 and P levels at 30 weeks gestation but no other consistent correlations between hormone levels were found at any gestation.

Carcinogens, such as benzo[a]pyrene (B[a]P), allow cells to evade G(1) arrest (the stealth property), thus increasing the chance that DNA damage will ultimately result in transformation. In this study we have investigated the effects of B[a]P in MCF-7 cells incubated in the presence or absence of oestrogens (beta-oestradiol, oestrone or oestriol). The cytokinesis block micronucleus assay was used to examine cells for chromosomal damage. Micronuclei were scored in 500 binucleate cells per treatment. Increased micronucleus formation (3-fold) occurred following 24 h treatment with 10(-6) M B[a]P alone. Following co-treatment with either 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol, 2- to 3-fold increases in micronuclei were observed with 10(-8) M B[a]P. When MCF-7 cells were pre-incubated for 96 h with 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol prior to the addition of B[a]P for 24 h, up to a 5-fold enhanced sensitivity to micronucleus formation was observed with beta-oestradiol and oestrone, while oestriol appeared to reduce levels of micronucleus formation. B[a]P-induced decreases in cell proliferation (per cent binucleate cells) and plating efficiency were reversed by all three oestrogens. Analysis of cell cycle distributions revealed that treatment with oestrogens or B[a]P alone did not induce marked effects on cell cycle distributions. However, in combination oestrogen and B[a]P induced increases in G(0)/G(1), decreases in S phase and increases in G(2)/M. This work suggests that whilst oestrogens appear to enhance carcinogen-induced DNA damage, they also appear, paradoxically, to trigger mechanisms that facilitate clonogenic survival, which may be relevant to breast cancer initiation.

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.

Urinary tract infections (UTI) are among the most frequent bacterial infections in the community and health care setting. Mostly young and, to some extent, postmenopausal women are affected by recurrent UTI (rUTI) defined as ≥3 UTI/year. On the other hand rUTI are frequently found in patients with complicating urological factors, e.g. urinary catheters. Modifiable predisposing factors in uncomplicated rUTI in women are rare. Continuous antibiotic prophylaxis or postcoital prophylaxis, if there is close correlation with sexual intercourse, are most effective to prevent rUTI. Nitrofurantoin, trimethoprim (or cotrimoxazole), and fosfomycin trometamol are available as first-line drugs. Oral cephalosporins and quinolones should be restricted to specific indications. Antibiotic prophylaxis reduces the number of uropathogens in the gut and/or vaginal flora and reduces bacterial"fitness". Given the correct indication, the recurrence rate of rUTI can be reduced by about 90%. In postmenopausal patients vaginal substitution of oestriol should be started first. Oral or parenteral immunoprophylaxis is another option in patients with rUTI. Other possibilities with varying scientific evidence are prophylaxis with cranberries or probiotics. The prophylaxis of catheter-associated UTI or asymptomatic bacteriuria should employ strategies which result in a reduction of frequency and duration of catheter drainage of the urinary tract. The currently available catheter materials have only little influence on reducing catheter-associated rUTI.

Adult sheep which has been castrated either before or after puberty were treated with a variety of steroids. The administration of testosterone propionate, oestrone, oestradiol-17 beta or diethylstilboestrol to animals castrated before puberty caused them to mount oestrous ewes. Oestradiol-17 alpha was less effective than these hormones in this regard, whilst oestriol, hexoestrol and 5 alpha-dihydrotestosterone were ineffective. The response to oestradiol-17 beta was not altered by the concurrent administration of dexamethasone to block the pituitary-adrenal axis which suggests that oestradiol-17 beta was not exerting its effect indirectly by causing the release of adrenal steroids. When 5 alpha-dihydrotestosterone was administered in conjunction with oestradiol-17 beta intromission and ejaculation were observed in addition to mounting behaviour. When rams were castrated as adults their mating behaviour slowly declined over the course of 2 years. After this time, mounting behaviour was rapidly restored by the administration of oestradiol-17 beta but not by 5 alpha-dihydrotestosterone. These results are consistent with the hypothesis that oestrogens are the ultimate agents responsible for promoting mating behaviour in male animals and hence aromatizable androgens, such as testosterone, are effective whereas non-aromatizable androgens, such as 5 alpha-dihydrotestosterone, are not.

The regulation of angiogenesis in the ovarian follicle and corpus luteum is unclear. Steroids are produced at very high concentrations in these tissues and we therefore examined the effect of steroids on angiogenesis in vitro. Explants of rat aorta were embedded in collagen gel and cultured in serum-free medium. Capillary-like microvessels were produced from the explants and microvessel number and length were measured in the presence and absence of steroids. At a concentration of 10 micrograms/ml, cortisol, progesterone, 17 alpha-hydroxyprogesterone and medroxyprogesterone acetate produced degeneration of microvessels after 7 days of steroid treatment (P < 0.01). Androstenedione and tetrahydro-S-(11-deoxytetrahydrocortisol) (tetrahydro S) produced degeneration at a slower rate: androstenedione inhibited microvessel growth after 11 days (P < 0.01) and tetrahydro S after 14 days (P < 0.05). Oestriol had no effect on microvessels; oestrone had a slow degenerative effect with significant inhibition seen after 14 days (P < 0.01). Oestradiol-17 beta at a concentration of 10 micrograms/ml completely inhibited microvessel growth from the explant cultures (P < 0.01) while at 1 microgram/ml it caused degenerative effects on growing microvessels. The effects of oestradiol and cortisol were reversible on removal of steroid-containing medium and replacement with 10% serum. We conclude that oestradiol may modulate angiogenesis in tissues in which the steroid concentration is high.

To examine the Down's syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non-IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE3), free beta-human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free alpha-hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE3 levels were 6% lower (P = 0.003), median free beta-hCG 9% higher (P = 0.024), and median total hCG 14% higher (P = 0.026) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE3 levels remain unexplained. In Down's syndrome screening in IVF pregnancies hCG and uE3 values should be adjusted to avoid the high screen positive rate.

A synthetic and a natural oestrogen were administered alternately for three months to nine women with primary amenorrhoea using a randomized cross-over schedule. Measurements of haemostatic function were performed before and at the end of each treatment period. No significant change in haemostatic function was observed after treatment with the 'natural' oestrogen, oestriol succinate. In contrast, treatment with a synthetic oestrogen, ethinyloestradiol, caused shortening of the prothrombin time and an increase in plasma concentration of factor VII and plasminogen. These data support other observations in suggesting that natural oestrogens may have fewer potentially adverse effects on haemostatic function than synthetic oestrogen.

BACKGROUND

Down's syndrome occurs when a person has three copies of chromosome 21 - or the specific area of chromosome 21 implicated in causing Down's syndrome - rather than two. It is the commonest congenital cause of mental retardation. Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.

OBJECTIVE

To estimate and compare the accuracy of second trimester serum markers for the detection of Down's syndrome.

METHODS

We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to May 2007), EMBASE (1980 to 18 May 2007), BIOSIS via EDINA (1985 to 18 May 2007), CINAHL via OVID (1982 to 18 May 2007), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2007, Issue 1), MEDION (May 2007), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (May 2007), The National Research Register (May 2007), Health Services Research Projects in Progress database (May 2007). We studied reference lists and published review articles.

METHODS

Studies evaluating tests of maternal serum in women at 14-24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.

METHODS

Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses.

RESULTS

Fifty-nine studies involving 341,261 pregnancies (including 1,994 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Seventeen studies made direct comparisons between tests. Fifty-four test combinations were evaluated formed from combinations of 12 different tests and maternal age; alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free beta human chorionic gonadotrophin (βhCG), free alpha human chorionic gonadotrophin (αhCG), Inhibin A, SP2, CA125, troponin, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PGF) and proform of eosinophil major basic protein (ProMBP).Meta-analysis of 12 best performing or frequently evaluated test combinations showed double and triple tests (involving AFP, uE3, total hCG, free βhCG) significantly outperform individual markers, detecting six to seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate. Tests additionally involving inhibin performed best (eight out of every 10 Down's syndrome pregnancies) but were not shown to be significantly better than standard triple tests in direct comparisons. Significantly lower sensitivity occurred in women over the age of 35 years. Women who miscarried in the over 35 group were more likely to have been offered an invasive test to verify a negative screening results, whereas those under 35 were usually not offered invasive testing for a negative screening result. Pregnancy loss in women under 35 therefore leads to under ascertainment of screening results, potentially missing a proportion of affected pregnancies and affecting the accuracy of the sensitivity.

CONCLUSIONS

Tests involving two or more markers in combination with maternal age are significantly more sensitive than those involving one marker. The value of combining four or more tests or including inhibin have not been proven to show statistically significant improvement. Further study is required to investigate reduced test performance in women aged over 35 and the impact of differential pregnancy loss on study findings.

Pulmonary artery thrombosis and an anti-ethinyl-oestradiol monoclonal IgGlambda were found to be associated in a 36-year-old woman (Mrs MAI.) who took an oral contraceptive containing 50 mug ethinyl-oestradiol and 500 mug nor-ethisterone daily. After appropriate purification including methods by which the IgG was separated of bound circulating hormones, its binding activity was demonstrated by several methods: passive haemagglutination of oestradiol-benzoate sensitized red blood cells; gel filtration on Sephadex G-25; ultracentrifugation and equilibrium dialysis. IgGlambda MAI bound ethinyl oestradiol (Ka=2-7 X 10(1) M-1) and also 17-beta-oestradiol, with a lower affinity (Ka=0-4 X 10(7) M-1). The valency for these two hormones was near 2. Ethinyl-oestradiol bound to the IgG was displaced by ethinyl-oestradiol itself and in decreasing order of potency by 17-beta-oestradiol, progesterone, oestriol, and testosterone. Oestrone and hydrocortisone had no effect. Although the localization of the binding sites of this IgGlambda was not studied, it is likely that they were the antibody sites of the molecule and, according to immunochemical criteria, it may be classified as a monoclonal anti-ethinyl-oestradiol antibody. It is felt that its association with the pulmonary thrombosis and the oral contraceptive may be significant. This supports the hypothesis of an immunological mechanism for the unexplained thrombotic risk of oral contraceptives.

We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.

Sulphotransferases (STs) are a family of closely related enzymes playing a key role in regulation of the bioavailability and activity of important endogenous molecules such as steroid hormones. A relationship between the expression of steroid STs and the diabetic state has been demonstrated in various laboratory animal models, and steroid sulphates such as dehydroepiandrosterone sulphate are known to have anti-diabetic properties. In order to further our understanding of the molecular basis for the association of steroid hormone sulphation and diabetes, we have examined the expression of oestrogen, phenol and dehydroepiandrosterone (DHEA) STs in mice carrying the obesity mutation (ob), which in the homozygous state (ob/ob) produces mice which are obese and diabetic. Our data show that, in male mice, ST activities towards oestrone (E1), oestriol (E3), DHEA and the xenobiotic 1-naphthol are elevated in ob/ob mice, whereas in female mice, only the oestrogen ST activities were elevated, with the DHEA and 1-naphthol ST activities reduced. Using antibodies directed against oestrogen ST, it was demonstrated that the induction of E1 and E3 ST activity in ob/ob mice correlated with the expression of an ST isoenzyme not constitutively expressed in control mouse liver.

OBJECTIVE

To measure the frequency of obstetrical complications and assess the outcome of pregnancies in Vietnam-born mothers; to compute birthweight percentile charts for their infants; and to compare these parameters in Vietnam-born women with those of a control group of Australian-born women.

METHODS

A retrospective study of all pregnancies in Vietnam-born and Australian-born mothers managed in the Mercy Hospital for Women over a 10-year period, 1979-1988 inclusive.

METHODS

The Mercy Hospital for Women provides primary and secondary obstetric care to public and private patients.

METHODS

All women born in Australia or Vietnam who delivered in the Mercy Hospital for Women, Melbourne, over the 10-year period and their infants. Twins, stillborn babies and infants with congenital malformations were not included in the calculation of birthweight percentiles.

RESULTS

Gestational diabetes (7.3% v. 4.3%, P less than 0.0001) and low oestriol excretion (14.4% v. 10.8%, P less than 0.0001) were more common whereas essential hypertension (0.3% v. 1.2%, P less than 0.001) and pre eclampsia (3.7% v. 8.6%, P less than 0.0001) were less common among Vietnam-born mothers. Intervention for labour and delivery was less common among Vietnam-born mothers: induction of labour (7.1% v. 24.7%, P less than 0.0001) and forceps delivery (17.8% v. 21.9%, P less than 0.001); caesarean section rates were similar. Infants of Vietnam-born mothers were significantly lighter than those of Australian-born; percentile charts for birthweight and gestational age are presented.

CONCLUSIONS

Pregnancies among Vietnam-born women migrants in Australia were associated with few complications in spite of a higher incidence of gestational diabetes and a low oestriol excretion. The infants were lighter than those born to Australian-born mothers. Our percentile charts for birthweight relative to gestational age will provide a more accurate assessment of intrauterine growth for these infants.

The effect of local oestriol treatment on the abdominal skin was studied in 14 postmenopausal women. Six control patients received a similar ointment without oestriol. The duration of the treatment in all cases was three weeks. The elastic fibers in the papillary dermis were thickened, better orientated and slightly increased in number in half of these patients but in none of the control patients. The epidermal thickness was slightly increased in four of the patients treated with oestriol. No significant changes were observed in the epidermal cell size, mitotic activity, dermal vascularization or inflammatory infiltrate between the specimens taken before and after the treatment or between the treatment groups.

With the growing incidence of HIV, there is a desperate need to develop simple, cheap and effective new ways of preventing HIV infection. Male circumcision reduces the risk of infection by about 60%, probably because of the removal of the Langerhans cells which are abundant in the inner foreskin and are the primary route by which HIV enters the penis. Langerhans cells form a vital part of the body's natural defence against HIV and only cause infection when they are exposed to high levels of HIV virions. Rather than removing this natural defence mechanism by circumcision, it may be better to enhance it by thickening the layer of keratin overlying the Langerhans cells, thereby reducing the viral load to which they are exposed. We have investigated the ability of topically administered oestrogen to induce keratinization of the epithelium of the inner foreskin. Histochemically, the whole of the foreskin is richly supplied with oestrogen receptors. The epithelium of the inner foreskin, like the vagina, responds within 24 hours to the topical administration of oestriol by keratinization, and the response persists for at least 5 days after the cessation of the treatment. Oestriol, a cheap, readily available natural oestrogen metabolite, rapidly keratinizes the inner foreskin, the site of HIV entry into the penis. This thickening of the overlying protective layer of keratin should reduce the exposure of the underlying Langerhans cells to HIV virions. This simple treatment could become an adjunct or alternative to surgical circumcision for reducing the incidence of HIV infection in men.

Saliva unconjugated, plasma unconjugated and plasma total oestriol (E3) levels were measured longitudinally, by radioimmunoassay, in 25 normal women from 13 weeks gestation until delivery. The increase in salivary unconjugated oestriol closely paralleled that of plasma unconjugated oestriol and to a lesser extent that of plasma total oestriol. In each patient the percentage value of salivary E3/plasma unconjugated E3 x 100 was virtually constant throughout pregnancy but this percentage varied from one patient to another (mean 14.4%). The overall correlation coefficient (r) for salivary and plasma unconjugated E3 was 0.90. The variability in salivary levels in samples collected at daily, hourly, 15 min and 5 min intervals (12.7, 13.4, 10.1 and 9.3%) was similar to that previously described for plasma unconjugated E3. There was no distinct pattern in diurnal variation. It seems probable that measurement of salivary E3 could adequately replace that of plasma unconjugated E3 in the assessment of fetoplacental function.

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66-91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p less than 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.

Long-term low dose oestrogen therapy has a protective effect on bone mineral content in the post-menopausal or castrated female. As yet the only obvious clinical side effect of such therapy has been transient leg muscle cramps. Several biochemical side effects could be observed. Low dose mestranol caused a persistent elevation of factor VII and a dose-dependent increase in both factors VII and X was observed using oestriol hemisuccinate. Such effects are more likely to be dose-related than related to the type of oestrogen prescribed. Effects of oestrogens on lipids, and cholesterol in particular, may be dose-related also. Changes in blood pressure in post-menopausal women are more likely to be related to obesity than to oestrogen treatment which would seem to have a protective effect against weight increase. No marked changes in the mean risk score for ischaemic heart disease could be detected during oestrogen treatment.

OBJECTIVE

It has been reported that, in prenatal screening programmes for Down syndrome, women who have false-positive results in one pregnancy have an increased risk of a false-positive result in a subsequent pregnancy. We examined the effect of this in the screening programme conducted from the Wolfson Institute of Preventive Medicine with a view to determining the magnitude of the effect, and to describe a method of avoiding the problem.

METHODS

Six thousand four hundred and forty-eight women were identified who had had two singleton pregnancies without Down syndrome in the screening programme based at the Wolfson Institute of Preventive Medicine, in which both pregnancies were screened using a Quadruple test (maternal age with alphafetoprotein (AFP), unconjugated oestriol (uE(3)), total or free beta-human chorionic gonadotrophin (hCG) and either free alpha-hCG or inhibin-A as the fourth serum marker).

RESULTS

Among women who had a false-positive result in their initial pregnancy, the false-positive rate in the subsequent pregnancy was high: 20% (46/229), about three times higher than both the overall observed false-positive rate (6.6%), and the expected false-positive rate, in subsequent pregnancies that were false-positive in their initial pregnancy (7.5%) (p < 0.001). This arises because serum marker levels in one pregnancy are associated with the levels in a subsequent pregnancy. Using the slope (the regression coefficient b) of each marker level in a subsequent pregnancy regressed on the value in the first pregnancy, it is possible to adjust all marker values in a subsequent pregnancy to allow for the higher-than-expected false-positive rate. This can be done by dividing the observed MoM value for each marker by the 'expected' MoM, which is the MoM value in a previous pregnancy raised to the power b.

CONCLUSIONS

If a woman has had a false-positive result in one pregnancy, she is much more likely to have a false-positive screening result in a subsequent pregnancy than women in general. The problem can be avoided by adjusting the serum markers in all women who have been screened in a previous pregnancy and who have not had a previous pregnancy with Down syndrome.

This study was done to evaluate the absorption of a single oral dose of 12 mg oestriol (Triovex, Leo AB, Sweden) and to confirm the hypothesis that the enterohepatic recirculation can prolong the plasma oestriol elevation obtained. Twelve menopausal women, six of whom had been cholecystectomized earlier, were given 12 mg oestriol orally. Fatty meals were given immediately after drug administration and then at four hourly intervals. Fat was given to induce the bileflow and provide oestriol to the intestine for deconjugation and enterohepatic recycling. One of the non-cholecystectomized women also remained fasting for 24 hours after oestriol administration. Plasma concentrations of unconjugated oestriol were measured by a specific RIA-method. In all women the plasma oestriol levels were considerably elevated for 24 hours. In the non-cholecystectomized women the plasma oestriol levels fluctuated in relation to meals whereas in the cholecystectomized women the fluctuations were not as pronounced, indicating that the release of biliary oestriol metabolites is the source of intestinal degradation and reabsorption to the systemic circulation. Fasting also gave increased and stable plasma oestriol levels. After a high oral dosage of oestriol, the enterohepatic recycling renders oestriol an enhanced potency since the plasma oestriol elevation time is prolonged.

In a double-blind, placebo-controlled study, 109 patients suffering from local and vasomotor postmenopausal complaints were randomly assigned to treatment with either depot vaginal suppositories containing 3.5 mg oestriol (E3) or a placebo. The treatment schedule comprised one vaginal suppository twice weekly for 3 weeks initially, followed by maintenance therapy with one vaginal suppository weekly for the 6-month study period. The effectiveness of the therapy was assessed on the basis of questionnaires (Kupperman index for vasomotor complaints and an original urogenital index for local complaints) and gynaecological examinations which included assessments of vaginal cytology, vaginal pH and Döderlein bacilli. To rule out induced endometrial proliferation, endometrial biopsies were performed in 50 women before and after the study. The vaginal depot (E3) formulation showed highly significant superiority over the placebo with respect to therapeutic effect on local urogenital complaints and alleviation of vasomotor complaints, including hot flushes. Analysis of the endometrial biopsies indicated that the monotherapy used caused no endometrial stimulation. Taking into account the minimal rate of adverse effects, the 3.5 mg E3 depot formulation studied represents a useful variant in the range of preparations available for the treatment of post-menopausal complaints.

The pregnancies of two patients with mild intrahepatic cholestasis of pregnancy (RCP) were followed with detailed analyses of bile acids in urine. About twenty-five different bile acids were determined by GC/MS following separation according to mode of conjugation. The results were collated with the clinical course of the disease. The first detectable change in bile acid excretion was the appearance of tetrahydroxylated bile acids at about the 30th gestational week. Somewhat later and concomitant with the rise in urinary oestriol, the total bile acid excretion started to increase. In one of the patients, who had a maximum total excretion of 84 mumol/24 h, deoxycholic acid was a major constituent, comprising about 40% of the total. The same patient had only slightly elevated levels of tetrahydroxylated bile acids and serum amino-transferases. The possible effect of low-fat diet on these results is discussed. Monohydroxylated bile acids were present throughout the pregnancies in small amounts and their role as aetiological factors is discussed. The care of RCP patients is outlined, and the need for simple, specific and quantitative methods for following the course of RCP is pointed out.