There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.

Second trimester maternal serum unconjugated oestriol levels were measured in the stored serum samples from 22 pregnancies associated with Down's syndrome and 110 unaffected control pregnancies, matched for maternal age, gestational age, duration of storage of the serum sample, smoking habits and maternal weight. The serum unconjugated oestriol level of each affected pregnancy was expressed as a multiple of the median (MoM) of its five matched controls. The unconjugated oestriol levels were significantly lower in the affected pregnancies than in the unaffected pregnancies; the median MoM was 0.79 (P less than 0.05). This association between low serum unconjugated oestriol and fetal Down's syndrome early in pregnancy raises the possibility that serum unconjugated oestriol measurement may be added to maternal age and alpha-fetoprotein measurement in the antenatal screening for Down's syndrome.

Characteristics probably associated with the fetal hormonal milieu have recently been shown to increase (birth size indicators, prematurity, neonatal jaundice) or decrease (pregnancy toxaemia) breast cancer risk in the female offspring. However, it is unknown whether differences in pregnancy hormone levels may contribute to the marked geographical variation in breast cancer incidence. We have compared, in a highly standardized manner, pregnancy hormone levels in a population with high incidence and one with low incidence of breast cancer. Three hundred and four pregnant Caucasian women in Boston and 334 pregnant Chinese women in Shanghai were enrolled from March 1994 to October 1995. Levels of oestradiol, oestriol, prolactin, progesterone, human growth hormone, albumin and sex hormone-binding globulin were measured in maternal blood at weeks 16 and 27 of gestation and compared between the two study sites using non-parametric Wilcoxon's rank-sum test. Demographical, anthropometrical and pregnancy characteristics were ascertained through interview, and relevant variables concerning delivery and the newborn were abstracted from medical records and paediatric charts. During the first visit, median serum levels of all studied hormones were statistically significant, and in most instances substantially, higher among Chinese women, who have a low incidence of breast cancer, compared with American women, who have a high incidence of breast cancer. An analogous pattern was evident during the second visit, although the relative differences tended to be smaller. Further research is needed to identify lifestyle or other exogenous determinants of pregnancy hormone levels, as well as possible mechanisms by which they may influence carcinogenic processes in the breast and possibly other organs.

Cumulative exposure to oestrogen has been linked to increased risk of breast cancer. Whilst oestrogens induce cancers in rodent bioassays it is unclear whether the mechanisms involved are genotoxic and/or epigenetic. The cytokinesis block micronucleus (CBMN) and the alkaline single cell-gel electrophoresis 'Comet' assays were used to examine MCF-7 cells for chromosomal damage and DNA single-strand breaks (SSBs), respectively. The comet-forming activities of oestrogens were also tested in a 72 h primary culture of cells isolated from freshly expressed breast milk. Micronuclei (MN) were scored in 500 binucleate cells per treatment and SSBs were quantified by comet tail length (CTL) (microm). Effects on mitotic rate (per cent binucleate cells) and cell viability (per cent plating efficiency) were also assessed. beta-Oestradiol, oestrone and oestriol were tested for genotoxicity in the 10(-10)-10(-4) M and 10(-10)-10(-2) M concentration ranges in the CBMN and Comet assays, respectively. Beta-Oestradiol, following 24 h treatment but not 120 h treatment, induced increases (up to 3-fold) in MN at a concentration of 10(-9) M. Oestrone induced dose-related increases in MN (up to 5-fold) following both 24 and 120 h treatment, whereas oestriol appeared not to induce MN. All three oestrogens induced dose-related increases in per cent binucleate cells suggesting that they enhance mitotic rate. In the Comet assay both beta-oestradiol and oestrone induced dose-related increases in SSBs (up to 7-fold over control CTL) and were significantly comet-forming (P < 0.0001) at concentrations as low as 10(-9) and 10(-8) M, respectively, whereas oestriol was less genotoxic. All three oestrogens were significantly comet-forming (P < 0.0001) in a primary culture of breast milk cells, suggesting that they can damage the target cells from which breast cancers may eventually arise.

To test the hypothesis that high levels of endogenous oestrogens increase the risk for developing breast cancer, concentrations of oestrone, oestradiol and oestriol were measured in 24 h urine samples from 1000 women participants in a prospective study of breast cancer on the island of Guernsey. Sixty-nine subjects were diagnosed with breast cancer subsequent to urine collection. Among women who were premenopausal at the time of urine collection, cases excreted less oestrogen than controls; the odds ratios (95% CI) for breast cancer in the middle and upper thirds of the distribution of oestrogen excretion, in comparison with the lower third (reference group, assigned odds ratio = 1.0), were 0.5(0.2-1.2) and 0.4(0.2-1.1) respectively for oestrone, 0.8(0.4-1.8 and 0.4(0.2-1.1) for oestradiol, 0.7(0.3-1.6) and 0.7(0.3-1.6) for oestriol and 0.9(0.4-2.0) and 0.5(0.2-1.3) for total oestrogens. Among women who were post-menopausal at the time of urine collection, the trend was in the opposite direction, with an increase in risk associated with increased oestrogen excretion; the odds ratios were 0.9(0.3-2.2) and 1.1(0.5-2.8) for oestrone, 0.8(0.3-2.3) and 1.9(0.8-4.6) for oestradiol, 1.5(0.6-3.9) and 1.8(0.7-4.6) for oestriol and 0.9(0.4-2.6) and 1.9(0.7-4.7) for total oestrogens. The trends of increasing risk with increasing oestrogen excretion among post-menopausal women were statistically significant for oestradiol (P = 0.022) and for total oestrogens (P = 0.016). We conclude that high levels of endogenous oestrogens in post-menopausal women are associated with increased breast cancer risk, but that the relationship of oestrogens in premenopausal women with risk is unclear.

OBJECTIVE

To investigate the associations between four defined adverse pregnancy outcomes and levels of first and second trimester maternal serum markers focusing in particular on how well combinations of markers predict these adverse outcomes.

METHODS

This was a retrospective review of associations between first and second trimester serum markers and adverse pregnancy outcomes among 141 698 women who underwent prenatal screening for Down syndrome in Ontario, Canada. Detection rates (DR), false positive rates (FPR), and odds ratios were estimated using both single and combinations of markers for the adverse outcomes defined.

RESULTS

Women with decreased second trimester unconjugated oestriol (uE3), deceased first trimester maternal serum pregnancy-associated plasma protein A (PAPP-A), increased second trimester serum alpha fetoprotein (AFP), or increased second trimester total human chorionic gonadotrophin (hCG) were at greater risk of developing adverse pregnancy outcomes. At a 5% FPR, combinations of these markers predicted at best 33.3% of fetal loss and 31.5% of preterm births (PTB) before 32 weeks of gestation.

CONCLUSIONS

There are significant associations between the levels of first and second trimester serum markers and adverse obstetric outcomes. However, even combinations of these markers can only predict adverse obstetric outcomes with modest accuracy.

Oestrogen deficiency in postmenopausal women is thought to be important in the genesis of lower urinary tract symptoms, in particular the 'urge syndrome'. Evidence to support the use of oestrogen therapy in symptomatic postmenopausal women is, however, limited. Oestriol is a weak, naturally occurring oestrogen that may be beneficial to the urogenital tissues without stimulating the endometrium. We have investigated the use of oestriol in the treatment of postmenopausal sensory and motor urge incontinence.

METHODS

A double-blind, placebo-controlled, randomised, multicentre study of 3 mg oral oestriol/day for 3 months in the treatment of women with urge incontinence was undertaken.

CONCLUSIONS

Sixty-four women were recruited into the study. Although oestriol produced both subjective and objective improvement in lower urinary tract function, it was not significantly better than placebo. Some of the difficulties of running a multicentre study were encountered.

It has been hypothesised that oestrogen exposure in utero influences the risk for breast cancer in adult life. Although several studies report associations between breast cancer and maternal factors associated with birthweight of the offspring - a marker for antenatal oestriol exposure - little is known about the relations between maternal oestrogen levels and these factors per se. We therefore analysed the association between oestriol levels in 188 women in the 17th, 25th, 33rd and 37th weeks of pregnancy, and maternal age, prepregnancy weight, height and pregnancy weight gain. Both maternal prepregnancy body mass index and maternal height were, after controlling for infant birthweight, independently and inversely associated with oestriol levels (P = 0.0021 and P = 0.0006 respectively). We found no association between maternal age or pregnancy weight gain and pregnancy oestriol levels. These findings suggest that the previously reported associations between maternal age and maternal pregnancy weight gain and the offsprings risk of breast cancer are due to factors other than antenatal exposure to oestriol.

In this small study, the effect of aminoglutethimide on the disposition of oestrogens in women with advanced breast cancer was investigated using bolus injections of 4-[14C]-oestradiol and 6,7-[3H]-oestrone sulphate, alone or in combination. No alterations in oestrogen disposition were seen after short term (6 hours) aminoglutethimide administration. During long term (3 weeks to 8 months) aminoglutethimide treatment mean 4-[14C]-oestradiol clearance was not changed. 14C-Oestrone sulphate AUC was reduced by 43% at a low dose of aminoglutethimide (125 mg twice daily) and by 65% at a high dose (250 mg 4 times daily) with hydrocortisone acetate 25 mg twice daily. The oestrone sulphate terminal elimination rate constant (lambda z) was concurrently increased (mean of 46 and 79%, respectively, with the 2 dosage regimens). A possible increase in oestrone sulphate clearance during long term treatment was tested for by injecting 6,7-[3H]-oestrone sulphate. These studies revealed a marked increase (mean 104%) in oestrone sulphate clearance in patients receiving the high dose aminoglutethimide schedule. Following injection of 4-[14C]-oestradiol plus 6,7-[3H]-oestrone sulphate, the fraction of 4-[14C]-oestradiol metabolised to oestrone sulphate was found to be reduced in all patients (mean 13%). A mean increase of 80% in the urinary excretion of 14C-oestriol was observed after 4-[14C]-oestradiol administration. Our results, although preliminary, suggest that aminoglutethimide is a potent inducer of aminoglutethimide metabolism, thereby producing a significant reduction in plasma bioavailability of oestrone sulphate. These effects may have a role in the action of aminoglutethimide, a finding which warrants further investigation.

The median maternal serum unconjugated oestriol level between 13 and 27 weeks gestation in 77 pregnancies associated with Down's syndrome was lower than the median level in 385 unaffected control pregnancies matched for maternal age, gestational age, and duration of serum sample storage (P less than 0.001). The median level for the affected pregnancies was 73% of that in the controls. Low unconjugated oestriol levels can be used to detect fetal Down's syndrome; at cut-off levels selected to detect at least 35% of affected pregnancies, unconjugated serum oestriol was a better screening test than either maternal age or serum alpha-fetoprotein (AFP). The use of all three variables in combination to select women with a 1:250 or greater risk of a Down's syndrome term pregnancy would yield a 45% detection rate with a false-positive rate of 5.2%. The same detection rate using maternal age alone or using age and serum AFP in combination would yield higher false-positive rates, 15% and 9.8% respectively. The addition of unconjugated oestriol to a Down's syndrome screening programme would therefore be more efficient than the use of age and AFP alone; for a given detection rate fewer women would need an amniocentesis or, for a given percentage of women having an amniocentesis, more pregnancies with Down's syndrome would be detected.

OBJECTIVE

To appraise a new method of prenatal screening for Down's syndrome based on maternal serum concentrations of alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin combined with maternal age--the "triple test."

METHODS

Examination of the cost effectiveness of the triple test relative to screening only by maternal age over a range of population detection rates.

METHODS

Leicestershire Health Authority.

METHODS

Costs per affected fetus detected.

RESULTS

The triple test is more cost effective than screening only by maternal age for risk cut off points for amniocentesis, resulting in a detection rate over 45%. The most efficient detection rate is around 60-65%, for which the cost per case detected is around 29,000 pounds, through screening with higher detection rates is still likely to be cost beneficial.

CONCLUSIONS

Prenatal screening for Down's syndrome based on the triple test should replace screening based only on maternal age. Individual women's preferences should be elicited by the use of structured decision analysis in order to maximise utility and so increase the benefits of the screening programme.

In a series of 2434 patients with pre-eclampsia, the prevalence of fetal growth retardation was 8.7 per cent compared with 8.6 per cent in the total hospital population. The prevalence was increased in early-onset pre-eclampsia (18.2 per cent) (P less than 0.001) and reduced in late-onset pre-eclampsia (5.6 per cent) (P less than 0.001). In patients who later developed early-onset pre-eclampsia with fetal growth retardation, the prevalence of subnormal oestriol excretion was significantly increased (79.5 per cent) (P less than 0.001) as was the prevalence of hypoglycaemia (33.3 per cent) (P less than 0.001) suggesting that fetal growth retardation in these pregnancies preceded the clinical signs of pre-eclampsia. The prevalence of placental abruption (8.3 per cent) and the prevalence of perinatal deaths (28.7 per cent) were both significantly higher in pregnancies with early-onset pre-eclampsia and fetal growth retardation (P less than 0.001).

Geographic differences in the rates of breast, endometrial, and ovarian cancer appear to be inversely correlated with dietary iodine intake. Endocrinological considerations suggest that a low dietary iodine intake may produce a state of increased effective gonadotrophin stimulation, which in turn may produce a hyperoestrogenic state characterised by relatively high production of oestrone and oestradiol and a relatively low oestriol to oestrone plus oestradiol ratio. This altered endocrine state may increase the risk of breast, endometrial, and ovarian cancer. Increasing dietary iodine intake may reduce the risk of these cancers.

Follicular-phase (Day 11) plasma prolactin, and plasma and urinary oestrogen levels of 70 nulliparous nuns were compared with those of 80 of their sisters, of whom 62 were parous. The nuns and their nulliparous sisters did not differ significantly in their prolactin and oestrogen levels. No differences in plasma oestrogens or urinary oestriol ratio were found between the parous and the nulliparous women. However, the mean prolactin level of the nuns and their nulliparous sisters was 35% higher than that of the parous women in the sample taken approximately 1 3/4 h after rising (p less than 0.0005), and 24% higher (P less then 0.01) in the 2nd sample taken 2 h later. The elevation was independent of age, weight, and age at menarché. Age at first full-term pregnancy, at least up to the age of 30, and second or subsequent full-term pregnancies had no further effect on prolactin level. This study suggests that the effect of early first full-term pregnancy in lowering breast cancer risk may be mediated, at least in part, by permanently lowering the level of circulating prolactin.

116 women with obstetric hepatosis gave birth in the years 1971-1972 at the First and Second Departments of Obstetrics and Gynaecology, University Central Hospital, Helsinki. This accounts for a 1.1% incidence of all deliveries at this hospital. During most of these pregnancies fetal well-being was monitored by amnioscopy, by the oxytocin challenge test, by maternal urinary oestriol determinations and by estimating the fetal biparietal diameter weekly. In 38% of these pregnancies, signs of fetal distress were found, mainly an abnormal heart rate, or heart rate pattern, and/or meconium-stained amniotic fluid. These led to increased frequencies of induction of labour and of Caesarean sections performed because of asphyxia or imminent asphyxia as compared with a control group with similar age and parity distribution. There was an increase in the occurrence of twin pregnancies in the hepatosis series (7.6%). There were 4 intrauterine and altogether 8 perinatal losses of 125 infants born to hepatosis mothers. These observations suppport the opinion that there are increased risks for the fetus in pregnancies complicated by obstetric hepatosis. Amnioscopy and fetal heart rate recording during the delivery and oxytocin challenge test were found to be valuable in monitoring the fetal condition. The use of oestriol determinations, at least by employing the method in general clinical practice, was found to be of limited value in the predictive assessment of fetal distress in hepatosis. This might be due to impurities disturbing the determinations or to changed oestrogen metabolism in cholestasis.

To ascertain the value of maternal serum free beta-human choriogonadotropin subunit measurement in Down's syndrome screening and to compare its effectiveness when screening with a variety of biochemical markers, we have evaluated maternal serum free beta-human choriogonadotropin, total human choriogonadotropin, alpha-fetoprotein and unconjugated oestriol in a large multicentre study of over 2800 unaffected cases and 90 affected cases, the largest collection of Down's cases ever reported. Of all the markers identified to date, free beta-human choriogonadotropin is the marker of choice for use in Down's syndrome screening. When used in early gestation (14-16 weeks) in combination with alpha-fetoprotein and maternal age, it will allow the detection of 77% of Down's cases. A side-by-side comparison with the performance of total human choriogonadotropin shows the superior detection efficiency of free beta-human choriogonadotropin. Unconjugated oestriol adds nothing further to the detection rate compared with the use of alpha-fetoprotein and free beta-human choriogonadotropin alone, and its use results in a 1% increase in false positive rate. We conclude that unconjugated oestriol has no value in Down's screening. The superior detection rate obtained using free beta-human choriogonadotropin is a result of superior detection of Down's cases in women under 30 years old, where the free beta-human choriogonadotropin combination detects 100% more cases than does the total human choriogonadotropin combination.

We examined the influence of hormone replacement therapy (HRT) on breast tumour biology by comparing the prognostic characteristics of breast cancers and survival in 121 women prescribed replacement hormones before diagnosis with those in 1468 women without such treatment. The women receiving HRT had a lowered relative risk of being diagnosed with tumours of more than 20 mm in diameter, OR = 0.7 (CI 0.5-1.0) and axillary lymph node dissemination, OR = 0.7 (CI 0.4-1.1). These risk reductions were most pronounced and statistically significant in the women who had been prescribed a combined estradiol-progestin regimen. The patients in this compound group also had a diminished relative risk of having poorly differentiated tumours. Further, there was an indication that the women prescribed HRT, and especially those with conjugated estrogens/estradiols alone, had a decreased relative risk of developing aneuploid tumours. There was no clear pattern for women receiving the biologically weak oestriol, although risk estimates were generally higher for unfavourable tumours in comparison with those receiving the higher potency compounds. Adjustments for indications of earlier detection (i.e. lead time bias) did not influence the pattern or magnitude of the risk estimates. No association between any type of HRT and survival after breast cancer diagnosis was noted, but analyses were based only on 19 breast cancer deaths among exposed patients. We conclude that breast cancers occurring after treatment with HRT, especially the combined estrogen-progestin regimen, seem to have more favourable tumour features than tumours in non-treated women. Our findings may reflect a less aggressive biological behaviour of breast cancers in women receiving HRT, or in part be explained by the earlier detection of the tumours in these women.

Symptomatic clinical changes and urodynamic changes are apparent in the female urinary tract system during pregnancy, the menstrual cycle and following the menopause. The sex hormones exert physiological effects on the female urinary tract, from the ureters to the urethra, with oestrogens having an additional influence on the structures of the pelvic floor. High affinity oestrogen receptors have been identified in bladder, trigone, urethra and pubococcygeus muscle of women. Oestrogen pretreatment enhances the contractile response of animal detrusor muscle to alpha-adrenoceptor agonists, cholinomimetics and prostaglandins, as well as enhancing the contractile response to alpha-agonists in ureter and urethra. Progesterone on the other hand decreases tone in the ureter, bladder and urethra by enhancing beta-adrenergic responses. The dependence on oestrogens of the tissues of the lower urinary tract contributes to increased urinary problems in postmenopausal women. Urinary symptoms due to atrophic mucosal changes respond well to oestrogen replacement therapy. However, because they recur when treatment is stopped, continuous therapy with low dose natural oestrogens is recommended. Oestrogens may be of benefit in postmenopausal women with stress incontinence, but the doses necessary for clinical effect are higher than for the treatment of atrophic urethritis. The practice of adding a progestagen to long term oestrogen therapy to reduce the risk of endometrial carcinoma may, however, exacerbate stress incontinence by decreasing urethral pressure. Cyclical therapy with oestrogens may therefore be more appropriate particularly in women who are not suitable for surgery or have a mild degree of stress incontinence, along with other conservative measures such as pelvic floor exercises and alpha-adrenoceptor agonists. The place of oestrogen therapy in motor urge incontinence has not been determined. The risk of developing endometrial carcinoma as a result of long term high dose oestrogen replacement therapy must be borne in mind but remains to be clarified. However, oestriol has less of a uterotrophic effect compared to other oestrogens in standard therapeutic doses and is to be preferred. Side effects are usually dose related and tend not to be a problem with low dose therapy.

OBJECTIVE

To investigate whether dexamethasone suppression of fetoplacental oestrogen production can reduce obstetric cholestasis.

METHODS

Observational study.

METHODS

Department of Obstetrics and Gynaecology, University of Tampere, Finland.

METHODS

10 women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy.

METHODS

Treatment with 12 mg oral dexamethasone daily for 7 days, after which the therapy was gradually discontinued over 3 days.

METHODS

Serum oestriol, oestradiol, total bile acids and ALAT were measured before and during therapy and on days 4 and 7 and ALAT also on day 12. Differences were tested by paired t test.

RESULTS

Itching disappeared or was relieved in all patients. Serum oestriol level fell significantly by day 1 of treatment, serum oestradiol and total bile acid levels by day 4 and ALAT by day 12 from the beginning of the therapy.

CONCLUSIONS

Dexamethasone is a drug of choice in the treatment of intrahepatic cholestasis of pregnancy.