Birth weight is positively associated with the risk of breast cancer in the offspring and the underlying process is likely to involve the pregnancy endocrine milieu. We have examined the association of diet and related factors during pregnancy with the levels (at the 16th and 27th gestational week) of maternal pregnancy oestradiol, oestriol, sex hormone-binding globulin (SHBG), progesterone and prolactin, in a cohort of 270 Caucasian women who delivered in a major hospital in Boston, USA. Oestradiol and oestriol were not strongly associated with any of the diet-related variables, but SHBG was significantly and consistently related inversely to pre-pregnancy body mass index and weight gain during pregnancy, and positively to vegetable and pulses intake. Pregnancy progesterone was associated positively with alcohol and inversely with polyunsaturated lipid and vitamin B12 intake, whereas pregnancy prolactin was inversely associated with cereal consumption. If the pregnancy hormones studied are indeed involved in the intra-uterine origin of breast cancer, these findings, if confirmed, would focus dietary advice to pregnant women, with a view to reducing the risk of breast cancer in the offspring, towards avoidance of excess energy intake and an emphasis on plant foods. This advice does not contradict current dietary advice on prudent diet during pregnancy and throughout life.

The objective of this study was to evaluate economically a screening programme within the Oxford Regional Health Authority for Down's syndrome, based on maternal serum alpha fetoprotein, unconjugated oestriol and human chorionic gonadotrophin as well as maternal age (the triple test) against maternal age alone. The design of the study involved cost-effectiveness analysis of the triple test relative to the maternal age screening programme, and the main outcome measure was the cost per Down's birth avoided. It was found that the triple test is more cost-effective over a wide range of assumptions concerning detection rates and procedure costs. Indirect costs are important in considering the cost-effectiveness of the screening programmes. The most efficient detection rate is around 58 per cent for which the cost per Down's birth avoided is approximately 29,600 pounds if only direct costs are evaluated, 20,100 pounds if all NHS costs are considered and -49,800 pounds if all resource consequences are analysed. It may be concluded that screening for Down's syndrome using the triple test is cost-effective over a wide range of assumptions concerning detection rate and procedure costs. If all resource costs are considered, the programme is highly cost-effective in comparison with other health care interventions.

Gas chromatographic/mass spectrometric (GC/MS) analysis of maternal urine and serum steroids from 13 pregnancies at 25% risk for Smith-Lemli-Opitz syndrome (SLOS) was undertaken. All patients were between 12 and 31 weeks' gestational age. From dehydrocholesterol/cholesterol ratios determined in amniotic fluid and chorionic villus cells, five patients were shown to carry SLOS affected fetuses and eight patients were negative for the condition. Because it had previously been shown that dehydro-oestriol and dehydropregnanetriol were novel steroids produced in SLOS, these compounds were measured in the serum and urine samples of the 13 mothers. All five urine samples from SLOS affected pregnancies had high levels of both dehydrosteroid metabolites, which were below the detection limit in the non-affected pregnancies. The ratios of dehydro-oestriol/oestriol (DHE(3)/E(3)) were between 0.073 and 1.42 for the affected patients and less than 0.01 for unaffected patients. Corresponding values for dehydropregnanetriol/pregnanetriol (DHPT/PT) were 0.037-1.02 for affected and less than 0.01 for unaffected. In the positive serum sample available for analysis, the DHE(3)/E(3) ratio was 0.20 [unaffected (n=5), <0.014]. It is proposed that the measurement of DHE(3) and DHPT in maternal urine and serum may allow non-invasive antenatal diagnosis of SLOS.

The effect of oestradiol treatment on the acetylation of histones of the immature rat uterus has been studied. A 10mug dose of oestradiol causes a 70% increase at 5min and a 140% increase at 10min after administration in the labelling of the histone fraction F2+F3. No effect of oestradiol is seen on the labelling of histones F1 or acidic non-histone chromatin proteins. The oestradiol stimulation is seen in animals pretreated with either cycloheximide or actinomycin D. The stimulation of labelling caused by oestradiol is completely abolished by pretreatment of the animals with the anti-oestrogen, nafoxidine. The stimulation is given by lower doses of oestradiol, by stilboestrol and oestriol, but is not given by testosterone. These results suggest that stimulation of histone acetylation in the uterus is the earliest known effect of the hormone on its target tissue.

The value of measuring inhibin-A (a beta A dimer) with human chorionic gonadotrophin (total or the sub-units free a-hCG and free beta-hCG separately), alpha-fetoprotein (AFP), and unconjugated oestriol (uE3) was examined to determine the effect on the performance of serum screening for Down's syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples from 77 Down's syndrome singleton pregnancies and 385 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the sample, supplemented by data from 970 white women with unaffected pregnancies. Inhibin-A was elevated in the serum of women with Down's syndrome pregnancies with a median of 1.79 multiples of the median (MOM). Using the four serum markers AFP, uE3, total hCG, and inhibin-A, in addition to maternal age, 70 per cent of Down's syndrome pregnancies were detected for a 5 per cent false-positive rate compared with 59 per cent with the conventional triple test (AFP, uE3, and total hCG with maternal age). If the estimate of gestational age were based on an ultrasound scan examination, the detection rate would be 77 per cent [95 per cent confidence interval (CI) 69-85 per cent] using the four serum markers including inhibin-A, compared with 67 per cent with the triple test or 79 per cent (95 per cent CI 71-87 per cent) if marker values were adjusted for maternal weight. If the detection rate were kept at 70 per cent and the gestational age were estimated by an ultrasound scan examination, the four-marker test would reduce the false-positive rate from 6-1 per cent using the triple test to 2-9 per cent. The results were virtually the same if free beta-hCG was used instead of total hCG. The inhibin-A-based four-marker test is the most effective method of prenatal screening for Down's syndrome suitable for routine use. If the extra cost required to carry out the inhibin-A test were less than about [symbol: see text]3 per woman screened, the four-marker test including inhibin-A would be financially cost-effective.

1. Microsomal preparations from rat liver, kidney and intestine were tested for UDP-glucuronyltransferase activity by using oestrone, oestradiol-17 beta, oestriol, testosterone, cortisol, cortisone, corticosterone, aldosterone, tetrahydrocortisol and tetrahydrocortisone as substrates. The microsomal preparation from the liver glucuronidated oestrone, oestradiol-17 beta and testosterone. 2. The specific activity of the enzyme was significantly higher in livers from female rats than in those from male rats. 3. Testosterone was actively glucuronidated by both sexes. Cortisol, cortisone, corticosterone, aldosterone, tetrahydrocortisol and tetrahydrocortisone were not glucuronidated by any of the three tissues. 4. The non-ionic detergent Lubrol WX activates liver microsomal UDP-glucuronyltransferase 2-3-fold with oestrone and testosterone as substrates. 5. Oestrone glucuronyltransferase was inhibited by oestradiol-17 beta, predominantly competitively and by testosterone non-competitively. Bilirubin was a non-competitive inhibitor of oestrone glucuronidation. p-Nitrophenol had no effect. 6. Oestrone glucuronyltransferase could not be stimulated by either acute or prolonged treatment of animals with phenobarbital, whereas a single dose of 3-methylcholanthrene led to a moderate stimulation. 7. Ovariectomy leads to a 56% decrease in oestrone glucuronyltransferase activity; administration of oestradiol-17 beta induces the enzyme to normal activity after 12 days, and after 15 days the activity is twice the control value. Actinomycin D and cycloheximide block the oestradiol-17 beta-induced increase in enzyme activity. 8. Castration has no effect on the activity of testosterone glucuronyltransferase, nor does administration of testosterone influence enzyme activity. The results provide strong evidence for the existence of multiple steroid glucuronyltransferases in the liver of the rat.

OBJECTIVE

To assess the efficacy of an oestradiol-releasing vaginal ring and oestriol pessaries in the alleviation of lower urinary tract symptoms occurring after the menopause.

METHODS

Randomised, parallel group, controlled trial.

METHODS

Twenty-six clinics of practising gynaecologists and one outpatient clinic at a department of obstetrics and gynaecology.

METHODS

Two hundred and fifty-one postmenopausal women, with a mean age of 66 years, reporting at least one bothersome lower urinary tract symptom.

METHODS

One hundred and thirty-four women were treated with the oestradiol-releasing ring for 24 weeks; 117 women were treated with oestriol pessaries 0.5 mg every second day for 24 weeks.

METHODS

Subjective scores of urgency, frequency, nocturia, dysuria, stress incontinence and urge incontinence.

RESULTS

The two treatments were equally efficacious in alleviating urinary urgency (51% vs 56%), urge incontinence (58% vs 58%), stress incontinence (53% vs 59%) and nocturia (51% vs 54%). Dysuria was alleviated in 76% vs 67%, equivalence was not demonstrated. No statistically significant difference was found for any primary efficacy endpoint. Sixty percent of the participants rated the form of administration via the vaginal ring as excellent, compared with 14% for the pessaries (P < 0.0001).

CONCLUSIONS

Low dose vaginally administered oestradiol and oestriol are equally efficacious in alleviating lower urinary tract symptoms which appear after the menopause. The form of administration of the vaginal ring, seems to be more acceptable than oestriol pessaries.

Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists.

Oestradiol increases the protein expression of connexin43 (Cx43) gap junctions in myometrium but the effect of oestriol on gap junction expression has not been described previously. Oestriol is the most abundant free oestrogen in pregnant women and there is a marked surge in oestriol concentrations before term and idiopathic preterm labour. In order to determine whether oestriol may have a physiological action on the myometrium, cultured human myometrial cells obtained from non-pregnant hysterectomy specimens were exposed to 10 nmol/l oestradiol or oestriol. Intercellular communication between myometrial cells was investigated by microinjection of confluent cultured cells with the gap junction-permeant tracer Cascade Blue. There was a progressive increase in coupling after exposure to oestradiol or oestriol (P < 0.0005). An increase in Cx43 protein expression was demonstrated by immunocytochemistry after 1 h (P < 0.01) and 3 days (P < 0.01) exposure, and by Western blotting after 1 h (P < 0.01) and 3 days (P < 0.05) exposure, to both oestradiol and to oestriol. We conclude that oestriol increases gap junction communication in human myometrium by increasing gap junction expression. Elevated oestriol concentrations may thus play a role in the initiation of labour in women, by increasing cell-cell communication in the myometrium.

Two prenatal centres in New England, routinely using a screening protocol for fetal Down syndrome that included maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG) measurements in combination with maternal age, adopted a separate screening protocol for trisomy 18. That protocol identified a pregnancy as being at high risk when AFP, uE3, and hCG measurements all fell at or below specified cut-offs (0.75, 0.60, and 0.55 multiples of the median, respectively), regardless of maternal age. Among the first 19,491 women screened, 98 (0.5 per cent) were found to have values which placed them in the high-risk category. Four of these women were subsequently found not to be pregnant. In two others, samples from non-pregnant individuals were found to have been incorrectly submitted for analysis in place of the samples from the pregnant women. All of the remaining 92 women were counselled and offered amniocentesis and fetal karyotyping. Eighty-eight (96 per cent) accepted. Karyotypes or birth outcomes were available on all 92 pregnancies. Six cases of trisomy 18 and one case of Turner syndrome were identified by karyotype. One case of trisomy 18 was identified for every 14 unaffected pregnancies offered amniocentesis. In the present prospective study, an estimated 85 per cent of the cases of trisomy 18 were identified. However, given the small number of cases (six), the 95 per cent confidence interval for the detection rate is broad (40-95 per cent).

Over a 2-year period from January 1991 to December 1992, second-trimester maternal serum screening for Down's syndrome using alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) was made available to five health districts in East Anglia, with a total population of 1.2 million. Amniocentesis was offered when the risk of Down's syndrome at term was 1:200 or greater. 25,359 singleton pregnancies were screened, representing an uptake of 77 per cent. The recall rate for the 24 per cent of women who had not had a dating scan prior to the test was 9.4 per cent compared with 3.9 per cent for those who had been scanned (P < 0.0005). Seventy-five per cent (36/48) of Down's syndrome pregnancies were detected for a false-positive rate of 4.0 per cent. Twenty-five out of 36 of detected Down's syndrome pregnancies were dated by scan prior to sampling, and in the 11 remaining cases, the dates were confirmed by scan after a high-risk result was obtained. The exclusion of uE3 from the screening protocol would have reduced the detection rate to 52 per cent (25/48) for the same false-positive rate. Eighty-five per cent of women identified at high risk accepted the offer of an amniocentesis. Other fetal abnormalities detected were trisomy 18 (3), trisomy 13 (2), 45,X (6), 69,XXX (5), other chromosome abnormalities (9), open neural tube defects (26), hydrocephalus (7), abdominal wall defects (4), and steroid sulphatase deficiency (6).

The value of measuring the separate sub-units of human chorionic gonadotrophin (free alpha-hCG and free beta-hCG) instead of total hCG together with alpha-fetoprotein (AFP) and unconjugated oestriol (uE3) was examined to determine the effect on the performance of serum screening for Down's syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples relating to 75 singleton pregnancies with fetal Down's syndrome and 367 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the serum sample, supplemented by data from 970 white women with unaffected pregnancies. Using the four serum markers AFP, uE3, free beta-hCG, and free alpha-hCG, in addition to maternal age, 65 per cent of Down's syndrome pregnancies were detected for a 5 per cent false-positive rate compared with 59 per cent with the conventional triple test (AFP, uE3, total hCG with maternal age). If gestation was based on an ultrasound scan examination, the detection rate was 72 per cent using the four serum markers compared with 67 per cent with the triple test. As an alternative illustration, if the detection rate was kept at 60 per cent and gestation was estimated by an ultrasound scan examination the four-marker test reduced the false-positive rate by one-third from 3 per cent using the triple test to 2 per cent with the four-marker test. Screening performance was hardly affected by adjusting marker levels for maternal weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Meta-analysis was used to calculate maternal serum marker distribution parameters for Down syndrome risk estimation in the first trimester. Data from 44 series were combined: relating to pregnancy associated plasma protein (PAPP)-A in 18, free beta human chorionic gonadotrophin (hCG) in 17, alpha-fetoprotein (AFP) in 26 and unconjugated oestriol (uE3) in 9. All levels were expressed in multiples of the normal median (MOM) for gestational age. Individual PAPP-A levels were available for 439 first and second-trimester Down syndrome pregnancies. The median MOM value increased with gestation: 0.35 at 6-8 weeks (31 cases), 0.40 at 9-11 weeks (197), 0.62 at 12-14 weeks (113) and 0.94 thereafter (98). A cubic regression equation was fitted so it could be estimated for each week of gestation. For the other markers the median value in Down syndrome was estimated from the weighted mean across all first-trimester series: 1.98 MOM for free beta-hCG in 579 cases; 0.79 MOM for AFP in 243 and 0.74 MOM for uE3 in 226. Variance-covariance matrices were calculated directly in unaffected pregnancies and from the difference between affected and unaffected pregnancies in Down syndrome. Based on these parameters we estimate that screening at 9-11 weeks with PAPP-A and free beta-hCG will yield a 64.6 per cent detection rate for a 5 per cent false-positive rate. Adding a third marker will increase detection to 66.6 per cent for AFP and 68.6 per cent for uE3; using all four markers it increases to 70.1 per cent. Routine ultrasound nuchal translucency measurement in addition to serum testing will increase the rates to 86.4 per cent, 87.2 per cent, 87.9 per cent and 88.3 per cent, respectively.

BACKGROUND

Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Down's Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Down's Syndrome pregnancies, and discuss their implications.

METHODS

SURUSS was a prospective study of 47,053 singleton pregnancies (including 101 pregnancies with Down's Syndrome) conducted in 25 maternity units. Nuchal translucency measurements were taken. Serum and urine samples collected between 9 and 13 weeks, and again between 14 and 20 weeks of pregnancy were stored. Samples from each affected pregnancy and five matched controls were tested for currently used or suggested biochemical Down's Syndrome screening markers. Pregnancies were followed up to determine the presence or absence of Down's Syndrome. For an 85% Down's Syndrome detection rate, the false-positive rate for the Integrated test (nuchal translucency and pregnancy associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy, and alpha-fetoprotein, unconjugated oestriol [uE(3)], free beta or total human chorionic gondaotrophin (hCG) and inhibin-A in the early second trimester) was 0.9%, the Serum integrated test (without nuchal translucency) 2.7%, the Combined test (nuchal translucency with free beta-hCG and PAPP-A at 11 weeks) 4.3%, the Quadruple test (alpha-fetoprotein, uE(3), free beta or total hCG and inhibin-A) 6.2%, and nuchal translucency at 11 weeks, 15.2%. All tests included maternal age. Using the Integrated test at an 85% detection rate, there would be six diagnostic procedure-related unaffected fetal losses following amniocentesis per 100,000 women screened compared with 35 using the Combined test or 45 with the Quadruple test.

CONCLUSIONS

The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester. The next best test is the Serum integrated test. The Quadruple test is the best test for women who first attend in the second trimester. There is no justification for retaining the Double (alpha-fetoprotein and hCG) or Triple (alpha-fetoprotein, uE(3), and hCG) tests, or nuchal translucency alone (with or without maternal age) in antenatal screening for Down's Syndrome.

Recent reports suggest that transfer of day 5 blastocysts improves implantation rates in in-vitro fertilization programmes. This paper reports a successful ongoing pregnancy after the transfer of zona-free day 6 expanded and hatching blastocysts. The patient was 37 years old and had undergone six stimulated and two thaw cycles previously, all of which had failed. Stimulation was by down-regulation and oocytes recovered transvaginally by ultrasound guidance. Two pronuclear embryos were co-cultured on Vero cells to day 6. The zonae of two hatching and two fully expanded blastocysts were removed using 0.5% pronase, and the zona-free blastocysts were then transferred. Pregnancy was confirmed on day 18 with a positive human chorionic gonadotrophin (HCG) and ultrasound at 6 weeks showed a single healthy fetal heart inside a clear sac. At 14 weeks a triple test (oestriol, J-HCG and alpha-fetoprotein) was normal and at 22 weeks a detailed ultrasound scan showed no congenital anomalies. This is the first report in the human of a normal ongoing pregnancy after the transfer of zona-free day 6 embryos.

The blood pressure level and the renin-angiotensin system were investigated in 24 menopausal women (12 normotensive and 12 hypertensive) before, during and after six months of treatment with either oestradiol or trisekvens (sequential preparation containing oestradiol, oestriol and norethisterone acetate). In the normotensive women no significant alterations in systolic or diastolic blood pressure were found during treatment for six months. In the hypertensive women systolic blood pressure fell significantly during treatment with oestradiol as well as with trisekvens, while diastolic pressure did not change. All individual variations of blood pressure were small. The plasma concentrations of renin, angiotensin II and aldosterone remained unchanged during the treatments. A statistically significant increase in plasma renin substrate concentration was observed in all groups with the exception of the normotensive women treated with oestradiol. Menopausal symptoms in hypertensive women may safely be treated with natural oestrogens on the same indications as used for normotensive women.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Two cases of Smith-Lemli-Opitz syndrome type II are presented. During the late stages of both pregnancies maternal oestriol levels were unrecordable and there was evidence of suppression of maternal adrenal function. We speculate on the existence of a primary defect in the fetal adrenals.

The effects on the haemostatic mechanism of oestrogen therapy, given to prevent bone loss in post-menopausal women, have been investigated. Oestriol succinate was given orally to 10 women at a level of 2 mg/day for 1 month and for a further 3 months with incremental increase of 2 mg each month. 6 of the 10 women were subsequently treated with 25 mug/day orally of ethinyl oestradiol. Oestriol succinate therapy resulted in a small increase in the level of factor VII, a decrease in factor VIII concentration and increased sensitivity of platelets to aggregating agents. Ethinyl oestradiol treatment resulted in much more widespread changes with marked increases in coagulation factors VII, VIII, IX and X, decreased levels of antithrombin and dramatic increases in circulating plasminogen levels and euglobulin lysis activity. The data suggested that the nature of oestrogens employed therapeutically is important in determining the qualitative and quantitative effect of oestrogen therapy on components of the haemostatic mechanism.

The effect of oral oestriol (3 mg/day for 4 weeks followed by 2 mg/day for a further 6 weeks) on the vaginal bacterial flora, vaginal cytology and urogenital symptoms was assessed in a double-blind, placebo-controlled study in 35 women with symptoms of the urogenital oestrogen deficiency syndrome. No significant differences were observed with regard to the occurrence or severity of urogenital symptoms, vaginal pH, karyopyknotic index (KPI) or the baseline results of vaginal bacterial cultures in the 18 patients (mean age 71.6 +/- 1.0 years) treated with oestriol and the 17 women (mean age 72.6 +/- 1.4 years) who received placebo tablets. A decrease in both vaginal pH (P less than 0.001) and the proportion of faecal-type bacteria (P less than 0.05), and an increase in the KPI (P less than 0.01) and the proportion of lactobacilli (P less than 0.001) were recorded after 10 weeks of treatment with oral oestriol. At the end of the following 10 medication-free weeks all of these parameters except vaginal pH had returned to values that were not significantly altered from the corresponding baseline levels. In the patients treated with placebo no significant changes occurred in vaginal pH, KPI or the proportion of lactobacilli in vaginal cultures during the course of this study. Urogenital symptoms improved in both groups after medication (and even after the medication-free period) in relation to the baseline assessment, which reflects the latter's subjective nature.

We evaluated the incidence of oral discomfort in post-menopausal women and the efficacy of hormone replacement therapy in patients complaining of such symptoms. Two studies were performed. In the first, we compared oral discomfort and oral mucosa smears in 47 patients receiving replacement therapy and in 40 untreated post-menopausal women. In the second, the efficacy of hormone replacement therapy with oestriol vaginal cream (22 patients) or conjugated oestrogens plus norethisterone acetate (10 patients) was evaluated. In the first study, oral exfoliative cytology showed a similar maturation index and volume in both groups. In the second, hormone replacement therapy improved subjective and objective symptoms in 12 out of 22 patients treated with oestriol and in 7 out of 10 patients treated with conjugated oestrogens plus norethisterone. These data suggest that oestrogen deficiency can be considered a possible cause of oral discomfort in some post-menopausal patients and that oestrogen replacement therapy may improve subjective symptoms.

BACKGROUND

No authors have investigated whether the administration of local oestrogens in addition to antimuscarinics could have a synergistic effect in the therapy of overactive bladder (OAB).

OBJECTIVE

To compare the efficacy of antimuscarinics alone versus antimuscarinics in combination with local oestrogens for OAB; to verify whether risk factors for lower antimuscarinic efficacy can be overcome by the concomitant use of local oestrogens.

METHODS

Some 229 postmenopausal women with symptomatic urodynamically proven detrusor overactivity were prospectively enrolled at a tertiary level urogynaecology centre and divided into two groups.

METHODS

Women in group 1 (n=129) were prescribed tolterodine extended release (ER) 4 mg once daily; women in group 2 (n=100) were prescribed both tolterodine ER 4 mg and concomitant oestriol cream application once daily.

METHODS

All women underwent clinical evaluation and urodynamics in accordance with the Good Urodynamic Practices Guidelines. After 12 wk of treatment the two groups were compared in terms of subjective efficacy for OAB symptom improvement using a three-point scale. Nonresponders were compared to the patients who improved or were cured in order to identify risk factors for resistance to therapy.

CONCLUSIONS

There was no significant difference between the two groups in terms of efficacy of therapy: 80.6% in group 1 versus 82% in group 2 (p=0.86). Patients with urodynamically proven detrusor overactivity (DO) occurring during provocative manoeuvres and patients with coital incontinence during orgasm reported a higher failure rate both in the overall study population and in group 2. A possible limitation of the study is the nonrandomised design.

CONCLUSIONS

No synergistic effect of local oestrogens and antimuscarinics in the treatment of OAB was found. Antimuscarinic treatment has lower cure rates in women with symptomatic DO complaining of incontinence at orgasm or in patients with DO following provocative manoeuvres. The association of local oestrogens does not influence the role of the two mentioned risk factors.