OBJECTIVE

To establish gestational age-specific mid-trimester normal medians for the prenatal serum markers alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE3) for a Belgian population by using the Beckman Coulter Access chemiluminiscent immunoassays; to compare these data with data obtained from other geographical regions; to propose regression coefficients for regressed medians and analyse variation induced by different regression equations; to evaluate the effect of formulas used for gestation correction on estimating risk in Down's syndrome.

METHODS

Data derived from 862 fresh serum samples from women being screened for Down's syndrome pregnancy, composed of selected pregnancies deemed to be normal, were examined in a retrospective study. Regressed medians were calculated by using a first-degree logarithmic-linear fit of the raw data. Multiples-of-median (MoM) values estimated by using a simple logarithmic-linear equation were compared with those calculated with higher-degree polynomials chosen with a goodness-of-fit analysis. Model-specific variation was estimated and the effect on risk for Down's syndrome was evaluated.

RESULTS

Regressed medians (Y) for Access serum markers AFP (IU/ml), HCG (IU/ml) and uE3 (nmol/l) for a Belgian population can be estimated with the equation Y = 10((A+BX)) with X = decimal weeks. The best fit was obtained with a third-degree and a second-degree polynomial for AFP and uE3, respectively. Differences between the medians and among the slopes of the geographical populations were found to be significant (analysis of covariance, p<0.001).

CONCLUSIONS

Belgian marker medians versus gestational time are found to show a pattern that is similar to that in the literature. The log-linear equation is observed to give a good fit and can be suggested as a tool for calculating median MoM values for Belgian laboratories that use Access biochemical prenatal markers.

Down's syndrome (DS) is the commonest cause of severe mental retardation in children. It is the result of trisomy of chromosome 21 which is usually a random event though it is commoner in older mothers. DS can be diagnosed by chorionic villus sampling (CVS) and amniocentesis followed by karyotyping. Because of the risks associated with these invasive procedures, they can only be offered to a high-risk group. At one time the sole basis for identifying this increased risk was maternal age, but within the past ten years a series of biochemical and ultrasound abnormalities have been shown in DS pregnancies. The biochemical abnormalities include changes in the levels of most fetal and placental products in the maternal circulation. The best-known of these changes are the reduced levels of alphafetoprotein (AFP) and oestriol (E3) and increased levels of human chorionic gonadotrophin (hCG). The mechanism underlying these biochemical phenomena is unknown. Screening programmes involving the measurement of hCG and AFP, with or without additional parameters such as E3, at 15-18 weeks of pregnancy can typically identify 60% or more of cases of DS with a screen-positive rate of 5%. The combined risk derived from the various biochemical parameters, together with maternal age, is calculated by one of a number of computer programmes which have been developed for this purpose. There has been considerable discussion as to the exact biochemical tests which should be used for DS screening. This had led to controversy as to whether measurement of E3 has a place, and whether or not measurement of the free beta-subunit of hCG should replace measurement of the intact molecule. A notable recent development is the suggestion that measurement of the urinary beta-core of the hCG could be a highly discriminatory marker. A number of factors can affect the results of biochemical screening for DS. These include maternal weight, gestational age, ethnic origin, smoking, and diabetes. In addition, abnormal levels of the biochemical products may be found in other chromosome abnormalities.

The haematological variables, haematinic state, and placental function of more than 2000 pregnant women, heterozygous for either alpha- or beta-thalassaemia genes, were examined during pregnancy. Four features emerged. Firstly, it was possible by discriminant function analysis of haematological variables to distinguish in pregnant patients between the anaemia caused by thalassaemia trait and that caused by iron deficiency. Secondly, patients with thalassaemia become significantly more anaemic in pregnancy, beta more than alpha, but this was mainly due to plasma dilution. From the data percentile curves were drawn for each type of thalassaemia which predicted the patients' expected "normal" haemoglobin throughout gestation. Thirdly, patients with alpha-thalassaemia had the same incidence of iron deficiency as normal pregnant patients, whereas in those with beta-thalassaemia it was four times less common. The incidence of folic acid and vitamin B12 deficiency was the same in all groups. Finally, as assessed by serum oestriol concentration, there did not appear to be any abnormality of placental function or fetal development associated with maternal thalassaemia, and, also, there seemed to be no increase in maternal or fetal morbidity in pregnancy.

To investigate the influence of maternal oestrogens on the fetal breast development, maternal urinary oestriol excretion, maternal plasma oestriol concentrations, and cord venous plasma oestradiol and oestriol concentrations were related to the size of the neonatal breast. A significant positive association between oestriol excretion and neonatal breast size was demonstrated, but the relationship was not strong and might be due to both measures having a positive relationship with birthweight. The infants' circulating concentrations of prolactin at birth and during the first weeks of life were also related to breast size. There was no cord venous-arterial difference in prolactin concentrations, and neither related to breast diameter. However there was a strong association between breast size and prolactin concentrations in mature infants aged between 5 and 7 days. In preterm infants breast tissue often develops after birth. Prolactin levels in preterm infants were higher between 2 and 6 weeks than they were in the first week of life. It would appear that the early development of the breast is influenced more by the infants's than the mother's endocrine activity.

Serum FSH and LH and total urinary oestrogens were measured in 20 mature onset postmenopausal diabetic women and compared to 20 nondiabetic women matched for age, years since menopause, surface area and per cent ideal weight. Significantly higher levels of urinary oestrone, oestradiol and oestriol and significantly lower levels of FSH and LH were found in the diabetic women. Closer analysis of these findings showed that the differences were maintained for the diabetics who required insulin for adequate control, whereas diabetics controlled on diet alone or diet and oral hypoglycaemic drugs were not significantly different from control subjects except in urinary oestrone excretion.

BACKGROUND

Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.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. However, no test can predict the severity of problems a person with Down's syndrome will have.

OBJECTIVE

The aim of this review was to estimate and compare the accuracy of first trimester serum markers for the detection of Down's syndrome in the antenatal period, both as individual markers and as combinations of markers. Accuracy is described by the proportion of fetuses with Down's syndrome detected by screening before birth (sensitivity or detection rate) and the proportion of women with a low risk (normal) screening test result who subsequently had a baby unaffected by Down's syndrome (specificity).

METHODS

We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 25 August 2011), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (Archived 2007), Health Services Research Projects in Progress database (25 August 2011). We did forward citation searching ISI citation indices, Google Scholar and PubMed 'related articles'. We did not apply a diagnostic test search filter. We also searched reference lists and published review articles.

METHODS

We included studies in which all women from a given population had one or more index test(s) compared to a reference standard (either chromosomal verification or macroscopic postnatal inspection). Both consecutive series and diagnostic case-control study designs were included. Randomised trials where individuals were randomised to different screening strategies and all verified using a reference standard were also eligible for inclusion. Studies in which test strategies were compared head-to-head either in the same women, or between randomised groups were identified for inclusion in separate comparisons of test strategies. We excluded studies if they included less than five Down's syndrome cases, or more than 20% of participants were not followed up.

METHODS

We extracted data as test positive or 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 (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC meta-analytical methods or random-effects logistic regression methods to analyse test performance and compare test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons between tests were undertaken.

RESULTS

We included 56 studies (reported in 68 publications) involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were generally of good quality, although differential verification was common with invasive testing of only high-risk pregnancies. We evaluated 78 test combinations formed from combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin and metalloprotease), AFP (alpha-fetoprotein), inhibin, PAPP-A (pregnancy-associated plasma protein A, ITA (invasive trophoblast antigen), free βhCG (beta human chorionic gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1), total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of eosinophil major basic protein), hPL (human placental lactogen), (free αhCG, and free ßhCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.Meta-analysis of the nine best performing or frequently evaluated test combinations showed that a test strategy involving maternal age and a double marker combination of PAPP-A and free ßhCG significantly outperformed the individual markers (with or without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations involving PAPP-A may be more sensitive than those without PAPP-A.

CONCLUSIONS

Tests involving two markers in combination with maternal age, specifically PAPP-A, free βhCG and maternal age are significantly better than those involving single markers with and without age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The addition of further markers (triple tests) has not been shown to be statistically superior; the studies included are small with limited power to detect a difference.The screening blood tests themselves have no adverse effects for the woman, over and above the risks of a routine blood test. However some women who have a 'high risk' screening test result, and are given amniocentesis or chorionic villus sampling (CVS) have a risk of miscarrying a baby unaffected by Down's. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a 'high risk' screening test result.

The effects of 14 steroids at concentrations between 0.1 and 10 micrograms/ml on human spermatozoal forward migration in vitro were tested. Oestradiol-17 beta at a concentration of 0.1 microgram/ml significantly activated spermatozoal forward migration in ejaculated human semen. However, the effect of oestradiol-17 beta at concentrations of 2 and 10 micrograms/ml on ejaculated human sperm motility was not significantly different from the control where no steroid was added. Progesterone, testosterone, oestriol, oestrone, oestradiol-17d, and ethinyl oestradiol significantly inhibited human spermatozoal forward migration at concentrations of 10 micrograms/ml. Chlormadinone acetate and medroxyprogesterone acetate at concentrations of 2 and 10 micrograms/ml significantly inhibited human spermatozoal forward migration, while norethynodrel, ethynodiol diacetate, norgestrel and lynoestrenol significantly inhibited human spermatozoal forward migration at concentrations between 0.1 and 10 micrograms/ml. However, norethindrone had no demonstrable effect on human spermatozoal forward migration at the above concentrations.

A gas chromatographic procedure for the quantitation of neutral steroid sulphates in maternal urine and its application to a suspected case of placental sulphatase deficiency is described. Low levels of oestriol coincident with elevated 16-hydroxylated metabolites of dehydroepiandrosterone in the maternal urine are shown to occur in this particular condition, and thus provide a convenient differentiation from fetal adrenal hypoplasia before birth.

OBJECTIVE

To examine the performance of Integrated Down syndrome screening (first- and second-trimester measurements integrated into a single screening test) when ratios of the levels of the same serum markers measured in both these trimesters (cross-trimester ratios) are added as new screening markers.

METHODS

Using data from Serum Urine and Ultrasound Screening Study (SURUSS), second-trimester concentrations (in multiples of the median, or MoM) of pregnancy associated plasma protein A (PAPP-A), alphafetoprotein (AFP), unconjugated oestriol (uE(3)), human chorionic gonadotrophin (hCG) (free beta and total), and inhibin-A were divided by the first-trimester concentration to obtain a cross-trimester (CT) ratio for each analyte in 74 Down syndrome and 492 unaffected pregnancies. We identified CT ratios that improved screening performance and then, using Monte Carlo simulations, estimated the efficacy and cost effectiveness of adding them to the Integrated and serum Integrated tests.

RESULTS

All the median CT ratios differed significantly between Down syndrome and unaffected pregnancies. Setting the Integrated test to achieve a 90% detection rate, the false-positive rate (FPR) was 0.7% with CT ratios for PAPP-A, uE(3), inhibin-A, and total hCG compared with 2.2% without CT ratios, a reduction of about two-thirds. Using the serum Integrated test to achieve the same 90% detection rate and the first-trimester measurements made at 11 completed weeks of pregnancy, the corresponding FPRs were 2.4 and 8.1%, a similar proportional reduction. The AFP CT ratio had little effect on screening performance. Using CT ratios did not increase the cost per Down syndrome pregnancy detected.

CONCLUSIONS

The addition of CT ratios to an Integrated test substantially improves the efficacy and safety of prenatal screening for Down syndrome. It is cost effective and could be usefully introduced into screening programmes.

A new method is described for calculating maternal serum marker distribution parameters which will improve risk estimation when screening for Down's syndrome. The approach is to calculate parameters using data from the local screened population and data obtained by meta-analysis from all published studies. The local data are used to derive the variance and covariance in unaffected pregnancies. The meta-analysis is used for the mean level in Down's syndrome pregnancies together with the differences in variance and covariance between affected and unaffected pregnancies. Forty-four published studies were analysed. The mean level for Down's syndrome in multiples of the normal median was 0.73 for alpha-fetoprotein (AFP) in total of 1140 pregnancies, 0.73 for unconjugated oestriol (uE3) in 613, 2.02 for human chorionic gonadotropin (hCG) in 850, and 2.30 for free beta-hCG in 477. For all four markers, the variance in Down's syndrome was higher than in unaffected pregnancies; for AFP and uE3, the covariances were also higher in Down's syndrome, but for the other markers they were lower. The method was illustrated using data from 6387 pregnancies screened in Leeds.

Maternal serum screening for Down syndrome is an established practise in many countries. In the second trimester human chorionic gonadotrophin (hCG) or free beta-hCG is the marker of first choice, with alpha-fetoprotein (AFP) as the second marker and unconjugated oestriol (uE(3)) the third. Statistical models with parameters derived by meta-analysis predict that a three marker combination will yield a 67% detection rate for a 5% false-positive rate. The model prediction have been confirmed in 21 large prospective intervention studies. A fourth marker, inhibin A, increases the detection rate by 7% for the same false-positive rate. In the first trimester, similar models predict that a combination of pregnancy associated plasma protein A, free beta-hCG, AFP and uE(3) will yield a 70% detection rate. This is increased to 88% if ultrasound nuchal translucency is used as an additional marker. Screening can also be extended to Edwards' syndrome, yielding high detection rates with little increase in the false-positive rate. Abnormal marker levels are also associated with a variety of adverse outcomes of pregnancy. High quality information and decision aids are needed to minimise anxiety among screenees.

The therapeutic principles covering sex hormone replacement therapy after menopause have undergone profound modification in recent years. Initial optimism regarding benefits, proven and unproven, was followed by deep pessimism because of potential serious adverse effects. Some degree of equilibrium has resulted from the application of risk-benefit and cost-effectiveness formulae to such hormone replacement regimens. Cost-effectiveness analysis in particular has highlighted the fact that different hormones or hormone combinations can markedly affect the therapeutic outcome. The purpose of the present paper is to examine the place of oestriol therapy after menopause based on such risk-benefit analyses. Oestriol, it would appear, has the potential for reduced risk but similar benefit to alternative oestrogen or oestrogen-progestogen combinations. The potential risks and benefits of long-term oestrogen therapy are therefore surveyed from the general standpoint of all oestrogens and the specific role of oestriol alone.

In contrast to all other oestrogens examined thus far oestriol hemisuccinate (12 mg/day) did not prevent bone loss in 28 postmenopausal women. The average bone loss, however, was somewhat less than expected from placebo studies, while the bone loss achieved by a group taking 4-6 mg/day was equal to that achieved by previous placebo groups. To be an effective agent for prevention of post-menopausal osteoporosis oestriol would have to be prescribed in daily doses considerably in excess of 12 mg.

Five different products secreted by the fetoplacental unit into the maternal circulation were measured in 272 patients when they were 34 weeks pregnant. The most useful indicator of present pathology or future complications of pregnancy was a placental protein, pregnancy associated plasma protein. A which was raised in pre-eclamptic toxaemia, antepartum haemorrhage and premature labour. The highest values were recorded in pre-eclampsia before any signs of the disease were evident. Schwangerschafts protein 1 was also raised in pre-eclampsia and antepartum haemorrhage but only after the disease had presented. Placental lactogen was also raised in pre-eclampsia and its measurement may have some predictive value. Total oestriol was lowered in fetal growth retardation and the unconjugated steroid raised in pre-eclampsia and lowered in retarded fetal growth.

OBJECTIVE

Oestetrol (15-alpha-hydroxyoestriol, E₄) is an endogenous oestradiol metabolite mainly produced at high concentrations in the fetal liver. In earlier studies E₄ was investigated for its use as marker for pregnancies at risk, especially with vascular problems. Some current investigations suggest that the use of E4 in hormone therapy or contraception may have advantages in terms of breast cancer risk when compared to other oestrogens.

METHODS

Proliferation of two oestrogen receptor-positive breast cancer cell lines (ZR 75-1 and HCC 1500) was investigated after incubation with oestrone (E₁), oestradiol (E₂), oestriol (E₃), and oestetrol (E₄). Receptor expression of oestrogen receptor-alpha (ERα) and -beta (ERβ) was determined by Western-Blot.

RESULTS

All four oestrogens elicited a significant proliferative stimulation at concentrations of 10(-10) und 10(-9) M as compared to controls. Oestrone displayed a significantly weaker effect than E₂. Oestetrol was significantly less effective than E₂ at the lower concentration. Expression of ERα and ERβ was significantly upregulated by all oestrogens tested, without differences between the latter.

CONCLUSIONS

Our results indicate a slightly lower proliferative effect of E₄, but only at low concentrations. However, no difference was found regarding receptor expression. Breast cancer risk associated with use of oestetrol should be tested in clinical trials.

A variety of organic compounds have been documented to bind to the oestrogen receptor and induce oestrogenic effects in different vertebrates. The presence of these environmental oestrogens or oestrogen mimics in the aquatic environment has been suspected of disrupting the normal endocrinology of wild populations of fish. In this study, induction of vitellogenin synthesis in primary hepatocytes from Atlantic salmon (Salmo salar) was optimized and validated as an oestrogenic in vitro bioassay using a sensitive capture vitellogenin enzyme-linked immunosorbent assay. After proper optimization (cell media supplements, cell density, temperature and exposure time), this assay gave a sensitive and reproducible response to both endogenous steroids (relative potency: 17beta-oestradiol>)oestriol)oestrone>17alpha-oestradiol) and a range of common oestrogen mimics (relative potency: ethynyloestradiol and diethylstilboestrol>)genistein and zearalenone>)bisphenol A and 4-t-octylphenol>4-n-nonylphenol and 2'-chloro,4-chloro-diphenyltrichloroethane (o,p'-DDT). However, the androgen testosterone and the putative oestrogen mimics dieldrin and toxaphene were not shown to be oestrogenic using this hepatocyte bioassay. Oestrogen-induced vitellogenin synthesis was efficiently inhibited by the anti-oestrogen ZM 189.154, suggesting that this bioassay may be used for testing both the oestrogenic and the anti-oestrogenic properties of chemicals.

In a double-blind, randomised trial, 62 postmenopausal women with genito-urinary symptoms were treated with oestriol or matching placebo for 4 weeks. Estriol (Synapause-E3, Nourypharma Nederland) was given orally for 4 weeks in a single daily dose (8 mg/day first week, 4 mg/day second and third week, 2 mg/day fourth week). The influence of estriol on the vaginal and urethral epithelium was assessed by using the karyopycnotic index and the maturation value. As we expected, it was confirmed that estriol has a remarkably beneficial effect on the vaginal epithelium. This also applies to the epithelium of the urethra, although the effect is much less obvious.

In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (-)-adrenaline. Oestradiol (40 mumol/l), 2-hydroxyoestradiol (2OHE2) (20 mumol/l), and 2-methoxyoestradiol (2MeOE2) (20 mumol/l) all sensitized the rabbit aorta to contractile responses to (-)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (-)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. Oestradiol and 2OHE2 did not increase responses of the aorta to (-)-noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE3. The potentiating effect of 2OHE2 on contractile responses to (-)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mumol/l). Conversely, pretreatment of the tissue with 2OHE2 prevented the augmented aortic contraction to (-)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE2 and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mumol/l). Oestradiol and 2MeOE2 reduced the formation of both the 3H-O-methylated, 3H-deaminated and the 3H-O-methylated deaminated metabolites of 3H-(-)-adrenaline (0.15 mumol/l) during exposure of the aorta to the tritiated catecholamine.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the safety and efficacy of oestriol in relieving post-menopausal symptoms 53 post-menopausal Japanese women with climacteric symptoms, 27 with natural menopause (group I) and 26 with surgically induced menopause (group II), received oral oestriol, 2 mg daily for 12 months. Clinical parameters including Kupperman index (KI) and the degree of satisfaction with symptomatic relief; serum concentrations of oestradiol, FSH and LH; serum lipids; blood pressure; bone mineral density, serum calcium (Ca), alkaline phosphatase (ALP), and urinary Ca were compared between the two groups. Oestriol improved KI in groups I and II by 49 and 80% respectively. Satisfaction with treatment was 85% in group I and 93% in group II. For both parameters, values were significantly different between groups I and II (P < 0.05 for both). Serum concentrations of oestradiol, FSH and LH changed in group I versus group II 6 months after initiation. A significant decrease in serum ALP and Ca/Cr was observed in group I at 6 months. Except for serum triglycerides, oestriol had no significant effect on lipids. Systolic and diastolic blood pressures were significantly decreased in group I at 3 months versus baseline. Slight vaginal bleeding occurred in 14.3% of group I. Histological evaluation of the endometrium in all women of group I and ultrasound assessment of the breasts following 12 months of oestriol treatment found normal results in all women. Therefore, oestriol appeared to be safe and effective in relieving symptoms of menopausal women. The beneficial biochemical effects of oestriol were marked in the natural menopause. Overall, oestriol may serve as a good choice for hormone replacement therapy to protect against other climacteric symptoms in post-menopausal women who do not need medication for osteoporosis or coronary artery disease.

Foeto-placental function and hormone levels in the maternal, foetal and amniotic compartments have been investigated in an acromegalic woman who was treated with 20 mg bromocriptine/day throughout gestation. Bromocriptine therapy during pregnancy had no effect on urinary oestriol excretion and plasma levels of unconjugated oestriol, progesterone, human placental lactogen, cystine aminopeptidase and heat-stable alkaline phosphatase. The maternal and foetal (cord )blood and amniotic fluid showed prolactin levels of 3.8, 6.5 and 1700 ng/ml, respectively, in the 39th week of pregnancy during bromocriptine therapy. Compared with data from normal pregnancies, these values demonstrated that bromocriptine or an active metabolite crossed the term placenta to suppress prolactin secretion from the foetal pituitary gland and that the prolactin level in amniotic fluid was scarcely affected by the drug. Maternal, foetal and amniotic fluid growth hormone levels were 27.0, 33.0 and 3.8 ng/ml, respectively, thus indicating that dopamine agonists suppress growth hormone only in acromegalic patients, and not in normal babies. Bromocriptine had no effect on thyroid-stimulating hormone concentrations in maternal, foetal and amniotic compartments.

OBJECTIVE

To investigate the effects of oral versus transdermal 17beta-oestradiol, given in both cases with sequential addition of oral norethisterone acetate, on serum lipid and lipoprotein levels in postmenopausal women.

METHODS

Open, randomised, parallel groups study.

METHODS

University Clinical Research Group.

METHODS

Sixty-four postmenopausal women with climacteric complaints who were otherwise healthy were screened. Of these, 58 fulfilled the entry criteria.

METHODS

Fifty-eight postmenopausal women were randomised to receive either oral 17beta-oestradiol/oestriol (Trisequens) or transdermal 17beta-oestradiol (Estrapak) together with cyclical addition of norethisterone acetate for 48 weeks.

METHODS

Serum levels of total cholesterol, triglycerides, high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), apolipoproteins, and lipoprotein(a) at baseline, and after 46 weeks (oestrogen-alone phase), and 48 weeks (oestrogen-progestogen phase) of treatment.

RESULTS

Oral oestradiol therapy did not affect serum total cholesterol levels during the oestrogen-alone phase, but during the combined phase there was a 5% fall (P < 0.05) due to a 7% decrease in LDL cholesterol levels (P < 0.01). Oral therapy also increased serum triglyceride levels by 9.4% during the oestrogen-alone phase (P < 0.05). During the combined phase of transdermal therapy, there was a 19% fall in serum triglyceride levels (P < 0.05) and a 6% fall in HDL levels (P < 0.05). Oral oestradiol reduced lipoprotein(a) levels by 31% during the oestrogen-alone phase and by 37% with norethisterone acetate addition (P < 0.05). Transdermal therapy had no significant effect on lipoprotein(a).

CONCLUSIONS

Other than a minor fall in HDL3 in women receiving transdermal 17beta-oestradiol, coadministration of oral progestogen in general improved, rather than worsened, this serum lipoprotein profile.

The effects of oestradiol (Oe2), oestrone (Oe1), oestriol (Oe3), oestetrol (Oe4) on the induction of the progesterone receptor (PgR) and growth of MCF-7 cells are compared. All the four oestrogens increased cell PgR concentration. Analysis of the dose-response curves shows induction by Oe2 to be 10 times and 50 times greater than Oe3 and Oe4, respectively. Oe1 and Oe2 are equally effective, even with consideration of metabolic conversion of O31 into Oe2. When compared with untreated cells, Oe2, Oe3, and Oe4 do not influence significantly the plating efficiency but all 3 hormones increase thymidine incorporation of the cells in log phase growth. Oe2, Oe3 and Oe4 are able to rescue the growth inhibition induced by antioestrogens. The respective potency compared to Oe2 is again in the range of 10 and 50 times lower for Oe3 and Oe4, respectively. On the other hand Oe1 decreases plating efficiency, thymidine incorporation and does not rescue the growth inhibition induced by antioestrogens when the metabolic conversion of Oe1 into Oe2 is prevented. Thus, Oe3 and Oe4 behave like complete Oe2 agonists whereas Oe1 has dissociated effects, agonist on PgR induction and antagonist on cell growth.