Nausea and/or vomiting in early pregnancy is common enough to be generally accepted as normal or 'physiological'. The specific etiology of these complaints is still obscure. One possibility is that endocrine factors may play some part. In this study, 102 healthy pregnant women, of whom 62 complained of nausea, were followed throughout pregnancy and the circulating levels of cortisol, testosterone, dehydroepiandrosterone sulphate (DHEA-S), progesterone, oestradiol and total and free oestriol were measured. In early pregnancy, serum levels of cortisol and progesterone were significantly lower in emetic subjects. In the last trimester, significantly higher DHEA-S concentrations and lower testosterone values were found in women who had suffered from nausea and vomiting in early pregnancy compared to asymptomatic subjects. Overt differences were found between emetic and non-emetic pregnancy and it is concluded that endocrine factors are of etiological importance in emesis gravidarum.

Information on maternal age and maternal serum alpha-fetoprotein, unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) levels was used to investigate retrospectively the effect of estimating Edward's syndrome risk in women having multi-marker screening for Down's syndrome. The screened population comprised 15 pregnancies affected by Edward's syndrome, 15 with Down's syndrome and 5472 unaffected pregnancies. The use of all three markers to estimate Edward's syndrome risk would have led to the detection of 10-12 (67-80 per cent) cases with a false-positive rate of 0.3-0.6 per cent depending on the risk cut-off. A further case would have been detected as a result of screening for Down's syndrome alone. Similar results were obtained when the Edward's syndrome risk was based on uE3 and hCG only. These data suggest that extending Down's syndrome screening to include Edward's syndrome risk will yield a high detection rate with only a small increase in the false-positive rate.

The urinary excretion of oestrone (E1), oestradiol (E2) and oestriol (E2) was measured in 42 obese post-menopausal women before and 6-12 mth after their participation in a weight reduction programme. The method of inducing weight loss was based on modification of eating behaviour without specific changes in dietary composition. Urinary oestrogen, as a ratio to creatinine, were measured by a specific radioimmunoassay after purification of the specific oestrogen fraction. Before weight reduction efforts, there is a significant correlation among E1, weight and the Quetelet-index and between E3 and the Quetelet-index. These correlations have disappeared after weight reduction. There is a significant positive correlation between changes in body-weight and changes in the excretion of E1, E3 and total oestrogens. There was no significant change in the so-called oestrogen ratio (E1 + E2/E3) in relation to change in body weight. With respect to the statistical association between endometrial cancer, breast cancer and overweight, our data give support to the concept that intervention programmes on weight reduction may influence both the incidence and the prognosis of these two diseases.

The mouse placenta possesses a soluble oestrogen sulphotransferase activity which increases markedly from at least 12 days of gestation until term. At about 16 days of gestation, a similar activity is found in the uterus. This activity also increases until term and disappears rapidly post partum. The uterine enzyme activity appears to require the presence of the foetal unit for its onset, since unoccupied horns, whether their endometrial stromal cells are differentiated to decidual cells or not, are essentially devoid of it. Uterine cytosols from non-pregnant mice are also inactive in this respect. In late gestation, the uterine sulphotransferase is confined to the decidua basalis, the areas to which the placentas are attached. The sulphotransferase(s) of placenta and uterus has an absolute requirement for 3'-phosphoadenosine 5'-phosphosulphate, and possesses little activity in the absence of exogenous thiol groups. Stimulation is also seen in the presence of Mn2+, Mg2+ or Ca2+. Oestrone and oestradiol, and to a lesser degree oestriol, are substrates for the enzyme(s), whereas testosterone, cortisol and dehydroepiandrosterone are not. Oestrone and oestradiol at higher concentrations (1.0-1.5 microM) completely inhibit the enzyme(s). These enzymes could play a role in altering tissue concentrations of active oestrogens during gestation in the mouse. Oestrogen sulphotransferase activity is low or absent in reproductive tissues of the pregnant rat.

The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE1S, 2.5 mg/day) and oestradiol valerate (E2V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 micrograms/day) were compared in 8 post-menopausal women, using a randomized cross-over design. The end points measured in peripheral plasma included oestrone (E1), oestradiol (E2), oestriol (E3), oestrone sulphate (E1S), oestradiol sulphate (E2S) and oestriol sulphate (E3S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed. The plasma levels of E3 were invariably below the detection limit (220 pmol/l). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E3S) following PE1S administration than those recorded after E2V ingestion. The terminal half-lives of the circulating oestrogens measured after PE1S administration did not differ from those found after E2V administration. After 21 days of PE1S administration (in combination with LNG for the last 10 days), the maximum levels of all the oestrogens (except those of E2) were significantly higher than those seen after the first dose. No such difference was observed after E2V administration. There was no difference between the effects of the two treatment regimens with regard to the E1/E2 ratios, but the E1/E1S ratios were significantly lower after PE1S treatment than after E2V administration. It is concluded that, compared with an equivalent dose of PE1S, daily repeated oral administration of E2V yields consistently lower peripheral plasma levels of E2 and its principal metabolites. However, in contrast to PE1S therapy, prolonged administration of E2V does not result in an accumulation of the circulating oestrogens measured.

To assess the value of inhibin A as an additional second-trimester maternal serum marker of Down's syndrome we studied 56 affected and 280 unaffected pregnancies matched for gestational age. The median level in the cases was 1.62 multiples of the gestation-specific median (MOM) in the controls, with 95 per cent confidence limits of 1.34-1.96. The distribution of inhibin levels in affected and unaffected pregnancies was approximately log Gaussian, with means about 1 standard deviation apart. This degree of separation was similar to that for human chorionic gonadotropin (hCG), free beta-hCG, and unconjugated oestriol (uE3), but about double that of alpha-fetoprotein (AFP) measured in the same samples. Inhibin was largely uncorrelated with AFP and uE3, whereas the log correlation coefficient with hCG was 0.29 (P = 0.19) for Down's syndrome and 0.41 (P < 0.0001) for unaffected pregnancies; with free beta-hCG, it was 0.18 (P = 0.38) and 0.38 (P < 0.0001), respectively. On the basis of these results and other published studies, we estimate that measuring inhibin A in addition to AFP and hCG or free beta-hCG (with or without uE3) will increase the detection rate for a fixed 5 per cent false-positive rate by about 7 per cent.

An enzyme that conjugates the 17beta-hydroxyl group of testosterone was found in the cytosol fraction of human liver. The same enzyme preparation also conjugates the 16alpha-hydroxyl group of oestriol. The enzymic activity could not be sedimented by centrifuging the cytosol fraction at 158000g(av.) for 120min. The testosterone-conjugating as well as the oestriol-conjugating activities were found in the precipitate obtained after 30% saturation of the cytosol fraction with ammonium sulphate. Filtration of the precipitate through Sephadex G-200 enriched the testosterone-conjugating enzyme 50-fold and the oestriol-conjugating enzyme 100-fold. No separation of the two activities was achieved. With labelled testosterone the product of the reaction, testosterone 17beta-glucuronide, was identified by paper chromatography and by crystallization to constant specific radioactivity. Testosterone 17beta-glucuronyltransferase was active between pH7.0 and 8.6 in tris-HCl and tris-maleate buffers. The apparent K(m) values for testosterone and UDP-glucuronic acid were 6.4 and 25mum respectively. The enzyme was active between 37 and 45 degrees C; the activation energy was calculated to be 5kcal/mol. Oestriol did not influence the glucuronidation of testosterone. Controlled heating as well as alternate freezing and thawing of the purified enzyme preparation led to an inactivation of both testosterone-conjugating and oestriol-conjugating activities at similar rates. Testosterone and oestriol, when incubated together, gave a reaction rate that was approximately equal to the sum of the rates when the two substrates were incubated separately. The present findings suggest that testosterone and oestriol are conjugated by two separate enzymes.

The effectiveness of maternal serum alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin in screening for Down's syndrome (DS) was evaluated on 840 women who underwent amniocentesis for fetal karyotype on account of their age. The risk of a DS pregnancy was established using the method of Wald et al. (1988b), which combines the age-specific risk with that indicated by the levels of the three serum markers. In women over 35, at cut-off risk levels of 1:250 and 1:380, the false-positive rate was 24 and 34 per cent, respectively. In all nine cases of DS, the estimated risk was higher than 1:250. The best screening strategy with the lowest false-positive rate was obtained by combining the three serum markers. The results suggest that this kind of screening can be proposed during genetic counselling for women under 35 and older women wishing to avoid the risk of miscarriage induced by amniocentesis.

This research involves the removal of contaminants of concern in water supplies using advanced oxidation technologies, in particular titanium dioxide photocatalysis. Photocatalysis for the removal of 1,4-dioxane and the natural (17 beta-oestradiol, oestriol) and synthetic (17 alpha-ethynyloestradiol) oestrogens in water was investigated using both UVA and solar radiation. The H2O2/UVC process, solar, UVC and UVA light alone were also investigated and the processes compared. It was found that TiO2 photocatalysis is an effective method for the degradation of the natural (17 beta-oestradiol and oestriol) and the synthetic (17 alpha-ethynyloestradiol) oestrogens in water in immobilised Degussa P25 and sol-gel spiral reactors with both UVA and solar radiation as the light source. Photocatalysis using the commercial catalyst Degussa P25 as an immobilised reactor with a UVA lamp shows the best performance. Photocatalysis was shown to completely mineralise 1,4-dioxane to CO2 in Degussa P25 suspension and sol-gel reactors using both UVA and solar radiation. The commercial catalyst Degussa P25 in suspension with UVA radiation shows the best performance. Photocatalysis is much more efficient than H2O2/UVC, UVA, UVC and solar radiation alone for all contaminants investigated.

A prenatal screening programme for Down's syndrome potentially detecting 76 per cent of affected pregnancies in the South Australian general population at an amniocentesis rate of 3.9 per cent was designed following analysis of mid-trimester serum samples from 57 women who carried an affected fetus. This equates to one affected pregnancy being detected for 41 chromosomal analyses performed. For the experimental series, 75.4 per cent of affected pregnancies were detected, while 4.1 per cent of control specimens produced estimated risk odds consistent with further action. A maternal risk odds of birth of a Down's syndrome fetus of 1:420 was taken as the decision value, which is the prevalence of Down's syndrome births to 35-year-old mothers in South Australia. This screening performance was achieved by investigating combinations of serum analytes not previously reported and by refining the calculation of maternal risk odds to include selective weighting of indicator analytes. Combination of the measurements of free alpha-subunits and beta-subunits of chorionic gonadotrophin, alpha-fetoprotein, unconjugated oestriol, and placental lactogen was found to be most effective in indicating Down's syndrome fetuses. In all combinations of analytes tested, replacing the measurements of free alpha-subunits and free beta-subunits of chorionic gonadotrophin with the measurement of intact chorionic gonadotropin produced a less effective screen.

Oestriol, a naturally occurring short-acting oestrogen, was used to treat acquired urinary incontinence in 129 bitches selected by 48 veterinary practitioners in the Netherlands, Belgium, France and Germany. The dogs were treated daily for 42 days with oestriol tablets, using a self-controlled study design. The dogs were examined and blood sampled at the beginning and end of the trial. According to the veterinary practitioners 83 per cent of the dogs either became continent or improved, but the others showed no change or became worse. The owners reported similar results: 82 per cent of the dogs responded to treatment and the others did not. The dose and treatment schedule for each dog were established on the basis of clinical efficacy. Mild and transient oestrogenic effects such as swelling of the vulva and attractiveness to male dogs were observed soon after the treatment began and at the higher dose schedule used in 12 of the dogs. A haematological examination of 114 of the dogs revealed no abnormalities.

A total of 222 pregnant women had repeated hormone assays between 20 weeks and delivery; 86 of the women were smokers. The maternal hormone balance appeared to be affected by smoking. Smoking affected maternal serum levels of hPL and hCG in pregnancies with a female fetus whereas maternal serum concentrations of oestriol and prolactin were affected in pregnancies with a male fetus. Significantly higher hCG levels were found in mothers who smoked and had a girl than in those who smoked and had a boy. On the basis of our results we feel that smoking mainly affects the placenta.

The uptake, metabolism and subcellular distribution of oestradiol and oestriol in endometrial, myometrial and vaginal tissue of postmenopausal women under physiological conditions were studied by giving 3H-labelled oestradiol or oestriol in subphysiological doses by continuous infusion lasting 12 h before hysterectomy. The three tissues obtained from each woman were separated into three fractions: two cytosol fractions (free oestrogens and specifically bound) and one nuclear fraction. The results show an accumulation of both oestrogens in the target tissues, we found an approximately 33 times higher [3H]E2 concentration in endometrium (dpm per g) than in plasma (dpm/ml), 20 times in myometrium and 10 times in vaginal tissue. After the E3 infusions the tissue/plasma gradient was 37 for endometrium, 19 for myometrium and 11 for vagina. In plasma and tissues a metabolite of E3 could tentatively be identified as 16 alpha-hydroxyoestrone. The subcellular distribution showed that 60-80% of E2 and E3 is accumulated in the nuclear fraction of all tissues studied, no nuclear bound oestrone could be detected. From these results the conclusion was drawn that oestradiol still is the major tissue oestrogen in postmenopausal women and that it is mainly nuclear bound. Endometrium of postmenopausal women accumulates higher concentrations of E2 and E3 than vaginal tissue from the same individual, no preferential uptake of oestriol occurs under physiological conditions.

Prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), oestrone (E1), and oestradiol (E2) levels were determined in 204 women who were receiving hormone replacement therapy for their climacteric symptoms. The changes in these hormone levels and the endometrial morphology were studied in order to determine the effects of the replacement therapy. The women were divided into two groups: the first group of 120 women was treated with conjugated oestrogens administered cyclically, plus norethisterone acetate. The second group of 84 women received oral oestriol succinate, also administered cyclically but without additional progestogens. The oestrogen-progestogen therapy resulted in a disappearance of the climacteric symptoms and a significant decrease of FSH and LH levels. Oestriol therapy was less effective than the conjugated oestrogens as a replacement therapy. Oestriol therapy also resulted in a less remarkable decrease of gonadotrophin levels. There were no significant changes in prolactin levels in either group of women. The endometrial histology did not change significantly after either of the two hormone replacement therapies.

The hormonal responses to exercise during later pregnancy were studied in relation to an exercise test in ten healthy women. At the end of the 10-min exercise, maternal heart rate had risen from 93 +/- 3.2 (mean +/- SEM) to 157 +/- 6.3 beats/min, and systolic blood pressure from 120 +/- 3.4 to 148 +/- 5.4 mmHg, but diastolic blood pressure was unchanged. Plasma concentrations of noradrenaline and adrenaline rose rapidly during the exercise, from 2.9 +/- 0.3 to 6.9 +/- 1.2 nmol/l and from 0.31 +/- 0.04 to 0.47 +/- 0.08 nmol/l respectively. The serum concentration of prolactin did not change during the test, but 30 min after the exercise the value had risen from 146 +/- 17 to 212 +/- 22 mg/ml, thereafter slowly declining. The serum concentration of cortisol remained unchanged. The mean concentration of oestriol rose from 31.5 +/- 2.6 to 33.9 +/- 3.0 nmol/l at least 5 min after the exercise, thereafter declining to 29 +/- 2.6 nmol/l. After the test, levels of progesterone and oestradiol also fell slightly. Mild irregular uterine activity was found in four subjects. Cardiotocography revealed a transient fetal tachycardia in two subjects.

OBJECTIVE

To compare blood pressure, heart rate, and peripheral vascular responsiveness in menopausal women who have hot flushes and in those who do not, and to assess the effect on these variables of treating women who have hot flushes with oestriol, a natural oestrogen, given vaginally.

METHODS

An open, non-randomised cohort study of flushing and non-flushing menopausal women. A before and after investigation of the effects of vaginal oestriol treatment on the circulation.

METHODS

Referral based endocrinology clinic.

METHODS

88 Consecutive menopausal women, 63 complaining of frequent hot flushes and 25 who had not flushed for at least a year.

METHODS

Treatment with vaginal oestriol 0.5 mg at night for six weeks in 18 of the women who had hot flushes.

RESULTS

Peripheral blood flow was measured by venous occlusion plethysmography at rest and in response to stressful mental arithmetic and anoxic forearm exercises. Blood flow in the forearm and its variability were significantly higher in flushing than in non-flushing women (4.1 (SD 1.7) and 3.1 (0.9) ml/100 ml tissue/min and 17% and 13% respectively). Blood pressure, heart rate, and blood flow in the hand were, however, similar in the two groups. No difference was found in the peripheral incremental response to either stress or anoxic exercise. Vaginal oestriol significantly lowered forearm blood flow from 4.4 (1.5) to 3.3 (1.1) ml/100 ml tissue/min but dilator responsiveness was unaffected.

CONCLUSIONS

The peripheral circulation is different in menopausal women who have hot flushes compared with those who do not, with selective vasodilatation in the forearm. The lowered blood flow in the forearm after vaginal oestriol in flushing women may be relevant to the alleviation of vasomotor symptoms induced by oestrogen treatment.