Endometrial and conceptus tissues were obtained on Days 10.5, 11, 12, 16 and 25 of pregnancy and Day 25 of pseudopregnancy of gilts and incubated for 6 h in Minimal Essential Medium (5 ml) containing 35 ng [3H]progesterone. Metabolism of [3H]progesterone to oestrone, oestradiol and oestriol was determined by gas and high-pressure liquid chromatography and successive recrystallizations with unlabelled standards. Conceptuses collected between Days 10.5 and 12 were spherical, tubular or filamentous and incubated with 500 mg endometrium and [3H]progesterone. Production of oestrone by spherical conceptuses was not detected, but was 44-47 pg/tubular conceptus and 21 pg/filamentous conceptus. A similar trend was observed for oestradiol. Conceptus tissues from Days 16 and 25 (chorion) were most active in producing oestrone (123 and 520 pg/mg tissue, respectively) and oestradiol (277 and 876 pg/mg tissue, respectively). Endometrial oestrogen production was less than that for conceptus tissue for oestrone and oestradiol on Days 16 and 25 of gestation. Coincubations of endometrium and conceptus tissues had lower oestrogen production than conceptus alone. Endometrium from Day 25 of pseudopregnancy metabolized [3H]progesterone to several non-polar metabolites, but no oestrogens were detected. An unidentified phenolic metabolite of [3H]progesterone was detected in higher quantities than either oestrone or oestradiol; 445 to 461 pg/conceptus at the tubular stage. These results indicate temporal changes in the conversion of [3H]progesterone to oestrogens by conceptus and endometrial tissue from pregnant gilts, but not endometrium from pseudopregnant gilts.

Treatment of menopausal symptoms with a combination of natural oestrogens (17beta-oestradiol and oestriol) and a gestagen (norethisterone acetate), given continuously without interruption, has been found to have a good effect on menopausal symptoms, at the same time as the endometrium is maintained or brought to an atrophic state. This method seems to be a new approach to oestrogenic therapy, and in spite of the inconvenience of rather frequent--though as a rule very slight--bleeding during the first months of treatment, it should be of value. After 3-4 mth of treatment bleeding practically never occurs and the endometrium almost invariably becomes completely atrophic. It would seem that this might imply a lowered risk of development of endometrial cancer. A series of 265 patients treated in accordance with this principle for up to more and than 4 yr is presented.

Women who bear their first child at an early age have lower breast-cancer incidence-rates than do women who are older at first birth or who remain nulliparous. The urine "oestriol ratio", the concentration of oestriol relative to the sum of the concentrations of oestrone and oestradiol, is inversely related to a population's breast-cancer rate. To evaluate the relationship between these two breast-cancer risk indicators the urine oestriol ratio was determined for recently delivered uniparous women aged 19-23, 25-27, and 29-34 years and nulliparous women of comparable ages. In the follicular phase, the youngest parous women had an oestriol ratio 40% higher than, and significantly different from, the ratios of all other groups which were otherwise quite similar. In the luteal phase, the oestriol ratio of the youngest parous women was again distinctively raised and generally the oestriol ratios of parous women were higher than those of nulliparae. The results are not explained by differing frequencies of ovulation among the groups or by confounding from several breast-cancer risk indicators. These findings support the hypothesis that oestrogen metabolism, as reflected by the urine oestriol ratio, is a determinant of breast-cancer risk.

A captive colony of baboons has been used for three decades for various reproductive studies where application of findings to human therapeutics was desired. The characteristics of the menstrual cycle in baboons are very similar to those of women, except that of the baboon is slightly longer and there is a lower luteal phase concentration of oestradiol. The duration of pregnancy in baboons is about two-thirds that of humans but patterns of oestrogen and progesterone secretion are virtually identical. The principal oestrogen produced by the pregnant baboon is oestrone, while oestriol is the most abundant in human pregnancies. Chorionic gonadotrophin (CG) is elevated significantly only in the first trimester of a baboon pregnancy, while human pregnancy concentrations of this hormone are about one-third of the first trimester level in the second and third trimesters. Breeding success of baboons in captivity depends on care being taken to cull infertile animals from the colony prior to commencing matings. Under optimal conditions, fertility rates can reach nearly 80%. Female baboons have been successfully used to gain insights into antifertility effects of contraceptive vaccines directed against CG, spermatozoa and ovum antigens. Extensive use of the colony for developing a human chorionic gonadotrophin (HCG) antifertility vaccine has been invaluable for progress in this field. Other pharmaceuticals and devices have been successfully tested in baboons, but costs and mandated regulations for the management of these nonhuman primates have made their current use in meaningful studies extremely difficult.

OBJECTIVE

To assess the efficacy of oral oestriol in the prevention of recurrent urinary tract infections in elderly women.

METHODS

Double-blind, randomised, parallel group, placebo controlled trial

METHODS

Urogynaecology Unit at King's College Hospital with some women recruited from the geriatric units of St. Pancras Hospital and Dulwich Hospital, London (UK).

METHODS

Seventy-two postmenopausal women older than 60 years of age (mean 73.2 years) suffering from recurrent urinary tract infections.

METHODS

Oral oestriol (3 mg per day) or placebo for six months. MAIN: outcome measures Urinary tract infection rates.

RESULTS

The study was difficult to conduct because of its design and the age of the participants. Oral oestriol (3 mg per day) was not shown to be superior to placebo in the prevention of recurrent urinary tract infections, but both oestriol and placebo improved urinary symptoms during the trial.

CONCLUSIONS

The power of the study might have been too low to detect a significant difference between the groups, or oral oestriol (3 mg per day) may have been either the wrong dose or the wrong route of administration for this indication.

OBJECTIVE

In order to verify the potential association between the aetiopathogenesis of adolescent idiopathic scoliosis (AIS) and the process of sexual maturation, we determined the concentrations of oestrogens in pre- and postmenarcheal girls affected by this condition. AIS, occurring mostly in pubescent girls, is one of the most frequent forms of faulty posture. Therefore, it was assumed that the multifactorial pathomechanism of AIS involves significant deficiency of oestrogens.

METHODS

The diagnosis of AIS was established on the basis of physical examination and analyses of radiograms. Concentrations of FSH, LH, oestrogens, progesterone, osteocalcin and RANKL were determined by ELISA. The activity of alkaline phosphatase (AP) was measured by kinetic method. The study included pre- and postmenarcheal girls with AIS and corresponding groups of scoliosis-free controls.

RESULTS

In premenarcheal scoliotic girls, the levels of FSH, LH and oestradiol were lower; the levels of progesterone, oestrone and oestriol were higher; and the concentrations of oestrone and oestriol were similar compared to premenarcheal controls. Higher levels of RANKL, osteocalcin and AP were observed in premenarcheal adolescents with AIS compared to controls. The concentrations of FSH, LH, oestradiol, and progesterone in postmenarcheal girls with scoliosis were lower, oestrone were slightly lower and oestriol did not differ compared with the control group. Significantly higher levels of RANKL, osteocalcin and AP were observed in postmenarcheal scoliotic adolescents compared with controls.

CONCLUSIONS

There is an interdependence between the concentration of oestradiol and development of scoliosis. Determination of estradiol may have diagnostic value in the screening of spinal pathologies associated with AIS.

Saliva oestriol, oestradiol, and progesterone concentrations were measured in 23 women who went into spontaneous preterm labour. The patients fell clinically and biochemically into two groups. The 13 who went into preterm labour with intact membranes had a saliva oestriol to progesterone ratio greater than one in every case and greater than the 95th centile for their length of gestation in 12 cases; by contrast, all those who went into spontaneous preterm labour after prolonged rupture of the membranes had an oestriol to progesterone ratio less than one and below the 50th centile for their period of gestation in the one to four days before delivery. Saliva oestradiol to progesterone ratios were randomly distributed throughout the normal range in both groups. It appears that preterm labour without prior prolonged rupture of the membranes is, like term labour, preceded by an increase in the saliva oestriol to progesterone ratio. It may therefore be possible to use this ratio to predict preterm labour.

Urinary tract infections (UTI) are among the most frequent bacterial infections in the community and health care setting. Mostly young and, to some extent, postmenopausal women are affected by recurrent UTI (rUTI) defined as ≥3 UTI/year or ≥2 UTI/half year. In contrast, rUTI is rare in healthy men. On the other hand, rUTI are frequently found in female and male patients with complicating urological factors, e.g. urinary catheters, infection stones. Remediable predisposing factors in uncomplicated rUTI in women are rare. In complicated rUTI the success depends mainly on the possibility to eliminate or at leastimprove the complicating risk factors. Continuous antibiotic prophylaxis or postcoital prophylaxis, if there is close correlation with sexual intercourse, are most effective to prevent rUTI. Nitrofurantoin, trimethoprim (or cotrimoxazole), and fosfomycin trometamol are available as first-line drugs. Oral cephalosporins and quinolones should be restricted to specific indications. Antibiotic prophylaxis reduces the number of uropathogens in the gut and/or vaginal flora and reduces bacterial "fitness". Given the correct indication, the recurrence rate of rUTI can be reduced by about 90%. Due to possible adverse events and the concern of selecting resistant pathogens, according to the guidelines of the European Association of Urology antimicrobial prophylaxis should be considered only after counselling, behavioural modification and non-antimicrobial measures have been attempted. In postmenopausal patients vaginal substitution of oestriol should be started first. Oral or parenteral immunoprophylaxis is another option in patients with rUTI. Other possibilities with varying scientific evidence are prophylaxis with cranberry products, specific plant combinations or probiotics. The prophylaxis of catheter-associated UTI should employ strategies which result in a reduction of frequency and duration of catheter drainage of the urinary tract. The currently available catheter materials have only little influence on reducing catheter-associated rUTI.

An intervention trial using oral oestriol to treat urinary incontinence was performed in a number of patients taken from a representative sample of 562 women aged 75 yr. The clinical series consisted of 34 patients who took part in a double-blind crossover study of the possible effects of oestriol, given in a single daily dose of 3 mg, and of a placebo over a period of 3 mth. The clinical examinations included bacteriological cultures and an assessment of the degree of atrophy of the surface membranes in the vagina. In most patients, oestriol was effective in reversing the atrophy. The clinical effect was excellent in urgency and mixed incontinence, but not in stress incontinence.

This study reports the fetal outcome in 500 pregnancies when the baby weighed less than the 10th centile for gestational age at birth, compared with that in a series of 500 pregnancies where there was a normal weight for gestation. Fetal growth retardation (0-9th centile) had a significant positive association with perinatal mortality (5.2% versus 1.2%, P greater than 0.001) and low oestriol excretion (42.4% versus 15%, P greater than 0.001), but not with major fetal malformations or fetal asphyxia. In the study group, 20 of the 26 perinatal deaths were associated with subnormal oestriol excretion. When severe fetal growth retardation was considered (less than the 5th centile), the associations with perinatal mortality (19%) and subnormal oestriol excretion (63%) were stronger and a significant correlation with major malformations emerged (17%, P greater than 0.001). Detection of subnormal oestriol excretion allows identification and appropriate treatment of severe fetal growth retardation which should improve survival and neurological development in these infants. This study confirms that birth-weight below the 10th centile is an appropriate definition of fetal growth retardation in terms of perinatal mortality and morbidity.

Delayed-type hypersensitivity (DTH), primary direct and indirect PFC, memory antibody response and suppressor cell induction against sheep red blood cells (SRBC) have been examined in oestriol (E3) pretreated mice. The results showed that DTH and primary direct and indirect PFC responses were suppressed by E3 treatment. These suppressive effects could, however, be overcome when oestrogenized mice were given supra-optimal doses of SRBC for each response. On the other hand, the memory antibody response was markedly enhanced when E3 was given prior to the primary antigen stimulation. Induction of the suppressor cells for the antibody response seemed not to be affected by E3 treatment, but the characterization of the suppressor cells revealed that those obtained from E3 treated mice were surface immunoglobulin positive (sIg+) cells whereas those from control mice were not. These results were discussed in terms of the altered antigen distribution due to the activated phagocytic activity of the reticuloendothelial system (RES) after E3 treatment.

This study compares the plasma gonadotrophin, oestradiol, and androgen and salivary progesterone concentrations in a single menstrual cycle between 25 normal pre-menopausal women who smoke cigarettes and 21 who are non-smokers. The effect of smoking on luteinizing hormone (LH) pulsatility and the urinary excretion of oestrogens is also described. Cigarette smoking did not consistently suppress LH pulsatility. There was no significant difference in the length of either the follicular or luteal phases. There were no significant differences in the mean plasma oestradiol concentrations in the follicular phase in smokers compared to non-smokers. There were no significant differences in the mean salivary progesterone concentration in the luteal phase in smokers compared to non-smokers. There was no significant difference in plasma concentrations of testosterone, androstenedione and dehydroepiandrosterone sulphate. There was also no significant difference between the urinary concentrations of oestradiol, oestrone or oestriol. We have been unable to demonstrate a detrimental effect of cigarette smoking on any of the important endocrine characteristics of the menstrual cycle, and we conclude that these data suggest that the anti-oestrogenic effect of smoking does not work through alterations in pituitary or follicular endocrine function or in alterations in the metabolism of oestrogens.

The effects of hydrocortisone, dexamethasone and prednisone on the morphology, replication, DNA synthesis, cell protein content and protein synthesis of cultured, human endothelial cells were evaluated. After culturing the cells with these glucocorticoids for 24-48 h, the cells covered a greater portion of the culture surface area. The mean surface area of the individual endothelial cell treated with glucocorticoids was 1.53 times greater than that of the untreated control endothelial cell. When compared with controls, the endothelial cover provided by the cells treated with glucocorticoids was more extensive and in many instances covered the entire culture surface. The change in morphology was associated with an increase in protein synthesis and protein content of the cells without an increase in DNA synthesis or cellular replication. Dexamethasone was approximately 10-fold more effective than hydrocortisone, while prednisone was the least effective. Aldosterone, DOCA, testosterone, progesterone, oestradiol and oestriol were ineffective. These studies indicate that glucocorticoids can alter the morphology and biochemistry of cultured endothelial cells and may have implications for the effects of steroids in the treatment of thrombocytopenic states and vascular disorders in man.

OBJECTIVE

We have carried out a systematic review of the association between elevated second trimester maternal serum alpha-fetoprotein (AFP) and singleton preterm birth in order to determine its accuracy and the best AFP cut-off level in clinical tests in the general population.

METHODS

24 studies published between January 1991 and October 2007 were included, comprising 207,135 women.

RESULTS

An elevated AFP test (expressed as multiple of the median, MoM) had high specificity but low sensitivity to predict preterm birth: using a 2.5 MoM as the cut-off in the AFP test improved the accuracy compared with 2.0 MoM. However, the overall likelihood ratios for positive and negative tests were not improved. The likelihood ratios for positive tests were: 2.99 (95% CI: 2.45-3.66) and 3.18 (95% CI: 2.07-4.88) for 2.0 MoM and 2.5 MoM, respectively; and for negative tests were: 0.94 (95% CI: 0.91-0.97) and 0.97 (95% CI: 0.95-0.98) for 2.0 MoM and 2.5 MoM, respectively. The available data do not allow us to distinguish whether the association between elevated AFP and preterm birth occurs in spontaneous preterm labour, in elective preterm delivery, or in both. Moreover, in these studies AFP was measured together with other biomarkers (e.g. human chorionic gonadotrophin, oestriol) which often were also elevated. When we included only women in whom AFP was elevated in isolation, there was no association with preterm birth (OR=1.80, 95%CI: 0.92-2.68).

CONCLUSIONS

Our findings suggest that maternal AFP levels are strongly related to preterm birth, but only in the context of other abnormal pregnancy markers. The results question the potential usefulness of AFP screening as a primary preterm birth marker and highlight the need for further studies on the functional role of AFP in pregnancy.

Maternal plasma levels of the trophoblast product, pregnancy-specific beta 1-glycoprotein (PS beta G), have been measured both in normal pregnancies and in pregnancies complicated by pre-eclampsia and/or fetal growth retardation. PS beta G levels correlate significantly with placental and fetal weight and fall below the normal range in about 60 per cent of all patients with fetal growth retardation. PS beta G measurements appear to give a considerably better indication of fetal size than measurements of either human placental lactogen (HPL) or plasma oestriol.

Peripheral serum levels of unconjugated (E1) and total (tE1) oestrone, unconjugated oestradiol-17 beta, unconjugated (E3) and total (tE3) oestriol, progesterone, unconjugated dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulphate (DHAS), and urinary tE3 excretion were determined in pre-eclamptic patients at gestational weeks 32 and 36 and in women with normal pregnancy at the corresponding length of gestation. DHA and DHAS were also analyzed in samples taken 6 weeks after delivery. There were no differences between pre-eclamptic and normal subjects in unconjugated oestrogens and progesterone. Serum tE1 and tE3 levels and urinary tE3 were significantly lower, and the E1/tE1 and E3/tE3 ratios significantly higher in the pre-eclampsia patients. Serum DNA and the DHA/DHAS ratio were significantly elevated in the pre-eclampsia patients during pregnancy, while no differences in these respects were found in the samples taken 6 weeks after delivery. There were no differences in serum DHAS levels. The findings are thought to reflect a general decrease in fetoplacental oestrogen production in combination with a reduced hepatic steroid conjugation in pre-eclamptic subjects.

The natural oestrogen, 17 beta-oestradiol, has been shown not to depress fibrinolysis and apparently has less influence on liver function and lipid metabolism than ethinyl oestradiol, the synthetic oestrogen in conventional 'combined' oral contraceptive tablets. A triple-blind study was therefore made of 215 women during 2051 treatment cycles with oral contraceptives containing either (i) 4 mg of micronized 17 beta-oestradiol and 3 mg norethisterone (Netagen 403), (ii) 4 mg 17 beta-oestradiol plus 2 mg of oestriol and 3 mg norethisterone (Netagen 423) or (iii) 50 microgram ethinyl oestradiol and 3 mg norethisterone (Netasyn). There were no pregnancies or thrombotic incidents. The numbers discontinuing treatment were about the same in the three groups, the main reasons being intermenstrual spotting in those on Netagen 423, amenorrhoea and weight gain in those on Netagen 403 and nausea and weight gain in those on Netasyn. The natural oestrogen showed promise as a new and safe component of the 'combined' pill.

An enzyme that conjugates the 16alpha-hydroxyl group of oestriol with glucuronic acid was found in the cytosol fraction of human liver. The enzymic activity could not be sedimented when the cytosol fraction was centrifuged at 158000g(av.) for 120min. The oestriol 16alpha-glucuronyltransferase was purified 100-fold by 0-30% saturation of the cytosol fraction with ammonium sulphate followed by filtration of the precipitate through Sephadex G-200. The activity was eluted at the void volume. The product of the reaction, oestriol 16alpha-monoglucuronide, was identified by paper chromatography and by crystallization of radioactive product to constant specific radioactivity. The optimum temperature was 37 degrees C, and the activation energy was calculated to be 11.1kcal/mol. The apparent Michaelis-Menten constants for oestriol and UDP-glucuronic acid were 13.3 and 100mum respectively. Cu(2+), Zn(2+) and Hg(2+) inhibited, whereas Mg(2+), Mn(2+) and Fe(2+) stimulated the enzyme. Substrate-specificity studies indicated that the amount of oestradiol-17beta, oestradiol-17alpha and oestrone conjugated was not more than about 5% of that found for oestriol. Oestriol 16alpha-monoglucuronide, a product of the reaction, did not inhibit the 16alpha-oestriol glucuronyltransferase; in contrast, UDP, another product of the reaction, inhibited the enzyme competitively with respect to UDP-glucuronic acid as the substrate, and non-competitively with respect to oestriol as the substrate. ATP and UDP-N-acetylglucosamine did not affect the oestriol 16alpha-glucuronyltransferase. 17-Epioestriol acted as a competitive inhibitor and 16-epioestriol as a non-competitive inhibitor of the glucuronidation of oestriol. 5alpha-Pregnane-3alpha,20alpha-diol also inhibited the enzyme non-competitively. It is most likely that the oestriol 16alpha-glucuronyltransferase described here is bound to the membranes of the endoplasmic reticulum.