Oestrogens play an important role in the development of breast cancer. Oestrone sulphate (E1S) acts as a huge reservoir of oestrogens in the breast and is converted to oestrone (E1) by oestrone sulphatase (E1STS). E1 is then reversibly converted to the potent oestrogen, oestradiol (E2) by oestradiol-17beta hydroxysteroid dehydrogenase (E2DH). The aim of this study was to assess the effects of transforming growth factor-beta1 (TGFbeta1), insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) on cell growth, E1STS and E2DH activities in the MCF-7 and MDA-MB-231 human breast cancer cell lines. TGFbeta1, IGF-I and IGF-II alone or in combination inhibited cell growth of both cell lines but no additive or synergistic effects were observed. The treatments significantly stimulated E1STS activity in the MCF-7 cell line, except for TGFbeta1 alone and TGFbeta1 and IGF-I in combination, where no effects were seen. Only TGFbeta1 and IGF-II acted synergistically to stimulate E1STS activity in the MCF-7 cells. There was no significant effect on E1STS activity in the MDA-MB-231 cells with any of the treatments. In the MCF-7 cells, TGFbeta1 and IGF-I, IGF-I and IGF-II, and TGFbeta1, IGF-I and IGF-II acted synergistically to stimulate the reductive E2DH activity, while only TGFbeta1, IGF-I and IGF-II synergistically stimulated the oxidative E2DH activity. There were no additive or synergistic effects on both oxidative and reductive E2DH activities in the MDA-MB-231 cells. In conclusion, TGFbeta1, IGF-I and IGF-II may have effects on oestrogen metabolism, especially in the MCF-7 cell line where they stimulated the conversion of E1S to E1 and E1 to E2 and, thus, may have roles to play in the development of breast cancer.

BACKGROUND

This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability.

METHODS

Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted 'blind' of the randomized drug treatment.

RESULTS

Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%, respectively, P = 0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events.

CONCLUSIONS

Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.

The invasion of melanoma is complex and multi-staged and involves changes in both cell/extracellular matrix (ECM) and cell/cell interactions. Female steroids and alpha-MSH have also been reported to influence metastatic melanoma progression, but their mechanisms of action are unknown. Accordingly, our aim was to establish in vitro models to examine (a) the influence of sex steroids and alpha-melanocyte-stimulating hormone (alpha-MSH) on tumour invasion and the influence of (b) ECM proteins and (c) adjacent cells on melanoma invasion. In the first model, melanoma cell invasion through fibronectin over 20 hr under serum-free conditions was used to investigate the effects of 17beta-oestradiol and oestrone on the invasion of human melanoma cell lines, A375-SM and HBL. A375-SM, but not HBL cells, proved very susceptible to inhibition by female steroids. However, invasion of the HBL line was inhibited by alpha-MSH. Using the second model of reconstructed human skin based on de-epidermised acellular dermis, we found that the HBL cells on their own failed to invade into the dermis (irrespective of the presence or absence of the basement membrane). However, there was a significant synergistic interaction between keratinocytes, fibroblasts and HBL cells, such that a modest invasion of HBLs into the dermis was seen within 2 weeks when other skin cells were present. In contrast, A375-SM cells showed a significant ability to invade the dermis in the absence of other cells, with less invasion when other skin cells were present. In summary, these models have provided new information on the extent to which melanoma cell invasion is sensitive to oestrogenic steroids and to alpha-MSH and to interaction, not only with adjacent skin cells but also to the presence of basement membrane antigens.

The occurrence of the main steroid hormones (oestrone, 17alpha-oestradiol, 17beta-oestradiol, 17alpha-testosterone, 17beta-testosterone, dehydroepiandrosterone, 4-androstenedione), especially in milk and eggs, was investigated. An analytical method based on GC-MS/MS was developed for steroid measurement at an ultra-trace level in food products. The limits of detection for oestrogens were about 5 and 30 ng kg(-1) in milk and eggs, respectively. For androgens, the limits of detection were around 10 and 50 ng kg(-1) in milk and eggs, respectively. The method was applied to milk and egg samples collected in a French supermarket. In milk, oestrone was found at levels between 100 and 300 ng l(-1), while 17beta-oestradiol levels were estimated to be near 20 ng l(-1). 17alpha-testosterone was found to be from 50 ng l(-1) in skimmed milk to 85 ng l(-1) in whole milk. In egg samples, oestrone and 17beta-oestradiol were found at 1.5 and 0.9 microg kg(-1), respectively, while 17alpha-oestradiol was found to be in lower concentrations (i.e. around 0.55 microg kg(-1)). Regarding androgens, 17alpha- and 17beta-testosterone were estimated at 1.9 and 1.3 microg kg(-1), respectively. These results represent a first attempt to estimate the food exposure to steroid hormones. In the future, the collection of additional data should permit the comparison between this exogenous dietary intake and the daily endogenous production in pre-pubertal children as a basis of risk assessment regarding endocrine disruption linked to these molecules for this critical population.

Qualitative and quantitative differences of purified hepatic 3 alpha-hydroxysteroid UDP-glucuronosyltransferase were investigated in Wistar and Sprague-Dawley rats. Individual differences in the glucuronidation rate of androsterone and chenodeoxycholic acid were observed in hepatic microsomal fractions from Wistar but not Sprague-Dawley rats. No individual variation was observed in the glucuronidation of testosterone, p-nitrophenol or oestrone. The 3 alpha-hydroxysteroid UDP-glucuronosyltransferases from livers of Wistar and Sprague-Dawley rats were isolated and highly purified by using Chromatofocusing and affinity chromatography. The amount of 3 alpha-hydroxysteroid UDP-glucuronosyltransferase in the liver of Wistar rats exhibiting low rates for androsterone glucuronidation is about 10% or less than that found in hepatic microsomal fractions obtained from Wistar rats having high rates for androsterone glucuronidation. The apparent Km for androsterone with purified 3 alpha-hydroxysteroid UDP-glucuronosyltransferase from Wistar rats with high glucuronidation activity (6 microM) was not different from that observed for the enzyme purified from Sprague-Dawley animals, whereas that for the enzyme purified from Wistar rats with low glucuronidation activity was substantially higher (120 microM). Despite the differences in apparent Km values for androsterone, the apparent Km for UDP-glucuronic acid (0.3 mM) was not different in the different populations of rats.

The production rate (PR) values of delta 4-androstenedione (A), testosterone (T), oestrone (E1) and oestradiol (E2) have been determined in a large group of post-menopausal women following constant infusions of radiolabelled hormones and radioimmunoassay of endogenous steroid concentration. The mean +/- SE age was 64 +/- 2 yr, ranging from 46 to 91 yr and the mean +/- SE weight was 144 +/- 4 lb. When the PR values were related to age by linear regression analysis no significant correlation could be found for PRA, PRT or PRE1 and the age of the subjects. There was, however, a significant correlation between PRE2 and age. There was a significant correlation between the PR values for each of the four steroids and the weights and body surface areas of the subjects. In addition, PRA correlated directly with both PRT and PRE1 in these subjects in which both PR values were measured. The PR values for each steroid were significantly smaller in the post-menopausal women compared to the mean PR values of a large group of pre-menopausal women. We conclude that age, per se, does not appear to influence the PR values for A, T and E1 but does for E2. The subjects weight, however, has a major influence for the PR values of all four steroids.

The interconversion of oestrone and oestradiol, androstenedione and testosterone, and dehydroepiandrosterone and 5-androstene-3 beta,17 beta-diol in mammalian tissues is catalysed by 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). To identify tissue sites of 17 beta-HSOR activity in the human fetus, microsomal fractions from 15 different fetal tissues obtained from first and second trimester pregnancies were used for evaluation of enzymatic activity by use of [17 alpha-3H] oestradiol as the substrate and NADP+ as the co-factor. With these reagents, the enzyme-catalysed reaction led to the production of both non-radiolabelled oestrone and NADP3H in equimolar amounts; the radioactivity associated with NADP3H was used to quantify 17 beta-HSOR activity. Activity of 17 beta-HSOR was present in microsomes of all the tissues evaluated. The specific activity of the enzyme was highest in liver and placental microsomes. The interconversion of oestradiol and oestrone in microsomal fractions of nine different fetal tissues was studied by the use of substrates labelled with tritium at stable nuclear positions ([6,7-3H]oestradiol and [6,7-3H]oestrone). The products, [3H]oestrone and [3H]oestradiol, were quantified by the use of established techniques; other metabolites formed in these incubations were not identified. The reductive pathway of metabolism (oestrone to oestradiol) appeared to be favoured in microsomal fractions prepared from placenta, fetal zone of the adrenal gland and, possibly, lung. The oxidative pathway (oestradiol to oestrone) appeared to be favoured in microsomes prepared from liver, intestine, stomach, kidney, brain and heart. 17 beta-HSOR activity in fetal liver also was assessed by the use of fresh and frozen-thawed tissue, homogenate, subcellular fractions, and, also, in primary hepatocytes maintained in culture; the specific activity of the enzyme was highest in the microsomal fraction of liver tissue and 17 beta-HSOR activity in liver microsomes was linear with time of incubation up to 1 h. In hepatocytes, the enzymatic activity was linear with time of incubation up to 2 h and with cell number up to 2.5 x 10(5) cells/ml; the apparent Michaelis constant of hepatocyte 17 beta-HSOR for oestradiol was 11 mumol/l. The specific activity of 17 beta-HSOR did not change after pretreatment of hepatocytes for 24 h with insulin, glucagon or dexamethasone.

Urine was collected from 6 female cotton-top tamarins (Saguinus o. oedipus) and urinary oestrone and oestradiol concentrations were measured by radioimmunoassay. Oestrone was excreted at 50-fold higher concentrations than oestradiol. Five females showed patterns of regular oestrone cyclicity, with a mean peak-to-peak oestrone cycle of 23.6 +/- 1.2 days. Levels of oestradiol tended to vary with levels of oestrone excretion, but peaks were less pronounced and more variable. The sixth female, diagnosed as having 'wasting marmoset syndrome', had very low levels of excreted oestrogens, suggesting infertility. We suggest that urinary oestrone provides a good index to ovarian cyclicity in female cotton-top tamarins.

Human genital skin fibroblasts were used to study aromatase activity by analysing the [3H]H2O released as [1 beta-3H]androstenedione is converted to oestrone. 4-Hydroxyandrostenedione was shown to be a competitive inhibitor of this aromatase activity, the concentration of inhibitor producing 50% inhibition being 1.29 nmol/l. Dexamethasone stimulated the enzyme complex in a dose-dependent manner with half-maximal stimulation at 11.5 nmol/l. A peak of induction occurred after 16 h of preincubation. Measurement of aromatase activity in normal cell strains provided a normal range for the Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of 6.72 +/- 0.54 nmol/l and 215.3 +/- 33.9 fmol/mg protein per h (mean +/- S.E.M., n = 20) respectively. Km values obtained for partial and complete androgen insensitivity syndrome (PAIS and CAIS) patient cell strains were all within the normal range. The mean Vmax +/- S.E.M. in cell strains from patients with PAIS (n = 13) and CAIS (n = 11) were 127.4 +/- 19.2 and 54.8 +/- 19.3 fmol/mg protein per h respectively. Vmax values for patients with CAIS were significantly (P less than 0.001) lower than normal subjects. This suggests that aromatase expression in genital skin fibroblasts is androgen-dependent.

In situ oestrogen synthesis makes an important contribution to the high oestrogen concentration found in breast tumours. Cytokines, including interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), have been shown to regulate aromatase activity in fibroblasts derived from normal and malignant breast tissues. In the present study, the ability of other cytokines in the IL-6 superfamily (IL-11 and oncostatin M) to stimulate aromatase activity has been confirmed. Formation of oestrone via the oestrone sulphatase pathway may be the major route of tumour oestrogen synthesis and in the present study TNF alpha was found to stimulate sulphatase activity in a dose-dependent manner. Human serum albumin was also found to be a potent stimulator of oestrone sulphatase activity. Its stimulatory effect was blocked by basic fibroblast growth factor, but not by several other growth factors tested. Insight into the regulation of oestrogen synthesis in breast tumours should enable the development of novel compounds to inhibit oestrogen synthesis in women with breast cancer.

The effect of one week of controlled fasting (31 of fluid containing 50 g of carbohydrate/day) upon the serum levels of hormones, sex hormone binding globulin, and albumin was studied in healthy subjects. Fasting caused decreased levels of prolactin and T3, no changes in the levels of TSH, FSH, LH, dehydroepiandrosterone, 4-androstene-3, 17-dione, total oestrone, and total testosterone, and increased levels of cortisol, dehydroepiandrosterone sulphate and albumin. A significant positive correlation was found between albumin and dehydroepiandrosterone sulphate. Fasting rapidly increased the levels of sex hormone binding globulin and decreased the percentage of free testosterone and the calculated free testosterone level in both sexes. A decreased metabolic clearance of certain steroids (cortisol, dehydroepiandrosterone sulphate) owing to an increased protein binding may be one of the endocrine consequences of fasting. An increased protein binding of testosterone may be outweighed by a decreased gonadal production, thus resulting in an unchanged total testosterone level. The increased sex hormone binding globulin level could not be explained by changes in gonadal and thyroid hormones.

The aim of this study was to examine the endocrinological response (15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate) of pregnant ewes which were constantly treated with flunixin meglumine (FM) after infection with Toxoplasma gondii. Seven Swedish Peltsheep ewes were dosed orally with 2,000 T. gondii oocysts at 90.5 (82-94) days of pregnancy. The ewes were treated with FM, 1 mg/kg, intramuscularly twice a day, starting one day before infection until the end of the gestation period. Further three ewes were treated with FM alone during the corresponding time of pregnancy. Another four ewes were used as uninfected and untreated controls. All infected ewes developed antibodies to T. gondii and aborted, but the FM treated control group and the non-treated control group, which remained seronegative, delivered the lambs in the normal gestation range. No early abortions (less than 10 days after infection) were seen in the infected group. The endocrinological changes reflected the pathological changes in the uterus and foetuses. FM could neither completely inhibit prostaglandin release during abortion nor the physiological change of the hormone before parturition even though it depressed prostaglandin release before abortion or parturition and eliminated fever. The infectious process caused by the organism was probably not affected. FM treatment alone had no observed negative effects on pregnant ewes and their foetuses.

The purpose of this study was to monitor ovarian hormone function response to intense exercise and body weight changes in female athletes. Ovarian hormone function was evaluated in 12 female lightweight rowers and 10 age-height-weight matched sedentary controls. Ovarian hormone function was assessed during consecutive competition season and off season, by measurement of peak and average alternative day overnight urinary oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG) excretion. Competition season was associated with a 5.8 kg (9.3%) body weight loss in the lightweight rowers. Significantly lower competition season peak and average urinary excretion of PdG were found in the lightweight rowers compared with the controls. Lower competition season peak and average urinary excretion of E1G were also found in the lightweight rowers compared with the controls, but the difference did not reach significance. The number of rowing training hours was a significant determinant of peak PdG excretion in the rowers (R2 = 0.40; p<0.02). The seasonal suppression of PdG excretion was associated with degree of weight loss (R2 = 0.46; p<0.01). The competition related decrease in E1G and PdG excretion for the lightweight rowers was predominantly restored during the off season when exercise intensity and duration were decreased and body weight increased. These results showed a significant (p<0.05) reduction in progesterone metabolite excretion and a non-significant decrease in oestrone metabolite excretion associated with intensive competition season training loads and body weight reduction in female lightweight rowers.

Using the DMBA-induced mammary tumour as a model, the effect of hormone manipulation on steroid sulphurylation and on oxidative and reductive metabolism has been investigated. Oestradiol-17 beta, or oestradiol-17 beta + progesterone, administered to oophorectomized animals, had no effect on adenosine-3'-phosphate-5'-phosphosulphate formation in the tumours. Dehydroepiandrosterone sulphotransferase was also unaffected. A large increase in oestrogen sulphotransferase following administration of oestrogen + progesterone was observed in some but not all tumours, and the overall results were not statically significant. The major metabolities of dehydroepiandrosterone, by both human and carcinogen-induced rat mammary tumours in vitro, are 7-oxygenated derivatives. Oestrogen administration led to a significantly decreased production of total 7-oxygenated derivatives of dehydroepiandrosterone. Conversion to 5-androstene-3 beta, 17 beta-diol was unaffected by the hormones. The rate of formation of oestradiol-17 beta from oestrone was increased 5-fold in growing tumours from animals receiving oestrogen, or oestrogen + progesterone, compared to regressing tumours in oophorectomized control animals.

In order to study the effect of Toxoplasma infection on hormonal levels in pregnant ewes, twenty-eight Scottish Blackface ewes were dosed orally with Toxoplasma gondii oocytes at 91 +/- 1 days of gestation. Fifteen of these ewes were vaccinated with an experimental Toxoplasma iscom vaccine prior to inoculation. Further three ewes were used as non-infected controls. All challenged ewes became infected. Plasma was analysed for the content of 15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate. The endocrinological changes appeared to reflect the pathological changes in the uterus. Infected animals tended to show an increase in the levels of the prostaglandin metabolite between two and eleven days after challenge, followed by a decrease in progesterone and later also of oestrone sulphate levels. Following the initial phase, the pattern was more variable but related to the outcome of gestation. There was a marked tendency towards more normal endocrinological patterns in the vaccinated animals in comparison to unvaccinated challenged ones.

A radioimmunoassay technique for the simultaneous measurement of eight unconjugated steroids (progesterone, pregnenolone, dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, oestrone and oestradiol) in the peripheral plasma of human males is described. Determinations of these steroids and of immunoreactive FSH and LH were carried out on the plasma of twenty-one normal individuals and the levels were compared to those of eleven and ten males exhibiting oligospermia and azoospermia, respectively. Mean values and tolerance limits for each hormone, based on a lognormal distribution of individual values, are presented for all groups. Oligospermia was associated with a significant reduction in plasma dihydrotestosterone and testosterone levels. Azoospermic subjects also exhibited decreased dihydrotestosterone levels but a normal range of testosterone concentrations. Mean peripheral plasma levels of FSH were significantly elevated in both pathological groups and this was paralleled in the azoospermic men by increased concentrations of plasma LH.

One hundred and ten (110) healthy early post-menopausal women with mild subjective vasomotor symptoms (mean Kupperman index score 11) participated in a long-term, double-blind, placebo-controlled therapeutic trial. The effects of 2 hormone regimens were evaluated. Group I received percutaneous oestrogen therapy for 2 yr, opposed by oral micronized progesterone (200 mg) during the second year, while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate (CPA). The serum oestrogen concentrations differed markedly in the 2 treatment groups. In Group I the serum/oestrone/oestradiol ratio was 1 (comparable to the pre-menopausal value), but in group II the ratio was greater than 5. Despite the difference in the serum oestradiol and oestrone concentrations, the mean symptom scores were rapidly and similarly reduced in both treatment groups (P less than 0.001). They remained low throughout the study and were not significantly different from pre-menopausal values.

BACKGROUND

Steroid sulphatase (STS) is one of the steroid-metabolising enzymes involved in desulphating inactive steroid sulphates and oestrogen sulphotransferase (EST) sulphates active oestrogen. The roles of both STS and EST have not been examined in oestrogen-dependent non-small-cell lung cancer (NSCLC).

METHODS

We evaluated the immunoreactivity of STS and EST in NSCLC cases using immunohistochemistry. The function of STS and EST was further demonstrated using NSCLC cell lines.

RESULTS

The immunoreactivity of STS and EST was detected in 49.5% and 27.8% of NSCLC cases, respectively. The immunoreactivity of STS was significantly higher in female adenocarcinoma cases. The STS-positive NSCLCs were also significantly correlated in an inversed manner with tumour size and cell proliferation and tended to be associated with better clinical outcome. However, the immunoreactivity of EST was significantly correlated with intracellular oestradiol concentration. Results of in vitro analysis demonstrated that oestrone sulphate (E1-S) induced and pregnenolone sulphate (Preg-S) inhibited the proliferation in STS-expressing cell lines. The inhibition by Preg-S was reversed by a specific progesterone receptor blocker. Simultaneous addition of E1-S and Preg-S significantly suppressed the proliferation.

CONCLUSIONS

In NSCLC patients, STS is considered a good prognostic factor. Results of our present study also indicated the benefits of potential progesterone therapy for NSCLC patients.

In order to elucidate the mechanism of impaired LH secretion, 60 female patients with anorexia nervosa were investigated. A control group consisted of 14 women of the same age, examined in the follicular phase of the menstrual cycle. The serum LH, FSH, prolactin, TSH, testosterone, dihydrotestosterone, dehydroepiandrosterone, delta 4-androstenedione, oestrone, oestradiol, oestriol, progesterone, thyroxine, triiodothyronine, reverse T3 and serum sex hormone binding globulin (SHBG) concentrations were measured. The results showed a significant increase in serum dehydroepiandrosterone, testosterone, oestriol and reverse T3 concentrations. However, oestrone, oestradiol, progesterone, SHBG and triiodothyronine levels were significantly lower than those of the control group. The mean serum LH concentration in patients with anorexia nervosa before and after LRH stimulation was significantly lower than that in the control group, but FSH secretion in response to LRH was normal. All hormonal changes in anorexia nervosa disappeared after weight gain during cyproheptadine treatment. Dramatically increased dehydroepiandrosterone levels suggest that the high testosterone in women with anorexia nervosa is derived from adrenal rather than from gonadal steroids. There was no correlation between serum testosterone, dehydroepiandrosterone, oestriol and LH concentrations indicating that steroid hormone disturbances do not cause impaired LH release in anorexia nervosa.

The effect of Toxoplasma gondii inoculation on pregnancy and on endocrine foetal-placental function in pregnant goats was studied. Five susceptible goats were inoculated subcutaneously with T. gondii bradyzoites at 71 +/- 2 days of gestation. Another five goats were used as controls. Plasma was analysed for progesterone, oestrone sulphate and 15-ketodihydro-PGF2 alpha. The condition of the foetuses was monitored by real-time ultrasonography. All inoculated goats aborted or delivered stillborn or weak kids 54-73 days after inoculation. None of the goats showed signs of general disease. In cases of foetal death, the ultrasound examination revealed that death occurred between day 1 and 12 before abortion or birth. The appearance of the foetuses varied from fresh to mummified, depending on the number of days between foetal death and expulsion. All five goats became serologically positive to T. gondii after inoculation. None of the goats used as controls aborted, but one goat delivered one mummified and one weak kid for unknown reasons. In inoculated animals an increase in 15-ketodihydro-PGF2 alpha levels in plasma and a subsequent tendency to a decrease in oestrone sulphate levels were observed from about day 40 after inoculation and until abortion or birth. High levels of 15-ketodihydro-PGF2 alpha were seen after foetal death. High levels of 15-ketodihydro-PGF2 alpha were not always followed by a drop in progesterone levels. The mean level of progesterone was slightly decreased after inoculation and onwards. The pattern of progesterone levels around abortion in the inoculated goats was very similar to the pattern around parturition in the control goats. However, 15-ketodihydro-PGF2 alpha levels were higher both before and after abortion in inoculated goats than in control goats. The level of oestrone sulphate did not increase in the inoculated group before abortion in contrast to the level in goats which delivered healthy kids. The patterns of changes in levels of 15-ketodihydro-PGF2 alpha and oestrone sulphate in inoculated animals indicate that the endocrine foetal-placental function was disturbed in most of the inoculated goats, probably due to the injury caused by the establishment and development of T. gondii infection in the placenta and foetus.

We have observed that oestradiol concentrations in breast and endometrial tumours are relatively higher than oestrone, in contrast to peripheral tissues. Infusion of radiolabelled oestrogen also suggested there was a difference in metabolism between normal and tumour tissue. We have therefore looked for factors which could modulate tissue steroid metabolism and conclude that progesterone may influence aromatase, and that the adrenal androgens can inhibit oestradiol dehydrogenase activity. The latter mechanism, in particular, may be important in increasing tissue exposure to oestradiol.

OBJECTIVE

Based on the hypothesis that high-meat diets may increase breast cancer risk through hormonal pathways, the present analysis compared oestrogens in serum and urine by meat-eating status.

METHODS

Intervention with repeated measures.

METHODS

Two randomized soya trials (BEAN1 and BEAN2) among premenopausal healthy women.

METHODS

BEAN1 participants completed seven unannounced 24 h dietary recalls and donated five blood and urine samples over 2 years. BEAN2 women provided seven recalls and three samples over 13 months. Serum samples were analysed for oestrone (E₁) and oestradiol (E₂) using RIA. Nine oestrogen metabolites were measured in urine by LC-MS. Semi-vegetarians included women who reported consuming <30 g of red meat, poultry and fish daily, and pescatarians those who reported consuming <20 g of meat/poultry but >10 g of fish daily. All other women were classified as non-vegetarians. We applied mixed models to compute least-square means by vegetarian status adjusted for potential confounders.

RESULTS

The mean age of the 272 participants was 41·9 (SD 4·5) years. Serum E₁ (85 v. 100 pg/ml, P = 0·04) and E₂ (140 v. 154 pg/ml, P = 0·04) levels were lower in the thirty-seven semi-vegetarians than in the 235 non-vegetarians. The sum of the nine urinary oestrogen metabolites (183 v. 200 pmol/mg creatinine, P = 0·27) and the proportions of individual oestrogens and pathways did not differ by meat-eating status. Restricting the models to the samples collected during the luteal phase strengthened the associations.

CONCLUSIONS

Given the limitations of the study, the lower levels of serum oestrogens in semi-vegetarians than non-vegetarians need confirmation in larger populations.

OBJECTIVE

Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors.

METHODS

Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005.

METHODS

A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships.

METHODS

Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status.

RESULTS

Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48).

CONCLUSIONS

Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.