Higher Estradiol Concentrations Research Articles

Red light is necessary to activate the reproductive axis in chickens independently of the retina of the eye

Photoperiod is essential in manipulating sexual maturity and reproductive performance in avian species. Light can be perceived by photoreceptors in the retina of the eye, pineal gland, and hypothalamus. However, the relative sensitivity and specificity of each organ to wavelength, and consequently the physiological effects, may differ. The purpose of this experiment was to test the impacts of light wavelengths on reproduction, growth, and stress in laying hens maintained in cages and to determine whether the retina of the eye is necessary. Individual cages in 3 optically isolated sections of a single room were equipped with LED strips providing either pure green, pure red or white light (red, green, and blue) set to 10 lx (hens levels). The involvement of the retina on mediating the effects of light wavelength was assessed by using a naturally blind line (Smoky Joe) of chickens. Red and white lights resulted in higher estradiol concentrations after photostimulation, indicating stronger ovarian activation, which translated into a significantly lower age at first egg when compared with the green light. Similarly, hens maintained under red and white lights had a longer and higher peak production and higher cumulative egg number than hens under green light. No significant difference in BW gain was observed until sexual maturation. However, from 23 wk of age onward, birds exposed to green light showed higher body growth, which may be the result of their lower egg production. Although corticosterone levels were higher at 20 wk of age in hens under red light, concentrations were below levels that can be considered indicative of stress. Because no significant differences were observed between blind and sighted birds maintained under red and white light, the retina of the eye did not participate in the activation of reproduction. In summary, red light was required to stimulate the reproductive axis whereas green light was ineffective, and the effects of stimulatory wavelengths do not appear to require a functional retina of the eye.

Endogenous sex hormones and risk of venous thromboembolism in women and men

Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations are also associated with risk of VTE is unknown. We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population. We studied 4658 women, not receiving exogenous estrogen, and 4673 men from the 1981-1983 Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]) during a follow-up of 21years (range, 0.02-32years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time-dependent covariates and corrected for regression dilution bias. Multifactorially adjusted hazard ratios of VTE for individuals with estradiol levels >75th vs. ≤25th percentile were 0.84 (95%CI, 0.25-2.85), 1.05 (0.53-2.08) and 1.05 (0.03-35.13) for pre- and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64 (0.03-12.32), 1.11 (0.66-1.86) and 1.30 (0.62-2.73). In addition, no associations were observed between extreme hormone percentiles (>95th vs. ≤75th) and risk of DVT, PE or recurrent VTE. This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE.

Apoptotic Effects of High Estradiol Concentrations on Endometrial Glandular Cells

High serum estradiol (E2) concentrations result in adverse reproductive outcome in in vitro fertilization cycles, and the detrimental effects are probably due to impaired endometrial receptivity. Endometrial glandular cells (EGCs) are the cells that embryos first interact with during implantation. Our objective is to examine the in vitro EGC alterations after high E2 treatment. This was a prospective study. The study was conducted at a tertiary university hospital. Six women in the follicular phase participated in the study. EGCs were purified from human endometrium and cultured with different concentrations (0, 10(-9), 10(-8), 10(-7), 10(-5), 10(-4) M) of E2. EGC apoptosis and its underlying mechanism were measured. In vitro BeWo spheroid-EGC implantation assay demonstrated that the stimulation with 10(-5) and 10(-4) M E2 for 2 days decreased embryo implantation potentials. Presence of apoptotic bodies and DNA fragmentation and an increased percentage of sub-G1 phase were found in EGCs treated with high E2 concentrations. The high E2-treated EGCs could be rescued from apoptosis after the addition of estrogen receptor antagonist ICI 182 780. Western blot revealed increased inhibitory-κB (IκB)-α expression and decreased nuclear factor-κB (NF-κB) expression in high E2-treated EGCs, and NF-κB binding site-driven luciferase activity was decreased as well. When EGCs were pretreated with IκB-α small interfering RNA, high E2-induced B cell lymphoma 2 (Bcl-2) down-regulation did not occur and EGCs apoptosis was reduced. Bcl-2 overexpression also rescued high E2-induced EGCs from apoptosis. High E2 concentrations induced EGCs apoptosis through enhancing IκB-α expression, which in turn suppressed NF-κB expression. The decreased nuclear NF-κB subsequently inhibited Bcl-2 expression and accordingly enhanced EGC apoptosis.

Steroid hormones and pain-related brain activity and functional connectivity in healthy women

BackgroundDespite strong clinical evidence that painful symptoms of many chronic conditions fluctuate with the menstrual cycle, studies investigating the effects of the menstrual cycle on pain perception are inconclusive. Few studies have investigated the effect of hormonal concentrations on response to pain. However, brain imaging studies linking steroid hormones to the central response to negative emotional stimuli have shown changes in activity in, and connectivity between, specific brain regions. We aimed to investigate whether various hormones could alter behavioural and central measures of the response to noxious stimulation, specifically to assess the analgesic properties of these hormones and identify mechanisms of action. Methods24 healthy women were recruited, 12 with natural menstrual cycles and 12 who were using the combined oral contraceptive pill (COCP). At three time-points in their menstrual cycle women completed questionnaires, provided serum, and underwent functional MRI scans with an individually calibrated, moderately painful, noxious thermal stimulus to the arm. The time-points for assessment were chosen to maximise endogenous hormonal variation, and a COCP group was included to investigate the effect of a very low oestradiol concentration. The effects of oestradiol, progesterone, and testosterone were assessed separately in very low, low, and high oestradiol states. Behavioural data were analysed with SPSS using linear mixed models and Pearson's partial correlations to control for repeated measures. Functional MRI data were analysed with FMRIB Expert Analysis Tool. FindingsCortisol was negatively related to pain intensity ratings (r=−0·382, p=0·031) and positively correlated with activity in brain regions known to highly express glucocorticoid receptors (Z>2·3, p<0·05). It was also associated with altered connectivity between regions of known pain inhibitory networks. Testosterone was antinociceptive at low and very low oestradiol concentrations but pronociceptive at high oestradiol concentrations. At low or very low oestradiol concentrations, testosterone appeared to act by mediating activity in the descending pain inhibitory system. Progesterone reduced pain unpleasantness specifically (r=−0·48, p=0·044), and in combination with oestradiol was related to both activity and functional connectivity within the emotional regulation network. InterpretationSteroid hormones appear to be mostly antinociceptive, with specific hormones affecting distinct components of the pain experience. These effects seem to be exerted by known pain modulatory mechanisms. These findings suggest that iatrogenic alteration of the hormonal state (eg, by use of contraceptives) could predispose to the development of chronic pain conditions. However, such effects could be harnessed to optimise analgesia for women being treated for chronic pain conditions. FundingPfizer.

Impact of BMI on serum estradiol and bone turnover markers in postmenopausal women with hormone-sensitive early breast cancer treated with anastrozole

Obesity increases the risk of all-cause and breast cancer mortality. As obese patients have higher levels of aromatase enzyme activity, conflicting results on the effect of body mass index (BMI) of a standard dose aromatase inhibitor on estradiol depletion have been reported. We prospectively investigated the effect of BMI on the efficacy of anastrozole in 70 postmenopausal women with early, ER-positive breast cancer to decrease serum estradiol assessed by a high-sensitive assay with a sensitivity limit of 5pg/ml over 24 months. Additionally, we examined the changes of bone markers expecting an inverse relationship. Overall, estradiol decreased from 12.6pg/ml (SD=5.4) to 4.0pg/ml (SD=5.6) over 24 months (p<0.001). In contrast, carboxy-terminal collagen crosslinks (CTX) and serum aminoterminal propeptide of type I collagen (PINP) increased from 0.26ng/ml (SD=0.18) to 0.40ng/ml (SD=0.24) and 41.5ng/ml (SD=19.7) to 59.1ng/ml (SD=29.1) (p<0.0001 for both). Baseline estradiol comprised significant differences comparing normal weight with overweight (p<0.01) or obese patients (p<0.001). After 12 and 24 months, overweight and obese patients showed a slightly, but insignificantly higher concentrations of estradiol compared to normal weight subjects. We found differences of CTX in comparison between normal weight and obese patients (0.33 vs. 0.21ng/ml; p<0.023) at baseline. At 12 and 24months, there was a significant BMI-independent increase in CTX. Estradiol concentrations in postmenopausal women with early, ER-positive breast cancer on anastrozole were significantly different in normal weight versus overweight or obese patients at baseline, but not at 12 and 24 months. CTX and PINP present a notable increase in the first 12months of anastrozole treatment, stabilizing thereafter.

Sexual development in prepubertal obese boys: a 4-year longitudinal study

The objective of the study was to evaluate whether or not sexual development differs between boys with prepubertal obesity and boys of normal weight. We enrolled healthy obese and normoweight schoolboys from Shenyang City, Liaoning, China. Eligible boys were at Tanner stage 1 and 8 years of age at baseline. We measured testosterone and estradiol concentrations in the saliva and assessed auxology annually for 4 years. In all 56 obese and 56 normoweight boys, the height, weight, body composition, and sex organ volume increased with age. The percentages of body fat, fat mass, and lean mass were all higher in obese than in normoweight boys. The mean testicular volume was smaller in obese boys than in normoweight boys. The sex hormone concentrations increased with age, except for testosterone in obese boys in year 3 of follow-up. In year 4, estradiol concentrations were significantly higher in obese boys than in normoweight boys. Excessive adiposity in prepubertal boys might affect testicular volume, possibly because of high estradiol and low testosterone concentrations.

Occurrence and characteristics of residual follicles formed after transvaginal ultrasound-guided follicle aspiration in cattle

Ultrasound-guided transvaginal follicle aspiration is used to recover cumulus-oocyte complexes (for IVF) and to synchronize follicular wave emergence (ablation of dominant follicle). Although aspirated follicles are generally supposed to undergo immediate atresia, there are indications that they may remain active. The objective was to evaluate the occurrence and characteristics of residual follicles (RF) after transvaginal follicle aspiration in cattle. Ovarian follicular wave emergence was synchronized in Holstein cows (N = 13) in the presence (groups 1 and 3) or absence (groups 2 and 4) of norgestomet implants. The largest follicle was aspirated at a diameter of 8 mm (groups 1 and 2) or 12 mm (groups 3 and 4). Ovarian follicles were visualized (transrectal ultrasonography) every 12 h after wave emergence. Follicular fluid samples were collected from the largest follicle and from the ensuing RF and concentrations of estradiol and progesterone were determined. After aspiration, 73.2% (52/71) of the follicles refilled with fluid, and a new antrum was detected 12 to 24 h later. Norgestomet did not affect (P > 0.05) RF occurrence or diameter, but in RF from group 4, concentrations of estradiol decreased (−530.7 ± 133.9 ng/mL; P < 0.01) whereas progesterone increased (+429.6 ± 171.7 ng/mL; P < 0.05) relative to preaspiration. In RF, there were three steroidogenesis patterns: (1) high estradiol concentration and high estradiol:progesterone ratio (estradiol-active RF); (2) low estradiol, but high progesterone concentrations (luteinized RF); and (3) low estradiol and low progesterone concentrations (inactive RF). Estradiol-active RF were more likely (P < 0.05) from follicles with high estradiol concentrations (regardless of diameter). In conclusion, fluid-filled structures (RF) with variable steroid production patterns are frequently formed after ultrasound-guided follicle aspiration. The occurrence and features of these RF depended on the diameter and status of these follicles before aspiration.

The pattern of cervical penetration and the effect of topical treatment with prostaglandin and/or FSH and oxytocin on the depth of cervical penetration in the ewe during the peri-ovulatory period

Artificial insemination in sheep has two major limiting factors: the poor quality of frozen-thawed ram semen and the convoluted anatomy of the sheep cervix that does not allow transcervical passage of an inseminating catheter. It has been demonstrated that in the ewe during estrus, there is a degree of cervical relaxation mediated by ovarian and possibly gonadotrohic hormones, and we set out to investigate factors that might enhance cervical relaxation. Five experiments were conducted on ewes of different breeds to determine: 1) the pattern of cervical penetration during the periovulatory period in ewes of several breeds (Welsh Mountain, Île-de-France, Vendéenne, Romanov and Sarda); 2) the effect of the “ram effect” a socio-sexual stimulus, on cervical penetration; and 3) the effects of the intracervical administration of follicle-stimulating hormone (FSH), oxytocin and a prostaglandin E agonist (misoprostol) on the depth of cervical penetration during the periovulatory period. The results showed that during the periovulatory period in all breeds examined, there was increased penetration of the cervical canal (P < 0.05) by an inseminating catheter. Cervical penetration increased to a maximum 54 h after the removal of progestagen sponges and then gradually declined. Furthermore, the depth of cervical penetration but not its pattern, was affected (P < 0.05) by the breed of ewe. The maximum depth of cervical penetration was lower (P < 0.05) in the Vendéenne breed compared to the Île-de-France and Romanov breeds, which did not differ from one another. In the presence of rams, the depth of cervical penetration was increased at 48 and 54 h after removal of sponges (P < 0.05) and reduced at 72 h (P < 0.05). The local administration of hormones FSH, misoprostol (a PGE agonist) and oxytocin alone and in various combinations did not have any significant effect on the depth of cervical penetration during the periovulatory period. In conclusion, the natural relaxation of the cervix observed in ewes of several breeds occurs at a time during estrus, 54 h after the removal of progestagen sponges, which is the most suitable for artificial insemination. The effect was enhanced by the presence of a ram but not by the local intracervical administration of FSH, misoprostol and oxytocin even though oxytocin and PGE2 are involved in cervical function. The time of maximum cervical penetration in the preovulatory period (54 h) coincides with high LH and estradiol concentrations suggesting they might be responsible for the relaxation of the cervix probably through an oxytocin-PGE mediated pathway.

Atrazine and PCB 153 and their effects on the proteome of subcellular fractions of human MCF-7 cells

Several man-made organic pollutants including polychlorinated biphenyls (PCBs) and several pesticides may exhibit endocrine disrupting (ED) properties. These ED molecules can be comparatively persistent in the environment, and have shown to perturb hormonal activity and several physiological functions. The objective of this investigation was to study the impact of PCB 153 and atrazine on human MCF-7 cells, and to search for marker proteins of their exposure. Cells were exposed to environmentally high but relevant concentrations of atrazine (200ppb), PCB 153 (500ppb), 17-β estradiol (positive control, 10nM) and DMSO (0.1%, negative control) for t=36h (n=3 replicates/exposure group). Proteins from cell membrane and cytosol were isolated, and studied by 2D-DiGE. Differentially regulated proteins were trypsin-digested and identified by MALDI-ToF-ToF and NCBInr database. A total of 36 differentially regulated proteins (>|1.5| fold change, P<0.05) were identified in the membrane fraction and 22 in the cytosol, and were mainly involved in cell structure and in stress response, but also in xenobiotic metabolism. 67% (membrane) and 50% (cytosol) of differentially regulated proteins were more abundant following atrazine exposure whereas nearly 100% (membrane) and 45% (cytosol) were less abundant following PCB 153 exposure. Western blots of selected proteins (HSBP1, FKBP4, STMN1) confirmed 2D-DiGE results. This study emphasizes the numerous potential effects that ED compounds could have on exposed humans.

The effects of letrozole on ovarian stimulation for fertility preservation in cancer-affected women

Survival rates for fertile women with cancer have increased significantly, lending importance to considering the possibility of motherhood after cancer. This study was a retrospective analysis of a prospective database comparing two groups of patients who underwent fertility preservation after being diagnosed with either breast cancer or a non-hormone-dependent cancer between 2009 and 2011. Nineteen oncology patients were included in the study. The objective was to assess the efficacy of ovarian stimulation with aromatase inhibitors versus a standard antagonist protocol. This study sought to quantify oestradiol concentrations in patients receiving letrozole and to determine the length of time between diagnosis of malignancy and onset of fertility preservation. Number of mature oocytes retrieved in the non-hormone-dependent cancer group was comparable to that in the breast cancer group (15.4±8.19 versus 16.3±7.31). Oestradiol concentrations were higher for patients with non-hormone-dependent cancer (1666.4±739.42pg/ml versus 829±551.11pg/ml, P=0.006). There were no differences between the groups in the length of time between diagnosis and fertility preservation (17.4±4.93 versus 16.4±1.74days). Oestradiol concentrations of breast cancer patients on the letrozole protocol remained much lower than those of patients on the antagonist protocol.The survival rates for fertile women with cancer have increased significantly, lending importance to considering the possibility of motherhood after cancer. In our study, we compared two groups of patients with cancer: a group with breast cancer, which is hormone dependent and is the most common type of cancer in women, and a group of non-hormone-dependent cancer patients. We compared the efficacy of two protocols in a retrospective analysis of a prospective database. In the patients with breast cancer, we used the protocol from the Controlled Ovarian Stimulation Treatment with Letrozole Supplementation Study (COST-LESS), modified to avoid the high concentrations of oestradiol to prevent the risks of the increase in hormone-dependent cancer. In the other group, we used the usual antagonist protocol. No difference was observed between the two groups in terms of the numbers of mature oocytes retrieved or in the time taken to complete the stimulation. The oestradiol concentrations of the breast cancer patients on the modified COST-LESS protocol remained much lower than those of the patients on the antagonist protocol, which is beneficial for preventing tumour growth in patients with hormone-dependent breast cancer. In addition, healthcare providers should inform their oncology patients of their options at the time of diagnosis and urge them not to delay initiating fertility preservation.

Effect of HCG-day serum progesterone and oestradiol concentrations on pregnancy outcomes in GnRH agonist cycles

This study analysed the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34nmol/l and oestradiol<19,124pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, group 4 had lower clinical pregnancy and live birth rates as well as the highest ectopic pregnancy rate (29.15% versus 45.91%; 18.67% versus 34.34%; 18.10% versus 5.82%; P<0.05). Group 3 had lower clinical pregnancy and live birth rates per embryo-transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively; P<0.05). Clinical pregnancy rates were similar in frozen–thawed embryo transfers (FET) among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. High serum oestradiol concentration on HCG day did not affect the IVF pregnancy outcome. In combination with the elevated progesterone, high oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes.The aim of this study was to analyse the relationship between serum progesterone/oestradiol concentrations and IVF pregnancy outcomes in gonadotrophin-releasing hormone agonist protocols. A total of 2921 infertile women undergoing IVF were assigned to four groups according to their serum progesterone and oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration: group 1 (control) progesterone<3.34nmol/l and oestradiol<19,124pmol/l; group 2 (high oestradiol); group 3 (high progesterone); group 4 (high progesterone and high oestradiol). Compared with group 1, patients in group 4 had lower clinical pregnancy (29.15% versus 45.91%) and live birth rates (18.67% versus 34.34%) as well as the highest ectopic pregnancy rate (18.1% versus 5.82%) (all P<0.05). Those in group 3 had lower clinical pregnancy and live birth rates per embryo transfer cycle (29.78% versus 45.91%; 20.28% versus 34.34%, respectively, P<0.05). Embryo quality appeared to be unaffected since similar clinical pregnancy rates in frozen–thawed embryo transfer (FET) cycles among the four groups. In conclusion, elevated progesterone was detrimental to live birth rates. A high serum oestradiol concentration on the day of HCG administration did not affect the IVF pregnancy outcome. In combination with the elevated progesterone and oestradiol concentrations had a potential negative effect. For these patients, FET should be suggested to improve the pregnancy outcomes.

Leukophilia during maturation of the leopard grouper Mycteroperca rosacea

In spring, peripheral blood of mature-ripe female leopard groupers showed leukophilia after an increase of lymphocytes and thrombocytes, followed by a differential increase of monocytes and granulocytes. In mature-ripe males, granulophilia and thrombophilia were evident. Leukocytes were distinguishable in some ovarian blood vessels where post-ovulatory follicles were present. These observations suggest coordination of endocrine-immune activity, where, after one spawning event, leukocytes infiltrate the gonad tissue from the peripheral blood to aid with immune surveillance and phagocyte activity, while a feedback of sex steroids and vitellogenesis occurs in preparation for the next spawning. An abundance of leukocytes may also aid in gonad reabsorption during post-spawning. Leukophilia coincided with high plasma concentrations of oestradiol and testosterone, which together with leukocytes, decreased greatly in immature-active groupers in summer. Blood cell counts, erythroblasts, and haematocrit of mature-ripe groupers in spring were significantly lower than immature-active groupers in summer, suggesting mild anorexia induced by reproductive behaviour.

Feminizing Adrenal Carcinoma Presenting with Heart Failure and Ventricular Tachycardia

We present a case of feminizing adrenal carcinoma with severe elevation in serum estradiol and otherwise unexplained congestive heart failure with ventricular arrhythmia and review the literature on feminizing adrenal tumors and the potential relationship between estrogen and cardiac problems. A 54-year-old man presented with congestive heart failure and ventricular arrhythmia. Imaging revealed a large adrenal mass. Hormonal evaluation revealed a very high serum level of estradiol, elevated DHEA-sulfate and androstenedione, and lack of cortisol suppression on a low-dose overnight dexamethasone suppression test. The patient underwent a left adrenalectomy with subsequent normalization of serum estradiol. Surgical pathology examination established adrenocortical carcinoma MacFarlane stage II. Upon 15-month followup, the patient continued to have a normal serum estradiol level, his cardiac function was significantly improved, and he had no further episodes of ventricular arrhythmia. To the best of our knowledge, the serum estradiol level that was detected in our case is the highest that has been reported. Further, we hypothesize that the very high serum concentration of estradiol in our case may have played a role in his cardiac presentation with congestive heart failure and arrhythmia, particularly as these problems resolved with normalization of his serum estradiol level.

P4-02-12: Plasma Estradiol Levels and Degree of Estrogen Receptor Positivity by Image Analysis in a Large Cohort of Breast Cancer Cases: Results from the Nurses' Health Study.

Abstract Background Breast cancer risk is strongly associated with endogenous reproductive hormones. There is also good evidence to suggest that endogenous estradiol levels are more strongly associated with the development of estrogen receptor (ER) positive breast cancers than with ER negative cancers. However, the degree of ER positivity in those cancers that develop is not yet established. Therefore, we sought to evaluate the proportion and intensity of tumor cells demonstrating ER positivity using image analysis in a large cohort of breast cancers for which we also had plasma estradiol levels. Design: Tissue microarray (TMA) sections of breast cancers from women enrolled in the Nurses’ Health Study were immunostained for ER (1D5, Dako Corporation, Carpinteria, CA). Slides were then scanned using the ScanScope slide scanning system (Aperio Technologies Inc., Vista, CA) and ER staining was assessed for both intensity and percent of nuclei staining positively using a specific algorithm, Nuclear v9, which evaluates nuclear size, intensity, roundness, curvature, compactness, and elongation. Plasma samples were collected prior to the date of diagnosis for all women in the study and estradiol levels were determined by radioimmunoassay following extraction and celite column chromatography. Result: Image analysis data for ER was available for 691 breast cancers. The mean percent of tumor cell positivity was approximately uniformly distributed, with a mean of 44.5%, (median=41.3%, max=99.6%). The proportion of tumor cells staining for ER from the TMA cores was positively associated with patient age (p&amp;lt;0.0001), and postmenopausal status (p=0.008), while inversely associated with tumor grade (p&amp;lt;0.0001). Among women with image analysis data for ER, plasma estradiol data were also available for 320 postmenopausal women. Estrogen receptor positivity (by proportion or intensity) did not vary according to plasma estradiol levels (p=0.17). Conclusion: While high concentrations of plasma estradiol are more strongly associated with the development of estrogen receptor positive breast cancer versus estrogen receptor negative cancers, the degree of estrogen receptor positivity in the breast cancers that develop is not influenced by this variable. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-12.

Blastocyst-stage versus cleavage-stage embryo transfer in women with high oestradiol concentrations: randomized controlled trial

This prospective, randomized, controlled trial tested the hypothesis that delaying embryo transfer to the blastocyst stage can increase the probability of clinical pregnancy and live birth in women with high oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) undergoing intracytoplasmic sperm injection using the long protocol. A total of 200 women with oestradiol >3000 pg/ml on the HCG day with four or more good-quality, day-3 embryos were randomized in a 1:1 ratio to undergo day-3 or day-5 embryo transfer. Clinical pregnancy rates (CPR; 41% versus 59%; relative risk 0.70, 95% CI 0.52–0.93) and ongoing pregnancy/live-birth rates (35% versus 52%; relative risk 0.67, 95% CI 0.46–0.93) were lower in women undergoing cleavage-stage than blastocyst-stage embryo transfer. Using receiver operating characteristic curves, among women undergoing cleavage-stage embryo transfer, a detrimental cut-off value for not achieving pregnancy for oestradiol was 4200 pg/ml, with lower CPR and ongoing pregnancy/live-birth rates ( P = 0.006 and 0.02, respectively). No detrimental cut-off value for oestradiol was identified among women undergoing blastocyst-stage embryo transfer. Delaying embryo transfer to the blastocyst stage can increase the probability of pregnancy in women with high oestradiol on the HCG day. This prospective, randomized, controlled, clinical trial tested the hypothesis that delaying embryo transfer to the blastocyst stage can increase the chances of pregnancy in women whose ovaries respond better than normal during ovulation induction and are undergoing their first IVF cycle with intracytoplasmic sperm injection (ICSI) using the long agonist protocol. A total of 200 women with high serum oestradiol concentrations (i.e. oestradiol >3000 pg/ml on the day of human chorionic gonadotrophin (HCG) injection) and four or more good-quality day-3 embryos were randomized equally into two groups to undergo day-3 or day-5 embryo transfer. Clinical pregnancy rate (CPR) was significantly lower in women with high oestradiol undergoing cleavage-stage embryo transfer than those undergoing blastocyst-stage embryo transfer (41% versus 59%). Similarly, ongoing pregnancy/live-birth rates were significantly lower in cleavage-stage embryo transfer (35% versus 52%). Further, using receiver operator characteristic (ROC) curves, among cleavage-stage embryo transfer a detrimental cut-off value for oestradiol for not achieving pregnancy was 4200 pg/ml; no cut-off was identified among women undergoing blastocyst-stage embryo transfer. Women with oestradiol ⩾4200 pg/ml undergoing cleavage-stage embryo transfer had significantly lower CPR and ongoing pregnancy/live-birth rates. Delaying embryo transfer to the blastocyst stage can increase the probability of pregnancy in women with high oestradiol concentrations on HCG day undergoing ICSI cycles using the long agonist protocol.

Estradiol induces JNK-dependent apoptosis in glioblastoma cells

Estrogens exert multiple regulatory actions on cellular events in a variety of tissues including the brain. In the present study, the signaling mechanisms of the concentration-dependent effects of 17-β-estradiol (estradiol) on glioblastoma cells were investigated. Cell viability was evaluated by the trypan blue exclusion assay. Cell growth and kinase activities were evaluated by immunocytochemistry and Western blotting. The results showed that high concentrations of estradiol inhibit growth and induce apoptosis in C6 rat glioma and T98G human glioblastoma cells. The blockade of the c-jun NH(2)-terminal kinase (JNK) signaling pathway prevented these effects of estradiol, indicating the critical role of the JNK/c-jun signaling cascade in glioblastoma cell growth inhibition and cell death in response to high concentrations of estradiol. Collectively, these findings highlight the potential of new discoveries in sensitizing estrogen-sensitive tumors to chemotherapeutic drugs, and may lead to the development of new JNK-based effective therapies.

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-κB pathway but not the mitogen-activated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period.

Endogenous oestrogens and breast cancer risk in premenopausal and postmenopausal women

Breast cancer risk is strongly related to several reproductive and hormonal factors, but the nature of the effects of endogenous oestrogens has been difficult to establish. Data are now available from several large prospective studies with biobanks of stored serum, enabling better characterization of the associations of endogenous oestrogens, and other endogenous hormones, with breast cancer risk. In postmenopausal women, relatively high serum concentrations of oestradiol are associated with a more than twofold increase in the risk for breast cancer, and this probably explains the increase in risk in obese postmenopausal women. In premenopausal women the data available on oestrogens are more limited and difficult to interpret due to the large variations in endogenous oestrogens during the menstrual cycle, but are compatible with a positive association between oestradiol and breast cancer risk. There is also evidence that breast cancer risk is positively associated with androgens, prolactin and insulin-like growth factor-I. Further data are required, with better assays and repeat measures, to provide more accurate estimates of risk and to clarify the role of oestrogens in premenopausal women and the roles of other endogenous hormones.

Sex hormones and gene expression signatures in peripheral blood from postmenopausal women - the NOWAC postgenome study

BackgroundPostmenopausal hormone therapy (HT) influences endogenous hormone concentrations and increases the risk of breast cancer. Gene expression profiling may reveal the mechanisms behind this relationship.Our objective was to explore potential associations between sex hormones and gene expression in whole blood from a population-based, random sample of postmenopausal womenMethodsGene expression, as measured by the Applied Biosystems microarray platform, was compared between hormone therapy (HT) users and non-users and between high and low hormone plasma concentrations using both gene-wise analysis and gene set analysis. Gene sets found to be associated with HT use were further analysed for enrichment in functional clusters and network predictions. The gene expression matrix included 285 samples and 16185 probes and was adjusted for significant technical variables.ResultsGene-wise analysis revealed several genes significantly associated with different types of HT use. The functional cluster analyses provided limited information on these genes. Gene set analysis revealed 22 gene sets that were enriched between high and low estradiol concentration (HT-users excluded). Among these were seven oestrogen related gene sets, including our gene list associated with systemic estradiol use, which thereby represents a novel oestrogen signature. Seven gene sets were related to immune response. Among the 15 gene sets enriched for progesterone, 11 overlapped with estradiol. No significant gene expression patterns were found for testosterone, follicle stimulating hormone (FSH) or sex hormone binding globulin (SHBG).ConclusionsDistinct gene expression patterns associated with sex hormones are detectable in a random group of postmenopausal women, as demonstrated by the finding of a novel oestrogen signature.

Erratum to “High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation” [Reprod. BioMed. Online 21 (2010) 331–337

Erratum to “High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation” [Reprod. BioMed. Online 21 (2010) 331–337