Estrogen Exposure Time Research Articles

#277 : Transcriptome Analysis Revealed a Delayed and Attenuated Estrogen Response in IUA Patients

Background and Aims: Intrauterine adhesion (IUA) is characterized by the formation of scar tissue in the endometrium following a variety of insults such as endometrial damage, miscarriage, and infection. Despite current management with intrauterine adhesion separation and adjuvant therapies such as estrogen supplementation, a high recurrence rate and inadequate therapeutic response persist in some patients. More importantly, compromised endometrial proliferation in these patients lead to subsequent infertility. However, effective therapies to improve the impaired response to estrogen have yet to be identified. This study seeks to elucidate the molecular basis for the adverse estrogen response in IUA patients and to identify novel therapeutic targets. Method: Whole-Transcriptome sequencing: proliferative endometrium of normal and IUA patients. Results: By performing differential and enrichment analysis of transcriptomic data, we observed a considerable downregulation of estrogen-relatedgenesets in IUA patients. The expression of enhancer RNAs (eRNAs) serves as a hallmark of transcriptional activation. By identifying eRNAs in transcriptomic data and co-analyzing with ERa ChIPseq and H3K27ac ChIPseq datasets, we identified a series of downregulated eRNAs, which is mediated by estrogen. We further confirmed the downregulation of eRNAs and target genes. Interestingly, the expression of ESR1 is similar in both groups, we performed immunofluorescence analysis and demonstrated a considerable reduction of ERa-positive cells with a loss of nuclear localization in IUA. This finding provides further evidence of the insensitivity of IUA patients to estrogen and suggests a loss of estrogen genomic effects. Furthermore, we found that prolonging estrogen exposure time and increasing estrogen concentration partially enhanced estrogen effects in IUA patients, yet remained compromised, indicating the need for alternative therapeutic strategies. Conclusion: The compromised response to estrogen in IUA patients is attributed to the attenuation of estrogen receptor alpha (ERa)-mediated genomic effect.

A second case of successful conception in a natural cycle despite a maximum endometrial thickness in the follicular phase of four mm

To report the second case of successful conception in a natural cycle despite a maximum endometrial thickness in the late follicular phase of four mm. A 31-year-old woman with short term infertility was evaluated for follicular endometrial maturation with pelvic sonography. She was treated with progesterone in the luteal phase. Despite attaining a very good serum estradiol and having a longer follicular phase (with then more time of estrogen exposure to increase the endometrial thickness) she conceived in this cycle of investigation. Reporting a successful second case makes it less likely that the first case was a miracle. The odds are that there have been other pregnancies with four-mm endometrial thickness in natural cycles,without follicle maturing drugs that have either not been reported, or more likely, not evaluated.

Is estrogen exposure a protective factor for pancreatic neuroendocrine tumours in female patients with multiple endocrine neoplasia syndrome type 1?

Pancreatic neuroendocrine tumours (PNETs) are the most common cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Women have been shown to have improved survival, which may suggest a possible protective effect of female sex hormones. The aim of this study was to evaluate the relationship between estrogen exposure and PNET tumourigenesis, tumour growth and survival in female MEN1 patients with these tumours. We performed a retrospective chart review of the existing MEN1 database in our institution. Detailed information about female patients' menstrual and reproductive history, and PNET clinicopathologic characteristics was collected. Questionnaires regarding estrogen exposure were used to collect information that was missing in the database. Of 293 confirmed MEN1 cases, 141 women met the inclusion criteria. We used measures of cumulative estrogen exposure time (CEET), parity, live birth pregnancies and bilateral oophorectomy to estimate estrogen exposure. There was no significant association between CEET and time to PNET diagnosis (hazard ratio=0·966, P=0·380). For the correlation between estrogen exposure and PNET type, size, numbers, distant metastasis, lymph node metastasis, lymphovascular invasion, AJCC (American Joint Committee on Cancer) stage and overall survival, only CEET was significantly correlated with PNET size (P=0·043). In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

PINCH Protein Expression in Normal Endometrium, Atypical Endometrial Hyperplasia and Endometrioid Endometrial Carcinoma

Background: Particularly interesting new cysteine-histidine rich protein (PINCH), as an adapter protein of the LIM family for signal transduction in the integrin and growth factor pathway, is upregulated in the stroma of several common types of cancers and involved in promoting tumor progression. In the present study, we examined PINCH expression in normal endometrium, atypical endometrial hyperplasia and endometrioid carcinoma, and further studied the relationships of PINCH expression with clinicopathological variables in cancer patients. Methods: PINCH expression was examined by immunohistochemistry in 23 normal endometrial samples, 18 atypical endometrial hyperplasias and 48 endometrioid endometrial carcinomas. Results: The PINCH expression in the stroma of cancer (71%) was significantly increased compared to either normal endometrium (17%, p < 0.0001) or atypical hyperplasia (39%, p = 0.017), along with 9 cancers that had stronger PINCH expressions at the invasive margin of the cancers compared to the inner cancers. PINCH expression in cancer was higher in the patients with hypertension (p = 0.041) and estrogen exposure time >30 years (p = 0.021). On the other hand, PINCH expression was not related to menopausal status, gravid status, blood sugar/lipid, family background of cancer, histological grade, myometrial invasion, cervical involvement, lymph nodal metastases, growth pattern, estrogen and progestogen receptors (p > 0.05). Conclusion: The results suggest that PINCH seems to play a role, presently unknown, in the tumorigenesis and development of endometrial cancer that merits further study.

Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty

Developmental stage of rat mammary gland at the time of estrogen exposure determines whether the exposure increases or reduces later breast cancer risk. For example, in utero exposure to 17β-estradiol (E2) increases, whereas prepubertal exposure to this hormone decreases susceptibility of developing carcinogen-induced mammary tumors. E2 mediates its actions by interacting with caveolin-1 (CAV1), a putative tumor suppressor gene in breast cancer. Mammary tissues from 2-month-old rats exposed to E2 in utero contained decreased levels of CAV1, whereas prepubertal E2 exposure increased the levels, when compared to vehicle controls. Low CAV1 expression was associated with increased cell proliferation and estrogen receptor α expression, and reduced apoptosis in the mammary glands of rats exposed to E2 in utero. In contrast, high CAV1 expression correlated with reduced cell proliferation and cyclin D1 and phospho-Akt levels, and increased apoptosis in the mammary glands of rats exposed to E2 during prepuberty. In support of the role of CAV1 as a negative regulator of a variety of pro-growth signaling proteins, we detected decreased levels of Src and ErbB2 in rats exposed to E2 during prepuberty. Thus, estrogen exposure during mammary gland development affects the expression and function of CAV1 in a manner consistent with observed changes in susceptibility to mammary tumorigenesis.

Total Estrogen Time and Obstructive Coronary Disease in Women: Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE)

It has been suggested that both endogenous reproductive hormones and hormone therapy may play a protective role against coronary artery disease (CAD). However, recent clinical trials have failed to demonstrate the benefit of a variety of forms of hormone therapy. The observational data on the role of endogenous reproductive hormones, using surrogate measures such as number of birth, age at menarche, and age at menopause are inconsistent. In addition, the longer-term associations have not been evaluated. The aim of this study was to evaluate the relationships between detailed measurements of endogenous and exogenous estrogen exposure time with angiographic CAD and major adverse cardiovascular events. We assessed total estrogen exposure time, quantitative CAD by a core angiography laboratory, and prospectively measured major adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected ischemia in the Women's Ischemia Syndrome Evaluation (WISE) study. Timing of postmenopausal exogenous hormone therapy (HT) use was associated with reduced CAD. Two summarized total estrogen time scores (TET and sTET) were not related to angiographic CAD after accounting for HT use. In addition, these scores were not related to cardiovascular events over a median of 6.0 years of follow-up. There was no independent relation of estrogen exposure time to angiographic CAD or major adverse cardiovascular events in a contemporary cohort of postmenopausal women evaluated for suspected ischemia. Our results suggest that the paradigm of estrogen protection from CAD in women may be more complex than estrogen exposure duration alone.

Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan

Cytosolic serine hydroxymethyltransferase (cSHMT) is key to intersection of folate-metabolic pathway, participating in the pyrimidine synthesis for DNA repair. Based on the hypothesis that variants of the cSHMT C1420T together with methionine synthase (MS A2756G) and 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) are associated with breast cancer, we performed a multigenic case-control study of the effects to breast cancer risk of four polymorphisms of folate-metabolizing genes against duration of estrogen exposure. Support of our hypothesis came from the following observations: (i) Allelic frequency of cSHMT C1420T was higher in the controls than in the cases, manifesting a 0.56-fold risk reduction in breast cancer (95%CI = 0.39-0.80); and this association was more significant in those women are susceptible to time of estrogen exposure. (ii) A joint effect of the cSHMT and MS polymorphisms significantly reduced susceptibility to breast cancer (aOR = 0.55; 95%CI = 0.34-0.88). (iii) There was a trend toward a reduced risk of breast cancer in women carrying a greater number of putative low-risk genotypes (Ptrend = 0.048). (iv) This synergistic effects on risk reduction was significantly interacted with length of estrogen exposure, exhibiting a longer time of estrogen exposure (> or =30 years), menarche-to-FFTP interval (>11 years), age at the first full-term pregnancy (< or =25 years), and body mass index (< or =24). In conclusion, our study provides support to account for the preferential role of cSHMT polymorphism to lower risk of female breast cancer, and such reduced risk would be more significant in carriers with the polymorphisms of MS and MTHFR genes.

Avaliação da composição corpórea e densidade mineral óssea em mulheres portadoras de artrite reumatóide

Decrease of bone mass and changes in body composition are common in patients with rheumatoid arthritis (RA) especially in users of glucocorticoids. To evaluate the bone mineral density (BMD) and its correlation to factors of body composition in women with RA. BMD and body composition (total and regional) were measured by DXA in 83 patients with rheumatoid arthritis. In addition, a lateral dorsal and lumbar spine x-ray was carried out as well as laboratory tests (rheumatoid factor, inflammatory exams). Information about activity of disease, functional class, physical activity and alimentary data were collected using specific questionnaires. The prevalence of osteoporosis in menopausal patients was 21.4% (12 patients), of osteopenia 46.4% (26 patients) while 32.1% were normal (18 patients). Osteoporosis was similar in the lumbar spine and the femoral neck. More than half the patients showed low BMD in the lumbar and/or femoral neck. Non Caucasian and premenopausal women had the highest values of BMD averages. The cumulative dose of glucocorticoids for the last two years was a negative determinant of total lean mass. Age had a negative effect on BMD and body composition measurements. BMI showed a positive effect in all BC variables. Functional classes 3 and 4 had a negative effect only on the BMD total. Physical activity had a positive effect on BMD of the total femur. Duration of RA had a negative effect on BMD in the lumbar spine. The GC dose used in the last 3 months showed a negative effect on the total lean mass (MMT) and doses of the last 2 years had a positive effect on the total fat percentage (TFP). Finally, the estrogen exposure time (EET) indicated a positive effect on total fat percentage (TFP). A decreased BMD found in 67.8% of patients suggests a better approach to prevention and treatment as from diagnosis of the disease. Age and non Caucasian race were negative factors for BMD values, while BMI was a positive factor for all BMD and body composition variables. The disease (RA) also had a negative influence on BMD of these women and use of GC produced changes in body composition, reducing the lean mass and increasing the fat percentage. Despite lack of evidence of a harmful direct action of oral corticoids on BMD, their use should be avoided. Therefore, preserving lean mass and enhancing BMD is important for these patients, in order to decrease fractures and falls.

Investigative Models for Determining Hormone Therapy‐Induced Outcomes in Brain: Evidence in Support of a Healthy Cell Bias of Estrogen Action

The profound disparities between the largely positive basic science findings of gonadal steroid action in brain and the adverse outcomes of recent hormone therapy clinical trials in women who are either aged postmenopausal or postmenopausal with Alzheimer's disease have led to an intense reassessment of gonadal hormone action and the model systems used in basic and clinical science. The power of model systems is their predictive validity for a target population--in this case, menopausal women considering the health benefits and risks of hormone therapy. Analysis of the model systems used across the basic to clinical research continuum separate into two broad classes: those that use prevention interventions in healthy organisms and those that use hormone interventions in organisms with compromised neurological function. Basic science analyses that led to elucidation of the neurotrophic and neuroprotective effects of estrogen and the underlying mechanisms of action typically used a prevention-based experimental paradigm. This paradigm relies on healthy neurons/brains/animals/humans as the starting foundation followed by exposure to estrogen/hormone followed by exposure to neurodegenerative insult. The prevention paradigm in basic science analyses parallels the analyses of Sherwin and colleagues (Psychoneuroendocrinology 13: 345-357, 1988), who investigated the cognitive impact of estrogen therapy in women with surgical- or pharmacological-induced menopause. Observational retrospective and prospective studies are also consistent with the healthy cell bias of estrogen action and a prevention paradigm of estrogen or hormone therapy intervention. For the most part, the epidemiological observational data indicate reduction in the risk of Alzheimer's disease in women who began estrogen or hormone therapy at the time of the menopause. In contrast, studies that fall within the second class, hormone intervention in organisms with compromised neurological function--that is, a treatment paradigm--exhibit a mixed profile. In a randomized double-blind clinical trial of estrogen therapy in a cohort of women aged 72 or more years and diagnosed with Alzheimer's disease, estrogen therapy resulted in a modest benefit in the short term (2 months) and adverse progression of disease in the long term (12 months). In the Women's Health Initiative Memory Study (WHIMS) cohort of women 65 or more years of age, with no indicators of neurological disease but with variable health status, estrogen and hormone therapy for 5 years increased the risk of developing Alzheimer's disease. These data would suggest that as the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neurological function and survival. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. Based on these and other data, a hypothesis of a healthy cell bias of gonadal hormone action is put forth. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the domains of scientific inquiry and to access future applications of estrogen and hormone therapeutic interventions.

ERGDB: Estrogen Responsive Genes Database.

ERGDB is an integrated knowledge database dedicated to genes responsive to estrogen. Genes included in ERGDB are those whose expression levels are experimentally proven to be either up-regulated or down-regulated by estrogen. Genes included are identified based on publications from the PubMed database and each record has been manually examined, evaluated and selected for inclusion by biologists. ERGDB aims to be a unified gateway to store, search, retrieve and update information about estrogen responsive genes. Each record contains links to relevant databases, such as GenBank, LocusLink, Refseq, PubMed and ATCC. The unique feature of ERGDB is that it contains information on the dependence of gene reactions on experimental conditions. In addition to basic information about the genes, information for each record includes gene functional description, experimental methods used, tissue or cell type, gene reaction, estrogen exposure time and the summary of putative estrogen response elements if the gene's promoter sequence was available. Through a web interface at http://sdmc.i2r.a-star.edu.sg/ergdb/ cgi-bin/explore.pl users can either browse or query ERGDB. Access is free for academic and non-profit users.

Estrogen effects on chromosome number and sister chromatid exchanges in uterine epithelial cells and kidney cells from neonatal mice

Female mice of the NMRI strain were treated with a high dose (5 micrograms) or a low dose (10(-2) micrograms) of the synthetic estrogen diethylstilbestrol (DES) or estradiol-17 beta (E2) 48 and 24 hr, 24 hr, or 12 hr before death on day 3 after birth. Cultures of epithelium from the uterine cervix and uterine horns as well as of kidney cells were set up, and, after a culture period of 3 days, cells were studied for chromosome number and sister chromatid exchanges. Cervical cells from control females had a distinct peak of tetraploid cells, which was depressed after DES treatment but less so after E2 treatment. The tetraploid peak was lower in uterine horn epithelium and was less influenced by DES. No indications were obtained for an estrogen-induced aneuploid cell population in the uterine horn epithelium or cervical epithelium. The incidence of cells with a high number of sister chromatid exchanges (HFCECs) was only about one-fifth in uterine horn epithelium from control females compared with cervical epithelium from the same females. In the cervical epithelium, DES at both dose levels and E2 at the high dose induced an increased and similar incidence of HFCECs (from about 12.5% in controls to about 35%), which was not related to estrogen exposure time. In uterine horn epithelium, the incidence of HFCECs increased from 2.5% in controls to 8.5% after DES treatment. It is postulated that there is a more pronounced genomic plasticity in the cervical epithelium compared with the uterine horn epithelium. The estrogens had no effect on chromosome number or HFCECs in kidney cells.