Progesterone and Breast Cancer Trabert, Britton; Sherman, Mark E; Kannan, Nagarajan ...
Endocrine reviews,
04/2020, Volume:
41, Issue:
2
Journal Article
Peer reviewed
Open access
Abstract
Synthetic progestogens (progestins) have been linked to increased breast cancer risk; however, the role of endogenous progesterone in breast physiology and carcinogenesis is less clearly ...defined. Mechanistic studies using cell culture, tissue culture, and preclinical models implicate progesterone in breast carcinogenesis. In contrast, limited epidemiologic data generally do not show an association of circulating progesterone levels with risk, and it is unclear whether this reflects methodologic limitations or a truly null relationship. Challenges related to defining the role of progesterone in breast physiology and neoplasia include: complex interactions with estrogens and other hormones (eg, androgens, prolactin, etc.), accounting for timing of blood collections for hormone measurements among cycling women, and limitations of assays to measure progesterone metabolites in blood and progesterone receptor isotypes (PRs) in tissues. Separating the individual effects of estrogens and progesterone is further complicated by the partial dependence of PR transcription on estrogen receptor (ER)α-mediated transcriptional events; indeed, interpreting the integrated interaction of the hormones may be more essential than isolating independent effects. Further, many of the actions of both estrogens and progesterone, particularly in “normal” breast tissues, are driven by paracrine mechanisms in which ligand binding to receptor-positive cells evokes secretion of factors that influence cell division of neighboring receptor-negative cells. Accordingly, blood and tissue levels may differ, and the latter are challenging to measure. Given conflicting data related to the potential role of progesterone in breast cancer etiology and interest in blocking progesterone action to prevent or treat breast cancer, we provide a review of the evidence that links progesterone to breast cancer risk and suggest future directions for filling current gaps in our knowledge.
Graphical Abstract
Graphical Abstract
Natural language processing (NLP), or the pragmatic research perspective of computational linguistics, has become increasingly powerful due to data availability and various techniques developed in ...the past decade. This increasing capability makes it possible to capture sentiments more accurately and semantics in a more nuanced way. Naturally, many applications are starting to seek improvements by adopting cutting-edge NLP techniques. Financial forecasting is no exception. As a result, articles that leverage NLP techniques to predict financial markets are fast accumulating, gradually establishing the research field of natural language based financial forecasting (NLFF), or from the application perspective, stock market prediction. This review article clarifies the scope of NLFF research by ordering and structuring techniques and applications from related work. The survey also aims to increase the understanding of progress and hotspots in NLFF, and bring about discussions across many different disciplines.
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CEKLJ, EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Estrogens regulate important processes in reproductive, skeletal, cardiovascular, and central nervous systems that impact women’s overall health. Understanding endogenous and exogenously administered ...estrogen metabolism is vital to determining therapeutic estrogen levels. The present review provides an overview of estrogen metabolites formed in non-pregnant and pregnant women, and those resulting from exogenous estrogen administration. There are four principal endogenous estrogens: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4). E4, which is produced only in pregnancy, has emerged recently as an estrogen with significant therapeutic potential. E1, E2, and E3 undergo extensive metabolism primarily through phase I (hydroxylation, oxidation, reduction) and phase II (primarily conjugation) reactions, whereas E4 undergoes only phase II reactions. Exogenous estrogens commonly used for menopausal treatment and/or contraception, including micronized E2, conjugated equine estrogens, and ethinyl estradiol, also undergo phase I and phase II reactions, but differ widely in the types of metabolites formed. The mechanisms by which estrogen metabolites are formed and their excretion in urine, bile, and feces, are still poorly understood. We highlight areas that require further research to foster a better understanding of how estrogen metabolism impacts dosing of oral estrogens for therapeutic use, as well as the physiological regulation of endogenous estrogens.
•Estrogens play an important role in health and disease.•Understanding metabolism is vital to determine therapeutic estrogen levels.•E1, E2, E3, conjugated equine estrogens, ethinyl estradiol undergo extensive metabolism.•Estetrol undergoes a distinctive metabolic pathway.•Regulation of these metabolic processes is poorly understood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent advances in the integration of deep recurrent neural networks and statistical inferences have paved new avenues for joint modeling of moments of random variables, which is highly useful for ...signal processing, time series analysis, and financial forecasting. However, introducing explicit knowledge as exogenous variables has received little attention. In this paper, we propose a novel model termed sentiment-aware volatility forecasting (SAVING), which incorporates market sentiment for stock return fluctuation prediction. Our framework provides an ensemble of symbolic and sub-symbolic AI approaches, that is, including grounded knowledge into a connectionist neural network. The model aims at producing a more accurate estimation of temporal variances of asset returns by better capturing the bi-directional interaction between movements of asset price and market sentiment. The interaction is modeled using Variational Bayes via the data generation and inference operations. We benchmark our model with 9 other popular ones in terms of the likelihood of forecasts given the observed sequence. Experimental results suggest that our model not only outperforms pure statistical models, e.g., GARCH and its variants, Gaussian-process volatility model, but also outperforms the state-of-the-art autoregressive deep neural nets architectures, such as the variational recurrent neural network and the neural stochastic volatility model.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. OBJECTIVE: To determine the associations ...between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. DESIGN, SETTING, AND PARTICIPANTS: Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. EXPOSURES: Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. MAIN OUTCOMES AND MEASURES: The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. RESULTS: A total of 750 women (mean age, 33.3 SD, 3.2 years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL n = 84) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% 95% CI, 70%-91% vs 75% 95% CI, 70%-79%, respectively). Women with high serum FSH values (>10 mIU/mL n = 83) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% 95% CI, 70%-89% vs 75% 95% CI, 70%-78%, respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine n = 69) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% 95% CI, 54%-80% vs 76% 95% CI, 72%-80%, respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). CONCLUSIONS AND RELEVANCE: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.
Topology captures the essence of what remains unchanged under a transformation. This study was motivated by a newly found topological invariant called super conformality that leads to local activity ...of a higher-integral-order electric element. As a result, the traditional periodic table of the electric elements can be dramatically reduced to have only six passive ones (resistor, inductor, capacitor, memristor, meminductor, and memcapacitor), in contrast to the unbounded table predicted 40 years ago. Our claim was experimentally verified by the fact that the two higher-integral-order memristors in the famous Hodgkin–Huxley circuit are locally active with an internal battery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Many studies have tested the 2-/16-hydroxyestrogen ratio-breast cancer risk theory.•There are deficiencies in assay specificity and/or accuracy in those studies.•Use of the 2-/16-hydroxylated ...estrogen pathway ratio as a biomarker is questionable.•Assays for unconjugated 2-OH-E1 and E2, and 16α-hydroxy-E1 in serum are needed.•Serum/urine assays for intact conjugated forms of relevant estrogens are also needed.
During the past 25 years or so a number of studies have been carried out to address the hypothesis that the ratio of 2-hydroxyestrone (2-hydroxy-E1) to 16α-hydroxyestrone (16α-hydroxy-E1) is associated with breast cancer risk. The rationale for this hypothesis is based on data from studies that suggest a tumorigenic and genotoxic effect of 16α-hydroxy-E1 and a protective effect of 2-hydroxy-E1 regarding breast cancer risk. The adverse effect of 16α-hydroxy-E1 has been attributed to its potential to form covalent adducts with macromolecules.
Initial studies used radiometric assays and enzyme immunoassays to test the hypothesis. However, concerns about the accuracy of these assays led to the development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that is capable of measuring 5 unconjugated and 15 conjugated endogenous estrogens, which include 2- and 16-hydroxylated estrogen metabolites, in serum or urine. The conjugated estrogens are quantified following a deconjugation (hydrolysis) step to remove the sulfate and glucuronide groups.
Epidemiologic studies have been using the LC-MS/MS assay to determine whether there is an association between breast cancer risk and the ratio of the sum of the concentrations of metabolites in the 2-hydroxylated estrogen pathway and in the 16-hydroxylated estrogen pathway. However, the validity of the pathways as biomarkers was not evaluated. The 16-hydroxylated estrogen pathway includes estriol, 16-epiestriol, 17-epiestriol and 16-ketoestradiol, in addition to 16α-hydroxy-E1. However, with the exception of 16α-hydroxy-E1, there is no evidence that any of the other estrogens in the pathway have tumorigenic or genotoxic properties, and they do not form covalent adducts with macromolecules.
Another deficiency in the epidemiological studies pertains to the accuracy of estrogen metabolite measurements obtained after the hydrolysis step in the LC-MS/MS assays. No validation was performed to demonstrate that a constant efficiency of hydrolysis is found for all the different structural forms of sulfated and glucuronidated conjugates.
Other deficiencies in the assays include the need for greater sensitivity so that the very low concentrations of unconjugated 2-hydroxy-E1, 2-hydroxy-E2, and 16α-hydroxy-E1 can be measured in serum. There is also a need to develop assays to measure intact forms of conjugated estrogens in both serum and urine, particularly the sulfates and glucuronides of 2-hydroxylated, 2-methoxylated, and 16α-hydroxylated E1 and E2. This will avoid inaccuracies that stem from hydrolysis procedures.
Improvements in LC-MS/MS assay methodology to obtain accurate measurements of unconjugated and conjugated 2-hydroxylated, 2-methoxylated, and 16α-hydroxylated estrogen metabolites are needed. This should provide valuable data for testing the 2-/16α-hydroxylated estrogen-breast cancer risk hypothesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective To elucidate the role of vitamin D in reproduction by examining the relationship between recipient vitamin D levels and pregnancy rates in donor-recipient IVF cycles. Design Retrospective ...cohort study. Setting Academic tertiary care center. Patient(s) Ninety-nine recipients of egg donation at University of Southern California Fertility. Intervention(s) Serum was collected from egg donor recipients before ET and was tested for vitamin D levels 25(OH)D. Main Outcome Measure(s) Clinical pregnancy as defined by sonographic presence of a heartbeat at 7–8 weeks of gestation. Result(s) In a diverse population of 99 recipients (53% Caucasian, 20% Asian, 16% Hispanic, 7% African American), adjusted clinical pregnancy rates were lower among vitamin D–deficient recipients than among vitamin D–replete recipients (37% vs. 78%). Live-birth rates were 31% among vitamin D–deficient recipients, compared with 59% among vitamin D–replete recipients. There were no differences in adjusted clinical pregnancy and live-birth rates among recipients who were vitamin D deficient 25(OH)D<20 ng/mL vs. among those who were vitamin D insufficient 20 ng/mL ≤ 25(OH)D<30 ng/mL. Conclusion(s) Nonreplete vitamin D status 25(OH)D<30 ng/mL was associated with lower pregnancy rates in recipients of egg donation. Since the oocyte donor-recipient model is able to separate the impact of vitamin D on oocyte vs. endometrium, these data suggest that the effects of vitamin D may be mediated through the endometrium.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Ring B unsaturated estrogens are formed by an alternate steroidogenesis.•Ring B unsaturated estrogens express biological activity mainly via ER β.•Some protective effects of CEE may involve ...inhibition of LDL and HDL oxidation.•CEE components modulate apoptosis and inhibit this form of cell death in neurons.•Eqn, Δ8-E1 and Δ3-17β-E2 may help prevent cardiovascular and Alzheimer's disease.
Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50–59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD.
CEE is a natural formulation of an extract prepared from pregnant mares’ urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17β-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17β-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor β and not the estrogen receptor α.
All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17β-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins.
Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer's disease in both aging women and men.
This article is part of a Special Issue entitled ‘Menopause’.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
This paper replicates the results of the stochastic volatility–Dirichlet process mixture (SV‐DPM) models proposed in Jensen and Maheu (2010) in both a narrow and a wide sense. By using a ...normal‐Wishart prior and the collapsed Gibbs sampling method, our algorithm can be applied for more general settings, and it is more efficient for sampling the Dirichlet process mixture. For the stochastic volatility component, we adopt the method in Chan (2017) to further increase the overall efficiency of our algorithm. Using the same dataset, we obtain mixed results. Some of the results have significant differences. If we use recent time period dataset, which includes the COVID‐19 pandemic period, the log market portfolio volatility seems to increase in terms of the number of clusters and size of magnitude.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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