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Nathan Goodyear

Communication between genomic and non-genomic signaling events coordinate steroid hormo... - 0 views

  • steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
  • This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
  • In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
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  • some steroid hormone-induced nuclear events can occur in minutes
  • the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
  • Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
  • NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
  • Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
  • ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
  • G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
  • hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
  • GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
  • androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
  • non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
  • Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
  • ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
  • 17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
  • Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
  • A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
    • Nathan Goodyear
       
      This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
  • Further, ER activates IGF-IR pathways including MAPK
  • GPER is involved in the transactivation of the EGFR independent of classical ER
  • tight interconnection between genomic and non-genomic effects of NRs.
  • non-genomic pathways can also lead to genomic effects
  • androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
  • However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
  • extranuclear steroid hormone actions can potentially reprogram nuclear NR events
  • estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
  • epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells
Nathan Goodyear

Development of protocols for the application of salivary steroid analysis to field cond... - 0 views

  • Our work confirms the feasibility of collecting samples for salivary steroid assay in field situations
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    salivary steroid testing
Nathan Goodyear

The dialectic role of progesterone - 0 views

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    Just the abstract available here.  Article states the complexity of hormones found in hormone metabolism.  I love the authors quote, "As steroid hormones are known to be converted to many other steroids occupying different receptors and thereby exerting various different effects..."  Doesn't fit into the "know your numbers" marketing deception does it?
Nathan Goodyear

Salivary steroid assays for assessing variation in... [J Steroid Biochem. 1983] - PubMe... - 0 views

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    Salivary steroid assays for assessing variation in endocrine activity.
Nathan Goodyear

Steroids in Saliva for Assessing Endocrine Function - 0 views

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    Another study validates saliva as a reliable method for hormone testing.  The author concludes: "steroid concentrations in saliva are independent of flow rate and reflect those in the free fraction in plasma".  This study also discuss potential collection problems and means to resolve them.
Nathan Goodyear

Rapid determination of natural steroidal hormones in saliva for the clinical diagnoses - 0 views

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    This study looked at combined sex hormone analysis via gas chromatography-mass spec.  Levels were able to be detected as low as 0.002 mcro/L in saliva.  This study validates the GC-MS for the use of multiple, simultaneous steroid hormone analysis
Nathan Goodyear

Low testosterone in a male adolescen... [J Paediatr Child Health. 2014] - PubMed - NCBI - 0 views

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    case study of secondary hypogonadism resulting from anabolic steroid use.
Nathan Goodyear

Steroid Analysis in Saliva for the Assessment of Endocrine Function - Read - 2006 - Ann... - 0 views

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    Steroid Analysis in Saliva for the Assessment of Endocrine Function
Nathan Goodyear

Steroid Analysis in Saliva: An overview - 0 views

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    Steroid Analysis in Saliva: An overview
Nathan Goodyear

Chronobiology in laboratory medicine: principles a... [Prog Clin Biol Res. 1990] - PubM... - 0 views

  • Without doubt, salivary steroid assays are valuable tools for use in clinical studies, not necessarily as a single time-qualified sample but more often as a series of samples that will describe the underlying endocrinological time-structure.
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    Chronobiology in laboratory medicine: principles and clinical applications illustrated from measurements of neutral steroids in saliva.
Nathan Goodyear

Insulin mediators are the signal transduction syst... [Endocrinology. 1991] - PubMed re... - 0 views

  • inositolglycan mediators are the signal transduction mechanism responsible for insulin's regulation of human placental steroid hormone biosynthesis.
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    inositolphosphoglycans act as signal transducers in steroid pathway synthesis
Nathan Goodyear

The reversibility of anabolic steroid-induced azoospe... [J Urol. 1995] - PubMed - NCBI - 0 views

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    Case study of 1 of a man with remote history of anabolic steroid use and current azoospermia.  HCG therapy for 3 months led to resolution of infertility.
Nathan Goodyear

Reduced testosterone and adrenal C19 steroid levels in obese men. - PubMed - NCBI - 0 views

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    Decreased adrenal steroid production occurred in men with obesity.  Estrone positively correlated.
Nathan Goodyear

Ibuprofen alters human testicular physiology to produce a state of compensated hypogona... - 0 views

  • The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
  • This increase was even more pronounced at 44 d, at 33%
  • We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial, which occurred as early as 14 d and was maintained until the end of the trial at 44 d
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  • We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
  • The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration
  • Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
  • Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA
  • Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.
  • Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
  • A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
  • We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
  • the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.
  • Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
  • ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
  • The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action
  • AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
  • ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis
  • a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human
  • The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription
  • Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
  • ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected
  • short-term exposure
  • In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality
  • compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
  • an inverse relationship was recently reported between endurance exercise training and male sexual libido
  • AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels
  • inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
  • the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
  • after administration of 600 mg of ibuprofen to healthy volunteers
  • 14 d or at the last day of administration at 44 d
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    ibuprofen alters genetic expression that results in decreased Testosterone production.
ashleyobama

Injectable Steroids Archives - Roids Meds - 0 views

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    Want medication for you and your family but not sure where to find the right one or on which site to be trusted ? Well, then your are on the right page because you are going to get all your answers or must say solutons to your worry right here. Roids Meds (www.roidsmeds.com) is all that you need to now about. Roids Meds is a medication online store, which provides the best of all medecines at low prices. It is a Florida Based company , which serves worldwide. it has a license to sell (prescripton) drugs by way of wholesale, issued by the government of the united states. At present Pharma Gen research Laboratries are their offcial partners and along with that 7 others pharmacies are partners with them
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    Want medication for you and your family but not sure where to find the right one or on which site to be trusted ? Well, then your are on the right page because you are going to get all your answers or must say solutons to your worry right here. Roids Meds (https://www.roidsmeds.com/product-category/injectable-steroids/) is all that you need to now about. Roids Meds is a medication online store, which provides the best of all medecines at low prices. It is a Florida Based company , which serves worldwide. it has a license to sell (prescripton) drugs by way of wholesale, issued by the government of the united states. At present Pharma Gen research Laboratries are their offcial partners and along with that 7 others pharmacies are partners with them
Nathan Goodyear

Secular Decline in Male Testosterone and Sex Hormone Binding Globulin Serum Levels in D... - 0 views

  • Serum SHBG levels are negatively associated with obesity and various measures of insulin resistance
  • SHBG levels increase during pharmacological oral estrogen treatment
  • insulin decreases SHBG productio
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  • The secular decline in SHBG and testosterone serum levels did not lead to a change in the level of free testosterone
  • existence of specific binding sites for SHBG at the cell membrane of steroid-responsive tissues has been shown
  • it is alarming that changes of this magnitude can be detected over such a relatively short time
  • Sex steroids stimulate SHBG production and secretion in vitro
  • Serum testosterone levels decreased and SHBG levels increased with increasing age
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    lower levels of SHBG and serum testosterone were found in more recently born men.  Preceding generations of men produced higher testosterone levels than men born in more recent generations.
Nathan Goodyear

Assessment of adrenal function by measurement of sa... [Steroids. 2007] - PubMed - NCBI - 0 views

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    Saliva shown to be "simple, safe, well-accepted and non-invasive" technique to evaluate cortisol levels.
Nathan Goodyear

Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5α... - 0 views

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    insulin, in women with PCOS, promotes increased 5-alpha reductase activity.  This results in a dysregulated HPA axis, promoting increased cortisol and androgen levels.
Nathan Goodyear

Low Steroid Levels Linked to Increased Risk of Cardiovascular Disease - 0 views

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    low DHEA associated with increased cardiovascular disease risk.  This was presented at the Endocrine Society 94th Annual meeting.
Nathan Goodyear

Steroids in Saliva for Assessing Endocrine Function - 0 views

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    One of the earlier studies showing the clinical benefit of saliva testing over that of blood.
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