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Nathan Goodyear

Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5α-Reduction But Not the Elevated Adrenal Steroid Production Rates - 0 views

jcem.endojournals.org/...5907.long

PCOS PCO polycystic ovaries insulin IR resistance steroid 5-alpha reductase androgens

shared by Nathan Goodyear on 13 Mar 12 - No Cached
  • Nathan Goodyear on 13 Mar 12
     
    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

Testosterone replacement in prostate cancer survivors with hypogonadal symptoms - Leibowitz - 2009 - BJU International - Wiley Online Library - 0 views

onlinelibrary.wiley.com/...full

testosterone replacement prostate cancer PSA 5-alpha reductase inhibitor

shared by Nathan Goodyear on 25 Sep 13 - No Cached
  • Nathan Goodyear on 25 Sep 13
     
    Good article.  This article (case series) found that 40% of the men included had no increase in PSA with Testosterone.  One point on the Testosterone dosage is that they used androgen, which is an overdose of Testosterone.  That gives 60% that the PSA did increase.  These men had higher PSA to begin with which leads to the suggestion that the prostate cells were abnormal.  Those men that had a prostatectomy were more likely to have little if any increase in PSA.  This study did use a the 5 alpha reductase inhibitor dutasteride.
Nathan Goodyear

Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5α-Reduction But Not the Elevated Adrenal Steroid Production Rates - 0 views

jcem.endojournals.org/...5907.short

PCOS women lean 11-betaHSD1 5-alpha-reductase androgens testosterone insulin syndrome

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    lean women with PCOS found to have reduced 11 beta-HSD1 and increased 5 alpha reductase activity.  This, in part, is associated with the elevated cortisol and androgens in these women.
Nathan Goodyear

Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma | BMC Cancer | Full Text - 0 views

bmccancer.biomedcentral.com/...1471-2407-4-27

breast cancer cancer progesterone metabolites progesterone hormones 5alpha reductase 5alpha-pregnane 5 alpha reductase 4-pregnenes

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    Breast cell culture study finds increase 5alpha-reductase 1/2 activity and decreased 3alpha HSO.  This fits previous previous studies that show that increased 5alpha pregnanes is associated with increased proliferation and increased detachment; in contrast to decreased 4-pregnene metabolites.
Nathan Goodyear

Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss - 0 views

www.eblue.org/...abstract

finasteride propecia male-pattern baldness

shared by Nathan Goodyear on 31 Mar 11 - No Cached
  • Nathan Goodyear on 31 Mar 11
     
    propecia, 5-alpha reductase inhibitor, improves male pattern baldness
Nathan Goodyear

Estrogen receptor β and the progression of prostate cancer: role of 5α-androstane-3β,17β-diol - 0 views

erc.endocrinology-journals.org/...731.long

3-beta androstanediol DHT Testosterone androgens prostate cancer ER beta ER-beta receptors ER men male hormone hormones

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • In the prostate, ERβ is highly expressed in the epithelial compartment, where it is the prevailing isoform
  • In the gland, DHT may be either reversibly 3α- or irreversibly 3β-hydroxylated by the different 3α- and 3β-hydroxysteroid dehydrogenases respectively (Steckelbroeck et al. 2004); these transformations generate two metabolites respectively 3α-diol and 3β-Adiol, which are both unable to bind the AR. Instead, 3β-Adiol displays a high affinity for ERβ (Kuiper et al. 1998, Nilsson et al. 2001), and it has been proposed that this metabolite may play a key role in prostate development
  • ERβ signaling, in contrast to ERα, seems to act as a suppressor of prostate growth, and may be positively involved in breast cancer
  • ...4 more annotations...
  • 3β-Adiol counteracts PC cell proliferation in vitro
  • 3β-Adiol counteracts the biological actions of its androgenic precursors testosterone and DHT
  • functional antagonism of 3β-Adiol appears to be molecularly independent from the activation of the androgenic pathway
  • the action of 3β-Adiol is mediated, at the molecular levels, by the estrogenic pathway.
  • Nathan Goodyear on 21 Jan 14
     
    another awesome article dealing with hormone metabolites. Physicians that don't understand metabolites and receptors may be doing more harm than good.   One of the mainstays of the treatment of metastatic prostate disease is androgen deprivation therapy.  This article requires a reassessment of this due to the DHT metabolite 3-beta androstanediol.  This metabolite is produced from DHT production via the enzyme 3beta HSD.  This metabolite binds to ER beta, an estrogen receptor, and inhibits proliferation, migration, promotes adhesion (limits spreading), and stimulates apoptosis.  This is contrast to 3-alpha androstanediol.  Androgen deprivation therapy will decrease 3-beta androstanediol.  This is the likely reason for the increased aggressive prostate cancer found in those men using 5 alpha reductase inhibitors.
Nathan Goodyear

Androgens and prostate disease Cooper LA, Page ST - Asian J Androl - 0 views

www.ajandrology.com/article.asp

prostate disease cancer Testosterone DHT 5-alpha reductase men male hormone hormones

shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • intraprostatic androgens are not concomitantly increased when serum androgen levels are raised.
  • The "saturation model" proposes that the prostate is sensitive to very low concentrations of circulating androgens, but that once maximal AR binding is achieved, which occurs at relatively low concentrations of circulating T, further increases in serum T have little impact
  • men with metastatic prostate cancer given T who had been previously treated with castration had worsening of disease, whereas those without prior castration did not
  • ...3 more annotations...
  • There is little data to support the withholding of T therapy on the basis of concern for precipitating prostate cancer.
  • Both intervention data and physiology studies point to minimal effects on the prostate gland when serum T levels are increased to the mid-normal range with T therapy
  • an individualized care plan to assess the possible risks and benefits of T therapy for each patient is critical to optimizing the use of androgens in male health.
  • Nathan Goodyear on 15 Jan 14
     
    Nice review of the mixed data on Testosterone and Prostate disease. It is clear that Testosterone does not precipitate prostate cancer.  The intraprostatic hormone milieu likely is different than that present in the serum.  No surprise there.  5alpha reductase decreases prostate volume, PSA, and low-grade prostate cancer, but actually increases aggressive prostate cancer. Supraphysiologic doping in young men associated with no increase in prostate disease. PSA no longer to be followed in men < 55.  Mortality rate not changed.  PSA change of 1.4 ng/ml is appropriate for additional prostate evaluation.  Testosterone therapy on average increased 0.5 ng/ml. Still, no mention of aromatase activity in this article.  Why is it that hormone sensitive disease in men is only with regards to androgens and women estrogen.
Nathan Goodyear

Activation of the hypothalamic-pituitary... [Growth Horm IGF Res. 2001] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...11527096

cortisol cortisone obesity obese adipose tissue 11-betaHSD1 5-alpha reductase

shared by Nathan Goodyear on 24 Apr 12 - No Cached
  • Nathan Goodyear on 24 Apr 12
     
    obesity is associated with increased cortisol metabolism.  This would be found in increased urinary metabolites, especially via the 5-allpha reductase pathway.  Increased cortisone to cortisol production occurs via 11 beta-HSD1.  This occurs predominately in adipose tissue.  The thought here is cortisol metabolism is tissue specific and functionally different.
Nathan Goodyear

Comparative Rates of Androgen Production and Metabolism in Caucasian and Chinese Subjects - 0 views

jcem.endojournals.org/...2104.abstract

testosterone therapy men 5 alpha-reductase

shared by Nathan Goodyear on 16 Jul 11 - No Cached
  • Nathan Goodyear on 16 Jul 11
     
    In conclusion, dietary or environmental factors, and not a diminution of 5α-reductase, appear to be responsible for differences in androgen metabolism between Caucasians living in the United States and Chinese living in China.  Powerful conclusion that environmental factors play a major role in the difference in Testosterone function between caucasian men in Western countries vs. Chinese men in Eastern countries
Nathan Goodyear

Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy - 0 views

erc.endocrinology-journals.org/...R175.full

prostate cancer DHT 3-beta-diol 3-alpha-diol metabolites metabolite male men hormone hormones androgen deprivation therapy

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Additional studies have similarly found that prostate tissue levels of DHT in PCa patients treated with ADT therapy before prostatectomy declined by only ∼75% versus declines of ∼95% in serum levels
  • In a recent study in healthy men, treatment for 1 month with a GnRH antagonist to suppress testicular androgen synthesis caused a 94% decline in serum testosterone, but only a 70–80% decline in prostate tissue testosterone and DHT
  • progression to CRPC was associated with increased intratumoral accumulation or synthesis of testosterone.
  • ...9 more annotations...
  • the intraprostatic synthesis of testosterone from adrenal-derived precursors likely accounts for the relatively high testosterone levels in prostate after ADT
  • In addition, AR activity in these cells is likely further enhanced by multiple mechanisms that sensitize AR to low levels of androgens
  • higher affinity ligand DHT (approximately eightfold higher affinity
  • type 2 5α-reductase (SRD5A2) being the major enzyme in prostate
  • reduce DHT to 5α-androstane-3α,17β-diol (3α-androstanediol; Ji et al. 2003, Rizner et al. 2003), which is then glucuronidated to form 3α-androstanediol glucuronide by the enzymes UDP glycosyltransferase 2, B15 (UGT2B15) or UGT2B17
  • DHT in prostate is inactivated by the enzyme AKR1C2, which is also termed 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD type 3
    • Nathan Goodyear
      Nathan Goodyear on 03 Feb 14
       
      The metabolite 3-alpha androstanediol is NOT inactive as this author states.  This DHT metabolite actually can stimulate  ER alpha receptors in the prostate.
  • AKR1C1, is also expressed in prostate. However, in contrast to AKR1C2, it converts DHT primarily to 5α-androstane-3β,17β-diol (3β-androstanediol; Steckelbroeck et al. 2004), which is a potential endogenous ligand for the estrogen receptor β
  • Significantly, intraprostatic testosterone levels were not substantially reduced relative to controls with normal serum androgen levels, although DHT levels were reduced to 18% of controls
  • testosterone levels in many of the CRPC samples were actually increased relative to control tissues (Montgomery et al. 2008). While DHT levels were less markedly increased, this may have reflected DHT catabolism
  • Nathan Goodyear on 03 Feb 14
     
    This article discusses the failure of androgen deprivation therapy and prostate cancer.  This failure is quite common.  The authors point to alpha-DHT as the primary mechanism through AR stimulation.  However, we know that DHT metabolites also stimulate estrogen receptors.
Nathan Goodyear

Long-term effects of finasteride on prostate specific antigen levels: results from the prostate cancer prevention trial. - 0 views

www.ncbi.nlm.nih.gov/...16093979

5 alpha reductase finasteride 5 alpha reductase inhibitors PSA BPH prostate disease cancer men male hormones

shared by Nathan Goodyear on 14 Oct 15 - No Cached
  • Nathan Goodyear on 14 Oct 15
     
    PSA increased more in men with prostate cancer compared to no disease in men on finasteride therapy. This supports the idea that finasteride has a greater PSA reduction in benign prostate disease compared to prostate cancer.
Nathan Goodyear

Promoting effects and mechanisms of action of androgen in bladder c... - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...9129932

bladder cancer bladder cancer Testosterone men male hormone hormones

shared by Nathan Goodyear on 04 Jan 15 - No Cached
  • Nathan Goodyear on 04 Jan 15
     
    Another animal study finds Testosterone plays a role in bladder cancer development.  The study used anti androgen and 5 alpha reductase inhibitor therapy to see if these add on therapies provided anything to ADR whether via castration or pituitary suppression--the answer was no.  The authors concluded that Testosterone played more of a role with AR versus the more active 5alpha-DHT metabolite.
Nathan Goodyear

An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and CYP7B1, regulates prostate growth - 0 views

www.pnas.org/...13589.full

3-beta androstanediol DHT metabolite prostate cancer ER-beta ER beta CYP7b1 cytochrome male hormone hormones men

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • Although the prostate is an androgen-dependent tissue, estrogens influence both normal functions and pathological changes in this gland
  • This dual action may be due to the existence of two estrogen receptors, ERα and ERβ
  • ERα and ERβ have similar affinities for estradiol-17β
  • ...6 more annotations...
  • In this study we have shown that regulation of the levels of 3βAdiol by CYP7B1 is a key factor in regulation of prostatic growth
  • We provide evidence that proliferating cells in the prostate epithelium have elevated levels of AR and that AR protein but not mRNA levels are regulated by ERβ and its ligand 3βAdiol in the prostate epithelium.
  • because inhibition of 5α-reductase causes accumulation of testosterone and removal of ERβ action increases the level of AR in the prostate, the overall effect of Finasteride would be to favor proliferation of the prostate epithelium
  • studies show that ERβ tends to be lost in advanced prostate cancer.
  • DHEA is converted in the body to 5-androstene-3β,17β-diol, which is also a ligand for estrogen receptors (25, 39) and a substrate for CYP7B1
  • At the peak of proliferation, the proliferating epithelial cells in the ventral prostate expressed high levels of CYP7B1 but had no detectable ERβ, whereas in nonproliferating cells the level of ERβ was high and that of CYP7B1 was low.
  • Nathan Goodyear on 27 Jan 14
     
    3-beta androstanediola, a product of 3alpha-HSD from DHT binds to ER beta and down regulates AR in prostate cancer.  This study proposes that the mechanism is via CYP7B1.  CYP7B1 inactivates 3-beta androstanediol.  Interesting, because 3-beta androstanediol is considered "inactive" when compared to 3-alpha androstanediol and its interaction with ER alpha.  
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF7, MDA-MB-231, T-47D) and nontumorigenic (MCF10A) human breast cancer cells - ResearchGate - 0 views

www.researchgate.net/...10A)_human_breast_cancer_cells

progesterone metabolites breast cancer 5-alpha-pregnanediol 4-pregnenediol

shared by Nathan Goodyear on 23 Jan 14 - No Cached
  • Nathan Goodyear on 23 Jan 14
     
    Intra mammary progesterone metabolism and its associated metabolites found to be associated with tumorigenic activity in cell lines.  This was independent from ER PR status.  5 alpha-pregnanes were found to be pro-tumor and 4-pregnanes were anti-tumor.
Nathan Goodyear

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors - 0 views

www.ncbi.nlm.nih.gov/...PMC3706910

progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
  • Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
  • When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
  • ...31 more annotations...
  • Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
  • Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
  • The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
  • hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
  • a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
  • about 90% of normal proliferating breast epithelial cells are receptor negative
  • Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
  • The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
  • In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
  • the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
  • Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
  • The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
  • The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
  • In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
  • When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
  • The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
  • Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
  • ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
  • 3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
  • serum from mice with tumors had significantly more 5αP than 3αHP
  • the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and &gt;10-fold higher 5αP than 3αHP levels
  • Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
  • Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
  • breast carcinomas are able to synthesize progesterone
  • The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
  • Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
  • 5α-reductase and 5αPR levels are upregulated by 5αP
  • in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
  • the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
  • because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
  • The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites and breast cancer
Nathan Goodyear

[The Prostate Cancer Prevention Trial (PCPT). Relevance for clinical practice]. - 0 views

www.ncbi.nlm.nih.gov/...17874228

5 alpha reductase inhibitors 5alpha reductase finasteride prostate disease cancer men male hormones PSA

shared by Nathan Goodyear on 14 Oct 15 - No Cached
  • Nathan Goodyear on 14 Oct 15
     
    Finasteride does not increase prostate cancer.
Nathan Goodyear

Effect of Finasteride on the Sensitivity of PSA for Detecting Prostate Cancer - 0 views

jnci.oxfordjournals.org/...1128.long

PSA prostate BPH prostate cancer 5 alpha reductase finasteride male hormones men

shared by Nathan Goodyear on 14 Oct 15 - No Cached
  • Nathan Goodyear on 14 Oct 15
     
    Finasteride more likely to lower PSA associated with benign prostate conditions compared to cancer of prostate.
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