Re: Subversion

[Guest guest]

Georgia Sam wrote:

....

> The first paper by King, Beer et al(1), describes the effect of 24

> hydroxylase on the role of vitamin D in maintaining a host of normal

> functions. In a nutshell: remove protective vitamin D and increase the

> risk (amongst other things) of prostate cancer. Subversion.

>

> The second paper is an old favourite of mine co-authored by

> Gustafsson(2) at Karolinska in 2002, showing that the pure DHT

> derivative 5alpha-androstane-3beta,17beta-diol (3betaAdiol) has a

> protective function on prostatic growth and development in the rat.

....

Sam,

I think that what you're talking about here is way beyond the

competence of most or all of us on this group to understand much

less evaluate. You might try writing to some of the medical

oncology researchers who have published the articles you cite.

Maybe one of them will discuss the issues with you.

There's also a sci.med.prostate.cancer newsgroup where you could

post. It's pretty moribund but I know there are a few scientists

that at least look there from time to time.

Best of luck.

Alan

[Guest guest]

> Earlier Sam wrote...snip...

> > Suppression of the DHT pathway is what triggers prostate cancer in the

adult, ageing male. Nothing more, nothing less.

>

> Sam...The paper you referenced (Eur Urol. 2008 Jan;53(1):106-11. Epub

> 2007 Apr 26, Dihydrotestosterone levels and survival in screening-

> detected prostate cancer: a 15-yr follow-up study. Kjellman A, Akre O,

> Norming U, Törnblom M, Gustafsson O. Department of Clinical Science,

> Intervention, and Technology, Karolinska Institutet, Stockholm,

> Sweden) pertains to the effect of DHT on PCa after diagnosis.  Various

> hormones, proteins, etc. can have a different effect upon PCa

> depending upon whether they are present before or after tumor

> formation.  In the statement of yours that I reproduced above it

> appears that we are discussing the effect of DHT in a healthy, pre-

> tumor scenario.  My comments aboe were addressing this point.  Here is

> the abstract of the paper I was referring to...ron

>

> Ann N Y Acad Sci. 2009 Feb;1155:43-56.

>

> 5alpha-reductase isozymes and androgen actions in the prostate.

>

> Zhu YS, Imperato-McGinley JL.

>

> Division of Endocrinology, Department of Medicine, Weill Cornell

> Medical College, New York, New York 10065, USA.

> yuz2...@...

>

> Androgens acting via the androgen receptor play critical roles in

> prostate development, growth, and pathogenesis. There are two potent

> androgens, testosterone and dihydrotestosterone (DHT), in humans and

> mammals. DHT is converted from testosterone by 5alpha-reductase

> isozymes. Two 5alpha-reductase isozymes have been identified. Although

> both isozymes are expressed, 5alpha-reductase-2 is the predominant

> isozyme in the human prostate. Mutations in 5alpha-reductase-2 gene

> cause the 5alpha-reductase-2 deficiency syndrome. Affected 46, XY

> individuals have a small, nonpalpable, and rudimentary prostate in

> adulthood. Neither benign prostate hyperplasia (BPH) nor prostate

> cancer has been reported in these patients. The prostate is small in

> animals with 5alpha-reductase-2 gene knockout or treated with specific

> 5alpha-reductase inhibitors. 5alpha-reductase isozymes are molecular

> targets for the prevention and treatment of BPH and prostate cancer.

> Moreover, androgen actions on prostate gene expression and cell growth

> are directly modulated by estrogen receptor ligands via protein-

> protein interactions. The studies of 5alpha-reductases and androgen

> actions highlight the importance of 5alpha-reductase isozymes in male

> sexual differentiation and prostate physiology and pathophysiology.

>

> PMID: 19250191

Ron,

Thanks for the PubMed reference > 5alpha-reductase isozymes and

androgen actions in the prostate.

Clearly, the role of 5alpha-reductase isozymes in the prostate and

other tissue is important. I certainly do not deny that !

However I think the old hand-waving chestnut about these pseudo-

hermaphrodites 'proving' that DHT causes PC is an unworthy argument

for a scientist to contemplate. Where is the substance to this

argument? It is nowhere, except in the minds of those who believe it.

We should have got beyond superstition at this point. The castration

cowboys' invocation of the androgen boogeyman with the pseudo-

hermaphrodites-don't-get-PC argument, should not render us with

shaking knees and loose bowels, but rather send us into peals of

laughter.

Ron, you said: > In the statement of yours that I reproduced [ > >

Suppression of the DHT pathway is what triggers prostate cancer in the

adult, ageing male. Nothing more, > > nothing less.] it appears that

we are discussing the effect of DHT in a healthy, pre-tumor

scenario. ......

Actually Ron, my statement does not presuppose a " healthy, pre-tumor

scenario " . I said that DHT suppression triggers prostate cancer. I did

not say that was the cause ! In fact the first cause of prostate

cancer goes back to the womb, when the prostate is differentiating

from the fetal tissue that has the potential to be male or female(1).

DHT has a role in PC causation, but to quote the Bard, " more in its

breach than its observance " . In other words, the absence (or

corruption) of DHT at a crucial time in male sexual development lays

the seeds for full blown prostate cancer in years to come(2). The

pseudo-hermaphrodites who do not get prostate cancer are protected by

the absence of prostatic tissue that would otherwise undergo estrogen

imprinting at the time of sexual differentiation, in those

contaminated with excess estrogen. Gail Prins has done some seminal

work on the issue of developmental estrogenization using ERalpha/beta

knockout mice(3).

As you will see below these paper by Gail Prins are all free full text

articles, available online, and ones that I recommend everyone read

and understand fully.

Briefly, Prins argues it is this _fetal imprinting_ (or developmental

estrogenization) crucially between weeks 5-10 of male fetal life that

is the _initial cause_ of prostate cancer - indeed, in humans

susceptibility to estrogenic influence extends into the second

trimester and beyond. Incidentally, a similar fate awaits those

unfortunates who get breast cancer. But the comparisons should not be

taken too far: Breast and prostate tissue are not identicle, if only

for the fact that prostate and breast epithelial / stromal cells

respectively contain different ratios of ERbeta/alpha and this will

affect the way estrogenic imprinting is imposed on the cell.

As I said in an earlier message, the suppression of DHT serves as a

_trigger_ in later life for prostate cancer. With your reasoned

questioning of that statement, I am confident that my expanding on the

subject will meet with equally reasoned debate. Perhaps I'll also be

permitted to talk about disease _promotion_ in a later post to help

distinguish the different phases of prostate cancer causes.

Key words: fetal imprinting (developmental estrogenization) ; initial

cause ; trigger ; promotion.

Cheers, and Happy New Year to All [ Let's make 2011 the year the

castration cowboys get busted ! ]

Sam.

For your delectation and edification:-

http://poetryfromtheprostrateyears.com/

~~~~~~

1. Ann N Y Acad Sci. 2006 Nov;1089:1-13. The role of estrogens in

normal and abnormal development of the prostate gland. Prins GS, Huang

L, Birch L, Pu Y. Department of Urology, University of Illinois at

Chicago, 820 South Wood, Chicago, IL 60612, USA. gprins@...

Estrogens play a physiologic role during prostate development with

regard to programming stromal cells and directing early morphogenic

events. However, if estrogenic exposures are abnormally high during

the critical developmental period, permanent alterations in prostate

branching morphogenesis and cellular differentiation will result, a

process referred to as neonatal imprinting or developmental

estrogenization.

These perturbations are associated with an increased incidence of

prostatic lesions with aging, which include hyperplasia, inflammation,

and dysplasia. To understand how early estrogenic exposures can

permanently alter the prostate and predispose it to neoplasia, we

examined the effects of estrogens on prostatic steroid receptors and

key developmental genes.

Transient and permanent alterations in prostatic AR, ERalpha, ERbeta,

and RARs are observed. We propose that estrogen-induced alterations in

these critical transcription factors play a fundamental role in

initiating prostatic growth and differentiation defects by shifting

the prostate from an androgen-dominated gland to one whose development

is regulated by estrogens and retinoids. This in turn leads to

specific disruptions in the expression patterns of key prostatic

developmental genes that normally dictate morphogenesis and

differentiation.

Specifically, we find transient reductions in Nkx3.1 and permanent

reductions in Hoxb-13, which lead to differentiation defects

particularly within the ventral lobe. Prolonged developmental

expression of Bmp-4 contributes to hypomorphic growth throughout the

prostatic complex. Reduced expression of Fgf10 and Shh and their

cognate receptors in the dorsolateral lobes leads to branching defects

in those specific regions in response to neonatal estrogens. We

hypothesize that these molecular changes initiated early in life

predispose the prostate to the neoplastic state upon aging. PMCID:

PMC2276871 PMID: 1726175 http://www.ncbi.nlm.nih.gov/pubmed/17261752

2. Reprod Toxicol. 2007 Apr-May;23(3):374-82. Epub 2006 Oct 24.

Developmental estrogen exposures predispose to prostate carcinogenesis

with aging. Prins GS, Birch L, Tang WY, Ho SM. Department of Urology,

University of Illinois at Chicago, 820 South Wood Street, MC 955,

Chicago, IL 60612, United States. gprins@...

Prostate morphogenesis occurs in utero in humans and during the

perinatal period in rodents. While largely driven by androgens, there

is compelling evidence for a permanent influence of estrogens on

prostatic development. If estrogenic exposures are abnormally high

during the critical developmental period, permanent alterations in

prostate morphology and function are observed, a process referred to

as developmental estrogenization.

Using the neonatal rodent as an animal model, it has been shown that

early exposure to high doses of estradiol results in an increased

incidence of prostatic lesions with aging which include hyperplasia,

inflammatory cell infiltration and prostatic intraepithelial neoplasia

or PIN, believed to be the precursor lesion for prostatic

adenocarcinoma. The present review summarizes research performed in

our laboratory to characterize developmental estrogenization and

identify the molecular pathways involved in mediating this response.

Furthermore, recent studies performed with low-dose estradiol

exposures during development as well as exposures to environmentally

relevant doses of the endocrine disruptor bisphenol A show increased

susceptibility to PIN lesions with aging following additional adult

exposure to estradiol. Gene methylation analysis revealed a potential

epigenetic basis for the estrogen imprinting of the prostate gland.

Taken together, our results suggest that a full range of estrogenic

exposures during the postnatal critical period - from environmentally

relevant bisphenol A exposure to low-dose and pharmacologic estradiol

exposures - results in an increased incidence and susceptibility to

neoplastic transformation of the prostate gland in the aging male

which may provide a fetal basis for this adult disease. PMCID:

PMC1927084 PMID: 17123779 -- http://www.ncbi.nlm.nih.gov/pubmed/17123779/

3. Cancer Res. 2001 Aug 15;61(16):6089-97. Estrogen imprinting of the

developing prostate gland is mediated through stromal estrogen

receptor alpha: studies with alphaERKO and betaERKO mice. Prins GS,

Birch L, Couse JF, Choi I, Katzenellenbogen B, Korach KS. Department

of Urology, University of Illinois at Chicago, Chicago, Illinois

60612, USA. gprins@...

Neonatal exposure of rodents to high doses of estrogen permanently

imprints the growth and function of the prostate and predisposes this

gland to hyperplasia and severe dysplasia analogous to prostatic

intraepithelial neoplasia with aging. Because the rodent prostate

gland expresses estrogen receptor (ER)-alpha within a subpopulation of

stromal cells and ERbeta within epithelial cells, the present study

was undertaken to determine the specific ER(s) involved in mediating

prostatic developmental estrogenization.

Wild-type (WT) mice, homozygous mutant ER (ERKO) alpha -/- mice, and

betaERKO -/- mice were injected with 2 microg of diethylstilbestrol

(DES) or oil (controls) on days 1, 3, and 5 of life. Reproductive

tracts were excised on days 5 or 10 (prepubertal), day 30 (pubertal),

day 90 (young adult), or with aging at 6, 12, and 18 months of age.

Prostate complexes were microdissected and examined histologically for

prostatic lesions and markers of estrogenization. Immunocytochemistry

was used to examine expression of androgen receptor, ERalpha, ERbeta,

cytokeratin 14 (basal cells), cytokeratin 18 (luminal cells), and

dorsolateral protein over time in the treated mice. In WT-DES mice,

developmental estrogenization of the prostate was observed at all of

the time points as compared with WT-oil mice.

These prostatic imprints included transient up-regulation of ERalpha,

down-regulation of androgen receptor, decreased ERbeta levels in adult

prostate epithelium, lack of DLP secretory protein, and a continuous

layer of basal cells lining the ducts. With aging, epithelial

dysplasia and inflammatory cell infiltrate were observed in the

ventral and dorsolateral prostate lobes. In contrast, the prostates of

alphaERKO mice exhibited no response to neonatal DES either

immediately after exposure or throughout life up to 18 months of age.

Furthermore, neonatal DES treatment of betaERKO mice resulted in a

prostatic response similar to that observed in WT animals. The present

findings indicate that ERalpha is the dominant ER form mediating the

developmental estrogenization of the prostate gland. If epithelial

ERbeta is involved in some component of estrogen imprinting, its role

would be considered minor and would require the presence of ERalpha

expression in the prostatic stromal cells. PMID: 11507058 --

http://www.ncbi.nlm.nih.gov/pubmed/11507058/