CM version of Pubmed Sammy?

October 3, 2003

In a message dated 10/2/2003 6:57:34 PM Eastern Daylight Time,

ga.bates writes:

This has been so finely worked out believe me, it is no lie, no paranoid

delusion. The cure for prostate cancer is to have a high level of

testosterone (Jing essence I guess eh ?). That essence has been shown to be

missing in men diagnosed with PC. Fifty years ago it was shown that

testosterone supplements would revive terminal metastatic cases of PC. There

are pre-PubMed photocopies on my EPCEL Files area see Pearson and Prout. So

what do these clever researchers do ? They " prove " that testosterone

" causes " prostate cancer and make it virtually impossible for anyone with

prostate cancer to be prescribed testosterone patches. Instead they are

castrated to remove the stimulation of testosterone altogether.

Hi Sammy,

I have very much appreciated your insights into many of the topics being

discussed including the prostrate posts. I would like some clarification on

a couple points around prostrate health if you don't mind.

AFAIK, part of the inherent problems with the prostrate is an enzyme that

converts testosterone in to dihydro testosterone. As free testosterone is

converted into dihydro testosterone, testosterone levels fall. This plays into

the low testosterone theory.

It is said that dihydro testosterone is a very aggressive hormone that

creates inflammation and eventually prostate cancer.

Virtually all the classic western herbology used for prostrate

hyperplasia blocks the enzyme that converts testosterone. The theory is there

is

ultimately less of the aggressive hormone, dihydro testosterone.

Although I agree that a decent level of yang (or testosterone) is

important for healing, if the testosterone converting enzyme isn't dealt with,

won't

increasing testosterone levels create more trouble in the future by

inadvertently creating more dihydro testosterone??

Thanks for your insight into this,

Chris

October 3, 2003

In a message dated 10/3/2003 6:08:33 AM Eastern Daylight Time,

ga.bates writes:

DHT with an antiinflammatory has been shown

to have a beneficial effect - how about that ! [4]

Sammy.

Blasphemous! But very interesting. I will absolutely give these

theories some deeper considerations.

I agree with you about the exercise and will add that in different ways,

many American men feels castrated by social expectations and not getting the

quality and amount of sex that satisfies.

Over extended finances, couples that are stressed, needing to hold back

primitive desires in lieu of the sensitivities that we know everyone deserves.

Ect. ect ect.

Many emotions unexpressed tend to create stagnation, inflammation and so

on.

Have you any thoughts on adding DHEA or other precursors to boost

testosterone without causing atrophy?

Thanks again,

Chris

October 3, 2003

Chris,

I will try to deal with your question regarding DHT.

First, DHT is a hypothalamus-pituitary (H-P) control hormone. DHT is

responsible for the homeostatic process that keeps testosterone more or less

constant in a healthy male by regulating the amount of luteinising hormone

releasing hormone (LHRH) that in turn controls luteinising hormone (LH) and

follicle stimulating hormone (FSH) - these control growth of the gonads. In

women estrogen plays a similar role with the complication that having a

monthly cycle brings. I mention the latter because the brains (H-P) in both

men and women do not discriminate terribly well between DHT and estrogen !

This means that if a man has high levels of estrogen for some reason then

that estrogen could turn down testosterone production just as surely as an

overabundance of DHT. Indeed, this can and does happen. See the LEF Male

hormone protocol (Google search will get you there) for more details on the

estrogen connection.

> It is said that dihydro testosterone is a very aggressive hormone that

creates inflammation and eventually prostate cancer.

You know Chris, I have heard this rumour as well but in my seven years of

researching the hormone connection in prostate cancer I have not found one

convincing bit of research that implicates DHT as a causal agent in PC.

Indeed, on the contrary, I have found loads of evidence to support the idea

that high levels of DHT actually KILL PC [1] If you do a PubMed search on

Logothetis DHT [2. see below] you will see the latest paper in the long line

of DHT support.

Having said that what you will find in the literature, especially early

literature, are invitro studies with sub physiological doses of DHT showing

a growth promoting effect on PC cells. This was probably the seed that gave

DHT a bad name.

Later research with physiological doses of DHT - the Logothetis paper below

uses an averaged out male reference value of 1 nmol/Litre [normal male range

0 - 2 nmol/L] - shows quite clearly that DHT kills PC cells.

Like many chemicals DHT induces a 'biphasic response' in PC cells: Low

levels cause growth, higher physiological amounts cause cancer cell

repression. The biphasic response also has been shown with testosterone, but

not with estrogen.

This biphasic response should not be too difficult for anyone who has been

exposed to the idea of Yin/Yang to comprehend. It is a dialectical property

of some chemicals and it is what makes biology and medicine a multifaceted

and complex discipline, not the one dimensional cardboard cut-out that WM

clinicians are trying to convince people it is, in order to promote designer

pharmaceuticals for every human ailment. The development of finasteride and

now avodart to suppress DHT isoenzymes converting testosterone to DHT is an

example of this. If you read the techno-babble I guarantee confusion for a

year or so until you learn to see through this cynical manipulation [2]

One of the things that really caused me to sit up and wonder was the

discovery that DHT is used in a clinical setting as a benchmark for

comparing other anti-PC agents against for their growth suppressing

capability. This strikes me as a really cynical exploitation of a natural

effect of a natural substance to create designer drugs that can be patented

to do the job instead - at great expense to the ignorant patient. That is

why I railed about the 'cancer industry'.

Too much DHT may cause a problem for women with hirsuitism, but I don't know

of too much DHT in a man causing problems. It is just in the way the

conventional literature is manipulated that makes DHT a problem. Sure if you

give DHT supplements (Andractim) it will cause testicular atrophy just the

same as testosterone supplement will cause testicular atrophy, because the

homeostatic loop is broken and a reduction in LHRH will ensue. My

understanding is that *not enough androgen* either testosterone or DHT is

responsible for prostae problems. The introduction of an anti androgen in

the case of BPH is simply reducing the existing sub-physiological stimulus

to zero. Raising the level of DHT could equally well suppress BPH, the

problem is that inflammatory intracellular processes prevent the

concentrations becoming high enough to do any good in a BPH setting where

there is stagnation and stasis. DHT with an antiinflammatory has been shown

to have a beneficial effect - how about that ! [4]

Sammy.

1. Endocrinology. 1990 Mar;126(3):1457-63. Related Articles, Links

The proliferative effect of " anti-androgens " on the androgen-sensitive human

prostate tumor cell line LNCaP.

Olea N, Sakabe K, Soto AM, Sonnenschein C.

Tufts University Health Science Schools, Department of Anatomy and Cellular

Biology, Boston, Massachusetts 02111.

The effect of steroidal and nonsteroidal " anti-androgens " on the

proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor

cells in culture was studied using charcoal-dextran stripped human

serum-supplemented media. Cyproterone and medroxyprogesterone acetates,

flutamide, hydroxyflutamide, and anandron (R23908) were administered alone

at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated

that although medroxyprogesterone induced maximal proliferation at 3 X

10(-9) M, the other " anti-androgens " (with the exception of flutamide that

was ineffective) were effective at 3 X 10(-8) M and higher concentrations;

the amplitude of the proliferative response by these compounds was

comparable to that elicited by estradiol-17 beta (3 to 5-fold over control).

None of the anti-androgens tested triggered the shutoff effect

characteristic of androgen action. When 3 X 10(-10) M DHT and the above

mentioned anti-androgens were administered simultaneously, a synergistic

pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the

proliferative effect of each of the anti-androgens when administered

simultaneously. The relative binding affinity of these anti-androgens to

androgen receptors present in LNCaP-FGC cells did not correlate well with

their proliferative efficiency. The data collected were interpreted within

the premises of the negative control hypotheses for the regulation of cell

proliferation in metazoans. Within those premises, results became compatible

with the notion that first, " anti-androgens " elicited the proliferation of

androgen-sensitive cells by neutralizing the effect of a serum-borne

inhibitor (androcolyone-I); this event seems not to be mediated by androgens

receptors. Second, anti-androgens did not trigger a proliferative shutoff

response like androgens do, i.e. the proliferative pattern induced by

anti-androgens was comparable to that elicited by estrogens and progestins.

Third, when administered simultaneously with 3 X 10(-10) M DHT,

anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff

effect consistently overrode the proliferative effect generated by

anti-androgens and estrogens when added alone. Finally, taken together these

results raise important questions regarding the therapeutic role of

anti-androgens in prostate cancer.

PMID: 2307113 [PubMed - indexed for MEDLINE]

2. J Urol. 2003 Apr;169(4):1553-7. Related Articles, Links

Comment in:

J Urol. 2003 Apr;169(4):1558.

Regulation of Bcl-2 expression by dihydrotestosterone in hormone sensitive

LNCaP-FGC prostate cancer cells.

Bruckheimer EM, Spurgers K, Weigel NL, Logothetis C, McDonnell TJ.

PURPOSE: Up-regulation of the anti-apoptotic bcl-2 proto-oncogene is

associated with androgen independent prostate cancer progression. This

observation suggests that the expression of bcl-2 may be negatively

regulated by androgens in prostate cancer cells. MATERIALS AND METHODS: The

expression of the proto-oncogene bcl-2 was assessed in the hormone sensitive

prostate cancer cell line LNCaP-FGC in the presence and absence of a

physiological concentration of 1 nM. dihydrotestosterone (DHT). Sequence

analysis of the bcl-2 promoter regions demonstrated the presence of 2

potential androgen response elements. Transient transfections of luciferase

reporter constructs containing these potential androgen response elements

into LNCaP-FGC cells in the presence and absence of DHT were performed.

Steady-state transcripts of bcl-2 were assessed using RNase protection

assays. RESULTS: Cells cultured in charcoal stripped serum in the presence

of DHT resulted in down-regulation of bcl-2 protein. Down-regulation of

bcl-2 protein and mRNA by DHT was inhibited by coincubation with the

antiandrogen bicalutamide, an agent that competitively inhibits binding of

DHT to androgen receptor. Luciferase reporter constructs containing

candidate androgen response elements were transrepressed in the presence of

DHT. Bcl-2 mRNA was also down-regulated by DHT and this down-regulation

could not be abolished by cycloheximide. CONCLUSIONS: Together these results

suggest that the suppression of bcl-2 expression by DHT in hormone sensitive

LNCaP-FGC prostate cancer cells occurs directly. In addition, these results

provide a possible mechanistic basis for the up-regulation (derepression) of

bcl-2 observed in hormone independent prostate cancers.

PMID: 12629413 [PubMed - indexed for MEDLINE]

3. J Androl. 2003 Sep-Oct;24(5):681-7. Related Articles, Links

Androgen-Induced Prostate-Specific Antigen Gene Expression Is Mediated via

Dihydrotestosterone in LNCaP Cells.

Zhu YS, Cai LQ, You X, Cordero JJ, Huang Y, Imperato-Mcginley J.

Department of Medicine/Endocrinology, Weill Medical College of Cornell

University, New York, New York.

Prostate cancer is a leading cause of cancer death in American males.

Androgens play an essential role in prostate development, growth and

pathogenesis of benign prostate hyperplasia, and prostate cancer. Although

testosterone is the main androgen secreted from the testes,

dihydrotestosterone (DHT), a more potent androgen converted from

testosterone by 5alpha-reductase isozymes, type 1 and 2, is the major

androgen in the prostate cells. Thus, 5alpha-reductase(s) are critical in

determining androgen activity in the prostate. However, it is unclear in

prostate tumor cells whether 1 or 2 5alpha-reductase isozymes are expressed

and whether they are functionally important. In the present report, we

studied the importance of 5alpha-reductase isozymes in the androgen

induction of prostate-specific antigen (PSA) gene expression in LNCaP

prostatic tumor cells. Treatment with either testosterone or DHT in LNCaP

cells produced dose- and time-dependent increases in PSA levels in the cell

media and in PSA messenger RNA (mRNA) levels in the cells. However,

testosterone-induced but not DHT-induced PSA gene expression was

significantly inhibited by finasteride, a 5alpha-reductase inhibitor, in a

dose-dependent manner. Furthermore, we demonstrated for the first time that

both 5alpha-reductase-1 and 5alpha-reductase-2 mRNAs were expressed in LNCaP

cells using reverse transcriptase-polymerase chain reaction (RT-PCR) and

RT-PCR Southern blot analysis. These results suggest that both

5alpha-reductase isozymes are present and functionally important in

prostatic tumor LNCaP cells and that DHT is a major mediator of androgen

induction of PSA gene expression in these cells.

PMID: 12954658 [PubMed - in process]

----------

----

4. 1: Cancer Chemother Pharmacol. 2002 Mar;49(3):179-86. Epub 2002 Jan 24.

Related Articles, Links

Dihydrotestosterone (DHT) modulates the ability of NSAIDs to induce

apoptosis of prostate cancer cells.

Andrews P, Krygier S, Djakiew D.

Department of Cell Biology, Georgetown University School of Medicine, 3900

Reservoir Road, N.W., Washington D.C. 20007, USA.

andrewsp

PURPOSE: Recent evidence indicates that nonsteroidal antiinflammatory drugs

(NSAIDs) are effective in the treatment and prevention of prostate cancer.

In the study reported here, we investigated the ability of the steroid

hormone dihydrotestosterone (DHT) to modulate NSAID-induced apoptosis of

prostate cancer cells. MATERIALS AND METHODS: Using in vitro models of

androgen-sensitive and androgen-insensitive human prostate cancer cells, we

evaluated the ability of a specific cyclooxygenase-2 inhibitor (NS-398) and

a nonspecific cyclooxygenase inhibitor (indomethacin) to induce apoptosis in

the presence of various concentrations of DHT. Apoptosis was quantified

using the TUNEL method and verified by electron microscopy. RESULTS: We

found that increasing concentrations of DHT significantly enhanced the

ability of NS-398 and indomethacin to induce apoptosis of androgen-sensitive

LNCaP cells. The ability of NSAIDs to induce apoptosis of

androgen-insensitive PC-3 cells, however, was not affected by the presence

of DHT. Higher levels of DHT in the incubation medium both before as well as

following exposure to NSAIDs enhanced apoptosis of LNCaP cells. Another

steroid hormone that interacts with the androgen receptor in LNCaP cells

(progesterone) also promoted apoptosis of these cells. Increasing

concentrations of DHT caused LNCaP cells to shift from the S and G(2)/M to

the G(0)/G(1) stages of the cell cycle. CONCLUSIONS: These observations

support the use of DHT in combination with NSAIDs in the treatment of

prostate cancer, and indicate that DHT is an important issue to address in

clinical trials of NSAIDs since androgen ablation is a common treatment for

prostate cancer.