Hi Curtis...I think it is generally recognized that ADT eventually
causes programmed cell death in the hormone-dependent cell population.
  Tumor shrinkage means less cells.
================hi ron - while apptosis does happen, the hormone sensitive cancer cells
are 'put to sleep"  they are trying to figure out how to get them to
self destruct, but haven't achieve it yet.  here's two articles that
help explain it for the ones who are interested in ADT and it's effects.

Apoptosis
For every cell, there is a time to live and a time to die.
There are two ways in which cells die:
They are killed by injurious agents.
They are induced to commit suicide.
Death by injury
Cells that are damaged by injury, such as by
mechanical damage
exposure to toxic chemicals
undergo a characteristic series of changes:
They (and their organelles like mitochondria) swell (because the ability
of the plasma membrane to control the passage of ions and water is
disrupted).
The cell contents leak out, leading to
inflammation of surrounding tissues.
Death by suicide
Cells that are induced to commit suicide:
shrink;
develop bubble-like blebs on their surface;
have the chromatin (DNA and protein) in their nucleus degraded;
have their mitochondria break down with the release of cytochrome c;
break into small, membrane-wrapped, fragments.
The phospholipid phosphatidylserine, which is normally hidden within the
plasma membrane, is exposed on the surface.
This is bound by receptors on phagocytic cells like macrophages and
dendritic cells which then engulf the cell fragments.
The phagocytic cells secrete cytokines that inhibit inflammation (e.g.,
IL-10 and TGF-β)
The pattern of events in death by suicide is so orderly that the process
is often called programmed cell death or PCD. The cellular machinery of
programmed cell death turns out to be as intrinsic to the cell as, say,
mitosis.
Programmed cell death is also called apoptosis. (There is no consensus
yet on how to pronounce it; some say  APE oh TOE sis; some say  uh
POP tuh sis.)
Why should a cell commit suicide?
There are two different reasons.
1. Programmed cell death is as needed for proper development as mitosis
is.
Examples:
The resorption of the tadpole tail at the time of its metamorphosis into
a frog occurs by apoptosis.

Cancer cells
Radiation and chemicals used in cancer therapy induce apoptosis in some
types of cancer cells.
What makes a cell decide to commit suicide?

The balance between:
the withdrawal of positive signals; that is, signals needed for
continued survival, and the receipt of negative signals.
Withdrawal of positive signals
The continued survival of most cells requires that they receive
continuous stimulation from other cells and, for many, continued
adhesion to the surface on which they are growing. Some examples of
positive signals:
growth factors for neurons
Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes
Receipt of negative signals
increased levels of oxidants within the cell damage to DNA by these
oxidants or other agents like
ultraviolet light
x-rays
chemotherapeutic drugs
accumulation of proteins that failed to fold properly into their proper
tertiary structure molecules that bind to specific receptors on the cell
surface and signal the cell to begin the apoptosis program. These death
activators include:
Tumor necrosis factor-alpha (TNF-α ) that binds to the TNF
receptor;
Lymphotoxin (also known as TNF-β ) that also binds to the TNF
receptor;
Fas ligand (FasL), a molecule that binds to a cell-surface receptor
named Fas (also called CD95).
The Mechanisms of Apoptosis
There are 3 different mechanisms by which a cell commits suicide by
apoptosis.
One generated by signals arising within the cell;
another triggered by death activators binding to receptors at the cell
surface:
TNF-α
Lymphotoxin
Fas ligand (FasL)
A third that may be triggered by dangerous reactive oxygen species.
1. Apoptosis triggered by internal signals: the intrinsic or
mitochondrial pathway
In a healthy cell, the outer membranes of its mitochondria express the
protein Bcl-2 on their surface.
Bcl-2 is bound to a molecule of the protein Apaf-1 ("apoptotic protease
activating factor-1".
Internal damage to the cell (e.g., from reactive oxygen species) causes
Bcl-2 to release Apaf-1;
a related protein, Bax, to penetrate mitochondrial membranes, causing
cytochrome c to leak out.
The released cytochrome c and Apaf-1 bind to molecules of caspase 9.
The resulting complex of
cytochrome c
Apaf-1
caspase 9
(and ATP)
is called the apoptosome.
These aggregate in the cytosol.
Caspase 9 is one of a family of over a dozen caspases. They are all
proteases. They get their name because they cleave proteins —
mostly each other — at aspartic acid (Asp) residues).
Caspase 9 cleaves and, in so doing, activates other caspases.
The sequential activation of one caspase by another creates an expanding
cascade of proteolytic activity (rather like that in blood clotting and
complement activation) which leads to
digestion of structural proteins in the cytoplasm,
degradation of chromosomal DNA, and
phagocytosis of the cell.
2. Apoptosis triggered by external signals: the extrinsic or death
receptor pathway
Fas and the TNF receptor are integral membrane proteins with their
receptor domains exposed at the surface of the cell binding of the
complementary death activator (FasL and TNF respectively) transmits a
signal to the cytoplasm that leads to
activation of caspase 8
caspase 8 (like caspase 9) initiates a cascade of caspase activation
leading to
phagocytosis of the cell.
Example (right): When cytotoxic T cells recognize (bind to) their
target,
they produce more FasL at their surface.
This binds with the Fas on the surface of the target cell leading to its
death by apoptosis.
The early steps in apoptosis are reversible — at least in C.
elegans. In some cases, final destruction of the cell is guaranteed only
with its engulfment by a phagocyte.
3. Apoptosis-Inducing Factor (AIF)
Neurons, and perhaps other cells, have another way to self-destruct that
— unlike the two paths described above — does not use
caspases.
Apoptosis-inducing factor (AIF) is a protein that is normally located in
the intermembrane space of mitochondria. When the cell receives a signal
telling it that it is time to die, AIF
is released from the mitochondria (like the release of cytochrome c in
the first pathway);
migrates into the nucleus;
binds to DNA, which
triggers the destruction of the DNA and cell death.
Apoptosis and Cancer
Some viruses associated with cancers use tricks to prevent apoptosis of
the cells they have transformed.
Several human papilloma viruses (HPV) have been implicated in causing
cervical cancer. One of them produces a protein (E6) that binds and
inactivates the apoptosis promoter p53.
Epstein-Barr Virus (EBV), the cause of mononucleosis and associated with
some lymphomas
produces a protein similar to Bcl-2
produces another protein that causes the cell to increase its own
production of Bcl-2. Both these actions make the cell more resistant to
apoptosis (thus enabling a cancer cell to continue to proliferate).
Even cancer cells produced without the participation of viruses may have
tricks to avoid apoptosis.
Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus
blocking apoptotic signals they may receive. The high levels result from
a translocation of the BCL-2 gene into an enhancer region for antibody
production. [Discussion].
Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis
by inhibiting the expression of the gene encoding Apaf-1.
Some cancer cells, especially lung and colon cancer cells, secrete
elevated levels of a soluble "decoy" molecule that binds to FasL,
plugging it up so it cannot bind Fas. Thus, cytotoxic T cells (CTL)
cannot kill the cancer cells by the mechanism shown above.
Other cancer cells express high levels of FasL, and can kill any
cytotoxic T cells (CTL) that try to kill them because CTL also express
Fas (but are protected from their own FasL).
==============            

© 2001 American Association for Cancer Research
Advances in Brief
A Mechanism for Androgen Receptor-mediated Prostate Cancer Recurrence
after Androgen Deprivation Therapy1
Christopher W. Gregory, Bin He, Raymond T. Johnson, O. Harris Ford,
James L. Mohler, Frank S. French and Elizabeth M. Wilson2
Laboratories for Reproductive Biology [C. W. G., B. H., R. T. J., F. S.
F., E. M. W.], Department of Pediatrics, [C. W. G., B. H., R. T. J., F.
S. F., E. M. W.], Lineberger Comprehensive Cancer Center [C. W. G., O.
H. F., J. L. M., F. S. F., E. M. W.], and Departments of Biochemistry
and Biophysics [B. H., E. M. W.] and Surgery [J. L. M.], Division of
Urology [J. L. M.], University of North Carolina, Chapel Hill, North
Carolina 27599

 
The development and growth of prostate cancer depends on the androgen
receptor and its high-affinity binding of dihydrotestosterone, which
derives from testosterone. Most prostate tumors regress after therapy to
prevent testosterone production by the testes, but the tumors eventually
recur and cause death. A critical question is whether the androgen
receptor mediates recurrent tumor growth after androgen deprivation
therapy. Here we report that a majority of recurrent prostate cancers
express high levels of the androgen receptor and two nuclear receptor
coactivators, transcriptional intermediary factor 2 and steroid receptor
coactivator 1. Overexpression of these coactivators increases androgen
receptor transactivation at physiological concentrations of adrenal
androgen. Furthermore, we provide a molecular basis for this activation
and suggest a general mechanism for recurrent prostate cancer growth.

 
Prostate cancer is a major cause of cancer-related deaths in American
men. In its initial stages, prostate cancer is responsive to androgen
deprivation therapy achieved by surgical or medical castration,
reflecting a dependence on androgen in tumor cell proliferation in early
stage disease. However, subsequent to androgen deprivation therapy,
prostate cancers recur and progress to a terminal stage despite reduced
circulating testosterone. The AR3 , a member of the steroid receptor
family that is activated by testicular androgens, is the major
regulatory transcription factor in normal prostate growth and
development and in the growth of androgen-dependent prostate cancer. The
AR may also contribute to prostate cancer growth during its recurrence
in the androgen-deprived patient. A role for AR-mediated gene activation
in recurrent prostate cancer is supported by its expression (1 , 2)
together with the expression of androgen-regulated genes (3) . Possible
mechanisms for AR reactivation in recurrent prostate cancer include
altered growth factor-induced phosphorylation (4, 5, 6, 7, 8) and AR
mutations (9) that broaden ligand specificity (10) . AR gene
amplification was observed after androgen deprivation in 30% of
recurrent prostate cancers (11) . AR overexpression is associated with
increased sensitivity to the growth-stimulating effects of low androgen
concentrations in recurrent prostate cancer-derived cell lines (12 , 13)

Immunohistochemistry.
Prostate specimens were acquired in compliance with the guidelines of
the University of North Carolina at Chapel Hill Clinical Cancer Protocol
Review Committee and Institutional Review Board (Chapel Hill, NC).
Histological diagnoses were verified by examination of frozen and
corresponding formalin-fixed, paraffin-embedded tissues. Samples of BPH
from eight men [mean age, 65 (range 58–71) years] and
androgen-dependent prostate cancer from eight men [mean age, 59 (range
49–71) years] were obtained from the transition zone and palpable
tumor nodules, respectively, in radical prostatectomy specimens. Gleason
sum grade was 6 in six men and 7 in two men, and mean serum
prostate-specific antigen was 26 (range, 3.5–93) ng/ml. Recurrent
prostate cancer was obtained by transurethral resection in eight men who
developed urinary retention from a local recurrence of prostate cancer
57 months (mean; range 12–162 months) after androgen deprivation by
surgical (four men) or medical (four men) castration. Recurrent tumors
were poorly differentiated (Gleason sum, 8 in two men, 9 in four men,
and 10 in two men) and serum prostate-specific antigen was 97 ng/ml
(mean; range, 0.3–177 ng/ml) despite low serum testosterone (<70
ng/ml) in all of the men. AR gene coding sequence for the prostate
cancer samples was wild-type based on denaturing gradient gel
electrophoresis and single-strand conformation polymorphism analysis for
the entire sequence and direct sequencing of the ligand binding domain
(14) .
Formalin-fixed, paraffin-embedded sections of BPH and androgen-dependent
and recurrent human prostate cancer and CWR22 human tumors propagated in
nude mice were antigen-retrieved by heating at 100°C for 30 min in a
vegetable steamer using CITRA or AR 10 buffer (BioGenex Laboratories,
San Ramon, CA) and cooled for 10 min. Slides were preincubated with 2%
normal horse serum for 5 min at 37°C and washed with automation buffer
(Fisher Scientific International, Inc., Pittsburgh, PA). Slides were
incubated with antihuman monoclonal antibodies for TIF2, SRC1, and
amplified in breast cancer-1 (Transduction Laboratories, Lexington, KY)
or AR (BioGenex Laboratories) at 1:300 dilutions followed by incubation
with antimouse peroxidase-linked secondary antibody at 1:200 dilution.
Immunoperoxidase reaction products were detected using diaminobenzidine.
Immunoblot Analysis.
Frozen patient samples and CWR22 tumors (50–100 µg) were pulverized
in liquid nitrogen, thawed on ice, and mixed with 1 ml of
radioimmunoprecipitation assay buffer containing protease inhibitors
[0.15 M NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 5 mM
EDTA, 50 mM Tris (pH 7.4), 0.5 mM phenylmethylsulfonyl fluoride, 10 µM
pepstatin, 4 µM aprotinin, 80 mg/ml leupeptin, 0.2 mM sodium vanadate,
and 5 mM benzamidine] and 1 µM DHT. Tissue was homogenized for 30 s on
ice, incubated for 30 min on ice, and centrifuged at 10,000 x g for 20
min twice. Supernatant proteins (50 µg) were electrophoresed on 12%
acrylamide gels containing SDS and electroblotted to Immobilon-P
membranes (Millipore Corp., Bedford, MA). Immunoblot analysis was
performed (3) using the antibodies described above and mouse monoclonal
anti-progesterone receptor (Affinity Bioreagents, Golden, CO) and rabbit
polyclonal anti-estrogen receptor  (Affinity Bioreagents).
Transcription Assays.
AR transcriptional assays were performed in the presence or absence of
TIF2 overexpression by measuring luciferase activity in CV1 cells
cotransfected with pCMVhAR (100 ng), wild-type or mutant
pCMVhAR507–919 (50 ng), pSG5TIF2 (3 µg), and mouse mammary tumor
virus-luciferase reporter vector (5 µg) using calcium phosphate
precipitation (15) . The absence of the metabolism of androstenedione to
testosterone was verified by high-pressure liquid chromatography of CV1
cell extracts.
GST Adsorption Studies.
GST adsorption incubations were performed (16) using in vitro-translated
35S-labeled AR ligand binding domain (amino acid residues 624–919) and
bacterial-expressed GST fusion proteins GST-AR1-333 and GST-TIF2 fusion
protein containing TIF2 amino acid residues 1143–1464 designated
GST-TIF2-M in the presence of 0.2 µM steroids. Equivalent amounts of
GST-AR1-333 and GST-TIF2 protein (2 µg based on Coomassie Blue
staining) were loaded on the gels. Approximately 4 µg of the GST-0
control protein was loaded to ensure the absence of nonspecific binding.
Autoradiographic signal intensities in the absence of steroid were
essentially identical to the GST-0 control that lacked the AR or TIF2
sequence, as shown previously (15 , 16) .

 
We investigated the role of AR and three nuclear coactivators in
recurrent prostate cancer by comparing expression levels in tissue
specimens of BPH, androgen-dependent prostate cancer, and recurrent
prostate cancer after androgen deprivation therapy. Immunoperoxidase
staining of TIF2 was more intense in the nuclei of recurrent prostate
cancer than in androgen-dependent prostate cancer or BPH (Fig. 1, b–d)
BPH served as the control for prostate cancer because it is more
common than normal prostate tissue in men 45 years of age. Tissue
morphology showed the characteristic glandular structure of BPH, the
small, closely spaced glands of early androgen-dependent prostate
cancer, and the poor differentiation of recurrent prostate cancer (Fig.
1) . Immunostaining for SRC1 was also more intense in recurrent prostate
cancer than in BPH or androgen-dependent prostate cancer (Fig. 1, f–h)
In contrast, no immunostaining was detected for the nuclear receptor
coactivator amplified in breast cancer-1 (data not shown).
Immunostaining also indicated high AR expression in recurrent prostate
cancer (Fig. 1, j–l) , and this was supported by immunoblot analysis
(Fig. 2, a–c) . Immunoblots confirmed the striking overexpression of
TIF2 in six of eight recurrent cancers (Fig. 2c) relative to its barely
detectable levels in eight specimens of BPH (Fig. 2a) and eight
androgen-dependent prostate cancer tissue lysates (Fig. 2b) . SRC1
overexpression was evident by immunoblotting in five of eight recurrent
cancers (Fig. 2c) . Thus, a majority of recurrent cancers had high
levels of TIF2 and/or SRC1. The increase in TIF2 in recurrent prostate
cancer was greater than that of SRC1, inasmuch as SRC1 was also detected
in BPH and androgen-dependent prostate cancer. In control immunoblots,
we did not detect progesterone receptor  or ß in prostate tissue
specimens, but estrogen receptor  was detected and no major difference
noted between BPH and androgen-dependent or recurrent prostate cancer
(data not shown).

  Fig. 1. TIF2, SRC1, and AR immunoperoxidase staining in human
prostate tissue. a, e, and i, androgen-dependent prostate cancer
negative controls lacking primary antibody. b, f, and j, BPH tissue. c,
g, and k, androgen dependent (AD) prostate cancer (CaP). d, h, and l,
recurrent CaP. x200.

  Fig. 2. Immunoblot analysis of TIF2, SRC1, and AR in human prostate
tissue. Immunoblotting was performed with TIF2, SRC1, and AR antibodies
and lysates from BPH specimens from 8 patients (a) androgen-dependent
prostate cancer specimens from eight patients (b); recurrent human
prostate tumor specimens from eight patients (c), and CWR22 human
prostate xenograft tissue from intact nude mice (CWR22; d) and at
different stages of tumor progression after the indicated days from
castration. Recurrent CWR22 tumor (recurrent) was harvested 150 days
after castration. Vertical set of samples within a, b, or c were from
the same patient. C, control protein extracts from monkey kidney COS
cells expressing pSG5TIF2, pSG5SRC1, or pCMVhAR. Migration positions of
molecular weight standard proteins are indicated in kilodaltons (kDa) on
the left.
 
We analyzed TIF2 and SRC1 expression in the CWR22 human prostate cancer
xenograft that retains the growth characteristics of human prostate
cancers. CWR22 prostate tumors regress after androgen deprivation but
recur after several months in the absence of testicular androgens (17 ,
18) . Immunoblots showed decreasing TIF2 levels from 6 to 64 days after
androgen deprivation (Fig. 2d) . TIF2 expression increased at 98 and 120
days after castration, which coincided with the onset of recurrent
prostate cancer cell proliferation and paralleled increased AR
expression in this model. SRC1 was also increased in the recurrent CWR22
tumor (Fig. 2d) . The results demonstrate that the levels of TIF2 and
SRC1 increase with AR expression during the recurrent growth of prostate
cancer cells after androgen deprivation.
Transient overexpression of TIF2 in cotransfection assays increased
AR-mediated transactivation of a mouse mammary tumor virus-luciferase
reporter gene in the presence of different steroids (Fig. 3a) . At
concentrations of 10-9 M, androstenedione, estradiol, and progesterone
became potent activators of AR in the presence of TIF2. This
concentration of androstenedione is within the physiological range of
adrenal androgen in the peripheral blood of human males. Transactivation
induced by 10-7 M DHEA was also increased by TIF2 expression.

  Fig. 3. Effect of TIF2 with AR transcriptional activity. a, AR
transactivation was determined in the absence and presence of increasing
concentrations (-log of hormone concentration) of androstenedione
(dione), DHEA (DHEA), 17ß-estradiol (E), progesterone (prog), and DHT
(DHT) with or without overexpressed TIF2. Fold induction relative to
activity in the absence of hormone is shown numerically above the bars
of a representative of multiple experiments. b, transcriptional activity
of AR DNA and ligand binding domain fragments with wild-type sequence
(507-919), the LNCaP cell AR mutation (507-919T877A), or CWR22 mutation
(507-919H874Y) were determined with or without coexpressed TIF2.
Activity was determined in the absence and presence of 10 nM DHT (D),
testosterone (T), androstenedione (A), dehydroepiandrosterone (De),
progesterone (P), 17ß-estradiol (E), and hydroxyflutamide (H). Fold
induction relative to activity determined in the absence of hormone is
shown numerically above the bars of a representative of multiple
experiments.
 
The AR DNA and ligand binding domain fragment AR507–919 lacks
substantial androgen-dependent transcriptional activity in the presence
of DHT or other steroids tested in the absence of overexpressed TIF2
(Fig. 3b and data not shown). But with the coexpression of TIF2,
AR507–919 is strongly activated by DHT or testosterone (Fig. 3b) ,
which supports the observation that an apparently weak interaction of
TIF2 with AF2 can be overcome by high TIF2 expression (16) . Ten nM
androstenedione also increased the transcriptional activity of
AR507–919 in the presence of overexpressed TIF2 (Fig. 3b) and SRC1
(not shown). Transactivation by ligand binding domain fragment
AR507–919 coexpressed with TIF2 required 0.1 nM DHT, 1 nM
androstenedione, or 250 nM DHEA (not shown).
The ability of lower-affinity steroids to induce wild-type AR
recruitment of TIF2 was confirmed by GST affinity matrix assays. DHEA,
estradiol, androstenedione, and progesterone promoted an interaction
between 35S-labeled AR ligand binding domain residues 624–919 and
GST-TIF2 residues 624-1141 that contain the 3 LxxLL motifs of TIF2
(TIF2-M, Fig. 4 , Lanes 2, 5, and 8). However, these lower-affinity
steroids were much less effective than DHT in promoting the interaction
between the AR ligand binding domain and AR NH2-terminal fragment
1–333 (Fig. 4 , Lanes 3, 6, and 9). Thus, in contrast to DHT, which
more readily promotes the interaction between the NH2-terminal and
carboxyl-terminal regions of AR, the binding of adrenal androgens and
other lower-affinity ligands to the AR ligand binding domain favors
recruitment of TIF2. The association of overexpressed TIF2 with AR
induced by lower affinity ligands provides a mechanism for AR-mediated
transactivation in the absence of circulating testosterone that could
account for the growth of recurrent prostate cancer in the
androgen-deprived patient.

  Fig. 4. Steroid dependence of TIF2 interaction with AR. GST affinity
matrix assays of AR ligand binding domain interactions with a TIF2
fragment and AR NH2-terminal domain fragment. Incubations included 0.2
µM DHT, DHEA, 17ß-estradiol (E2), androstenedione (dione) or
progesterone (prog) and 35S-labeled AR ligand binding domain residues
624–919 with GST-AR1-333 and GST-TIF2 (1143–1464; GST-TIF2-M).
Autoradiographic signal intensities in the absence of added steroids was
identical to the GST-0 control (data not shown).
 
LNCaP prostate cancer AR mutant T877A (19 , 20) and CWR22 prostate
cancer xenograft AR mutant H874Y (10) have broader ligand specificities
than wild-type AR, which contributes to their activation after androgen
deprivation. Here we demonstrate that in the presence of overexpressed
TIF2, each of these mutations increases the ability of the adrenal
androgens, DHEA and androstenedione, as well as other steroids to
activate transcription by the DNA and ligand binding domain fragment
AR507–919 (Fig. 3b) . The broadened ligand specificity caused by these
and certain other AR mutations could enhance AR binding of adrenal
androgens and increase the recruitment of TIF2 under conditions of
androgen deprivation and coactivator overexpression.
The results indicate that a majority of recurrent prostate cancers
overexpress TIF2 and SRC1 coincidentally with the onset of recurrent
prostate cancer growth. TIF2 overexpression increases the responsiveness
of AR activation by adrenal androgens that may circulate at sufficiently
high concentrations to recruit highly expressed coactivators. Under
normal physiological conditions, AR transactivation is induced
specifically by testosterone or DHT, causing AF2 in the AR ligand
binding domain to interact with the NH2-terminal LxxLL-like sequence
23FQNLF27 (15 , 16 , 21 , 22) . However, the AF2 hydrophobic surface
also forms an overlapping binding site for the LxxLL motifs of the p160
coactivators. Under conditions of lower coactivator expression, AF2
would be occupied by the AR NH2-terminal domain that could have the
effect of inhibiting p160 coactivator recruitment by AF2 (15) .
Ligand-induced interaction of AR AF2 with the p160 coactivators requires
their overexpression, which results in increased AR transactivation in
transient transfection assays (16 , 23) . In recurrent prostate cancer
growing in the absence of testis androgens, increased coactivator
expression could facilitate the induction of AR transactivation by
lower-affinity steroids such as the adrenal androgens by shifting the
equilibrium toward the formation of AR-TIF2 complexes. Increased AR
transactivation induced by lower-affinity ligands seems to result from
coactivator-induced AR activity rather than from a change in steroid
binding affinity, inasmuch as previous studies indicated that TIF2
overexpression does not alter the dissociation rate of bound androgen.4
High expression of TIF2 and SRC1 in recurrent prostate cancer increases
AR transactivation in response to physiological concentrations of
adrenal androgens or other steroids with affinity for AR. Coactivation
of AR transactivation may be increased further by the phosphorylation of
p160 coactivators (24 , 25) , thereby linking AR with growth factor
signaling pathways. The results provide a mechanism for AR-mediated
tumor growth in recurrent prostate cancer.
   ACKNOWLEDGMENTS
 
We thank Natalie T. Bowen, John T. Minges, Qu Collins, Natalie Edmund,
and K. Michelle Cobb for technical assistance.

To whom requests for reprints should be addressed, at Laboratories for
Reproductive Biology, CB# 7500, Room 374 Medical Science Research
Building, University of North Carolina, Chapel Hill, NC 27599. Phone:
(919) 966-5168; Fax: (919) 966-2203; E-mail: emw@med.unc.edu.
The abbreviations used are: AR, androgen receptor; TIF2,
transcriptional intermediary factor 2; SRC1, steroid receptor
coactivator 1; BPH, benign prostatic hyperplasia; DHEA,
dehydroepiandrosterone; AF2, activation function 2; GST,
glutathione-S-transferase; DHT, dihydrotestosterone;
LxxLL,L,Leucine,x,any amino acid.

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knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."
http://community.webtv.net/PALMER_ENT/doc

Well, it might be... After failed RRP, it, (it comes back...) radiation usually
might be tried then hormones, but more aggressive early therapy might work.
Taxotere and emcyt are pretty tough- I had them last year, after wasting a year
on leukine and thalidomide.

There are so many unknowns in all of this.

If you refuse HT and get a recurrence of cancer, then you have to
wonder if you could have avoided it with HT.  But you don't really
know.  Maybe you could.  Or maybe you would only have delayed
the PSA rise for a year or so, after which you might be in exactly
the same boat, but perhaps with a year less of HT benefit ahead
of you.

If you get HT and don't get a recurrence.  You won't know
whether the HT prevented it, or whether you'd have been
fine without it.

My doctor recommended against HT.  I asked for it anyway
because I read the results of a clinical trial of people with
my pathology (Gleason 7) showing 88% 5 year disease free
rate compared to 63% without HT for radiation patients.  But
not all clinical trials have shown that big an advantage and
some show none.

I did not notice any depression (other than the depression of
having cancer - which could depress anybody) or any loss of
concentration.  But I did have hot flashes, a decline of libido to
near zero (which, surprisingly, didn't prevent me from having
sex, only from wanting to before we started), and fatigue - though
I continued exercising and the fatigue cut into my reserves but
didn't make me too tired in daily living.

One symptom I think I got that few people mention is joint
problems.  I have arthritis like symptoms in my fingers and
hands that started after the end of HT.  They seem to be
permanent.  I checked the Lupron company website and found
that this could indeed be an after effect of Lupron.  I also got
dangerously elevated liver enzymes which appear to have come
and gone with the Lupron.

On balance, taking into account the scientific articles summarized
by Curtis (I'll have to trust his summary because I couldn't follow
them), and taking into account your own life style and personal
desires, I'd be inclined to say that if you decide not to get HT, your
decision would be perfectly reasonable.

As with many other PCa treatment decisions, I don't think there's
one right answer on this one.  Maybe you've just got to trust your
gut feelings and go with them.

I will say this.  If you decide to not get HT and the cancer comes
back - don't assume you made the wrong choice.  If Curtis is
right, it very likely would have come back anyway.  Or, even if the
HT does kill tumor cells, there's no guarantee that it would have
killed all of them.

Good luck.

    Alan

You might be overly concerned about HT IP.  I experienced very little by way
of side effects in the last 1 year 4 months.  Some experience even less.

Alan,

This seems to be just the sort of information I have been seeking.

Two months ago I ended two years of HT, the first six months of which
was prior to EBRT.  (HT didn't shrink the prostate enough for seeding).

How long were you on HT?

I like to imagine that I am seeing some improvement after two months,
but from your experience it appears that by far the greatest progress
was made in the last two months of your six month recovery.

I have read that testosterone levels follow a yearly cycle, being lowest
during the winter.  Based on that it might take longer to recover during
the wintertime.  

What time of year did you make your recovery?

John Lason-Age 62

I.P.,
There certainly are some unpleasant side effects that come with ADT,
however, being on Lupron for the past year, I have some experience with it
and while I don't disagree with your list of potential side effects, in
reality it appears greatly exaggerated. The worst effects I've experienced
were the lack of libido, hot flashes and some anemia that was corrected with
B-12. I continue to be physically active on a daily basis
With respect to your cousin's minister friend, there's no doubt that having
an orchiectomy will have some negative psychological effect other than what
is caused by little or no testosterone.
With the surgeries you've gone through to try and beat cancer is seems to me
that advice from your doctors should carry more weight than your cousin.

Just my cents
Tom

And therein lies the dilemma. HT responses in this forum range from
"horrific" to "what the heck?", which encourages at least trying HT. OTOH,
research indicates that patients who aren't getting the side effects aren't
getting the benefit, probably because the side effects are caused by the
lack of testosterone, not the chemicals.

I have several motivations to choose between WW and HT ASAP, and am adding
experiences from this forum to the dozens of pages of notes I've gathered
from authoritative websites and books on HT's good and bad effects. Why are
anecdotal experiences important in the presence of large controlled studies?
Because the studies have shown a pretty darn small benefit to adjuvant HT,
especially early HT, so the anecdotesMATTER, IMO. I hope to summarize my
"research" into a page or so before long, and will offer it here, FWIW,
including both facts and my personal biases. I also hope to find and consult
a VA psychologist -- because they see a TON of old men -- to see if my
cousin's experience is valid. But . . . OOPS . . . my cousin IS a VA
psychologist . . . and a Medicare psychologist . . . and a consulting
psychologist across the nation in the treatment of the aged in both private
and government practice, and MAN is she down on HT unless a patient is eager
to give up his personality for a few more  months of heartbeat.

But you struck an even BIGGER chord, the one about arguing with ignorant
people. I only began giving politics ANY thought at ALL in the mid-1990s.
Before that I had no clue whatsoever whether I was liberal or conservative,
what party a candidate was in, or the differences between the parties and/or
wings. Our political system and politicians are disgusting, so I avoided the
topic for over 50 years. But once I realized 3-4 years ago that this stuff
actually MATTERS, I began debating it on non-political forums that tolerated
it. WHAT AN EYE-OPENER! Fully half of both wings are totally uninterested in
little things like facts, logic, or rational discourse. They just want to
assassinate one another's character and spout rhetoric and mantras, and most
of the observers enable the vitriolic half by silently tolerating their
venom. Politely rebut their angry bile with substantiated FACTS, and they
sidestep the issue and tell another personal lie about you. I've encountered
only one person like that in real life, so I was surprised how common and
commonly tolerated it is even in what used to be circles of cyber-friends of
very long standing. Am I more mature as a result of that? Well, I'm
certainly a hell of a lot WISER!

I gather your comment about interest in women was aimed at libido, which we
EXPECT to lose with HT. But "my psychologist" made it clear that it very
often goes much farther, to the point of feeling no emotions whatsoever
about even a life-long soul mate. Now that's scary. I've got one hell of a
wife, and I'm not willing to give up my love for her even if I must fake or
forego its physical expression.

I.P.

Now you're getting close to home . . . and thus maybe more relevant to my
case. My cousin said to me, "You've often shown an aggressive, even arrogant
[I call it "assertive"], edge to your personality, so the test will be
whether HT simply dulls that edg