Honestly I really don't know what makes sense. I found a decent collection of studies on another website concerning the issue:
"There isn't much available on the immunosuppressive effects of
testosterone. A few recent papers suggest a direct effect but to my
knowledge it hasn't been uncovered and explained yet. The first paper
suggests testosterone has a direct effect but estrogen is a metabolite
of T and is known to directly stimulate Tregs. The second study
indicates that there's something about the androgen receptor itself
probably responsible for the first result. It also looks like this
whole complex might create some interesting sex-related differences in
the human gut where a lot of autoimmunity gets going.
A couple of personal observations:
There might be a reason for the low testosterone levels in AIDS patients
given how HIV hijacks Tregs.
This connection explains the benefits of blockading the androgen
receptor in prostate tumors since tumors often hide from the immune
system behind a Treg umbrella. Anything which lowers that umbrella
leaves the tumor vulnerable (and the patient more at risk for allergies
and other assorted forms of autoimmunity while getting treatment).
If, however, there is any truth to male pattern baldness being an
autoimmune disorder, then blockading the androgen receptor could have
mixed effects. It would certainly worsen allergies. Total ablation
stops the process but doesn't reverse it. However, deleting and
rebooting the immune system - a cure for autoimmunity - has been known
to totally reverse some male pattern baldness. Does androgen
deprivation fail to reverse the process because Treg action is also
blocked by lowered androgen levels? Androgens do interact with
TCF-4/beta-catenin but I can't find anything that ties this together
with regulatory T cells, except maybe through IgG4 and histamines off on
the side [PMID 14563838].
Following beta-catenin takes you down some interesting roads...
Am J Physiol Endocrinol Metab. 2006 May;290(5):E856-63. Epub 2005 Dec
13. Related Articles, Links
Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell
IFN-gamma expression, and NK cells: a physiological role for
testosterone and/or its metabolites.
Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, Amory
JK, Nelson PS, Wu JD.
Department of Medicine, University of Washington, Seattle, WA, USA.
The higher prevalence of autoimmune disease among women compared with
men suggests that steroids impact immune regulation. To investigate how
sex steroids modulate cellular immune function, we conducted a
randomized trial in 12 healthy men aged 35-55 yr treated for 28 days
with placebo, a GnRH antagonist, acyline to induce medical castration,
or acyline plus daily testosterone (T) gel to replace serum T, followed
by a 28-day recovery period. Serum hormones were measured weekly and
peripheral blood lymphocytes (PBLs) were collected biweekly for analyses
of thymus-derived lymphocyte (T cell) subtypes and natural killer (NK)
cells. Compared with the other groups and to baseline throughout the
drug exposure period, men receiving acyline alone had significant
reductions in serum T (near or below castrate levels),
dihydrotestosterone, and estradiol (P < 0.05). Medical castration
significantly reduced the percentage of CD4+ CD25+ T cells (P < 0.05),
decreased mitogen-induced CD8+ T cell IFN-gamma expression, and
increased the percentage of NK cells without affecting the ratio of CD4+
to CD8+ T cells and the expression of NK cell-activating receptor NKG2D
or homing receptor CXCR1. No changes in immune composition were observed
in subjects receiving placebo or acyline with replacement T. These data
suggest that T and/or its metabolites may help maintain the
physiological balance of autoimmunity and protective immunity by
preserving the number of regulatory T cells and the activation of CD8+ T
cells. In addition, sex steroids suppress NK cell proliferation. This
study supports a complex physiological role for T and/or its metabolites
in immune regulation.
* Randomized Controlled Trial
* Research Support, N.I.H., Extramural
* Research Support, U.S. Gov't, Non-P.H.S.
PMID: 16352669 [PubMed - indexed for MEDLINE]
J Immunol. 2005 Feb 15;174(4):2387-95.
Middle-age male mice have increased severity of experimental autoimmune
encephalomyelitis and are unresponsive to testosterone therapy.
Matejuk A, Hopke C, Vandenbark AA, Hurn PD, Offner H.
Department of Neurology, Oregon Health and Science University, Portland,
OR 97239, USA.
Treatment with sex hormones is known to protect against experimental
autoimmune encephalomyelitis (EAE), an animal model of multiple
sclerosis. However, little is known about how age affects the course of
EAE or response to hormone treatment. This study demonstrates striking
differences between middle-age vs young C57BL/6 male mice in the
clinical course of EAE and response to both testosterone (T4) and
estrogen (E2) hormone therapy. Unlike young males that developed an
acute phase of EAE followed by a partial remission, middle-age males
suffered severe chronic and unremitting EAE that was likely influenced
by alterations in the distribution and function of splenic immunocytes
and a significant reduction in suppressive activity of CD4+CD25+
regulatory T cells in the spleen and spinal cord. Middle-age males had
reduced numbers of splenic CD4+ T cells that were generally
hypoproliferative, but enhanced numbers of splenic macrophages and MHC
class II-expressing cells, and increased secretion of the
proinflammatory factors IFN-gamma and MCP-1. Surprisingly, middle-age
males were unresponsive to the EAE-protective effects of T4 and had only
a transient benefit from E2 treatment; young males were almost
completely protected by both hormone treatments. T4 treatment of young
males inhibited proliferation of myelin oligodendrocyte glycoprotein
35-55-specific T cells and secretion of TNF-alpha and IFN-gamma. The
effects of T4 in vivo and in vitro were reversed by the androgen
receptor antagonist, flutamide, indicating that the regulatory effects
of T4 were mediated through the androgen receptor. These data are the
first to define age-dependent differences in EAE expression and response
to hormone therapy.
* Comparative Study
* Research Support, Non-U.S. Gov't
* Research Support, U.S. Gov't, P.H.S.
PMID: 15699175 [PubMed - indexed for MEDLINE]
Am J Pathol. 1999 Jan;154(1):29-35.* Links
Restricted high level expression of Tcf-4 protein in intestinal and
mammary gland epithelium.
Barker N, Huls G, Korinek V, Clevers H.
Department of Immunology, University Hospital, Utrecht, The Netherlands.
Tcf-4 is a member of the Tcf/Lef family of transcription factors that
interact functionally with beta-catenin to mediate Wnt signaling in
vertebrates. We have previously demonstrated that the tumor suppressor
function of APC in the small intestine is mediated via regulation of
Tcf-4/beta-catenin transcriptional activity. To gain further insight
into the role of Tcf-4 in development and carcinogenesis we have
generated several mouse monoclonal antibodies, one of which is specific
for Tcf-4 and another of which recognizes both Tcf-3 and Tcf-4.
Immunohistochemistry performed with the Tcf 4- specific monoclonal
antibody revealed high levels of expression in normal intestinal and
mammary epithelium and carcinomas derived therefrom. Additional sites of
Tcf-3 expression, as revealed by staining with the Tcf-3/-4 antibody,
occurred only within the stomach epithelium, hair follicles, and
keratinocytes of the skin. A temporal Tcf-4 expression gradient was
observed along the crypt-villus axis of human small intestinal
epithelium: strong Tcf-4 expression was present within the crypts of
early (week 16) human fetal small intestine, with the villi showing
barely detectable Tcf-4 protein levels. Tcf-4 expression levels
increased dramatically on the villi of more highly developed (week 22)
fetal small intestine. We conclude that Tcf-4 exhibits a highly
restricted expression pattern related to the developmental stage of the
intestinal epithelium. The high levels of Tcf-4 expression in mammary
epithelium and mammary carcinomas may also indicate a role in the
development of this tissue and breast carcinoma.
PMID: 9916915 [PubMed - indexed for MEDLINE]
Endocrinology. 2006 Jan;147(1):141-54. Epub 2005 Oct 6.
Testosterone inhibits adipogenic differentiation in 3T3-L1 cells:
nuclear translocation of androgen receptor complex with beta-catenin and
T-cell factor 4 may bypass canonical Wnt signaling to down-regulate
adipogenic transcription factors.
Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez-Cadavid NF,
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles
R. Drew School of Medicine, Los Angeles, California 90059, USA.
Testosterone supplementation in men decreases fat mass; however, the
mechanisms by which it inhibits fat mass are unknown. We hypothesized
that testosterone inhibits adipogenic differentiation of preadipocytes
by activation of androgen receptor (AR)/beta-catenin interaction and
subsequent translocation of this complex to the nucleus thereby
bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1
cells that differentiate to form fat cells in adipogenic medium. We
found that these cells express AR and that testosterone and
dihydrotestosterone dose-dependently inhibited adipogenic
differentiation as analyzed by Oil Red O staining and down-regulation of
CCAAT/enhancer binding protein-alpha and -delta and peroxisome
proliferator-activated receptor-gamma2 protein and mRNA. These
inhibitory effects of androgens were partially blocked by flutamide or
bicalutamide. Androgen treatment was associated with nuclear
translocation of beta-catenin and AR. Immunoprecipitation studies
demonstrated association of beta-catenin with AR and T-cell factor 4
(TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited
adipogenic differentiation, whereas a dominant negative TCF4 cDNA
construct induced adipogenesis and blocked testosterone's inhibitory
effects. Our gene array analysis indicates that testosterone treatment
led to activation of some Wnt target genes. Expression of constitutively
activated AR fused with VP-16 did not inhibit the expression of
CCAAT/enhancer binding protein-alpha in the absence of androgens.
Testosterone and dihydrotestosterone inhibit adipocyte differentiation
in vitro through an AR-mediated nuclear translocation of beta-catenin
and activation of downstream Wnt signaling. These data provide evidence
for a regulatory role for androgens in inhibiting adipogenic
differentiation and a mechanistic explanation consistent with the
observed reduction in fat mass in men treated with androgens.
* Research Support, N.I.H., Extramural