Androgen receptor gene expression in leucocytes is hormonally regulated: implications for gender differences in disease pathogenesis.
OBJECTIVE
There is evidence that male sex hormones influence the rate of progression of inflammatory and cardiovascular diseases. We have previously shown that human leucocytes and arterial cells isolated from male donors express more androgen receptor (AR) than those from female cells, with potentially pro-atherogenic effects. We now investigate whether the gender difference in AR expression is due to genetic or hormonal regulation.


METHODS
The influence of hormones on AR expression were studied in hpg mice (a mouse model of androgen deficiency) treated with testosterone, oestradiol or dihydrotestosterone (DHT). Blood samples were obtained for leucocyte AR expression and hormone levels from 53 subjects, grouped into: 12 male [six young adult (27-45 years), six elderly (71-79 years)] and six female (young adult 25-45 years) healthy controls; six male-to-female transsexuals (M2F; 20-50 years) receiving stable pharmacological oral oestrogen treatment; six female-to-male transsexuals (F2M; 31-51 years) receiving stable androgen replacement therapy; five younger men (18-56 years) who had been receiving long-term androgen replacement therapy for hypogonadal disease; six elderly men (72-88 years) who had undergone medical castration for prostate cancer treatment; and 12 male bone marrow transplant recipients (BMT; 23-65 years) from either male or female donors.


METHODS
Serum testosterone and oestradiol concentrations were measured by established immunoflurometric assays from unextracted human serum. AR mRNA levels were measured by RT-PCR and AR protein levels by western blot (cell culture) or immunohistochemistry (mouse arteries).


RESULTS
We found that AR mRNA levels were significantly down-regulated in the leucocytes of hpg mice that were treated with exogenous testosterone, oestradiol or DHT. AR protein levels were also lower in aortic tissue from the same mice. In humans, we found AR expression was significantly down-regulated by exogenous treatment with testosterone in F2M (31 +/- 13%, compared with control) or oestradiol in M2F (22 +/- 5%) but was significantly up-regulated by endogenous testosterone in BMT (128 +/- 17%). Low androgen levels measured in castrated older men were associated with markedly increased AR expression (207 +/- 26%, P < 0.05) compared with age-matched older male controls (100 +/- 2%).


CONCLUSIONS
Our results indicate a regulated ability of vascular cells to respond to sex hormones, with the effects of exogenous therapies differing markedly from those due to endogenous sex hormones. We conclude that the gender difference in AR expression in vascular cells is hormonally, rather than genetically, controlled.
Sader
Mark A
MA
Department of Cardiology, Royal Prince Alfred Hospital, NSW, Australia.
McGrath
Kristine C Y
KC
Hill
Michelle D
MD
Bradstock
Ken F
KF
Jimenez
Mark
M
Handelsman
David J
DJ
Celermajer
David S
DS
Death
Alison K
AK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism*; D016022:Case-Control Studies; D018450:Disease Progression; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood
D012739:Gonadal Steroid Hormones; D011944:Receptors, Androgen; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol