Sex steroid receptors in male human bladder: expression and biological function.
BACKGROUND
In male, lower urinary tract symptoms (LUTS) have been associated, beside benign prostatic hyperplasia, to some unexpected comorbidities (hypogonadism, obesity, metabolic syndrome), which are essentially characterized by an unbalance between circulating androgens/estrogens. Within the bladder, LUTS are linked to RhoA/Rho-kinase (ROCK) pathway overactivity.


OBJECTIVE
To investigate the effects of changing sex steroids on bladder smooth muscle.


METHODS
ER α, ER β, GPR30/GPER1 and aromatase mRNA expression was analyzed in male genitourinary tract tissues, and cells isolated from bladder, prostate, and urethra. Estrogen and G1 effect on RhoA/ROCK signaling output like cell migration, gene expression, and cytoskeletal remodeling, and [Ca(2+) ](i) was also studied in hB cells. Contractile studies on bladder strips from castrated male rats supplemented with estradiol and testosterone was also performed.


METHODS
The effects of classical (ER α, ER β) and nonclassical (GPR30/GPER1) estrogen receptor ligands (17 β-estradiol and G1, respectively) and androgens on RhoA/ROCK-.mediated cell functions were studied in hB cells. Contractility studies were also performed in bladder strips from castrated male rats supplemented with testosterone or estradiol.


RESULTS
Aromatase and sex steroid receptors, including GPR30, were expressed in human bladder and mediates several biological functions. Both 17 β-estradiol and G1 activated calcium transients and induced RhoA/ROCK signaling (cell migration, cytoskeleton remodeling and smooth muscle gene expression). RhoA/ROCK inhibitors blunted these effects. Estrogen-, but not androgen-supplementation to castrated rats increased sensitivity to the ROCK inhibitor, Y-27632 in isolated bladder strips. In hB cells, testosterone elicited effects similar to estrogen, which were abrogated by blocking its aromatization through letrozole.


CONCLUSIONS
Our data indicate for the first time that estrogen-more than androgen-receptors up-regulate RhoA/ROCK signaling. Since an altered estrogen/androgen ratio characterizes conditions, such as aging, obesity and metabolic syndrome, often associated to LUTS, we speculate that a relative hyperestrogenism may induce bladder overactivity through the up-regulation of RhoA/ROCK pathway.
Chavalmane
Aravinda K
AK
Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Comeglio
Paolo
P
Morelli
Annamaria
A
Filippi
Sandra
S
Fibbi
Benedetta
B
Vignozzi
Linda
L
Sarchielli
Erica
E
Marchetta
Matilde
M
Failli
Paola
P
Sandner
Peter
P
Saad
Farid
F
Gacci
Mauro
M
Vannelli
Gabriella B
GB
Maggi
Mario
M
D000728:Androgens / Q000097:blood; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000235:genetics / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D004967:Estrogens / Q000097:blood; D005837:Genitalia, Male / Q000503:physiopathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000503:physiopathology; D018613:Microscopy, Confocal; D009130:Muscle, Smooth / Q000503:physiopathology*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013739:Testosterone / Q000097:blood; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D001743:Urinary Bladder / Q000503:physiopathology*; D001748:Urinary Bladder Neck Obstruction / Q000235:genetics* / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000235:genetics* / Q000503:physiopathology*; D054460:rho-Associated Kinases / Q000235:genetics* / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000502:physiology*
D000728:Androgens; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C109584:GPER1 protein, human; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C066737:RHOA protein, human; D013739:Testosterone; D001141:Aromatase; C561410:CYP19A1 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein