Sex steroid receptors in male human bladder: expression and biological function

J Sex Med. 2010 Aug;7(8):2698-713. doi: 10.1111/j.1743-6109.2010.01811.x. Epub 2010 Apr 20.


Introduction: 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.

Aim: 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.

Main outcome measures: 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.

Conclusion: 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.

MeSH terms

  • Androgens / blood
  • Animals
  • Aromatase / genetics
  • Aromatase / physiology
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Cells, Cultured
  • Cytoskeleton / genetics
  • Cytoskeleton / physiology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / physiology
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / physiology
  • Estrogens / blood
  • Genitalia, Male / physiopathology
  • Humans
  • Hypogonadism / genetics
  • Hypogonadism / physiopathology
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / physiopathology
  • Microscopy, Confocal
  • Muscle, Smooth / physiopathology*
  • Obesity / genetics
  • Obesity / physiopathology
  • Prostatic Hyperplasia / genetics*
  • Prostatic Hyperplasia / physiopathology*
  • RNA, Messenger / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Testosterone / blood
  • Up-Regulation / genetics
  • Up-Regulation / physiology
  • Urinary Bladder / physiopathology*
  • Urinary Bladder Neck Obstruction / genetics*
  • Urinary Bladder Neck Obstruction / physiopathology*
  • Urinary Bladder, Overactive / genetics*
  • Urinary Bladder, Overactive / physiopathology*
  • rho-Associated Kinases / genetics*
  • rho-Associated Kinases / physiology*
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / physiology*


  • Androgens
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • GPER1 protein, human
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • RHOA protein, human
  • Testosterone
  • Aromatase
  • CYP19A1 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein