Sex Steroid Receptors in Male Human Bladder: Expression and Biological Function

Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Journal of Sexual Medicine (Impact Factor: 3.15). 08/2010; 7(8):2698-713. DOI: 10.1111/j.1743-6109.2010.01811.x
Source: PubMed


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

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    • "It is important to note that circulating T is actively metabolized to estrogens and part of T hormonal activity depends upon its binding to the estrogen receptors (ERs), that are present in both the prostate and bladder [26]. In addition, the enzyme P450 aromatase which converts androgens to estrogens [27] is highly expressed not only in fat tissue but also in the urogenital tract [28]. Evidence of an increased estrogen/androgen ratio was originally provided by Marmorston et al. almost half a century ago [29] reporting that the estrogen/androgen ratio in 24-hour urinary collections was elevated in men with BPH, as compared to normal controls. "
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    ABSTRACT: Metabolic syndrome (MetS) is a well-recognized cluster of cardiovascular (CV) risk factors including obesity, hypertension, dyslipidemia, and hyperglycaemia, closely associated with an increased risk of forthcoming cardiovascular disease and type 2 diabetes mellitus. Emerging evidence indicates that benign prostate hyperplasia (BPH) and its related lower urinary tract symptoms (LUTS) represent other clinical conditions frequently observed in subjects with MetS. Several modifiable factors involved in MetS determinism, such as inadequate diet, lack of physical exercise, and smoking and drinking behaviours are emerging as main contributors to the development of BPH. The pathogenetic mechanisms underlying the connection between MetS and BPH have not been completely clarified. MetS and its components, hypogonadism, and prostate inflammation probably play an important role in inducing BPH/LUTS. Although historically considered as a "normal" consequence of the aging process, BPH/LUTS should now be faced proactively, as a preventable disorder of the elderly. Type of diet and level of physical activity are now considered important factors affecting prostate health in the aging male. However, whether physical exercise, weight loss, and modifications of dietary habit can really alter the natural history of BPH/LUTS remains to be determined. Further research is advisable to better clarify these points.
    Full-text · Article · Feb 2014 · International Journal of Endocrinology
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    • "Purified OPCs plated at a density of 2 Â l0 4 on round glass cover - slips ( 25 mm diameter ) were grown for 2 – 3 days in PM and then maintained in DM for additional 6 days . Cytosolic Ca 2þ concentra - tion was evaluated in fura - 2 loaded cells as described elsewhere ( Chavalmane et al . , 2010 ) . Briefly , cells were loaded with 4 lM fura - 2AM ( Molecular Probes - Invitrogen Life Technologies , San Giuliano Milanese , Italy ) for 45 min at RT and then washed with DM . Cover - slips were mounted in a perfusion chamber and placed on the stage of an epifluorescence microscope ( TMD Diaphot , Nikon Co , Tokyo , Japan ) equipped"
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    ABSTRACT: In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K(+) currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G-protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K(+) currents. Specifically, receptor stimulation by its agonist UDP-glucose enhances delayed rectifier K(+) currents without affecting transient K(+) conductances. This effect was observed in a subpopulation of OPCs and immature pre-OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP-glucose on K(+) currents is concentration-dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K(+) channel blocker tetraethyl-ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K(+) currents is responsible for GPR17-induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post-traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma.
    Full-text · Article · Jul 2013 · Glia
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    • "IR is found to stimulate ovarian androgenesis [25] and significant positive correlation was found between total testosterone level and urgency and nocturia in females with a IR related disease, polycystic ovary syndrome, and indicates that women with higher serum testosterone levels are more likely to have bladder symptoms [26]. In contrast, the result of IR in men is a relative hyperestrogenemia which is reported to be related to detrusor overactivity in rats [27]. "
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    ABSTRACT: Metabolic syndrome and obesity have been advocated to be risk factors for the development of overactive bladder (OAB). Additionally, insulin resistance is the underlying mechanism of metabolic syndrome. We aimed to investigate the association of insulin resistance with overactive bladder in female patients. We prospectively conducted the study in our urology department. Female patients aged between 30 and 76 years old applied to our policlinics with or without OAB symptoms were enrolled. One hundred and twenty-two patients with OAB and 62 age-matched controls without OAB were included into the study. Fasting serum insulin, glucose, high-density lipoprotein (HDL-c), and triglycerides levels were measured. Insulin resistance value was obtained via the homeostasis model assessment of insulin resistance (HOMA-IR) calculator. The chi-square and Mann-Whitney U tests were used to compare differences in variables. Serum insulin level was found higher in female patients with OAB (11.5±6.2 µU/mL) relative to controls (6.4±2.1 µU/mL), statistically significant (P=0.036). In addition, HOMA-IR was significantly found higher in the OAB group, 2.86 (0.76 to 17.04) in comparison to controls, 1.32 (0.67 to 224), P=0.018. High-density lipoprotein cholesterol levels (HDL-c) were significantly found lower in females with OAB. Insulin resistance can be associated to overactive bladder and may play significant role in pathogenesis.
    Full-text · Article · Dec 2012 · International neurourology journal
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