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Benign Prostatic Hyperplasia
BENIGN PROSTATIC HYPERPLASIA
261
lower urinary tract. These interactions are complex, and structural or functional alterations may result in varying degrees of voiding dysfunction, including problems with bladder filling and storage, bladder emptying or both. Urinary incontinence and other forms of voiding dysfunction are more common in older adults but should not be considered a normal or inevitable part of the aging process. This small prospective study sought to examine the relationships between changes in brain networking and urinary urge incontinence using functional magnetic resonance imaging technology. A total of 10 healthy continent women, including 5 younger (30 to 46 years) and 5 older women (67 to 90 years), underwent fMRI during bladder filling and emptying. Imaging revealed activation of the well-known micturition control centers during bladder filling. Some age specific changes were identified in certain areas of the brain in response to bladder filling and emptying. These pilot data in healthy continent older and younger women are important as a baseline for future neurophysiological research on this topic. It will be interesting to see what findings are observed in older women with various forms of urinary incontinence. As the authors correctly note, some observed changes may be due to previously unrecognized brain pathology, which could be associated with advancing age. Depending on the specific anatomical and physiological factors involved, there is a potential for development of targeted treatments that could improve continence status. Tomas L. Griebling, M.D., M.P.H.
Benign Prostatic Hyperplasia Oestrogen and Benign Prostatic Hyperplasia: Effects on Stromal Cell Proliferation and Local Formation From Androgen C. K. Ho, J. Nanda, K. E. Chapman and F. K. Habib Prostate Research Group, University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom J Endocrinol 2008; 197: 483– 491.
Oestrogens have been implicated as a cause of benign prostatic hyperplasia (BPH). Previous animal studies led to the hypothesis that oestrogens can stimulate prostate growth, resulting in hyperplasia of the gland. In humans, the precise role of oestrogens in BPH pathogenesis is currently unclear. We investigated the direct effects of oestradiol on the proliferation of BPH-derived prostate cells in culture. Oestradiol (10(⫺7) and 10(⫺6) M) moderately increased the proliferation of stromal cells in culture; this stimulation was antagonised by anti-oestrogen ICI 182 780, indicating an oestrogen receptor (ER)-mediated mechanism. By contrast, oestradiol had no effects on the proliferation of epithelial cells in culture. Parameters that can determine the response of stromal cells to oestrogens, including expression of the two ER subtypes and aromatase activity, were investigated. ER beta expression in stromal cells in culture was demonstrated by immunohistochemistry and western blot analysis, and was confirmed by semi-quantitative RT-PCR showing higher expression of ER beta than ER alpha mRNA in stromal cells. Aromatase, the enzyme that converts androgen precursors to oestrogens, was also examined. Aromatase mRNA and activity were detected in stromal, but not epithelial cells in culture, suggesting a mechanism whereby oestrogen concentrations can be regulated in the BPH stroma. Taken together, these findings support the hypothesis that oestrogens play a role in the pathogenesis of BPH, a disease characterised predominantly by stromal overgrowth. Editorial Comment: According to classic urological teaching, 2 factors are required for BPH to develop—aging and androgens. As men age, plasma androgens decrease gradually while estrogen levels remain fairly constant. Stated otherwise, there are increasing ratios of estrogen to androgen levels in plasma. Estrogens via binding to intracellular estrogen receptors exert their effects as hormone inducible transcription factors. Moreover, aromatase, a member of the cytochrome P450 group of enzymes, converts C19 androgen
262
BENIGN PROSTATIC HYPERPLASIA
precursors to C18 estrogens. Additionally expression of aromatase in estrogen target tissue may represent a method whereby estrogens are regulated. Previous studies suggest that estrogens may have a role in BPH development, specifically the glandular epithelium. This study suggests that, in fact, estrogens increase the proliferation of stromal cells that are antagonized by antiestrogens. Furthermore, aromatase mRNA activity is similarly present in stromal but not epithelial cells. Given the relative preponderance of stromal versus epithelial cells in the human prostate, these data suggest that estrogen metabolism and estrogen regulation may be important targets to modulate prostate growth. Moreover, the relative effects of abdominal obesity on estrogen metabolism and, by extension, prostate growth may be an interesting avenue of translational research in the future. Steven A. Kaplan, M.D.
Benign Prostatic Hyperplasia: The Hypogonadal-Obesity-Prostate Connection P. G. Cohen Department of Pharmaceutical Sciences, Mercer University, Southern School of Pharmacy, Atlanta, Georgia Med Hypotheses 2009; 73: 142–143.
Prostatic enlargement occurs over the course of a lifetime and is associated with many risk factors. Recent observations demonstrate that valvular damage, occurring in the internal spermatic veins results in increased hydrostatic pressures that lead to venous backflow. Two consequences of venous backflow are the prolonged exposure to hydrostatic pressure and high testosterone levels that effect the prostate directly. Furthermore, aging and obesity related states have long been associated with BPH and diminished testosterone concentrations, which by itself, predisposes and allows for the preferential deposition of abdominal/visceral fat. The increasing abdominal obesity leads to elevated intra-abdominal pressure, which over time, causes increased venous pressure. Chronically elevated intra-abdominal venous pressure eventually causes progressive failure of the one way valves in the internal spermatic veins and venous insufficiency that leads to prostate damage. All of these factors promote conditions that cause chronic progressive prostatic disease and eventually BPH. Editorial Comment: The association between central obesity and pelvic dysfunction has been a source of interest and research during the last few years. What seems clear is that central obesity and metabolic dysfunction are associated with larger prostates, sexual dysfunction and worsening voiding symptoms. Similarly obesity is a major risk factor for overactive bladder symptoms in women. The causative factors for this association are less well understood. In men it is thought that central obesity leads to increased insulin resistance, hyperinsulinemia, increased sympathetic activity and decreased apoptosis in the prostate. The author proposes an interesting hypothesis that incorporates the concept that in men with benign prostatic hyperplasia there is increased hydrostatic pressure that impairs venous outflow. Simultaneously the increased venous hydrostatic pressure is the result of damage to the one-way valves of the internal spermatic veins. Consistent with this premise is the fact that the prostate becomes exposed to increased venous concentrations of testosterone. The hypogonadal-obesity cycle is based on the premise that decreased levels of testosterone and increased levels of aromatase lead to preferential deposition of abdominal and visceral fat. Finally chronic and changing back pressure causes venous congestion, which exposes the prostate to increased concentrations of testosterone. This proposed cycle of obesity, changes in testosterone, aging and prostate growth represents a novel approach to our understanding of metabolic dysfunction and BPH. This concept may partly explain the association of overactive bladder symptoms in women with central obesity, ie a hormonal and venous congestion etiology. Steven A. Kaplan, M.D.
261
lower urinary tract. These interactions are complex, and structural or functional alterations may result in varying degrees of voiding dysfunction, including problems with bladder filling and storage, bladder emptying or both. Urinary incontinence and other forms of voiding dysfunction are more common in older adults but should not be considered a normal or inevitable part of the aging process. This small prospective study sought to examine the relationships between changes in brain networking and urinary urge incontinence using functional magnetic resonance imaging technology. A total of 10 healthy continent women, including 5 younger (30 to 46 years) and 5 older women (67 to 90 years), underwent fMRI during bladder filling and emptying. Imaging revealed activation of the well-known micturition control centers during bladder filling. Some age specific changes were identified in certain areas of the brain in response to bladder filling and emptying. These pilot data in healthy continent older and younger women are important as a baseline for future neurophysiological research on this topic. It will be interesting to see what findings are observed in older women with various forms of urinary incontinence. As the authors correctly note, some observed changes may be due to previously unrecognized brain pathology, which could be associated with advancing age. Depending on the specific anatomical and physiological factors involved, there is a potential for development of targeted treatments that could improve continence status. Tomas L. Griebling, M.D., M.P.H.
Benign Prostatic Hyperplasia Oestrogen and Benign Prostatic Hyperplasia: Effects on Stromal Cell Proliferation and Local Formation From Androgen C. K. Ho, J. Nanda, K. E. Chapman and F. K. Habib Prostate Research Group, University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom J Endocrinol 2008; 197: 483– 491.
Oestrogens have been implicated as a cause of benign prostatic hyperplasia (BPH). Previous animal studies led to the hypothesis that oestrogens can stimulate prostate growth, resulting in hyperplasia of the gland. In humans, the precise role of oestrogens in BPH pathogenesis is currently unclear. We investigated the direct effects of oestradiol on the proliferation of BPH-derived prostate cells in culture. Oestradiol (10(⫺7) and 10(⫺6) M) moderately increased the proliferation of stromal cells in culture; this stimulation was antagonised by anti-oestrogen ICI 182 780, indicating an oestrogen receptor (ER)-mediated mechanism. By contrast, oestradiol had no effects on the proliferation of epithelial cells in culture. Parameters that can determine the response of stromal cells to oestrogens, including expression of the two ER subtypes and aromatase activity, were investigated. ER beta expression in stromal cells in culture was demonstrated by immunohistochemistry and western blot analysis, and was confirmed by semi-quantitative RT-PCR showing higher expression of ER beta than ER alpha mRNA in stromal cells. Aromatase, the enzyme that converts androgen precursors to oestrogens, was also examined. Aromatase mRNA and activity were detected in stromal, but not epithelial cells in culture, suggesting a mechanism whereby oestrogen concentrations can be regulated in the BPH stroma. Taken together, these findings support the hypothesis that oestrogens play a role in the pathogenesis of BPH, a disease characterised predominantly by stromal overgrowth. Editorial Comment: According to classic urological teaching, 2 factors are required for BPH to develop—aging and androgens. As men age, plasma androgens decrease gradually while estrogen levels remain fairly constant. Stated otherwise, there are increasing ratios of estrogen to androgen levels in plasma. Estrogens via binding to intracellular estrogen receptors exert their effects as hormone inducible transcription factors. Moreover, aromatase, a member of the cytochrome P450 group of enzymes, converts C19 androgen
262
BENIGN PROSTATIC HYPERPLASIA
precursors to C18 estrogens. Additionally expression of aromatase in estrogen target tissue may represent a method whereby estrogens are regulated. Previous studies suggest that estrogens may have a role in BPH development, specifically the glandular epithelium. This study suggests that, in fact, estrogens increase the proliferation of stromal cells that are antagonized by antiestrogens. Furthermore, aromatase mRNA activity is similarly present in stromal but not epithelial cells. Given the relative preponderance of stromal versus epithelial cells in the human prostate, these data suggest that estrogen metabolism and estrogen regulation may be important targets to modulate prostate growth. Moreover, the relative effects of abdominal obesity on estrogen metabolism and, by extension, prostate growth may be an interesting avenue of translational research in the future. Steven A. Kaplan, M.D.
Benign Prostatic Hyperplasia: The Hypogonadal-Obesity-Prostate Connection P. G. Cohen Department of Pharmaceutical Sciences, Mercer University, Southern School of Pharmacy, Atlanta, Georgia Med Hypotheses 2009; 73: 142–143.
Prostatic enlargement occurs over the course of a lifetime and is associated with many risk factors. Recent observations demonstrate that valvular damage, occurring in the internal spermatic veins results in increased hydrostatic pressures that lead to venous backflow. Two consequences of venous backflow are the prolonged exposure to hydrostatic pressure and high testosterone levels that effect the prostate directly. Furthermore, aging and obesity related states have long been associated with BPH and diminished testosterone concentrations, which by itself, predisposes and allows for the preferential deposition of abdominal/visceral fat. The increasing abdominal obesity leads to elevated intra-abdominal pressure, which over time, causes increased venous pressure. Chronically elevated intra-abdominal venous pressure eventually causes progressive failure of the one way valves in the internal spermatic veins and venous insufficiency that leads to prostate damage. All of these factors promote conditions that cause chronic progressive prostatic disease and eventually BPH. Editorial Comment: The association between central obesity and pelvic dysfunction has been a source of interest and research during the last few years. What seems clear is that central obesity and metabolic dysfunction are associated with larger prostates, sexual dysfunction and worsening voiding symptoms. Similarly obesity is a major risk factor for overactive bladder symptoms in women. The causative factors for this association are less well understood. In men it is thought that central obesity leads to increased insulin resistance, hyperinsulinemia, increased sympathetic activity and decreased apoptosis in the prostate. The author proposes an interesting hypothesis that incorporates the concept that in men with benign prostatic hyperplasia there is increased hydrostatic pressure that impairs venous outflow. Simultaneously the increased venous hydrostatic pressure is the result of damage to the one-way valves of the internal spermatic veins. Consistent with this premise is the fact that the prostate becomes exposed to increased venous concentrations of testosterone. The hypogonadal-obesity cycle is based on the premise that decreased levels of testosterone and increased levels of aromatase lead to preferential deposition of abdominal and visceral fat. Finally chronic and changing back pressure causes venous congestion, which exposes the prostate to increased concentrations of testosterone. This proposed cycle of obesity, changes in testosterone, aging and prostate growth represents a novel approach to our understanding of metabolic dysfunction and BPH. This concept may partly explain the association of overactive bladder symptoms in women with central obesity, ie a hormonal and venous congestion etiology. Steven A. Kaplan, M.D.