© 1991 Karger AG, Basel 0302-2838/91/0206-0027 $ 2.75/0
Euro Urol 1991;20(suppl 2):27-30
Pathogenesis of Benign Prostatic Hyperplasia 1605952
R.J.L.H. Bosch Department of Urology. Erasmus University Hospital, Rotterdam. The Netherlands
Key Words. Dihydrotestosterone • Stromal cell ■ Fibroblast • Stem cells • Androgen Abstract. The pathogenesis of benign prostatic hyperplasia (BPH) remains largely unresolved. Three major theo ries have evolved over the years, each emphasizing a possible causative mechanism. The first theory, the dihydrotestos terone hypothesis, is based on the failure of BPFI to develop in men castrated prior to puberty. The second, the embry onic reawakening theory, assumes a reawakening of the embryonic induction potential of prostatic stroma. The third, or stem cell theory, postulates the development of BPFI through an increase in the number of stem cells or through an abnormal increase in clonal expansion of amplifying or transit cells. These mechanisms may act in concert.
From a clinical perspective, much interest attaches to the pathogenesis of the clinical syndrome attributed to benign prostatic hyperplasia (BPH). The first step in unraveling this problem is to understand the pathogenesis of the histopathologic abnormalities of BPH. The clinical syndrome of BPH, also known as prosta tism, is characterized by well-known obstructive and irri tative symptoms. Although almost every man who lives long enough will develop microscopic BPH, only about 50% will go on to develop macroscopic BPH, and only about 50% of the patients who develop macroscopic BPH will actually develop the clinical syndrome [1]. Decreas ing the size of the prostate will not necessarily lead to fewer symptoms of prostatism. In our study, in which we used cyproterone acetate or the luteinizing hormone releasing hormone agonist buserelin, we found that these medications led to a 30% decrease in volume, but that no clinically important improvement in symptoms occurred [2]. Furthermore, a spontaneous decrease in subjective symptoms does occur in about one third of patients fol lowed for 3 years [3]. Because prostate size does not usu ally decrease spontaneously, it is possible for symptom atic improvement to occur even without reduction in pros
tatic volume. Therefore, it cannot be size alone that determines the development of the clinical syndrome. Unraveling the etiology of pathologic BPH does not necessarily mean that we will then understand prostatism. However, histopathologic BPH is apparently the first step on the path to prostatism. The pathogenesis of BPH has remained largely unre solved. Over the years, 3 major approaches that emphasize different possible causative mechanisms have evolved; these mechanisms may act in concert. There is no direct proof that any of these theories is correct with respect to the human male. These approaches are: (1) theories based on hormonal mechanisms; (2) the stem cell theory; and (3) theories relating to stromal-epithelial interaction.
Theories Based on Hormonal Mechanisms The Dihydrotestosterone Hypothesis That BPH does not develop in men castrated prior to puberty points to a testicular dependence of BPH. Because androgen withdrawal leads to a reduced prostate volume, androgens, most notably dihydrotestosterone (DHT), appear to be implicated in the development and/ or maintenance of BPH.
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
Introduction
Bosch
DHT is the major intracellular androgenic metabolite in the human prostate. Wilson et al. [4, 5J suggested that the development of BPH was related to an increase in prostatic DHT content, which was thought to increase with age. However, Walsh et al. [6] showed that DHT lev els are no higher in BPH tissue than in normal prostatic tissue. They contended that previous reports stating the opposite were actually based on artifacts. Furthermore, abnormal prostatic growth in dogs continues despite declining serum testosterone and tissue DHT levels. Therefore, DHT is needed for the development and maintenance of BPH but cannot be the only factor involved in its induction. Estrogen!Androgen Synergism The synergism between estrogen and androgen is another mechanism hypothesized to induce BPH. Estro gens are produced in the male by aromatization of androstenedione (forming estrone) or testosterone (forming estradiol). Data on the role of estrogens in BPH were recently summarized by Walsh [7]. Some of the more important arguments against estrogen/androgen syner gism as a pathogenetic factor are that BPH tissue contains fewer estrogen receptors than does normal prostate tissue and that age-related alterations in estrogen/androgen production are minor and definitely occur only after the onset of the pathologic process. However, the induction by estrogen of the androgen receptor in dogs and the ele vated level of nuclear androgen receptor in human BPH argue for estrogen/androgen synergism. In general, direct proof for the steroid-induced patho genesis of BPH in the human is still lacking. It appears that steroid hormones are not the major cause, but rather have a permissive effect.
The Stem Cell Theory Isaacs and Coffey have proposed the stem cell theory [8]. A stem cell is defined as a cell type capable of exten sive renewal despite physiologic or accidental removal or loss of cells from the population. From experimental data, these researchers concluded that the development of stem cells is androgen-sensitive until their full number has developed. In the rat, the full number is reached at 5% of the total life span; in the dog at 20%. Animals castrated before that number has been reached will not show full prostate regrowth after androgen supplementation, in contrast to animals castrated after the critical period. Thereafter, stem cells are androgen-insensitive.
Amplifying cells originate from stem cells and prolifer ate for only a limited number of cell divisions. They lead to a major amplification of the total number of cells pres ent. Amplifying cells do not depend on hormones for their survival, but can be stimulated by androgens to clonal expansion, forming transit cells. The transit cells become the majority of cells present in the prostate. According to these concepts, BPH could develop in 2 ways: (1) through an abnormal increase in the number of stem cells and/or (2) through an abnormal increase in clonal expansion of amplifying or transit cells. Isaacs and Coffey [8] based their theory on data on growth rates dur ing the development of the prostate to normal adult size, and growth rates during both spontaneous development of BPH and restoration of prostate size, after discontinua tion of androgen withdrawal. The restoration rate of human BPH after discontinuation of androgen withdraw al is more than threefold faster than the growth rate dur ing spontaneous BPH development and during early development of the normal prostate. This suggests that the total number of stem cells, as well as the total number of amplifying and transit cells, increases during sponta neous development of BPH [8]. Furthermore, the bio chemical and morphometric difference of BPH tissue from normal prostatic tissue suggests that an increase in the total number of stem cells cannot be the only mech anism operating in the pathogenesis of BPH. An abnor mal increase in the total number of stem cells would only result in an enlarged prostate, i.e., more tissue but not phenotypically different from that of the normal prostate.
Theories Relating to Stromal-Epithelial Interaction Embryonic Reawakening McNeal [9] observed that the primary lesion of BPH was not the formation of stromal nodules, but a glandular bud ding and branching mechanism that gives rise to new alveoli in a small periurethral area of the prostate, which he called the transition zone. He considers this acinar formation to be the expression of the reawakened ‘embryonic’ capacity of this tissue. He further theorizes that some stromal-humoral factor might induce epithelial proliferation. In embryonic development, androgens induce bud ding of prostatic ducts into surrounding stroma. In exper iments in which either intact embryonic urogenital sinus tissue or only its epithelial or mesenchymal components were implanted in adult mice prostates, Chung [10] has shown that only the mesenchyme has an inductive poten tial. Cunha [11] found that the mesenchyme is the target
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
28
Pathogenesis of Benign Prostatic Hyperplasia
Basic Fibroblast Growth Factor Several scenarios have been postulated to explain reawakened proliferation of stromal or epithelial tissues. Lawson [ 12] proposes a role for basic fibroblast growth factor (BFGF). the major growth factor found in the human prostate. Itcanbe modulated by androgens, estro gens, and steroids, as well as by transforming growth fac tor ß (TGF-ß). Epithelial or stromal cells can produce BFGF, which can bind to heparan sulfate, a glycosaminoglycaninthe basement membrane. Theoretically, stromal and glandular hyperplasia could be induced by increased cellular release through either secretion or from injured cells. Alternatively, the substance might be released from the basement membrane by action of the enzyme heparinitase on the heparan/BFGF complex. Basement Membrane Another scenario places more emphasis on the base ment membrane itself [13]; the glycosaminoglycan hepa ran and related substances have been shown to inhibit smooth muscle cell proliferation in vivo and in vitro. This scenario is derived from possible analogies with fibromuscular proliferation in arterial blood vessels. Endothelial damage and removal of the antiproliferative glycosami noglycan layer in these blood vessels leads to fibromuscular proliferation. It is therefore conceivable that an altered or declining production of extracellular matrix molecules could lead to a reduced inhibitory effect. This again could be the initiating step for fibroblast or smooth muscle cell proliferation. Epithelial Chalones TGF-ß is an epithelial chalone that stimulates fibronectin and collagen type I production. These substances inhibit basement membrane remodeling and could pos sibly lead to a nonproliferative state of epithelium and stromal cells. If this theory should prove to be correct, deficient production or lowered sensitivity to this chalone may be important [13].
Discussion Although the aforementioned theories seem to differ in their explanation of the development of BPH, it is not
unlikely that hormonal changes and aberrations in stro mal-epithelial interactions act in concert in the etiology of this disease. Most of the present concepts of the development of BPH have been developed on the basis of results obtained in animal research. These concepts are now being tested in human BPH. The DHT hypothesis has led to human trials of androgen withdrawal in BPH. The fact that androgen withdrawal leads to a reversible decrease in prostate size [2], proves that androgens play some role in the development or maintenance of human BPH. Therefore, treatments aimed at reducing plasma testosterone or inhibiting androgen metabolism inside the prostate cell may be of value. If estro gen/androgen synergism is a mechanism of importance, treatments such as aromatase inhibition, which aim at reducing estrogen levels, are justified. Clinical research in the form of well-designed trials will have to prove or disprove these concepts in humans. Pros tate size will be only one of the variables of interest in such trials. In a clinical setting, symptoms and objective mea sures of voiding function are even more important variables in the determination of treatment success. Future clinical research will have to establish whether a strong relation exists between volume increase and voiding dysfunction, or whether the voiding dysfunction is caused (in part) by fac tors unrelated to volume increase of the prostate.
Conclusion Despite many years of research, the pathogenesis of BPH has remained obscure. The only two factors that are definitely known to be of importance in its onset are the presence of testes and age. Direct proof is lacking regard ing a definite association between BPH and any or all of the mechanistic theories postulated thus far. However, such theories do provide interesting avenues for research into the development of new modalities of treatment.
References 1 Isaacs JT: Epidemiology and natural history of benign prostatic hyperplasia, in: Prostate et alpha-bloquants. Amsterdam, Excerp ta Medica, 1988. pp 1-10. 2 Bosch RJLH. Griffiths DJ, Blom JHM, et al: Treatment of benign prostatic hyperplasia by androgen deprivation: Effects on prostate size and urodynamic parameters. J Urol 1989:141:68-72. 3 Birkhoff JD: Natural history of benign prostatic hypertrophy, in Hinman F (ed): Benign Prostatic Hypertrophy. New York, Springer-Verlag, 1983, pp 5-9.
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
for androgenic stimulation and mediates this effect to the epithelium. However, no evidence as yet supports the idea that adult smooth muscle cells or fibroblasts have retained the capacity to induce glandular growth.
29
Bosch
30
11 Cunha GR, Chung LWK, Shannon JM: Stromal-epithelial inter
actions in sex differentiation. Biol Reprod 1980;22:19—41. 12 Lawson RK: Growth factor and benign prostatic hyperplasia.
World J Urol 1989;6:190-193. 13 Mawhinney M: The extracellular matrix and cellular proliferation
in the etiology of benign prostatic hyperplasia, in Ackermann R. Schröder FH (eds): Prostatic Hyperplasia. Berlin, W de Gruyter, 1989, pp 55-62.
R.J.L.H. Bosch, MD Department of Urology Erasmus University Hospital Dr. Molewaterplein 40 NL-3015 GD Rotterdam (The Netherlands)
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
4 Wilson JD; The pathogenesis of benign prostatic hyperplasia. Am J Med 1980;68:745-756. 5 Sitteri PK, Wilson JD: Dihydrotestosterone in prostatic hypertro phy. I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man. J Clin Invest 1970;49:1737-1745. 6 Walsh PC, Hutchins GM. Ewing LL: The tissue content of dihydro testosterone in human prostatic hyperplasia is not supranormal. J Clin Invest 1983;72:1772-1777. 7 Walsh PC: Benign prostatic hyperplasia, in: Walsh PC, Gittes RF, Perlmutter AD. et al (eds): Campbell’s Urology, Philadelphia, WB Saunders, 1986, pp 1248-1265. 8 Isaacs JT, Coffey DS: Etiology and disease process of benign pros tatic hyperplasia. Prostate 1989;(suppl 2):33-50. 9 McNealJE: Originandevaluationofbenignprostaticenlargement. Invest Urol 1978;15:340-345. 10 Chung LWK, Matsuura J, Runner MR: Tissue interactions and prostatic growth. I. Induction of adult mouse prostatic hyperplasia by fetal urogenital sinus implants. Biol Reprod 1984:31:155-163.
Euro Urol 1991;20(suppl 2):27-30
Pathogenesis of Benign Prostatic Hyperplasia 1605952
R.J.L.H. Bosch Department of Urology. Erasmus University Hospital, Rotterdam. The Netherlands
Key Words. Dihydrotestosterone • Stromal cell ■ Fibroblast • Stem cells • Androgen Abstract. The pathogenesis of benign prostatic hyperplasia (BPH) remains largely unresolved. Three major theo ries have evolved over the years, each emphasizing a possible causative mechanism. The first theory, the dihydrotestos terone hypothesis, is based on the failure of BPFI to develop in men castrated prior to puberty. The second, the embry onic reawakening theory, assumes a reawakening of the embryonic induction potential of prostatic stroma. The third, or stem cell theory, postulates the development of BPFI through an increase in the number of stem cells or through an abnormal increase in clonal expansion of amplifying or transit cells. These mechanisms may act in concert.
From a clinical perspective, much interest attaches to the pathogenesis of the clinical syndrome attributed to benign prostatic hyperplasia (BPH). The first step in unraveling this problem is to understand the pathogenesis of the histopathologic abnormalities of BPH. The clinical syndrome of BPH, also known as prosta tism, is characterized by well-known obstructive and irri tative symptoms. Although almost every man who lives long enough will develop microscopic BPH, only about 50% will go on to develop macroscopic BPH, and only about 50% of the patients who develop macroscopic BPH will actually develop the clinical syndrome [1]. Decreas ing the size of the prostate will not necessarily lead to fewer symptoms of prostatism. In our study, in which we used cyproterone acetate or the luteinizing hormone releasing hormone agonist buserelin, we found that these medications led to a 30% decrease in volume, but that no clinically important improvement in symptoms occurred [2]. Furthermore, a spontaneous decrease in subjective symptoms does occur in about one third of patients fol lowed for 3 years [3]. Because prostate size does not usu ally decrease spontaneously, it is possible for symptom atic improvement to occur even without reduction in pros
tatic volume. Therefore, it cannot be size alone that determines the development of the clinical syndrome. Unraveling the etiology of pathologic BPH does not necessarily mean that we will then understand prostatism. However, histopathologic BPH is apparently the first step on the path to prostatism. The pathogenesis of BPH has remained largely unre solved. Over the years, 3 major approaches that emphasize different possible causative mechanisms have evolved; these mechanisms may act in concert. There is no direct proof that any of these theories is correct with respect to the human male. These approaches are: (1) theories based on hormonal mechanisms; (2) the stem cell theory; and (3) theories relating to stromal-epithelial interaction.
Theories Based on Hormonal Mechanisms The Dihydrotestosterone Hypothesis That BPH does not develop in men castrated prior to puberty points to a testicular dependence of BPH. Because androgen withdrawal leads to a reduced prostate volume, androgens, most notably dihydrotestosterone (DHT), appear to be implicated in the development and/ or maintenance of BPH.
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
Introduction
Bosch
DHT is the major intracellular androgenic metabolite in the human prostate. Wilson et al. [4, 5J suggested that the development of BPH was related to an increase in prostatic DHT content, which was thought to increase with age. However, Walsh et al. [6] showed that DHT lev els are no higher in BPH tissue than in normal prostatic tissue. They contended that previous reports stating the opposite were actually based on artifacts. Furthermore, abnormal prostatic growth in dogs continues despite declining serum testosterone and tissue DHT levels. Therefore, DHT is needed for the development and maintenance of BPH but cannot be the only factor involved in its induction. Estrogen!Androgen Synergism The synergism between estrogen and androgen is another mechanism hypothesized to induce BPH. Estro gens are produced in the male by aromatization of androstenedione (forming estrone) or testosterone (forming estradiol). Data on the role of estrogens in BPH were recently summarized by Walsh [7]. Some of the more important arguments against estrogen/androgen syner gism as a pathogenetic factor are that BPH tissue contains fewer estrogen receptors than does normal prostate tissue and that age-related alterations in estrogen/androgen production are minor and definitely occur only after the onset of the pathologic process. However, the induction by estrogen of the androgen receptor in dogs and the ele vated level of nuclear androgen receptor in human BPH argue for estrogen/androgen synergism. In general, direct proof for the steroid-induced patho genesis of BPH in the human is still lacking. It appears that steroid hormones are not the major cause, but rather have a permissive effect.
The Stem Cell Theory Isaacs and Coffey have proposed the stem cell theory [8]. A stem cell is defined as a cell type capable of exten sive renewal despite physiologic or accidental removal or loss of cells from the population. From experimental data, these researchers concluded that the development of stem cells is androgen-sensitive until their full number has developed. In the rat, the full number is reached at 5% of the total life span; in the dog at 20%. Animals castrated before that number has been reached will not show full prostate regrowth after androgen supplementation, in contrast to animals castrated after the critical period. Thereafter, stem cells are androgen-insensitive.
Amplifying cells originate from stem cells and prolifer ate for only a limited number of cell divisions. They lead to a major amplification of the total number of cells pres ent. Amplifying cells do not depend on hormones for their survival, but can be stimulated by androgens to clonal expansion, forming transit cells. The transit cells become the majority of cells present in the prostate. According to these concepts, BPH could develop in 2 ways: (1) through an abnormal increase in the number of stem cells and/or (2) through an abnormal increase in clonal expansion of amplifying or transit cells. Isaacs and Coffey [8] based their theory on data on growth rates dur ing the development of the prostate to normal adult size, and growth rates during both spontaneous development of BPH and restoration of prostate size, after discontinua tion of androgen withdrawal. The restoration rate of human BPH after discontinuation of androgen withdraw al is more than threefold faster than the growth rate dur ing spontaneous BPH development and during early development of the normal prostate. This suggests that the total number of stem cells, as well as the total number of amplifying and transit cells, increases during sponta neous development of BPH [8]. Furthermore, the bio chemical and morphometric difference of BPH tissue from normal prostatic tissue suggests that an increase in the total number of stem cells cannot be the only mech anism operating in the pathogenesis of BPH. An abnor mal increase in the total number of stem cells would only result in an enlarged prostate, i.e., more tissue but not phenotypically different from that of the normal prostate.
Theories Relating to Stromal-Epithelial Interaction Embryonic Reawakening McNeal [9] observed that the primary lesion of BPH was not the formation of stromal nodules, but a glandular bud ding and branching mechanism that gives rise to new alveoli in a small periurethral area of the prostate, which he called the transition zone. He considers this acinar formation to be the expression of the reawakened ‘embryonic’ capacity of this tissue. He further theorizes that some stromal-humoral factor might induce epithelial proliferation. In embryonic development, androgens induce bud ding of prostatic ducts into surrounding stroma. In exper iments in which either intact embryonic urogenital sinus tissue or only its epithelial or mesenchymal components were implanted in adult mice prostates, Chung [10] has shown that only the mesenchyme has an inductive poten tial. Cunha [11] found that the mesenchyme is the target
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
28
Pathogenesis of Benign Prostatic Hyperplasia
Basic Fibroblast Growth Factor Several scenarios have been postulated to explain reawakened proliferation of stromal or epithelial tissues. Lawson [ 12] proposes a role for basic fibroblast growth factor (BFGF). the major growth factor found in the human prostate. Itcanbe modulated by androgens, estro gens, and steroids, as well as by transforming growth fac tor ß (TGF-ß). Epithelial or stromal cells can produce BFGF, which can bind to heparan sulfate, a glycosaminoglycaninthe basement membrane. Theoretically, stromal and glandular hyperplasia could be induced by increased cellular release through either secretion or from injured cells. Alternatively, the substance might be released from the basement membrane by action of the enzyme heparinitase on the heparan/BFGF complex. Basement Membrane Another scenario places more emphasis on the base ment membrane itself [13]; the glycosaminoglycan hepa ran and related substances have been shown to inhibit smooth muscle cell proliferation in vivo and in vitro. This scenario is derived from possible analogies with fibromuscular proliferation in arterial blood vessels. Endothelial damage and removal of the antiproliferative glycosami noglycan layer in these blood vessels leads to fibromuscular proliferation. It is therefore conceivable that an altered or declining production of extracellular matrix molecules could lead to a reduced inhibitory effect. This again could be the initiating step for fibroblast or smooth muscle cell proliferation. Epithelial Chalones TGF-ß is an epithelial chalone that stimulates fibronectin and collagen type I production. These substances inhibit basement membrane remodeling and could pos sibly lead to a nonproliferative state of epithelium and stromal cells. If this theory should prove to be correct, deficient production or lowered sensitivity to this chalone may be important [13].
Discussion Although the aforementioned theories seem to differ in their explanation of the development of BPH, it is not
unlikely that hormonal changes and aberrations in stro mal-epithelial interactions act in concert in the etiology of this disease. Most of the present concepts of the development of BPH have been developed on the basis of results obtained in animal research. These concepts are now being tested in human BPH. The DHT hypothesis has led to human trials of androgen withdrawal in BPH. The fact that androgen withdrawal leads to a reversible decrease in prostate size [2], proves that androgens play some role in the development or maintenance of human BPH. Therefore, treatments aimed at reducing plasma testosterone or inhibiting androgen metabolism inside the prostate cell may be of value. If estro gen/androgen synergism is a mechanism of importance, treatments such as aromatase inhibition, which aim at reducing estrogen levels, are justified. Clinical research in the form of well-designed trials will have to prove or disprove these concepts in humans. Pros tate size will be only one of the variables of interest in such trials. In a clinical setting, symptoms and objective mea sures of voiding function are even more important variables in the determination of treatment success. Future clinical research will have to establish whether a strong relation exists between volume increase and voiding dysfunction, or whether the voiding dysfunction is caused (in part) by fac tors unrelated to volume increase of the prostate.
Conclusion Despite many years of research, the pathogenesis of BPH has remained obscure. The only two factors that are definitely known to be of importance in its onset are the presence of testes and age. Direct proof is lacking regard ing a definite association between BPH and any or all of the mechanistic theories postulated thus far. However, such theories do provide interesting avenues for research into the development of new modalities of treatment.
References 1 Isaacs JT: Epidemiology and natural history of benign prostatic hyperplasia, in: Prostate et alpha-bloquants. Amsterdam, Excerp ta Medica, 1988. pp 1-10. 2 Bosch RJLH. Griffiths DJ, Blom JHM, et al: Treatment of benign prostatic hyperplasia by androgen deprivation: Effects on prostate size and urodynamic parameters. J Urol 1989:141:68-72. 3 Birkhoff JD: Natural history of benign prostatic hypertrophy, in Hinman F (ed): Benign Prostatic Hypertrophy. New York, Springer-Verlag, 1983, pp 5-9.
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
for androgenic stimulation and mediates this effect to the epithelium. However, no evidence as yet supports the idea that adult smooth muscle cells or fibroblasts have retained the capacity to induce glandular growth.
29
Bosch
30
11 Cunha GR, Chung LWK, Shannon JM: Stromal-epithelial inter
actions in sex differentiation. Biol Reprod 1980;22:19—41. 12 Lawson RK: Growth factor and benign prostatic hyperplasia.
World J Urol 1989;6:190-193. 13 Mawhinney M: The extracellular matrix and cellular proliferation
in the etiology of benign prostatic hyperplasia, in Ackermann R. Schröder FH (eds): Prostatic Hyperplasia. Berlin, W de Gruyter, 1989, pp 55-62.
R.J.L.H. Bosch, MD Department of Urology Erasmus University Hospital Dr. Molewaterplein 40 NL-3015 GD Rotterdam (The Netherlands)
Downloaded by: American University of Beirut - Jafet Library 193.188.128.21 - 6/25/2018 7:38:42 AM
4 Wilson JD; The pathogenesis of benign prostatic hyperplasia. Am J Med 1980;68:745-756. 5 Sitteri PK, Wilson JD: Dihydrotestosterone in prostatic hypertro phy. I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man. J Clin Invest 1970;49:1737-1745. 6 Walsh PC, Hutchins GM. Ewing LL: The tissue content of dihydro testosterone in human prostatic hyperplasia is not supranormal. J Clin Invest 1983;72:1772-1777. 7 Walsh PC: Benign prostatic hyperplasia, in: Walsh PC, Gittes RF, Perlmutter AD. et al (eds): Campbell’s Urology, Philadelphia, WB Saunders, 1986, pp 1248-1265. 8 Isaacs JT, Coffey DS: Etiology and disease process of benign pros tatic hyperplasia. Prostate 1989;(suppl 2):33-50. 9 McNealJE: Originandevaluationofbenignprostaticenlargement. Invest Urol 1978;15:340-345. 10 Chung LWK, Matsuura J, Runner MR: Tissue interactions and prostatic growth. I. Induction of adult mouse prostatic hyperplasia by fetal urogenital sinus implants. Biol Reprod 1984:31:155-163.
