0021-972X/92/7403-504A$O3,00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society
Editorial:
Benign
Vol. 74, No. 3 Printed in U.S.A.
Prostatic
Hyperplasia:
The human prostate remains a mysterious organ. There is no evidence that it contributes significantly to fertility, and its absence is not associated per se with any syndrome or endocrine disorder. However, its nearly ubiquitous enlargement during aging leads to urinary hesitancy, frequency, urgency, nocturia, and incontinence. Partial obstruction alters bladder function, retention of urine, and may lead to acute retention. Resistance to flow is associated with bladder wall hypertrophy, increased risk of urinary tract infection, and chronic renal disease. Recent NIH sponsored symposia and scientific groups have attempted to increase research attention to the problem of prostate hyperplasia (BPH) (l-3). It is the most frequent neoplasm in men, enlarges in over 75% over 50 yr of age, and is one of the most common causes of surgery in older men. The annual health care costs of BPH must be in the billions. It certainly takes a toll in the quality of life in aging men. New therapies based hopefully on mechanisms are sorely needed. The earlier work of Jean Wilson (1) and Donald Coffey and collaborators (2) has provided a firm foundation for understanding the pathophysiology of this disorder of the urogenital system. A basic concept is that growth and development of the prostate is under hormonal control, and BPH may be the result of an alteration in androgen metabolism or action. The prostate is derived from the urogenital sinus and is imprinted for later development by a surge of testosterone during early fetal development. There is an adolescent growth spurt coincident with testosterone secretion and a later period of growth starting probably in the fifth decade. BPH does not develop in castrate or hypogonadal individuals. In the rare disorders of androgen resistance (testicular feminization) or 5a-reductase deficiency, only a remnant prostate is present. Experimentally, androgen given in excess to young or castrate dogs can prematurely induce canine BPH. However, BPH is not a clear-cut disorder of androgen excess. While somewhat controversial, total and free serum concentrations of testosterone and testosterone blood secretion rates slowly fall in aging men even when Received December 15,199O. Address requests for reprints: Dr. Richard Horton, Southern California County Hospital, 1200 North State 18-632, Los Angeles, California 90033.
University of Street, Unit I
New Insights
not additionally complicated by various medical problems. Androgen action based on end organ responses, inhibition of gonadotropin feedback, androgen receptor number and affinity, does not appear to be increased. Thus, we are faced with increased growth of an androgen, dependent organ in the presence of a reduced androgen signal from the testis associated with aging. Our current understanding of androgen action provides some clues to this apparent discrepancy. Whereas testosterone is the circulating androgen, a peripheral conversion product, dihydrotestosterone (DHT), is the major nuclear androgen in sexual tissue (l-4). Unbound testosterone enters sexual tissue and is 5a reduced by the action of the enzyme steroid 5cr-reductase in the presence of the coenzyme NADPH. DHT bound to the androgen receptor then acts on gene expression inducing growth, development, and function. The prostate particularly is dependent upon DHT formation and receptor interaction. The pseudohermaphroditism of 5a-reductase deficiency or androgen receptor abnormalities are associated with lack of prostate development in fetal and adult life. The uniqueness of DHT as a prostate growth factor is especially demonstrated in the 5a-reductase syndrome, where circulating concentrations of testosterone are normal or increased. Experimentally, 5cY-reductase inhibitors can reproduce the syndrome in animal models and prostate development is blocked. Thus, the stage was set to explore the role of peripheral androgens in BPH. Earlier reports suggested that DHT concentrations in human BPH tissue were increased; however, analysis of fresh surgically removed tissue indicates that levels are not increased, but they are maintained in aging men even though their total and free serum testosterone concentrations are reduced. Blood production rates of DHT similarly do not fall with age, unlike testosterone and other steroids. More importantly, in the canine model of BPH, testosterone, DHT, or androstanediol (a metabolite of DHT) injections can produce BPH in young mongrel or beagle dogs. The induction of BPH in this species by large doses of testosterone can be prevented by concomitant administration of a 5cu-reductase inhibitor. Compounding the interpretation of these observations, is that androgen plus estrogen produces greater growth than androgen alone. This effect may be mediated via effects on androgen receptors or through production of peptide
504A
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
504B
EDITORIAL
growth factors. The rate-limiting step in DHT formation is the irreversible 5Lu-reductase reaction forming DHT, although a reduction in DHT degradation via formation of androstanediol (3a-diol) could alter DHT flux (T + DHT+3a-diol). There is some evidence both in viva and in vitro for both alterations in aging dogs and men (5). Whereas controversy continues about many of these observations, DHT remains clearly as a key factor in prostate growth and in prostate hyperplasia. Assays of 5a reductase activity in BPH by indirect means give contradictory results. The recent cloning of the 5a-reductase gene and synthesis of 5a-reductase messenger RNA (mRNA) should allow more direct studies of changes in 5cu-reductase from sexual tissue (6). These advances in our understanding of prostate endocrinology suggest a number of potential medical approaches. Reduction in testosterone secretion (medical castration), blockade of androgen action (antiandrogens), and the use of 5a-reductase inhibitors all appear to be rational approaches to therapy. Previous reports of the effect of medical castration with GnRH analog given by injection have appeared. Nafarelin acetate, a GnRH superagonist given for 6 months reduced testosterone to castrate levels, decreased prostate size by ultrasound 25%, and improved symptoms (7). Similar results occurred with leuprolide, another GnRH agonist. However, these approaches require parenteral therapy, are currently expensive, and reduce androgen levels throughout the body. Changes in libido, and potentia, as well as the chronic effects of decreased muscle mass and osteoporosis, would be expected. In contrast, inhibition of DHT formation by an oral agent that acts only in certain target tissues but does not alter circulating androgen (testosterone) might provide an effective approach that avoids important side effects. Beginning in the early 198Os, Liang, T., J. Brooks, and colleagues synthesized a series of 4-aza-Cl9 steroids that could inhibit 5a reductase (8). Whereas the earlier compounds that inhibited 5cu-reductase possessed some aftinity to the androgen receptor, N-(2 methyl-2 propyl)3-oxo-4-aza-5a-androst-1-ene-17&carboxamine (finasteride) acts specially on steroid 5cu-reductase. Given to normal men, it reduces plasma DHT and androstanediol glucuronide (a DHT metabolite) without altering plasma testosterone. This 4-aza-steroid has not been observed to have toxic or side effects. The report by McConnell et al. (9) in this issue, on the effect of finasteride (MK 906) on men with BPH is therefore of considerable interest. This report on 69 men treated with varying amounts of the drug for 7 days extends the earlier study by Geller, who found similar changes in a smaller group receiving high doses (100 mg daily) of the drug. In a double blind study for 7 days, finasteride reduced prostate DHT levels to 15% of con-
JCE & M .1992 Vol74.No3
trol and reciprocally increased tissue testosterone. In both groups the tissue was obtained from a planned transurethral resection and was frozen immediately, thereby avoiding any possible metabolism. The effects of finasteride occurred in doses as low as 1 mg daily (1, 5, 10, 50, and 100 mg daily were studied). Serum DHT concentrations also fell in the finasteride-treated groups, but no changes in serum testosterone were noted. Importantly, these tissue changes were as dramatic as those from long-acting GnRH agonist treatment which also markedly lowered blood testosterone. The present study and other reports indicate that in young and aging men testosterone concentrations in blood are 10 or more fold higher than DHT concentrations despite the higher affinity of the sex hormonebinding globulin for DHT. However, in prostate tissue the reverse is present. This difference suggests that DHT is a paracrine hormone formed in peripheral tissues, and blood concentrations of DHT may not reflect tissue formation. Studies comparing the specific activity of DHT in blood and urine also support this concept, as does the present observation that the reduction in tissue concentrations of DHT from finasteride were much more profound than in plasma. The predominance of DHT over testosterone supports the concept that DHT is the androgen that is active in the nucleus and that 5areductase plays a key role in androgen action on prostate. This encouraging ex uiuo study suggests that an orally active inhibitor of peripheral androgen formation might be an effective medical means of palliating or preventing symptomatic BPH. The clinical studies underway will be awaited with great interest. This study raises a number of questions about androgen action. The inhibition of prostate DHT formation results in a striking increase in tissue testosterone (and probably other metabolite) levels. Will this increase in part negate or alter the reduction in DHT? A recent paper by Geller (9) suggested that some androgen effects persist in this situation. Even if the more potent effects of DHT are ignored, the combined levels of both androgens are reduced by finasteride. A second question is whether libido and potentia will be altered and whether preservation of circulating testosterone will spare muscle and bone long term, in contrast to GnRH therapy, which reduces testosterone secretion. Based upon our knowledge of the 5a reductase deficiency syndrome, sexual drive, muscle, and bone should be minimally altered. The critical question, however, is what symptomatic and objective improvement will ensue from finasteride. It is encouraging that alternative therapies even short term, such as GnRH analogs or antiandrogens, significantly reduce prostate size, improve voiding indices, and reduce nocturia. These potential therapies are coming none too soon as
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
504c
EDITORIAL
the population ages. The physician can look forward to choices for the treatment or palliation of this common disorder. BPH. that include hormonal or a-adreneraic blockade, and mechanical (dilation or thermal), or sirgical approaches. Richard Horton Department of Medicine University of Southern California References Wilson JD. Recent studies on the mechanism of action of testosterone. N Engl J Med. 1972;287:1284-94. Rogers C, Coffey D, Cunha G, Grayback J, Henman F, Horton R, eds. Benign prostatic hyperplasia. U.S. Dept. Health and Human Service NIH Publication 87-2881, vol II. Medical Management of Prostate Disease (Symposia). J Androl.
1991;12:346-434. 4. Liao S, Fang S. Receptor proteins for androgens and the mode of action of androgens on gene transcription in ventral prostate. Vit Horm. 1969;27:17-26. 5. Ishimaru T, Pages L, Horton R. Altered metabolism of androgens in elderly men with BPH. J Clin Endocrinol Metab. 197745: 695-701. ___ ._-. Andersson S, Bishop R, Russell D. Expression cloning and regulation of steroid 5a-reductase, an enzyme essential for male sexual differentiation. J Biol Chem. I989;264:16249-55. Craig P, Walsh P. The effect of nafarelin acetate. an LHRH aeonist on benign prostatic hyperplasia. New Engl ‘J Med. 198?;317: 599-604. Brooks J, Baptista E, Berman C, Ham F, Hichens M, Johnston D, Primka R, Rasmisson G, Reynolds G, Schmitt S, Arth G. Response of rat ventral prostate to a new and novel 5a reductase inhibitor. Endocrinology. 1981;109:830-5. 9. McConnell J, Wilson JD, George FW, Geller J, Pappas F, Stoner E. Finasteride, an inhibitor of 5cY-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74:505-8.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
Editorial:
Benign
Vol. 74, No. 3 Printed in U.S.A.
Prostatic
Hyperplasia:
The human prostate remains a mysterious organ. There is no evidence that it contributes significantly to fertility, and its absence is not associated per se with any syndrome or endocrine disorder. However, its nearly ubiquitous enlargement during aging leads to urinary hesitancy, frequency, urgency, nocturia, and incontinence. Partial obstruction alters bladder function, retention of urine, and may lead to acute retention. Resistance to flow is associated with bladder wall hypertrophy, increased risk of urinary tract infection, and chronic renal disease. Recent NIH sponsored symposia and scientific groups have attempted to increase research attention to the problem of prostate hyperplasia (BPH) (l-3). It is the most frequent neoplasm in men, enlarges in over 75% over 50 yr of age, and is one of the most common causes of surgery in older men. The annual health care costs of BPH must be in the billions. It certainly takes a toll in the quality of life in aging men. New therapies based hopefully on mechanisms are sorely needed. The earlier work of Jean Wilson (1) and Donald Coffey and collaborators (2) has provided a firm foundation for understanding the pathophysiology of this disorder of the urogenital system. A basic concept is that growth and development of the prostate is under hormonal control, and BPH may be the result of an alteration in androgen metabolism or action. The prostate is derived from the urogenital sinus and is imprinted for later development by a surge of testosterone during early fetal development. There is an adolescent growth spurt coincident with testosterone secretion and a later period of growth starting probably in the fifth decade. BPH does not develop in castrate or hypogonadal individuals. In the rare disorders of androgen resistance (testicular feminization) or 5a-reductase deficiency, only a remnant prostate is present. Experimentally, androgen given in excess to young or castrate dogs can prematurely induce canine BPH. However, BPH is not a clear-cut disorder of androgen excess. While somewhat controversial, total and free serum concentrations of testosterone and testosterone blood secretion rates slowly fall in aging men even when Received December 15,199O. Address requests for reprints: Dr. Richard Horton, Southern California County Hospital, 1200 North State 18-632, Los Angeles, California 90033.
University of Street, Unit I
New Insights
not additionally complicated by various medical problems. Androgen action based on end organ responses, inhibition of gonadotropin feedback, androgen receptor number and affinity, does not appear to be increased. Thus, we are faced with increased growth of an androgen, dependent organ in the presence of a reduced androgen signal from the testis associated with aging. Our current understanding of androgen action provides some clues to this apparent discrepancy. Whereas testosterone is the circulating androgen, a peripheral conversion product, dihydrotestosterone (DHT), is the major nuclear androgen in sexual tissue (l-4). Unbound testosterone enters sexual tissue and is 5a reduced by the action of the enzyme steroid 5cr-reductase in the presence of the coenzyme NADPH. DHT bound to the androgen receptor then acts on gene expression inducing growth, development, and function. The prostate particularly is dependent upon DHT formation and receptor interaction. The pseudohermaphroditism of 5a-reductase deficiency or androgen receptor abnormalities are associated with lack of prostate development in fetal and adult life. The uniqueness of DHT as a prostate growth factor is especially demonstrated in the 5a-reductase syndrome, where circulating concentrations of testosterone are normal or increased. Experimentally, 5cY-reductase inhibitors can reproduce the syndrome in animal models and prostate development is blocked. Thus, the stage was set to explore the role of peripheral androgens in BPH. Earlier reports suggested that DHT concentrations in human BPH tissue were increased; however, analysis of fresh surgically removed tissue indicates that levels are not increased, but they are maintained in aging men even though their total and free serum testosterone concentrations are reduced. Blood production rates of DHT similarly do not fall with age, unlike testosterone and other steroids. More importantly, in the canine model of BPH, testosterone, DHT, or androstanediol (a metabolite of DHT) injections can produce BPH in young mongrel or beagle dogs. The induction of BPH in this species by large doses of testosterone can be prevented by concomitant administration of a 5cu-reductase inhibitor. Compounding the interpretation of these observations, is that androgen plus estrogen produces greater growth than androgen alone. This effect may be mediated via effects on androgen receptors or through production of peptide
504A
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
504B
EDITORIAL
growth factors. The rate-limiting step in DHT formation is the irreversible 5Lu-reductase reaction forming DHT, although a reduction in DHT degradation via formation of androstanediol (3a-diol) could alter DHT flux (T + DHT+3a-diol). There is some evidence both in viva and in vitro for both alterations in aging dogs and men (5). Whereas controversy continues about many of these observations, DHT remains clearly as a key factor in prostate growth and in prostate hyperplasia. Assays of 5a reductase activity in BPH by indirect means give contradictory results. The recent cloning of the 5a-reductase gene and synthesis of 5a-reductase messenger RNA (mRNA) should allow more direct studies of changes in 5cu-reductase from sexual tissue (6). These advances in our understanding of prostate endocrinology suggest a number of potential medical approaches. Reduction in testosterone secretion (medical castration), blockade of androgen action (antiandrogens), and the use of 5a-reductase inhibitors all appear to be rational approaches to therapy. Previous reports of the effect of medical castration with GnRH analog given by injection have appeared. Nafarelin acetate, a GnRH superagonist given for 6 months reduced testosterone to castrate levels, decreased prostate size by ultrasound 25%, and improved symptoms (7). Similar results occurred with leuprolide, another GnRH agonist. However, these approaches require parenteral therapy, are currently expensive, and reduce androgen levels throughout the body. Changes in libido, and potentia, as well as the chronic effects of decreased muscle mass and osteoporosis, would be expected. In contrast, inhibition of DHT formation by an oral agent that acts only in certain target tissues but does not alter circulating androgen (testosterone) might provide an effective approach that avoids important side effects. Beginning in the early 198Os, Liang, T., J. Brooks, and colleagues synthesized a series of 4-aza-Cl9 steroids that could inhibit 5a reductase (8). Whereas the earlier compounds that inhibited 5cu-reductase possessed some aftinity to the androgen receptor, N-(2 methyl-2 propyl)3-oxo-4-aza-5a-androst-1-ene-17&carboxamine (finasteride) acts specially on steroid 5cu-reductase. Given to normal men, it reduces plasma DHT and androstanediol glucuronide (a DHT metabolite) without altering plasma testosterone. This 4-aza-steroid has not been observed to have toxic or side effects. The report by McConnell et al. (9) in this issue, on the effect of finasteride (MK 906) on men with BPH is therefore of considerable interest. This report on 69 men treated with varying amounts of the drug for 7 days extends the earlier study by Geller, who found similar changes in a smaller group receiving high doses (100 mg daily) of the drug. In a double blind study for 7 days, finasteride reduced prostate DHT levels to 15% of con-
JCE & M .1992 Vol74.No3
trol and reciprocally increased tissue testosterone. In both groups the tissue was obtained from a planned transurethral resection and was frozen immediately, thereby avoiding any possible metabolism. The effects of finasteride occurred in doses as low as 1 mg daily (1, 5, 10, 50, and 100 mg daily were studied). Serum DHT concentrations also fell in the finasteride-treated groups, but no changes in serum testosterone were noted. Importantly, these tissue changes were as dramatic as those from long-acting GnRH agonist treatment which also markedly lowered blood testosterone. The present study and other reports indicate that in young and aging men testosterone concentrations in blood are 10 or more fold higher than DHT concentrations despite the higher affinity of the sex hormonebinding globulin for DHT. However, in prostate tissue the reverse is present. This difference suggests that DHT is a paracrine hormone formed in peripheral tissues, and blood concentrations of DHT may not reflect tissue formation. Studies comparing the specific activity of DHT in blood and urine also support this concept, as does the present observation that the reduction in tissue concentrations of DHT from finasteride were much more profound than in plasma. The predominance of DHT over testosterone supports the concept that DHT is the androgen that is active in the nucleus and that 5areductase plays a key role in androgen action on prostate. This encouraging ex uiuo study suggests that an orally active inhibitor of peripheral androgen formation might be an effective medical means of palliating or preventing symptomatic BPH. The clinical studies underway will be awaited with great interest. This study raises a number of questions about androgen action. The inhibition of prostate DHT formation results in a striking increase in tissue testosterone (and probably other metabolite) levels. Will this increase in part negate or alter the reduction in DHT? A recent paper by Geller (9) suggested that some androgen effects persist in this situation. Even if the more potent effects of DHT are ignored, the combined levels of both androgens are reduced by finasteride. A second question is whether libido and potentia will be altered and whether preservation of circulating testosterone will spare muscle and bone long term, in contrast to GnRH therapy, which reduces testosterone secretion. Based upon our knowledge of the 5a reductase deficiency syndrome, sexual drive, muscle, and bone should be minimally altered. The critical question, however, is what symptomatic and objective improvement will ensue from finasteride. It is encouraging that alternative therapies even short term, such as GnRH analogs or antiandrogens, significantly reduce prostate size, improve voiding indices, and reduce nocturia. These potential therapies are coming none too soon as
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
504c
EDITORIAL
the population ages. The physician can look forward to choices for the treatment or palliation of this common disorder. BPH. that include hormonal or a-adreneraic blockade, and mechanical (dilation or thermal), or sirgical approaches. Richard Horton Department of Medicine University of Southern California References Wilson JD. Recent studies on the mechanism of action of testosterone. N Engl J Med. 1972;287:1284-94. Rogers C, Coffey D, Cunha G, Grayback J, Henman F, Horton R, eds. Benign prostatic hyperplasia. U.S. Dept. Health and Human Service NIH Publication 87-2881, vol II. Medical Management of Prostate Disease (Symposia). J Androl.
1991;12:346-434. 4. Liao S, Fang S. Receptor proteins for androgens and the mode of action of androgens on gene transcription in ventral prostate. Vit Horm. 1969;27:17-26. 5. Ishimaru T, Pages L, Horton R. Altered metabolism of androgens in elderly men with BPH. J Clin Endocrinol Metab. 197745: 695-701. ___ ._-. Andersson S, Bishop R, Russell D. Expression cloning and regulation of steroid 5a-reductase, an enzyme essential for male sexual differentiation. J Biol Chem. I989;264:16249-55. Craig P, Walsh P. The effect of nafarelin acetate. an LHRH aeonist on benign prostatic hyperplasia. New Engl ‘J Med. 198?;317: 599-604. Brooks J, Baptista E, Berman C, Ham F, Hichens M, Johnston D, Primka R, Rasmisson G, Reynolds G, Schmitt S, Arth G. Response of rat ventral prostate to a new and novel 5a reductase inhibitor. Endocrinology. 1981;109:830-5. 9. McConnell J, Wilson JD, George FW, Geller J, Pappas F, Stoner E. Finasteride, an inhibitor of 5cY-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74:505-8.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 01:18 For personal use only. No other uses without permission. . All rights reserved.
