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Prolactin concentration in prostates with benign hypertrophy
PROLACTIN
CONCENTRATION
IN PROSTATES
WITH BENIGN HYPERTROPHY M. RON, M.D. A. FICH A. SHAPIRO, M. CAINE,
M.D. M.D.
M. BEN-DAVID,
PH.D.
From the Departments of Obstetrics and Gynecology, Urology, and Pharmacology, Hadassah University Hospital, Jerusalem, Israel
ABSTRACT - Twenty-two hypertrophied prostates removed in surgery were checked for prolactin concentration by the radioimmunoassay method. The mean concentration in the prostatic tissue was found to be 38.2 + 1.9 ng.lGm. while the mean basal serum level was 11.9 + 1.3 ng.Iml. It is concluded that serum prolactin levels do not reject prostatic prolactin concentration. The possibility that interrelationship in action exists between androgens and prolactin affecting each other’s concentration, both injluencing prostatic metabolism is discussed.
It has been shown in recent years that prolactin may have a role in the growth and hypertrophy of male secondary sex organs in laboratory animals. lm3Specific receptors for prolactin have been found in the rat’s prostate4-s and recently in man.’ The significance of prolactin in the etiology of benign hypertrophy of the prostate in man is not clear. Birkhoff et al. in 19748 did not find higher serum prolactin levels in men over fifty years as compared with younger age groups, thus claiming that prolactin plays no role in the pathogenesis of BHP in men. Hammond9 on the other hand did find an elevation of serum prolactin levels in men over sixty. It is well documented that serum hormonal levels do not reflect its concentration in a target organ. lo It is influenced by changes in the concentration and saturation of its specific recep tors . lo Preliminary studies done by us suggested high prolactin levels in the prostate of man.11,‘2 The aim of this study was to determine prolac-
UROLOGY
/
MARCH1981
/ VOLUME
XVII, NUMBER 3
tin concentration in prostatic tissue removed for benign hypertrophy, in order to collect more data about the possible role that prolactin plays in the origin of this disease. Material and Methods The study group included twenty-two males (age fifty-two to sixty-five) who underwent retropubic prostatectomy for benign hypertrophy of the prostate. Surgery was performed under epidural anesthesia. Blood sample for prolactin assessment was taken on admission and at surgery, immediately prior to the removal of the prostate. The serum was separated and stored at -20” C. Prolactin determination was performed by the radioimmunoassay method. r3*r4 The prostates removed were weighed and examined pathologically. A slice of each prostate was stored at -40” C. until further examination. Later processing of the tissue included hardening by liquid nitrogen and pulverization by mortar and pestle cooled by liquid nitrogen. The powder obtained from
235
I. Basal serum prolactin concentration (ng.lml.) and prostatic prolactin concentration (ng.lGm.)*
TABLE
Serum
Prostate
11.9545 6.227 1.328
38.2 9.015 1.922
Serum prolactin levels during operation (ng.lmL) and prostatic prolactin concentration (ng.lGm.)*
TABLE II.
Sk. S.E.
*N = 22; Student’st test: T value -12.63;
p < 0.001.
each prostate was weighed and dissolved in Tris buffer (10mM Tris HCL + 1mM MgCLa pH 7.7) at a ratio of 3: 1 (volume: weight). The solution obtained was homogenized at 0” C. using a glass-Teflon homogenizer. The homogenate was centrifuged at 0” C. in 2,000 r.p.m. for twenty minutes. Prolactin concentration in the supernatant obtained was determined using the radioimmunoassay method. 13a14 Results Prostatic prolactin concentration per gram wet weight of tissue was found to be 21.6 to 57.9 ng./ Gm. (Table I). These values are about three to four times those of serum basal levels. During surgery just before the removal of the prostate, serum prolactin levels were higher than control levels taken on admission (due most probably to anesthesia and stress).15.16 Prostatic prolactin concentration and serum levels at surgery are shown in Table II. No correlation was found between the size of the prostate, its prolactin content, and serum prolactin levels before or during surgery. Comment
The etiology of benign hypertrophy of the prostate (BHP) is still unknown. The prostate is under influence of various hormones, yet no specific hormonal changes could be detected at the fifth and sixth decades of life which could explain BHP.8*g Growth and regression of the prostate are known to be affected by sex hormones, including testosterone, estrogens,17,‘* and prolactin. 1,3~1*Prolactin has been proved to enhance the production of ribonucleic acid and deoxyribonucleic acid protein synthesis in rats’ pr0states.l It contributes to the elevation of prostatic zinc lg and citric acid18 concentration. Prolactin increases testosterone uptake by the prostate,20 and might also increase testosterone secretion by the testis. 21-23On the other hand
236
Sk. S.E.
Serum
Prostate
19.3714 13.361 2.916
38.40 9.187 2.005
*N = 21; Student’st test: T value -5.96; p < 0.0001.
(at least in the rat) androgens can increase the concentration of prolactin binding sites in the prostate. 44 It is apparent, therefore, that interrelationship in action exists between androgens and prolactin, affecting each other’s concentration both influencing prostatic metabolism. It has been shown that serum prolactin level does not reflect prostatic level which is dependent both on the concentration and saturation of its receptors. Receptor levels to prolactin in rat’s prostate are not affected by serum prolactin levels.24 It is assumed, therefore, that serum prolactin level does not reflect prolactin action on the target organ. The results obtained in this study demonstrate that prolactin concentration in hypertrophied prostatic tissue is about three to four times higher than serum levels. This suggests that the prostate itself regulates its final prolactin concentration. lo The significance of these findings in relation to the pathogenesis of benign hypertrophy of the prostate is not yet clear. Further studies are necessary to find the relation between prostatic prolactin concentration and the concentration and saturation of its specific receptors to expand our knowledge of how prolactin, by itself or together with androgens, affects prostatic metabolism and perhaps contributes to the development of BHP. Jerusalem, Israel (DR. RON) References 1. Thomas JA, et al: Effect of prolactin and dihydrotestosterone upon the rat prostate gland, Ural. Int. 31: 265 (1976). 2. Aasamo M, Kanaki S, Sekiguch E, and Tasaka T: Inhibition of prostatic growth in rabbits with antibovine prolactin serum, J. Ural. 106: 248 (1971). 3. Grayhack JT, and Lebowitz JM: Effect of prolactin on citric acid of lateral lobe of prostate of Sprague-Dawley rat, Invest. Ural. 5: 87 (1967). 4. Charreau EH, et al: Androgen stimulation of prolactin receptors in rat prostate, Mollec. Cell. Endocrinol. 7: 1 (1977). 5. Witorsch RJ, and Smith JP: Evidence for androgen dependent intracellular binding of prolactin in rat ventral prostate gland, Endocrinology 101: 929 (1977).
UROLOGY /
MARCH 1981
/
VOLUME
XVII, NUMBER 3
6. Ha&n ML, and Yount PA: Prolactin binding in the rat ventral prostate, Endocr. Res. Comm. 2: 489 (1975). 7. Keenan EJ, et al: Specific binding of prolactin by the prostate gland of the rat and man, J. Urol. 122: 43 (1979). 8. Birkhoff JD, Lattimer JK, and Frantz AC: Role of prolactin in benign prostatic hypertrophy, Urology 4: 557 (1974). 9. Hammond GL, et al: Serum FSH, LH and prolactin in normal males and patients with prostatic diseases, Chn. Endocrinol. 7: 129 (1977). 10. Krieg M, et al: Quantitation of androgen binding, androgen tissue levels and sex hormone binding globulin in prostate, muscle and plasma of patients with benign hypertrophy of prostate, Acta Endocrinol. 86: 200 (1977). 11. Ron M, et al: Serum pro&tin levels in men during retropubic prostatectomy, Urology 15: 150 (1980). 12. Segal S, Ron M, Laufer N, and Ben-David M: Prolactin in seminal plasma of infertile men, Arch. Androl. 1: 49 (1978). 13. Bed T, et al: Osmotic control of prolactin release and its effect on renal water excretion in man, Kid. Int. 10: 158 (1976). 14. Ben-David M, and Chramback A: Preparation of bio- and immuno-reactive human prolactin in milligram amounts from amniotic fluid in 60 per cent yield, Endocrinology 101: 250 (1977). 15. Chapler FK, Sherman BM, and Swanson JA: The effect of an antihistamine and/or a glucocorticoid on the prolactin response to surgicai procedures, Am. J. Obstet. Gynecol. 132: 367 (1978). 16. Noel LG, Suh KH, Stone JG, and Frantz GA: Human pro&in and growth hormone release during surgery and other conditions of stress, J. Clin. Endocrin. Metab. 35: 840 (1972). 17. Wende EF, Bronnen GE, Patony PB, and Grayhack JT:
UROLOGY
/
MARCH
1981
/
VOLUME
XVII, NUMBER
3
The effect of orchiectomy and estrogens on benign prostatic hyperplasia, J. Urol. 108: 116 (1972). 18. Waivoord DJ, Resnick MI, and Grayhack JT: Effect of testosterone, dihydrotesterone, estradiol and prolactin on the weight and citric acid content of the lateral lobe of the rat prostate, Invest. Ural. 14: 60 (1976). 19. Moger WH, and Geschwind II: The action of prolactin in the sex accessory glands of male rat, Proc. Sot. Exp. Biol. Med. 141: 1017 (1972). 20. Magrini G, Ebiner JR, Burckhandt P, and Felber JP: Study on the relationship between plasma prolactin levels and androgen metabolism in man, J. Clin. Endocrinol. Metab. 43: 944 (1976). 21. Rubin RT, et al: Nocturnal increase of plasma testosterone in men: relation to gonadotropins and prolactin, ibid. 49: 1027 (1975). 22. Haiiez AA, Lloyd CW, and Bartke A: The role of prolactin in the regulation of testis function: the effect of prolactin and luteinizing hormone on the plasma levels of testosterone and androstenedione in hypophysectomized rats, J. Endocrinol. 52: 327 (1972). 23. Boyns AR, et al: Prolactin studies with the prostate, in Boyns AR and GrifRths K (Eds): Prolactin and Carcinogenesis, Cardiff, Wales, Alpha Omega Alpha Publishing, 1972, pp. 207-216. 24. Aragona C. Bohnet HG, and Friesen HG: Localization of prolactin binding in prostate and testis: the role of serum prolactin concentration on the testicular LH receptors, Acta Endocrinol. 84: 40 (1977).
237
CONCENTRATION
IN PROSTATES
WITH BENIGN HYPERTROPHY M. RON, M.D. A. FICH A. SHAPIRO, M. CAINE,
M.D. M.D.
M. BEN-DAVID,
PH.D.
From the Departments of Obstetrics and Gynecology, Urology, and Pharmacology, Hadassah University Hospital, Jerusalem, Israel
ABSTRACT - Twenty-two hypertrophied prostates removed in surgery were checked for prolactin concentration by the radioimmunoassay method. The mean concentration in the prostatic tissue was found to be 38.2 + 1.9 ng.lGm. while the mean basal serum level was 11.9 + 1.3 ng.Iml. It is concluded that serum prolactin levels do not reject prostatic prolactin concentration. The possibility that interrelationship in action exists between androgens and prolactin affecting each other’s concentration, both injluencing prostatic metabolism is discussed.
It has been shown in recent years that prolactin may have a role in the growth and hypertrophy of male secondary sex organs in laboratory animals. lm3Specific receptors for prolactin have been found in the rat’s prostate4-s and recently in man.’ The significance of prolactin in the etiology of benign hypertrophy of the prostate in man is not clear. Birkhoff et al. in 19748 did not find higher serum prolactin levels in men over fifty years as compared with younger age groups, thus claiming that prolactin plays no role in the pathogenesis of BHP in men. Hammond9 on the other hand did find an elevation of serum prolactin levels in men over sixty. It is well documented that serum hormonal levels do not reflect its concentration in a target organ. lo It is influenced by changes in the concentration and saturation of its specific recep tors . lo Preliminary studies done by us suggested high prolactin levels in the prostate of man.11,‘2 The aim of this study was to determine prolac-
UROLOGY
/
MARCH1981
/ VOLUME
XVII, NUMBER 3
tin concentration in prostatic tissue removed for benign hypertrophy, in order to collect more data about the possible role that prolactin plays in the origin of this disease. Material and Methods The study group included twenty-two males (age fifty-two to sixty-five) who underwent retropubic prostatectomy for benign hypertrophy of the prostate. Surgery was performed under epidural anesthesia. Blood sample for prolactin assessment was taken on admission and at surgery, immediately prior to the removal of the prostate. The serum was separated and stored at -20” C. Prolactin determination was performed by the radioimmunoassay method. r3*r4 The prostates removed were weighed and examined pathologically. A slice of each prostate was stored at -40” C. until further examination. Later processing of the tissue included hardening by liquid nitrogen and pulverization by mortar and pestle cooled by liquid nitrogen. The powder obtained from
235
I. Basal serum prolactin concentration (ng.lml.) and prostatic prolactin concentration (ng.lGm.)*
TABLE
Serum
Prostate
11.9545 6.227 1.328
38.2 9.015 1.922
Serum prolactin levels during operation (ng.lmL) and prostatic prolactin concentration (ng.lGm.)*
TABLE II.
Sk. S.E.
*N = 22; Student’st test: T value -12.63;
p < 0.001.
each prostate was weighed and dissolved in Tris buffer (10mM Tris HCL + 1mM MgCLa pH 7.7) at a ratio of 3: 1 (volume: weight). The solution obtained was homogenized at 0” C. using a glass-Teflon homogenizer. The homogenate was centrifuged at 0” C. in 2,000 r.p.m. for twenty minutes. Prolactin concentration in the supernatant obtained was determined using the radioimmunoassay method. 13a14 Results Prostatic prolactin concentration per gram wet weight of tissue was found to be 21.6 to 57.9 ng./ Gm. (Table I). These values are about three to four times those of serum basal levels. During surgery just before the removal of the prostate, serum prolactin levels were higher than control levels taken on admission (due most probably to anesthesia and stress).15.16 Prostatic prolactin concentration and serum levels at surgery are shown in Table II. No correlation was found between the size of the prostate, its prolactin content, and serum prolactin levels before or during surgery. Comment
The etiology of benign hypertrophy of the prostate (BHP) is still unknown. The prostate is under influence of various hormones, yet no specific hormonal changes could be detected at the fifth and sixth decades of life which could explain BHP.8*g Growth and regression of the prostate are known to be affected by sex hormones, including testosterone, estrogens,17,‘* and prolactin. 1,3~1*Prolactin has been proved to enhance the production of ribonucleic acid and deoxyribonucleic acid protein synthesis in rats’ pr0states.l It contributes to the elevation of prostatic zinc lg and citric acid18 concentration. Prolactin increases testosterone uptake by the prostate,20 and might also increase testosterone secretion by the testis. 21-23On the other hand
236
Sk. S.E.
Serum
Prostate
19.3714 13.361 2.916
38.40 9.187 2.005
*N = 21; Student’st test: T value -5.96; p < 0.0001.
(at least in the rat) androgens can increase the concentration of prolactin binding sites in the prostate. 44 It is apparent, therefore, that interrelationship in action exists between androgens and prolactin, affecting each other’s concentration both influencing prostatic metabolism. It has been shown that serum prolactin level does not reflect prostatic level which is dependent both on the concentration and saturation of its receptors. Receptor levels to prolactin in rat’s prostate are not affected by serum prolactin levels.24 It is assumed, therefore, that serum prolactin level does not reflect prolactin action on the target organ. The results obtained in this study demonstrate that prolactin concentration in hypertrophied prostatic tissue is about three to four times higher than serum levels. This suggests that the prostate itself regulates its final prolactin concentration. lo The significance of these findings in relation to the pathogenesis of benign hypertrophy of the prostate is not yet clear. Further studies are necessary to find the relation between prostatic prolactin concentration and the concentration and saturation of its specific receptors to expand our knowledge of how prolactin, by itself or together with androgens, affects prostatic metabolism and perhaps contributes to the development of BHP. Jerusalem, Israel (DR. RON) References 1. Thomas JA, et al: Effect of prolactin and dihydrotestosterone upon the rat prostate gland, Ural. Int. 31: 265 (1976). 2. Aasamo M, Kanaki S, Sekiguch E, and Tasaka T: Inhibition of prostatic growth in rabbits with antibovine prolactin serum, J. Ural. 106: 248 (1971). 3. Grayhack JT, and Lebowitz JM: Effect of prolactin on citric acid of lateral lobe of prostate of Sprague-Dawley rat, Invest. Ural. 5: 87 (1967). 4. Charreau EH, et al: Androgen stimulation of prolactin receptors in rat prostate, Mollec. Cell. Endocrinol. 7: 1 (1977). 5. Witorsch RJ, and Smith JP: Evidence for androgen dependent intracellular binding of prolactin in rat ventral prostate gland, Endocrinology 101: 929 (1977).
UROLOGY /
MARCH 1981
/
VOLUME
XVII, NUMBER 3
6. Ha&n ML, and Yount PA: Prolactin binding in the rat ventral prostate, Endocr. Res. Comm. 2: 489 (1975). 7. Keenan EJ, et al: Specific binding of prolactin by the prostate gland of the rat and man, J. Urol. 122: 43 (1979). 8. Birkhoff JD, Lattimer JK, and Frantz AC: Role of prolactin in benign prostatic hypertrophy, Urology 4: 557 (1974). 9. Hammond GL, et al: Serum FSH, LH and prolactin in normal males and patients with prostatic diseases, Chn. Endocrinol. 7: 129 (1977). 10. Krieg M, et al: Quantitation of androgen binding, androgen tissue levels and sex hormone binding globulin in prostate, muscle and plasma of patients with benign hypertrophy of prostate, Acta Endocrinol. 86: 200 (1977). 11. Ron M, et al: Serum pro&tin levels in men during retropubic prostatectomy, Urology 15: 150 (1980). 12. Segal S, Ron M, Laufer N, and Ben-David M: Prolactin in seminal plasma of infertile men, Arch. Androl. 1: 49 (1978). 13. Bed T, et al: Osmotic control of prolactin release and its effect on renal water excretion in man, Kid. Int. 10: 158 (1976). 14. Ben-David M, and Chramback A: Preparation of bio- and immuno-reactive human prolactin in milligram amounts from amniotic fluid in 60 per cent yield, Endocrinology 101: 250 (1977). 15. Chapler FK, Sherman BM, and Swanson JA: The effect of an antihistamine and/or a glucocorticoid on the prolactin response to surgicai procedures, Am. J. Obstet. Gynecol. 132: 367 (1978). 16. Noel LG, Suh KH, Stone JG, and Frantz GA: Human pro&in and growth hormone release during surgery and other conditions of stress, J. Clin. Endocrin. Metab. 35: 840 (1972). 17. Wende EF, Bronnen GE, Patony PB, and Grayhack JT:
UROLOGY
/
MARCH
1981
/
VOLUME
XVII, NUMBER
3
The effect of orchiectomy and estrogens on benign prostatic hyperplasia, J. Urol. 108: 116 (1972). 18. Waivoord DJ, Resnick MI, and Grayhack JT: Effect of testosterone, dihydrotesterone, estradiol and prolactin on the weight and citric acid content of the lateral lobe of the rat prostate, Invest. Ural. 14: 60 (1976). 19. Moger WH, and Geschwind II: The action of prolactin in the sex accessory glands of male rat, Proc. Sot. Exp. Biol. Med. 141: 1017 (1972). 20. Magrini G, Ebiner JR, Burckhandt P, and Felber JP: Study on the relationship between plasma prolactin levels and androgen metabolism in man, J. Clin. Endocrinol. Metab. 43: 944 (1976). 21. Rubin RT, et al: Nocturnal increase of plasma testosterone in men: relation to gonadotropins and prolactin, ibid. 49: 1027 (1975). 22. Haiiez AA, Lloyd CW, and Bartke A: The role of prolactin in the regulation of testis function: the effect of prolactin and luteinizing hormone on the plasma levels of testosterone and androstenedione in hypophysectomized rats, J. Endocrinol. 52: 327 (1972). 23. Boyns AR, et al: Prolactin studies with the prostate, in Boyns AR and GrifRths K (Eds): Prolactin and Carcinogenesis, Cardiff, Wales, Alpha Omega Alpha Publishing, 1972, pp. 207-216. 24. Aragona C. Bohnet HG, and Friesen HG: Localization of prolactin binding in prostate and testis: the role of serum prolactin concentration on the testicular LH receptors, Acta Endocrinol. 84: 40 (1977).
237