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The Varicocele: Elevated Serotonin and Infertility
0022-534 7/80 /1235-0683$02.00 /0 Vol.123, May Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
THE VARICOCELE: ELEVATED SEROTONIN AND INFERTILITY ANTHONY A. CALDAMONE, AMER AL-JUBURI
AND
ABRAHAM T. K. COCKETT
From the Division of Urology, The University of Rochester School of Medicine and Dentistry, Rochester, New York
ABSTRACT
Serotonin is known to be toxic to testicular function. In a series of canine studies serotonin was found to be elevated in both spermatic veins after creation of a varicocele by partial ligation of the left renal vein. A total of 42 consecutive infertile male patients with a palpable varicocele and a seminal stress pattern had peripheral and spermatic vein serotonin levels determined at the time of high spermatic vein ligation. Of these patients 27 (64 per cent) had spermatic vein serotonin levels equal to or greater than peripheral levels. These patients demonstrated significantly lower sperm motility, percentage of live sperm and elevated percentages of immature and tapered sperm forms compared to those patients with lower spermatic vein serotonin levels. The interrelationships among the varicocele, premature sloughing of immature sperm and serotonin are discussed. The exact mechanisms by which a varicocele affects spermatogenesis and the resulting infertility still are conjectural. Several theories that have been proposed to explain the detrimental effects of a varicocele include increased scrotal temperature from pooled venous blood, 1 increased venous pressure with hypoxic damage to the testes2 and the retrograde flow of substances deleterious to spermatogenesis down the spermatic vein and into the testicular environment. 3 Serotonin has been shown to affect testicular function adversely. The effects of serotonin include alteration in androgen synthesis and a vasoconstrictive effect on the testis, probably encouraging premature sloughing of immature spermatozoa. Experimental varicoceles were created in a series of dog studies in our laboratory.4 After several months alterations in seminal parameters were seen, which were consistent with a seminal stress pattern often seen in infertile patients with varicoceles. Spermatic vein serotonin levels were determined and demonstrated a significantly higher mean spermatic vein serotonin level than concentrations found in the corresponding peripheral venous blood. Based on these findings the spermatic vein serotonin levels of infertile patients undergoing a varicocelectomy were determined.
at least 20 per cent of the immature sperm forms on 3 consecutive semen examinations the patients became a candidate for an operation. A total of 42 consecutive patients with a palpable varicocele and a seminal stress pattern underwent high spermatic vein ligation. Simultaneous peripheral venous blood and spermatic vein blood samples were obtained for serotonin determination. Blood samples were obtained from the spermatic vein in the inferior direction after proximal ligation was done. Five healthy male subjects served as controls for peripheral blood serotonin determinations. Blood serotonin levels were determined by a quantitative fluorometric method. 5 RESULTS
In the series of 8 dogs with a surgically created varicocele semen quality was altered significantly and simulated the stress pattern (table 1). There was a marked decrease in sperm density from a preoperative value of 82.4 X 106/ml. to 31.3 X 106 /ml., as well as a decrease in motility score, per cent active sperm and per cent oval sperm 16 weeks after creation of the experimental varicocele (table 1). The post-varicocele blood samples in these dogs demonstrated significantly higher serotonin values in both spermatic vein samples when compared to peripheral blood levels (table
MATERIALS AND METHODS
2).
In a preliminary animal study base line semen samples were obtained twice weekly for a 4-week period from 8 male mongrel dogs. After this period an experimental varicocele was created by placing a ligature around the left renal vein proximal to the junction of the spermatic vein and tightening the ligature by approximately 70 per cent so as to restrict renal vein blood flow without causing complete occlusion. At the time of operation peripheral blood samples were obtained for serotonin. After allowing a 4-week recovery period semen samples were obtained from each dog twice weekly for 12 weeks. The animals were sacrificed at the end of the experimental period. Peripheral venous blood and bilateral spermatic vein blood samples were obtained for serotonin determinations. Patients referred for an infertility evaluation were screened for the presence of a varicocele. The initial diagnosis was made on the basis of a physical examination with the patient performing Valsalva's maneuver in an upright position. Each patient underwent at least 3 base line semen analyses. When sperm motility was reduced and was associated with the presence of Accepted for publication June 22, 1979. Read at annual meeting of American Urological Association, New York, New York, May 13-17, 1979.
Based on the spermatic vein and peripheral blood serotonin values patients were divided into 2 groups (table 3). Group I consisted of 15 patients in whom the serotonin level in the spermatic vein was significantly lower than that from the peripheral blood and group II consisted of 27 patients in whom the spermatic vein serotonin level was higher than the peripheral blood levels. Peripheral blood serotonin determinations were done on 5 male control patients and are listed. The mean preoperative semen parameters in both patient groups are listed in table 4. There were no significant differences between the 2 groups regarding semen volume and sperm density. However, patients in whom the spermatic vein serotonin level is greater than or equal to peNpheral blood (group II) demonstrate a significantly lower motility score (92.3 versus 123.5) and a lower percentage of live sperm (41.2 versus 55.7 per cent). A normal motility score is ~150. The percentage of immature and tapered sperm forms is significantly higher in group II (35.4 versus 27.8 per cent). When compared to the 5 control patients mean peripheral serotonin blood values (252 ± 14 ng./ml.) were not significantly different from that of the varicocele patients. In patients with bilateral varicoceles both spermatic vein serotonin levels had the same relationship to peripheral blood levels.
683
684
CALDAMONE, AL-JUBURI AND COCKETT TABLE
Preop. Postop. Change in standard error
1. Semen analyses before and after creation of a varicocele in dogs
Volume (ml.)
Sperm Density (xl06/ml.)
Total Sperm Count (Xl0 6 )
Active Sperm (%)
Motility Score (,;;150 ng.)
Live Sperm (%)
Oval Sperm (%)
14.8 ± 3.4 16.9 ± 2.1 2.6
82.4 ± 14.4 31.3 ± 3.5* 152.0
864.6 ± 173.2 426.2 ± 84.5* 2.88
77.9 ± 4.1 59.2 ± 2.7* 4.4
228 ± 17 117±11* 18.7
58.5 ± 7.4 54.4 ± 1.6 1.76
93.4 ± 0.2 90.0 ± 0.7* 5.17
Data expressed as mean ± standard error of mean. * p at least <0.05.
TABLE 2.
Post-varicocele serotonin levels in 8 dogs Peripheral Serotonin (ng./ml.)
Base line Post-varicocele
605 ± 32 620 ± 108
TABLE 3.
Serotonin levels for 42 patients with varicoceles
Spermatic Vein Serotonin (ng./ml.) Lt.
Rt.
924 ± 131
970 ± 119
Data expressed as mean ± standard error of mean.
DISCUSSION
Serotonin (5-HT) is a biogenic amine that normally is found in mammalian testes. Serotonin can inhibit androgen synthesis in vitro, that is the transformation of progesterone to testosterone. This interference results in increased androstenedione/ testosterone ratios. 6 ' 7 In addition, monoamine oxidase activity has been reported in interstitial cells and seminiferous tubules and has been associated with functional changes in the male rat gonad related to aging. 7 ' 8 It has been postulated that 5-HT must be inactivated for development and proper maintenance of spermatogenesis. Monoamine oxidase activity has been demonstrated to be partially under follicle-stimulating hormone control. 6 ' 9 Exogenously administered 5-HT accumulates in the testes and induces a reduction in testicular weight. 10 Histologic abnormalities consisting of a diminution in size of the seminiferous tubules associated with progressive destruction of the germinal epithelium have been reported after 5-HT administration. 11 Serotonin also has been implicated in the arrest of spermatogenesis observed after immobilizing subhuman primates.12 Complementing this observation, Frehn and associates noted decreased monoamine oxidase activity in the testes of squirrels subjected to crowding. 13 Previous studies from our laboratory have demonstrated that urinary levels of 5-hydroxyindole acetic acid (5-HIAA), the principal metabolite of serotonin, are elevated with sperm concentrations <10 X 106 /ml. 14 Follicle-stimulating hormone followed the same pattern as urinary 5-HIAA, while plasma testosterone was noted to be decreased with sperm concentrations <5 X 106 /ml. Segal and associates determined daily urinary excretions of serotonin and 5-HIAA in fertile and subfertile male subjects. 15 The mean daily urinary serotonin and 5-HIAA excretions were elevated significantly in patients with sperm concentrations <40 X 106 /ml. compared to fertile control patients with normal sperm concentrations. Testicular biopsies also were examined and demonstrated that elevated 5-HIAA was correlated in 73 per cent of the patients with abnormalities such as decreased spermatocytes, maturation arrest or peritubular fibrosis. 16 It has been postulated recently that the effect of serotonin on spermatogenesis may be mediated through the production of prostaglandins. 17 Desai and associates determined spermatic vein levels of prostaglandin F 2a in a group of patients with subfertility and varicoceles. 18 Elevated prostaglandin F 2a levels in the spermatic vein compared to the femoral vein were found in 10 of 18 patients studied. This finding also may have important therapeutic implications, since there are several agents that suppress prostaglandin release, that is indomethacin and aspirin. In addition, specific antagonists to serotonin now are available. Central serotonergic nerves appear to have a significant role in the regulation of arterial blood pressure in normal animals and in some models of experimental hypertension. 19 Recent
Peripheral Serotonin (ng./ml.)
Spermatic Vein Serotonin (ng./ml.)
383 ± 31 299 ± 20 <0.02
276 ± 34 388 ± 27 <0.02
Group I, 15 pts. Group II, 27 pts. p value
Data expressed as mean ± standard error of mean.
TABLE
4.
Semen analyses for 42 patients with varicoceles
Volume (ml.) Group I Group II p value
Sperm Density (X 106 /ml.)
2.46 ± 0.37 34.73 ± 8.2 3.07 ± 0.25 50.66 ± 9.1 Not signifi- Not significant cant
Motility Score (,;;150 nl.)
Live Sperm (%)
Immature and Tapered Sperm(%)
123 ± 7.7 92 ± 5.7 <0.005
55.7 ± 2.1 41.2 ± 2.1 <0.001
27.8 ± 2.9 35.4 ± 2.5 <0.04
Data expressed as mean ± standard error of mean.
studies have demonstrated that serotonin is released selectively from mast cells by angiotensin II and that control oftryptophan hydroxylase activity, which regulates the biosynthetic pathway of serotonin in the hypothalamus and brainstem, involves the stimulatory effects of angiotensin II. 20 If this dependent relationship between serotonin and the renin-angiotensin system proves to be operational with respect to the renal-testicular axis, it is conceivable that the renin-angiotensin system may mediate elevated serotonin levels in the spermatic veins of certain varicocele patients through retrograde flow down the spermatic vein. Premature sloughing of immature spermatozoa into the ejaculate is a probable consequence of the vasoconstrictive effect of serotonin. We currently are determining spermatic vein angiotensin and serotonin levels in varicocele patients to test this hypothesis. We continue to evaluate selected patients with varicoceles and a stress pattern on semen analysis who delay an operation for s;;;l year. 21 Serotonin blocking drugs may be beneficial in this small group. A second group of post-varicocelectomy patients, who display elevated spermatic vein serotonin levels and respond slowly in reducing the perc-entage of immature sperm, may be candidates for a serotonin blocking agent. Our results indicate that in many patients with a varicocele spermatic vein serotonin is elevated compared to peripheral blood levels. In these patients sperm motility and the percentage of live sperm are depressed and the percentage of immature and tapered sperm forms is elevated when compared to varicocele patients in whom the spermatic vein serotonin is lower than peripheral levels. This would imply that the fertility potential of patients with varicocele with elevated spermatic vein serotonin levels is further compromised compared to patients with spermatic vein serotonin levels lower than peripheral levels. The relationship between spermatic vein and peripheral blood serotonin levels in patients without a varicocele needs further documentation. We currently are pursuing this investigation on patients undergoing a retroperitoneal or inguinal operation for other reasons. Further followup of our varicocelectomy patients may reveal a more significant response perhaps with regard to pregnancy after spermatic vein ligation, based on the spermatic vein serotonin level.
VARICOCELE: ELEVATED SEROTONIN AND INFERTILITY REFERENCES
1. Zorgniotti, A. W. and McLeod, J.: Studies in temperature, human semen quality, and varicocele. Fertil. Steril., 24: 854, 1973. 2. Charny, C. W.: Effect of varicocele on fertility. Fertil. Steril., 13: 47, 1962. 3. Cohen, M. S., Plaine, L. and Brown, J. S.: The role of internal spermatic vein plasma catecholamine determinations in subfertile men with varicoceles. Fertil. Steril., 26: 1254, 1975. 4. Al-Juburi, A., Pranikoff, K., Dougherty, K. A., Urry, R. L. and Cockett, A. T. K.: Alteration of semen quality in dogs after creation of varicocele. Urology, 13: 535, 1979. 5. Geeraerts, F., Schimpfessel, L. and Crokaert, R.: A simple routinemethod to preserve and determine blood serotonin. Experientia, 30: 837, 1974. 6. Ellis, L. C.: Inhibition of rat testicular androgen synthesis in vitro by melatonin and serotonin. Endocrinology, 90: 17, 1972. 7. Ellis, L. C., Jaussi, A. W., Baptista, M. H. and Urry, R. L.: Correlation of age changes in monoamine oxidase activity and androgen synthesis by rat testicular minced and teased-tubular preparation in vitro. Endocrinology, 90: 1610, 1972. 8. Kormano, M. and Penttila, A.: Distribution of endogenous and administered 5-hydroxytryptamine in the rat testis and epididymis. Ann. Med. Exp. Biol. Fenn., 46: 468, 1968. 9. Urry, R. L., Frehn, J. L. and Ellis, L. C.: Control of rat testicular monoamine oxidase (MAO) activity: hypophysectomy, adrenalectomy, FSH, LH, prolactin, HCG and testosterone. Acta Endocr., 76: 392, 1974. 10. Boccabella, A. V., Salgado, E. D. and Alger, E. A.: Testicular function and histology following serotonin administration. Endocrinology, 71: 827, 1962. 11. Liu, C.-C. and Kinson, G. A.: Testicular gametogenic and endocrine responses to melatonin and serotonin peripherally administered
685
to mature rats. Contraception, 7: 153, 1973. 12. Cockett, A. T. K., Elbadawi, A., Zemjanis, R. and Adley, W. R.: The effects of immobilization on spermatogenesis in subhuman primates. Fertil. Steril., 21: 610, 1970. 13. Frehn, J. L., Urry, R. L., Balph, D. F. and Ellis, L. C.: Photoperiod and crowding effects on testicular serotonin metabolism and lack of effects on melatonin synthesis in Uinta ground squirrels (Spermophilus armatus). J. Exp. Zool., 183: 139, 1973. 14. Urry, R. L., Dougherty, K. A. and Cockett, A. T. K.: Correlation between follicle stimulating hormone, luteinizing hormone, testosterone and 5-hydroxyindole acetic acid with sperm cell concentration. J. Urol., 116: 322, 1976. 15. Segal, S., Sadovsky, E., Palti, Z., Pfeifer, Y. and Polishuk, W. Z.: Serotonin and 5-hydroxyindole acetic acid in fertile and subfertile men. Fertil. Steril., 26: 314, 1975. 16. Urry, R. L. and Cockett, A. T. K.: Elevated urinary levels of 5hydroxyindole acetic acid and its relationship among levels of plasma follicle stimulating hormone, testosterone and testicular pathology in patients with severe oligospermia and/or azoospermia. J. Urol., 118: 591, 1977. 17. Ellis, L. C., Hargrove, J. L., Johnson, J. M. and Seely, R. K.: Physiology of the testicular secretions: prostaglandins and the dual endocrine role of the testes. Res. Reprod., 4: 2, 1972. 18. Desai, S. B., Cohen, M. S. and Orkin, L. A.: Left spermatic vein prostaglandin F 2a levels in subfertile men with varicoceles. Infertility, 1: 59, 1978. 19. Chalmers, J.P.: Brain amines and models of experimental hypertension. Circ. Res., 36: 469, 1975. 20. Nahmod, V. E., Finkielman, S., Benarroch, E. E. and Pirola, C. J.: Angiotensin regulates release and synthesis of serotonin in brain. Science, 202: 1091, 1978. 21. Cockett, A. T. K., Urry, R. L. and Dougherty, K. A.: The varicocele and semen characteristics. J. Urol., 121: 435, 1979.
THE JOURNAL OF UROLOGY
Copyright© 1980 by The Williams & Wilkins Co.
THE VARICOCELE: ELEVATED SEROTONIN AND INFERTILITY ANTHONY A. CALDAMONE, AMER AL-JUBURI
AND
ABRAHAM T. K. COCKETT
From the Division of Urology, The University of Rochester School of Medicine and Dentistry, Rochester, New York
ABSTRACT
Serotonin is known to be toxic to testicular function. In a series of canine studies serotonin was found to be elevated in both spermatic veins after creation of a varicocele by partial ligation of the left renal vein. A total of 42 consecutive infertile male patients with a palpable varicocele and a seminal stress pattern had peripheral and spermatic vein serotonin levels determined at the time of high spermatic vein ligation. Of these patients 27 (64 per cent) had spermatic vein serotonin levels equal to or greater than peripheral levels. These patients demonstrated significantly lower sperm motility, percentage of live sperm and elevated percentages of immature and tapered sperm forms compared to those patients with lower spermatic vein serotonin levels. The interrelationships among the varicocele, premature sloughing of immature sperm and serotonin are discussed. The exact mechanisms by which a varicocele affects spermatogenesis and the resulting infertility still are conjectural. Several theories that have been proposed to explain the detrimental effects of a varicocele include increased scrotal temperature from pooled venous blood, 1 increased venous pressure with hypoxic damage to the testes2 and the retrograde flow of substances deleterious to spermatogenesis down the spermatic vein and into the testicular environment. 3 Serotonin has been shown to affect testicular function adversely. The effects of serotonin include alteration in androgen synthesis and a vasoconstrictive effect on the testis, probably encouraging premature sloughing of immature spermatozoa. Experimental varicoceles were created in a series of dog studies in our laboratory.4 After several months alterations in seminal parameters were seen, which were consistent with a seminal stress pattern often seen in infertile patients with varicoceles. Spermatic vein serotonin levels were determined and demonstrated a significantly higher mean spermatic vein serotonin level than concentrations found in the corresponding peripheral venous blood. Based on these findings the spermatic vein serotonin levels of infertile patients undergoing a varicocelectomy were determined.
at least 20 per cent of the immature sperm forms on 3 consecutive semen examinations the patients became a candidate for an operation. A total of 42 consecutive patients with a palpable varicocele and a seminal stress pattern underwent high spermatic vein ligation. Simultaneous peripheral venous blood and spermatic vein blood samples were obtained for serotonin determination. Blood samples were obtained from the spermatic vein in the inferior direction after proximal ligation was done. Five healthy male subjects served as controls for peripheral blood serotonin determinations. Blood serotonin levels were determined by a quantitative fluorometric method. 5 RESULTS
In the series of 8 dogs with a surgically created varicocele semen quality was altered significantly and simulated the stress pattern (table 1). There was a marked decrease in sperm density from a preoperative value of 82.4 X 106/ml. to 31.3 X 106 /ml., as well as a decrease in motility score, per cent active sperm and per cent oval sperm 16 weeks after creation of the experimental varicocele (table 1). The post-varicocele blood samples in these dogs demonstrated significantly higher serotonin values in both spermatic vein samples when compared to peripheral blood levels (table
MATERIALS AND METHODS
2).
In a preliminary animal study base line semen samples were obtained twice weekly for a 4-week period from 8 male mongrel dogs. After this period an experimental varicocele was created by placing a ligature around the left renal vein proximal to the junction of the spermatic vein and tightening the ligature by approximately 70 per cent so as to restrict renal vein blood flow without causing complete occlusion. At the time of operation peripheral blood samples were obtained for serotonin. After allowing a 4-week recovery period semen samples were obtained from each dog twice weekly for 12 weeks. The animals were sacrificed at the end of the experimental period. Peripheral venous blood and bilateral spermatic vein blood samples were obtained for serotonin determinations. Patients referred for an infertility evaluation were screened for the presence of a varicocele. The initial diagnosis was made on the basis of a physical examination with the patient performing Valsalva's maneuver in an upright position. Each patient underwent at least 3 base line semen analyses. When sperm motility was reduced and was associated with the presence of Accepted for publication June 22, 1979. Read at annual meeting of American Urological Association, New York, New York, May 13-17, 1979.
Based on the spermatic vein and peripheral blood serotonin values patients were divided into 2 groups (table 3). Group I consisted of 15 patients in whom the serotonin level in the spermatic vein was significantly lower than that from the peripheral blood and group II consisted of 27 patients in whom the spermatic vein serotonin level was higher than the peripheral blood levels. Peripheral blood serotonin determinations were done on 5 male control patients and are listed. The mean preoperative semen parameters in both patient groups are listed in table 4. There were no significant differences between the 2 groups regarding semen volume and sperm density. However, patients in whom the spermatic vein serotonin level is greater than or equal to peNpheral blood (group II) demonstrate a significantly lower motility score (92.3 versus 123.5) and a lower percentage of live sperm (41.2 versus 55.7 per cent). A normal motility score is ~150. The percentage of immature and tapered sperm forms is significantly higher in group II (35.4 versus 27.8 per cent). When compared to the 5 control patients mean peripheral serotonin blood values (252 ± 14 ng./ml.) were not significantly different from that of the varicocele patients. In patients with bilateral varicoceles both spermatic vein serotonin levels had the same relationship to peripheral blood levels.
683
684
CALDAMONE, AL-JUBURI AND COCKETT TABLE
Preop. Postop. Change in standard error
1. Semen analyses before and after creation of a varicocele in dogs
Volume (ml.)
Sperm Density (xl06/ml.)
Total Sperm Count (Xl0 6 )
Active Sperm (%)
Motility Score (,;;150 ng.)
Live Sperm (%)
Oval Sperm (%)
14.8 ± 3.4 16.9 ± 2.1 2.6
82.4 ± 14.4 31.3 ± 3.5* 152.0
864.6 ± 173.2 426.2 ± 84.5* 2.88
77.9 ± 4.1 59.2 ± 2.7* 4.4
228 ± 17 117±11* 18.7
58.5 ± 7.4 54.4 ± 1.6 1.76
93.4 ± 0.2 90.0 ± 0.7* 5.17
Data expressed as mean ± standard error of mean. * p at least <0.05.
TABLE 2.
Post-varicocele serotonin levels in 8 dogs Peripheral Serotonin (ng./ml.)
Base line Post-varicocele
605 ± 32 620 ± 108
TABLE 3.
Serotonin levels for 42 patients with varicoceles
Spermatic Vein Serotonin (ng./ml.) Lt.
Rt.
924 ± 131
970 ± 119
Data expressed as mean ± standard error of mean.
DISCUSSION
Serotonin (5-HT) is a biogenic amine that normally is found in mammalian testes. Serotonin can inhibit androgen synthesis in vitro, that is the transformation of progesterone to testosterone. This interference results in increased androstenedione/ testosterone ratios. 6 ' 7 In addition, monoamine oxidase activity has been reported in interstitial cells and seminiferous tubules and has been associated with functional changes in the male rat gonad related to aging. 7 ' 8 It has been postulated that 5-HT must be inactivated for development and proper maintenance of spermatogenesis. Monoamine oxidase activity has been demonstrated to be partially under follicle-stimulating hormone control. 6 ' 9 Exogenously administered 5-HT accumulates in the testes and induces a reduction in testicular weight. 10 Histologic abnormalities consisting of a diminution in size of the seminiferous tubules associated with progressive destruction of the germinal epithelium have been reported after 5-HT administration. 11 Serotonin also has been implicated in the arrest of spermatogenesis observed after immobilizing subhuman primates.12 Complementing this observation, Frehn and associates noted decreased monoamine oxidase activity in the testes of squirrels subjected to crowding. 13 Previous studies from our laboratory have demonstrated that urinary levels of 5-hydroxyindole acetic acid (5-HIAA), the principal metabolite of serotonin, are elevated with sperm concentrations <10 X 106 /ml. 14 Follicle-stimulating hormone followed the same pattern as urinary 5-HIAA, while plasma testosterone was noted to be decreased with sperm concentrations <5 X 106 /ml. Segal and associates determined daily urinary excretions of serotonin and 5-HIAA in fertile and subfertile male subjects. 15 The mean daily urinary serotonin and 5-HIAA excretions were elevated significantly in patients with sperm concentrations <40 X 106 /ml. compared to fertile control patients with normal sperm concentrations. Testicular biopsies also were examined and demonstrated that elevated 5-HIAA was correlated in 73 per cent of the patients with abnormalities such as decreased spermatocytes, maturation arrest or peritubular fibrosis. 16 It has been postulated recently that the effect of serotonin on spermatogenesis may be mediated through the production of prostaglandins. 17 Desai and associates determined spermatic vein levels of prostaglandin F 2a in a group of patients with subfertility and varicoceles. 18 Elevated prostaglandin F 2a levels in the spermatic vein compared to the femoral vein were found in 10 of 18 patients studied. This finding also may have important therapeutic implications, since there are several agents that suppress prostaglandin release, that is indomethacin and aspirin. In addition, specific antagonists to serotonin now are available. Central serotonergic nerves appear to have a significant role in the regulation of arterial blood pressure in normal animals and in some models of experimental hypertension. 19 Recent
Peripheral Serotonin (ng./ml.)
Spermatic Vein Serotonin (ng./ml.)
383 ± 31 299 ± 20 <0.02
276 ± 34 388 ± 27 <0.02
Group I, 15 pts. Group II, 27 pts. p value
Data expressed as mean ± standard error of mean.
TABLE
4.
Semen analyses for 42 patients with varicoceles
Volume (ml.) Group I Group II p value
Sperm Density (X 106 /ml.)
2.46 ± 0.37 34.73 ± 8.2 3.07 ± 0.25 50.66 ± 9.1 Not signifi- Not significant cant
Motility Score (,;;150 nl.)
Live Sperm (%)
Immature and Tapered Sperm(%)
123 ± 7.7 92 ± 5.7 <0.005
55.7 ± 2.1 41.2 ± 2.1 <0.001
27.8 ± 2.9 35.4 ± 2.5 <0.04
Data expressed as mean ± standard error of mean.
studies have demonstrated that serotonin is released selectively from mast cells by angiotensin II and that control oftryptophan hydroxylase activity, which regulates the biosynthetic pathway of serotonin in the hypothalamus and brainstem, involves the stimulatory effects of angiotensin II. 20 If this dependent relationship between serotonin and the renin-angiotensin system proves to be operational with respect to the renal-testicular axis, it is conceivable that the renin-angiotensin system may mediate elevated serotonin levels in the spermatic veins of certain varicocele patients through retrograde flow down the spermatic vein. Premature sloughing of immature spermatozoa into the ejaculate is a probable consequence of the vasoconstrictive effect of serotonin. We currently are determining spermatic vein angiotensin and serotonin levels in varicocele patients to test this hypothesis. We continue to evaluate selected patients with varicoceles and a stress pattern on semen analysis who delay an operation for s;;;l year. 21 Serotonin blocking drugs may be beneficial in this small group. A second group of post-varicocelectomy patients, who display elevated spermatic vein serotonin levels and respond slowly in reducing the perc-entage of immature sperm, may be candidates for a serotonin blocking agent. Our results indicate that in many patients with a varicocele spermatic vein serotonin is elevated compared to peripheral blood levels. In these patients sperm motility and the percentage of live sperm are depressed and the percentage of immature and tapered sperm forms is elevated when compared to varicocele patients in whom the spermatic vein serotonin is lower than peripheral levels. This would imply that the fertility potential of patients with varicocele with elevated spermatic vein serotonin levels is further compromised compared to patients with spermatic vein serotonin levels lower than peripheral levels. The relationship between spermatic vein and peripheral blood serotonin levels in patients without a varicocele needs further documentation. We currently are pursuing this investigation on patients undergoing a retroperitoneal or inguinal operation for other reasons. Further followup of our varicocelectomy patients may reveal a more significant response perhaps with regard to pregnancy after spermatic vein ligation, based on the spermatic vein serotonin level.
VARICOCELE: ELEVATED SEROTONIN AND INFERTILITY REFERENCES
1. Zorgniotti, A. W. and McLeod, J.: Studies in temperature, human semen quality, and varicocele. Fertil. Steril., 24: 854, 1973. 2. Charny, C. W.: Effect of varicocele on fertility. Fertil. Steril., 13: 47, 1962. 3. Cohen, M. S., Plaine, L. and Brown, J. S.: The role of internal spermatic vein plasma catecholamine determinations in subfertile men with varicoceles. Fertil. Steril., 26: 1254, 1975. 4. Al-Juburi, A., Pranikoff, K., Dougherty, K. A., Urry, R. L. and Cockett, A. T. K.: Alteration of semen quality in dogs after creation of varicocele. Urology, 13: 535, 1979. 5. Geeraerts, F., Schimpfessel, L. and Crokaert, R.: A simple routinemethod to preserve and determine blood serotonin. Experientia, 30: 837, 1974. 6. Ellis, L. C.: Inhibition of rat testicular androgen synthesis in vitro by melatonin and serotonin. Endocrinology, 90: 17, 1972. 7. Ellis, L. C., Jaussi, A. W., Baptista, M. H. and Urry, R. L.: Correlation of age changes in monoamine oxidase activity and androgen synthesis by rat testicular minced and teased-tubular preparation in vitro. Endocrinology, 90: 1610, 1972. 8. Kormano, M. and Penttila, A.: Distribution of endogenous and administered 5-hydroxytryptamine in the rat testis and epididymis. Ann. Med. Exp. Biol. Fenn., 46: 468, 1968. 9. Urry, R. L., Frehn, J. L. and Ellis, L. C.: Control of rat testicular monoamine oxidase (MAO) activity: hypophysectomy, adrenalectomy, FSH, LH, prolactin, HCG and testosterone. Acta Endocr., 76: 392, 1974. 10. Boccabella, A. V., Salgado, E. D. and Alger, E. A.: Testicular function and histology following serotonin administration. Endocrinology, 71: 827, 1962. 11. Liu, C.-C. and Kinson, G. A.: Testicular gametogenic and endocrine responses to melatonin and serotonin peripherally administered
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