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Seminal zinc and male infertility
STERILITY-FERTILITY
SEMINAL
ANTHONY MARY
ZINC AND MALE INFERTILITY
A. CALDAMONE,
K. FREYTAG,
ABRAHAM
M.D.
R.N.
T. K. COCKETT,
From the Division School of Medicine
M.D.
of Urology, The University and Dentistry, Rochester,
of Rochester New York
- Low seminal plasma zinc is an indication of prostatic secretory dysfunction. We have identajieda group of patients referred for infertility evaluation who demonstrated low seminal plasma zinc and decreased sberm motilitv. in the absence of infection. Treatment of these patients with oral zinc sulfate results in imprdved sperm kbtility.
ABSTRACT
J
J
The exact relationship between seminal plasma zinc and fertility is not clear. Zinc is secreted into the seminal plasma by the prostate g1and.l It has been demonstrated that zinc levels are excellent indicators of prostatic secretory function. Zinc has been implicated in the antibacterial activity of prostatic fluid and has been shown to be decreased in prostatitis.2-4 In addition, low seminal zinc levels have been correlated with decreased fertility potential.5,6 Therefore, the treatment of patients with low seminal zinc levels may result in improved seminal parameters. 5 We have identified a group of patients referred to our andrology clinic who demonstrated low seminal plasma zinc levels in the absence of other causes of infertility. After careful workup based on at least three semen analyses, these patients were treated with oral zinc sulfate. Methods
samples intervals
were obtained after initiation
for analysis of treatment.
at monthly
Results The baseline semen analyses of this group of patients are listed in Table I. Data indicate that in addition to reduced seminal plasma zinc levels (mean 10.4 mg./lOO ml. compared with normal 2 15 mg./lOO ml.), there was also decreased sperm motility (mean motility score was 125 compared with a normal of 150). The remainder of the semen parameters were normal. Rectal examination did not demonstrate a tender prostate. Prostatic secretions were not expressed, and the first portion of the cleanly voided urine was normal. There was no evidence of increased white blood cells in the stained semen smears to indicate infection as the cause of reduced seminal zinc levels. After treatment with oral zinc sulfate, there was a significant increase in sperm motility (mean motility score 147) in spite of only a slight rise in seminal plasma zinc which was not statistically significant. Sperm count also showed a slight increase. Serum zinc levels during treatment remained normal. In addition, three pregnancies were confirmed while the male partner was on zinc therapy.
Patients referred for infertility evaluation underwent three semen analyses to establish baseline values of semen volume, sperm count, motility score, per cent active sperm, per cent live sperm, morphology, and zinc and magnesium levels. From this population we were able to identify 20 patients who demonstrated low seminal plasma zinc levels (normal 3 15 mg./lOO ml.) in the absence of concomitant infection or other causes of infertility. These patients were treated for at least sixty days with 220 mg. zinc sulfate orally twice daily. Semen
The prostate gland contains zinc in higher quantities than any other soft tissue in the human body.’ Seminal plasma zinc has been
280
UROLOGY
Comment
/ MARCH 1979 / VOLUME
XIII,
NUMBER 3
TABLE
Volume Pre-treatment During treatment
I.
Mean semen analyses
(ml.)
Sperm Count (X 106/ml.)
Motility Score (normal > 150)
% Live Sperm
Zinc (mg./lOO ml.)
Magnesium (mg./lOO ml.)
3.3 3.3
66.7 75.3
125 147*
53.3 52.1
10.4 10.8
6.21 8.07
*p < 0.025. correlated with the secretory function of the prostate gland. It has been demonstrated that prostatic inflammation can reduce secretion of zinc. Additionally, both Janick, Zeitz, and Whitmore’ and Marmar et ale5 showed that reduced seminal zinc without the presence of prostatic inflammation has been correlated with decreased fertility potential. In our group of patients a low seminal zinc was found without any evidence of prostatic inflammation. In addition, these patients had reduced sperm motility scores. There were no other causes for infertility identified. Treatment with oral zinc sulfate for at least sixty days resulted in only slight improvement in the seminal zinc level. However, sperm motility increased significantly, with a trend toward increased sperm count. This finding would indicate that an improved fertility potential can result in similar patients by treatment with oral zinc sulfate. A second group of patients from our clinic were observed with low seminal zinc levels and evidence of prostatic inflammation as evidenced by a significant number of white blood cells in the semen. These patients showed improvement in their sperm motility after treatment with antibiotics for at least twenty-eight days. However, after antibiotic therapy was discontinued, the motility score and seminal zinc level again reverted to the abnormally low, pretreatment values. This finding suggests to us the need for supplemental therapy with zinc sulfate in addition to or following antibiotic treatment. The exact mechanism by which zinc affects sperm function is unclear. Millar and associates’ demonstrated that z,inc is needed for the maintenance of intact germinal epithelium and for spermatogenesis in the rat. Lindholmer and Eliasson*,g have shown that epididymal as well as mature spermatozoa contain zinc and magnesium in high concentrations. Additionally, many spermatozoa1 enzyme systems contain Eliasson, zinc and magnesium. lo Specifically Johnsen, and Lindholmer’l have reported that zinc has a role in the regulation of sperm metabolism, especially at the site of succinate
UROLOGY
/
MARCH
1979
i
VOLUME
XIII,
NUMBER
3
oxidation. A combination of zinc and other seminal factors, such as albumin or magnesium, is thought to affect the structural stability of sperm and play a role in sperm metabolic regulation. Summary Our findings indicate: (1) Zinc is an important element in the regulation of spermatozoa1 function, although the exact mechanisms are unclear. (2) Low seminal zinc indicates secretory dysfunction of the prostate gland and may be correlated with reduced sperm motility. (3) Treatment of infertile males with low seminal plasma zinc may result in improved fertility potential. A broad-based study is needed to evaluate carefully all of the many interrelationships. Such a study including patients with prostatitis is under consideration in our laboratory. Rochester,
New York 14642 (DR. COCKE’IT)
References 1. Mawson CA, and Fischer MJ: The occurrence of zinc in the human prostate gland, Can. J. Med. Sci. 30: 336 (1952). 2. Eliasson R: Seminal plasma, accessory genital glands and infertilitv, in Cockett ATK and Urrv RL. Eds: Male Infertilitv. , New York, crune & Stratton, Inc., 1977, p. 189. 3. Fair WR, Couch J, and Wehner N: Prostatic antibacterial factor, Urology 7: 169 (1976). 4. Bostriim K, and Andersson L: Creatinine phosphokinase relative to acid phosphatase, lactate dehydrogenase, zinc and fructose in human semen with special reference to chronic prostatitis, Stand. J. Urol. Nephrol. 5: 123 (1971). 5. Marmar J, Katz S, Praiss DE, and DeBenedictis TJ: Semen zinc levels in infertile and postvasectomy patients and patients with prostatitis, Fertil. Steril. 26: 1057 (1975). 6. Janick J, Zeitz L, and Whitmore WL: Seminal fluid and spermatozoon zinc levels and their relationships to human spermatozoon motility, ibid. 22: 573 (1971). 7. Millar MJ, Fischer MJ, and Mawson CA: The effect of dietary zinc deficiency on the reproductive system of the male rat, Can. J. Biochem. Pbysiol. 36: 557 (1958). 8. Lindholmer C, and Ehasson R: Zinc and magnesium in human spermatozoa, Int. J. Fert. 17: 153 (1972). 9. IDEM: In vitro release and uptake of zinc and magnesium by human spermatozoa, ibid. 19: 45 (1974). 10. Colleen S, M&dh P-A. and Schvtz A: Maenesium and zinc in seminal fluid of healthy males and patients with non-acute prostatitis with and without gonorrhea, Stand. J. Ural. Nephrol. 9: 192 (1975). 11. Eliasson R, Johnsen 0, and Lindholmer C: Effect of zinc on human sperm respiration, Life Sci. 10: 1317 (1971).
281
SEMINAL
ANTHONY MARY
ZINC AND MALE INFERTILITY
A. CALDAMONE,
K. FREYTAG,
ABRAHAM
M.D.
R.N.
T. K. COCKETT,
From the Division School of Medicine
M.D.
of Urology, The University and Dentistry, Rochester,
of Rochester New York
- Low seminal plasma zinc is an indication of prostatic secretory dysfunction. We have identajieda group of patients referred for infertility evaluation who demonstrated low seminal plasma zinc and decreased sberm motilitv. in the absence of infection. Treatment of these patients with oral zinc sulfate results in imprdved sperm kbtility.
ABSTRACT
J
J
The exact relationship between seminal plasma zinc and fertility is not clear. Zinc is secreted into the seminal plasma by the prostate g1and.l It has been demonstrated that zinc levels are excellent indicators of prostatic secretory function. Zinc has been implicated in the antibacterial activity of prostatic fluid and has been shown to be decreased in prostatitis.2-4 In addition, low seminal zinc levels have been correlated with decreased fertility potential.5,6 Therefore, the treatment of patients with low seminal zinc levels may result in improved seminal parameters. 5 We have identified a group of patients referred to our andrology clinic who demonstrated low seminal plasma zinc levels in the absence of other causes of infertility. After careful workup based on at least three semen analyses, these patients were treated with oral zinc sulfate. Methods
samples intervals
were obtained after initiation
for analysis of treatment.
at monthly
Results The baseline semen analyses of this group of patients are listed in Table I. Data indicate that in addition to reduced seminal plasma zinc levels (mean 10.4 mg./lOO ml. compared with normal 2 15 mg./lOO ml.), there was also decreased sperm motility (mean motility score was 125 compared with a normal of 150). The remainder of the semen parameters were normal. Rectal examination did not demonstrate a tender prostate. Prostatic secretions were not expressed, and the first portion of the cleanly voided urine was normal. There was no evidence of increased white blood cells in the stained semen smears to indicate infection as the cause of reduced seminal zinc levels. After treatment with oral zinc sulfate, there was a significant increase in sperm motility (mean motility score 147) in spite of only a slight rise in seminal plasma zinc which was not statistically significant. Sperm count also showed a slight increase. Serum zinc levels during treatment remained normal. In addition, three pregnancies were confirmed while the male partner was on zinc therapy.
Patients referred for infertility evaluation underwent three semen analyses to establish baseline values of semen volume, sperm count, motility score, per cent active sperm, per cent live sperm, morphology, and zinc and magnesium levels. From this population we were able to identify 20 patients who demonstrated low seminal plasma zinc levels (normal 3 15 mg./lOO ml.) in the absence of concomitant infection or other causes of infertility. These patients were treated for at least sixty days with 220 mg. zinc sulfate orally twice daily. Semen
The prostate gland contains zinc in higher quantities than any other soft tissue in the human body.’ Seminal plasma zinc has been
280
UROLOGY
Comment
/ MARCH 1979 / VOLUME
XIII,
NUMBER 3
TABLE
Volume Pre-treatment During treatment
I.
Mean semen analyses
(ml.)
Sperm Count (X 106/ml.)
Motility Score (normal > 150)
% Live Sperm
Zinc (mg./lOO ml.)
Magnesium (mg./lOO ml.)
3.3 3.3
66.7 75.3
125 147*
53.3 52.1
10.4 10.8
6.21 8.07
*p < 0.025. correlated with the secretory function of the prostate gland. It has been demonstrated that prostatic inflammation can reduce secretion of zinc. Additionally, both Janick, Zeitz, and Whitmore’ and Marmar et ale5 showed that reduced seminal zinc without the presence of prostatic inflammation has been correlated with decreased fertility potential. In our group of patients a low seminal zinc was found without any evidence of prostatic inflammation. In addition, these patients had reduced sperm motility scores. There were no other causes for infertility identified. Treatment with oral zinc sulfate for at least sixty days resulted in only slight improvement in the seminal zinc level. However, sperm motility increased significantly, with a trend toward increased sperm count. This finding would indicate that an improved fertility potential can result in similar patients by treatment with oral zinc sulfate. A second group of patients from our clinic were observed with low seminal zinc levels and evidence of prostatic inflammation as evidenced by a significant number of white blood cells in the semen. These patients showed improvement in their sperm motility after treatment with antibiotics for at least twenty-eight days. However, after antibiotic therapy was discontinued, the motility score and seminal zinc level again reverted to the abnormally low, pretreatment values. This finding suggests to us the need for supplemental therapy with zinc sulfate in addition to or following antibiotic treatment. The exact mechanism by which zinc affects sperm function is unclear. Millar and associates’ demonstrated that z,inc is needed for the maintenance of intact germinal epithelium and for spermatogenesis in the rat. Lindholmer and Eliasson*,g have shown that epididymal as well as mature spermatozoa contain zinc and magnesium in high concentrations. Additionally, many spermatozoa1 enzyme systems contain Eliasson, zinc and magnesium. lo Specifically Johnsen, and Lindholmer’l have reported that zinc has a role in the regulation of sperm metabolism, especially at the site of succinate
UROLOGY
/
MARCH
1979
i
VOLUME
XIII,
NUMBER
3
oxidation. A combination of zinc and other seminal factors, such as albumin or magnesium, is thought to affect the structural stability of sperm and play a role in sperm metabolic regulation. Summary Our findings indicate: (1) Zinc is an important element in the regulation of spermatozoa1 function, although the exact mechanisms are unclear. (2) Low seminal zinc indicates secretory dysfunction of the prostate gland and may be correlated with reduced sperm motility. (3) Treatment of infertile males with low seminal plasma zinc may result in improved fertility potential. A broad-based study is needed to evaluate carefully all of the many interrelationships. Such a study including patients with prostatitis is under consideration in our laboratory. Rochester,
New York 14642 (DR. COCKE’IT)
References 1. Mawson CA, and Fischer MJ: The occurrence of zinc in the human prostate gland, Can. J. Med. Sci. 30: 336 (1952). 2. Eliasson R: Seminal plasma, accessory genital glands and infertilitv, in Cockett ATK and Urrv RL. Eds: Male Infertilitv. , New York, crune & Stratton, Inc., 1977, p. 189. 3. Fair WR, Couch J, and Wehner N: Prostatic antibacterial factor, Urology 7: 169 (1976). 4. Bostriim K, and Andersson L: Creatinine phosphokinase relative to acid phosphatase, lactate dehydrogenase, zinc and fructose in human semen with special reference to chronic prostatitis, Stand. J. Urol. Nephrol. 5: 123 (1971). 5. Marmar J, Katz S, Praiss DE, and DeBenedictis TJ: Semen zinc levels in infertile and postvasectomy patients and patients with prostatitis, Fertil. Steril. 26: 1057 (1975). 6. Janick J, Zeitz L, and Whitmore WL: Seminal fluid and spermatozoon zinc levels and their relationships to human spermatozoon motility, ibid. 22: 573 (1971). 7. Millar MJ, Fischer MJ, and Mawson CA: The effect of dietary zinc deficiency on the reproductive system of the male rat, Can. J. Biochem. Pbysiol. 36: 557 (1958). 8. Lindholmer C, and Ehasson R: Zinc and magnesium in human spermatozoa, Int. J. Fert. 17: 153 (1972). 9. IDEM: In vitro release and uptake of zinc and magnesium by human spermatozoa, ibid. 19: 45 (1974). 10. Colleen S, M&dh P-A. and Schvtz A: Maenesium and zinc in seminal fluid of healthy males and patients with non-acute prostatitis with and without gonorrhea, Stand. J. Ural. Nephrol. 9: 192 (1975). 11. Eliasson R, Johnsen 0, and Lindholmer C: Effect of zinc on human sperm respiration, Life Sci. 10: 1317 (1971).
281