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Genital Infection and Sperm Agglutinating Antibodies in Infertile Men
Vol. 99, Jan. Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright
© 1968 by The Williams & Wilkins Co.
GENITAL INFECTION AND SPERM AGGLUTINATING ANTIBODIES IN INFERTILE MEN EMILIO M. QUESADA, C. DEAN DUKES, GORDON H. DEEN
AND
ROBERT R. FRANKLIN
From the Cora and Webb Mading Department of Surgery, Division of Urology and the Departments of Microbiology, and Obstetrics and Gynecology, Baylor University College of Medicine, Houston, Texas
Two aspects of male infertility should receive particular attention by the urologist: 1) the relationship between the presence of genital infection and reduced fertility and 2) the occurrence and possible significance of antispermatozoal antibodies in infertile men. We believe that infection of the genital tract occurs more frequently than is generally suspected in men of reproductive age and that the presence of infection may play an important role in altering the quality of the ejaculate in certain individuals. These alterations may consist of abnormalities of the pH, viscosity, liquefaction, and motility and morphology of the spermatozoa. The combination of any or all of these alterations with a persistently high leukocyte and bacterial count, in our opinion, deserves investigation and treatment. In niany patients, the elin1ination of infection frequently is followed by a remarkable improvement of the quality of their semen and a subsequent increase of their fertilizing capacity. In addition, some of the clinical observations made during the past 3 years have directed our attention to another aspect of male infertility. The finding of circulating antispermatozoal antibodies in some of our patients suggested the possibility of an autoimmune response associated with reduced fertility in man. The concept of immunologic control of reproduction has been well-established in the experimental animal,1 and there is sufficient clinical information available to support the hypothesis that this also may occur in human beings. 2 - 9 Accepted for publication February 14, 1967. Read at the annual meeting of the South Central Section, American Urological Association, Inc., Mexico City, Mexico, October 16-22, 1966. Supported in part by Grant HD-00068 from the National Institute of Child Health and Human Development. 1 Katsh, S. and Katsh, G. F.: Perspectives in immunological control of reproduction: Past, present and future. Pacific Med. Surg., 73: 28, 1965. 2 Bandhauer, K., lVIarberger, E. and Marberger, H.: Immunologische Einfhisse auf mannliche Fertilitatsstorungen (Experimentelle und klinische Untersuchungen.) Urologe, 3: 222, 1964.
Studies made in our institution have indicated a high incidence (67.2 per cent) of circulating sperm agglutinating antibodies in women with otherwise unexplained infertility. 10 • 11 Furthermore, the incidence of pregnancy following the disappearance of these circulating antibodies has provided a strong indication that a state of immunologic infertility may develop in susceptible women. Ever since circulating antispermatozoal antibodies were detected in the sera of infertile men by Wilson8 • 9 and by Ri.imke, 4 - 7 the possibility of an autoimmune mechanism has been suspected. Whether the presence of these antibodies is related directly to infertility in men remains to be proven. In the present study, 650 male partners of infertile couples were studied serologically by a method previously described by Franklin and Dukes. 10 In essence, the patient's serum is tested, in serial dilutions, against a standard concentration of spermatozoa and microscopic agglutina3 Cruickshank, B. and Stuart-Smith, D. A.: Orchitis associated with sperm-agglutinating antibodies. Lancet, 1: 708, 1959. 4 Ri.imke, P.: The presence of sperm antibodies in the serum of two patients with oligozoospermia. Vox Sang., 4: 135, 1954. 5 Ri.imke, P.: Auto-antibodies against spermatozoa in sterile men. In: Immnnopathology. Edited by P. Grabar and P. Miescher. Basel, Switzerland: Benno Schwabe & Co., 1959, p. 145. 6 Ri.imke, P. and Hellinga, G.: Autoantibodies against spermatozoa in sterile men. Amer. J. Clin. Path., 32: 357, 1959. 7 Segal, S., Tyler, E. T., Rao, S., Ri.imke, P. and N akabayashi, N.: Immunologic factors in infertility. In: Sterility: Office Management of the Infertile Couple. Edited by E. T. Tvler. New " York: McGraw-Hill Co., 1961. 8 Wilson, L.: Sperm agglutinins in human semen and blood. Proc. Soc. Exp. Biol. & Med., 85: 652, 1954. 9 Wilson, L.: Sperm agglutination due to autoantibodies: A new cause of sterility. Fertil. Steril., 7: 262, 1956. 1 ° Franklin, R.R. and Dukes, C. D.: Antispermatozoal antibody and unexplained infertility. Amer. J. Obst. & Gynec., 89: 6, 1964. 11 Franklin, R. R. and Dukes, C. D.: Further studies on sperm-agglutinating antibody and unexplained infertility. J.A.M.A., 190: 682, 1964.
106
107
!VIALE INFERTILITY TAHLE
l. Incidence of cirwlating antibodies in 650
nwn, classified by ferlility slcitus No. with So. 1Men Antibody
Fertile men Unknown fertility Infertility patients Totals
sr
96 328 22G
51
3.1 22.6
650
61
9.4
0 10
0
tion or immobilization of SJJermato.zoa is obserYed (table 1). · The men with known fertility had neither clinical nor laboratory abnormalities relative to the genital tract and were able to produce preg-· nancv shortlv after their wiyes received appropriate t~·eatme1~t. None of these men were found to have circulating antibodie~. The fertility status of the men included in the second group ,,·as unknown, since no pregnancies resulted. Ten of these individuals were found to possess circulating antibodies (3.1 per cent). The semen analyses of thrse 10 individuals were otherwise normal. In the last group were included all the patients in whom clinical and/or laboratory abnormalities were demonstrated. Included are men with oligospermia of undetermined etiology, endocrinopathies, and obstructive and inflammatory lesions of the genital tracts. It is significant that the incidence of circulating antibodies is much greater than in the case of fertile men (22.6 per cent). From the group of patients ·with documented inflammatory and/or obstructive processes of their genital tract, 109 men were selected for study primarily because each was suspected of being the sole contributing factor to the infertility, Of these, 50 patients were found to have genital infection alone and 59 patients were found to possess circulating antispermatozoal antibodies in addition to genital infection and/or obstruction. All 109 patients were evaluated similarly and received comparable treatment: prostatic massage and appropriate antibacterial therapy when infection was demonstrated and surgical correction if possible, when an obstructive lesion was detected. Among the 50 infertile men with documented genital infection and without circulating antibodies, the correlation of the clinical history, physical and laboratory findings permitted the separation into 3 groups: 1) The first group consisted of patients with physical findings
and symptoms compatible with scrn1novesiculoprostatitis, ,vith abundant, abacterial prostatic secretions, Sern.en cultlues from these men revealed the presence of intermittent bac terial infections, 2) The second group iududcd all. patients with clinical, phy~ical and baGterinlogical findings characteristic of chrnnic prostatitis. 3) The third group included those pa tients who were asyrn.ptomatif" and physical findings suggestive of H o,vever, semen cultures revealed elevated counts of bacteria commonl:v considered to be pathogenic in the urogenital tract TlH-, majority of these 50 individuals showed improYP.· ment of the quality of their sernen prostatic massage, specific antibacterial thrra11:· and/or suppressive chemotherapy, In 12 of these patient.s (24 per cent) fertility was restored (table 2), Of the 59 patients with documented iufectiou and/or obstruction and in whom. CH'· culating antispermatozoal antibodies were detected, circulating antibodic" disappeared follfming treatment of infection in only 6 ancl 3 pregnancies resulted. In the remaining patients, the antibodies persisted and only pregnancy (1.9 per cent) resulted (table :3), ln the patient in whom fertility was restored, it is significant that the infection had been eliminated at the time his wife became pregnant, and the 2. Results of therapy in patients with genital infection and without 1:'.,.r1'.·11.,.nu,rw antiboclie.1
TABLE
No.
Congestive prostatitis (abacterial) Bacterial prostatitis Infected semen Totals
TABLE
Preg-
nancies
%
6
1
16. 7
18
26
3 8
30.8
.50
12
24.0
rn.
3. Results of therapy in patients with genital infection ancl circulating aniiboclies PregNo. nanoes
I. Disappearance of antibodies 2. Persistence of antibodies
Totals
* Infection eliminated.
6 53
3 1*
50.0 1. 9
59
4
6.8
108
QUESADA AND ASSOCINI'ES
circulating antibodies disappeared from his sera 2 months later. DISCUSSION
Hypothetically, it is not difficult to visualize the occurrence of circulating antibodies in patients with traumatic, inflammatory, or obstru.~ tive lesions of the genital tract. In these cases, the antigens (spermatozoa, seminal plasma, prostatic fluid, etc.) may extravasate into the interstitial tissue and hence pass to the reticuloendothelial system, eliciting antibody production in susceptible individuals.
From our observations, it is apparent that, when genital infection was present, in the absence of antibodies, appropriate antibacterial therapy improved the fertility status in a significant number of patients, 24 per cent. When infection and antibodies were present, only 6.8 per cent of these patients improved. This poses a different and still unresolved therapeutic problem. We feel that our data provide further supportive evidence that both genital infection and auto-antibodies are not only inter-related but are also associated with infertility in man, and they must be considered in the clinical management of this problem.
THE JOURNAL OF UROLOGY
Copyright
© 1968 by The Williams & Wilkins Co.
GENITAL INFECTION AND SPERM AGGLUTINATING ANTIBODIES IN INFERTILE MEN EMILIO M. QUESADA, C. DEAN DUKES, GORDON H. DEEN
AND
ROBERT R. FRANKLIN
From the Cora and Webb Mading Department of Surgery, Division of Urology and the Departments of Microbiology, and Obstetrics and Gynecology, Baylor University College of Medicine, Houston, Texas
Two aspects of male infertility should receive particular attention by the urologist: 1) the relationship between the presence of genital infection and reduced fertility and 2) the occurrence and possible significance of antispermatozoal antibodies in infertile men. We believe that infection of the genital tract occurs more frequently than is generally suspected in men of reproductive age and that the presence of infection may play an important role in altering the quality of the ejaculate in certain individuals. These alterations may consist of abnormalities of the pH, viscosity, liquefaction, and motility and morphology of the spermatozoa. The combination of any or all of these alterations with a persistently high leukocyte and bacterial count, in our opinion, deserves investigation and treatment. In niany patients, the elin1ination of infection frequently is followed by a remarkable improvement of the quality of their semen and a subsequent increase of their fertilizing capacity. In addition, some of the clinical observations made during the past 3 years have directed our attention to another aspect of male infertility. The finding of circulating antispermatozoal antibodies in some of our patients suggested the possibility of an autoimmune response associated with reduced fertility in man. The concept of immunologic control of reproduction has been well-established in the experimental animal,1 and there is sufficient clinical information available to support the hypothesis that this also may occur in human beings. 2 - 9 Accepted for publication February 14, 1967. Read at the annual meeting of the South Central Section, American Urological Association, Inc., Mexico City, Mexico, October 16-22, 1966. Supported in part by Grant HD-00068 from the National Institute of Child Health and Human Development. 1 Katsh, S. and Katsh, G. F.: Perspectives in immunological control of reproduction: Past, present and future. Pacific Med. Surg., 73: 28, 1965. 2 Bandhauer, K., lVIarberger, E. and Marberger, H.: Immunologische Einfhisse auf mannliche Fertilitatsstorungen (Experimentelle und klinische Untersuchungen.) Urologe, 3: 222, 1964.
Studies made in our institution have indicated a high incidence (67.2 per cent) of circulating sperm agglutinating antibodies in women with otherwise unexplained infertility. 10 • 11 Furthermore, the incidence of pregnancy following the disappearance of these circulating antibodies has provided a strong indication that a state of immunologic infertility may develop in susceptible women. Ever since circulating antispermatozoal antibodies were detected in the sera of infertile men by Wilson8 • 9 and by Ri.imke, 4 - 7 the possibility of an autoimmune mechanism has been suspected. Whether the presence of these antibodies is related directly to infertility in men remains to be proven. In the present study, 650 male partners of infertile couples were studied serologically by a method previously described by Franklin and Dukes. 10 In essence, the patient's serum is tested, in serial dilutions, against a standard concentration of spermatozoa and microscopic agglutina3 Cruickshank, B. and Stuart-Smith, D. A.: Orchitis associated with sperm-agglutinating antibodies. Lancet, 1: 708, 1959. 4 Ri.imke, P.: The presence of sperm antibodies in the serum of two patients with oligozoospermia. Vox Sang., 4: 135, 1954. 5 Ri.imke, P.: Auto-antibodies against spermatozoa in sterile men. In: Immnnopathology. Edited by P. Grabar and P. Miescher. Basel, Switzerland: Benno Schwabe & Co., 1959, p. 145. 6 Ri.imke, P. and Hellinga, G.: Autoantibodies against spermatozoa in sterile men. Amer. J. Clin. Path., 32: 357, 1959. 7 Segal, S., Tyler, E. T., Rao, S., Ri.imke, P. and N akabayashi, N.: Immunologic factors in infertility. In: Sterility: Office Management of the Infertile Couple. Edited by E. T. Tvler. New " York: McGraw-Hill Co., 1961. 8 Wilson, L.: Sperm agglutinins in human semen and blood. Proc. Soc. Exp. Biol. & Med., 85: 652, 1954. 9 Wilson, L.: Sperm agglutination due to autoantibodies: A new cause of sterility. Fertil. Steril., 7: 262, 1956. 1 ° Franklin, R.R. and Dukes, C. D.: Antispermatozoal antibody and unexplained infertility. Amer. J. Obst. & Gynec., 89: 6, 1964. 11 Franklin, R. R. and Dukes, C. D.: Further studies on sperm-agglutinating antibody and unexplained infertility. J.A.M.A., 190: 682, 1964.
106
107
!VIALE INFERTILITY TAHLE
l. Incidence of cirwlating antibodies in 650
nwn, classified by ferlility slcitus No. with So. 1Men Antibody
Fertile men Unknown fertility Infertility patients Totals
sr
96 328 22G
51
3.1 22.6
650
61
9.4
0 10
0
tion or immobilization of SJJermato.zoa is obserYed (table 1). · The men with known fertility had neither clinical nor laboratory abnormalities relative to the genital tract and were able to produce preg-· nancv shortlv after their wiyes received appropriate t~·eatme1~t. None of these men were found to have circulating antibodie~. The fertility status of the men included in the second group ,,·as unknown, since no pregnancies resulted. Ten of these individuals were found to possess circulating antibodies (3.1 per cent). The semen analyses of thrse 10 individuals were otherwise normal. In the last group were included all the patients in whom clinical and/or laboratory abnormalities were demonstrated. Included are men with oligospermia of undetermined etiology, endocrinopathies, and obstructive and inflammatory lesions of the genital tracts. It is significant that the incidence of circulating antibodies is much greater than in the case of fertile men (22.6 per cent). From the group of patients ·with documented inflammatory and/or obstructive processes of their genital tract, 109 men were selected for study primarily because each was suspected of being the sole contributing factor to the infertility, Of these, 50 patients were found to have genital infection alone and 59 patients were found to possess circulating antispermatozoal antibodies in addition to genital infection and/or obstruction. All 109 patients were evaluated similarly and received comparable treatment: prostatic massage and appropriate antibacterial therapy when infection was demonstrated and surgical correction if possible, when an obstructive lesion was detected. Among the 50 infertile men with documented genital infection and without circulating antibodies, the correlation of the clinical history, physical and laboratory findings permitted the separation into 3 groups: 1) The first group consisted of patients with physical findings
and symptoms compatible with scrn1novesiculoprostatitis, ,vith abundant, abacterial prostatic secretions, Sern.en cultlues from these men revealed the presence of intermittent bac terial infections, 2) The second group iududcd all. patients with clinical, phy~ical and baGterinlogical findings characteristic of chrnnic prostatitis. 3) The third group included those pa tients who were asyrn.ptomatif" and physical findings suggestive of H o,vever, semen cultures revealed elevated counts of bacteria commonl:v considered to be pathogenic in the urogenital tract TlH-, majority of these 50 individuals showed improYP.· ment of the quality of their sernen prostatic massage, specific antibacterial thrra11:· and/or suppressive chemotherapy, In 12 of these patient.s (24 per cent) fertility was restored (table 2), Of the 59 patients with documented iufectiou and/or obstruction and in whom. CH'· culating antispermatozoal antibodies were detected, circulating antibodic" disappeared follfming treatment of infection in only 6 ancl 3 pregnancies resulted. In the remaining patients, the antibodies persisted and only pregnancy (1.9 per cent) resulted (table :3), ln the patient in whom fertility was restored, it is significant that the infection had been eliminated at the time his wife became pregnant, and the 2. Results of therapy in patients with genital infection and without 1:'.,.r1'.·11.,.nu,rw antiboclie.1
TABLE
No.
Congestive prostatitis (abacterial) Bacterial prostatitis Infected semen Totals
TABLE
Preg-
nancies
%
6
1
16. 7
18
26
3 8
30.8
.50
12
24.0
rn.
3. Results of therapy in patients with genital infection ancl circulating aniiboclies PregNo. nanoes
I. Disappearance of antibodies 2. Persistence of antibodies
Totals
* Infection eliminated.
6 53
3 1*
50.0 1. 9
59
4
6.8
108
QUESADA AND ASSOCINI'ES
circulating antibodies disappeared from his sera 2 months later. DISCUSSION
Hypothetically, it is not difficult to visualize the occurrence of circulating antibodies in patients with traumatic, inflammatory, or obstru.~ tive lesions of the genital tract. In these cases, the antigens (spermatozoa, seminal plasma, prostatic fluid, etc.) may extravasate into the interstitial tissue and hence pass to the reticuloendothelial system, eliciting antibody production in susceptible individuals.
From our observations, it is apparent that, when genital infection was present, in the absence of antibodies, appropriate antibacterial therapy improved the fertility status in a significant number of patients, 24 per cent. When infection and antibodies were present, only 6.8 per cent of these patients improved. This poses a different and still unresolved therapeutic problem. We feel that our data provide further supportive evidence that both genital infection and auto-antibodies are not only inter-related but are also associated with infertility in man, and they must be considered in the clinical management of this problem.