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The Effect of Sympathomimetic Drugs on Post-Lymphadenectomy Aspermia
0022-5347 /83/1294-0837$02.00/0 Vol. 129, April Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1983 by The Williams & Wilkins Co.
THE EFFECT OF SYMPATHOMIMETIC DRUGS ON POSTLYMPHADENECTOMY ASPERMIA KENNETH G. PROCTOR*
AND
STUARTS. HOWARDS
From the Departments of Physiology and Urology, University of Virginia School of Medicine, Charlottesville, Virginia
ABSTRACT
A double-blind controlled study of the effects on semen quality of 4 alpha-adrenergic agents with and without antihistamines was conducted in a patient who had failure of emission secondary to retroperitoneal lymphadenectomy for testis cancer. No other controlled studies are available. All of the alpha-adrenergic drugs allowed the patient to produce an ejaculate. The effects were similar. The addition of antihistamine did not improve the semen quality. Four days of treatment were consistently more effective than a single dose, especially for sperm motility. A pregnancy resulted. It is concluded that long-term treatment with alpha-adrenergic drugs is indicated in men with failure of emission secondary to retroperitoneal lymphadenectomy. Although testicular tumors comprise <1 per cent of malignant neoplasms they represent the major cause of cancer deaths in men between 20 and 40 years old. 1 Fortunately, notable advances in diagnosis and chemotherapy within the last 10 years have reduced mortality markedly. Bilateral retroperitoneal lymph node dissection has been an invaluable method for staging and removing metastatic disease. However, the operation usually causes aspermia because the autonomic innervation to the ductus deferens and seminal vesicles is interrupted. 2 The aspermia may be secondary to retrograde ejaculation but is usually related to failure of emission. There are scattered reports that various sympathomimetic drugs and antihistamines have restored emission and viable spermatozoa to the ejaculate in a few patients. 3- 7 However, we could find no data in the literature comparing various drugs and dosage requirements. Herein we systematically evaluate the efficacy of 4 commonly used sympathomimetic drugs, alone and in combination with an antihistamine, for the treatment of aspermia in a postlymphadenectomy testicular cancer patient. CASE REPORT
A 28-year-old, well developed, well nourished white man presented with a small painless nodule on the right testicle, which proved to be embryonal carcinoma upon radical orchiectomy. Neither a-fetoprotein nor {:?-human chorionic gonadotropin hormone levels were elevated in the urine or plasma. Subsequent surgical exploration of the retroperitoneum revealed 2 enlarged, diseased nodes and lymphadenectomy was performed. Except for a moderately large lymphocyst in the left lower quadrant of the abdomen, the patient tolerated the procedure well. He has been followed carefully at monthly intervals and remains free of disease 1.5 years postoperatively. Approximately 6 months before initial presentation the patient had fathered a child. He presently reports normal sensitivity, potency and frequency of intercourse. However, since lymphadenectomy he has had no episodes of antegrade ejaculation and there were no spermatozoa in the urine after intercourse. Protocol: The study was divided into 2 phases. In phase 1 a 4-day course of drug was administered and semen samples were analyzed (within 1 to 2 hours after collection) on day 1 (2 hours after the first dose) and on day 4. In phase 2 the most efficacious drug from phase 1 was combined with a placebo or chlorphen-
iramine, and administered for 4 days with samples analyzed on days 1 and 4. Each phase was repeated once. The results presented in the table represent the average of 2 values. The drug sequence was randomized and the analyses were doubleblind. Statistical analyses seemed inappropriate because observations were confmed to only 1 individual and the number of repetitions was small. The drugs, all of which were administered orally, and dosage schedules used in phase 1 included 5 mg. dextroamphetamine sulfate 4 times a day, 25 mg. ephedrine 4 times a day, 75 mg. phenylpropanolamine twice daily and 60 mg. pseudoephedrine 4 times a day. In phase 2, 25 mg. ephedrine with placebo or with 4 mg. chlorpheniramine was given orally 4 times a day. RESULTS AND DISCUSSION
None of the drugs produced any serious side effect and each produced some emission, which was absent without the drug. Based on the mean data for all 4 drugs in phase 1 it is obvious that the patient is severely oligospermic, with a large fraction of abnormal and nonmotile sperm, and functionally infertile, despite the restoration of ejaculate. Less motility and more abnormal forms were observed with phenylpropanolamine, although the drugs appeared equipotent for eliciting a response
Day
% Motility 3-4+
Pseudoephedrine Phenylpropano!amine Mean± standard deviation
0
0 8 0 2 2 5 2 0 2±3
100 77 100 80 93 88 97 100 92 ± 9
0 2 2 8 3±3
95 86 96 82 90 ± 5
% Abnormal
4 1 4 1 4 1 4
1.0 3.0 2.0 2.5 2.0 2.0 2.5 3.0 2.3 ± 0.7
0 15 0 18 5 7 1 0 6±7
50 30 48 60 28 48 50 90 50± 9
Results of phase 2 Ephedrine combination: Placebo
Mean± standard deviation
1 4 1 4
5 2 1 4 3±2
5 10 2 10
7±5
* Sample volume ranged between 1 and 3 ml.
837
1-2+
Results of phase 1 Drug:* Dextroamphetamine sulfate Ephedrine
Chlorpheniramine
Accepted for publication August 6, 1982. Supported in part by University of Virginia Departmental Funds and Grant 06234 from the National Institutes of Health. • Requests for reprints: Department of Physiology and Biophysics, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163.
Count X 106 /ml.
10 10 10 10 10
838
PROCTOR AND HOWARDS
in terms of sperm count (see table). It also appeared that longterm treatment was consistently more effective than a single dose, especially for sperm motility. The data in the table regarding phase 2 demonstrate a general trend of increasing motility after long-term treatment. The total count was equal to that in phase 1 but the number of abnormal forms was surprisingly low in this trial. Additional experiments would be necessary to determine if this correlated to the duration of therapy or if it was an artifact. The addition of the antihistamine, chlorpheniramine, was apparently not efficacious. The interpretation of the data presented in this study could be described as cautious but encouraging. Cautious, because it is impossible to draw any meaningful, far-reaching conclusion from trials on a single patient. Encouraging, because a single dose of a sympathomimetic agent restored emission in an individual who had previously experienced dry ejaculation and because long-term treatment might eventually restore marginal fertility if the trend, evident after 4 days, continued. Athough variability is the hallmark of patient responsiveness to drug therapy our data suggest that a 4-day course of relatively low doses of a-adrenergic drugs, without antihistamines, is effective for restoring emission in a patient who suffered aspermia secondary to bilateral lymph node dissection. We speculate that prolonged treatment with a agents might also
prove useful in other instances of infertility secondary to defective sperm transport in the male subject. Two months after completion of the protocols, following 1 week of treatment with 25 mg. ephedrine orally 4 times a day, conception was achieved. REFERENCES 1. Nilsson, S., Anderstrom, C., Hedelin, H. and Unsgaard, B.: Signs and symptoms of adult testicular tumours. Int. J. Androl., suppl., 4: 146, 1981. 2. Fraley, E. E., Lange, P.H. and Kennedy, B. J.: Germ-cell testicular cancer in adults (second of two parts). New Engl. J. Med., 301: 1420, 1979. 3. Markland, C.: Special problems in managing patients with testicular cancer. Urol. Clin. N. Amer., 4: 427, 1977. 4. Stewart, B. H. and Bergant, J. A.: Correction of retrograde ejaculation by sympathomimetic medication: preliminary report. Fertil. Steril., 25: 1073, 1974. 5. Andaloro, V. A., Jr. and Dube, A.: Treatment of retrograde ejaculation with brompheniramine. Urology, 5: 520, 1975. 6. Thiagarajah, S., Vaughan, E. D., Jr. and Kitchin, J. D., III: Retrograde ejaculation: successful pregnancy following combined sympathomimetic medication and insemination. Fertil. Steril., 30: 96, 1978. 7. Kelly, M. E. and Needle, M. A.: Imipramine for aspermia after lymphadenectomy. Urology, 13: 414, 1979.
THE JOURNAL OF UROLOGY
Copyright © 1983 by The Williams & Wilkins Co.
THE EFFECT OF SYMPATHOMIMETIC DRUGS ON POSTLYMPHADENECTOMY ASPERMIA KENNETH G. PROCTOR*
AND
STUARTS. HOWARDS
From the Departments of Physiology and Urology, University of Virginia School of Medicine, Charlottesville, Virginia
ABSTRACT
A double-blind controlled study of the effects on semen quality of 4 alpha-adrenergic agents with and without antihistamines was conducted in a patient who had failure of emission secondary to retroperitoneal lymphadenectomy for testis cancer. No other controlled studies are available. All of the alpha-adrenergic drugs allowed the patient to produce an ejaculate. The effects were similar. The addition of antihistamine did not improve the semen quality. Four days of treatment were consistently more effective than a single dose, especially for sperm motility. A pregnancy resulted. It is concluded that long-term treatment with alpha-adrenergic drugs is indicated in men with failure of emission secondary to retroperitoneal lymphadenectomy. Although testicular tumors comprise <1 per cent of malignant neoplasms they represent the major cause of cancer deaths in men between 20 and 40 years old. 1 Fortunately, notable advances in diagnosis and chemotherapy within the last 10 years have reduced mortality markedly. Bilateral retroperitoneal lymph node dissection has been an invaluable method for staging and removing metastatic disease. However, the operation usually causes aspermia because the autonomic innervation to the ductus deferens and seminal vesicles is interrupted. 2 The aspermia may be secondary to retrograde ejaculation but is usually related to failure of emission. There are scattered reports that various sympathomimetic drugs and antihistamines have restored emission and viable spermatozoa to the ejaculate in a few patients. 3- 7 However, we could find no data in the literature comparing various drugs and dosage requirements. Herein we systematically evaluate the efficacy of 4 commonly used sympathomimetic drugs, alone and in combination with an antihistamine, for the treatment of aspermia in a postlymphadenectomy testicular cancer patient. CASE REPORT
A 28-year-old, well developed, well nourished white man presented with a small painless nodule on the right testicle, which proved to be embryonal carcinoma upon radical orchiectomy. Neither a-fetoprotein nor {:?-human chorionic gonadotropin hormone levels were elevated in the urine or plasma. Subsequent surgical exploration of the retroperitoneum revealed 2 enlarged, diseased nodes and lymphadenectomy was performed. Except for a moderately large lymphocyst in the left lower quadrant of the abdomen, the patient tolerated the procedure well. He has been followed carefully at monthly intervals and remains free of disease 1.5 years postoperatively. Approximately 6 months before initial presentation the patient had fathered a child. He presently reports normal sensitivity, potency and frequency of intercourse. However, since lymphadenectomy he has had no episodes of antegrade ejaculation and there were no spermatozoa in the urine after intercourse. Protocol: The study was divided into 2 phases. In phase 1 a 4-day course of drug was administered and semen samples were analyzed (within 1 to 2 hours after collection) on day 1 (2 hours after the first dose) and on day 4. In phase 2 the most efficacious drug from phase 1 was combined with a placebo or chlorphen-
iramine, and administered for 4 days with samples analyzed on days 1 and 4. Each phase was repeated once. The results presented in the table represent the average of 2 values. The drug sequence was randomized and the analyses were doubleblind. Statistical analyses seemed inappropriate because observations were confmed to only 1 individual and the number of repetitions was small. The drugs, all of which were administered orally, and dosage schedules used in phase 1 included 5 mg. dextroamphetamine sulfate 4 times a day, 25 mg. ephedrine 4 times a day, 75 mg. phenylpropanolamine twice daily and 60 mg. pseudoephedrine 4 times a day. In phase 2, 25 mg. ephedrine with placebo or with 4 mg. chlorpheniramine was given orally 4 times a day. RESULTS AND DISCUSSION
None of the drugs produced any serious side effect and each produced some emission, which was absent without the drug. Based on the mean data for all 4 drugs in phase 1 it is obvious that the patient is severely oligospermic, with a large fraction of abnormal and nonmotile sperm, and functionally infertile, despite the restoration of ejaculate. Less motility and more abnormal forms were observed with phenylpropanolamine, although the drugs appeared equipotent for eliciting a response
Day
% Motility 3-4+
Pseudoephedrine Phenylpropano!amine Mean± standard deviation
0
0 8 0 2 2 5 2 0 2±3
100 77 100 80 93 88 97 100 92 ± 9
0 2 2 8 3±3
95 86 96 82 90 ± 5
% Abnormal
4 1 4 1 4 1 4
1.0 3.0 2.0 2.5 2.0 2.0 2.5 3.0 2.3 ± 0.7
0 15 0 18 5 7 1 0 6±7
50 30 48 60 28 48 50 90 50± 9
Results of phase 2 Ephedrine combination: Placebo
Mean± standard deviation
1 4 1 4
5 2 1 4 3±2
5 10 2 10
7±5
* Sample volume ranged between 1 and 3 ml.
837
1-2+
Results of phase 1 Drug:* Dextroamphetamine sulfate Ephedrine
Chlorpheniramine
Accepted for publication August 6, 1982. Supported in part by University of Virginia Departmental Funds and Grant 06234 from the National Institutes of Health. • Requests for reprints: Department of Physiology and Biophysics, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163.
Count X 106 /ml.
10 10 10 10 10
838
PROCTOR AND HOWARDS
in terms of sperm count (see table). It also appeared that longterm treatment was consistently more effective than a single dose, especially for sperm motility. The data in the table regarding phase 2 demonstrate a general trend of increasing motility after long-term treatment. The total count was equal to that in phase 1 but the number of abnormal forms was surprisingly low in this trial. Additional experiments would be necessary to determine if this correlated to the duration of therapy or if it was an artifact. The addition of the antihistamine, chlorpheniramine, was apparently not efficacious. The interpretation of the data presented in this study could be described as cautious but encouraging. Cautious, because it is impossible to draw any meaningful, far-reaching conclusion from trials on a single patient. Encouraging, because a single dose of a sympathomimetic agent restored emission in an individual who had previously experienced dry ejaculation and because long-term treatment might eventually restore marginal fertility if the trend, evident after 4 days, continued. Athough variability is the hallmark of patient responsiveness to drug therapy our data suggest that a 4-day course of relatively low doses of a-adrenergic drugs, without antihistamines, is effective for restoring emission in a patient who suffered aspermia secondary to bilateral lymph node dissection. We speculate that prolonged treatment with a agents might also
prove useful in other instances of infertility secondary to defective sperm transport in the male subject. Two months after completion of the protocols, following 1 week of treatment with 25 mg. ephedrine orally 4 times a day, conception was achieved. REFERENCES 1. Nilsson, S., Anderstrom, C., Hedelin, H. and Unsgaard, B.: Signs and symptoms of adult testicular tumours. Int. J. Androl., suppl., 4: 146, 1981. 2. Fraley, E. E., Lange, P.H. and Kennedy, B. J.: Germ-cell testicular cancer in adults (second of two parts). New Engl. J. Med., 301: 1420, 1979. 3. Markland, C.: Special problems in managing patients with testicular cancer. Urol. Clin. N. Amer., 4: 427, 1977. 4. Stewart, B. H. and Bergant, J. A.: Correction of retrograde ejaculation by sympathomimetic medication: preliminary report. Fertil. Steril., 25: 1073, 1974. 5. Andaloro, V. A., Jr. and Dube, A.: Treatment of retrograde ejaculation with brompheniramine. Urology, 5: 520, 1975. 6. Thiagarajah, S., Vaughan, E. D., Jr. and Kitchin, J. D., III: Retrograde ejaculation: successful pregnancy following combined sympathomimetic medication and insemination. Fertil. Steril., 30: 96, 1978. 7. Kelly, M. E. and Needle, M. A.: Imipramine for aspermia after lymphadenectomy. Urology, 13: 414, 1979.