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Parameters of Response to Clomiphene Citrate in Oligospermic Men
0022-534 7/80 /1241-0053$02.00/0 Vol. 124,
THE JOURNAL OF UROLOGY
Printed in
Copyright© 1980 by The Williams & Wilkins Co.
PARAMETERS OF RESPONSE TO CLOMIPHENE CITRATE IN OLIGOSPERMIC l\!IEN THOMAS M. JONES, VICTOR S. FANG, ROBERT L. ROSENFIELD AND HARRY W. SCHOENBERG From the University of Chicago, Pritzker School of Medicine, Chicago, Illinois
ABSTRACT Twenty oligospermic young men have undergone a 6-month trial of intermittent low dose domiphene therapy. Three-fourths of the patients enjoyed an increase in semen quality and 8 patients impregnated their wives. Plasma luteinizing hormone, follicle-stimulating hormone and testosterone levels increased in all patients on clomiphene. Development of stringent criteria for the use of clomiphene citrate should result in a conception rate of more than 50 per cent in selected patients. Hypotheses concerning the mechanism of therapeutic response to domiphene included the induction of higher levels of testosterone locally around the germinal epithelium and the induction of increased follide-stimu.lating hormone levels. peated. Subjects stopped the drug either at the time of verified conception or at the end of 6 cycles.
The widely accepted use of clomiphene citrate in the treatment of failure in women has not been paralleled similar acceptance in the treatment of hypospermatogenesis in men despite the fact that the drug seems to affect the hypothalamo-pituitary axis of both sexes in a similar fashion. 1 • 2 Part of this reluctance may stem from earlier clinical studies, showthat clomiphene in higher doses could cause decreases in sperm counts, increases in abnormal forms and potentially alarming changes in testis biopsy." For several years published studies dealt with clomiphene as a potential diagnostic and investigative agent on a short-term basis in men 4 - 7 but little was heard about long-term use until Paulson and Wacksman resome success with significantly smaller doses of clomiphene than are used in women. 8 We report our experience with clomiphene in a regimen slightly altered from that of Paulson and W acksman in the treatment of men with oligospermia.
RESULTS
Of 20 men who completed the therapy 8 impregnated their wives. Careful examination of the 12 men who did not impregnate their wives revealed some additional findings: 1 patient had a recurrence of varicocele, 2 patients had sperm with unusually low motility and the wives of 2 additional patients had unpredicted difficulties (polycystic ovary and sperm agglutinating antibodies). Thus, 7 patients failed to respond without explanation. Mean sperm concentration counts in the entire group increased from 11 to 39 million per cc (table 1). In addition, percentage of motile sperm and percentage of mature oval forms increased but these increases were not statistically nificant. It should be noted that not all patients enjoyed an improved semen analysis (5 failed to show improvement) but all patients who impregnated their wives had improved counts. In the 8 successful patients mean counts increased from 9 to 40 million per cc, with comparable increases in motility and mature forms. Patients varied in the time course of their response to clomiphene. An occasional patient showed a significant response after the first cycle, while others did not show a response until after 6 cycles. One patient impregnated his wife after the first cycle, while another impregnated his wife 2 months after clomiphene was discontinued. No patients have reported conception >2 months after therapy. Table 2 shows parameters of hormonal response to clomiphene. Mean testosterone levels increased from 599 to 1,104 ng./dl. in the first cycle and remained at about the same level throughout therapy. Similar observations were made for lutei.nizing hormone and follicle-stimulating hormone. All patients showed increases in these hormones but the degree of increase did not appear to correlate with the therapeutic outcome. Longterm clomiphene therapy actually induced a higher absolute follicle-stimulating hormone level in this group of patients than did the 100 µg. bolus of luteinizing hormone releasing factor (table 3). However, luteinizing hormone levels induced luteinizing hormone releasing factor easily surpassed those mduced by this regimen of clomiphene.
METHODS AND MATERIALS
Young men with a chief complaint of infertility were admitted to a trial of low dose clomiphene if the following criteria were met: 1) infertility for at least 2 years, 2) ifvaricocele had been present it had been corrected surgically at least l year 3) spouse had at least a biphasic basal body temperature as presumptive evidence of ovulation, 4) sperm counts were <40 million per cc on 3 separate occasions, 5) basal folliclehormone was within normal limits and 6) testis not show either tubular hyalinization or widespread maturation arrest. All patients in the trial had basal hormonal levels consisting of testosterone, estrogen, prolactin, luteinizing hormone and follicle-stimulating hormone. All hormones were measured by radioimmunoassay by methods previously reported. 9 Most patients also had the same hormonal battery repeated after challenge with a 100 µg. intravenous bolus of luteinizing hormone releasing factor. After the bolus samples were drawn at 5, 10, 15, 30, 45, 60 and 90 minutes, and 2 and 3 hours. All patients underwent bilateral testicular biopsy. Specimens were fixed in fixative and stained with toluidine blue. 10 •01uuuuueue was given in a dose of 25 mg. daily for 3 weeks l week of no drug. This cycle was repeated 6 times. Patients were seen on day 21 of each cycle, at which time an was obtained and basal hormone analyses were re-
DISCUSSION
Accepted for publication August 24, 1979. Read at annual meeting of American Urological Association, Washington, D. C., May 21-25, 1978. Supported in part by United States Public Health Service Grant 2 MOl RR00055.
We believe that clomiphene can be a useful drug in the treatment of certain men with oligospermia. The emphasis should be on the word "certain". Using prospective criteria we noted a 40 per cent pregnancy rate and a 75 per cent improve53
54
JONES AND ASSOCIATES
ment in semen analysis. These prospective criteria were hormonal and histological. We believe that no patient with elevated basal follicle-stimulating hormone levels can be expected to respond to clomiphene. Furthermore, patients with biopsies showing seriously disrupted spermatogenesis were not included (part A of figure), while patients with uncomplicated hypospermatogenesis were (part B of figure). Retrospective criteria in this series would yield a smaller population of suitable subjects. In our hands clomiphene was of no use in patients who had severely impaired motility and we would not recommend using clomiphene in such patients. The patient who had recurrent varicocele as well as the patients whose outcome was complicated by factors in the spouse should be dropped from the trial pool. Thus, if we carefully select our patients we might expect a conception rate of >50 per cent. Our results then are compatible with those of Paulson and W acksman8 and are more favorable than other published studies using clomiphene. 11 We can only assume that dosage regimen and patient selection are key factors in explaining this difference. We should mention that none of our patients experienced any side effects while on clomiphene. Libido and sexual performance were not altered and there were no reports of breast tenderness or gynecomastia. There is still a fair amount of uncertainty concerning how clomiphene acts to enhance spermatogenesis. Our data suggest at least 2 hypotheses. It is clear that chronic clomiphene administration induces chronically elevated testosterone in plasma. One can only assume that this increase in circulating testosterone is associated with higher local concentrations of testosterone around the germinal epithelium. If one accepts the notion that local concentrations of testosterone are critical for mammalian spermatogenesis 12 then clomiphene's action on the Leydig cell may be the key to its therapeutic effect. The alternate hypothesis would argue that since folliclestimulating hormone is known to be an essential factor in human spermatogenesis 1'3 the therapeutic response to clomiphene is mediated by the chronic elevation in plasma folliclestimulating hormone levels. The matter of dosage and duration of therapy is hardly settled at present. Further therapeutic trials may show that patients who fail on this regimen may respond to either higher doses or longer treatment. The intermittent regimen was simply an empirical approach adopted because of the favorable results TABLE
1. Improvement in semen analyses after clomiphene Concentration (million/cc)'
Basal Post-clomiphene
11
39
% Motile
% Oval Forms
33.7 40.1
56.9 62.7
'p <0.01 by paired t test.
TABLE
noted by Paulson and Wacksman. 8 It may not be necessary. Because a placebo group was not used one cannot be absolutely certain that clomiphene alone accounted for the response in our patients. Yet the otherwise dismal prognosis encountered in male infertility permits us to consider our >50 per cent success rate in selected patients evidence of a therapeutic effect of clomiphene. We have been encouraged sufficiently by our results with clomiphene to continue its use in selected oligosperm1c men.
2. Hormonal response during clomiphene Basal (ng./dl.)
1st Cycle Clomiphene (ng./dl.)
599 37 258
1,104 62 488
Testosterone Luteinizing hormone Follicle-stimulating hormone
TABLE
A, representative cross section of seminiferous tubule from patient who would not be expected to respond to clomiphene. Note reduction in tubular diameter, relative abundance of Sertoli cells and thickened tubular wall. B, representative cross section of seminiferous tubule from patient who responded to clomiphene. All stages of spermatogenesis are present, Sertoli cell nuclei (with prominent nucleolus) are around periphery.
3. Hormonal responses to clomiphene and luteinizing
hormone releasing factor
Testosterone Luteinizing hormone Follicle-stimulating hormone
Basal (ng./dl.)
1st Cycle Clomiphene (ng./dl.)
Post-Luteinizing Hormone Releasing Factor (ng./dl.)
599 37 258
1,104 62 488
641 468 352
REFERENCES 1. Kistner, R. W.: Induction of ovulation with clomiphene citrate
(clomid). Obst. Gynec. Surv., 20: 873, 1965. 2. Miechi, H. R., Turner, D., Guitelman, A., Aparicio, N. J. and Schwarzstein, L.: Pituitary-gonadal response to acute I. M. stimulation with clomiphene citrate in normal men. J. Clin. Endocr. Metab., 40: 1114, 1975. 3. Heller, C. G., Rowley, M. J. and Heller, G. V.: Clomiphene citrate: a correlation of its effect on sperm concentration and morphology, total gonadotropins, ICSH, estrogen and testosterone excretion and testicular cytology in normal men. J. Clin. Endocr. Metab., 29: 638, 1969. 4. Bardin, C. W., Ross, G. T. and Lipsett, M. B.: Site of action of clomiphene citrate in men: a study of the pituitary-Leydig cell axis. J. Clin. Endocr. Metab., 27: 1558, 1967. 5. Boyar, R. B., Perlow, M., Kapen, S., Lefkowitz, G., Weitzman, E. and Hellman, L.: The effect of clomiphene citrate on the 24-hour LH secretory pattern in normal men. J. Clin. Endocr. Metab.,
PARAMETERS OF RESPONSE TO CLOMIPHENE CITRATE IN OLIGOSPERMIC MEN
36: 561, 1973. 6. Nankin, H. R., Yanaihara, T. and Troen, P.: Response of gonadotropins and testosterone to clomiphene stimulation in a pubertal boy. J. Clin. Endocr. Metab., 33: 360, 1971. 7. Snoep, M. C., de Lange, W. E., Sluiter, W. J. and Doorenbos, H.: Differential response to serum LH in hypogonadotropic hypogonadism and delayed puberty to LH-RH stimulation before and after clomiphene citrate administration. J. Clin. Endocr. Metab., 44: 603, 1977. 8. Paulson, D. F. and Wacksman, J.: Clomiphene citrate in the management of male infertility. J. Urol., 115: 73, 1976. 9. Jones, T. M., Fang, V. S., Landau, R. L. and Rosenfield, R. L.: The effects of fluoxymesterone administration on testicular function.
55
J. Clin. Endocr. Metab., 44: 121, 1976. 10. Jones, T. M., Anderson, W. A., Fang, V. S., Landau, R. L. and Rosenfield, R. L.: Experimental cryptorchidism in adult male rats: histological and hormonal sequelae. Anat. Rec., 189: 1, 1977. 11. Mellinger, R. C. and Thompson, R. J.: Effect of clomiphene citrate in male infertility. Fertil. Steril., 17: 94, 1966. 12. Steinberger, E.: Hormonal control of mammalian spermatogenesis. Physiol. Rev., 51: 1, 1971. 13. Mancini, R. E., Seiguer, A. C. and Lloret, P.: The effect of gonadotropins on the testis of hypophysectomized patients. In: Gonadotropins 1968. Proceedings of the Workshop Conference, Vista Hermosa, Mor., Mexico, 1968. Edited by E. Rosemberg. Los Altos: Geron-X, p. 503, 1968.
THE JOURNAL OF UROLOGY
Printed in
Copyright© 1980 by The Williams & Wilkins Co.
PARAMETERS OF RESPONSE TO CLOMIPHENE CITRATE IN OLIGOSPERMIC l\!IEN THOMAS M. JONES, VICTOR S. FANG, ROBERT L. ROSENFIELD AND HARRY W. SCHOENBERG From the University of Chicago, Pritzker School of Medicine, Chicago, Illinois
ABSTRACT Twenty oligospermic young men have undergone a 6-month trial of intermittent low dose domiphene therapy. Three-fourths of the patients enjoyed an increase in semen quality and 8 patients impregnated their wives. Plasma luteinizing hormone, follicle-stimulating hormone and testosterone levels increased in all patients on clomiphene. Development of stringent criteria for the use of clomiphene citrate should result in a conception rate of more than 50 per cent in selected patients. Hypotheses concerning the mechanism of therapeutic response to domiphene included the induction of higher levels of testosterone locally around the germinal epithelium and the induction of increased follide-stimu.lating hormone levels. peated. Subjects stopped the drug either at the time of verified conception or at the end of 6 cycles.
The widely accepted use of clomiphene citrate in the treatment of failure in women has not been paralleled similar acceptance in the treatment of hypospermatogenesis in men despite the fact that the drug seems to affect the hypothalamo-pituitary axis of both sexes in a similar fashion. 1 • 2 Part of this reluctance may stem from earlier clinical studies, showthat clomiphene in higher doses could cause decreases in sperm counts, increases in abnormal forms and potentially alarming changes in testis biopsy." For several years published studies dealt with clomiphene as a potential diagnostic and investigative agent on a short-term basis in men 4 - 7 but little was heard about long-term use until Paulson and Wacksman resome success with significantly smaller doses of clomiphene than are used in women. 8 We report our experience with clomiphene in a regimen slightly altered from that of Paulson and W acksman in the treatment of men with oligospermia.
RESULTS
Of 20 men who completed the therapy 8 impregnated their wives. Careful examination of the 12 men who did not impregnate their wives revealed some additional findings: 1 patient had a recurrence of varicocele, 2 patients had sperm with unusually low motility and the wives of 2 additional patients had unpredicted difficulties (polycystic ovary and sperm agglutinating antibodies). Thus, 7 patients failed to respond without explanation. Mean sperm concentration counts in the entire group increased from 11 to 39 million per cc (table 1). In addition, percentage of motile sperm and percentage of mature oval forms increased but these increases were not statistically nificant. It should be noted that not all patients enjoyed an improved semen analysis (5 failed to show improvement) but all patients who impregnated their wives had improved counts. In the 8 successful patients mean counts increased from 9 to 40 million per cc, with comparable increases in motility and mature forms. Patients varied in the time course of their response to clomiphene. An occasional patient showed a significant response after the first cycle, while others did not show a response until after 6 cycles. One patient impregnated his wife after the first cycle, while another impregnated his wife 2 months after clomiphene was discontinued. No patients have reported conception >2 months after therapy. Table 2 shows parameters of hormonal response to clomiphene. Mean testosterone levels increased from 599 to 1,104 ng./dl. in the first cycle and remained at about the same level throughout therapy. Similar observations were made for lutei.nizing hormone and follicle-stimulating hormone. All patients showed increases in these hormones but the degree of increase did not appear to correlate with the therapeutic outcome. Longterm clomiphene therapy actually induced a higher absolute follicle-stimulating hormone level in this group of patients than did the 100 µg. bolus of luteinizing hormone releasing factor (table 3). However, luteinizing hormone levels induced luteinizing hormone releasing factor easily surpassed those mduced by this regimen of clomiphene.
METHODS AND MATERIALS
Young men with a chief complaint of infertility were admitted to a trial of low dose clomiphene if the following criteria were met: 1) infertility for at least 2 years, 2) ifvaricocele had been present it had been corrected surgically at least l year 3) spouse had at least a biphasic basal body temperature as presumptive evidence of ovulation, 4) sperm counts were <40 million per cc on 3 separate occasions, 5) basal folliclehormone was within normal limits and 6) testis not show either tubular hyalinization or widespread maturation arrest. All patients in the trial had basal hormonal levels consisting of testosterone, estrogen, prolactin, luteinizing hormone and follicle-stimulating hormone. All hormones were measured by radioimmunoassay by methods previously reported. 9 Most patients also had the same hormonal battery repeated after challenge with a 100 µg. intravenous bolus of luteinizing hormone releasing factor. After the bolus samples were drawn at 5, 10, 15, 30, 45, 60 and 90 minutes, and 2 and 3 hours. All patients underwent bilateral testicular biopsy. Specimens were fixed in fixative and stained with toluidine blue. 10 •01uuuuueue was given in a dose of 25 mg. daily for 3 weeks l week of no drug. This cycle was repeated 6 times. Patients were seen on day 21 of each cycle, at which time an was obtained and basal hormone analyses were re-
DISCUSSION
Accepted for publication August 24, 1979. Read at annual meeting of American Urological Association, Washington, D. C., May 21-25, 1978. Supported in part by United States Public Health Service Grant 2 MOl RR00055.
We believe that clomiphene can be a useful drug in the treatment of certain men with oligospermia. The emphasis should be on the word "certain". Using prospective criteria we noted a 40 per cent pregnancy rate and a 75 per cent improve53
54
JONES AND ASSOCIATES
ment in semen analysis. These prospective criteria were hormonal and histological. We believe that no patient with elevated basal follicle-stimulating hormone levels can be expected to respond to clomiphene. Furthermore, patients with biopsies showing seriously disrupted spermatogenesis were not included (part A of figure), while patients with uncomplicated hypospermatogenesis were (part B of figure). Retrospective criteria in this series would yield a smaller population of suitable subjects. In our hands clomiphene was of no use in patients who had severely impaired motility and we would not recommend using clomiphene in such patients. The patient who had recurrent varicocele as well as the patients whose outcome was complicated by factors in the spouse should be dropped from the trial pool. Thus, if we carefully select our patients we might expect a conception rate of >50 per cent. Our results then are compatible with those of Paulson and W acksman8 and are more favorable than other published studies using clomiphene. 11 We can only assume that dosage regimen and patient selection are key factors in explaining this difference. We should mention that none of our patients experienced any side effects while on clomiphene. Libido and sexual performance were not altered and there were no reports of breast tenderness or gynecomastia. There is still a fair amount of uncertainty concerning how clomiphene acts to enhance spermatogenesis. Our data suggest at least 2 hypotheses. It is clear that chronic clomiphene administration induces chronically elevated testosterone in plasma. One can only assume that this increase in circulating testosterone is associated with higher local concentrations of testosterone around the germinal epithelium. If one accepts the notion that local concentrations of testosterone are critical for mammalian spermatogenesis 12 then clomiphene's action on the Leydig cell may be the key to its therapeutic effect. The alternate hypothesis would argue that since folliclestimulating hormone is known to be an essential factor in human spermatogenesis 1'3 the therapeutic response to clomiphene is mediated by the chronic elevation in plasma folliclestimulating hormone levels. The matter of dosage and duration of therapy is hardly settled at present. Further therapeutic trials may show that patients who fail on this regimen may respond to either higher doses or longer treatment. The intermittent regimen was simply an empirical approach adopted because of the favorable results TABLE
1. Improvement in semen analyses after clomiphene Concentration (million/cc)'
Basal Post-clomiphene
11
39
% Motile
% Oval Forms
33.7 40.1
56.9 62.7
'p <0.01 by paired t test.
TABLE
noted by Paulson and Wacksman. 8 It may not be necessary. Because a placebo group was not used one cannot be absolutely certain that clomiphene alone accounted for the response in our patients. Yet the otherwise dismal prognosis encountered in male infertility permits us to consider our >50 per cent success rate in selected patients evidence of a therapeutic effect of clomiphene. We have been encouraged sufficiently by our results with clomiphene to continue its use in selected oligosperm1c men.
2. Hormonal response during clomiphene Basal (ng./dl.)
1st Cycle Clomiphene (ng./dl.)
599 37 258
1,104 62 488
Testosterone Luteinizing hormone Follicle-stimulating hormone
TABLE
A, representative cross section of seminiferous tubule from patient who would not be expected to respond to clomiphene. Note reduction in tubular diameter, relative abundance of Sertoli cells and thickened tubular wall. B, representative cross section of seminiferous tubule from patient who responded to clomiphene. All stages of spermatogenesis are present, Sertoli cell nuclei (with prominent nucleolus) are around periphery.
3. Hormonal responses to clomiphene and luteinizing
hormone releasing factor
Testosterone Luteinizing hormone Follicle-stimulating hormone
Basal (ng./dl.)
1st Cycle Clomiphene (ng./dl.)
Post-Luteinizing Hormone Releasing Factor (ng./dl.)
599 37 258
1,104 62 488
641 468 352
REFERENCES 1. Kistner, R. W.: Induction of ovulation with clomiphene citrate
(clomid). Obst. Gynec. Surv., 20: 873, 1965. 2. Miechi, H. R., Turner, D., Guitelman, A., Aparicio, N. J. and Schwarzstein, L.: Pituitary-gonadal response to acute I. M. stimulation with clomiphene citrate in normal men. J. Clin. Endocr. Metab., 40: 1114, 1975. 3. Heller, C. G., Rowley, M. J. and Heller, G. V.: Clomiphene citrate: a correlation of its effect on sperm concentration and morphology, total gonadotropins, ICSH, estrogen and testosterone excretion and testicular cytology in normal men. J. Clin. Endocr. Metab., 29: 638, 1969. 4. Bardin, C. W., Ross, G. T. and Lipsett, M. B.: Site of action of clomiphene citrate in men: a study of the pituitary-Leydig cell axis. J. Clin. Endocr. Metab., 27: 1558, 1967. 5. Boyar, R. B., Perlow, M., Kapen, S., Lefkowitz, G., Weitzman, E. and Hellman, L.: The effect of clomiphene citrate on the 24-hour LH secretory pattern in normal men. J. Clin. Endocr. Metab.,
PARAMETERS OF RESPONSE TO CLOMIPHENE CITRATE IN OLIGOSPERMIC MEN
36: 561, 1973. 6. Nankin, H. R., Yanaihara, T. and Troen, P.: Response of gonadotropins and testosterone to clomiphene stimulation in a pubertal boy. J. Clin. Endocr. Metab., 33: 360, 1971. 7. Snoep, M. C., de Lange, W. E., Sluiter, W. J. and Doorenbos, H.: Differential response to serum LH in hypogonadotropic hypogonadism and delayed puberty to LH-RH stimulation before and after clomiphene citrate administration. J. Clin. Endocr. Metab., 44: 603, 1977. 8. Paulson, D. F. and Wacksman, J.: Clomiphene citrate in the management of male infertility. J. Urol., 115: 73, 1976. 9. Jones, T. M., Fang, V. S., Landau, R. L. and Rosenfield, R. L.: The effects of fluoxymesterone administration on testicular function.
55
J. Clin. Endocr. Metab., 44: 121, 1976. 10. Jones, T. M., Anderson, W. A., Fang, V. S., Landau, R. L. and Rosenfield, R. L.: Experimental cryptorchidism in adult male rats: histological and hormonal sequelae. Anat. Rec., 189: 1, 1977. 11. Mellinger, R. C. and Thompson, R. J.: Effect of clomiphene citrate in male infertility. Fertil. Steril., 17: 94, 1966. 12. Steinberger, E.: Hormonal control of mammalian spermatogenesis. Physiol. Rev., 51: 1, 1971. 13. Mancini, R. E., Seiguer, A. C. and Lloret, P.: The effect of gonadotropins on the testis of hypophysectomized patients. In: Gonadotropins 1968. Proceedings of the Workshop Conference, Vista Hermosa, Mor., Mexico, 1968. Edited by E. Rosemberg. Los Altos: Geron-X, p. 503, 1968.