|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Semen Quality and Reproductive Hormones Before Orchiectomy in Men With Testicular CancerFrom the Departments of Growth and Reproduction, and Oncology, Finsencenter, Copenhagen University Hospital, Rigshospitalet, and Department of Pharmacology, University of Copenhagen, Copenhagen, Denmark. Address reprint requests to Peter Meidahl Petersen, MD, Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, Copenhagen, Denmark
PURPOSE: To obtain information about preorchiectomy gonadal function in patients with testicular germ cell cancer to improve the clinical management of fertility and other andrologic aspects in these men. PATIENTS AND METHODS: In group 1, a group of 83 consecutive patients with testicular germ cell cancer (TGCC) investigated before orchiectomy, semen analysis was carried out in 63 patients and hormonal investigations, including measurement of follicle-stimulating hormone, luteinizing hormone (LH), testosterone, estradiol, sex hormone–binding globulin (SHBG), inhibin B, and human chorionic gonadotropin (hCG), in 71 patients. Hormone levels in patients with elevated hCG (n = 41) were analyzed separately. To discriminate between general cancer effects and specific effects associated with TGCC, the same analyses were carried out in a group of 45 consecutive male patients with malignant lymphoma (group 2). Group 3 comprised 141 men employed in a Danish company who served as controls in the comparison of semen parameters. As a control group in hormone investigations, 193 men were selected randomly from the Danish National Personal Register to make up group 4. RESULTS: We found significantly lower sperm concentration (median, 15 x 106/mL; range, 0 to 128 x 106/mL) and total sperm count (median, 29 x 106/mL; range, 0 to 589 x 106) in patients with testicular cancer than in patients with malignant lymphomas (sperm concentration: median, 48 x 106/mL; range, 0.04 to 250 x 106/mL; sperm count: median, 146 x 106; range, 0.05 to 418 x 106) (P < .001 and P < .001) and healthy men (sperm concentration: median, 48 x 106/mL; range, 0 to 402 x 106/mL; sperm count: median, 162 x 106; range, 0 to 1253 x 106) (P < .001 and P < .001). FSH levels were increased in men with testicular cancer (median, 5.7 IU/L; range, 2.0 to 27 IU/L) compared with both men with malignant lymphomas (median, 3.3 IU/L; range, 1.01 to 12.0 IU/L) and healthy controls (median, 4.1 IU/L; range, 1.04 to 21 IU/L) (P = .001 and P = .007, respectively). Surprisingly, we found significantly lower LH in the group of men with TGCC (median, 3.6 IU/L; range, 1.12 to 11.9 IU/L) than in healthy men (median, 4.7 IU/L; range, 1.3 to 11.9 IU/L) (P = .01). We could not detect any differences between men with testicular cancer and men with malignant lymphomas and healthy men with regard to serum levels of testosterone, SHBG, and estradiol. Men with testicular cancer who had increased hCG levels had significantly lower LH and significantly higher testosterone and estradiol than those without detectable hCG levels. CONCLUSION: Spermatogenesis is already impaired in men with testicular cancer before orchiectomy. Neither local suppression of spermatogenesis by tumor pressure nor a general cancer effect seems to fully explain this impairment. The most likely explanation is pre-existing impairment of spermatogenesis in the contralateral testis in men with testicular cancer. The question of whether also a pre-existing Leydig cell dysfunction is present in men with testicular cancer could not be answered in this study because the tumor seems to have a direct effect on the Leydig cells. Men with testicular cancer had low LH values as compared with controls. We speculate that increased intratesticular level of hCG also in men without measurable serum hCG may play a role by exerting LH-like effects on the Leydig cells, causing increased testosterone and estrogen levels and low LH values in the blood.
LITTLE IS KNOWN about semen quality and serum levels of reproductive hormones in men with testicular germ cell cancer (TGCC) before orchiectomy. The few studies that have dealt with this topic have been based on small numbers of patients (less than 20).1-5 Histologic investigations have shown that a high proportion of men with unilateral TGCC have abnormalities of spermatogenesis in the contralateral testis.6 However, in these investigations, no control group was included. This is relevant because data on the incidence of abnormalities of spermatogenesis in the general population have shown large variations (from 5% to 28%).7,8 Furthermore, epidemiologic investigations have indicated that men with TGCC already have an increased risk of infertility before the diagnosis of cancer.9,10 Thus, more investigations of gonadal function in these men are needed to elucidate the state of spermatogenesis and production of reproductive hormones. The fertility aspects have been shown to be important to men with TGCC,11 and knowledge of testicular function is very important for the counseling of these men. The need for more information is strengthened by the evidence of an association between testicular cancer and conditions such as cryptorchidism and small testes, which imply an increased risk of poor spermatogenetic function and infertility. Additionally, more information about reproductive hormones and semen quality before orchiectomy in men with TGCC might provide information relevant for the understanding of the etiology of testicular cancer. The aim of the study presented here was to obtain information about preorchiectomy gonadal function in patients with TGCC, in order to (1) improve the clinical management of fertility and other andrologic aspects in these men and (2) further elucidate the possible common etiology of poor gonadal function and TGCC.
Patients Group 1. The group of patients with testicular cancer comprised 85 consecutive patients referred to urology departments in the Copenhagen area for unilateral testicular cancer from 1994 to 1997. Eighty-three of the patients agreed to participate. Hormonal investigations were done in 82 patients and semen analyses were done in the 63 patients (75%) who agreed to deliver a semen sample for the study. Eleven men, including eight men who had delivered semen samples for the investigation, were not included in the part of the study concerning hormone investigation because appropriate human chorionic gonadotropin (hCG) analyses by the very sensitive assay were not available. Data on men with elevated hCG in serum (n = 41) were analyzed separately and were not included in the comparisons of hormone levels in groups 2 and 3. Characteristics of the included patients are listed in Tables 1  and 2. Thirty-two of 82 men with known fertility status had fathered one or more children (median, 1; range, 1 to 3). The median age at first child was 28 years (range, 20 to 33 years).
Group 2. To discriminate between a possible general cancer effect and specific effects associated with TGCC, we examined during the above-mentioned period a group of 45 consecutive patients with malignant lymphoma before initiation of antineoplastic treatment. Forty (89%) of these men agreed to deliver semen samples (Tables 1 and 2). Seventeen (37%) of the 45 men had fathered one or more children (median, 2; range, 1 to 4). The median age at first child was 27 years (range, 20 to 37 years). Group 3. Healthy men, recruited in an epidemiologic study among men employed in various types of jobs, such as mechanics, clerks, and computer workers in a large Danish company, served as controls in analyses of semen data. In total, 797 men was asked to participate, and 212 (27%) agreed. Of these men, 13 had had a vasectomy and 58 refused to deliver semen samples (Table 1). The group thus consisted of 141 men, who were examined from 1989 to 1990. Group 4. As a control group for the hormone investigations, 327 men were selected randomly from the Danish National Personal Register. A total of 193 men (59%) agreed to participate in the study (Table 2).
Semen Analyses
Hormonal Analyses
Testicular Volume
Statistical Methods
Spermatogenesis The results of semen analyses in men with testicular cancer, men with malignant lymphomas, and healthy controls are listed in Table 3. The most striking findings were significantly lower sperm concentration and total sperm count in patients with testicular cancer compared with patients with malignant lymphomas (P < .001 and P < .001) and healthy men (P < .001 and P < .001). The only other semen characteristics in men with TGCC, which differed statistically significantly from those of the controls, were the lower volume of ejaculate and longer abstinence time. A history of cryptorchidism was significantly more common in men with TGCC than in controls. Statistically significant differences in sperm concentration and total sperm count between men with TGCC (group 1) and men without (groups 2 and 3) were still present when men with cryptorchidism were excluded from the analyses (P < .001 and P < .001). To elucidate whether the low sperm counts were exclusively due to the fact that the tumor-bearing testis did not contribute to sperm production, we compared the levels of sperm concentration and total sperm count in patients with TGCC with the 50% corresponding values in healthy men (group 3). Sperm concentrations and total sperm counts in group 1 were significantly lower than the 50% values of the same parameters in group 3 (P = .02 and P < .001).
Men in group 1 with increased levels of hCG did not differ from patients without hCG elevation with respect to sperm concentration and total sperm count (Table 4) and the sperm concentration and total sperm count values were still significantly lower those of the controls if these men were excluded from the comparative analyses (sperm concentration and total sperm count, P < .001 compared with both groups 2 and 3). Moreover no differences were seen between patients with stage I disease (n = 50) and patients with disseminated disease (n = 13) with respect to sperm concentration or total count (P = .25 and P = .11).
A significant correlation between abstinence time and sperm concentration and total sperm count was found in all three groups (group 1, p = .02 and .05, respectively; group 2, P = .04 and P = .05, respectively; group 3, P = .03 and P < .001, respectively). The abstinence time was slightly longer in healthy men than in men with testicular cancer (Table 3). However, mean values of total sperm count and sperm concentration in men with TGCC were lower at all levels of abstinence time and still significantly lower in a regression model that took abstinence time into account (P < .001 and P < .001). Because the data set did not show normal distribution, these analyses were done with (log)2-transformed data, which gave acceptable distributions of residual plots. The abstinence time in groups 2 and 3 did not differ significantly. To test the possible confounding effect of age differences in the groups, the correlation between age and sperm count was tested. A statistically significant correlation between age and total sperm count was seen in group 3 (r = .17, P = .04), whereas no correlation was seen between age and total sperm count in groups 1 and 2 (P = .93 and P = .79). No correlation was seen between age and sperm concentration in any of the groups. The effect of birth year was analyzed because men in group 3 were examined from 1989 to 1990 and those in groups 1 and 2 from 1994 to 1997. Statistically significant negative correlation between birth year and total sperm count was seen in group 3 (r = -.17, P = .04) but not in groups 1 and 2, and no statistically significant correlation was detected between year of birth and sperm concentration in any of the groups. Sperm concentration and total sperm count in group 1 were still significantly lower than those in groups 2 and 3 in regression models that included age and year of birth (P < .001 for both sperm concentration and total sperm count). The time distributions during the year of semen analyses in groups 1 and 2 were uniform. In group 3, semen analyses peaked in May and June. Testicular volume was similar in group 1 (median, 14.5 mL; range, 4 to 21 mL) and group 3 (median, 14.5 mL; range, 6.5 to 26 mL) (P = .38). The frequency of men in groups 1 and 2 who had children was similar (P = .53); moreover, no differences were seen in the age at first child (P = .67) and the number of children (P = .86). Levels of FSH were increased in men with testicular cancer compared with both men with malignant lymphomas and healthy controls (Table 3). Inhibin levels were significantly lower in men with TGCC than in the reference group (P < .001), but they were not significantly different from the level in men with malignant lymphoma (P = .34).
Leydig Cell Function We found a significantly lower LH level in the group of men with TGCC, who did not have increased hCG levels in serum, as compared with controls (P = .01), while the LH levels were similar to those of men with malignant lymphoma (P = .52) (Table 5). We did not find any differences between men with testicular cancer without detectable hCG levels in serum and men with malignant lymphomas and healthy controls with regard to serum levels of testosterone, SHBG, and estradiol. Men with testicular cancer who had increased hCG levels had significantly lower LH and significantly higher testosterone and estradiol than men without detectable hCG levels (Table 4). Four men had increased LH possibly due to cross-reactivity of hCG and LH in the assay. Neither LH, testosterone, estradiol, nor SHBG showed any correlation to age or year of birth.
In this study, which included 83 men with testicular cancer, we found that there was already a considerable impairment of semen quality before orchiectomy for TGCC. The present study differs from the few previous investigations that have investigated the gonadal function in men with TGCC before orchiectomy1,2,5,17 by the higher number of investigated men. Moreover, the possible confounding factors, abstinence time, year of birth, age, and seasonal variation, were taken into consideration.
Abstinence time.
Role of age.
Cohort effect.
Seasonal variations. The extremely low sperm counts in patients with TGCC compared with healthy men were thus not due to the observed minor differences in abstinence time, age, or year of birth among the three groups. This conclusion is supported by the observation of significantly higher FSH and lower inhibin B levels in men with TGCC than in controls. It should be noted that even though motility and morphology seem to be unaffected in men with TGCC, we cannot exclude that the group as such has impaired sperm morphology and/or motility because the data on these aspects may be biased, because analyses of sperm morphology and motility are impossible in ejaculates with severe oligozoospermia and azoospermia. This means that these characteristics are not assessed in samples with very low sperm counts. Impairment of spermatogenesis in the tumor-bearing testis has previously been shown.26 Is it due to the tumor itself or to a pre-existing defect in the spermatogenesis? The present data showed that median values of sperm concentration and total sperm count in men with TGCC were approximately 35% and 20%, respectively, of the values in lymphoma patients and healthy controls, ie, significantly lower than 50% of the values in controls, which would be the expected value if the remaining testis was normal. Moreover, we found a further impairment of spermatogenesis after orchiectomy as compared with preorchiectomy values in our study of the effect of orchiectomy on gonadal function in men with TGCC.27 Thus, the very low sperm concentration and total sperm count in patients with TGCC cannot be explained alone by suppression of spermatogenesis by the tumor itself or by tumor products. The most likely explanation is a pre-existing impairment of spermatogenesis also in the contralateral testis in men with TGCC. Thus, the present study confirmed the observations in histologic studies showing a high incidence of histologic abnormalities in the contralateral testes in men with unilateral TGCC,28 abnormalities that are associated with poor semen quality. We did not see decreased androgen levels in serum or an increased proportion of men with other signs of Leydig cell dysfunction among men with TGCC, even after exclusion of men with measurable serum levels of hCG in the analyses. The finding of significantly lower LH levels despite equal levels of testosterone and estradiol in men with TGCC is surprising. One possible explanation for the lower level of LH could be altered pituitary LH secretion caused by decreased LH-releasing hormone from hypothalamus because of the cancer. This suggestion is supported by the observation of equal levels of LH in men with TGCC and men with malignant lymphoma. The normal level of testosterone and estradiol in men with TGCC could be explained by an increase of intratesticular levels of hCG, as proposed recently on the basis of an investigation of testicular venous blood during orchiectomy,29 or other agents produced by the tumor leading to stimulation of testosterone and estradiol production in Leydig cells in the tumor-bearing testis. Another possible explanation could be that such an increase in intratesticular hCG levels could lead to increased testosterone and/or estradiol levels as compared with the levels before development of TGCC and thereby to decreased LH levels without any hypothalamic influence of the cancer disease. This is supported by the finding of even lower serum LH levels in patients with increased hCG. Impaired Leydig cell function has previously been described in men unilateraly orchiectomized for TGCC as compared with men orchiectomized for other reasons.30 The present study does not exclude such an impairment even if normal testosterone levels were found in men with TGCC without detectable serum hCG levels. A surprisingly high proportion of patients with testicular cancer had detectable hCG levels when the very sensitive assay was used (58%). Patients with increased serum levels of hCG had significantly decreased LH and increased estradiol and testosterone levels, probably because of direct hCG stimulation of Leydig cells. Interestingly, we saw a 2.3-fold increase of estradiol values and only a 1.3-fold increase of testosterone values in TGCC patients with increased serum levels of hCG compared with patients without. Thus, estradiol shows a relatively more marked increase than testosterone in men with TGCC. Another interesting observation was that only four of 24 men with increased hCG levels had increased LH values when this very specific LH assay was used. Previous studies have shown increased LH levels possibly caused by higher cross-reactivity with hCG,5,31 whereas we observed decreased levels, as expected in men with primary increased testosterone and estradiol levels. The etiology of TGCC is unknown, but the observations of increased risk of testicular cancer in men with testicular atrophy, a history of cryptorchidism, infertility32-37 and testicular dysgenesis,38 and the observations of increasing incidence of testicular cancer concomitant with increasing incidence of other abnormalities in male reproductive health have led to the suggestions of common etiology of poor male reproductive function and TGCC.39,40 The finding of very poor semen quality, which is probably due to a pre-existing impairment of spermatogenesis, is in line with these suggestions. We did not observe impaired Leydig cell function in these patients. However, because of the possibility of increased intratesticular hCG level, we cannot exclude such impairment. It possible that a significant impairment could be hidden by an increased intratesticular level of hCG and/or other agents stimulating the Leydig cells in the tumor-bearing testis. In conclusion, semen quality is impaired in men who have already testicular cancer before orchiectomy; neither local suppression of spermatogenesis by tumor pressure nor a general cancer effect explains this impairment; the most likely explanation is a pre-existing impairment of spermatogenesis also in the contralateral testis. Men with testicular cancer have normal androgen levels before orchiectomy. We speculate that increased intratesticular levels of hCG may play a role by exerting LH-like effects on the Leydig cells, resulting in increased testosterone and estrogen levels and low LH values.
Supported by the Danish Cancer Society and The Danish Environmental Research Program
1. Nijman JM, Schraffordt Koops H, Kremer J, et al: Fertility and hormonal function in patients with a nonseminomatous tumor of the testis. Arch Androl 14:239-246, 1985[Medline] 2. Carroll PR, Whitmore WF Jr Herr HW, et al: Endocrine and exocrine profiles of men with testicular tumors before orchiectomy. J Urol 137:420-423, 1987[Medline]
3.
Nijman JM, Schraffordt Koops H, Kremer J, et al: Gonadal function after surgery and chemotherapy in men with stage II and III nonseminomatous testicular tumors. J Clin Oncol 5:651-656, 1987 4. Jewett MAS, Thachil JV, Harris JF: Exocrine function of testis with germinal testicular tumour. Br Med J 286:1849-1850, 1983 5. Lunglmayr G, Kuber W, Kratzik C, et al: The gonadotropin response to synthetic gonadotropin releasing factor in patients with testicular cancer. Urol Res 11:69-73, 1983[Medline] 6. Hansen PV, Trykker H, Andersen J, et al: Germ cell function and hormonal status in patients with testicular cancer. Cancer 64:956-961, 1989[Medline] 7. Giwercman A, Müller J, Skakkebæk NE: Prevalence of carcinoma-in-situ and other histopathological abnormalities in testes from 399 men who died suddenly and unexpectedly. J Urol 145:77-80, 1991[Medline]
8.
Pajarinen J, Laippala P, Penttila A, et al: Incidence of disorders of spermatogenesis in middle aged Finnish men, 1981-91: Two necropsy series. Br Med J 314:13-18, 1997 9. Swerdlow AJ, Huttly SRA, Smith PG: Testis cancer: Post-natal factors, sexual behaviour and fertility. Int J Cancer 43:549-553, 1989[Medline] 10. Møller H: Trends in sex-ratio, testicular cancer and male reproductive hazards: Are they connected? in Rajpert-De Meyts E, Grigor KM, Skakkebæk NE (eds): Neoplastic Transformation of Testicular Germ Cells. Proceedings of the 4th Copenhagen Workshop on the Carcinoma In Situ and Cancer of the Testis: Molecular and Endocrine Aspects. Copenhagen, Denmark, APMIS, 1998 11. Moynihan C: Testicular cancer: The psychosocial problems of patients and their relatives. Cancer Surv 6:477-510, 1987[Medline] 12. World Health Organization: WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. New York, NY, Cambridge University Press, 1987 13. World Health Organization: WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge, UK, Cambridge University Press, 1992 14. Illingworth PJ, Groome NP, Bryd W, et al: Inhibin-B: A likely candidate for the physiologically important form of inhibin in men. J Clin Endocrinol Metab 81:1321-1325, 1996[Abstract] 15. Anawalt BD, Bebb RA, Matsumoto AM, et al: Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 81:3341-3345, 1996[Abstract] 16. Lenz S, Giwercman A, Elsborg A, et al: Ultrasonic testicular texture and size in 444 men from the general population: Correlation to semen quality. Eur Urol 24:231-238, 1993[Medline] 17. Bouchot O, Plougastel ML, Karam G: Sterilite et tumeurs du testicule. J Urol (Paris) 95:367-371, 1989[Medline]
18.
Schwartz D, Laplanche A, Jouannet P, et al: Within-subject variability of human semen in regard to sperm count, volume, total number of spermatozoa and length of abstinence. J Reprod Fertil 57:391-395, 1979
19.
Irvine S, Cawood E, Richardson D, et al: Evidence of deteriorating semen quality in the United Kingdom: Birth cohort study in 577 men in Scotland over 11 years. Br Med J 312:467-471, 1996 20. Van Waeleghem K, De Clercq N, Vermeulen L, et al: Deterioration of sperm quality in young healthy Belgian men. Hum Reprod 11:325-329, 1996
21.
Auger J, Kunstmann JM, Czyglik F, et al: Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 332:281-285, 1995 22. Tjoa WS, Smolensky MH, Hsi BP, et al: Circannual rhythm in human sperm count revealed by serially independent sampling. Fertil Steril 38:454-459, 1982[Medline] 23. Levine RJ, Brown MH, Bordson BI, et al: Deterioration of semen quality during summer in New Orleans. Fertil Steril 49:900-907, 1988[Medline] 24. Levine RJ, Mathew RM, Chenault CB, et al: Differences in the quality of semen in outdoor workers during summer and winter. N Engl J Med 323:1216, 1990[Medline] 25. Politoff L, Birkhauser M, Almendral A, et al: New data confirming a circannual rhythm in spermatogenesis. Fertil Steril 52:486-489, 1989[Medline] 26. Ho GT, Gardner H, De Wolf WC, et al: Influence of testicular carcinoma on ipsilateral spermatogenesis. J Urol 148:821-825, 1992[Medline] 27. Petersen PM, Skakkebæk NE, Rørth M, et al: Semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. J Urol (in press) 28. Berthelsen JG, Skakkebæk NE: Gonadal function in men with testis cancer. Fertil Steril 39:68-75, 1983[Medline] 29. Berger P, Kranewitter W, Madersbacher S, et al: Eutopic production of human chorionic gonadotropin beta (hCG beta) and luteinizing hormone beta (hLH beta) in the human testis. FEBS Lett 343:229-233, 1994[Medline] 30. Willemse PHB, Sleijfer DT, Sluiter WJ, et al: Altered Leydig cell function in patients with testicular cancer: Evidence for a bilateral testicular defect. Acta Endocrinol 102:616-624, 1983
31.
Morrish DW, Venner PM, Barron G, et al: Mechanisms of endocrine dysfunction in patients with testicular cancer. J Natl Cancer Inst 82:412-418, 1990 32. Giwercman A, Grindsted J, Hansen B, et al: Testicular cancer risk in boys with maldescended testis: A cohort study. J Urol 138:1214-1216, 1987[Medline]
33.
Strader CH, Weiss NS, Daling JR, et al: Cryptorchism, orchiopexy, and the risk of testicular cancer. Am J Epidemiol 127:1013-1018, 1988 34. Ford TF, Parkinson MC, Pryor JP: The undescended testis in adult life. Br J Urol 57:181-184, 1985[Medline] 35. Møller H, Prener A, Skakkebæk NE: Testicular cancer, cryptorchidism, inguinal hernia, testicular atrophy, and genital malformations: Case-control studies in Denmark. Cancer Causes Control 7:264-274, 1996[Medline]
36.
Schottenfeld D, Warshauer ME, Sherlock S, et al: The epidemiology of testicular cancer in young adults. Am J Epidemiol 112:232-246, 1980 37. Depue RH, Pike MC, Henderson BE: Estrogen exposure during gestation and risk of testicular cancer. J Natl Cancer Inst 71:1151-1155, 1983 38. Müller J: Morphometry and histology of gonads from twelve children and adolescents with the androgen insensitivity (testicular feminization) syndrome. J Clin Endocrinol Metab 59:785-789, 1984[Abstract] 39. Sharpe RM, Skakkebæk NE: Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341:1392-1395, 1993[Medline] 40. Sharpe RM: Falling sperm counts in men: Is there an endocrine cause? J Endocrinol 137:357-366, 1993 Submitted July 20, 1998; accepted November 20, 1998. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
–ßB uses a monoclonal capture antibody raised against the ßB subunit and a secondary monoclonal enzyme–conjugated antibody raised against a sequence of the 
2 test. 
