Jacobsen, Rune; Bostofte, Erik; Engholm, Gerda; Hansen, Johnni; Olsen, Jorgen H; Skakkebaek, Niels E; Moller, Henrik . [Abstract] [Long Display]
Abstract
Objective
To explore the associations between semen characteristics and subsequent risk of
testicular cancer.
Design Cohort study.
Participants
32 442 men who had a semen analysis done at the Sperm Analysis Laboratory in
Copenhagen during 1963-95.
Main outcome measure
Standardised incidence ratios of testicular cancer compared with total
population of Danish men.
Results
Men in couples with fertility problems were more likely to develop testicular
cancer than other men (89 cases, standardised incidence ratio 1.6; 95%
confidence interval 1.3 to 1.9). The risk was relatively constant with
increasing time between semen analysis and cancer diagnosis. Analysis according
to specific semen characteristics showed that low semen concentration
(standardised incidence ratio 2.3), poor motility of the spermatozoa (2.5), and
high proportion of morphologically abnormal spermatozoa (3.0) were all
associated with an increased risk of testicular cancer. The only other cancer
group that showed increased incidence was "peritoneum and other digestive
organs" (six cases; 3.7, 1.3 to 8.0). Of these, two cases were probably and
two cases were possibly extragonadal germ cell tumours.
Conclusions
The results point towards the existence of common aetiological factors for low
semen quality and testicular cancer. Low semen quality may also be associated
with increased incidence of extragonadal germ cell tumours.
Introduction
Over recent decades a possible decrease in semen quality 1 2 and an increase in the incidence of testicular cancer have been reported in many populations. 3-5 It is unclear whether these temporal trends are independent phenomena or somehow connected to each other. 6-8 Case-control studies on subfertility and subsequent risk of testicular cancer have given conflicting results. 8 9 However, a recent Danish population based cohort study found an increased risk of testicular cancer in men with few children for their age. 10 These findings supported the results of an earlier Danish case-control study. 8 Both of these Danish studies used the number of children fathered at a given age as the measure of fertility. Thus some men with normal reproductive potential will inevitably have been classified as having low relative fertility because they had no or few children for reasons that were unrelated to their fertility. Subfertility can be measured more directly by analysis of semen for characteristics such as spermatocyte concentration, motility, and morphology. 11 12
Men with testicular cancer often have abnormal semen characteristics, 13 14 but the association between abnormal semen characteristics and testicular cancer has not been investigated prospectively. We studied the incidence of testicular cancer in relation to semen characteristics in 32 442 men who had semen analysis at the Sperm Analysis Laboratory in Copenhagen during 1963-95.
Participants and methods
We linked information on all men in couples with fertility problems who had a semen analysis done at the Sperm Analysis Laboratory in Copenhagen during 1963-95 (n = 32 442) with data in the Danish Cancer Registry, which holds information on all cases of cancer in the Danish population from 1943 to 1995. 15 Men who visited the laboratory for other reasons (such as semen analysis after vasectomy) were excluded from the analysis. The Copenhagen laboratory is one of several public semen analysis laboratories in Denmark and examines semen samples mostly from men in the area of Copenhagen. Men are referred to the clinic by general practitioners and urologists, and the investigations are paid for through the public health system. Men with cancer before the date of semen analysis were excluded. For men who had multiple semen tests only their first test was used in the analysis. Similarly, only the first cancer diagnosis in a given man was included in the analysis. The methods used for analysis of semen (sperm concentration and motility and proportion of morphologically abnormal spermatozoa) have been described previously. 16 For each man we also obtained information on date of birth, dates of birth of his children, and date of death from the Central Population Register and the National Death Register.
We calculated the expected numbers of cancer cases in the cohort (by multiplying years at risk with primary cancer rates in the Danish population) and standardised incidence ratios and 95% confidence intervals using a Fortran computer program. 17 The standardised incidence ratios were calculated for each type of cancer by time since first semen analysis, stratifying by semen characteristics according to standard definitions of subfertility. 12 The group of azoospermic men was divided into those with and without children in order to address the possibility that some azoospermic men had not given information on sterilisation or other circumstances resulting in a sudden azoospermia. To examine the separate and joint effects of the three semen characteristics, the cohort was stratified into groups according to their combination of semen measures.
Results
Overall, the cohort members had an increased risk of testicular cancer and of cancers of the peritoneum and other digestive organs (table 1). Risk of other types of cancer was not increased in the cohort Eighty nine men developed testicular cancer, giving a standardised incidence ratio of 1.6 (95% confidence interval 1.3 to 1.9). Of these 89 men, 50 had seminomas (standardised incidence ratio 1.5, 1.1 to 1.9), 37 had non-seminomas (1.8, 1.2 to 2.4), and two were unspecified. For cancer of the peritoneum and other digestive organs the standardised incidence ratio was 3.7 (1.3 to 8.0) based on six observed cases. The standardised incidence ratio for cancers of all other sites combined was 1.0 (0.9 to 1.1).
Table 1 Standardised incidence ratios and 95% confidence intervals for different cancers in cohort of 32 442 men having sperm analysis in Copenhagen, 1963-95
Observed Expected Standardised
No of No of incidence ratio
Type of cancer cases cases (95% Cl)
All malignant neoplasms 481 452.6 1.1 (1.0 to 1.2)
Peritoneum and other 6 1.6 3.7 (1.3 to 8.0)(*)
digestive organs
Testis 89 57.1 1.6 (1.3 to 1.9)(*)
Others 386 393.3 1.0 (0.9 to 1.1)
(*) P<0.05.
Table 2 shows the standardised incidence ratios for testicular cancer stratified by time between first semen analysis and cancer diagnosis. The highest risk of testicular cancer was in the first two years after the first semen analysis (standardised incidence ratio 1.8). The risk was 1.5-1.6 for two to 11 years after the first semen analysis and 1.3 for more than 11 years since first semen analysis. The trend in the standardised incidence ratios over the four periods of follow up was not significant (P = 0.46).
Table 2 Standardised incidence ratios and 95% confidence intervals for testicular cancer, stratified by time since semen analysis
Time between semen analysis and Observed No Expected No diagnosis (years) of cases of cases 0-2 23 12.8 - 6 30 20.1 -11 24 15.3 >11 12 9.0 Trend Time between semen Standardised analysis and incidence ratio diagnosis (years) (95% Cl) 0-2 1.8 (1.1 to 2.7)(*) -6 1.5 (1.0 to 2.1)(*) -11 1.6 (1.0 to 2.3)(*) >11 1.3 (0.7 to 2.3) Trend P=0.46 (*) P<0.05.
Table 3 Standardised incidence ratios and 95% confidence intervals for testicular cancer according to semen characteristics
Total Observed
No of No of
Variable men cases
Concentration ( 10.sup.6 /ml)
0 and no children before 1 031 7
analysis
0 and children before 1 644 6
analysis
0-20 10 509 33
>20 18 668 42
Not available 590 1
Motility¶
Poor 1 312 7
Good 19 362 44
Not available 9 093 25
Proportion abnormal (%)¶
>75 528 4
0-75 27 618 64
Not available 1 621 8
Expected Standardised
No of incidence ratio
Variable cases (95% Cl)
Concentration ( 10.sup.6 /ml)
0 and no children before 2.0 3.5 (1.4 to 7.2)(*)
analysis
0 and children before 3.0 2.0 (0.7 to 4.3)
analysis
0-20 14.4 2.3 (1.6 to 3.2)(*)
>20 36.9 1.1 (0.8 to 1.5)
Not available 0.8 1.3 (0.0 to 7.0)
Motility¶
Poor 2.8 2.5 (1.0 to 5.2)(*)
Good 28.0 1.6 (1.1 to 2.1)(*)
Not available 21.3 1.2 (0.8 to 1.7)
Proportion abnormal (%)¶
>75 1.4 3.0 (0.8 to 7.6)
0-75 47.8 1.3 (1.0 to 1.7)(*)
Not available 29.0 2.7 (1.2 to 5.4)(*)
(*) P < 0.05.
¶ Excluding 2675 azoospermic men.
The univariate, separate, and joint effects of the three semen quality measures were analysed in the subgroup of 29 177 men who had some spermatozoa in the semen sample (table 4). The separate effect of low concentration on the risk of testicular cancer was roughly the same as the univariate effect (standardised incidence ratio 2.1 and 2.3, respectively). Of 10 509 men with low semen concentration, 9187 had low concentration as the only abnormal characteristic. Very few men had poor motility only or a high proportion of abnormal spermatozoa only, and no case of testicular cancer was observed in these groups. We therefore could not identify a separate effect of poor motility or of having a high proportion of abnormal spermatozoa. However, the risk of testicular cancer increased with increasing number of subfertility measures present The standardised incidence ratio was 1.9 for one subfertility measure, 2.7 for two measures, and 9.3 for all three subfertility measures.
Table 4 Separate and joint effects of three semen quality measures on risk of testicular cancer among 29 177 men with some spermatozoa in semen
Total Observed
No of No of
Variable men cases
Univariate effects
Low concentration 10 509 33
( is less than or equal to
20x 10.sup.6 /ml)
Poor motility 1 298 7
Many abnormal (> 75%) 528 4
Separate effects
Low concentration (only) 9 187 24
Low motility (only) 187 0
Many abnormal (only) 213 0
Other 19 590 52
Joint effects
One subfertility measure 9 587 24
Two subfertility measures 1 251 7
Three subfertility measures 82 2
Other 18 257 43
Expected Standardised
No of incidence ratio
Variable cases (95% CI)
Univariate effects
Low concentration 14.5 2.3 (1.6 to 3.2)(*)
( is less than or equal to
20x 10.sup.6 /ml)
Poor motility 2.8 2.5 (1.0 to 5.2)(*)
Many abnormal (> 75%) 1.4 3.0 (0.8 to 7.6)
Separate effects
Low concentration (only) 11.6 2.1 (1.3 to 3.1)(*)
Low motility (only) 0.4 --
Many abnormal (only) 0.6 --
Other 39.5 1.3 (1.0 to 1.7)
Joint effects
One subfertility measure 12.6 1.9 (1.2 to 2.8)(*)
Two subfertility measures 2.6 2.7 (1.1 to 5.5)(*)
Three subfertility measures 0.2 9.3 (1.0. to 33.4)
Other 36.7 1.2 (0.9 to 1.6)
(*) P < 0.05.
Table 5 Evaluation of the six cases of cancers of peritoneum and other digestive organs based on notification forms received from Danish Cancer Registry
Age (years)
Year At
of semen At cancer At
Case birth analysis diagnosis death
1 1949 30 39 45
2 1953 19 30 --
3 1956 32 33 34
4 1926 52 68 68
5 1948 29 35 --
6 1950 30 33 34
Case Topography Morphology
1 1580 Retroperitoneum 90643 Germinoma
2 1580 Retroperitoneum 81403 Adenocarcinoma, not
otherwise specified
3 1580 Retroperitoneum 80003 Neoplasm unclassified,
malignant
4 1589 Peritoneum 99903 No microscopic confirmation;
clinically benign tumour
5 1580 Retroperitoneum 90803 Teratoma, malignant, not
otherwise specified
6 1580 Retroperitoneum 88003 Sarcoma, not otherwise
specified
Consistent
with
extragonadal
Comment, based on germ cell
Case notification forms cancer?
1 Uncertain diagnosis. Died 1994 Possibly
from leukaemia. Notification
indicates "leukaemia secondary to
testicular cancer"
2 Uncertain diagnosis. Notification Possibly
form indicates: "partly
differentiated adenocarcinoma"
as well as "extragonadal germ cell
tumour" and "tumour marker
concentrations increased"
3 Three notifications suggest Probably
extragonadal germ cell tumour
4 Metastatic tumour of unknown Unlikely
origin
5 Diagnosis on notification form is: Probably
extragonadal germ cell tumour" and
and "embryonal carcinoma."
Testicular biopsy samples were
negative for carcinoma in situ
6 Sarcoma, not otherwise specified Unlikely
Discussion
Our retrospective cohort study, based on more than 30 000 men in infertile couples, found a strong association between subfertility and subsequent risk of testicular cancer. All men of couples with fertility problems were 1.6 times more likely to develop testicular cancer than the Danish male population in general, and the increase was evident for both seminoma and non-seminoma. The overall analysis included some fully fertile men from couples in which only the woman was subfertile, and the observed higher risk of testicular cancer in the cohort overall would be even higher if only subfertile men were included. Men in the cohort with abnormal semen characteristics had a twofold to threefold increased risk. Our findings are consistent with the results of investigations into spermatogenesis in patients with unilateral testicular cancer 18 and risk of testicular cancer in men considered subfertile on the basis of a low number of children for their age. 8 10
The observation that men with unilateral testicular cancer have impaired spermatogenesis 18 does not preclude the possibility that impaired reproductive capacity is secondary to the cancer. We found that the risk of testicular cancer was relatively constant with increasing time since semen analysis. Impaired spermatogenesis may therefore have been present many years before testicular cancer was diagnosed, pointing towards a permanent state of impaired spermatogenesis.
Our use of semen characteristics to assess subfertility eliminates the misclassification problems in studies based on numbers of children, where men with normal reproductive potential who have no or few children for other reasons may bias the result towards unity. All together, the available data point towards the existence of common risk factors for impaired spermatogenesis and testicular cancer.
Some evidence suggests that testicular cancer has its origin in fetal life. Incidence of testicular cancer is lower among men born during the second world war than men born before and after the war in Denmark, Norway, and Sweden. 19-21 Other risk factors for testicular cancer, such as low birth weight 22 and congenital malformations of the testes, 23 24 also support a fetal origin for testicular cancer. In addition, carcinoma in situ (the precursor of both seminomas and nonseminomas) has several characteristics in common with fetal germ cells. 25 The specific aetiological factors in testicular cancer are unknown, but maternal oestrogens and hormonal disrupting agents have been proposed as causal factors acting on the male fetus. 26 27
We also found an increased risk of cancer of the peritoneum and other digestive organs. One explanation for this association is that some of the observed cancers in this category were misclassified testicular or extragonadal germ cell tumours. Extragonadal germ cell tumours have been associated with testicular carcinoma in situ, 28 29 suggesting a common aetiology with testicular cancer.
From a public health perspective, our study provides some reassurance to men identified with abnormal semen characteristics, despite the increased relative risks. The absolute excess of cancers is about 36 cases per 32 442 men followed for 297 750 person years. The absolute increase in risk for the individual is therefore very small.
What is already known on this topic
Contributors: RJ was responsible for the study design, data collection,
statistical analysis, interpretation, and reporting and is the guarantor. EB,
GE, JH, JHO, NES, and HM contributed to the study design, data collection,
interpretation, and reporting.
Funding: Danish Research Councils.
Competing interests: None declared.
1 Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609-13.
2 Swan SH, Elkin EP, Fenster L. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 1997;105:1228-32.
3 Coleman MP, Esteve J, Damiecki P, Arslan A, Renard H. Trends in cancer incidence and mortality. Lyons: International Agency for Research on Cancer, 1993. (IARC Scientific Publication No 121.)
4 Forman D, Moller H. Testicular cancer. Cancer Surv 1994;19-20:323-41.
5 Adami HO, Bergstrom R, Mohner M, Zatonski W, Storm H, Ekbom A, et al. Testicular cancer in nine northern European countries. Int J Cancer 1994;59:33-8.
6 James WH. Secular trends in monitors of reproductive hazard. Hum Reprod 1997;12:417-21.
7 Moller H. Trends in sex-ratio, testicular cancer and male reproductive hazards: are they connected? APMIS 1998;106:232-39.
8 Moller H, Skakkebaek NE. Risk of testicular cancer in subfertile men: case-control study. BMJ 1999;318:559-62.
9 Swerdlow AJ, Huttly SR, Smith PG. Testis cancer: post-natal hormonal factors, sexual behaviour and fertility. Int J Cancer 1989;43:549-53.
10 Jabsen R, Antoniades B, Bostofte E, Engholm G, Hansen J, Skakkebaek NE, et al. Fertility and offspring sex ratio of men who develop testicular cancer: a record linkage study. Hum Reprod 2000;15:1958-61.
11 Bostofte E, Serup J, Rebbe H, Interrelations among the characteristics of human semen, and a new system for classification of male infertility. Fertil Steril 1989;41:95-102.
12 World Health Organization. Laboratory manual for examination of human semen and sperm-cervical mucus interaction. Cambridge: Cambridge University Press, 1999.
13 Nijman JM, Schraffordt Koops H, Kremer J, Willemse PHB, Sleijfer DT, Oldhoff J. Fertility and hormonal function in patients with nonseminomatous tumor of the testis. Arch Andrology 1985;14:239-46.
14 Carroll P, Whitmore WF Jr, Herr HW, Morse MJ, Sogani PC, Bajorunas D, et al. Endocrine and exocrine profiles of men with testicular tumors before orchidectomy. J Urol 1987;137:420-3.
15 Storm HH. The Danish Cancer Registry, a self-reporting national cancer registration system with elements of active data collection. Lyons: International Agency for Research on Cancer, 1991:220-36. (IARC Scientific Publication No 95.)
16 Bostofte E, Bagger P, Michael A, Stakemann G. Fertility prognosis for infertile men: results of follow-up study of semen analysis in infertile men from two different populations evaluated by the Cox regression model. Fertil Steril 1990;54:1100-6.
17 Coleman M, Douglas A, Hermon C, Peto J. Cohort study analysis with a Fortran computer program. Int J Epidemiol 1986;15:134-7.
18 Berthelsen JG, Skakkebaek NE. Gonadal function in men with testis cancer. Fertil Steril 1983;39:68-75.
19 Moller H. Clues to the aetiology of testicular germ cell tumours from descriptive epidemiology. Eur Urol 1993;23:8-13.
20 Bergstrom R, Adami HO, Mohner M, Zatonski W, Storm H, Ekbom A, et al. Increase in testicular cancer incidence in six European countries: a birth cohort phenomenon. J Natl Cancer Inst 1996;88:727-33.
21 Wanderas EH, Grotmol T, Fossa SD, Tretli S. Maternal health and pre- and perinatal characteristics in the etiology of testicular cancer: a prospective population- and register-based study on Norwegian males born between 1967 and 1995. Cancer Causes Control 1998;9:475-86.
22 Moller H, Skakkebaek NE. Testicular cancer and cryptorchidism in relation to prenatal factors: case-control studies in Denmark. Cancer Causes Control 1997;8:904-12.
23 United Kingdom Testicular Cancer Study Group. Aetiology of testicular cancer: association with congenital abnormalities, age at puberty, infertility, and exercise. BMJ 1994;308:1393-9.
24 Moller H, Prener A, Skakkebaek NE. Testicular cancer, cryptorchidism, inguinal hernia, testicular atrophy, and genital malformations: Case control studies in Denmark. Cancer Causes Control 1995;7:264-74.
25 Skakkebaek NE, Berthelsen JG, Giwercman A, Muller J. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumors except spermacytoma. Int J Andrology 1987;10:19-28.
26 Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993;341:1392-5.
27 Henderson BE, Benton B, Jing J, Yu MC, Pike MC. Risk factors for cancer of the testis in young men. Int J Cancer 1979;23:598-602.
28 Daugaard G, Rorth M, von der Maase H, Skakkebaek NE. Management of extragonadal germ-cell tumors and the significance of bilateral testicular biopsies. Ann Oncol 1992;3:283-9.
29 Daugaard G, von der Maase H, Olsen J, Rorth M, Skakkebaek NE, Carcinoma-in-situ testis in patients with assumed extragonadal germ-cell tumours. Lancet 1987;ii:528-30.
(Accepted 19 June 2000)
Editorial by Krepster
Centre for Research in Health and Social Statistics, Danish National Research Foundation, DK-2100 Copenhagen, Denmark
Rune Jacobsen researcher
Gerda Engholm senior researcher
Sperm Analysis Laboratory, Health Service Physicians Organisation, DK-1112 Copenhagen, Denmark
Erik Bostofte consultant
Institute of Cancer Epidemiology, Danish Cancer Society, Box 839, DK-2100 Copenhagen, Denmark
Johnni Hansen researcher
Jorgen H Olsen head of department
Department of Growth and Reproduction, National University Hospital, DK-2100 Copenhagen, Denmark
Niels E Skakkebaek professor
Thames Cancer Registry, Guy's, King's, and St Thomas' School of Medicine, London SE1 3QD
Henrik Moller professor
Correspondence to: Rune Jacobsen, Department of Epidemiology, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen, Panum Institute, DK-2200 Copenhagen, Denmark R.jacobsen@pubhealth.ku.dk
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