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Subfertility: An etiologic factor in development of testicular cancer?
SUBFERTILITY: AN ETIOLOGIC FACTOR IN DEVELOPMENT OF TESTICULAR CANCER? D. E. JOHNSON, J. J. FUEGER,
M.D.
M.D.
P J. ALFARO M. R. SPITZ,
M.D.
G. R. NEWELL,
M.D.
From the Departments of Urology and Cancer Prevention and Control, The University of Texas M.D. Anderson Hospita1 and Tumor Institute at Houston, Texas
ABSTRACT-Gonadal dysfunction with resultant subfertility has been implicated as a possible etiologic factor in testicular cancer. A survey of 57 men who had been married before testicular cancer developed reveuled that only four marriages (9 70,) had problems with fertility. Our findìngs fail to support a premìse that testicular carcinoma is associated with prior male infertility.
The incidence of testicular cancer, especially in the fifteen-year to thirty-four-year age group, has increased in the United States over the past four decades,’ and similar trends have been reported in other Western countries2x3 Despite intensive epidemiologic study of this malignancy, only a few risk factors have been identified: (1) cryptorchism, either treated or untreated (with the risk extending to include the contralateral testis); (2) treatment for a previous testicular cancer; (3) increased testicular temperature; (4) prenatal irradiation; and (5) subfertility.2,4*5 Although much bas been reported recently associating gonadal dysfunction with testicular malignancy, the incidence of previous subfertility in patients with testicular carcinoma has been poorly documented. Available data usually have come either from infertility clinicse~s or from analyses of semen following unilateral orchiectomy performed to diagnose the malignancy.lO-l2 If gonadal dysfunction with resultant subfertility plays a significant role in the etiology of testicular cancer, patients with testicular cancer should have experienced problems in procreating. To better document this association we have attempted to interview al1 married men with a testicular carcinoma seen at The University of Texas M.D. Anderson Hos-
UROLOGY
i SEPTEMBER1987
/ VOLUMEXXX,NUMBER3
pital and Tumor Institute at Houston over a twenty-four-month period to determine if their fertility rate is different from that of the rate in the genera1 population. Material and Methods The records of al1 U.S.-resident patients older than twenty years with a histologically confirmed diagnosis of a testicular germ cel1 tumor seen at UT M.D. Anderson Hospita1 from January, 1983, through December, 1984, (134 patients) were reviewed. Of these patients, 42 (31%) had never been married before the malignancy developed and 12 were deceased, leaving 80 potentially eligible patients. Fifty-seven TABLE 1.
Fertility data for 57 married men with testicular carcinoma
Finding Conceived at least one child Practiced birth control Wives infertile or sterilized “Voluntarily” childless (not trying) Tried unsuccessfully to have children TOTAL
No. of Pk
40
5 4 4 4
57
199
patients (71% of those eligible) were successfully traced and interviewed over the telephone by a trained interviewer. Each patient was specifically questioned as to his dates of birth and marriage, whether he had conceived any children, and if not, whether his infertility was voluntary. When pertinent, inquiries were made to his wife’s possible fertility problems and to any known medical findings. Results The records of the patient interviews are shown in Table 1. Forty patients (70%) had conceived at least one child before cancer was diagnosed. Five patients had practiced birth control during their entire marriage; 4 stated that their wives were infertile or had been sterilized; and 4 declared themselves to be voluntarily childless. Only 4 of 44 men actively trying for children (9 % ) had been unsuccessful. Of these 4 possibly infertile men, tumor was histologically diagnosed as seminoma in 3 and as teratoma in 1. The age of these patients at the time of diagnosis was twenty-six, twentyeight, thirty-one, and thirty-two years, respectively; their ages were slightly less than the median age for the entire series, which was 35.6 years (range 23 to 67 years). Detailed questioning revealed that 2 of these 4 patients had successfully impregnated their wives, but both women had aborted and never conceived again .
Comment It is estimated that 10 to 15 per cent of marriages are childless and that in 30 to 50 per cent of such cases,13 the man is infertile. Our findings of only four marriages (9 %) having problems with fertility support the premise that men do not have a significantly altered fertility potential before development of a testicular tumor. Similar findings have been recorded by other investigators . l4 Although a high incidence (24%) of severe spermatogenic failure in the contralateral testis of patients with germ cel1 cancers has been documented after orchiectomy but immediately before irradiation or chemotherapy,” a causa1 relationship has not been proved. The impairment of gonadal function in these patients can be explained, at least in part, by the removal of one of the testes, by elevated serum human chorionic gonadotropin levels caused by the malignancy, and by an increase in scrotal temperature caused by the tumor, affecting spermatogenesis in the contralateral tes-
200
tis. Although Berthelsen and Skakkebaek” have suggested that these changes are irreversible, the low incidence (2 % ) of a neoplasm developing in the remaining testicle provides additional support that subfertility per se conveys little obvious risk for malignant transformation. Our recent findings indicate that after the age of thirty, single men are more susceptible to nonseminomatous testicular cancer than married men.15 In light of this and other studies reporting a higher incidence of testicular tumors occurring in single men,2~1e one might argue that confining our evaluation only to married men might have altered our final conclusions regarding the role of subfertility in testicular cancer. However, marital status is more likely an index of sexual activity, which does not necessarily reflect fertility, Therefore we tionclude that there is no evidente to suggest that testicular carcinoma is associated with prior male infertility. Houston, Texas 77030 (DR. JOHNSON) References 1. Newell GR, et al: Epidemiologic comparison of cancer of the testis and Hodgkin’s disease among young malen, Cancer 54: 1117 (1984). 2. Davies JM: Is testicular cancer incidence related to marital status? Int J Cancer 28: 721 (1981). 3. Clemmenson J: Doubling morbidity from testis carcinoma in Copenhagen 1943-1962, Acts Pathol Microbiol Stand 72: 345 (1968). 4. Henderson BE, et al: Risk factors for cancer of the testis in young men, Int J Cancer 23: 598 (1979). 5. Loughlin JE, Robboy SJ, and Morrison AS: Risk factors for cancer of the testis, N Eng1 J Med 303: 112 (1980). 6. Skakkebaek NE: Carcinoma in situ of the testis: frequency and relationship to invasive germ cel1 tumours in infertile men, Histopathology 2: 157 (1978). 7. Sigg C, and Hedinger C: Atypical germ cells in testicular biopsy in male sterility, Int J Androl (Suppl) 4: 163 (1981). 8. Pryor JR et al: Carcinoma in situ in testicular biopsies from men presenting with infertility, Br J Urol 55: 780 (1983). 9. West AB, et al: Testicular tumors in subfertile men: report of 4 cases with implications for management of patients presenting with infertility, J Urol 133: 107 (1985). 10. Fossa SD, et al: Testicular function after unilateral orchiectomy for cancer and before further treatment, Int J Androl 5: 179 (1981). ll. Berthelsen KG, and Skakkebaek NE: Gonadal function in men with testis cancer, Fertil Steril 39: 68 (1983). 12. Evenson DR et aZ: Flow cytometric evaluation of sperm from patients with testicular carcinoma, J Urol 132: 1220 (1984). 13. Smitb DR: Infertility, in: General Urology, Los Altos, California, Lange Medical Publications, 1972, p 416. 14. OreckIin JR, Kaufman JJ, and Thompson RW: Fertility in patients treated for malignant testicular tumors, J Urol 109: 293 (1973). 15. Spitz MR, et al: Incidence and descriptive features of testicular cancer among United States whites, bla& and hispanics, 1973-82, Cancer 58: 1785 (1986). 16. Newell GR, et aZ: The incidence of testicular cancer in the United States related to marital status and histology, J Nat1 Cancer Inst (in press).
UROLOGY
i
SEPTEMBER 1987
i
VOLUME XxX, NUMBER 3
M.D.
M.D.
P J. ALFARO M. R. SPITZ,
M.D.
G. R. NEWELL,
M.D.
From the Departments of Urology and Cancer Prevention and Control, The University of Texas M.D. Anderson Hospita1 and Tumor Institute at Houston, Texas
ABSTRACT-Gonadal dysfunction with resultant subfertility has been implicated as a possible etiologic factor in testicular cancer. A survey of 57 men who had been married before testicular cancer developed reveuled that only four marriages (9 70,) had problems with fertility. Our findìngs fail to support a premìse that testicular carcinoma is associated with prior male infertility.
The incidence of testicular cancer, especially in the fifteen-year to thirty-four-year age group, has increased in the United States over the past four decades,’ and similar trends have been reported in other Western countries2x3 Despite intensive epidemiologic study of this malignancy, only a few risk factors have been identified: (1) cryptorchism, either treated or untreated (with the risk extending to include the contralateral testis); (2) treatment for a previous testicular cancer; (3) increased testicular temperature; (4) prenatal irradiation; and (5) subfertility.2,4*5 Although much bas been reported recently associating gonadal dysfunction with testicular malignancy, the incidence of previous subfertility in patients with testicular carcinoma has been poorly documented. Available data usually have come either from infertility clinicse~s or from analyses of semen following unilateral orchiectomy performed to diagnose the malignancy.lO-l2 If gonadal dysfunction with resultant subfertility plays a significant role in the etiology of testicular cancer, patients with testicular cancer should have experienced problems in procreating. To better document this association we have attempted to interview al1 married men with a testicular carcinoma seen at The University of Texas M.D. Anderson Hos-
UROLOGY
i SEPTEMBER1987
/ VOLUMEXXX,NUMBER3
pital and Tumor Institute at Houston over a twenty-four-month period to determine if their fertility rate is different from that of the rate in the genera1 population. Material and Methods The records of al1 U.S.-resident patients older than twenty years with a histologically confirmed diagnosis of a testicular germ cel1 tumor seen at UT M.D. Anderson Hospita1 from January, 1983, through December, 1984, (134 patients) were reviewed. Of these patients, 42 (31%) had never been married before the malignancy developed and 12 were deceased, leaving 80 potentially eligible patients. Fifty-seven TABLE 1.
Fertility data for 57 married men with testicular carcinoma
Finding Conceived at least one child Practiced birth control Wives infertile or sterilized “Voluntarily” childless (not trying) Tried unsuccessfully to have children TOTAL
No. of Pk
40
5 4 4 4
57
199
patients (71% of those eligible) were successfully traced and interviewed over the telephone by a trained interviewer. Each patient was specifically questioned as to his dates of birth and marriage, whether he had conceived any children, and if not, whether his infertility was voluntary. When pertinent, inquiries were made to his wife’s possible fertility problems and to any known medical findings. Results The records of the patient interviews are shown in Table 1. Forty patients (70%) had conceived at least one child before cancer was diagnosed. Five patients had practiced birth control during their entire marriage; 4 stated that their wives were infertile or had been sterilized; and 4 declared themselves to be voluntarily childless. Only 4 of 44 men actively trying for children (9 % ) had been unsuccessful. Of these 4 possibly infertile men, tumor was histologically diagnosed as seminoma in 3 and as teratoma in 1. The age of these patients at the time of diagnosis was twenty-six, twentyeight, thirty-one, and thirty-two years, respectively; their ages were slightly less than the median age for the entire series, which was 35.6 years (range 23 to 67 years). Detailed questioning revealed that 2 of these 4 patients had successfully impregnated their wives, but both women had aborted and never conceived again .
Comment It is estimated that 10 to 15 per cent of marriages are childless and that in 30 to 50 per cent of such cases,13 the man is infertile. Our findings of only four marriages (9 %) having problems with fertility support the premise that men do not have a significantly altered fertility potential before development of a testicular tumor. Similar findings have been recorded by other investigators . l4 Although a high incidence (24%) of severe spermatogenic failure in the contralateral testis of patients with germ cel1 cancers has been documented after orchiectomy but immediately before irradiation or chemotherapy,” a causa1 relationship has not been proved. The impairment of gonadal function in these patients can be explained, at least in part, by the removal of one of the testes, by elevated serum human chorionic gonadotropin levels caused by the malignancy, and by an increase in scrotal temperature caused by the tumor, affecting spermatogenesis in the contralateral tes-
200
tis. Although Berthelsen and Skakkebaek” have suggested that these changes are irreversible, the low incidence (2 % ) of a neoplasm developing in the remaining testicle provides additional support that subfertility per se conveys little obvious risk for malignant transformation. Our recent findings indicate that after the age of thirty, single men are more susceptible to nonseminomatous testicular cancer than married men.15 In light of this and other studies reporting a higher incidence of testicular tumors occurring in single men,2~1e one might argue that confining our evaluation only to married men might have altered our final conclusions regarding the role of subfertility in testicular cancer. However, marital status is more likely an index of sexual activity, which does not necessarily reflect fertility, Therefore we tionclude that there is no evidente to suggest that testicular carcinoma is associated with prior male infertility. Houston, Texas 77030 (DR. JOHNSON) References 1. Newell GR, et al: Epidemiologic comparison of cancer of the testis and Hodgkin’s disease among young malen, Cancer 54: 1117 (1984). 2. Davies JM: Is testicular cancer incidence related to marital status? Int J Cancer 28: 721 (1981). 3. Clemmenson J: Doubling morbidity from testis carcinoma in Copenhagen 1943-1962, Acts Pathol Microbiol Stand 72: 345 (1968). 4. Henderson BE, et al: Risk factors for cancer of the testis in young men, Int J Cancer 23: 598 (1979). 5. Loughlin JE, Robboy SJ, and Morrison AS: Risk factors for cancer of the testis, N Eng1 J Med 303: 112 (1980). 6. Skakkebaek NE: Carcinoma in situ of the testis: frequency and relationship to invasive germ cel1 tumours in infertile men, Histopathology 2: 157 (1978). 7. Sigg C, and Hedinger C: Atypical germ cells in testicular biopsy in male sterility, Int J Androl (Suppl) 4: 163 (1981). 8. Pryor JR et al: Carcinoma in situ in testicular biopsies from men presenting with infertility, Br J Urol 55: 780 (1983). 9. West AB, et al: Testicular tumors in subfertile men: report of 4 cases with implications for management of patients presenting with infertility, J Urol 133: 107 (1985). 10. Fossa SD, et al: Testicular function after unilateral orchiectomy for cancer and before further treatment, Int J Androl 5: 179 (1981). ll. Berthelsen KG, and Skakkebaek NE: Gonadal function in men with testis cancer, Fertil Steril 39: 68 (1983). 12. Evenson DR et aZ: Flow cytometric evaluation of sperm from patients with testicular carcinoma, J Urol 132: 1220 (1984). 13. Smitb DR: Infertility, in: General Urology, Los Altos, California, Lange Medical Publications, 1972, p 416. 14. OreckIin JR, Kaufman JJ, and Thompson RW: Fertility in patients treated for malignant testicular tumors, J Urol 109: 293 (1973). 15. Spitz MR, et al: Incidence and descriptive features of testicular cancer among United States whites, bla& and hispanics, 1973-82, Cancer 58: 1785 (1986). 16. Newell GR, et aZ: The incidence of testicular cancer in the United States related to marital status and histology, J Nat1 Cancer Inst (in press).
UROLOGY
i
SEPTEMBER 1987
i
VOLUME XxX, NUMBER 3