Fertility after Chemotherapy in Male Patients with Genital Tuberculosis

Transcription

1 Fertility after Chemotherapy in Male Patients with Genital Tuberculosis KARL OLA OBRANT, M.D., and STEN LINDQVIST, M.D. THERE HAS BEEN considerable difference in the attention given to genital tuberculosis in the male and in the female, from the standpoint of sterility. That tuberculosis plays an important part and often leads to sterility in women has been shown by J edberg and Halbrecht, among others. The effect of chemotherapy on the maintenance of fertility has also been investigated. Kirchhof found that 15 cases of pregnancy occurred after chemotherapy in 111 women with genital tuberculosis. In addition to the role of chemotherapy, Kirchhof stressed the importance of early diagnosis of the disease. The bacteriologic examination of menstrual blood with the guinea-pig test has been shown to be of help in the diagnosis of female genital tuberculosis by Kirchhof and Obrant. 5 Genital tuberculosis in men has, in contrast, been the subject of only a few studies. The chief interest has been to investigate the possibility of improving diagnosis by means of semen analysis. Obrant 4 pointed out that there may be a diminution in the amount of semen secreted during the early stages of tuberculous prostatovesiculitis, and the motility of the sperm was proved to be reduced. Veenema and Lattimer 6 confirmed these findings, and in addition they found that the presence of bilateral epididymal nodules does not block the vasa in all cases; this is of great interest when considered in connection with fertility. We could not find, in the earlier literature, a systematic investigation of fertility in male patients who had undergone chemotherapy for genital tuberculosis. This present work attempts to evaluate data on patients who had received chemotherapy some years previously, and who had all undergone semen analysis at the time of treatment. Follow-up examinations included a new semen analysis and fertility estimations. From the Surgical Clinic I, Sahlgrenska sjukhuset and Riivlanda Sanatorium, University of Goteborg, Goteborg, Sweden. We wish to express our appreciation to Prof. Lars-Erik Gelin, M.D., and to Prof. Einar Ljunggren, M.D., for their advice and encouragement. 440

2 VOL. 15, No.4, 1964 POSTCHEMOTHERAPEUTIC FERTILITY 441 MATERIAL The group was composed of 53 men. In all but 2, genital tuberculosis was bacteriologically verified (bacteria found in the semen and/or urine). In the 2 patients excepted, the diagnosis was based upon histologic examination of the epididymis as removed at operation. In 44 cases, genital tuberculosis was accompanied by urotuberculosis. In all cases, palpation of the genital organs confirmed that tubercular changes existed there also. The chemotherapy that these patients received differed somewhat due to the fact that treatment took place at times during which the amount and types of preparations available varied, as did the principles of treatment. The majority were, however, treated with a triple-drug combination consisting of PAS plus streptomycin plus isoniazid. The total time for this treatment varied between 6 months and 34 months, and averaged somewhat over 15 months. The time which elapsed from the first semen analysis, taken at the time of the chemotherapy, until the second semen analysis, taken at follow-up examination, is shown below. Yr (H No. of patients 2 20(3) 19(5) 9(2) 3(1) Numbers within parentheses show the distribution of the number of patients who became fathers during the period between the two investigations. The age of the patients upon follow-up examination is presented below. Age (yr.) Over 60 No. of patients 3 11(6) 28(5) 9 2 Numbers within parentheses show the distribution of the number of patients who became fathers during the period between the two investigations. These data show that a proportionally large group of patients were to be found in the higher age-groups, and that even during the chemotherapy period, many of the patients were outside the age limits where family increase normally occurs. This must be taken into account in an evaluation of fertility in the material under examination. The first semen analyses included volume estimation, counting of the

3 442 OBRANT & LINDQVIST FERTILITY & STERILITY total number of sperm, estimation of sperm motility, and a differential morphological count of the sperm heads. It was not possible to carry out all these investigations in all cases at follow-up due to the widespread scattering of patients and the subsequent difficulties of obtaining test material. Motility tests could not be carried out on all patients, and in a number of cases, differential counts were not performed. Volume estimation and counting of the total number of sperm were carried out consistently. At follow-up examination, a record was made as to whether the patient had become a father during the time since the end of chemotherapy. A record was also made of whether the patient had suffered from some additional illness or other hazard which might have decreased fertility. RESULTS In 30 of the cases examined, it was impossible to determine fertility after chemotherapy other than through the results of semen analysis. These patients constitute Group 1. In the remaining 23 cases, the patients were married and conception was attempted. These constitute Group 2. Group 1 Of the 30 patients in Group 1, four were unmarried. In 9 cases, conception was judged to be impossible as a result of the wife's age or illness, and in 17 cases, sterility was said to be voluntary. Of these 30 patients, 19 had fathered children before the onset of genital tuberculosis. In most cases, the last child had been born at least 5 years before the diagnosis of genital tuberculosis was made, but in 2 cases, the last child had been born in the same year that treatment had been started. Both of these men were the fathers of 3 children. One of these cases had shown diffuse symptoms of his illness 2 yr. before the start of treatment, which occurred in December of the year in which his child was born. The birth of the child took place in August. In this case, the prostate and seminal vesicles were, on palpation, of a hard and uneven consistency, whereas the external genital organs revealed no abnormalities on palpation. The second of these men became the father of his third child 5 months after the start of chemotherapy. Three months previously, he had complained of lumbar pain. At the start of chemotherapy, hard nodules were felt on palpation bilaterally in the prostate and vesicles, while the testes and epididymes revealed no abnormalities on palpation. In the Rrst of these patients, the initial semen analysis showed an average volume of 4 ml., 72 million sperm/ml., and 10% abnormal heads. The Rgures on follow-up examination 6 yr. later were: volume, 4.5 ml., and 53

4 VOL. 15, No.4, 1964 POSTCHEMOTHEHAPEUTIC FERTILITY 443 million sperm/mi. The initial analysis of the second patient showed a volume of 2.0 mi., and 60 million sperm/mi., with 18% abnormal heads. On follow-up examination, 5 yr. later, the values were: volume, 4.0 mi. and 80 million sperm/mi., with 15% abnormal heads. Thus, as far as it is possible to judge from these values, fertility was maintained unchanged in both cases. Four patients in this group showed, on initial examination, a semen volume of 0.5 mi. or less. In 2, this reduced volume was also present on follow-up examination, but in 2 cases (with 0.2 and 0.3 mi., respectively), the volume had increased at follow-up examination to 1.0 mi. On the other hand, a decrease in volume had occurred in 3 patients (from 1.0 mi. to 0.4 mi.; from 0.8 mi. to 2 or 3 drops; and from 1.5 mi. to 0.5 mi.). Aspermia was found in 3 patients at the first investigation. At the time of the follow-up examination, one still had aspermia, the second showed 5-10 sperm per microscopic field, while in the third patient, the number of sperm had risen to 22 million/mi. Significant changes in the q;lantity of sperm between the two investigations had occurred in another 5 cases in this group. Four of these showed a marked reduction in the number of sperm: one man, born in 1895, showed, in 1951, 45 million/mi., but in 1962, only isolated immobile sperm were found; the cause for this change remained unestablished. Three other patients, born in 1914, 1916, and 1922 respectively, showed, at the first examination, values of at least 100 million sperm/mi., but at the second examination, values between 22 and 29 million sperm/mi. Finally, in one case, an increase in the quantity of sperm occurred, from 18 to 65 million/ml. Group 2 This group of married men who attempted conception after treatment for genital tuberculosis is of even greater interest than the preceding group. Group 2 included 23 patients, of whom 11 became fathers after treatment, while the remaining 12 did not produce children. Age distribution is somewhat different between the patients who became fathers and the remainder of Group 2. The ages of the fertile group at follow-up examination varied between 31 and 50 years, with a mean value of 40 years, whereas the ages of the childless group was from 22 to 56 years, with a mean age of 45 years. Table 1 shows the year of birth of the child in relation to the year of treatment. If the treatment lasted longer than one year, the first year was regarded as the year of treatment. Six patients had had no children prior to chemotherapy; 4 patients fathered more than one child after treatment ended; 5 patients had had children before treatment and have fathered

5 444 OBRANT & LINDQVIST FERTILITY & STERILITY TABLE 1. Year of Children's Birth in Relation to Year Father was Treated for Genital Tuberculosis Patient No. Total No. of children t Before treatment (yr.) 10,6,1 3 5, 1 3,2 5,3 Tillie of birth After treatment (yr.) 1 2 2,3,5" 5, ,5 10 2,4 3 *Birth of twins. tone child born during year of treatment. further children since then-in one case during the year of chemotherapy. The point of time for the birth of the children appears to have been similar to that in ordinary middle-sized families. Within the group of 12 men who did not father children after treatment, there were those who had had children prior to treatment: 4 had had two children born within the period of 2-16 years before chemotherapy; and 1 had had three children, the last of which was born during the year of treatment. Within this group, there were 7 men with completely sterile marriages, the largest percentage of sterility within any of the groups. The results of semen analyses in Group 2 are shown in Tables 2 and 3. Those patients who showed fertility after treatment (Table 2) had, on the whole, high values both before and after treatment. Two cases are especially interesting in that before treatment they showed a greatly reduced quantity of sperm, but after chemotherapy this returned to normal levels. In one case, semen analysis could not be carried out due to psychological reasons, but upon irrigating the seminal vesicles in connection with vesiculography, a large number of motile sperm were observed. Among the patients with involuntary sterility after treatment (Table 3) there were several cases with low sperm values. One of the cases who showed aspermia, had, however, fathered his second child 7 years previously. As in Group 1, there was one case which showed a striking reduction in sperm quantity, and in contrast, 3 cases that showed an increase in sperm quantity.

6 VOL. 15, No.4, 1964 POSTCHEMOTHERAPEUTIC FERTILITY 445 TABLE 2. Semen Analyses~ During and After Chemotherapy for Genital Tuberculosis Semen analyses during chemotherapy Semen analyses after chemotherapy % ab- Yr. % ab- Age (yr.) Case Vol. Million normal between Vol. Million normal at No. (mi.) sperm/mi. heads analyses (mi.) sperm/ml. heads analysis Irrigation fluid /sf ]8.. 5 ~ *From 11 men who became fathers after end of treatment. TABLE 3. Semen Analyses~ During and After Chemotherapy for Genital Tuberculosis Children born before Million % ab- Yr. be- Million % ab- Age (yr.) Case treat- Vol. sperm/ normal tween Vol. sperm/ normal at No. ment (mi.) mi. heads analy.~es (mi.) mi. heads analysis 4 X xt X X X *From 12 men who had involuntary sterility after end of treatment. tlast child born 7 years before first semen analysis.

7 446 OBRANT & LINDQVIST FERTILITY & STERILITY The distribution of the tuberculous lesions within the genital organs of the patients who became fathers is of great interest (Table 4). In 3 patients, palpation revealed changes in the internal genital organs without coexistent changes in the epididymis or visible prostatic alteration upon X-ray. In 2 of these, diagnosis was confirmed by a positive guinea-pig test from the semen. For the third patient, who had undergone nephrectomy for renal tuberculosis, the diagnosis was based entirely on the palpatory observations. Six of the men underwent epididymectomy during the first period of treatment, and one underwent unilateral prophylactic vasectomy. All of these patients, with one exception, showed cavities in the prostate, and these were shown in one other patient. Case No.7, who had previously undergone an orchidectomy on the left side, is of special interest. The right seminal vesicle showed, on follow-up examination, pronounced changes on palpation. Vesiculography (Fig. 1) confirmed the organic changes. In the liquid obtained by washing out the vesicles, many sperm with a good degree of motility were observed. After chemotherapy, this man fathered 4 children (the birth recorded in Table 1 as occurring 5 years after therapy was that of twins). Case No. 16 is also worthy of note. This patient showed bilateral TABLE 4. Tuberculous Lesions in Genital Organs of 11 Men Who Became Fathers After End of Chemotherapy Rectal Cavities on Case Epididy- palpation urethro- No. Epididymitis mectomy findings cystography Remarks Hard noduli + Unilateral prophylactic vasectomy 5 Right Right Left Left Hard noduli + Vesiculography (Fig. 1.) Hard noduli Semen: guineapig positive 11 Left Left Hard noduli 13 Left Left Hard noduli + 16 Bilateral Left Hard noduli 17 Right Right Hard noduli Hard noduli Hard noduli Semen: guineapig positive Hard noduli Semen: guineapig negative

8 VOL. 15, No.4, 1964 POSTCHEMOTHERAPEUTIC FERTILITY 447 epididymal changes, roughly the same on each side. The patient underwent a unilateral operation, and the specimen obtained at operation showed tuberculosis. During continued chemotherapy, the swelling on the remaining side decreased. He fathered one child after treatment. Fig. 1. (Case 7) Vesiculography on right side. (Orchidectomy performed on left side 8 years earlier in coniunction with chemotherapy.) Follow-up palpation of left seminal vesicle showed very hard consistency. Vesiculography shows irregular cavities in vesicle. Liquid obtained on washing out vesicle showed large quantity of motile sperm. Patient fathered 4 children after chemotherapy. DISCUSSION The results of these investigations have been surprising. In view of earlier observations of changes which occur in the semen in genital tuberculosis and in view of the fact that the tuberculous changes in the internal genital organs are so often bilateral, we had anticipated a high rate of sterility among these patients. Experience from the time before chemotherapy supported this point of view. The common occurrence of bilateral tuberculous epididymitis led to the introduction of prophylactic vasectomy to save at least the internal secretory functions. The operation was often carried out because fertility was assumed to be impossible. The men in Groups 1 and 2 who became fathers during the period of chemotherapy are of considerable interest. Even though it is impossible to demonstrate, it appears reasonable to assume that these patients had had genital tuberculosis at the time of conception. Thus, a toxic effect on the sperm to the extent of functional importance is improbable in these cases. After prolonged chemotherapy (lasting an average of 15.9 months), nearly half the patients who had coitus and attempted conception had be.. come fathers. In many of these cases, there were marked changes in the internal genital organs, with cavities in the prostate revealed by X-ray examination, and in the majority, the epididymis had been unilaterally removed.

9 448 OBRANT & LINDQVIST FERTILITY & STERILITY The question of whether prolonged chemotherapy can cause a reduction in sperm production is impossible to answer. A considerable reduction in the number of sperm occurred in some cases, but on the other hand, an increase in the number of sperm took place in other cases (the most noticeable being the change from 25 sperm per microscopic field, of which 7 sperm were normal, to 151 million/ml.). The cause for such an improvement can be assumed to be that treatment has reduced the edema produced by the tuberculous inflammatory foci which had blocked the seminal ducts. Even if we cannot entirely eliminate the possibility that prolonged chemotherapy can, in isolated cases, contribute to a reduction in spermatogenesis, this appears to be of minor importance, from a practical point of view, when compared with the results as a whole. These investigations lead to more careful consideration of treatment of genital tuberculosis. Prophylactic vasectomy ought to be abolished as a therapeutic measure. Instead, the unaffected epididymis can be protected from the propagation of tuberculosis from the internal genital organs by prolonged chemotherapy and careful control after the end of treatment, to ensure that any possible recurrence is dealt with as quickly as possible. Epididymectomy should be more restricted in practice. Even in these cases, conservative medical treatment should be attempted, supported, if necessary, by the simple incision of abscesses. SUMMARY Genital tuberculosis in 53 men was treated by prolonged chemotherapy. Semen analyses were made both at the time of chemotherapy and at varying intervals thereafter. After treatment, 23 married men attempted conception; this was successful in 11 cases, in spite of the fact that the majority of them had pronounced changes in the genital organs. More than half of the patients had cavities in the prostate, visible on X-ray examination, and more than half had undergone a unilateral epididymectomy. The prolonged chemotherapy does not appear to have caused any sig: nificant reduction in the production of sperm in most patients. In isolated cases, a marked reduction in the quantity of sperm occurred, but, in contrast, other cases showed a marked increase in the number of sperm. The majority of cases in the fertile group showed relatively unchanged sperm values. The practical conclusions to be drawn from these investigations are that

10 VOL. 15, No.4, 1964 POSTCHEMOTHERAPEUTIC FERTILITY 449 1) prophylactic vasectomy ought to be abolished in cases of tuberculosis in the internal genital organs, and 2) tuberculous epididymitis should be treated conservatively, in view of the fact that the possibility of future fertility exists. REFERENCES Sahlgrenska sjukhuset Goteborg SV, Sweden 1. HALBRECHT, 1. Cortisone in the treatment of tubal occlusion caused by healed genital tuberculosis. Fertil. & Steril. 13:371, JEDBERG, H. Female genital tuberculosis and pregnancy. Acta obst. et gynec. scandinav. 35:534, KIRCHHOFF, H. Uber das Zusammentreffen von Schwangerschaft und GenitaItuberkulose. Miinchen med. Wchnschr. 975, OBRANT, K. O. Semen analysis in cases of tuberculous prostato-vesiculitis and its importance for the indications of prophylactic vasectomy. Brit. ]. Ural. 23:46, OBRANT, K. O. En kirurgs synpunkter pa dispensarverksamheten. Svenska liik. 54:2029, VEENEMA, R. J., and LATTIMER, J. K. Genital tuberculosis in the male: Clinical pathology and effect on fertility. ]. Ural. 78:65, 1957.