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Side-effects of salazopyrin on male fertility
361
Europ. J. Obstet. Gynec. reprod. Biol., 18 (1984) 361-364 Elsevier
wo
00186
Side-effects of salazopyrin on male fertility Omer P. Steen0 Department
of Internal Medicine, Divrsion of Endocrinology, Nutrition and Andrologv, University Hospital Sinr Rafalel Gasthuisberg, Catholic University of Leuuen, B 3000, Lewen, Belgium
The author critically studied the twelve papers and letters to the editor published since 1979 regarding toxic effects of Salazopyrin on male fertility. A direct toxic side-effect of Salazopyrin on the maturation of sperm cells is apparent, but associated influencing factors are the basic illness itself and associated therapy forms, such as steroids, that also influence spermatogenesis. The mechanism of action of Salazopyrin is still a matter of dispute. Possible (and possibly combined) interfering factors are: an anti-folate action with influence on the rapid turnover of dividing spermatogenie cells, an anti-prostaglandin effect on motility and toxic effects of the sulphapyridine substance of Salazopyrin. Salazopyrin;
male fertility;
side-effects;
sperm-head
size
Introduction Salazopyrin (trade name for salicylazosulfapyridine (SASP) or Sulphasalazine) has been widely used since 1942 and is considered superior to other sulfonamides for treatment of ulcerative colitis. Several dose-dependent side-effects have been refever, reticulocytosis, arthralgies, ported, such as nausea, vomiting, headaches, bronchospasm, pulmonary eosinophilia and peripheral neuropathy. In 1979, Levi et al., from Middlesex (UK), and Toth, from New York (U.S.A.), independently of each other, published their observations with respectively 4 and 6 patients, in which they found a marked influence on male fertility capacity. This and added more prompted further studies, which confirmed their observations information to the evaluation of this side-effect. Published observations Levi et al. (1979) treated four young immigrants, suffering from ulcerative colitis, with a daily salazopyrin dose of 3-4 g and noted oligozoospermia with infertility even during the first month of treatment. After ending the treatment improvement was observed in all four, both regarding concentration and motility of sperm cells, which resulted in four pregnancies for three of the patients’ wives. Reintroduction of 002%2243/84/$03.00
0 1984 Elsevier Science Publishers
B.V.
362
salazopyrin with two of these patients was again followed by rapid deterioration of the semen. We must add, however, that the patients also received prednisolone as additional treatment. During treatment with salazopyrin, a lowered sperm concentration, very poor motility and a high number of abnormal head forms were noted. No hormonal changes were recorded and the histology of testicular tissue (one patient) showed no alterations. This publication in the Lancet provoked a few letters to the Editor. Grieue (1979), from Newcastle upon Tyne, reported the case of a 24-yr-old Scotsman whose repeated sperm examinations showed that he suffered from oligozoospermia under salazopyrin treatment, with improvement in concentration and morphology 2 months after ending the treatment, also resulting in a pregnancy. Truub et al. (1979), from Belfast, reported the case of a patient with 4 yr of infertility and oligo-astheno-teratozoospermia under salazopyrin treatment. These authors also ascertained a great number of immature spermatozoa. Two months after ending the treatment the number of immature forms became normal and 4 months later his wife became pregnant. Toth (1979a) observed 6 patients taking 2-8 g Salazopyrin daily. Under therapy the motility of sperm cells was reduced and the presence of a characteristic megalo sperm cell-type was the most marked feature at morphological examination (swollen cell, giving the impression of osmotic swelling involving acrosome as well as postequatorial segments). Besides he also found mid-piece and tail abnormalities. Putting an end to the therapy with 3 patients was followed by a drastic improvement in the sperm picture, with three pregnancies within 3 months. After publication of the study by Levi et al., Toth (1979b) reported to the editor of The Lancet that he observed _in the meantime 10 similar patients with 6 pregnancies for 6 patients who had stopped salazopyrin treatment. Regeneration of spermatogenesis was observed after 3 months. Bo2tiu.s et al. (1980) checked the spermiogram before, during and after salazopyrin treatment with 2 patients. Reduction in spermatozoa concentration and motility and increase in abnormal head forms was confirmed. Pregnancy occurred respectively 3 and 2 months after termination of salazopyrin treatment. They noticed, however, that pregnancies occurred although still no marked improvement in the sperm pictures could be noted at that time. Fettes (1981), from Gore (New Zealand), found a recuperation of sperm count 3 months after ending the treatment and substitution of an alternative therapy, followed by conception 1 month later. In 1981 Toovey et af., from Levi’s group in Middlesex, published their observations on 28 patients, examined before, during and after treatment. Sperm divergencies (concentration, motility and morphology) occurred in 18 patients after at least 2 months under therapy. Recovery was observed after another 2 months, followed by 10 pregnancies averaging 2-5 months after stopping salazopyrin treatment. They did not notice hormonal changes. Heineman et al. (1981), from Nijmegen, published two case-reports with observations identical to those of Toovey. In the first case pregnancy occurred 3 months after ending salazopyrin treatment, with once more pathological sperm pictures after restarting the treatment. In the second case salazopyrin had been replaced by
363
betamethasone enemas. Sperm pictures only improved after stopping betamethasone. They too found no hormonal changes. Tobius et al. (1982), from Cape Town, published a single case report. Their patient had been treated with salazopyrin and prednisone. The spermiogram showed extreme oligo-necrozoospermia with elevated plasma FSH and decreased plasma testosterone level. After ending salazopyrin treatment and reduction of prednisone a return to normal of the spermiogram as well as of the plasma testosterone level could be observed and was followed by pregnancy. Freeman et al. (1982), from Newcastle upon Tyne, compared their data, obtained from a group of 12 patients treated with salazopyrin, with those from a control group treated alternatively. Oligo-asthenozoospermia occurred only in the salazopyrin-treated group, but abnormal morphological head forms were found in both groups. They point out also the increased ejaculate volume from salazopyrin-treated patients. Hz&on et al. (1982), from Middlesex (also belonging to the group of Toovey and Levi), made measurements of the size of spermatozoa heads (by image analysis) with 8 salazopyrin-treated patients and compared their data with the sperm head sizes in non-colitic men with normal spermiogram and with non-colitic oligozoospermic men. Salazopyrin-treated patients had significantly larger sperm-head sizes. After stopping treatment head sizes increased still further before decreasing, although without returning to normal (not even after 284 days).
Proposed mechanisms Levi et al. (1979) postulated a direct toxic effect on the seminiferous epithelium. Traub et al. (1979) point out the maturation arrest in spermatogenesis. According to them, salazopyrin has, by enzyme inhibition, an antifolate action and may suppress the rapid turnover of cells which occurs in normal spermatogenesis. Another adverse effect on sperm motility may be blamed on its anti-prostaglandin action. Toth (1979a) noticed that salazopyrin splits in the colon into sulfapyridine (SP) and 5aminosalicylic acid (5-ASA). The latter may serve as an inhibitor of prostaglandin synthesis, which may explain the sperm changes. He also attributes the morphological divergences to osmotic changes. Heineman et al. (1981), however, noticed that 5-ASA is excreted very rapidly and that the concentration of 5-ASA in semen is negligible. Toovey et al. (1982), on the other hand, think that sulfapyridine (SP) may be the toxic mediator. Tobias et al. (1982) suspect a suppressive effect on the Leydig cells as explanation for the lowered plasma testosterone level (with normal LH). They remind us that steroid therapy also inhibits spermatogenesis and may explain partially the oligozoospermic state. Freeman et al. (1982) presume that the increased ejaculate volume may influence the sperm count. Hudson et al. (1982) deduce from their observations the conclusion that active colitis as such may cause changes in the sperm-head size.
364
Conclusion
Salazopyrin appears to have a toxic effect on the maturation of sperm cells, resulting in infertility through oligo-astheno-teratozoospermia. This influence starts after 2-3 months of treatment and is reversible 2-3 months after stopping the treatment, which corresponds with the duration of the spermatogenetic cycle. Typical is the occurrence of a megalo-cell type, but it has been found that this cell-type is possibly more related to the colitis itself than to the salazopyrin therapy. Interfering factors are thus not only the salazopyrin treatment, but also the basic illness itself and possibly associated alternative therapy forms, such as steroids, that also influence spermatogenesis. A direct toxic effect of salazopyrin is likely in view of the normal hormonal findings. But here also several mechanisms may play a role, such as an anti-folate action influencing turnover of rapidly dividing cells, and anti-prostaglandin effect on sperm motility and a toxic effect of the sulphapyridine substance of salazopyrin. References Bottius, G., Stuurman, A. and Bol, J. (1980): Onvruchtbaarheid van de man tijdens behandeling met salazosylfapyridine. Ned. Tijdschr. Geneesk., 124, 1835-1836. Fettes, P.W. (1981): Reversible male infertility. N. Z. med. J., 94, 395. Freeman, J.G., Reece, V.A.C. and Venables, C.W. (1982): Sulphasalazine and spermatogenesis. Digestion, 23, 68-71. Grieve, J. (1979): Male infertility due to sulphasalazine. Lancet, ii, 464. Hudson, E., Don?, C., Sowter, C., Toovey, S. and Levi, A.J. (1982): Sperm size in patients with inflammatory bowel disease on sulfas&z.ine therapy. Fertil. and Steril., 38, 77-84. Heineman, M.J., Dony, J.M.J. and Rolland, R. (1981): Salicylazosulfapyridine and male infertility. Europ. J. Obstet. Gynec. reprod. Biol., 12, 297-303. Levi, A.J., Fisher, A.M., Hughes, L. and Hendry, W.F. (1979): Male infertility due to sulphasalazine. Lancet, ii, 276-278. Tobias, R., Sapire, K.E., Coetzee, T. and Marks, I.N. (1982): Male infertility due to sulphasalazine. Postgrad. med. J., 58, 102-103. Toovey, S., Hudson, E., Hendry, W.F. and Levi, A.J. (1981): Sulphasalazine and male infertility: reversibility and possible mechanism. Gut, 22, 445-451. Toth, A. (1979a): Reversible toxic effect of salicylazosulfapyridine on semen quality. Fertil. and Steril., 31, 538-540. Toth, A. (1979b): Male infertility due to sulphasalazine. Lancet, ii, 904. Traub, A.I., Thompson, W. and Carville, J. (1979): Male infertility due to sulphasalazine. Lancet, ii, 639-640.
Europ. J. Obstet. Gynec. reprod. Biol., 18 (1984) 361-364 Elsevier
wo
00186
Side-effects of salazopyrin on male fertility Omer P. Steen0 Department
of Internal Medicine, Divrsion of Endocrinology, Nutrition and Andrologv, University Hospital Sinr Rafalel Gasthuisberg, Catholic University of Leuuen, B 3000, Lewen, Belgium
The author critically studied the twelve papers and letters to the editor published since 1979 regarding toxic effects of Salazopyrin on male fertility. A direct toxic side-effect of Salazopyrin on the maturation of sperm cells is apparent, but associated influencing factors are the basic illness itself and associated therapy forms, such as steroids, that also influence spermatogenesis. The mechanism of action of Salazopyrin is still a matter of dispute. Possible (and possibly combined) interfering factors are: an anti-folate action with influence on the rapid turnover of dividing spermatogenie cells, an anti-prostaglandin effect on motility and toxic effects of the sulphapyridine substance of Salazopyrin. Salazopyrin;
male fertility;
side-effects;
sperm-head
size
Introduction Salazopyrin (trade name for salicylazosulfapyridine (SASP) or Sulphasalazine) has been widely used since 1942 and is considered superior to other sulfonamides for treatment of ulcerative colitis. Several dose-dependent side-effects have been refever, reticulocytosis, arthralgies, ported, such as nausea, vomiting, headaches, bronchospasm, pulmonary eosinophilia and peripheral neuropathy. In 1979, Levi et al., from Middlesex (UK), and Toth, from New York (U.S.A.), independently of each other, published their observations with respectively 4 and 6 patients, in which they found a marked influence on male fertility capacity. This and added more prompted further studies, which confirmed their observations information to the evaluation of this side-effect. Published observations Levi et al. (1979) treated four young immigrants, suffering from ulcerative colitis, with a daily salazopyrin dose of 3-4 g and noted oligozoospermia with infertility even during the first month of treatment. After ending the treatment improvement was observed in all four, both regarding concentration and motility of sperm cells, which resulted in four pregnancies for three of the patients’ wives. Reintroduction of 002%2243/84/$03.00
0 1984 Elsevier Science Publishers
B.V.
362
salazopyrin with two of these patients was again followed by rapid deterioration of the semen. We must add, however, that the patients also received prednisolone as additional treatment. During treatment with salazopyrin, a lowered sperm concentration, very poor motility and a high number of abnormal head forms were noted. No hormonal changes were recorded and the histology of testicular tissue (one patient) showed no alterations. This publication in the Lancet provoked a few letters to the Editor. Grieue (1979), from Newcastle upon Tyne, reported the case of a 24-yr-old Scotsman whose repeated sperm examinations showed that he suffered from oligozoospermia under salazopyrin treatment, with improvement in concentration and morphology 2 months after ending the treatment, also resulting in a pregnancy. Truub et al. (1979), from Belfast, reported the case of a patient with 4 yr of infertility and oligo-astheno-teratozoospermia under salazopyrin treatment. These authors also ascertained a great number of immature spermatozoa. Two months after ending the treatment the number of immature forms became normal and 4 months later his wife became pregnant. Toth (1979a) observed 6 patients taking 2-8 g Salazopyrin daily. Under therapy the motility of sperm cells was reduced and the presence of a characteristic megalo sperm cell-type was the most marked feature at morphological examination (swollen cell, giving the impression of osmotic swelling involving acrosome as well as postequatorial segments). Besides he also found mid-piece and tail abnormalities. Putting an end to the therapy with 3 patients was followed by a drastic improvement in the sperm picture, with three pregnancies within 3 months. After publication of the study by Levi et al., Toth (1979b) reported to the editor of The Lancet that he observed _in the meantime 10 similar patients with 6 pregnancies for 6 patients who had stopped salazopyrin treatment. Regeneration of spermatogenesis was observed after 3 months. Bo2tiu.s et al. (1980) checked the spermiogram before, during and after salazopyrin treatment with 2 patients. Reduction in spermatozoa concentration and motility and increase in abnormal head forms was confirmed. Pregnancy occurred respectively 3 and 2 months after termination of salazopyrin treatment. They noticed, however, that pregnancies occurred although still no marked improvement in the sperm pictures could be noted at that time. Fettes (1981), from Gore (New Zealand), found a recuperation of sperm count 3 months after ending the treatment and substitution of an alternative therapy, followed by conception 1 month later. In 1981 Toovey et af., from Levi’s group in Middlesex, published their observations on 28 patients, examined before, during and after treatment. Sperm divergencies (concentration, motility and morphology) occurred in 18 patients after at least 2 months under therapy. Recovery was observed after another 2 months, followed by 10 pregnancies averaging 2-5 months after stopping salazopyrin treatment. They did not notice hormonal changes. Heineman et al. (1981), from Nijmegen, published two case-reports with observations identical to those of Toovey. In the first case pregnancy occurred 3 months after ending salazopyrin treatment, with once more pathological sperm pictures after restarting the treatment. In the second case salazopyrin had been replaced by
363
betamethasone enemas. Sperm pictures only improved after stopping betamethasone. They too found no hormonal changes. Tobius et al. (1982), from Cape Town, published a single case report. Their patient had been treated with salazopyrin and prednisone. The spermiogram showed extreme oligo-necrozoospermia with elevated plasma FSH and decreased plasma testosterone level. After ending salazopyrin treatment and reduction of prednisone a return to normal of the spermiogram as well as of the plasma testosterone level could be observed and was followed by pregnancy. Freeman et al. (1982), from Newcastle upon Tyne, compared their data, obtained from a group of 12 patients treated with salazopyrin, with those from a control group treated alternatively. Oligo-asthenozoospermia occurred only in the salazopyrin-treated group, but abnormal morphological head forms were found in both groups. They point out also the increased ejaculate volume from salazopyrin-treated patients. Hz&on et al. (1982), from Middlesex (also belonging to the group of Toovey and Levi), made measurements of the size of spermatozoa heads (by image analysis) with 8 salazopyrin-treated patients and compared their data with the sperm head sizes in non-colitic men with normal spermiogram and with non-colitic oligozoospermic men. Salazopyrin-treated patients had significantly larger sperm-head sizes. After stopping treatment head sizes increased still further before decreasing, although without returning to normal (not even after 284 days).
Proposed mechanisms Levi et al. (1979) postulated a direct toxic effect on the seminiferous epithelium. Traub et al. (1979) point out the maturation arrest in spermatogenesis. According to them, salazopyrin has, by enzyme inhibition, an antifolate action and may suppress the rapid turnover of cells which occurs in normal spermatogenesis. Another adverse effect on sperm motility may be blamed on its anti-prostaglandin action. Toth (1979a) noticed that salazopyrin splits in the colon into sulfapyridine (SP) and 5aminosalicylic acid (5-ASA). The latter may serve as an inhibitor of prostaglandin synthesis, which may explain the sperm changes. He also attributes the morphological divergences to osmotic changes. Heineman et al. (1981), however, noticed that 5-ASA is excreted very rapidly and that the concentration of 5-ASA in semen is negligible. Toovey et al. (1982), on the other hand, think that sulfapyridine (SP) may be the toxic mediator. Tobias et al. (1982) suspect a suppressive effect on the Leydig cells as explanation for the lowered plasma testosterone level (with normal LH). They remind us that steroid therapy also inhibits spermatogenesis and may explain partially the oligozoospermic state. Freeman et al. (1982) presume that the increased ejaculate volume may influence the sperm count. Hudson et al. (1982) deduce from their observations the conclusion that active colitis as such may cause changes in the sperm-head size.
364
Conclusion
Salazopyrin appears to have a toxic effect on the maturation of sperm cells, resulting in infertility through oligo-astheno-teratozoospermia. This influence starts after 2-3 months of treatment and is reversible 2-3 months after stopping the treatment, which corresponds with the duration of the spermatogenetic cycle. Typical is the occurrence of a megalo-cell type, but it has been found that this cell-type is possibly more related to the colitis itself than to the salazopyrin therapy. Interfering factors are thus not only the salazopyrin treatment, but also the basic illness itself and possibly associated alternative therapy forms, such as steroids, that also influence spermatogenesis. A direct toxic effect of salazopyrin is likely in view of the normal hormonal findings. But here also several mechanisms may play a role, such as an anti-folate action influencing turnover of rapidly dividing cells, and anti-prostaglandin effect on sperm motility and a toxic effect of the sulphapyridine substance of salazopyrin. References Bottius, G., Stuurman, A. and Bol, J. (1980): Onvruchtbaarheid van de man tijdens behandeling met salazosylfapyridine. Ned. Tijdschr. Geneesk., 124, 1835-1836. Fettes, P.W. (1981): Reversible male infertility. N. Z. med. J., 94, 395. Freeman, J.G., Reece, V.A.C. and Venables, C.W. (1982): Sulphasalazine and spermatogenesis. Digestion, 23, 68-71. Grieve, J. (1979): Male infertility due to sulphasalazine. Lancet, ii, 464. Hudson, E., Don?, C., Sowter, C., Toovey, S. and Levi, A.J. (1982): Sperm size in patients with inflammatory bowel disease on sulfas&z.ine therapy. Fertil. and Steril., 38, 77-84. Heineman, M.J., Dony, J.M.J. and Rolland, R. (1981): Salicylazosulfapyridine and male infertility. Europ. J. Obstet. Gynec. reprod. Biol., 12, 297-303. Levi, A.J., Fisher, A.M., Hughes, L. and Hendry, W.F. (1979): Male infertility due to sulphasalazine. Lancet, ii, 276-278. Tobias, R., Sapire, K.E., Coetzee, T. and Marks, I.N. (1982): Male infertility due to sulphasalazine. Postgrad. med. J., 58, 102-103. Toovey, S., Hudson, E., Hendry, W.F. and Levi, A.J. (1981): Sulphasalazine and male infertility: reversibility and possible mechanism. Gut, 22, 445-451. Toth, A. (1979a): Reversible toxic effect of salicylazosulfapyridine on semen quality. Fertil. and Steril., 31, 538-540. Toth, A. (1979b): Male infertility due to sulphasalazine. Lancet, ii, 904. Traub, A.I., Thompson, W. and Carville, J. (1979): Male infertility due to sulphasalazine. Lancet, ii, 639-640.