- Email: [email protected]
GONADAL FUNCTION IN BOYS WITH STEROID-RESPONSIVE NEPHROTIC SYNDROME TREATED WITH CYCLOPHOSPHAMIDE FOR SHORT PERIODS
1177 This study was supported by the Paulo Foundation and Orion Corporation Research Foundation. The drugs used in this study were kindly donated by Xeofarma Ltd, Helsinki, Finland.
of sperm production; nevertheless, great caution is still required in the use of the drug.
Requests for reprints should be addressed to A. K., Department of Obstetrics and Gynaecology, University of Oulu, SF-90220 Oulu 22, Finland.
Introduction
REFERENCES
1 Tucker HA. Endocrinology of lactation. Sem Perinatol 1979; 3: 199-223. AR, Finberg L. Breast milk for term and premature infants-optimal
2 Fleischman
nutrition? Sem Perinatol 1979; 3: 397-405. Winikoff B, Baer EC. The obstetrician’s opportunity: Translating "breast is best" from theory to practice. Am Obstet J Gynecol 1980; 138: 105-17. 4. Yen BH, Keye WR, Jaffe RB. Human prolactin. secretion, regulation and pathophysiology. Obstet Gynecol Survey 1973; 28: 527-51. 5 Anderson PO. Drugs and breast feeding. Sem Perinatol 1979; 3: 271-78. 6 Hammond GL, Kontturi M, Määttälä P, Puukka M, Vihko R. Serum FSH, LH and prolactin in normal males and patients with prostatic disease. Clin Endocrinol 1977; 3
7: 129.
McNeilly AS, Thorner MO, Volans G, Besser GM. Metoclopramide and prolactin Br Med J 1974; ii: 729. 8 McCallum RW, Sowers JR, Hershman JM, Sturdevant RAL. Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 1976; 42: 1148-52. 9 Healy DL, Burger HG. Increased prolactin and thyrotropin secretion following oral metoclopramide: Dose-response relationships. Clin Endocrinol 1977; 7: 195-201. 10. Guzmán V, Tpscano G, Canales ES, Zárate A. Improvement of defective lactation by using oral metoclopramide. Acta Obstet Gynecol Scand 1979; 58: 53-55. 11 Kauppila A, Kivinen S, Ylikorkala O. Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropm and thyroid hormones. J Clin Endocrinol Metab 1981; 52: 436-39. 12 Gross BA, Eastman CI, Bowen KM, McElduff A. Integrated concentrations of prolactin in breast-feeding mothers. Aust N Z J Obstet Gynaecol 1979; 19: 150-53. 13 Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Wadhwa SR, Josimovich JB. Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 1974; 7
119: 466-72.
T, Shioji T, Shoda T, Kurachi K. The initiation of human lactation and prolactin response to suckling. J Clin Endocrinol Metab 1977; 44: 1101-06. 15 Archer DF. Physiology of prolactin. Clin Obstet Gynecol 1980; 23: 325-35. 16 Howie PW, McNeilly AS, McArdle T, Smart L, Houston M. The relationship between suckling-induced prolactin response and lactogenesis. J Clin Endocrinol Metab 1980; 50: 670-73. 17. Berg TA. Nursing the newborn. Sem Perinatol 1979; 3: 241-48. 18 Sousa PLR. Metoclopramide and breast-feeding. Br Med J 1975; i: 512. 19 Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol 1980; 9: 217-19. 20. Pinder RM, Broyden RN, Sawyer PR, Speight TM, Avery GS. Metoclopramide: A review of its pharmacological properties and clinical use. Drugs 1976; 12: 81-131. 14. Aono
GONADAL FUNCTION IN BOYS WITH STEROID-RESPONSIVE NEPHROTIC SYNDROME TREATED WITH CYCLOPHOSPHAMIDE FOR SHORT PERIODS R. S. TROMPETER P. R. EVANS T. M. BARRATT
Department of Paediatrics, Guy’s Hospital, London SE1, Department of Urology, The London Hospital, London E1, and Department of Nephrology, Institute of Child Health, London WC1 Semen analysis was undertaken in 19 men over the age of 18 years who had been treated during childhood for steroid-responsive nephrotic syndrome with a single course of cyclophosphamide 3 mg/kg bodyweight for 8 weeks. A further 4 men who received two such courses of treatment were also studied. Plasma total androgens and gonadotropins were also determined. A comparison group consisted of medical students investigated as potential donors for artificial insemination. Lower éjaculate volumes and sperm densities with a higher percentage of immotile and abnormal forms were detected in patients who had received cyclophosphamide. However, the abnormalities were not severe enough to suggest infertility. Plasma total androgens were lower in the patients, but there were no differences in gonadotropic hormones. The data suggest that a course of treatment with cyclophosphamide known to influence the natural history of the nephrotic Syndrome is not necessarily followed by a severe abnormality
Summary
OVER the past two decades the use of cyclophosphamide in the prevention of relapse of steroid-responsive nephrotic syndrome of childhood has become well established.’-’ There is, however, a potential for gonadal damage from cyclophosphamide which is apparently greater in boys than girls and was first reported by Fairley et al.5 Analysis of data from three studies6-8 in which 45 boys with minimal-change nephrotic syndrome were assessed for gonadal function after treatment with cyclophosphamide (fig. 1) shows a significant inverse correlation between sperm density and cyclophosphamide dosage. Although this side effect remains a source of concern, review of the literaturé-1O reveals little information on the potential damage in boys treated with limited courses of cyclophosphamide-such as 3 mg/kg bodyweight per day for 8 weeks (total dose 168 mg/kg), which is considered a standard regimen for the maintenance of longterm
remission.4
We therefore undertook a study into the gonadal effect of the limited-dosage cyclophosphamide regimen that has been used to treat patients with steroid-responsive nephrotic syndrome at the Hospital for Sick Children and Guy’s Hospital, London. Patients Between 1966 and 1974, 82 children with steroid-responsive nephrotic syndrome were treated with cyclophosphamide at the Hospital for Sick Children in a dose of 3 mg/kg body-weight (50th centile ideal weight for per day for 8 weeks. The results have been described elsewhere. 54 were boys, and all 23 of those over the age of 18 years at the time of study were recalled for assessment of gonadal function. 19 had received a single course of cyclophosphamide and 4 had had two courses of 8 weeks each. Another 6 patients similarly treated at Guy’s Hospital with a single course between 1970 and 1975, and 1 who received two courses, were also recalled. The mean age at the time of treatment with cyclophosphamide was 10 3 years (range 7 8 to 16 7), the mean time from completion of treatment to study 9 - 7 years (range 4 - 4 to 11 - 7), and the mean age at time of study 22 years (range 18.2 to 2 5 - 8). An age-related comparison group of 17 men over 18 years (mean age 23 years, range 19 to 26) was drawn from medical students who presented sequentially as potential semen donors to an artificial-insemination donor clinic.
height)
1178 TABLE I-RESULTS OF SEMEN ANALYSIS IN PATIENTS TREATED WITH A SINGLE COURSE OF CYCLOPHOSPHAMIDE
(3 mg/kg/day) FOR
8 WK
AND THE COMPARISON GROUP*
*Results expressed
as
mean±SE.
Methods The purpose of the study was explained to all patients, and their informed consent was obtained. 10 patients were not included in the study: the 3 who had fathered children declined to participate, as did another 4 for personal reasons; 2 patients were unable to provide semen samples, and 1 was lost to follow-up. Semen was obtained in the patient’s home by masturbation, following a period of abstinence of 48 h, into sterile inert plastic containers. Semen was analysed, within 24 h of collection, for volume, sperm concentration, percentage motility, and percentage of abnormal forms. It is important to note that semen samples obtained from the comparison group were obtained at home and transferred to the laboratory for analysis within 3 h of production. Patients were asked about their sexual performance and libido and classified as described by Chapman et al." (sexual intercourse or masturbation "strong" >4 times weekly), "moderate" (2-4 times weekly), "mild" (once per month to once per week) or "none" (no sexual activity). Blood samples were taken for the estimation of plasma total androgens and gonadotropins (luteinising hormone [LH] and follicle-stimulating hormone [FSH]) by specific radioimmunoassay, and for the detection of plasma agglutinating antisperm antibodies.12 At the time of study all patients were symptom-free and in remission, and neither patients nor medical students were receiving any medication.
Results Of the 19 patients who received a single course of treatment, 16 had their semen analysed, and the results are compared with those of the age-related group of medical students in table I. Differences were observed between the groups in sperm density, motility, and percentage of abnormal forms. The time from sample collection to analysis in the patient group may account for the observed differences in sperm motility, although deterioration in motility is negligible when samples are kept at temperatures of20°C for periods of up to 18 h.13 In the 4 patients who received two courses of cyclophosphamide at 3 mg/kg body-weight per day for 8 weeks, the mean value for sperm density was lower (fig. 2), mainly because patient 2 (table n) was oligospermic, as confirmed by two separate semen analyses. Only in this patient were the two courses of cyclophosphamide prescribed within a year of each other. A fifth patient, who received two courses of treatment separated by an interval of exactly a year TABLE II-RESULTS OF SEMEN ANALYSIS IN
Fig. 2-Sperm densities in patients treated with 1 and 2 courses of cyclophosphamide (3 mg/kg/day) for 8 weeks and a comparison group.
and whose semen was not analysed, was known to have fathered a child. Libido and sexual performance were assessed as being normal in all patients except the 2 who were unable to produce semen samples. Plasma agglutinating antisperm antibodies were not detected in patients or the comparison group. Values for the serum total androgens were lower in 14 patients who received one course of treatment than in 12 medical students, but no difference was observed for gonadotropic hormones (table III). In particular there was no correlation between individual low sperm densities and either elevated gonadotropin levels or the lowest values for total
androgens. Discussion
Cyclophosphamide has been used in the treatment of the nephrotic syndrome since 1963.’ The minimum effective dose to maintain remission remains uncertain, although there is evidence that 3 mg/kg body-weight for 2 weeks has little effect. 14 Cyclophosphamide in a daily dose of 3 mg/kg ideal weight-for-height for 8 weeks, started when steroid-induced remission has been achieved, has been shown to be effective in the management of the frequently relapsing steroid-
responsive nephrotic child.3 Previous reports on the assessment of gonadal function in boys treated with cyclophosphamide have consisted of patients receiving varying doses of the drug, usually in excess of the regimen used to treat our patients, or they have included patients with other histopathological lesions suchas focal glomerular sclerosis or membranous nephropathv.’-
4 PATIENTS WHO RECEIVED TWO 8-WK COURSES OF CYCLOPHOSPHAMIDE (3 mg/kgJday)
1179 TABLE III-TOTAL ANDROGENS AND GONADOTROPINS IN PATIENTS TREATED WITH A SINGLE COURSE OF CYCLOPHOSPHAMIDE
(3 mg/kg/day) FOR
8 WK AND IN THE COMPARISON GROUP*
EFFECT OF TREATMENT WITH SODIUM VALPROATE AND DIAZEPAM ON PLASMA CORTICOTROPIN IN NELSON’S SYNDROME MORTYN T. JONES BRIAN GILLHAM URSULA BECKFORD
Sherrington School of Physiology and Department of Biochemistry, St Thomas’s Hospital Medical School, London SE1 7EH References LH: 1st International Reference Preparation 68/40. FSH: 1st International Reference Preparation 69/104. Androgens: Grant DB, Laurence BM, Atherden SM, Ryness J. HCG stimulation test in children with abnormal sexual development. Arch Dis Child 1976; 51: 596-601. ’Results expressed as mean±SE.
ANNE DORNHORST MARY SEED
Alexander Simpson Laboratory for Metabolic Research, St Mary’s Hospital Medical School, London W2
patients with Nelson’s syndrome were given sodium valproate with or without diazepam for 3 or 5 weeks. Initial high plasma adrenocorticotropic hormone (ACTH) concentrations were greatly reduced by treatment and returned to high levels when treatment was stopped. Diazepam did not add significantly to the effects of sodium valproate alone. Three patients reported a decrease in the severity and frequency of headaches while on sodium valproate. In five patients abnormal skin pigmentation was reduced. Sodium valproate is a gammaaminobutyric acid (GABA) transaminase inhibitor and it is suggested that the drug raises GABA levels in the hypothalamus and that this is responsible for the reduction in ACTH secretion. The data are consistent with the hypothesis that Nelson’s syndrome is a neuroendocrine disease caused by a deficiency in the hypothalamic GABA-ergic system. Summary
spermatogenesis has been reported in patients after long-term therapy with high doses of cyclophosphamide, 15,16 suggesting individual variation in sensitivity of the testes to the drug. Return of
Our results suggest that treatment even with limited doses of cyclophosphamide at 3 mg/kg body-weight for 8 weeks may result in lower ejaculate volume and sperm densities, with a higher percentage of immotile and abnormal forms. However, the abnormalities are not severe enough to suggest infertility even in patients who received two courses of treatment provided they were separated by an interval of at least
one
year.
The lower normal limit for sperm density has often been set at 20 million/ml,’18 although recent experience with semen analysis in fertile men seeking vasectomy has suggested a wide variation, with densities recorded as low as 5 million/ml (P. R. Evans, unpublished). On this basis, only 1 of our patients had a definitely abnormal sperm density. Profound gonadal damage, sufficient to disrupt pituitarygonadal feedback, would be expected to result in an elevated level of FSH and LH in some children.9, 19, 20Kirkland et al.,21 who tested post-pubertal patients’ with LH-releasing factor, reported an exaggerated response of LH and FSH activity in some and suggested that these patients may have sustained testicular damage. It is recognised, however, that the gonadotropin levels have pronounced fluctuations during a 24 h period. Our data provide no evidence for impairment of the gonadal-pituitary feedback mechanism, but the elevated total androgen levels may reflect a long-term side effect of corticosteroid therapy. Our data indicate the possibility of a mild effect of a single 8-week course of cyclophosphamide, 3 mg/kg per day, on spermatogenesis, but in no patient was the defect of sperm production such that infertility would be expected; and 3 of the men are believed to have fathered children. Nevertheless, the drug must still be used cautiously, for the long-term costbenefit ratio remains to be evaluated. We thank Mrs Sheila Atherden and Miss
laboratory, Institute of Child Health, for
Jennifer Jones, of the endocrine androgen and gonadotropin
the
assays.
Requests for reprints should be addressed to R. S. T., Department of Paediatrics, Guy’s Hospital, London SE 1 9RT. REFERENCES 1 Coldbeck
JH Experience with alkylating agents in the treatment of children with the nephrotic syndrome Med J Aust 1963; ii: 987-89. 2 Moncrieff MW, White RHR, Ogg CS, Cameron JS. Cyclophosphamide therapy in the nephrotic syndrome of childhood. Br Med J 1962; i: 666-71. 3 Barratt TM, Soothill JF. Controlled trial of cyclophosphamide in steroid-responsive nephrotic syndrome of childhood. Lancet 1970; ii: 479-88.
RALPH R. ABRAHAM VICTOR WYNN
Six
4. Barratt
TM, Osofsky SG, Bercowscy A, Soothill JF. Cyclophosphamide in steroidnephrotic syndrome of childhood. Lancet 1975; i: 55-58. 5. Fairley KR, Barne JU, Johnson W. Sterility and testicular atrophy related to cyclophosphamide treatment. Lancet 1972; i: 568-69. 6. Etteldorf JN, West CD, Pitcock JA, Williams DL. Gonadal function, testicular histology and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome J Paediat 1976; 88: 206-12. 7. Lentz RD, Bergstein J, Steffes MW, Brown DR, Prem K, Michael AF, Vernier RL. Post pubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty. J Paediat 1977; 91: 385-94. 8. Hsu AC, Folami AO, Bain J, Phillips Rance C. Gonadal function in males treated with cyclophosphamide for nephrotic syndrome. Fertil Steril 1979; 31: 173-77 9. Penso J, Lippe B, Ehrlich R, Smith FG. Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephrotic syndrome. J sensitive
Paediat 1974; 84: 831-36. 10. Pennisi AJ, Grushkin CM, Liberman E. Gonadal function in children with treated with cyclophosphamide. Am J Dis Child 1975; 129: 315-18.
nephrosis
11. Chapman RM, Rees LH, Sutcliffe SB, Edwards CRW, Malpas JS. Cyclical combination chemotherapy and gonadal function Lancet 1979; i: 285-89 12. Kibrick S, Belding DL, Merrill B. Methods for the detection of antibodies against mammalian spermatozoa. Fertil Steril 1952; 3: 430-38. 13. Appell RA, Evans PR, Blandy JP. The effect of temperature on the motility and viability of sperm. Br J Urol 1977; 49: 751-56. 14. Barratt TM, Cameron JS, Chantler C, Ogg CS, Soothill JF. Comparative trial of 2 weeks and 8 weeks cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome of childhood. Arch Dis Child 1973; 48: 286—90. 15 Kumar R, McEvoy J, Biggart JD, McGeown MC. Cyclophosphamide and reproductive function Lancet 1972; i: 1212-14. 16. Buchanan JD, Fairley KF, Barrie JU. Return of spermatogenesis after stopping cyclophosphamide therapy. Lancet 1975; ii: 156-57 17. MacLeod J, Gold RZ. The male factor in fertility and infertility. II, Spermatozoa counts in 1000 men of known fertility and in 1000 cases of infertile marriage J Urol 1951, 66: 436-99. 18. Amelar RD. Infertility in men: diagnosis and treatment. 1966. Philadelphia: FA Davis. 19. De Groot GW, Fairman CA, Winter JSD. Cyclophosphamide and the prepubertal gonad: A negative report. JPaediat 1974; 94: 123-25. 20. Parra A, Santos D, Cervantes C, Sojo I, Carranco A, Cortes-Gallegos V Plasma gonadotrophins and gonadal steroids in children treated with cyclophosphamide.J Paediat 1978; 92: 117-24. 21. Kirkland R, Bongiovanni AM, Cornfeld D, McCormick JB, Parks JS, Tenore A. Gonadotrophin response to luteinising releasing hormone in boys treated with cyclophosphamide for nephrotic syndrome. J Paediat 1976; 89: 941-44.
of sperm production; nevertheless, great caution is still required in the use of the drug.
Requests for reprints should be addressed to A. K., Department of Obstetrics and Gynaecology, University of Oulu, SF-90220 Oulu 22, Finland.
Introduction
REFERENCES
1 Tucker HA. Endocrinology of lactation. Sem Perinatol 1979; 3: 199-223. AR, Finberg L. Breast milk for term and premature infants-optimal
2 Fleischman
nutrition? Sem Perinatol 1979; 3: 397-405. Winikoff B, Baer EC. The obstetrician’s opportunity: Translating "breast is best" from theory to practice. Am Obstet J Gynecol 1980; 138: 105-17. 4. Yen BH, Keye WR, Jaffe RB. Human prolactin. secretion, regulation and pathophysiology. Obstet Gynecol Survey 1973; 28: 527-51. 5 Anderson PO. Drugs and breast feeding. Sem Perinatol 1979; 3: 271-78. 6 Hammond GL, Kontturi M, Määttälä P, Puukka M, Vihko R. Serum FSH, LH and prolactin in normal males and patients with prostatic disease. Clin Endocrinol 1977; 3
7: 129.
McNeilly AS, Thorner MO, Volans G, Besser GM. Metoclopramide and prolactin Br Med J 1974; ii: 729. 8 McCallum RW, Sowers JR, Hershman JM, Sturdevant RAL. Metoclopramide stimulates prolactin secretion in man. J Clin Endocrinol Metab 1976; 42: 1148-52. 9 Healy DL, Burger HG. Increased prolactin and thyrotropin secretion following oral metoclopramide: Dose-response relationships. Clin Endocrinol 1977; 7: 195-201. 10. Guzmán V, Tpscano G, Canales ES, Zárate A. Improvement of defective lactation by using oral metoclopramide. Acta Obstet Gynecol Scand 1979; 58: 53-55. 11 Kauppila A, Kivinen S, Ylikorkala O. Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropm and thyroid hormones. J Clin Endocrinol Metab 1981; 52: 436-39. 12 Gross BA, Eastman CI, Bowen KM, McElduff A. Integrated concentrations of prolactin in breast-feeding mothers. Aust N Z J Obstet Gynaecol 1979; 19: 150-53. 13 Archer DF, Nankin HR, Gabos PF, Maroon J, Nosetz S, Wadhwa SR, Josimovich JB. Serum prolactin in patients with inappropriate lactation. Am J Obstet Gynecol 1974; 7
119: 466-72.
T, Shioji T, Shoda T, Kurachi K. The initiation of human lactation and prolactin response to suckling. J Clin Endocrinol Metab 1977; 44: 1101-06. 15 Archer DF. Physiology of prolactin. Clin Obstet Gynecol 1980; 23: 325-35. 16 Howie PW, McNeilly AS, McArdle T, Smart L, Houston M. The relationship between suckling-induced prolactin response and lactogenesis. J Clin Endocrinol Metab 1980; 50: 670-73. 17. Berg TA. Nursing the newborn. Sem Perinatol 1979; 3: 241-48. 18 Sousa PLR. Metoclopramide and breast-feeding. Br Med J 1975; i: 512. 19 Lewis PJ, Devenish C, Kahn C. Controlled trial of metoclopramide in the initiation of breast feeding. Br J Clin Pharmacol 1980; 9: 217-19. 20. Pinder RM, Broyden RN, Sawyer PR, Speight TM, Avery GS. Metoclopramide: A review of its pharmacological properties and clinical use. Drugs 1976; 12: 81-131. 14. Aono
GONADAL FUNCTION IN BOYS WITH STEROID-RESPONSIVE NEPHROTIC SYNDROME TREATED WITH CYCLOPHOSPHAMIDE FOR SHORT PERIODS R. S. TROMPETER P. R. EVANS T. M. BARRATT
Department of Paediatrics, Guy’s Hospital, London SE1, Department of Urology, The London Hospital, London E1, and Department of Nephrology, Institute of Child Health, London WC1 Semen analysis was undertaken in 19 men over the age of 18 years who had been treated during childhood for steroid-responsive nephrotic syndrome with a single course of cyclophosphamide 3 mg/kg bodyweight for 8 weeks. A further 4 men who received two such courses of treatment were also studied. Plasma total androgens and gonadotropins were also determined. A comparison group consisted of medical students investigated as potential donors for artificial insemination. Lower éjaculate volumes and sperm densities with a higher percentage of immotile and abnormal forms were detected in patients who had received cyclophosphamide. However, the abnormalities were not severe enough to suggest infertility. Plasma total androgens were lower in the patients, but there were no differences in gonadotropic hormones. The data suggest that a course of treatment with cyclophosphamide known to influence the natural history of the nephrotic Syndrome is not necessarily followed by a severe abnormality
Summary
OVER the past two decades the use of cyclophosphamide in the prevention of relapse of steroid-responsive nephrotic syndrome of childhood has become well established.’-’ There is, however, a potential for gonadal damage from cyclophosphamide which is apparently greater in boys than girls and was first reported by Fairley et al.5 Analysis of data from three studies6-8 in which 45 boys with minimal-change nephrotic syndrome were assessed for gonadal function after treatment with cyclophosphamide (fig. 1) shows a significant inverse correlation between sperm density and cyclophosphamide dosage. Although this side effect remains a source of concern, review of the literaturé-1O reveals little information on the potential damage in boys treated with limited courses of cyclophosphamide-such as 3 mg/kg bodyweight per day for 8 weeks (total dose 168 mg/kg), which is considered a standard regimen for the maintenance of longterm
remission.4
We therefore undertook a study into the gonadal effect of the limited-dosage cyclophosphamide regimen that has been used to treat patients with steroid-responsive nephrotic syndrome at the Hospital for Sick Children and Guy’s Hospital, London. Patients Between 1966 and 1974, 82 children with steroid-responsive nephrotic syndrome were treated with cyclophosphamide at the Hospital for Sick Children in a dose of 3 mg/kg body-weight (50th centile ideal weight for per day for 8 weeks. The results have been described elsewhere. 54 were boys, and all 23 of those over the age of 18 years at the time of study were recalled for assessment of gonadal function. 19 had received a single course of cyclophosphamide and 4 had had two courses of 8 weeks each. Another 6 patients similarly treated at Guy’s Hospital with a single course between 1970 and 1975, and 1 who received two courses, were also recalled. The mean age at the time of treatment with cyclophosphamide was 10 3 years (range 7 8 to 16 7), the mean time from completion of treatment to study 9 - 7 years (range 4 - 4 to 11 - 7), and the mean age at time of study 22 years (range 18.2 to 2 5 - 8). An age-related comparison group of 17 men over 18 years (mean age 23 years, range 19 to 26) was drawn from medical students who presented sequentially as potential semen donors to an artificial-insemination donor clinic.
height)
1178 TABLE I-RESULTS OF SEMEN ANALYSIS IN PATIENTS TREATED WITH A SINGLE COURSE OF CYCLOPHOSPHAMIDE
(3 mg/kg/day) FOR
8 WK
AND THE COMPARISON GROUP*
*Results expressed
as
mean±SE.
Methods The purpose of the study was explained to all patients, and their informed consent was obtained. 10 patients were not included in the study: the 3 who had fathered children declined to participate, as did another 4 for personal reasons; 2 patients were unable to provide semen samples, and 1 was lost to follow-up. Semen was obtained in the patient’s home by masturbation, following a period of abstinence of 48 h, into sterile inert plastic containers. Semen was analysed, within 24 h of collection, for volume, sperm concentration, percentage motility, and percentage of abnormal forms. It is important to note that semen samples obtained from the comparison group were obtained at home and transferred to the laboratory for analysis within 3 h of production. Patients were asked about their sexual performance and libido and classified as described by Chapman et al." (sexual intercourse or masturbation "strong" >4 times weekly), "moderate" (2-4 times weekly), "mild" (once per month to once per week) or "none" (no sexual activity). Blood samples were taken for the estimation of plasma total androgens and gonadotropins (luteinising hormone [LH] and follicle-stimulating hormone [FSH]) by specific radioimmunoassay, and for the detection of plasma agglutinating antisperm antibodies.12 At the time of study all patients were symptom-free and in remission, and neither patients nor medical students were receiving any medication.
Results Of the 19 patients who received a single course of treatment, 16 had their semen analysed, and the results are compared with those of the age-related group of medical students in table I. Differences were observed between the groups in sperm density, motility, and percentage of abnormal forms. The time from sample collection to analysis in the patient group may account for the observed differences in sperm motility, although deterioration in motility is negligible when samples are kept at temperatures of20°C for periods of up to 18 h.13 In the 4 patients who received two courses of cyclophosphamide at 3 mg/kg body-weight per day for 8 weeks, the mean value for sperm density was lower (fig. 2), mainly because patient 2 (table n) was oligospermic, as confirmed by two separate semen analyses. Only in this patient were the two courses of cyclophosphamide prescribed within a year of each other. A fifth patient, who received two courses of treatment separated by an interval of exactly a year TABLE II-RESULTS OF SEMEN ANALYSIS IN
Fig. 2-Sperm densities in patients treated with 1 and 2 courses of cyclophosphamide (3 mg/kg/day) for 8 weeks and a comparison group.
and whose semen was not analysed, was known to have fathered a child. Libido and sexual performance were assessed as being normal in all patients except the 2 who were unable to produce semen samples. Plasma agglutinating antisperm antibodies were not detected in patients or the comparison group. Values for the serum total androgens were lower in 14 patients who received one course of treatment than in 12 medical students, but no difference was observed for gonadotropic hormones (table III). In particular there was no correlation between individual low sperm densities and either elevated gonadotropin levels or the lowest values for total
androgens. Discussion
Cyclophosphamide has been used in the treatment of the nephrotic syndrome since 1963.’ The minimum effective dose to maintain remission remains uncertain, although there is evidence that 3 mg/kg body-weight for 2 weeks has little effect. 14 Cyclophosphamide in a daily dose of 3 mg/kg ideal weight-for-height for 8 weeks, started when steroid-induced remission has been achieved, has been shown to be effective in the management of the frequently relapsing steroid-
responsive nephrotic child.3 Previous reports on the assessment of gonadal function in boys treated with cyclophosphamide have consisted of patients receiving varying doses of the drug, usually in excess of the regimen used to treat our patients, or they have included patients with other histopathological lesions suchas focal glomerular sclerosis or membranous nephropathv.’-
4 PATIENTS WHO RECEIVED TWO 8-WK COURSES OF CYCLOPHOSPHAMIDE (3 mg/kgJday)
1179 TABLE III-TOTAL ANDROGENS AND GONADOTROPINS IN PATIENTS TREATED WITH A SINGLE COURSE OF CYCLOPHOSPHAMIDE
(3 mg/kg/day) FOR
8 WK AND IN THE COMPARISON GROUP*
EFFECT OF TREATMENT WITH SODIUM VALPROATE AND DIAZEPAM ON PLASMA CORTICOTROPIN IN NELSON’S SYNDROME MORTYN T. JONES BRIAN GILLHAM URSULA BECKFORD
Sherrington School of Physiology and Department of Biochemistry, St Thomas’s Hospital Medical School, London SE1 7EH References LH: 1st International Reference Preparation 68/40. FSH: 1st International Reference Preparation 69/104. Androgens: Grant DB, Laurence BM, Atherden SM, Ryness J. HCG stimulation test in children with abnormal sexual development. Arch Dis Child 1976; 51: 596-601. ’Results expressed as mean±SE.
ANNE DORNHORST MARY SEED
Alexander Simpson Laboratory for Metabolic Research, St Mary’s Hospital Medical School, London W2
patients with Nelson’s syndrome were given sodium valproate with or without diazepam for 3 or 5 weeks. Initial high plasma adrenocorticotropic hormone (ACTH) concentrations were greatly reduced by treatment and returned to high levels when treatment was stopped. Diazepam did not add significantly to the effects of sodium valproate alone. Three patients reported a decrease in the severity and frequency of headaches while on sodium valproate. In five patients abnormal skin pigmentation was reduced. Sodium valproate is a gammaaminobutyric acid (GABA) transaminase inhibitor and it is suggested that the drug raises GABA levels in the hypothalamus and that this is responsible for the reduction in ACTH secretion. The data are consistent with the hypothesis that Nelson’s syndrome is a neuroendocrine disease caused by a deficiency in the hypothalamic GABA-ergic system. Summary
spermatogenesis has been reported in patients after long-term therapy with high doses of cyclophosphamide, 15,16 suggesting individual variation in sensitivity of the testes to the drug. Return of
Our results suggest that treatment even with limited doses of cyclophosphamide at 3 mg/kg body-weight for 8 weeks may result in lower ejaculate volume and sperm densities, with a higher percentage of immotile and abnormal forms. However, the abnormalities are not severe enough to suggest infertility even in patients who received two courses of treatment provided they were separated by an interval of at least
one
year.
The lower normal limit for sperm density has often been set at 20 million/ml,’18 although recent experience with semen analysis in fertile men seeking vasectomy has suggested a wide variation, with densities recorded as low as 5 million/ml (P. R. Evans, unpublished). On this basis, only 1 of our patients had a definitely abnormal sperm density. Profound gonadal damage, sufficient to disrupt pituitarygonadal feedback, would be expected to result in an elevated level of FSH and LH in some children.9, 19, 20Kirkland et al.,21 who tested post-pubertal patients’ with LH-releasing factor, reported an exaggerated response of LH and FSH activity in some and suggested that these patients may have sustained testicular damage. It is recognised, however, that the gonadotropin levels have pronounced fluctuations during a 24 h period. Our data provide no evidence for impairment of the gonadal-pituitary feedback mechanism, but the elevated total androgen levels may reflect a long-term side effect of corticosteroid therapy. Our data indicate the possibility of a mild effect of a single 8-week course of cyclophosphamide, 3 mg/kg per day, on spermatogenesis, but in no patient was the defect of sperm production such that infertility would be expected; and 3 of the men are believed to have fathered children. Nevertheless, the drug must still be used cautiously, for the long-term costbenefit ratio remains to be evaluated. We thank Mrs Sheila Atherden and Miss
laboratory, Institute of Child Health, for
Jennifer Jones, of the endocrine androgen and gonadotropin
the
assays.
Requests for reprints should be addressed to R. S. T., Department of Paediatrics, Guy’s Hospital, London SE 1 9RT. REFERENCES 1 Coldbeck
JH Experience with alkylating agents in the treatment of children with the nephrotic syndrome Med J Aust 1963; ii: 987-89. 2 Moncrieff MW, White RHR, Ogg CS, Cameron JS. Cyclophosphamide therapy in the nephrotic syndrome of childhood. Br Med J 1962; i: 666-71. 3 Barratt TM, Soothill JF. Controlled trial of cyclophosphamide in steroid-responsive nephrotic syndrome of childhood. Lancet 1970; ii: 479-88.
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TM, Osofsky SG, Bercowscy A, Soothill JF. Cyclophosphamide in steroidnephrotic syndrome of childhood. Lancet 1975; i: 55-58. 5. Fairley KR, Barne JU, Johnson W. Sterility and testicular atrophy related to cyclophosphamide treatment. Lancet 1972; i: 568-69. 6. Etteldorf JN, West CD, Pitcock JA, Williams DL. Gonadal function, testicular histology and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome J Paediat 1976; 88: 206-12. 7. Lentz RD, Bergstein J, Steffes MW, Brown DR, Prem K, Michael AF, Vernier RL. Post pubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty. J Paediat 1977; 91: 385-94. 8. Hsu AC, Folami AO, Bain J, Phillips Rance C. Gonadal function in males treated with cyclophosphamide for nephrotic syndrome. Fertil Steril 1979; 31: 173-77 9. Penso J, Lippe B, Ehrlich R, Smith FG. Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephrotic syndrome. J sensitive
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11. Chapman RM, Rees LH, Sutcliffe SB, Edwards CRW, Malpas JS. Cyclical combination chemotherapy and gonadal function Lancet 1979; i: 285-89 12. Kibrick S, Belding DL, Merrill B. Methods for the detection of antibodies against mammalian spermatozoa. Fertil Steril 1952; 3: 430-38. 13. Appell RA, Evans PR, Blandy JP. The effect of temperature on the motility and viability of sperm. Br J Urol 1977; 49: 751-56. 14. Barratt TM, Cameron JS, Chantler C, Ogg CS, Soothill JF. Comparative trial of 2 weeks and 8 weeks cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome of childhood. Arch Dis Child 1973; 48: 286—90. 15 Kumar R, McEvoy J, Biggart JD, McGeown MC. Cyclophosphamide and reproductive function Lancet 1972; i: 1212-14. 16. Buchanan JD, Fairley KF, Barrie JU. Return of spermatogenesis after stopping cyclophosphamide therapy. Lancet 1975; ii: 156-57 17. MacLeod J, Gold RZ. The male factor in fertility and infertility. II, Spermatozoa counts in 1000 men of known fertility and in 1000 cases of infertile marriage J Urol 1951, 66: 436-99. 18. Amelar RD. Infertility in men: diagnosis and treatment. 1966. Philadelphia: FA Davis. 19. De Groot GW, Fairman CA, Winter JSD. Cyclophosphamide and the prepubertal gonad: A negative report. JPaediat 1974; 94: 123-25. 20. Parra A, Santos D, Cervantes C, Sojo I, Carranco A, Cortes-Gallegos V Plasma gonadotrophins and gonadal steroids in children treated with cyclophosphamide.J Paediat 1978; 92: 117-24. 21. Kirkland R, Bongiovanni AM, Cornfeld D, McCormick JB, Parks JS, Tenore A. Gonadotrophin response to luteinising releasing hormone in boys treated with cyclophosphamide for nephrotic syndrome. J Paediat 1976; 89: 941-44.