At what accumulated dose of cyclophosphamide does the risk of male infertility increase?/nA 25-year

Fråga: At what accumulated dose of cyclophosphamide does the risk of male infertility increase?

A 25-year-old man with Goodpasture´s syndrome is treated with Sendoxan (cyclophosphamide) 50 mg daily. The dose has recently been lowered from 100 mg daily. The accumulated dose so far is about 8 grams. The man weighs 100 kg and is also treated with hemodialysis three times per week. Concomitant medication includes prednisolone, omeprazole, nystatin, trimethoprim-sulphametoxazole, erythropoetin and vitamines.

Sammanfattning: The influence of cyclophosphamide on spermatogenesis seems to correlate to the total accumulated dose and also to the treatment period, but not to the age of the patient at the time of the treatment. A rough approximation of the data given in the literature indicates that an accumulated dose of less than 10 grams (or 200 mg/kg) is less likely to cause persistent azoospermia. Total doses of more than 20 grams seem frequently to be associated with persistent or transient reduction in sperm production. In patients previously treated with cyclophosphamide spermatogenesis may improve even after more than 12 years of poor or absent sperm production.

Svar: yclophosphamide is known to interfere with spermatogenesis. A Medline search revealed several follow-up studies of men receiving cyclophosphamide for nephrotic syndrom before or after onset of puberty.

Semen analysis data from eight men (mean age 19 years) treated with cyclophosphamide 6-10 years earlier showed normal sperm counts in four men who had received an accumulated dose of 104-200 mg/kg and azospermia in four men who had received 312-1325 mg/kg (1).

In a study on 26 adult men receiving 50-100 mg cyclophosphamide daily during at least six months, all had azoospermia at the end of treatment. In 12 of the patients spermatogenesis returned within 15-49 months after the treatment was stopped. In this report no patient had been followed for more than four years. No significant relation was found between the total dose or duration of therapy and return of spermatogenesis (2).

Thirty patients receiving cyclophosphamide 2-3 mg/kg daily for a mean of 9 months during childhood or adolescense were followed. At a mean of 12 (6-15) years after treatment, four had no sperm production, nine were oligospermic (sperm count less than 20 x 10(6)/ml) and 17 normospermic. After another seven years, three patients that had been oligospermic and one azospermic patient had normal sperm counts. There was a significant inverse correlation between cyclophosphamide dosage and duration of treatment and sperm production. None of the patients that had been treated for less than four months and received less than 10 gram (or 300 mg/kg) were azoo- or oligospermic (3).

Five out of 17 men, who had been treated in childhood with a mean dose of 16 gram cyclophosphamide, were azoospermic after approximately 10 years. In this study also, an inverse correlation between dose and treatment period was found. Total doses of less than 20 grams, or 540 mg/kg, or a treatment period of less than seven months were not associated with sperm counts below 20 x 10(6)/ml (4).

Semen analyses were performed in 16 men (mean age 22 years) who had received a single, limited course of cyclophosphamide (3mg/kg for eight weeks or a total dose of 168 mg/kg) during childhood. All had somewhat lower sperm densities as compared with a group of healthy medical students, but not low enough to suggest infertility. Among another four patients who had received two eight week cyclophosphamide courses (a total of 336 mg/kg) one man was oligospermic and one was azospermic. The latter was the only one who had received both courses within one year (5).

There were no significant differences between boys treated before and after the onset of puberty in any of the studies above. 1 Etteldorf JN, West CD, Pitcock JA, Williams DL: Gonadal function, testicular histology, and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome. J Pediatrics 1976; 88: 206-212 2 Buchanan JD, Fairley KF, Barrie JU: Return of spermatogenesis after stopping cyclophosphamide therapy. Lancet 1975; II: 156-157 3 Watson AR, Rance CP, Bain J: Long term effects of cyclophosphamide on testicular function. Br Med J 1985; 291: 1457-1460 4 Bogdanovic R, Banicevic M, Cvoric A: Testicular function following cyclophosphamide treatment for childhood nephrotic syndrome: long-term follow-up study. Pediatr Nephrol 1990; 4: 451-454 5 Trompeter RS, Evans PR, Barratt TM: Gonadal function in boys with steroid-responsive nephrotic syndrome treated with cyclophosphamdie for short periods. Lancet 1981; I: 1177-1179