High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood

Cancer. 2001 Feb 1;91(3):613-21. doi: 10.1002/1097-0142(20010201)91:3<613::aid-cncr1042>3.0.co;2-r.


Background: Therapy with alkylating agents, such as cyclophosphamide, can be associated with irreversible gonadal toxicity in male survivors of adult cancer. To the authors's knowledge the effect of high dose therapy with cyclophosphamide during childhood on adult testicular reproductive and endocrine function has not been established.

Methods: Gonadal function was studied in 17 adult male survivors of childhood sarcomas treated with high dose pulse cyclophosphamide therapy as part of a VAC (vincristine, actinomycin, and cyclophosphamide) or Adria-VAC (doxorubicin, vincristine, actinomycin, and cyclophosphamide) chemotherapy regimen. Patients answered a questionnaire concerning sexual functioning and underwent a comprehensive physical examination, semen analysis, and hormonal evaluation.

Results: Of the 17 males who underwent semen analysis, 10 (58.8%) had azoospermia, 5 (29.4%) had oligospermia, and only 2 (11.8%) were found to have a normal sperm count. All patients treated prior to the onset of puberty had an abnormal semen analysis. The 2 patients with normal sperm counts received the lowest doses of cyclophosphamide (< 7.5 g/m(2)). The baseline follicle-stimulating hormone level was elevated in only 10 of 14 patients with abnormal sperm counts (71.4%). Testosterone levels were normal in 15 of 16 patients (93.8%); however, the baseline luteinizing hormone (LH) level was elevated in 6 of 15 patients with normal testosterone levels (40%). Gonadotropin-releasing hormone-stimulated LH levels were > 3 times that of baseline in 13 of /14 patients (92.9%), suggesting some degree of Leydig cell insufficiency.

Conclusions: The results of the current study show a high risk of gonadal dysfunction in men exposed to cyclophosphamide during childhood as part of a VAC/Adria-VAC chemotherapy regimen. Exposure prior to puberty was not found to be protective, and the risk of infertility appeared to increase with higher doses of therapy. To the authors' knowledge the clinical significance of impaired Leydig cell function beginning at a young age is unknown and merits further study.

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / adverse effects*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Child
  • Child, Preschool
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects*
  • Cyclophosphamide / therapeutic use
  • Follicle Stimulating Hormone / metabolism
  • Genitalia, Male / drug effects*
  • Humans
  • Infertility, Male / chemically induced*
  • Infertility, Male / complications
  • Infertility, Male / epidemiology
  • Luteinizing Hormone / metabolism
  • Male
  • Risk Factors
  • Sarcoma / complications
  • Sarcoma / drug therapy*
  • Sarcoma / metabolism
  • Testosterone / metabolism


  • Antineoplastic Agents, Alkylating
  • Testosterone
  • Cyclophosphamide
  • Luteinizing Hormone
  • Follicle Stimulating Hormone