Effects of chemotherapy and radiotherapy on spermatogenesis in humans

Abstract

Treatment of cancer with chemo- or radiotherapy causes reduction of sperm counts often to azoospermic levels that may persist for several years or be permanent. The time course of declines in sperm count can be predicted by the sensitivity of germ cells, with differentiating spermatogonia being most sensitive, and the known kinetics of recovery. Recovery from oligo- or azoospermia is more variable and depends on whether there is killing of stem cells and alteration of the somatic environment that normally supports differentiation of stem cells. Of the cytotoxic therapeutic agents, radiation and most alkylating drugs are the most potent at producing long-term azoospermia. Most of the newer biologic targeted therapies, except those used to target radioisotopes or toxins to cells, seem to have only modest effects, mostly on the endocrine aspects of the male reproductive system; however, their effects when used in combination with cytotoxic agents have not been well studied.

Keywords: Cancer; biologic targeted therapy; chemotherapy; radiotherapy; spermatogenesis.

Figure 1

Sequence, kinetics, and survival after irradiation of spermatogenic cells in the human male. Drawings cells courtesy of Dr. Y Clermont. Arrows indicate time required for cells to mature from one state to another. Numbers in parentheses are based on histological counts of the surviving fraction of cells at 2 weeks after 1 Gy of irradiation, reflecting the direct killing of cells by irradiation and 2 weeks of maturation depletion (3)

Figure 2

Declines in sperm counts in patients treated with two different chemotherapy regimens. (A) NOVP (9) chemotherapy consisting of Novantrone (mitoxantrone), Oncovin (vincristine), vinblastine, and prednisone for Hodgkin's disease. Small open circles are individual sperm counts. Large filled circles are averages of counts grouped into time ranges. (Reprinted with permission from Meistrich et al., Journal of Clinical Oncology 15: 3488, 1997) The subsequent recovery of sperm counts to normal levels is also shown. (B) CY(V)ADIC (8) chemotherapy consisting of cyclophosphamide, Adriamycin (doxorubicin), DIC (DTIC, dacarbazine), with or without vincristine for Ewing and soft-tissue sarcoma. Pretreatment counts are indicated by solid symbols. Dashed lines connect longitudinal counts for individual patients. (Reprinted with permission from Meistrich et al., Cancer 70: 2703, 1992)

Figure 3

Recovery of sperm counts in individual patients treated with (A) hemi-pelvic radiotherapy for seminoma (22, 23), or (B) pelvic radiotherapy for Hodgkin's disease (24). Gonadal doses are indicated next to each plot.

Figure 4

(A) Examples of delayed recovery of sperm count occurring after 2 to 5 years of azoospermia in 5 patients treated with chemotherapy agents that are toxic to stem spermatogonia. (◯,●) CVPP-ABDIC consisting of cyclophosphamide, vincristine, procarbazine, prednisone, Adriamycin, bleomycin, dacarbazine, and lomustine (CCNU) (26) treatment for Hodgkin's disease patients; (▲) CHOP-Bleo which consists of cyclophosphamide, Adriamycin (hydroxydaunorubicin), Oncovin, prednisone, and bleomycin (27) treatment for a non-Hodgkin's lymphoma. (B) Kaplan-Meier actuarial estimation of sperm count recovery to 10 million/ml showing the overall rates and extents of recovery in sarcoma patients were treated with the CY(V)ADIC regimen, but receiving different total doses of cyclophosphamide (8) (Reprinted with permission from Meistrich et al., Cancer 70: 2703, 1992).