Probing the contribution of internal cavities to the volume change of protein unfolding under pressure

BACKGROUND: Testicular dysfunction with elevated follicle-stimulating hormone (FSH) levels (indicating oligospermia and/or azoospermia) is a major late sequelae after treatment for Hodgkin's disease (HD) with high cumulative doses of procarbazine, cyclophosphamide, or chlorambucil. Etoposide is a newer antineoplastic agent that is effective in the treatment of HD. However, little is known regarding its testicular toxicity, especially in the pediatric age group. METHODS: The authors evaluated testicular function in 46 young adults in first continuous complete remission after stage-dependent treatment for HD with the vincristine, etoposide, prednisone, and doxorubicin (OEPA) or OEPA/cyclophosphamide, vincristine, procarbazine, and prednisone [COPP] chemotherapy regimens and involved field irradiation, excluding patients with ilioinguinal radiotherapy. Pubertal development was documented and a standardized intravenous gonadotropin-releasing hormone test was performed measuring testosterone and basal and stimulated levels of FSH and luteinizing hormone (LH). RESULTS: Testicular volumes, Tanner stages of pubic hair, and genital development were found to be appropriate or slightly delayed for the patients' chronologic age. All 27 patients had normal basal levels of FSH and LH after treatment of Ann Arbor Stage I-IIA HD with 2 courses of OEPA. Stimulated FSH and LH levels were found to be elevated only in rare patients, thus indicating normal endocrine function and spermatogenesis. However, basal and stimulated FSH levels were outside the +2 standard deviation range in 37.5% and 83.3% of patients receiving 2 cycles of OEPA and 2 cycles of COPP chemotherapy, and in 36.4% and 66.7% of patients receiving 2 cycles of OEPA and 4 cycles of COPP chemotherapy, demonstrating a high risk of oligospermia or azoospermia with these regimens. Basal LH levels essentially were normal, whereas stimulated LH levels frequently were elevated. CONCLUSIONS: Testicular function was found to be normal in patients with Stage I-IIA HD when etoposide was used in combination with vincristine, prednisone, and doxorubicin (2 cycles of OEPA). Additional chemotherapy with cyclophosphamide and procarbazine (2 cycles of OEPA and 2 or 4 cycles of COPP) negatively affected spermatogenesis and possibly Leydig cell function in a considerable number of patients. This major gonadotoxic effect most likely is due to procarbazine, although an additional effect of etoposide and cyclophosphamide cannot be excluded.