Recovery of spermatogenesis after total-body irradiation

Abstract

At our institution, male patients gave written consent to be enrolled in a long-term posttransplantation follow-up study, including annual semen analysis (SA). Of the 74 patients enrolled in the study, 40 were male, and 35 underwent a SA. The indication for allo-SCT was chronic myelogenous leukemia (CML; 25 patients), myelodysplastic syndrome (MDS; 5 patients), acute myelogenous leukemia (AML; 3 patients), acute lymphoblastic leukemia (ALL; 1 patient), and chronic lymphocytic leukemia (CLL; 1 patient). Median follow-up after transplantation was 6 years (range, 3-13 years). Most (33) patients (median age, 38 years; range, 17-56 years) received a fractionated TBI (12-13.6 Gy)–based myeloablative stem cell transplantation (MST); 2 patients (aged 39 and 40 years) received a non-TBI nonmyeloablative stem cell transplantation (NST). Follicle-stimulating hormone (FSH) levels ranged from 6 to 46 U/L (median, 19 U/L; reference range, 2-15 U/L), and free testosterone levels ranged from 0.18738 to 0.82586 μM (5.4-23.8 ng/dL) (median, 0.449365 μM [12.95 ng/dL]; reference range, 0.3123-1.041 μM [9-30 ng/dL]) in all patients except for 1, who was treated with a testosterone patch. SA and morphology were assessed as described previously.^1,2 Five (14.3%) patients showed evidence of sperm production (3 [9%] MST recipients and the 2 NST recipients; Table 1). Sperm production was associated with younger age at transplantation (≤ 30 years old; P = .04), and a follow-up of 7 years or more (3 of 5 vs 0 of 28; P = .002) in MST recipients. Both NST recipients had spermatogenesis and the highest sperm counts, despite their older age. We did not find a relationship with disease type (P = .874), acute graft-versus-host disease (aGVHD; P = .371), or chronic GVHD (cGVHD; P = .600). In fact, all 5 patients with sperm production had developed cGVHD at some timepoint after transplantation. We also found no relationship between FSH and testosterone levels and spermatogenesis. Mouse models suggest that Leydig cells (producing testosterone) may be a target for GVHD,³ but normal testosterone levels in all but 1 patient suggests that Leydig cells were not a target of cGVHD in these patients. Our data therefore confirm those of the Basel group¹ and emphasize that male fertility is seriously compromised by TBI, with delayed recovery only possible in younger transplant recipients. Furthermore, it should be noted that only the recipients of NST had near-normal sperm counts, and that no patient has yet proven to be fertile. The most practical approach to preserving fertility after transplantation, therefore, appears to be the use of non-TBI–based regimens or sperm-banking prior to TBI when possible. It remains to be determined whether intracytoplasmic sperm injection (ICSI) techniques might permit fertilization in individuals with low but detectible motile sperm after transplantation.⁴ In summary, unless more encouraging data are forthcoming with longer follow-up, male patients receiving TBI-based preparative regimens should be advised that return of fertility after transplantation is most unlikely.