Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Biol Blood Marrow Transplant. 2020 Sep;26(9):1635-1645. doi: 10.1016/j.bbmt.2020.05.009. Epub 2020 May 21.
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insight into patterns of male gonadal function at long-term is limited by retrospective studies without semen sample data. In this study, we investigated the risk of azoospermia and testosterone deficiency, the diagnostic value of markers of spermatogenesis, and paternity at long-term follow-up after pediatric allogeneic HSCT. All male HSCT survivors age ≥18 years, transplanted in Denmark or Finland between 1980 and 2010, were invited to participate in this cross-sectional study. Examinations included a semen sample, measurements of reproductive hormones and testicular volume, and screening for chronic graft-versus-host disease (GVHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated, at a median 18 years (range, 8 to 35 years) after undergoing HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24. A higher cumulative testicular irradiation dose was associated with increased risk of azoospermia and testosterone substitution (odds ratio [OR] per +1 Gy, 1.27; 95% confidence interval [CI], 1.14 to 1.46 [P < .001] and 1.21; 95% CI, 1.11 to 1.38 [P < .001], respectively). All patients treated with >12 Gy had azoospermia, and all but 1 patient treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n = 23), a higher cumulative cyclophosphamide equivalent dose was associated with an increased risk of azoospermia (OR per +1 g/m, 1.34; 95% CI, 1.01 to 2.15; P = .037). Prepubertal stage at HSCT was a risk factor for testosterone substitution (OR, 15.31; 95% CI, 2.39 to 315; P = .017), whereas chronic GVHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve, .91; 95% CI, .85 to .98; 90% sensitivity and 83% specificity) compared with follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, 6 had fathered children. In conclusion, the risk of male gonadal dysfunction after pediatric HSCT is high and depends primarily on the cumulative testicular irradiation dose and pubertal stage at transplantation. Our findings support the need for fertility preservation before HSCT, as well as for prolonged follow-up of pediatric HSCT recipients into adulthood.
男性性腺功能障碍是儿科造血干细胞移植（HSCT）后的常见晚期效应，但由于缺乏精液样本数据的回顾性研究，对长期男性性腺功能模式的详细了解受到限制。在这项研究中，我们调查了儿科异基因 HSCT 后长期随访中无精子症和睾酮缺乏的风险、生精标志物的诊断价值和生育能力。所有年龄≥18 岁的男性 HSCT 幸存者，1980 年至 2010 年间在丹麦或芬兰接受移植，均被邀请参加这项横断面研究。检查包括精液样本、生殖激素和睾丸体积测量以及慢性移植物抗宿主病（GVHD）筛查。计算了累积（移植前加移植后）治疗剂量。在 181 名符合条件的患者中，有 98 名患者参加了研究，HSCT 后中位数为 18 年（范围为 8 至 35 年）。在 30 名患者中发现了精子，42 名患者无精子症，24 名患者在接受睾酮替代治疗时无精子症。累积睾丸照射剂量越高，无精子症和睾酮替代的风险越高（每增加+1 Gy 的比值比 [OR]，1.27；95%置信区间 [CI]，1.14 至 1.46 [P<0.001]和 1.21；95%CI，1.11 至 1.38 [P<0.001]）。所有接受>12 Gy 治疗的患者均出现无精子症，所有接受>16 Gy 治疗的患者均需要接受睾酮替代治疗。在仅接受化疗的患者（n=23）中，累积环磷酰胺等效剂量越高，无精子症的风险越高（每增加+1 g/m 的 OR，1.34；95%CI，1.01 至 2.15；P=0.037）。HSCT 时的青春期前阶段是睾酮替代的危险因素（OR，15.31；95%CI，2.39 至 315；P=0.017），而慢性 GVHD 与性腺功能障碍无关。抑制素 B 是无精子症的最佳替代标志物（曲线下面积，0.91；95%CI，0.85 至 0.98；90%敏感性和 83%特异性），优于卵泡刺激素和睾丸体积。在 24 名试图生育的男性中，有 6 名已经生育了孩子。总之，儿科 HSCT 后男性性腺功能障碍的风险很高，主要取决于累积睾丸照射剂量和移植时的青春期阶段。我们的研究结果支持在 HSCT 前进行生育能力保存的必要性，以及对儿科 HSCT 受者成年后进行长期随访的必要性。
