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/m², 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.