Childhood reproductive hormone levels after pediatric hematopoietic stem cell transplantation in relation to adult testicular function

Abstract

Objectives: Longitudinal assessment of testicular function after pediatric hematopoietic stem cell transplantation (HSCT) is needed to guide clinical follow-up. We investigated dynamics in male reproductive hormones after pediatric HSCT, focusing on pubertal timing and associations with testosterone deficiency and azoospermia in adulthood. Methods: This retrospective, longitudinal study included 39 survivors median 19 years after pediatric HSCT. Serum concentrations of LH, testosterone, FSH, and inhibin B from time of HSCT, during puberty, and into adulthood were analyzed. Pubertal timing (rise in LH and testosterone) was compared to a reference cohort of 112 healthy boys. Associations between reproductive hormone levels during puberty and adult testicular function (including semen quality) were investigated. Results: Pubertal induction with testosterone was needed in 6/26 patients who were prepubertal at HSCT. In the remaining patients, pubertal timing was comparable to the reference cohort. However, 9/33 patients (without pubertal induction) developed testosterone deficiency in early adulthood, which was associated with higher LH levels from age 14–16 years. Azoospermia in adulthood was found in 18/26 patients without testosterone substitution. Higher FSH and lower inhibin B levels from mid-pubertal age were associated with azoospermia in adulthood, in patients being prepubertal at HSCT. Conclusion: Our results indicate a substantial risk of deterioration in testicular function after pediatric HSCT, despite normal pubertal timing. Although reproductive hormone levels from mid-puberty indicated adult testicular function, prolonged follow-up into adulthood is needed in these patients, including clinical examination, reproductive hormone analysis, and semen sample for patients interested in their fertility potential.

Gonadal development and function after immature testicular tissue banking as part of high‐risk gonadotoxic treatment

“…Previous follow-up studies after childhood cancer treatment or allogeneic HSCT reported higher LH and FSH levels, low-normal T levels, and lower INHB and anti-Müllerian hormone levels at adulthood, compared to the general population. [22][23][24]31 Mathiesen et al 23 highlighted T deficiency in early adulthood after pediatric HSCT that was associated with higher LH levels from mid-puberty onwards.…”

“…This is a four‐fold increase compared to the earlier reported international survey from 2012 9 . In recent years, small‐scale long‐term follow‐up studies after high‐risk gonadotoxic treatment have been conducted, some of which focusing on HSCT 21–24 . However, not only the gonadotoxic treatment, but also the testicular biopsy itself could have an impact on gonadal function and future fertility.…”

“…The for LH and 15 IU/L for FSH and a lower limit of 10 nmol/L for T and 50 pg/mL for INHB were used as references for normal serum levels. 23,24 Patient follow-up data recorded between 2002 and 2020 were retrospectively collected from the patients' medical records at the UZ Brussel and HUDERF. Exact alkylating-dose and cyclophosphamide equivalent dose (CED) were not available for all included patients, but they were all referred to the UZ Brussel's fertility preservation pro-gram by oncologists or hematologists because of highly gonadotoxic treatment protocols.…”

“…9 In recent years, small-scale longterm follow-up studies after high-risk gonadotoxic treatment have been conducted, some of which focusing on HSCT. [21][22][23][24] However, not only the gonadotoxic treatment, but also the testicular biopsy itself could have an impact on gonadal function and future fertility. Several studies have reported on short-term surgical complications after testicular biopsy for fertility preservation.…”

“…No significant difference for LH, FSH, T, and INHB could be observed between the TTB groups. TTB, testicular tissue banking; LH, luteinizing hormone; FSH, follicle-stimulating hormone; T, testosterone; INHB, inhibin B.follow-up studies in males treated by high-risk gonadotoxic treatment reported very rare need for pubertal induction 22,23,31. The need for puberty induction in our patient cohort is not yet comparable with previous studies, as one-third of our patients were still prepubertal at their last visit and therefore their future need for T-substitution treatment is currently unknown.The present study discusses the rather unknown impact of a testicular biopsy procedure performed as part of immature TTB.…”