Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies

Abstract

Summary:Most bone marrow transplant recipients are infertile due to reversible or irreversible testicular failure. However, little is known about the gonadotoxic potential of the newly introduced nonmyeloablative transplants. We undertook a 24-month longitudinal study in a cohort of 32 recipients of nonmyeloablative transplantation to test whether the combined regimen of fludarabine, melphalan and CAMPATH-1H can induce damage to germ cell (GC) and Leydig cell (LC) compartments. Testicular function was assessed immediately prior to transplantation and at four time points post-transplant to compare hormonal levels before and after the procedure. Two other groups treated with BEAM-and TBI-related regimes were also included in the study group for comparative purposes. GC function was assessed by measuring basal serum follicle stimulating hormone (FSH). LC function was assessed by measuring basal luteinising hormone (LH) and testosterone (T) levels. LC reserve was assessed by measuring the T/LH ratio. As a group, patients who received a non myeloablative transplant sustained severe damage to the GC compartment, as evident from a substantial elevation in the FSH level post-transplant (12 IU/l vs 18.4 IU/l, Po0.001). Similar to the GC injury, patients as a group sustained significant damage to the LC compartment following the transplant (5.4 IU/l vs 9.6 IU/ l, Po0.001). In general, patients had reduced LC reserve post-BMT, as evident from a diminished T/LH ratio (2.6 pretransplant vs 1.6 post-transplant P ¼ 0.05). Patients who received a nonmyeloablative transplant had a similar effect on the GC and LC compartments compared to those who had a BEAM autograft. On the other hand, patients who received a TBI-based transplant sustained more damage to their GC and LC compartments compared to those who received a nonmyeloblative transplant; however, this was not statistically significant (P ¼ 0.09). Our data suggest that this type of regimen is potentially gonadotoxic and consideration should be given to fertility counselling and testosterone replacement therapy posttransplant.

Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

“…Similarly, a greater cumulative probability for injury of germinal cells was previously reported in patients treated with radiation therapy when compared to those treated with chemotherapy only [17, 25, 41, 48, 49]. In addition, lower sperm counts were observed in long-term survivors affected by cGVHD when compared to unaffected patients, suggesting some possible effects of this chronic posttransplant complication on gonadal status [39, 50].…”

Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters

“…13,[52][53][54] This is explained by the higher likelihood of males having preserved androgen production as compared with preservation of female oestrogen production. 13,24,[52][53][54][55][56] Previous reports depict GVHD and its treatment as RFs for many LE. [5][6][7]15,44 Surprisingly, we are not able to confirm these data either for acute or chronic GVHD.…”

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases

“…Data on this are as yet disappointingly scanty. It is clear that the FLU/ melphalan regimen is significantly gonadotoxic in adults, resulting in elevation of both luteinizing hormone and follicle-stimulating hormone, implying damage to both germ cells and Leydig cells, 43 but the clinical effects of this on pubertal development and fertility are as yet unknown. Clearly such effects are very likely to be regimen specific.…”