medwireNews: Testicular dysfunction after treatment for childhood haematological malignancy is “mostly reversible” but warrants long-term endocrine surveillance in survivors, Argentinian researchers say.
The prospective longitudinal study included 63 boys and adolescents aged 1–18 years in Argentina who were diagnosed between 2013 and 2019 with acute lymphoblastic leukaemia (ALL; 65.1%), a form of non-Hodgkin’s lymphoma (NHL; 27.0% including lymphoblastic leukaemia [LBL]) or acute myeloid leukaemia (AML; 7.9%). The majority (77.8%) of participants were prepubertal at time of diagnosis.
The patients received standard treatment protocols consisting of induction, early intensification, phases 1 and 2 of reinduction and maintenance, they explain. The patients were monitored for up to 36 months after completing chemotherapy. None of the patients experienced relapse or required bone marrow transplant, say Romina Grinspon and colleagues, from Hospital de Niños Ricardo Gutiérrez in Buenos Aires.
Prepubertal patient outcomes
The researchers grouped the 44 prepubertal boys with ALL or LBL who received similar treatment protocols.
“The analysis focused on the seminiferous tube function since Leydig cells are largely inactive in prepuberty,” and therefore measured levels of anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH), the researchers explain in The Journal of Clinical Endocrinology & Metabolism.
They found that median serum AMH at diagnosis was significantly lower in this subgroup than would be expected in the general population, but only one (2.3%) of the boys had a severe decrease (<3rd centile) at diagnosis, increasing to 5.4% of boys during phase 1 of reinduction.
There was a significant increase in AMH between diagnosis and induction therapy and this continued until receipt of consolidation therapy, at which time serum AMH decreased and remained low throughout reinduction, before recovering after 9 months of maintenance and remaining stable until 3 years post-therapy. Further analysis showed that methotrexate dosing, which differed with diagnosis, “did not influence Sertoli cell function,” they add.
Serum FSH levels were also below the expected median (0.49 IU/L) at diagnosis and decreased during induction therapy, but recovered significantly during intensification therapy and remained stable during consolidation therapy. FSH levels decreased again during reinduction therapy but recovered thereafter.
“Summing up, gonadotrope activity was impaired at diagnosis, recovered after induction and remained within normal limits in the vast majority of patients until 3 years [post-treatment],” the researchers say. “Remarkably, a decline in gonadotrope function was observed in coincidence with exposure to high-dose corticosteroids,” they add.
The investigators comment that there were no “relevant variations” in pituitary-Leydig cell axis function in the prepubertal patients, as indicated by levels of serum luteinising hormone (LH) and testosterone.
Finally, the researchers note that three of the four prepubertal patients with other forms of NHL had serum AMH levels below the 3rd centile, but their levels recovered at the start of treatment and remained within normal range 1 year after completing therapy. FSH was normal at diagnosis and remained so in this subgroup.
Pubertal patient findings
Of the 14 patients who had begun puberty at diagnosis, five had ALL, five had NHL (three with LBL) and four had AML.
The eight boys with ALL or LBL were at Tanner stage G2 (n=1), G3 (n=3), G4 (n=1), or G5 (n=3), with testicular volumes of 20–25 mL 3 years after completing treatment.
At diagnosis, these patients had low age- and pubertal stage-adjusted standard deviation scores (SDS) of serum FSH (–0.56), inhibin B (–0.27) and AMH (–0.42), with levels of FSH and inhibin B indicating that “tubular function was affected during chemotherapy and recovered gradually after the [end of treatment]”, the researchers say. None of the boys had elevated FSH or low levels of inhibin B at 3 years after completing chemotherapy. Median AMH was within reference levels throughout follow-up.
The researchers also assessed the testis interstitial compartment for LH and testosterone, with median SDS at baseline of 0.08 and –0.81, respectively. Median SDS for LH was 0.59–2.37 from early treatment intensification until end of follow-up, while testosterone recovered during consolidation therapy and remained stable thereafter.
Although elevated LH was common throughout, affecting 25% of boys at diagnosis and increasing to 57.1% during chemotherapy, and up to 66.7% during follow-up, the researchers emphasise that “absolute values of serum LH never exceeded 17.2 IU/L.” And testosterone was generally within reference levels, except for three boys at Tanner stage 1–2 who had serum levels below 2 SDS.
“These observations suggest the existence of a persistently compensated mild Leydig cell insufficiency,” Grinspon et al say.
Among the six boys with AML or other forms of NHL, serum FSH SDS was –0.95 at diagnosis. It remained within 2 SDS for the two NHL patients whereas the four patients with AML had elevated FSH from the start of treatment to 6 months after completion.
The authors also report that these six boys had below median SDS of inhibin B for age and Tanner stage at diagnosis and throughout follow-up, whereas serum AMH was within reference range throughout the study, and patterns of LH and testosterone were similar to those of the patients with ALL.
‘Largely reversible’ testicular dysfunction after childhood haematological malignancy
“[T]his study demonstrates that early testicular dysfunction associated with hematological malignancies is largely reversible, with recovery of Sertoli cell function following the completion of chemotherapy,” Grinspon and co-authors summarise.
“However, the persistence of compensated hypogonadism of the LH–Leydig axis in adolescents, along with delayed Sertoli cell maturation in those who enter puberty after treatment, highlights a latent vulnerability within the testicular tissue,” they say.
The researchers therefore conclude: “Beyond disease remission, these findings emphasize that excellence in pediatric oncology care should incorporate proactive endocrine monitoring, ensuring that survival is accompanied by optimal hormonal and reproductive health in adulthood.”
By Lynda Williams
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