Pubertal Testicular Function in Childhood Cancer Survivors and Future Fertility.
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IMPORTANCE: Childhood cancer treatment can result in male infertility. Understanding which patients are at risk of future infertility would facilitate early fertility counseling. OBJECTIVES: To investigate associations between pubertal reproductive hormone levels and adult gonadal outcomes and cancer treatment exposures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted at Helsinki Children's Hospital among male childhood cancer survivors who received a diagnosis under the age of 17 years between 1964 and 2000, for whom at least 1 reproductive hormone concentration (measured 1982-2017) was available. Data were analyzed from May to December 2025. EXPOSURE: Alkylating chemotherapy, quantified using cyclophosphamide equivalent dose (CED), and testicular radiotherapy. MAIN OUTCOMES AND MEASURES: Serum hormone levels (follicle-stimulating hormone [FSH], luteinizing hormone [LH], or testosterone) were collected at 2-year intervals between ages 12 and 18 years and at age 20 or older; hormone concentrations were converted to age-specific z scores. Data on gonadal outcomes were obtained in adulthood. RESULTS: The study included 221 childhood cancer survivors (median age at diagnosis, 6.0 years [IQR, 3.2-11.7 years]). FSH showed a dose-dependent pattern with testicular radiotherapy, with elevated FSH z scores seen from age 12 years among patients who received more than 1 Gy of testicular radiotherapy. Compared with the group that received less than 4 g/m2 CED (median FSH z score, 0.1; IQR, -1.2 to 1.2) at age 18 years, higher FSH z scores occurred among patients who received 4 to less than 12 g/m2 CED (median FSH z score, 1.4; IQR, 0.5-2.6; P = .04) or received 12 g/m2 or more CED (median FSH z score, 1.6; IQR, 0.7-2.5; P = .007). There was evidence of normalization at age 20 years or older for patients who received 4 to less than 12 g/m2 CED (median FSH z score, 0.7; IQR, -0.6 to 1.7) but not those who received 12 g/m2 or more CED (median FSH z score, 1.7; IQR, 0.9-2.5). The highest FSH z score at age 14 to 16 years was associated with azoospermia in adulthood, with an optimal cutoff corresponding to 11.2 IU/L at age 14 years and 12.5 IU/L at age 16 years (area under the curve, 0.87). Elevated LH z scores occurred from age 12 years onward among patients receiving more than 14 Gy of radiotherapy, but exposure to high CED was not associated with impaired Leydig cell function. CONCLUSIONS AND RELEVANCE: In this cohort study of male patients treated for childhood cancer, gonadotrophin levels during puberty were associated with future testicular function. Impairment of testicular function after radiotherapy persisted into adulthood, while there was evidence of recovery after alkylating chemotherapy. The results suggest increased sensitivity of the Sertoli cell-germ cell compartment compared with Leydig cells. These findings can be used to guide reproductive counseling for male survivors of childhood cancer.