Gonadal function in pediatric Fanconi anemia patients treated with hematopoietic stem cell transplant

Abstract

Gonadal dysfunction and reduced fertility are clinical manifestations well described in patients with Fanconi anemia (FA) and following hematopoietic stem cell transplantation (HSCT). It is difficult to differentiate gonadal dysfunction from the primary disease itself or from HSCT procedures. Therefore, it is important to manage expectations about gonadal failure and infertility for all patients with FA, regardless of the HSCT status. We performed a retrospective analysis of 98 pediatric patients with FA who were transplanted between July 1990 and June 2020 to evaluate the incidence of gonadal dysfunction in female and male patients with FA. New-onset premature ovarian insufficiency (POI) was diagnosed in a total of 30 (52.6%) patients. Follicle-stimulating hormone and luteinizing hormone levels were increased in patients diagnosed with POI. Anti- Mullerian hormone levels declined in POI patients after HSCT (r2=0.21; P=0.001). Twenty (48.8%) male patients were diagnosed with testicular failure. Follicle-stimulating hormone levels increased after HSCT even in patients without testicular failure (r2=0.17; P=0.005). Inhibin B levels decreased over time after HSCT in patients with testicular failure (r2=0.14; P=0.001). These data indicate brisk decline in already impaired gonadal function in transplanted children with FA.

Figure 1.

Hormonal data analysis for female Fanconi anemia patients with premature ovarian insufficiency and without premature ovarian insufficiency. Hormonal data analysis of female Fanconi anemia (FA) patients with premature ovarian insufficiency (POI) or no POI. These hormone levels were measured pre- and post-hematopoietic stem cell transplantation (HSCT) (A) The median serum follicle-stimulating hormone (FSH) hormone level is 12.6 mIU/L in POI patients and 6.8 mIU/L in patients without POI; P<0.0001. (B) The median serum luteinizing hormone (LH) hormone level is 7.4 mIU/L in POI patients compared to 4.1 mIU/L in patients without POI; P=0.0002. (C) The median serum oestradiol level is 11.1 pg/mL in POI patients compared to 29.95 pg/mL in patients without POI; P<0.0001. (D) The median anti-Mullerian hormone (AMH) is 0.0155 ng/mL in POI patients compared to 0.16 ng/mL in patients without POI; P=0.39.

Figure 2.

Longitudinal analysis of follicle stimulating hormone and anti-Mullerian hormone levels in transplanted female Fanconi anemia patients. Simple linear regression analysis of serum (A) follicle-stimulating hormone (FSH) and (B) anti-Mullerian hormone (AMH) levels in patients with primary ovarian insufficiency (POI) compared to female patients without POI over time in years from hematopoietic stem cell transplant (HSCT). The overall regression was not statistically significant for serum FSH levels in patients diagnosed with POI (r=0.01; P=0.26). The overall regression was statistically significant for serum AMH levels in patients with POI (r= 0.21; P=0.001).

Figure 3.

Reproductive hormonal data analysis for male Fanconi anemia patients with testicular failure and without testicular failure. Hormonal data analysis of male Fanconi anemia (FA) patients with testicular failure or no testicular failure. (A) The median serum follicle-stimulating hormone (FSH) hormone level is 20.45 mIU/L in testicular failure patients and 4.1 mIU/L in patients without gonadal insufficiency; P<0.0001. (B) The median serum luteinizing hormone (LH) hormone level is 6.1 mIU/L in testicular failure patients compared to 1.4 mIU/L in patients without testicular failure; P<0.0001. (C) The median serum testosterone level is 348.4 ng/mL testicular failure patients compared to 58.8 ng/dL in patients without testicular failure; P<0.0001. (D) The median inhibin B 44 pg/mL in testicular failure patients compared to 111 pg/mL in patients without testicular failure; P=0.003.

Figure 4.

Longitudinal analysis of follicle stimulating hormone and inhibin B levels in transplanted male Fanconi anemia patients. Simple linear regression analysis of serum (A) follicle-stimulating hormone (FSH) and (B) inhibin B levels in patients with testicular failure compared to male patients without testicular failure over time in years from hematopoietic stem cell transplantation (HSCT). The overall regression was not statistically significant for serum FSH levels (r=0.01; P=0.29) in patients diagnosed with testicular failure. The overall regression was statistically significant for serum inhibin B levels (r=0.14; P=0.001) in patients diagnosed with testicular failure.