Hydroxyurea Treatment Before Puberty Does Not Impair Future Sperm Quality in Boys With SCD

Childhood hydroxyurea (hydroxycarbamide) treatment does not impair future sperm parameters in boys with severe sickle cell disease (SCD), according to research published in Blood. These findings may reduce concerns among parents and clinicians, as previous research has indicated that hydroxyurea may negatively affect spermatogenesis in men, wrote lead author Laure Joseph, MD, of the Necker–Enfants Malades Hospital in Paris, and colleagues.

To determine how hydroxyurea treatment during childhood affects future semen quality in male patients with SCD, Dr. Joseph and investigators analyzed sperm samples from men who underwent sperm banking between 2007 and 2019 at three major fertility centers in Paris. The investigators retrospectively identified patients with SCD who had started hydroxyurea before puberty (n=15) and a second group of hydroxyurea-naïve patients who were about to start treatment (n=23). To rule out the confounding factor of age on sperm quality, patients older than 25 years were excluded.

The following semen parameters were assessed:

  • volume ≥1.5 mL
  • sperm concentration ≥15 million/mL
  • total sperm count ≥39 million/ejaculate
  • progressive motility ≥32%
  • total motility ≥40%
  • viability >58%

The median age at hydroxyurea start was 6 years (range = 1-14), and the median duration of treatment was 4 years (range = 0.5-10). Patients received a mean daily hydroxyurea dose of 22.4±3.7 mg/kg.

Patients in the hydroxyurea-naïve group were slightly older at time of semen analysis compared with the hydroxyurea-exposed groups (20 years vs. 17 years; p=0.0048). Also, “although the two groups did not differ significantly in terms of the frequency of vaso-occlusive events, acute chest syndrome was more frequent in the hydroxyurea-exposed group,” the authors noted.

The study included 26 sperm samples from the hydroxyurea-exposed group and 46 sperm samples from the hydroxyurea-naïve group. The investigators found no evidence of azoospermia in either group. There were no differences between the hydroxyurea-naïve and hydroxyurea-exposed groups in regard to sperm parameter abnormalities, including:

  • Semen volume (percent abnormal values [PAV]=36.96 vs. 26.92; p=0.5265)
  • Sperm concentration (PAV=56.52 vs. 50.00; p=0.3952)
  • Total sperm count (PAV=64.44 vs. 40.91; p=0.0625)
  • Progressive motility (PAV=45.65 vs. 50.00; p=0.4541)
  • Typical forms (PAV=88.00 vs. 93.75; p=0.2081)
  • Vitality (PAV=48.72 vs. 59.09; p=0.4396)
  • Sexual abstinence (PAV=14.29 vs. 33.33; p=0.1860)

“The same abnormalities were observed in the hydroxyurea-exposed group; hence, despite the continuous division of spermatogonia during this ‘quiescent’ childhood period, hydroxyurea did not have an irreversible, additional cytotoxic effect (i.e., in addition to SCD) on spermatogenesis,” the authors reported. They added that oligospermia (defined as <20 million spermatozoa per ejaculate) was actually less frequent in the hydroxyurea-exposed group (13% [n=2/15] vs. 48% [n=11/23]).

Approximately 52% of hydroxyurea-naïve patients and 100% of hydroxyurea-exposed patients required transfusion for vasculopathy. A positive correlation was observed between sperm count and transfusion duration in hydroxyurea-exposed patients, as well as in all transfused patients. There was no significant association between transfusion and sperm parameters in this small study. “We hypothesize that transfusion therapy may be beneficial (and possibly necessary for the recovery of spermatogenesis) in patients treated with hydroxyurea during childhood,” the researchers wrote. A larger study in the future may be needed to determine whether spermatogenesis recovery in hydroxyurea-treated boys necessitates transfusion therapy.

Limitations of the study included its small sample size as well as the lack of data on hydroxyurea adherence, which may have influenced the results. The investigators added that additional study may be necessary to determine effects of hydroxyurea, when started in infancy, on long-term sperm parameters.

The authors report no relevant conflicts of interest.

Reference

Joseph L, Jean C, Manceau S, et al. Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease.