Hydroxyurea Treatment Impairs Spermatogenesis in Men With SCA

The prognosis for patients living with sickle cell anemia (SCA) has improved in the past few decades, thanks in part to the availability of hydroxyurea – one of two therapies approved by the U.S. Food and Drug Administration for the treatment of this blood disorder.

However, this mainstay of SCA treatment may have detrimental effects on fertility for adult male patients with SCA, according to research published in Blood.

In a prospective, multicenter study, Isabelle Berthaut, PhD, from the Assistance Publique-Hôpitaux de Paris at the Universität Paris in France, and co-authors assessed the effects of six months of hydroxyurea treatment on total sperm count (TSC) in 35 men with severe SCA, finding that “hydroxyurea … causes significant, rapid, and unpredictable impairment of spermatogenesis in treated men.”

Patients were recruited from two sickle cell referral centers and one internal medicine department. Patients were excluded if they had a history of gonadotoxic treatment or any other situation that impacted spermatogenesis.

Hydroxyurea was taken orally at doses ranging from 15 to 30 mg/kg/day. “All participants appeared adherent to hydroxyurea therapy,” the researchers noted, based on patient questionnaires and analysis of hematologic parameters (defined as decrease in white blood cells, increase in mean corpuscular volume, and hemoglobin [Hb] and fetal Hb levels).

The patients (mean age = 33.6±9.2 years; range = 20-51 years) were referred to members of the French national sperm-banking network CECOS; researchers analyzed medical history and sperm parameters, comparing TSC outcomes from baseline through six months of treatment. Normal sperm volume and values were considered ≥1.5 mL and ≥39 million/ejaculate, respectively.

After six months of treatment, mean TSC decreased from 129.815 million at baseline to 24.1±54.1 million. Median TSC dropped from 61.6 million (range = 6.5-210 million) at baseline to 0.63 million (range = 0.0001-17 million) at six months (p<0.0001), “representing a strong reduction by approximately a factor of five,” the authors reported.

Prior to treatment, 14 men (40%) had abnormal TSC values, including one patient with cryptozoospermia (defined as rare sperm cells). After treatment, however, the number of men with abnormal TSC values increased to 30 patients (86%; p>0.0001). The number of men with cryptozoospermia also increased at six months to five patients (14%). An additional six patients (17%) became azoospermic (defined as no sperm cells). Of the 24 remaining patients, 19 were oligozoospermic (low sperm concentration), and only five displayed a normal TSC (14%) at six months, compared with 21 men at baseline (60%).

Hydroxyurea did not impact semen volume, the other parameter involved in the TSC’s determination, the authors reported (2.34±1.66 mL at baseline vs. 2.50±1.97 mL at 6 months; p>0.05).

Investigators also evaluated whether other SCA-related factors (including transfusion volume, a clinical history of priapism, and vaso-occlusive crises [VOC] during study) significantly affected TSC values at six months, but they found no correlation between those factors and impaired spermatogenesis. Mean TSC values were:

37.65±82.86 million for transfused patients vs. 19.34±41.07 million for non-transfused patients (p=0.64)

24.84±50.16 million for 26 patients with priapism vs. 26.05±60.82 million for 9 patients who did not have a clinical history of priapism (p=0.95)

21.76±2.62 million for patients with VOC during the study vs. 25.97±7.36 million for those without VOC (p=0.23)

There was also no significant correlation between TSC at six months and the prescribed individual hydroxyurea dose (–16%; p=0.38) or patient age (17% at baseline vs. 0.9% at 6 months; p=0.96).

Though the results clarify the detrimental effects of hydroxyurea on the TSC values of men with SCA, the authors noted that the study is limited by its short follow-up and incomplete information about treatment compliance. In addition, they outlined several questions that will need to be answered before any recommendations can be made about hydroxyurea and fertility treatment, including:

  • Can the reduction in TSC be reversed after cessation of hydroxyurea?
  • Does hydroxyurea affect spermatogenesis when initiated in children with SCA?
  • What is the impact of hydroxyurea on male fertility (as semen analysis does not test for this)?

“These results may lead to [the consideration of] preventive sperm cryostorage for adult [men with] SCA requiring [hydroxyurea] treatment,” the authors concluded.

The authors report no financial conflicts.

Reference

Berthaut I, Bachir D, Kotti S, et al. Adverse effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after six months of treatment. Blood. 2017 September 28. [Epub ahead of print]

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