October 30, 2017
2 min read

Hydroxyurea linked to ‘significant, rapid’ reduction of sperm count

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Six months of hydroxyurea therapy detrimentally effected spermatogenesis in men with sickle cell anemia, according to a small prospective study published in Blood.

“Hydroxyurea, at current doses, causes significant, rapid and unpredictable impairment of spermatogenesis in treated men,” Isabelle Berthaut, PhD, professor of histology and biology of reproduction at Tenon Hospital in Paris, and colleagues wrote.

Hydroxyurea — approved by the FDA in 1998 for the treatment of sickle cell anemia — helps reduce the production of sickle hemoglobin. Its side effects include low blood counts, gastrointestinal symptoms and loss of appetite.

Three previous retrospective studies showed an association between hydroxyurea and potentially detrimental effects on sperm parameters in men with sickle cell anemia. However, those observations occurred on studies involving as few as eight men, seven of whom did not have any comparative semen assessment prior to hydroxyurea initiation.

Berthaut and colleagues designed a prospective, multicenter study to assess the effect of 6 months of hydroxyurea on total sperm count in 35 sexually active men aged 18 to 60 years (mean age, 33.6 years, range, 20-51; mean weight, 146 pounds; mean height, 5 feet 10 inches; mean BMI, 21.1 kg/m2; mean age at beginning of puberty, 16.2 years) with severe forms of sickle cell anemia.

Patients in the HYDREP — hydroxyurea and reproduction — study received hydroxyurea (15-30 mg/kg per day) according to hematological tolerance. All patients appeared adherent to hydroxyurea therapy.

Researchers calculated total sperm count by multiplying the number of spermatozoa/mL by the volume of ejaculate. The normal value for volume was 1.5 mL or more, and the normal value for total sperm count was 39 million or greater per ejaculate.

Researchers defined patients with no sperm cells as azoospermic and those with rare sperm cells as cryptozoospermic.

Before introduction of hydroxyurea treatment, 40% of participants had an abnormal total sperm count value, and one patient had cryptozoospermia, confirming the alteration of sperm parameters related to sickle cell anemia.

Six months after hydroxyurea initiation, researchers collected and analyzed new sperm samples. At that time, the mean total sperm count decreased from 129.8 million (median, 61.6) to 24.1 million (median, 0.63; P < .0001).

The number of men with an abnormal value of total sperm count at 6 months more than doubled compared with initiation (86% vs. 40%).

Additionally, 86% of men displayed a decrease in total sperm count at 6 months, regardless of their level at initiation.


A sharp increase occurred in the number of men deemed cryptozoospermic (n = 5) and azoospermic (n = 6). These data indicated natural conception was unlikely for these 11 men (31%), compared with one man (2.8%) prior to hydroxyurea therapy.

Moreover, only 14% of men recorded a normal total sperm count after 6 months of therapy, compared with 60% prior to hydroxyurea treatment.

A patient’s age had no influence on the total sperm count at hydroxyurea initiation or at 6 months. Hydroxyurea treatment also had no discernible impact on the volume of semen (2.34 mL vs. 2.5 mL).

Researchers noted their study did not answer three key questions: whether the reduction of total sperm count is reversible after discontinuation of hydroxyurea; the long-term effects of hydroxyurea treatment on the spermatogenesis of boys with sickle cell anemia; and the impact of hydroxyurea therapy on male fertility.

“Indeed, semen analysis is not a test of fertility and even patients with severe abnormalities may father children,” Berthaut and colleagues wrote. “[However,] these results may lead to the consideration of preventive sperm cryostorage for adult men with sickle cell anemia requiring this treatment.” – by Chuck Gormley

Disclosures: The French Ministry of Health helped fund this study. The authors report no relevant financial disclosures.