Future of Spermatogenesis in Men With Sickle Cell Disease Medically Treated
Condition: Drepanocytic Men Treated by Hydroxyurea for the First Time
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 4

Summary: 
      The project's background: Sickle cell disease is, at present in France, the most frequent
      genetic illness. Recent progress in its treatment, in particular the use of hydroxyurea, has
      considerably modified the prognosis of this disease. Many more patients now reach
      reproductive age and do consider fathering. Exceptional studies have reported the potential
      impact of this medical treatment on the sperm parameters and fertility of male patients. In a
      retrospective analysis, the investigators found that the observed alterations of semen
      parameters due to sickle cell disease seem to be exacerbated by hydroxyurea treatment.

      The study hypothesis: A large prospective study is essential to assess the potential adverse
      impact of the medical treatment of sickle cell disease on spermatogenesis and consider the
      advisability of proposing sperm cryopreservation before this treatment is started.

      Primary purpose of the protocol: evaluate the impact of a treatment by hydroxyurea (20-30
      mg/kg/day), 6 months after its beginning, in 34 men with sickle cell disease (18-60 years
      old). The main trial criterion will be the average difference of the concentration of
      spermatozoa s (millions/ml) in the ejaculate, before and after 6 months of medical treatment.
    

Detailed description: 
      Purpose of the study

      Sickle cell disease is, at present in France, the most frequent genetic illness. Recent
      progress in its treatment, in particular the use of hydroxyurea, has considerably modified
      the prognosis of this disease. Many more patients now reach reproductive age and do consider
      fathering. Exceptional studies have reported the potential impact of this medical treatment
      on the sperm parameters and fertility of male patients. In a retrospective analysis, the
      investigators found that the observed alterations of semen parameters due to sickle cell
      disease seem to be exacerbated by hydroxyurea treatment. Moreover, after hydroxyurea
      cessation, while global results in 30 patients were not statistically different before and
      after hydroxyurea treatment, in four individuals follow-up sperm parameters did not seem to
      recover quickly and the total number of spermatozoa per ejaculate fell below the normal range
      in about half the cases.

      Therefore, a large prospective study is essential to assess the potential adverse impact of
      the medical treatment of sickle cell disease on spermatogenesis and consider the advisability
      of proposing sperm cryopreservation before this treatment is started.

      Main outcomes

      Evaluate the impact of a treatment by hydroxyurea (20-30 mg/kg/day), 6 months after its
      beginning, in 34 men with sickle cell disease (18-60 years old). The primary outcome will be
      the average difference of the concentration of spermatozoa s (millions/ml) in the ejaculate,
      before and after 6 months of medical treatment. Six months represent 2 complete cycles of
      spermatogenesis.

      The secondary outcomes will be the other sperm parameters: vitality, mobility, motility,
      morphology of spermatozoa and the assessment of sperm nuclear DNA fragmentation by TUNEL
      assay (terminal deoxynucleotidyl transferase dUTP nick end labelling).

      This prospective, multicenter, cohort study should allow evaluating the impact of a treatment
      by hydroxyurea on spermatogenesis in men with sickle cell anemia.

      With the hypothesis of a five time reduction in spermatozoa concentration (38 millions ± 43
      before treatment), at least 34 analyzable patients are required (aged 18 to 60 years old) who
      have never received any compound known to be toxic for spermatogenesis.

      Protocol

      Drepanocytic men who are eligible for a first treatment by hydroxyurea will be sent to the
      CECOS (center for the study and cryopreservation of oocytes and spermatozoa) at Tenon, Cochin
      or Jean Verdier hospitals. Their medical history will be recorded and sperm parameters will
      be analyzed according to WHO criteria. Part of the ejaculate will be fixed and stored (-
      20°C) for further DNA fragmentation assay. The rest of the semen could be cryopreserved,
      according to the patients' will, in case of a potential deleterious effect of the medical
      treatment on male fertility. Six months after the beginning of the treatment by hydroxyurea,
      another sperm recovery will be required for the same analysis and the already described
      parameters will be evaluated and compared to initial results.

      Prospects

      The study should bring valuable data on the effects of hydroxyurea on human spermatogenesis.
      If any significant impairment is observed, it would be recommended to perform sperm
      cryopreservation before the treatment's start.

      The study could also help to distinguish between the detrimental effects due to the acute
      adverse events of sickle cell disease itself and those linked to the administration of
      hydroxyurea.
    

Intervention name(s): Hydrea® (hydroxyurea )
Intervention type(s): Drug
Intervention description(s): treatment by hydroxyurea (20-30 mg/kg/day) for 6 months
Intervention MeSH terms: Hydroxyurea
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: sickle-cell anemia; spermatogenesis; hydroxyurea