Adverse Effects of a Clinically Relevant Dose of Hydroxyurea Used for the Treatment of Sickle Cell Disease on Male Fertility Endpoints

Abstract

Abstract:Two experiments were conducted to determine: 1) whether the adult male transgenic sickle cell mouse (Tg58 × Tg98; TSCM), exhibits the patterns of reproductive endpoints (hypogonadism) characteristic of men with sickle cell disease (SCD) and 2) whether hydroxyurea (HU) exacerbates this condition. In Experiment 1, blood samples were collected from adult age-matched TSCM and ICR mice (ICRM) (N = 10/group) for plasma testosterone measurements. Subsequently, mice were sacrificed, testes excised and weighed and stored spermatozoa recovered for the determination of sperm density, progressive motility and percentage of spermatozoa with normal morphology. In experiment 2, adult male TSCM were orally treated with 25 mg HU/kg body weight/day for 28 or 56 days. Control mice received the vehicle for HU (saline) as described above. At the end of the treatment periods, blood samples were collected for quantification of circulating testosterone. Subsequently, mice were sacrificed, testes and epididymides were recovered and weighed and one testis per mouse was subjected to histopathology. Stored OPEN ACCESS Int. J. Environ. Res. Public Health 2009, 61125 spermatozoa were recovered for the determination of indices of sperm quality mentioned in Experiment 1. Testis weight, stored sperm density, progressive motility, percentage of spermatozoa with normal morphology and plasma testosterone concentrations of TSCM were significantly lower by 40, 65, 40, 69 and 66%, respectively than those of ICRM. These data indicate that adult TSCM used in this study suffered from hypogonadism, characteristically observed among adult male SCD patients. In Experiment 2, HU treatment significantly decreased testis weight on day 28, (0.09 ± 0.004g) that was further decreased on day 56 (0.06 ± 0.003g; treatment x time interaction) compared with controls (day 28, 0.15 ± 0.01g; day 56, 2, 0.16 ± 0.01g). Concomitant with a 52% shrinkage (P<0.001) in area of testes in 56 days of HU treatment, testes from HU-treated TSCM exhibited significant atrophic degeneration in the seminiferous tubules compared with controls. Furthermore, treated TSCM had only Sertoli cells and cell debris remaining in most of the seminiferous tubules in comparison with controls. Leydig cell prominence and hyperplasia were more evident (P<0.05) in the steroidogenic compartments of testes of HU-treated TSCM compared with controls. However, plasma testosterone concentrations were reduced by HU treatment (P<0.05; treatment x time interaction) compared with controls on the two time periods studied. Epididymides from HU-treated TSCM sustained a 25% shrinkage (P<0.05), along with 69 (P<0.005) and 95% reduction (P<0.005), in stored sperm density and sperm progressive motility (treatment x time interaction P<0.05), respectively on day 56 of treatment compared with controls. These data demonstrate that TSCM used in this study exhibited SCD-induced hypogonadism, thus authenticating their use for studying the effect of HU on male reproductive endpoints observed in SCD patients. Secondaril...

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

“…They found that 91% of men with SCD had at least one parameter that was abnormal (lower than 5th percentile) [127]. Additionally, experiments in transgenic sickle cell mice suggest that hydroxyurea therapy decreases spermatogenesis and causes testicular atrophy exacerbating SCD-related hypogonadism [128]. Limited observational studies have reported similar findings in men with SCD [127]; however, large-scale studies are lacking.…”

The Role of Hu in the Management of Vaso-Occlusive Crises in Sickle Cell Anemia.

“…The benefits of HU in sickle cell disease were evaluated in a number of studies, some of which facilitate the wider use of HU, and others highlighted some of its adverse effects. (20)(21)(22)(23)(24)(25) Although the condition is widely prevalent in Saudi Arabia, research around SCA management and the use of HU remains limited. In this study, we explore the perception of SCA patients admitted with VOC on the use of HU, and any accompanying clinical or biomedical changes.…”

“…This dose was increased at a rate of (5) mg/kg/week, as long as the hematologic indices remained within acceptable range, and given that the patient showed no evidence of adverse effects. The maximum dose of HU reached per patient was between (25) to (35) mg/kg/day. All patients remained on HU for six to nine months, and was only discontinued when adverse events were reported, the latter included symptoms such as hair loss, gastrointestinal upset and rash, or disturbance of their blood indices; Hb drop to (6) g/dl, platelet count <80,000 or a neutrophil count <2,500.…”

Sickle cell disease: primum non nocere (first do no harm)

“…Regional clustering has been described for Chuvash polycythemia, which is endemic in the Chuvash Republic, part of the Russian Federation, 18 and for the MPL-S505N mutation, which was present in four out of five Italian families with thrombocytosis studied. 19 The fact that all of these families originated from the region around Rome suggests…”

“…18 Since then, a study in male transgenic sickle mice revealed 69% and 95% decreases in sperm density and motility, respectively. 19 A comparison of semen before and after cessation of treatment in 44 SCD patients showed that observed alterations of semen due to SCD seemed to be exacerbated by hydroxyurea treatment. 20 The development of new technologies is lengthening the life of patients with SCD and improving its quality.…”