A 35-years-old man has been treated for myeloid leukemia since 1990. He has been treated with Hydre

Fråga: A 35-years-old man has been treated for myeloid leukemia since 1990. He has been treated with Hydrea tablets (hydroxyurea or hydroxycarbamide) since the onset of the leukemia. He has also been treated with high-dose interferon for one and a half months during the autumn 1994.

About one year ago he left a sperm sample to the fertility laboratory at Karolinska hospital, no living sperm was found.

Can the lack of living sperm be an adverse effect of Hydrea?

Sammanfattning: Some animal studies have showed that hydroxyurea in high doses can cause testis atrophy and aspermiogenesis. A few corresponding case reports in man have been found. However, there are no studies to confirm that the same effect can be seen in humans taking hydroxyurea at ordinary doses. A causal relationship is therefore uncertain but not impossible.

Svar: Hydrea is a cytotoxic agent, not approved in Sweden. It has a specific effect on dividing cells which are in the early S-phase of the cell cycle. In cells treated with hydroxyurea there is a specific inhibition of DNA synthesis which results in the formation of giant cells, and these very high levels of inhibition of DNA synthesis result in cell death. The inhibition of DNA synthesis is probably due to inhibition of the enzyme ribonucleoside diphosphate reductase causing a depletion of deoxyribonucleotides essential for DNA synthesis in proliferating cells. Like most cytotoxic agents, hydroxyurea is embryotoxic and teratogenic in various mammalian species. It is only weakly mutagenic but causes chromosome aberrations. It was not found to be carcinogenic when mice were given weekly doses for up to a year (1).

A thorough literature search, including Medline, Drugline and common pharmacological handbooks gave only a few animal studies.

One study showed that 10 mg hydroxyurea per kg was sufficient to lower the sperm number in treated hamsters and a progressive decline in sperm number to 70 per cent with increasing hydroxyurea doses up to 250 mg/kg occurred within 4-12 weeks. Even though most exposures suppressed sperm number, sperm morphology remained unaffected in hydroxyurea-treated hamsters. Loss of testis weight, testis atrophy and loss of body weight was also seen. The loss of testis weight and decreased sperm number may have resulted from the testicular damage and impaired spermatogenesis caused by hydroxyurea (2).

Another study investigated the effect of hydroxyurea on testicular cell kinetics and sperm chromatin differentiation in mice. 400-500 mg hydroxyurea per kg significantly decreased the testes weight but all doses above 25 mg/kg affected testis weight. A reduction of the normal pool size of pachytene spermatocytes was observed leading to depletion of meiotic daughter cells and a disruption in the flow of spermiogenesis (3).

Another study on mice on hydroxyureas effect on spermatogenesis and sperm chromatin structure was found. Testis weight was reduced by 40-45 per cent, compared with controls, after about 30 days. Atrophied tubules were seen in 50 per cent of the mice given 200 mg hydroxyurea per kg for 5 days (4).

Personal communication with the manufacturer revealed that three cases with testis atrophy or aspermiogenesis in humans had been reported but the causal relationship was uncertain in all three cases. 1 Dollery, Therapeutic Drugs, 1991 2 Singh h, Taylor C: Effects of thio-tepa and hydroxyurea on sperm production in lakeview hamsters. J Toxicol Environ Health 1981; 8: 307-16 3 Evenson DP, Jost LK: Hydroxyurea exposure alters mouse testicular kinetics and sperm chromatin structure. Cell Prolif 1993; 26: 147-159 4 Wiger P, Hongslo JK, Evenson DP, De Angelis P, Schwarze PE, Holme JA: Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice. Reprod Toxicol 1995; 9: 21-33