Hydroxyurea Discontinuation May Improve Sperm Levels in Hematologic Patients

Andrea Salonia, MD, PhD

Credit: LinkedIn

A pair of case reports support findings from a literature review suggesting consistent improvement of male fertility by semen parameters among men who discontinue hydroxyurea for treatment of essential thrombocythemia (ET) and polycythaemia vera (PV).¹

New data from a team of Italy-based investigators show association between spermatogenesis normalization and hydroxyurea discontinuation among men with hematologic diseases. The findings suggest a likely “detrimental effect” of the common drug on spermatogenesis, though more research into specific conditions like sickle cell disease are needed still to interpret the role of hydroxyurea on male infertility.

The international findings are the latest iteration of research into the impact of male sexual health and development among those who receive hydroxyurea. Data presented at the American Society of Hematology (ASH) 2023 Annual Meeting in December showed the therapy had no impact on puberty onset in treated males with sickle cell disease—though semen abnormalities were observed in a “significant proportion” of the observed cohort.²

Led by Andrea Salonia, MD, PhD, of the division of experimental oncology and unit of urology at the Urological Research Institute at San Raffaele Hospital in Milan, investigators conducted a systematic review of published research on fertility in male patients treating sickle cell disease, ET, or PV with hydroxyurea. They paired their findings with 2 paradigmatic case reports of patients with PV and ET, respectively, who were assessed for such outcomes. A centuries-old synthesized anti-proliferative drug, hydroxyurea is a first-line therapy for each of these hematologic conditions.¹

“As these patients get older, one of the problems they may encounter is the impairment of spermatogenesis due to a decreased spermatogonial maturation, resulting in worsening of sperm parameters till azoospermia and eventually fertility issues,” investigators wrote. “Consequently, on the one hand considering the need for a relatively secure treatment for myeloproliferative diseases and hemoglobinopathy, and, on the other, the willingness of fatherhood, current systematic review aims at summarizing the published evidence on the impact of hydroxyurea toward male fertility.”

The team conducted their systematic review using relevant published articles derived from PubMed, EMBASE and Cochrane, indexed up to March 2022. Investigators identified parameters including hematological disease type; duration of hydroxyurea treatment; sperm parameters and/or testicular tissue analyses before, during or after treatment; and healthy control outcomes.

Of the 48 identified articles, 8 met inclusion criteria for the review, featuring 161 patients.A majority (n = 6) of trials featured patients with sickle cell disease. Median patient age ranged from 7.9 – 38.0 years old; length of hydroxyurea administration was 1.4 – 10.5 years.

In general, Salonia and colleagues observed an overall decrease in spermatogonia per round cross section of seminiferous tubule in patients with sickle cell disease versus health controls. Treatment with hydroxyurea was always associated with worsening of semen parameters in patients hematologic disease.

The team additionally noted that treatment discontinued was linked with improved semen parameters, as well as trends toward normalized levels among patients with PV and ET—much more significantly so than in patients with sickle cell disease who also discontinued hydroxyurea.

Regarding the case studies, investigators observed that both patients with either PV or ET showed significant improvement of spermatogenesis, including successful spontaneous pregnancies, when patients discontinued hydroxyurea.

Salonia and colleagues concluded that published data do not consistently report sperm level normalization following hydroxyurea discontinuation in men with sickle cell disease.

“Conversely, the literature almost consistently reported an improvement of semen parameters at the discontinuation of hydroxyurea therapy in PV and ET cases,” they wrote. “Our real-life two cases confirmed those findings.”

They stressed that need for more effective fertility treatment for affected men interested in becoming fathers warrants further research that considers work-up management in hematology.

References

1. ^{Cilio S, Fallara G, Stanghellini MTL, et al. Impact of Hydroxyurea to Treat Haematological Disorders on Male Fertility: Two Case Reports and a Systematic Review. World J Mens Health. Published online January 2, 2024. doi:10.5534/wjmh.230069}
2. ^{Smith T. Hydroxyurea Therapy Shown Not to Impact Onset of Puberty in Male Sickle Cell Disease Patients. HCPLive. Published December 9, 2023. https://www.hcplive.com/view/hydroxyurea-therapy-shown-not-to-impact-onset-of-puberty-in-male-sickle-cell-disease-patients}