Rapamycin-induced oligospermia

Rapamycin, a fungicide macrolide isolated from the bacteria Streptomyceshygroscopicus, has potent antimicrobial, immunosuppressant, and antitumoral properties (1). Rapamycin has a good safety profile when used in combination with other immunosuppressive agents. In November 1998, a 36-year-old male received a kidney transplant. He had been receiving hemodialysis for 1 year. In 1997, his wife gave birth to a girl, and later she had two induced abortions between 1997 and 2000. After transplantation, the patient was treated with 10 mg per day of prednisone, 200 mg per day of cyclosporine, and 2 mg per day of rapamycin for the first 3 months and then 10 mg per day of prednisone and 7 mg per day of rapamycin for the next 33 months. During that time, levels of blood rapamycin ranged between 10 and 15 ng/mL. The serum creatinine value was 180 μmol/L. Because the patient’s wife failed to become pregnant, he had an outpatient sperm analysis in June 2001, showing a dramatic diminution of sperm count,percentage of normal-shaped sperm heads, and sperm motility (Table 1). The laboratory values for testosterone and follicle-stimulating hormone were 2.5 ng/mL and 8 mUI/mL, respectively. Rapamycin was stopped in January 2002 and replaced with 5 mg per day of tacrolimus. Two months later, another sperm analysis showed no significant change. A third analysis was performed 6 months after rapamycin cessation and was considered normal. Table 1: Sperm analyses before and after withdrawal of rapamycin in January 2002Rapamycin binds intracellularly to the immunophilin FK506 binding protein 12, and the formed complex inhibits the protein kinase activity of the mammalian target of rapamycin. Rapamycin treatment results in marked dephosphorylation of p70S6 kinase, thus suppressing its activity (2). The development of the male germ cells in the seminiferous tubule consists of spermatogonial proliferation and meiosis. The stem cell factor/c-kit system is believed to regulate germ cell proliferation, meiosis, and apoptosis (3). This system uses a rapamycin-sensitive PI3 kinase/AKT/p70S6k/cyclin D3 pathway to promote spermatogonia proliferation. In vivo, the disruption of PI3 kinase-binding to cKit results in male sterility because of a blockage in the early stages of spermatogenesis (4). In addition, the reproduction toxicity studies of preclinical safety data for rapamycin demonstrated decreased fertility in male rats. Partly reversible reductions in sperm counts and reductions in testicular weights and tubular atrophy were reported in a 13-week rat study (5). In our patient, the sperm abnormalities were both quantitative and functional. Cessation of rapamycin treatment was followed by complete normalization of the sperm parameters. This favorable outcome, combined with clinical studies in animals, strongly supports the hypothesis of a rapamycin-induced oligospermia. Mechanisms leading to rapamycin-induced oligospermia still need to be clarified. The testosterone levels were normal in our patient, but the role of sexual hormones in this side effect cannot be excluded and needs further investigation. Consequently, the risk of oligospermia must be considered when rapamycin is administered to young male patients. Because it may be increasingly used in clinical practice, we would suggest that young patients given rapamycin should be closely monitored by sperm analysis, until more is learned about this possible side effect. Follow-up of such patients should provide additional information on the natural history of rapamycin toxicity and recovery from chronic exposure to the drug.