Antiviral Drug Valganciclovir Linked to Reversible Azoospermia in Transplant Patient

A single dose of hyperthermia during a trail race set off a chain of events that eventually led doctors to an unexpected suspect in male infertility: a common antiviral drug. In a case report published in Basic and Clinical Andrology, a French medical team describes a 33-year-old man who developed complete azoospermia, the absence of spermatozoa in his ejaculate, after receiving valganciclovir as part of his immunosuppressive regimen following an emergency liver transplant. Sperm production recovered after the drug was stopped, and the couple went on to achieve a pregnancy and the birth of a healthy baby boy through intracytoplasmic sperm injection. The authors report that this is the first documented case of azoospermia in a man treated with valganciclovir after a liver transplant, the second case of transient azoospermia after valganciclovir treatment following transplantation, and the first published instance of a live birth after valganciclovir-related azoospermia.

The story began with an infertility work-up. The man and his partner had experienced primary-secondary infertility for 12 months, complicated by an ectopic pregnancy treated with methotrexate and an early miscarriage. His partner’s evaluation revealed deep endometriosis with bilateral endometriomas, but his own semen analysis at age 33 was reassuring: a sperm concentration of 110 million per milliliter, well above the World Health Organization reference threshold of 16 million per milliliter, a total count of 383 million per ejaculate, normal progressive motility of 50 percent, and only moderate isolated teratozoospermia. One month later, during a trail race, he suffered malignant exertional hyperthermia with a body temperature of 41.7 degrees Celsius, triggering multi-organ failure and coma. He spent seven days intubated in intensive care and required an emergency hepatic transplant three days after the race. His complications included rhabdomyolysis, dialysis-treated renal failure, disseminated intravascular coagulation with venous thrombosis, resuscitation neuromyopathy, and a suspected E. coli prostatitis treated with piperacillin-tazobactam.

After the transplant, anti-rejection therapy was started with tacrolimus, mycophenolate mofetil, co-trimoxazole, and valganciclovir, the last prescribed to prevent cytomegalovirus infection. Because mycophenolate mofetil is known to be mildly clastogenic and is recommended to be suspended for one spermatogenesis cycle in a pre-conception setting, the medical team temporarily stopped it, along with co-trimoxazole as a precaution, three months later to initiate sperm freezing. In December 2023, six months after his hospitalization, the man attended a center for the study and preservation of human eggs and semen. He had experienced two febrile peaks in October, at 38.8 and 39.3 degrees Celsius, with no identified cause. His medications at that point were azathioprine, tacrolimus, atovaquone, aspirin, amlodipine, and valganciclovir.

The semen analysis that followed was devastating. After a four-day period of abstinence, no spermatozoa were found on direct examination, even after thorough inspection of the entire centrifugation pellet. The semen pH was normal, and the sample contained one million round cells per milliliter, 58 percent of them leukocytes. Hormonal testing pointed to spermatogenic failure: follicle-stimulating hormone and luteinizing hormone were elevated at 11 and 9 IU/L respectively, inhibin B was decreased at 9 ng/L, and bioavailable testosterone was diminished at 1.1 nmol/L despite total testosterone in the upper range. His karyotype was normal and testicular ultrasound showed no abnormalities, ruling out obstructive or chromosomal causes and pointing to a secretory, that is, a production, problem.

Valganciclovir was discontinued in mid-December 2023 after six months of treatment, in line with international consensus guidelines. The drug is the oral prodrug of ganciclovir, an antiviral that targets herpesviruses by inhibiting viral DNA polymerase. Once converted to its triphosphorylated form, ganciclovir acts as an analogue of deoxyguanosine triphosphate and is incorporated into viral DNA, terminating chain elongation. Because this mechanism also affects rapidly dividing human cells, hematopoietic cells and germ cells among them, preclinical studies classify ganciclovir as mutagenic, teratogenic, and reprotoxic, with an estimated 0.1 to 1 percent potential for reproductive toxicity. Patients on the drug require blood count monitoring because of the risk of cytopenia and bone marrow aplasia.

Recovery followed a timeline consistent with a spermatogenic cycle. Fourteen weeks after stopping valganciclovir, a new semen analysis showed resumption of spermatogenesis at 2.6 million sperm per milliliter, and cryopreservation began. Concentrations then climbed to 10.1 million per milliliter and, 24 weeks after discontinuation, to 70 million per milliliter. In total, 20 sperm straws were cryopreserved, though straws from the first three months after discontinuation were set aside on the advice of the French Reference Center on Teratogenic Agents because of the drug’s genotoxicity. By May 2024, six months after stopping the drug, sperm characteristics had almost returned to the pre-transplant state, with 70 million sperm per milliliter, 45 percent progressive motility, and 20 percent typical forms. The couple proceeded with their first ICSI cycle using a fresh sample, and a single blastocyst transferred at day five resulted in pregnancy and the birth of a healthy boy in January 2025.

Establishing causality was not straightforward, and the authors are careful about it. Using the French pharmacovigilance method described by Bégaud and colleagues, they judged intrinsic causality likely, combining likely chronological and plausible semiological causality, with notable extrinsic causality. The Naranjo algorithm scored the reaction as possible, with a score of 4. The patient had experienced several acute events known to impair spermatogenesis, including the febrile episodes of October 2023, the initial malignant hyperthermia, multi-organ hepatic failure, and prostatitis. Hyperthermia and systemic inflammation can disrupt sperm production through germ cell apoptosis and impaired Sertoli cell function, hepatic dysfunction may alter the hormonal environment, and prostatitis can reduce sperm quality. Because semen was not assessed exactly three months after the febrile episodes while valganciclovir was still being taken, a contribution from fever cannot be entirely excluded. Still, spermatogenesis resumed one spermatogenic cycle after the drug was stopped, whereas the fever spikes preceded that window, a temporal pattern the authors interpret as supporting a plausible role for valganciclovir, with caution.

The animal and human evidence base lends plausibility to that interpretation. In 1995, Neyts and colleagues showed that ganciclovir caused atrophy of the testicular germinal epithelium in mice, with no spermatozoa in the epididymal channels while Sertoli cells were preserved. In 1997, Faqi and colleagues reported in rats a reversible reduction of daily sperm production and sperm count below therapeutic levels, with damage mostly in early spermatogenesis stages; effects were partially reversible 12 weeks after stopping treatment and fully reversible at 24 weeks, a pattern strikingly similar to the human case. The only human trial of ganciclovir’s spermatotoxicity, conducted by McLeroth and colleagues in 2020, followed 38 male renal transplant recipients receiving prophylactic doses of 900 mg per day for 200 days in a prospective, multicenter, open-label, non-randomized design. Semen parameters improved more slowly after transplant in the ganciclovir group but were comparable between cohorts six months after treatment, and sperm DNA fragmentation did not differ significantly. A 2021 systematic review concluded that animal and human studies indicate temporary inhibition of spermatogenesis and genotoxic damage from ganciclovir, but that no human clinical studies have yet investigated its potential to damage sperm DNA. A separate case report described transient azoospermia after valganciclovir following a kidney transplant, and another study reported one case of azoospermia among 40 patients treated for cytomegalovirus uveitis.

The competing medications were reviewed and largely exonerated. Tacrolimus showed no mutagenic or clastogenic effects in preclinical testing, and no adverse effects attributable to paternal treatment have been reported among the roughly 40 recorded pregnancies conceived by men on the drug. Mycophenolate is mildly clastogenic and genotoxic in animal studies, but no adverse paternal effects have been reported in humans, and suspension for three months before conception is a precaution rather than evidence of azoospermia. No data suggesting reprotoxicity of cotrimoxazole in men have been published. Azathioprine, atovaquone, aspirin, and amlodipine likewise show no convincing evidence of impaired male fertility or harm to offspring from paternal exposure.

The authors argue that the implications extend beyond one patient. Given the growing number of people receiving valganciclovir, particularly transplant recipients, its potential reproductive toxicity deserves consideration, and men of reproductive age should be offered fertility counseling and sperm cryopreservation before treatment begins. Alternative prophylactic strategies exist: high-dose valaciclovir is effective for cytomegalovirus prevention in kidney transplant recipients with less myelotoxicity than oral ganciclovir, and letermovir, a viral terminase complex inhibitor, has demonstrated efficacy as primary prophylaxis in liver transplant recipients. These agents could represent safer alternatives if spermatotoxicity shares mechanistic pathways with myelotoxicity, an assumption the authors flag as unproven. They call for prospective clinical studies of comparative reproductive safety and for further research on the reproductive toxicity of ganciclovir and valganciclovir and on the health of children conceived by exposed fathers. As a single case, the report cannot prove the drug caused the azoospermia, but the recovery timeline, the animal data, and the pharmacology together make valganciclovir a suspect that fertility specialists treating transplant patients can no longer overlook.

Subject of Research: A case report of reversible azoospermia attributed to valganciclovir treatment after liver transplantation

Article Title: A case of secretory azoospermia: is valganciclovir responsible?

Article References: Michenaud, L., Lapoirie, M., Fraison, E., Salle-Leyris-de-Campredon, B., Plotton, I., & Giscard-d’Estaing, S. (2026). A case of secretory azoospermia: is valganciclovir responsible?. Basic and Clinical Andrology, 36(1), Article 20. https://doi.org/10.1186/s12610-026-00299-0

Image Credits: AI Generated

DOI: 10.1186/s12610-026-00299-0

Keywords: valganciclovir, ganciclovir, azoospermia, male infertility, liver transplantation, spermatogenesis, cytomegalovirus, reproductive toxicity, sperm cryopreservation, ICSI, immunosuppression, case report