Ibuprofen use may limit fertility in men
In healthy men, ibuprofen use for 6 weeks was associated with the development of compensated hypogonadism when compared with men assigned a placebo, with the association confirmed in organ and cell models, according to study findings published in the Proceedings of the National Academy of Sciences.
“The so-called ‘over-the-counter’ mild analgesics, such as acetaminophen/paracetamol, acetylsalicylic acid/aspirin and ibuprofen, are among the most commonly used pharmaceutical compounds worldwide,” David Mobjerg Kristensen, MD, of the Danish Headache Center and the department of neurology at the University of Copenhagen, Denmark, and colleagues wrote in the study background. “Increasing evidence from recent years shows that exposure to analgesics can generate negative endocrine and reproductive effects during fetal life. Nonetheless, no in-depth studies have analyzed the effect of mild analgesics on the human pituitary-gonadal axis.”
Kristensen and colleagues performed a combination of three interconnected approaches in their analysis: a randomized, double-blind, placebo-controlled trial; an ex vivo organ model using adult human testis explants; and a standardized in vitro model system, based on a steroidogenic cell line of human origin.
For the human trial, researchers assigned 31 healthy white men to receive either ibuprofen (600 mg twice daily; n = 14) or placebo (n = 17) for 2 weeks before and 30 days after a single exercise session, as part of a broader study focusing on muscle biopsies. Participants provided blood samples at 3 and 2 weeks before the exercise session, and again on the day of exercise and 2, 4, 7 and 30 days after. Researchers analyzed measurements of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, 17beta estradiol, anti-Müllerian hormone, inhibin B and sex hormone binding globulin.
For the ex vivo study, researchers analyzed testes from patients with prostate cancer or multiorgan donors (mean age, 47 years), assessing hormone levels and extracting RNA samples after testes were exposed to ibuprofen doses that corresponded to the oral doses administered to human trial participants. For the in vitro cell line analysis, researchers performed experiments on a human adrenocortical carcinoma cell line. Steroids were analyzed after exposure to ibuprofen, abiraterone and the enzyme prostaglandin D2.
In men assigned to receive ibuprofen doses, LH levels increased by a mean of 23% at 14 days (P = .05) and 33% at day 44 (P = .01) when compared with men assigned placebo. Researchers also observed a slight increase in average FSH concentration at 14 days for men assigned ibuprofen vs. placebo, though this increase did not rise to significance and no between-group differences for FSH were observed at 44 days. Ibuprofen and LH levels in plasma were also positively correlated at 14 days (r = .73; P = .003).
Men assigned to ibuprofen also experienced a mean 18% decrease in free testosterone at 44 days, compared with those assigned placebo (P = .02).
“Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial, which occurred as early as 14 days and was maintained until the end of the trial at 44 days,” the researchers wrote.
Additionally, researchers observed that anti-Müllerian hormone data showed that the hypogonadism affected not only Leydig cells, but also Sertoli cells, at both 14 days and 44 days.
In the ex vivo organ model, researchers investigated testosterone production after 24 and 48 hours of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Researchers observed an inhibition of testosterone that was dose-dependent at both 24 and 48 hours (P = .01 and .0001, respectively) and was augmented over time. Researchers also found that, after 48 hours of ibuprofen exposure, levels of gene expression involved in testicular steroidogenesis decreased for all genes studied except CYP19A1 when compared with controls.
“Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes, consistent with that seen in our ex vivo organ model,” the researchers wrote. “Taken together, these data examining effects of on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.” – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.