Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques

Objective: To determine the dose-dependent effect of delta-9-tetrahydrocannabinol (THC) exposure on male testes and reproductive health in a nonhuman primate model. Design: Research animal study. Setting: Research institute. Animal(s): Adult male rhesus macaques 8–10 years of age (n = 6). Intervention(s): Daily edible THC at medically and recreationally relevant doses. Main Outcome Measure(s): Testicular volume and epididymal head width, serum levels of inhibin B, albumin, total testosterone, prolactin, follicle-stimulating hormone, estradiol, and luteinizing hormone; semen volume; and sperm motility, morphology, and concentration. Result(s): For each 1 mg/7 kg/day increase in THC dosing, there was a marked loss in total bilateral testicular volume of 11.8 cm³ (95% confidence interval [CI]: 8.3–15.4). In total, average bilateral testicular volume decreased by 58%. Significant dose-response decreases in mean total testosterone level by 1.49 ng/mL (95% CI: 0.83–2.15) and in estradiol level by 3.8 pg/mL (95% CI: 2.2–5.4) were observed, but significant increases in the levels of follicle-stimulating hormone by 0.06 ng/mL (95% CI: 0.02–0.10), luteinizing hormone by 0.16 ng/mL (95% CI: 0.08–0.25), and prolactin by 7.4 ng/mL (95% CI: 3.4–11.3) were observed. There were no statistically significant changes in semen parameters. Conclusion(s): In rhesus macaques, chronic exposure to THC resulted in significant dose-response testicular atrophy, increased serum gonadotropin levels, and decreased serum sex steroids, suggestive of primary testicular failure. Further studies are needed to determine if reversal of these observed adverse effects would occur if THC was discontinued and for validation of thefindings in a human cohort.