Introduction: Marijuana is the most commonly used federally illegal drug in the US, but our understanding of its effects on male fertility is limited. The objective of our study was to determine the dose-response effect of chronic contemporary marijuana (delta-9-tetrahydrocannabinol, THC) use on male testes and reproductive health in a non-human primate (NHP) model.
Methods: Adult reproductive age male rhesus macaques (n=6) of similar weight and prior proven fertility were on a standard chow diet with a daily THC edible. All animals were titrated to 2.5 mg/7kg/day of THC (equivalent to a heavy human medical marijuana dose) over 280 days. Testicular volume, serum hormones, and semen samples were assessed at pre-THC, moderate-THC and heavy-THC dosing timepoints. A subcohort of animals (n=3) also underwent a 140 day period of THC discontinuation with testicular, serum and semen evaluations at 70 and 140 days. Random intercept mixed effects models with a linear spline at start of THC abstinence were used to determine the average change in testes, serum, and semen measurements with increasing THC dose and after discontinuation.
Results: For every 1mg/7kg/day increase in THC dosing, there was a significant decrease in total testicular volume bilaterally by 13 cm3 (95% CI -15.40- -10.9, p<0.001 (Fig. 1A). A similar dose-response significant decrease in liquid semen ejaculate volume (p=0.043), mean total testosterone (p < 0.001) and estradiol (p < 0.001), but significant increase in FSH (p=0.017), LH (p=0.013), and prolactin (p=0.01) was observed (Fig 1B). No other significant changes in semen parameters were present (Fig 1C).
Every 70 days of THC abstinence (n=3), total testicular volume increased significantly by 5 cm3 (95% CI 3.2-6.9, p<0.001) to 82% of its original volume by 140 days after THC discontinuation (Fig. 1D). Serum T (p=0.001) and LH (p=0.019) both rose significantly, and FSH (p=0.008) decreased significantly (Fig. 1E). There were no significant changes to semen parameters after THC discontinuation (Fig. 1F).
Conclusions: Chronic THC use in rhesus macaques resulted in significant dose-response testicular atrophy, increased gonadotropins, decreased serum sex steroids, and semen volume. Abstinence from THC resulted in incomplete recovery of testicular volume.
Source of Funding: ASRM, NIH/NICHD K12 HD00849, Medical Research Foundation - OHSU
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