Tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit androgen biosynthesis in H295R cells

The role of the cannabinoid system in human reproduction, and particularly in androgen biosynthesis, remains highly controversial. We recently observed significantly higher serum concentrations of testosterone and androstenedione in cannabis users than in the control group of a cohort of young Swiss men. To determine whether there is a direct causal relationship between cannabinoid exposure and androgen levels, we tested in vitro the effect of tetrahydrocannabinol (THC) and cannabidiol (CBD) on androgen biosynthesis in H295R cells. Modulation of steroidogenesis by phytocannabinoids and other agents was analysed in cell culture medium by liquid chromatography coupled to tandem mass spectrometry. Both THC and CBD significantly reduced in vitro DHEA, androstenedione and testosterone production by H295R cells in a concentration-dependent manner. The inhibitory action of cannabinoids was rapid and affected principally late steps of steroidogenesis. It was not prevented by rimonabant, a specific antagonist of the CB1 cannabinoid receptor. In addition, CBD (but not THC) appeared to affect the steroidogenic step involving the CYP17A1 enzyme. These results exclude a direct stimulation of steroidogenesis by phytocannabinoids in vivo as a putative mechanism for the positive association observed between cannabis use and blood androgen concentration in young men. Alternative explanations are discussed. Given that cannabis is frequently consumed by men of reproductive age, a better understanding of THC and CBD action on the reproductive system seems highly relevant in the context of the decline in male fertility observed in the general population.