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

• Published in: Fertility and sterility Vol. 117; no. 4; pp. 698 - 707
• Main Authors: Hedges, Jason C., Hanna, Carol B., Bash, Jasper C., Boniface, Emily R., Burch, Fernanda C., Mahalingaiah, Shruthi, Roberts, Victoria H.J., Terrobias, Juanito Jose D., Mishler, Emily C., Jensen, Jared V., Easley, Charles A., Lo, Jamie O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2022
• Subjects: Animals; Cannabis; delta-9-tetrahydrocannabinol; Dronabinol - toxicity; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Macaca mulatta; Male; male reproductive health; marijuana; Reproductive Health; Sperm Count; Sperm Motility; testicular volume; Testis - physiology; Testosterone; Cannabis; delta-9-tetrahydrocannabinol; marijuana; testicular volume; male reproductive health
• ISSN: 0015-0282; 1556-5653
• DOI: 10.1016/j.fertnstert.2021.12.028

To determine the dose-dependent effect of delta-9-tetrahydrocannabinol (THC) exposure on male testes and reproductive health in a nonhuman primate model. Research animal study. Research institute. Adult male rhesus macaques 8–10 years of age (n = 6). Daily edible THC at medically and recreationally relevant doses. 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. 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. 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. La exposición crónica al delta-9-tetrahidrocanabinol impacta el volumen testicular y la salud reproductiva del macho en macacos Rhesus. Determinar el efecto dosis-dependiente de la exposición a delta-9-etrahidrocanabinol (THC) en testículos de macho y en la salud reproductiva en un modelo de primate no humano. Estudio de investigación en animales. Instituto de investigación. Macacos Rhesus macho adultos de 8 a 10 años de edad (n = 6). THC comestible diario en dosis médica y recreacionalmente relevantes. Volumen testicular y anchura de la cabeza del epidídimo, niveles séricos de inhibina B, albúmina, testosterona total, prolactina, hormona foliculoestimulante, estradiol y hormona luteinizante; volumen de semen y movilidad, morfología y concentración del esperma. Por cada incremento de 1 mg/7 kg/día en la dosis de THC, hubo una marcada pérdida de volumen testicular de 11,8 cm3 (intervalo de confianza del 95% [IC95]: 8,3 – 15,4). En total, el volumen testicular bilateral medio decreció un 58%. Se observaron bajadas significativas y dosis-dependientes en nivel medio de testosterona total de 1,49 ng/mL (IC95: 0,83 - 2,15) y de estradiol de 3,8 pg/mL (IC95: 2,2 – 5,4), pero se observaron incrementos significativos en los niveles de hormona foliculoestimulante de 0,06 ng/mL (IC95: 0,02 – 0,10), hormona luteinizante de 0,16 ng/mL (IC95: 0,08 – 0,25) y prolactina de 7,4 ng/mL (IC95: 3,4 – 11,3). No hubo cambios estadísticamente significativos en los parámetros de semen. En macacos Rhesus, la exposición crónica al TCH resultó en atrofia testicular, aumento de niveles de gonadotropinas y disminución de niveles séricos de esteroides sexuales de manera significativa y dosis-dependiente, sugiriendo un fallo testicular primario. Se necesitan futuros estudios para determinar si estos cambios son reversibles al descontinuar el THC y para validar estos hallazgos en una cohorte humana.