Effects of cannabidiol, cannabichromene, cannabidivarin, cannabigerol and cannabinol in endometrial cells: Implications for endocrine and senescence modulation

Throughout a woman's menstrual cycle, endometrial stromal cells (ESCs) undergo cyclic morphological and functional alterations, involving proliferation, differentiation and senescence, modulated in part by steroid hormones and the endocannabinoid system. Disruptions in these processes can lead to endometrial conditions, like endometriosis or miscarriage. In this work, we examined the impact of the phytocannabinoids cannabidiol (CBD), cannabichromene (CBC), cannabidivarin (CBDV), cannabigerol (CBG) and cannabinol (CBN) at 2 µM, by using the St-T1b cell line, a representative model of ESCs. CBDV, CBD and CBN increased ESR1 transcription, while it was decreased by CBG. Estrogen receptor α (ER) protein was reduced by CBG and CBN. ER activation, assessed via TFF1 expression, was promoted by all cannabinoids except CBN, which suppressed it. Progesterone receptor gene expression increased for CBC, CBDV and CBG treatments, decreasing for CBN. Furthermore, androgen receptor (AR) transcription was upregulated by CBC and CBN, with protein levels increased only by CBN. All the cannabinoids inhibited AR activation. CBN enhanced AKT and ERK1/2 phosphorylation and upregulated AREG expression. Senescence-associated markers YPEL3 and LMNB1 were modulated by CBC, CBD, and CBN, accompanied by increased β-galactosidase accumulation. Additionally, CBC and CBD upregulated NAPE-PLD mRNA levels, the anandamide synthesis enzyme, although CBC and CBN reduced its protein expression. CBDV increased gene and protein expression of FAAH, the anandamide degrading enzyme. These results suggest that phytocannabinoids may disrupt the interplay between the endometrial endocrine signaling and the endocannabinoid system, as well as modulate senescence in ESCs, potentially affecting female fertility.