The regulation of the estrogen receptor a (i.e., ERa) cellular levels is a critical issue that could modify the cells ability to respond to its cognate hormone 17b-estradiol (E2) and, thus, the resulting E2 effects. Indeed, E2 induces ERa? down-regulation thus coordinating the cellular response with the hormone extracellular fluctuations. Remarkably, several natural (i.e., naringenin, Nar) or synthetic (i.e., Bisphenol A, BPA) molecules present in the environment, now classified as endocrine disruptors (EDs), could bind to ERa and selectively modify its signalling. However, if the action of these molecules also include the modulation of the ERa cellular content is completely unknown. Here, we report that besides E2, also Nar and BPA actively regulate ERa cellular content by modulating both mRNA levels and ERa protein. Interestingly, while BPA mimics the E2 effects in inducing the 26S proteasome-dependent ERa degradation, Nar induces the receptor accumulation by blocking ERa proteolitic degradation. On the contrary, all of the ERa ligands reduce ERa mRNA levels, thus suggesting a complex posttranscriptional regulation of ERa content. Most importantly, upon EDs stimulation, E2 looses its capacity to regulate ERa turnover and as a consequence the ability of the ERa to act as a transcription factor is unbalanced. These discoveries suggest that the loss of the negative feedback that leads to ERa down-regulation could impact on ERa-regulated cellular processes (e.g., proliferation, differentiation and apoptosis), thus possibly leading to sceneries that strongly diverge from the physiological ones.