The anterior pituitary is a gland with considerable plasticity, alterations in the mechanisms that physiologically regulate anterior pituitary cell turnover can be involved in the pathogenesis of pituitary tumors. Since all endocrine pituitary cells, including lactotropes, express prolactin receptors, PRL is assumed to participate in the regulation of anterior pituitary functions including tissue homeostasis. Hence, alterations of PRLR signaling may play a role in anterior pituitary tumor development. According to the effects described for PRL in the majority of its target tissues, it was initially proposed that this hormone may exert trophic action on anterior pituitary cells. However, studies using PRLR knockout mice subsequently showed that PRL actually exerts an opposite effect on lactotropes, since these mice develop pituitary adenomas. Using a specific PRLR antagonist able to partially block PRLR signaling in biological systems where both the ligand and the receptor are expressed, we recently demonstrated that unlike what happens in most other tissues, PRL induced apoptosis and reduced proliferation of anterior pituitary cells from male rats, acting through an autocrine/paracrine mechanism. In females, however, regulation of pituitary homeostasis is a more complex process that remains uncharacterized. The anterior pituitary gland of female rodents undergoes constant remodeling during each estrous cycle. Furthermore, under specific conditions such as pregnancy and lactation, it also responds to particular physiological demands. Anterior pituitary cell turnover is about 3% per day in female rats. During each estrous cycle, a peak of proliferation occurs specifically at estrus whereas the highest rate of apoptosis is observed at proestrus. This cell turnover is a tightly regulated process in which several factors, e.g. estradiol, dopamine, and 16 kDa PRL, were demonstrated to participate. Interestingly, during the afternoon of proestrus, i.e. when the rate of apoptosis is the highest, there is a concomitant peak of serum PRL in response to high circulating levels of estrogens. We hypothesize that the proestrus surge of PRL release participates in anterior pituitary cell renewal that occurs during the estrous cycle. The PRLR is expressed as different isoforms generated by alternative splicing. They include one long and one short isoform in rats and one long and three short isoforms in mice. The long and short isoforms differ in the polypeptide chain of the intracellular domain; hence, they are all able to bind PRL equally but exhibit different abilities to trigger the canonical PRLR intracellular signaling pathways. Although PRLR isoforms are usually co–expressed in the same tissue, one of the isoforms often predominates over the others, depending on the tissue and the physiological context. For example, in the mouse ovary, PRLRlong is the most abundantly expressed isoform, followed by S2 and S3 PRLRshort isoforms.