The study of prolactin function evolution provides key insights into the diverse effects of this hormone in mammals, both in health and disease, which is relevant from both theoretical and practical perspectives. This article reviews both original and literature data concerning the role of prolactin and its receptors in regulating the sexual dimorphism of freshwater adaptation in the three-spined stickleback Gasterosteus aculeatus L. It is demonstrated that mRNA expression of prolactin gene 1 (one of two prolactin paralogs) and its receptor PRLRA increases in the brains of female sticklebacks only upon transitioning to freshwater. The brain and kidneys of sticklebacks, as androgen-dependent organs, exhibit sex-dependent expression of Prlra in seawater. It is suggested that sex-dependent osmoregulatory effects of prolactin are mediated through the PRLRA receptor in these organs. The PRLRB receptor, expressed in the kidneys and brains of sticklebacks regardless of sex in seawater, shows increased sensitivity to reduced salinity, suggesting a more active role in implementing sex-independent osmoregulatory functions of prolactin. Gills and intestines, as osmoregulatory organs, express the PRLRA and PRLRB receptors independent of sex in both seawater and freshwater. With freshwater adaptation, there is a concurrent increase in the expression of Prl1 in the brains of females and the expression of Atp1a1 (α1a subunit of Na+/K+-ATPase), Nhe3 (NHE3 sodium-proton antiport gene), and Ecac (epithelial calcium channel gene) in their gills. It is presumed that these gill genes are under positive control by prolactin. Exploring the potential for prolactin’s osmoregulatory function in mammals revealed that it may manifest in conditions such as pathologies accompanied by increased expression of prolactin receptor isoforms in osmoregulatory organs. One of such pathologies is cholestasis in female rats, which was associated with an increase in Prlr isoform expression and changes in activity and ratio of Na+/K+-ATPase subunits in the kidney. Thus, it is concluded that in fish, the osmoregulatory function of prolactin is sex-dependent, while in mammals, it may manifest under conditions of disrupted water-salt exchange.
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