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What Can We Learn from Rodents about Prolactin in Humans?

Nira Ben-Jonathan, Christopher R. LaPensee, and Elizabeth W. LaPensee

Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.

SINCE ITS DISCOVERY in the 1930s as a distinct pituitary hormone that stimulates milk production in rabbits, prolactin (PRL) has attracted considerable attention among clinicians and basic scientists with diversified interests. Uniquely among the pituitary hormones, PRL has a propensity for hypersecretion and is under tonic inhibition. PRL also has more diverse biological functions than all other pituitary hormones combined. A close scrutiny of the PRL literature reveals that its spectrum of activities varies with the species studied. For example, whereas PRL is essential for the initiation of lactation in all mammals, its roles in other reproductive processes differ markedly from one species to another. The sources of PRL and the control of its production and release are also dissimilar. In addition to the pituitary, PRL in humans is produced by multiple tissues, where it is regulated in a cell-specific manner and acts as a cytokine. With few exceptions, PRL production in other animals is restricted to the pituitary, with PRL acting as a classical circulating hormone.

This review compares multiple aspects of PRL, from structure to physiology, in rats, mice, and humans. Most of our knowledge of PRL comes from studies with rats. This species with its impressive reproductive fecundity, short generation time, relatively large size, and low costs has served as the animal of choice for endocrinologists. The vast database on PRL in rats supports continuous studies with this species. Mice became useful after the development of the transgenic technology, filling a critical niche in research that cannot be done with rats. Despite their similar physiology, mice and rats are distinct species that should not be confused. Whereas humans are the one species we wish to know more about, it is also the species least accessible to experimental manipulations. Although some features of PRL in humans are well documented, e.g., effects of drugs, prolactinoma formation, and variants of PRL and its receptor, others remain obscure. By necessity, information derived from laboratory animals is essential for our understanding of PRL in human health and disease. Nonetheless, given the versatility and adaptive nature of PRL, extrapolation from rodents to humans should be done selectively and judiciously. At each chapter, we raise issues whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Each section includes a short synopsis of the most critical points.

Based on structural homology and overlapping biological properties, PRL belongs to a large family of proteins. Initially, the family was comprised of PRL, GH, and placental lactogens (PL) only, but it has been expanded to include PRL-like proteins, PRL-related proteins, proliferins, and proliferin-related protein, which exhibit variable degrees of sequence homology. The different members of the PRL/GH/PL family are expressed in species-, cell-, and temporal-specific patterns in the pituitary, the uteroplacental compartment, and other nonpituitary sites.

GH is involved in the regulation of postnatal growth and metabolism, with its actions often mediated by IGF-I. Mice and rats have a single GH gene on chromosomes 11 and 10, respectively, which is expressed only in the pituitary gland. Humans, on the other hand, have five GH-related genes that are clustered on chromosome 17. These include GH-N (normal), whose expression is restricted to the pituitary, and four GH/CS (chorionic somatomammotropin) proteins expressed in the placental syncytiotrophoblast: GH-V (variant GH), CS-A (PL-A), CS-B (PL-B) and CS-L (variant PL). Human (h) GH binds not only to its cognate receptor (GHR) but also to the PRL receptor (PRLR), and it mimics some PRL actions. In contrast, nonprimate GH binds only to the GHR. hPL regulate maternal carbohydrate and lipid metabolism. Despite the higher sequence homology of hPL to hGH than to hPRL and their GH-like metabolic functions, hPL bind to the PRLR.

PRL has a much broader spectrum of activities than GH, and these are classified as reproduction, metabolism, osmoregulation, immunoregulation, and behavior. Rodents express many PRL-related genes, clustered on chromosome 13 in mice and 17 in rats. In rodents, PRL is mainly expressed in the pituitary, but also in the decidua and the lactating mammary gland. Other PRL-related genes are expressed only in the uterus and placenta. In rodents, PL play an important role during the second half of pregnancy, replacing the markedly suppressed pituitary PRL. Humans express a single PRL gene on chromosome 6, although its expression is not restricted to the pituitary but occurs at multiple extrapituitary sites, where it is under tissue-specific control.