Prolactin: Regulation and Actions
- Robert S. BridgesRobert S. BridgesDepartment of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University
Prolactin (PRL) is a protein hormone with a molecular weight of approximately 23 KD, although variants in size exist. It binds to receptor dimers on the cytoplasmic surface of its target cells and acts primarily through the activation of the STAT5 pathway, which in turn alters gene activity. Pituitary prolactin, while being the main, but not only, source of PRL, is primarily under inhibitory control by hypothalamic dopaminergic neurons. Release of dopamine (DA) into the hypothalamo-hypophyseal portal system binds on DA D2 receptors on PRL-producing lactotrophs within the anterior pituitary gland. Prolactin’s functions include the regulation of behaviors that include maternal care, anxiety, and feeding as well as lactogenesis, hepatic bile formation, immune function, corpora lutea function, and more generally cell proliferation and differentiation. Dysfunctional conditions related to prolactin’s actions include its role in erectile dysfunction and male infertility, mood disorders such as depression during the postpartum period, possible roles in breast and hepatic cancer, prostate hyperplasia, galactorrhea, obesity, immune function, and diabetes. Future studies will further elucidate both the underlying mechanisms of prolactin action together with prolactin’s involvement in these clinical disorders.
History and Structure of Prolactin
The hormone prolactin (PRL) was first identified by Oscar Riddle and his research associates in the early 1930s (Riddle, Bates, & Dykshorn, 1933). It was named based upon its ability to stimulate lactation in mammals and milk crop gland development in birds. The primary source of PRL is the lactotrophs of the anterior pituitary gland, which comprise approximately 15–25% of the cells in the adenohypophysis. PRL is a large protein composed of 199 amino acids with three disulfide bonds (see Figure 1) with molecular weights of approximately 23 KD. However, PRL can also appear as a so-called “big” PRL as well as a “big-big” PRL with a molecular weight of 44–56 and 100+ KD, respectively. For many years it was uncertain whether human PRL existed distinct from growth hormone. Then, in the 1970s Henry Friesen, using purified human pituitary glands and immunological tools, demonstrated that PRL and growth hormone were two distinct hormones (Friesen, 1995). It is noted that the 23 KD PRL molecule can also serve as a precursor for a cleaved 16 KD fragment that can exert a range of biological actions, including the regulation of angiogenesis (Clapp et al., 2006; Triebel et al., 2015). In addition to a pituitary source of PRL, PRL has been detected in extra-pituitary (e) tissues, where it can exert autocrine activities. In humans, ePRL has been found in tissues that include the thymus, lymph glands, mammary glands, endothelial cells, skin, prostate, ovaries, decidual, adipose tissue, and perhaps the brain (see Marano & Ben-Jonathan, 2014, for a review of ePRL). In rodents, ePRL has been detected in the testes (Imaoka, Matsuda, & Mori, 1998), whereas the status of PRL in the brain remains equivocal and is not compelling. The regulation of ePRL can differ from that of pituitary PRL. For example, mammary tissue in mice employs a phosphatidylinositol 3-kinase–Akt pathway in PRL regulation (Chen et al., 2012). More importantly, the activity of ePRL differs from pituitary PRL in that an additional 150 bp in the ePRL transcript present in primates drives the promoter even though both pituitary PRL and ePRL bind to the same PRL receptors. (For additional comprehensive reviews of prolactin physiology, see Freeman, Kanyicska, Lerant, & Nagy, 2000; Grattan, 2001; Horseman & Gregerson, 2014.)
The Prolactin Receptor—The Actions of Prolactin
Prolactin acts by binding to PRL receptors located on the extracellular surface of the target tissue. The PRL receptor composition is determined by the intracellular structure of the receptor (see Figure 2). In rats and mice there is one long and one or more forms of the short form of the receptor. In order to activate the PRL receptor, the ligand (23 KD) must bind to the extracellular domains of two adjacent receptor dimers. This results in activation of a cascade of signal transductions that include the phosphorylation of Janus Kinase (Jak) 2 and Signal Transduction and Activator of Transcription (STAT) 5, which then act upon the relevant genes, e.g., that of tyrosine hydroxylase or the beta-casein gene to stimulate dopamine or milk proteins, respectively. Activation of the JAK-STAT signal transduction pathway appears obligatory for most biological actions of the prolactin molecule (Horseman & Gregerson, 2014). The purported biological actions of PRL have characteristically involved the long form of the PRL receptor. The short as well as an intermediate domain of the receptor also may affect cell activity, although the short form of the PRL receptor does not do so through activation of the STAT pathway. It has been proposed that the short form of the PRL receptor may function as a dominant negative, thus inhibiting or attenuating the actions of the PRL molecule (Bole-Feysot, Gofin, Edery, Binart, & Kelly, 1998). A mismatch of the combination of a long and short receptor form may functionally inactivate the PRL signal. It is noted that whereas the standard transduction pathway for PRL’s action is via the Jak-STAT pathway, the 16 KD PRL that inhibits capillary growth on endothelial cells does not utilize this pathway, but rather binds to a different high-affinity receptor apart from the PRL receptor (Clapp & Weiner, 1992).
Prolactin receptors are localized in a range of tissues. The most studied PRL target tissue is the mammary gland, where PRL stimulates the synthesis of a number of milk proteins, such as the caseins, together with milk production (Oakes, Rogers, Naylor, & Ormandy, 2008). PRL receptors are also present in the brain, with a strong presence in the cells of choroid plexus (Walsh, Posner, & Patel, 1987) and the hypothalamus (Augustine, Kokay, Andrews, Ladyman, & Grattan, 2003). PRL receptors in the liver play an important role in bile production as PRL stimulates bile synthesis (Cao et al., 2001). Additional sites of PRL action include the pancreas, kidney, lymphocytes, and skin.
The PRL receptor system is upregulated by PRL itself as well as the steroid hormones, estradiol and progesterone (Bridges & Hays, 2005; Sugiyama, Minoura, Kawabe, Tanaka, & Nakashima, 1994). Furthermore, in the rat the neural PRL receptor system’s resting level is enhanced on a long-term basis in selected parts of the brain, including the medial preoptic area and the arcuate region of the hypothalamus, by the prior reproductive experiences of pregnancy and lactation (Anderson, Grattan, van der Ancker, & Bridges, 2006; Sjӧeholm, Bridgegs, Grattan, & Anderson, 2011). Specifically, the ability of systemic PRL to stimulate the expression of the long form of PRL receptor is enhanced in previously parous cycling rats compared to its expression in nulliparous females (Anderson et al., 2006; see Figure 3). Likewise, the ability of PRL to stimulate phosphorylated STAT5 in the brain is potentiated in reproductively experienced female rats (Sjӧeholm et al., 2011). These data support the idea that the functionality of this system can be modified on a long-term basis by developmental events, such as birth and lactation.
Regulation of PRL Secretion
The secretion of PRL from lactotrophs in the adenohypophysis is affected by a number of biochemical factors. The major regulator of PRL release is the neurotransmitter dopamine (DA), which is secreted from neurons in the tuberal region of the ventral hypothalamus into the hypothalamic-pituitary portal system and transported to pituitary lactotrophs where DA binds to D2 receptors to inhibit PRL release (Ben-Jonathan, 1985). The relationship between PRL and neural DA neurons involves a classic negative feedback relationship with DA inhibiting PRL secretion and PRL stimulating DA activity. As illustrated in Figure 4, using immunocytochemistry, the relationship between PRL and DA in the brains is apparent (Grattan, 2001). Using immunocytochemistry, Grattan and colleagues showed that PRL receptors are co-localized on numerous tyrosine hydroxylase staining neurons in the arcuate region of the rat brain.
It is also of interest from a perspective of the neuroendocrine regulation of pituitary gland hormone secretion that the regulation of PRL secretion is unique in the sense that it is predominantly under hypothalamic inhibitory control rather than major stimulatory control. Experimental support for this regulation is provided by studies that demonstrated that transplant of adenohypophyseal tissue beneath the kidney capsule results in increased PRL secretion, i.e., the lactotrophs are no longer subject to hypothalamic inhibition by dopamine. There are, however, hormones and neuropeptides that can stimulate PRL secretion, although their physiological importance has not been clarified. For example, the tripeptide thyrotropin-releasing hormone (TRH) is capable of stimulating PRL secretion, but TRH at best appears to play a modulatory role in PRL secretion. Estrogens also act at the level of the adenohypophysis to stimulate production and release of PRL, and estradiol has a stimulatory role in the eventual release of PRL into the systemic circulation. More recent studies have reported the presence of a hypothalamic prolactin-stimulating peptide, termed prolactin-releasing peptide (PrRP), that binds to its own receptor to stimulate a number of biological functions, including PRL secretion from the anterior pituitary gland (Hinuma et al., 1998). PrRP’s actions appear to be mediated centrally, since receptors for PrRP have not been identified on pituitary lactotrophs but are present in the hypothalamus. It is, however, unclear what the mechanism of action for PrRP and its role in the physiological regulation of PRL is: Does it act directly on tuberoinfundibular dopamine neurons in the control of pituitary PRL secretion?
Prolactin secretion and circulating levels can also be affected by developmental factors. For example, exposure to high levels of androgens in rodents during the neonatal period results in the masculinization of the neuroendocrine system that controls PRL and gonadotropin secretion. This early developmental organizational effect associated with masculinization may occur as a result of changes in sensory processing of peripheral stimuli that affect PRL secretion or, alternatively, through modification of central regulatory pathways.
Patterns of Prolactin Secretion
PRL secretion changes as a function of the stage of the female’s reproductive cycle. The increased secretions of estrogens during the female’s reproductive cycle are typically associated with elevations in circulating PRL. In the rat, during the latter part of the light period on proestrus, PRL levels surge and then return to basal concentrations most of the remainder of the estrous cycle. Witcher and Freeman (1985) have suggested that this increase in PRL on proestrus may help enhance female sexual receptivity, likely in combination with elevations in estradiol and progesterone. This action, however, merits confirmation and further study.
Following mating, circulating PRL levels increase. In rats and mice PRL levels remain elevated as a result of the sensory stimulation received by the female from the male for the first half of pregnancy. The mating stimulus activates a neuroendocrine process, referred to as a mnemonic mechanism or neuroendocrine memory, which, once activated by mating stimuli, results in both daily diurnal and nocturnal surges of PRL release (Erskine, 1995; Smith & Neill, 1976). The activation of the neuroendocrine memory that stimulates PRL secretion is mediated by the mating pattern displayed by the male and female rat such that fewer intromissions from the male are required to activate this memory when the female “paces” the mating bouts (Erskine, 1995). This activation of PRL is critical for pregnancy maintenance through its stimulation of ovarian progesterone production. At mid-pregnancy in the rat and mouse, the endocrine placenta becomes functional and pituitary PRL secretion is suppressed by increasing titers of placental lactogens (PLs), which act like PRL to stimulate neural dopamine activity, thereby inhibiting pituitary PRL secretion. During the second half of gestation, PL levels are elevated and PRL secretion continues to be dampened. Shortly prior to parturition, the reduction of circulating progesterone together with the increase in estrogen secretion appears to promote increased PRL release once again (see Figure 5). It is of interest that the magnitude of PRL secretion during the diurnal and nocturnal PRL surges are dampened during a second pregnancy when compared to levels present during an initial pregnancy, reflective of shifts in the regulatory control of PRL secretion as a function of the female’s reproductive history (Bridges, Felicio, Pellerin, Stuer, & Mann, 1993).
One of the best characterized patterns of PRL secretion is that induced by suckling during lactation (Forsyth, 1986; see Figure 6). Prolactin is released in significant amounts in response to suckling from young in most mammals studied. The suckling stimuli induce a rapid release of pituitary PRL into the circulation, which subsequently declines in the absence of suckling (Grosvenor & Mena, 1971). One of PRL’s primary functions is to stimulate milk synthesis, which includes the production of a host of milk proteins, most notably the caseins (Oakes et al., 2008). PRL secretion in response to suckling involves a central release of the opioid beta-endorphin, which appears to block the inhibitory actions of dopamine on PRL release. Infusions of beta-endorphin into the brain of female rats is capable of stimulating a suckling-like surge in circulating PRL (Selmanoff & Gregerson, 1986). Administration of the opiate antagonist naloxone to suckling rats blunts the normal increase in PRL release stimulated by nursing (Mann & Bridges, 1992). Other central factors that contribute to suckling-induced PRL secretion include serotonin (stimulatory) and possibly TRH. Suckling, possibly through the release of PRL itself, is thought to feedback centrally to inhibit luteinizing hormone (LH) secretion during much of lactation (Smith & Fox, 1984). As lactation progresses, the stimuli provided by the young become less effective in inducing PRL release, such that suckling stimuli induces a smaller increase in circulating PRL. Therefore, a period of declining PRL during the latter part of lactation helps reactivate the resumption of LH secretion and reproductive cyclicity.
PRL secretion in the male mammal is best characterized as basal and tonic. Like in the female, the neurotransmitter dopamine produced by tuberoinfundibular neurons in the arcuate region of the hypothalamus exert an inhibitory influence on pituitary PRL secretion in the male. There appears to be an increase in PRL levels during sleep, but PRL appears to be less affected by acute endocrine or environmental changes than in the female. PRL’s role in males is also less clear. It has been shown that in hamsters PRL stimulates LH receptors in the testes and thus plays a role in male reproduction (Bartke et al., 1980). PRL also appears to play a role in parental care in both mammals and birds (Bridges, 2015; Buntin, Becker, & Ruzycki, 1991; Buntin, Strader, & Ramakrishnan, 2008). In marmosets PRL levels in the father of the pair-bonded parents are correlated with paternal care activity (Zeigler, Wegner, & Snowden, 1996). In the mouse Mus californicus, in which both parents provide care for their young, circulating PRL levels have been reported to rise in the male in association with his mate’s pregnancy, reaching higher levels late during pregnancy (Gubernick & Nelson, 1989). PRL also facilitates parental behavior in male ring doves; injections of PRL increase nesting activities (Lehrman, 1955).
The secretion of PRL is altered by factors such as stress (Moore, Demarest, & Lookingland, 1987). Exposure to acute stresses, such as ether or handling, can result in increases in PRL release, whereas chronic or repeated stress has the ability to lower PRL release. Hence, the nature and extent of environmental perturbations of PRL vary based on the type and duration of inputs.
Irving Rothchild, a renowned endocrinologist and reproductive biologist, referred to PRL as a general reproductive hormone, a molecule that served a multitude of reproductive functions. Key PRL functions include the maintenance of corpora lutea function and hence progesterone secretion, the stimulation of lactation through its actions on the mammary gland, the regulation of bile transport and metabolism, and the regulation of maternal behavior (see Figure 7). Prolactin’s overall actions include the ability to stimulate cell proliferation and to promote cell differentiation. These actions are important within the context of both normal physiology and pathophysiology, such as cancer.
In terms of PRL’s actions during pregnancy, PRL is luteotrophic and helps maintain a viable pregnancy through its stimulation of ovarian corpora lutea activity and progesterone production during gestation. The luteotrophic actions of PRL are mostly evident in rodents, as luteal function in primates is not under pituitary regulation. Elevated progesterone levels in all mammals, however, function to maintain a quiescent uterus, thus preventing premature uterine contractions. PRL and progesterone, together with insulin and corticoids, are part of the hormonal milieu that stimulate mammary gland development during gestation in preparation for the onset of lactation at parturition.
Prolactin’s primary behavioral actions include the regulation of maternal behavior, feeding, and anxiety. The early work of Zarrow and colleagues implicated PRL in maternal nest building in rabbits. Treatment with the dopamine agonist ergocornine during late pregnancy reduced the incidence of hair pulling and the quality of nest building prior to parturition in does (Anderson, Zarrow, Fuller, & Denenberg, 1971). In the 1980s, after some failed attempts to demonstrate a role for PRL in maternal behavior in rodents (Baum, 1978), we demonstrated a role for PRL in the induction of maternal behavior in female rats (Bridges, DiBiase, Loundes, & Doherty, 1985). Treatment of virgin rats with a steroid hormone regimen that stimulated a rapid onset of maternal care toward foster young was ineffective in hypophysectomized steroid-treated subjects (Bridges et al., 1985). However, treatment of hypophysectomized female rats with anterior pituitary glands surgically placed under the kidney capsule, a procedure that selectively elevates circulating PRL levels, resulted in a rapid induction of maternal care toward foster young with 50% of graft recipients displaying full maternal care within the first hour of testing compared with 0% of sham-grafted controls. Subsequent studies found that systemic injections of PRL mimicked the effects of the pituitary grafts (Bridges & Ronsheim, 1990). Examination of possible central sites of PRL action revealed that bilateral infusions of PRL into the medial preoptic area (MPOA) of the hypothalamus of virgin rats that were primed with steroids and given bromocriptine to suppress endogenous PRL effectively induced a very rapid onset of maternal behavior (see Figure 8; Bridges, Numan, Ronsheim, Mann, & Lupini, 1990). A similar action for placental lactogens (PL) was subsequently identified. Based upon these findings, it was proposed that elevated levels of PRL and PLs bind to PRL receptors on cells of the choroid plexus where these hormones or their moieties are transported into the cerebrospinal fluid (Bridges, Robertson, Shiu, Friesen, Stuer, & Mann, 1996; Walsh, Slaby, & Posner, 1987), thereby gaining access to biobehaviorally active neural structures, such as the MPOA, to stimulate maternal care. Additional evidence supporting a role for PRL’s action in the MPOA was provided by studies that demonstrated that direct infusions of the PRL receptor antagonist S179-D PRL into the MPOA delayed the rate of onset of maternal behavior in steroid-treated nulliparous rats (Bridges, Rigero, Byrnes, Yang, & Walker, 2001). Recently, using gene knockouts of the PRL receptor in all MPOA neurones in adult female mice, it was found that PRL receptor deletions produced profound deficits in postpartum maternal behavior as well as a decline in lactational performance itself (Brown et al., 2017). Thus, an intact PRL receptor system in the MPOA appears critical for the normal expression of maternal care postpartum.
Complementary genetic studies in mice further supported a role for PRL and the PRL receptor in maternal behavior (Lucas, Ormandy, Binart, Bridges, & Kelly, 1998). Using mice with overall systemic null mutations of the PRL receptor, it was shown that virgin females lacking the PRL receptor displayed deficits in their responses to foster young with the most significant deficits present in homozygous knockouts and intermediate responses present in heterozygotes relative to wild-type controls.
PRL also has been demonstrated to play a role in the development of maternal behavior in female rats. When PRL secretion is reduced in lactating rats during early lactation, their offspring, when adults, display deficits in their latencies to respond to foster pups. It is thought that exposure to PRL in the mother’s milk may facilitate maternal care when the young reach adulthood and are exposed to young (Melo, Perez-Ledezma, Clapp, Arnold, Rivera, & Fleming, 2009). The impact of PRL exposure postnatally, and perhaps even prenatally, may therefore result in long-term developmental programming that affects the expression of maternal behavior.
Interestingly, the very early work by Lehrman identified a role for PRL in incubation behavior in ring doves (Lehrman, 1955). Thus, there is a consistent and abundant set of data that support a role for PRL in maternal behavior. Less is known about the possible role for the PRL system in maternal care in primates and humans, although this possibility certainly merits consideration.
Feeding and PRL
Studies in rodents and birds have demonstrated an involvement of PRL in feeding behavior (Buntin & Figge, 1988; Noel & Woodside, 1993); PRL stimulates feeding in rats and ring doves. This hyperphagic action fits well with the pronounced increase secretion of PRL during lactation and incubation together with the increased caloric demands placed upon the lactating or providing mother. The actions of PRL during pregnancy and lactation may be modulated by the hormone leptin, as during these reproductive states there is an increase in leptin resistance and reduced leptin activity (Ladyman & Grattan, 2004; Nagaishi et al., 2014; Woodside, Augustine, Ladyman, Naef, & Grattan, 2008). The mechanism through which PRL may alter leptin activity involves the ability of PRL to induce SOCS proteins, which in turn may inhibit STAT3 pathways that appear to interfere with downstream leptin pathways.
PRL has also been implicated in brown adipose tissue (BAT) regulation, which can contribute to energetic homeostatis. BAT biomass is reduced in PRL receptor knock out mice compared to wild-type littermates (Viengchareun et al., 2004). Enhanced PRL receptor expression reinstated the regulation of BAT differentiation in mice.
PRL has also been shown to act in the brain to reduce anxiety (Torner, Toschi, Pohlinger, Landgraf, & Neumann, 2001). Central treatment of lactating rats with PRL reduced anxiety (anxiolytic action) when administered to the hypothalamus. It is known that mother rats are less anxious and more exploratory during lactation (Lonstein, 2007), possibly to increase their feeding ranges and foraging abilities. It is interesting to postulate that the enhanced exploratory responses of lactating females and an apparent reduction in postpartum anxiety is modulated by enhanced central PRL activity.
Recent studies in mice have reported that PRL has the ability to induce neurogenesis (Shingo et al., 2003). During pregnancy mice exhibit an increase in neurospore production in the subventricular zone (SVZ) of the hypothalamus, an effect mimicked by treatment with PRL. The proliferation of precursors to neurons in this region of the brain apparently facilitates migration of these cells to the olfactory region via the rostral migratory stream. It has been proposed that alterations in the connectivity of the olfactory system may, in fact, facilitate olfactory learning and maternal care in the postpartum animal. A subsequent study by Larsen and Grattan (2010) demonstrated that interfering with the increase in neurogenesis during early pregnancy in mice by treating females with compounds that either suppressed PRL or neurogenesis resulted in an increase in depressive-like behaviors when the females gave birth (see Figure 9). Hence, pregnancy-induced neurogenesis may normally help the postpartum female to adapt to the new demands of motherhood, reducing depression. In rats, early pregnancy treatment with the dopamine agonist bromocriptine that attenuates circulating PRL levels also disrupted components of postpartum maternal care (Price & Bridges, 2014), possibly by reducing neurogenesis in the SVZ. Further research is needed to determine the breadth of behavioral impairment associated with possible reductions in neurogenesis and how environmental factors may contribute to these impairments.
PRL appears to facilitate lymphocyte proliferation and reduces macrophage mortality (Bernton, Meltzer, & Holaday, 1988). The PRL receptor is expressed on leukocytes and in spleen and thymus (Dogusan, Book, Verdood, Yu-Lee, & Hooghe-Peters, 2000). It is interesting that 1–3 weeks post-weaning, female rats display decreases in peritoneal macrophage activity compared with females that have never given birth (Carvahlo-Freitas, Anselmo-Franci, Teodorov, Nasello, Palmermo-Neto, & Felicio, 2007). This shift in activity is associated with lower circulating PRL levels, supporting a role for PRL in immune functions. PRL itself is more capable of stimulating macrophage activity following greater reproductive experience; PRL induces a greater response in multigravid versus primigravid dams (Carvalho-Freitas, Anselmo-Franci, Marioke, Palermo-Neto, & Felicio, 2011). Other studies have raised questions as to the physiological impact of PRL on immune functions. Both PRL and PRL receptor knockouts have levels of CD4+ and CD8+ that are similar to those of wild-type subjects (Dorshkind & Horseman, 2000). In a clinical setting a correlation between elevations in lactogenic hormone secretion during pregnancy and a decline in relapse rates has been reported in patients with multiple sclerosis (Confavreux, Hutchison, Hours, Corinovia-Tourniaire, Grimaud, & Moreau, 1999), suggesting that PRL may impact immune function during this physiological state. A more recent study using null mutation mice, however, found that neither PRL nor the PRL receptor appears to be required for experimentally induced autoimmune encephalomyelitis, thus raising questions as to the role of PRL in immune functions (Costanza, Musio, Abou-Hamdan, Binart, & Pedotti, 2013). Further studies are needed that examine PRL’s involvement in immune function using additional animal model systems.
In rats PRL acts on PRL receptors located on beta cells in the pancreas (Arumugam, Fleenor, & Freemark, 2014). During pregnancy PRL appears to play an important role in beta cell expansion and shifts in insulin and glucose activity. Likewise, during pregnancy PLs, like PRL, play a role in this process by acting on pancreatic beta cell PRL receptors through the JAK-STAT5 pathway (Friedrichsen, Galsgaard, Nielsen, & Moldrup, 2001) to stimulate a range of nuclear proteins using diverse pathways (Gorwin, 2015).
The myriad of actions of PRL lends itself to a large range of possible abnormalities when its actions fall outside of physiological parameters. Table 1 lists some of the established conditions associated with either hyperprolactinemia or hypoprolactinemia in mammals. Significant shifts in PRL secretion and PRL receptor activity have been implicated in a range of diseases and functions that include an involvement in breast cancer, immune activity, reproductive processes, and neurobiological activities.
Table 1. Prolactin and Its Clinical Consequences
Hyperprolactinemia promotes lactation, but also is associated with galactorrhea and tumorigenesis, including breast cancer
Hyperprolactinemia is associated with male infertility and sexual performance
Eating and Metabolism
Hyperprolactinemia can promote hyperphagia
Elevated prolactin can also alter immune responses
Hyperprolactinemia stimulates insulin secretion
Elevations in neural prolactin exposure modulate anxiety levels
First, a possible role for PRL has been identified in cancer, including breast and liver cancer. Early studies reported that prolactin and the PRL receptor are expressed in human breast carcinoma (Clevenger, Chang, Ngo, Pasha, Montone, & Tomaszewski, 1995; Reynolds, Montone, Powell, Tomaszewski, & Clevenger, 1997). In mouse cell lines PRL appears to inhibit the tumor suppression activity of BRCA1 by interfering with BRCA1’s enhanced regulation of p21, a cell cycle inhibitor (Chen & Walker, 2016). Thus, an increase in PRL activity may interfere with the normal the cell cycle, affecting the rate of cell proliferation. Clinical studies have found that an early pregnancy is associated with a lower incidence of breast cancer during later life in women (Leon, 1989). A prior pregnancy also results in long-term reductions in circulating PRL levels (Musey, Collins, Musey, Martino-Saltzman, & Preedy, 1987). Whether the reduced incidence of breast cancer after an early pregnancy is mediated by shifts in endocrine activity (i.e., PRL activity) is unknown but warrants consideration. It is acknowledged that while PRL itself may not be the primary mediator of this disease, it may play a role in this complex disease process.
PRL also has been reported to prevent hepatocellular carcinoma in mice (Hartwell, Petrosky, Fox, Horseman, & Rogers, 2014). In mice, PRL constrains tumor-promoting liver inflammation by inhibiting MAP3K-dependent activation of c-Myc; PRL deficiency accelerates liver tumorigenesis. Interestingly, the actions of PRL appear to be mediated through the short form of the PRL receptor, which is abundant in the liver.
Hyperprolactinemia itself can lead to galactorrhea in women and has been proposed to contribute to erectile dysfunction and prostatic hyperplasia in males (Wennbo, Kindblom, Isaksson, & Tornell, 1997). Hyperprolactinemia may also contribute to obesity through a concurrent development of leptin resistance, which increases food and caloric intake.
PRL’s role in immune function clinically is associated with a possible suppression of immune function, most notably during pregnancy in women. During pregnancy women with multiple sclerosis undergo a transitory remission during late gestation, which has been posited to involve the actions of PRL in combination with progesterone, a hormone that itself has immunomodulatory actions (i.e., is immunosuppressive).
In addition, PRL as well as other lactogenic hormones such as placental lactogens that bind to the PRL receptor stimulate insulin secretion through their actions on pancreatic beta cells, possibly serving to protect the pregnant mother from excess glucose exposure during gestation, facilitating glucose homeostasis. Following eating there also appears to be an enhanced release of insulin from the pancreas in patients who are hyperprolactinemic. Hence, elevated circulating titers of PRL appear to place the patient at higher risk for glucose imbalances. That this increased susceptibility to lactogenic hormones appears restricted to late pregnancy and is not found during other physiological states of hyperprolactinemia, such as lactation, indicates that the actions of PRL during gestation on pancreatic function and insulin are likely modulated by additional endocrine factors, including elevations in glucocorticoids and progesterone.
The behavioral effects produced by shifts in PRL activity are most apparent during the reproductive states of pregnancy and lactation. PRL has an established role in maternal behavior in rodents (Bridges, 2015) and modulates the expression of anxiety during lactation (Torner, Toschi, Pohlinger, Landgraf, & Neumann, 2001). It is interesting to consider that excessive activity of PRL in the brain can result in varying intensities of maternal care and mood shifts, affecting the extend of anxiety during the postpartum period. Hypoprolactinemia during phases of gestation may also impact postpartum mood by increasing depressive-like behaviors of the mother postpartum (Larsen & Grattan, 2010).
Elucidation of the status of prolactin’s actions and regulations provides a background for future research endeavors that explore vital topics related to prolactin’s activities. First, there is a need for a better understanding of the changes in prolactin regulation over the course of development. It is established, for example, that PRL regulation can shift as a consequence of normative developmental events in women as well as rodents (Anderson, Grattan, van der Aucker, & Bridges, 2006; Bridges, 2015; Musey, Collins, Musey, Martino-Saltzman, & Preedy, 1987). In females basal PRL secretion is reduced following pregnancy and lactation, while neural feedback sensitivity to PRL in rats is enhanced in previously parous subjects. Likewise, women display shifts in dopaminergic regulation of PRL as a function of parity (De los Monteros, Cornejo, & Perra, 1991). Hence, it is important to know how other life events and environmental factors in both sexes might impact the release and actions of PRL. Next, a greater understanding of the functions and regulation of extra-pituitary PRL is needed in order to better grasp the autocrine and paracrine actions of ePRL. For example, does ePRL interact with pituitary PRL in regulating tissue functions? Third, understanding the possible role of PRL in neural functions is warranted. There is a disagreement based upon published and non-published research findings as to whether there exists neural production of PRL and what it may do. Does a putative neural PRL affect behavioral and/or neuroendocrine activity or indeed does neural PRL in fact exist. There also is a need for further elucidation of how PRL secretion is controlled and its actions on genomic expression. Are there common transcriptional pathways regulating potentially diverse forms of prolactin and lactogenic molecules? Finally, elucidation of the possible involvement of prolactin dysregulation in disease and physiological functions is needed. What prolactin-based treatments are feasible in the control of depression, poor parental care, and anxiety in humans? How can reproductive-related problems associated with hyperprolactinemia be managed? Further research is needed to clarify the actions and regulation of this vital pituitary hormone.
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