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We studied possible involvement of prolactin in the regulation of bicarbonate biodynamics using female rat model of cholestasis of pregnancy induced by transplantation of the donor pituitary under the renal capsule of a recipient (hyperprolactinemia) and bile duct ligation (cholestasis). The concentration of bicarbonates in the bile and blood, their excretion, clearance, and reabsorption, as well as glomerular filtration rate and excretion of sodium ions were assessed. It was found that the main effect of prolactin was directed to the kidney-regulated pool of bicarbonates and consisted in stimulation of their clearance and inhibition of reabsorption, which led to a decrease in bicarbonate blood concentration. Parallel influence of prolactin on the clearance of bicarbonates and sodium ions was observed.

Prolactin is fundamental for the expression of maternal behaviour. In virgin female rats, prolactin administered upon steroid hormone priming accelerates the onset of maternal care. By contrast, the role of prolactin in mice maternal behaviour remains unclear. This study aims at characterizing central prolactin activity patterns in female mice and their variation through pregnancy and lactation. This was revealed by immunoreactivity of phosphorylated (active) signal transducer and activator of transcription 5 (pSTAT5-ir), a key molecule in the signalling cascade of prolactin receptors. We also evaluated non-hypophyseal lactogenic activity during pregnancy by administering bromocriptine, which suppresses hypophyseal prolactin release. Late-pregnant and lactating females showed significantly increased pSTAT5-ir resulting in a widespread pattern of immunostaining with minor variations between pregnant and lactating animals, which comprises nuclei of the sociosexual and maternal brain, including telencephalic (septum, nucleus of the stria terminalis, and amygdala), hypothalamic (preoptic, paraventricular, supraoptic, and ventromedial), and midbrain (periaqueductal grey) regions. During late pregnancy, this pattern was not affected by the administration of bromocriptine, suggesting it to be elicited mostly by non-hypophyseal lactogenic agents, likely placental lactogens. Virgin females displayed, instead, a variable pattern of pSTAT5-ir restricted to a subset of the brain nuclei labelled in pregnant and lactating mice. A hormonal substitution experiment confirmed that estradiol and progesterone contribute to the variability found in virgin females. Our results reflect how the shaping of the maternal brain takes place prior to parturition and suggest that lactogenic agents are important candidates in the development of maternal behaviours already during pregnancy.

In the majority of vertebrates, survival of offspring to sexual maturation is important for increasing population size, and parental investment in the young is important for reproductive success. Consequently, parental care is critical for the survival of offspring in many species, and many vertebrates have adapted this behavior to their social and ecological environments. Parental care is defined as any behavior that is performed in association with one's offspring (Rosenblatt, Mayer, Siegel. Maternal behavior among nonprimate mammals. In: Adler, Pfaff, Goy, editors. Handbook of behavioral neurobiology. New York: Plenum; 1985. p. 229-98) and is well characterized in mammals and birds. In birds (class Aves), this is due to the high level of diversity across species. Parental behavior in birds protects the young from intruders, and generally involves nest building, incubation, and broody behavior which protect their young from an intruder, and the offspring are reared to independence. Broodiness is complexly regulated by the central nervous system and is associated with multiple hormones and neurotransmitters produced by the hypothalamus and pituitary gland. The mechanism of this behavior has been extensively characterized in domestic chicken (Gallus domesticus), turkey (Meleagris gallopavo), and pigeons and doves (family Columbidae). This chapter summarizes broodiness in birds from a physiology, genetics, and molecular biology perspective.

Adenomyosis is uterine dysfunction defined as the presence of endometrial glands within the myometrium. It is suggested that adenomyosis is estrogen-dependent pathology, and prolactin (PRL) also affects its development. In the uterus of ruminants, PRL stimulates gland proliferation and function. We hypothesized that in the bovine uterus, the expression of PRL and its receptors (PRLRs) during adenomyosis is disturbed and modulated by estradiol (E 2 ). Uterine tissues were collected postmortem from cows; epithelial, stromal, and myometrial cells were isolated; and cultured and treated with E 2 . Material was divided into 2 groups: control (nonadenomyotic) and uteri with adenomyosis. In adenomyotic uterine tissue, PRL and its long-form receptor protein were increased, as determined by Western blotting. Immunohistostaining showed that during adenomyosis, PRL and its receptors are highly expressed in adenomyotic lesions. In cultured myometrial cells, protein expression of PRL and its receptors was increased during adenomyosis. Estradiol decreased PRLRs protein expression in nonadenomyotic stromal cells and in adenomyotic myometrial cells, and increased PRL secretion by adenomyotic myometrial cells. Moreover, PRL secretion was increased in untreated epithelial and stromal cells during adenomyosis. On the other hand, in stromal cells, PRLRs messenger RNA and protein expression was decreased, as determined by real-time PCR and Western blotting, respectively. Obtained results show that significant changes in PRL and PRLRs expression are observed in uterine tissue and cells during adenomyosis, which were also affected by E 2 . These data suggest involvement of PRL in adenomyosis development and the link between PRL and E 2 actions during the dysfunction in cows., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Suction pressure has been reported to be a key driving force of lactation. An infant's sucking at its mother's breasts is the major stimulus to post-natal prolactin (PRL) secretion, and PRL is the essential hormone for lactation and milk production. It is unknown what role suction pressure has in PRL secretion and milk supply postnatally., Objectives: To explore the relationship between the suction pressure, PRL level, lactation, and milk supply in breastfeeding mother-infant dyads., Methods: Healthy women with normal full-term infants were enrolled (n = 122). Data collection included suction pressure, PRL level, and the mother's perception of both the onset of her lactation and her milk supply at 1 month. Suction pressure was measured with a pressure sensor connected to a tube placed alongside the nipple. The chemiluminescence method was used to quantify maternal serum PRL level both before and after a breastfeed to explore the effect of suckling on PRL increment. The mother's perception of the onset of her lactation was evaluated by the mother's sense of fullness in her breast. The mother's perception of milk supply was evaluated by using the H&H Lactation Scale., Results: Data from 117 participants were included in this analysis. Low suction pressure, a shorter gestational age, a high pre-gestational body mass index (BMI), and high infant birth weight were associated with a smaller than average PRL increment. High suction pressure, longer sucking duration, and a low gestational weight gain were related to a mother's perception of an earlier onset of her lactation. However, low suction pressure, a high frequency of giving formula, a small PRL increment, and the mother's perception of a later onset of her lactation were correlated with her perception of an insufficient milk supply., Conclusions: Suction pressure varied directly with the post-natal PRL increment. Suction pressure was associated with the timing of the mother's perception of her lactation. Strong suction pressure by the infant is likely to enhance the mother's confidence in her lactation. Additionally, sucking duration, frequency of giving formula, maternal BMI, and infant birth weight played a role in early breastfeeding success.

In all mammalian species, a combination of neuroendocrine and experiential factors contributes to the emergence of remarkable behavioral changes observed in parental behavior. Yet, our understanding of neuroendocrine bases of paternal behavior in humans is still preliminary and more research is needed in this area. In the present review, the authors summarized hormonal bases of paternal behavior in both human and nonhuman mammalian species and focused on studies on the regulatory role of prolactin in occurrence of paternal behavior. All peer-reviewed journal articles published before 2015 for each area discussed (parental brain, hormonal bases of maternal behavior, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in nonhuman mammalian species, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in humans) were searched by PubMed, Medline, and Scopus for original research and review articles. Publications between 1973 and 2015 were included. Similar to female parents, elevated prolactin levels in new fathers most probably contribute to child-caring behavior and facilitate behavioral and emotional states attributed to child care. Moreover, elevated parental prolactin levels after childbirth decrease the parents' libidos so that they invest more in parental care than in fertility behavior. According to the available clinical studies, elevation in the amounts of prolactin levels after childbirth in male parents are probably associated with paternal behavior observed in humans.

Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications., (© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Mammalian parental care is essentially provided by the mother and it occupies most of the reproductive period for female. The synchronization of maternal behavior with parturition and lactation ensures that the mother responds to the needs of the young at the appropriate time. This temporal synchrony is accomplished by hormonal changes that underly both the onset of maternal behavior and of parturition and lactation. The aim of this review is to describe and compare the hormonal mechanisms that regulate the onset of maternal behavior across a variety of mammals, including humans, that represent different behavioral strategies. Are involved the steroid hormones, estradiol and progesterone synthesized by the ovaries which primed the future mother to repond maternally. In response to these steroids, oxytocin release induced by vaginocervical stimulation and prolactin release affect the maternal brain. The medial preoptic area integrates the hormonal signals to regulate maternal behavior. The hormonal cocktail that stimulates maternal behavior varies across mammalian species. Because most of the studies in humans are correlative and because human environment is complex, direct causality between hormones and maternal behavior is unclear. However, one can reasonably think that hormones create a positive bias towards the baby increasing the occurrence of maternal behavior., (Copyright © 2016. Published by Elsevier Masson SAS.)

An immune challenge can affect the reproductive process in females. Peripheral administration of bacterial endotoxin (lipopolysaccharide; LPS) decreases LH secretion and disrupts ovarian cyclicity. The aim of the present study was to determine the effects of a cyclo-oxygenase (COX)-2 inhibitor (meloxicam) on gonadotropin-releasing hormone (GnRH) and LH secretion in anoestrous ewes during systemic inflammation induced by LPS. LPS (400ngkg -1 per day) suppressed LH release. In three individuals, meloxicam (500μgkg -1 , i.v.) abolished LPS-induced LH suppression. In another three ewes LH was ineffective. Similar changes were observed in hypothalamic GnRH expression. The effect of meloxicam depended on the circulating level of prolactin: meloxicam abolished inflammatory-dependent suppression of GnRH and LH secretion when plasma prolactin levels were similar to those in untreated animals, but was ineffective in those with elevated levels of prolactin. We conclude that COX-2 inhibitors minimise the negative effect of inflammation on the reproductive system but that this effect may be antagonised by prolactin.

The prolactin (PRL) family of hormones and cytokines participates in the regulation of optimal reproductive performance in the mouse and rat. Members of the PRL family are expressed in the anterior pituitary, uterus, and/or placenta. In the present study, we investigated the ontogeny of PRL family 7, subfamily b, member 1 (PRL7B1; also called PRL-like protein-N, PLP-N) expression in the developing mouse placenta and established a mouse model for investigating the biological function of PRL7B1. Transcripts for Prl7b1 were first detected on Gestation Day (d) 8.5. From gestation d8.5 through d14.5, Prl7b1 was expressed in trophoblast cells residing at the interface between maternal mesometrial decidua and the developing placenta. On gestation d17.5, the predominant cellular source of Prl7b1 mRNA was migratory trophoblast cells invading into the uterine mesometrial decidua. The Prl7b1 null mutant allele was generated via replacement of the endogenous Prl7b1 coding sequence with beta-galactosidase (LacZ) reporter and neomycin cassettes. The mutant Prl7b1 allele was successfully passed through the germline. Homozygous Prl7b1 mutant mice were viable and fertile. Under standard animal housing conditions, Prl7b1 had undetectable effects on placentation and pregnancy. Hypoxia exposure during pregnancy evoked adaptations in the organization of the wild-type placenta that were not observed in Prl7b1 null placentation sites. In summary, PRL7B1 is viewed as a part of a pathway regulating placental adaptations to physiological stressors., (© 2016 by the Society for the Study of Reproduction, Inc.)

Prolactin (PRL) is a polypeptide hormone produced and released from the pituitary and extrapituitary tissues. It regulates activity of nociceptors and causes hyperalgesia in pain conditions, but little is known the molecular mechanism. We report here that PRL can exert a potentiating effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons. First, PRL dose-dependently increased the amplitude of ASIC currents with an EC50 of (5.89 ± 0.28) × 10(-8) M. PRL potentiation of ASIC currents was also pH dependent. Second, PRL potentiation of ASIC currents was blocked by Δ1-9-G129R-hPRL, a PRL receptor antagonist, and removed by intracellular dialysis of either protein kinase C inhibitor GF109203X, protein interacting with C-kinase 1(PICK1) inhibitor FSC-231, or PI3K inhibitor AS605240. Third, PRL altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Four, PRL exacerbated nociceptive responses to injection of acetic acid in female rats. Finally, PRL displayed a stronger effect on ASIC mediated-currents and nociceptive behavior in intact female rats than OVX female and male rats and thus modulation of PRL may be gender-dependent. These results suggest that PRL up-regulates the activity of ASICs and enhances ASIC mediated nociceptive responses in female rats, which reveal a novel peripheral mechanism underlying PRL involvement in hyperalgesia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

MGP-40 is a chitinase-like protein which is over expressed during mammary gland involution. However, its physiological function in the mammary gland is poorly understood. In the present investigation, we have reported the functional significance of buffalo specific MGP-40 in the mammary gland by using an in vitro model of the buffalo mammary epithelial cell (BuMEC) line. MGP-40 was highly up regulated in BuMECs in serum starved condition as well as after treatment with prolactin suggesting its role in the stress response. Subsequently, to study the effect of MGP-40 on BuMECs, the cells were transfected with a mammalian expression construct of pCI neo harboring MGP-40 gene. It was observed that over expression of MGP-40 enhanced proliferation of BuMECs and protected the cells from apoptosis under serum free condition. In contrast, MGP-40 attenuated the mitogenic effect of insulin in BuMECs. Besides, over expression of the MGP-40 reduced dome formation, acinar polarization and casein synthesis in BuMECs in the presence of lactogenic hormones, it also induced Stat3 phosphorylation and epithelial to mesenchymal transition (EMT) -like features. Together, our data suggest that MGP-40 is involved in protection of BuMECs under stress conditions, inhibits cellular differentiation and induces EMT-like features. A schematic diagram depicting possible association of MGP-40 in various molecular pathways has been presented.

Prolactin has different functions, including cytokine secretion and inhibition of the suppressor effect of regulatory T (Treg) cells in healthy individuals. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defects in the functions of B, T, and Treg cells. Prolactin plays an important role in the physiopathology of SLE. Our objective was to establish the participation of prolactin in the regulation of the immune response mediated by Treg cells from patients with SLE. CD4CD25CD127 cells were purified using magnetic beads and the relative expression of prolactin receptor was measured. The functional activity was evaluated by proliferation assay and cytokine secretion in activated cells, in the presence and absence of prolactin. We found that both percentage and function of Treg cells decrease in SLE patients compared to healthy individuals with statistical significance. The prolactin receptor is constitutively expressed on Treg and effector T (Teff) cells in SLE patients, and this expression is higher than in healthy individuals. The expression of this receptor differs in inactive and active patients: in the former, the expression is higher in Treg cells than in Teff cells, similar to healthy individuals, whereas there is no difference in the expression between Treg and Teff cells from active patients. In Treg:Teff cell cocultures, addition of prolactin decreases the suppressor effect exerted by Treg cells and increases IFNγ secretion. Our results suggest that prolactin plays an important role in the activation of the disease in inactive patients by decreasing the suppressor function exerted by Treg cells over Teff cells, thereby favoring an inflammatory microenvironment.

This article is part of a Special Issue "Parental Care". In vertebrates, adjustments of physiology and behavior to environmental changes are often mediated by central physiological mechanisms, and more specifically by hormonal mechanisms. As a consequence, these mechanisms are thought to orchestrate life-history decisions in wild vertebrates. For instance, investigating the hormonal regulation of parental behavior is relevant to evaluate how parents modulate their effort according to specific environmental conditions. Surprisingly and despite being classically known as the 'parental hormone', prolactin has been overlooked in birds relative to this context. Our aim is to review evidence that changes in prolactin levels can mediate, at least to some extent, the response of breeding birds to environmental conditions. To do so, we first examine current evidence and limits for the role of prolactin in mediating parental behavior in birds. Second, we emphasize the influence of environmental conditions and stressors on circulating prolactin levels. In addition, we review to what extent prolactin levels are a reliable predictor of breeding success in wild birds. By linking environmental conditions, prolactin regulation, parental behavior, and breeding success, we highlight the potential role of this hormone in mediating parental decisions in birds. Finally, we also review the potential role of prolactin in mediating other life history decisions such as clutch size, re-nesting, and the timing of molt. By evaluating the influence of stressors on circulating prolactin levels during these other life-history decisions, we also raise new hypotheses regarding the potential of the prolactin stress response to regulate the orchestration of the annual cycle when environmental changes occur. To sum up, we show in this review that prolactin regulation has a strong potential to allow ecological physiologists to better understand how individuals adjust their life-history decisions (clutch size, parental behavior, re-nesting, and onset of molt) according to the environmental conditions they encounter and we encourage further research on that topic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This chapter addresses what is known about the endocrine system components growth hormone (GH)-insulin-like growth factor (IGF) axis, thyroid axis, and prolactin relative to exercise and exercise training. Each one of these hormone axes contributes to the maintenance of homeostasis in the body through impact on a multitude of physiological systems. The homeostatic disruption of exercise causes differing responses in each hormone axis. GH levels increase with sufficient stimulation, and IGFs are released in response to GH from the anterior pituitary providing multiple roles including anabolic properties. Changes in the thyroid hormones T3 and T4 vary greatly with exercise, from increases/decreases to no change in levels across different exercise types, intensities and durations. These ambiguous findings could be due to numerous confounding factors (e.g. nutrition status) within the research. Prolactin increases proportionally to the intensity of the exercise. The magnitude may be augmented with extended durations; conflicting findings have been reported with resistance training. While the responses to exercise vary, it appears there may be overall adaptive and regenerative impacts on the body into recovery by these hormones through immune and tissue inflammatory responses/mediations. Nonetheless, well-designed exercise research studies are still needed on each of these hormones, especially thyroid hormones and prolactin., (© 2016 S. Karger AG, Basel.)

In most mammals, prolactin (PRL) is essential for maintaining lactation, and the suppression of PRL inhibits lactation. However, the involvement of PRL in the control of ruminant lactation is less clear, because inconsistent effects on milk yield have been observed with the short-term suppression of PRL by bromocriptine. Therefore, several experiments have been conducted to assess the galactopoietic role of PRL. In an initial experiment, cows in early lactation received daily injections of the dopamine agonist quinagolide for 9 wk. Quinagolide reduced milking-induced PRL release and caused a faster decline in milk production. Quinagolide also reduced mammary epithelial cell activity, survival, and proliferation. In goats, cabergoline, another dopamine agonist, caused a 28% decrease in milk yield the day after injection. In another experiment, cows were injected for 5d with quinagolide, with quinagolide plus bovine PRL injected at milking time, or with vehicles only. Again, quinagolide reduced milk, protein, and lactose yields. Although PRL injections were not sufficient to restore milk yield, they tended to increase milk protein and lactose yields and increased the viability of mammary epithelial cells purified from milk. Recently, our team stimulated PRL secretion with daily injections of the dopamine antagonist domperidone for 5 wk. Milk production increased gradually and was greater in domperidone-treated cows during the last 4 wk of the treatment period. In most experiments where PRL secretion was manipulated, feed intake paralleled the changes of PRL concentration, supporting the idea that PRL increases feed intake to provide the nutrients necessary to support lactation in dairy ruminants. In late-lactation cows, quinagolide and cabergoline decreased milk production within the first day of treatment and induced more rapid changes in several markers of mammary gland involution after drying-off. In addition, quinagolide improved the resistance to intramammary infection, suggesting that PRL inhibition could be an alternative strategy for facilitating drying-off. Prolactin appears to directly affect mammary gland functions, but mammary gland responsiveness to PRL appears to be modulated by local and systemic factors. Therefore, the modulation of the number and isoforms of the PRL receptors as well as the expression of intracellular modulators of cell signaling in the mammary gland require further investigation. In conclusion, these data, combined with those from other studies, provide a good body of evidence that PRL is galactopoietic in dairy ruminants., (Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The mammary gland (MG) is one of a few organs that undergoes most of its growth after birth. Much of this development occurs concurrently with specific reproductive states, such that the ultimate goal of milk synthesis and secretion is coordinated with the nutritional requirements of the neonate. Central to the reproductive-MG axis is its endocrine regulation, and pivotal to this regulation is the ovarian secretion of estrogen (E). Indeed, it is widely accepted that estrogens are essential for growth of the MG to occur, both for ductal elongation during puberty and for alveolar development during gestation. As the factors regulating MG development continually come to light from the fields of developmental biology, lactation physiology, and breast cancer research, a growing body of evidence serves as a reminder that the MG are not as exclusively dependent on estrogens as might have been thought. The objective of this review is to summarize the state of information regarding our understanding of how estrogen (E) has been implicated as the key regulator of MG development, and to highlight some of the alternative E-independent mechanisms that have been discovered. In particular, we review our findings that dietary trans-10,cis-12 conjugated linoleic acid promotes ductal elongation and that the combination of progesterone (P) and prolactin (PRL) can stimulate branching morphogenesis in the absence of E. Ultimately, these examples stand as a healthy challenge to the question of just how important estrogens are for MG development. Answers to this question, in turn, increase our understanding of MG development across all mammals and the ways in which it can affect milk production., (Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

This article is part of a Special Issue "Parental Care". Although paternal care is generally rare among vertebrates, care of eggs and young by male birds is extremely common and may take on a variety of forms across species. Thus, birds provide ample opportunities for investigating both the evolution of and the proximate mechanisms underpinning diverse aspects of fathering behavior. However, significant gaps remain in our understanding of the endocrine and neuroendocrine influences on paternal care in this vertebrate group. In this review, I focus on proximate mechanisms of paternal care in birds. I place an emphasis on specific hormones that vary predictably and/or unpredictably during the parental phase in both captive and wild birds: prolactin and progesterone are generally assumed to enhance paternal care, whereas testosterone and corticosterone are commonly-though not always correctly-assumed to inhibit paternal care. In addition, because endocrine secretions are not the sole mechanistic influence on paternal behavior, I also explore potential roles for certain neuropeptide systems (specifically the oxytocin-vasopressin nonapeptides and gonadotropin inhibitory hormone) and social and experiential factors in influencing paternal behavior in birds. Ultimately, mechanistic control of fathering behavior in birds is complex, and I suggest specific avenues for future research with the goal of narrowing gaps in our understanding of this complexity. Such avenues include (1) experimental studies that carefully consider not only endocrine and neuroendocrine mechanisms of paternal behavior, but also the ecology, phylogenetic history, and social context of focal species; (2) investigations that focus on individual variation in both hormonal and behavioral responses during the parental phase; (3) studies that investigate mechanisms of maternal and paternal care independently, rather than assuming that the mechanistic foundations of care are similar between the sexes; (4) expansion of work on interactions of the neuroendocrine system and fathering behavior to a wider array of paternal behaviors and taxa (e.g., currently, studies of the interactions of testosterone and paternal care largely focus on songbirds, whereas studies of the interactions of corticosterone, prolactin, and paternal care in times of stress focus primarily on seabirds); and (5) more deliberate study of exceptions to commonly held assumptions about hormone-paternal behavior interactions (such as the prevailing assumptions that elevations in androgens and glucocorticoids are universally disruptive to paternal care). Ultimately, investigations that take an intentionally integrative approach to understanding the social, evolutionary, and physiological influences on fathering behavior will make great strides toward refining our understanding of the complex nature by which paternal behavior in birds is regulated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aims of the study were to evaluate whether adiposity was among the determinants of circulating prolactin levels and to determine whether serum prolactin independently predicted metabolic abnormalities in patients with polycystic ovary syndrome (PCOS). A total of 322 PCOS patients with normal serum prolactin levels were recruited between January 2007 and January 2014. Anthropometric, metabolic, and hormonal parameters were measured in all of the patients. HOMA-IR was calculated as an index of insulin resistance. Serum prolactin was negatively correlated with age (p < 0.0001), all the adiposity indices [body mass index p < 0.0001; waist circumference p < 0.0001; waist-hip ratio (WHR) p < 0.0001], visceral adiposity index (VAI, p = 0.043), fasting insulinemia (p = 0.002), and HOMA-IR (p = 0.002), and was positively correlated with serum adiponectin (p = 0.034), but not with circulating androgens or serum leptin levels. Serum adiponectin, but not HOMA-IR or fasting insulinemia, was independently associated with serum prolactin after adjustment for age, leptin, and anthropometrical adiposity parameters. Of the adiposity parameters, only WHR and VAI were independent predictors of serum prolactin after adjustment for adiponectin. Circulating prolactin was also negatively correlated with fasting glycemia (only in patients with normal glucose metabolism, p = 0.037) and was inversely correlated with the presence of metabolic syndrome (p < 0.001), but this association was not maintained after adjustment for possible confounders. In PCOS patients, serum prolactin level was related to adipose tissue quantity and function, and adiponectin was a possible mediator of this relationship. Low serum prolactin levels were associated with an unfavorable metabolic profile, but this association seemed to be due to the complex interplay among prolactin, adiposity, and insulin resistance rather than to a direct metabolic effect of prolactin.

Objective: To review the current literature regarding the prevalence of macroprolactin (macroPRL) in hyperprolactinemic patients and determine recommendations for testing., Methods: An electronic United States National Library of Medicine PubMed search (through October, 2014) was conducted for search term "macroprolactin." Only English-language articles were considered., Results: MacroPRL is an under-recognized cause of elevated prolactin (PRL) and is present in approximately 4% to 40% of hyperprolactinemic patients depending on the referral population. Clinical findings which could be due to hyperprolactinemia are the impetus for testing for PRL. Because of this there is significant overlap in the clinical presentation of patients with true hyperprolactinemia and those with macroPRL, differentiation cannot always be made on the basis of symptoms. A lack of recognition of the presence of macroPRL can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment., Conclusion: Until there is a commercially available PRL assay that is not subject to interference by macroPRL, clinicians should consider the possibility of macroPRL, especially if the clinical presentation, imaging findings, and/or response to therapy reveal inconsistencies.

Prolactin is a polypeptide hormone which mainly acts on the reproductive system and plays an important role in penile erection and ejaculation. Prolactin receptors have a variety of short forms apart from the classic long form, which are widely expressed in male reproductive glands. High levels of prolactin can induce erectile dysfunction and results in secondary male infertility, which are mainly associated with the inhibition of dopaminergic activity, reduction of the testosterone level, and contraction of the cavernous smooth muscle. Moreover, low levels of prolactin can result in ejaculatory dysfunction. This article updates the views on the expressions of prolactin receptors in the male reproductive system, the effects of prolactin on penile erection and ejaculation, and its action mechanisms.

Prolactin (PRL) has been long deemed as a hormone involved only in female reproduction. However, PRL is a surprising hormone and, since its identification in the 1970s, its attributed functions have greatly increased. However, its specific role in male health is still widely unknown. Recently, low PRL has been associated with reduced ejaculate and seminal vesicle volume in infertile subjects. In addition, in men consulting for sexual dysfunction, hypoprolactinemia has been associated with erectile dysfunction and premature ejaculation, findings further confirmed in the general European population and infertile men. Several metabolic derangements, recapitulating metabolic syndrome, have also been associated with low PRL both in men with sexual dysfunction and from the general European population. In men with sexual dysfunction, followed-up for more than 4 years, low PRL was identified as an independent predictor of the incidence of major adverse cardiovascular events. Finally, an association with anxiety or depressive symptoms has been found in men with sexual dysfunction and from the general European population. While a direct role for impaired PRL function in the pathogenesis of these reproductive, sexual, metabolic and psychological disorders is conceivable, the possibility that low PRL is a mirror of an increased dopaminergic or a decreased serotonergic tone cannot be ruled-out. Hyperactivity of the dopaminergic system can explain only a few of the aforementioned findings, whereas a hypo-serotonergic tone fits well with the clinical features associated with low PRL, and there is significant evidence supporting the hypothesis that PRL could be a mirror of serotonin in the brain.

The hormone/cytokine prolactin (PRL) is implicated in breast cancer cell invasion and metastasis. PRL-induced pathways are mediated by two non-receptor tyrosine kinases, JAK2 and Src. We previously demonstrated that prolactin stimulates invasion of breast cancer cells TMX2-28 through JAK2 and its target serine/threonine kinase PAK1. We hypothesize herein that the actin-binding protein cortactin, a protein involved in invadopodia formation and cell invasion, is activated by PRL. We demonstrate that TMX2-28 cells are more invasive than T47D breast cancer cells in response to PRL. We determine that cortactin is tyrosyl phosphorylated in response to PRL in a time and dose-dependent manner in TMX2-28 cells, but not in T47D cells. Furthermore, we show that PRL mediates cortactin tyrosyl phosphorylation via Src, but not JAK2. Finally, we demonstrate that maximal PRL-mediated TMX2-28 cell invasion requires both Src and JAK2 kinase activity, while T47D cell invasion is JAK2- but not Src-dependent. Thus PRL may induce cell invasion via two pathways: through a JAK2/PAK1 mediated pathway that we have previously demonstrated, and Src-dependent activation and tyrosyl phosphorylation of cortactin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Prolactin (PRL) is a hormone, mainly secreted by lactotroph cells of the anterior pituitary gland. Recent studies have shown it may also be produced by many extrapituitary cells. Its well-recognized PRL plays an important role in lactation during pregnancy, but it is involved in other biological functions such as angiogenesis, immunoregulation and osmoregulation. Hyperprolactinemia is a typical condition producing reproductive dysfunction in both sexes, resulting in hypogonadism, infertility and galactorrhea. It may be also asymptomatic. Lactotroph adenomas (prolactinoma) is one of the most common cause of PRL excess, representing approximately 40% of all pituitary tumors. Several other conditions should be excluded before a clear diagnosis of hyperprolactinemia is made. Hyperprolactinemia may be secondary to pharmacological or pathological interruption of hypothalamic-pituitary dopaminergic pathways or idiopathic. Stress, renal failure or hypothyroidism are other frequent conditions to exclude in patients with hyperprolactinemia. We will review biochemical characteristics and physiological functions of that hormone. Clinical and pharmacological approach to hyperprolactinemia will also be discussed.

The core of the leptin resistance hypothesis promulgated several years ago to explain obesity as a result of environmental causes consists of 2 tenets: the extinction of leptin-induced intracellular signaling downstream of leptin binding to the long form of the neuronal receptor LTRb in the hypothalamus and the impedance to leptin entry imposed at the blood-brain barrier (BBB). A recent comprehensive investigation concluded that a central leptin insufficiency associated with obesity can be attributed to a decreased efficiency of BBB leptin transport and not to leptin insensitivity within the hypothalamus. Interestingly, anorectic leptin's effects are counteracted in some individuals by a natural resistance associated with hyperleptinemia, which is related to changes in hypothalamic sensitivity to leptin (eg, due to malnutrition, obesity, or seasonal variations due to day-length-dependent reproduction changes). In sheep, it has been observed that the hypothalamus is resistant to leptin in some periods, which is related to the adaptation of these animals to annual changes in energy supply and demand. However, a broad range of ambiguities exists regarding the implications that the intracellular signaling of signal transducer and activator of transcription-2/suppressor of cytokine signaling 3 (STAT2/SOCS3) imparts central leptin resistance. Furthermore, several plausible alternative possibilities have been proposed, such as compensatory functional and anatomic reorganizations in the appetite regulating network, rearrangements in the afferent hormonal feedback signaling involved in weight homeostasis, and modifications in leptin transport to the hypothalamus across the BBB. Taken together, these observations suggest that the contention that impaired intracellular signaling downstream of leptin entry into the appetite regulating network expedites environmentally induced obesity remains unsubstantiated and requires further evidence. Furthermore, pregnancy decreases hypothalamic sensitivity to leptin (or other unknown mechanisms), and lactation can also alter the appetite-suppressing central activity of leptin. The objective of this review was to offer an approach to understanding (1) how information regarding nutritional status is transmitted to and interpreted within the hypothalamus in animals, with special attention on seasonally breeding animals and (2) whether central leptin resistance and/or leptin insufficiency in the hypothalamus favors the development of obesity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR.

Adult stem/progenitor cells are found in many tissues, where their primary role is to maintain homeostasis. Recent studies have evaluated the regulation of adult stem/progenitor cells by prolactin in various target tissues or cell types, including the mammary gland, the prostate, the brain, the bone marrow, the hair follicle, and colon cancer cells. Depending on the tissue, prolactin can either maintain stem cell quiescence or, in contrast, promote stem/progenitor cell expansion and push their progeny towards differentiation. In many instances, whether these effects are direct or involve paracrine regulators remains debated. This minireview aims to overview the current knowledge in the field.

Thyroid disorders include autoimmune thyroid diseases (AITD), thyroid goiter, nodule and cancer. AITD mainly consist of autoimmune thyroiditis and Graves disease. The common characteristic of thyroid disorders is female preponderance in their prevalence. The female-to-male rate ratio is reported at 4~6:1 for AITD and about 3~4:1 for thyroid nodule. For PTC, it is greatest during reproductive age and drops from five and more in patients aged 20-24, to 3.4 in patients aged 35-44 to one in patients over 80. The effects of female gonadal hormones and X chromosome inactivation on thyroid gland and immune system greatly contribute to the female predilection of AITD. The former mainly include prolactin and estrogen. The direct actions of estrogen on the thyroid tissue contribute to the development of thyroid goiter, nodule and cancer in women.

The immunomodulatory functions of prolactin (PRL) are well recognized. Augmented PRL plasma levels were observed in patients with advanced tuberculosis (TB). Recently, we have reported that LPS and Mycobacterium bovis (M. bovis) induced differential expression of PRL receptor (PRLR) isoforms in THP-1 cells and bovine macrophages, respectively. The aim of this work was to determine whether PRL should be considered as a potential modulator of the signaling pathways and cytokine synthesis, induced by culture filtrate protein (CFP) from M. bovis in THP-1 monocytes. The THP-1 cells were stimulated with PRL (20ng/mL), M. bovis CFP (50μg/mL). PRLR as well as phosphorylated STAT3, STAT5, Akt1/2/3, ERK1/2 and p38 expression were evaluated by Western blot. IL1-β, TNF-α, IL-6, IL-12, IL-8, and IL-10 concentrations were measured by ELISA. Our results demonstrated that the expression pattern of PRLR short isoforms is induced by M. bovis CFP. M bovis CFP induced phosphorylation of Akt2, ERK1/2, p38, STAT3, and STAT5 pathways. In turn, PRL only activated the JAK2/STAT3-5 signaling pathway. However, when combined both stimuli, PRL significantly increased STAT3-5 phosphorylation and downregulated Akt2, ERK1/2, and p38 phosphorylation. As expected, M. bovis CFP induced substantial amounts of IL1-β, IL-6, TNF-α, IL-8, IL-12, and IL-10. However, the PRL costimulation considerably decreased IL1-β, TNF-α, and IL-12 secretion, and increased IL-10 production. This results suggest that up-regulation of IL-10 by PRL might be modulating the pro-inflammatory response against mycobacterial antigens through the MAPK pathway., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

New information concerning the effects of prolactin (PRL) on metabolic processes warrants reevaluation of its overall metabolic actions. PRL affects metabolic homeostasis by regulating key enzymes and transporters associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose, and lipids. In adipose tissue, PRL generally suppresses lipid storage and adipokine release and affect adipogenesis. A specific case is made for PRL in the human breast and adipose tissues, where it acts as a circulating hormone and an autocrine/paracrine factor. Although its overall effects on body composition are both modest and species-specific, PRL may be involved in the manifestation of insulin resistance.

Prolactin (PRL) released from lactotrophs of the anterior pituitary gland in response to the suckling by the offspring is the major hormonal signal responsible for stimulation of milk synthesis in the mammary glands. PRL secretion is under chronic inhibition exerted by dopamine (DA), which is released from neurons of the arcuate nucleus of the hypothalamus into the hypophyseal portal vasculature. Suckling by the young activates ascending systems that decrease the release of DA from this system, resulting in enhanced responsiveness to one or more PRL-releasing hormones, such as thyrotropin-releasing hormone. The neuropeptide oxytocin (OT), synthesized in magnocellular neurons of the hypothalamic supraoptic, paraventricular, and several accessory nuclei, is responsible for contracting the myoepithelial cells of the mammary gland to produce milk ejection. Electrophysiological recordings demonstrate that shortly before each milk ejection, the entire neurosecretory OT population fires a synchronized burst of action potentials (the milk ejection burst), resulting in release of OT from nerve terminals in the neurohypophysis. Both of these neuroendocrine systems undergo alterations in late gestation that prepare them for the secretory demands of lactation, and that reduce their responsiveness to stimuli other than suckling, especially physical stressors. The demands of milk synthesis and release produce a condition of negative energy balance in the suckled mother, and, in laboratory rodents, are accompanied by a dramatic hyperphagia. The reduction in secretion of the adipocyte hormone, leptin, a hallmark of negative energy balance, may be an important endocrine signal to hypothalamic systems that integrate lactation-associated food intake with neuroendocrine systems., (© 2015 American Physiological Society.)

Elevated exposure to prolactin (PRL) is epidemiologically associated with an increased risk of aggressive ER+ breast cancer. To understand the underlying mechanisms and crosstalk with other oncogenic factors, we developed the NRL-PRL mouse. In this model, mammary expression of a rat prolactin transgene raises local exposure to PRL without altering estrous cycling. Nulliparous females develop metastatic, histotypically diverse mammary carcinomas independent from ovarian steroids, and most are ER+. These characteristics resemble the human clinical disease, facilitating study of tumorigenesis, and identification of novel preventive and therapeutic approaches.

The physiological role of prolactin (PRL) in the prostate gland is not clearly understood. Genetically-modified mouse models that have invalidated actors of the PRL signaling axis failed to identify an essential regulatory function on this tissue. However, a large body of evidence suggests an important role for PRL in prostate tumorigenesis. Mainly through the activation of its downstream target STAT5, PRL can induce growth and survival of prostate cancer cells and tissues in several experimental settings. In the clinic, PRL expression and STAT5 activation in human prostate tumors correlate with disease severity. Available data point to a role of local (autocrine/paracrine) rather than circulating (endocrine) PRL in the induction of disease progression. In mice, transgenic expression of PRL in the prostate leads to enhanced epithelial hyperplasia and dysplasia, with amplification of basal/stem cells which have been recently identified as prostate cancer-initiating cells. Thus, targeting PRL receptor (PRLR)/STAT5 signaling may provide an alternative therapy for the treatment of prostate cancer. Corresponding targeted therapies currently in preclinical development include antagonists or blocking antibodies for the PRLR and small molecule inhibitors directed against the tyrosine kinase JAK2 upstream of STAT5. Present efforts are aimed at validating these therapies for the treatment of prostate cancer, while understanding the mechanisms of disease progression induced by PRL/STAT5.

Prolactin (PRL) is a peptide hormone produced by the pituitary gland and diverse extrapituitary sites, which triggers activation of various signaling pathways after binding to its receptor (PRLr) resulting in the activation of specific genes associated with the pleiotropic activities of PLR. To date, various PRLr isoforms have been described, generated by post-transcriptional or post-translational processes. PRL has been associated with the modulation of a variety of actions in the immune response and inflammatory processes in several physiologic and pathologic conditions. However, PRL can have opposite effects, which might be regulated by interaction with the various isoforms of PRLR and PRL variants, as well as the cellular and molecular microenvironment influence.

Hyperprolactinaemia is a major cause of infertility in both males and females, although the mechanism by which prolactin inhibits the reproductive axis is not clear. The aim of the present study was to test the hypothesis that elevated prolactin causes suppression of kisspeptin expression in the hypothalamus, resulting in reduced release of gonadotrophin-releasing hormone (GnRH) and consequent infertility. In oestrogen-treated ovariectomised mice, chronic prolactin-treatment prevented the rise in luteinising hormone (LH) seen in vehicle-treated mice. Kiss1 mRNA was significantly suppressed in both the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus after prolactin treatment. Exogenous prolactin treatment induced phosphorylated signal transducer and activator of transcription 5 (pSTAT5) in kisspeptin neurones, and suppression of endogenous prolactin using bromocriptine reduced levels of pSTAT5 in kisspeptin neurones, suggesting that prolactin acts directly on kisspeptin neurones. By contrast, fewer than 1% of GnRH neurones expressed pSTAT5 in either dioestrous or lactating mice. As reported previously, there was significant suppression of kisspeptin mRNA and protein in the RP3V on day 7 of lactation, although not in the arcuate nucleus. Bromocriptine treatment significantly increased Kiss1 mRNA expression in the RP3V, although not to dioestrous levels. Unilateral thelectomy, aiming to eliminate sensory inputs from nipples on one side of the body, failed to alter the reduction in the number of kisspeptin neurones observed in the RP3V. These data demonstrate that chronic prolactin administration suppressed serum LH, and reduced Kiss1 mRNA levels in both the RP3V and arcuate nucleus, consistent with the hypothesis that prolactin-induced suppression of kisspeptin secretion might mediate the inhibitory effects of prolactin on GnRH secretion. During lactation, however, the suppression of Kiss1 mRNA in the RP3V was only partially reversed by the administration of bromocriptine to block elevated levels of prolactin, suggesting that, although elevated prolactin contributes to lactational anovulation, additional non-neural factors must also contribute to the lactation-induced suppression of kisspeptin neurones., (© 2014 British Society for Neuroendocrinology.)

The zinc transporter ZnT2 imports zinc into secretory vesicles and regulates zinc export from the mammary epithelial cell. Mutations in ZnT2 substantially impair zinc secretion into milk. The lactogenic hormone prolactin (PRL) transcriptionally increases ZnT2 expression through the Jak2/STAT5 signaling pathway, increasing zinc accumulation in secretory vesicles and zinc secretion. Herein, we report that PRL post-translationally stimulated ZnT2 ubiquitination, which altered ZnT2 trafficking and augmented vesicular zinc accumulation and secretion from mammary epithelial cells in a transient manner. Ubiquitination then down-regulated zinc secretion by stimulating degradation of ZnT2. Mutagenesis of two N-terminal lysine residues (K4R and K6R) inhibited ZnT2 ubiquitination, vesicular zinc accumulation and secretion, and protein degradation. These findings establish that PRL post-translationally regulates ZnT2-mediated zinc secretion in a multifactorial manner, first by enhancing zinc accumulation in vesicles to transiently enhance zinc secretion and then by activating ubiquitin-dependent ZnT2 degradation. This provides insight into novel mechanisms through which ZnT2 and zinc transport is tightly regulated in mammary epithelial cells., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Changes in mRNA levels of prolactin (PRL) during the upstream migration were examined in fry of the amphidromous fish, ayu Plecoglossus altivelis. Quantification of mRNA has been done with real-time PCR and expressed as whole body or pituitary contents depending the body size of fry. PRL mRNA levels of ayu caught in seawater of the coastal area remained low during early spring. Prior to the start of the upstream migration, the fish caught in the coastal area in mid spring showed increased levels of PRL mRNA. There were further increases in PRL levels in the fish caught in the river. Analysis of proportions revealed that there were significant differences among PRL mRNA in the fish caught in different environmental salinities. Body weight showed a positive relation with PRL mRNA in ayu caught in seawater. A landlocked population of ayu, which migrates from lake to river, showed no significant change in PRL mRNA levels before and after upstream migration. Results in this study indicate the importance of up-regulation of PRL gene expression of ayu during the upstream migration from seawater to fresh water. There is a possible relationship between body size and PRL in the early developmental stage of ayu in seawater, but not in the fish in fresh water.

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.

Prolactin (PRL) is an important hormone with many diverse functions. Although it is predominantly produced by lactrotrophs of the pituitary there are a number of other organs, cells, and tissues in which PRL is expressed and secreted. The impact of this extrapituitary PRL (ePRL) on localized metabolism and cellular functions is gaining widespread attention. In 1996, a comprehensive review on ePRL was published. However, since this time, there have been a number of advancements in ePRL research. This includes a greater understanding of the components of the control elements located within the superdistal promoter of the ePRL gene. Furthermore, several new sites of ePRL have been discovered, each under unique control by a range of transcription factors and elements. The functional role of ePRL at each of the expression sites also varies widely leading to gender and site bias. This review aims to provide an update to the research conducted on ePRL since the 1996 review. The focus is on new data concerning the sites of ePRL expression, its regulation, and its function within the organs in which it is expressed.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

The role of prolactin in MS pathogenesis was investigated. Prolactin levels were higher in MS subjects both during remission and exacerbation compared to control subjects. Prolactin increased JAK2 expression and Stat phosphorylation on B cells, up-regulated anti-MOG antibody secreting cell numbers, BAFF levels, and Bcl-2expression, and down-regulated expression of Trp63. Prolactin levels correlated positively with anti-MOG secreting cell numbers, and negatively with induced apoptotic B cells. Additionally, prolactin decreased B cell receptor-mediated activation threshold, and induced CD40 expression in B cells. These findings suggest that prolactin promotes B cell autoreactivity in MS through different mechanisms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Obesity, characterized by low grade inflammation, induces adipose tissue macrophage (ATM) infiltration in white adipose tissue (AT) in both humans and rodents, thus contributing to insulin resistance. Previous studies have shown altered prolactin secretion in obesity, however, studies linking ATM infiltration and prolactin (PRL) secretion to the pathogenesis of the metabolic syndrome, obesity and diabetes are lacking., Methods/results: In vivo, qPCR and Western blot analysis demonstrated that prolactin expression was increased in AT of obese rats and also in human AT from obese, obese pre-diabetic and obese diabetic compared to lean counterparts. Immunohistochemistry of obese rat and human AT sections demonstrated a specific expression of prolactin in macrophages. In vitro, we demonstrated that hyperglycemia and inflammation stimulated macrophages (human THP-1 cell line and sorted rat ATM) to express PRL, when challenged with different glucose concentrations with or without IL1β. In in vivo and in vitro experiments, we assessed the expression of Pit-1 (PRL-specific transcription factor) and found that its expression was parallel to PRL expression., Conclusions: In this study, we show that rodent and human macrophages synthesize prolactin in response to inflammation and high glucose concentrations., General Significance: Our data shed new light on the potential role of macrophages in the physiopathology of diabesity via the PRL expression and on its expression mechanism and regulation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1α, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.

Plasma membrane-bound carboxypeptidase-D (CPD) cleaves C-terminal arginine from extracellular substrates. In the cell, arginine is converted to nitric oxide (NO). We have reported that up-regulation of CPD mRNA/protein levels by 17β-estradiol and prolactin (PRL) in breast cancer cells, and by testosterone in prostate cancer cells, increased NO production and cell survival. The CPD promoter contains a consensus γ-interferon-activated sequence (GAS) and 3 putative androgen response elements (ARE.1, ARE.2, ARE.3) that could potentially bind PRL-activated transcription factor Stat5 (signal transducer and activator of transcription 5) and the liganded androgen receptor (AR), respectively. This study showed that synthetic androgen R1881 and PRL elevated CPD mRNA/protein levels in human MCF-7 and T47D breast cancer cells in a time-/dose-dependent manner. PRL/R1881-elevated CPD expression was blocked by actinomycin-D, and a CPD promoter construct containing these GAS and AREs was stimulated by PRL or R1881, indicating transcriptional regulation by both hormones. Luciferase reporter assays showed that GAS and the adjacent ARE.1 only were active. Mutation of GAS in the ΔGAS-CPD construct (ARE.1 intact) abolished CPD promoter activity in response to PRL and, surprisingly, to R1881 as well. ΔGAS-CPD promoter activity was restored by PRL+R1881 in combination, and enhanced by ectopic Stat5, but abolished by Stat5 gene knockdown. Chromatin immunoprecipitation analysis confirmed binding of activated Stat5 and liganded AR to GAS and ARE.1, respectively. Activated Stat5 also induced binding of unliganded AR to ARE.1, and liganded AR induced binding of unactivated Stat5 to GAS. In summary, PRL and R1881, acting through Stat5 and AR, act cooperatively to stimulate CPD gene transcription in breast cancer cells.

Evaluation for endocrine function is a pivotal part of the male infertility workup. Endocrine dysfunction may result from endogenous and exogenous sources. This article describes the traditional roles that the hypothalamic-pituitary-gonadal endocrine axis plays in spermatogenesis and testicular dysfunction, as well as other insults that may contribute to hypospermatogenesis. Recent research into the role alternative hormonal axes play in spermatogenesis and promising new technologies that may correct inborn or acquired endocrinopathies leading to impaired sperm growth and maturation are discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Considerable evidence attests to the role of the hypothalamic-pituitary endocrine axis (HPA) in the maintenance of normal immunocompetence. The immune and neuroendocrine systems are integrally linked and coordinated with bidirectional communication maintaining immune balance. Any disturbance of the normal function of the HPA may significantly alter native immunocompetence and therefore be associated with the development of disorders which have a clearly established autoimmune basis. Molecular and functional evidence shows prolactin, produced by the anterior pituitary, to be a cytokine, exerting its effect via both paracrine and endocrine mechanisms [1]. Its involvement in the activation of multiple immune responses may adversely upregulate certain autoimmune diseases. Myasthenia gravis (MG) has long been recognized as an autoimmune disorder. In this mini review, we present the coterminous presentation of MG and prolactin-secreting macroadenoma. We review published cases in the world literature, discuss pathological mechanism, and consider future targeted therapies.