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Showing papers on "Prolactin published in 2008"


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

469 citations


Journal ArticleDOI
TL;DR: All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels.
Abstract: Dopamine (DA) holds a predominant role in the regulation of prolactin (PRL) secretion. Through a direct effect on anterior pituitary lactotrophs, DA inhibits the basally high-secretory tone of the cell. It accomplishes this by binding to D2 receptors expressed on the cell membrane of the lactotroph, activation of which results in a reduction of PRL exocytosis and gene expression by a variety of intracellular signalling mechanisms. The hypothalamic dopaminergic neurons, which provide DA to the anterior pituitary gland, are themselves regulated by feedback from PRL through a 'short-loop feedback mechanism'. A variety of other modulators of prolactin secretion act at the hypothalamic level by either disinhibition of the dopaminergic tone (e.g. serotonin, GABA, oestrogens and opioids) or by reinforcing it (e.g. substance P). All typical antipsychotic medications are associated with sustained hyperprolactinaemia due to their high affinity for the D2 receptor and their slow dissociation from the receptor once bound, but atypicals differ quite dramatically in their propensity to cause prolonged high prolactin levels. Of those atypicals that are associated with prolactin elevation, the main causative factor appears to be a higher peripheral-to-central dopamine receptor potency of either the parent drug or its active metabolite (e.g. risperidone, 9-hydroxy-risperidone and amisulpride). Antipsychotics that easily cross the blood-brain barrier and exhibit fast dissociation from the dopamine receptor once bound do not result in sustained hyperprolactinaemia.

333 citations


Journal ArticleDOI
TL;DR: Some of the original studies that first characterised the unusual features of prolactin neuroendocrinology are highlighted, and areas of new progress and/or controversy are attempted to identify.
Abstract: The neuroendocrine control of prolactin secretion is unlike that of any other pituitary hormone. It is predominantly inhibited by the hypothalamus and, in the absence of a regulatory feedback hormone, it acts directly in the brain to suppress its own secretion. In addition to this short-loop feedback action in the brain, prolactin has been reported to influence a wide range of other brain functions. There have been few attempts to rationalise why a single hormone might exert such a range of distinct and seemingly unrelated neuroendocrine functions. In this review, we highlight some of the original studies that first characterised the unusual features of prolactin neuroendocrinology, and then attempt to identify areas of new progress and/or controversy. Finally, we discuss a hypothesis that provides a unifying explanation for the pleiotrophic actions of prolactin in the brain.

264 citations


Journal ArticleDOI
TL;DR: Pituitary tissue specimens of 77 MEN1 patients from the GTE register were compared with unselected non-MEN1 sporadic pituitary tumors and also to a control subgroup of 296 cases, where 1 MEN1 tumor was matched with 4 sporadic tumors of the same hormonal immunoprofile.
Abstract: Patients affected by the multiple endocrine neoplasia type I syndrome (MEN1) display a high incidence of pituitary adenomas, though it is still unknown whether these pituitary tumors have specific pathologic features that would distinguish them from sporadic pituitary adenomas. Pituitary tissue specimens of 77 MEN1 patients from the GTE (Groupe d'etude des Tumeurs Endocrines) register were compared with unselected 2509 non-MEN1 sporadic pituitary tumors and also to a control subgroup of 296 cases, where 1 MEN1 tumor was matched with 4 sporadic tumors of the same hormonal immunoprofile. Sex, age, size, and invasiveness of tumors, and menin gene mutations were documented. Histologic analysis took into account 33 items, including immunocytochemical data, the proliferative marker Ki-67, and an examination of the juxtatumoral pituitary. MEN1 tumors were significantly larger and more often invasive by histology. MEN1 patients with large pituitary tumors (grade IV) were younger than non-MEN1 patients. MEN1 tumors had no other characteristic histologic features and no predominance of any one hormone producing subtype. However, plurihormonal adenomas versus monohormonal and nonimmunoreactive adenomas were more frequent in MEN1 tumors (39%) than in the control non-MEN1 group (P = 0.001). Especially, the growth hormone and prolactin plurihormonality with unusual association with follicle-stimulating hormone, luteinizing hormone, or adrenocorticotropic hormone was more frequent in MEN1 tumors. In addition, multiple adenomas were significantly more frequent (4% vs. 0.1%; P < 0.0001), especially prolactin-adrenocorticotropic hormone. Somatotroph hyperplasia, with or without a microadenoma was found in only 3 MEN1 patients, with growth hormone-releasing hormone hypersecretion by a pancreatic tumor in 2 of them. All types of mutation were observed, including frameshifts, nonsenses, missenses, and 1 case of germline MEN1 encompassing large deletion, strongly suggesting the absence of any phenotype-genotype correlation.

182 citations


Journal ArticleDOI
TL;DR: Levels of AMH show a statistically significant change during the menstrual cycle and may influence the circulating gonadotropin and steroid hormone levels.

151 citations


Journal ArticleDOI
TL;DR: This work focuses on providing an over-view of prolactin action during development of the model murine mammary gland, and hopes thatalgamation of these two aspects will increase the understanding of cell proliferation and differentiation within the mammary glands.
Abstract: Mammary morphogenesis is orchestrated with other reproductive events by pituitary-driven changes to the systemic hormone environment, initiating the formation of a mammary ductal network during puberty and the addition of secretory alveoli during pregnancy. Prolactin is the major driver of development during pregnancy via regulation of ovarian progesterone production (in many species) and direct effects on mammary epithelial cells (in all species). Together these hormones regulate two aspects of development that are the subject of intense interest: (1) a genomic regulatory network that integrates many additional spatial and temporal cues to control gene expression and (2), the activity of a stem and progenitor cell hierarchy. Amalgamation of these two aspects will increase our understanding of cell proliferation and differentiation within the mammary gland, with clear application to our attempts to control breast cancer. Here we focus on providing an over-view of prolactin action during development of the model murine mammary gland.

137 citations


Journal ArticleDOI
TL;DR: Overall, epidemiologic data suggest that prolactin is involved in breast cancer etiology and limited genetic data suggest a role of polymorphisms in the Prolactin and prolactIn receptor genes in risk of breast cancer.
Abstract: A number of epidemiologic studies of prolactin and breast cancer etiology have recently become available. Retrospective case-control studies have suggested a modest positive or null relationship between circulating prolactin concentrations and risk of breast cancer. However these studies are limited by small sample sizes and the collection of blood after case diagnosis. Several large prospective studies, in which blood was collected prior to diagnosis, have observed modest positive associations between prolactin and risk. In a pooled analysis of ~80% of the world’s prospective data, the relative risk (RR) comparing women in the top vs bottom quartile of prolactin levels was 1.3 (95% confidence interval (CI): 1.1, 1.6, p-trend = 0.002). The results were similar for premenopausal and postmenopausal women. Most notably, high prolactin levels were associated with a 60% increased risk of estrogen receptor (ER) positive tumors, but not with ER negative tumors. Limited genetic data suggest a role of polymorphisms in the prolactin and prolactin receptor genes in risk of breast cancer. Studies of survival have suggested that high pretreatment prolactin levels were associated with treatment failure, earlier recurrence, and worse overall survival. Parity and certain medications are the only confirmed factors associated with prolactin levels in women. Overall, epidemiologic data suggest that prolactin is involved in breast cancer etiology. Further research to better elucidate these associations and their underlying mechanisms is warranted.

126 citations


Journal ArticleDOI
TL;DR: The changing patterns of prolactin secretion during pregnancy in the rat is described and the neuroendocrine mechanisms controlling these changes are discussed, and dopamine secretion from TIDA neurones is reduced during late pregnancy.
Abstract: During pregnancy, neuroendocrine control of prolactin secretion is markedly altered to allow a state of hyperprolactinaemia to develop. Prolactin secretion is normally tightly regulated by a short-loop negative-feedback mechanism, whereby prolactin stimulates activity of tuberoinfundibular dopamine (TIDA) neurones to increase dopamine secretion into the pituitary portal blood. Dopamine inhibits prolactin secretion, thus reducing prolactin concentrations in the circulation back to the normal low level. Activation of this feedback secretion by placental lactogen during pregnancy maintains relatively low levels of prolactin secretion during early and mid-pregnancy. Despite the continued presence of placental lactogen, however, dopamine secretion from TIDA neurones is reduced during late pregnancy. Moreover, the neurones become completely unresponsive to endogenous or exogenous prolactin at this time, allowing a large nocturnal surge of prolactin to occur from the maternal pituitary gland during the night before parturition. In this review, we describe the changing patterns of prolactin secretion during pregnancy in the rat, and discuss the neuroendocrine mechanisms controlling these changes. The loss of response to prolactin is an important maternal adaptation to pregnancy, allowing the prolonged period of hyperprolactinaemia required for mammary gland development and function and for maternal behaviour immediately after parturition, and possibly also contributing to a range of other adaptive responses in the mother.

121 citations


Journal ArticleDOI
TL;DR: The results underlie the significant effects that obesity has on circadian organization of hormone secretion and individual plasma glucose values correlating with circulating corticosterone in high-fat fed rats only are analyzed.
Abstract: Circadian rhythmicity is affected in obese subjects. This article analyzes the effect of a high-fat diet (35% fat) on 24-h changes circulating prolactin, luteinizing hormone (LH), testosterone, corticosterone, thyroid-stimulating hormone (TSH) and glucose, and pineal melatonin content, in rats. When body weight of rats reached the values of morbid obesity, the animals were sacrificed at six different time intervals throughout a 24-h cycle, together with age-matched controls fed a normal diet (4% fat). Plasma hormone levels were measured by specific radioimmunoassays and glucose concentration by an automated glucose oxidase method. In rats under a high-fat diet, a significant disruption of the 24-h pattern of plasma TSH, LH, and testosterone and a slight disruption of prolactin rhythm were found. Additionally, high-fat fed rats showed significantly lower total values of plasma TSH and testosterone and absence of correlation between testosterone and circulating LH levels. Plasma corticosterone levels increased significantly in high-fat fed rats and their 24-h variation became blunted. In obese animals, a significant hyperglycemia developed, individual plasma glucose values correlating with circulating corticosterone in high-fat fed rats only. The amplitude of the nocturnal pineal melatonin peak decreased significantly in high-fat fed rats. The results underlie the significant effects that obesity has on circadian organization of hormone secretion.

115 citations


Journal ArticleDOI
TL;DR: The data suggest that male pheromones induce a prolactin-mediated increase in neurogenesis in female mice, resulting in advanced maternal behavior.

107 citations


Journal ArticleDOI
03 Apr 2008-Ibis
TL;DR: These processes of neuro- endocrine and “psycho-endocrine” regulation provide a link, in certain areas, between the work of physiologists, ethologists, ecologists, and animal psychologists.
Abstract: Summary. 1 Within the breeding seasons regulated by annual changes in environmental conditions, there exist detailed changes in the pattern of hormone secretion from stage to stage within the season, which are in part responsible for the successive changes in behaviour during the season. 2 In many species of birds the general environmental variables induce greater development in the male reproductive system than in the female, so that males arriving at the breeding grounds in spring are usually more advanced toward full spermatogenesis than are the females toward ovulation. Experimentally, additional illumination alone is capable of bringing about full testicular development, but not full ovarian development. 3 Stimuli arising from courtship behaviour induce the secretion of follicle-stimulating hormone by the pituitary gland of the female in many species of birds. 4 The presence of nesting material and of the nest, and/or participation in nest-building behaviour, further contribute to the advancement of the reproductive cycle, probably contributing to the stimulation of luteinizing hormone secretion by the pituitary. 5 Stimuli provided by the eggs appear to be able to induce prolactin secretion, and to inhibit the secretion of FSH. The prolactin secretion so stimulated probably, in turn, contributes to the maintenance of incubation, and of the brood patch. 6 Stimuli provided by the young are capable of inhibiting or delaying the onset of a new laying cycle, although the physiological basis of this is rather obscure. 7 Recently discovered details of the physiological and anatomical relationships between the brain and the pituitary gland provide insight into the anatomical and physiological mechanisms by means of which external stimuli can reflexly cause changes in hormone secretion. 8 The synchronization of the behaviour of the members of a mated pair, necessary for effective reproduction, is probably in part effected by the effects upon their endocrine glands of stimuli which they provide to each other, and which they receive from the eggs and young. 9 These processes of neuro-endocrine and “psycho-endocrine” regulation provide a link, in certain areas, between the work of physiologists, ethologists, ecologists, and animal psychologists.

Journal ArticleDOI
TL;DR: Chronic high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance, which is associated with hyperphagia, increased fat deposition, and elevated plasma leptin concentrations.
Abstract: Pregnancy in rats is associated with hyperphagia, increased fat deposition, and elevated plasma leptin concentrations. Elevated leptin would be expected to inhibit food intake, but hypothalamic leptin resistance develops around midpregnancy, allowing hyperphagia to be maintained and excess energy to be stored as fat in preparation for future metabolic demands of lactation. To investigate the hormonal mechanisms inducing leptin resistance during pregnancy, the anorectic response to leptin was examined during pseudopregnancy. Pseudopregnant rats have identical hormonal profiles to early pregnancy, but no placenta formation, allowing differentiation of maternal and placental hormone effects on appetite. To investigate the effect of leptin on food intake, d-9 pseudopregnant rats were injected with leptin (4 microg) via an intracerebroventricular (icv) cannula, and then food intake was measured 24 h later. Pseudopregnant rats were hyperphagic but had normal anorectic responses to leptin. We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on d 14 of pregnancy. Pseudopregnant rats were given progesterone to prolong pseudopregnancy beyond the time that leptin resistance develops during pregnancy. However, rats remained responsive to icv leptin. To model the placental lactogen secretion that occurs during pregnancy, pseudopregnant rats were given progesterone and chronic icv ovine prolactin infusion. Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance.

Journal ArticleDOI
TL;DR: The findings show that 17beta-estradiol, progesterone, or both hormones administered together significantly influenced the expression of numerous genes in the mouse meibomian gland.
Abstract: PURPOSE. The purpose of the study was to test the hypothesis that estrogen and progesterone regulate gene expression in the meibomian gland. METHODS. Meibomian glands were obtained from young adult, ovariectomized mice that were administered 17-estradiol, progesterone, 17-estradiol plus progesterone, or vehicle for 14 days. Glands were pooled according to treatment, processed for the extraction of RNA, and analyzed for differentially expressed mRNAs by using mouse gene microarrays. Bioarray data were evaluated with sophisticated bioinformatics software and statistical programs. The expression of selected genes was confirmed with gene chips and quantitative realtime PCR techniques. RESULTS. The findings show that 17-estradiol, progesterone, or both hormones administered together significantly influenced the expression of numerous genes in the mouse meibomian gland. Notable were the effects of 17-estradiol on genes related to lipid metabolism, tyrosine kinases, immune factors, extracellular matrix components, steroidogenesis, and prolactin dynamics. Also very significant were the actions of progesterone or 17-estradiol plus progesterone on ribosome or localization gene ontologies, respectively. The various hormone treatments led to many analogous, opposite, or unique effects on gene expression. CONCLUSIONS. These findings support the study hypothesis that estrogen and progesterone modulate gene expression in the meibomian gland. (Invest Ophthalmol Vis Sci. 2008;49: 1797‐1808) DOI:10.1167/iovs.07-1458

Journal ArticleDOI
TL;DR: In adult men, urinary 3-PBA levels were associated with increased LH and reduced E2 levels, which suggested that pyrethroids are capable of disrupting the male endocrine function.

Journal ArticleDOI
TL;DR: CX CR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitaries cell proliferation and, possibly, to adenoma development `in humans.
Abstract: Purpose: Hypothalamic or locally produced growth factors and cytokines control pituitary development, functioning, and cell division. We evaluated the expression of the chemokine stromal cell–derived factor 1 (SDF1) and its receptor CXCR4 in human pituitary adenomas and normal pituitary tissues and their role in cell proliferation. Experimental Design: The expression of SDF1 and CXCR4 in 65 human pituitary adenomas and 4 human normal pituitaries was determined by reverse transcription-PCR, immunohistochemistry, and confocal immunofluorescence. The proliferative effect of SDF1 was evaluated in eight fibroblast-free human pituitary adenoma cell cultures. Results: CXCR4 mRNA was expressed in 92% of growth hormone (GH)-secreting pituitary adenomas (GHoma) and 81% of nonfunctioning pituitary adenomas (NFPA), whereas SDF1 was identified in 63% and 78% of GHomas and NFPAs, respectively. Immunostaining for CXCR4 and SDF1 showed a strong homogenous labeling in all tumoral cells in both GHomas and NFPAs. In normal tissues, CXCR4 and SDF1 were expressed only in a subset of anterior pituitary cells, with a lower expression of SDF1 compared with its cognate receptor. CXCR4 and SDF1 were not confined to a specific cell population in the anterior pituitary but colocalized with discrete subpopulations of GH-, prolactin-, and adrenocorticorticotropic hormone–secreting cells. Conversely, most of the SDF1-containing cells expressed CXCR4. In six of eight pituitary adenoma primary cultures, SDF1 induced a statistically significant increase in DNA synthesis that was prevented by the treatment with the CXCR4 antagonist AMD3100 or somatostatin. Conclusions: CXCR4 and SDF1 are overexpressed in human pituitary adenomas and CXCR4 activation may contribute to pituitary cell proliferation and, possibly, to adenoma development `in humans.

Journal ArticleDOI
TL;DR: Treatment with oestradiol during a short period immediately after parturition protects the mouse from a post‐partum flare of the disease, and that treatment with bromocriptine, a drug known to inhibit the endogenous PRL release, has a significant though less marked effect.
Abstract: Pregnancy is known to influence the course of rheumatoid arthritis (RA) in women, as well as type II collagen-induced arthritis (CIA) in DBA/1 mice. A characteristic feature is the remission during gestation and the exacerbation of the diseases during the post-partum period. In the case of CIA in DBA 1 mice, two hormonal changes have been assumed to be critical for the induction of the post-partum flare: (i) the fall in steroid hormone levels from those present during pregnancy; and (ii) surges of prolactin (PRL) release at and after delivery. Our results show that treatment with oestradiol during a short period immediately after parturition protects the mouse from a post-partum flare of the disease, and that treatment with bromocriptine, a drug known to inhibit the endogenous PRL release, has a significant though less marked effect. Studies of lactating (i.e. animals with physiological stimulation of endogenous PRL release) and non-lactating arthritic mice revealed no clear-cut differences, indicating that PRL is of minor importance for the induction of the post-partum flare. Some steroids other than oestradiol, which may be implicated in the exacerbation of arthritis, namely progesterone and hydrocortisone, had no clinical effect. Analyses of agalactosyl IgG levels in mice with CIA, and anti-collagen II antibodies in sera collected at the end of the experiments revealed no significant differences between the oestradiol and the control groups. The successful oestradiol treatment of the mice indicates that the drop in endogenous oestradiol levels prior to delivery ends the oestrogen-mediated protection against arthritis during pregnancy.

Journal ArticleDOI
TL;DR: This review summarizes current information regarding the nature of the multiple endocrine-paracrine-autocrine systems that may be necessary for normal testicular function in the stallion.

Journal ArticleDOI
TL;DR: The present study is, as far as the authors know, the first to examine the direct actions of kisspeptin on the secretion of GH and PRL from the bovine pituitary gland.

Journal ArticleDOI
TL;DR: Results showed that the hypothalamic NMDA‐GnRH‐LH axis was altered in old rats, and GnRH efflux in response to NMDA was significantly attenuated with increasing age.
Abstract: Reproductive aging in the Brown Norway rat occurs because of testicular as well as hypothalamic-pituitary dysfunction. Excitatory amino acids (EAA) participate in the regulation of pulsatile secretion of hypothalamic GnRH and pituitary LH. In the present study, we studied the EAA-GnRH-LH axis for possible age-related alterations in prepubertal (35 days), young (3-4 months), middle-aged (12-13 months) and old (21-23 months) rats. In the first experiment, an intra-atrial cannula was implanted in rats of different ages to evaluate the pituitary response to small, physiological intravenous bolus administration of GnRH (0.5 or 1.0 nmol/100 g body weight). The results showed no age-related significant differences in in-vivo serum LH or FSH responsiveness to GnRH. In a second experiment, blood samples for the gonadotropins were withdrawn immediately before and 10 min after an iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg, a dose that induces a physiological LH pulse in young rats). Administration of NMDA induced significant increases in LH and prolactin in all groups of animals (P<0.05) and a significant FSH response in young and middle-aged but not old rats. NMDA-induced LH, FSH and prolactin release was higher (P<0.05) in prepubertal rats than in all other age groups. Compared with young rats, NMDA-induced increase in plasma LH and prolactin was lower (P<0.05) in old rats. In the third experiment, to ascertain whether this reduced LH response to NMDA in old rats was exerted at the hypothalamic level, the effects of NMDA on GnRH release in vitro from preoptic area-medial basal hypothalamus (POA-MBH) fragments were compared among rats of different ages. GnRH efflux in response to NMDA was significantly attenuated with increasing age. GnRH release in vitro was higher in prepubertal and lower in old than in young rats (P<0.05). Lastly, we measured amino acid concentrations in hypothalamic tissue (POA-MBH fragments). Prepubertal rats had higher levels of glutamate and taurine than young rats. Significant reductions in glutamate and gamma-aminobutyric acid (GABA) levels were found in old compared to young rats. In conclusion, these results showed that the hypothalamic NMDA-GnRH-LH axis was altered in old rats. The decreased hypothalamic content of some of the EAA and the reduced responsiveness of GnRH neurons to NMDA (both in vivo and in vitro) may contribute to an altered LH pulsatile secretion observed in old rats.

Journal ArticleDOI
TL;DR: Around 40% of emerging SSE in schizophrenia are attributable to the prolactin-raising properties of antipsychotic medication, and around one-third to two-thirds is directly reducible to the effects of serum Prolactin.

Journal ArticleDOI
TL;DR: Pregnancy regulation in the dog is not yet fully elucidated, and since plasma progesterone concentrations are similar in pregnant versus non-pregnant animals, it is a poor reflection on CL function and progestersone metabolism.

Journal ArticleDOI
TL;DR: It appears that the damage to HPT axis is both in pituitary and testicular levels, and further studies are needed to better elucidate the underlying pathophysiology of HPTaxis dysregulation.
Abstract: Several endocrine and sexual disturbances have been demonstrated in multiple sclerosis (MS) patients of both sexes. The endocrine profile, hypothalamic-pituitary-testis (HPT) axis and semen quality were evaluated in male patients with MS. A total of 68 male MS patients aged 18 years or older were recruited. Forty-eight age-matched healthy male volunteers served as controls. All subjects underwent complete physical examination and routine semen analysis. Two blood samples were drawn from each participant at 15-min intervals for the determination of the resting levels of: luteinising-hormone (LH), follicle-stimulating hormone (FSH), prolactin, testosterone, oestradiol and sex hormone binding globulin. The HPT axis was assessed using gonadotrophin-releasing hormone (GnRH) and human chorionic gonadotrophin tests. The mean basal serum levels for LH, FSH and testosterone in MS patients were significantly lower than the mean for normal controls (P = 0.01). The injection of GnRH analogue did not yield a significant increase in FSH and LH levels in the MS patients compared to normal controls (P = 0.001). Total sperm count, sperm motility and percent normal sperm morphology were lower in MS patients compared to controls. MS subjects with progressive disease had higher and more severe HPT axis abnormalities than that for patients with relapsing remitting MS. Most subjects with MS have hypogonadotrophic hypogonadism state and fertility impairment. It appears that the damage to HPT axis is both in pituitary and testicular levels. Further studies are needed to better elucidate the underlying pathophysiology of HPT axis dysregulation.

Journal ArticleDOI
TL;DR: The principle focus of this review is on the regulation of PRLr expression and activity in breast cancer with a brief overview of different isoforms of PR Lr, their expression, signaling capabilities and the biological outcomes ofPRL/PRLr signaling.
Abstract: From its traditional identity as a hormone involved in growth and differentiation of mammary epithelium and in lactation, to having a pertinent role in the development of mammary carcinoma, the peptide hormone/cytokine prolactin (PRL) has emerged as a versatile signaling molecule. There has been significant progress in our understanding of the fine working of PRL in the past several years. Notably, much effort has been concentrated on the mediator of PRL action, namely, the prolactin receptor (PRLr). The causal link between increased PRLr expression and breast cancer is being increasingly appreciated. Considering that the level of the receptor on the surface is a critical determinant of signaling output in response to PRL, the uncovering of regulatory elements that control receptor expression becomes important. The principle focus of this review is on the regulation of PRLr expression and activity in breast cancer with a brief overview of different isoforms of PRLr, their expression, signaling capabilities and the biological outcomes of PRL/PRLr signaling.

Journal ArticleDOI
TL;DR: It is concluded that hyperprolactinaemia is associated with an increase in breast cancer risk in both post and premenopausal women, that rat carcinogenicity studies are predictive of the human response, and that in a regulatory toxicology context prolactin-induced mammary tumours from nongenotoxic drugs and chemicals are an adverse effect that should not be ignored.
Abstract: Drugs and chemicals shown to induce mammary carcinogenesis in the rat/rodent via prolactin excess have traditionally been argued to pose little or no risk to humans in a regulatory toxicology context. The basis for this assumption is reviewed and placed into context with new evidence in humans that prolactin may be a tumour promoter in the breast and prostate. This evidence includes epidemiology, patient studies involving endocrine evaluation and molecular biology in human cells. It is concluded that hyperprolactinaemia is associated with an increase in breast cancer risk in both post and premenopausal women, that rat carcinogenicity studies are predictive of the human response, and that in a regulatory toxicology context prolactin-induced mammary tumours from nongenotoxic drugs and chemicals are an adverse effect that should not be ignored. More evidence is required concerning prostate cancer risk but molecular biology indicates that prolactin also induces prostate cell proliferation and inhibits apoptosis, which are similar to the responses observed in breast cancer cells.

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TL;DR: In order to take advantage of the potential beneficial effects of hormones such as GH or PRL, it is essential to take into consideration the overall cytokine network and the regulatory effects of SOCS proteins.

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TL;DR: Regulators of prolactin receptor signaling show heterogeneity in their expression in benign vs malignant breast tissue, which suggest multiple targets for modulating prolACTin receptor-mediated growth and differentiation in breast cancer.

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TL;DR: Results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors, and EGFR inhibitors could therefore be useful for the control ofPRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolact inomas undergoing rare malignant transformation.
Abstract: Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis, and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, the effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGF receptor (EGFR) and p185 c-neu protein expression in GH3 lacto-somatotroph but not in adrenocorticotropic hormone–secreting AtT20 pituitary tumor cells. EGF (5 nmol/L) selectively enhanced baseline (∼4-fold) and serum-induced (>6-fold) prolactin (PRL) mRNA levels, whereas gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not phosphoinositide-3-kinase or protein kinase C, mediated the gefitinib response. Tumors in athymic mice implanted s.c. with GH3 cells resulted in weight gain accompanied by increased serum PRL, growth hormone, and insulin growth factor 1. Gefitinib decreased tumor volumes and peripheral hormone levels by ∼30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and down-regulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for the control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation. [Cancer Res 2008;68(15):6377–86]

Journal ArticleDOI
TL;DR: Shifts in gene expression related to PRL signaling may provide an environmentally mediated mechanism to alter production and health in cows as they transition into lactation.
Abstract: Photoperiodic manipulation has dramatic physiological and production effects in dairy cows. During lactation, exposure to long day photoperiod (LDPP) increases milk yield and circulating IGF-I and prolactin (PRL) concentrations. Conversely, cows housed under a short day photoperiod (SDPP) during the dry period produce more milk in the subsequent lactation than cows exposed to LDPP or natural photoperiod. Exposure to SDPP depresses PRL secretion but increases PRL receptor mRNA levels in mammary, immune, and hepatic tissues. In dry cows under SDPP, PRL signaling is a potential mechanism to drive more extensive mammary cell differentiation and growth relative to LDPP. In mammary biopsies taken during the dry period and into lactation, the amount of IGF-II mRNA was greater in SDPP vs. LDPP cows during the dry period, whereas IGFBP-5 mRNA increased in both groups during lactation even though photoperiodic treatments ended at parturition and all cows were on an ambient lighting schedule when lactating. Levels of IGF-I mRNA did not differ over time or between treatments; however, during the dry period, lower IGFBP-5 and increased IGF-II expression in SDPP cows may enhance mammary cell growth and survival. Key among the potential modulators of PRL signaling is the suppressors of cytokine signaling (SOCS) family. Mammary transcription of mRNA for SOCS proteins was low during the dry period but increased in lactation. During the dry period, SOCS mRNA level in the mammary gland of cows on SDPP was reduced compared with cows on LDPP, which may enhance PRL-induced proliferation and subsequent milk production. However, improved mammary capacity and immune function alone are likely insufficient to support increased milk yield. Using improved milk yield as a functional indicator of greater animal well-being during the transition, it is clear that some metabolic accommodation is necessary for expression of that capacity. Emerging evidence supports a link between PRL signaling and hepatic lipid metabolism, with decreases in PRL being beneficial to lipid metabolism. Extending that concept to broad environmental responses, it can be speculated that altered PRL signaling impairs lipid metabolism, mammary growth, and immune function under conditions of stress (e.g., heat stress) also. Thus, shifts in gene expression related to PRL signaling may provide an environmentally mediated mechanism to alter production and health in cows as they transition into lactation.

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TL;DR: The data show that the 900 MHz EMF exposure, at least under the experimental conditions, does not appear to affect endocrine functions in men.
Abstract: The potential health risks of radiofrequency electromagnetic fields (RF EMFs) emitted by mobile phones are currently of considerable public interest. The present study investigated the effect of exposure to 900 MHz GSM radiofrequency radiation on steroid (cortisol and testosterone) and pituitary (thyroid-stimulating hormone, growth hormone, prolactin and adrenocorticotropin) hormone levels in 20 healthy male volunteers. Each subject was exposed to RF EMFs through the use of a cellular phone for 2 h/day, 5 days/ week, for 4 weeks. Blood samples were collected hourly during the night and every 3 h during the day. Four sampling sessions were performed at 15-day intervals: before the beginning of the exposure period, at the middle and the end of the exposure period, and 15 days later. Parameters evaluated included the maximum serum concentration, the time of this maximum, and the area under the curve for hormone circadian patterns. Each individual's pre-exposure hormone concentration was used as his control. All hormone concentrations remained within normal physiological ranges. The circadian profiles of prolactin, thyroid-stimulating hormone, adrenocorticotropin and testosterone were not disrupted by RF EMFs emitted by mobile phones. For growth hormone and cortisol, there were significant decreases of about 28% and 12%, respectively, in the maximum levels when comparing the 2-week (for growth hormone and cortisol) and 4-week (for growth hormone) exposure periods to the pre-exposure period, but no difference persisted in the postexposure period. Our data show that the 900 MHz EMF exposure, at least under our experimental conditions, does not appear to affect endocrine functions in men.

Journal ArticleDOI
David Haig1
01 Mar 2008-Placenta
TL;DR: The placentas of ruminants and muroid rodents express prolactin (PRL)-related genes whereas the placenta of anthropoid primates express growth hormone (GH-related genes); the evolution of placental expression is associated with accelerated evolution of the corresponding pituitary hormone and destabilization of conserved endocrine systems.