Showing papers on "Prolactin published in 2018"

Prolactin and Autoimmunity.

Abstract: The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.

Prolactin Biology and Laboratory Measurement: An Update on Physiology and Current Analytical Issues.

Abstract: Prolactin is a 23 kDa single chain protein of 199 amino acids synthesised and released principally by lactotrophs in the anterior pituitary gland. The secretion is mainly under inhibitory control by hypothalamic dopamine and regulated in a negative feedback manner, with prolactin itself providing the afferent signal: short-loop feedback. The main function of prolactin is during pregnancy and lactation in the development of mammary glands, milk synthesis and maintenance of milk secretion. Serum prolactin levels rise rapidly during pregnancy with increase in the size and number of lactotrophs. During lactation suckling induces rapid secretion of prolactin via a neuroendocrine reflex pathway. In the absence of pregnancy, hyperprolactinaemia may present with symptoms of hypogonadotropic hypogonadism including menstrual disturbance and infertility or visual symptoms from a pituitary mass effect by a prolactinoma, the most common pituitary tumour. Hyperprolactinaemia is diagnosed by laboratory measurement of serum prolactin. There is considerable variability in routinely available prolactin immunoassays as a result of differing reactivity towards monomeric prolactin and macroprolactin and lack of commutability of the WHO 3rd International Standard between routine methods. Macroprolactinaemia is a relatively common cause of interference in the prolactin assay that may lead to incorrect diagnosis and unnecessary investigations. Measurement of prolactin post polyethylene glycol precipitation (PEG) when prolactin levels are above the reference interval is routinely used to identify macroprolactin, however harmonisation of PEG precipitation process and reporting may improve clinical care.

Circulating prolactin concentrations and risk of type 2 diabetes in US women

Abstract: Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of prolactin are associated with risk of type 2 diabetes remains uncertain. We analysed the prospective relationship between circulating prolactin concentrations and type 2 diabetes risk in the Nurses’ Health Study (NHS) and NHSII with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8615 women free of type 2 diabetes and cardiovascular disease at baseline blood collection (NHS 1989–1990; NHSII 1996–1999) and a subset of 998 NHS women providing a second blood sample during 2000–2002. Baseline bioactive prolactin was measured in a subset of 2478 women using the Nb2 bioassay. HRs were estimated using Cox regression. A total of 699 incident type 2 diabetes cases were documented during 156,140 person-years of follow-up. Total plasma prolactin levels were inversely associated with type 2 diabetes risk; the multivariable HR comparing the highest with the lowest quartile was 0.73 (95% CI 0.55, 0.95; ptrend = 0.02). The associations were similar by menopausal status and other risk factors (pinteraction > 0.70). Additional adjustment for sex and growth hormones, adiponectin, and inflammatory and insulin markers did not significantly alter the results. The association of plasma bioactive prolactin with type 2 diabetes risk was non-significantly stronger than that of total prolactin (HR comparing extreme quartiles, 0.53 vs 0.81 among the subset of 2478 women, pdifference = 0.11). The inverse association of total prolactin with type 2 diabetes was significant during the first 9 years after blood draw but waned linearly with time, whereas for bioactive prolactin, the inverse relationship persisted for a longer follow-up time after blood draw. A normally high circulating total prolactin concentration was associated with a lower type 2 diabetes risk within 9–10 years of follow-up since blood draw in US women. Our findings are consistent with experimental evidence, suggesting that among healthy women, prolactin within the biologically normal range may play a protective role in the pathogenesis of type 2 diabetes.

Prolactin inhibits the progression of intervertebral disc degeneration through inactivation of the NF-κB pathway in rats.

Abstract: Intervertebral disc degeneration (IVDD) is one of the key predisposing factors for low back pain. Although the exact mechanism remains unclear, inflammatory response and nucleus pulposus (NP) apoptosis are known to play important roles in this process. Prolactin protects against inflammation-associated chondrocyte apoptosis in arthritis. Based on prior studies, we hypothesized that prolactin might have therapeutic effects on IVDD by inhibiting the apoptosis of degenerative human disc NP cells. An experimental model of IVDD was established in 3-month-old Sprague-Dawley rats by submitting them to percutaneous disc puncture with a 20-gauge needle on levels 7–8 and 8–9 of the coccygeal vertebrae. Then the rats were injected with 20 or 200 ng prolactin on a weekly basis. Radiologic and histologic analyses were performed on days 4, 7, 14, and 28. The expression of prolactin and its receptor was analyzed in human tissue obtained from symptomatic patients undergoing microencoscopy discectomy, or from scoliosis patients undergoing deformity correction surgery. The results showed that intradiscal injection of prolactin maintained disc height and the mean signal intensity of the punctured disc. Histological analysis indicated that prolactin treatment significantly retained the complete structure of the NP and annulus fibrosus compared with the vehicle group. In addition, more collagen II, but fewer collagen I-containing tissues were detected in the prolactin treatment groups compared to the vehicle group. Moreover, low levels of tumor necrosis factor-α, interleukin-1β, cleaved-caspase 3, and TUNEL staining were observed in the prolactin treatment groups. We also demonstrated that prolactin impaired puncture-induced inflammation and cell apoptosis by downregulating activation of the NF-κB pathway. The degenerated NP tissues from patients had decreased expression of prolactin and its receptor, whereas expression was increased in the NP tissues removed from scoliosis patients. These results suggest that prolactin may be a novel therapeutic target for the treatment of IVDD.

Analysis of prolactin receptor expression in the murine brain using a novel prolactin receptor reporter mouse

Abstract: Prolactin influences a wide range of physiological functions via actions within the central nervous system, as well as in peripheral tissues. A significant limitation in studies investigating these functions is the difficulty in identifying prolactin receptor (Prlr) expression, particularly in the brain. We have developed a novel mouse line using homologous recombination within mouse embryonic stem cells to produce a mouse in which an internal ribosome entry site (IRES) followed by Cre recombinase cDNA is inserted immediately after exon 10 in the Prlr gene, thereby targeting the long isoform of the Prlr. By crossing this Prlr-IRES-Cre mouse with a ROSA26-CAGS-tauGFP (τGFP) reporter mouse line, and using immunohistochemistry to detect τGFP, we were able to generate a detailed map of the distribution of individual Prlr-expressing neurones and fibres throughout the brain of adult mice without the need for amplification of the GFP signal. Because the τGFP is targeted to neurotubules, the labelling detected not only cell bodies, but also processes of prolactin-sensitive neurones. In both males and females, Cre-dependent τGFP expression was localised, with varying degrees of abundance, in a number of brain regions, including the lateral septal nucleus, bed nucleus of the stria terminalis, preoptic and hypothalamic nuclei, medial habenula, posterodorsal medial amygdala, and brainstem regions such as the periaqueductal grey and parabrachial nucleus. The labelling was highly specific, occurring only in cells where we could also detect PrlrmRNA by in situ hybridisation. Apart from two brain areas, the anteroventral periventricular nucleus and the medial preoptic nucleus, the number and distribution of τGFP-immunopositive cells was similar in males and females, suggesting that prolactin may have many equivalent functions in both sexes. These mice provide a valuable tool for investigating the neural circuits underlying the actions of prolactin.

Unique features of pregnancy-related meningiomas: lessons learned from 148 reported cases and theoretical implications of a prolactin modulated pathogenesis.

Abstract: Meningiomas are some of the most frequently encountered adult intracranial tumors. Dramatic flare ups in size may occasionally be observed during pregnancy, leading to complicated clinical scenarios, with profound effects and substantial risks for both the mother's and the fetus's well-being. Despite the fact that such changes have largely been attributed to progesterone-based mechanisms, recent studies have put this theory into question or defied it. In order to assess these particular tumors carefully and to try and clarify the pathophysiology of such pregnancy-related meningioma growth, an in-depth review of the pertinent literature was undertaken. Based on clinical, radiographic, and pathological data gathered from 148 reported cases, we have found several unique features characterizing these pregnancy-related meningiomas. The presence of such observed features was found to be of high statistical significance when compared to their expected prevalence in the general population and included the following: (1) parasellar location, (2) anterior circulation blood supply, (3) visual symptoms at presentation, (4) high rate of clear-cell and chordoid morphology. A hypothesis is developed that these features are related to hormonal influences of the pituitary gland, and we discuss that this may be due to elevated prolactin levels. We encourage further research to test this exciting new theory.

Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin.

Abstract: Sex differences are important to consider when studying different psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD). These disorders can be affected by dimorphic changes in the central nervous system and be influenced by sex-specific hormones and neuroactive steroids. In fact, AD is more prevalent in women than in men. One of the main characteristics of AD is the formation of neurofibrillary tangles, composed of the phosphoprotein Tau, and neuronal loss in specific brain regions. The scope of this work is to review the existing evidence on how a set of hormones (estrogen, progesterone, and prolactin) affect tau phosphorylation in the brain of females under both physiological and pathological conditions.

Neural and Endocrinal Pathobiochemistry of Vitiligo: Comparative Study for a Hypothesized Mechanism

Abstract: The etiology of vitiligo is still unclear. The aim is to investigate a neural and hormonal etio-pathology of vitiligo. A sixty acrofacial vitiligo patients were divided into two subgroups as active vitiligo patients group (AVP; n=35) and stable vitiligo patients group (SVP; n=25). Forty healthy subjects without any systemic or dermatological disease were used as controls. Blood samples were collected, and the samples were used for measurement of free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), cortisol, estrogen, testosterone, melatonin and prolactin levels by ELISA, while norepinephrine (NE), epinephrine (Epi), dopamine (DA), homovanilic acid (HVA), serotonin, and 5-hydroxy indole acetic acid (5-HIAA) by high-pressure liquid chromatography. The current results showed a significant increase in plasma levels of Epi, NE, DA, HVA, serotonin, 5-HIAA, melatonin, and in serum level of TSH and prolactin either in SVP or AVP groups than the control group and in AVP than SVP group. The Serum levels of fT3 and fT4 were significantly decreased either in SVP or AVP groups than the control group. A significant increase in estradiol levels was observed in females within AVP than females in either SVP or control groups. There was a significant increase in serum level of cortisol in AVP than either SVP or control group. There was a significant decrease in serum level of ACTH in either AVP or SVP than control and in AVP than SVP group. In conclusion, there are some neural and endocrine markers that play a pivotal role in pathogenesis and/or consequences of vitiligo. The abnormally disturbed levels of theses markers lead to melanocyte destruction and/or depigmentation.

The maternal hormone in the male brain: Sexually dimorphic distribution of prolactin signalling in the mouse brain.

Abstract: Research of the central actions of prolactin is highly focused on females, but this hormone has also documented roles in male physiology and behaviour. Here, we provide the first description of the pattern of prolactin-derived signalling in the male mouse brain, employing the immunostaining of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) after exogenous prolactin administration. Next, we explore possible sexually dimorphic differences by comparing pSTAT5 immunoreactivity in prolactin-supplemented males and females. We also assess the role of testosterone in the regulation of central prolactin signalling in males by comparing intact with castrated prolactin-supplemented males. Prolactin-supplemented males displayed a widespread pattern of pSTAT5 immunoreactivity, restricted to brain centres showing expression of the prolactin receptor. Immunoreactivity for pSTAT5 was present in several nuclei of the preoptic, anterior and tuberal hypothalamus, as well as in the septofimbrial nucleus or posterodorsal medial amygdala of the telencephalon. Conversely, non-supplemented control males were virtually devoid of pSTAT5-immunoreactivity, suggesting that central prolactin actions in males are limited to situations concurrent with substantial hypophyseal prolactin release (e.g. stress or mating). Furthermore, comparison of prolactin-supplemented males and females revealed a significant, female-biased sexual dimorphism, supporting the view that prolactin has a preeminent role in female physiology and behaviour. Finally, in males, castration significantly reduced pSTAT5 immunoreactivity in some structures, including the paraventricular and ventromedial hypothalamic nuclei and the septofimbrial region, thus indicating a region-specific regulatory role of testosterone over central prolactin signalling.

From Consternation to Revelation: Discovery of a Role for IGSF1 in Pituitary Control of Thyroid Function

Abstract: Immunoglobulin superfamily, member 1 (IGSF1) is a transmembrane glycoprotein highly expressed in the mammalian pituitary gland. Shortly after its discovery in 1998, the protein was proposed to function as a coreceptor for inhibins (and was even temporarily renamed inhibin binding protein). However, subsequent investigations, both in vitro and in vivo, failed to support a role for IGSF1 in inhibin action. Research on IGSF1 nearly ground to a halt until 2011, when next-generation sequencing identified mutations in the X-linked IGSF1 gene in boys and men with congenital central hypothyroidism. IGSF1 was localized to thyrotrope cells, implicating the protein in pituitary control of the thyroid. Investigations in two Igsf1 knockout mouse models converged to show that IGSF1 deficiency leads to reduced expression of the receptor for thyrotropin-releasing hormone (TRH) and impaired TRH stimulation of thyrotropin secretion, providing a candidate mechanism for the central hypothyroidism observed in patients. Nevertheless, the normal functions of IGSF1 in thyrotropes and other cells remain unresolved. Moreover, IGSF1 mutations are also commonly associated with other clinical phenotypes, including prolactin and growth hormone dysregulation, and macroorchidism. How the loss of IGSF1 produces these characteristics is unknown. Although early studies of IGSF1 ran into roadblocks and blind alleys, armed with the results of detailed clinical investigations, powerful mouse models, and new reagents, the field is now poised to discover IGSF1's function in endocrine tissues, including the pituitary and testes.

Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist.

Abstract: The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated - apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension - with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson's disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson's disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.

Mechanism of prolactin inhibition of miR-135b via methylation in goat mammary epithelial cells.

Abstract: Prolactin is an important endocrine activator of lactogenesis. This study investigated the function and mechanism of miR-135b in the enhancement of lactation by prolactin in goat mammary epithelial tissue. We utilized S-Poly (T) sequencing to evaluate changes in gene regulation in the goat mammary gland after incubation with 2.5 μg/ml prolactin and 2.5 μg/ml IGF-1 by examining highly expressed miRNAs during early lactation and late-lactation. The results illustrated that miR-135b is highly expressed in the goat mammary gland during early lactation and late-lactation, and also after treatment with 2.5 μg/ml prolactin and 2.5 μg/ml IGF-1. We used Q-RT PCR, Western Blot, immunofluorescence, and luciferase reporter assay analysis, and found that PRL was significantly down-regulated in response to the expression of miR-135b in a manner that was functionally related to TAG synthesis via the large tumor suppressor 2 gene (Lats2), an important regulator of adipocyte proliferation via Hippo Signaling. Furthermore, using bisulfite-sequencing PCR (BSP), Q-PCR, and Western Blot we discovered an increase in expression of DNMT I (DNA methyl transferase I) in goat mammary epithelial cells with the 2.5 μg/ml PRL incubation, which led to DNA methylation of the CpG island upstream of miR-135b and inhibited the transcription and expression of miR-135b.

Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice.

Abstract: Triclosan (TCS), a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone, and gonadotrophin-releasing hormone (GnRH) mRNA with the lack of LH surge and elevation of prolactin (PRL). TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Moreover, the estrogen (E2)-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH) and thyroid releasing hormone (TRH). In TCS mice, the treatment with Levothyroxine (L-T4) corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg) reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

Adrenal, thyroid and gonadal axes are affected at high altitude.

Abstract: Humans cannot live at very high altitude for reasons, which are not completely understood Since these reasons are not restricted to cardiorespiratory changes alone, changes in the endocrine system might also be involved Therefore, hormonal changes during prolonged hypobaric hypoxia were comprehensively assessed to determine effects of altitude and hypoxia on stress, thyroid and gonadal hypothalamus-pituitary hormone axes Twenty-one male and 19 female participants were examined repetitively during a high-altitude expedition Cortisol, prolactin, thyroid-stimulating hormone (TSH), fT4 and fT3 and in males follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone were analysed as well as parameters of hypoxemia, such as SaO2 and paO2 at 550 m (baseline) (n = 40), during ascent at 4844 m (n = 38), 6022 m (n = 31) and 7050 m (n = 13), at 4844 m (n = 29) after acclimatization and after the expedition (n = 38) Correlation analysis of hormone concentrations with oxygen parameters and with altitude revealed statistical association in most cases only with altitude Adrenal, thyroid and gonadal axes were affected by increasing altitude Adrenal axis and prolactin were first supressed at 4844 m and then activated with increasing altitude; thyroid and gonadal axes were directly activated or suppressed respectively with increasing altitude Acclimatisation at 4844 m led to normalization of adrenal and gonadal but not of thyroid axes In conclusion, acclimatization partly leads to a normalization of the adrenal, thyroid and gonadal axes at around 5000 m However, at higher altitude, endocrine dysregulation is pronounced and might contribute to the physical degradation found at high altitude

Transcriptome analysis revealed the possible regulatory pathways initiating female geese broodiness within the hypothalamic-pituitary-gonadal axis.

Abstract: Geese have the strongest tendency toward broodiness among all poultry. The mechanisms initiating broodiness within the goose hypothalamic-pituitary-gonadal axis (HPGA) are still unclear. Here, we reported the transcriptome differences between laying and initial nesting within the HPGA tissues of geese. We constructed a unigene database based on HPGA tissues and identified 128,148 unigenes, 100% of which have been annotated. By using Digital Gene Expression (DGE) sequencing, we screened 19, 110, 289, and 211 differentially expressed genes (DEGs) in the hypothalamus, pituitary gland, stroma ovarii, and follicles, respectively, between laying and nesting geese. Expression changes of hypocretin (HCRT) and pro-opiomelanocortin (POMC) in the hypothalamus of nesting geese may cause appetite reduction, which is possibly the first step and a prerequisite to initiate broodiness. In addition to prolactin (PRL), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), genes including oxytocin-neurophysin (OXT), chordin-like protein 1 (CHRDL1) and growth hormone (GH), expressed in the pituitary gland, are new candidate molecules that may be involved in broodiness in geese. Heme oxygenase 1 (HMOX1) in the pituitary gland, the proto-oncogene c-Fos (FOS), heat shock protein 90-alpha (HSP90AA), and cyclin-dependent kinase 1 (CDK1) in the ovary that may consolidate and transduce signals regulating the HPGA during broodiness in geese.

Prolactin-induced and neuronal activation in the brain of mother mice

Abstract: Nursing has important consequences on mothers. To separate the prolactin-mediated and the neuronally-mediated actions of nursing, neurons directly affected by prolactin were visualized using pSTAT5 immunohistochemistry in relation to Fos-expressing neurons in suckled mother mice. In response to pup exposure following 22-h pup deprivation, we found a markedly elevated number of pSTAT5-containing neurons in several brain regions, including the lateral septum, medial amygdaloid nucleus, subparafascicular area, caudal periaqueductal gray, dorsal raphe, lateral parabrachial nucleus, nucleus of the solitary tract, and the periventricular, medial preoptic, paraventricular, arcuate and ventromedial nuclei of the hypothalamus. Pup exposure also induced Fos expression in all of these brain regions except the arcuate and ventromedial hypothalamic nuclei. Bromocriptine treatment known to reduce prolactin levels eliminated pSTAT5 from most brain regions while it did not affect Fos activation following suckling. The degree of colocalization for pSTAT5 and Fos ranged from 8 to 80% in the different brain regions suggesting that most neurons responding to pup exposure in mother mice are driven either by prolactin or direct neuronal input from the pups, while the number of neurons affected by both types of inputs depends on the examined brain area. In addition, both pSTAT5 and Fos were also double-labeled with estrogen receptor alpha (ERα) in mother mice, which revealed a very high degree of colocalization between pSTAT5 and ERα with much less potential interaction between Fos- and ERα-containing neurons suggesting that estrogen-sensitive neurons are more likely to be affected by prolactin than by direct neuronal activation.

Metformin inhibits growth and prolactin secretion of pituitary prolactinoma cells and xenografts

Abstract: Metformin (MET) is a diabetes drug that activates AMP-activated protein kinase (AMPK), and is suggested to have anticancer efficacy. Here, we investigated the role of AMPK signalling in prolactinoma (PRLoma), with particular respect to MET and bromocriptine (BC) as a PRLoma treatment. We analysed AMPK phosphorylation, dopamine D2 receptor (D2R), and oestrogen receptor (ER) expression in both BC-sensitive and -resistant PRLoma samples; effects of the AMPK agonist MET (alone or with BC) on in vitro proliferation and apoptosis, xenograft growth and prolactin (PRL) secretion of BC-sensitive and -resistant cells, and ER expression in xenografts. Some BC-resistant PRLomas showed high D2R expression but extremely low AMPK activation. MET significantly inhibited proliferation of cultured PRLoma cells; MET + BC notably restrained their PRL secretion. MET + BC further decreased tumour growth and serum PRL levels in xenografts than BC treatment alone. ER was down-regulated after AMPK activation in both cultured cells and xenografts. Together, we propose that the AMPK signalling pathway down-regulates ERα and ERβ, and suppresses PRLoma growth as well as PRL secretion. Combined MET + BC is a potential treatment for PRLomas.

Abstract MP54: Circulating Prolactin Concentrations and Risk of Type 2 Diabetes in US Women

Abstract: Background: Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental and cross-sectional human studies. However, whether circulati...

Prolactin selectively transported to cerebrospinal fluid from blood under hypoxic/ischemic conditions.

Abstract: Aim The aim of this study was to determine and to verify the correlation between the amount of prolactin (PRL) levels in the blood and in the cerebrospinal fluid (CSF) by various causes of death as an indicator for acute hypoxia in autopsy cases. It is to confirm the cause of the change in prolactin level in CSF by in vitro system. Materials and methods In autopsy materials, the PRL levels in blood from the right heart ventricle and in the CSF were measured by chemiluminescent enzyme immunoassay, and changes in the percentage of PRL-positive cells in the pituitary gland were examined using an immunohistochemical method. Furthermore, an inverted culture method was used as an in vitro model of the blood-CSF barrier using epithelial cells of the human choroid plexus (HIBCPP cell line) and SDR-P-1D5 or MSH-P3 (PRL-secreting cell line derived from miniature swine hypophysis) under normoxic or hypoxic (5% oxygen) conditions, and as an index of cell activity, we used Vascular Endothelial Growth Factor (VEGF). Results and discussion Serum PRL levels were not significantly different between hypoxia/ischemia cases and other causes of death. However, PRL levels in CSF were three times higher in cases of hypoxia/ischemia than in those of the other causes of death. In the cultured cell under the hypoxia condition, PRL and VEGF showed a high concentration at 10 min. We established a brain-CSF barrier model to clarify the mechanism of PRL transport to CSF from blood, the PRL concentrations from blood to CSF increased under hypoxic conditions from 5 min. These results suggested that PRL moves in CSF through choroidal epithelium from blood within a short time. PRL is hypothesized to protect the hypoxic/ischemic brain, and this may be because of the increased transportation of the choroid plexus epithelial cells.

Autocrine actions of prolactin contribute to the regulation of lactotroph function in vivo

Abstract: Prolactin (PRL), whose principal role is regulation of lactation, is mainly synthesized and secreted by lactotroph anterior pituitary cells. Its signaling is exerted via a transmembrane PRL receptor (PRLR) expressed in a wide variety of tissues, including the anterior pituitary. Dopamine, which is secreted by tuberoinfundibular hypothalamic neurons, is the major inhibitory regulator of prolactin secretion. Although PRL is well established to stimulate hypothalamic dopamine secretion, thereby exerting a negative feedback regulation on its own release, autocrine or paracrine actions of PRL on lactotroph cells have also been suggested. Within the pituitary, PRL may inhibit both lactotroph proliferation and secretion, but in vivo evaluation of these putative functions is limited. To determine whether the autocrine actions of prolactin have a significant role in the physiologic function of lactotrophs in vivo, we examined the consequences of conditional deletion of Prlr in lactotroph cells using a novel mouse line with loxP sites flanking the Prlr gene ( Prlrlox/lox) and Cre-recombinase (Cre) expressed under the control of the pituitary-specific Prl promoter. Prlrlox/lox/Prl-Cre mice have normal PRL levels and did not develop any pituitary lactotroph adenoma, even at 20 mo of age. Nevertheless, Prlrlox/lox/Prl-Cre mice displayed an increased dopaminergic inhibitory tone compared with control Prlrlox/lox mice. These results elegantly confirm an autocrine/paracrine feedback of PRL on lactotroph cells in vivo, which can be fully compensated by an intact hypothalamic feedback system.-Bernard, V., Lamothe, S., Beau, I., Guillou, A., Martin, A., Le Tissier, P., Grattan, D., Young, J., Binart, N. Autocrine actions of prolactin contribute to the regulation of lactotroph function in vivo.

Impact of Kidney Transplantation on Reproductive Hormone Levels in Males: A Longitudinal Study

Abstract: Background/Aims: Male patients with end-stage renal disease suffer from sexual disturbances and infertility. Disturbances in the hypothalamic-pituitary-gonadal axis are one of the causes of this. Decreased testosterone synthesis in Leydig cells of the testes and hyperprolactinemia are common. Kidney transplantation, unlike hemodialysis, normalizes these changes. However, how kidney transplantation affects Sertoli cell function is poorly understood. This study is aimed at investigating the changes in fertility-related hormones in men before, during, and after renal transplantation. Methods: This longitudinal and prospective single center study enrolled 12 men undergoing living donor kidney transplantation. Plasma levels of creatinine, cystatin C, and serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, sex hormone-binding globulin, inhibin B, and anti-Mullerian hormone (AMH) were assayed at 10 different time points before, during, and after kidney transplantation. Results: A rapid decrease in creatinine and cystatin C levels indicated successful renal transplantation. High pre-transplantation plasma levels of prolactin (mean 516 ± 306 mIE/L) and LH (9.4 ± 4.7 IU/L) were normalized after 7 days (248 ± 161 mIE/L and 6.1 ± 3.1 IU/L, respectively). Testosterone decreased rapidly during transplantation and increased again one week post-transplantation. Sertoli cell-derived hormone inhibin B decreased after transplantation, and there was a small non-significant trend of increased AMH after 12 months. Conclusion: Sertoli cell function, based on AMH and inhibin B levels, does not improve to the same extent or as fast as Leydig cell function after kidney transplantation, as determined by testosterone and LH levels. (Less)

Interpretation of Serum Gonadotropin Levels in Hyperprolactinaemia.

Abstract: Background/Aims: Hyperprolactinaemia is a common cause of amenorrhoea due to hypogonadotropic hypogonadism. Prolactin is hypothesised to impede the reproductive axis through an inhibitory action at the hypothalamus. However, limited data exist to aid the interpretation of serum gonadotropins in the context of hyperprolactinaemia. Methods: Serum gonadotropin values were reviewed in 243 patients with elevated serum monomeric prolactin due to discrete aetiologies at a tertiary reproductive endocrine centre between 2012 and 2015. The cause of hyperprolactinaemia was categorised by an experienced endocrinologist/pituitary multidisciplinary team, unless superseded by histology. The most frequently encountered diagnoses were microprolactinoma ( n = 88), macroprolactinoma ( n = 46), non-functioning pituitary adenoma (NFPA) ( n = 72), drug-induced hyperprolactinaemia ( n = 22) and polycystic ovarian syndrome (PCOS) ( n = 15). Results: In patients with prolactinoma and modestly raised serum prolactin levels ( 4,000 mU/L) were more likely to have a reduction in serum levels of both FSH and LH, consistent with direct pituitary gonadotrope dysfunction. Patients with macroadenoma and extremes of serum gonadotropin values (either serum FSH or LH > 8 IU/L) were more likely to have NFPA than prolactinoma. Patients with PCOS and hyperprolactinaemia had LH-predominant secretion in keeping with increased GnRH pulsatility despite a raised prolactin level. Conclusion: The pattern of gonadotropin secretion in patients with hyperprolactinaemia reflects the underlying aetiology.

Impaired prolactin actions mediate altered offspring metabolism induced by maternal high-fat feeding during lactation

Abstract: Maternal diet during lactation affects offspring metabolic health throughout life Prolactin (PRL) is present in high quantities in maternal milk; however, the effects of milk PRL on the offspring remain poorly characterized In this study, we evaluated whether feeding a high-fat diet (HFD) to rats during lactation alters PRL, both in the mother's serum and in milk, and whether this factor contributes to HFD-induced metabolic dysfunction in the offspring Maternal HFD resulted in decreased PRL levels in milk (but not in serum), reduced mammary gland (MG) PRL receptor expression, and altered MG structure and function Offspring from HFD-fed dams had increased body weight and adiposity, and developed fatty liver, hyperinsulinemia, and insulin resistance at weaning Increasing PRL levels in the HFD-fed mothers by subcutaneous osmotic minipumps releasing PRL normalized MG function and PRL levels in milk Moreover, PRL treatment in HFD-fed mothers, or directly in their pups via oral PRL administration, increased liver STAT5 phosphorylation, reduced visceral adiposity, ameliorated fatty liver, and improved insulin sensitivity in offspring Our results show that HFD impairs PRL actions during lactation to negatively affect MG physiology and directly impair offspring metabolism-De los Rios, E A, Ruiz-Herrera, X, Tinoco-Pantoja, V, Lopez-Barrera, F, Martinez de la Escalera, G, Clapp, C, Macotela, Y Impaired prolactin actions mediate altered offspring metabolism induced by maternal high-fat feeding during lactation