An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis.

Hypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, diet-induced obesity (DIO) by high fat diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR, to mice. In the HFD context, LiPR rescued the survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. LiPR also rescued the reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. In addition, some of these neurogenic effects were exerted by another anti-obesity compound, Liraglutide. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.

Hyperprolactinemia Due to Prolactinoma has an Adverse Impact on Bone Health with Predominant Impact on Trabecular Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has holistically analysed and summarized the effect of prolactin excess due to prolactinomas on bone mineral metabolism. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for studies having patients with hyperprolactinemia due to prolactinoma and the other being a matched control group. The primary outcome was to evaluate the differences in BMD Z-scores at different sites. The secondary outcomes of this study were to evaluate the alterations in bone mineral density, bone mineral content and the occurrence of fragility fractures. RESULTS: Data from 4 studies involving 437 individuals was analysed to find out the impact of prolactinoma on bone mineral metabolism. Individuals with prolactinoma had significantly lower Z scores at the lumbar spine [MD -1.08 (95 % CI: -1.57 - -0.59); P < 0.0001; I2 = 54 % (moderate heterogeneity)] but not at the femur neck [MD -1.31 (95 % CI: -3.07 - 0.45); P = 0.15; I2 = 98 % (high heterogeneity)] as compared to controls. Trabecular thickness of the radius [MD -0.01 (95 % CI: -0.02 - -0.00); P = 0.0006], tibia [MD -0.01 (95 % CI: -0.02 - -0.00); P=0.03] and cortical thickness of the radius [MD -0.01 (95 % CI: -0.19 - -0.00); P = 0.04] was significantly lower in patients with prolactinoma as compared to controls. The occurrence of fractures was significantly higher in patients with prolactinoma as compared to controls [OR 3.21 (95 % CI: 1.64 - 6.26); P = 0.0006] Conclusion: Bone mass is adversely affected in patients with hyperprolactinemia due to prolactinoma with predominant effects on the trabecular bone.

Sex-specific behavioral and physiological changes during single parenting in a biparental species, Columba livia.

Many species exhibit biparental care to maximize fitness. When a partner is lost, the surviving partner may alter their behavior to compensate offspring. Whether both sexes use the same physiological mechanisms to manifest their change in behavior remains elusive. We investigated behaviors and mechanisms associated with the alteration of parental care post-partner removal in a biparental avian species, the rock dove (Columba livia). We hypothesized that rock dove single parents experience sex-biased changes in neural genomic transcription and reproductive behaviors, and these changes are related to chick development. We manipulated parental partner presence and measured parental attendance, offspring growth, gene expression of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) in the pituitary, and GR, MR, and estrogen receptor beta (ER-ß) in the hypothalamus. We also measured circulating plasma concentrations of the stress-associated hormone corticosterone and the parental care-associated hormone prolactin. We also quantified prolactin gene (PRL) expression changes in the pituitary, as well as prolactin receptor (PRLR) expression in the hypothalamus and pituitary. We found that single mothers and fathers maintained similar provisioning levels as paired parents, but spent less cumulative time brooding chicks. Chicks of single parents were smaller than paired-parented chicks after three days post-hatch. Mothers in both treatment groups experienced higher expression of hypothalamic GR as compared to fathers. Single parents experienced lower PRL gene expression in the pituitary as compared to paired parents. No significant differences were found for the circulating hormones or other genes listed.

Silicone prosthetics and anti-thyroid autoimmunity.

INTRODUCTION: In esthetic surgery, the use of silicone implants is a topic of hot discussion. MATERIAL AND METHODS: An analysis of 119 esthetic surgical interventions on the mammary gland was performed. A study of the immune and endocrine parameters after mammoplasty was carried out. RESULTS: The phenomenon of an increase in the levels of autoantibodies to the TSH receptor was revealed. The phenomenon of pre-operative growth of prolactin and TSH levels has been confirmed. An increase in thyroid autoimmunity after silicone mammoplasty is interpreted as a result of a silicone adjuvant action. An increase in the incidence of ASIA syndrome in patients who underwent breast surgery was registered. However, it was observed in both patients with silicone and non-silicone breast surgeries and therefore could not be solely explained by the use of silicone. Within 12 months following silicone mammoplasty, the patients with an increase of anti-TSH receptor autoimmunity nevertheless did not show any clinical and laboratory signs of overt thyroid disease, thus staying in a pre-nosological state. PRACTICAL RECOMMENDATIONS: Based on these results, we recommend the following for esthetic surgery: (a) all patients planned for silicone implant surgery should be examined for autoantibodies to the TSH receptor and (b) patients who have undergone breast endoprosthesis, starting 6 months after the operation, need long-term follow-up for thyroid status with mandatory testing for the level of these autoantibodies.

Influence of Vitamin D on the Incidence of Metabolic Syndrome and Hormonal Balance in Patients with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that affects 8-13% of women of reproductive age. It is one of the most common causes of infertility and is associated with hyperandrogenism in the form of hirsutism and acne, non-ovulatory cycles, and characteristic ovarian morphology. The available research on serum vitamin D deficiency in patients with PCOS and the appropriateness of vitamin D supplementation in this group of women is inconclusive, so we decided to investigate the influence of vitamin D on the incidence of metabolic syndrome and hormonal balance in patients with polycystic ovary syndrome. The study comprised 120 women aged between 18 and 42 years, who were divided into two groups: a group with diagnosed polycystic ovary syndrome (PCOS) and a group of regularly menstruating women without features of androgenisation, in whom polycystic ovary syndrome was excluded. Each patient underwent a history and physical examination, including a gynecological examination, anthropometric measurements were taken, including height, weight, waist, and hip circumference, and blood pressure was measured using the Korotkow method. In the female patients, the following parameters were also determined from the blood: follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, TSH, ft4, prolactin (PRL), total testosterone, DHEASO4, 17-hydroxyprogesterone (17-OHP), sex-hormone-binding globulin (SHBG), androstendione, 25(OH) vitamin D3 metabolite. The majority of the patients with polycystic ovary syndrome were found to have deficient or suboptimal serum vitamin D levels, and the effects of vitamin D on the SHBG levels and free-androgen indices in these patients was examined. The effects of vitamin D on the incidence of metabolic syndrome and BMI, waist-to-hip ratio, waist circumference, and blood pressure in patients with polycystic ovary syndrome were also found.

Age-related differences in the neuromuscular performance of fatigue-provoking exercise under severe whole-body hyperthermia conditions.

PURPOSE: The purpose of this study was to determine if aging would lead to greater decline in neuromuscular function during a fatiguing task under severe whole-body hyperthermia conditions. METHODS: Twelve young (aged 19-21 years) and 11 older (aged 65-80 years) males were enrolled in the study, which comprised a randomized control trial under a thermoneutral condition at an ambient temperature of 23°C (CON) and an experimental trial with passive lower body heating in 43°C water (HWI-43°C). Changes in neuromuscular function and fatigability, and physical performance-influencing factors such as psychological, thermoregulatory, neuroendocrine, and immune responses to whole-body hyperthermia were measured. RESULTS: A slower increase in rectal temperature, and a lower heart rate, thermal sensation, and sweating rate were observed in older males than young males in response to HWI-43°C trial (p < 0.05). Nevertheless, prolactin increased more in response to hyperthermia in young males, while interleukin-6 and cortisol levels increased more in older males (p < 0.05). Peripheral dopamine levels decreased in older males and increased in young males in response to hyperthermia (p < 0.05). Surprisingly, older males demonstrated greater neuromuscular fatigability resistance and faster maximal voluntary contraction (MVC) torque recovery after a 2-min sustained isometric MVC task under thermoneutral and severe hyperthermic conditions (p < 0.05). CONCLUSION: Neuromuscular performance during fatigue-provoking sustained isometric exercise under severe whole-body hyperthermia conditions appears to decline in both age groups, but a lower relative decline in torque production for older males may relate to lower psychological and thermophysiological strain along with a diminished dopamine response and prolactin release.

Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts.

Folic acid (FA) food fortification in Australia has resulted in a higher-than-expected intake of FA during pregnancy. High FA intake is associated with increased insulin resistance and gestational diabetes. We aimed to establish whether maternal one-carbon metabolism and hormones that regulate glucose homeostasis change in healthy pregnancies post-FA food fortification. Circulating folate, B12, homocysteine, prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy maternal blood in women with uncomplicated pregnancies prior to (SCOPE: N = 604) and post (STOP: N = 711)-FA food fortification. FA food fortification resulted in 63% higher maternal folate. STOP women had lower hPL (33%) and GH2 (43%) after 10 weeks of gestation, but they had higher PRL (29%) and hPL (28%) after 16 weeks. FA supplementation during pregnancy increased maternal folate and reduced homocysteine but only in the SCOPE group, and it was associated with 54% higher PRL in SCOPE but 28% lower PRL in STOP. FA food fortification increased maternal folate status, but supplements no longer had an effect, thereby calling into question their utility. An altered secretion of hormones that regulate glucose homeostasis in pregnancy could place women post-fortification at an increased risk of insulin resistance and gestational diabetes, particularly for older women and those with obesity.

Melatonin's actions are not limited to sleep.

Melatonin is widely available as a supplement, usually for sleep disorders. The consumption of melatonin supplements has increased considerably in recent years. An overlooked aspect of melatonin's administration is the resulting increase in prolactin secretion, via its action on hypothalamic dopaminergic neurons. We believe that since the effect of melatonin on prolactin is tangible, the laboratory finding of hyperprolactinemia could be encountered more often, given the increase in melatonin's use. This is an issue that merits further study.

Productive and physiological implications of top-dress addition of branched-chain amino acids and arginine on lactating sows and offspring.

BACKGROUND: Branched-chain amino acids (BCAAs), including L-leucine (L-Leu), L-isoleucine (L-Ile), L-valine (L-Val), and L-arginine (L-Arg), play a crucial role in mammary gland development, secretion of milk and regulation of the catabolic state and immune response of lactating sows. Furthermore, it has recently been suggested that free amino acids (AAs) can also act as microbial modulators. This study aimed at evaluating whether the supplementation of lactating sows with BCAAs (9, 4.5 and 9 g/d/sow of L-Val, L-Ile and L-Leu, respectively) and/or L-Arg (22.5 g/d/sow), above the estimated nutritional requirement, could influence the physiological and immunological parameters, microbial profile, colostrum and milk composition and performance of sows and their offspring. RESULTS: At d 41, piglets born from the sows supplemented with the AAs were heavier (P = 0.03). The BCAAs increased glucose and prolactin (P < 0.05) in the sows' serum at d 27, tended to increase immunoglobulin A (IgA) and IgM in the colostrum (P = 0.06), increased the IgA (P = 0.004) in the milk at d 20 and tended to increase lymphocyte% in the sows' blood at d 27 (P = 0.07). Furthermore, the BCAAs tended to reduce the Chao1 and Shannon microbial indices (P < 0.10) in the sows' faeces. The BCAA group was discriminated by Prevotellaceae_UCG-004, Erysipelatoclostridiaceae UCG-004, the Rikenellaceae_RC9_gut_group and Treponema berlinense. Arginine reduced piglet mortality pre- (d 7, d 14) and post-weaning (d 41) (P < 0.05). Furthermore, Arg increased the IgM in the sow serum at d 10 (P = 0.05), glucose and prolactin (P < 0.05) in the sow serum at d 27 and the monocyte percentage in the piglet blood at d 27 (P = 0.025) and their jejunal expression of NFKB2 (P = 0.035) while it reduced the expression of GPX-2 (P = 0.024). The faecal microbiota of the sows in Arg group was discriminated by Bacteroidales. The combination of BCAAs and Arg tended to increase spermine at d 27 (P = 0.099), tended to increase the Igs (IgA and IgG, P < 0.10) at d 20 in the milk, favoured the faecal colonisation of Oscillospiraceae UCG-005 and improved piglet growth. CONCLUSION: Feeding Arg and BCAAs above the estimated requirements for milk production may be a strategy to improve sow productive performance in terms of piglet average daily gain (ADG), immune competence and survivability via modulation of the metabolism, colostrum and milk compositions and intestinal microbiota of the sows. The synergistic effect between these AAs, noticeable by the increase of Igs and spermine in the milk and in the improvement of the performance of the piglets, deserves additional investigation.

Effects of Tele-Pilates and Tele-Yoga on Biochemicals, Physical, and Psychological Parameters of Females with Multiple Sclerosis.

BACKGROUND: People with multiple sclerosis (PwMS) suffer from some comorbidities, including physical and psychiatric disorders, low quality of life (QoL), hormonal dysregulation, and hypothalamic-pituitary-adrenal axis dysfunction. The current study aimed to investigate the effects of eight weeks of tele-yoga and tele-Pilates on the serum levels of prolactin and cortisol and selected physical and psychological factors. METHODS: Forty-five females with relapsing remitting multiple sclerosis, based on age (18-65), expanded disability status scale (0-5.5), and body mass index (20-32), were randomly assigned to tele-Pilates, tele-yoga, or control groups (n = 15). Serum blood samples and validated questionnaires were collected before and after interventions. RESULTS: Following online interventions, there was a significant increase in the serum levels of prolactin (p = 0.004) and a significant decrease in cortisol (p = 0.04) in the time × group interaction factors. In addition, significant improvements were observed in depression (p = 0.001), physical activity levels (p < 0.001), QoL (p ≤ 0.001), and the speed of walking (p < 0.001). CONCLUSION: Our findings suggest that tele-yoga and tele-Pilates training could be introduced as patient-friendly, non-pharmacological, add-on therapeutic methods for increasing prolactin and decreasing cortisol serum levels and achieving clinically relevant improvements in depression, walking speed, physical activity level, and QoL in female MS patients.

Whole-body vibration versus supervised aerobic exercise on hormonal parameters and inflammatory status in women with premenstrual syndrome: A randomized controlled trial.

OBJECTIVES: To compare the effects of whole-body vibration (WBV) and aerobic exercise on the hormonal profile and inflammatory status in women with premenstrual syndrome (PMS). METHODS: A prospective, randomized, pre-post-test, single-blind, controlled trial was conducted in 105 women diagnosed with PMS. They were randomized into three equal groups. All women received magnesium and vitamin B complex supplementation once daily. WBV training was added three times per week to the WBV group. The aerobic exercise group added aerobic exercise three times per week, while the control group received no additional intervention. The Premenstrual Syndrome Questionnaire (PMSQ) was used to assess PMS symptoms. Blood analysis was performed to measure hormone assays (estradiol, progesterone, prolactin, and cortisol) and high-sensitivity C-reactive protein at the start and after the end of the treatment program. RESULTS: There was no statistically significant difference between WBV and aerobic exercise according to PMSQ and high-sensitivity C-reactive protein (P = 0.99 and P = 0.98, respectively), but there was a statistically significant difference between both groups in cortisol, progesterone, prolactin, and estradiol (P = 0.001), with more favor given to the WBV group. CONCLUSION: WBV and aerobic exercise have positive effects on women with PMS, with more favor given to WBV.

Hypothalamic-prolactin axis regulation in major depressed patients with suicidal behavior.

BACKGROUND: So far, little is known about the control of hypothalamic-prolactin axis activity by dopamine (DA) and thyrotropin-releasing hormone (TRH) in depressed patients with suicidal behavior disorder (SBD). METHODS: We evaluated prolactin (PRL) responses to apomorphine (APO; a DA direct receptor agonist) and 0800 h and 2300 h protirelin (TRH) tests in 50 medication-free euthyroid DSM-5 major depressed inpatients with SBD (either current [n = 22], or in early remission [n = 28]); and 18 healthy hospitalized controls (HCs). RESULTS: Baseline (BL) PRL levels were comparable across the three diagnostic groups. SBDs in early remission did not differ from HCs regarding PRL suppression to APO (PRLs), PRL stimulation to 0800 h and 2300 h TRH tests (∆PRL), and ∆∆PRL values (difference between 2300 h-∆PRL and 0800 h-∆PRL values). Current SBDs showed lower PRLs and ∆∆PRL values than HCs and SBDs in early remission. Further analyses revealed that current SBDs with a history of violent and high-lethality suicide attempts were more likely to exhibit co-occurrence of low ∆∆PRL and PRLS values. CONCLUSIONS: Our results suggest that regulation of the hypothalamic-PRL axis is impaired in some depressed patients with current SBD, particularly those who have made serious suicide attempts. Considering the limitations of our study, our findings support the hypothesis that decreased pituitary D2 receptor functionality (possibly adaptive to increased tuberoinfundibular DAergic neuronal activity) together with decreased hypothalamic TRH drive might be a biosignature for high-lethality violent suicide attempts.

Myo-Inositol Potentiates the Inhibitory Effect of Metformin on Prolactin Levels.

INTRODUCTION: Metformin was found to reduce elevated levels of anterior pituitary hormones. Its thyrotropin-lowering effect was more pronounced in individuals receiving myo-inositol. The aim of the present study was to investigate whether the concomitant supplementation of myo-inositol determines the impact of metformin on prolactin levels. METHODS: The study population consisted of two groups of women with mild-to-moderate hyperprolactinemia. Group 1 included 24 individuals receiving myo-inositol preparations (2 g daily for at least 6 months), while 24 inositol-naïve women belonged to group 2. Both groups were matched for age, insulin sensitivity, and prolactin concentration. For the following 6 months, all women were treated with metformin (1.7 daily). Plasma glucose levels, the homeostatic model assessment of insulin resistance ratio (HOMA-IR), glycated hemoglobin, as well as plasma levels of total prolactin, monomeric prolactin, thyrotropin, free thyroid hormones, adrenocorticotropic hormone, and insulin-like growth factor-1 were measured at baseline and after 6 months of metformin treatment. RESULTS: Metformin reduced plasma glucose, HOMA-IR, and glycated hemoglobin in both study groups, but this effect was more pronounced in group 1 than group 2. Treatment-induced changes in total and monomeric prolactin levels were significant only in group 1. There were no differences between follow-up and baseline values of thyrotropin, free thyroxine, free tri-iodothyronine, adrenocorticotropic hormone, and insulin-like growth factor-1. Treatment-induced changes in prolactin concentration correlated with baseline prolactin levels, baseline values of HOMA-IR, and the impact of treatment on HOMA-IR. DISCUSSION: The obtained results suggest that myo-inositol supplementation potentiates the inhibitory effect of metformin on prolactin levels in women with hyperprolactinemia.

Hypothalamic GnRH expression and pulsatility depends on a balance of prolactin receptors in the plains vizcacha, Lagostomus maximus.

In mammals, gestation is considered a physiological hyperprolactinemia status. Prolactin (PRL) is one of the modulators of gonadotropin-releasing hormone (GnRH) neurons function. The South American plains vizcacha (Lagostomus maximus) is a unique model to study the regulation of hypothalamic GnRH neurons by direct and indirect steroid-dependent pathways. The aim was to characterize the hypothalamic expression of endocrine markers in vizcacha during gestation as well as their response to experimental induced hyperprolactinemia. The possible involvement of PRL regulatory pathways on GnRH in the context of hypothalamic and pituitary reactivation in mid-gestating vizcachas was discussed. Using two in vivo approaches, we determined changes in the hypothalamic expression and distribution of prolactin receptor (PRLR), tyrosine hydroxylase (TH), and dopamine type 2 receptor. A significant increment in the number of tuberoinfundibular dopaminergic (TIDA) neurons was determined in the arcuate nucleus from early to term pregnancy. On the other hand, at preoptic area, the number of both TH+PRLR+ and GnRH+PRLR+ double-labeled neurons significantly decreased at mid-pregnancy probably allowing the recovery of GnRH expression indicating that both types of neurons may represent the key points of PRL indirect and direct pathways modulating GnRH. Moreover, in a model of induced hyperprolactinemic vizcachas, the inhibitory effect of PRL on GnRH at both expression and delivery levels were confirmed. These results suggest the concomitant participation of both PRL regulatory pathways on GnRH modulation and pinpoint the key role of PRL on GnRH expression enabling the recovery of the hypothalamic activity during the gestation in this species.

Alterations in Hypothalamic Mechanisms Associated with Reduced Suckling-Induced Prolactin Secretion in the Lactation-Deficient OFA hr/hr Rat.

INTRODUCTION: OFA hr/hr rats have deficient lactation with impaired suckling-induced PRL release. Unlike their background strain, Sprague-Dawley (SD) rats, OFA rats display abnormal mediobasal hypothalamus (MBH) dopaminergic tone during late pregnancy and lactation. We explored if the expression of MBH components, including various receptors (R) and proteins that regulate the dopaminergic system, is altered in mid-lactating OFA compared to SD rats, which may be associated with the abnormality. METHODS: Four groups of mid-lactating rats were used: continuous lactation; pups separated overnight; 30-min suckling (S); and 2 h or 4 h S after separation. Mothers were sacrificed to obtain serum for PRL RIA and MBHs to determine tyrosine hydroxylase (TH), PRL-R, PRL signaling molecules (activator: STAT5b; inhibitors: SOCS1, SOCS3, CIS), opioids (PENK, PDYN), and µ- and κ-opioid R (MOR, KOR) mRNA expression by qPCR and phospho-TH (p-TH) and TH proteins by Western blot. RESULTS: Suckling-induced PRL was lower in OFA and p-TH expression diminished in both strains. Separation increased TH mRNA and protein in SD, which decreased after 4 h S, but OFA protein levels remained unchanged. Separation of pups also resulted in decreased PRL-R and CIS expression in SD but increased PRL-R and SOCS3 in OFA. Despite the lower PRL-R, STAT5b, SOCS1, and SOCS3 levels in OFA compared to SD, suckling diminished them further. We observed subtle changes in SD opioids and their R, but in OFA, suckling decreased PENK, KOR, and MOR. CONCLUSION: The different patterns of TH, opioids, their R, and PRL signaling inhibitor expression with conserved TH activation by suckling may disturb the balance between stimulation and inhibition of PRL release resulting in impaired suckling-induced PRL secretion in OFA rats.

Lactogenic effect of Polyscias scutellaria extract to maintain postpartum prolactin and oxytocin in lactating rats.

BACKGROUND: Hypogalactia remains a challenge for mother to complete exclusive breastfeeding. Shield aralia (Polysicias scutellaria) has been used by Indonesian society to increase breast milk production. OBJECTIVE: This study aimed to elucidate the novel galactopoietic effect of P. scutellaria extract (PSE) in lactating rats for three weeks. MATERIALS AND METHODS: PSE were assayed for total phenolic content (TPC), total flavonoid content (TFC), and antioxidant capacity. The secondary metabolites of PSE were determined by liquid chromatography-high-resolution mass spectrometry (LC-HRMS). After parturition, dams were randomly divided into four groups: lactating rats (LR) + distilled water (LRO), LR + Asifit, and LR + PSE at doses of 250 and 500 mg/kg body weight (BW). Virgin rats served as the control group. The treatments were given for 14 days. RESULTS: There were no significant differences (p > 0.05) in TPC, TFC, and antioxidant capacity among the three solvents. LC-HRMS revealed 22 compounds greater than 70 of the best-match, which were categorised as flavonoids, terpenoids, phenolic acids, and lignan. PSE increased the weight gain and survival rate of pups from our 3-week observation. Serum Prl was significantly higher (p < 0.05) in lactating rats treated with PSE 250 mg/kg BW at the first and third weeks than in the LRO group. Oxt serum was significantly higher (p < 0.05) in lactating rats treated with PSE (500 mg/kg BW) in the first and second weeks than in the LRO group. CONCLUSION: PSE-rich polyphenols are promising galactopoietics by orchestrating Prl and Oxt and reducing the mortality of pups.

Influence of form of selenium supplementation and tall fescue endophyte toxicity on growth performance, serum parameters, and tissue masses of grazing beef steers.

To test the hypothesis that average daily gain (ADG) and clinical parameters of steers grazing novel non-toxic (NTE) or toxic KY-31 (TE) endophyte-infected tall fescue would be improved by ad libitum intake of vitamin-mineral mixes (V-M) that contain 27 ppm Se as a 1:1 blend of SELPLEX:sodium selenite (MIX) vs. sodium selenite (ISe), 32 fescue-naïve beef steers partially depleted of Se were randomly assigned to ad libitum consumption ISe vs. MIX for 35 days and fed enough of a NTE/alfalfa/grain diet to achieve 0.57 kg BW gain/day. Then, within Se-form treatments, two steers were randomly assigned to each of four NTE (ISe = 316 ± 31 kg BW, MIX = 315 ± 22 kg BW) or TE (ISe = 316 ± 37 kg BW, MIX = 314 ± 39 kg BW) paddocks for 84 days and had ad libitum access to their respective V-M. The MIXED procedure of SAS was used to assess effects of day, Se-form (ISe, MIX) and endophyte (NTE, TE) treatments, and their interactions. Whole blood Se decreased (P < 0.01) 31% from days 0 to 84 and was 6.2% greater (P < 0.01) for MIX steers. Serum prolactin decreased (P < 0.01) 18% for NTE and 48% for TE steers from days 0 to 84 and was 17% greater (P = 0.01) for MIX vs. ISe for TE steers. Serum alkaline phosphatase activity decreased (P < 0.02) 27% from days 0 to 84 and was 15% greater (P < 0.02) for MIX steers. Serum urea nitrogen increased (P < 0.02) 8.2% from days 0 to 84 for TE but not NTE steers. Average daily gain was less (P < 0.01) for steers grazing TE (-0.18 kg/day) compared with NTE (0.09 kg/d). Although there was increased serum alkaline phosphatase activity and increased serum prolactin for TE + MIX steers compared with TE + ISe steers, MIX supplementation was unable to increase serum prolactin concentrations or ADG to the same levels as steers grazing NTE. Longer adaptation to MIX supplementation ad libitum may be necessary for maximal Se assimilation to restore serum prolactin levels in steers grazing TE.

Total Barley Maiya Alkaloids Prevent Increased Prolactin Levels Caused by Antipsychotic Drugs and Reduce Dopamine Receptor D2 via Epigenetic Mechanisms.

Background: The dopamine D2 receptor (DRD2) plays an important role in the increased prolactin (PRL) levels associated with the pathogenesis of antipsychotic drugs (ADs). Elevated prolactin levels can affect people's quality of life. Maiya alkaloids has been used to treat diseases associated with high PRL levels. Maiya, is a processed product of the mature fruits of Hordeum vulgare L. (a gramineous plant) after sprouting and drying and also a common Chinese herbal drug used in the clinic, is traditionally used to treat abnormal lactation, and is currently used clinically for the treatment of abnormal PRL levels. Aims: Epigenetic mechanisms can be related to DRD2 expression. We investigated the role of DRD2 methylation in the induction of PRL expression by ADs and the mechanism underlying the effects of total barley maiya alkaloids (TBMA) on this induction. Methods: The methylation rate of DRD2 in 46 people with schizophrenia who took risperidone was detected by MassARRAY sequencing. Humans were long term users of Ris. Seventy Sprague Dawley female rats were divided into seven groups. A rat model of risperidone-induced PRL was established, and the potential protective effects of TBMA and its components [e.g., hordenine (Hor)] on these increased PRL levels were investigated. The PRL concentration was detected by Enzyme-linked immunosorbent assay. PRL, DRD2, and DNA methyltransferase (DNMT1, DNMT3α, and DNMT3ß) protein and mRNA expression were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The positive rate of methylation in the DRD2 promoter region of rats was detected by MassARRAY sequencing. Results: Clinical studies showed that the positive rate of DRD2 methylation associated with increased PRL levels induced by ADs was significantly higher than in the normal prolactinemia (NPRL) group. In vivo and vitro, TBMA and Hor inhibited this induction of PRL expression and increased DRD2 expression by inhibiting the expression of the DNMTs. Conclusions: TBMA and hordenine increased DRD2 expression by inhibiting DNMT-dependent DRD2 methylation.

Hyperandrogenism induces proportional changes in the expression of Kiss-1, Tac2, and DynA in hypothalamic KNDy neurons.

BACKGROUND: Kisspeptin released from Kiss-1 neurons in the hypothalamus plays an essential role in the control of the hypothalamic-pituitary-gonadal axis by regulating the release of gonadotropin-releasing hormone (GnRH). In this study, we examined how androgen supplementation affects the characteristics of Kiss-1 neurons. METHODS: We used a Kiss-1-expressing mHypoA-55 cell model that originated from the arcuate nucleus (ARC) of the mouse hypothalamus. These cells are KNDy neurons that co-express neurokinin B (NKB) and dynorphin A (DynA). We stimulated these cells with androgens and examined them. We also examined the ARC region of the hypothalamus in ovary-intact female rats after supplementation with androgens. RESULTS: Stimulation of mHypoA-55 cells with 100 nM testosterone significantly increased Kiss-1 gene expression by 3.20 ± 0.44-fold; testosterone also increased kisspeptin protein expression. The expression of Tac3, the gene encoding NKB, was also increased by 2.69 ± 0.64-fold following stimulation of mHypoA-55 cells with 100 nM testosterone. DynA gene expression in these cells was unchanged by testosterone stimulation, but it was significantly reduced at the protein level. Dihydrotestosterone (DHT) had a similar effect to testosterone in mHypoA-55 cells; kisspeptin and NKB protein expression was significantly increased by DHT, whereas it significantly reduced DynA expression. In ovary-intact female rats, DTH administration significantly increased the gene expression of Kiss-1 and Tac3, but not DynA, in the arcuate nucleus. Exogenous NKB and DynA stimulation failed to modulate Kiss-1 gene expression in mHypoA-55 cells. Unlike androgen stimulation, prolactin stimulation did not modulate kisspeptin, NKB, or DynA protein expression in these cells. CONCLUSIONS: Our observations imply that hyperandrogenemia affects KNDy neurons and changes their neuronal characteristics by increasing kisspeptin and NKB levels and decreasing DynA levels. These changes might cause dysfunction of the hypothalamic-pituitary-gonadal axis.

Dysregulation of serum prolactin links the hypothalamus with female nociceptors to promote migraine.

Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms. A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats-Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats-Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice. Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.