Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.

Concentrations of Ca, Mg, P, Prostaglandin E2 in Bones and Parathyroid Hormone; 1,25-dihydroxyvitamin D3; 17-ß-estradiol; Testosterone and Somatotropin in Plasma of Aging Rats Subjected to Physical Training in Cold Water.

Exposure to low temperatures can be considered a stressor, which when applied for a specific time can lead to adaptive reactions. In our study we hypothesized that cold, when applied to the entire body, may be a factor that positively modifies the aging process of bones by improving the mechanisms related to the body's mineral balance. Taking the above into account, the aim of the study was to determine the concentration of calcium (Ca), magnesium (Mg), and phosphorus (P) in bones, and to examine bone density and concentrations of the key hormones for bone metabolism, namely parathyroid hormone (PTH), somatotropin (GH), 1,25-dihydroxyvitamin D3, 17-ß estradiol, testosterone (T) in plasma, and prostaglandin E2 (PGE2) in the bone of aging rats subjected to physical training in cold water. The animals in the experiment were subjected to a series of swimming sessions for nine weeks. Study group animals (male and female respectively) performed swimming training in cold water at 5 ± 2 °C and in water with thermal comfort temperature (36 ± 2 °C). Control animals were kept in a sedentary condition. Immersion in cold water affects bone mineral metabolism in aging rats by changing the concentration of Ca, Mg, and P in the bone, altering bone mineral density and the concentration of key hormones involved in the regulation of bone mineral metabolism. The effect of cold-water immersion may be gender-dependent. In females, it decreases Ca and Mg content in bones while increasing bone density and 17-ß estradiol and 1,25-dihydroxyvitamin D3 levels, and with a longer perspective in aging animals may be positive not only for bone health but also other estrogen-dependent tissues. In males, cold water swimming decreased PTH and PGE2 which resulted in a decrease in phosphorus content in bones (with no effect on bone density), an increase in 1,25-dihydroxyvitamin D3, and increase in T and GH, and may have positive consequences especially in bones and muscle tissue for the prevention of elderly sarcopenia.

The effects of 14-week betaine supplementation on endocrine markers, body composition and anthropometrics in professional youth soccer players: a double blind, randomized, placebo-controlled trial.

OBJECTIVE: Betaine supplementation may enhance body composition outcomes when supplemented chronically during an exercise program. The purpose of this study was to evaluate the effect of betaine supplementation on development-related hormones, body composition, and anthropometrics in professional youth soccer players during a competitive season. METHODS: Twenty-nine players (age, 15.45 ± 0.25 years) were matched based upon position and then randomly assigned to a betaine group (2 g/day; n = 14, BG) or placebo group (PG, n = 15). All subjects participated in team practices, conditioning, and games. If a subject did not participate in a game, a conditioning protocol was used to ensure workload was standardized throughout the 14-week season. Growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol, height, weight, and body composition were assessed at pre-season (P1), mid-season (P2) and post-season (P3). Anthropometric variables were also measured following a one-year follow-up (F). RESULTS: Significant (p < 0.05) group x time interactions were found for testosterone and testosterone to cortisol ratio (T/C). Both variables were greater in BG at P2 and P3 compared to P1, however, the testosterone was less in the PG at P3 compared to P2. There was no significant group by time interactions for GH, IGF-1, lean body mass, or body fat. There was a significant (p < 0.05) group x time interaction in height and weight at F, with the greater increases in BG compared to PG. CONCLUSION: Betaine supplementation increased testosterone levels and T/C ratio in youth professional soccer players during a competitive season. Betaine supplementation had no negative effects on growth (height and weight) and may attenuate reductions in testosterone due to intense training during puberty.

In ovo green light photostimulation during the late incubation stage affects somatotropic axis activity.

Targeted green light photostimulation during the last stage of broiler incubation increases expression of the somatotropic axis. The purpose of this study was to further shorten the in ovo green light photostimulation and determine the critical age for photostimulation in broilers embryos, as a future strategy for broiler incubation. Fertile broilers eggs (n = 420) were divided into 5 treatment groups. The first group was incubated under standard conditions (in the dark) as the negative control group. The second was incubated under intermittent monochromatic green light using light-emitting diode lamps with an intensity of 0.1 W/m2 at shell level from embryonic day (ED) 0 of incubation until hatch, as a positive control. The third, fourth, and fifth groups were incubated under intermittent monochromatic green light from ED 15, 16, and 18 of incubation, respectively, until hatch. All treatment groups showed elevated somatotropic axis expression compared with the negative control, with the group incubated under monochromatic green light from ED 18 until hatch showing results closest to the positive control. This suggests that broiler embryos can be exposed to in ovo green light photostimulation from a late stage of incubation (when transferring the eggs to the hatchery) and exhibit essentially the same outcome as obtained by photostimulation during the entire incubation period.

Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6-/Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.

[Effect of heat-sensitive moxibustion at "Zhongwan" (CV 12) on serum GH and PG in chronic atrophic gastritis rats].

OBJECTIVE: To observe the effect of heat-sensitive moxibustion at "Zhongwan" (CV 12) on serum growth hormone (GH) and pepsinogen (PG) in chronic atrophic gastritis (CAG) rats, and to explore the potential mechanism of heat-sensitive moxibustion for CAG. METHODS: A total of 66 male SD rats were randomized into a blank group (12 rats) and a model establishment group (54 rats). No intervention was given in the blank group. Rats in the model establishment group were intervented with compound pathogeny method for 12 weeks to establish CAG model, which were further divided into a model group (11 rats), a vitacoenzyme group (11 rats) and a moxibustion group (22 rats). In the moxibustion group, suspending moxibustion was applied at "Zhongwan" (CV 12) for 40 min. After the intervention of moxibustion, 0.9% sodium chloride solution was given by gavage (2 mL·kg-1·d-1). According to the changes of tail temperature, rats in the moxibustion group were divided into a heat-sensitive moxibustion group (11 rats) and a non-heat-sensitive moxibustion group (8 rats). The vitacoenzyme group was given vitacoenzyme as the same dose by gavage. The intervention was adopted once a day for 28 days. Changes of body weight were observed among the groups. Expressions of serum GH, PGⅠand PGⅡwere detected by ELISA, and the ratio of PGⅠand PGⅡ (PGR) was calculated. The morphological changes of gastric mucosa were observed by macroscopy and light microscope. RESULTS: ①After modeling, the body weight of rats in the model establishment group was lower than the blank group (P<0.01). Compared with the model group, the body weight of rats in the vitacoenzyme group, the heat-sensitive moxibustion group and the non-heat-sensitive moxibustion group was increased after intervention (P<0.05), and there were no significant differences among the intervention groups (P>0.05). ②Under macroscopy and light microscope, gastric tissue of rats after modeling showed dark red and pale gastric mucosa, lower plica and mucosal congestion. The glands of lamina propria were atrophied or disappeared with sparse and disordered arrangement, in which, lymphoid follicles and inflammatory cells could be observed. After intervention, morphology of gastric mucosa was improved in the vitacoenzyme group, the heat-sensitive moxibustion group and the non-heat-sensitive moxibustion group. ③Compared with the blank group, the serum levels of GH, PGⅠ, PGⅡ and PGR were decreased in the model group (P<0.05, P<0.01). Compared with the model group, the serum levels of GH, PGⅠand PGⅡwere increased in the vitacoenzyme group, the heat-sensitive moxibustion group and the non-heat-sensitive moxibustion group (P<0.05, P<0.01), the levels of PGR were increased without statistical difference (P>0.05). Compared with the vitacoenzyme group and the non-heat-sensitive moxibustion group, the serum levels of GH and PGⅠwere increased in the heat-sensitive moxibustion group (P<0.05). CONCLUSION: Heat-sensitive moxibustion at "Zhongwan" (CV 12) can improve the morphology of gastric mucosa in chronic atrophic gastritis rats, its mechanism may be related to the up-regulation of serum GH and PGⅠ.

Effects of vitamin D3 supplementation for 12 weeks on serum levels of anabolic hormones, anaerobic power, and aerobic performance in active male subjects: A randomized, double-blind, placebo-controlled trial.

Maintenance of the serum 25-hydroxyvitamin D (25-OH-D) concentration at recommended levels is essential due to its role in the regulation of anabolic hormones and athletic performance. However, the results of the clinical experiments in athletes are controversial. The present study aimed to investigate the effect of vitamin D3 supplement on serum levels of anabolic hormones, cortisol, anaerobic and aerobic performance in active males. In this double-blind, randomized controlled trial, 46 active males randomly assigned to vitamin D3 supplement (VDS; 2000 IU/day) or placebo for 12 weeks. The Wingate test, VO2max, and serum levels of 25-OH-D, Parathyroid hormone (PTH), total testosterone, growth hormone (GH), Insulin-like growth factor-1 (IGF-1), and cortisol were assessed. Subjects in the VDS group had a higher serum level of 25-OH-D (p = 0.004), VO2max (p = 0.016), and average power (p = 0.044) compared to the placebo at the end of the study. Also, lower levels of PTH (p = 0.004) and fatigue index (p < 0.001) were observed in VDS group at the end of the study. The serum cortisol levels were reduced significantly only in subjects with vitamin D deficiency in VDS group (p = 0.042). There was a significant reduction in serum testosterone levels in VDS group (p = 0.013). No change was indicated in serum levels of GH and IGF-1 in VDS group compared to the placebo (p > 0.05). The present study showed an improvement in aerobic capacity, anaerobic performance, and vitamin D status following vitamin D3 supplementation. However, more studies are required for the effect of vitamin D3 on serum concentration of anabolic hormones.

Effect of in ovo feeding of ß-hydroxy-ß-methylbutyrate on hatchability, muscle growth and performance in prenatal and posthatch broilers.

BACKGROUND: ß-Hydroxy-ß-methylbutyrate (HMB) is the metabolite of leucine that plays an important role in muscle protein metabolism. The objective of the present study was to determine the effects of in ovo feeding (IOF) of HMB at 7 days of incubation (DOI) via air cell or 18 DOI via amnion on hatchability, muscle growth and performance in prenatal and posthatch broilers. RESULTS: IOF of HMB via air cell at 7 DOI increased hatchability by 4.34% compared with the control (89.67% versus 85.33%). Birds in IOF groups exhibited higher body weight, average daily body weight gain and pectoral muscle percentage. Furthermore, IOF of HMB significantly increased the level of plasma growth hormone, insulin and insulin-like growth factor-1. Chicks hatched from IOF treatment had larger diameters of muscle fiber and higher mitotic activity of satellite cells at early posthatch age. IOF of HMB activated satellite cells by upregulation of mRNA expression of myogenic transcription factors, myogenic differentiation one (MyoD) and myogenin. Chicks hatched from air cell injection group had higher pectoral muscle percentage at 5 d posthatch and greater satellite cell mitotic activity at 7 d posthatch than counterparts from amnion injection group. CONCLUSIONS: IOF of HMB via amnion at 18 DOI or especially via air cell at 7 DOI could be used as an effective approach to enhance hatchability, productive performance and breast muscle yield in broilers. © 2019 Society of Chemical Industry.

Bioactive growth hormone in humans: Controversies, complexities and concepts.

OBJECTIVE: To revisit a finding, first described in 1978, which documented existence of a pituitary growth factor that escaped detection by immunoassay, but which was active in the established rat tibia GH bioassay. METHODS: We present a narrative review of the evolution of growth hormone complexity, and its bio-detectability, from a historical perspective. RESULTS: In humans under the age of 60, physical training (i.e. aerobic endurance and resistance training) are stressors which preferentially stimulate release of bioactive GH (bGH) into the blood. Neuroanatomical studies indicate a) that nerve fibers directly innervate the human anterior pituitary and b) that hind limb muscle afferents, in both humans and rats, also modulate plasma bGH. In the pituitary gland itself, molecular variants of GH, somatotroph heterogeneity and cell plasticity all appear to play a role in regulation of this growth factor. CONCLUSION: This review considers more recent findings on this often forgotten/neglected subject. Comparison testing of a) human plasma samples, b) sub-populations of separated rat pituitary somatotrophs or c) purified human pituitary peptides by GH bioassay vs immunoassay consistently yield conflicting results.

Effect of dietary copper sources on performance, gastric ghrelin-RNA expression, and growth hormone concentrations in serum in piglets.

Two performance studies were conducted to investigate the effects of 3 different sources of Cu on production parameters of piglets. A total of 256 piglets weaned at 24 ± 2 d were randomly allocated into 4 treatments with 10 or 8 replicates per treatment of 4 or 3 piglets per pen in Exp. 1 and 2, respectively. The experimental period was divided into 3 feeding phases: Phase 1 (24 to 35 d), Phase 2 (36 to 49 d), and Phase 3 (50 to 70 d). Treatments included a Control group (fed 10 mg/kg of Cu from CuSO4), a group fed 160 mg/kg of either CuSO4 (CuSO4-160) or tri-basic copper chloride (TBCC), and a group fed Cu methionine hydroxy analogue chelated (Cu-MHAC) at 150, 80, and 50 mg/kg in Phases 1, 2, and 3, respectively. The methionine value of Cu-MHAC was accounted during diet formulation to achieve the same levels of methionine across treatments. Phases 1 and 2 diets contained 2,200 and 1,500 ppm of ZnO, respectively; and antibiotics were used as growth promoters. Performance parameters were analyzed as completely randomized block design, in which each experiment was considered as a block. In trial 2, blood serum and mucosal samples, from the fundic region of the stomach, were collected from 1 piglet per replicate at day 70 and tested for serum growth hormone levels (GH) and ghrelin mRNA expression, respectively. The contrast between Cu-MHAC vs. CuSO4-160 + TBCC showed that piglets fed Cu-MHAC exhibited better feed conversion ratio (FCR) in all feeding phases compared with feeding inorganic Cu (P < 0.05). Overall, feeding Cu-MHAC improved body weight (BW), BW gain, feed intake (FI), and FCR vs. Control diet fed piglets; yet, it improved BW and FCR vs. TBCC fed piglets, and improved BW, BW gain, and FI vs. CuSO4-160 fed piglets (P < 0.05). Feeding TBCC promoted similar performance than feeding CuSO4-160, regardless of age (P > 0.05). Both ghrelin expression and growth hormone serum levels were significantly increased by feeding Cu-MHAC vs. Control diet fed animals (P < 0.01). Feeding CuSO4-160 upregulated ghrelin expression vs. Control (P < 0.01) while GH serum levels and ghrelin expression did no change by feeding TBCC compared with Control diet fed animals (P > 0.05). It was concluded that feeding Cu-MHAC at the levels tested herein can improve growth performance of piglets beyond feeding 160 ppm of either CuSO4 or TBCC, which may be partially explained by the increased expression of ghrelin and GH serum levels.

Effects of combined treatment with blood flow restriction and low-current electrical stimulation on muscle hypertrophy in rats.

This study aimed to clarify the effects of a combined treatment comprising blood flow restriction and low-current electrical stimulation on skeletal muscle hypertrophy in rats. Male Wistar rats were divided into control (Cont), blood flow restriction (Bfr), electrical stimulation (Es), or Bfr with Es (Bfr + Es) groups. Pressure cuffs (80 mmHg) were placed around the thighs of Bfr and Bfr + Es rats. Low-current Es was applied to calf muscles in the Es and Bfr + Es rats. In experiment 1, a 1-day treatment regimen (5-min stimulation, followed by 5-min rest) was delivered four times to study the acute effects. In experiment 2, the same treatment regimen was delivered three times/wk for 8 wk. Body weight, muscle mass, changes in maximal isometric contraction, fiber cross-sectional area of the soleus muscle, expression of phosphorylated and total-ERK1/2, phosphorylated-rpS6 Ser235/236, phosphorylated and total Akt, and phosphorylated-rpS6 Ser240/244 were measured. Bfr and Es treatment alone failed to induce muscle hypertrophy and increase the expression of phosphorylated rpS6 Ser240/244. Combined Bfr + Es upregulated muscle mass, increased the fiber cross-sectional area, and increased phosphorylated rpS6 Ser240/244 expression and phosphorylated rpS6 Ser235/236 expression compared with controls. Combined treatment with Bfr and low-current Es can induce muscle hypertrophy via activation of two protein synthesis signaling pathways. This treatment should be introduced for older patients with sarcopenia and others with muscle weakness.NEW & NOTEWORTHY We investigated the acute and chronic effect of low-current electrical stimulation with blood flow restriction on skeletal muscle hypertrophy and the mechanisms controlling the hypertrophic response. Low-current electrical stimulation could not induce skeletal muscle hypertrophy, but a combination treatment did. Blood lactate and growth hormone levels were increased in the early response. Moreover, activation of ERK1/2 and mTOR pathways were observed in both the acute and chronic response, which contribute to muscle hypertrophy.

[The influence of chronic intermittent hypoxia on hypothalamic-somatotropic axis in rats].

Objective: To investigate the effects of chronic intermittent hypoxia on somatotropic axis hormone levels in rats. Methods: Mature male Wistar rats were exposed to air or intermittent hypoxia randomly.The serum levels of growth hormone-releasing hormone (GHRH), growth hormone (GH) and somatostatin (SS) were measured before exposure, at the 4th, 8th, and 12th week after exposure. Different hormone levels in two groups were compared and analyzed. Results: Compared with the control group, GHRH levels in chronic intermittent hypoxic group showed a significant decline at the 4th week [(732.77±46.99)pg/ml vs. (893.59±40.00) pg/ml, P<0.05], while SS levels at the 8th week [(30.71±2.27) pg/ml vs. (44.69±3.36) pg/ml, P<0.05] and GH levels at the 12th week [(1.20±0.29) ng/ml vs. (2.06±0.13) ng/ml, P<0.05] were similarly reduced. As the duration of intermittent hypoxia was prolonged, the GHRH levels did not decrease further [4th week (732.77±46.99) pg/ml vs. 8th week (607.54±131.61) pg/ml vs. 12th week (730.05±40.63) pg/ml, P>0.05].However, the serum SS levels decreased further from the 8th week to the 12th week [(30.71±2.27) pg/ml vs. (24.41±4.06) pg/ml, P<0.05]. Conclusion: Chronic intermittent hypoxia might inhibit the function of somatotropic axis. Hypothalamic hormones are the earlyonesto be influenced, thereafter the entire axis.

Influence of Sodium Citrate Supplementation after Dehydrating Exercise on Responses of Stress Hormones to Subsequent Endurance Cycling Time-Trial in the Heat.

Background and objectives: In temperate environments, acute orally induced metabolic alkalosis alleviates exercise stress, as reflected in attenuated stress hormone responses to relatively short-duration exercise bouts. However, it is unknown whether the same phenomenon occurs during prolonged exercise in the heat. This study was undertaken with aim to test the hypothesis that ingestion of an alkalizing substance (sodium citrate; CIT) after dehydrating exercise would decrease blood levels of stress hormones during subsequent 40 km cycling time-trial (TT) in the heat. Materials and Methods: Male non-heat-acclimated athletes (n = 20) lost 4% of body mass by exercising in the heat. Then, during a 16 h recovery period prior to TT in a warm environment (32 °C), participants ate the prescribed food and ingested CIT (600 mg·kg-1) or placebo (PLC) in a double-blind, randomized, crossover manner with 7 days between the two trials. Blood aldosterone, cortisol, prolactin and growth hormone concentrations were measured before and after TT. Results: Total work performed during TT was similar in the two trials (p = 0.716). In CIT compared to PLC trial, lower levels of aldosterone occurred before (72%) and after (39%) TT (p ˂ 0.001), and acute response of aldosterone to TT was blunted (29%, p ˂ 0.001). Lower cortisol levels in CIT than in PLC trial occurred before (13%, p = 0.039) and after TT (14%, p = 0.001), but there were no between-trial differences in the acute responses of cortisol, prolactin or growth hormone to TT, or in concentrations of prolactin and growth hormone before or after TT (in all cases p > 0.05). Conclusions: Reduced aldosterone and cortisol levels after TT and blunted acute response of aldosterone to TT indicate that CIT ingestion during recovery after dehydrating exercise may alleviate stress during the next hard endurance cycling bout in the heat.

Vitamin D and growth hormone in children: a review of the current scientific knowledge.

BACKGROUND: Human growth is a complex mechanism that depends on genetic, environmental, nutritional and hormonal factors. The main hormone involved in growth at each stage of development is growth hormone (GH) and its mediator, insulin-like growth factor 1 (IGF-1). In contrast, vitamin D is involved in the processes of bone growth and mineralization through the regulation of calcium and phosphorus metabolism. Nevertheless, no scientific study has yet elucidated how they interact with one another, especially as a dysfunction in which one influences the other, even if numerous biochemical and clinical studies confirm the presence of a close relationship. MAIN BODY: We reviewed and analyzed the clinical studies that have considered the relationship between vitamin D and the GH/IGF-1 axis in pediatric populations. We found two main areas of interest: the vitamin D deficiency status in patients affected by GH deficit (GHD) and the relationship between serum vitamin D metabolites and IGF-1. Although limited by some bias, from the analysis of the studies presented in the scientific literature, it is possible to hypothesize a greater frequency of hypovitaminosis D in the subjects affected by GHD, a reduced possibility of its correction with only substitution treatment with recombinant growth hormone (rGH) and an improvement of IGF-1 levels after supplementation treatment with vitamin D. CONCLUSIONS: These results could be followed by preventive interventions aimed at reducing the vitamin D deficit in pediatric age. In addition, further research is needed to fully understand how vitamin D and growth are intertwined.

Effects of EBN on embryo implantation, plasma concentrations of reproductive hormones, and uterine expressions of genes of PCNA, steroids, growth factors and their receptors in rats.

This study was conducted to determine the effect of edible bird's nest (EBN) supplement on uterine function and embryo-implantation rate. A total of 24 adult female rats, divided equally into four groups, were treated with different doses of EBN for 8 weeks. In the last week of treatment, intact fertile male rats were introduced into each group (three per group) for overnight for mating. On day 7 post-mating (post-implantation), blood samples were collected from the hearts of anaesthetised rats that were later sacrificed. The uteri were removed for assessment of embryo implantation rate, histological and electron microscopic examination, and immunohistochemical analyses. Results showed that as the concentration of EBN supplemented increased, the pregnancy and embryo implantation rates were also increased in the treated groups; significantly at G3 and G4. Although histological evaluation did not show much difference among the groups, scanning electron microscopic examination showed enhanced development of elongated microvilli and pinopods in G4. Results also revealed up-regulated expressions of epidermal growth factor (EGF), EGF receptor (EGFR), vascular endothelial growth factor (VEGF), proliferating cell nulear antigen (PCNA), and progesterone and estrogen receptors (P4R, E2R) in the uteri of treated groups. Moreover, plasma E2, P4, growth hormone (GH) and prolactin (P) levels were higher (p < 0.05) in G3 and G4. The EBN increased the antioxidant (AO) and total AO capacities (TAC) and reduced oxidative stress (OS) levels in pregnant rats. In conclusion, findings of this study revealed that EBN enhances fertility and embryo implantation rate via promoting proliferation and differentiation of uterine structures as evidenced by the upregulation of the expressions of steroid receptors, EGF, EGFR, VEGF, and PCNA in the uterus. Furthermore, observations of improved growth of ultrastructural pinopods that assist in embryo attachment with uterine epithelium, increased concentrations of E2, P4, GH and P levels, as well as increased AO capacities with reduced OS levels in the treated groups might reflect additional possible mechanisms by which EBN enhances embryo implantation rate and pregnancy success.

Interrelationship between late gestational ewe factor and early life lamb factors in semi-arid tropical region.

The limitation in feed availability in the semi-arid region during the lean period can result in a variation of the body condition, body weight of pregnant ewe which in turn may affect the lamb birth weight, colostrum immunoglobulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Therefore, the present study was initiated to assess the interrelationship between late gestational ewe factor and early life lamb factors in the semi-arid tropical region. For this purpose, 83 Malpura and 45 Avikaline pregnant ewes were selected and their body condition score (BCS) at late gestation, body weight at lambing, and birth weight of lambs was recorded. The BCS of ewes in late gestation had significant (P < 0.001) positive correlation (r2 = 0.465) with the birth weight of lambs. The body weight at lambing was significantly (P < 0.05) higher in single-lamber ewes as compared to twin-bearing ewes. The plasma IGF-1 of lamb increased significantly (P < 0.05) with the increase of BCS of ewe at the late gestation as well as body weight after lambing. The colostrum of twin-lamb producing ewes had higher (P < 0.05) IgG content than single-lamb producing ewes. The concentration of IGF-1 was significantly (P < 0.05) higher in single-born lamb as compared to twin-born lamb. Based on the results of the present study, it is to conclude that higher BCS at late gestation and higher body weight of ewes at lambing is desirable for producing lambs with a higher birth weight having higher growth potential as well as chances of survival.

Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats.

PURPOSE: Growth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats. MATERIALS AND METHODS: The serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects. RESULTS: Oral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However, oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagogue receptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression. CONCLUSION: Our results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatory effect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.

PLAG1 expression and target genes in the hypothalamo-pituitary system in male mice.

Knockout of pleomorphic adenoma gene 1 (PLAG1) in mice results in reduced fertility. To investigate whether PLAG1 is involved in reproductive control by the hypothalamo-pituitary system in males, we determined PLAG1 expression sites and compared gene expression between hypothalami and pituitary glands from Plag1 knockout and wildtype animals. Abundant expression of PLAG1 was detected throughout the pituitary gland, including gonadotropes and somatotropes. The hypothalamus also contained a large number of PLAG1-expressing cells. PLAG1 was expressed in some gonadotropin-releasing hormone neurons, but not in kisspeptin neurons. Gene ontology analysis indicated upregulation of cell proliferation in both structures, and of cholesterol biosynthesis in the hypothalamus, but functional confirmation is required. Expression levels of pituitary gonadotropins and gonadotropin-releasing hormone receptor, and of brain gonadotropin-releasing hormone and kisspeptin mRNA were unaffected in knockout mice. We conclude that PLAG1 deficiency does not have a major impact on the reproductive control by the hypothalamo-pituitary system.

Ghrelin stimulates growth hormone release from the pituitary via hypothalamic growth hormone-releasing hormone neurons in the cichlid, Oreochromis niloticus.

Ghrelin, a gut-brain peptide hormone, is implicated in a multiplicity of biological functions, including energy homeostasis and reproduction. Neuronal systems that are involved in energy homeostasis as well as reproduction traverse the hypothalamus; however, the mechanism by which they control energy homeostasis is not fully understood. The present study analyzes the anatomical relationship of neurons expressing gonadotropin-releasing hormone (GnRH), neuropeptide Y (NPY) and growth hormone-releasing hormone (GHRH) in a cichlid, tilapia (Oreochromis niloticus). Additionally, we examine in vivo effects of ghrelin on these hypothalamic neurons and plasma growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. Double-immunofluorescence showed neuronal fiber associations between GnRH, NPY and GHRH in the brain and pituitary. Intracerebroventricular injection of ghrelin had no effect on numbers, soma size, or optical density of GnRH and NPY neurons, whereas the number of GHRH neurons was significantly decreased in the animals injected with ghrelin when compared to controls, which may indicate administered ghrelin promoted GHRH release. Plasma GH and pituitary GH mRNA levels were significantly increased in the animals injected with ghrelin. These results suggest that central administration of ghrelin primarily act on hypothalamic GHRH neurons to stimulate GH release from the pituitary in the tilapia.

Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice.

Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period.