Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macimorelin in Children with Suspected Growth Hormone Deficiency: An Open-Label, Group Comparison, Dose-Escalation Trial.

BACKGROUND/AIMS: Diagnosis of growth hormone deficiency (GHD) in children requires the use of provocative growth hormone (GH) stimulation tests, which can have limited reliability and are potentially contraindicated in some patients. This is the first paediatric study to test the safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics (PD) of macimorelin, an oral GH secretagogue, approved for diagnosis of adult GHD. METHODS: In this open-label, group comparison, single-dose escalation trial (EudraCT 2018-001988-23), sequential cohorts of patients (C1-C3) received ascending single doses of macimorelin: 0.25 (C1), 0.5 (C2), and 1.0 (C3) mg/kg. Primary endpoints were safety and tolerability, and secondary endpoints were PK/PD. RESULTS: Twenty-four patients aged between 2 and <18 with suspected GHD participated in the study. No macimorelin-related adverse events were reported, and macimorelin was well tolerated. Plasma macimorelin concentrations increased with dose: mean areas under the curve were 6.69 (C1), 18.02 (C2), and 30.92 (C3) h × ng/mL; mean maximum concentrations were 3.46 (C1), 8.13 (C2), and 12.87 (C3) ng/mL. GH concentration increased following macimorelin administration: mean times of maximum measured concentration were 52.5 (C1), 37.5 (C2), and 37.5 (C3) min. CONCLUSION: All 3 doses of macimorelin had excellent safety and tolerability with PK/PD profiles in expected ranges. These results support the use of 1.0 mg/mL macimorelin in a Phase 3 test validation trial in children.

Interleukin-2 Transiently Inhibits Pulsatile Growth Hormone Secretion in Young but not Older Healthy Men.

CONTEXT: Interleukin-2 (IL-2), a proinflammatory cytokine, has been used to treat malignancies. Increased cortisol and adrenocorticotropin (ACTH) were noted, but growth hormone (GH) secretion was not investigated in detail. OBJECTIVE: We quantified GH secretion after a single subcutaneous injection of IL-2 in 17 young and 18 older healthy men in relation to dose, age, and body composition. METHODS: This was a placebo-controlled, blinded, prospectively randomized, crossover study. At 20:00 hours IL-2 (3 or 6 million units/m2) or saline was injected subcutaneously. Lights were off between 23:00 and 07:00 hours. Blood was sampled at 10-minute intervals for 24 hours. Outcome measures included convolution analysis of GH secretion. RESULTS: GH profiles were pulsatile under both experimental conditions and lower in older than young volunteers. Since the effect of IL-2 might be time limited, GH analyses were performed on the complete 24-hour series and the 6 hours after IL-2 administration. Total and pulsatile 24-hour GH secretion decreased nonsignificantly. Pulsatile secretion fell over the first 6 hours after IL-2 (P = .03), with visceral fat as a covariate (P = .003), but not age (P = .10). Plots of cumulative 2-hour bins of GH pulse mass showed a distinction by treatment and age groups: A temporary GH decrease of 32% and 28% occurred in the first 2-hour bins after midnight (P = .02 and .04) in young participants, whereas in older individuals no differences were present at any time point. CONCLUSION: This study demonstrates that IL-2 temporarily diminishes GH secretion in young, but not older, men.

Pregnancy, but not dietary octanoic acid supplementation, stimulates the ghrelin-pituitary growth hormone axis in mice.

Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4-13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P < 0.001), regardless of diet. At ZT13, serum concentrations of total ghrelin (P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

Nicotine inhibits expression of Prrx1 in pituitary stem/progenitor cells through epigenetic regulation, leading to a delayed supply of growth-hormone-producing cells.

OBJECTIVE: Nicotine, a toxic component of smoking, adversely affects animal growth and reproduction by decreasing secretion of anterior pituitary hormones. However, it has not been clarified whether nicotine inhibits the supply of endocrine cells in the pituitary gland. The present study investigated short- and long-term effects of persistent nicotine exposure on the pituitary glands of young animals. DESIGN: Three-week-old male Wistar rats were exposed to nicotine (1 mg/kg body weight/day) for 7 days, and gene expression, cell numbers, and DNA methylation status were analyzed on the following day and 4 weeks after final treatments. RESULTS: The expression level of the stem cell marker Sox2 was not changed by nicotine exposure throughout the experiment. On the other hand, nicotine inhibited expression of a progenitor cell marker, Prrx1, and growth hormone (Gh). Immunohistochemical analysis showed that the SOX2-positive cells positive for PRRX1 in nicotine-treated groups decreased to 61% (4-week-old) and 70% (8-week-old) of the saline-treated controls. In addition, the proportion of GH-positive cells in nicotine-treated group was 14% lower than that of saline-treated controls. Furthermore, first intron hypermethylation of Prrx1 was detected by a bisulfite sequence of genomic DNA from the anterior lobe of the rat pituitary gland. CONCLUSIONS: We show that persistent nicotine exposure in young animals inhibits expression of Prrx1 in pituitary stem/progenitor cells through epigenetic regulation, leading to a delayed supply of GH-producing cells.

Effects of recombinant bovine interleukin-8 (rbIL-8) treatment on health, metabolism, and lactation performance in Holstein cattle IV: Insulin resistance, dry matter intake, and blood parameters.

We have shown in 2 independent studies that cows who received recombinant bovine interleukin-8 (rbIL-8) administered intrauterinely shortly after parturition have a significant and long-lasting increase in milk yield. In the present study, we hypothesized that the increased milk production associated with rbIL-8 treatment is a consequence of increased postpartum dry matter intake (DMI) and orchestrated homeorhetic changes that prioritize milk production. Cows were enrolled into 1 of 3 treatment groups: those assigned to the control group (CTR; n = 70) received an intrauterine (IU) administration of 500 mL of Dulbecco's phosphate-buffered saline (DPBS) solution and 1 mL of DPBS solution intravenously (IV; jugular vein), those assigned to the rbIL-8 IV group (rbIL8-IV, n = 70) received an IV injection of 167 µg of rbIL-8 and 500 mL of DPBS solution IU, and cows assigned to the rbIL-8 IU group (rbIL8-IU, n = 70) received an IU administration with 1,195 µg of rbIL-8 diluted in 499.5 mL of DPBS solution and 1 mL of DPBS solution IV. Animals were housed in a tiestall from calving to 30 d in milk (DIM) to measure DMI. Blood samples were collected daily from calving to 7 DIM and weekly until 28 DIM. Insulin resistance was evaluated using an intravenous glucose tolerance test and intravenous insulin challenge test (IVICT) in a subgroup of cows (n = 20/treatment) at 10 and 11 DIM, respectively. Additionally, liver biopsy samples were taken at 14 DIM from the same subgroup of cows to measure triglyceride levels and cell proliferation and apoptosis. Cows treated with rbIL8-IU produced more milk (CTR = 36.9 ± 1.5; rbIL8-IU = 38.5 ± 1.5; rbIL8-IV = 36.6 ± 1.5 kg/d), energy-corrected milk (CTR = 42.9 ± 0.9; rbIL8-IU = 46.1 ± 0.8; rbIL8-IV = 43.7 ± 0.9 kg/d), and fat-corrected milk (CTR = 44.3 ± 0.9; rbIL8-IU = 47.8 ± 0.9; rbIL8-IV = 45.2 ± 0.9 kg/d) yields when compared with CTR cows, and no differences were observed between rbIL8-IV and CTR cows. The administration of rbIL8-IU significantly increased DMI compared with CTR (CTR = 18.8 ± 0.3; rbIL8-IU = 19.9 ± 0.3; rbIL8-IV = 19.3 ± 0.3 kg/d). Recombinant bIL-8 treatment did not affect glucose, insulin, or fatty acids (i.e., IVICT only) concentrations or their area under the curve in response to an intravenous glucose tolerance test and IVICT when compared with CTR. Moreover, rbIL-8 treatment administered IU or IV increased liver triglyceride levels. Additionally, cows treated with rbIL8-IU tended to have lower odds of developing hyperketonemia (odds ratio = 0.46, 95% confidence interval: 0.19 to 1.10), lower odds of clinical ketosis and displaced abomasum combined (odds ratio = 0.17, 95% confidence interval: 0.03 to 0.89), and lower odds of diseases combined (odds ratio = 0.43, 95% confidence interval: 0.21 to 0.86) when compared with CTR. We conclude that the administration of rbIL8-IU increases DMI, milk production, fat-corrected milk, and energy-corrected milk while improving overall health during the postpartum period. This study supports the use of rbIL-8 administered IU shortly after calving to improve health and production responses in lactating cows.

Association of total, acylated and unacylated ghrelin with apolipoprotein A1 and insulin concentrations in acromegalic patients.

BACKGROUND: Ghrelin is a hormone that occurs in acylated (AG) or unacylated (UG) form. Ghrelin strongly stimulates growth hormone (GH) secretion from anterior pituitary, as well as regulates the energy balance and various metabolic parameters. Increased consideration is given to UG, thought to be inactive. OBJECTIVES: We aimed to evaluate the levels of total ghrelin, AG and UG in medically naive and treated patients with biochemically active acromegaly, with respect to variables of lipid and glucose metabolism. MATERIAL AND METHODS: We studied total ghrelin, AG and calculated UG levels in a group of 24 patients with active acromegaly and 15 healthy controls. Plasma levels of GH, insulin-like growth factor 1 (IGF-1), insulin, glucose, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and calculated low-density lipoprotein (LDL) cholesterol, triglycerides (TG), apolipoproteins A1 (APO A1), and B-100 (APO B-100) were measured. RESULTS: Patients with acromegaly revealed lower levels of total ghrelin than healthy controls. In pooled data of all subgroups, simple linear regression analysis revealed that total ghrelin concentration was significantly associated with APO A1 concentration (ß = 0.8087; p = 0.0315) and AG concentration was significantly associated with fasting insulin concentration (ß = 15.5183; p = 0.011). There was an inverse association between UG and the patients' age, and positive association between UG and APO A1. CONCLUSIONS: Our results suggest that ghrelin may influence metabolic disturbances in acromegaly. It seems that the assessment of AG and UG is superior to total ghrelin measurement. Mechanisms regulating ghrelin acylation and function of each form need elucidation in order to improve diagnostics and treatment of metabolic disturbances, not only acromegaly.

Myostatin regulates pituitary development and hepatic IGF1.

Circulating myostatin-attenuating agents are being developed to treat muscle-wasting disease despite their potential to produce serious off-target effects, as myostatin/activin receptors are widely distributed among many nonmuscle tissues. Our studies suggest that the myokine not only inhibits striated muscle growth but also regulates pituitary development and growth hormone (GH) action in the liver. Using a novel myostatin-null label-retaining model (Jekyll mice), we determined that the heterogeneous pool of pituitary stem, transit-amplifying, and progenitor cells in Jekyll mice depletes more rapidly after birth than the pool in wild-type mice. This correlated with increased levels of GH, prolactin, and the cells that secrete these hormones, somatotropes and lactotropes, respectively, in Jekyll pituitaries. Recombinant myostatin also stimulated GH release and gene expression in pituitary cell cultures although inhibiting prolactin release. In primary hepatocytes, recombinant myostatin blocked GH-stimulated expression of two key mediators of growth, insulin-like growth factor (IGF)1 and the acid labile subunit and increased expression of an inhibitor, IGF-binding protein-1. The significance of these findings was demonstrated by smaller muscle fiber size in a model lacking myostatin and liver IGF1 expression (LID-o-Mighty mice) compared with that in myostatin-null (Mighty) mice. These data together suggest that myostatin may regulate pituitary development and function and that its inhibitory actions in muscle may be partly mediated by attenuating GH action in the liver. They also suggest that circulating pharmacological inhibitors of myostatin could produce unintended consequences in these and possibly other tissues.

Dynamic Ghrelin and GH serum levels during combined simultaneous arginine clonidine stimulation test in children with dwarfism.

BACKGROUND: Combined simultaneous arginine clonidine stimulation (CSACS) test represents a more appropriate stimulus to detect Ghrelin, for it does not affect glucose metabolism. METHODS: Fifty prepubertal children with dwarfism were recruited and further classified into normal growth hormone (NGH) and growth hormone deficiency (GHD) group with growth hormone (GH) peak cut-off value of 10 µg/l. In both groups, GH and Ghrelin serum levels were determined after the GH provocation test at 30, 60, and 120 min and the height standard deviation score (SDS) for bone age was measured six months later. RESULTS: The participants were classified into NGH (n = 24) and GHD group (n = 26). A decrease in the circulating Ghrelin levels prior to the GH peak was observed in the NGH children, whereas both GH and Ghrelin levels demonstrated a rise in the GHD children. Ghrelin level in GHD group was higher compared with NGH group and the GH peak in GHD group is lower than NGH group. The 6 months CSACS treatment could increase the height SDS in both groups. CONCLUSION: Although analogous changes were not detected in GHD group, the inverse correlation between GH and Ghrelin in NGH indicates a negative feedback lying between GH and Ghrelin.

Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions.

The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.

The effects of aflatoxin B1 on growth hormone regulated gene-1 and interaction between DNA and aflatoxin B1 in broiler chickens during hatching.

Many types of aflatoxin cause problems for both public and animal health. Aflatoxin B1 (AFB1) is the most toxic and commonly encountered fungal toxin that appears in poultry feed and in feeds stored under unsuitable conditions. AFB1 decreases feed quality, egg production and fertility of hatching eggs. Also, AFB1 alters the development of embryos by infecting eggs. We investigated using sequence analysis the changes caused by different concentrations of AFB1 on the promoter sequences of the growth hormone regulated gene-1 (GHRG-1) in chick embryo at 13, 17, 19 and 21 days incubation. DNA isolated from the liver of chick embryos treated with different concentrations of AFB1 was separated using agarose gel electrophoresis to detect apoptosis, and DNA interaction with AFB1 was investigated using plasmids to detect changes in electrophoretic mobility and their effects on DNA. Base changes of the promoter sequences of GHRG-1 in 5 ng/egg, 15 ng/egg and 40 ng/egg doses of AFB1 were increased on day 19 compared to base changes of the same AFB1 doses on day 13. We also found that AFB at different concentrations changed the mobility of DNA by binding to it, and that high doses of AFB1 destroyed DNA. The DNA interaction study using plasmid demonstrated that AFB1 at high doses was bound to plasmid DNA, slowed its mobility and inhibited restriction cuts.

Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice.

Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of hexarelin (200 µg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with hexarelin treatment. Interestingly, although food intake of hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of hexarelin in treatment of lipid disorders associated with the metabolic syndrome.

Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe.

Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.

Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins.

Context: Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined. Objective: The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. Materials and Methods: In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. Results: Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. Conclusions: Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway.

Effect of pre- and postpartum supplementation with lipid-encapsulated conjugated linoleic acid on reproductive performance and the growth hormone-insulin-like growth factor-I axis in multiparous high-producing dairy cows.

The objective of the study was to evaluate the effect of prepartum and postpartum (PP) supplementation with 2 isomers of conjugated linoleic acid (CLA) on reproductive parameters and some related metabolic factors in dairy cows. High-producing, multiparous Holstein Friesian cows (n = 60) were allotted to 3 treatment groups: the CLA1 group (n = 20) was supplemented with 70 g of lipid-encapsulated CLA providing 7 g each of cis-9,trans-11 and trans-10,cis-12 CLA from d 21 (d 21) before expected calving until d 7 after artificial insemination (AI), that is, until 77 to 91 d PP; the CLA2 group (n = 20) was supplemented with the same amount of CLA beginning at calving until d 7 after AI; and the control group (n = 20) received an isocaloric, isonitrogenous, and isolipidic diet. Blood samples were taken weekly to measure glucose, insulin, insulin-like growth factor-I (IGF-I), and leptin. Liver biopsy was performed in 10 cows per group for growth hormone receptor 1A and IGF-I mRNA analyses. At d 49 to 63 PP, ovulation was synchronized with the Pre-Synch protocol followed by fixed-time AI. Milk progesterone was monitored from calving until d 35 post-AI. Cows returning to estrus following AI were inseminated. Supplementation with CLA before calving improved the recovery of plasma leptin levels in the early PP period (from the day of calving until wk 3 PP; treatment effect). Later PP (wk 5), plasma IGF-I, and leptin remained significantly higher in both CLA1 and CLA2 groups compared with control, although hepatocellular IGF-I mRNA was not different among groups. Plasma IGF-I levels remained higher in both CLA-treated groups on the day of AI. Growth hormone receptor 1A mRNA levels in hepatic tissue decreased in all groups, reaching a nadir in the first week PP. Days to first PP ovulation did not differ between groups; however, both supplemented groups conceived earlier compared with control (d 97 ± 19, d 97 ± 23, and d 113 ± 30 for CLA1, CLA2, and control, respectively). Plasma progesterone concentration was higher in both supplemented groups on d 2 to 5 following the synchronized ovulation than in controls. We concluded that CLA supplementation around calving alters PP metabolic signals as reflected by higher plasma leptin and IGF-I levels. Conjugated linoleic acid stimulated early luteal function and reduced the PP interval to conception.

Effects of a dietary crude fibre concentrate on growth in weaned piglets.

Many fibre sources can help the adaptation of piglets at weaning, improving the growth. In this study, the effects of a dietary crude fibre concentrate (CFC) on piglet's growth was investigated. From 31 to 51 days of age, 108 weaned piglets (D×(Lw×L)), had access to two isofibrous, isoenergetic and isonitrogenous diets, supplemented with 1% of CFC (CFC group) or not (control (CON) group). From days 52 to 64 all piglets received the same starter diet. During the dietary treatment period the CFC group showed higher average daily gain, average daily feed intake and feed efficiency (P<0.001) than CON group. At 64 days of age, BW was higher in CFC group compared with CON group (P<0.001). Blood samples were collected at days 31, 38, 45 and 52 of age. From days 31 to 52 significant differences in the somatotropic axis between groups were observed. In particular, growth hormone levels were higher only at the end of the 1st week of dietary treatment (P<0.05) in CFC group animals compared with CON group animals. The IGF-I trend was similar between groups even if the IGF-I levels were higher in the CFC group than CON group 1 week after starting treatment (P<0.01). The IGF-binding protein 3 (IGFBP-3) levels were higher in the first 2 weeks of dietary treatment and lower in the 3rd week in CON group compared with CFC group (P<0.01). Specifically, the IGFBP-3 profile was consistent with that of IGF-I in CFC group but not in CON group. At the same time, an increase of leptin in CFC compared with CON group was observed (P<0.05). Piglets fed the CFC diet showed a lower diarrhoea incidence (P<0.05) and a lower number of antibiotic interventions (P<0.05) than CON diet from 31 to 51 days of age. Pig-major acute-phase protein plasma level (P<0.01) and interleukin-6 gene expression (P<0.05) were higher in CON group than CFC group at the end of 1st week of dietary treatment. In conclusion, this study showed that CFC diet influences the hormones related to energy balance enhancing the welfare and growth of piglets. Furthermore, the increase in feed intake during 3 weeks of dietary treatment improved the feed efficiency over the entire post-weaning period.

2,4,6-Tribromophenol Interferes with the Thyroid Hormone System by Regulating Thyroid Hormones and the Responsible Genes in Mice.

2,4,6-Tribromophenol (TBP) is a brominated flame retardant (BFR). Based on its affinity for transthyretin, TBP could compete with endogenous thyroid hormone. In this study, the effects of TBP on the thyroid hormone system were assessed in mice. Briefly, animals were exposed to 40 and 250 mg/kg TBP. Thyroid hormones were also administered with or without TBP. When mice were treated with TBP, deiodinase 1 (Dio1) and thyroid hormone receptor ß isoform 2 (Thrß2) decreased in the pituitary gland. The levels of deiodinase 2 (Dio2) and growth hormone (Gh) mRNA increased in response to 250 mg/kg of TBP, and the relative mRNA level of thyroid stimulating hormone ß (Tshß) increased in the pituitary gland. Dio1 and Thrß1 expression in the liver were not altered, while Dio1 decreased in response to co-treatment with thyroid hormones. The thyroid gland activity decreased in response to TBP, as did the levels of free triiodothyronine and free thyroxine in serum. Taken together, these findings indicate that TBP can disrupt thyroid hormone homeostasis and the presence of TBP influenced thyroid actions as regulators of gene expression. These data suggest that TBP interferes with thyroid hormone systems.

Estradiol and corticosterone stimulate the proliferation of a GH cell line, MtT/S: Proliferation of growth hormone cells.

OBJECTIVES: Estrogens are known as a potent growth-stimulator of the anterior pituitary cells such as prolactin cells and somatomammotroph cell lines, while glucocorticoids often inhibit cellular proliferation in the pituitary gland as well as in the extra-pituitary tissues. In this study, the involvement of these steroid hormones in the regulation of proliferation was examined in the MtT/S cells, secreting growth hormone (GH). DESIGN: Effects of estrogens and glucocorticoids were examined in MtT/S cells grown in the medium containing dextran-coated charcoal treated serum. The relative cell density after culture was estimated by the Cell Titer-Glo Luminescent Cell Viability Assay System, and the proliferation rate was determined by the BrdU incorporation method. The mRNA levels were determined by real-time PCR. RESULTS: Estradiol and the specific agonist for both estrogen receptor (ER) α and ERß stimulated MtT/S growth at a dose dependent manner. The membrane impermeable estrogen, 17ß-estradiol-bovine serum albumin conjugate also stimulated the MtT/S proliferation. The effects of all estrogens were inhibited by an estrogen receptor antagonist, ICI182780. Corticosterone stimulated the proliferation of MtT/S cells at doses lower than 10nM without stimulating GH gene transcription, whereas it did not change the proliferation rate at 1µM. The effects of corticosterone were inhibited by glucocorticoid receptor inhibitor, RU486, but not by the mineralocorticoid receptor antagonist, spironolactone. Both estrogens and glucocorticoids were found to stimulate the proliferation of MtT/S, increasing the mRNA expression of cyclins D1, D3, and E. CONCLUSIONS: The results suggest that estrogens and glucocorticoids may be involved in the mechanisms responsible for the proliferation of GH cells in the course of pituitary development, to maintain the population of GH cells in the adult pituitary gland, and also in the promotion of GH cell tumors.

Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives.

OBJECTIVES: Estetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4 blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. METHODS: This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 µg LNG; or 20 µg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated. RESULTS: A total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4 groups, and the effects on triglycerides elicited by the E4 groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4 groups. CONCLUSIONS: E4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters.

The appropriate standardized ileal digestible tryptophan to lysine ratio improves pig performance and regulates hormones and muscular amino acid transporters in late finishing gilts fed low-protein diets.

This study investigated the effects of various standardized ileal digestible (SID) Trp to Lys ratios on the performance and carcass characteristics of late finishing gilts receiving low-CP (9.6%) diets supplemented with crystalline AA. Ninety gilts (89.1 ± 5.1 kg) were used in a dose-response study conducted for 35 d. Crystalline Trp (0, 0.1, 0.2, 0.4, or 0.6 g/kg) was added to a corn-wheat bran basal diet providing SID Trp to Lys ratios of 0.12, 0.15, 0.18, 0.21, or 0.24. Each diet was fed to 6 pens of pigs with 3 gilts per pen. At the end of the experiment, 30 gilts (1 pig per pen) were slaughtered to evaluate carcass traits and meat quality (BW = 121 kg). Increasing the SID Trp to Lys ratio increased ADG (linear and quadratic effect, < 0.05) and also improved G:F (linear and quadratic effect, < 0.05). Serum urea nitrogen (SUN) decreased as the SID Trp to Lys ratio increased (linear and quadratic effects, < 0.05). A quadratic effect of L* light and marbling in the longissimus dorsi was observed as the dietary SID Trp to Lys ratio increased ( < 0.05). Increasing the SID Trp to Lys ratio increased the level of serum GH (quadratic effect, < 0.05) and also increased the level of serum IGF-1 (linear and quadratic effect, < 0.05). Increasing the SID Trp to Lys ratio increased the protein abundance of the muscular AA transporter of sodium-coupled neutral amino acid transporter 2 (SNAT2) in the longissimus dorsi muscle (linear and quadratic effect, < 0.05). The optimum SID Trp to Lys ratios to maximize ADG and G:F as well as to minimize SUN levels were 0.16, 0.17, and 0.16 using a linear-breakpoint model and 0.20, 0.20, and 0.20 using a quadratic model. Tryptophan could influence serum GH and IGF-1 secretion and protein abundance of the muscular AA transporter of SNAT2 in the longissimus dorsi muscle in late finishing gilts fed low-protein diets.

Effect of cancer treatment on hypothalamic-pituitary function.

The past 30 years have seen a great improvement in survival of children and young adults treated for cancer. Cancer treatment can put patients at risk of health problems that can develop many years later, most commonly affecting the endocrine system. Patients treated with cranial radiotherapy often develop dysfunction of the hypothalamic-pituitary axis. A characteristic pattern of hormone deficiencies develops over several years. Growth hormone is disrupted most often, followed by gonadal, adrenal, and thyroid hormones, leading to abnormal growth and puberty in children, and affecting general wellbeing and fertility in adults. The severity and rate of development of hypopituitarism is determined by the dose of radiotherapy delivered to the hypothalamic-pituitary axis. Individual growth hormone deficiencies can develop after a dose as low as 10 Gy, whereas multiple hormone deficiencies are common after 60 Gy. New techniques in radiotherapy aim to reduce the effect on the hypothalamic-pituitary axis by minimising the dose received. Patients taking cytotoxic drugs do not often develop overt hypopituitarism, although the effect of radiotherapy might be enhanced. The exception is adrenal insufficiency caused by glucocorticosteroids which, although transient, can be life-threatening. New biological drugs to treat cancer can cause autoimmune hypophysitis and hypopituitarism; therefore, oncologists and endocrinologists should be vigilant and work together to optimise patient outcomes.