Effects Of GH Research Articles

Corneal biomechanical properties of patients with acromegaly

PurposeGrowth hormone (GH) and insulin-like growth factor-1 (IGF-1) excess in acromegaly have various effects on many organs. The ophthalmologic effects of GH and IGF-1 excess have not yet been investigated...

Comparison of Growth Hormone Treatment in Patients with Idiopathic Short Stature and Idiopathic Growth Hormone Deficiency

After recombinant human growth hormone (rhGH) was introduced in the treatment of patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS), many studies have addressed the effect of GH treatment and changes in the height standard deviation score (SDS) after GH treatment. However, few studies comparing the effect of GH in Korean patients with idiopathic GHD and ISS have been designed. Therefore, this study focused on the difference in effect of GH treatment between the two groups. We retrospectively reviewed the height SDS of 34 patients with idiopathic GHD and 12 patients with ISS. The mean ages of the patients with idiopathic GHD and ISS were 9.84±2.09 and 10.72±1.48 years, respectively. All patients were treated with GH for 1 year and body parameters were recorded before and after the GH treatment. Change in height SDS in patients with idiopathic GHD was significantly higher than that in patients with ISS (0.62±0.33 vs. 0.40±0.27, p=0.03). However, body mass index, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were not significantly different between the two groups after GH treatment. These results suggest that GH treatment has a more powerful effect on increasing height SDS in patients with idiopathic GHD than in patients with ISS.

Effects of Recombinant Human Growth Hormone Therapy on Bone Mineral Density in Adults With Growth Hormone Deficiency: A Meta-Analysis

GH deficiency is associated with decreased bone mineral density (BMD) and increased fracture risk. Because the effects of recombinant human GH (rhGH) therapy on BMD and bone mineral content have not been systematically investigated, we conducted a meta-analysis of pertinent studies. A thorough search of the literature (MEDLINE, EMBASE, and the Cochrane Register) was performed. Relevant studies were divided and analyzed according to their design (randomized/controlled or prospective/retrospective) and duration of rhGH therapy (≤12 months and > 12 months). Administration of rhGH led to a significant increase in lumbar spine (LS) and femoral neck (FN) BMD in randomized/controlled studies of more than 1 year [weighted mean difference (95% confidence interval)] of 0.038 g/cm(2) (0.011-0.065) and 0.021 g/cm(2) (0.006-0.037) at the LS and FN, respectively, and a nonsignificant drop at the same sites in studies of shorter duration. In prospective studies, a significant increase in the LS and FN BMD was obtained. On meta-regression, a negative association was observed between the change in LS and FN BMD and subjects' age and a positive association between the BMD change and treatment duration. In a subgroup analysis, the increase in LS and FN BMD was significant in men [0.048 g/cm(2) (0.033-0.064) and 0.051 g/cm(2) (0.003-0.098), respectively] but not in women. This meta-analysis suggests a beneficial effect of rhGH replacement on BMD in adults with GH deficiency. This effect is affected by gender, age, and treatment duration. Larger studies are needed to evaluate the effect of rhGH on fracture risk.

Chapter 28 - Uncertainties in endocrine substitution therapy for central endocrine insufficiencies: growth hormone deficiency

The growth hormone deficiency (GHD) syndrome is associated with several metabolic abnormalities and it has been postulated that the increased cardiovascular disease (CVD) morbidity and mortality in GHD patients may be related to the missing metabolic effects of GH. Many CVD risk factors show improvements after GH therapy. Reduced bone mineral density (BMD) has been recorded both in patients with isolated GHD and in those with multiple pituitary deficiencies, indicating that GHD per se is responsible for the low BMD in both types of patients. These matters are, however, more complicated, as hypopituitary patients with GHD may have different phenotypes due to differences in underlying diagnoses. These phenotypes may not be clear-cut in individual patients. Moreover, patients may transit between different phenotypes over time due to extension of the pathology in the pituitary and/or the consequences of the treatment (surgery and/or radiotherapy). Three different phenotypes of hypopituitary patients will be discussed, with a focus on CVD risk and bone health: (1) patients with isolated GHD, e.g. due to prophylactic cranial radiotherapy for lymphoblastic leukaemia in childhood; (2) patients with GHD and multiple hormone deficiencies due to pituitary macroadenomas treated by surgery; (3) patients with GHD caused by craniopharyngiomas with multiple hormone deficiencies and hypothalamic involvement, where hypothalamic damage frequently dominates the positive metabolic effects of GH therapy. These phenotypes illustrate the differential impact of various pituitary pathologies on the phenotype of patients with GHD.

Short-Term Administration of Pegvisomant Improves Hepatic Insulin Sensitivity and Reduces Soleus Muscle Intramyocellular Lipid Content in Young Adults With Type 1 Diabetes

Data on the metabolic effects of GH derived from studies using GH suppression by pharmacological agents may not reflect selective actions. The purpose of this study was to evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). In a randomized, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline and after 4 weeks of treatment with either 10 mg of pegvisomant or placebo. The assessments included an overnight euglycemic steady state followed by a hyperinsulinemic euglycemic clamp and used glucose and glycerol cold stable isotopes. Hepatic and peripheral insulin sensitivity (IS), lipid turnover, and intramyocellular lipid (IMCL) were measured. Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (P < .001). During the overnight steady state, insulin requirements for euglycemia (P = .019), insulin levels (P = .008), and glucose production rates (Ra) (P = .033) were reduced. During the clamp study, glucose infusion rates (P = .031) increased and glucose Ra (P = .015) decreased whereas glucose disposal rates were unchanged. Free fatty acid levels were similar during the steady state but were lower during the clamp (P = .040) after pegvisomant. Soleus muscle IMCL decreased after treatment (P = .024); however, no change in tibialis anterior muscle was observed. The study demonstrates that GH antagonism in T1D results in improved hepatic insulin sensitivity. Lack of consistent changes in free fatty acid levels may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH-induced alterations in IMCL may not be causally linked to glucose metabolism.

Impact of the growth hormone replacement on bone status in growth hormone deficient adults

IntroductionGrowth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated. ObjectivesThe objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD. Patients and MethodsAdult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2years. Lumbar spine (L1–L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24. ResultsIn total, 147 GHD patients (age 35.1years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2years, respectively; p<0.0001).Bone markers increased during the first 12months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p=0.02).BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p=0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p=0.004). ConclusionGH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.

In Memoriam: William H. Daughaday, MD (1918–2013)

Dr William H. Daughaday, the 51st President of The Endocrine Society, died at age 95 on May 3, 2013. His contributions to endocrinology and to the Society were wide-ranging and numerous, not the least of which was the large cohort of physicians attracted to fundamental and clinical endocrine research by his enthusiasm, energy, and overwhelming intellectual curiosity. Bill Daughaday grew up in greater Chicagoland and attended Harvard College. There he was captain of the wrestling team and was inducted into Phi Beta Kappa. After graduation from Harvard Medical School in 1943, where he was selected for the Alpha Omega Alpha honor society, he served in the Army as a medical officer for 20 months during the latter part of World War II and then returned stateside to continue his clinical and scientific training, initially with Robert H. Williams at Boston City Hospital. In 1947, he moved to Washington University School of Medicine in St Louis as an Assistant Resident in Medicine at Barnes Hospital. He joined the laboratory of Carl and Gerty Cori in 1949 as a Research Fellow and began to investigate the metabolic actions of GH on isolated rat diaphragm. Despite the failure of these studies to explain the (even then) well-known anti-insulin effects of GH, this apparently unpromising exploratory project set into motion a life-long interest in all things GH (1). In 1951, Bill Daughaday formed his own research laboratory and became head of a new Metabolism Division in the Department of Medicine at Washington University (he was acting head in 1950), which he continued to lead for the next 34 years. Under his guidance, the Metabolism Division developed into one of the premier endocrinology units in the country, known for high-level research productivity and superb scientific training, as evidenced by the dozens of former fellows who have occupied leadership positions in academic medicine throughout the world. This drive for excellence was amplified by combined clinical and research activities with the Division of Bone and Mineral Metabolism at neighboring Jewish Hospital of St Louis and with the Division of Endocrinology and Metabolism at St Louis Children’s Hospital. The environment nurtured by Bill guaranteed that trainees

MEAT SCIENCE AND MUSCLE BIOLOGY SYMPOSIUM—Mechanism of growth hormone stimulation of skeletal muscle growth in cattle1

Growth hormone, also called somatotropin (ST), is a polypeptide hormone produced by the anterior pituitary. The major functions of GH include stimulating bone and skeletal muscle growth, lipolysis, milk production, and expression of the IGF-I gene in the liver. Based on these functions, recombinant bovine ST (bST) and recombinant porcine ST (pST) have been used to improve milk production in dairy cows and lean tissue growth in pigs, respectively. However, despite these applications, the mechanisms of action of GH are not fully understood. Indeed, there has been a lot of controversy over the role of liver-derived circulating IGF-I and locally produced IGF-I in mediating the growth-stimulatory effect of GH during the last 15 yr. It is in this context that we have conducted studies to further understand how GH stimulates skeletal muscle growth in cattle. Our results do not support a role of skeletal muscle-derived IGF-I in GH-stimulated skeletal muscle growth in cattle. Our results indicate that GH stimulates skeletal muscle growth in cattle, in part, by stimulating protein synthesis in muscle through a GH receptor-mediated, IGF-I-independent mechanism. In this review, besides discussing these results, we also argue that liver-derived circulating IGF-I should be still considered as the major mechanism that mediates the growth-stimulatory effect of GH on skeletal muscle in cattle and other domestic animals.

Action of GH on skeletal muscle function: molecular and metabolic mechanisms

Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports and muscle function in the elderly. This paper critically reviews information on the effects of GH on muscle function covering structure, protein metabolism, the role of IGF1 mediation, bioenergetics and performance drawn from molecular, cellular and physiological studies on animals and humans. GH increases muscle strength by enhancing muscle mass without affecting contractile force or fibre composition type. GH stimulates whole-body protein accretion with protein synthesis occurring in muscular and extra-muscular sites. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. GH exerts complex multi-system effects on skeletal muscle function in part mediated by the IGF system.

Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

SUMMARYMembers of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

Effects of GH on Body Composition and Cardiovascular Risk Markers in Young Men With Abdominal Obesity

Visceral adiposity is associated with increased cardiometabolic risk and decreased GH secretion. Our objective was to determine the effects of GH administration in abdominally obese young men on body composition, including liver fat, mitochondrial function, and cardiovascular (CV) risk markers. This was a 6-month, randomized, double-blind, placebo-controlled study with 62 abdominally obese men (IGF-1 below the mean, no exclusion based on GH level), 21 to 45 years of age. We evaluated abdominal fat depots, thigh muscle and fat (computed tomography), fat and lean mass (dual-energy x-ray absorptiometry), intramyocellular and intrahepatic lipids (proton magnetic resonance spectroscopy), mitochondrial function (dynamic phosphorous magnetic resonance spectroscopy), CV risk markers, carotid intimal-medial thickness, and endothelial function. GH administration resulted in a mean IGF-1 SD score increase from -1.9 ± 0.08 to -0.2 ± 0.3 in the GH group and a decrease in visceral adipose tissue (VAT), VAT/sc adipose tissue, trunk/extremity fat, intrahepatic lipids, high-sensitivity C-reactive protein and apolipoprotein B/low-density lipoprotein vs placebo after controlling for the increase in weight observed in both groups. There were inverse associations between change in IGF-1 levels and change in VAT, VAT/sc adipose tissue, trunk fat, trunk/extremity fat, high-sensitivity C-reactive protein, and apolipoprotein B. Mitochondrial function improved in the GH group compared with placebo after controlling for change in glucose. There was no change in thigh fat, muscle mass, intramyocellular lipids, cholesterol, fibrinogen, intimal-medial thickness, or endothelial function. There was no increase in fasting glucose or hemoglobin A1c in the GH vs placebo group, although glucose during the 2-hour oral glucose tolerance test increased slightly. GH replacement in abdominally obese men improves body composition, including liver fat, mitochondrial function, and markers of CV risk. Although fasting glucose was unchanged, a slight increase in 2-hour glucose during an oral glucose tolerance test was noted.

Therapy of Endocrine disease: Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review

BackgroundThe beneficial effects of recombinant human GH (rhGH) therapy in GH deficient (GHD) adults are well-established in the short term. However, data documenting the effects during prolonged follow-up are relatively scarce.ObjectiveTo evaluate the reported effects of rhGH replacement (≥5 years) in GHD adults on biochemical and anthropometric parameters, quality of life (QoL), bone metabolism, muscle strength, serious adverse events and mortality.MethodsWe conducted a systematic literature search. Quality assessment of retrieved papers was performed using a quality assessment based on the modified STROBE statement.ResultsWe included 23 prospective studies with a rhGH treatment duration ranging from 5 to 15 years. Overall, beneficial effects were reported on QoL, body composition, lipid profile, carotid intima media thickness and bone mineral density. In contrast, the prevalence of the metabolic syndrome, glucose levels, BMI and muscle strength were not, or negatively, influenced. Most of the studies were uncontrolled, lacked the presence of a control group (of non-treated GHD patients), and reported no data on lipid-lowering and anti-diabetic medication. Overall mortality was not increased.ConclusionrhGH treatment in adult GHD patients is well-tolerated and positively affects QoL in the long term. However, the metabolic and cardiovascular effects during long-term treatment are variable. The low numbers of long-term studies and studied patients and lack of control data hamper definite statements on the efficacy of prolonged treatment. Therefore continuous monitoring of the effects of rhGH replacement to enable an adequate risk-benefit analysis that may justify prolonged, potentially life-long, treatment is advisable.

Differential effects of GH and GH-releasing peptide-6 on astrocytes

GH and GH secretagogues (GHSs) are involved in many cellular activities such as stimulation of mitosis, proliferation and differentiation. As astrocytes are involved in developmental and protective functions, our aim was to analyse the effects of GH and GH-releasing hexapeptide on astrocyte proliferation and differentiation in the hypothalamus and hippocampus. Treatment of adult male Wistar rats with GH (i.v., 100 μg/day) for 1 week increased the levels of glial fibrillary acidic protein (GFAP) and decreased the levels of vimentin in the hypothalamus and hippocampus. These changes were not accompanied by increased proliferation. By contrast, GH-releasing hexapeptide (i.v., 150 μg/day) did not affect GFAP levels but increased proliferation in the areas studied. To further study the intracellular mechanisms involved in these effects, we treated C6 astrocytoma cells with GH or GH-releasing hexapeptide and the phosphatidylinositol 3'-kinase (PI3K) inhibitor, LY294002, and observed that the presence of this inhibitor reverted the increase in GFAP levels induced by GH and the proliferation induced by GH-releasing hexapeptide. We conclude that although GH-releasing hexapeptide is a GHS, it may exert GH-independent effects centrally on astrocytes when administered i.v., although the effects of both substances appear to be mediated by the PI3K/Akt pathway.

Growth Hormone Potentiates 17β-Estradiol-Dependent Breast Cancer Cell Proliferation Independently of IGF-I Receptor Signaling

Estrogen action in mammary gland development and breast cancer progression is tightly linked to the GH/IGF-I axis. Although many of the effects of GH on mammary gland growth and development require IGF-I, the extent to which GH action in breast cancer depends on IGF-I is not known. We examined GH action in a panel of estrogen receptor-positive breast cancer cell lines and found that T47D cells express significant levels of GH receptor and that GH significantly enhances 17β-estradiol (E2)-stimulated proliferation in these cells. GH action in the T47D cells was independent of changes in IGF-I and IGF-I receptor (IGF-IR) expression and IGF-IR signaling, suggesting that GH can exert direct effects on breast cancer cells. Although E2-dependent proliferation required IGF-IR signaling, the combination of GH+E2 overcame inhibition of IGF-IR activity to restore proliferation. In contrast, GH required both Janus kinase 2 and epidermal growth factor receptor signaling for subsequent ERK activation and potentiation of E2-dependent proliferation. Downstream of these pathways, we identified a number of immediate early-response genes associated with proliferation that are rapidly and robustly up-regulated by GH. These findings demonstrate that GH can have important effects in breast cancer cells that are distinct from IGF-IR activity, suggesting that novel drugs or improved combination therapies targeting estrogen receptor and the GH/IGF axis may be beneficial for breast cancer patients.

Disruption of JAK2 in Adipocytes Impairs Lipolysis and Improves Fatty Liver in Mice With Elevated GH

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic expression of the metabolic syndrome, and its prevalence is increasing. The factors that influence the development of fatty liver and its progression to steatohepatitis and cirrhosis are not well understood. The pleiotropic hormone, GH, has been associated with an increased risk of NAFLD in humans and mice. GH is known to have diverse effects on lipid metabolism including decreasing body fat in vivo, presumably through stimulation of lipolysis via an undefined mechanism. Previously we described mice with hepatocyte-specific deletion of the GH signaling mediator, Janus kinase 2 (JAK2L). JAK2L animals have elevated serum GH, reduced body fat, high liver triglyceride content, and increased serum markers of hepatocyte injury (alanine transaminase and aspartate transaminase). We aimed to determine whether the elevation of GH in JAK2L mice contributed to fatty liver by promoting lipolysis directly in adipocytes. We generated mice with adipocyte-specific disruption of JAK2 (JAK2A) and found that GH resistance in adipocytes reduced lipolysis and increased body fat. JAK2A mice were then crossed to JAK2L mice, and the resultant JAK2L/A animals had increased body fat and decreased lipolysis, despite elevated circulating GH. Furthermore, the increased triglyceride content, serum alanine transaminase, and serum aspartate transaminase observed in JAK2L mice were nearly normalized with the additional disruption of JAK2 in adipocytes (JAK2L/A mice). Our results offer novel mechanistic insights into the long-recognized effects of GH on lipid flux and suggest that GH signaling may play an important regulatory role in the development of NAFLD.

Endoplasmic Reticulum Stress and Apoptosis Contribute to the Pathogenesis of Dominantly Inherited Isolated GH Deficiency Due to GH1 Gene Splice Site Mutations

Dominantly inherited isolated GH deficiency is mainly caused by a heterozygous donor site mutation of intron 3 in the GH1 gene. An exon 3 deletion in GH (del32-71 GH) is produced from a mutant allele, whereas wild-type GH is produced from the other allele. Several studies have demonstrated a dominant negative effect of del32-71 GH on wild-type GH secretion, but the precise molecular mechanisms remain unclear. We hypothesized that unfolded del32-71 GH accumulates in the endoplasmic reticulum (ER) and causes ER stress and apoptosis in somatotrophs, promoting GH deficiency. To evaluate del32-71 GH-mediated ER stress, we established GH4C1 cell lines with doxycycline (dox)-controlled del32-71 GH expression. In 20 of 23 dox-controlled cell lines, the concentration of wild-type GH in the culture medium significantly decreased with del32-71 GH induction, demonstrating the dominant negative effect of this mutant. Cell viability, mRNA abundance of ER stress-response genes, caspase activation, and DNA fragmentation were evaluated in 5 dox-controlled cell lines selected as cellular models. In 4 of the 5 cell lines, del32-71 GH induction decreased cell viability, increased expression of 3 major ER stress response pathways (PRKR-like endoplasmic reticulum kinase [PERK], activating transcription factor-6 [ATF6], and inositol requirement 1 [IRE1]), and induced caspase-3 and caspase-7 activation. In 1 of the 4 cell lines, DNA fragmentation was demonstrated. Finally, overexpression of XBP1(S), a nuclear transcription factor downstream of IRE1, completely reversed the observed caspase activation. These data suggested that del32-71 GH-mediated ER stress and apoptosis contributed to the decrease in wild-type GH secretion observed in GH deficiency due to the GH1 gene slice-site mutations.

Idiopathic Growth Hormone Deficiency in Adults, Ben Johnson and the Somatopause

In his update on the syndrome of adult GH deficiency in this issue of the JCEM, Melmed (1) draws attention to the growing number of people being diagnosed with “idiopathic GH deficiency in adults.” He also states that “the propensity by some practitioners for inappropriate IAGHD (idiopathic adult-onset GH deficiency) diagnosis as a prelude to administering unsafe nonapproved GH supplementation for athletes or for the frail elderly underscores the need for a stringent diagnostic approach”— thus implying that the increase in idiopathic adult-onset GH deficiency diagnosis, typified by that seen in the HYPOCCS postmarketing surveillance database that he quotes (2), is because fellow practitioners are overdiagnosing the condition in order to legitimize undesirable practice. These are strong words. Although few doctors would prescribe GH (recombinant human GH [rhGH]) as a performance-enhancing drug for an athlete, few of us would not prescribe a trial of therapy in someone we believed to be suffering from GH deficiency and appearing to have ill health as a consequence. Let us not forget that in the early days of the use of rhGH in adults, there was considerable skepticism and some frank hostility to this from some established endocrinologists. It is difficult to distinguish the GH deficiency in older people from the GH deficiency secondary to pituitary or hypothalamic damage. There is a clear rationale for prescribing a trial of rhGH for prevention and/or treatment of frailty in suitable patients (3–5). Let us put this in context: athletes and their coaches were the first to discover the powerful anabolic actions of GH in adults (6, 7). GH was given a glowing write-up by the California “doping guru” Daniel Duchaine in “The Underground Steroid Handbook” (6); in 1982, he wrote: “We find that GH is the most expensive, most fashionable, and least understood of the new athletic drugs. It has firmly established itself in power-lifting and within a few years will be a commonly used drug in all strength athletics.” Thus, human GH was established as a drug of abuse in sport some 7 years before the results of the first 2 randomized controlled trials confirming its powerful anabolic actions in humans were published in the bona fide medical literature (8, 9). A year earlier, the sprinter Ben Johnson won a gold medal at the Olympic Games in Seoul, only to lose it 3 days later when his urine test confirmed that he had been taking the anabolic steroid stanozol; he subsequently admitted under oath that at the time he was also taking GH. These performance-enhancing effects of GH have now been confirmed using randomized controlled trials—first in abstinent, previously steroid-dependent athletes by Graham et al (10); and, together with sex steroids in young athletes, by Meinhardt et al (11), 29 years after Duchaine’s first publication. I use these anecdotes to illustrate that it is not always the scientists who make the discoveries; sometimes, like the athletes, it is the people who are most likely to benefit and who are always hungry for an effective new therapy. If they find such a substance, try it, and find that it works, then the word spreads and later we, as clinician scientists, come along and discover it “officially.” Athletic competition is so strong and the rewards are so great that new ways of improving performance are constantly being sought. The intelligent athletes and their coaches are constantly using the “trial of one” paradigm (12) to test new training regimes, diets, supplements, and substances. Athletes know their best performance for a given event to a

Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4

ObjectiveSupraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.Materials and methodsTo study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic–euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic–euglycemic clamp technique.ResultsGhrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.Conclusionsi) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.

GH therapy and effect on ovarian function and morphology in short prepubertal SGA girls

GH therapy and effect on ovarian function and morphology in short prepubertal SGA girls

Characterization and endocrine regulation of proliferation and differentiation of primary cultured preadipocytes from gilthead sea bream (Sparus aurata)

A preadipocyte primary cell culture was established to gain knowledge about adipose tissue development in gilthead sea bream (Sparus aurata), one of the most extensively produced marine aquaculture species in the Mediterranean. The preadipocytes obtained from the stromal-vascular cell fraction of adipose tissue proliferated in culture, reaching confluence around day 8. At that time, the addition of an adipogenic medium promoted differentiation of the cells into mature adipocytes, which showed an enlarged cytoplasm filled with lipid droplets. First, cell proliferation and differentiation were analyzed under control and adipogenic conditions during culture development. Next, the effects of insulin, GH, and IGF-I on cell proliferation were evaluated at day 8. All peptides significantly stimulated proliferation of the cells after 48 h of incubation (P < 0.002 for GH and IGF-I and P < 0.05 for insulin), despite no differences were observed between the different doses tested. Subsequently, the effects of insulin and IGF-I maintaining differentiation when added to growth medium were studied at day 11, after 3 d of induction with adipogenic medium. The results showed that IGF-I is more potent than insulin enhancing differentiation (P < 0.01 for IGF-I compared with the control). In summary, a primary culture of gilthead sea bream preadipocytes has been characterized and the effects of several regulators of growth and development have been evaluated. This cellular system can be a good model to study the process of adipogenesis in fish, which may help improve the quality of the product in aquaculture.