Biological roles of growth hormone/prolactin from an evolutionary perspective.

Although growth hormone (GH) and prolactin (PRL) are usually recognized as pituitary hormones, their expression is not restricted to the adenohypophysis and can also be found in extra-pituitary tissues including placenta. Furthermore, GH, PRL, and their receptors structurally belong to the cytokine family of proteins, and indeed they have remarkable pleiotropic effects. In this review, we analyzed the biological roles of GH/PRL from an evolutionary perspective. We have recognized that the biological significance of GH/PRL can be summarized as follows: cytokines (metabokines) that regulate the shift of nutrients and even of whole bodies to live in the most appropriate environment(s) for conducting growth and reproduction. In this sense, the common keyword of the two metabokines is "shift" for environmental adaptation. Considering that these metabokines flexibly changed their biological roles, GH/PRL may have played important roles during vertebrate evolution.

Reduced Growth Hormone Response to Anaerobic Exercise Among Children With Overweight and Obesity.

ABSTRACT: Hejla, D, Dror, N, Pantanowitz, M, Nemet, D, and Eliakim, A. Reduced growth hormone response to anaerobic exercise among children with overweight and obesity. J Strength Cond Res 36(8): 2194-2197, 2022-The aim of the present study was to examine the effect of an anaerobic exercise test on growth hormone (GH) secretion in children with overweight and obesity compared with children with normal weight. Fifteen children with overweight (body mass index percentile [BMI%ile] ≥85 < 95) and obesity (BMI%ile ≥95) and 10 children with normal weight (BMI%ile >5 < 85) participated in the study. Subjects performed a modification of the Wingate anaerobic test (WAnT), with 10 bouts of 15-second cycling separated by 1 minute of rest. Blood samples for GH and lactate were collected before and 15, 30, 45, and 60 minutes after the beginning of the exercise test. There was a significant increase in GH levels following the modified repeated WAnT in both groups, but the increase in GH levels was significantly greater among the normal weight children compared with those with overweight and obesity ( p < 0.003). Seven of the 10 subjects with normal weight had GH increase above the threshold for GH sufficiency compared with only 2 subjects with overweight and obesity. Growth hormone response to the modified repeated WAnT was significantly reduced among children with overweight and obesity compared with those with normal weight. Anaerobic interval-type training may not be a sufficient exercise alternative to stimulate appropriate GH levels among children with obesity.

Resistance exercise-induced hormonal response promotes satellite cell proliferation in untrained men but not in women.

The purpose of this work was to determine the effect of resistance exercise (RE)-induced hormonal changes on the satellite cell (SC) myogenic state in response to muscle damage. Untrained men (n = 10, 22 ± 3 yr) and women (n = 9, 21 ± 4 yr) completed 2 sessions of 80 unilateral maximal eccentric knee extensions followed by either an upper body RE protocol (EX) or a 20-min rest (CON). Muscle samples were collected and analyzed for protein content of Pax7, MyoD, myogenin, cyclin D1, and p21 before (PRE), 12 h, and 24 h after the session was completed. Serum testosterone, growth hormone, cortisol, and myoglobin concentrations were analyzed at PRE, post-damage, immediately after (IP), and 15, 30, and 60 min after the session was completed. Testosterone was significantly (P < 0.05) higher immediately after the session in EX vs. CON for men. A significant time × sex × condition interaction was found for MyoD with an increase in EX (men) and CON (women) at 12 h. A significant time × condition interaction was found for Pax7, with a decrease in EX and increase in CON at 24 h. A significant time effect was found for myogenin, p21, and cyclin D1. Myogenin and p21 were increased at 12 and 24 h, and cyclin D1 was increased at 12 h. These results suggest that the acute RE-induced hormonal response can be important for men to promote SC proliferation after muscle damage but had no effect in women. Markers of SC differentiation appeared unaffected by the hormonal response but increased in response to muscle damage.

[Aging and growthhormone: assumptions and facts (review of literature).]

Growth hormone is a powerful metabolic hormone with pleiotropic effects, which is positioned as a "source of youth". Somatotropin has various functions: stimulation of bone growth, regulation of carbohydrate, protein, lipid metabolism, metabolic function of the liver and energy balance. At the cellular level, somatotropic hormone regulates cell growth, differentiation, apoptosis, and cytoskeleton reorganization. The review article presents the results of topical studies that reflect the relationship of growth hormone deficiency or resistance to it with the development of aging and diseases associated with age, as well as with an increase in life expectancy.

Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations.

The receptors for the pituitary hormones growth hormone (GH), prolactin (PRL) and somatolactin (SL), and the hematopoietic hormones erythropoietin (EPO) and thrombopoietin (TPO), comprise a structurally related family in the superfamily of cytokine class-I receptors. GH, PRL and SL receptors have a wide variety of effects in development, osmoregulation, metabolism and stimulation of growth, while EPO and TPO receptors guide the production and differentiation of erythrocytes and thrombocytes, respectively. The evolution of the receptors for GH, PRL and SL has been partially investigated by previous reports suggesting different time points for the hormone and receptor gene duplications. This raises questions about how hormone-receptor partnerships have emerged and evolved. Therefore, we have investigated in detail the expansion of this receptor family, especially in relation to the basal vertebrate (1R, 2R) and teleost (3R) tetraploidizations. Receptor family genes were identified in a broad range of vertebrate genomes and investigated using a combination of sequence-based phylogenetic analyses and comparative genomic analyses of synteny. We found that 1R most likely generated EPOR/TPOR and GHR/PRLR ancestors; following this, 2R resulted in EPOR and TPOR genes. No GHR/PRLR duplicate seems to have survived after 2R. Instead the single GHR/PRLR underwent a local duplication sometime after 2R, generating separate syntenic genes for GHR and PRLR. Subsequently, 3R duplicated the gene pair in teleosts, resulting in two GHR and two PRLR genes, but no EPOR or TPOR duplicates. These analyses help illuminate the evolution of the regulatory mechanisms for somatic growth, metabolism, osmoregulation and hematopoiesis in vertebrates.

The growth hormone signaling system: Insights into coordinating the anabolic and catabolic actions of growth hormone.

Although growth hormone (GH) is a multifunctional factor that coordinates various aspects of feeding, reproduction, osmoregulation, and immune system function, perhaps two of its most studied actions are the regulation of growth and metabolism, particularly lipid metabolism. In this review, we describe the major growth-promoting and lipid metabolic actions of GH and then discuss how the GH system regulates these actions. Numerous intrinsic and extrinsic factors provide information about the metabolic status of the organism and influence the production of release of GH. The actions of GH are mediated by GH receptors (GHR), which are widely distributed among tissues. Teleosts possess multiple forms of GHRs that arose through the evolution of this group. Modulation of tissue responsiveness to GH is regulated by molecular and functional expression of GHRs, and in teleosts GHR subtypes, by various factors that reflect the metabolic and growth status of the organism, including nutritional state. The action of GH is propagated by the linkage of GHRs to several cellular effector systems, including JAK-STAT, ERK, PI3K-Akt, and PKC. The differential activation of these pathways, which is governed by nutrient status, underlies GH stimulation of growth or GH stimulation of lipolysis. Taken together, the multi-functional actions of GH are determined by the distribution and abundance of GHRs (and GHR subtypes in teleosts) as well as by the GHR-effector system linkages.

Determination and regulation of body composition in elite athletes.

In 2011, the International Association of Athletics Federations (IAAF) and IOC introduced a 'hyperandrogenism' rule that excluded women with a serum testosterone >10 nmol/L from participating in elite sport. This rule was based on the false premise that the greater lean body mass in men was a consequence of their higher serum testosterone. This rule did not have scientific backing and the Court of Arbitration for Sport subsequently rescinded the rule following an appeal from an Indian athlete barred from the Commonwealth Games. This review covers the scientific knowledge about the development and regulation of body composition in humans but also considers the lessons learnt from evolution and breeding in animals. The importance of heredity has been documented in family and twin studies. The roles of growth hormone and sex steroids are reviewed. The Androgen Insensitivity Syndrome (AIS) is considered as a model of the role of testosterone in development of body composition and also as evidence of the importance of other factors carried on the Y-chromosome that are of prime importance but have been systematically ignored. Finally the key factors determining body composition are considered and placed in a suggested order of importance.

Effects of Anorexia Nervosa on the Endocrine System.

Anorexia nervosa (AN) is characterized by severe undernutrition associated with alterations in multiple endocrine axes, which are primarily adaptive to the state of caloric deprivation. Hormonal changes include growth hormone (GH) resistance with low insulin like growth factor-1 (IGF-1) levels, hypothalamic hypogonadism, relative hypercortisolemia and changes in appetite regulating hormones, including leptin, ghrelin, and peptide YY. These alterations contribute to abnormalities in bone metabolism leading to low bone mass, impaired bone microarchitecture, and increased risk for fracture, and may also negatively impact cognition, emotions and mood. The best strategy to improve all biologic outcomes is weight and menstrual recovery. Physiological estrogen replacement improves bone accrual rates and measures of trait anxiety in adolescents with AN. Other therapies including testosterone and IGF-1 replacement, and use of DHEA with oral estrogen-progesterone combination pills, bisphosphonates and teriparatide have also been studied to improve bone outcomes.

Insulin-Like Growth Factor-I is a Marker for the Nutritional State.

Measurement of the serum concentration of insulin-like growth factor-I (IGF-l) is generally used as a screening investigation for disorders of the growth hormone (GH)/IGF-I axis in children and adolescents with short stature. IGF-I concentration is sensitive to short-term and chronic alterations in the nutritional state, and the interpretation of IGF-I measurements requires knowledge of the child's nutritional status. In this review, we summarize the effects of nutrition on the GH/IGF-I axis, and review the clinical implications of these interactions throughout childhood, both in under-nutrition and over-nutrition.

Human placental lactogen induces CYP2E1 expression via PI 3-kinase pathway in female human hepatocytes.

The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1α, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.

GH/IGF1 axis disturbances in the fibromyalgia syndrome: is there a rationale for GH treatment?

Fibromyalgia Syndrome (FMS) is a frequent idiopathic condition in which patients experience intense pain in specific tender points, profound fatigue and sleep disturbances. Although pain had not account so far in growth hormone deficiency syndrome (GHD) description, symptoms of FMS are very similar; and there is strong evidence of decreased GH secretion at least in a subset of FMS patients. Is there an overlap of the two diseases? A systematic Medline/Embase search for preliminary proof-of-concept trials, but also larger placebo-controlled studies, have shown that GH replacement in low-IGF1 patients can significantly improve some symptoms of FMS and quality of life, suggesting a direct causal effect of GH deficiency. Despite the use of relatively high doses of GH in these patients, treatment seems to be well tolerated. Several mechanisms of action for GH in FMS relief have been suggested, including both central modulation of pain and peripheral musculo-tendinous effects, as already described in classic GHD.

The influence of growth hormone on bone and adipose programming.

In utero growth hormone exposure is associated with distinct immediate growth responses and long term impacts on adult physiological parameters that include obesity, insulin resistance, and bone function. Growth hormone accelerates cellular proliferation in many tissues but is exemplified by increases in the number of cells within the cartilaginous growth plate of bone. In some cases growth hormone also potentiates differentiation as seen in the differentiation of adipocytes that rapidly fill upon withdrawal of growth hormone. Growth hormone provokes these changes either by direct action or through intermediaries such as insulin-like growth factor-I and other downstream effector molecules. The specific mechanism used by growth hormone in programming tissues is not yet fully characterized and likely represents a multipronged approach involving DNA modification, altered adult hormonal milieu, and the development of an augmented stem cell pool capable of future engagement as is seen in adipose accrual. This review summarizes findings of growth hormone's influence on in utero and neonatal cellular and metabolic profiles related to bone and adipose tissue.

Adolescent growth: genes, hormones and the peer group. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.

The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.

Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone-mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5 (STAT5) transactivation.

Growth hormone (GH) is a key metabolic regulator mediating glucose and lipid metabolism. Ataxia telangiectasia mutated (ATM) is a member of the phosphatidylinositol 3-kinase superfamily and regulates cell cycle progression. The orphan nuclear receptor small heterodimer partner (SHP: NR0B2) plays a pivotal role in regulating metabolic processes. Here, we studied the role of ATM on GH-dependent regulation of hepatic gluconeogenesis in the liver. GH induced phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase gene expression in primary hepatocytes. GH treatment and adenovirus-mediated STAT5 overexpression in hepatocytes increased glucose production, which was blocked by a JAK2 inhibitor, AG490, dominant negative STAT5, and STAT5 knockdown. We identified a STAT5 binding site on the PEPCK gene promoter using reporter assays and point mutation analysis. Up-regulation of SHP by metformin-mediated activation of the ATM-AMP-activated protein kinase pathway led to inhibition of GH-mediated induction of hepatic gluconeogenesis, which was abolished by an ATM inhibitor, KU-55933. Immunoprecipitation studies showed that SHP physically interacted with STAT5 and inhibited STAT5 recruitment on the PEPCK gene promoter. GH-induced hepatic gluconeogenesis was decreased by either metformin or Ad-SHP, whereas the inhibition by metformin was abolished by SHP knockdown. Finally, the increase of hepatic gluconeogenesis following GH treatment was significantly higher in the liver of SHP null mice compared with that of wild-type mice. Overall, our results suggest that the ATM-AMP-activated protein kinase-SHP network, as a novel mechanism for regulating hepatic glucose homeostasis via a GH-dependent pathway, may be a potential therapeutic target for insulin resistance.

Differential effects of exogenous and autocrine growth hormone on LNCaP prostate cancer cell proliferation and survival.

The prostate gland is regulated by multiple hormones and growth factors that may also affect prostate tumorigenesis. Growth hormone (GH) contributes to prostate development and function, but the direct effects of GH on prostate cancer cells are not well understood. The expression of endogenous GH in prostate cancer cell lines has also been observed, suggesting the potential for an effect of autocrine GH. In the present study, we measure the levels of GH and GH receptor (GHR) mRNA in multiple prostate cancer and normal prostate-derived cell lines, and compare the effects of exogenous and autocrine GH on LNCaP prostate cancer cell proliferation and apoptosis, and the associated signal transduction pathways. We found that GHR and GH expression were higher in the prostate cancer cell lines, and that exogenous GH increased LNCaP cell proliferation, but had no effect on apoptosis. In contrast, autocrine GH overexpression reduced LNCaP cell proliferation and increased apoptosis. The distinct actions of exogenous and autocrine GH were accompanied by differences in the involvement of GHR-associated signal transduction pathways, and were paralleled by an alteration in the subcellular localization of GHR, in which autocrine GH appeared to sequester GHR in the Golgi and endoplasmic reticulum. This alteration of GHR trafficking may underlie a distinct mode of GH-mediated signaling associated with the effect of autocrine GH. These findings clarify the potential effects of GH on prostate cancer cell function, and indicate that the activity of autocrine GH may be distinct from that of endocrine GH in prostate cancer cells.

Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes.

Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system.

Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA).

INTRODUCTION: Besides hypogonadism, other endocrine disorders have been associated with male sexual dysfunction (MSD). AIM: To review the role of the pituitary hormone prolactin (PRL), growth hormone (GH), thyroid hormones, and adrenal androgens in MSD. METHODS: A systematic search of published evidence was performed using Medline (1969 to September 2011). Oxford Centre for Evidence-Based Medicine-Levels of Evidence (March 2009) was applied when possible. MAIN OUTCOME MEASURES: The most important evidence regarding the role played by PRL, GH, thyroid, and adrenal hormone was reviewed and discussed. RESULTS: Only severe hyperprolactinemia (>35 ng/mL or 735 mU/L), often related to a pituitary tumor, has a negative impact on sexual function, impairing sexual desire, testosterone production, and, through the latter, erectile function due to a dual effect: mass effect and PRL-induced suppression on gonadotropin secretion. The latter is PRL-level dependent. Emerging evidence indicates that hyperthyroidism is associated with an increased risk of premature ejaculation and might also be associated with erectile dysfunction (ED), whereas hypothyroidism mainly affects sexual desire and impairs the ejaculatory reflex. However, the real incidence of thyroid dysfunction in subjects with sexual problems needs to be evaluated. Prevalence of ED and decreased libido increase in acromegalic patients; however, it is still a matter of debate whether GH excess (acromegaly) may create effects due to a direct overproduction of GH/insulin-like growth factor 1 or because of the pituitary mass effects on gonadotropic cells, resulting in hypogonadism. Finally, although dehydroepiandrosterone (DHEA) and its sulfate have been implicated in a broad range of biological derangements, controlled trials have shown that DHEA administration is not useful for improving male sexual function. CONCLUSIONS: While the association between hyperprolactinemia and hypoactive sexual desire is well defined, more studies are needed to completely understand the role of other hormones in regulating male sexual functioning.

Dietary arginine and linear growth: the Copenhagen School Child Intervention Study.

The amino acid arginine is a well-known growth hormone (GH) stimulator and GH is an important modulator of linear growth. The aim of the present study was to investigate the effect of dietary arginine on growth velocity in children between 7 and 13 years of age. Data from the Copenhagen School Child Intervention Study during 2001-2 (baseline), and at 3-year and 7-year follow-up, were used. Arginine intake was estimated via a 7 d precoded food diary at baseline and 3-year follow-up. Data were analysed in a multilevel structure in which children were embedded within schools. Random intercept and slopes were defined to estimate the association between arginine intake and growth velocity, including the following covariates: sex; age; baseline height; energy intake; puberty stage at 7-year follow-up and intervention/control group. The association between arginine intake and growth velocity was significant for the third and fourth quintile of arginine intake (2.5-2.8 and 2.8-3.2 g/d, respectively) compared with the first quintile ( < 2.2 g/d) (P for trend = 0.04). Protein intake (excluding arginine) was significantly associated with growth velocity; however, the association was weaker than the association between arginine intake and growth velocity (P for trend = 0.14). The results of the present study suggest a dose-dependent physiological role of habitual protein intake, and specifically arginine intake, on linear growth in normally growing children. However, since the study was designed in healthy children, we cannot firmly conclude whether arginine supplementation represents a relevant clinical strategy. Further research is needed to investigate whether dietary arginine may represent a nutritional strategy potentially advantageous for the prevention and treatment of short stature.

Sex hormone-binding globulin at the crossroad of body composition, somatotropic axis and insulin/glucose homeostasis in young healthy men.

OBJECTIVES: Sex hormone-binding globulin (SHBG) modulates the bioavailability of sex steroids at tissue level. Genetic, hormonal and lifestyle-related factors determine the SHBG levels, and low SHBG levels are a known risk factor for the development of the metabolic syndrome, diabetes and cardiovascular diseases. We investigated to what extent different determinants contribute to the variation in SHBG levels in healthy young men. DESIGN AND PATIENTS: Healthy male siblings (n = 677) aged 25-45 year were recruited in a cross-sectional, population-based study. MEASUREMENTS: Lean and fat mass were measured using dual-energy X-ray absorptiometry (DXA), and immunoassays were used to determine the serum hormonal levels. Additional information about smoking and physical activity was obtained using questionnaires. Carriers of two SHBG polymorphisms, the Asp327Asn polymorphism and the (TAAAA)(n) repeat polymorphism, were identified. RESULTS: Weight, BMI, whole body fat mass and truncal fat mass were negatively associated with SHBG levels. Body composition characteristics did not differ between SHBG genotype groups, indicating that body composition controls SHBG levels rather than the other way around. The associations may be mediated by adipokines because leptin and adiponectin were, respectively, inversely and positively associated with SHBG levels. Insulin and glucose were negatively associated with SHBG levels, as well as IGF-1 and IGF-BP3, while no associations were found with free thyroid hormone status. CONCLUSIONS: In conclusion, we found that fat mass, insulin and IGF-1 levels are important negative determinants of SHBG levels in young healthy men. The association with fat mass could be mediated by the effects of adiponectin and/or leptin on SHBG synthesis.