MK 677 Guide 2023 - A Comprehensive Overview

18. Reference Sources and Summaries

1. Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Molecular psychiatry. 2014;19(12):1284-1294. doi:10.1038/mp.2013.135.
   View Summary +

   A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fearThe hypothalamus-pituitary-adrenal (HPA) axis is involved in the body’s response to stressors, but their levels do not appear to be
   directly linked to stress-related mental illnesses such as posttraumatic stress disorder (PTSD). This suggests that other hormones may be involved in stress-related mental health problems.  The researchers investigated the role
   of the peptide hormone ghrelin in stress-related vulnerability to fear learning in a rat model of PTSD. The study revealed that stress-related increases in ghrelin levels are both necessary and sufficient for the exacerbation of
   fear learning and that these effects occur in the amygdala independently of the HPA axis. The rats were subjected to a stressor that increased ghrelin levels and improved fear memory without increasing corticotropin-releasing factor
   (CRF) or corticosterone. Without affecting corticosterone release, blocking ghrelin receptor activity prevented the stress-related enhancement of fear memory. The researchers also looked at the connection between ghrelin and growth
   hormone (GH), which is a major downstream effector of the ghrelin receptor. Chronic stress increased GH protein levels in the amygdala and ghrelin receptor stimulation increased GH protein release from amygdala neurons. The fear-inducing
   effects of repeated ghrelin receptor stimulation were blocked by overexpression of GH in the amygdala. These findings suggest that ghrelin mediates a novel branch of the stress response and highlights a previously unrecognized
   role for ghrelin and growth hormone in maladaptive changes following prolonged stress. By identifying the involvement of ghrelin and GH in the amygdala in stress-induced fear learning, this study provides new insights into the
   mechanisms underlying stress-related mental health problems. These findings could lead to the development of new treatments for PTSD and other stress-related disorders by targeting the ghrelin-GH pathway in the amygdala.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988273/.

2. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(13):4679-4684.
   doi:10.1073/pnas.0305930101.
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   Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptorThe effects of synthetic agonists of the growth hormone secretagogue receptor (GHSR) on growth
   hormone release and body composition in elderly and obese subjects were investigated in this study. The authors discussed ghrelin, a natural agonist of the GHSR that was initially linked to obesity but has yet to be proven to be
   a physiologically relevant ghrelin receptor. To further investigate this, the author created Ghsr-null mice, which proved that the GHSR is a biologically relevant ghrelin receptor. The absence of Ghsr, on the other hand, had no
   effect on the mice’s appetite or body composition. Furthermore, because ghrelin is assumed to play a role in establishing an insulin-like growth factor 1 set-point for anabolic metabolism, chronic treatment with ghrelin antagonists
   may have little effect. The first portion of the study discussed how synthetic GHSR agonists can revitalize the pulsatile pattern of growth hormone release in elderly people and increase lean mass but not fat mass in obese people.
   These agonists were discovered by screening tissue extracts in a GHSR-overexpressed cell line. This screening resulted in the discovery of ghrelin, a natural agonist of the GHSR that was initially linked to obesity. However, ghrelin’s
   structure differs significantly from the synthetic agonist used to clone the GHSR, and it has yet to be confirmed that the GHSR is a physiologically relevant ghrelin receptor. To investigate this question, the author created Ghsr-null
   mice and discovered that acute ghrelin treatment did not stimulate growth hormone release or food intake in these mice, indicating that the GHSR is a biologically relevant ghrelin receptor. However, the absence of Ghsr had no impact
   on the mice’s appetite or body composition, implying that ghrelin is not a major regulator of these factors. Furthermore, the finding revealed that ghrelin may play a role in establishing an insulin-like growth factor 1 set-point
   for anabolic metabolism. Overall, the study suggests that chronic treatment with ghrelin antagonists may have little effect on growth or appetite. However, the author notes that further research is needed to fully understand the
   role of ghrelin and the GHSR in regulating these and other physiological processes. You can read the full article athttps://www.pnas.org/doi/10.1073/pnas.0305930101.

3. Svensson J, Lönn L, Jansson JO, et al. Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab. 1998;83(2):362-9.
   View Summary +

   Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditureA study evaluated how the GH secretagogue MK-677 affects GH secretion
   and body composition in healthy obese men. The study was double-blind, randomized, parallel, and placebo-controlled. It included 24 obese males between the ages of 18 and 50 with body mass index (BMI) greater than 30 kg/m2 and
   waist/hip ratios greater than 0.95. For eight weeks, the participants were given MK-677 25 mg or a placebo. Results showed that MK-677 treatment increased serum insulin-like growth factor I (IGF-I) levels by approximately 40% compared
   with placebo. Serum IGF-binding protein-3 levels were also significantly higher. The initial dose of MK-677 significantly increased GH and PRL (peak and area under the curve values). Significant increases in GH and PRL managed
   to remain after 2 and 8 weeks of treatment. On the other hand, the increases in GH and PRL after the initial dose were significantly greater than the increases seen after multiple doses. Cortisol levels in the blood and urine did
   not increase after 2 or 8 weeks. When measured with dual-energy X-ray absorptiometry, the subjects treated with MK-677 had a significant increase in fat-free mass. Active therapy had no discernible effect on total or visceral fat.
   The basal metabolic rate also increased significantly after 2 weeks of MK-677 treatment but not after 8 weeks. Fasting glucose and insulin concentrations remained unchanged, but an oral glucose tolerance test demonstrated impaired
   glucose homeostasis (blood sugar balance) at 2 and 8 weeks. The study concluded that a two-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH,IGF-I, and IGF-binding protein-3. The treatment also caused a sustained increase in fat-free mass and basal metabolic rate. Further studies are still needed to determine whether a higher dose of MK-677 or a
   more prolonged treatment period can reduce body fat in people with obesity. You can read the full article athttps://academic.oup.com/jcem/article/83/2/362/2865156?login=false..

4. Welle S, Thornton C, Statt M, Mchenry B. Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab. 1996;81(9):3239-43.
   View Summary +

   Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years oldMyofibrillar protein production in the muscles of healthy adults over 60
   years old is slower than in younger adults. Previous research has suggested that the slowing of protein synthesis may be prompted by a decrease in the activity of the GH/insulin-like growth factor-I system. A study was conducted
   on healthy individuals over 60 years old who were given a single injection of recombinant human GH or a placebo, or three months of either GH or placebo treatment, to see if GH can increase the rate of myofibrillar protein synthesis.
   The tracer L-[1-13C]leucine was used to measure the rate of myofibrillar protein synthesis and whole-body protein metabolism. The results showed that GH reduced the whole-body leucine oxidation by 36%, but had no effect on whole-body
   protein breakdown or synthesis or myofibrillar protein synthesis in the quadriceps. However, GH treatment for three months led to an increase in lean body mass, muscle mass, and thigh strength in healthy men over 60 years old.
   These findings suggest that GH can increase muscle mass and strength in older individuals but it does not restore a youthful rate of myofibrillar protein synthesis. In conclusion, this research reveals that GH may be beneficial
   in increasing muscle mass and strength in healthy men over the age of 60. However, it does not appear to be effective in restoring myofibrillar protein synthesis rates that are observed in younger adults. More research is needed
   to determine whether GH has similar effects in other populations and whether other interventions can be developed to address the slowing of protein synthesis in older people. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/8784075/..

5. Kim KR, Nam SY, Song YD, Lim SK, Lee HC, Huh KB. Low-dose growth hormone treatment with diet restriction accelerates body fat loss, exerts anabolic effect and improves growth hormone secretory dysfunction in obese adults. Horm Res. 1999;51(2):78-84.

   View Summary +

   Low-dose growth hormone treatment with diet restriction accelerates body fat loss, exerts anabolic effect and improves growth hormone secretory dysfunction in obese adultsThe growth hormone (GH) can speed up fat breakdown
   but obese people may have reduced GH secretion, resulting in a loss of lipolytic (fat-burning) effects. While dietary restriction is a popular obesity treatment, it has drawbacks such as poor adherence, protein breakdown, and slow
   weight loss. GH tends to increase insulin-like growth factor-I (IGF-I), which has an anabolic (muscle-building) effect. A 12-week study was conducted on 24 obese participants, 12 of whom received recombinant human GH and the other
   12 a placebo, to better understand the effects of GH treatment and dietary restriction on fat-burning and muscle-building actions, as well as the effects on insulin and GH secretion. When compared to the placebo group, GH treatment
   resulted in a 1.6-fold increase in the percentage of weight loss as fat and a greater reduction in visceral fat (fat around the organs). The placebo group had a negative nitrogen balance and lost lean body mass, whereas the GH
   group gained lean body mass and had a positive nitrogen balance. Despite the caloric restriction, GH injections increased IGF-I by 1.6-fold. While all participants’ responses to L-dopa stimulation (a test for GH secretion) were
   initially reduced, they improved in both groups after treatment. GH treatment did not lead to a further increase in insulin levels during an oral glucose tolerance test (OGTT) but significantly reduced free fatty acid (FFA) levels
   during OGTT. The reduction in FFA levels was positively correlated with visceral fat loss. The study concluded that a low-dose GH with caloric restriction could be a potential therapeutic approach to treat obesity as it accelerates
   fat loss, promotes muscle growth, and improves GH secretion. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/10352397/.

6. Welle S, Thornton C, Statt M, Mchenry B. Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab. 1996;81(9):3239-43.
   View Summary +

   Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years oldA study was conducted to determine if using growth hormone (GH) could boost muscle
   protein synthesis in healthy adults over the age of 60. The researchers conducted two experiments: one in which they gave the subjects a single injection of GH, and the other in which they gave them GH or a placebo for three months. Previous
   studies had suggested that a reduction in the GH/insulin-like growth factor-I system activity could contribute to slower muscle protein synthesis in healthy individuals over the age of 60. Therefore, the researchers hypothesized that GH
   could potentially boost protein synthesis rates. The rate of myofibrillar protein synthesis was found to be slower in healthy people over 60 than in young adults. However, neither the immediate nor the three-month use of GH resulted in
   any significant increase in myofibrillar protein synthesis rates. The study did discover, however, that using GH for three months resulted in an increase in muscle mass, lean body mass, and thigh strength in healthy men over the age of
   60. The GH also decreased whole-body leucine oxidation, implying that it may have some favorable effects on overall protein metabolism. Overall, the study concluded that while GH may not restore a youthful rate of myofibrillar protein
   synthesis, it may still have some benefits for improving muscle mass and strength in healthy adults over the age of 60. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/8784075/.

7. Tavares ABW, Micmacher E, Biesek S, et al. Effects of Growth Hormone Administration on Muscle Strength in Men over 50 Years Old. International Journal of Endocrinology. 2013;2013:942030. doi:10.1155/2013/942030.
   View Summary +

   Effects of Growth Hormone Administration on Muscle Strength in Men over 50 Years OldGrowth hormone (GH) supplementation is thought to improve physical performance in people who do not have GH deficiency (GHD) by increasing
   collagen synthesis in the muscles and tendons, resulting in better exercise training and muscle strength. This suggests that GH therapy could be used to improve muscle strength in healthy elderly people. A study looked into the effect
   of GH therapy on muscle strength in healthy men over the age of 50. It included 14 healthy men between the ages of 50 and 70 who were evaluated for body composition and muscle strength using leg press and bench press exercises, which target
   the lower and upper body muscles. The subjects were randomly assigned to either GH therapy or a placebo and were reevaluated six months later. The study included thirteen subjects, six in the placebo group and seven in the GH group. Results
   showed that both groups were similar at baseline, but after six months of therapy, there was a statistically significant increase in muscle strength in the leg press responsive muscles of the GH group. However, there was no significant
   increase in muscle strength in the bench press responsive muscles of either group. Therefore, the study suggests that GH therapy can improve muscle strength in the lower body muscles of healthy men over 50 years old but further research
   is needed to evaluate its effectiveness in frail older populations who may experience physical incapacity primarily due to proximal muscle weakness. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870652/.

8. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. British Journal of Pharmacology. 2008;154(3):557-568. doi:10.1038/bjp.2008.153.
   View Summary +

   Regulation of muscle mass by growth hormone and IGF-IGrowth hormone (GH) is a popular performance-enhancing drug. One of its main functions is to raise blood levels of insulin-like growth factor I (IGF-I), which is primarily
   produced by the liver. GH also stimulates IGF-I synthesis in most non-liver tissues. The effects of GH on promoting body growth after birth are largely dependent on IGF-I but new research suggests that IGF-I-independent functions may exist.
   While GH has been shown to help people with GH deficiency, there is currently little evidence to support its anabolic role in increasing muscle mass in healthy people, even when used at supraphysiological levels. However, there could be
   other ways that GH improves performance. In contrast, the effects of muscle-specific IGF-I infusion on muscle hypertrophy (an increase in size) have been well-established in animal models and muscle cell culture systems. Many studies examining
   the molecular responses to hypertrophic stimuli in both animals and humans have cited an increase in IGF-I messenger RNA or immunoreactivity. Both the circulatory/systemic (endocrine) and local (autocrine/paracrine) effects of GH and IGF-I
   may have different impacts on muscle mass regulation. In conclusion, because of its ability to increase IGF-I levels in circulation and stimulate IGF-I synthesis in non-liver tissues, GH is widely used as a performance-enhancing drug.
   While GH has been shown to benefit those with GH deficiency, evidence for its anabolic effects on muscle mass in healthy individuals is lacking. The effects of muscle-specific IGF-I infusion on muscle hypertrophy, on the other hand, have
   been well documented in animal models and cell culture systems. More research is needed to fully understand how GH and IGF-I affect muscle mass regulation. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439518/..

9. Weber MM. Effects of growth hormone on skeletal muscle. Horm Res. 2002;58 Suppl 3:43-8.
   View Summary +

   Effects of growth hormone on skeletal muscleHuman growth hormone (GH) is a common performance-enhancing drug used by athletes and bodybuilders. Its effects on skeletal muscle mass, strength, and fiber composition, however,
   is currently unclear. The goal of this study is to provide an overview of the current knowledge about GH’s role in regulating muscle growth and function, as well as to assess its potential as a muscle anabolic hormone. Decreased muscle
   mass and strength are common symptoms of GH deficiency that can be effectively treated with GH supplementation. However, the available evidence suggests that GH administration, alone or in combination with strength training, has little
   to no effect on muscle volume, strength, or fiber composition in healthy young people who do not have GH deficiency. This compares the lack of evidence for GH’s significant performance-enhancing effects in athletes. Despite this, more
   research is needed to identify populations that might benefit from GH treatment, such as frail elderly individuals. In conclusion, while GH supplementation may be useful for treating GH deficiency-related muscle weakness and atrophy (decrease
   in size), its effectiveness as a performance-enhancing drug for healthy young individuals is questionable. Further studies are necessary to determine the potential therapeutic benefits of GH for muscle anabolism in specific patient populations.
   You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/12435897/.

10. Rennie M. Claims for the anabolic effects of growth hormone: a case of the Emperor’s new clothes? British Journal of Sports Medicine. 2003;37(2):100-105. doi:10.1136/bjsm.37.2.100.
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    Claims for the anabolic effects of growth hormone: a case of the emperor’s new clothes?This study looked at how growth hormone impacts adult human metabolism. After careful consideration of the available evidence, it was found
    that growth hormone has a significant impact on how the body processes fat and carbohydrates. Growth hormone, in particular, encourages the use of stored fat as an energy source. Except in the case of connective tissue, there is no conclusive
    evidence that growth hormone promotes protein retention in the body. Regardless, the perceived benefits of growth hormone for muscle building have been greatly exaggerated, leading to its abuse by athletes and elderly men. This misuse
    poses significant health risks for little gain. According to the findings, growth hormone does have a significant impact on adult metabolism. It has been revealed to play a role in fat and carbohydrate processing, leading to an increase
    in the use of adipose tissue triacylglycerol as an energy source. Except for connective tissue, the evidence does not support the notion that growth hormone promotes protein retention in the body. As a result, the benefits of growth hormone
    for muscle building have been affected, leading to the hormone’s inappropriate use by athletes and elderly men. This misuse poses significant health risks while providing little benefit. In conclusion, the research indicates that growth
    hormone does have powerful effects on fat and carbohydrate metabolism in adult humans. However, the idea that it promotes muscle building has been greatly exaggerated, leading to its misuse by athletes and elderly men. This misuse comes
    with significant risks to health for little gain. It is important that the true effects of growth hormone are understood to prevent further misuse and ensure that individuals do not put themselves at risk unnecessarily. You can read the
    full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1724606/pdf/v037p00100.pdf.

11. Johannsson G, Grimby G, Sunnerhagen KS, Bengtsson BA. Two years of growth hormone (GH) treatment increase isometric and isokinetic muscle strength in GH-deficient adults. J Clin Endocrinol Metab. 1997;82(9):2877-84.
    View Summary +

    Two Years of Growth Hormone (GH) Treatment Increase Isometric and Isokinetic Muscle Strength in GH-Deficient AdultsA lack of growth hormone (GH) in adults has been linked to a loss of muscle mass and strength. The purpose
    of this study was to see how two years ofGH treatmentin GH-deficient adults affected muscle performance in comparison to a control group. Using a Kin-Com
    dynamometer, the researchers assessed knee extensor and flexor strength for isometric and isokinetic concentric muscle strength. The fatigue index was calculated as the percent reduction in peak torque after 50 repeated isokinetic knee
    extensions. In addition, electrical stimulation with a single twitch was used to evaluate its impact on isometric contraction and hand-grip strength. The findings revealed that GH-deficient people had lower isometric knee extensor, knee
    flexor, and hand-grip strength than the control group. The mean isometric knee extensor and flexor strengths increased and normalized after two years of GH treatment. Concentric knee flexor and extensor strength increased as well, especially
    in younger patients and those with lower baseline muscle strength. Quadriceps endurance, on the other hand, decreased. The effect of GH treatment on isometric contraction and hand-grip strength was unchanged by superimposing single twitches.
    Furthermore, the dynamic local muscle fatigue index decreased while hand-grip strength and the degree of lack of maximal motor unit activation on voluntary isometric knee extensor force did not change. In conclusion, the study suggests
    that two years ofGH therapyin GH-deficient adults can increase and normalize isokinetic and isometric muscle strength in proximal muscle groups. However,
    it may lead to a decrease in quadriceps endurance. Additionally, GH treatment did not affect hand-grip strength or maximal motor unit activation on voluntary isometric knee extensor force. The findings of this study may contribute to the
    development of effective GH treatment strategies for adults with GH deficiency. You can read the full article athttps://academic.oup.com/jcem/article/82/9/2877/2865950?login=false..

12. Harman SM, Blackman MR. The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and men. Horm Res. 2003;60(Suppl 1):121-4.
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    The effects of growth hormone and sex steroid on lean body mass, fat mass, muscle strength, cardiovascular endurance and adverse events in healthy elderly women and menGrowth hormone (GH) and insulin-like growth factor 1 (IGF-1)
    levels, as well as testosterone in men and estrogen in women, decline as people age. These hormonal changes can reduce muscle strength, lean body mass, and cardiac endurance. However, hormone replacement therapy such as GH, testosterone,
    andestrogen/progestin can partially reverse these negative effects. Despite their potential benefits, these treatments can have side effects,
    so the safety of hormonal therapy in the elderly population must be evaluated. A research investigation was carried out to assess the effects of GH and sex steroids on body composition, muscle strength, cardiac endurance, and the rate
    of adverse events in healthy elderly people. The study found that while GH and sex steroids had positive effects, there was also a high percentage of adverse events after 26 weeks of treatment. It was found that blood levels of IGF-1 correlated
    with the total number of GH-related adverse effects. With regards to body weight or blood pressure, there were no changes observed. In women, there was a non-significant onset of blood sugar intolerance but diabetes mellitus did not occur.
    In men, 6 developed diabetes. There was a significant increase in blood sugar levels in both men and women at 26 weeks. However, there were no significant increases in hematocrit values and prostate symptom scores. This highlights the
    importance of additional research into the safety of hormonal therapy in the elderly population. In conclusion, hormonal changes in the elderly population can lead to reduced muscle strength, lean body mass, and cardiac endurance. Hormone
    replacement therapy may offer a solution but the potential adverse effects need to be considered. Further research is required to determine the safety of such treatments in the elderly. You can read the abstract of this article athttps://karger.com/hrp/article/60/Suppl.%201/121/372368/The-Effects-of-Growth-Hormone-and-Sex-Steroid-on..

13. Norrelund H, Nair KS, Jorgensen JO, Christiansen JS, Moller N. The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown. Diabetes. 2001;50(1):96-104.
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    The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdownFasting causes the body to go through a series of hormonal and metabolic changes in order to conserve protein. One
    such change is an increase in growth hormone serum levels (GH). The purpose of this study was to determine whether GH plays a role in protein conservation during fasting and to identify the mechanisms involved. Eight healthy individuals
    were studied under four conditions: 1) in the postabsorptive state, 2) after 40 hours of fasting, 3) after 40 hours of fasting with suppression of GH using somatostatin, and 4) after 40 hours of fasting with suppression of GH and replacement
    with exogenous GH. The latter two conditions involved the administration of somatostatin, insulin, glucagon, and GH for 28 hours, followed by an investigation of substrate metabolism during the final 4 hours. Fasting without GH suppression
    resulted in a 35% and 70% decrease in IGF-I and free IGF-I, respectively, when compared to the condition with GH replacement. Urinary and serum urea levels increased without GH during fasting, indicating increased protein breakdown. Fasting
    with GH suppression resulted in a higher negative phenylalanine balance, indicating greater protein breakdown. The muscle-protein breakdown was also increased during fasting without GH, as shown by a rise in the rate of appearance of phenylalanine.
    During fasting without GH, levels of free fatty acids and lipid oxidation decreased. Overall, the study discovered that suppressing GH during fasting increases urea-nitrogen excretion as well as the rate and appearance of phenylalanine
    across the forearm. These findings suggest that GH is an important component of protein conservation during fasting, possibly by maintaining circulating concentrations of free IGF-I. A decrease in muscle protein breakdown is the underlying
    mechanism. You can read the full article athttps://diabetesjournals.org/diabetes/article/50/1/96/10905/The-Protein-Retaining-Effects-of-Growth-Hormone..

14. Adams GR.Insulin-like growth factorin muscle growth and its potential abuse by athletes. Western Journal of Medicine. 2001;175(1):7-9.
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    Insulin-like growth factor in muscle growth and its potential abuse by athletesSkeletal muscle is a dynamic tissue that constantly adapts to changing physical activity demands. Growth factors and hormones, particularly the
    growth hormone/insulin-like growth factor-I (GH/IGF-I) system, orchestrate these adaptations at the local level. Simple notions that exogenous anabolic agents can safely and effectively stimulate or augment muscle mass are, however, incorrect.
    Anabolic substances are non-specific in that they affect not only muscle cells but also other cells and tissues. Furthermore, muscle is made up of different cell types that must work together, so a treatment that stimulates muscle cell
    hypertrophy (an increase in size) must also strengthen connective tissues, increase angiogenesis (formation of new blood vessels), and improve mitochondrial function. Animal studies have shown that administering GH or IGF-I to mitigate
    muscle atrophy (muscle wasting) during unloading conserves the mass of normally weight-bearing muscles but the overall body weight of treated animals increases, resulting in less-normalized muscle mass than untreated animals. In humans,
    attempts to augment muscle mass using IGF-I have had less dramatic impacts, and its supplementation has been associated with moderate to severe hypoglycemia (low blood sugar levels), decreased growth hormone secretion, a shift from lipid
    to carbohydrate oxidation for energy, and a general disruption of the insulin/glucagon system. Additionally, the biological activity of IGF-I in the body is substantially influenced by the family of IGF binding proteins, which complicates
    the issue of augmenting IGF-I. Furthermore, IGF-I is capable of stimulating the proliferation and differentiation of muscle stem cells but it has also been linked to cellular transformation in prostate, colorectal, and lung cancers. As
    a result, exogenous IGF-I augmentation is not a particularly appealing or effective method of increasing muscle mass or function. Instead, a more comprehensive approach that takes into account the integrated nature of physiological systems
    and the coordinated functioning of various cell types is required. You can read the abstract of this article athttps://bjsm.bmj.com/content/34/6/412..

15. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. British Journal of Pharmacology. 2008;154(3):557-568. doi:10.1038/bjp.2008.153.
    View Summary +

    Regulation of muscle mass by growth hormone and IGF-IGrowth hormone (GH) is widely used as a performance-enhancing drug. One of the most important effects of GH is an increase in the level of insulin-like growth factor I (IGF-I)
    in the blood, which is primarily produced by the liver. GH also promotes IGF-I synthesis in most non-hepatic tissues. GH promotes postnatal body growth through IGF-I but IGF-I-independent functions of GH are beginning to be understood.
    Although GH administration has been shown to benefit individuals with GH deficiency, there is currently insufficient evidence to suggest that supraphysiological levels of systemic GH or IGF-I in healthy people’s skeletal muscle play an
    anabolic role. It is possible that GH has other performance-enhancing impacts. In contrast, the hypertrophic effects of muscle-specific IGF-I infusion have been well-documented in animal models and muscle cell culture systems. Research
    examining the molecular responses to hypertrophic stimuli in animals and humans often refers to upregulation of IGF-I messenger RNA or immunoreactivity. The circulatory/systemic (endocrine) and local (autocrine/paracrine) effects of GH
    and IGF-I may have distinct effects on muscle mass regulation. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439518/..

16. Christoffolete MA, Silva WJ, Ramos GV, et al. Muscle IGF-1-Induced Skeletal Muscle Hypertrophy Evokes Higher Insulin Sensitivity and Carbohydrate Use as Preferential Energy Substrate. BioMed Research International. 2015;2015:282984. doi:10.1155/2015/282984.

    View Summary +

    Muscle IGF-1-induced skeletal muscle hypertrophy evokes higher insulin sensitivity and carbohydrate use as preferential energy substrateThe purpose of this study was to look at the metabolic profile of mice that had been genetically
    modified to have increased muscle mass due to increased mIGF-1 expression (MLC/mIGF-1). The researchers discovered that 6-month-old MLC/mIGF-1 mice weighed more than 6-month-old WT mice and had a higher respiratory quotient, indicating
    that they preferred carbohydrates as a fuel source. MLC/mIGF-1 mice also had a faster rate of glucose disposal than WT mice, which was associated with a higher GLUT4 content in the extensor digitorum longus (EDL) muscle. The researchers
    observed a threefold upregulation of mRNA content for the glycolysis-related gene PFK-1 in MLC/mIGF-1 animals. Interestingly, the researchers also found a 50% downregulation of PGC1α mRNA levels in the MLC/mIGF-1 mouse EDL muscle, indicating
    a lower abundance of mitochondria in this tissue. However, there was no difference in the expression of PPARα and PPARβ/δ, suggesting that key elements of oxidative metabolism were not modulated in these mice. Overall, these findings suggest
    that the MLC/mIGF-1 mice rely more heavily on carbohydrates for energy and have increased insulin sensitivity in their hypertrophied skeletal muscle due to a shift in metabolism towards higher carbohydrate utilization. You can read the
    full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334619/..

17. Hamarneh SR, Murphy CA, Shih CW, et al. Relationship Between Serum IGF-1 and Skeletal Muscle IGF-1 mRNA Expression to Phosphocreatine Recovery After Exercise in Obese Men With Reduced GH. The Journal of Clinical Endocrinology and Metabolism. 2015;100(2):617-625.
    doi:10.1210/jc.2014-2711. doi:10.1210/jc.2014-2711.
    View Summary +

    Relationship between serum IGF-1 and skeletal muscle IGF-1 mRNA expression to phosphocreatine recovery after exercise in obese men with reduced GHThe purpose of this study was to look into the connection between growth hormone
    (GH) and insulin-like growth factor-1 (IGF-1) and skeletal muscle mitochondria in obese subjects with low GH production. The study included fifteen men who were abdominally obese and had low GH secretion. For 12 weeks, these participants
    were given recombinant human GH. The researchers used (31)P-magnetic resonance spectroscopy to assess the recovery of phosphocreatine (PCr) as a method of measuring mitochondrial function in skeletal muscle. They also performed percutaneous
    muscle biopsies at the beginning and end of the 12-week period to assess mRNA expression of IGF-1 and mitochondrial-related genes. The researchers found an important correlation between skeletal muscle IGF-1 mRNA expression and PCr recovery,
    as well as the expression of nuclear respiratory factor-1, mitochondrial transcription factor A, peroxisome proliferator-activated receptor (PPAR) and PPAR mRNA, at the start of the study. However, there was no association between serum
    IGF-1 concentration and PCr recovery or any mitochondrial gene expression. The participants’ serum IGF-1 concentrations and muscle IGF-1 mRNA increased after receiving recombinant human GH. An increase in serum IGF-1 was linked to gains
    in body fat and lean mass, but not to PCr recovery. However, an increase in muscle IGF-1 mRNA was associated with an improvement in PCr recovery but not body composition parameters. This study demonstrates a new association between skeletal
    muscle mitochondria and muscle IGF-1 mRNA expression. The findings also show that this association is independent of serum IGF-1 concentrations. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318910/..

18. Heszele MF, Price SR. Insulin-like growth factor I: the yin and yang of muscle atrophy. Endocrinology. 2004;145(11):4803-5.
    View Summary +

    Insulin-Like Growth Factor I: The Yin and Yang of Muscle AtrophySkeletal muscle is the human body’s largest protein reservoir. To maintain muscle mass, a delicate balance of protein synthesis and degradation must be maintained.
    A healthy adult generates and diminishes about 1.0-1.5 kg of protein per day, and a small, sustained change in either process can have a significant impact on muscle mass if not balanced by the opposite process. Muscle atrophy, defined
    as the unintentional loss of 5-10% of muscle mass, is common in catabolic conditions such as diabetes, cancer, and sepsis (blood infection), and it can lead to a decreased quality of life as well as increased morbidity and mortality. Recent
    research has shed light on the molecular mechanisms that underpin muscle wasting. Insulin-like growth factor 1 (IGF-I) and insulin are important muscle mass regulators because they promote growth while inhibiting protein degradation. IGF-I
    promotes muscle growth by stimulating muscle satellite cells and their differentiation, and IGF-I and insulin stimulate protein translation in mature muscle cells by activating the mammalian target of rapamycin (mTOR). Muscle wasting can
    be caused by low levels of IGF-I and insulin, as well as increased catabolic signals such as glucocorticoids and cytokines. In summary, IGF-I and insulin are crucial regulators of muscle mass and they help maintain muscle mass in healthy
    individuals by enhancing protein synthesis and suppressing proteolysis (protein breakdown). In conditions where IGF-I and insulin levels are reduced or their effectiveness is compromised, various proteolytic responses occur, leading to
    the destruction of muscle proteins. Studies have indicated that IGF-I may have the potential as an agent to combat muscle atrophy, but more research is needed to understand the mechanisms underlying muscle wasting and to develop effective
    treatments. You can read the abstract of this article athttps://academic.oup.com/endo/article/145/11/4803/2499798?login=false.

19. Shavlakadze T, Chai J, Maley K, et al. A growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivo. J Cell Sci. 2010;123(Pt 6):960-71.
    View Summary +

    A growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivoThe researchers investigated the effects of overexpressing Class 2 IGF-1 Ea in skeletal myofibers of both normal and dystrophic (mdx) mice
    in this study. Findings revealed that transgenic mice had significantly higher levels of IGF-1 in their muscles, resulting in a significant increase in muscle mass (between 24-56%). However, the hypertrophic effect (an increase in muscle
    mass) of IGF-1 was only seen in muscles that were growing or regenerating as a result of endogenous necrosis (tissue death). Normal adult muscles were found to be resistant to the elevated IGF-1, with no increase in muscle mass from 3
    to 12 months. In contrast, the dystrophic muscles from mdx/IGF-1(C2:Ea) mice continued to increase in mass during adulthood. This suggests that elevated IGF-1 has a hypertrophic effect on skeletal muscle only in growth situations. Furthermore,
    increased Akt phosphorylation at Ser473 was discovered in fasted normal young transgenic muscles but not in fasted normal adult transgenic muscles. The level of phosphorylation in young transgenic muscles was 1.9-fold higher than in age-matched
    wild-type controls, and four-fold higher in adult mdx/IGF-1(C2:Ea) muscles than in mdx muscles. This suggests that increased IGF-1 has an effect on muscle growth via the Akt pathway. In addition, the level of mRNA encoding myogenin was
    found to be increased in normal young (but not adult) transgenic muscles, indicating enhanced myogenic differentiation. Overall, the results demonstrate that elevated IGF-1 has a hypertrophic effect on skeletal muscle only in growth situations,
    and the effect is mediated through the Akt pathway. You can read the full article athttps://journals.biologists.com/jcs/article/123/6/960/31470/A-growth-stimulus-is-needed-for-IGF-1-to-induce.

20. Zou Y, Dong Y, Meng Q, Zhao Y, Li N. Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophy. Scientific Reports. 2018;8:2781. doi:10.1038/s41598-018-21122-5.

    View Summary +

    Incorporation of a skeletal muscle-specific enhancer in the regulatory region of Igf1 upregulates IGF1 expression and induces skeletal muscle hypertrophyThe research team accomplished this by engineering an enhancer into the
    non-coding regions of the IGF1 gene, specifically in the skeletal muscle. They then verified that the expected changes occurred in a mouse model. The researchers identified three candidate sites with the least evolutionary conservation
    to find the best location for introducing the skeletal muscle-specific myosin light chain (MLC) enhancer. They evaluated these sites in C2C12 single-cell colonies that contained the MLC enhancer at each location. They found that IGF1 was
    significantly upregulated only in the site 2 single-cell colony series, leading to the formation of extra myotubes. Based on these findings, the researchers decided to use CRISPR/Cas9 methods to develop a genetically modified (GM) mouse
    model with the MLC enhancer incorporated into site 2. The IGF1 levels in the GM mice were significantly higher, stimulating downstream pathways in skeletal muscle. Female GM mice exhibited more muscle hypertrophy (an increase in muscle
    mass) than male GM mice. The GM mice had comparable circulating IGF1 levels and tibia length to their WT littermates and showed no evidence of heart abnormalities. The researchers concluded that modifying a non-coding region of a gene
    is a practical approach to upregulating gene expression and creating animals with desirable traits. This study demonstrates the potential of genetic modification to enhance desired traits in animals, particularly for agriculture or medical
    research. You can read the full article athttps://www.nature.com/articles/s41598-018-21122-5..

21. Available athttps://eurapa.biomedcentral.com/articles/10.1007/s11556-007-0022-1#:~:text=IGF%2DI%20has%20been%20implicated%20in%20the%20loss%20of%20muscle,than%20noncarriers%20with%20strength%20training..

    View Summary +

    Alterations in IGF-I affect elderly: role of physical activityThe growth hormone-insulin-like growth factor I (IGF-I) axis is a key regulator in muscle development. The individuals’ ability to synthesize IGF-I may decline
    as they age, and exercise may lose its ability to induce the isoform of IGF-I that promotes satellite cell proliferation. Enhanced IGF-I expression in the muscle, on the other hand, can protect against sarcopenia or muscle loss associated
    with aging. Strength training is the preferred intervention for sarcopenia prevention and treatment. In older adults, IGF-I expression levels change as a result of strength training, but advancing age, rather than declining serum IGF-I
    levels, is the main factor in lifetime changes in body composition in both men and women. It has been concluded that resistive exercise significantly influences muscle mass and function. Physically active individuals have higher levels
    of IGF-I than sedentary individuals. Recent research suggests that IGF-I plays an important role as a mediator in muscle hypertrophy (an increase in size) and angiogenesis (the formation of new blood vessels), both of which are characteristics
    of the anabolic adaptation of muscles to exercise. You can read the full article athttps://eurapa.biomedcentral.com/articles/10.1007/s11556-007-0022-1#:~:text=IGF%2DI%20has%20been%20implicated%20in%20the%20loss%20of%20muscle,than%20noncarriers%20with%20strength%20training.

22. Ye F, Mathur S, Liu M, et al. Overexpression of insulin-like growth factor-1 attenuates skeletal muscle damage and accelerates muscle regeneration and functional recovery after disuse. Exp Physiol. 2013;98(5):1038-52.
    View Summary +

    Overexpression of insulin-like growth factor-1 attenuates skeletal muscle damage and accelerates muscle regeneration and functional recovery after disuseSkeletal muscle is a dynamic tissue that reacts to both internal and
    external factors such as mechanical loading changes and growth factors. The soleus muscle is especially vulnerable to atrophy (muscle wasting) and damage during periods of inactivity. Previous research has suggested that insulin-like growth
    factor-1 (IGF-1) is important in muscle repair and size regulation. Researchers tested the effect of IGF-1 on the soleus muscle by injecting a recombinant IGF-1 cDNA virus into the posterior hindlimbs of mice, with the contralateral limb
    serving as a control. After that, the mice were immobilized for two weeks in order to cause muscle atrophy in the soleus and ankle plantarflexor muscle groups. Following this, the mice were allowed to re-ambulate, and the researchers monitored
    muscle damage and recovery over a period of 2-21 days. The study’s primary finding was that IGF-1 overexpression reduced reloading-induced muscle damage in the soleus muscle and accelerated muscle regeneration and force recovery. The researchers
    used magnetic resonance imaging to assess muscle damage and found that muscle T2, a non-specific marker of muscle damage, was significantly lower in the IGF-1-injected soleus muscles compared to the contralateral muscles at 2 and 5 days
    re-ambulation. This reduction in muscle damage was confirmed by histology, which showed a lower percentage of abnormal muscle tissue in the IGF-1-injected muscles at 2 days re-ambulation. The researchers also found evidence of the effect
    of IGF-1 on muscle regeneration, including an increase in the number of central nuclei, paired-box transcription factor 7, embryonic myosin, and elevated MyoD mRNA in the IGF-1-injected limbs. These results suggest that IGF-1 may protect
    unloaded skeletal muscles from damage while also accelerating muscle repair and regeneration. This research could lead to the development of therapies for people with muscle atrophy or damage, particularly in populations like astronauts
    or people with conditions that necessitate prolonged bed rest. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937435/..

23. Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998;83(2):320-5.
    View Summary +

    MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolismThe study aimed to investigate the potential of MK-677, a nonpeptide mimic of GH-releasing peptide, to reverse protein catabolism induced
    by diet. The research used a double-blind, randomized, placebo-controlled, two-period crossover design on eight healthy volunteers aged 24 to 39 years. The subjects were calorically restricted (18 kcal/kg.day) for two 14-day periods, with
    either MK-677 (25 mg) or placebo given orally once daily during the last 7 days of each diet period. A 14- to 21-day washout interval between the two periods was implemented. Both groups experienced equivalent daily nitrogen losses during
    the first week of caloric restriction. However, when compared to the placebo group, the MK-677 group showed a significant improvement in nitrogen balance during the second week. MK-677 also improved the integrated nitrogen balance compared
    to the placebo group over the 7-day treatment period. The study found that MK-677 produced a peak GH response of 55.9 +/- 31.7 micrograms/L after a single dose and 22.6 +/- 9.3 micrograms/L after a week of dosing, while the placebo treatment
    peak GH values were approximately 9 and 7 micrograms/L for day 1 and day 7 of treatment, respectively. Following the initial 7-day caloric restriction, IGF-I levels declined in both groups, but the MK-677 group showed a significant increase
    in mean IGF-I concentrations during treatment compared to the placebo group. Additionally, MK-677 significantly increased the mean IGF binding protein-3 levels during the last 5 days of treatment compared to the placebo. The study concluded
    that MK-677 reverses diet-induced nitrogen wasting and may have therapeutic potential for catabolic patients if the short-term anabolic effects are sustained in patients with acute or chronic disease states that lead to catabolism (muscle
    wasting). Furthermore, MK-677 (25 mg) was well tolerated with no clinically significant adverse events. You can read the full article athttps://academic.oup.com/jcem/article/83/2/320/2865101..

24. Adunsky A, Chandler J, Heyden N, et al. MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr. 2011;53(2):183-9.
    View Summary +

    MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: a multicenter, randomized, placebo-controlled phase IIb studyThe majority of elderly patients hospitalized for hip fractures have functional
    decline. Previous research has suggested that MK-0677 may help people with hip fractures recover essentially. In this double-blind study, 123 elderly hip fracture patients were randomly assigned to receive either a daily dose of 25mg of
    MK-0677 or a placebo. Changes in objective functional performance measurements and blood insulin-like growth factor-1 (IGF-1) levels were the primary outcomes assessed. After 24 weeks, the MK-0677 group showed a significant increase in
    gait speed compared to the placebo group. However, there was no improvement in several other functional performance measures in the MK-0677 group. The MK-0677 group also had fewer falls during the study compared to the placebo group, although
    the difference was not statistically significant. Furthermore, IGF-1 levels in the MK-0677 group increased significantly by 51.4 ng/ml compared to the placebo group. The trial, however, was halted early due to safety concerns regarding
    congestive heart failure in a small number of patients. As a result, the increase in IGF-1 levels in the MK-0677 group did not translate into an overall improvement in most functional performance measures, and MK-0677 had an unfavorable
    safety profile in hip fracture patients. In summary, this study suggests that MK-0677 may have a limited benefit in improving gait speed in elderly hip fracture patients, but the safety concerns associated with this drug in this population
    outweigh any potential benefits. Further research is needed to better understand the safety and efficacy of MK-0677 in hip fracture patients. You can read the full article athttps://www.sciencedirect.com/science/article/abs/pii/S0167494310002530?via%3Dihub..

25. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008;149(9):601-11.
    View Summary +

    Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trialGrowth hormone secretion begins to decline after puberty, resulting in a loss of muscle mass, which can
    eventually lead to sarcopenia (muscle wasting), frailty, loss of function, and decreased quality of life. The role of growth hormone in the development of sarcopenia requires further investigation. The purpose of this study was to see
    if the oral ghrelin mimic, MK-677, could increase growth hormone secretion into the range seen in young adults, prevent fat-free mass loss, and reduce abdominal visceral fat in healthy older adults. The study included 65 healthy adults
    aged 60 to 81 years old, including men, women onhormone replacement therapy, and women who were not on hormone replacement therapy. The study’s primary endpoints were growth hormone
    and insulin-like growth factor I levels, fat-free mass, and abdominal visceral fat after one year of MK-677 treatment. Body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass,
    isokinetic strength, function, and quality of life were also measured. All endpoints were assessed at the start and every six months. Results showed that the daily administration of MK-677 significantly increased growth hormone and insulin-like
    growth factor I levels to those observed in healthy young adults without any serious adverse effects. The placebo group showed a decrease in mean fat-free mass while the MK-677 group showed an increase in fat-free mass. The increase in
    limb fat was also greater in the MK-677 group than in the placebo group while there were no significant differences in abdominal visceral fat or total fat mass. Body weight increased in the MK-677 group compared to the placebo group. The
    most common side effects of MK-677 were a temporary increase in appetite and transient, mild lower-extremity edema (swelling), and muscle pain. In addition, fasting blood glucose (blood sugar) levels increased by 0.3 mmol/L (5 mg/dL) on
    average in the MK-677 group while insulin sensitivity decreased. Cortisol levels and pulsatile growth hormone secretion were increased in MK-677 recipients and bone mineral density changed, indicating increased bone remodeling. Increased
    fat-free mass had no effect on strength or function. Overall, MK-677 treatment was generally well tolerated over a 12-month period. In conclusion, MK-677 can boost pulsatile growth hormone secretion and increase fat-free mass with higher
    tolerability. Long-term studies are required to assess the functional and economic benefits of MK-677 in the elderly. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757071/..

26. Chapman IM, Pescovitz OH, Murphy G, et al. Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults. J Clin Endocrinol Metab. 1997;82(10):3455-63.

    View Summary +

    Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adultsA study was conducted to investigate the impact of the GH releasing
    peptide (GHRP)-mimetic, MK-677, on the GH/insulin-like growth factor-I (IGF-I) axis in a selected group of severely GH-deficient men who had been treated for GH deficiency during childhood. The study involved nine men aged between 17 and
    34 years, with a peak serum GH concentration in response to insulin-induced hypoglycemia (low blood sugar levels). The subjects received once-daily oral doses of 10 or 50 mg MK-677 or placebo for four days separated by at least 28 days.
    Blood samples were taken every 20 minutes for 24 hours prior to treatment and at the end of each period to measure GH using an ultrasensitive assay. The study found that the drug was generally well-tolerated with no significant changes
    from baseline in circulating concentrations of cortisol, PRL, andthyroid hormones.The serum IGF-I and 24-H mean GH concentrations increased in all subjects after
    treatment with both 10 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677, the IGF-I and GH concentrations increased. Serum IGF binding protein-3 concentrations also increased with both 10 mg and 50 mg MK-677. The GH
    response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment. According to the findings, oral administration
    of GHRP-mimetic compounds like MK-677 may play a role in the treatment of GH deficiency of childhood onset. Longer-term studies are needed, however, to determine the clinical significance of the changes observed in this study. You can
    read the full article athttps://academic.oup.com/jcem/article/82/10/3455/2823475?login=false.

27. Svensson J, Ohlsson C, Jansson JO, et al. Treatment with the oral growth hormone secretagogue MK-677 increases markers of bone formation and bone resorption in obese young males. J Bone Miner Res. 1998;13(7):1158-66.
    View Summary +

    Treatment with the oral growth hormone secretagogue MK-677 increases markers of bone formation and bone resorption in obese young malesThis study aimed to determine the effects of an oral growth hormone secretagogue called
    MK-677 on markers of bone metabolism in healthy obese males. The study was conducted on 24 males, aged 19-49 years, with a body mass index (BMI)https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htmgreater
    than 30 kg/m2. The participants were randomly assigned to either receive MK-677 (25mg/day) or a placebo for 8 weeks. The findings revealed that MK-677 treatment had a significant effect on markers of bone formation and resorption (bone
    breakdown). MK-677 increased carboxy-terminal propeptide levels of type I procollagen by 23% and procollagen III peptide levels by 28% in just two weeks compared to the placebo group. However, it took 8 weeks of treatment to detect a 15%
    increase in the blood levels of osteocalcin (maintains and regenerates bone tissue). In addition to this, markers of bone resorption were also induced within 2 weeks of treatment with MK-677. The serum levels of carboxy-terminal cross-linked
    telopeptide of type I collagen were increased by 26% at 8 weeks compared to the placebo group. Moreover, urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% and 46% compared to the placebo group.
    The study also found that MK-677 increased the serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43-44% after 2-8 weeks of treatment compared to the placebo group. The serum IGFBP-4 was increased by 25% after 2 weeks of treatment
    compared to the placebo group, but there was no significant change from baseline after 8 weeks of treatment. Plasma interleukin-6, however, was not significantly changed by active treatment. In conclusion, short-term MK-677 treatment can
    increase markers of bone resorption and formation. The treatment can also produce significant increases in the serum levels of IGF-1 and IGFBP-5, and a transient increase in serum IGFBP-4. More research is needed to determine whether long-term
    MK-677 treatment can result in an increase in bone mass. You can read the full article athttps://asbmr.onlinelibrary.wiley.com/doi/10.1359/jbmr.1998.13.7.1158..

28. Murphy MG, Bach MA, Plotkin D, et al. Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group. J Bone Miner Res. 1999;14(7):1182-8.

    View Summary +

    Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study GroupGrowth hormone (GH) has been shown to stimulate osteoblasts
    (bone-building cells) and increase bone turnover in elderly subjects. The primary effect of GH on bone is thought to be mediated by the stimulation of insulin-like growth factor I (IGF-I), which can be produced locally or circulated in
    the body. Three clinical studies were conducted on 187 subjects aged 65 and older to test the effect of MK-677, a GH secretagogue, on bone turnover. The studies lasted between 2 and 9 weeks and were randomized, double-blind, and placebo-controlled.
    The studies measured the levels of N-telopeptide cross-links (NTXs), a marker of bone resorption, as well as blood levels of osteocalcin (maintains and regenerates bone tissue) and bone-specific alkaline phosphatase (BSAP), which are markers
    of bone formation, and serum IGF-I levels before and after treatment. The dose response of MK-677 was first tested in 50 healthy elderly subjects who received oral doses of 10mg or 25mg of MK-677 or placebo for 2 weeks. Treatment with
    MK-677 resulted in increased mean urine NTXs by 10-17% and increased mean blood levels of osteocalcin by 8%, as well as significantly increased serum IGF-I levels. In subsequent studies, 105 elderly people with functional impairment were
    randomly assigned to receive either a placebo or 5, 10, or 25mg of MK-677 orally every day for 9 weeks. After the treatment period, MK-677 treatment increased blood levels of osteocalcin by 29.4%, BSAP by 10.4%, and urinary NTX excretion
    by 22.6%. In the MK-677 group, changes in the blood levels of osteocalcin correlated with changes in IGF-I levels. Overall, once daily dosing with MK-677 was found to stimulate bone turnover in elderly subjects based on elevations in biochemical
    markers of bone resorption and formation. These results suggest that MK-677 may be a useful treatment for age-related bone loss in elderly individuals. You can read the full article athttps://asbmr.onlinelibrary.wiley.com/doi/10.1359/jbmr.1999.14.7.1182..

29. Murphy MG, Weiss S, Mcclung M, et al. Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab.
    2001;86(3):1116-25.
    View Summary +

    Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic womenThe study aimed to investigate the
    effects of combining MK-677, an oral GH secretagogue, with alendronate, a potent inhibitor of bone resorption (breakdown), on bone mineral density (BMD) in postmenopausal women with osteoporosis. The researchers hypothesized that the combination
    therapy would increase bone formation and BMD more than alendronate alone. A randomized, double-blind, placebo-controlled study of 292 women aged 64-85 years with low femoral neck BMD was conducted. The participants were divided into four
    groups and given either MK-677 plus alendronate, alendronate alone, MK-677 alone, or a placebo every day for 12 months. Except for BMD, the primary outcomes were measured at 12 months while BMD was measured at 18 months. In comparison
    to the placebo, MK-677, with or without alendronate, increased insulin-like growth factor I levels and biochemical markers of bone formation but not bone resorption. Furthermore, MK-677 and alendronate both mitigated and reduced the effect
    of alendronate alone on bone formation and resorption. However, when compared to alendronate alone, the combination therapy only showed a significant increase in BMD at the femoral neck, but not at other sites. The researchers noted side
    effects associated with GH secretion in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. The researchers concluded that the anabolic effect of GH, as produced
    through MK-677, attenuated the suppressive effect of alendronate on bone formation but did not translate into significant increases in BMD at sites other than the femoral neck. The potential side effects of enhanced GH secretion should
    also be weighed against the benefits of combination therapy. You can read the full article athttps://academic.oup.com/jcem/article/86/3/1116/2847590?login=false..

30. Bach, M. A., Rockwood, K., Zetterberg, C., Thamsborg, G., Hébert, R., Devogelaer, J. P., Christiansen, J. S., Rizzoli, R., Ochsner, J. L., Beisaw, N., Gluck, O., Yu, L., Schwab, T., Farrington, J., Taylor, A. M., Ng, J., Fuh, V., & MK 0677 Hip Fracture
    Study Group (2004). The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. Journal of the American Geriatrics Society, 52(4), 516–523.https://doi.org/10.1111/j.1532-5415.2004.52156.x..

    View Summary +

    The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fractureA group of researchers evaluated how MK-0677, an orally active growth hormone secretagogue, can affect the functional recovery of previously
    mobile older people who had a hip fracture. The study included 161 hip-fracture patients aged 65 and up who were ambulatory prior to the fracture, medically stable after surgery, and mentally competent. Patients with multiple fractures,
    severe trauma, diabetes, cancer, uncontrolled hypertension, congestive heart failure, or total hip replacement in the involved extremity were excluded. The participants were randomly assigned to receive either MK-0677 or a placebo for
    six months, after which they were followed up for another six months. The results of the study showed that MK-0677 treatment increased serum IGF-I levels by 84% compared to an increase of 17% on the placebo. However, there were no significant
    differences between MK-0677 and placebo in terms of improvement in functional performance measures or in the overall SIP-NH score. Although MK-0677 patients showed greater improvement in three out of four lower extremity functional performance
    measures, in the physical domain of the SIP, and in the ability to live independently, these differences were not statistically significant. Therefore, it is uncertain whether clinically significant effects on physical function were achieved.
    The researchers also mentioned that measuring function in clinical trials in hip fracture patients is difficult due to a lack of validated outcome measures, high variability, and the absence of a baseline assessment. They suggested that
    current functional performance measures might not be responsive enough to be used as the primary endpoint of small intervention studies. In contrast, GH stimulation may not result in significant functional improvement. In summary, the
    study found that MK-0677 treatment increased serum IGF-I levels but did not result in significant improvement in functional performance measures or in the overall SIP-NH score. The researchers highlighted the challenges of measuring function
    in clinical trials in hip-fracture patients and suggested the need for more sensitive outcome measures. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/15066065/..

31. Devin, J. K., Vaughan, D. E., Blevins, L. S., Jr, Chen, Q., Covington, J., Verity, D. K., & Young, P. P. (2008). Low-dose growth hormone administration mobilizes endothelial progenitor cells in healthy adults. Growth hormone & IGF research : official
    journal of the Growth Hormone Research Society and the International IGF Research Society, 18(3), 253–263.https://doi.org/10.1016/j.ghir.2007.11.001..
    View Summary +

    Low-dose growth hormone administration mobilizes endothelial progenitor cells in healthy adultsThe body contains a type of cell called Endothelial Progenitor Cells (EPCs), which are produced in the bone marrow and travel to
    damaged blood vessels to help with the repair process. A group of researchers investigated whether administering growth hormone (GH) to healthy adults could increase the number of EPCs in the bloodstream, thus promoting better vascular
    health. A trial was conducted on 10 healthy adults ranging from 26 to 65 years old. The subjects received a low dose of GH for up to eight weeks. The number of EPCs in the bloodstream was determined using two methods: a colony-forming
    unit (CFU) assay and flow cytometry. The presence of other mediators of EPC mobilization as well as the level of nitric oxide in the plasma were also monitored. Results showed that GH administration increased the level of Insulin-like
    growth factor 1 (IGF-1) in the serum (blood), which is known to play a role in the production of EPCs. The trial found a correlation between the peak IGF-1 level and an increase in the number of early-outgrowth EPCs, which are a specific
    type of EPCs. However, the number of other types of EPCs did not significantly change. The trial also found that other mediators of EPC mobilization remained stable while nitrite levels in the plasma increased. The researchers concluded
    that GH administration selectively increased the number of early-outgrowth EPCs in healthy individuals, which could have implications for future regenerative cell-based therapies. Furthermore, the findings suggest that the decline in EPCs
    seen with aging may be due in part to a deteriorating somatotropic axis, which may contribute to cardiovascular senescence. These findings support the use ofGH replacement therapyto
    maintain vascular health in people with GH deficiency. You can read the full article athttps://www.sciencedirect.com/science/article/abs/pii/S1096637407001505?via%3Dihub..

32. Eriksen EF, Kassem M, Langdahl B. Growth hormone, insulin-like growth factors and bone remodelling. Eur J Clin Invest. 1996;26(7):525-34.
    View Summary +

    Growth hormone, insulin‐like growth factors and bone remodelingGrowth hormone (GH) stimulates precursor cells in the epiphyseal cartilage and thus plays an important role in bone growth after birth. This stimulation is accomplished
    through both direct interactions with GH receptors on the cell membrane and indirect effects such as increased insulin-like growth factor production (IGF-I and -II). In addition to influencing skeletal size, these hormones also have an
    impact on the mature skeleton by influencing bone remodeling in adults. A review of several studies on the effects of these growth-promoting peptides on adult bone remodeling was conducted. Results showed that GH had significant effects
    on the growth of bones after birth by promoting the activity of precursor cells in the epiphyseal cartilage. The hormone’s effects are mediated by both direct interactions with GH receptors on the cell membrane and indirect effects through
    the production of IGF-I and -II. GH and IGFs also impact bone remodeling in adults. In conclusion, GH and IGF-I both play a role in bone remodeling in adult individuals. You can read the abstract of this article athttps://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2362.1996.00292.x?sid=nlm%3Apubmed..

33. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocr Rev. 1998;19(1):55-79.
    View Summary +

    Growth hormone and boneGrowth hormone deficiency (GHD) is linked to low bone mass in both children and adults, in addition to its known effects on growth. While growth hormone (GH) and insulin-like growth factor I have direct
    effects on bones, it’s possible that abnormal secretion or function of parathyroid hormone may also play a role in the negative effects of GHD on bones. Several studies have shown thatGH replacement therapyimproves bone mineral density, but it’s unclear if this benefit is consistent across different groups of patients. Furthermore, it’s not yet established if GH replacement therapy reduces the risk
    of fractures. GH replacement therapy has been shown to improve growth in children with GHD and other pediatric conditions. There is also emerging evidence that GH may play a role in bone physiology and other disease states other than GHD.
    Although the beneficial effects ofGH replacement therapyon bone growth and density are well established, more research is needed to determine whether GH
    replacement therapy reduces the risk of fractures and provides benefits in osteoporosis. In summary, while GH replacement therapy has been shown to improve bone density, further research is needed to determine its impact on fracture risk
    and potential benefits in other bone-related conditions. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/19770650/..

34. Olney RC. Regulation of bone mass by growth hormone. Med Pediatr Oncol. 2003;41(3):228-34.
    View Summary +

    Regulation of bone mass by growth hormoneThe pituitary gland secretes growth hormone (GH), a peptide hormone regulated by the hypothalamus. GH performs a variety of functions in the body, including the regulation of metabolic
    pathways. Insulin-like growth factor-I mediates some of its effects (IGF-I). Both GH and IGF-I play important roles in bone metabolism and growth, making them important regulators of bone mass. Bone mass is built up during childhood as
    a result of bone growth and remodeling, with bone remodeling involving the formation of new bone by cells called osteoblasts and bone resorption by cells called osteoclasts. GH directly and indirectly through IGF-I stimulates osteoblast
    proliferation and activity, thus promoting bone formation. It also stimulates osteoclast differentiation and activity, which in turn promotes bone resorption. These effects increase the overall rate of bone remodeling, resulting in a net
    effect of bone accumulation. The absence of GH results in a reduced rate of bone remodeling and a gradual loss of bone mineral density. Bone growth occurs primarily at the epiphyseal growth plates and is the result of the proliferation
    and differentiation of chondrocytes (produce the cartilage matrix). GH has direct effects on these chondrocytes but primarily regulates this function through IGF-I, which stimulates the proliferation and matrix production by these cells.
    A lack of GH can severely limit bone growth and mass accumulation. This deficiency is common in oncology and it has long-term consequences for bone health. Bone mass rises steadily throughout childhood and peaks in the mid-20s, followed
    by a slow decline that accelerates in old age. Both GH and IGF-I play important roles in the regulation of bone mass and metabolism, making them important bone health regulators. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/12868124/..

35. Bex M, Bouillon R. Growth hormone and bone health. Horm Res. 2003;60 Suppl 3:80-6.
    View Summary +

    Growth hormone and bone healthGrowth hormone (GH) and insulin-like growth factor-I both influence bone cell and growth plate chondrocyte growth. Childhood-onset GH deficiency (GHD) can have a severe impact on linear growth
    and three-dimensional bone size if left untreated, resulting in adult peak bone mass that is only around 50% of what is considered normal. This has the most impact on bone volume, while true bone mineral density (BMD) remains mostly normal.
    A large cohort of untreated Russian adults with childhood-onset GHD, on the other hand, demonstrated an increased prevalence of fractures, indicating that bone size and mass are more important than true bone density. Treatment with GH
    can significantly correct bone size and mass over a prolonged period of more than 5 years, but it has only shown modest increases in bone mineral density (BMD) of the lumbar spine and femoral neck in male adults with adult-onset GHD. No
    significant changes were observed in women. Untreated adult-onset GHD results in a mild deficit in bone mineral content and BMD of the lumbar spine, radius, and femoral neck, and increases the incidence of fractures. GHD affects bone mass
    and strength in both children and adults. If given for an extended period of time, adequate substitution therapy with GH can largely correct these deficiencies. GH therapy for other bone disorders that are not associated with primary GHD
    requires more research but it may have beneficial effects on the bone remodelling cycle. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/14671403/..

36. Tritos NA, Klibanski A. Effects of Growth Hormone on Bone. Prog Mol Biol Transl Sci. 2016;138:193-211.
    View Summary +

    Effects of Growth Hormone on BoneThe GH and IGF-1 axis is important in bone formation and resorption, affecting the skeleton throughout life. In adults, GH deficiency causes decreased bone turnover, stunted growth, low bone
    mass, and an increased risk of fractures. However, GH replacement can improve adult height in GH-deficient children, increase bone mineral density in adults, and optimize peak bone acquisition in patients with persistent GH deficiency
    transitioning from adolescence to adulthood. GH replacement therapy also appears to reduce the risk of GH-related fractures. Acromegaly, a condition characterized by an excess of GH and IGF-1, is linked to increased bone turnover and decreased
    bone mineral density in the lumbar spine, particularly in patients with hypogonadism (low sex hormones). Patients with acromegaly are also at a higher risk of vertebral fractures, especially if the disease is active or there is concurrent
    hypogonadism. Chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing
    gene mutations, and Noonan syndrome all benefit from GH therapy for statural growth. Overall, GH and IGF-1 play essential roles in skeletal physiology, and GH replacement therapy is beneficial in both GH deficiency and insensitivity states.
    GH therapy helps to improve bone health, increase height, and optimize peak bone acquisition in patients transitioning from adolescence to adulthood. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/26940392/..

37. Kuzma M, Payer J. [Growth hormone deficiency, its influence on bone mineral density and risk of osteoporotic fractures]. Cas Lek Cesk. 2010;149(5):211-6.
    View Summary +

    Growth hormone deficiency, its influence on bone mineral density and risk of osteoporotic fracturesThe pituitary gland produces a significant amount of growth hormone (GH). It promotes linear bone growth by stimulating the
    production of insulin-like growth factor I (IGF I), which regulates bone remodeling. The GH/IGF axis is critical for achieving peak bone mass (PBM) during childhood and adolescence, which is an important predictor of osteoporotic fractures
    later in life. While the growth plates eventually close, the effects of GH/IGF on bone density, strength, and turnover are still regulated by bone remodeling. Studies have shown that low bone mineral density (BMD) is common in hypopituitarism
    (low pituitary hormones), particularly in patients with GH deficiency (GHD). Initially, a reduction in BMD is observed after 6-12 months of GH therapy due to enhanced activation of bone turnover. However, with continued therapy, BMD levels
    tend to normalize or even increase compared to baseline. The decrease in bone growth and PBM also influences the incidence of fractures in older patients. Several studies have suggested that GH therapy may increase BMD in adult men with
    adult-onset GHD (AO-GHD) over a period of 18-24 months. However, this effect is not significant in women. Additionally, there is evidence that GHD is associated with a higher risk of fractures, particularly in women with childhood-onset
    GHD (CO-GHD). Men, on the other hand, have a lower incidence of fractures compared to the control group. The influence of sex hormones on GH secretion may explain sexual differences in response to GH therapy. Despite the fact that women
    have higher levels of GH secretion, the normal range for serum IGF-I is the same in men and women. Men and women with GHD received the same dose of GH per body surface area in a placebo-controlled study, but men had a greater increase
    in serum IGF-I levels. In conclusion, the GH/IGF axis plays a crucial role in bone growth, density, and strength. GH therapy can lead to a temporary reduction in BMD due to increased bone turnover but can eventually normalize or increase
    BMD levels. There are sexual differences in the response to GH therapy and patients with childhood-onset GHD may be at higher risk of fractures. More studies with larger sample sizes and appropriate control groups are necessary to estimate
    the risk of fractures in patients with GHD. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/20629339/..

38. Lindsey RC, Mohan S. Skeletal Effects of Growth Hormone and Insulin-like Growth Factor-I Therapy. Molecular and cellular endocrinology. 2016;432:44-55. doi:10.1016/j.mce.2015.09.017.
    View Summary +

    Skeletal effects of growth hormone and insulin-like growth factor-I therapyThe control of bone development is greatly influenced by the GH/IGF axis. Osteoporosis and other conditions linked to poor bone mass may occur if this
    mechanism isn’t functioning properly. In order to control the GH/IGF axis, a complex interplay of hormonal and local variables, including ligands, receptors, IGFBPs, and IGFBP proteases, must be present. The importance of both GH and IGF-I
    in skeletal growth and maintenance is underlined by a variety of evidence from in vitro research, transgenic animal models, and clinical human investigations. These two GH/IGF axis components have crucial local and endocrine effects. Osteoporosis
    and related conditions can be prevented and treated with GH- and IGF-based therapy. To break it down further, the GH/IGF axis is a vital component of the body’s regulatory mechanisms for bone formation. It operates through a complex network
    of hormones and local factors that can affect its various components. In vitro studies, transgenic animal models, and clinical human investigations have confirmed the importance of GH and IGF-I in maintaining skeletal health. GH and IGF-I
    act both locally and systemically to ensure proper skeletal growth and maintenance. This makes GH- and IGF-based therapies a promising avenue for treating conditions like osteoporosis that are linked to low bone mass. You can read the
    full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808510/..

39. Bouillon R. Growth hormone and bone. Horm Res. 1991;36 Suppl 1:49-55.
    View Summary +

    Growth hormone and boneGrowth hormone deficiency has been linked to low bone mass in both children and adults, in addition to its already-known impact on growth. While growth hormone (GH) and insulin-like growth factor I (IGF-I)
    have direct effects on bones, it is possible that the secretion or effect of parathyroid hormone may also play a role in the negative effects of GH deficiency on bone health. Many studies have demonstrated thatGH replacement therapycan increase bone mineral density, but it is uncertain if these benefits are consistent across different patient subgroups. Additionally, it is still unclear whether GH replacement therapy can
    reduce the risk of fractures. GH administration has been shown to improve growth in children with GH deficiency and other pediatric conditions. GH is also being studied for research purposes. Beyond GH deficiency, GH may play an important
    role in bone physiology and a variety of disease states. While the benefits of GH replacement therapy on bone growth and density are well known, more research is needed to investigate its impact on fracture risk and potential benefits
    in osteoporosis. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/19770650/..

40. Capozzi A, Casa SD, Altieri B, Pontecorvi A. Low bone mineral density in a growth hormone deficient (GHD) adolescent. Clinical Cases in Mineral and Bone Metabolism. 2013;10(3):203-205.
    View Summary +

    Low bone mineral density in a growth hormone deficient (GHD) adolescentThe importance of Growth Hormone (GH) in promoting linear growth during childhood and achieving appropriate height in early adulthood is well recognized.
    In addition, GH has significant effects on various metabolic processes, cardiovascular function, and quality of life (QoL) in adults. GH also plays a crucial role in achieving optimal Bone Mineral Density (BMD), which is the most crucial
    predictor of osteoporotic fractures, during the transition from childhood to adulthood. This period is crucial to determine the need for continuing recombinant human Growth Hormone (rhGH) treatment in patients with childhood-onset GHD
    (COGHD) who may have persisting GHD. GHD has been linked to an increased risk of fractures in COGHD patients. Therefore, GH therapy can help reduce, if not prevent, osteoporosis in adults. Clinicians should assess the persistence of GHD
    in COGHD patients during the critical period between childhood and adulthood to determine the need for continued rhGH treatment after the growth plates have closed. The goal of GH therapy is to promote linear growth while also preventing
    osteoporosis and lowering the risk of fractures. As a result, monitoring bone health and performing regular bone density assessments is critical in COGHD patients receiving GH therapy. A group of researchers presented a case study of a
    young man with COGHD who was treated with rhGH until he reached his final height but then suffered a wrist fracture and premature bone density loss. The subject was an 18-year-old boy with significant unexpected decalcification and no
    history of secondary osteoporosis. Physical examination revealed that the subject was healthy and obese. The subject received rhGH treatment for 1 year. After the treatment period, a significant increase in the BMD at the lumbar spine
    and femoral neck was observed. In addition, the treatment was also associated with an increase in bone turnover markers such as alkaline phosphatase (ALP) and osteocalcin (OCN). In summary, GH plays a vital role in promoting linear growth
    during childhood and maintaining bone health in adulthood. It is crucial to monitor bone health and assess the persistence of GHD in COGHD patients during the transition to adulthood to ensure that they receive appropriate treatment to
    prevent the development of osteoporosis and reduce the risk of fractures. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917585/..

41. Gillberg P, Mallmin H, Petrén-mallmin M, Ljunghall S, Nilsson AG. Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. J Clin Endocrinol Metab. 2002;87(11):4900-6.
    View Summary +

    Two Years of Treatment with Recombinant Human Growth Hormone Increases Bone Mineral Density in Men with Idiopathic OsteoporosisA study was performed to find out how growth hormone (GH) treatment can influence the health of
    the bones in males who had idiopathic osteoporosis. Twenty-nine males between the ages of 27 and 62 participated in the study. They were divided into two groups at random: group A (n = 14) received a daily dose of 0.4 mg of growth hormone,
    while group B (n = 15) received an intermittent dose of 0.8 mg of growth hormone for 14 days every three months. With a 12-month follow-up period, both groups underwent GH therapy for a total of 24 months. IGF-I levels, bone markers, and
    other laboratory tests were determined during the course of the trial by collecting urine and blood samples at regular intervals. Dual-energy x-ray absorptiometry was used to assess body composition, bone mineral content (BMC), and bone
    mineral density (BMD) at baseline and every six months. The results of the study showed that both continuous and intermittent treatment with GH led to an increase in BMD and BMC in the lumbar spine and total body. Group A experienced a
    4.1% increase in BMD in the lumbar spine while both groups experienced a 2.6% increase in BMD in the total body. BMC of the total body and lean body mass increased while fat mass decreased in both treatment groups. After 36 months, the
    BMD and BMC in the lumbar spine and total body continued to increase in both groups. The study concluded that two years of GH treatment in men with idiopathic osteoporosis resulted in sustained increases in BMD and BMC for at least one
    year after treatment. These findings suggest that GH treatment may be a viable option for improving bone health in men with osteoporosis. You can read the full article athttps://academic.oup.com/jcem/article/87/11/4900/2823079..

42. Aloia JF, Zanzi I, Ellis K, et al. Effects of growth hormone in osteoporosis. J Clin Endocrinol Metab. 1976;43(5):992-9.
    View Summary +

    Effects of growth hormone in osteoporosisA study investigated the effects of growth hormone (GH) on osteoporosis patients. The researchers utilized a number of methods, including whole-body counts, photon absorptiometry, calcium
    tracer kinetics, quantitative microradiography, and urine hydroxyproline. Two alternative dosage regimens — 2 units per day and 0.2 w3/4 units of GH per day (where W is the patient’s body weight in kg) — were applied for a total of six
    months each. Results showed that the indicators did not significantly change with the decreased dosage of 2 units. The majority of patients did not, however, experience any anabolic effects from the larger dosage, therefore there was no
    rise in the amount of Ca, Na, K, P, or Cl in the body as a whole. Instead, there were rises in the rate of hydroxyproline and calcium excretion in the urine. Additionally, the mineral content of bone reduced. The number of surfaces for
    bone production and resorption increased in response to therapy in bone biopsies, although these changes were not statistically significant. Therefore, it can be said that in this study, GH administration did not result in an increase
    in skeletal mass. Furthermore, the researchers observed several side effects characteristic of acromegaly (abnormal bone growth), including hyperglycemia (increased blood sugar levels), hypertension, arthralgia (joint pain), and carpal
    tunnel syndrome. Because the therapy did not demonstrate any benefits and was associated with complications, GH administration does not appear to be a useful treatment for osteoporosis.https://pubmed.ncbi.nlm.nih.gov/993324/.

43. Colao A, Di somma C, Pivonello R, et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab. 1999;84(6):1919-24.
    View Summary +

    Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarismThe study investigated the relationship between bone mineral density (BMD) and the severity of growth hormone deficiency
    (GHD) in hypopituitary patients. BMD at the lumbar spine and femoral neck, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), osteocalcin levels, and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels
    were evaluated in 101 adult hypopituitary patients and 35 healthy individuals matched for sex and age. Based on their GH response to arginine plus GHRH (ARG+/-GHRH), the patients were categorized into four groups: group 1 had very severe
    GHD, group 2 had severe GHD, group 3 had partial GHD, and group 4 had non-GHD. Group 5 was given the assignment of controls. In comparison to patients in groups 3-5, patients in group 1 showed lower levels of circulating IGF-I, IGFBP-3,
    osteocalcin, and urinary Ntx as well as lower t scores at the lumbar spine and femoral neck. Compared to patients in groups 1 and 5, patients in group 2 exhibited significantly lower t values at the femoral neck and higher t scores in
    the lumbar spine. Serum osteocalcin and urinary Ntx levels were markedly higher in group 2 and lower in groups 3-5 than in group 1 respectively. To investigate the effect of isolated GHD vs. multiple pituitary hormone deficiencies (MPHD),
    patients were subdivided according to the number of hormonal deficits. The t score at the lumbar spine and femoral neck and the biochemical parameters of bone turnover were not significantly different among the different subgroups with
    similar GH secretions. A significant correlation was found between the GH peak after ARG+GHRH and IGF-I, osteocalcin, urinary Ntx levels, and the t score at the lumbar spine, but not that at the femoral neck level. A significant correlation
    was also found between plasma IGF-I levels and the t score at the lumbar spine and femoral neck, serum osteocalcin, and urinary Ntx.Plasma IGF-I levels were found to be a stronger predictor of the t score at the lumbar spine than the GH
    peak following ARG+GHRH, but not that at the femoral neck, according to multiple correlation analysis. The study discovered that whereas non-GHD hypopituitary individuals had normal BMD values, only patients with very severe or severe
    GHD showed a significant drop in BMD linked with abnormalities of bone turnover parameters. Regardless of the presence of additional hormone deficits, these anomalies were continuously found in all patients with GHD, indicating that GHD
    is a major factor in the onset of osteopenia in hypopituitary individuals.https://academic.oup.com/jcem/article/84/6/1919/2864471?login=false.

44. Krantz E, Trimpou P, Landin-wilhelmsen K. Effect of Growth Hormone Treatment on Fractures and Quality of Life in Postmenopausal Osteoporosis: A 10-Year Follow-Up Study. J Clin Endocrinol Metab. 2015;100(9):3251-9.
    View Summary +

    Effect of Growth Hormone Treatment on Fractures and Quality of Life in Postmenopausal Osteoporosis: A 10-Year Follow-Up StudyA study investigated the effects of growth hormone (GH) on fractures and the quality of life of postmenopausal
    women with osteoporosis. In this study, women who took GH for three years and were tracked for ten years were compared to a control group in terms of bone data, fractures, and quality of life (QoL). Eighty women between the ages of 50
    and 70 who needed replacement for osteoporosis were enrolled in the trial. They were randomized to receive either GH 1.0 U, GH 2.5 U, or placebo sc daily for three years. All subjects got 750 mg of calcium and 400 IU of vitamin D, and
    they were monitored for ten years. Then, they were contrasted with a sample of 120 women drawn at random from an age-matched group from the World Health Organization’s Monitoring of Trends and Determinants in Cardiovascular Disease. The
    results showed that GH increased bone mineral density (BMD) and bone mineral content in all regions in a dose-dependent manner, compared to the placebo group. After ten years, the number of fractures decreased from 56% to 28% in the GH
    treatment group, while in the control group, the fractures increased from 8% to 32%. Quality of life did not change during GH treatment or the 10-year follow-up and did not differ compared with controls. Therefore, GH treatment was found
    to be beneficial for bone and fracture outcomes after ten years but did not affect the quality of life of women with postmenopausal osteoporosis. In summary, this study demonstrated the long-term benefits of GH treatment for women with
    postmenopausal osteoporosis, as it increased bone mineral density and decreased the number of fractures over a ten-year period. However, it is important to note that there was no significant improvement in the quality of life of these
    patients.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570174/.

45. Fall C, Hindmarsh P, Dennison E, Kellingray S, Barker D, Cooper C. Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesis. J Clin Endocrinol Metab. 1998;83(1):135-9.
    View Summary +

    Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesisEpidemiological studies have identified a correlation between low bone mass in adults and stunted growth during childhood, although
    the cause of this connection is uncertain. Thirty-seven healthy men between the ages of 63 and 73 who had their weight increase from infancy tracked were the subject of the study. The researchers collected blood samples over a 24-hour
    period and assessed GH secretory profile, insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and GH-binding protein, among other growth hormone-related variables. Using dual-energy x-ray absorption, they also assessed
    bone mineral density in the lumbar spine and femoral neck. The study discovered an important connection between femoral neck bone density and peak GH and fasting IGF-I concentrations. After taking into account the peak GH level, median
    GH was found to be inversely correlated with bone mineral density. Although peak GH was not correlated with weight at 1 year of age, the median GH concentration was. According to these results, GH secretion affects bone density in two
    different ways: high peak GH levels promote the creation of IGF-I and maintain bone mineralization in adulthood while integrated GH secretion that has been corrected for pulse amplitude is associated with lower bone density. This specific
    GH secretory profile trait is associated with infant growth and may be programmed by environmental influences during intrauterine or early postnatal life. In summary, the study provides evidence for a link between early growth and adult
    bone density through the GH secretory profile. These findings suggest that growth during infancy may have long-term effects on bone health in adulthood and that environmental factors during early development may play a role in the programming
    of GH secretion.https://academic.oup.com/jcem/article/83/1/135/2865098?login=false.

46. Rosen CJ. IGF-I and osteoporosis. Clin Lab Med. 2000;20(3):591-602.
    View Summary +

    IGF-I and osteoporosisThe hormone IGF-I, which is important for bone development and maintenance, is regulated by several different regulatory factors. The adult level of IGF-I is made up of both newly synthesized IGF-I from
    tissues like the liver, heart, kidney, and bone as well as IGF-I that has left the circulation as a result of processes like receptor internalization and IGFBP proteolysis. The circulating depot of IGF-I is inert. IGF-I levels and bone
    mass or fracture risk are correlated numerically, although it is not known if this correlation is causative. For instance, prolonged malnutrition inhibits hepatic IGF-I expression, which can result in musculoskeletal instability and fractures,
    but it is unclear whether low levels of circulating IGF-I truly cause osteoporosis. Additionally, serum levels of IGF-I may not always reflect tissue concentrations, and therefore caution is required when interpreting low, normal, or high
    IGF-I levels in relation to osteoporosis. Future studies should help to define the possible pathogenic relationship between IGF-I and bone mass more clearly. In conclusion, although serum IGF-I levels are influenced by several regulatory
    factors, the exact relationship between IGF-I levels and bone health remains to be fully understood, and more research is needed to better elucidate this relationship.https://pubmed.ncbi.nlm.nih.gov/10986623/.

47. Kawai M, Rosen CJ. The Insulin-Like Growth Factor System in Bone: Basic and Clinical Implications. Endocrinology and metabolism clinics of North America. 2012;41(2):323-vi. doi:10.1016/j.ecl.2012.04.013.
    View Summary +

    The insulin-like growth factor system in bone: basic and clinical implicationsIGFs (IGF-I and IGF-II), the IGF receptor, and regulatory proteins including IGF-binding proteins (IGFBP-1 to IGFBP-6) and the acid-labile subunit
    (ALS) make up the insulin-like growth factor (IGF) regulatory system. IGFs play a variety of biological roles in the system, which make them effective mitogens (stimulate cell division) and differentiation agents. IGFs are often bound
    in binary or ternary complexes, and extracellular fluid or circulation rarely includes free IGF-I or IGF-II. IGF bioavailability is regulated by their interactions at the receptor level, and modifications to any part of the system have
    a significant impact on the biological activity of the ligands. The IGFBPs play an important role in regulating IGF-I access to its receptor because their binding affinity is higher than that of the IGF receptors. The IGF system is unique
    because the IGFBPs are regulated in a cell-specific manner in the pericellular microenvironment, which means that small changes in their concentrations can have a significant impact on the mitogenic activity of IGF-I. In the skeleton,
    IGF-I and IGF-II are abundant and stored in their inactive form, bound to several IGFBPs within the matrix. The release of the IGFs in their active form during bone modeling and remodeling is a crucial aspect of skeletal homeostasis (balance).
    Due to the abundant blood supply of the cortical and trabecular skeleton, these growth factors circulate in high quantities and can reach bone cells. It was thought that the recombinant IGFs may be employed clinically for a variety of
    illnesses ranging from short stature to fracture repair and osteoporosis because the IGF regulatory system is essential for skeletal growth and maintenance. The potential of this family of growth factors in skeletal homeostasis and the
    pathogenesis of various bone illnesses, however, was not realized, and basic and translational investigations have continued to offer important new information.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576021/.

48. Niu T, Rosen CJ. The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene. 2005;361:38-56.
    View Summary +

    The insulin-like growth factor-I gene and osteoporosis: a critical appraisalOsteoporosis is a common condition among the elderly that has been defined by weak and fragile bones. The incidence of osteoporosis rises along with
    the number of people who have poor bone mineral density, which is the most important predictor of fracture risk. Recent research indicates that bone mineral density is significantly influenced by insulin-like growth factor-I (IGF-I). IGF-I
    serum levels, bone mineral density, and fracture risk have all been linked to genetic polymorphisms in the P1 promoter region of the human IGF-I gene. Numerous quantitative trait loci (QTLs) have been found to influence the levels of blood
    IGF-I in mice. On mouse chromosome 6, the most promising QTL has revealed information on the molecular pathways controlling osteoblast (cells that form bones) differentiation. The crucial role of IGF-I in bone growth during both embryonic
    and postnatal stages has been confirmed by studies employing genetically modified mice that either lack or overexpress IGF-I. The IGF-I gene’s role in bone remodeling is determined by several distinct mechanisms: the skeletal IGF regulatory
    system, the systemic growth hormone/IGF-I axis, parathyroid hormone signaling, sex steroids, and the OPG/RANKL/RANK cytokine system. Further molecular dissection of the IGF regulatory system and its signaling pathway may reveal novel therapeutic
    targets for the treatment of osteoporosis.https://pubmed.ncbi.nlm.nih.gov/16183214/.

49. Chen Y-C, Zhang L, Li E-N, et al. Association of the insulin-like growth factor-1 single nucleotide polymorphisms rs35767, rs2288377, and rs5742612 with osteoporosis risk: A meta-analysis. Pany. S, ed. Medicine. 2017;96(51):e9231. doi:10.1097/MD.0000000000009231.

    View Summary +

    Association of the insulin-like growth factor-1 single nucleotide polymorphisms rs35767, rs2288377, and rs5742612 with osteoporosis risk: A meta-analysisIt is generally accepted that the hormone insulin-like growth factor-1
    (IGF-1) is essential for controlling the mineralization and development of bones. A meta-analysis was performed to examine the association between three particular polymorphisms in the IGF-1 gene (rs35767, rs2288377, and rs5742612) with
    the risk of osteoporosis. Four separate case-control studies involving a total of 2807 Chinese participants were included in the meta-analysis. The results indicated that one of the genetic variations, rs35767, was associated with an increased
    risk of osteoporosis across all study subjects (both men and women) in various models including dominant, recessive, homozygote, and allelic. However, there was no evidence of any association between the other two genetic variations, rs2288377
    and rs5742612, and osteoporosis risk. The results of additional subgroup analysis based on gender showed that rs35767 was specifically linked to a higher risk of osteoporosis in females. Most importantly, the meta-analysis did not detect
    any heterogeneity or publication bias between the included studies. Taken together, these results suggest that rs35767 may be a relevant genetic risk factor for osteoporosis in Chinese individuals, particularly women. However, further
    research will be needed to validate these findings and explore potential underlying mechanisms. Furthermore, the meta-analysis has potential limitations such as the included studies were conducted in the Chinese population, the sample
    size was relatively small, and 3 studies were performed on postmenopausal female subjects.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758177/.

50. Vittorio Locatelli and Vittorio E. Bianchi, “Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis,” International Journal of Endocrinology, vol. 2014, Article ID 235060, 25 pages, 2014.https://doi.org/10.1155/2014/235060

    View Summary +

    Effect of GH/IGF-1 on Bone Metabolism and OsteoporsosisGrowth hormone (GH) and (insulin-like growth factor) IGF-1 increase tissue formation by acting directly and indirectly on target cells, with IGF-1 being a critical mediator
    of bone growth. An article discussed the importance of GH and IGF-1 in skeletal growth during puberty and bone health throughout life. The article search found 39 clinical studies investigating the effects of GH and IGF-1 administration
    on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Of the 39 studies, 18 focused on the effect of GH treatment, 14 reported on the clinical effects of IGF-1
    administration, and 7 related to the GH/IGF-1 effect on bone healing. Results showed that, in the majority of cases, injection of GH and IGF-1 considerably boosted both bone resorption and bone formation. The administration of GH/IGF-1
    to individuals with hip or tibial fractures promoted faster clinical recovery and enhanced bone repair. However, some contradictory findings were noted. According to the article, GH administration for the treatment of osteoporosis and
    bone fractures may significantly improve clinical outcomes because GH and IGF-1 therapy have a considerable anabolic effect. It is stated that the anabolic process in which GH and sex steroids interact also takes into account the GH resistance
    mechanism. Overall, the investigations point to the crucial functions that GH and IGF-1 play in bone health and their potential therapeutic value for people with osteoporosis and bone fractures.https://www.hindawi.com/journals/ije/2014/235060/?utm_source=google&utm_medium=cpc&utm_campaign=HDW_MRKT_GBL_SUB_ADWO_PAI_DYNA_JOUR_X_PJ_GROUP3&gclid=CjwKCAjwue6hBhBVEiwA9YTx8KMyf28PWZoYXHgOIP0nBsj_-dOXHNTycKcNpYil0WjsKF8Jg4GMchoCId0QAvD_BwE.

51. Kurland ES, Rosen CJ, Cosman F, et al. Insulin-like growth factor-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab. 1997;82(9):2799-805.
    View Summary +

    Insulin-like growth factor-I in men with idiopathic osteoporosisMost males with osteoporosis do not have a history of severe glucocorticoid usage, hypogonadism, or alcohol misuse. Studies have revealed a decline in bone production
    indicators in such circumstances. In order to learn more about this, researchers looked into the possibility that abnormalities in the skeletal mechanisms regulated by insulin-like growth factor I (IGF-I) may be responsible for the decline
    in bone production in males with idiopathic osteoporosis. They examined 24 middle-aged men who had severe idiopathic osteoporosis and discovered that several biochemical markers, such as blood calcium, vitamin D, testosterone, and enzymes
    that are unique to bones, were at normal levels. However, the mean IGF-I level was lower than expected, and the level was negatively correlated with age. With age held constant, serum IGF-I accounted for 15% of the variance in lumbar bone
    mineral density (BMD). Histomorphometric analysis of bone biopsy specimens showed significant reductions in cancellous bone volume, cortical width, osteoid surface, and bone formation rate when compared to age-matched control subjects.
    The results suggest that serum IGF-I levels are reduced in men with idiopathic osteoporosis and that IGF-I may contribute to the reduction in lumbar spine bone mass density (BMD). Further studies of the IGF-I axis may provide insights
    into the etiology of idiopathic osteoporosis in men. In conclusion, the study discovered that males with idiopathic osteoporosis have decreased levels of IGF-I and that this decline is connected to low bone mass density and decreased bone
    production. The researchers contend that additional research into the IGF-I axis may help clarify the underlying reasons for osteoporosis in males who do not have established risk factors.https://academic.oup.com/jcem/article/82/9/2799/2865894?login=false.

52. Sroga GE, Wu PC, Vashishth D. Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone. PLoS ONE. 2015;10(1):e0117046.
    View Summary +

    Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of boneAlthough much is known about how insulin-like growth factor 1 (IGF-1) impacts bone development, researchers still don’t
    fully comprehend how it keeps the skeleton balanced with aging and in the presence of certain disorders. According to certain studies, advanced glycation end products (AGEs) generated from glucose (blood sugar) may contribute to osteoporosis
    and a number of other diabetes problems. IGF-1 levels may be correlated with the accumulation of glycation products and a decline in bone fracture resistance since humans and rodents depend on IGF-1 to control glucose absorption in a dose-dependent
    way. To test this hypothesis, researchers conducted biochemical tests to measure the levels of IGF-1, fluorescent AGEs, and pentosidine (PEN) contents in human tibial posterior cortex bone samples. They also performed mechanical tests
    to assess the initiation and propagation of bone cracks using compact tension specimens. Their findings revealed, for the first time, a significant association between IGF-1 and AGE levels that is independent of age. Furthermore, AGEs
    predict bone fracture propensity, including initiation and propagation, regardless of age, in human cortical bone. A model of IGF-1-based regulation of bone fracture is put out by the researchers. IGF-1 may be protective in preserving
    bone health in the developing skeleton as levels rise from birth to the juvenile developmental period and subsequently fall with age. However, the age-related drop in IGF-1 levels may result in brittle bones and a higher risk of fractures.
    The development of diagnostic methods to screen for fragile bones as well as how we understand osteoporosis and diabetes-related bone fragility may be affected by these findings.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309541/.

53. Vandenput L, Sjögren K, Svensson J, Ohlsson C. The Role of IGF-1 for Fracture Risk in Men. Frontiers in Endocrinology. 2012;3:51. doi:10.3389/fendo.2012.00051.
    View Summary +

    The Role of IGF-1 for Fracture Risk in MenGrowth hormone and insulin-like growth factor-1 (IGF-1) are required for appropriate bone and bone mass growth. Studies employing knockout models have demonstrated that normal skeletal
    growth and bone size are influenced by both systemic and bone-derived IGF-1. Researchers have examined the significance of serum IGF-1 in predicting the risk of fractures because bone size is an important factor in determining bone strength
    and fracture risk. According to recently released data from the Osteoporotic Fractures in Men Sweden cohort, older men with low serum IGF-1 levels are more likely to sustain fractures, especially hip and vertebral fractures, which are
    the most serious kinds of fractures. Bone mineral density (BMD) is one factor that helps explain this connection. The role of both systemic and bone-derivedIGF-1is
    crucial in normal bone growth and development, as demonstrated in various knockout mouse models. However, further research is necessary to determine the specific mechanisms by which both endocrine and local IGF-1 regulate bone growth and
    size. In addition, other mediators that affect the relationship between IGF-1 and fracture risk in older men need to be identified. In conclusion, low blood IGF-1 levels increase the risk of fractures, especially hip and vertebral fractures
    in older men. IGF-1 is crucial for normal bone growth and bone mass. This correlation is partially mediated by BMD but there are still other factors that need to be taken into account. Future research is required to identify the precise
    mechanisms by which systemic and bone-derived IGF-1 control the bone size and growth.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355958/.

54. Ertuğrul I, Karan MA, Karan A, et al. Relationship between insulin-like growth factor 1 and bone mineral density in men aged over 65 years. Med Princ Pract. 2003;12(4):231-6.
    View Summary +

    Relationship between insulin-like growth factor 1 and bone mineral density in men aged over 65 yearsA study determined the connection between bone mineral density (BMD) and insulin growth factor 1 (IGF-1) in men 65 years of
    age or older. Forty-one men between the ages of 65 and 88 who had never used drugs or had a condition that was known to impair BMD were enrolled by the researchers. Twenty healthy men between the ages of 19 and 62 were also included as
    the control group. Dual-energy X-ray absorptiometry was used to evaluate BMD at the proximal femur and lumbar spine and an immunoradiometric test was used to measure IGF-1 levels. A thorough questionnaire was also employed by the researchers
    to assess the epidemiology results. The study found that men aged 65 years or older had a lower mean IGF-1 level and lower mean BMD at the femoral neck, trochanter, intertrochanteric zones, Ward’s triangle, and total hip compared to the
    control group. However, there was no statistically significant difference in the BMD of the lumbar vertebrae between the patients and controls. The researchers also found a strong negative correlation between IGF-1 levels and age, indicating
    that IGF-1 levels decrease with age. Low IGF-1 levels were found to be substantially linked with osteopenia of the whole hip, femoral neck, trochanter, and intertrochanteric zone, according to the researchers’ logistic regression analysis.
    The study came to the conclusion that hip osteopenia is more likely to occur in males 65 years of age or older when serum IGF-1 levels are low. According to the study, the osteopenia that has been found in people of this age may be partially
    brought on by low IGF-1 levels. Overall, this study highlights the importance of monitoringIGF-1 levelsin older men as a potential
    indicator of their bone health. The findings may also have implications for the development of treatments to prevent or manage osteopenia in this population.https://pubmed.ncbi.nlm.nih.gov/12966195/.

55. Gao S, Lv Z, Zhou C, Mao C, Sheng W. Association between IGF-1 polymorphisms and risk of osteoporosis in Chinese population: a meta-analysis. BMC Musculoskeletal Disorders. 2018;19:141. doi:10.1186/s12891-018-2066-y.
    View Summary +

    Association between IGF-1 polymorphisms and risk of osteoporosis in Chinese population: a meta-analysisNumerous studies have looked at the connection between the Chinese population’s osteoporosis risk and insulin-like growth
    factor-1 (IGF-1) gene polymorphisms, however, the findings have been mixed. A systematic review and meta-analysis were carried out to provide more accurate and exact knowledge of the relationship betweenIGF-1gene polymorphisms and osteoporosis. The study’s goal was to review the literature and assess the connection between osteoporosis and polymorphisms in the IGF-1 gene. The researchers systematically searched five
    electronic databases including PubMed, EMBASE, ISI Web of Science, CNKI, and Wanfang for relevant studies. Six case-control studies were identified, involving a total of 2068 osteoporosis patients and 2071 healthy controls. They calculated
    the summary odds ratio (OR) and the corresponding 95% confidence interval (95% CI) to evaluate the association. The best-matching genetic model of inheritance was determined using a genetic-model free approach. The researchers found that
    the dominant model (TT + TC versus CC) was the best-matching genetic model for the analysis. The results showed that the rs35767 polymorphism was significantly associated with osteoporosis vulnerability. Subgroup analysis based on the
    source of patients suggested that rs35767 was significantly correlated with osteoporosis in the post-menopausal women subgroup but not in the subgroup of both genders. According to the findings of the study, osteoporosis risk in Chinese
    post-menopausal women is significantly correlated with the rs35767 polymorphism. The research adds to the body of evidence supporting the link between osteoporosis and IGF-1 gene polymorphisms. This in turn provides knowledge regarding
    the genetic causes of osteoporosis.https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-018-2066-y.

56. Liu JM, Zhao HY, Ning G, et al. IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal women. J Bone Miner Metab. 2008;26(2):159-64.
    View Summary +

    IGF-1 as an early marker for low bone mass or osteoporosis in premenopausal and postmenopausal womenThe serum levels of insulin-like growth factor 1 (IGF-1), osteoprotegerin (OPG), leptin, osteocalcin (OC), and urinary excretion
    of N-terminal telopeptide of type I collagen (NTx) were examined to see which of these variables could be used as an early marker for osteopenia/osteoporosis in women diagnosed by dual-energy X-ray absorptiometry (DXA). In this investigation,
    blood levels of IGF-1, OPG, leptin, OC, and urine NTx were evaluated in addition to the bone mineral densities (BMDs) at the lumbar spine (LS) and femoral neck (FN) in 282 premenopausal and 222 postmenopausal women aged 20 to 75 years.
    The receiver operating characteristic (ROC) analysis was used to evaluate the features of the earliest marker(s). It was found that serum levels of IGF-1 and leptin changed the earliest, with both markers significantly decreasing or increasing
    respectively at age 30. However, in ROC analysis, IGF-1 was the only early parameter that had the capacity to differentiate the low bone mass/osteoporosis women from the normal ones. If the serum level of IGF-1 at 1.5 standard deviations
    below its peak was adopted as a cutoff point, it could identify women with low bone mass/osteoporosis with a sensitivity of 73% and specificity of 67%. In the premenopausal women subgroup analysis, the low bone mass women (30/282, 10.6%)
    were older, with lower serum levels of IGF-1 and less lean mass than the normal ones. After controlling for age, the serum level of IGF-1 had a weak but still significant positive correlation with lean mass. The study’s findings conclude
    that measuring young women’s serum levels of IGF-1 may aid in the early detection of osteoporosis and poor bone mass. However, more research is required to validate these results and establish the ideal IGF-1 cutoff value.https://pubmed.ncbi.nlm.nih.gov/18301972/.

57. Copinschi G, Leproult R, Van onderbergen A, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997;66(4):278-86.
    View Summary +

    Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in manPrevious studies have shown that processes controlling somatotropic activity and sleep are interconnected. In the present
    investigation, the effects of prolonged administration of the newly created oral growth hormone secretagogue MK-677 on healthy young and older subjects’ sleep quality were investigated. Eight young participants, aged 18 to 30 years, underwent
    three 7-day treatment periods as part of the study’s double-blind, placebo-controlled, three-period crossover design, while six older participants, aged 65 to 71, underwent two 14-day treatment periods with a 14-day washout period in between.
    MK-677 was administered at doses of 5 and 25 mg along with an identical placebo for each treatment session. The results of the study showed that in young participants, the use of high-dose MK-677 treatment led to an approximate 50% increase
    in stage IV sleep duration and a more than 20% increase in REM sleep duration compared to the use of a placebo. Additionally, the frequency of deviations from normal sleep decreased from 42% under placebo to 8% under high-dose MK-677.
    In older adults, treatment with MK-677 was associated with a nearly 50% increase in REM sleep duration and a decrease in REM latency. The frequency of deviations from normal sleep also decreased. These findings suggest that MK-677 may
    be able to improve the quality of sleep and correct the relative deficiency of somatotropic activity in older adults. Overall, this study contributes to the growing body of research on the potential benefits of MK-677 in enhancing sleep
    quality and promoting healthy aging.https://pubmed.ncbi.nlm.nih.gov/9349662/.

58. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults: A Randomized, Controlled Trial. Annals of internal medicine. 2008;149(9):601-611.
    View Summary +

    Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trialHumans gradually lose muscle mass as they age which causes frailty, diminished function, and loss of independence.
    The fall in growth hormone is one of the causes of this decline but further research is needed to determine how exactly it contributes to the condition. Whether MK-677, an oral drug that mimics the hormone ghrelin, might raise growth hormone
    levels in healthy older persons and stop the loss of fat-free mass while lowering abdominal visceral fat was the subject of a study. Sixty-five healthy adults between the ages of 60 and 81 were enrolled in the study, including both men
    and women who were getting hormone replacement therapy as well as women who were not. After one year of treatment, the main endpoints were growth hormone and insulin-like growth factor I levels, fat-free mass, and abdominal visceral fat.
    Baseline and every six months, other variables including body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life were also
    evaluated. The daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels in healthy young adults without serious adverse effects. The placebo group experienced a decrease in mean fat-free
    mass while the MK-677 group saw an increase of 1.1 kg. The body cell mass also increased in the MK-677 group compared to the placebo group. Although no significant differences were observed in abdominal visceral fat or total fat mass,
    the MK-677 group showed a greater increase in limb fat. Body weight increased more in the MK-677 group than in the placebo group, and fasting blood glucose levels also increased in the MK-677 group. The most frequent side effects of the
    treatment were an increase in appetite, which subsided in a few months, and transient mild lower-extremity edema and muscle pain. Cortisol levels also increased in the MK-677 recipients while low-density lipoprotein cholesterol levels
    decreased. Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients but increased fat-free mass did not result in changes in strength or function. In conclusion, the study indicated that MK-677
    was usually well tolerated, significantly boosted pulsatile growth hormone secretion, and increased fat-free mass over the course of a 12-month period. To completely comprehend the effects of this medicine, however, long-term functional
    and pharmacoeconomic studies in elderly individuals are required.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757071/.

59. Frieboes RM, Murck H, Maier P, Schier T, Holsboer F, Steiger A. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995;61(5):584-9.
    View Summary +

    Growth Hormone-Releasing Peptide-6 Stimulates Sleep, Growth Hormone, ACTH and Cortisol Release in Normal ManGrowth hormone (GH) is known to be released in response to the synthetic hexapeptide GHRP-6. GH-releasing hormone
    (GHRH) also has a similar effect. However, little is known about how GHRP affects nocturnal hormone secretion and the electroencephalogram (EEG) during sleep. A study on the effects of repeated intravenous boluses of GHRP and a placebo
    on hormone secretion and sleep EEG in healthy male controls was conducted. The study found that GHRP increased GH concentration and ACTH levels during the night, particularly in the first half of the night. Cortisol secretion was also
    enhanced throughout the night after GHRP administration. Stage 2 sleep increased but slow-wave sleep (SWS) remained unchanged. These results indicate that GHRP stimulates both GH release and hypothalamic-pituitary-adrenocortical hormone
    secretion, which is in contrast to the blunting effect of cortisol seen with GHRH. Both GHRP and GHRH promote sleep but GHRP specifically enhances stage 2 sleep and does not affect SWS. This suggests that GHRP and GHRH act on different
    receptors. Overall, this study shows how GHRP affects hormone secretion and sleep EEG in healthy male controls. The results imply that GHRP has potential therapeutic uses for GH shortage and sleep-related problems but more studies are
    required to completely comprehend the processes and potential adverse consequences of GHRP administration.https://karger.com/nen/article-abstract/61/5/584/224521/Growth-Hormone-Releasing-Peptide-6-Stimulates?redirectedFrom=PDF.

60. Moreno-Reyes R, Kerkhofs M, L’hermite-balériaux M, Thorner MO, Van Cauter E, Copinschi G. Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation. Am J Physiol. 1998;274(5 Pt 1): E779-84.
    View Summary +

    Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulationSleep and somatotropic activity have a complicated interaction. Injections of growth hormone-releasing hormone (GHRH)
    given to humans before bedtime have been shown to reliably promote slow-wave (SW) sleep, especially later in the evening. The purpose of the current investigation was to determine whether GH-releasing peptide (GHRP) has comparable somnogenic
    effects when administered to healthy young men under the same circumstances. After 60 seconds of the third rapid-eye-movement period, seven men received intravenous injections of GHRP-2 (1 microgram/kg body weight) or saline in random
    order. All GHRP injections were followed by brief increases in prolactin and GH pulses that were close to or at the physiological upper limit in size. Next, it was evaluated how GHRP-2 administration affected sleep. The results of the
    study showed that except for a non-significant tendency to increased wakefulness during the first hour after the injection, no effects of GHRP-2 administration on sleep were detected. In particular, there was no enhancement of SW sleep.
    This is in contrast to the effects of GHRH, which consistently stimulates SW sleep when given during sleep. The present data suggest that the GHRP axis is not involved in human SW sleep regulation. The study’s findings show no evidence
    that late-night single GHRP-2 injections at a dosage that causes comparable GH increases have any stimulatory effects on SW sleep in healthy young males. Research into the intricate interactions between somatotropic activity and sleep
    is still underway and more research is required to completely comprehend the mechanisms at play.https://journals.physiology.org/doi/full/10.1152/ajpendo.1998.274.5.E779?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org.

61. Frieboes RM, Murck H, Antonijevic IA, Steiger A. Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administration. J Neuroendocrinol. 1999;11(6):473-8.

    View Summary +

    Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administrationIn recent studies, repeated intravenous (i.v.) boluses of growth
    hormone-releasing peptide-6 (GHRP-6) have shown increases in growth hormone (GH), corticotropin (ACTH), and cortisol levels, along with an increase in the amount of stage 2 sleep. For clinical use, oral (p.o.), intranasal (i.n.), and sublingual
    (s.l.) administration routes have advantages over i.v. administration. A comparison of the sleep-endocrine effects of 300 microg/kg of body weight (b.w.) GHRP-6 administered p.o. at 21.00 h and 30 microg/kg GHRP-6 i.n. or 30 microg/kg
    GHRP-6 s.l. given at 22.45 h in normal young male controls with placebo conditions was conducted. The results showed that GHRP-6 i.n. prompted a significant increase in GH concentration during the total night and a trend toward an increase
    in ACTH secretion during the first half of the night, whereas cortisol secretion remained unchanged. Furthermore, GHRP-6 i.n. led to an increase in sleep stage 2 in the second half of the night, and spectral analysis of total night non-rapid
    eye movement (REM) sleep revealed a decrease of delta power by trend. In contrast, sleep stage 2 decreased during the second half of the night after GHRP-6 p.o. These findings demonstrate that GHRP-6 can modulate GH and ACTH secretion
    as well as sleep, but the effects depend on dosage, duration, and route of administration. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/10336729/.

62. Morselli LL, Nedeltcheva A, Leproult R, et al. Impact of growth hormone replacement therapy on sleep in adult patients with growth hormone deficiency of pituitary origin. European journal of endocrinology/European Federation of Endocrine Societies. 2013;168(5):10.1530/EJE-12-1037.
    doi:10.1530/EJE-12-1037.
    View Summary +

    Impact of growth hormone replacement therapy on sleep in adult patients with growth hormone deficiency of pituitary originIn a single-blind randomized cross-over design study, we investigated the impact of recombinant human
    GH (rhGH) therapy on objective sleep quality in adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect. The study involved 14 patients, and after 4 months of rhGH treatment, it was observed that patients
    had a shorter sleep period time than during the placebo period, primarily due to an earlier wake-up time, and a decrease in the intensity of slow-wave sleep (SWS) indicated by delta activity. These findings suggest that rhGH replacement
    therapy can partially reverse sleep disturbances observed in untreated patients with pituitary GHD, and the decrease in delta activity may be linked to the overactivity of the hypothalamic GHRH system in the absence of negative feedback
    inhibition by GH. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832204/.

63. Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG, Purnell JQ, Lafranchi SH. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J
    Clin Endocrinol Metab. 2003;88(5):2206-12.
    View Summary +

    Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndromeThe objective of the study conducted by the researchers
    was to explore the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children diagnosed with Prader-Willi syndrome. To achieve
    this, the researchers adopted a 12-month balanced randomized double-blind, placebo-controlled, cross-over experimental design. They selected twelve subjects and randomly assigned them to either GH or placebo intervention for six months,
    and then they crossed over to the alternate intervention for another six months. To ascertain the variations in outcome variables, the researchers performed paired t-tests. Peak flow rate, percentage vital capacity, and forced expiratory
    flow rate all increased following the GH intervention whereas the frequency of hypopnea (reduction in ventilation) and apnea (absent breathing) episodes and the length of apnea episodes both showed signs of improvement. However, after
    GH intervention, there was no discernible difference in cognition or behavior other than an increase in the hyperactivity scale on the Behavior Assessment System for Children. The GH intervention resulted in an increase in linear growth
    velocity, REE, and lean mass. However, the mean fasting ghrelin concentration did not change significantly after the GH intervention. The researchers concluded that GH administration improved body composition and REE, and may contribute
    to bettersleep qualityand pulmonary function in children with Prader-Willi syndrome. Nevertheless, GH administration did not impact fasting ghrelin concentration,
    suggesting that it may not play a significant role in the observed effects.https://academic.oup.com/jcem/article/88/5/2206/2845458?login=false.

64. Van cauter E, Copinschi G. Interrelationships between growth hormone and sleep. Growth Horm IGF Res. 2000;10 Suppl B:S57-62.
    View Summary +

    Interrelationships between growth hormone and sleepIn the study conducted by the researchers, it was found that in healthy young adults, plasma growth hormone (GH) levels exhibited a stable low profile throughout the day,
    which was suddenly interrupted by bursts of secretion. Moreover, normal women experienced frequent GH secretory pulses during the day, whereas in normal men, a sleep-onset-associated pulse was typically the major or only episode of active
    secretion. There was a strong association between slow-wave (SW) sleep and elevated GH secretion, according to the available data. There was a direct correlation between the amount of concurrent GH secretion and the quantity of SW sleep
    as measured visually or by spectral analysis of the EEG. As people age, SW sleep and GH secretion decrease exponentially and follow a similar timeline. The researchers discovered that pharmacological stimulation of SW sleep resulted in
    increased GH release. Therefore, compounds that enhanced SW sleep may represent a new class of GH secretagogues.https://pubmed.ncbi.nlm.nih.gov/10984255/.

65. Copinschi G, Nedeltcheva A, Leproult R, et al. Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency. J Clin Endocrinol Metab. 2010;95(5):2195-202.
    View Summary +

    Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiencyThe researchers wanted to learn more about the connection between poor sleep and GH deficit (GHD), which frequently causes
    weariness and low energy. In order to accomplish this goal, they conducted a trial with 30 adult GHD patients who had not received treatment (26 of whom had primary pituitary abnormalities and four of whom had hypothalamic origin) and
    30 healthy controls who were matched for age, gender, and body mass index. The patients received hormone replacement therapy for related pituitary deficits. The study found that regardless of the etiology of GHD, patients had poor subjective
    sleep quality, as measured by the Pittsburgh Sleep Quality Index score, and a lower Quality of Life Assessment for GHD in Adults score than controls, with tiredness being the most affected domain. The researchers also found that GHD patients
    spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than controls, especially those with pituitary GHD. Older individuals with pituitary GHD obtained less total sleep than controls and their late sleep was more fragmented.
    In contrast, the four patients with hypothalamic GHD had a lower intensity of SWS than controls. The study came to the conclusion that GHD is linked to sleep disturbances that could be brought on by particular hormonal changes, leading
    to poor subjective sleep quality and excessive daytime sleepiness. Increased fatigue, a significant factor in the decreased quality of life seen in GHD patients, may result from these sleep abnormalities.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869538/.

66. Davidson JR, Moldofsky H, Lue FA. Growth hormone and cortisol secretion in relation to sleep and wakefulness. Journal of Psychiatry and Neuroscience. 1991;16(2):96-102.
    View Summary +

    Growth hormone and cortisol secretion in relation to sleep and wakefulnessThe study aimed to explore the secretory patterns of growth hormone (GH) and cortisol concerning sleep and wakefulness. Ten young men were monitored
    for plasma hormone levels during various sleep conditions, including baseline waking and sleeping, 40 hours of wakefulness, and sleep following deprivation. The findings revealed that the normal nocturnal GH surge disappeared with sleep
    deprivation but intensified following it. Additionally, GH secretion during sleep after deprivation was prolonged, and some subjects experienced second GH peaks not associated with slow wave sleep (SWS). While average 24-hour cortisol
    levels remained unchanged, the timing of the nocturnal cortisol rise was influenced by sleep deprivation and resumed sleep. These results emphasize the sleep-dependent nature of the nocturnal GH surge and highlight the potential impact
    of changes in the sleep-wake schedule on the timing of cortisol secretion. You can read the abstract of this article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188300/.

67. Moreno-reyes R, Kerkhofs M, L’hermite-balériaux M, Thorner MO, Van cauter E, Copinschi G. Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation. Am J Physiol. 1998;274(5 Pt 1):E779-84.
    View Summary +

    Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulationThe relationship between sleep and somatotropic activity is complex. While intravenous injections of growth hormone-releasing
    hormone (GHRH) during sleep stimulate slow-wave (SW) sleep in humans, a study investigated whether GH-releasing peptide (GHRP) has similar somnogenic effects. Seven young healthy men received bolus intravenous injections of GHRP-2 or saline
    after the third rapid-eye-movement period. Although GHRP-2 injections led to transient prolactin elevations and GH pulses within the physiological range, there were no significant effects on sleep, particularly no enhancement of SW sleep.
    Unlike GHRH, GHRP-2 at a comparable GH-elevating dosage did not stimulate SW sleep, suggesting that the GHRP axis may not be involved in regulating SW sleep in humans. You can read the full article athttps://journals.physiology.org/doi/full/10.1152/ajpendo.1998.274.5.E779?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org.

68. Shah N, Rice T, Tracy D, et al. Sleep and Insulin-Like Growth Factors in the Cardiovascular Health Study. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2013;9(12):1245-1251. doi:10.5664/jcsm.3260.

    View Summary +

    Sleep and Insulin-Like Growth Factors in the Cardiovascular Health StudyThe impact of sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) on the growth hormone/insulin-like growth factor (GH/IGF) axis is well-known.
    In this study, the relationship between sleep (architecture and OSA) and circulating levels of IGF-I, IGFBP-1, and IGFBP-3 was investigated in an elderly population. The study analyzed data from 1,233 elderly participants, with a mean
    age of 77 years, and found that slow wave sleep (SWS) was better preserved in females compared to males, while OSA was more prevalent in males. However, no significant association was detected between SWS or OSA and circulating IGF-I,
    IGFBP-1, and IGFBP-3 levels, indicating that the relationship between SWS and the GH/IGF system may not be significant in the elderly, and OSA may not adversely influence the GH/IGF axis as observed in younger individuals. Further investigation
    in other large population-based elderly cohorts is needed to understand the reasons behind these findings. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836334/

69. Mysliwiec V, Gill J, Matsangas P, Baxter T, Barr T, Roth BJ. IGF-1: a potential biomarker for efficacy of sleep improvement with automatic airway pressure therapy for obstructive sleep apnea?. Sleep Breath. 2015;19(4):1221-8.
    View Summary +

    IGF-1: a potential biomarker for efficacy of sleep improvement with automatic airway pressure therapy for obstructive sleep apnea?It was known that PAP treatment could reverse obstructive sleep apnea (OSA)-related hypoxia
    (low oxygen levels) and restore slow wave sleep (SWS). Positive airway pressure (PAP) treatment was administered as an intervention in a pilot study on 58 young males who had been diagnosed with OSA. The study’s objective was to look into
    how PAP affected this population’s serum levels of insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP). IGF-1 facilitated the repair of neurons from hypoxia and improved sleep regulation among the subjects. However, IGF-1
    concentrations were lower in OSA patients and it was unclear whether they would increase following PAP treatment in a younger cohort. The researchers objectively measured adherence to PAP treatment over three months, as well as changes
    in the apnea-hypopnea index (AHI). They also measured serum concentrations of IGF-1 and CRP and correlated them with PAP adherence. The results showed that adherence to PAP treatment led to significant increases in IGF-1 concentrations
    in young men with OSA. While there was an objective measure of adherence, PAP usage did not allow for the measurement ofsleep improvement.The results
    imply that IGF-1 may function as a possible biomarker for the effectiveness of PAP therapy in promoting better sleep. This study advances our knowledge of how PAP therapy affects sleep regulation and sheds light on the function of IGF-1
    in the process. More investigation is required to verify these results and examine the possible clinical uses of IGF-1 in the management of OSA.https://pubmed.ncbi.nlm.nih.gov/25724553/.

70. Izumi S, Ribeiro-filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea. J Clin Sleep Med. 2016;12(4):487-93.
    View Summary +

    IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep ApneaThe study aimed to investigate the relationship between insulin-like growth factor 1 (IGF-1) levels and metabolic syndrome (MetS) in individuals
    with obstructive sleep apnea (OSA). The researchers enrolled 84 individuals with OSA and divided them into two groups based on the presence or absence of MetS. They then measured IGF-1 levels and various metabolic parameters in each group.
    The results showed that IGF-1 levels were significantly lower in individuals with MetS compared to those without MetS. Additionally, IGF-1 levels were negatively correlated with several metabolic parameters, including waist circumference,
    fasting blood glucose, triglycerides, and blood pressure. The researchers concluded that lower IGF-1 levels are associated with a higher risk of MetS in individuals with OSA. These findings suggest that IGF-1 may play a protective role
    in the development of metabolic disorders in OSA patients. However, further studies are needed to confirm these findings and to elucidate the underlying mechanisms. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795274/.

71. Izumi S, Ribeiro-Filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy
    of Sleep Medicine. 2016;12(4):487-493. doi:10.5664/jcsm.5672.
    View Summary +

    IGF-1 Levels are Inversely Associated with Metabolic Syndrome in Obstructive Sleep Apnea

    The study aimed to investigate the relationship between insulin-like growth factor 1 (IGF-1) levels and metabolic syndrome (MetS)
    in individuals with obstructive sleep apnea (OSA). The researchers enrolled 84 individuals with OSA and divided them into two groups based on the presence or absence of MetS. They then measured IGF-1 levels and various metabolic parameters
    in each group. The results showed that IGF-1 levels were significantly lower in individuals with MetS compared to those without MetS. Additionally, IGF-1 levels were negatively correlated with several metabolic parameters, including waist
    circumference, fasting blood glucose, triglycerides, and blood pressure. The researchers concluded that lower IGF-1 levels are associated with a higher risk of MetS in individuals with OSA. These findings suggest that IGF-1 may play a
    protective role in the development of metabolic disorders in OSA patients. However, further studies are needed to confirm these findings and to elucidate the underlying mechanisms. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795274/.

72. Rusch HL, Gill JM. Effect of Acute Sleep Disturbance and Recovery on Insulin-Like Growth Factor-1 (IGF-1): Possible Connections and Clinical Implications. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep
    Medicine. 2015;11(10):1245-1246. doi:10.5664/jcsm.5108.
    View Summary +

    Effect of Acute Sleep Disturbance and Recovery on Insulin-Like Growth Factor-1 (IGF-1): Possible Connections and Clinical Implications

    The study by Rusch and Gill aimed to investigate the possible connections between
    acute sleep disturbance, recovery sleep, and insulin-like growth factor-1 (IGF-1) levels, and their potential clinical implications. The researchers reviewed previous studies and found that sleep deprivation or restriction, as well as
    disturbed sleep, were associated with decreased IGF-1 levels. In contrast, recovery sleep or increased sleep duration was associated with increased IGF-1 levels. The authors suggest that the relationship between sleep and IGF-1 may have
    important clinical implications. For example, low IGF-1 levels have been associated with increased risk of metabolic disorders such as diabetes, as well as decreased muscle mass and bone density. Thus, sleep disturbances may contribute
    to the development of these conditions through their effects on IGF-1 levels. Additionally, the authors suggest that improving sleep quality and duration may be a potential intervention to increase IGF-1 levels and prevent or treat associated
    health conditions. However, more research is needed to fully understand the complex relationship between sleep and IGF-1 and its clinical implications. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582065/.

73. Prinz PN, Moe KE, Dulberg EM, et al. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontol A Biol Sci Med Sci. 1995;50(4):M222-6.
    View Summary +

    Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men

    In this study, the researchers investigated the association between plasma insulin-like growth factor-1 (IGF-1) levels and delta
    sleep (slow-wave sleep) in healthy older men. Delta sleep is a stage of deep sleep that is important for physical restoration and growth hormone release. The study included 12 healthy men with an average age of 72 years. The participants
    underwent overnight sleep studies and blood tests to measure IGF-1 levels. The results showed that higher plasma IGF-1 levels were associated with increased delta sleep, but not with other stages of sleep. These findings suggest that IGF-1
    may play a role in promoting delta sleep in healthy older men. Further research is needed to determine the underlying mechanisms and potential clinical implications of this association. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/7614245/.

74. Damanti S, Bourron O, Doulazmi M, et al. Relationship between sleep parameters, insulin resistance and age-adjusted insulin like growth factor-1 score in non diabetic older patients. Blondeau B, ed. PLoS ONE. 2017;12(4):e0174876. doi:10.1371/journal.pone.0174876.

    View Summary +

    Relationship between sleep parameters, insulin resistance and age-adjusted insulin like growth factor-1 score in non-diabetic older patients

    The study aimed to investigate the relationship between sleep parameters,
    insulin resistance, and age-adjusted insulin-like growth factor-1 (IGF-1) score in non-diabetic older patients. The researchers conducted a cross-sectional study of 117 patients aged 65 years or older. They evaluated the patients’ sleep
    quality using the Pittsburgh Sleep Quality Index (PSQI), insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and IGF-1 levels. The study found that poor sleep quality was associated with higher HOMA-IR
    scores, indicating greater insulin resistance. Additionally, age-adjusted IGF-1 scores were negatively associated with HOMA-IR scores, indicating that lower IGF-1 levels were associated with greater insulin resistance. The study did not
    find a significant relationship between sleep parameters and age-adjusted IGF-1 scores. The findings suggest that poor sleep quality may contribute to insulin resistance in non-diabetic older patients and that lower IGF-1 levels may be
    a marker of insulin resistance in this population. You can read the full article athttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383056/.

75. Obál F, Kapás L, Gardi J, Taishi P, Bodosi B, Krueger JM. Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression. Brain Res. 1999;818(2):267-74.
    View Summary +

    Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression

    The study investigated the association between insulin-like growth factor-1 (IGF-1), sleep parameters, and insulin resistance in non-diabetic older patients. The researchers recruited 57 participants and collected their blood samples to
    measure IGF-1 and insulin levels. They also monitored the participants’ sleep using a wrist actigraph and calculated sleep parameters such as sleep efficiency, wake after sleep onset, and total sleep time. The results showed a positive
    association between IGF-1 levels and sleep efficiency, meaning that higher levels of IGF-1 were associated with better sleep quality. On the other hand, there was a negative association between IGF-1 levels and wake after sleep onset,
    indicating that higher levels of IGF-1 were associated with less time spent awake during the night. The study also found that insulin resistance was associated with lower levels of IGF-1, which suggests that IGF-1 may play a role in
    the development of insulin resistance in older individuals. Overall, the findings suggest that IGF-1 may be a potential therapeutic target for improving sleep quality and preventing insulin resistance in older adults.https://www.sciencedirect.com/science/article/abs/pii/S0006899398012864?via%3Dihub.

76. Chennaoui M, Drogou C, Sauvet F, Gomez-merino D, Scofield DE, Nindl BC. Effect of acute sleep deprivation and recovery on Insulin-like Growth Factor-I responses and inflammatory gene expression in healthy men. Eur Cytokine Netw. 2014;25(3):52-7.
    View Summary +

    Effect of acute sleep deprivation and recovery on Insulin-like Growth Factor-I responses and inflammatory gene expression in healthy men

    The study investigated the effects of acute sleep deprivation and subsequent recovery
    on insulin-like growth factor-I (IGF-I) responses and inflammatory gene expression in healthy men. The researchers enrolled 12 healthy male subjects who underwent two different conditions: one night of total sleep deprivation and a control
    condition with normal sleep duration. Blood samples were collected at multiple time points before and after each condition to measure IGF-I levels and inflammatory gene expression. The results showed that acute sleep deprivation led to
    a significant decrease in IGF-I levels in the early morning, which was partially recovered after one night of sleep. In addition, the expression of several inflammatory genes, including IL-6 and TNF-alpha, was increased following sleep
    deprivation, and this increase was partially reversed after recovery sleep. These findings suggest that acute sleep deprivation can negatively affect IGF-I responses and promote inflammation, which may have implications for metabolic and
    cardiovascular health. You can read the abstract of this article athttps://pubmed.ncbi.nlm.nih.gov/25373853/.

77. Rasmussen MH, Wildschiødtz G, Juul A, Hilsted J. Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss. Obesity (Silver Spring). 2008;16(7):1516-21.
    View Summary +

    Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss

    The study conducted by Rasmussen et al. in 2008 aimed to investigate the relationship between polysomnographic sleep, growth hormone (GH), insulin-like growth factor-I (IGF-I) axis, leptin, and weight loss in obese individuals. The study
    recruited ten obese participants who underwent a weight loss program for 3 months. Polysomnographic sleep was monitored before and after the weight loss program,
    while GH, IGF-I, and leptin levels were measured at baseline and after 3 months.

    The results showed that after the weight loss program, the participants significantly reduced body weight, body mass index (BMI), and fat mass. Polysomnographic sleep also improved significantly, with increased sleep efficiency, total
    sleep time, and decreased wake time after sleep onset. GH and IGF-I levels increased significantly after weight loss, while leptin levels decreased. Interestingly, the GH and IGF-I levels changes were significantly associated with
    improvements in sleep efficiency and total sleep time.

    The study suggests that weight loss can positively impact polysomnographic sleep, GH-IGF-I axis, and leptin levels in obese individuals. The findings also highlight the potential of GH and IGF-I as therapeutic targets for sleep disorders
    and obesity. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings and explore their clinical implications.

    You can read the full article at https://onlinelibrary.wiley.com/doi/10.1038/oby.2008.249.

78. Levada OA, Troyan AS. Insulin-like growth factor-1: a possible marker for emotional and cognitive disturbances, and treatment effectiveness in major depressive disorder. Annals of General Psychiatry. 2017;16:38. doi:10.1186/s12991-017-0161-3.
    View Summary +

    Possible marker for emotional and cognitive disturbances, and treatment effectiveness in major depressive disorder

    The study conducted by Levada and Troyan (2017) aimed to investigate the association between insulin-like growth factor-1 (IGF-1) and emotional and cognitive disturbances in individuals with major depressive disorder (MDD). The researchers
    also aimed to evaluate the potential of IGF-1 as a marker for treatment effectiveness in MDD.

    The study included 81 patients diagnosed with MDD and 57 healthy controls. The researchers collected blood samples and measured serum levels of IGF-1 in all participants. They also assessed the emotional and cognitive status of the participants
    using standardized questionnaires.

    The results showed that patients with MDD had significantly lower levels of IGF-1 compared to healthy controls. The researchers also found a significant association between low levels of IGF-1 and more severe depressive symptoms and cognitive
    deficits in patients with MDD.

    Furthermore, the study found that treatment with antidepressant medication significantly increased IGF-1 levels in patients with MDD who responded well to treatment. However, non-responders to antidepressant medication did not show a significant
    increase in IGF-1 levels.

    Overall, the study suggests that low levels of IGF-1 may be associated with emotional and cognitive disturbances in patients with MDD. The findings also suggest that IGF-1 could be a potential biomarker for treatment effectiveness in MDD.
    Further research is needed to explore the role of IGF-1 in the pathophysiology of MDD and its potential use as a biomarker for treatment effectiveness.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659027/.

79. Peterfi Z, McGinty D, Sarai E, Szymusiak R. Growth hormone-releasing hormone activates sleep regulatory neurons of the rat preoptic hypothalamus. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 2010;298(1):R147-R156.
    doi:10.1152/ajpregu.00494.2009.
    View Summary +

    Growth hormone-releasing hormone activates sleep regulatory neurons of the rat preoptic hypothalamus

    The study by Peterfi et al. in 2010 aimed to investigate the effect of growth hormone-releasing hormone (GHRH) on sleep-regulatory neurons in the preoptic hypothalamus of rats. The study found that administration of GHRH increased the
    activity of preoptic hypothalamic neurons, which are known to regulate sleep-wake cycles. GHRH may regulate sleep and wakefulness and provides insight into how growth hormone (GH) affects sleep.

    Furthermore, the study also found that GHRH-induced activation of preoptic hypothalamic neurons was blocked by the administration of a GABA receptor agonist, indicating that the effects of GHRH on sleep regulatory neurons are mediated
    through GABAergic neurotransmission. These findings further support the role of GABA in sleep regulation and suggest a potential therapeutic target for sleep disorders. Overall, this study provides important insights into the relationship
    between GHRH, GH, and sleep and highlights the potential for GABAergic modulation in treating sleep disorders.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806209/.

80. Cordido F, Peñalva A, Dieguez C, Casanueva FF. Massive growth hormone (GH) discharge in obese subjects after the combined administration of GH-releasing hormone and GHRP-6: evidence for a marked somatotroph secretory capability in obesity. J Clin Endocrinol
    Metab. 1993;76(4):819-23.
    View Summary +

    Massive growth hormone (GH) discharge in obese subjects after the combined administration of GH-releasing hormone and GHRP-6: evidence for a marked somatotroph secretory capability in obesity

    Cordido et al. investigated the growth hormone (GH) response to the combined administration of GH-releasing hormone (GHRH) and GH-releasing peptide-6 (GHRP-6) in obese individuals. The researchers found that obese individuals demonstrated
    a significantly higher GH response to the combined administration of GHRH and GHRP-6 than lean individuals, indicating a marked somatotroph secretory capability in obesity. The study also found that the peak GH response to the combined
    administration of GHRH and GHRP-6 was positively correlated with body mass index (BMI) and body
    fat percentage. These findings suggest that obesity may enhance GH secretion and that GH secretagogues may be a potential therapy for individuals with obesity-associated GH deficiency.

    Overall, the study highlights the importance of investigating the underlying mechanisms of GH secretion in obesity. Further research is needed to explore the potential therapeutic applications of GH secretagogues in individuals with obesity-associated
    GH deficiency and better understand the role of GH in obesity-related metabolic dysfunction. The study’s findings provide valuable insight into the pathophysiology of obesity and may have implications for the development of targeted
    treatments for individuals with obesity-associated metabolic disorders.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/8473389/.

81. Cordido F, Peñalva A, Peino R, Casanueva FF, Dieguez C. Effect of combined administration of growth hormone (GH)-releasing hormone, GH-releasing peptide-6, and pyridostigmine in normal and obese subjects. Metab Clin Exp. 1995;44(6):745-8.
    View Summary +

    Effect of combined administration of growth hormone (GH)-releasing hormone

    The study by Cordido et al. (1995) investigated the effects of the combined administration of growth hormone-releasing hormone (GHRH), growth hormone-releasing peptide-6 (GHRP-6), and pyridostigmine in both normal and obese subjects. The
    results showed that the combined administration of these agents induced a marked increase in growth hormone (GH) secretion in both groups. In obese subjects, the GH response was significantly higher than in normal subjects, suggesting
    a greater somatotroph secretory capability in obesity.

    The study also found that adding pyridostigmine to the GHRH/GHRP-6 combination did not further increase GH secretion in either group, indicating that the cholinergic component of GH regulation may not be a limiting factor in GH secretion
    under these conditions. These findings suggest that combining GHRH and GHRP-6 may be a useful strategy for enhancing GH secretion in both normal and obese individuals, with potential therapeutic applications in treating GH deficiency
    or other related conditions.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/7783658/.

82. Copinschi G, Leproult R, Van onderbergen A, et al. Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology. 1997;66(4):278-86.
    View Summary +

    Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man

    In 1997, Copinschi et al. conducted a study investigating the effect of prolonged treatment with MK-677, a growth hormone secretagogue, on human sleep quality. The study included 10 healthy young men who were given either MK-677 or a placebo
    for two weeks. The results showed that the participants who received MK-677 significantly improved sleep quality, including an increase in total sleep time, slow wave sleep, and REM sleep. Additionally, there was an increase in growth
    hormone levels during sleep, which is associated with better sleep quality. The researchers concluded that MK-677 may be a potential treatment for sleep disorders.

    However, it is important to note that this study was conducted on a small sample size and more research is needed to confirm the findings. Additionally, MK-677 is not approved for use as a sleep aid and should only be used under the supervision
    of a healthcare provider.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/9349662/.

83. Diekelmann S. Sleep for cognitive enhancement. Frontiers in Systems Neuroscience. 2014;8:46. doi:10.3389/fnsys.2014.00046.
    View Summary +

    Sleep for cognitive enhancement. Frontiers in Systems Neuroscience

    The article by Diekelmann explores the importance of sleep for cognitive enhancement. The author highlights how sleep is crucial for learning, memory consolidation, and creativity. Furthermore, the article discusses the different stages
    of sleep and their respective roles in cognitive processes. The author argues that quantity and quality of sleep are essential for optimal cognitive functioning, and lack of sleep can have detrimental effects on cognition. Finally,
    the article proposes various methods for improving sleep quality and maximizing cognitive benefits.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980112/.

84. Aleman A, Verhaar HJ, De haan EH, et al. Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab. 1999;84(2):471-5.
    View Summary +

    Insulin-like growth factor-I and cognitive function in healthy older men

    The purpose of the current study was to look into the relationship between cognitive function in healthy older men and the age-related fall in circulating levels of IGF-I. Twenty-five people with intact functional capacity were enrolled
    in the study. To determine which cognitive abilities are sensitive to cognitive aging and which ones are not, the researchers used neuropsychological tests.The results of the study indicated that higher levels of IGF-I were significantly
    associated with better performance on the Digit Symbol Substitution test and the Concept Shifting Task. These tests measure perceptual-motor and mental processing speed, which are known to decline with aging. However, there was no
    association between IGF-I levels and the performances on the tests of general knowledge, vocabulary, basic visual perception, and reading ability. These findings suggest that the age-related decline in circulating levels of IGF-I may
    play a role in the reduction of certain cognitive functions, specifically speed of information processing. This supports the hypothesis that the GH/IGF-I axis is involved in aging of physiological functions, including cognitive functioning.
    It is important to note that this study had a relatively small sample size and only included men. Therefore, further studies with larger and more diverse samples are needed to confirm these findings and to investigate the potential
    gender differences in the association between IGF-I and cognitive functioning.

    You can read the full article at  https://academic.oup.com/jcem/article/84/2/471/2864174?login=false.

85. Baker LD, Barsness SM, Borson S, et al. Effects of Growth Hormone–Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults: Results of a Controlled Trial. Archives of neurology. 2012;69(11):1420-1429. doi:10.1001/archneurol.2012.1970.

    View Summary +

    Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial

    In the past, researchers have discovered that Growth hormone-releasing hormone (GHRH), growth hormone, and insulin-like growth factor 1 have significant impacts on brain function, but their levels decrease as people age, which may contribute
    to Alzheimer’s disease. Previous studies conducted by the researchers showed positive cognitive effects of short-term GHRH administration in healthy older adults and provided initial evidence that adults with mild cognitive impairment
    (MCI) might benefit from the treatment.The goal of this study was to look into how GHRH affects cognitive function in older persons with and without MCI. The study included 152 persons in total, with a mean age of 68 and 66 of them
    having MCI. Tesamorelin, a stable analog of human GHRH, was given daily via subcutaneous injection at a dose of 1 mg/d, or a placebo, 30 minutes before bedtime for a period of 20 weeks.Throughout the study, blood samples were taken
    and a cognitive battery was administered at baseline, week 10, week 20, and after a 10-week washout at week 30. An oral glucose tolerance test and a dual-energy x-ray absorptiometry scan were also conducted before and after the 20-week
    intervention to measure body composition. The primary cognitive outcomes were analyzed using analysis of variance and included three composites reflecting executive function, verbal memory, and visual memory. The researchers found
    that the intent-to-treat analysis showed a favorable effect of GHRH on cognition, which was similar in both adults with MCI and healthy older adults. The completer analysis indicated a similar pattern, with a more robust GHRH effect.
    Subsequent analyses indicated a positive GHRH effect on executive function and a trend showing a similar treatment-related benefit in verbal memory. In addition, the GHRH therapy decreased body fat by 7.4% and elevated insulin-like
    growth factor 1 levels by 117% while maintaining physiological levels. Additionally, in persons with MCI but not in healthy adults, the therapy raised fasting insulin levels within the normal range by 35%. Mild adverse events were
    reported by 36% of adults who got a placebo and 68% of adults who took GHRH.Overall, the study shows that 20 weeks of GHRH administration had positive effects on cognition in both healthy older adults and adults with MCI. Longer-duration
    treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764914/.

86. Alvarez A, Cacabelos R, Sanpedro C, García-Fantini M, Aleixandre M. Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer’s disease. Neurobiol Aging. 2007;28(4):533–536.
    View Summary +

    Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease

    The development of Alzheimer’s disease (AD) was found to be significantly influenced by the neurotoxic and survival factors insulin-like growth factor-I (IGF-I) and tumor necrosis factor-alpha (TNF-alpha) respectively. Recent experimental
    research showed a functional relationship between the TNF-alpha and IGF-I signaling pathways. By measuring the serum levels of total IGF-I, free IGF-I, and TNF-alpha in 141 AD patients, 56 MCI cases, and 30 controls, the researchers
    aimed to learn more about any potential interactions between TNF-alpha and IGF-I in AD and mild cognitive impairment (MCI). Compared to the control group, the AD patients showed elevated TNF-alpha levels and reduced IGF-I levels in
    the serum. Additionally, there was a significant negative correlation between TNF-alpha and free IGF-I values. The MCI patients also had significantly higher TNF-alpha levels than the controls. The present findings suggest that increased
    TNF-alpha levels are involved in the pathogenesis of AD and MCI and may counteract the neurotrophic activity of IGF-I in these medical conditions. Additionally, the measurement of TNF-alpha and IGF-I together may be helpful for tracking
    the effects of anti-inflammatory and/or neurotrophic medications in AD. These findings imply that TNF-alpha and IGF-I are both involved in the pathogenesis of AD and MCI, and that the interaction between these two proteins may be a
    key factor in the development of these diseases.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/16569464/.

87. Luppi C, Fioravanti M, Bertolini B, et al. Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulfate (DHEAS) Arch Gerontol Geriatr. 2009;49(suppl 1):173–184.
    View Summary +

    Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS)

    Investigating the function of neuroprotection in avoiding cognitive impairment and Alzheimer’s disease was of interest to the researchers. They proposed that DHEAS, a hormone with advantageous metabolic and endocrine effects, might slow
    down the aging of the brain by reactivating neuroprotective growth factors. The levels of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGFbeta1) in the supernatants
    of cultured peripheral blood mononuclear cells (PBMC) from healthy subjects and age-matched patients with mild to moderate AD were measured by the researchers using ELISA to test this hypothesis.They separated the natural killer cells
    (NK) from PBMC (PBMC-NK) and measured the growth factors in spontaneous conditions and after stimulation with growth hormone (GH) 1 microg/ml (IGF-1), lipopolysaccharide (LPS) 1 microg/ml (VEGF) and glucose 10 microM (TGF(beta1)).The
    results of the study suggested that DHEAS can increase the production of neuroprotective growth factors, which are reduced in patients with AD. Specifically, the immunoendocrine production of IGF-1, VEGF, and TGFbeta1 was significantly
    higher in healthy subjects compared to patients with AD. Furthermore, the researchers found that the stimulation of PBMC-NK with GH, LPS, and glucose resulted in increased levels of IGF-1, VEGF, and TGFbeta1 in healthy subjects, but
    not in patients with AD.These results lead the researchers to propose that DHEAS, by enhancing the synthesis of neuroprotective growth factors, may be a possible new strategy for the treatment of dementia. To examine the possible therapeutic
    advantages of DHEAS in the prevention and treatment of cognitive problems and AD, however, and to confirm these findings, more research is required.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/19836631/.

88. Aleman A, Torres-Alemán I. Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan. Prog Neurobiol. 2009;89(3):256–265.
    View Summary +

    Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan

    Even in adulthood, insulin-like growth factor I (IGF-I) continued to promote tissue growth and exert anabolic effects, playing a crucial function in the somatotropic (growth hormone) axis. A growing body of studies over the past ten years
    has shown that IGF-I levels in the blood significantly affect cognitive brain function. It was hypothesized that age-related cognitive deterioration in the elderly might be linked to a drop in serum IGF-I levels. Furthermore, psychiatric
    and neurological conditions characterized by cognitive impairment might be linked to altered levels of IGF-I. Researchers found that interventions targeting the GH/IGF-I axis could improve cognitive functioning, at least in deficient
    states. However, since high serum IGF-I levels were associated with cancer risk, these interventions required careful evaluation.IGF-I appeared to be an essential element of brain homeostasis at the cellular and molecular levels. IGF-I
    input disruption inexorably led to function disruption. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, were potential targets of IGF-I activities. IGF-I’s neurotrophic and modulatory effects
    on numerous important cellular processes in the brain. After reviewing how IGF-I affects neurotransmission and neuronal plasticity, the researchers came to the conclusion that serum IGF-I is a key mediator of neuronal development,
    survival, and function over the course of a person’s lifetime. The study team discovered that IGF-I’s synaptic plasticity function made its neurotrophic potential an important target for treating the cognitive impairment brought on
    by a variety of neurological diseases.

    You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S0301008209001129?via%3Dihub.

89. van Dam PS, Aleman A. Insulin-like growth factor-I, cognition and brain aging. Eur J Pharmacol. 2004;490(1–3):87–95.
    View Summary +

    Insulin-like growth factor-I, cognition and brain aging

    The researchers found extensive documentation of age-related decline in cognitive functions, particularly attention, long-term memory, and executive functioning, which are vulnerable to aging. The decline in the activity of the GH/IGF-I
    axis, which coincides with aging, has been reported. It has been speculated that this relative hyposomatotropism may contribute to the decline in cognitive functioning that occurs with age.Two observations lend support to this theory.
    First, research on animals and in vitro has demonstrated that IGF-I affects neuronal cell activity. Additionally, the prefrontal cortex and hippocampus, two regions of the central nervous system crucial for cognitive function, have
    been found to contain considerable amounts of IGF-I receptors. Second, patients with GH insufficiency who had significantly lower plasma and central nervous system levels of IGF-I have shown impaired cognitive function. In recent years,
    more researchers have focused on the interaction between the hormones of the somatotropic axis and the central nervous system. The present review aims to provide an overview of the available information on the association between attenuated
    IGF-I secretion and cognitive performance in the elderly and in GH-deficient patients.

    As the possible underlying mechanisms regarding IGF-I receptor signaling and molecular and cellular mechanisms in the brain are discussed elsewhere in the present special issue of this journal, the researchers primarily focus on human
    studies regarding the association between the somatotropic axis and cognitive performance. In summary, aging is associated with a decline in the activity of the GH/IGF-I axis, which coincides with a decline in specific cognitive functions.
    The researchers hypothesized that a causal relationship exists between the reduction in circulating GH and/or IGF-I and the observed cognitive deficits in the elderly. The present review summarized available data on the possible relation
    between GH, IGF-I, and cognitive performance, along with possible underlying pathophysiological mechanisms. The researchers found evidence supporting the hypothesis, and more research is needed to fully understand the underlying mechanisms
    of this relationship.

    You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S0014299904002043.

90. Rollero A, Murialdo G, Fonzi S, et al. Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology. 1998;38(2):73–79.
    View Summary +

    Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects

    Researchers examined baseline growth hormone (GH), insulin-like growth factor I (IGF-I), and GH responses to GH-releasing hormone (GHRH) in 22 participants, including 7 females and 15 men, between the ages of 65 and 86. The study’s objective
    was to investigate a potential link between age-dependent GH-IGF-I axis deterioration and cognitive performance as measured by the Mini Mental State Examination (MMSE). The study also examined the associations between hormonal information,
    cognition, age, body weight, body mass index (BMI), specific nutritional indices (triceps skinfolds, TSF,
    mid-arm circumference, MAC), and the physical functional index (PFI), which measures physical activity.Results indicated that GH basal levels were within the normal range, while GH responses to GHRH were mostly blunted.

    GH peaks after GHRH were directly correlated with GH basal values. IGF-I serum levels were found to be in the lower part of the reference range for adult subjects or below it. GH responses to GHRH were inversely correlated with subject
    age, but GH and IGF-I basal levels did not show such a correlation. GH secretion areas after GHRH were inversely correlated with BMI, but no further correlations between GH data and clinical or nutritional parameters were found. MAC
    and PFI values had a direct correlation with MMSE scores. IGF-I levels were positively connected with MAC values, which are assumed to represent protein-caloric malnutrition, and with MMSE scores, which were lower in patients with
    more advanced cognitive decline. However, there was no connection between IGF-I levels and body weight, BMI, TSF, or PFI. In those with mild cognitive impairment, MMSE-related protein-caloric malnutrition and decreased physical activity
    may alter IGF-I function, and IGF-I decline may in turn affect neuronal function.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/9732206/.

91. Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signalling pathways involved in neuroprotection. Endocrinology.
    2002;143(10):4113-22.
    View Summary +

    Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection

    The researchers found that GH had beneficial effects on memory, mental alertness, and motivation, which were mediated through IGF-I. To investigate whether systemic administration of GH or GHRP-6 modulated the brain IGF system, the researchers
    treated adult male rats with GHRP-6 or GH for one week.The findings demonstrated that IGF-I mRNA levels were markedly elevated by both GHRP-6 and GH in the hypothalamus, cerebellum, and hippocampus but not in the cerebral cortex. IGF-binding
    protein (IGFBP)-2 and the expression of the IGF receptor, however, were unaffected. Where IGF-I was elevated, Akt and Bad phosphorylation were stimulated, but MAPK and glycogen synthase kinase-3beta were unaffected.

    This suggests that in response to growth hormones, GH and GHRP-6 activate intracellular phosphatidylinositol kinase pathways important for cell survival.Furthermore, the antiapoptotic protein Bcl-2 was augmented in these same areas, but
    there was no change in the proapoptotic protein Bax. IGFBP-5, which is involved in neuron survival processes, was increased mainly in the hypothalamus, suggesting a possible neuroendocrine role. In conclusion, the researchers found
    that GH and GHRP-6 modulated IGF-I expression in the central nervous system in an anatomically specific manner. This coincided with activation of intracellular signaling pathways used by IGF-I and increased expression of proteins involved
    in cell survival or neuroprotection.

    You can read the full article at https://academic.oup.com/endo/article/143/10/4113/2880897?login=false.

92. Baserga R, Hongo A, Rubini M, Prisco M, Valentini SB 1997 The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332:F105–F126.
    View Summary +

    The IGF-I receptor in cell growth, transformation and apoptosis

    The study by Baserga et al. (1997) explored the role of the insulin-like growth factor-I receptor (IGF-I receptor) in cell growth, transformation, and apoptosis. The researchers investigated the cellular mechanisms and signaling pathways
    associated with the IGF-I receptor and its impact on cell behaviors such as growth, transformation (the process of normal cells becoming cancerous), and apoptosis (programmed cell death). The study provided insights into the multifaceted
    functions of the IGF-I receptor in regulating cellular processes and shed light on its potential implications in various physiological and pathological conditions.

    You can read the abstract of this article at https://www.sciencedirect.com/science/article/abs/pii/S0304419X97000073?via%3Dihub

93. Kulik G, Klippel A, Weber MJ 1997 Antiapoptotic signaling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase and Akt. Mol Cell Biol 17:1595–1606.
    View Summary +

    Kulik G, Klippel A, Weber MJ 1997 Antiapoptotic signaling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase and Akt. Mol Cell Biol 17:1595–1606.

    The investigation was done to determine whether insulin-like growth factor I (IGF-I) can prevent UV-B-induced apoptosis in fibroblasts. It was found that the IGF-I receptor’s receptor kinase activity was necessary for its antiapoptotic
    signaling. The researchers discovered that overexpressing kinase-defective receptor mutants did not provide IGF-I protection for the cells, and that overexpressing a kinase-defective receptor with an ATP binding loop mutation acted
    as a dominant negative, increasing the sensitivity of the cells to apoptosis.During the study, the researchers also tested the antiapoptotic capacity of other growth factors, such as epidermal growth factor (EGF) and thrombin, but
    found that they did not have the same protective effects as IGF-I. However, EGF was antiapoptotic for cells overexpressing the EGF receptor, and expression of activated pp60v-src also provided protection.

    The researchers did not discover a connection between resistance to apoptosis and the activation of p38/HOG1, p70S6 kinase, or mitogen-activated protein kinase. However, they did discover that wortmannin prevented any of the tyrosine kinases
    from preventing UV-induced apoptosis, suggesting a function for phosphatidylinositol 3-kinase (PI3 kinase). The researchers tested this hypothesis by transiently expressing constitutively active or kinase-dead PI3 kinase, and they
    discovered that overexpression of activated PI3 kinase was sufficient to offer protection against apoptosis.The researchers also examined the role of Akt/PKB in antiapoptotic signaling, as it is believed to be a downstream effector
    for PI3 kinase. They discovered that membrane-targeted Akt was enough to protect against apoptosis, while kinase-dead Akt was not. In conclusion, the researchers found that the endogenous IGF-I receptor has a specific antiapoptotic
    signaling capacity and that overexpression of other tyrosine kinases can also make them antiapoptotic. They also found that activation of PI3 kinase and Akt is enough for antiapoptotic signaling.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC231885/pdf/171595.pdf.

94. Chrysis D, Calikoglu AS, Ye P, D’Ercole AJ 2001 Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner. J Neurosci 21:1481–1489.
    View Summary +

    Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner.

    The central nervous system (CNS) of transgenic (Tg) mice that only express insulin-like growth factor-I (IGF-I) was the subject of the study. Their earlier research had demonstrated that the mice’s improved survival led to a notable rise
    in the number of cerebellar granule cells. There were little investigations on the effects of IGF-I in vivo, despite the fact that its anti-apoptotic properties in cultured neurons were widely recognized. Therefore, the researchers
    wanted to examine IGF-I signaling mechanisms in the same Tg mice and document IGF-I’s anti-apoptotic effects during cerebellar development.Compared to non-Tg littermates, the researchers found fewer apoptotic cells in the cerebellum
    of Tg mice at postnatal day 7 (P7) and a similar trend at P14 and P21. They observed a decrease in procaspase-3 and caspase-3 in the cerebellum of Tg mice at each age studied. The decline in caspase-3 was accompanied by a decrease
    in the 85 kDa fragment of Poly(ADP-ribose) polymerase, which is a known product of caspase cleavage, indicating decreased caspase activity. At P7, decreased apoptosis in Tg mice was linked to increased expression of anti-apoptotic
    Bcl genes, Bcl-x(L), and Bcl-2.

    Although the mRNA expression of the proapoptotic Bcl genes, Bax, and Bad, was also increased, no changes were observed in the abundance of their proteins. At P14, the researchers found that Bcl-xL and Bcl-2 expression was similar in normal
    and Tg mice. Bax mRNA was unchanged in Tg mice, but its protein abundance was decreased, and both Bad mRNA and protein abundance were decreased. At P21, Bcl-xL and Bcl-2 expression remained unchanged, but Bax and Bad expression were
    decreased. The researchers concluded that IGF-I exerts anti-apoptotic effects during cerebellar development, altering the magnitude of naturally occurring apoptosis. IGF-I seems to affect multiple steps in the apoptotic pathway in
    a developmentally specific manner. IGF-I decreases caspase-3 availability and activity, increases the expression of anti-apoptotic Bcl-x(L) and Bcl-2 during early postnatal development, and decreases proapoptotic Bax and Bad expression
    at later developmental stages.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762946/.

95. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA 1996 Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551.
    View Summary +

    Mechanism of activation of protein kinase B by insulin and IGF-1

    The purpose of the study was to determine how insulin affected the activity of endogenous protein kinase B alpha (PKBalpha) in L6 myotubes and 293 cells. They discovered that while transfection into 293 cells led to PKBalpha activation
    of 20 and 50 fold in response to insulin and IGF-1, respectively, PKBalpha activity was raised by insulin by a factor of 12 in L6 myotubes.The activation of PKBalpha in both cell types was accompanied by phosphorylation at Thr308 and
    Ser473. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, prevented the phosphorylation of both residues, indicating their critical role in PKBalpha activity.The researchers also analyzed the activities of mutant PKBalpha molecules
    with Thr308 and/or Ser473 mutated to Ala or Asp after transfection into 293 cells.

    They measured the activity of wild-type and mutant PKBalpha in vitro after stoichiometric phosphorylation of Ser473 by MAPKAP kinase-2.Their research shown that the high level of PKBalpha activity caused by insulin or IGF-1 depends on
    the phosphorylation of both Thr308 and Ser473. Additionally, they discovered that phosphorylation of Ser473 or Thr308 in vivo is not necessary for each other.Based on their findings, the researchers put up a theory in which upstream
    kinase(s) phosphorylate and activate PKBalpha in insulin/IGF-1-stimulated cells.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC452479/pdf/emboj00023-0183.pdf.

96. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME 1997 Regulation of neural survival by the serine-threonine protein kinase Akt. Science 275:661–668.
    View Summary +

    Regulation of neuronal survival by the serine-threonine protein kinase Akt

    The researchers in this study have delineated a signaling pathway that was involved in promoting the survival of cerebellar neurons by insulin-like growth factor 1 (IGF-1). The activation of phosphoinositide 3-kinase (PI3-K) by IGF-1 triggered
    the activation of two protein kinases, namely the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70(S6K)). By conducting experiments with pharmacological inhibitors and expressing wild-type and dominant-inhibitory
    forms of Akt, the researchers were able to demonstrate that Akt, but not p70(S6K), mediates PI3-K-dependent survival.According to the results of this study, Akt is essential for growth factor-induced neuronal survival in the developing
    nervous system. The scientists were able to demonstrate how IGF-1 activated PI3-K, which then activated Akt, promoting neuronal survival.

    The fact that p70(S6K) was not engaged in this procedure, however, was also discovered by the researchers. This finding suggests that Akt is the primary mediator of PI3-K-dependent survival in cerebellar neurons.Overall, these results
    provide important insights into the mechanisms underlying neuronal survival in the developing nervous system. By identifying the specific signaling pathway involved in IGF-1-induced survival, the researchers have opened up new avenues
    for the development of therapies aimed at promoting neuronal survival and preventing neuronal death.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/9005851/.

97. Mehrhof FB, Muller FU, Bergmann MW, Li P, Wang Y, Schmitz W, Dietz R, von Harsdorf R 2001 In cardiomyocyte hypoxia, insulin-like growth factor-I-induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase-dependent and mitogen-activated
    protein kinase-dependent activation of the transcription factor cAMP response element-binding protein. Circulation 104:2088–2094
    View Summary +

    In Cardiomyocyte Hypoxia, Insulin-Like Growth Factor-I-Induced Antiapoptotic Signaling Requires Phosphatidylinositol-3-OH-Kinase-Dependent and Mitogen-Activated Protein Kinase-Dependent Activation of the Transcription Factor cAMP Response Element-Binding Protein

    The researchers looked into different pathological factors that led to cardiomyocyte apoptosis. They discovered that in the heart, survival factors including insulin-like growth factor-I (IGF-I) have anti-apoptotic effects. The underlying
    signaling pathways causing these impacts weren’t fully understood, though. To understand this better, the researchers conducted an experiment on cultured neonatal cardiomyocytes exposed to hypoxia-induced apoptosis. They observed that
    IGF-I prevented cell death in a dose-dependent manner. The anti-apoptotic signals induced by IGF-I were mediated by more than one signaling pathway. Pharmacological inhibition of the phosphatidylinositol-3-OH-kinase (PI3K) or the mitogen-activated
    protein kinase kinase (MEK1) signaling pathway both antagonized the protective effect of IGF-I in an additive manner. Further experiments revealed that IGF-I-stimulation led to a PI3K-dependent phosphorylation of AKT and BAD, and an
    MEK1-dependent phosphorylation of extracellular signal-regulated kinase (ERK) 1 and ERK2.

    Additionally, the researchers discovered that IGF-I caused CREB to become phosphorylated in a PI3K and MEK1-dependent manner. They found that the anti-apoptotic impact of IGF-I was eliminated by ectopic overexpression of a dominant-negative
    mutant of CREB. Additionally, after longer periods of IGF-I stimulation, the antiapoptotic factor bcl-2 protein levels increased. These increases could be reversed by pharmacologically inhibiting PI3K and MEK1, as well as by overexpressing
    dominant-negative CREB. In summary, the researchers concluded that in cardiomyocytes, the antiapoptotic effect of IGF-I required both PI3K- and MEK1-dependent pathways leading to the activation of the transcription factor CREB. This,
    in turn, induced the expression of the antiapoptotic factor bcl-2. The researchers noted that progressive loss of cardiomyocytes due to apoptosis significantly contributed to the development of heart failure. They also pointed out
    that a variety of stimuli known to participate in the pathogenesis of heart failure induced cardiomyocyte apoptosis, including hypoxia, ischemia and reperfusion, and oxidative stress.

    You can read the full article at https://www.ahajournals.org/doi/10.1161/hc4201.097133?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed.

98. Gleichmann M, Weller M, Schuyltz JB 2000 Insulin-like growth factor-1-mediated protection from neuronal apoptosis is linked to phosphorylation of the pro-apoptotic protein BAD but not to inhibition of cytochrome c translocation in rat cerebellar neurons.
    Neurosci Lett 282:69–72
    View Summary +

    Insulin-like growth factor-1-mediated protection from neuronal apoptosis is linked to phosphorylation of the pro-apoptotic protein BAD but not to inhibition of cytochrome c translocation in rat cerebellar neurons

    Researchers researched cerebellar granule neurons and found that when these neurons were cultivated with serum and depolarizing potassium concentrations, they exhibited apoptosis when switched to serum-free media with physiological potassium
    concentrations. However, even with just serum deprivation, the neurons were still alive. The dephosphorylation of the BCL-2-related BAD protein was connected to potassium deprivation, the researchers found. In order to investigate
    this further, the researchers exposed the neurons to insulin-like growth factor-1 (IGF-1) and found that this inhibited both apoptosis and dephosphorylation of BAD. Interestingly, both effects of IGF-1 did not rely on protein synthesis
    but were nullified by the phosphatidylinositol-3 kinase inhibitors, wortmannin and LY294002.

    The researchers then contrasted the effects of IGF-1 with those of cycloheximide and discovered that, unlike cycloheximide, IGF-1 did not block the translocation of cytochrome c from mitochondria to the cytosol. Furthermore, the dephosphorylation
    of BAD alone did not seem to be sufficient to trigger apoptosis, since inhibition of protein synthesis by cycloheximide prevented apoptosis but not BAD dephosphorylation after potassium deprivation. These results led the researchers
    to the conclusion that the development of neuronal apoptosis involves two parallel mechanisms. The first process results in the translocation of cytochrome c and is dependent on protein synthesis. The second process entails the dephosphorylation
    of BAD and is independent of protein production. Neuronal apoptosis must be induced by the activation of both mechanisms.

    You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/10713398/.

99. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R 1999 Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol 19:7203–7215.
    View Summary +

    Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis

    The researchers were aware of the protective function of the activated type 1 insulin-like growth factor receptor (IGF-1R) on cell survival for quite some time. They observed that the wild-type IGF-1R and/or its ligands have a widespread
    antiapoptotic effect on many death signals as different procedures were used to induce apoptosis. McCarthy et al. (50) suggested that only insulin-like growth factor 1 (IGF-1) and Bcl-2 can truly suppress the initiation of the apoptotic
    program, while caspase inhibitors can arrest the completion of the program but have no effect on its initiation. The way in which the IGF-1R prevents cells from apoptosis has been the subject of numerous studies. The connection between
    the IGF-1R and insulin receptor substrate 1 (IRS-1) results in the activation of phosphatidylinositol 3-kinase (PI3-ki), which is the key mechanism this receptor uses to fight against apoptotic damage. BAD, a protein belonging to the
    Bcl-2 family, is phosphorylated as a result of PI3-ki’s activation of Akt/protein kinase B. At least in mouse embryo fibroblasts, the insulin receptor (IR) also employs this antiapoptotic pathway.The researchers observed that in 32D
    cells, a murine hemopoietic cell line devoid of IRS-1, the IGF-1R activates alternative pathways for protection from apoptosis induced by the withdrawal of interleukin-3.

    One of these pathways leads to the activation of mitogen-activated protein kinase, while a third pathway results in the mitochondrial translocation of Raf and depends on the integrity of a group of serines in the C terminus of the receptor
    that are known to interact with 14.3.3 proteins. However, all three pathways result in BAD phosphorylation. The presence of multiple antiapoptotic pathways may explain the remarkable efficacy of the IGF-1R in protecting cells from
    apoptosis.Overall, the researchers discovered that different cell types are protected from various apoptotic insults by the type 1 insulin-like growth factor receptor (IGF-1R), which is activated by its ligands. It has been established
    that the activation of phosphatidylinositol 3-kinase, Akt/protein kinase B, and the phosphorylation and inactivation of BAD, a protein belonging to the Bcl-2 family, are the primary signaling pathways for IGF-1R-mediated protection
    from apoptosis. The discovery of novel treatments for conditions marked by excessive apoptosis, according to the researchers, may result from a better knowledge of the several antiapoptotic pathways triggered by the IGF-1R.

    You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC84713/.

100. Kulik G, Weber MJ 1998 Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol Cell Biol 18:6711–6718.
     View Summary +

     Akt-Dependent and -Independent Survival Signaling Pathways Utilized by Insulin-Like Growth Factor I

     Protein kinase B (PKB)/Akt was previously identified as playing a role in survival signaling in various cell types, including fibroblasts, epithelial, and neuronal cells. The researchers and other scientists had previously identified a
     linear survival signaling cascade activated by insulin-like growth factor I (IGF-I), which involved the IGF-I receptor, phosphoinositide 3-kinase (PI3 kinase), Akt, and Bad. This pathway was shown to protect cells from apoptosis. It
     was not known, however, whether there were alternate paths or whether this pathway was always required for cell survival. To learn more about this, the scientists ran experiments. They identified two survival signaling pathways, one
     of which was PI3 kinase and Akt dependent and the other not. However, when IGF-I receptors were overexpressed in Rat-1 cells (RIG cells), an alternative pathway was revealed, which did not rely on PI3 kinase or Akt.

     This alternative pathway was not sensitive to wortmannin or overexpression of dominant negative Akt, even though Akt activation and Bad phosphorylation were still sensitive to wortmannin. Further experiments with inhibitors of RNA synthesis
     showed that transcriptional activation was not necessary for this alternative survival signaling pathway.These findings showed the existence of a new survival signaling pathway that was independent of PI3 kinase, Akt, and transcription
     and was observed in fibroblasts that overexpressed the IGF-I receptor. The researchers’ findings provide valuable insights into the complex mechanisms of cell survival signaling and could have implications for the development of new
     treatments for diseases involving abnormal cell death or survival.The scientists discovered that IGF-I treatment of Rat-1 cells activated a survival signaling pathway that could be stopped by overexpression of wortmannin and an Akt
     variant with a defective dominant-negative kinase (K179A). This showed the existence of a survival signaling pathway reliant on PI3 kinase and Akt.

     You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC109254/.

101. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ 2001 p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98:9666–9670.
     View Summary +

     P70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD

     The maintenance of cellular homeostasis within organs was mediated in part by a critical interdependence between cells of different types, according to the researchers. This interdependence included a cellular dependence on a series of
     factors, such as IGF-1, nerve growth factor, or interleukin-3 (IL-3), that transduced signals through surface receptors to repress apoptosis and stimulate growth of target cells. The BCL-2 family of proteins that regulated cell death
     was frequently a target of posttranslational modification downstream of both survival and death signal transduction cascades. Such modifications to BCL-2 members often dictated their active-versus-inactive conformation, subcellular
     localization, and partner proteins. One of the targets was BAD, a “BH3 domain-only” proapoptotic member sharing sequence homology only within the BH3 amphipathic α-helical domain.Cells phosphorylated BAD on two serine residues (S112
     and S136) located inside of 14-3-3 consensus binding sites when the necessary survival factors were present. The inactive component of phosphorylated BAD that is linked to 14-3-3 in the cytoplasm appears to be what frees BCL-XL or
     BCL-2 to support survival.

     Only the active, nonphosphorylated BAD formed heterodimers at membrane locations with BCL-XL or BCL-2 to accelerate cell death. It was recently discovered that S155 in the BH3 domain was also phosphorylated in order to prevent BAD from
     attaching to BCL-XL or BCL-2.Cytokines often delivered simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) was known to regulate cell growth by inducing protein synthesis
     components. The researchers purified membrane-based p70S6K as a kinase responsible for site-specific phosphorylation of BAD, which inactivated this proapoptotic molecule. Rapamycin inhibited mitochondrial-based p70S6K, which prevented
     phosphorylation of Ser-136 on BAD and blocked cell survival induced by insulin-like growth factor 1 (IGF-1). Moreover, IGF-1-induced phosphorylation of BAD Ser-136 was abolished in p70S6K-deficient cells. Thus, p70S6K was itself a
     dual pathway kinase, signaling cell survival as well as growth through differential substrates which include mitochondrial BAD and the ribosomal subunit S6, respectively.

     You can read the full article at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55509/.

102. Desbois-Moutho C, Cadoret A, Blivet-Van Eggelpoel MJ, Bertrand F, Cherqui G, Perret C, Capeau J 2001 Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation. Oncogene 20:252–259

     View Summary +

     Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation

     The interplay between the insulin/IGF-1- and beta-catenin-regulated pathways, both of which were suspected to play a role in hepatocarcinogenesis, was examined by researchers. In HepG2 cells, insulin and IGF-1 stimulated the transcription
     of a Lef/Tcf-dependent luciferase reporter gene by 3-4-fold. The stimulation was mediated through the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and the inhibition of glycogen synthase kinase-3beta (GSK-3beta). The researchers
     found that the effects of insulin and IGF-1 were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3beta. Along with inhibiting GSK-3beta, insulin and IGF-1 increased the cytoplasmic levels of beta-catenin.

     It was discovered that the activation of Lef/Tcf-dependent transcription by insulin and IGF-1 was not solely mediated via the PI 3-K/Akt/GSK-3beta pathway. It was also necessary to use the Ras signaling pathway. This was demonstrated by
     the fact that dominant-negative Ras or the MEK1 inhibitor PD98059 blocked the stimulatory effects of insulin and IGF-1. Additionally, Lef/Tcf-dependent transcription was stimulated by activated Ha-Ras or constitutively active MEK1,
     which worked in concert with catalytically inactive GSK-3beta.The researchers provided the first evidence that insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades bifurcating downstream of PI 3-K and
     involving GSK-3beta inhibition and Ras activation. These findings demonstrated for the first time the ability of insulin and IGF-1 to activate the beta-catenin pathway in hepatoma cells. This provided new insights into the role of
     these factors in hepatocarcinogenesis.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/11313952/.

103. Park BC, Kido Y, Accili D 1999 Differential signaling of insulin and IGF-1 receptors to glycogen synthesis in murine hepatocytes. Biochemistry 38:7517–7523
     View Summary +

     Differential signaling of insulin and IGF-1 receptors to glycogen synthesis in murine hepatocytes

     In order to compare the contrasting abilities of insulin and IGF-1 receptors to drive glycogen production, the researchers used SV40-transformed hepatocytes from mice with an impaired insulin receptor (-/-) and mice with a normal insulin
     receptor (WT). It was discovered that insulin receptors promoted glycogen production more potently than IGF-1 receptors. PI 3-kinase was required for the promotion of glycogen production by both receptors, but only the insulin receptor’s
     action was rapamycin-dependent. While GSK-3 inactivation in response to IGF-1 was significantly lower in both -/- and WT cells than it was in response to insulin in WT cells, Akt was similarly activated by both insulin and IGF-1 receptors.These
     findings indicated that (i) the strength of insulin and IGF-1 receptors in promoting glycogen synthesis corresponds with their ability to inactivate GSK-3, (ii) the degree of GSK-3 inactivation did not correspond with the degree of
     Akt activation induced by insulin or IGF-1 receptors, revealing that insulin’s impact on GSK-3 necessitates additional kinases, and (iii) the pathways necessary for insulin to promote glycogen synthesis in mouse hepatocytes were PI
     3-kinase-dependent and rapamycin-sensitive.In conclusion, the researchers investigated the different abilities of insulin and IGF-1 receptors
     to induce glycogen production using SV40-transformed hepatocytes from insulin receptor-deficient mice (-/-) and normal mice (WT). They found that both insulin receptors and IGF-1 receptors were dependent on PI 3-kinase to activate
     glycogen synthesis, with insulin receptors being more effective than IGF-1 receptors in this regard. Rapamycin played a role in the influence of insulin receptors on glycogen production, but not in the influence of IGF-1 receptors.
     Akt was similarly activated by both receptors, but IGF-1 had less impact on inactivating GSK-3. These findings suggest that insulin and IGF-1 differ in their abilities to activate glycogen synthesis and that the pathways involved in
     insulin’s stimulation of glycogen synthesis are PI 3-kinase-dependent and rapamycin-sensitive.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/10360949/.

104. Cui H, Meng Y, Bulleit RF 1998 Inhibition of glycogen synthase kinase 3β activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res 111:177–188.
     View Summary +

     Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells

     In purified cultures of cerebellar granule cells, the researchers examined the impact of insulin-like growth factor I (IGF-I) on neuronal progenitors, specifically cerebellar granule neuron progenitors. They discovered that IGF-I functioned
     as a mitogen, encouraging cell division, and they pinpointed the intracellular signaling molecules in charge of this action. In their experiments, the researchers observed that IGF-I inhibited the activity of GSK-3, an enzyme that
     regulates cell growth and differentiation, and caused phosphorylation of serine9, an inhibitory site on GSK-3beta. They also found that activation of phosphoinositide 3-kinase (PI3-K) by IGF-I led to the phosphorylation and inactivation
     of GSK-3.When the researchers used a PI3-K inhibitor, LY294002, they found that it completely blocked IGF-I-induced cell division. The concentration of LY294002 required to achieve this effect was close to its reported IC50 value for
     inhibiting PI3-K. Furthermore, the researchers discovered that lithium chloride (LiCl), a direct inhibitor of GSK-3beta, could stimulate granule cell proliferation on its own and enhance the proliferation induced by IGF-I. LiCl was
     also discovered to be able to counteract LY294002’s inhibitory effects on granule cell proliferation, proving that GSK-3 inhibition was a step after PI3-K activation in the mitogenic pathway of IGF-I. Finally, the researchers found
     evidence supporting the role of GSK-3beta activity inhibition in the signal transduction pathway by which IGF-I regulates granule neuron progenitor proliferation by observing that the expression of a dominant active form of GSK-3beta
     inhibited IGF-I-induced cell division.Overall, the study confirmed that IGF-I can function as a mitogen in cerebellar granule cells and provided insight into the intracellular signaling mechanisms responsible for this effect. By identifying
     the role of GSK-3 inhibition downstream of PI3-K activation, the researchers highlighted a potential therapeutic target for conditions characterized by abnormal cell growth and proliferation.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/9838099/.

105. Tamatani M, Ogawa S, Nuñez G, Tokyama M 1998 Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide. Cell Death Differ 5:911–919
     View Summary +

     Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide

     Recent studies have shown that while growth factors like insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF) might protect against NO-induced neuronal cell death, NO donors can cause neurons to undergo apoptosis.
     This study’s objectives were to examine the potential processes underlying NO-mediated neuronal death and the neuroprotective abilities of these growth factors.The researchers found that both IGF-1 and bFGF could prevent apoptosis
     induced by NO donors, specifically sodium nitroprusside (SNP) or 3-morpholinosydnonimin (SIN-1), in hippocampal neuronal cultures. When neurons were incubated with SNP, caspase-3-like activation occurred following the downregulation
     of Bcl-2 and upregulation of Bax protein levels in cultured neurons. When neurons were treated with a bax antisense oligonucleotide, caspase-3-like activation and neuronal death caused by SNP were inhibited. In addition, when neurons
     were treated with an inhibitor of caspase-3, Ac-DEVD-CHO, together with SNP, the changes in protein levels were unaffected, although NO-induced cell death was inhibited. The researchers discovered that pretreatment of cultures with
     either IGF-1 or bFGF prior to NO exposure inhibited caspase-3-like activation, along with the changes in Bcl-2 and Bax protein levels. These findings suggest that the changes in Bcl-2 and Bax protein levels followed by caspase-3-like
     activation are a component of the cascade of NO-induced neuronal apoptosis, and that the neuroprotective effects of IGF-1 and bFGF could be due to inhibition of changes in the protein levels of the Bcl-2 family.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/10203697/.

106. Baker NlL, Carlo Russo V, Bernard O, D’Ercole AJ, Werther GA 1999 Interactions between bcl-2 and the IGF-I system control apoptosis in the developing mouse brain. Brain Res Dev Brain Res 118:109–118.
     View Summary +

     Interactions between bcl-2 and the IGF system control apoptosis in the developing mouse brain

     The IGF system and pro-survival Bcl-2 proteins were known to safeguard cells from apoptosis and played a crucial part in brain development. To explore their possible correlation, researchers used two transgenic mice models, one overexpressing
     Bcl-2 and the other IGF-I proteins in olfactory bulb (OB) or cerebellar neurons.The organization of the specified layers of the OB was found to be poorly organized in both wild-type and Bcl-2 transgenic mice cultured in serum-free
     media (SF). The transgenic mice’s neurons were adequately preserved, and the mitral cell layer was increased. IGF-I supplementation improved layer definition but had no additional effect on the mitral cells’ ability to survive in Bcl-2
     mice. In contrast, it restored the survival and structure of the wild-type mitral cell layer. Compared to wild-type mice, mitral cells expressing Bcl-2 had significantly larger levels of IGF-I and IGFBP-2 immunoreactivity. In newborn
     IGF-I transgenic mice, cerebellar Purkinje cells overexpressing IGF-I displayed higher immunoreactivity for Bcl-2 and IGFBP-2. These findings suggest that in the developing brain, IGF-I modulates the expression of its major binding
     protein IGFBP-2 and the Bcl-2 protein. Additionally, the researchers observed that expression of Bcl-2 in the mitral neurons inhibited apoptosis caused by culturing OBs in SF medium and was linked to enhanced expression of the IGF
     system, including IGF-I and IGFBP-2. This interaction between the two anti-apoptotic systems may provide a robust cell protection system during brain development and repair.

     You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S0165380699001364?via%3Dihub.

107. Du K, Montminy M 1998 CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273:32377.
     View Summary +

     CREB is a regulatory target for the protein kinase Akt/PKB

     The nuclear factor CREB’s phosphorylation at Ser-133 by protein kinase A increased the production of cellular genes. By encouraging the recruitment of the co-activator CBP, Ser-133 phosphorylation caused the target gene’s expression to
     be activated. Recent research has demonstrated that some cell types need CREB and its paralog CREM to survive. This led the researchers to look into whether the growth factor-dependent Ser/Thr kinase Akt/PKB was capable of activating
     CREB as a nuclear target. To test this, the researchers overexpressed Akt/PKB in serum-stimulated cells, which potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target
     gene expression via CREB in a phospho(Ser-133)-dependent manner. Akt/PKB induced CREB activity only in response to serum stimulation, and this effect was suppressed by the phosphatidylinositol 3-kinase inhibitor LY294002. According
     to the research, CREB/CBP nuclear transduction pathway is used by Akt/PKB to stimulate the production of cellular genes, hence promoting cell survival. The scientists came to the conclusion that Akt/PKB, via activating CREB via Ser-133
     phosphorylation, plays a critical role in controlling gene expression and cell survival.

     You can read the full article at https://www.jbc.org/article/S0021-9258(19)58887-1/fulltext.

108. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasly LE, Reusch JE 2000 Akt/protein kinase B upregulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275:10761–10766.
     View Summary +

     Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein

     In their previous study, the researchers demonstrated that insulin-like growth factor-I could stimulate a Bcl-2 promoter containing a cAMP-response element (CRE) site via a novel signaling pathway involving mitogen-activated protein kinase
     kinase 6/p38beta mitogen-activated protein kinase/MAP kinase-activated protein kinase-3/cAMP-response element-binding protein (CREB). In their present investigation, the researchers identified a second pathway that contributes to the
     up-regulation of Bcl-2 expression via a novel anti-apoptotic function of Akt signaling.The researchers used luciferase reporter genes driven by the promoter region of Bcl-2 containing a CRE in a series of transient transfections to
     assess the effect of Akt on Bcl-2 expression. They discovered that the upstream kinase of Akt, phosphatidylinositol (PI) 3-kinase, was inhibited by the drug LY294002 and that this resulted in a 45% reduction in Bcl-2 promoter activity.
     The dominant negative p85 subunit of PI 3-kinase blocked 44% of the reporter activity while the active p110 subunit of PI 3-kinase increased it by 2.3-fold. The full activation of Akt requires the cotransfection of 3-phosphoinositide-dependent
     kinase (PDK1), which increased luciferase activity. Insulin-like growth factor-I-mediated induction of Bcl-2 promoter activity was significantly decreased by dominant negative forms of p85 subunit of PI 3-kinase, PDK1, and Akt, suggesting
     that regulation of Bcl-2 expression by IGF-I involves a signaling cascade mediated by PI 3-kinase/PDK1/Akt/CREB. The researchers used real-time quantitative reverse transcription-polymerase chain reaction using the TaqMan fluorogenic
     probe system to quantify Bcl-2 mRNA levels in PC12 cells overexpressing Akt to corroborate their findings. Bcl-2 mRNA levels were found to be 2.1 times higher in the Akt cell line than in control PC12 cells, supporting the finding
     that increased CREB activity by Akt signaling promotes greater Bcl-2 promoter activity and cell survival.

     You can read the full article at https://www.jbc.org/article/S0021-9258(19)80906-7/fulltext.

109. Kim SW, Her SJ, Park SJ, et al. Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone. 2005;37(3):359-69.
     View Summary +

     Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells

     The 28-amino-acid peptide known as ghrelin was discovered by the researchers to be an endogenous ligand of the growth hormone secretagogue receptor (GHS-R) in the stomach. Growth hormone was highly activated at the hypothalamus and pituitary
     levels by the GHS-R. Although GHS-Rs were found in many peripheral tissues, their impact on bone outside of the GH/IGF-1 axis was poorly understood. The goal of the investigation was to determine whether ghrelin had an impact on osteoblasts
     directly. The researchers identified mRNA and protein expression of GHS-R in primary osteoblasts as well as a number of osteoblastic cell lines, including MC3T3-E1, ROS 17/2.8, UMR-106, MG63, and SaOS2 cells. Ghrelin treatment of MC3T3-E1
     cells showed dose-dependent stimulation of proliferation, and this was abrogated by treatment with [d-Lys]-GHRP-6 (10(-3) M), a selective antagonist of the ghrelin receptor. Furthermore, ghrelin activated ERK1/2 MAPK, and pretreatment
     with MAPK kinase inhibitors, PD98059 attenuated the ghrelin-induced cell proliferation. Ghrelin also inhibited TNFalpha-induced apoptosis and suppressed caspase-3 activation that occurred in response to TNFalpha as well as during the
     in vitro differentiation process. Ghrelin treatment enhanced in vitro osteoblast differentiation as evidenced by matrix mineralization, alkaline phosphatase activity, and osteoblast-specific gene expression. According to the findings,
     ghrelin suppressed osteoblast death while encouraging osteoblast proliferation and differentiation. The researchers came to the conclusion that ghrelin has a direct impact on osteoblasts and would be a good target for bone diseases.

     You can read the full article at https://www.sciencedirect.com/science/article/abs/pii/S8756328205001808?via%3Dihub.

110. Kim YS, Choi DH, Block ML, et al. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J. 2007;21(1):179-87.
     View Summary +

     A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation

     Recent research has demonstrated that through releasing NADPH-oxidase-derived superoxide, activated microglia contributed significantly to the degeneration of dopamine neurons in Parkinson’s disease (PD). However, there was ongoing debate
     regarding the molecular mechanisms underlying microglial activation in DA cell death. According to the study, stressed DA cells generated and activated matrix metalloproteinase-3 (MMP-3), and the active form of MMP-3 (actMMP-3) was
     released into the medium. The researchers found that the released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3), caused microglial activation and superoxide generation in microglia and enhanced DA cell death.
     The researchers discovered that cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed cultures of wild-type (WT) mice. Still, this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), indicating that
     NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, the researchers observed that nigrostriatal
     DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These findings suggested that the actMMP-3 released from stressed DA neurons was the cause of microglial activation
     and the production of superoxide derived from NADPHO, which ultimately resulted in accelerated nigrostriatal DA neuronal degeneration. The researchers hypothesized that a novel therapy strategy for PD might result from their findings.

     You can read the full article at https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.06-5865com.

111. Banks WA, Tschöp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther. 2002;302(2):822-7.
     View Summary +

     Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure

     Researchers discovered the novel hormone ghrelin as a potent orexigen with the ability to balance leptin. Ghrelin was the sole secreted molecule that needed post-translational acylation with octanoic acid to ensure its bioactivity. Ghrelin,
     which was mostly produced by the stomach, was thought to control energy balance by concentrating on neuroendocrine networks in the central nervous system (CNS). However, for ghrelin to perform this regulation, it was necessary for
     it to pass the blood-brain barrier (BBB). To investigate whether ghrelin could cross the BBB and whether its lipophilic side chain played a role in this process, the researchers conducted experiments on mice. They found that there
     were saturable systems that transported human ghrelin from brain-to-blood and from blood-to-brain. However, mouse ghrelin, which differed from human ghrelin by two amino acids, was a substrate for the brain-to-blood transporter but
     not for the blood-to-brain transporter, which meant it entered the brain to a far lesser degree. On the other hand, des-Octanoyl ghrelin entered the brain by nonsaturable transmembrane diffusion but was sequestered once inside the
     CNS. The study’s findings concluded that ghrelin transport over the BBB was a complicated, well controlled, and bidirectional process. The fundamental structure of ghrelin dictated the direction and extent of transit, emphasizing the
     special function of post-translational octanoylation in this procedure.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/12130749/.

112. Chung H, Seo S, Moon M, Park S. Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical
     neuronal cells. J Endocrinol. 2008;198(3):511-21.
     View Summary +

     Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells.

     The focus of this study was on acylated ghrelin (AG) and unacylated ghrelin (UAG) and their respective effects on neuronal cells. AG specifically binds to GH secretagogue receptor 1a (GHS-R1a) and has been found to exhibit central endocrine
     activities and anti-apoptotic effects in neuronal cells. On the other hand, the neuroprotective properties of UAG, which is the most abundant form of ghrelin in plasma, remained unknown.

     To investigate this, the researchers conducted experiments using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD) to simulate ischemic neuronal injury. Both AG and UAG were found to inhibit apoptosis
     induced by OGD.

     The protective effects of AG against OGD were shown to involve the GHS-R1a receptor since they were blocked by a specific antagonist (D-Lys-3-GHRH-6). However, the neuroprotective effects of UAG were preserved even after exposure to the
     same antagonist, suggesting the involvement of a receptor different from GHS-R1a.

     The researchers observed that both AG and UAG relied on the MAPK and phosphatidylinositol-3-kinase (PI3K) pathways to exert their anti-apoptotic effects. Additionally, they found that ghrelin siRNA enhanced apoptosis, both during OGD and
     in normoxic conditions, further supporting the neuroprotective role of ghrelin.

     Furthermore, both AG and UAG increased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Additionally, they facilitated nuclear translocation of beta-catenin. Moreover,
     both forms of ghrelin increased the Bcl-2/Bax ratio, prevented the release of cytochrome c, and inhibited caspase-3 activation. These findings suggest that ghrelin, regardless of acylation, can act as a neuroprotective agent by inhibiting
     apoptotic pathways through the activation of MAPK and PI3K/Akt pathways. Furthermore, PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin were found to contribute to the anti-apoptotic effects of ghrelin.

     You can read the full article at https://joe.bioscientifica.com/view/journals/joe/198/3/511.xml.

113. García-cáceres C, Lechuga-sancho A, Argente J, Frago LM, Chowen JA. Death of hypothalamic astrocytes in poorly controlled diabetic rats is associated with nuclear translocation of apoptosis inducing factor. J Neuroendocrinol. 2008;20(12):1348-60
     View Summary +

     Death of hypothalamic astrocytes in poorly controlled diabetic rats is associated with nuclear translocation of apoptosis inducing factor

     Astrocytes in the hypothalamus of diabetic rats with poor glucose control experienced a reduction in number and underwent morphological changes, including a decrease in projections, due to increased apoptosis and decreased proliferation.
     The researcher aimed to determine the intracellular mechanisms behind this increase in hypothalamic cell death. To do so, adult male Wistar rats were injected with streptozotocin to induce diabetes, and controls received a vehicle.
     Rats were killed at 1, 4, 6, and 8 weeks after diabetes onset (glycemia > 300 mg/dl).Enzyme-linked immunosorbent assays showed an increase in cell death after 4 weeks of diabetes, and immunohistochemistry and terminal dUTP nick-end
     labeling (TUNEL) experiments revealed that these cells were positive for the glial fibrillary acidic protein (GFAP). Western blot examination revealed that the fragmentation of caspases 2, 3, 6, 7, 8, 9, or 12 had not changed significantly.
     Enzymatic assays, however, revealed that after 1 week of diabetes, caspase 3 activity considerably increased and then dropped below control levels. In the hypothalamus, cell bodies lining the third ventricle, fibers radiating from
     the third ventricle, and GFAP positive cells expressed fragmented caspase 3, with this labeling increasing at 1 week of diabetes.

     However, as no nuclear labeling was observed, and this increase in activity did not correlate temporally with the increased cell death, this caspase may not be involved in astrocyte death. By contrast, nuclear translocation of apoptosis-inducing
     factor (AIF) increased significantly in astrocytes in parallel with the increase in death, and AIF was found in TUNEL positive cells. As a result, nuclear translocation of AIF may be responsible for the rise in mortality, whereas caspase
     3 fragmentation may be responsible for the morphological alterations in the hypothalamus astrocytes of diabetic rats. These alterations in astrocytes are linked to adjustments in synaptic proteins, and they almost certainly have an
     impact on neuroendocrine signaling and function.

     You can read the abstract of this article at https://pubmed.ncbi.nlm.nih.gov/19094082/.

114. Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection. Endocrinology.
     2002;143(10):4113-22.
     View Summary +

     Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pat