5 Main Research Findings for MK-677 (Ibutamoren):

1. Enhances growth hormone (GH) secretion and increases fat-free mass in healthy adults [1], [2]
2. Protects against “somatopause” (age-associated decline in growth hormone production by the body) [3]
3. Inhibits neuroinflammation and neurodegeneration [4], [5]
4. Improves bone mineral density [1], [6]
5. Increases IGF-1 growth factor levels in adults [7]

 

Selected Clinical Data

1. “Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults: A Randomized Trial” [1]

Growth hormone secretion and muscle mass decline from mid-puberty throughout life, culminating in loss of muscle strength, decreased function, and eventual loss of independence. The decline of growth hormone (GH) in the development of this universal condition is one of many risk factors, and its role needs to be better evaluated. This study sought to determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevent the decline of fat-free mass, and decrease abdominal visceral fat in healthy older adults.  This was a 2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial, performed at a clinical research center within a university hospital. 65 healthy adults (men and women) ranging from 60 to 81 years of age, received oral doses of MK-677 @ 25 mg, or placebo once daily. Growth hormone and insulin-like growth factor I levels were measured, along with fat-free mass and abdominal visceral, after 1 year of treatment. Other endpoints measured were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, and quality of life. All end points were assessed at baseline and every 6 months.

Fig. 1. Growth hormone (GH) and insulin-like growth factor I (IGF-I) levels at baseline and at 6 and 12 months, and a representative GH profile. Line graphs show averages and 95% confidence intervals. Panel A: Average 24-hour GH levels. The dashed line indicates 24-hour mean GH level for young men and women combined. Panel B: Serum IGF-I levels. The lower dotted line indicates the lower limit of the IGF-I normal range for older adults, and the upper dashed line indicates the lower limit in adults age 21 to 25 years. Panel C: Representative 24-hour GH profile in a 70-year-old man who received MK-677 for 1 year. The pulsatile pattern of GH secretion at baseline is maintained and enhanced at 6 and 12 months, primarily because of increased secretion per peak.

 

Fig. 2. Changes in body composition at 12 months after MK-677.

DXA= dual energy x-ray absorptiometry; ECW= extracellular water; FFM= fat-free mass; ICW= intracellular water; SC= subcutaneous (directly beneath the skin); TASM= total appendicular skeletal mass; TBW= total body water. The increase in TBW and ICW with MK-677 are consistent with the anabolic effects of the drug.

 

Results

Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677, as did body mass, as reflected by intracellular. No significant differences were observed in abdominal visceral fat or total fat mass; Body weight increased 0.8 kg in the placebo group and 2.7 kg in the MK-677 group. Fasting blood glucose level increased in the MK-677 group while insulin sensitivity slightly decreased. The most frequent side effect was an increase in appetite that subsided in a few months. LDL “bad cholesterol” levels decreased in the MK-677 group relative to baseline values and no differences between groups were observed in total or HDL “good cholesterol” levels. Cortisol levels increased slightly in MK-677 recipients. Changes in bone mineral density consistent with improved bone remodeling occurred in MK-677 recipients. Two-year exploratory analyses confirmed the one-year results.

 

Discussion

 

In this study, healthy adults who received the ghrelin hormone mimetic MK-677 experienced a substantial increase in growth hormone secretion and IGF-I levels comparable to those seen in young adults. The likely mechanism was activation of the ghrelin receptor by MK-677, with feedback by IGF-I preventing excess growth hormone (GH) production. MK-677 increased fat-free mass by 1.6 kg relative to placebo. To put that in perspective, the average adult’s lifetime loss of fat-free mass is about 5.5 kg [8]. The observed increase in intracellular water, which reflects body cell mass, was probably the mechanism for the increase in fat-free mass.

Ghrelin stimulates growth hormone secretion, but it also has effects that are not attributable to increased growth hormone levels. A ghrelin mimetic transiently increases appetite, a new effect that might counteract physiologic anorexia, a cause of weight loss in elderly persons. Unlike growth hormone, which is lipolytic, ghrelin increases fat stores. These authors found that body mass increased more in MK-677 recipients than in placebo recipients. Surprisingly, thigh muscle cross-sectional area did not increase, although this study was not powered enough to detect small but potentially important differences because the single-slice computed tomography method used was insufficiently precise. Growth hormone reduces abdominal visceral fat in growth hormone-deficient adults and abdominally obese, postmenopausal women but not in normal elderly participants. Although MK-677 increased growth hormone levels, it did not affect abdominal visceral fat, possibly because it counteracted the lipolytic effects of enhanced growth hormone. Finally, although MK-677 did not reduce abdominal visceral fat, it did reduce LDL “bad cholesterol” levels at 12 months, an effect not seen with growth hormone in normal elderly participants.

Strength, function, and quality of life did not improve after administration of MK-677 in this small, healthy cohort, which is result that should possibly have been expected. Although strength improved in elderly patients with hypopituitarism after daily injections of growth hormone for 2 to 3 years, growth hormone alone does not increase strength in healthy elderly persons. Strength improved only in healthy older men receiving growth hormone plus testosterone for 26 weeks. Finally, the relationship between strength and physical performance is complicated, because increased physical capacity might considerably improve performance in frail adults but not healthy adults.

Loss of muscle mass is a hallmark of frailty and is associated with increased mortality in older adults. In this study, MK-677 counteracted three important factors that contribute to loss of muscle mass: reduced secretion of growth hormone, loss of fat-free mass, and inadequate food intake. This study did not evaluate patients with loss of muscle mass, and their response to a ghrelin mimetic such as MK-677 is unknown.

Fortunately, all of the study participants tolerated daily administration of MK-677 for the entire 2-year study period without major issues. The most frequent side effects were mild, transient, lower-extremity swelling; mild muscle discomfort; and increased appetite, which actually subsided in a few months. In contrast, individuals who inject growth hormone (GH) often encounter severe adverse effects, including tissue swelling, carpal tunnel syndrome, gynecomastia, impaired glucose tolerance and even diabetes mellitus.

Both growth hormone and MK-677 can increase insulin resistance and blood glucose in elderly persons, albeit nominally. This study revealed small increases in fasting blood glucose and HbA1c levels after 12 months of treatment. Considering the results of short-term studies with MK-677 [9], [10], which found no statistically significant increase in serum cortisol, the small increase in serum cortisol that this current study found is unlikely to underlie the increase in fasting glucose level. In contrast to MK-677, patients who are treated with growth hormone injection actually experience bone mineral density decreases [11] until 18 months of treatment, after which bone mineral density gradually recovers [12]. Thus, MK-677 is superior to GH injection since it supports bone mineral density without latency. Fracture risk would be the best measure of the effects of MK-677 on bone; however, this outcome would require studies of large patient cohorts over many years.

This study has certain limitations. Its duration was relatively short, and the sample size was small. Combining the results for men and women may have missed important sex effects. As a randomized study in healthy older adults, this was a crucial proof-of-principle study. It showed, for the first time, that a drug can maintain the IGF-I levels and physiologic pattern of growth hormone secretion seen in young adults for at least 1 year and partially reverse age-related body composition changes.

 

2. “Two-Month Treatment with the Oral Growth Hormone (GH) Secretagogue MK-677 Increases GH Secretion, Fat-Free Mass, and Energy Expenditure” [2]

Carrying excess body fat is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with MK-677 on GH secretion and body composition in otherwise healthy overweight males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four males aged 18–50 were treated with MK-677 25 mg (n = 12 patients) or placebo (n = 12 patients) daily for 8 weeks.

Serum insulin-like growth factor I (IGF-I) increased approximately 40% with MK-677 treatment. Serum IGF-binding protein-3 (IGFBP-3) was also significantly increased. GH was significantly increased after the initial dose of MK-677. These observed increases persisted at 2 and 8 weeks of treatment. The increases in GH after the initial dose were significantly greater than the increase seen after multiple doses, suggesting early benefit. Fortunately, serum and urinary concentrations of cortisol were not increased at 2 and 8 weeks. Fat-free mass increased significantly in the MK-677 treatment group as determined by x-ray absorptiometry. Total and visceral fat were not significantly changed. Basal metabolic rate (BMR) was significantly increased at 2 weeks of MK-677 treatment but not at 8 weeks. Lastly, fasting concentrations of glucose and insulin were unchanged.

Overall, a 2-month treatment with MK-677 in healthy males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3. The effects on cortisol secretion were transient. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate. Further studies would be needed to evaluate whether a higher dose of MK-677 or a more prolonged treatment duration can promote a reduction in body fat.

Fig. 3. Serum concentrations of Insulin-like Growth Factor (IGF-I) and  Insulin-like Growth Factor Binding Protein (IGFBP-3) during 2-month treatment with MK-677 (25 mg) or placebo daily in males. Increases in both IGF and IGFBP-3 promote gain of lean mass.

Fig. 4. Patients who exhibited larger increases in IGF-1 due to MK-677 also had less visceral fat volume.

Fig. 5. Basal metabolic rate (BMR) (left) and BMR corrected for the increase in fat-free mass (right) during 2-month treatment with MK-677 (25 mg) or placebo daily in 24 males. MK-677 causes the body to burn more calories.

 

Discussion

This clinical trial demonstrates that a 2 month treatment of healthy males with MK-677 produces a significant GH response throughout the study period, capable of increasing serum IGF-I and IGFBP-3 and fat-free mass (FFM). Basal metabolic rate (BMR) was increased at 2 weeks, but not at 8 weeks. Body fat was not significantly changed. Diastolic blood pressure and heart rate were modestly affected at 8 weeks. The effects on cortisol secretion were brief. Baseline values of fasting blood glucose and insulin were unchanged.

Previously, it was shown that short-term administration (2 weeks) of MK-677 treatment was found to increase GH secretion. In the present study, GH levels were increased by MK-677 treatment throughout the entire 8-week study period, even though the GH response to MK-677 was lower at 2 and 8 weeks compared to the initial response. It is possible that the negative feedback that IGF-I exerts on GH secretion could explain this reduction in GH response to MK-677 administration. Moreover, such a mechanism would also be supported by the constant level of increased serum IGF-I found throughout this study. It is unknown whether desensitization contributed to the decrease in the GH response between initiation and 2 weeks of treatment in this study. Crucially, the response to MK-677 was not abolished even after 8 weeks of treatment, which may also indicate that MK-677 does not deplete the pituitary gland reserves of GH, possibly because of a stimulatory effect on GH synthesis.

This study also confirms that the stimulatory effect of GH-stimulating compounds on cortisol secretion is brief and not sustained. Increased cortisol levels have been noted after single dose administration of other GH secretagogues, but not after 1 or 2 weeks of MK-677 treatment [10], [13]. This study also revealed a slight increase in serum cortisol after the first MK-677 administration, but no increases were found at 2 or 8 weeks. Moreover, urinary cortisol was unchanged throughout the study. These results are clinically important with regard to the safety of MK-677, as visceral fat accumulation is accompanied by relative increases in cholesterol and cortisol, which does not occur with MK-677 dosing.

An anabolic effect was seen with respect to fat-free mass (lean mass) in the MK-677 group, with a maximum increase of 3 kg, corresponding to the overall increase in body weight of this group. This was expected, considering previous studies evaluating GH treatment of GH-deficient adults [14] and elderly subjects [15], [16]. The increase in lean mass is not explained by an increase in body water, since total body water estimations did not show any significant difference between the groups. However, it is possible that the decrease in body weight in the MK-677 group from the study end to the post-study visit at least in part can be due to loss of water. It is also possible that different estimations of body water are due to the inherent differences between models in estimating the increases in lean mass and body cell mass, respectively.

Body fat was unchanged, which was unexpected based on the results of previous studies of GH treatment of GH-deficient adults. GH induces fat-burning with an increase in FFA levels (36), but no increase in free fatty acid levels was observed in this study to support increased fat-burning with MK-677 treatment. Previously, continuous infusion of GH via injection has been shown to produce a greater reduction in total body fat than subcutaneous GH injections. Therefore, it is possible that the GH secretory pattern produced by MK-677 is slightly less effective in inducing body fat reduction than GH injection, but MK-677 carries considerably fewer side effects, making MK-677 a superior choice.

A strong inverse correlation was found between the changes in serum IGF-I and visceral fat in the MK-677 group. Linear regression analysis showed that a greater than 30–35% increase in serum IGF-I was needed to reduce visceral fat mass. This suggests that a higher dose of MK-677, resulting in enhanced levels of serum GH and IGF-I, may cause a reduction in visceral fat. In overweight males, GH treatment reduces the visceral fat mass over a 9-month period [17], and it is possible that a more prolonged MK-677 treatment period could cause a decrease in visceral fat.

Past studies have demonstrated an increase in basal metabolic rate (BMR) during GH treatment; this study confirmed this result, showing an increase in BMR at 2 weeks of treatment even when corrected for the increase in fat-free mass. However, to be clear, there was no statistically-significant increase in BMR at conclusion of study. This could be explained by the lower GH response to MK-677 at 2 and 8 weeks of treatment compared to the response at the first administration. It is possible that a down-regulation of the initial increase in BMR occurs during long term GH or MK-677 treatment of some subjects, an effect not seen with GH treatment in adult GH deficiency.

Fasting levels of glucose and insulin were unchanged in the present study. A similar pattern has been observed in a study of GH deficiency, in which an initial deterioration of insulin resistance was restored to baseline values after 6 months of GH treatment [18]. Skeletal muscle is the major site of glucose disposal, and IGF-I stimulates glucose transport into skeletal muscle. Furthermore, GH treatment of rats is known to increase the proportion of insulin-sensitive type I muscle fibers [19]. Therefore, the increase in FFM found in the present study or any related changes in muscle metabolism or morphology that may have occurred might help to explain the improvement in glucose homeostasis between 2 and 8 weeks of treatment.

 

Overall, this groundbreaking clinical trial revealed that 2 month treatment duration with the oral GH secretagogue MK-677 was generally well tolerated, and caused a significant GH response, followed by increases in serum IGF-I and IGFBP-3, whereas effects on cortisol secretion were brief. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate (BMR). Further studies would beneeded to determine whether body fat can be affected by a higher dose of MK-677 or more prolonged treatment.

 

Selected Preclinical Findings

1. MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer’s Disease [4]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuron death. The primary cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) plaque proteins in the brain. Ghrelin, which is a peptide hormone predominantly secreted from the stomach, is an body-produced activator ofthe growth hormone secretagogue-receptor type 1a (GHS-R1a). MK-0677 is a ghrelin mimic that strongly stimulates the ghrelin receptor. Interestingly, previous studies have shown that ghrelin improves cognitive impairments and prevents neuronal death and neuroinflammation in several neurological disorders. However, it is unknown whether MK-0677 can affect Aβ accumulation or Aβ-mediated pathology in the brains of patients with Alzheimer’s disease. This study examined the effects of MK-0677 administration on Alzheimer’s disease-related pathology in 5XFAD mice, an Aβ-overexpressing genetically-engineerdd mouse model of Alzheimer’s disease. MK-0677 was administered to three-month-old 5XFAD mice. To visualize Aβ accumulation, neuroinflammation, and neurodegeneration, thioflavin-S staining and staining of Aβ (4G8), ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), and synaptophysin were conducted in the brains of 5XFAD and wild-type mice. The brain tissue staining analysis indicated that MK-0677-treated 5XFAD mice showed reduced Aβ deposition, less neuronal and loss in the deep brain cortex. These results showe that activation of the ghrelin receptor with MK-0677 inhibited the Aβ plaque burden, neuroinflammation, and neurodegeneration, which suggeststhat MK-0677 might have potential as a treatment of the early phase of Alzheimer’s disease.

Fig. 6. Overview of how MK-0677 (otherwise known as MK-677) functions in the brain to counteract Alzheimer’s disease. MK-0677 blocks neuroinflammation and loss of synapses (connections between brain cells), diminishes Aβ plaque burden, and prevents loss of neurons.

Fig. 7. MK-0677 treatment significantly reduced Aβ plaques in the deep cortical layers of 5XFAD (Alzheimer’s Disease) mice. The burden of Aβ was estimated by measuring thoflavin-S levels and staining for 4G8. 5XFAD mice treated with MK-0677 (n = 6) showed a decreased positive area (%) in both thioflavin-S (left) and 4G8 (right) stained brains, compared with placebo-treated 5XFAD mice (n = 7).

Fig. 8. MK-0677-treated 5XFAD (Alzheimer’s Disease) mice exhibited a significant reduction in neurodegeneration compared with the vehicle group. Immunofluorescent staining was performed to detect the markers of neuron cells (NeuN) and neuron connection synapses (SYN) in the frontal cortex of wild-type mice (normal mice) (n = 8) or 5XFAD mice. MK-0677 significantly increased the number of NeuN (+) cells (live neurons) (top panels) and optical density of SYN (+) area (bottom panels) in 5XFAD mice (n = 6), compared with placebo-treated (vehicle) 5XFAD mice (n = 7).

 

Discussion

 

Because the evidence for a correlation between the ghrelin system and neural function continues to grow, the roles of ghrelin in neurodegenerative and cognitive impairment diseases have been widely studied. Furthermore, the effects of ghrelin on the pathological changes resulting from Aβ plaque-induced pathogenesis might be used as a possible strategy for Alzheimer’s disease treatment. However, while a previous randomized clinical trial reported that MK-0677 had no effects on cognitive function in patients with AD, it did not assess any pathologic changes, including Aβ plaque levels [20] . Moreover, the effects of MK-0677 on Aβ plaque accumulation in studies of ghrelin agonists and antagonists have been conflicting [21]–[23], which led this particular study which sought to examine if a ghrelin activator like MK-0677 reduced Aβ plaque accumulation and Aβ plaque progression in Alzheimer’s disease animals. In the present study, the authors examined the effects of MK-0677 on Alzheimer’s disease markers in 5XFAD mice. The thioflavin-S staining and staining results revealed that MK-0677 reduced Aβ plaque accumulation, neurodegeneration, and neuroinflammation in the 5XFAD mice, which suggested that MK-0677 reduced Aβ plaque accumulation, as well as Aβ plaque associated disease.

 

The authors examined the effects of MK-0677 on neurodegeneration in the neocortex regions of the brain. NeuN and SYN, which are markers of neuron and synaptic (cell connection) loss, respectively, were examined. The staining results suggested that both neuronal/synaptic losses were reduced by the administration of MK-0677. In accordance with the neurodegenerative pathology in Alzheimer’s disease, Aβ plaque accumulation is known to play key roles in that disease progression. The Aβ plaque accumulation and accompanying neuronal loss were reflected in a previous study that used the same mice as this study did [24]. Therefore, these results strongly suggested that treatment with MK-0677 would sufficiently reduce neurodegeneration by inhibiting Aβ plaque formation in brains.

 

Aside from the beneficial effects of ghrelin on Aβ plaque–induced disease progression, ghrelin demonstrates appetite stimulant properties [25]. Ghrelin increases feeding by stimulating neuropeptides in the brain. These demonstrated that the administration of 3 mg/kg of MK-0677 resulted in an 11.6% increase in food intake and 64% lean mass gain in the mice compared with the vehicle (control) group. These findings were consistent with those of previous studies which reported that MK-0677 increased food intake and lean body mass [26]. Interestingly, MK-0677 did not increase the cumulative food intake or changes in body weight in the 5XFAD mice. Although the mechanisms to explain this discrepancy were not clear, it may be assumed that different species may affect the results. Regardless of the specific mechanism, these results strongly indicate that MK-0677 has beneficial effects on Aβ plaque accumulation and Aβ plaque pathogenesis.

 

In this study, the ghrelin agonist MK-0677 demonstrated great potential for decreasing the burden of amyloid Aβ plaques. To solidify this result, studies on the precise molecular mechanisms of the Aβ-lowering effects of MK-0677 are essential. In other words, additional studies are needed to investigate the effects of MK-0677 both on amyloid precursor protein processing and the gene expression or activity of Aβ-degrading enzymes.

 

In conclusion, this study reveals for the first time that the ghrelin activator MK-0677 suppressed Aβ pathology and Aβ-mediated disease progression in vivo. These results clearly suggest that MK-0677 is be a promising therapeutic agent for the early phase of Alzheimer’s disease and that activation of the ghrelin receptor with a mimetic like MK-0677 can be a legitimate and exciting therapeutic target for the treatment of Alzheimer’s disease.

 

OVERALL CONCLUSIONS

MK-677 is a fascinating and powerful therapeutic candidate to help manage and improve a number of common health conditions. In both clinical and preclinical settings, MK-677 has been shown to enhance growth hormone (GH) secretion and increases lean mass in healthy adults, protects against age-associated declines in natural growth hormone production by the body, inhibit neuroinflammation and neurodegeneration, improves bone mineral density, and increases IGF-1 growth factor levels in adults.

 

References

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[2]      J. Svensson 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.

[3]      G. P. Ceda et al., “Update on new therapeutic options for the somatopause,” Acta Biomedica. 2010.

[4]      Y. O. Jeong et al., “Mk-0677, a ghrelin agonist, alleviates amyloid beta-related pathology in 5XFAD mice, an animal model of Alzheimer’s disease,” Int. J. Mol. Sci., 2018.

[5]      S. M. Lee, M. H. Hong, H. Y. Chung, and M. Moon, “Ghrelin mimetic MK-677 alleviates amyloid beta-related pathology in 5XFAD mice, an animal model of Alzheimer’s disease,” Eur. Neuropsychopharmacol., 2017.

[6]      M. G. Murphy 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.

[7]      J. T. Sigalos et al., “Growth Hormone Secretagogue Treatment in Hypogonadal Men Raises Serum Insulin-Like Growth Factor-1 Levels,” Am. J. Mens. Health, 2017.

[8]      I. Janssen, S. B. Heymsfield, Z. M. Wang, and R. Ross, “Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr,” J. Appl. Physiol., 2000.

[9]      J. Svensson 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 1 ,” J. Clin. Endocrinol. Metab., vol. 83, no. 2, pp. 362–369, Feb. 1998.

[10]    I. M. Chapman et al., “Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects.,” J. Clin. Endocrinol. Metab., vol. 81, no. 12, pp. 4249–4257, Dec. 1996.

[11]    G. Götherström, B. Å. Bengtsson, I. Bossæus, G. Johansson, and J. Svensson, “Ten-year GH replacement increase bone mineral density in hypopituitary patients with adult onset GH deficiency,” Eur. J. Endocrinol., 2007.

[12]    K. Landin-Wilhelmsen, A. Nilsson, I. Bosaeus, and B. Å. Bengtsson, “Growth hormone increases bone mineral content in postmenopausal osteoporosis: A randomized placebo-controlled trial,” J. Bone Miner. Res., 2003.

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[14]    H. De Boer, G. J. Blok, and E. A. Van Der Veen, “Clinical aspects of growth hormone deficiency in adults,” Endocr. Rev., 1995.

[15]    R. Marcus et al., “Effects of short term administration of recombinant human growth hormone to elderly people,” J. Clin. Endocrinol. Metab., 1990.

[16]    D. Rudman et al., “Effects of human growth hormone in men over 60 years old,” N. Engl. J. Med., 1990.

[17]    G. Johannsson et al., “ Growth Hormone Treatment of Abdominally Obese Men Reduces Abdominal Fat Mass, Improves Glucose and Lipoprotein Metabolism, and Reduces Diastolic Blood Pressure 1 ,” J. Clin. Endocrinol. Metab., 1997.

[18]    F. Salomon, R. C. Cuneo, R. Hesp, and P. H. Sönksen, “The Effects of Treatment with Recombinant Human Growth Hormone on Body Composition and Metabolism in Adults with Growth Hormone Deficiency,” N. Engl. J. Med., 1989.

[19]    C. M. Ayling, B. H. Moreland, J. M. Zanelli, and D. Schulster, “Human growth hormone treatment of hypophysectomized rats increases the proportion of type-1 fibres in skeletal muscle,” J. Endocrinol., 1989.

[20]    J. J. Sevigny, J. M. Ryan, C. H. Van Dyck, Y. Peng, C. R. Lines, and M. L. Nessly, “Growth hormone secretagogue MK-677: No clinical effect on AD progression in a randomized trial,” Neurology, 2008.

[21]    E. J. Dhurandhar, D. B. Allison, T. van Groen, and I. Kadish, “Hunger in the Absence of Caloric Restriction Improves Cognition and Attenuates Alzheimer’s Disease Pathology in a Mouse Model,” PLoS One, 2013.

[22]    N. Kunath, T. Van Groen, D. B. Allison, A. Kumar, M. Dozier-Sharpe, and I. Kadish, “Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer’s disease mouse model,” Sci. Rep., 2015.

[23]    S. Madhavadas, B. M. Kutty, and S. Subramanian, “Amyloid ß lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity,” Indian J. Biochem. Biophys., 2014.

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