What is ibutamoren

Ibutamoren also known as ibutamoren mesylate, MK 677, MK-0677 or L163,191, is an oral ghrelin receptor agonist, an orally active nonpeptide with a long half-life growth hormone secretagogue which promotes the secretion of growth hormone through a pituitary and hypothalamic receptor that is different from the growth hormone–releasing hormone receptor ¹, ². Ibutamoren MK-677 was considered to have potential for treating catabolic states or wasting states. Ibutamoren mesylate has also been used in the setting of growth hormone deficient children, with a single study demonstrating increases in growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels after only 7 days of therapy, without examining growth rates ¹. When a catabolic state is induced by dietary caloric restriction, nitrogen loss is accompanied by a decrease in IGF-I and an increase in growth hormone ³. The increase in growth hormone is due to reduction in IGF-1-mediated negative feedback on growth hormone release and the decrease in circulating IGF-1 is probably caused by reduced sensitivity of IGF-1 producing cells in the liver to growth hormone stimulation ⁴. However, growth hormone resistance is not complete because treatment with exogenous growth hormone increases IGF-1 and promotes nitrogen retention ⁵. Ibutamoren has been shown to sustain activation of the growth hormone–IGF-1 axis and to increase lean body mass with no change in total fat mass or visceral fat ⁶, ⁷. Human studies in healthy and functionally impaired elderly adults ⁸ and postmenopausal osteoporotic women ⁹ have shown it to increase both muscle mass and bone mineral density respectively, making it a promising potential therapy for the treatment of frailty in the elderly ¹⁰. Furthermore, ibutamoren MK-677 has been shown to reverse diet-induced nitrogen wasting, suggesting that it may be useful in treating catabolic conditions ¹¹.

Ibutamoren mesylate was used by Murphy et al. in 1998 ¹² to slow nitrogen wasting in a catabolic state. In this study, 8 healthy young volunteers were calorically restricted for 14 days, and for the last 7 days were given ibutamoren or placebo. After a 14–21 day washout period, the other treatment (placebo for the ibutamoren group and ibutamoren for placebo group) was given during the second week of the second 14 day period of caloric restriction. During the second week of the study, mean daily nitrogen balance was 0.31±0.21 g/day in the ibutamoren group compared with −1.48±0.21 g/day in the placebo group, demonstrating preservation of nitrogen balance in the setting of ibutamoren ¹².

Ibutamoren has been used in healthy obese men for longer periods than growth hormone releasing peptide ². A two-month randomized, double-blind, parallel, placebo-controlled trial with 24 men showed a 3 kg increase in fat free mass (lean mass) in the ibutamoren group when compared with placebo ¹³. This trial did not show changes in visceral or abdominal fat mass when these parameters were examined ¹³. Recently, a study of 25 women and 21 men with Prader-Willi syndrome examined the impact of long-term exogenous growth hormone vs. placebo on body composition in these patients. Significant fat losses were observed, with visceral fat decreasing by an average 22.9 ml, abdominal subcutaneous fat by 70.9 ml and thigh fat by 21.3 ml ¹⁴. These fat losses occurred in conjunction with increases in thigh muscle (6.0 ml) and lean body mass (2.25 kg), with a decrease in total fat mass of 4.20 kg ¹⁴. After one year, open label treatment for an additional 2 years demonstrated that the positive effects on body composition were maintained ¹⁴.

Changes in body composition mediated by enhancement of growth hormone signaling can also benefit the elderly. Nass and colleagues ⁶, in a two-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial of 65 healthy elderly patients, found that daily ibutamoren increased growth hormone and IGF-1 levels to those of healthy young adults without serious adverse effects. Fat free mass increased 1.1 kg in the ibutamoren group, in contrast with a decrease of −0.5 kg in the controls ⁶. Furthermore, low density lipoprotein cholesterol decreased −5.4 mg/dL in the Ibutamoren group, with no differences in total or high density lipoprotein cholesterol observed. In this trial, increased lean mass did not result in increased strength, and abdominal visceral fat content was not affected ⁶.

Bone turnover in the elderly may also be improved by ibutamoren, with 9 weeks of ibutamoren treatment showing a 29.4% increase in mean serum osteocalcin, a 10.4% increase in bone-specific alkaline phosphatase and a 22.6% increase in urinary N-telopeptide cross-links (NTx) excretion when compared with placebo ⁸. Subsequent work examined the role of ibutamoren in facilitating recovery of elderly patients from hip fracture. A double-blind, placebo controlled study that included 161 hip fracture patients examined the impact of ibutamoren vs. placebo on functional improvements during rehabilitation ¹⁵. More significant increases in IGF-1 levels were observed in the ibutamoren group when compared with placebo (84% vs. 17%, respectively). When assessing functional outcomes, the ibutamoren group did not evidence a significant impact in quality of life, although 3 out of 4 lower extremity performance measures improved in this group. There was also a trend towards more independent living in the ibutamoren group in all patients, and in particular in 70% of those who were independent prior to hip fracture ¹⁵. A second, smaller study (n=123) with a similar design evaluating ibutamoren compared with placebo in hip fracture recovery observed improved stair climbing power and gait speed in the ibutamoren group ¹⁶. However, these increases were so small that they were not considered meaningful improvement ¹⁶. Though the above work suggests a positive impact of ibutamoren on anabolism, additional study is needed to determine whether the slowing of catabolism by ibutamoren affects mortality, hospital length of stay, or results in functional improvements by reducing protein breakdown and increasing anabolism ².

Is ibutamoren legal?

Ibutamoren MK-677 is not currently U.S. Food and Drug Administration (FDA) approved. However, ibutamoren is available by prescription through compounding pharmacies both in the United States and abroad ¹⁷. Private entities have marketed ibutamoren, ibutamoren mesylate or MK 677 as supplements, and the drugs are also available through internet sites that focus on supplementation. Of note, sermorelin and tesamorelin are growth hormone releasing peptides with similar mechanisms of action as ibutamoren ². Sermorelin and tesamorelin mimic growth hormone releasing hormone (GHRH) and act as G protein-coupled GHRH receptor agonists, acting synergistically with ibutamoren. Similarly to the growth hormone releasing peptides, growth hormone releasing hormone (GHRH) analogs are not FDA approved, but are available by prescription through compounding pharmacies and internet vendors.

Ibutamoren benefits

Several publications have assessed ibutamoren MK 677 influence on growth hormone release and body composition. Chapman et al. ¹⁸ assessed ibutamoren’s effects on serum levels of both growth hormone and IGF-1 in a randomized, double-blind placebo-controlled trial. A total of 32 healthy elderly subjects (15 women and 17 men) 64 to 81 years old were randomized into two groups of 16 ¹⁸. The first group received once daily dosing of either 2, 10, or 25 mg of ibutamoren or placebo. The second group received a daily dose in both the morning and the evening with at least one of these doses being a placebo. Participants underwent 2 separate 14-day treatment periods which were separated by a 2 to 3-week washout period. An additional 14 days of treatment followed the second treatment period. Measured outcomes included serum growth hormone, IGF-1, cortisol, prolactin, IGFBP-1, IGFBP-3, T3, T4, TSH, and fasting glucose and insulin.

When compared to baseline, both 10 and 25 mg ibutamoren doses increased the mean 24-hour growth hormone concentration by 57% and 97%, respectively. These ibutamoren treatments boosted pulsatile growth hormone release yielding a 1.7-fold increase in growth hormone secretion over 24 hour. For the 25 mg dose, IGF-1 levels were also increased by 55% at 2 weeks and 88% by 4 weeks. The IGF-1 levels of all subjects rose to levels normal for young adults. Ibutamoren did not significantly impact cortisol levels but did elevate prolactin, fasting glucose and insulin levels. These findings confirmed that ibutamoren is a potent growth hormone and IGF-1 stimulator for patients with lower baseline growth hormone and IGF-1 levels ¹⁹.

Svensson and colleagues ²⁰ conducted a prospective, double-blind randomized controlled trial to evaluate ibutamoren’s effect on body composition and energy expenditure. The trial included 24 men between 19 and 49 years old with a BMI >30 kg/m² and waist-hip ratios >0.95. These men were given either daily 25 mg ibutamoren or placebo for 8 weeks. Assessed outcomes included growth hormone, IGF-1, prolactin, cortisol, hydroxycorticosteroids, body weight, visceral fat, fat-free mass (lean mass), basal metabolic rate (BMR), glucose, and insulin. Ibutamoren increased serum growth hormone peak levels and area under the curve. The largest increase in these parameters was observed 2 weeks following treatment. Serum IGF-1 and IGFBP-3 were also significantly increased at 2 weeks post treatment. Paralleling the Chapman et al. study, ibutamoren led to an elevation in serum prolactin at 2 and 8 weeks but no significant changes were observed in serum or urine cortisol.

The ibutamoren treatment group experienced a significant weight gain of 2.7 kg at 8 weeks, which decreased to a nonsignificant 1.8 kg weight gain 1 week after the end of treatment. This change in weight was attributed to mild fluid retention that was noted with the ibutamoren treatment arm that resolved with treatment cessation. In addition, lean mass significantly increased by 3 kg with ibutamoren treatment compared to placebo while there were no changes in total body fat. BMR (basal metabolic rate) was increased at 2 weeks of treatment with ibutamoren but there were no changes in daily caloric intake, fasting concentrations of free fatty acids, glycerol, or ketones compared to baseline or placebo. These findings once again showcased the growth hormone-stimulatory effects of ibutamoren. Although there were no significant decreases in body fat, the increases in lean body mass indicated that ibutamoren has the potential to affect body fat levels with a possibly longer duration of higher dose treatment ²¹.

In a follow-up study, Svensson et al. ²² used the same experimental design described above to investigate ibutamoren’s effects on serum leptin, thyroid hormones, testosterone, and gonadotropin levels. While the authors found that total body fat was unchanged as previously observed, the mean total body fat decreased by a non-significant 0.2 kg at 2 weeks and 0.4 kg at 8 weeks compared to baseline. Additionally, serum leptin levels, which reflect the amount of total body fat, and leptin/body fat ratio were increased at 2 weeks of treatment despite there being no increases in body fat or appetite ²³. Increases in leptin and leptin/body fat ratio may promote earlier satiety and confer further benefit to patients seeking to alter their body composition. Ibutamoren also led to an increase in thyroid stimulating hormone (TSH) and increases in serum T3 levels at 8 weeks. Ibutamoren treatment did not affect follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, but did lead to decreased total testosterone levels with conserved free testosterone levels. Despite small sample sizes and short evaluation periods, both studies by Svensson et al. showed the promise of exploring ibutamoren use in hypogonadal men and eugonadal men with subclinical hypogonadism ²¹.

Nass et al. ⁶ conducted a 2-year randomized, double-blind, placebo-controlled, modified-crossover trial evaluating ibutamoren’s effects on body composition. Sixty-five healthy men and women 60 to 81 years old were divided into a once daily 25 mg ibutamoren treatment group (n=43) or a placebo group (n=22) for the first year of the study, whereas during year two, the placebo group received 25 mg ibutamoren. The original ibutamoren treatment group was separated into either a placebo or continued ibutamoren treatment group. Measured outcomes included growth hormone, IGF-1, lipids, cortisol, insulin sensitivity, body composition, physical function, and muscle strength.

During the first year, ibutamoren resulted in a significant 1.8-fold increase in 24-hour mean growth hormone levels and a 1.5-fold increase in serum IGF-1 levels. Body composition increases in lean body mass, limb lean mass, and thigh muscle area were observed. At 12 months, a 0.14 mmol/L decrease in LDL cholesterol was observed with ibutamoren treatment, although no changes in total testosterone levels were observed. At two years, the changes observed during the first year with ibutamoren were sustained. The group that started ibutamoren during the second year saw the same changes while the group that switched to placebo in the second year saw a reversal of the changes induced by ibutamoren treatment in the first year. These findings demonstrate that ibutamoren treatment can increase growth hormone and IGF-1 levels for up to 2 years ²¹.

Ibutamoren effects in catabolic states

Ibutamoren MK-677 increases growth hormone and IGF-1, but IGF-1-mediated negative feedback prevents ibutamoren MK-677 from producing major increases in growth hormone and IGF-1 that are possible by administering exogenous growth hormone ⁴. However, by increasing the pulse amplitude of endogenous growth hormone release to mimic normal physiology, it was believed that benefits would be achieved by administering ibutamoren MK-677. To test for efficacy, a once daily oral dose (25 mg) of ibutamoren MK-677 was administered to healthy young men subjected to short-term diet-induced nitrogen wasting ²⁴. Treatment with ibutamoren MK-677 for 7 days produced a sustained increase in serum concentrations of growth hormone and IGF-1 as well as reversal of nitrogen wasting. Hence, ibutamoren might prove useful for treating wasting associated with HIV and cancer ⁴.

Ibutamoren effects in obese subjects

Obesity is associated with insensitivity to further immediate stimulation of growth hormone release by classical stimuli; therefore, it was important to determine whether chronic oral treatment with ibutamoren MK-677 would have sustained effects on the growth hormone/IGF-1 axis. Healthy obese males were treated once daily with 25 mg ibutamoren MK-677 for 8 weeks. Increased basal metabolic rate was observed after 2 weeks, but not after 4 weeks of treatment. Sustained increases in serum levels of growth hormone, IGF-1, and IGF binding protein-3 occurred, as well as a 3-kg gain in weight ⁴. Dual energy x-ray absorptiometry scanning revealed that weight gain was explained by an increase in fat-free mass (lean mass). Neither total nor visceral fat was affected. Although food intake was not measured, the sustained increase in lean mass (fat-free mass) is likely explained by increased appetite and deposition of calories into lean tissue. The finding that ibutamoren MK-677 increased weight as lean mass, coupled with reversal of nitrogen loss observed in the diet-induced catabolism study ²⁴, suggest that long-acting growth hormone secretagogue, like ibutamoren MK-677, would provide benefit to cancer cachexia patients.

Ibutamoren effects on osteoporosis

Because growth hormone is known to stimulate bone turnover and activate osteoblast activity, it was postulated that administration of ibutamoren MK-677 together with an inhibitor of bone resorption would increase the rate of bone formation ⁴. Hence, the combination should provide enhanced benefit in women with postmenopausal osteoporosis. The effects of ibutamoren MK-677 alone and in combination with the bisphosphonate alendronate, were evaluated during 12 and 18 months of treatment in a multicenter, randomized, double-blind, placebo-controlled study ⁹. A total of 292 women (ages, 64–85 years) with low femoral neck bone mineral density (BMD) participated in the study ⁹. To evaluate efficacy, serum IGF-1, biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase), and a marker of bone resorption [urinary N-telopeptide cross-links (NTx)], as well as bone mineral density (BMD) were measured. Women were randomly assigned to one of four daily regimens for 12 months: ibutamoren MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); ibutamoren MK-677 (25 mg); or double placebo ⁹. Those patients receiving ibutamoren MK-677 alone or placebo through month 12 received ibutamoren MK-677 (25 mg) plus alendronate (10 mg) for months 12–18. Other patients remained on their assigned therapy.

Ibutamoren MK-677, with or without alendronate, increased IGF-1 levels by 39 and 45%, respectively ⁹. Similarly, osteocalcin and urinary N-telopeptide cross-links (NTx) increased by 22 and 41% relative to placebo. The combination of ibutamoren MK-677 and alendronate increased bone formation compared with alendronate alone, reduced the effect of alendronate on resorption (NTx), and increased bone mineral density at the femoral neck by 4.2% compared with 2.5% with alendronate alone. However, the combination did not enhance bone mineral density of the lumbar spine, total hip, or total body beyond that achieved with alendronate alone. Before interpreting these results, it is important to remember that the study was discontinued after 18 months, which is too short a time to see optimal effects of stimulating the growth hormone/IGF-1 axis. The beneficial effect of growth hormone treatment on bone mineral density occurs slowly because growth hormone stimulates bone remodeling. Indeed, growth hormone administration to growth hormone-deficient individuals leads first to a reduction followed by an increase in bone mineral density, and the increase is not usually seen until after 2 year of therapy ²⁵. The observed increase in bone mineral density at the femoral neck after 18 months of treatment with ibutamoren MK-677 should be considered encouraging because this may translate to prevention of fractures at a sight of frequent occurrence in the elderly.

Ibutamoren treatment of elderly hip fracture patients

Based on results derived from studies showing that dogs treated with a close structural analog of ibutamoren MK-677 recovered more quickly than placebo-treated dogs after immobilization of their hind limb, the potential benefit of ibutamoren MK-677 treatment on recovery in elderly hip fracture patients was evaluated ²⁶. A placebo-controlled, randomized, double-blind trial was implemented at 13 acute care hospitals and rehabilitation centers in England, Sweden, Denmark, Belgium, Switzerland, Canada, and the United States. A total of 161 hip fracture patients were recruited at 3 to 14 days after surgery or not more than 18 days after fracture. The entry criteria included consenting patients aged 65 and older who were ambulatory before their fracture, medically stable, and mentally competent. Patients with multiple fractures, severe trauma, diabetes mellitus, cancer, uncontrolled hypertension, congestive heart failure, or total hip replacement in the involved extremity were excluded.

Patients were randomly assigned to daily treatment with ibutamoren MK-677 or placebo for 6 months and then followed for an additional 6 months after completing therapy ²⁷. IGF-1 levels were measured, and each patient was evaluated from 6 to 26 weeks using a panel of functional performance measures. These evaluations included outcome measures such as changes in the Sickness Impact Profile for Nursing Homes and ability to live independently. ibutamoren MK-677 treatment caused an 84% increase in serum IGF-1. There were no significant changes between ibutamoren MK-677 and placebo in improving functional performance measures or in the overall Sickness Impact Profile for Nursing Homes score, but ibutamoren MK-677 treated patients showed greater improvement compared with placebo in three of four lower extremity functional performance measures, in the physical domain of the Sickness Impact Profile for Nursing Homes, and in the ability to live independently. Although it is uncertain whether clinically significant outcomes on physical function were achieved, making clear conclusions from functional studies in clinical trials with hip fracture patients is complicated by the lack of validated outcome measures and absence of a baseline assessment. Indeed, present functional performance measures may not be sufficiently responsive to be used as an endpoint in small intervention studies.

Ibutamoren in children with short stature

Ibutamoren mesylate has also been used in the setting of growth hormone deficient children with a single study demonstrating increases in growth hormone and IGF-1 levels after only 7 days of therapy, without examining growth rates ¹.

Ibutamoren dosage

Sigalos et al ² recommend a starting dose of 25 mg by mouth daily for ibutamoren given that this is the dose studied in randomized controlled trials. They also recommend following these patients with regular examinations for changes in body composition and IGF-1 levels during ibutamoren treatment, as well as with blood glucose and Hb A1c monitoring.

Ibutamoren side effects

The current literature supports an increased risk for hyperglycemia in the context of ibutamoren use, with few other side effects that are directly attributable to ibutamoren use. However, larger safety studies are needed to accurately compare the safety of ibutamoren with that of exogenous growth hormone. Side effects reported in the literature include:

• Transient increase in cortisol and prolactin ⁷
• Musculoskelectal pain and fluid retention ⁶
• Increase in insulin insensitivity ²⁸
• Transient increase in appetite ⁶.

Ibutamoren summary

Relatively few studies examining the effects of ibutamoren are currently available, though existing studies support beneficial roles for ibutamoren in raising growth hormone levels and as a potent IGF-1 stimulator that can significantly impact body composition including impacting patient outcomes. Few studies evaluating large cohorts for sustained durations of ibutamoren treatments are currently available, limiting the ability to rigorously compare the effects of ibutamoren with those of growth hormone ². Available data support increases in growth hormone and IGF-1 levels with ibutamoren treatment, but provide few objective insights on the effects of ibutamoren on body composition or other important endpoints. Although available studies support a beneficial effect of ibutamoren on growth velocity in children, appetite stimulation, positive effects in wasting states and in obese individuals, bone turnover, lean body mass and sleep, parameters that remain to be investigated include hospital recovery time, functional muscle parameters or adiposity changes in the context of an exercise program, and long-term large safety data ². Future work should also focus on determining the effects of ibutamoren on patient outcomes in a variety of conditions, as well as on body composition in the setting of exercise and recovery from catabolic states.

Based on the literature, current indications for the use of ibutamoren includes treatment of wasting and as treatment for growth hormone deficiency. Ibutamoren has a potential for use in the management of body composition concerns associated with hypogonadism and metabolic syndrome, as either monotherapy or adjunct therapy in combination with testosterone therapy ²¹.

References

1. Codner E, Cassorla F, Tiulpakov AN, Mericq MV, Avila A, Pescovitz OH, Svensson J, Cerchio K, Krupa D, Gertz BJ, Murphy G. Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children. Clin Pharmacol Ther. 2001 Jul;70(1):91-8. doi: 10.1067/mcp.2001.116514
2. Sigalos, J. T., & Pastuszak, A. W. (2018). The Safety and Efficacy of Growth Hormone Secretagogues. Sexual medicine reviews, 6(1), 45–53. https://doi.org/10.1016/j.sxmr.2017.02.004
3. Ho KY, Veldhuis JD, Johnson ML, Furlanetto R, Evans WS, Alberti KG, Thorner MO 1988 Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 81:968–975
4. Roy G. Smith, Development of Growth Hormone Secretagogues, Endocrine Reviews, Volume 26, Issue 3, 1 May 2005, Pages 346–360, https://doi.org/10.1210/er.2004-0019
5. Snyder DK, Clemmons DR, Underwood LE 1988 Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition. J Clin Endocrinol Metab 67:54–61
6. Nass, R., Pezzoli, S. S., Oliveri, M. C., Patrie, J. T., Harrell, F. E., Jr, Clasey, J. L., Heymsfield, S. B., Bach, M. A., Vance, M. L., & Thorner, M. O. (2008). Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Annals of internal medicine, 149(9), 601–611. https://doi.org/10.7326/0003-4819-149-9-200811040-00003
7. Svensson J, Lonn L, Jansson JO, Murphy G, Wyss D, Krupa D, 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. The Journal of clinical endocrinology and metabolism. 1998;83(2):362–9.
8. Murphy MG, Bach MA, Plotkin D, Bolognese J, Ng J, Krupa D, Cerchio K, Gertz BJ. 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 Jul;14(7):1182-8. doi: 10.1359/jbmr.1999.14.7.1182
9. M. G. Murphy, S. Weiss, M. McClung, T. Schnitzer, K. Cerchio, J. Connor, D. Krupa, B. J. Gertz, 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, The Journal of Clinical Endocrinology & Metabolism, Volume 86, Issue 3, 1 March 2001, Pages 1116–1125, https://doi.org/10.1210/jcem.86.3.7294
10. Smith RG, Sun Y, Jiang H, Albarran-Zeckler R, Timchenko N. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging. Ann N Y Acad Sci. 2007 Nov;1119:147-64. doi: 10.1196/annals.1404.023
11. Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998 Feb;83(2):320-5. doi: 10.1210/jcem.83.2.4551
12. M. G. Murphy, L. M. Plunkett, B. J. Gertz, W. He, J. Wittreich, W. M. Polvino, D. R. Clemmons, MK-677, an Orally Active Growth Hormone Secretagogue, Reverses Diet-Induced Catabolism, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 2, 1 February 1998, Pages 320–325, https://doi.org/10.1210/jcem.83.2.4551
13. Svensson J, Lönn L, Jansson JO, Murphy G, Wyss D, Krupa D, Cerchio K, Polvino W, Gertz B, Boseaus I, Sjöström L, Bengtsson BA. 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 Feb;83(2):362-9. doi: 10.1210/jcem.83.2.4539
14. Sode-Carlsen R, Farholt S, Rabben KF, Bollerslev J, Schreiner T, Jurik AG, Christiansen JS, Höybye C. Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study. Endocrine. 2012 Apr;41(2):191-9. doi: 10.1007/s12020-011-9560-4
15. Bach MA, Rockwood K, Zetterberg C, Thamsborg G, Hébert R, Devogelaer JP, Christiansen JS, Rizzoli R, Ochsner JL, Beisaw N, Gluck O, Yu L, Schwab T, Farrington J, Taylor AM, Ng J, Fuh V; MK 0677 Hip Fracture Study Group. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc. 2004 Apr;52(4):516-23. doi: 10.1111/j.1532-5415.2004.52156.x
16. Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, Liu N, Papanicolaou DA. 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 Sep-Oct;53(2):183-9. doi: 10.1016/j.archger.2010.10.004
17. Bulk Drug Substances Nominated for Use in Compounding Under Secti on 503Bof the Federal Food, Drug, and Cosmetic Act. Updated July 30, 2020 https://www.fda.gov/media/94164/download
18. Chapman IM, Bach MA, Van Cauter E, Farmer M, Krupa D, Taylor AM, Schilling LM, Cole KY, Skiles EH, Pezzoli SS, Hartman ML, Veldhuis JD, Gormley GJ, Thorner MO. 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. 1996 Dec;81(12):4249-57. doi: 10.1210/jcem.81.12.8954023
19. Sherlock M, Toogood AA. Aging and the growth hormone/insulin like growth factor-I axis. Pituitary. 2007;10(2):189-203. doi: 10.1007/s11102-007-0039-5
20. J. Svensson, L. Lönn, J.-O. Jansson, G. Murphy, D. Wyss, D. Krupa, K. Cerchio, W. Polvino, B. Gertz, I. Boseaus, L. Sjöström, B.-Å. Bengtsson, Two-Month Treatment of Obese Subjects with the Oral Growth Hormone (GH) Secretagogue MK-677 Increases GH Secretion, Fat-Free Mass, and Energy Expenditure, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 2, 1 February 1998, Pages 362–369, https://doi.org/10.1210/jcem.83.2.4539
21. Sinha, D. K., Balasubramanian, A., Tatem, A. J., Rivera-Mirabal, J., Yu, J., Kovac, J., Pastuszak, A. W., & Lipshultz, L. I. (2020). Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational andrology and urology, 9(Suppl 2), S149–S159. https://doi.org/10.21037/tau.2019.11.30
22. Svensson J, Carlsson B, Carlsson LM, Jansson JO, Bengtsson BA. Discrepancy between serum leptin values and total body fat in response to the oral growth hormone secretagogue MK-677. Clin Endocrinol (Oxf). 1999 Apr;50(4):451-6. doi: 10.1046/j.1365-2265.1999.00667.x
23. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactiveleptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-5. 10.1056/NEJM199602013340503
24. Murphy MG, Plunkett LM, Gertz BJ, He W, Wittreich J, Polvino WM, Clemmons DR 1998 MK-0677, an orally active growth hormone secretagogue reverses diet-induced catabolism. J Clin Endocrinol Metab 83:320–325
25. Gillberg P, Mallmin H, Petren-Mallmin M, Ljunghall S, Nilsson AG 2002 Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. J Clin Endocrinol Metab 87:4900–4906
26. Bach MA, Rockwood K, Zetterberg C, Thamsborg G, Hebert R, Devogelaer JP, Christiansen JS, Rizzoli R, Ochsner JL, Beisaw N, Gluck O, Yu L, Schwab T, Farrington J, Taylor AM, Ng J, Fuh V 2004 The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc 52:516–523
27. Smith RG, Cheng K, Pong S-S, Leonard RJ, Cohen CJ, Arena JP, Hickey GJ, Chang CH, Jacks TM, Drisko JE, Robinson ICAF, Dickson SL, Leng G 1996 Mechanism of action of GHRP-6 and nonpeptidyl growth hormone secretagogues. In: Bercu BB, Walker RF, eds. Growth hormone secretagogues. Serono Symposia. New York: Springer-Verlag; 147–163
28. Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology. 2008;71(21):1702–8.