MK-677 (Ibutamoren)

MK-677, otherwise referred to as Ibutamoren, is a growth hormone secretagogue via acting as a ghrelin mimetic. Through this action, MK-677 has a positive influence on growth hormone, which is advantageous for some different situations such as growth hormone deficiency due to age or disorder.

Research suggests that while MK-677 does indeed lead to elevations of growth hormone and its downstream targets, its influence on body composition and bone health is a bit uncertain.

Fortunately, despite mild side effects and a potential connection to coronary heart failure, research regarding MK-677 continues in the hopes of finding a growth hormone alternative.

The Need For A GH Alternative

Growth hormone (GH) is considered to be one of the most important hormones for the development and maintenance of our bodies. GH not only plays an integral role in how our bodies develop through childhood but also how our bodies maintain health and function into old age (1, 2).

Growth hormone is secreted in a pulse-like fashion every few hours throughout the day. However, research shows that growth hormone pulses are most significant during sleeping hours. These pulses are a result of many factors such as our energy status, gender, and daily circadian rhythm.

Unfortunately, age is also a primary factor, leading to declines of GH in addition to many other important hormones like testosterone and estrogen. These are integral to the age-related ailments we often observe like frailty, weak bones and loss of muscle mass and function (1).

As you can imagine, GH declining with age is not the only consideration. Many children, for example, have GH deficiency, requiring exogenous GH for proper growth and development (3, 4).

Unfortunately, however, GH alone is not the best option. Much like with steroid hormones, growth hormone administration comes with side effects such as edema (swelling), headache, nausea, and even carpal tunnel syndrome. Not to mention, oral bioavailability of GH is low, requiring injections (5, 6, 7, 8).

Other potential opportunities like growth hormone releasing peptides such as GHRP-6 have been explored. While GHRP-6 has become a likely candidate for GH replacement, it's also been suggested that it's not entirely specific in its action and potentially elevates cortisol and prolactin; both of which have unique effects (9, 10, 11).

Because of this need for a GH replacement, experimental chemicals like MK-677 have been and are under experimentation. As you'll read, MK-677 does have some promising and some not-so-promising effects; calling into question, its use outside of a clinical setting.

MK-677 also know as Ibutamoren

MK-677 is part of a class of chemicals known as growth hormone secretagogues and has a primary role in producing more robust GH responses for a wide array of individuals (6, 12).

MK-677 is a ghrelin mimetic in that it simulates the action of ghrelin by docking onto ghrelin receptors. Ghrelin, which is widely considered to be the hormone that stimulates hunger, has a primary endpoint of activating the Growth Hormone Secretagogue Receptor (GHS-R). In doing so, ghrelin acts on the pituitary gland to stimulate the release of GH (9).

By mimicking the effect of ghrelin on the GHS-R receptor, MK-677 similarly influences these receptors, improving the release of growth hormone and it’s downstream effects (13).

Understanding MK-677’s Mechanism of Action

MK-677 acts by functioning like ghrelin but why would mimicking our body's main hunger hormone stimulate growth hormone?

Ghrelin, being a significant contributor to hunger, plays a role in appetite and feeding. From an evolutionary standpoint, ghrelin likely functioned by encouraging us to eat food when our bodies needed energy. Mainly, during times of food deprivation or according to normal eating patterns, ghrelin is released to stimulate hunger under the pretense that you’ll consume calories (14, 15, 16).

Mostly, it seems that ghrelin and the resultant GH release are tied closely to the regulation of blood sugar. During times of energy restriction, ghrelin elevates and stimulates the pituitary to release GH. This GH then stimulates the liver to release glucose as well as initiate gluconeogenesis; the production of glucose from non-carbohydrate sources. But in doing so, this GH also seems to limit the use of glucose outside of circulation, such as in muscle (13, 17).

To simplify:

1. During times of low energy intake, ghrelin secretion elevates to encourage hunger.
2. This ghrelin interacts with the pituitary gland to stimulate the release of growth hormone.
3. Growth hormone then stimulates the release of glucose from the liver in addition to stimulating gluconeogenesis and lipolysis (release of fat).
4. This growth hormone then causes some insulin resistance in muscle. While not optimal, this ensures that blood glucose remains elevated for survival.

But regulating blood sugar is not the only influence of GH. Its release also stimulates the production and action of Insulin-Like Growth Factor 1 (IGF-1), which is likely a primary reason for use by those looking to improve body composition, as it’s associated with growth (13, 18).

In a similar manner as before, GH results in an elevation of IGF-1, which acts in the body by stimulating protein synthesis and growth of tissue. As you can imagine, this is relevant for an elderly population experiencing growth hormone related declines of IGF-1. Further, this again makes it attractive for healthy individuals looking to gain a competitive edge (13).

While it's quite clear that growth hormone plays a role in how our bodies store and metabolize nutrients (often favorably), returning to a healthy level of GH (such as with the elderly) may have profoundly beneficial effects.

Conversely, a healthy individual looking to elevate GH (above normal levels) might experience the adverse effects of elevated GH, such as glucose intolerance, insulin resistance and the potentially unfavorable effects of raising IGF-1 (19, 20).

Fortunately, there is research regarding MK-677, specifically in humans to help us understand if these conclusions are accurate and also if it's both safe and effective.

Research On MK-677

Since MK-677 has been around for quite some time, there isn't an entire shortage of research, particularly in humans. Unsurprisingly, MK-677 is a potential alternative to true growth hormone replacement and even growth hormone releasing peptides like GHRP-6.

Since growth hormone is associated with the growth of the body as a whole, primary endpoints of research include changes to body composition like muscle and fat mass, bone health and even sleep improvement.

MK-677 for Body Composition

One of the more obvious potential uses for MK-677 is an adjustment to body composition. Since growth hormone is often used or prescribed to help build body mass, understanding if MK-677 can achieve the same is essential (21).

Mostly, MK-677 presents a unique opportunity to help individuals build or at least maintain lean mass when their body can't do so alone. For instance, growth hormone, as with many other hormones, declines with age leading to obesity, loss of muscle mass and in turn, reduced quality of life (22).

Additionally, since growth hormone is often prescribed for individuals with growth hormone deficiency, MK-677 presents a novel opportunity to achieve the same effects as growth hormone, while possibly circumventing the adverse effects.

Studies On MK-677 & Body Composition

Since MK-677 has been available for some time, extended duration studies have been conducted.

Study 1: 2 Years & Elderly

In one such study, elderly male and female participants experiencing age-related hormonal decline were provided with MK-677 or placebo for two years.

Fascinatingly, researchers in this study recruited not only elderly participants but also some individuals already using hormone therapy. This is an interesting point because it tests the interaction between MK-677 and hormone treatment in a population that might experience just the same in the real world.

In year one of the study, participants were randomly assigned to one of two groups. Group 1 orally received 25mg of MK-677 while group 2 received a placebo. In year two, the study design was adjusted slightly.

In year 2, subjects in group one were further divided in half. The first half of group 1 participants continued receiving 25 mg of MK-677 each day while the second half received placebo. The idea here was to observe how individuals would respond to the removal of MK-677, after a year of consistent use and then compare differences to those continuing to use the drug. Finally, participants from group two during year one were then transitioned into daily administration of 25mg of MK-677.

The results indicate a mild effect of MK-677 on body composition. The data showed a small but significant increase in fat-free mass, but as the authors note, this is likely due to an elevation of water retention, which is often mistaken for lean mass. Further, subjects also showed a significant increase in fat mass as well, suggesting that MK-677 influences body weight rather than specifically body composition (12).

Worth noting is the fact that MK-677 also led to a significant decline in femoral neck bone density. Authors note that this reduction in bone density is typical of bone remodeling with growth hormone (12).

However, those in the placebo group showed elevations of bone density in contrast and considering the two-year duration of this study, this is relevant (12).

Study 2: The Diet Study

An area of interest regarding growth hormone is the preservation of lean mass particularly during times of reduced food intake. Many people use growth hormone with the intent of preserving lean body mass while dieting, so understanding the potential use and safety profile for this purpose is relevant.

Eight young males were placed on a calorically restricted diet and given either a placebo or MK-677 for seven days. Since this study was considered a crossover design, subjects then underwent a 14-21 day washout period where they received no drug or placebo.

Following the washout period, subjects were administered the opposite treatment for an additional seven days. Mostly, if subjects received MK-677 in the first round, they switched to placebo for the second half.

The results indicate that MK-677 led to an initially robust elevation of growth hormone, IGF-1, IGF binding protein 3, and cortisol, which all reduced by the end of the study. These findings suggest that the body might develop tolerance to MK-677 quite rapidly (6).

Importantly, however, was MK-677’s influence on nitrogen balance. Nitrogen balance is a standard measure of muscle growth or loss with positive numbers potentially being indicative of muscle growth. The data indicates that despite being in a calorically restrictive state, MK-677 led to significant improvements of nitrogen balance while placebo showed a decline (6, 23).

Notably, use of MK-677 reduced weight loss compared to placebo. However, considering the change to nitrogen balance, this suggests that MK-677 prioritized body fat reduction, while placebo directly led to global weight loss (6).

Study 3: Young and Healthy But Obese

In a third study, young, obese males aged 19-49 were recruited to receive either 25 mg of MK-677 or placebo for eight weeks. Subjects received the substance orally each day. During this time, researchers evaluated changes to GH secretion, body composition, energy expenditure and also glucose tolerance. As a secondary measure, researchers also tested any changes to bone metabolism.

Similarly to study two, use of MK-677 initially led to significant and robust elevations of growth hormone, IGF-1, and cortisol. However, after eight weeks, both GH and IGF-1 levels declined, albeit, remaining significant. Cortisol, however, fell to non-significant levels by the end of the eight-week study (24).

As with other studies, results indicate a significant elevation of fat-free mass, reaching significance by the end of the 8-week trial. However, this was alongside an increase in total body weight and no change to fat mass. Further, data indicates a potentially significant influence on prolactin and cortisol, which should be considered (24)

These findings tell us that while MK-677 might help build muscle mass, it likely won't help with reducing fat mass unless in combination with diet. For an obese population that probably requires more significant reductions in fat mass as opposed to elevations of lean mass, this is relevant.

Summary

Overall, these studies show us that in terms of body composition, MK-677 might be valuable, specifically for maintaining lean body mass or increasing it in the absence of exercise.

Results indicate that MK-677 does successfully elevate GH, IGF-1, and IGF binding protein, but also prolactin and cortisol. However, many of these elevations are short-lived, suggesting that tolerance develops rapidly. Overall, data indicates that MK-677 might be useful for developing body mass but has relatively no influence on reducing fat mass and in some cases, increases it (6, 12, 24).

MK-677 for Bone Health

With progressing age comes a multitude of ailments including the reduction of growth hormone production. In addition to the many adverse effects this decline affords, growth hormone deficiency is also associated with reduced bone density, strength and overall health (25).

Growth hormone alone does seem to play a role in the formation and degradation of bone via changes of circulating IGF-1 levels. Since GH is tightly associated with IGF-1 production, it makes sense why this might happen. Unfortunately, the use of GH for bone health has revealed mixed results.

Studies on this subject have indicated that in some cases, growth hormone does lead to improvements in bone density and mass, but often, if not most times, these improvements are preceded by elevations of markers for bone resorption or degradation (26, 27, 28, 29).

Researchers in this space believe that this change in bone formation suggests that GH induces bone remodeling rather than merely promoting growth, in a sense, rebuilding the bone. Because of this discrepancy and other adverse events associated with growth hormone use, MK-677 has been considered as a replacement (29, 30).

Unfortunately, however, studies regarding MK-677 and bone health have returned similar findings.

One review including three different studies of varying durations showed that dosing ranging from 2-9 weeks produced significant elevations in both markers of bone formation and bone resorption. While there was no substantial change to bone density, the differences observed could be indicative of the bone remodeling mentioned. However, even at nine weeks, subjects still displayed significant elevations of markers of bone resorption (26).

Other studies seem to indicate more of the same. In one 8-week study, MK-677 was provided to young, obese males, who had markers of bone growth tested, similarly to other studies. Researchers found that by week eight of consuming 25 mg of MK-677 daily, there were significant elevations in markers of bone formation but also the same for markers of bone resorption, placing us in a similar situation (27).

MK-677 + Alendronate

In a slightly different format, one study took a different approach, combining MK-677 with a known anti-resorption and pro-formation agent known as alendronate, which is often used for patients experiencing osteoporosis (29, 31).

The idea was simple: test MK-677 alone, test alendronate alone, and then test the combination of the two to observe any effect. It was considered that the combination of these substances could allow greater bone formation than either alone.

This study then investigated the usefulness of these agents in females with osteoporosis but otherwise good health. Subjects were placed into one of the following four groups for the first year:

1. 25 mg MK-677 + 10 mg of Alendronate
2. Placebo + 10 mg of Alendronate
3. 25 mg MK-677 + Placebo
4. Placebo + Placebo

Following the one year trial, subjects then had dosing adjusted to the following, based on their initial group to observe both long-term effects, as well as changes that arise after beginning or ceasing one or both of the drugs:

1. 25 mg MK-677 + 10 mg of Alendronate
2. Placebo + 10 mg of Alendronate
3. 25 mg MK-677 + 10 mg of Alendronate
4. 25 mg MK-677 + 10 mg of Alendronate

The results indicate that MK-677, while well tolerated, had very little positive influence on bone mineral density, either when combined with alendronate or alone. In fact, the authors note that there was no significant benefit on bone density at any time point for MK-677 by itself (29).

However, in a similar fashion to other studies, use of MK-677 in isolation led to a consistent decline in bone density, which was only reversed by month 18, after six months of combining MK-677 and alendronate (29).

Summary

Overall, evidence regarding MK-677’s influence on bone health is not entirely promising.

Consistently across studies, we see that MK-677 initiates processes consistent with both bone resorption and bone formation, suggesting that this drug stimulates bone remodeling rather than merely promoting growth. This reality often leads to a decline in bone density, which could eventually lead to an overall net increase in bone density (26, 27, 28, 29).

Unfortunately, even one study lasting close to two years showed no significant improvement in bone density or health. In fact, that same study showed a consistent decline of bone density with isolated MK-677 use that only returned to baseline after using a traditional anti-osteoporosis agent (29, 31).

Lastly, we don't know for sure that this bone remodeling will occur. So far, we have evidence that it happens with growth hormone, but trials investigating MK-677 have not lasted long enough for drastic improvements to occur. Further, we don’t know if any potential benefits will be maintained after ceasing treatment.

Considering that even 18 months of use was not long enough to display significant improvement, MK-677's influence on bone health is minimal and mostly unknown.

MK-677 for Sleep

It's relatively well known that sleep and growth hormone are closely related, in that growth hormone substantially elevates shortly after the onset of sleep, specifically during the beginning of slow-wave or “deep sleep.” (32, 33)

It's then unsurprising that with age and the resultant reduction of growth hormone, we also often see a decline in overall sleep quality. Because of this relationship, researchers hypothesized that using MK-677 might improve slow-wave sleep via elevations of growth hormone pulse intensity or frequency.

In this interesting study, researchers tested varying dosages of MK-677 or placebo in both young and older adults, utilizing two different procedures.

Young subjects, aged 18-30 underwent three separate protocols, each lasting seven days. Subjects in this group consumed either 5 or 10 mg of MK-677 or placebo and underwent sleep analysis.

Older subjects, aged 65-71 underwent similar procedures, but did not test with placebo. Subjects consumed 2 mg during the first test and 25 mg for the second while having sleep analyzed for 14 days each, rather than only seven.

During both trials, various parameters of sleep quality such as sleep latency (time to fall asleep), sleep efficiency (time spent in bed vs. asleep), amount of time in REM (dream) sleep, amount of time in the different stages of sleep, and the amount of time spent in slow wave were tested.

Findings indicate that for young individuals, consuming the 25 mg dose led to the most “normal” sleep patterns. Subjects in this group displayed standard values for the variables measured while the other groups had a higher incidence of issues like long sleep latency, or low time spent in REM and slow wave sleep. Older subjects responded similarly, but showed better values when consuming the low dose of MK-677, suggesting that age may change the effectiveness of MK-677 (34).

Mostly, it seems that MK-677 administration only leads to potential improvements in REM sleep and slow wave sleep duration, despite significantly elevating growth hormone. It is, however, worth noting that the length of these studies were quite short. It's relatively unknown how MK-677 might affect sleep after prolonged use (34).

Consideration: Changes To Body Composition Were Lackluster

The current evidence suggests that MK-677 does lead to increases in body weight, including lean and fat mass. Mostly, research on body composition regarding this chemical suggests that alone, MK-677 leads to increases in total body weight, while neither prioritizing lean nor fat mass, with much of lean mass improvements being attributed to water retention (12, 24).

However, when MK-677 was administered to healthy individuals placed on a calorically restrictive diet, results were different. In this scenario, MK-677 use did not lead to fat accumulation, but it did spare lean mass while bodyweight declined, suggesting a muscle-sparing effect while dieting (6).

Importantly, none of these studies incorporated an exercise routine. While avoiding exercise is essential for studies like this, future studies should include the use of a programmed resistance training protocol alone and with MK-677 to determine influence.

Overall, MK-677 does seem to protect lean mass while dieting. But in the absence of reduced calories, MK-677 leads to increased body mass, including significant elevations of fat mass (6, 12).

Consideration: Unknown Consequences For Bone

The majority of studies testing bone health show that markers of bone remodeling occur when using GH or Mk-677. This means that initially, markers of turnover and resorption are elevated and do so for relatively long periods (26, 27, 29).

This is an issue, in particular, for elderly patients already experiencing bone health decline. While bone remodeling may be advantageous, one study showed unimpeded bone resorption with MK-677 for at least 12 months, with no sign of returning. (29)

Despite the potential upside of complete bone remodeling, elevated bone resorption lasting 12 months or longer could undoubtedly lead to an increased risk of fracture, in a sense, accelerating bone health decline.

While bone remodeling may occur with use of MK-677, current evidence suggests this process may take a long time, with relatively unknown consequences.

Consideration: Side Effects

Lastly, the overall side effects of short and long-term use of MK-677 are relatively unknown. Some studies indicate that side effects are mild and similar to that of growth hormone, such as edema, discomfort, headache, and nausea (6, 35, 36).

Importantly though, one clinical trial testing MK-677 in the elderly was terminated due to the incidence of coronary heart failure. In fact, of the six cases reported, four of them were patients using MK-677. Additionally, the authors note an increase in blood pressure and glucose and muscle aches could have been associated with MK-677 use (35).

Mostly, side effects are mild, typically only causing discomfort. However, the incidence of coronary heart failure in elderly individuals suggests that MK-677 could have some adverse influence on cardiovascular health. At the very least, this reality should be strongly considered.

Final Word

Research suggests that MK-677, a ghrelin mimetic and growth hormone secretagogue does indeed lead to significant improvements in growth hormone and its downstream influences like IGF-1 (6, 12).

In terms of body composition, MK-677 does seem promising when combined with diet and potentially exercise. In the absence of dietary interventions however, MK-677 does lead to elevations in total body weight, rather than specifically lean mass (6, 12, 24).

Bone health, however, is a different story. Use of Mk-677 seems to induce complete bone remodeling, which leads to an initial increase in bone resorption. For the elderly, this could prove damaging and must be considered (26, 27, 29).

Finally, while the majority of reported side effects are minor, one study was terminated due to a high incidence of coronary heart failure, particularly in elderly subjects using MK-677. This reality should be strongly considered before using MK-677 outside of a clinical setting (35).

References: Click + to Expand

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