Peptides for Women Education

Restoring Growth Hormone in Aging
Anthony Campbell, PharmD

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There are few things in life as relentless as aging. It is an inescapable part of life; ever pursuing us from the moment we draw our first breath to the day we breathe our last. Patiently, aging slowly chips away at one’s youthful vigor and vitality, gradually deteriorating things such as lean body mass, bone density, aerobic exercise capacity, and cognitive function to name a few. Because of the aggressive and unprovoked assault on human longevity, aging may be categorized by some as an adversary; a disease necessitating eradication. Truthfully, however, aging is as normal a life process as is breathing and while it does take its toll and demands its dues over time, aging should not be viewed as an ailment in need of a cure. Yet, due to increased frailty and because many of the traditional signs of aging appear to mirror the features associated with the distinct clinical entity of Adult Growth Hormone Deficiency (AGHD), providing growth hormone (GH) directly to individuals as they age would appear to be the most direct and obvious route to restoring declining levels of GH. However, due to the wide array of potential side effects in older adults (i.e. edema, arthralgia, elevated blood glucose, etc.) it is typically undesired and many times contraindicated. Moreover, while initiating therapy at lower doses may decrease the likelihood of developing these common side effects, its use for anti-aging purposes (outside of controlled clinical research studies) is currently prohibited by US Federal law, 21 U.S.C. 333(e). Nevertheless, with the discovery and implementation of GH secretagogues in aged individuals (i.e. Growth Hormone Releasing Hormone [GHRH], Growth Hormone Releasing Peptides [GHRP], and similar mimetics the signs and symptoms of aging have recently become vulnerable to an alternative method of having their deleterious effects on the body decreased and slowed in rate of appearance.

Growth Hormone Secretion And Regulation

A substantial number of studies and published literature indicate that while there is an exponential decline in GH secretion after puberty, there is a progressive and nearly linear rate of decline of GH secretion after the third decade of life in otherwise normal, healthy adults. In clinical literature, Melmed reports that GH secretion typically peaks at puberty at about 150pg/kg/day, then gradually and relentlessly decreases to approximately 25|1g/kg/day by the age of 55.1 Of particular interest is the fact that while the amplitude, or strength, of recurring GH pulses throughout the day are significantly reduced in older individuals, the frequency, or number of pulses, remain nearly unchanged; moreover, the nocturnal pulsatile release of GH secretion is most significantly reduced in an aged individual (Figure 1). It has been reported in the literature that there are as many as 10 pulses of GH secretion per day, each lasting approximately 90 minutes with a separation of about 2 hours with the highest secretory activity occurring within an hour after the onset of deep sleepizll-m’3l Due to this physiologic occurrence, many protocols utilizing GHRH and/or GHRP therapy call for a once-daily dose provided prior to bedtime. The release of GH subsequently stimulates the production of insulin-like growth factor- 1 (IGF-1), which in addition to mediating many of GH’s positive effects, happens to be a potent inhibitor in the negative feed-back loop of growth hormone releasing hormone (GHRH) and GH secretion. Therefore, because IGF-1 production is primarily regulated by GH, the consequence is a decrease in GH secretion via this negative feed-back loop (Figure 2). Perhaps for this reason, many clinicians find that treated patients will initially see IGF-1 levels surge, only to plateau or decrease with continued, uninterrupted use_ This will be discussed a bit later as well as potential modalities to prevent this phenomenon from occurring or at least limit the severity of inhibition. In addition to iGF-1, there are three hypothalamic factors regulating GH secretion: (i) Somatostatin, a non-competitive inhibitor of GH secretion; (ii) GHRH, the principal stimulator for GH production/release; and (m) Ghrelin, secreted by the stomach, an endogenous ligand to the GH secretagogue receptor.2”ml intertwined with one another and combined with other peripheral factors (e.g. exercise, sleep, food intake, stress, and body composition), all of these elements are involved in an intricate symphony regulating the physiologic patterns of pulsatile GH secretion.

Growth Hormone Benefits And The Associated Relative Risk

It is true that a number of clinical trials have reported that by providing GH to adults with GHD many of the features often associated with AGHD are significantly reversed or improved. Fat mass/volume is decreased, reductions in abdominal fat are obtained, and while there is little change in overall body weight, increases in lean body mass and skeletal muscle volume are observed signifying a shift away from fat to lean body mass. Additionally, there’s no denying the thousands of published papers indicating better exercise capacity and cardiovascular function, improved bone mineral density, and enhanced quality of life in adults with GHD treated with GH. In spite of these advantageous findings, there remains an equal number of potential risks that have been described associated with the use of GH. In experimental trials, =40% of users reported clinical edema, e-20% develop joint swelling and myalgia, and =-10% develop carpal tunnel syndrome? Additionally, many report hyperglycemia, hypertension, glucose intolerance and hyperinsulinemia. Interestingly, a number of these adverse events can be attributed to incorrect dosing in that they were much too high. In other words, they were the result of over-dosing and over-exposure to physiologic levels of GH. This is where the use of GHRH and other associated peptides have come to be advantageous as their mechanism of increasing GH preclude the potential for over- exposure or tachyphylaxis.

Ghrh: A Better Method Of Increasing Growth Hormone

Physiologic And Clinical Advantages Of Ghrh

Rather than introducing exogenous and supraphysiologic doses of GH directly to the liver, GH secretagogues like GHRH (i.e. Sermorelin and others), stimulate the normal and physiologic secretion of GH in an intact and responsive pituitary (Figure 3). This normal and physiologic secretion results in a normal, time- separated, pulsatile release of GH, rather than prolonged elevation of exogenous exposure; thereby, avoiding tachyphylaxis and preserving the capability for negative feed-back inhibition of GH by the rising levels of IGF-1.2-1 It is because of this normal, negative feed-back regulation that treatment with GHRH results in much less frequent and milder side effects as compared to those experienced strictly with GH use. The most frequent side effects associated with GHRH (e.g. Sermorelin) use in clinical trials were reported to be localized injection site reactions such as pain, swelling, or redness; occurring in approximately 16% of users. Other events such as headache, flushing, dysphagia, dizziness, hyperactivity, somnolence, and urticaria were reported in less than 1%.

Ghrp: Eliciting Enhanced Outcomes Through Drug-Drug Synergism

Growth Hormone Releasing Peptides

Concurrent administration of GHRH and GHRP has been well documented and established to provide synergistic release of GH from the pituitary. While there are a number of GHRPs that have been researched and/or studied, the two that have garnered much attention and clinical use are GHRP2 and GHRP6. Others that have been used are lpamorelin and Hexarelin, but are typically un-favored favored due to the former being a weaker GH promoter and the latter having a stronger, adverse effect on cortisol and prolactin. GHRP2/6 are both very potent at promoting GH release, yet have little to no effect on cortisol or prolactin. While several studies have concluded increases in GH secretion and IGF-1 are achievable with solitary use, concurrent use with GHRH is more than additive. This is, in part, due to the fact that GHRH is much less capable of increasing GH when physiologic levels of somatostatin are high and GHRP inhibits somatostatin. Recommended doses for GHRP 2 or 6 are typically around 15Omcg as there is a receptor saturation point and delivering more yields little benefit and may promote desensitization with chronic dosing.

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