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Is sermorelin the ‘new’ GH?

November 29th, 2016

Is sermorelin the ‘new’ GH?


Sermorelin is being heralded as the breakthrough for the delivery of growth hormone (GH). GH itself is a hormone that has been recognised for a long time as having significant effects as an anti-aging tool, ever since Dr. Daniel Rudman’s experiments in the 1980’s. Those clinical trials suggested that over some months injectable GH could reverse biological age in the 60-80 year old group by as much as 20-years; factors that were measured included fat to muscle ratios, skin thickness and elasticity, hair growth and density, hand grip strength, plus there were positive reports of improved libido, energy and well being levels.

But GH has always had to be used by injection to be efficacious and has required some careful blood monitoring to ensure overdosing does not take place. Furthermore, numerous governments have now placed restrictions on injectable GH and its classification as an anabolic steroid has reduced its availability.

So what about sermorelin? In this interview, a world class anti-aging physician and one of the key researchers of sermorelin- Dr. Richard Walker discusses it in detail with IAS’s Phil Micans.

Phil: Dr. Walker, thank you very much for taking time today out of your busy schedule to discuss with me the role of sermorelin and GH in aging. I wonder if I may ask you, just to begin with, could you please inform our readers of your background?

Dr. Walker: Hi Phil.  I’m glad to be here to discuss the use of sermorelin as a neuroendocrine intervention in aging.  It’s been the subject of my research for many years.  Regarding my background, I first focused my studies on pharmacy for which I received a BS degree from Rutgers University.  Subsequently, I realized that my greatest interests were in the study of physiology and biochemistry, so as to better understand the normal human condition across the life span.  Accordingly, I received an MS in Biochemistry from New Mexico State University and a PhD in comparative physiology from Rutgers University.  Immediately after receiving my terminal degree I accepted the position of Assistant Professor of Biology at Clemson University and became tenured faculty at that institution after a few years.  However, I realized that I was still lacking specialty training to complete my education.  To fill this void I accepted an internship in neuroanatomy at Emory University College of Medicine, and then postdoctoral fellowships in neuroendocrinology and neuropharmacology at Duke University College of Medicine (Center for the Study of Aging and Human Development) and the University of California, Berkeley, respectively.  Thereafter, I again received faculty tenure, this time at the University of Kentucky College of Medicine (Department of Anatomy and Molecular Biology/Sanders-Brown Research Center on Aging).  Based upon my background and research at the UK, I was recruited to serve as Director of Reproductive Toxicology at SmithKline Beecham Pharmaceutical Corp and also as Research Professor in the Department of Pharmacology at the Medical College of Pennsylvania.  Thereafter, I moved my research program to the University of South Florida (USF), where I also served as Director of Compliance and Director of USF CARES (Clinical Alliance for Research, Education and Service).  Over the course of my academic career I’ve been fortunate to have been the recipient of many federal (NSF, NIH, DOD), state and local research grants which have allowed me to publish extensively in my specialty field of interest; that of understanding the cause of senescence and treating functional deficits associated with organismal aging.  Since retiring from academia, I serve as Editor-in-Chief of the peer-reviewed, MedLine referenced journal, Clinical Interventions in Aging, a source of evidence based information for practitioners of age-management medicine published by Dove Medical Press (Auckland and London). In addition I head a consulting firm for physicians and health care practitioners of age-management medicine called Paradox Regulatory and Scientific Services, Inc. I hope that this overview hasn’t been too wordy and boring for your audience.

Phil: Surely not! Indeed it’s very impressive and I am aware that your name has appeared on the majority of published papers related to the role and effects of sermorelin. So I suppose the next obvious question would be to ask you, can you please tell us what sermorelin is?

Dr. Walker: Sermorelin is the bioactive analog of growth hormone releasing hormone or GHRH.  GHRH is a neuropeptide that is released from specific axon terminals of tuberoinfundibular neurons into the portal capillary system that brings blood to the pituitary gland.  As the name implies, the neuropeptide, GHRH, is produced in neurons, specifically those located in the basolateral region of the hypothalamic arcuate nucleus. When GHRH arrives in the pituitary gland via the portal capillary system, it binds to specific receptors on somatotrophs, the cells that produce and secrete human growth hormone (hGH). Upon binding it causes somatotroph DNA to transcribe message (make messenger RNA; mRNA) and also to translate that message into protein (hGH). The final hGH product is stored in the pituitary until being released by more GHRH stimulatory signals.  As we age, production of GHRH declines while influence of its inhibitory neurohormone, somatostatin increases. These changes underlie the progressive loss of growth hormone production and secretion in the pituitary that contribute to loss of muscle, increase in fat mass, disruption of glucose homeostasis and other such maladaptive alterations associated with aging. As a functional analog of GHRH, sermorelin has the same activity as the naturally occurring molecule despite the fact it has different structure. Thus, sermorelin is used clinically to shift the imbalance between GHRH and somatostatin in favor of the stimulatory neurohormone thereby opposing age-related, hGH insufficiency.

Phil: So can we say that sermorelin is a bioidentical molecule?

Dr. Walker:  No. Bioidentical hormones are those having the exact structure and function as hormones that are naturally produced by the body. These are generally end-products of neuroendocrine pathways such as estrogen, progesterone, testosterone, hGH and others that directly produce effects on the body but are grandually lost during aging. They are prescribed by anti-aging physicians to replace the hormone deficits and imbalances so as to simulate a more youthful endocrine phenotype. In contrast, sermorelin is not an end hormone that acts directly on the body as are the others, although it does have some direct effects on the brain. Its major action are those of a secretagogue capable of stimulating hGH production/secretion and thereby to initiate events higher up in the neuroendocrine cascade, i.e., within the pituitary gland itself. It simulates the effects of GHRH, because it an analog of the naturally occurring neurohormone. However, it does not have the same structure as GHRH. The natural neurohormone consists of 44 amino acids (there are other forms, but the dominant contains 44 amino acids) while sermorelin is smaller. The structure of GHRH was first discovered in the 1970’s by the Nobel Laureates, R. Guilleman and A. Shalley. Thereafter, one of their students, William Wehrenberg sought to determine which part of the GHRH molecule was needed for its pituitary stimulating response. By eliminating individual amino acids and then examining the remaining peptide, he found that only the first 29 amino acids were required to stimulate pituitary production and secretion of hGH. Thus, sermorelin was discovered, synthesized and identified as the acetate salt of an amidated 29- amino acid peptide (GRF 1-29 NH 2 ) that corresponds to the amino-terminal segment of the naturally occurring GHRH.  So, since sermorelin and GHRH do not have the same structure, sermorelin is not a bioidentical hormone. However, it functions the same as GHRH, from binding the same somatotroph receptor, to activating the second messenger cyclic AMP and stimulating production and secretion of hGH from the pituitary. Also, because sermorelin is a smaller molecule than GHRH, it is more bioavailable even to the extent that it can be effectively administered as a sublingual formulation.

Phil: That’s interesting, so sermorelin helps to induce the release GH, but why would we want to use sermorelin in place of GH anyhow?

Dr. Walker: There are several reasons to use sermorelin in place of hGH including legal restrictions and medical/scientific logic. Regarding the law, recombinant hGH (rhGH) has rather specific limits on its use, especially in the USA, where the Code of Federal Regulations restricts doctors from prescribing it except for treatment of short stature, AIDS wasting and pathologic, adult-onset growth hormone deficiency (AGHD). Although some doctors have taken the position that hGH insufficiency associated with aging is a form of AGHD, legal challenges have often made that opinion indefensible.  Thus, routine use of rhGH in age-management medicine increases practitioner liability for potentially severe penalties.

In addition to the potential for legal problems associated with routine use of rhGH, the molecule also has the potential to paradoxically accelerate age-related changes in pituitary function. Recall that aging is associated with decline in somatotroph function due to loss of GHRH stimulation and gain in somtatostatin inhibition. This results in deactivation of pituitary somatotrophs, which produce and secrete endogenous hGH. As you know, endocrine system secretory activity is regulated by feedback. Although positive feedback occurs, the dominant form is negative feedback. This means that as concentrations of a given hormone increase in the circulation, they ‘feedback’ upon sites in the pathway(s) that stimulate their production and secretion to dampen or reduce their influence.  This negative feedback lowers circulating hormone concentrations and inhibits cellular activity within sites that increase it. If such inhibition persists for exceptionally long periods of time, ‘disuse atrophy’ of the stimulating site occurs such that they eventually become dysfunctional. While rhGH is known to oppose many of the degenerative effects of aging upon the body especially those causing loss of muscle and increase in fat, little attention has been paid to the fact that the hormone also accelerates the effects of aging upon the pituitary gland itself. It causes this maladaptive effect as the results of exaggerated negative feedback inhibition of somatotroph function. Normally, hGH is released from the somatotroph in bursts or episodes associated with the alternative influences of GHRH and somatostatin arriving in the pituitary gland. Similarly, hGH from the somatotroph feeds back upon the brain to appropriately adjust the release of GHRH and somatostatin. This neuroendocrine regulatory network supports form and function in all elements of the neuroendocrine axis. However, when rhGH is injected, it causes sustained and hyper-elevated concentrations of the hormone throughout the day, especially when injected as a subcutaneous bolus. The persistent presence of high concentrations of hGH in effect shuts down the cellular machinery within the cells producing GHRH and also that within the somatotroph that produces endogenous hGH. Alternatively, the high concentrations of circulating rhGH stimulate cells producing somatostatin to increase their output since the body senses what seems to be excessive somatotroph activity. Thus, the somatotroph stimulatory centers in the brain as well as the pituitary cells themselves receive both negative and direct inhibition by rhGH and excessive somatostatin, respectively. These effects exacerbate the maladaptive changes in the same sites that normally occur during aging. Thus, and paradoxically, while rhGH may oppose some of the undesirable anatomical changes of aging, it also accelerates neuroendocrine decay and erosion of hormonal homeostasis responsible for somatic senescence in the first place. In contrast, sermorelin simulates the stimulatory effect of GHRH upon the somatotroph and sustains normal feedback relationships because it causes natural, episodic release of pituitary hGH. This effect results from the subtle effect of sermorelin to stimulate hGH release while under a more balanced influence of somatostatin.  Because sermorelin does not directly add hGH to the circulation as occurs when the rhGH is injected, circulating amounts can be better titrated by opposing release of somatostain upon the somatotroph. In summary then, sermorelin is better for use in age management medicine because of at least three important advantages over rhGH. These include the facts that:

  1. There is no legal restriction against the use of sermorelin to sustain youthful form and function during aging.
  2. Sermorelin does not cause circulating hGH to rise excessively and thereby to profoundly suppress somatotroph function through disuse atrophy, i.e., it does not simulate and/or accelerate the effects of aging, and
  3. More normal feedback relationships are maintained within the hGH neuroendocrine axis allowing for more physiological profiles of hormone production and secretion to be sustained.

 Phil: Gosh there’s quite a lot there to take it. So you’re saying that sermorelin is a safer drug to use than GH because it is ‘regulated’ inside the body- which GH itself is not- plus having read some of your studies I know that sermorelin can even be administered via non-injectable routes- which is not possible with GH. I’m sure a lot of people would prefer to take a drug by mouth rather than having to inject it each day.

Dr. Walker:  Yes, rhGH is too large a molecule to be taken orally, buccally or sublingually. Regarding the latter two routes, because rhGH is hydrophyllic unlike lipophyllic hormones such as testosterone, it is blocked from passing directly through the skin or in this case, membranes of the mouth. It is also vulnerable to attack by enzymes that destroy its folded or quarternary structure which is necessary for stereospecific receptor binding and thus, its activity in vivo. In contrast to the 191 amino acid content of rhGH, sermorelin contains only 29 amino acids and its receptor affinity is not dependent upon folding of the molecule. However, despite its smaller size, it is still vulnerable to endopeptidase attack within the gastrointestinal tract. Such attack cleaves the molecule leaving fragments that are not effective in stimulating somatotroph GHRH receptors. On the other hand, if it were possible for sermorelin to pass directly from the oral mucosa into the bloodstream bypassing the GI tract, then it could retain its essential structure and be an effective GH secretagogue. The only problem with this approach is that because sermorelin is a peptide, it is polar and thus hydrophyllic. As I said previously, lipophyllic not hydrophyllic molecules are membrane permeable. Thus, in the past sermorelin has been administered by subcutaneous injection. Nonetheless, recent study of pharmaceutical agents that facilitate transport of small peptides has shown that certain combinations of alcohols, oils, and certain acids are effective in making sermorelin bioavailable by the sublingual route. Based upon this information, sublingual formulations are now available to provide ‘needle-shy’ patients the more desirable option of enjoying the benefits of sermorelin without having to inject it.

Phil: Can I ask therefore, what kind of positive effects have been seen in patients using sermorelin?

Dr. Walker: The clinical benefits of sermorelin are not unlike those of rhGH, and include improvements in body composition (increased muscle, decreased fat), better skin tone, improved cognition, increased hair and nail growth, better quality sleep, reduced risk for intrinsic diseases e.g., heart disease, stroke, diabetes, etc., and generally good quality of life. The only significant activity difference between the two molecules is that the onset and progression of sermorelin-induced benefits is slower than that for rhGH. This difference derives from two facts including that sermorelin must first activate the somatotroph to produce, store and release hGH and that once available for use, the endogenus hGH is released episodically from the pituitary. This delay in synthesis and subsequent intermittent release results in lower mean levels of circulating hGH than result from injection of rhGH. However, the effects of sermorelin simulate the normal physiology of production/secretion while as previously mentioned, the high, pharmacological levels of rhGH resulting from sc administration of the recombinant protein are not necessarily safe nor do they achieve the total anti-aging effects of therapy that are sought.

Phil: When should people take sermorelin and what kinds of doses are normal?

Dr. Walker: It has been suggested that sermorelin be taken at bedtime based upon the fact that GHRH (as well as sermorelin) is known to increase slow wave, restful deep sleep in some people.  Such sleep is associated with the large nocturnal bursts of hGH from the pituitary gland. However, in others, sermorelin induced GH release before sleep results in increased mental activity and may actually delay sleep onset. Thus, depending upon specific patient results, those who benefit with improved sleep quality from sermorelin should take it at bedtime. Otherwise, morning or daytime administration is appropriate. No specific time is better than another unless sleep architecture is improved. Regarding dosage, patient specificity again is the most important consideration. Efficacy has been reported with subcutaneous doses as low as 0.2 mg daily; whereas some patients need as much as 1 or 2 mg daily to gain desirable results. Because sublingual bioavailability is less than that achieved by subcutaneous administration, the higher dose range of 1 – 2 mg of sermorelin daily is recommended.

Phil: And of course I must also ask, what can of side effects or contraindications have been noted with sermorelin?

Dr. Walker: Remarkably, little or no side effects of sermorelin have been reported over the course of decades that it has been used. Since it was invented, sermorelin is known to produce antibodies in about twenty percent of users. This is probably because the molecule is sufficiently different from GHRH to be recognized by the body as being ‘foreign.’ However, the sermorelin antibodies have no adverse effects on the body, are transient, disappearing after repeated use of the product, and they are not deactivating, i.e., efficacy of sermorelin is not destroyed by the antibodies. The only other undesirable issue is irritation or redness at the injection site for some individuals. This effect is of course, irrelevant to those using the sublingual formulation. All in all, sermorelin is an extremely safe product that has never been associated with severe adverse events.

Phil: Are there any other supplements or lifestyle changes that people can incorporate with their sermorelin to make it even more effective?

Dr. Walker:  As with rhGH, the most effective lifestyle change to enhance the efficacy of sermorelin is regular exercise. Dynamic cardiovascular as well as resistance exercises provide the hGH resulting from sermorelin administration to realize its anabolic and other beneficial effects to the maximum due to the somatic remodeling that is induced by work-out. In addition to physical exercise, nutritional supplements including  glutamine, alanine, ornithine, ornithine alpha-ketoglutarate (OKG),  arginine pyroglutamate combined with L-lysine hydrochloride, glycine, and gamma-amino butryric acid (GABA) have been reported to improve the effects of hGH on the body. Many of these actually enhance neural signaling to improve hGH release from the pituitary, and some such as glutamine which has been reported to be reduced by rhGH administration, should be supplemented to ensure a good source of nitrogen for muscle repair and synthesis associated with sermorelin administration.

Phil: Of course the internet is awash with GH agonists, many of which are poorly studied or perhaps poorly bioavailable/ active. Where do you see sermorelin on this list of available supplements, at least from the perspective of its effectiveness to significantly raise GH levels in humans?

Dr. Walker: I agree that there are numerous ‘secretagogues’ that are marketed as being effective hGH releasers. They generally are combinations of amino acids. In fact, most of them will release some hGH from the pituitary. However, their effects are not reliable and for the most part, not consistently reproducible. The reason for this fact is that all secretagogues except for sermorelin and the ghrelin analogs (GHRPs) are non-specific in their actions. By being non-specific I mean that the other secretagogues are intermittently effective by sometimes causing changes in CNS activity that favor release of GHRH from the hypothalamus. However, these effects are not quantitative nor do the non-specific secretagogues bind and stimulate the somatotroph directly. On the other hand, sermorelin and the GHRP’s have specific, saturable receptors and second messenger systems in the somatotrophs that make their effects quantifiable and reproducible. Thus, sermorelin, which binds the GHRH receptor, mimics the natural and primary stimulus for hGH production and secretion by the pituitary gland. The GHRPs mimic the effects of ghrelin which is an amplifier of the primary stimulus.  As a result of this fact,  sermorelin represents the best and only true hGH secretagogue currently available on the market.

Phil: I wanted to ask something that’s been on my mind- it’s quite well known that GH levels rapidly fall in blood tests past the age of 35. Of course the labs look for IGF-1 levels because of the difficulty to examine GH levels themselves. However, there have been some studies to suggest that GH production actually continues to be effective, even well into our seventh decade of life, but that the pituitary gland appears to fail to release GH into the bloodstream, hence because it never gets delivered it never gets its jobs done. Do you feel that sermorelin may be a missing link in this regard? By which I mean, is sermorelin not actually stimulating the production of GH, but rather helping to release into the blood what’s already available?

Dr. Walker: To the contrary. With advancing age, stimulation of the pituitary by GHRH declines.  As a result, pituitary hGH reserve falls, reducing the amount of hormone available for release into the circulation. As I previously mentioned, GHRH is responsible for transcription as well as translation of the hGH gene residing within somatotroph DNA. Because of this fact, as GHRH stimulation declines during aging, less hGH is produced and consequently less secreted because pituitary reserve declines. However, unless somatotrophs become so atrophic that they die and are lost from the population of pituitary endocrine cells, they are capable of recrudescence by stimulation of the GHRH receptor with sermorelin.  Under these conditions, initial hGH secretory responses to sermorelin may be modest because pituitary reserve is low. On the other hand, with continued stimulation with sermorelin causing increased production of endogenous hGH, pituitary reserve rises and the amount of hormone released into the circulation goes up. So in conclusion, sermorelin is not only a releaser of hGH that is present within the pituitary, it also increases its content and thereby is perhaps one of the most effective and restorative ‘antiaging’ hormones for the neuroendocrine system that is currently available.

Phil: Fascinating! Would you care to add anything more to this exciting debate about the role and performance of sermorelin to improve our age related GH levels? And perhaps I should ask you, how do you personally rate the role of GH in the battle against aging?

Dr. Walker: Really nothing more to add other than to underscore the importance of reminding the patient that every individual responds differently to sermorelin. Some people are more sensitive than others because somatotroph responsiveness varies as a function of stimulation history, e.g., age and physiological state. Thus, a bit of dose experimentation is required to achieve patient specificity that subserves maximum efficacy. Regarding your question about the role of hGH in the ‘battle against aging’ I must stress that the hormone is effective in opposing many of the consequences of aging, but has absolutely no effect on the underlying mechanism of senescence. So while hGH restores more youthful body composition and protects against early onset of intrinsic diseases, the erosive influence of aging on physiological homeostasis proceeds unabated. In a way, you can say the hGH has greater cosmetic value than therapeutic in the battle against aging.  However, feeling good, being healthy and retaining physical and mental vitality throughout life cannot be demeaned since these factors all translate into good quality of life. And so, until we can attack the cause of aging, which I have identified as developmental inertia in a recent paper; Developmental Theory of Aging Revisited, Rejuvenation Research, 14 (4): 429-436, 2011, treating its consequences with sermorelin and other restorative agents to sustain the most youthful life style possible is certainly an attractive alternative.

Phil: Dr. Walker I congratulate you on your research into this fascinating molecule. You have accomplished much over many years and I am pleased that at last the word about sermorelin is coming to the fore. Thank you very much all your time with us today.

Dr. Walker: My pleasure Phil.


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