Growth hormone (GH) replacement is at the top of the list of therapies for aging individuals wishing to preserve youthful vigor, physiology, and body composition.  For many years, injectable GH, produced by recombinant DNA technology, was the primary medical intervention used to replace age-related deficits of this essential hormone. But negative consequences associated with repeated use of the recombinant product resulted in the search for safer and effective alternatives. The good news is, research has identified an analog of a naturally produced neuropeptide that restores physiological GH production and secretion. Let’s examine the advantages and benefits of this remarkable peptide analog, known as sermorelin, in re-establishing youthful GH levels while at the same time promoting neuroendocrine health and function.

Importance of GH Replacement in Aging Humans

GH is a peptide hormone synthesized, stored, and secreted by the pituitary gland. It is a major regulator of body growth in youth, but plays crucial maintenance, regeneration and repair functions throughout life; it regulates carbohydrate and lipid metabolism, cardiovascular, immune, and brain function, bone density and skin integrity. As an anabolic hormone, GH influences the ratio of lean muscle mass to adipose tissue (body fat) mass. As with other hormones, due to the general age-related decline of neuroendocrine function, levels of GH fall with advancing years, leading to reduced lean muscle mass, increased body fat, thinning skin, decreased bone density, lowered immune and cardiovascular function, even brain aging.

(1-9) Studies show that intravenous GH administration results in increased lean muscle mass, skin thickness, and bone density; decreased body fat; enhanced immune and cardiovascular function; and improvements in learning and memory. (2,4) In 1990, a ground-breaking study reported that in men aged 61 to 81, six months of intravenous GH therapy reversed physiological changes incurred during 10 to 20 years of aging. (2) GH replacement therapy can literally subtract years from one’s apparent age and is among the most powerful anti-aging strategies available today ─ but at a cost: injections of recombinant human growth hormone (rhGH) are prohibitively expensive, not readily available, and not without side effects and negative consequences, as we’ll see below. Fortunately, a safe and effective alternative ─ sermorelin ─ has been clinically demonstrated to spur endogenous GH production and restore youthful levels of this critical hormone. But before we can truly understand the benefits and advantages of sermorelin, and its mechanism of action, we need to take a brief (but painless) tour of the GH axis of the neuroendocrine system.

GH Feedback Regulation and the Impact of Aging

As with other hormones, GH production and secretion is regulated by a complex feedback control mechanism. Two primary controllers are peptide hormones produced by the brain’s hypothalamus, growth hormone releasing hormone (GHRH) and somatostatin, which act in a dynamic equilibrium to regulate circulating GH levels: when the hypothalamus detects reduced blood levels of GH, it releases GHRH which stimulates specialized cells in the pituitary to synthesize and secrete GH. Once adequate circulating GH levels are reached, the hypothalamus turns off GHRH stimulation and releases inhibitory somatostatin to temporarily halt GH secretion in a process known as “negative feedback.” In addition to GHRH and somatostatin, the GH axis is also regulated by the interplay of other factors, such as the hormones ghrelin (a GH-stimulatory peptide secreted from the stomach) and IGF-1 (an insulin-like hormone produced by the liver in response to GH), as shown below:


Figure 1: GH Feedback Regulation (10)

All of these elements are integrated into a synchronized feedback loop consisting of alternating GH stimulation and inhibition which results in the sporadic or pulsatile secretion of GH. Pulses are released every three to four hours, with the largest secretions occurring at night. If we were to construct a plot of GH concentration versus time of day (in hours) from data on young and old individuals, we would see that the amplitude and frequency of GH pulses are highest during youth, but decline steadily with age, as shown below:


Figure 2: GH Pulse Amplitude and Frequency Decline with Age

Research indicates that a reduction in GHRH secretion from the hypothalamus is the principal cause of diminished GH production with age. (8,9,11)

Problems Associated with rhGH Injections

A significant problem associated with rhGH is that it is injected as a bolus, (i.e., a large dose) that rapidly achieves and sustains high or potentially supra-physiological concentrations in the bloodstream. The elevated circulating level of GH (or IGF-1, once it is processed by the liver) sends a huge inhibitory message to the hypothalamus that suppresses or over time shuts down the brain’s intricate control feedback mechanism that we have just examined. The pituitary, which was formerly stimulated to produce and secrete GH, now lies dormant due to suppression by the hypothalamus in response to elevated GH (or IGF-1) blood levels from the recombinant product. Prolonged suppression can lead to erosion of pituitary function altogether, a condition described as “disuse atrophy” (analogous to an unused muscle). So we can see that injectable rhGH is a double-edge sword: while it produces rejuvenating effects on some of the body’s tissues, it accelerates pituitary aging and furthers neuroendocrine decline! Another difficulty with rhGH injections is accurate dose determination. Since the negative feedback mechanism which normally regulates pulsatile GH release is circumvented, the possibility of overdose is significant. And tissue exposure to high levels of GH can lead to side effects. It’s clear that rhGH is not an ideal anti-aging therapy, especially when legal restrictions on its use and exorbitant cost are added in.

Sermorelin ─ a Physiologically Safe and Needle-Free Alternative to rhGH

Sermorelin targets the root cause of age-related GH decline: reduced GHRH stimulation by the hypothalamus. Sermorelin is an analog of GHRH that mimics its effects.  The dominant form of GHRH consists of 44 amino acids; sermorelin is a synthetic peptide consisting of the first 29 of the GHRH amino acid chain. It has been shown to possess the full biological activity of GHRH and specifically stimulate growth hormone secretion from the anterior pituitary (12) ─ therein lies the major advantage of sermorelin over injections. In contrast to “disuse atrophy” of the pituitary and the accelerated neuroendocrine decline resulting from bolus injections of the recombinant product, sermorelin promotes physiological GH release: it stimulates the pituitary to produce endogenous GH and preserves the brain’s negative feedback mechanism, involving somatostatin and other hormones. This ensures that GH is released in a pulsatile fashion in the appropriate physiological range, without the possibility of overdose, and with negligible, if any, side effects.

Another advantage of sermorelin over rhGH injections is dosage form and ease of use. Although injection was the original means of sermorelin administration and the form used in the clinical studies, a bioavailable sublingual formulation has been developed. Since sermorelin is a relatively small 29-amino acid peptide, it can enter the bloodstream directly when placed in contact with the mucous membranes under the tongue. GH, on the other hand, is a large 191-amino acid peptide that must be injected to enter the bloodstream intact.

Clinical Studies on Sermorelin

Some early studies found that sermorelin is effective in treating children with GH deficiency and it has had some use as an alternative to GH injections in youngsters with slowed growth or short stature. (12,13) But further studies indicate that aging adults experience the most dramatic effects from the GHRH-analog, as we’ll see below.

In a placebo-controlled trial, researchers at the University of California evaluated the effects of sermorelin on the GH axis and immune system in nine men (mean age 67) and ten women (mean age 65) who received injections for 16 weeks. Sermorelin administration resulted in a significant increase in both GH secretion and immune system activation by four weeks in both men and women, with no adverse effects. (5) (Note that aging is associated with the decline of activity of both the immune system and the GH axis, and that sermorelin had rejuvenating effects on both). Another study at the NIH National Institute on Aging investigated whether treatment with sermorelin could restore GH secretion in older men to youthful levels. Researchers compared GH secretion in nine unmedicated young men (mean age 26) to ten older men (mean age 68) who had received low (0.5 mg) and high (1 mg) dose injections twice daily for 14 days. At baseline, as expected, GH release was lower in the older men; but after high dose treatment, the youthful pattern of pulsatile GH secretion was restored, with no significant differences between age groups in mean 24 hour GH level, or peak area or amplitude of pulsatile secretions. The researchers concluded that short-term administration of sermorelin to healthy older men reverses age-related decreases in GH and may improve body composition with prolonged treatment. (6) These results were corroborated in another experiment at Johns Hopkins in which eleven healthy men aged 64 to 76 received nightly 2-mg injections of sermorelin for six weeks. As in the previous experiment, sermorelin treatment increased mean GH release and peak area and amplitude of individual pulsatile secretions. Researchers also noted improvements in some measures of muscle strength and endurance, with no significant adverse effects. (7)

Research clearly demonstrates that sermorelin is a superior and physiologically safe approach to GH restoration, and that results can be obtained relatively quickly, within a few weeks time (or less) as indicated by the studies above. And in addition to improvements in body composition and enhanced immune function, it follows that sermorelin, by stimulating endogenous GH production and release, positively impacts skin health, brain function, and sleep quality; reduces the risk of certain diseases; and improves overall quality of life, not to mention its role in preserving pituitary function. What’s more, sermorelin is commercially available in a sublingual liquid formulation (no needles necessary) at a fraction of the cost of injections of the recombinant product. One dropper (approximately one ml) placed under the tongue is all that is required for administration. Sermorelin is undoubtedly the method of choice for aging individuals wishing to restore youthful GH production and secretion while promoting neuroendocrine health and function.


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