Form of Growth Hormone

HGH
By David Leonardi, M. D.


INTRODUCTION


Growth Hormone is a polypeptide hormone. This means it is composed of a long chain of amino acids, 191 to be exact. Under normal physiologic conditions, growth hormone is secreted by the anterior pituitary gland. This is a gland that lies at the base of the brain in a bony cavity called the Sella Turcica. In addition to growth hormone, the anterior pituitary also secretes prolactin, thyroid stimulating hormone, luteinizing hormone, follicle stimulating hormone, and adrenal corticotropic hormone. The secretion of growth hormone by the pituitary gland is initiated by the hypothalamus, another gland in the brain that lies right next to the pituitary. The hypothalamus initiates growth hormone secretion by secreting growth hormone releasing hormone (GHRH); at the same time it stops secreting a growth hormone inhibitory hormone called somatostatin. When somatostatin is turned off and GHRH is turned on, the pituitary will release growth hormone in bursts of activity. These bursts of growth hormone release occur primarily during deep stages of sleep, such as stage 3 and stage 4. Once released in the blood, growth hormone is very short lived. It is generally completely metabolized and gone within a half-hour. During that time, however, it manages to reach the liver and many other cells in the body, and induce them to make another polypeptide hormone called Insulin-like Growth Factor One (IGF-1). It is really IGF-1 that travels around to the various tissues of the body to effect most of the benefits that we attribute to growth hormone. The secretion of growth hormone itself is regulated by a classic biofeedback loop. This means when levels of growth hormone in the blood reach a certain threshold, growth hormone stimulates receptors in the pituitary to stop further growth hormone secretion. It also stimulates receptors in the hypothalamus to stop GHRH and turn on somatostatin. IGF-1, which goes up in response to growth hormone, also feeds back on the pituitary and hypothalamus to help control growth hormone secretion. This is nature's system of checks and balances to assure we don't have too much of any one hormone.


NOMENCLATURE


The nomenclature for growth hormone is a bit complicated, but understanding it from the beginning can save much confusion in the future. Somatropin refers to growth hormone of the same amino acid sequence as the naturally occurring growth hormone. Somatropin extracted from the human pituitary gland was originally designated (hGH, or pit-hGH). Manufactured growth hormone is made by recombinant DNA technology. This is a system of genetically modifying either bacteria cells or mammalian cells in tissue culture so that they include in their genome, the gene that directs the cell to make human growth hormone. As the cells in the tissue culture grow and function, they will synthesize human growth hormone by the exact same process in the human pituitary. Since this is a natural process, human growth hormone is not considered a synthetic. The proper abbreviation for manufactured (recombinant) human growth hormone is rGH. Unfortunately, the abbreviations have been misused even in the medical community, and recombinant human growth hormone is commonly represented by the abbreviation hGH. The designation is no longer critical since human growth hormone of pituitary origin is no longer used in the United States, or anywhere in the world that I'm aware of. The term hGH or GH therefore, refers to human growth hormone from recombinant DNA technology. It is pure and 100% free of any contaminants or micro-organisms.


HISTORY




Prior to the advent of recombinant DNA technology, the only source of growth hormone was from human cadavers. More than 27,000 children worldwide were treated with growth hormone of this source (pit-hGH). Due to short supply, children were treated with low doses and interrupted regimens. As a result, their response and ultimate height was mitigated. Distribution of pit-hGH was stopped in the United States and most of Europe in 1985, with the emergence of Creutzfeldt-Jakob Disease. This is a rare and fatal spongiform encephalopathy, caused by a small pathogen called a prion. This is the same pathogen that causes "Mad Cow Disease" recently seen in Europe from infected cattle. It is impossible to catch Creutzfeldt-Jakob Disease or any other infection from recombinant human growth hormone because it is not derived from a human or animal source, but from a purified tissue culture. For purposes of this discussion, the term growth hormone, GH or hGH will mean growth hormone made by recombinant DNA technology.


The bio-potency of commercially available growth hormone is typically represented by either milligrams or units. To put it simply, 1 milligram of growth hormone is equivalent to 3 units. The international units were developed by the World Health Organization in order to standardize growth hormone preparations because of the various production techniques used early on in the manufacturing process. By now, the manufacturing process has been streamlined and largely perfected so the bio-equivalency of the various brands of growth hormone (at least those manufactured and approved by the FDA for sale in the United States) are identical. Therefore, a typical 15-unit vial of growth hormone contains 5 mg, and a 4-unit vial contains 1.33 mg.

USES OF GROWTH HORMONE
Growth hormone was initially used for children of short stature who are growth hormone deficient, either because of an inactive pituitary, a tumor of the pituitary, or destruction of the pituitary by surgery or by radiation to remove a tumor. The other pituitary hormones were replaced along with GH. Growth hormone was used only until the children reached an acceptable adult height and then it was stopped because it was thought to be useful only for growth. The other pituitary hormones, however, which were thought to be more critical, were continued throughout adulthood. It wasn't until much later that adult growth hormone deficiency was recognized to be a problem. It was discovered that adults who were deficient in growth hormone suffered from premature cardiovascular disease, reduced bone density, central obesity, decreased muscle mass, depressed mood, elevated levels of LDL (bad) cholesterol, slower wound healing, fatigue, poor exercise tolerance and poor immune function. At that point the use of growth hormone began in this unfortunate population, resulting in improvement of all of the above. It wasn't until 1990, however, that the benefits of growth hormone and the treatment of normal aging were recognized. The most recent new use of growth hormone is for the treatment of AIDS Wasting Syndrome. This is the condition of weakness, fatigue, and loss of muscle mass in AIDS patients. Since we at Cenegenics® specialize in metabolic and hormonal control of aging, we will limit this discussion to the use of growth hormone in the treatment of normal aging.


SOMATOPAUSE




Somatopause is an extrapolation of the term "menopause." Menopause is the condition in women whereby the ovaries atrophy and cease to produce the sex hormones Estrogen, Progesterone and Testosterone. Somatopause signifies the gradual decline in growth hormone production by the adult pituitary gland in both men and women that begins at approximately age 30 and continues at a steady rate throughout life. The decline in growth hormone level that occurs with Somatopause is accompanied by deterioration in the structure and functional capacity of our body, which is ultimately devastating to the human condition. In fact, there is absolutely no difference between the clinical signs and symptoms of aging and those of adult growth hormone deficiency described above. The late Dr. Daniel Rudman first described the benefits of growth hormone therapy in normal aging adults. Dr. Rudman published a landmark article in the New England Journal of Medicine on July 7th, 1990. In his article, Dr. Rudman showed that by putting healthy aging men on growth hormone for six months, he was able to decrease their body fat by 14.4%, increase muscle mass by 8.8%, increase skin thickness by 7.1%, and increase lumbar bone density by 1.6%. These exciting findings clearly inaugurated the movement to supplement growth hormone in healthy aging adults, which today is becoming commonplace.


TREATMENT REGIMENS


Growth hormone can be given either subcutaneously or by intra-muscular injection with equal therapeutic activity. Subcutaneous administration is now used almost exclusively because intra-muscular administration is fraught with an increase in side effects without any additional therapeutic benefit. Back in Dr. Rudman's time, growth hormone was typically dosed three times a week in what we now consider a high dose regimen. People would typically receive 12-18 units per week given in injections of 4-6 units, three times a week. Although great benefits were seen, side effects were very common, and much more bothersome than those we see today. Currently we use only about half the weekly dose used in Dr. Rudman's study, by smaller and more frequent injections, which provide both a better clinical response and far fewer side-effects. In one study on growth hormone deficient children, those that received daily injections increased their height during the study period by 9.7 centimeters more than those who received thrice-weekly injections. Besides the low dose-high frequency technique, the physicians at Cenegenics® also employ morning injections as opposed to evening. The reason for this has to do with the biofeedback mechanism for growth hormone. Most of our natural pituitary growth hormone secretion occurs at night during deep stages of sleep. Injecting growth hormone at night raises the serum level of growth hormone precisely during the time the pituitary is scheduled to become active. This high serum level of growth hormone from the injection can suppress our natural pituitary function by negative feedback. We then not only lose the benefit of our own endogenous growth hormone, but also run the risk of surpressing the pituitary, thus making it "lazy". For the most part, the pituitary has completed its function and is at rest by 5 a.m. Therefore injecting after awakening in the morning results in injecting "on top of the peak" of endogenous (our own) growth hormone, so as not to suppress the pituitary. By the time the pituitary is ready again for its nighttime activity, the growth hormone given in the morning injection has been completely metabolized. This eliminates the risk of pituitary suppression.


BENEFITS




The benefits of growth hormone use in somatopause which have been clearly documented in the medical literature include the following: a decrease in body fat, an increase in muscle mass, thickening of the skin with decreased wrinkling, improvement in the cholesterol profile, an increase in bone density, enhanced feeling of well being, a decrease in the waist to hip ratio (meaning fat is removed primarily from around the waist where it is associated with a high risk of coronary disease), improvement in aerobic capacity, enhanced immune function and a decrease in the frequency of illness. The changes that our patients at Cenegenics® seem to be most pleased with are the elevation in mood, increase in energy level, improved sleep, decrease in body fat, increase in muscle mass and enhanced ability to handle adversity with confidence and optimism.


SIDE-EFFECTS




Side effects of growth hormone are generally mild and are largely associated with salt and water retention. The minority of patients that experience this typically complain of mild weight gain from water retention associated with a vague feeling of puffiness. This is sometimes accompanied by joint discomfort, particularly in the fingers, with a feeling of tightness when making a fist. Other joints may also become uncomfortable. Carpal Tunnel Syndrome is a well-known side effect of growth hormone that was more common in the early days when growth hormone was given in higher dose with lower frequency. Carpal Tunnel Syndrome is also a function of fluid retention, which causes water to accumulate in the closed carpal tunnel compartment of the wrist, compressing the median nerve. This results in numbness and tingling in the palm and fingers. These side effects are easily remedied by abstaining from growth hormone for about a week, and then resuming the treatment with a 20% dose reduction. Older patients are more subject to side effects and are generally started at a low dose of growth hormone than younger adults. Another potential side-effect of growth hormone is the elevation of blood sugar. Growth hormone mobilizes body fat, causing our fat cells to break themselves down and release free fatty acids into the blood stream. These free fatty acids are energy molecules which can be taken up by organs and many of our organs to be used for energy. When our muscles are consuming free fatty acids as a fuel, they are far less interested in sugar, therefore they tend to resist the effects of insulin, and extract less sugar from the blood. At the same time, growth hormone can increase glucose output from the liver to the blood. This combination of effects can raise blood sugar and raise insulin levels, neither of which is good. Fortunately, this is only a problem in people who eat a diet high in sugar and starch, and do little exercise. At Cenegenics® we teach our patients to eat a low glycemic diet (low in sugar and starch) and exercise regularly. The effect of our nutrition and exercise program in lowering blood glucose and insulin levels far outweighs the effect of growth hormone in raising glucose and insulin levels. The net effect in our patients, therefore, is the lowering of glucose and insulin levels. This is a very health-promoting benefit that prevents disease and extends life span.


ACROMEGALY




Acromegaly and giantism are diseases of growth hormone excess. These are typically seen by persons who have growth hormone secreting tumors. Giantism refers to the condition of growth hormone excess in children, where their ultimate height is far above normal because the growth hormone excess occurs when the epiphyseal plates of the bones are still open and the bones are growing. Acromegaly refers to growth hormone excess in adulthood after the epiphyses are closed and the bones are no longer growing. In these people the cartilage continues to grow, and the disease is characterized by enlargement of the nose, chin, ears, supra-orbital ridge (eyebrow area), hands and feet. Patients occasionally ask if acromegaly can result from growth hormone supplementation in adulthood. The answer is absolutely not. Acromegaly results in growth hormone levels that are two to ten times that of a normal adult. Keep in mind that when we supplement growth hormone in a controlled and monitored medical program, we bring the level only up to the mid-normal range of an adult. In fact, one would have to use ridiculously high doses by today's standards to achieve the growth hormone levels seen in acromegaly.


MONITORING




Since growth hormone is metabolized so quickly, it is not easily measured in a blood test. The levels fluctuate widely, and measuring growth hormone is notoriously inaccurate. The best laboratory marker we have for growth hormone is the measurement of Insulin-like Growth Factor One (IGF-1). IGF-1 levels are much more stable in the blood and not only reflect the average daily growth hormone level, but directly reflect growth hormone activity; because IGF-1 is the hormone that carries out most of the benefits of growth hormone. So, despite claims about its shortcomings, it remains an excellent marker of growth hormone effect, and certainly the best one available in the laboratory. There is one better marker of the benefit of growth hormone, however. It's what we call the "clinical benefit". This is the feedback we get from patients who are taking growth hormone. How they are feeling in terms of energy, well being, body composition, frequency of illness, their own physical appearance, etc. is far more valuable a marker than any blood test can be. What we really use the IGF-1 level for is to be certain beyond a doubt that we're not giving too much growth hormone. We titrate the dose of growth hormone to get an optimal clinical response (a happy patient) even if the IGF-1 hasn't reached a particular goal range. This often allows us to limit the dose and minimize patient costs. After all, we're treating the patient, not the blood test.


SECRETAGOGUES



Secretagogues are preparations taken orally that are designed to stimulate the pituitary to secret more of our own (endogenous) growth hormone. Secretagogues are composed of amino acids or chains of amino acids called peptides. The usefulness and benefit of these products is extremely variable, with the benefit ranging from moderate to none whatsoever. A very large, and unfortunately, very deceptive industry has grown up around these products, and we recommend they be used only in a monitored program because they often simply don't work. Measuring the IGF-1 level prior to commencing, and three months after starting a secretagogue program will give you a much better idea of its benefit or lack thereof. For more information on secretagogues, please visit that document:
http://www.888younger.com/abstracts/abs3.html




PREPARATIONS OF GROWTH HORMONE
Although growth hormones is still under patent, several companies have paid royalties to the original developers of human growth hormone for the rights to manufacture and sell it. There are therefore a large number of companies now manufacturing and distributing growth hormone worldwide. Those available in the United States are, by brand name and the manufacturer's name:

Pharmacia and Upjohn -Genotropin

Lilly -Humatrope

Novonordisk -Nordatropin

Genentech -Nutropin

Serono Laboratories -Saizen & Serostim

GEREF

Another option to the use of growth hormone is the use of growth hormone releasing hormone (GHRH) now manufactured only by Serono Laboratories and branded Geref. GHRH works by stimulating our pituitary to make our growth hormone. This seems a more natural and rational approach because we are stimulating the endocrine axis at a higher level, and increasing levels of growth hormone more naturally. We don't prefer GHRH however, because we find it more difficult to achieve adequate levels of IGF-1, and it is a bit more expensive.


SUMMARY


Originally taken only from human cadavers, and used only in children of short stature, growth hormone has had an interesting and controversial history. Fortunately, the understanding of its importance in adult physiology came at approximately the same time as recombinant DNA technology, which led to greater availability along with virtual safety. Soon after this, the comparison was made between growth hormone deficient adults and aging adults. Because of the tremendous similarities, growth hormone began to be used and soon gained great popularity in the treatment of normal aging. Growth hormone is clearly useful and therapeutic in this regard as long as it is used in a carefully monitored, professionally managed program. Any growth hormone program must include proper nutrition and exercise with emphasis on a low glycemic diet.


Cenegenics® has a number of comprehensive programs regarding metabolic and hormonal control of aging. Our patient representatives will be happy to discuss with you any of our programs, and to send you additional information.


MEDICAL ABSTRACTS:
Medical Abstract:

Hormone Research 1999, Vol. 51(2)

K.R. Kim, S.Y. Nam, Y.D. Song, S.K. Lim, H.C. Lee, K.B. Huh


Low-dose growth Hormone Treatment with Diet Restriction Accelerates Body Fat Loss,
Exerts Anabolic Effect and Improves Growth Hormone Secretory Dysfunction in Obese Adults


Growth hormone (GH) can induce an accelerated lipolysis. Impaired secretion of GH in obesity results in the consequent loss of the lipolytic effect of GH. Dietary restriction as a basic treatment for obesity is complicated by poor compliance, protein catabolism, and slow rates or weight loss. GH has an anabolic effect by increasing insulin-like growth factor (IGF)-I. We investigated the effects of GH treatment and dietary restriction on lipolytic and anabolic actions, as well as the consequent changes in insulin and GH secretion in obesity. 24 obese subjects (22 women and 2 men; 22-46 years old) were fed a diet of 25 kcal/kg ideal body weight (IBW) with 1.2 g protein/kg IBW daily and were treated with recombinant human GH (n = 12, 0.18 U/kg IBW/week) or placebo (n = 12, vehicle injection) in a 12-week randomized, double-blind and placebo-controlled trial. GH treatment caused a 1.6-fold increase in the fraction of body weight lost as fat and a greater loss of visceral fat area than placebo treatment (35.3 vs. 28.5%, p < 0.05). In the placebo group, there was a loss in lean body mass (-2.62 +/- 1.51 kg) and a negative nitrogen balance (-4.52 +/- 3.51 g/day). By contrast, the GH group increased in lean body mass (1.13 +/- 1.04 kg) and had a positive nitrogen balance (1.81 +/- 2.06 g/day). GH injections caused a 1.6-fold increase in IGF-1, despite caloric restriction. GH response to L-dopa stimulation was blunted in all subjects and it was increased after treatment in both groups. GH treatment did not induce a further increase in insulin levels during an oral glucose tolerance test (OGTT) but significantly decreased free fatty acid (FFA) levels during OGTT. The decrease in FFA area under the curve during OGTT was positively correlated with visceral fat loss. This study demonstrates that in obese subjects given a hypocaloric diet, GH accelerates body fat loss, exerts anabolic effects and improves GH secretion. These findings suggest a possible therapeutic role of low-dose GH with caloric restriction for obesity


Medical Abstract:

Abstracted By Thord Rosen, Gudmundar Johannsson,

Jan-Ove Johannsson, Bengt-Ake Bengtsson


Consequences of Growth Hormone Deficiency in Adults and the Benefits and Risk of Recombinant Human Growth Hormone Treatment


Growth hormone deficiency (GHD) in adults is now recognized as a specific clinical syndrome with characteristic symptoms and signs. Thus, the patients are overweight, have an abnormal body composition (excess body fat and a decrease in the extra-cellular water volume) and a low bone mineral content compared to normals. Furthermore, the GHD patients have lipid abnormalities, decreased insulin sensitivity and a decreased fibrinolysis. Finally, the "quality of life" is low in terms of energy and social life. Short and long-term studies with recombinant human GH (rhGH) treatment have shown normalization of body composition, increase in the lipid pattern and marked improvement of the psychological well-being. The treatment seems safe with no serious side effects reported. In analogy with other hormonal replacement therapies, the rhGH dose should be individualized.


Medical Abstract:

Journal of the American Medical Association

August 16, 2000, Vol. 284 No. 7


Eve Van Cauter, Ph.D., Rachel Leproult, M.S., Laurence Plat, M.D.


Age-Related Changes in Slow Wave Sleep and REM Sleep and Relationship with Growth Hormone and Cortisol Levels in Healthy Men


Decreased subjective sleep quality is one of the most common health complaints of older adults. The most consistent alterations associated with normal aging include increased number and duration awakenings and decreased amounts of deep slow wave (SW) sleep (i.e., stages three and four of non-rapid eye movement (non-REM) sleep. REM sleep appears to be relatively better preserved during aging. The age at which changes in amount and distribution of sleep stages appear is unclear because the majority of studies have been based on comparison of young vs. older adults. Several investigators have noticed that there are marked decreases in SW sleep in early adulthood in men but not in women.


Sleep is a major modulator of endocrine function, particularly of pituitary-dependent hormonal release. Growth hormone (GH) secretion is stimulated during sleep and, in men, 60% to 70% of daily GH secretion occurs during early sleep, in association with SW sleep. Whether decrements in SW sleep contribute to the well-known decrease in GH secretion in normal aging is not known.


Context In young adults, sleep affects the regulation of growth hormone (GH) and cortisol. The relationship between decreased sleep quality in older adults and age-related changes in the regulation of GH and cortisol is unknown.


Objective To determine the chronology of age-related changes in sleep duration and quality (sleep stages) in healthy men and whether concomitant alterations occur in GH and cortisol levels.


Design and Setting Data combined from a series of studies conducted between 1985 and 1999 at four laboratories.


Subject A total of 149 healthy men, aged 16 to 83 years, with a mean (SD) body mass index of 24.1 (2.3)kg/m2, without sleep complaints or histories of endocrine, psychiatric, or sleep disorders.


Main Outcome Measures Twenty-four-hour profiles of plasma GH and cortisol levels and polygraphic sleep recordings.


Results The mean (SEM) percentage of deep slow wave sleep decreased from 18.9% (1.3%) during early adulthood (age 16-25 years) to 3.4% (1.0%) during midlife (age 36-50 years) and was replaced by lighter sleep (stages one and two) without significant increases in sleep fragmentation or decreases in rapid eye movement (REM) sleep. The transition from midlife to late life (age 71-83 years) involved no further significant decrease in slow wave sleep but an increase in time awake of 28 minutes per decade at the expense of decrease in both light non-REM sleep (-24 minutes per decade; P < .001) and REM sleep (-10 minutes per decade; P < .001). The decline in slow wave sleep from early adulthood to midlife was paralleled by a major decline in GH secretion (-372 ug per decade; P < .001). From midlife to late life, GH secretion further declined at a slower rate (-43 ug per decade; P < .02). Independently of age, the amount of GH secretion was significantly associated with slow wave sleep (P < .001). Increasing age was associated with an elevation of evening cortisol levels (+19.3 nmol/L per decade; P< .001) that became significant only after age 50 years, when sleep became more fragmented and REM sleep declined. A trend for an association between lower amounts of REM sleep and higher evening cortisol concentrations independent of age was detected (P < .10).


Conclusions In men, age-related changes in slow wave sleep and REM sleep occur with markedly different chronologies and are each associated with specific hormonal alterations. Future studies should evaluate whether strategies to enhance sleep quality may have beneficial hormonal effects.


Medical Abstract:

American Journal of Clinical Nutrition

October, 1998, 68(4)


M.B. Jensen, P. Kissmeyer-Nielsen, S. Laurberg


Perioperative Growth Hormone Treatment Increases Nitrogen and Fluid Balance and Results in Short-term and Long-term Conservation of Lean Tissue


The surgical procedure for forming an ileoanal anastomosis with a J pouch (IAA) usually involves a temporary ileostomy. Patients undergoing IAA surgery thus need to recover quickly because they return for ileostomy closure three months later. We evaluated the effects of perioperative biosynthetic growth hormone (GH) treatment on short- and long-term changes in body composition and on nutritional intake. Patients with ulcerative colitis undergoing IAA surgery were randomly assigned to double-blind treatment with placebo (n = 12) or 6 IU GH twice daily (n = 12) from two day before to seven days after the operation. Examinations were from two days before to nine days after the operation and on days 30 and 90. Body composition was assessed with a dual-energy X-ray absorptiometry scanner. The two groups had similar nutritional intakes. On postoperative day seven, placebo-treated patients had lost 4.2 kg (95% CI: 3.0, 5.4) total tissue mass, 3.6 kg (2.1, 5.1) lean tissue mass, and 0.5 kg (-0.1, 1.2) fat mass. These reductions persisted three months later. Compared with placebo, GH improved nitrogen balance, changes in lean tissue mass [gain of 4.0 kg (1.9, 6.0), P=0.001], and changes in total tissue mass [gain of 3.2 kg (1.6, 4.9), P=0.001], but increased the loss of fat mass [loss of 0.7 kg (0.0, 1.5), P=0.049] on postoperative day seven. Three months later, the placebo-treated patients had lost 2.4 kg (0.7, 4.2) more lean tissue mass than GH-treated patients (P=0.009), whereas changes in total tissue and fat mass were not significantly different. Hence, GH treatment enhanced the long-term regain of tissue mass.


Medical Abstract: Oral hGH, What Works?

By Anton Dotson, M.D., Cenegenics® Institute Physician

What is Growth Hormone?




Human growth hormone (hGH) is a long chain amino acid molecule produced by the anterior pituitary gland, located at the base the brain. It is a large fragile protein molecule with a molecular weight of 20,000. HGH acts on many different tissues to promote healthy metabolism. The bulk of the effect accomplished by hGH is performed by a related hormone called Insulin-like Growth Factor-1 (IGF-1), which is released predominantly by the liver and, to some extent, by other tissues in response to the presence of hGH. It is one of the primary hormones of importance for maintaining optimal cellular performance.


What are the potential benefits of raising Growth Hormone levels?




Natural levels of hGH and IGF-1 decline progressively after young adulthood, leading to many of the bodily changes associated with aging. Raising hGH and IGF-1 levels to those associated with younger physiology slows down or delays the age related decline frequently seen in many organs.


Studies reliably demonstrate that the following are among the many beneficial effects of modulating hGH/IGF-1:

1. Enhanced skin thickness and elasticity

2. Improved healing time and reduced infection rates after trauma or surgery

3. Diminished sun damage-type wrinkling

4. Decreased total body fat

5. Increased lean muscle mass

6. Increased bone mineral density

7. Improved cholesterol profile

8. Decreased LDL (bad) cholesterol

9. Increased HDL (good) cholesterol

10. Improved exercise capacity

11. Decreased recovery time between workouts

12. Improved blood flow to the kidney

13. Improved mood, coping skills, and over-all well-being

14. Improved general energy levels

These effects do not occur over night, after the first several weeks of therapy, the first change that is typically noted is a feeling of enhanced well-being, with most of the compositional changes, such as fat loss or muscle or bone gain noted after 3 to 11 months of therapy.


What are acceptable methods of raising hGh/IGF-1 levels?




There are many companies that promote various pills, elixirs, sprays, or creams that are claimed to contain useful amounts of hGH; they claim that these products are actually taken up by the body through topical, oral, sublingual or nasal administration. One should be skeptical of such claims, as none of the published benefits of injected hGH have been objectively measured with oral tablets, capsules, or sprays.


It is important to understand that hGH is a very large polypeptide hormone--191 amino acids in exact sequence, maintained in a required three-dimensional shape. The only sources of safe and accurately assembled hGH are those that use recombinant DNA technology that requires elaborate, precise, and monitored methods. HGH, from any other source, even from other animals, simply does not work in humans. Similar animal molecules have been shown to be species-specific and unable to mimic the effect of the human molecule; and there is absolutely no naturally occurring plant source of hGH. The Food and Drug Administration (FDA) licenses and oversees companies that manufacture hGH. They must register and verify their methods and product regarding uniformity of quality, bioavailability, safety, and demonstrated effectiveness. This large protein molecule is unable to penetrate intact membranes to any significant degree, making any spray or oral use of hGH almost completely a waste. The technology to make hGH is patented by large pharmaceutical companies and is restricted by law to their use. It is an expensive manufacturing process, making waste prohibitively expensive. HGH may only be administered via injection by prescription under the supervision of a licensed physician through a licensed clinic or pharmacy.


Given the above requirements, there are several concerns that arise regarding the claims made by non-FDA approved companies that offer hGH products in oral or spray forms:


1. As stated above there are only a few companies approved by the FDA to manufacture hGH. Because of the patent parameters, manufacturing hGH is complex and extremely expensive. Any claim that a product contains hGH would, by federal law, require its production be verified, overseen, and approved by the FDA to meet its standards for quality and content. This creates a double bind for the purveyors of these oral and other form "hGH" products, because if they do contain any significant amount of hGH, it would be illegal to provide it without a prescription, exact content disclosure, or origin of production. The fact that these products do not have to meet the accepted oversight and dispensing standards would indicate that they do not actually contain any significant amount of HGH.

2. Molecules as large as hGH cannot be absorbed into the body across skin or mucous membranes. Even insulin, a molecule only half the size of hGH, and of similar type and construction, cannot be absorbed in this manner. Given this limitation, hGH is digested, or broken down into simpler compounds if it is not injected. Any claim that it can be absorbed in the oral mucosa and then transported to the Pituitary Gland, is nonsense, as hGH has no beneficial effect at the pituitary gland. The pituitary gland is the normal source of hGH in young adults. The pituitary releases hGH into the circulation so that it can have its effects elsewhere. Any claim that stimulating dose works by being absorbed into the feedback system of the Pituitary Gland, is total nonsense, meant to deceive scienti-fically unsophisticated consumers.

3. There are no published physiologic studies that show any appreciable improvement in systemic hGH/IGF-1 levels when delivered orally or by spray. If it were currently possible, the FDA approved pharmaceutical companies that manufacture hGH (and for that matter insulin) would dearly love to use delivery methods other than injection.

4. Given the expense involved in the manufacture of actual hGH, even if it were to be able to be administered orally or topically, the cost of delivering the proper dose of hGH would be equivalent to the current injection solutions, which have proven very high bioavailability and well-demonstrated correlation between dose and subsequent level.

5. HGH is a very fragile molecule; it is dependant upon the retention of a precise complete amino acid sequence and three-dimensional structure, with some parts of the molecule necessarily linked to others. It works on cell receptors exactly like a key in a lock, so, even if the chemical formula remains the same, any change in shape blocks hGH activity. The cross-linkages break very easily and become unstable soon after dissolving in solution. When refrigerated, biological activity may be maintained for up to two weeks before it loses its function.

6. Products that are shipped and stored at room temperature in uncontrolled or sub-optimal environments cannot retain any functional amount of hGH. [There are only 2 FDA-approved companies which manufacture injectable hGH which can be stored at room temperature for a defined period of time until mixing]


Considered as a whole, claims that over the counter or direct-marketed products contain or provide alternate forms of hGH are taking unwarranted advantage of consumer hopes, trust, and lack of medical knowledge. Using authentic claims about the benefits of human Growth Hormone which is injected, furthermore, is highly misleading, as that is not what they are selling.




What About Secretagogues or hGH Precursors?




In the realm of body hormones in general, there are two ways to attempt to augment the amount of a hormone in circulation. The first, as already mentioned, is to give it directly, through injection. The second is to try to stimulate the body in such a way as to increase the amount of hormone that is produced by the body itself, or to enhance the function of hormone that has already been produced. Regarding hGH there are several ways to attempt this:


1) Secretagogues. A secretagogue is a substance that stimulates the pituitary gland to produce hGH. This has been an intriguing avenue of research. Over the last twenty years, several short-chain, orally absorbable compounds have been investigated. Containing as few as three (commonly six to eight) amino acid molecules, some compounds have been shown to stimulate the production of significant amounts of hGH. Of the truly effective molecules, the pituitary gland was stimulated in a too broad manner, and levels of other hormones that are not desirable were also raised. Most unfortunately, the most common accompanying hormone rise was seen in cortisol levels. In a way, cortisol is the nemesis of hGH, antagonizing the beneficial effects of hGH action. These secondary hormonal changes have severely limited the general role secretagogues may play in hGH supplementation, and have stymied the ability of pharmaceutical research to develop useful compounds. To date, none have proven to be consistent enough in their actions or safety profile to warrant a specific product release.


Some claimed secretagogues are available in the over-the-counter market; these products are generally safe, but in general do not demonstrate a certain hGH response in every individual. They seem to have their greatest effectiveness in young (under age 35) and highly athletic people, and require high dose to generate a meaningful response. The number of people who respond is typically around 35%, and in those who respond there is only a 10-30% increases in level. With advancing age there is a progressively smaller response rate and magnitude of response. Exceptions exist, and it is regarded as a safe category of compound to use in a trial, after a baseline hormone level is established and, after a three- month course of secretagogues, additional retesting of hormone levels is done. A total reevaluation should be made after no more than 6 months to determine effectiveness. Only if there is objective as well as subjective improvement documented should use of the product be continued. Even an FDA approved injectable secretagogue is of limited value even in very young people. The secretagogue market brings to mind an important caveat regarding any medical or health directed program: The most important aspect of any medical/health undertaking is the open exchange of information; people should know precisely what they put into their bodies. Even patented drugs must disclose what they contain so appropriate decisions can be made regarding safety. Rule number one with secretagogues should be that any marketing company must tell the consumer exactly what he or she is ingesting.


2) HGH Precursors. The concept of hGH precursor use is that if the body is supplied with the constituent parts of hGH, then it may be more apt to decide to use that fortuitous blend of amino acids to more easily make hGH. (Most secretagogue products on the market would really be more accurately placed in this category.) This effect is seen, but, as above, is limited primarily to young athletic individuals. The most frequent outcome with this approach is no change in hGH level, but with no harm or undesirable hormonal changes. Very high doses may be required, necessitating a gentle approach in patients with decreased renal function, or who are on medications that require excretion by the kidney, especially aspirin related compounds. Response rates can be as low as 10%, with only a small actual rise in hGH levels. Again, response rates and amounts fall with age, and IGF-1 levels should be checked before beginning and after 5-6 weeks, to verify any response. If there is no change, then this intervention should be abandoned.


3) Anti-somatostatin Therapy. There is a concept of therapy that tries to identify compounds or hormones that antagonize the effect of hGH, and tries to foil them. This might be considered the medical equivalent of a double negative or "the enemy of my friend is my enemy". The body produces a hormone called somatostatin. This hormone is the antithesis of hGH. Therapeutic attempts have been made to attack somatostatin function in hopes of freeing the hGH that is already present for a net increase in hGH function or effect. These anti-somatostatin treatments have been intellectually honest but of disappointing effect; typically showing a 1% or so rise in IGF-1 levels, and no measurable clinical difference in patient outcomes. There is no current recommendation favoring the use of these compounds.


What's the Bottom Line?




The current paradigm regarding the most efficacious way to augment hGH/IGF-1 levels is still the direct administration of hGH via injection. Dependable correlation exists between dose and level, and accurate monitoring is easily accomplished. Cenegenics® has an investment in the proper approach to this endeavor and is open to future data showing the validity of as yet undeveloped strategies. We will always try to be the first and most definitive source of implementing the state of the art therapies, as they become available.


Every rational medical decision to begin a treatment of any kind must be preceded by an appropriate evaluation as a baseline and must also include periodic monitoring to guarantee safety and effectiveness.



References

Daniel Rudman, M.D., Axel G. Feller, M.D., Hoskote S. Nagraj, M.D., Gregory A. Gergans, M.D., Pardee Y. Lalitha, M.D., Allen F. Goldberg, D.D.S., Robert A. Schlenker, Ph.D., Lester Cohn, M.D., Inge W. Rudman, B.S., and Dale E. Mattson, Ph.D.: Effects of Human Growth Hormone in Men Over 60 Years Old; NEJM July 5, 1990 vol.323, no.1


Blackman, Mark: Oral Presentation: The Interaction of Growth Hormone with Sex Steroids" Serono Symposium 1998


Longobardi S et al: Effects of two years of growth hormone (GH) replacement therapy on bone metabolism and mineral density in childhood an adulthood onset GH deficient patients; J Enocrinol Invest 1999 May:22(5):333-9


iv Calao A et al: Severity of bone loss correlated with GH deficiency; J Clin Endocrinol Metab 1999 Jun; 84(6):1919-24


v. J Clin Endocrinol Metab: Withdrawal of long-term physiological growth hormone (GH) administration: differential effect on bone density and body composition in men with adult-onset GH deficiency.


vi. Longobardi: Bone density significantly improved with hGH therapy; J Endocrinol Invest, May 1999




vii. Oxlund H et al: Growth hormone and mild exercise in combination markedly enhance cortical bone formation and strength in old rats; Endocrinology, April 1998, p. 1899-1904 Vol.1 39, No.4


viii. Colao A: Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism; J Clin Endocrinol Metab 1999 Jun;84(6): 1919-24