Antiaging Atlanta

By Alan P. Mintz, M.D., CEO, CMO and the Cenegenics Medical Institute Physicians

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.