Growth Hormone IGF-1 cancer

Rashid A Buttar D.O. Visiting Scientist, North Carolina State University As published in "Anti-Aging Medical Therapies, Volume 5"

ABSTRACT

The benefits of growth hormone (GH, also known as human growth hormone or hGH) have received increasing attention from not only the media but the medical profession as well, as a result of studies indicating GH may have the ability to restore a more youthful physiology and enhance the quality of life. However, there is controversy centered on the possibility that maintaining youthful GH levels may actually be harmful in the long run and may result in shortening life span by inducing cancer.

The first foundational objective essential to gaining an insight into these issues is to clearly understand the hypothalamic-pituitary axis. More often than not, we forget the physiological safety mechanisms designed within our systems to protect us. In this case, we refer to the negative inhibitory feedback loop designed to decrease or stop the release of endogenous GH when levels exceed the physiological range. This inhibitory feed back loop plays a significant role in the hypothalamic-pituitary axis and realizing its significance is vital to understanding the advantages of using growth hormone releasing hormone (GHRH) to increase endogenous GH as opposed to using exogenous GH.

This will lead to the discussion of why assessing increases in insulin-like growth factor type1 (IGF-1) as a marker of GH efficacy may not only be unreliable, but a compelling argument will be presented that the practice may be nothing more than the perpetuation of a medical myth. In fact, conclusive data from multiple sources showing that increases in IGF-1 are conducive to the propagation of oncogenesis will be presented and then supported by general physiological concepts, scientific observation and published research.

Finally, the inter-relationship of GH, GHRH, and IGF-1, as well as how each individual component correlates with incidence of cancer, will be thoroughly explained.

Keywords: Growth Hormo ne ; IGF-1; Cancer; Trans-D Tropin; Geref; GHRH analog

INTRODUCTION

The benefits of growth hormone (GH, also known as human growth hormone or hGH) have received increasing attention from not only the media but the medical profession as well, as a result of studies indicating GH may have the ability to restore a more youthful physiology and enhance the quality of life. However, there is controversy centered on the possibility that maintaining youthful GH levels may actually be harmful in the long run and may result in shortening life span by inducing cancer.

Intuitively, it is obvious that naturally occurring endogenous GH released within physiological parameters itself could not possibly cause cancer. The reasoning for this statement is actually quite simple because all mammalian species achieve the maximum level of GH levels when reaching late adolescence and young adulthood. If endogenous GH were actually a cause of cancer, then all mammalian species including man would have the highest incidence of cancer during late adolescence and young adulthood. However, as we all know, this is not what occurs.

So, what then causes cancer? The answer unfortunately, is more than a little involved. We know that a minimum of 75% of all cancers have been shown to have environmental etiologies. In addition, there are certain factors that predispose individuals to have a higher propensity to develop uncontrolled cellular proliferation and induce the suppression of apoptosis, leading to oncogenesis or the formation of cancer. In addition, we know that the incidence of cancer generally occurs later in life as opposed to late adolescence and young adulthood when we have the highest levels of GH.

The first foundational objective essential to gaining an insight into these issues is to clearly understand the hypothalamic-pituitary axis. More often than not, we forget the physiological safety mechanisms designed within our systems to protect us. In this case, we refer to the negative inhibitory feedback loop designed to decrease or stop the release of endogenous GH when levels exceed the physiological range. This inhibitory feed back loop plays a significant role in the hypothalamic-pituitary axis and realizing its significance is vital to understanding the advantages of using growth hormone releasing hormone (GHRH) to increase endogenous GH as opposed to using exogenous GH.

This will lead to the discussion of why assessing increases in insulin-like growth factor type1 (IGF-1) as a marker of GH efficacy may not only be unreliable, but a compelling argument will be presented that the practice may be nothing more than the perpetuation of a medical myth. In fact, conclusive data from multiple sources showing that increases in IGF-1 are conducive to the propagation of oncogenesis will be presented and then supported by published research. This conclusion is very well supported by scientific observation, clinical data, and published research, as well as being supported by general physiological concepts - all of which will be presented later in this chapter.

Finally, the inter-relationship between GH, GHRH, and IGF-1, as well as how each individual component correlates with incidence of cancer, will be thoroughly explained. It is important however, to first discuss the common characteristics of cancer and the various treatment options available so that all readers have the same foundational knowledge essential to understanding and conceptually comprehending the material being presented.

CANCER CHARACTERISTICS

The vast majority of cancers exhibit certain common characteristics including, but not limited to, uncontrolled cellular proliferation, suppression of apoptosis, and anaerobic metabolism. They also require a specific environmental state within the biological system. Cancer is also characterized as being an opportunistic process, inflammatory in nature, an obligate glucose feeder, and is associated at least in the early stages with a hyperinsulinemic state.

Despite the traditional methods of fighting cancer which include surgery, chemotherapy, and radiation, as well as the non-traditional treatments including nutrition, supplementation, herbs, lifestyle changes, detoxification, metabolism optimization, IV treatments, hyperthermia, immune modulation using peptides, insulin potentiation techniques, and the hundreds of other methods which can not be listed due to space constraints, the best defensive strategy against cancer remains maintaining a good offensive stance. What exactly do we mean by this statement? Remember, the process of oncogenesis begins not weeks or months before it manifests itself as cancer, but actually starts years before the cancer reaches a point where it can be diagnosed.

What this means is that it is essential to be proactive earlier in the game prior to the cancer being diagnosed. This strategy is most evident in the cardiovascular model where physicians intervene prior to the manifestation of heart disease, by managing hypertension and hypertriglyceridemia while encouraging life style changes such as reducing body fat, increasing exercise, and facilitating smoking cessation. Despite the trillions of dollars spent in the war against cancer, the mortality rate from cancer is secondary only to cardiac disease, with the incidence steadily rising. Therefore, the key to solving the issue of cancer, just as in cardiovascular disease, is prevention.

METHODS OF INCREASING GROWTH HORMONE

Extensive research to further the understanding of the aging process is currently being conducted at a number of leading institutions. Some of the findings from these studies show that as we age, GH levels steadily decline. The numerous potential benefits associated with GH treatments to stem this decline have generated an incredible plethora of products claiming to increase GH and IGF-1 levels. The studies necessary to validate these various anti-aging treatments as a result of this marketing surge unfortunately have not followed suit.

The answer that we seek as clinicians is how to effectively inhibit, or at least slow down the aging process and thus prevent the associated debilitating limitations, which are accepted by society as being inevitable as we grow older. The benefits of GH have increasingly received attention as a result of the ability of GH to restore a more youthful physiology and enhance the quality of life. However, controversy has centered on the possibility that maintaining youthful growth hormone levels may actually be harmful in the long run, actually shortening life span by promoting cancer. The topic of GH and cancer will be discussed in detail later but it is now becoming clear that in the quest for a longer life, we may possibly be hurting our patients by contributing to the increased incidence of cancer. We must be ever vigilant of the first rule of medicine as epitomized by Hippocrates, to Do No Harm.

Currently, there are only two clinically documented methods of increasing GH. The first method is by injecting recombinant, synthetic GH (a 198 amino acid peptide with a terminal end). There are a number of choices available to physicians who choose to pursue this method of increasing GH in their patients. The pitfalls of this choice will be clearly delineated. Tosimply summarize, the physiological safety mechanism, namely the negative, inhibitory feedback loop between the hypothalamus and pituitary is violated, leading to many potentially serious consequences.

The increased attention to the benefits attributed to GH has also given rise to hundreds of products that reportedly claim to increase GH levels. This second method of increasing GH levels is achieved by stimulating the pituitary to increase endogenous levels of GH. This technique of simulating the action of growth hormone releasing hormone (GHRH) has rapidly become a popular method, although the vast majority of products claiming to achieve these results have no scientific validity, having failed medical scrutiny.

The first foundational objective is to clearly understand the hypothalamic-pituitary axis (Figure 1). More often than not, we forget the physiological safety mechanisms designed within the biological system to protect us. In the case of GH, the reference is being made to the negative inhibitory feedback loop designed to decrease or stop the release of GH if the levels being released are beyond physiological range. This inhibitory feedback loop plays a significant role in the hypothalamic-pituitary axis and realizing its significance is vital to understanding the advantages of using GHRH manipulation to increase endogenous GH as opposed to simply injecting exogenous GH.

Although the GH injections and secretagogues (substances that cause the release of GH, including GHRH and other substances like GHRH) do offer many benefits to counteract the limitations associated with aging, the need for a safer and more effective modality of therapy has long been warranted. The necessity for a therapy offering a greater spectrum of results while providing an accelerated and rapid onset of subjective and objectively measurable efficacy, with a safer profile, a more efficient delivery mechanism, and an ease of administration leading to better patient compliance has led to the advent of many innovative and promising therapeutics. One among these has been uni que due to having created some interesting controversy as a result of going against the current fundamental understanding of the relationship between GH and IGF-1.

Figure 1. The hypothalamic-pituitary axis.

To date, there are only two GHRH analog products that have been clinically validated and scientifically studied. Both are available only via prescription. The first is Geref (NDC # 44087- 4010-1), which is marketed by Serono Laboratories, one of the largest producers of injectable growth hormone. Their product, Geref, is a 22 amino acid analog of GHRH, administered via subcutaneous injection. The second GHRH analog on the market is Trans-D Tropin (NDC # 65448-2115-1) marketed by a European company named Balance Dermaceuticals. Compared to Geref, Trans-D Tropin has the uniqueness of being the first and only GHRH analog that is administered transdermally (TD-GHRH-A). Trans-D Tropin is a polypeptide combinant, consisting of four different naturally conjugated amino acid sequences that are not recombinant in nature. Although not animal derived, these peptide combinants are also not synthetically sequenced. Rather, they are sequenced in a natural proprietary manner most easily explained as being as close to the in vivo process as we currently understand.

In an editorial review appearing in the Journal of Clinical Endocrinology (1999;50:547-556) Scott Chappel, PhD of Serono Laboratories wrote:

"Long-term stimulation of pituitary cells with GHRH will shift the GHRH/somatostatin tone by exogenous [injection] therapy to increase GHRH responsivity and pituitary GH stores. It is predicted that this therapy will reverse the chronic inhibitory state induced by long-term somatostatin domination and create an environment now responsive to the endogenous GHRH toneand allow for the normal [physiological] pulsatile GH release to reappear. This would produce a greater therapeutic benefit and a better safety profile compared with once daily injections of a bolus of recombinant GH...[the need for] repeated stimulation of GHRH receptors is required in a patient friendly formatefforts are ongoing"

From a long-term efficacy, safety, physiological, functional, and compliance standpoint, Trans-D Tropin (henceforth referred to as the trans-dermal GHRH analog or TD-GHRH-A in this chapter), appears to accomplish the goals that Chappel delineates. But some further interesting additional observations were noted during the clinical studies conducted on this TD-GHRH-A by the author, shedding light on a subject that is of great importance to any physician considering manipulation of their patient's hypothalamic-pituitary axis and vital for any patient who may be considering GH therapy as a treatment option.

It was during the initial clinical testing of this TD-GHRH-A, while undergoing the characteristic rigid scrutiny used for medical therapeutics, where the observation was made of IGF-1 deviating from the expected trend. Later, during subsequent clinical studies, the same observations were reproduced with findings being confirmed not only by other independently conducted studies but also found to be well documented within the published medical literature.

At the same time, other clinicians and researchers studying IGF-1 independent of the author, began observing and documenting similar findings. When these scientists began to report their findings starting in 1999, they enabled a greater understanding of the actual nature of IGF-1.

STUDY SHOWS INCREASED GROWTH HORMONE WITH DECREASED IGF-1

In 1998, we conducted a subjective study based upon the SF-36 patient outcome based research model, evaluating 30 patients taking the TD-GHRH-A. The study, which was published in published in the Journal of Integrative Medicine (2000;4:51-61), measured 22 subjective life style criteria and 5 objective criteria including overall strength, endurance, and IGF-1. Although every patient reported significant improvement in most criteria being monitored, a departure from the expected trend of IGF-1 was noted.

The observation of decreasing levels of IGF-1 prompted a second small study, this time to evaluate endogenous GH by drawing serum GH radioimmunoassays and comparing the response to changes measured in IGF-1. A total of 53 sets of serum GH levels were drawn before and after treatment, and analyzed using radioimmunoassays. IGF-1 levels were also collected at baseline and again at three weeks post treatment with the TD-GHRH-A.

Endogenous GH levels measured 90 minutes post treatment showed a 631.46% increase compared to baseline levels (Figure 2). The data was then re-evaluated using the first set of blood drawn and compared to the second set of blood drawn two weeks later in order to assess if changes in GH levels were only dose dependent or if the response were transitory in nature (Figure 3). There was also a concern that the response measured in GH would decrease after a few weeks due to desensitization or acclimatization to the TD-GHRH-A. The results were again diametrically opposed to what was expected. There was actually an improvement in GH release measured after two weeks of treatment with the TD-GHRH-A compared to first time usage. The results indicated an actual increase in sensitization or improvement in pituitary responsivity with continuous usage. This subject will be addressed in greater detail later in this chapter.

Figure 2. Effect of TD-GHRH treatment on endogenous growth hormone levels.

One of the criticisms when this data was presented was regarding the amount of change that was measured in GH levels. The increases in GH levels were felt to be insignificant since they were less than 5 ng/ml. However, the opposing argument questioned how an increase of greater than 600% within a two-week period could be considered insignificant. This argument can only be settled by defining what level of GH increase is necessary in order to achieve therapeutic benefit.

Endocrinology and physiology textbooks indicate that an absolute level of GH above 5 ng/ml is needed before efficacy can be attained. However, the "efficacy" being referred to is a "diagnostic" response (for purposes of diagnosis), not a "therapeutic" response. The "diagnostic" response would be defined as a change to elicit a response far beyond the normal physiological range by taxing and overloading the system. An example of this would be seen in the insulin and dopamine challenges done by endocrinologists to determine GH deficiency.

Figure 3. Comparison of growth hormone levels after initial treatment and after two weeks of treatment.

However, a "therapeutic" response would simply elicit a subtle response well within the normal physiological range in order to achieve a "therapeutic" effect. Although the average range of GH levels measured during this study was well below the 5 ng/ml level defining the diagnostic criteria, an increase in endogenous GH levels greater than 600% compared to baseline measurements is clinically and statistically significant. Furthermore, by keeping the levels of GH below 5 ng/ml, we experience a more physiological increase in endogenous GH as opposed to exceeding the physiological parameters achieved by exogenous, recombinant, injectable GH.

The interesting component of this study was the relationship of "increasing endogenous GH' to a concomitant measurable "decrease in IGF-1 levels' (ng/ml) on a consistent basis. TD-GHRH- A caused not only an increase in endogenous GH but also a decrease in IGF-1. If IGF-1 is an active metabolite of GH and is known to be converted in the liver from GH to one of the many growth factors responsible for normal growth, then why would IGF-1 levels decrease when the GH levels are increasing? Before discussing this important question, let's first discuss the data.

Figure 4. Serum IGF-1 levels at baseline and at three weeks post treatment with TD-GHRH-A

The IGF-1 levels reported in Figure 4 were drawn at baseline and three weeks post treatment with the TD-GHRH-A. There was over a 14% drop measured in IGF-1 levels in the males participating in the study. The female participants showed a greater drop in IGF-1 exceeding a 26% drop. The overall drop in IGF-1 was over a 20% decline in IGF-1 levels compared to baseline measurements over the three-week period. The evidence based on this study seemed to show an inverse correlation between IGF-1 and GH levels. Upon reviewing the published literature, it became clearly evident that IGF-1 and GH have at best, an unreliable correlation.

DOUBLE BLIND STUDY CONFIRMS DECREASING IGF-1

Eventually, the above mentioned data showing the increase in endogenous GH and decrease in IGF-1 became the pilot for a larger, more definitive study to determine not only the correlation between GH and IGF-1 but also to evaluate the effect the TD-GHRH-A had on cortisol, glucose, chemistry, and lipid parameters. The preliminary results of this multi-centered, double blind, placebo controlled, crossover study evaluating endogenous GH levels with serial GH radioimmunoassay levels after TD-GHRH-A administration showed some very interesting results and reinforced the earlier findings of the smaller previous studies.

The requirements for this study were stringent due to the transitory nature of serum GH so all data collection was tightly regulated in order to insure accuracy of the information collected. Patient selection criteria was simple, with age over 30 and non-gravid state being the only absolute exclusion criteria. The primary end point was eight weeks post treatment when the placebo group was scheduled to crossover into the treated group with the secondary endpoint being 16 weeks after the initiation of either treatment or placebo. The placebo (control) was completely indistinguishable from the TD-GHRH-A (treatment) with both utilizing the exact same carrier, with the same consistency, smell, color, and appearance, and with the packaging kept identical.

All control and treatment bottles were labeled with a numerical code and randomly distributed among the patient population selected for the study. The numerical codes facilitated the double blind component with supervising physicians unaware of which patients received placebo versus treatment . Study participants were scheduled for blood draws at very specific time intervals. If a study patient did not present as scheduled for blood draws, the patient was eliminated from the study. Out of 25 centers selected for participation, only eight centers completed the study, with 117 patients out of 317 patients reaching the stated endpoints without deviances from the testing schedule.

All study patients had blood drawn at specified intervals, starting with baseline GH radio- immunoassay levels as well as IGF-1, cortisol, lipid panels, and basic chemistry panels, followed immediately by administration of either the placebo in the control group or the TD-GHRH-A in the treated group. All study patients then had to have repeat blood draws at 30, 60, and 90 minutes after treatment administration. Each of these subsequent blood draws consisted of all the above mentioned serum parameters, with each set of blood draws obtained at a very specific weekly interval. If a study participant did not present at the specified time for a scheduled blood draw, they were eliminated from the study. This was the primary reason why only 117 patients completed the study.

The blood specimen analysis schedule for the treated group (on the TD-GHRH-A) was at the onset of the study, followed up again at the end of the second week, the fifth week and finally on the eighth week after study initiation. The blood specimen analysis schedule for the control group (on placebo) was at the onset of the study and then repeated at eight weeks after the initiation of the study. The blood specimens obtained during the second and fifth week blood draws in the placebo group were discarded, primarily due to the study's financial constraints but also because no significant change was anticipated in the placebo group. Only the start and the endpoint specimens, prior to the crossover point, were analyzed in the control (placebo) group. However, the blood had to be drawn in both placebo and treatment groups at the same time in order to preserve the double blind component of the study.

The percent change measured in endogenous GH levels as measured by GH radioimmunoassay in the 117 patients that completed the study were statistically significant. The change from the baseline blood draw to the blood drawn 90 minutes after the TD-GHRH-A treatment showed a 462.39% increase upon first time usage. At the end of two weeks after using the TD-GHRH-A, an increase of 815.59% in endogenous GH levels was noted, compared to baseline base line levels drawn 90 minutes earlier. By the fifth week, an increase of 1754.22% in endogenous GH was measured from baseline to 90 minutes post treatment with the TD-GHRH-A. However, by the eighth week, there was actually a drop in GH levels when compared to the fifth week, but overall, endogenous GH levels still increased over 609% over a 90 minute period compared to baseline.

The statistical analysis of the data was conducted by an independent source, showing a baseline mean of 0.295918367 with a 90-minute mean of 2.213636364 and a P value < 0.001. The baseline standard deviation was 0.464112 with the 90-minute standard deviation being 2.673173, establishing that the increase s in endogenous GH levels observed in this study were statistically significant. The most dramatic increases in endogenous GH release were measured between the 60 and 90 minute time periods post treatment, regardless of what weekly interval in the study the serum GH samples were drawn. All four time periods (initial baseline, second week, fifth week, and eighth week) clearly showed the time interval between 60 and 90 minutes as the most significant for endogenous GH release.

Figure 5. The change in endogenous growth hormone levels from baseline to 90 minutes after TD-GHRH-A treatment over an eight week period.

Although an increase in endogenous GH levels was clearly established, the decrease in GH levels at week eight compared to week five (Figure 5) was initially confusing. However, referring back to basic physiological principals, it became evident that there were only two possible postulates explaining the reason for a decrease in GH levels during the eight week of usage of the TD-GHRH-A.

The first possibility revolved around somatostatin. An increase of over 1750% in endogenous GH levels by the fifth week is a very significant increase. It would therefore logically follow that with such a tremendous increase in GH from baseline in such a short period, the negative inhibitory feedback loops would be initiated, causing the release of somatostatin from the hypothalamus in order to inhibit the release of GH by the pituitary. An increase in somatostatin (GH antagonist) would result in decreased levels of endogenous GH being released. This hypothesis based on clinical observation will be confirmed or refuted in future studies. The second postulate involves the issue of pituitary reserves. The pituitary gland holds only a limited amount of GH in store, releasing it in a pulsatile manner. Due to the effectiveness of the TD- GHRH-A, the pituitary reserves of GH may have been rapidly depleted and by the eight week, required additional time necessary for the pituitary to replenish its GH stores.

Figure 6. Serum cortisol levels obtained at baseline and 90-minutes after TD-GHRH-A administration.

As the possibilities were being entertained regarding the drop in GH observed at the eighth week compared to the fifth week in the TD-GHRH-A treated group, the placebo data was also being analyzed. The increase in GH in the treated group was measured at 1754 % at the fifth week interval but in the placebo group, although the blood was drawn, the samples were not analyzed as previously mentioned because the placebo group had the second and fifth weeks blood draws discarded. Therefore, a comparison of the fifth week data in the treated versus the placebo group could not be made. However, the data for the eighth week for both the treated group (on the TD-GHRH-A) and the control group (on placebo) were analyzed. Although this comparison did not allow for an explanation for the relative drop in GH from the fifth week to the eighth week in the treated group, it did give additional confirmation to previously conducted research unrelated to this study, further intriguing the study investigators.

The eighth week data for the treated group on the TD-GHRH-A showed 609.04 % increase in endogenous GH. However, surprisingly, the placebo group showed an increase of endogenous GH of 118.13% during the same time period. Although initially unexpected, this increase in GH in the placebo group validated previous research regarding the effect of diet and exercise on GH release. Life style modifications that all study patients were instructed to follow while participating in the study included a specific combination of aerobic and resistance exercise, as well as a high protein, low carbohydrate diet.

These findings validate some earlier independent studies showing that even without medical intervention, one can significantly increase endogenous GH levels by simple lifestyle modifications in diet and exercise. All patients in this study were crossed over into the treated group at the eighth week and subjectively followed for another eight weeks. Subjective improvements reported by patients were recorded in the form of a detailed questionnaire based upon the SF-36 patient outcome based research model, answered every two weeks by all study participants. Results correlated well with the objective data collected.

The most significant changes noted were in renal function, with bilirubin dropping 34.56% and creatinine dropping 22.23%. In addition, significant decreases were noted in serum glucose, serum cortisol and IGF-1 levels.

Figure 7. Percentage drop in serum cortisol levels over the 8-week study period.

Serum cortisol levels dropped significantly within a 90-minute interval on each consecutive blood draw (Figure 6). With the exception of a slight increase in baseline cortisol measured during the second week, all cortisol levels drawn decreased in a consistent manner. As depicted in Figure 7, cortisol levels not only dropped from baseline blood draw to the 90-minute blood draw during every occasion, but were also observed to consistently decrease throughout the study period as well. These changes in cortisol were significant for a number of reasons.

First, subjective improvements in attitude, depression, anxiety, sense of well being, ability to focus, concentration and ability to handle periods of stress were reported by a large number of patients participating in this study. These changes were reported later in the course of treatment, usually experienced by the third or fourth month of therapy. The steadily decreasing levels of cortisol correlate with the subjective response reported by patients in their patient self-assessment forms. Second, cortisol, being commonly referred to as the stress hormone, is known to have a significant inflammatory component and contributes to increased rate of aging. Reduction in any inflammatory component may have a substantial effect by reducing oxidative stress on the physiology and improving the "peak and trough" nature of cortisol, as opposed to chronically elevated levels. Reduction in serum cortisol levels was pronounced and consistent.

In addition, IGF-1 and serum Glucose levels were also noted to consistently drop (Figure 8).

Figure 8. Effect of TD-GHRH-A on serum IGF-1 and glucose levels.

The TD-GHRH-A appears to have a distinct "euglycemic" effect on serum glucose. Glucose level modulation was evidenced by glucose levels below 75 mg/dl trending up to approximately the 100 mg/dl levels while the levels above 150 mg/dl trending down to approximately the 110 mg/dl levels. Patients with Insulin-dependent diabetes mellitus (IDDM) experienced 50 to 70 mg/dl drops in serum glucose levels within 90 minutes after using the TD-GHRH-A. The IGF-1 levels were expected to drop based upon the earlier pilot study results, and were observed to drop on a consistent basis as expected.

Figure 9. Response in serum IGF-1 levels to TD-GHRH-A treatment.

The response in serum IGF-1 levels in the treated group showed a consistent and significant drop while on the TD-GHRH-A, dropping acutely within 90 minutes of administration of the TD- GHRH-A compared to baseline levels, and overall throughout the study period intervals as well. Despite endogenous GH levels increasing over 1750% by the 5 week, the mean serum IGF-1 t h levels dropped over 60 ng/ml in the treated group on the TD-GHRH-A. Figure 9 shows the consistently decreasing IGF-1 levels as the study progressed. This was the final indication that an increase in IGF-1 levels was not an appropriate method of monitoring efficacy of GH therapy.

In fact, an inverse correlation between IGF-1 and GH efficacy seemed to be established based on this data, which upon further review was well supported in published literature, current research, and in clinical observation. But further investigation revealed another component of IGF-1 that seemed to have been ignored despite extensive documentation in the medical literature. It was during this study and resulting subsequent inquiry into the IGF-1 controversy that led to the following observations, conclusions, and discovery regarding the correlation between IGF-1 and cancer. The evidence of this correlation is overwhelmingly clear and well supported.

THE NEW PARADIGM IN UNDERSTANDING IGF-1

IGF-1 insulin-like growth factor type is regarded as the most important metabolite of growth hormone, an anabolic hormone that promotes tissue growth. IGF-1 has a structure highly similar in morphology and function to that of insulin, while the receptor site of IGF-1 is indistinguishable from the insulin receptor site. Many of the effects attributed to IGF-1 are also attributable to, and overlap with, those of insulin.

Figure 10. Molecular Structure of IGF-1

The traditional view is that growth hormone is "translated" in the liver into IGF-1, and expresses its activity through IGF-1, even though it has been documented that low levels of IGF-1 are not a reliable indicator of growth hormone deficiency. Yet, many clinicians continue to use IGF-1 as a monitor of efficacy for GH treatment. The problem however is that numerous studies have shown IGF-1 to be modulated by factors completely independent from GH levels.

Many in the research arena have long felt that the chief culprits responsible for reducing life expectancy are likely to be excessive levels of insulin as well as IGF-1. In fact, excessive insulin and IGF-1 are precisely the type of pathological endocrine profiles that are observed in sedentary, obese patients. This has been reported in a number of studies, and recently confirmed in a massive National Institute of Aging study, which singled out low insulin as the best predictor of longevity in men.

All physicians treating patients with any modality used to manipulate growth hormone levels should make themselves familiar with the research on the extraordinary longevity of dwarf mice, which are deficient in IGF-1. Dr A Bartke, one of the chief investigators involved in the dwarf mouse research, was interviewed by Ivy Greenwell for the consumer oriented periodical LifeExtention Magazine (February 2001). When questioned regarding his opinion on the controversy of IGF-1, Bartke expressed that it is high IGF-1 that is likely to be harmful. Low IGF-1 correlates with longevity and is "virtually absent" from the serum of the long-lived dwarf mice according to Bartke. He stated that aiming at high IGF-1 levels might not be desirable not only in terms of life expectancy but also in those of cancer susceptibility as well. However, Bartke points out that the confusion regarding this issue is in great part, due to the difficulty and trouble with separating the effects of GH itself from those of its metabolites, specifically IGF-1. There is growing consensus that IGF-1 levels are indeed not related to GH levels. In a study published in the Journal of Metabolism Research (1999;10:576-579) , Inuki et al found that thyroid hormone modulates IGF-1 and IGF-BP3, without mediation by GH. Just a few months later, Janssen et al, published a study in the Journal of Clinical Endocrinology and Metabolism (2000:85:464-466), where the authors reported finding a direct relationship between serum levels of estradiol and IGF-1 levels, completely independent of GH levels.

Both these studies have set precedence in developing new strategies in treating cancer patients, which will be discussed in detail later in this chapter. However, before delving into the topic of IGF-1 and its relationship to cancer, it is important to review a few fundamental physiological concepts that may enhance the understanding of the nature of IGF-1.

Review of General Physiological Principals

When considering basic science physiological principals, the nature of IGF-1 becomes easier to understand and the controversy surrounding IGF-1 is removed. In order to accomplish this goal, the reader is asked to consider the following two questions and answer them before continuing to read. By answering these two questions, a logical explanation for the decrease in IGF-1 levels witnessed in the aforementioned studies will become self-evident.

Question 1: EXERCISE AND INSULIN SENSITIVITY Do sedentary people or athletes have lower glucose levels?

Exercise leads to an increase in insulin sensitivity. In other words, an increase in exercise leads to the body becoming more "sensitive" to the effects of insulin, thus requiring less insulin to accomplish the same task. The function of insulin is to drive glucose into the cell. Since exercise sensitizes the cells of the body to the effects of insulin, the body needs less insulin to drive the same amount of glucose into the cell. Thus, exercise leads to lower insulin levels by increasing insulin sensitivity.

There is also a higher efficiency in the use of glucose in individuals who exercise. This is due to a number of reasons. First, individuals who exercise have a higher metabolism because they have a greater lean body mass compared to sedentary individuals. Since it takes more energy (glucose) to maintain a greater lean body mass, i ndividuals who exercise have lower levels of circulating gl ucose. This is due to higher fuel consumption as a result of higher levels of activity, as well as a higher requirement to maintain an increased resting metabolism. The higher lean body mass plus higher levels of activity lead to more glucose usage.

Using a car as an analogy, an individual who exercises (exerciser) is like a racecar. The racecar (exerciser) has a larger engine (more lean body mass) and travels greater distances in a shorter period of time (more activity due to exercise), which leads to lower fuel levels due to increased consumption (lower glucose levels due to increased utilization). This in turn, reduces the need for a fuel injector that pushes fuel into the engine (insulin). A decrease in insulin requirements is referred to as becoming insulin sensitive.

This basic physiological concept is evidenced in clinical medicine every day. Individuals who exercise regularly have lower circulating glucose levels, and as a result require less insulin. The sedentary, obese, non-exercising patients have higher glucose levels, eventually having to increase their insulin requirements due to becoming insulin resistant. Insulin resistance is more commonly referred to as non insulin-dependent diabetes (NIDDM). Our obvious goal as clinicians should be to drive the physiology of our patients towards that of the exercising, athletic patient with lower insulin levels.

Question 2: EXERCISE AND YOUNGER PHYSIOLOGY Are people who exercise, biologically (physiologically) younger or older?

Exercise has always been considered a natural form of anti-aging or longevity therapy. From the study on the TD-GHRH-A, we know the placebo group was able to increase GH levels simply by lifestyle modifications including exercise. Other studies have also shown that exercise will increase GH. However, exercise will increase other hormones as well, including testosterone. In fact, exercise has been shown to improve the overall hormonal response within the entire biological system.

Exercise causes a decrease in blood pressure, heart rate, respiratory rate, and peripheral vascular resistance, making the system more efficient and allowing the "engine" to idle at a lower threshold. Exercise increases endorphin release, lean body mass, immunity, range of motion, endurance, stamina, libido, etc. These physiological changes induced by exercise are well established and extensively documented in the medical literature. All these responses are evidence of a younger physiology and are characteristics of younger individuals. Therefore, exercise leads to the physiology of a younger state. This is one of the primary reasons that exercise has long been recommended for better health.

EXPLANATION OF DECREASING IGF-1 LEVELS

The answers to our two questions at this point should be clear. The answer to the first question is that athletes have lower serum glucose levels secondary to an increase in insulin sensitivity. The answer to the second question is that exercise leads to a younger physiological age, i.e., increase in lean body mass, increase in insulin sensitivity (decrease in insulin levels), increase in GH, etc.

Now lets look at IGF-1 versus insulin. First, why is the molecule commonly referred to as IGF-1, named "Insulin-like growth factor type 1?" Insulin-like growth factor type 1 is just one of many growth factors. The polypeptide sequence of the general class of molecules referred to as IGF overall are very similar to the insulin molecule. The fact that IGF-1 is an acronym for "insulin-like growth factor type 1" should be the first indication that insulin and IGF-1 may be highly similar molecules. In fact, insulin and IGF-1 are extremely similar and have many of the same morphological characteristics, appearing to share many of the same properties and traits as one another much more so than the other insulin like growth factors

Figure 11. The Insulin-like growth factors, their receptors, and their binding proteins. SOURCE: The International Society for IGF Research website, http://www.igf-society.org

In Figure 11, note that the receptor site for insulin and the receptor site for IGF-1 are morphologically identical. Also note the significant difference in IGF-1 and insulin receptor sites compared to that of the IGF-2 receptor site. IGF-1 and insulin receptors appear to be completely interchangeable. Therefore, any molecule that binds to these receptor sites could also be interchangeable, indicating that insulin and IGF-1 should be able to interchangeably bind to either receptor site. All evidence indicates this theory to be correct with the findings appearing to be well confirmed on a clinical basis as well as confirmed within the didactic and research communities.

GENERAL PHYSIOLOGICAL PRINCIPALS

Based upon the answers to the two questions asked earlier, we can now support the conclusion that athletes have lower insulin levels and are biologically younger compared to their counterparts who do not exercise. As an example, a 79 year-old patient who exercises regularly is biologically younger than his 79 year-old sedentary counterparts. Based on this supposition, we can now logically conclude that exercise equates to a slowing down of the aging process or, a form of "anti-aging" therapy. Put another way, exercise promotes longevity.

Recognizing that exercise creates a physiological situation that results in an increase in lean body mass, an increase in GH levels, an overall increase in hormonal levels, an increase in insulin sensitivity, a decrease in physiological age and a decrease in insulin levels, we can now understand why exercise equals "anti-aging". These physiological changes represent the goal all physicians desire to achieve in all their patients. These biological parameters are what doctors strive to accomplish, regardless of a patient seeking to simply optimize their health and live a longer life or facing a life threatening chronic illness such as diabetes, heart disease, or cancer.

If we recognize that all the above-mentioned desired physiological parameters are a consequence of exercise, then it would follow that as physicians, we would want to embrace any treatment modality for our patients that would recreate the same physiological parameters achieved by exercising, i.e., creating lower glucose levels, leading to insulin sensitivity and resulting in lower insulin levels as observed in young athletes. Conversely, we would want to refrain from any treatment modality that would oppose the effects of exercise, i.e., creating higher glucose levels, leading to insulin resistance and resulting in higher insulin levels as observed in sedentary, obese, diabetic patients. As previously discussed, the problem is that IGF-1 and insulin are very similar to one another morphologically. Even more importantly, IGF-1 and insulin receptor sites are virtually identical and interchangeable.

If lower insulin levels, such as those found in young athletes, are desirable from a longevity standpoint, then wouldn't we expect IGF-1 to also be lower in young athletes? The answer of course is "yes'. This is due to one simple reason that as a result of IGF-1 and insulin being morphologically identical, these two substances generally cannot be opposed in a normally functioning biological system. If IGF-1 is high, then the insulin levels will also be high.

IGF-1 should be lower in young athletes, just as insulin levels are lower in athletes. And in fact, this is exactly what is clinically observed! The same observation is noted when insulin begins to drop in individuals who begin to exercise. We tested this basic physiological principal and applied it clinically. The above conclusions were easily verified in a small clinical study, demonstrating IGF-1 to be demonstratively lower in athletes.

IGF-1 IN ATHLETES VS. SEDENTARY PATIENTS

In a small, outcome based study to assess IGF-1 levels in un-manipulated patients (patients who had no hormonal manipulation), the true nature of IGF-1 was clearly elucidated (Figure 12). The aged, inactive, obese subjects (sedentary group) had very high levels of IGF-1 when compared to the younger, active subjects (athletic group) who had levels as low as 88 ng/ml.

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