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Growth Hormone IGF-1 cancer
 

The Inter-Relationship Between Growth Hormone, IGF-1, and 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.  To simply 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 tone…and 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 format…efforts 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.

  • phosphate dropped 3.39%;
  • total protein dropped 4.74%;
  •  alkaline phosphate dropped 0.05%
  • glutamic-pyruvate transaminase (GPT) dropped 6.04%;
  • lutamate oxaloacetate transaminase (GOT) increased 8.37%;
  • cholesterinase dropped 4.21%;
  • cholesterine increased 0.47%;
  • blood urea nitrogen (BUN) dropped 5.61%;
  • urea dropped 3.55%;
  • potassium dropped 4.49%;
  • sodium increased 3.23%;
  • calcium dropped 4.58%;
  • triglycerides increased 3.23%;
  • HDL cholesterol increased 2.59%;
  • LDL cholesterol decreased 1.67%;
  • albumin increased 3.28%;
  • alpha-1-globulin decreased 3.59%;
  • alpha-2-globulin decreased 3.96%;
  • beta-1-globulin dropped 4.04%;
  • gamma globulin dropped 6.15%;
  • gamma glutamyl transpeptidase (GGT) increased 12.47%.

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, 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.

A total of 38 study patients were divided into 2 groups, the first consisting of 21 sedentary male and female patients defined as having no previous history of regular exercise. The mean age in this sedentary group was 55.3 years, with the range between 30 to 84 years, and a median age of 57 years. The mean IGF-1 in this group was 153.0 ng/ml with the range between 61 ng/ml to 304 ng/ml, and a median level of 182.5 ng/ml.

Despite the older, sedentary group having a mean age 21.2 years older than the athletic group, the sedentary group still managed to have an average IGF-1 higher than the athletic group. Just as exercise decreases insulin levels, it also clearly decreases IGF-1 levels. This is evidenced in athletes who have a lower IGF-1 level compared to their sedentary counterparts. These findings that were also clearly established in this study, clinically correlate with the findings of hundreds of clinicians worldwide.


Figure 12. IGF-1 levels in athletes and sedentary patients.

TRUE RELATIONSHIP OF IGF-1 AND GH

The lack of correlation between IGF-1 and GH is not new and in fact, has been well documented in the literature for over 10 years. For example Furlanetto et al ( Hormone Research 1990;33:25-30) found that "IGF-I levels are age dependent and subject to regulation by other hormones and nutritional variables; these features complicate the interpretation of IGF-I levels in individual patients and greatly limit the usefulness of these measurements, especially in establishing GH deficiency or [assessing GH replacement efficacy]". But the evidence of an unreliable relationship between GH and IGF-1 levels does not stop here. In fact, there is growing consensus that IGF-1 levels are NOT related to GH levels at all.

IGF-1 levels may increase with GH injection treatments, but it is important for the reader to recognize the fact that the use of synthetic GH (recombinant GH) is inherently designed to supercede the normal physiological range, thereby violating the negative inhibitory feedback loops designed by nature to safeguard our hypothalamic-pituitary axis. There is nothing "physiologically natural" taking place with the use of GH injected into the system. If you inject a synthetic substance into the body and exceed physiological parameters and then, observe a specific change (such as IGF-1 increasing), the conclusion cannot be made that the response observed while exceeding the normal physiological parameters, is the body's natural, normal, physiological response. Very simply, if you exceed "normal" physiological range, the response observed while exceeding the normal range is no longer the "normal" physiological response.

POSTULATE EXPLAINING DECREASING IGF-1

There are a number of possible reasons for the consistent drop observed in IGF-1 with concomitant efficacious increase in GH as noted during the use of TD-GHRH-A. One possibility involves the increase in IGF-1 utilization leading to a decrease in free IGF-1, which in turn, results in a reduction of measurable circulating serum IGF-1 levels. IGF-1 may actually be more efficiently utilized (decreasing levels due to increased utilization) when an increase in GH levels is achieved while staying within physiological parameters.

This would be the same as insulin being utilized (decreasing levels due to increased utilization) more efficiently with an increase in exercise, with the stimulus being exercise instead of GH. The key is that both exercise and GH should remain within physiological parameters. Too much exercise for example can result in premature death, as seen with marathon runners. This is the advantage of using a treatment modality allowing for the negative inhibitory feedback loop to remain intact and thereby, never permitting normal physiological parameters to be exceeded.

Another possibility involves the up-regulation of IGF-1 receptor sites. Assuming an effective treatment modality (such as TD-GHRH-A) has the ability to create an up-regulation of IGF-1 receptor sites, a higher level of IGF-1 binding would be observable. This higher binding of IGF-1 would be manifested as a drop in IGF-1 levels. Thus, an up-regulation in the IGF-1 receptor sites would lead to an increase in IGF-1 binding, resulting in a reduction of measurable circulating serum IGF-1 levels. In both of these scenarios, insulin-like growth factor binding protein 3 (IGF- BP3) may serve as a better marker instead of IGF-1 for assessing efficacy of GH treatments. Further research however is necessary in order to validate and confirm these postulates.

The greater weight of proof leans towards supporting one of the two above discussed possibilities. There is pressing evidence that the use of the TD-GHRH-A increases receptor site activity in addition to increasing endogenous GH.


Figure 13. The results of a study where 24-hour urinary GH levels were measured in four patients ranging
in age from 30 to 82. Baseline urinary GH levels were obtained, followed by administration of TD-GHRH-A.

Figure 13 shows the results of 24-hour urinary GH levels measured in four patients. Baseline urinary GH levels were obtained, followed by administration of the TD-GHRH-A. Subsequent 24-hour urinary GH levels were obtained on a weekly basis over the next 4 weeks. As can be seen in Figure 13, from the baseline urinary GH collection obtained (prior to initiating treatment) and during the first week of treatment, all four patients were noted to have a large drop in urinary GH, almost down to the lowest possible measurable level. However, each patient reported improvement in various subjective criteria ranging from improved sleep and sense of well being to increase in strength and endurance during this same initial week of treatment. In addition, serum GH measured by radioimmunoassays showed an increase in serum GH levels of all four patients during the first week while the urinary GH levels were precipitously declining.

It is important to note at this juncture that urinary GH levels, although a well-accepted method of determining GH levels, do not measure total GH levels in the body, but rather, indicate the level of GH not being utilized. The GH that is actually being measured during urinary GH collections is the amount of GH that exceeds the renal threshold. This is similar to the dynamics noted with glucose spilling over beyond the renal threshold in diabetic patients. The amount of glucose found in the urine of diabetics is only what spills over beyond the renal threshold.

The fact that urinary GH levels measure only the GH that is not being utilized and exceeding the renal threshold is well supported when we look at the baseline levels of urinary GH in Figure 13. Each of these patients had various baseline measurements of urinary GH. Also note, the oldest patient (aged 82) had the highest urinary GH level measured, while the youngest patient (aged 30) had the lowest urinary GH level measured. However, serum GH levels were completely opposite with the 82 year old having the lowest serum GH level measured, and the 30 year old having the highest serum GH level measured. There was a direct correlation with increase in age and increase in urinary GH levels (GH spilled beyond the renal threshold). This finding directly supports the observation regarding urinary GH only measuring the amount of GH spilling beyond the renal threshold and thus, not being utilizable.

Returning to Figure 13, we see strong evidence of up-regulation of GH receptors at local target tissue sites. This is evidenced by the decreasing urinary GH levels, despite a simultaneous increase in serum GH levels supported by findings of improvement in subjective patient self assessed criteria. The decrease in measured urinary GH levels with increasing serum GH levels (measured from baseline to 90 minutes post treatment) during the first week indicates evidence of an increase in the activity (up regulation) of GH receptor sites.

From the end of the first week to the third week, we see a steady rise in urinary GH levels. Despite the GH receptor site activity increasing (up-regulation of GH receptor sites), serum GH levels continue to steadily increase beyond the baseline values measured initially, providing evidence of GH receptor site saturation and providing further support to the earlier evidence of increasing serum GH production/release with the use of TD-GHRH-A. The evidence found during the 24-hour urinary GH collections provided support of the idea of receptor site up regulation at the target tissue level, leading to an increased utilization of GH at local target tissue sites.

Merriam et al ( Today's Therapeutic Trends 2000;18:335-354) published an interesting paper supporting the urinary GH observations just discussed. The authors state that "GH exerts its effects by binding to its own receptor sites as well as by stimulating the synthesis of IGF-1. The liver is the primary contributor to levels of IGF-1 in the systemic circulation. But IGF-1 is generated in many GH target tissues [and as a result], local effects may be more important than those of circulating IGF-1 of hepatic origin."

This paper brings up another intriguing issue regarding the current understanding of the nature of IGF-1. Merriam and colleagues write: "IGF-1 is generated in many GH target tissues and local effects may be more important than those of circulating of IGF-1." What are the local effects of IGF-1? As previously mentioned, IGF-1 is regarded as the most important metabolite of growth hormone and is an anabolic hormone that promotes tissue growth. Those who advocate the use of IGF-1 or condone the increase of IGF-1 have argued that IGF-1 from hepatic conversion of GH is essential for normal growth and development, and in its absence, short stature syndromes and other growth deficiencies will occur.

However, two separate studies have conclusively shown this assumption to be less than reliable and probably without much basis. Work by both Yaker et al ( Proc Natl Acad Sci USA 1999;96:7324-7329) and Ohlsson et al ( Pediatr Nephrol . 2000;14:541-543) impressively demonstrated normal growth in mice in which hepatic IGF-1 synthesis was completely eliminated. These studies conclusively support Merriam and colleague's conclusions regarding the greater importance of the local effects of IGF-1 generated in GH target tissues than those of circulating IGF-1 of hepatic origin.

SUSTAINED IMPROVEMENT IN PITUITARY RESPONSIVENESS

As previously mentioned, evidence from the studies appeared to indicate an actual increase in sensitization and improvement in pituitary responsiveness with continuous usage of the TD- GHRH-A. The sustained clinical improvement in physiological responses observed with the use of the TD-GHRH-A further supports the evidence from other independent studies indicating an increase in sensitization and improvement in pituitary responsiveness with ongoing use of the TD-GFHR-A, a component which may prove unique only to this trans-dermal treatment modality.


Figure 14. The results of a study where hourly GH levels were measured in 24 patients, comparing GH release in non-stimulated vs previously stimulated patients. 12 non-stimulated patients were compared with 12 patients administrated TD- GHRH-A earlier that day. Chart shows comparisons of GH released at night.

Figure 14 shows conclusive evidence of the TD-GHRH-A increasing the responsiveness of the pituitary in a small comparison study reported by Rene Martina MD, PhD and Arnold Segredo MD, PhD. Martina and Segredo conducted this study to assess the residual effects of the TD-GHRH-A with the conclusion that the TD-GHRH-A acts directly on the pituitary to stimulate synthesis and release of GH, definitively increasing pituitary responsiveness.

Martina and Segredo administered the TD-GHRH-A to 12 patients at 9am, noon, 3pm and 6pm. Residual effects were then compared to another 12 non-stimulated patients, monitored by hourly GH radioimmunoassays drawn from 6 pm on the same day as administration until 8 am the following morning. All serum samples were drawn via IV's running normal saline at TKO rates in order to prevent sleep disruption, which may have potentially caused changes in GH release evident in subsequent samples. All analyzed samples were preceded with a discard blood specimen to insure the TKO fluids via the IV did not have a dilution effect on the samples. The results noted in Figure 14 clearly show that, although no treatment was administered from 8 pm until 8 am the following day, the stimulated group (treated with the TD-GHRH-A earlier in the day) had between a 2 and 6 fold increase in endogenous GH released during the night compared to the non-stimulated group. This was especially significant around 8 pm, 2 am and 5 am.

Martina and Segredo's conclusion was "most people with idiopathic GH deficiency have an intact pituitary but one that does not release adequate GH. Trans-D Tropin® may be the answer in these cases because it works to stimulate the pituitary to restore the natural physiologic pulsatile release of endogenous GH and is the only physiologic choice to mimic the body's natural pattern of GH release." No other treatment has been established as being able to improve the function and increase the responsiveness of the pituitary to date.

IGF-1 – CANCER

IGF-1 is known to be one of many growth factors and has been thought to be responsible for normal growth. IGF-1 is known to convert in the liver from GH as well as being produced by certain GH target tissues. IGF-1 circulates in the serum, coordinating cellular function and regulating cell growth, division and differentiation, and is considered particularly important in development of children. Yet, despite all these important functions, IGF-1 has been increasingly linked by modern research to human cancer development and progression.

Already innovative cancer therapies and treatment modalities utilizing this crucial information are being developed. For example, at the 93 annual meeting of the American r d Association for Cancer Research, a successful treatment regimen for recurrent gliomas was presented. It involved the active reduction of IGF-1 combined with the previously mentioned findings of Inuki and colleagues ( Metabolism Research 1999;10:576-579) where they found thyroid hormone modulates IGF-1 and IGF-binding protein 3, without mediation by GH. Gliomas are an aggressive form of brain tumors highly resistant to traditional chemotherapy and have a poor survival rate.

Aleck Hercbergs, a radiation oncologist at the Cleveland Clinic Cancer Center in Ohio, observed that individuals with recurrent gliomas responded poorly to the anticancer drug tamoxifen. It is widely known that IGF-1 blocks tamoxifen's ability to kill cancer cells due to its ability to induce cellular proliferation and suppress apoptosis (cellular death). Because Hercbergs was aware that IGF-1 is modulated by the thyroid based on Inuki's work, he reasoned that inducing hypothyroidism might reduce the amounts of IGF-1 and thereby enhance the response rate to tamoxifen. Hercbergs' team developed a treatment strategy involving the inducement of hypothyroidism followed by the administration of tamoxifen. Patients receiving this treatment strategy lived for an average of 7 months longer than those patients not receiving the treatment.

There is growing consensus that IGF-1 levels are not correlated with GH, and now there is a preponderance of evidence showing a significant relationship between IGF-1 and cancer. There are a number of additional published studies that clearly make this correlation between IGF-1 and cancer. A listing of a few of these studies can be found in the recommended reading section. GHRH & IGF-1 CANCER

Kiaris et al from Tulane University wrote a very important paper ( Neoplasia. 2000;2:242- 250.) demonstrating the use of GHRH inhibitors (opposite effect of TD-GHRH-A) to suppress growth of various cancer cell lines. During a conference where the author was presenting a lecture on this subject, a physician familiar with the research of Kiaris and colleagues made a point to use this data as a foundation to counter the author's argument.

The authors of the Kiaris study clearly state that although their paper discussed the use of GHRH inhibitors to suppress cancer growth, that no studies have ever been able to show that GHRH itself stimulates the proliferation of cancer cells. In fact, the actual mechanism cited by these authors for suppression of cancer cells was by reducing the levels of IGF's, which according to Kiaris and colleagues "are known cancer-causing agents secreted by the liver and by tumors themselves." A detailed discussion between the author and one of the Kiaris study authors had taken place 10 months prior, revolving around this very topic.

Kiaris and colleagues used the conventional and widely accepted assumptions regarding IGF- 1. They projected that by administrating GHRH inhibitors, they would decrease the release of GH from the pituitary. The resulting decrease in GH levels would translate into less GH being hepatically converted to IGF-1, thus leading to a decrease in IGF-1. These authors successfully decreased IGF in order to suppress cancer, in this case by inhibiting the release of GH.

This mechanism for suppressing cancer per Kiaris et al was by the actual decrease of IGF-1, exactly the same contention of this author. And if cancer suppression is achieved by decreasing the hepatic conversion of IGF-1 levels as per Kiaris and colleagues, then use of synthetic, recombinant GH injection therapy, which reportedly increases IGF-1 levels, may not only be undesirable but potentially dangerous due to the possibility for promotion of oncogenesis.

Studies have attempted to show possible correlations between GH injection therapy and cancer proliferation. However, none of these studies has been able to single out the variables with an isolated increase in endogenous GH without an increase in IGF-1. Intuitively, most physicians and scientists should recognize that endogenous GH itself could not be responsible for the development of cancer. If that were true, then all cancers would be primarily diagnosed in the late adolescent years of life, which correspond to peak GH levels. But in reality, cancer is a condition that primarily affects most individuals later in life, when IGF-1 levels along with Insulin and Cortisol are observed to be far higher than when the individual was an adolescent.

Since treatment with the TD-GHRH-A conclusively decreased IGF-1 levels as demonstrated in three separate studies, its use may have some benefits to offer patients who suffer from cancer. Currently, there is a plan for a pending trial to assess the TD-GHRH-A in cancer patients but clinical evidence compiled so far supports this conclusion. The use of TD-GHRH-A has been shown to be very helpful in a number of cancer patients with substantial improvements noted in anorexia, insomnia, pain, fatigue, malaise, and the increased ability to ambulate.

IGF-1 AND GH: PROBLEMS WITH CURRENT THEORY

The current thought process regarding the interrelationship of IGF-1 and GH is as follows: IGF-1 results from hepatic conversion of GH. The more GH injected into the body, the higher the IGF-1 levels accumulate. As the limited numbers of IGF-1 receptor sites become saturated from the increasing GH levels being injected (and being converted to IGF-1), IGF-1 serum levels begin to rise. Therefore, the assumption is that increasing levels of GH equate to increasing levels of IGF-1, which represents the ultimate desired result.

However, there is a slight problem with this theory. As we have already discussed in detail, IGF-1 is highly similar to insulin and increasing insulin levels is widely recognized throughout medicine to be a substantially negative occurrence. Chronic hyperinsulinemia is obviously a characteristic of non-insulin dependent diabetes and has now been clearly associated with cardiac disease as well. Remember also, cancer is an obligate sugar feeder, and numerous cancers release their own IGF-1 in order to facilitate glucose uptake.

The solution to the problem is very clear and simple. IGF-1 receptor sites should never be saturated to the point where excess serum IGF-1 levels begin accumulating. The essential components for treatment should be to effectively increase not only GH levels but also increase, if possible, the number of IGF-1 receptor sites. The crucial rate-limiting step in GH replacement treatment must be to never allow serum IGF-1 levels (unbound IGF-1) to exceed physiological limits. The case for the use of any therapeutic that can accomplish these unique parameters (of increasing GH as well as IGF-1 receptor sites) without exceeding normal physiological constraints and without violating the safety negative inhibitory feed back loops implemented by nature, becomes very strong.

CONCLUSIONS

Efficacious GH therapy does not increase IGF-1. Furthermore, a substantial increase of IGF-1 is counter productive, leading to cancer, heart disease, and earlier death. Initial stages of cancer are accompanied by high levels of IGF-1, while certain treatments that suppress IGF-1 have also been shown to inhibit cancer. Regardless of the controversy with IGF-1, the goal of treatment should certainly not be to achieve higher IGF-1 levels since it has clearly been shown that IGF-1 has an association with cancer and is at the very least, an unreliable indicator of GH treatment efficacy, if not inversely related to efficacious GH treatment.

The evidence of a distinct and obvious relationship between cancer and IGF-1 is far more extensive. It is the obligation and responsibility of every physician even remotely considering prescribing a treatment to increase GH levels to review the facts for themselves and make an informed decision. In fact, it is paramount that physicians make their own critical decision regarding this subject after reviewing the facts themselves. History supports the fact that truth in medicine is often manipulated in order to paint a picture beneficial to a specific group or sector with a strong vested financial interest. The future will rightly judge these physicians and sectors harshly. But for most physicians who will suffer the wrath of the law suits that will inevitably unfold in the future as a result of intentionally increasing IGF-1, their fault will only be of blindly following unsound medical principals based on a lack of fundamental understanding of human physiology.

The quest for the truth regarding the IGF-1 controversy and the resulting crusade to correct the IGF-1 misconception began almost five years ago. The controversial nature of the subject sometimes left the author alone in a corner, usually fending of the proponents of increasing IGF- 1. But slowly, the truth has been vindicated as more and more data supports the conclusions drawn by other scientists as far back as 13 years ago. As an ending, this author could not find a more appropriate finale for the subject of IGF and it's correlation to cancer than the direct quote below, taken from a paper published by Yu and Rohan ( J Natl Cancer Inst . 2000;92:1472-1489) entitled " Role of Insulin-Like Growth Factor Family in Cancer Development and Progression".

"Laboratory studies have shown that IGF's exert strong mitogenic and antiapoptotic actions on various cancer cells…IGF's also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth…The role of IGF's in cancer is supported by epidemiologic studies, which have found that hi gh levels of circulating IGF-1 and l ow levels of IGFBP-3 are associated with increased risk of [many] cancers ...IGF's are related to increased cell proliferation, suppression of apoptosis and increased cancer risk."

The goal of all medical therapies is not only to extend life but to improve the quality of that extended life. Upon the advent of GH, this goal was thought to have been achieved. However, the irrefutable correlation between increasing IGF-1 and cancer clearly shows otherwise. The possibility of cancer mandates a thorough consideration and understanding of the information presented for all physicians considering manipulation of their patient's hypothalamic-pituitary axis. The ethical and fiduciary relationship to the patient necessitates this understanding of the inter-relationship between GH and IGF-1 and the correlation between IGF-1 and cancer so as to abide by the first and foremost rule of medicine - Do No Harm.

REFERENCES

  1. Aimaretti G, Corneli G, Razzore P, et al.  Usefulness of IGF-1 assay for the diagnosis of GH deficiency in adults.   Journal of Endocrinology Investigation  1998;21:506-511.

  2. Bio technology and the American agricultural industry. Council on Scientific Affairs, American Medical Association.  JAMA . 199 ; 265:1429-1436.

  3. Attard -Montalto SP, Camachoo-Hubner C, Cotterill AM.  Changes in protein turnover, IGF-1 and IGF binding proteins in children with cancer.   Acta  Paediatrica  1998;87:54-60.

  4. Balteskard L, Unneberg K, Mjaaland M, et al.  GH and IGF-1 promote intestinal uptake and hepatic release of glutamine in sepsis.   Annals of Surgery  1998;228:131-139.

  5. Barb arino A, Corsello SM, Della Casa S, et al: Corticotropin-releasing hormone inhibition of GHRH-induced GH release in man.  Journal of Clinical Endocrinology and Metabolism  1990;71: 1368-1374.

  6. Barry MC, Mealy K, O’Neill S, et al. Nutritional, respiratory, and psychological effects of recombinant human growth hormone in patients undergoing abdominal aortic aneurysm repair.  Journal of Parenteral and Enteral Nutrition  1999;23:128-135.

  7. Bartke, A October 2000 Conference Report, as reported by Ivy Greenwell.  Private communication between Greenwell and  A. Bartke, PhD, LifeExtension Magazine, February 2001

  8. Bates AS, Evans AJ, Jones P, et al.  Assessment of GH status in adults  with GH deficiency  using serum GH, serum IGF-1 and urinary GH excretion.  Clinical Endocrinology  1995;42:425-430.

  9. Borges MH, Pinto AC, DiNinno FB, et. Al.  IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in  man.  Journal of Endocrinological Investigation  1999;22:12-7.

  10. Brunner, Eric. Safety of b ovine somatotropin. The Lancet, September 10, 1988, p. 629 (letter to the editor)

  11. Bulow B, Erfurth EM. A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-1 without significant deterioration in glucose tolerance. Clinical Endocrinology  1999;50:45-55.

  12. Buttar RA, Viktora DC, Quinn ME.  Accelerated and efficacious results using variable somatotroph and hypothalamotroph specific poly-peptide combinants utilizing a trans-dermal delivery mechanism (TD-GHRH-A) as an alternative to recombinant human growth hormone injection therapy. Journal of Integrative Medicine  2000;4:51-61.

  13. Buttar RA, October 2000 Conference Report for the American College for Advancement in Medicine, reported by Ivy Greenwell, reporter for LifeExtension Magazine, February 2001.

  14. Buttar RA, Halpner A. The impact of essential fatty acids on the aging process.  In: Ghen MJ. The Advanced Guide to Longevity Medicine. IMPAKT Communications, Inc;  2001: 221-237.

  15. Campbell PC, Baumrucker CR. Characterization of insulin-like growth factor-l/somatomedin-C receptors in bovine mammary gland  Endocrinology  1985; 116 (Suppl. Abstract:L223).

  16. Carani C, Granata AR, De Rosa M, et al. The effect of chronic treatment with GH on gonadal function in men with isolated GH deficiency.  European Journal of Endocrinology  1999;140:224-230.

  17. Casanueva FF, Burguera B, et al. Depending on the time of administration, dexamethaso ne potentiates or blocks GHRH-induced GH.  Neuroendocrinology  1988; 47: 46-49.

  18. Cascinu S, Del Ferro  E, Grianti C, et al. Inhibition of tumor cell kinetics and serum insulin growth factor I levels b y octreotide in colorectal cancer patients.       Gastroen terology . 1997;113:767-772.

  19. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.  Science.  1998;279:563-566.

  20. Chapman IM, Hartman ML, Pieper KS, et al. Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I.   Journal of Clinical Endocrinology and Metabolism  1998;83:2836-2842.

  21. Chwals WJ, Bistrian BR. Ro le of exogenous GH and IGF-1 in malnutrition and acute metabolic stress: a hypothesis.  Critical Care Medicine  1991;19:1317-1322.

  22. Cittadini A, Longobardi S, Fazio S, Sacca L. Growth hormone and the heart. Miner Electrolyte Metab . 1999;25:51-55.

  23. Coghlan, Andy. Arguing till the cows come home. New Scientist 1994; October 29:14-15.

  24. Coghlan, Andy. Milk hormone data bottled up for years. New Scientist 1994; October 22:4.

  25. Cohen P, Peehl DM, Lamson G, Rosenfeld RG. Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab . 1991;73:401-407.

  26. Coiro V, Volpi R, Capretti L, Caffarri G, Davoli C, Chiodera P. Age-dependent decrease in the growth hormone response to growth hormone-releasing hormone in normally cycling women.  Fertil Steril . 1996;66:230-234.

  27. Daughaday, WH, Barbano DM. Bovine Somatotropin supplementation of dairy cows - Is the milk safe?  Journal of the American Medical Association  1990;264:1003-1005.

  28. Donovan SM, Growth Factors in Milk as mediators of infant development. Annual Review of Nutrition 1994;14:147-167.

  29. Epstein SS. Potential public health hazards of biosynthetic milk hormones. International Journal of Health Services  1990;20:73-84.

  30. Epstein SS. Questions and answers on synthetic bovine growth hormones.  International Journal of Health Services  1990;20;573-582.

  31. Epstein SS. Unlabeled milk from cows treated with biosynthetic growth hormones: a case of regulatory abdication.  International Journal of Health Services  1996;26:173-185.

  32. Evans WS, Vance ML, Kaiser DL, et al. Effects of IV, SQ, and intranasal administration of GHRH-40 on seru m GH concentration in adult men. Journal of Clinical Endocrinology and Metabolism 1985;61:846-850.

  33. Farmer C, Dubreuil P, Couture Y, et al. Hormonal changes following an acute stress in control and somatostatin-immunized pigs.  Domestic Animal Endocrinology  1991;8:527-536.

  34. Ferraccioli G, Guerra P, Rizzi V, et al. Somatomedin C (IGF-1) levels decrease during acute changes of stress related hormones. Relevance for fibro myalgia. Journal of Rheumatology  1994;21:1332-1334.

  35. Furlanetto RW. Insulin-like growth factor measurements in the evaluation of gro wth hormone secretion.  Hormonal Research  1990;33:25-30.

  36. Gelato MC. Aging and immune function: a possible role for growth hormone. Hormonal Research 1996;45:46-49.

  37. Ghigo E, Goffi S, Arvat E, et al:   Pyridostigmine partially restores the GH responsiveness to GHRH in normal aging.  Acta Endocrinology   (Copenh)  1990;123:169-173.

  38. Girard N, Boulanger L, Denis S, et al. Differential in vivo regulation of the pituitary GHRH (GH releasing hormone) receptor by GHRH in young and aged rats.  Endocrinology  1999;140:2836-2842.

  39. Giusti M, Marini G, Sessarego P, et al. Effect of cholinergic tone on GHRH induced secretion of growth hormone in normal aging.  Aging  1992;4:231-237.

  40. Giusti M, Marini G, Sessarego P, et al. Growth hormone secretion in aging. Effect of pyridostigmine on growth hormone responsiveness to growth hormone-releasing hormone.  Recenti Progress Medicine 1991;82:665-668.

  41. Giustina A, Bossoni S, Bodini C, et al. The role of cholinergic tone in modulating the GH response to GHRH in normal man.  Metabolism  1991;40: 519-523.

  42. Giustina A, Doga M, Bodini C, et al. Acute effects of cortisone acetate on GH response to GHRH in normal adult subjects.  Acta Endocrinol (Copenh)  1990;122:206-210.

  43. Grossman, CJ. Genetic engineering and the use of bovine somatotropin.  JAMA  1990;264:1028.

  44. Grossman T.  The Baby Boomers Guide to Living Forever . The Hubristic Press: 2001.

  45. Gupta SK, Krishnan RR, Ellinwood EH, Ritchie JC, Nemeroff CB. Pharmacokinetics of growth hormone secretion in humans induced by growth hormone releasing hormone.     Life Sci . 1990;47:1887-1893.

  46. Hagberg JM, Seals DR, Yerg JE, et al. Metabolic responses to exercise in young and older athletes and sedentary men.  Journal of Applied Physiology  1988;65:900-908.

  47. Hakkaart-Van RL, Roijen L, et al. The burden of illness of hypo-pituitary adults with growth hormone deficiency.  Pharmacoeconomics  1998;14:395-403.

  48. Hendrix DK, Klien TE, Kuntz ID. Macromolecular docking of a three-body system: the recognition of human growth hormone by its receptor.  Protein Science  1999;8:1010-1022.

  49. Houston-Bolze MS, Downing MT, Sayed AM, et al. Serum IGF binding protein-3 responds differently to trauma in men and women.  Critical Care Medicine  1999;24:1988-1992.

  50. Inuki T, Takanashi K, Takebayashi K, et al. Thyroid hormone modulates insulin-like growth factor-1(IGF-1) and IGF-binding protein-3, without mediation by growth hormone, in patients with autoimmune thyroid disease.  Metabolism Research  1999;10:576-579.

  51. Isgaard J, Tivesten A, Friberg P, et al. The role of the GH / IGF-1 axis for cardiac function and structure.  Hormonal Metabolism Research  1999;31:50-54.

  52. Jaffe CA, DeMott-Friberg R, Barkan AL. Endogenous growth hormone (GH)-releasing hormone is required for GH resp onses to pharmacological stimuli. J Clin Invest. 1996;97:934-940.

  53. Jaffe CA, Ho PJ, Demott-Friberg  R, Bowers CY, Barkan  AL. Effects of a  prolonged growth  hormone (GH)-releasing peptid e infusion on pulsatile GH secretion in normal men. J Clin Endocrinol Meta b .1993;77:1641-1647.

  54. Janssen YJ, Helmerhorst F, Frolich M, et al. A switch from oral (2 mg/day) to trans-dermal (50 micro/day) 17 beta-estradiol therapy increases serum IGF-I levels in recombinant hGH substituted women with GH deficiency. J Clin Endocrinol Metab  2000;85:464-466.

  55. Jorgensen JO, Pedersen SB, Borglum J, et al. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. European Journal of Endocrinology  1995;133:65-70.

  56. Juskevich, JC, Guyer, CG. Bovine growth hormone food safety evaluation.  Science  1990;249:875-884.

  57. Juul A, Andersson AM, Pedersen SA, et al. Effects of growth hormone replacement therapy on IGF- related parameters and on the pituitary-gonadal axis in GH-deficient males. A double- blind, placebo- controlled crossover stud y.  Hormonal Research  1998;49:269-278.

  58. Kawai N, Kanzaki S, Takano-Watou S, et al. Serum free insulin-like growth factor I (IGF-I), total IGF- I, and IGF- binding protein-3 concentrations in normal children and children with growth hormone deficiency.  J Clin Endocrinol Metab  1999;84:82-89.

  59. Kelijman M, Frohman LA: Impaired inhibitory effects of somatostatin on GHRH stimulation of GH secretion after short term infusion. Journal of Clinical Endocrinology and Metabolism 1990 July; 71(1): 157-163.

  60. Khalsa, DS. Exelon: A new drug for Alzheimer's Disease.  International Journal of Anti-Aging Medicine  1998;1:54-46.

  61. Kiaris H, Schally AV, Varga JL. Antagonists of gro wth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice.  Neoplasia . 2000;2:242-250.

  62. Kozakowski J, Adamkiewicz M, Krasso wski J, et al. The beneficial effects of GH replacement therapy on elderly men [in Polish].  Polish Merku riusz Lek  1999;6:131-134.

  63. Kronfeld DS. Bovine somatotropin.  JAMA  1991;265:1389-1391.

  64. LeRoith D, Werner H, Neuenschwander S, Kalebic T, Helman LJ. The role of the insulin-like growth factor-I receptor in cancer.  Ann N Y Acad Sci . 1995;766:402-408.

  65. LeRoith D, Clemmons D, Nissley P, Rechler MM. NIH conference. Insulin-like gro wth factors in health and disease. Ann Intern Med. 1992;116:854-62.

  66. Lippman ME. The development of biological therapies for breast cancer. Science  1993;259:631-632.

  67. Low LC. GHRH clinical studies and therapeutic aspects. Neuroendocrinology  1991;53:37-40.

  68. Malarkey WB, Burleson M, Cacioppo JT, et al. Differential effects of estrogen and medroxyprogesterone on basal and stress-induced growth hormone release, IGF-1 levels, and cellular immunity in postmenopausal women.  Endocrine  1997;7:227-233.

  69. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer. 1997;76:1115-1118.

  70. Marcell TJ, Wiswell RA, Hawkins SA, Tarpenning KM. Age-related blunting of growth hormone secretion d uring exercise may not be soley due to increased somatostatin tone. Metabolism. 1999;48:665-70.

  71. Martha PM Jr, Blizzard RM, McDonald JA, Thorner MO, Rogol AD. A persistent pattern of varying pituitary responsivity to exogenous growth hormone (GH)-releasing hormone in GH-deficient children: evidence supporting periodic somatostatin secretion.     J Clin Endocrinol Metab . 1988;67:449- 54.

  72. Mazzoccoli G, Giuliani A, Bianco G, et al. Decreased serum levels of insulin-like growth factor (IGF)- I in patients with lung cancer: temporal relatio nship with growth ho rmone (GH) levels. AnticancerResearch . 1999;19:1397-1399.

  73. McCusker RH. Controlling IGF activity and the modulation of IGF binding protein and receptor binding.  Journal of Dairy Science   1998;81:1790-1800.

  74. Mepham TB, Schofield PN, Zumkeller W, Cotterill AM. Safety of milk from cows treated with bovine somatotropin. Lancet. 1994;344:1445-1446.

  75. Mepham TB. Bovine somatotropin and public health. BMJ. 1991;302:483-484.

  76. Merriam GR, Kletke M, Barsness S, et al.  GHRH in Normal Agin g: An Update. Today’s TherapeuticTrends  2000;18:335-354.

  77. Murphy LJ, Seneviratne C, Moreira P, et al. The effects of insulin and growth hormone administration. Endocrinology  1991;128:689-696.

  78. National Institutes of Health, Technology Assessment Conference Statement on Bovine Somatotropin. JAMA  1991;265:1423-1425.

  79. Norrelund H, Fisker S, Vahl N, et al. Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels.  Growth  Horm IGF Res   (Denmark)  1999;9:52-60.

  80. Ohlsson C, Sjogren K, Jansson JO, Isaksson OG. The relative importance of endocrine versus autocrine/paracrine IGF-1 in the regulation of body growth.  Pediatric Nephrology   2000;14:541-543.

  81. Papa V, Gliozzo B, Clark GM, et al. Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer.  Cancer Res . 1993;53:3736-3740.

  82. Playford RJ, Woodman AC, Clark P, et al. Effect of luminal growth factor preservatio n on intestinal growth.  Lancet . 1993;341:843-848

  83. Pontiroli AE, Lanzi R, Monti LD, Sandoli E, Pozza G. Growth hormone (GH) autofeedback on GH response to GH-releasing hormone. Role of free fatty acids and somatostatin. J Clin Endocrinol Metab . 1991;72:492-495.

  84. Pyka G, Wiswell RA, Marcus R. Age-dependent effect of resistance exercise on growth hormone secretion in people.  J Clin Endocrinol Metab . 1992;75:404-407.

  85. Rattan SI. Is gene therap y for aging possible? Indian J Exp Biol . 1998;36:233-236.

  86. Ganong WF, Lange J, et al.  Review of Medical Physiology . 15th Edition. McGraw-Hill/Appleton & Lange; 1991: 214-236, 350-352.

  87. Rollero A, Murialdo G, Fonzi S, et al. Relationship between cognitive function, growth hormone and insulin-like gro wth factor I plasma levels in aged subjects. Neuropsychobiology . 1998;38:73-79.

  88. Rooyackers OE, Nair KS. Hormonal regulation of human muscle protein metabolism. Annu Rev Nutr. 1997;17:457-485.

  89. Rosenfeld, RG, et al. Insulin-like growth factor binding proteins in neoplasia. Paper presented at: Hormones and Growth Factors in Development and Neoplasia, Fogarty International Conference; June 26-28, 1995;Bethesda, MD.

  90. Ross RJ, Tsagarakis S, Grossman A, et al. GH feedback occurs through modulation of hypothalamic somatostatin  under cholinergic control: studies with pyridostigmine and GHRH. Clinical Endocrinology  1987;27:727-733.

  91. Rubin AL, Goodman M. Milk safety.  Science  1993;264:889-890.

  92. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med . 1990;323:1-6.

  93. Spoudeas HA, Matthews DR, Brook CG, et al. The effect of changing somatostatin tone on the pituitary GH and TSH responses to their respective releasing factor  stimuli. J Clin Endocrinol Metab. 1992;75:453-458.

  94. Spoudeas HA, Winrow AP, Hindmarsh PC, Brook CG. Low-dose growth hormone-releasing hormone tests: a dose-response study.  Eur J Endocrinol . 1994;131:238-245.

  95. Stoll BA. Breast cancer: further metabolic-endocrine risk markers? Br J Cancer.  1997;76:1652-1654.

  96. Stromer H, Cittadini A, Douglas PS, Morgan JP. Exogenously administered growth ho rmone and insulin-like growth factor-I alter intracellular Ca2+ handling and enhance cardiac performance. In vitro evaluation in the isolated isovolumic buffer-perfused rat heart.  Circ Res . 1996;79:227-236.

  97. Jorgensen JO, Pedersen SB, Borglum J, et al. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. Eur J Endocrinol. 1995;133:65-70.

  98. Vance ML, Kaiser DL, Rivier J, Vale W, Thorner MO. Dual effects of growth hormone (GH)-releasing hormone infusion in no rmal men: somatotroph desensitizatio n and increase in releasable GH. J Clin Endocrinol Metab . 1986;62:591-594.

  99. Vance ML, Kaiser DL, Evans WS, et al. Evidence for a limited growth hormone (GH)-releasing hormone (GHRH)-releasable quantity of GH: effects of 6-hour infusions of GHRH on GH secretion in normal man. J Clin Endocrinol Metab . 1985;60:370-375.

  100. Wilson, J D,  Foster, D W, eds.  Williams Textbook of Endocrinology , 8th edition. London, England: W.B. Saunders Company; 1992: 1096-1106.

  101. Wolf SE, Barrow RE, Herndon DN. Growth hormone and IGF-I therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab . 1996;10:447-463.

  102. Yakar S, Liu JL, Stannard B, et al. Normal growth and development in the absence of  hepatic insulin- like growth factor I.  Proc Natl Acad Sci U S A.  1999;96:7324-7329.

  103. Yohay D, Lunenfeld E, Giat Y, et al. Do changes in growth hormone levels correlate with IGF-I levels in patients undergoing IVF-ET?  Gynecol Endocrinol . 1997;11:269-274.

  104. Yu H, Ro han T. Role of the insulin-like growth factor family in cancer d evelopment and progressio n. J Natl Cancer Inst. 2000; 92:1472-1489.

RECOMMENDED READING

GH and IGF-1 Levels

  1. Juul A, Andersson AM, Pedersen SA, et al. Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitary-gonadal axis in GH-deficient males. A double- blind, placebo-controlled crossover study.  Hormonal Research  1998; 49:269-278.

  2. Yohay D, Lunenfeld E, Giat Y, et al. Do changes in gro wth  hormone levels correlate with IGF-I levels in patients undergoing IVF-ET?  Gynecol Endocrinol . 1997;11:269-274.

  3. Aimaretti G, Corneli G, Razzore P, et al.  Usefulness of IGF-1 assay for the diagnosis of GH deficiency in adults.   Journal of Endocrinology Investigation  1998;21:506-511.

  4. Murphy LJ, Seneviratne C, Moreira P, et al. The effects of insulin and growth hormone administration. Endocrinology  1991;128:689-696.

  5. Norrelund H, Fisker S, Vahl N, et al. Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels. Gro wth Horm IGF Res (Denmark)  1999;9:52-60.

  6. Borges MH, Pinto AC, DiNinno FB, et. Al.  IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man. Journal of Endocrinological Investigation  1999;22:12-7.

  7. Mazzoccoli G, Giuliani A, Bianco G, et al. Decreased serum levels of insulin-like growth factor (IGF)-I in patients with lung cancer: temporal relationship with gro wth ho rmone (GH) levels. Anticancer Research . 1999;19:1397-1399.

  8. Furlanetto RW. Insulin-like gro wth factor measurements in the evaluation of growth hormone secretion. Hormonal Research  1990;33:25-30.

IGF-1 Cancer

  1. Cohen P, Peehl DM, Lamson G, Rosenfeld RG. Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab. 1991;73:401-407.

  2. Lippman ME. The development of biological therapies for breast cancer. Science  1993;259:631-632.

  3. Papa V, Gliozzo B, Clark GM, et al. Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res . 1993;53:3736-3740.

  4. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563-566.

  5. Stoll BA. Breast cancer: further metabolic-endocrine risk markers? Br J Cancer.  1997;76:1652-1654.

  6. LeRoith D, Werner H, Neuenschwand er S, Kalebic T, Helman LJ. The role of the insulin-lik e growth factor-I receptor in cancer. Ann N Y Acad Sci. 1995;766:402-408.

  7. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos D, Adami HO. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer . 1997;76:1115-1118.
  8. Cascinu S, Del Ferro E, Grianti C, et al. Inhibition o f tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients. Gastroenterology . 1997;113:767-772.

ABOUT THE AUTHOR

Dr. Buttar attended Medical School at the University of Osteopathic Medicine and Health Sciences, College of Osteopathic Med icine and Surgery in Des Moines, Iowa. He is board certified in Preventive Medicine and Clinical Metal Toxicology and bo ard eligible in Emergency Medicine. Dr. Buttar practices in Charlotte, NC, where he is the Medical Director of Advanced Concepts in Medicine, a clinic specializing in the treatment of cancer, heart disease, and other chronic medical conditions in patients refractory to conventional medical treatments. He also serves as Director of Clinical Research and Development for V- SAB Medical Laboratories where he is extensively involved in research with polypeptide sequencing and identification technologies, as well as unique methodologies for efficient drug delivery mechanisms.

Correspondence: For physicians who desire to contact the author or to obtain further information regarding various treatment protocols, send an email to DrBAssistant@DrButtar.com or call (+1) 704-895-9355. Physicans seeking additional technical information TD-GHRA-A (Trans-D Tropin® or who may wish to purchase Trans-D Tropin® may contact their local pharmacy or email docinquiry@drbuttar.com.




Philadelphia Seminar