As discussed previously, IGF-1 levels are useful in assessing a subject’s adult growth hormone deficiency status as well as monitoring response to growth hormone therapy.  IGF-1 also is a well-accepted independent marker of disease risk in its own right. 

Roubenoff and Cappola both pointed out the inverse association between IGF-1 levels and mortality risk.  Both studies revealed that in patients with lower IGF-1 levels, there is generally increased risk for mortality compared to an otherwise matched normal cohort. ^{14 15} 

These studies use IGF-1 as an objective marker of actuarial risk. This use of IGF-1 establishes a direct relationship between its measurement and patient outcomes in the same way we use other well-established markers of disease/mortality risk. 

Roubenoff’s study followed subjects who were part of the Framingham Heart Study over a 22-year period and found 13% lower mortality for IGF-1 values in the upper two quartiles (all subjects above the mean) versus those in the lower two quartiles. ¹⁴  slide16

This was independent of all other risk factors and remained consistent when adjusted for the presence of other risk markers, such as smoking history, lipids, etc.   

Denti, in 2004, looked at the connection between IGF-1 levels and stroke outcome in elderly patients.  Outcomes were stratified as to both mortality risk and “quality” of outcome.  

This study found there was a potent inverse relationship between IGF-1 levels and outcome quality and mortality risk. For each 20 ng/ml increase in IGF-1 levels seen in stroke patients, the mortality risk was reduced by 30%.  The conclusion was that low levels of circulating IGF-1 may predict clinical outcomes of stroke in elderly patients. ¹⁶

In a study similar to Framingham, the Rancho Bernardo Study, an ongoing community-based study of healthy aging adults followed over long-time intervals. Over a 13-year, follow-up span, IGF-1 levels again were inversely associated with both total mortality and cardiovascular disease risk rates.  

For every 40ng/ml decrease of IGF-1 below the mean, there was a 38% increase in total mortality.  This study also was controlled for any potential effect of IGF-1 on any specific type of mortality. IGF-1 was not associated with any elevation of risk for any other etiology of subject mortality.  Their conclusion was that low baseline levels of IGF-1 are associated with increased risk heart disease mortality among aging patients. ¹⁷

Thus far, with regard to the clinical utility of using IGF-1 laboratory values in the clinical setting, we have demonstrated the following points:

• IGF-1 levels are, in fact, most likely adequate for the evaluation of a subject’s growth hormone status.

• IGF-1 levels are well-accepted as treatment markers with regard to assessing growth hormone dosing for adult deficiencies, with a direct and dependable relationship, existing between growth hormone dose and IGF-1 levels.

• IGF-1 has been demonstrated to be an independent marker of disease risk in community dwelling populations; there is an inverse correlation between IGF-1 and disease risk.

In addition to using IGF-1 to determine patient diagnostic status, clinical trials have been undertaken looking only at outcomes after growth hormone intervention in certain clinical settings.  In multiple studies, the use of growth hormone as a clinical intervention of adult deficiencies has demonstrated a positive impact on other markers of disease risk. 

In 2005, Franco demonstrated a reduction in abdominal visceral fat in obese patients in association with growth hormone therapy.  Albert, in 2004, showed similar findings with regard to improving clinical outcomes in obese patients; Johannsson found similar outcomes and additionally reported improvements in glucose and lipoprotein metabolism.  These studies demonstrate the utility of growth hormone replacement therapy with no regard placed on the requirement for “failing” an insulin tolerance test before a patient is allowed access to therapy. ^{19 67 68}

In 2004, the American Heart Association published a review by Conti, illustrating the vascular protective effects of IGF-1. Their findings demonstrated multiple positive findings, regarding IGF-1’s beneficial impact on heart disease risk and heart disease and other metabolic outcomes. Looking at factors associated with increased cardiovascular risk, they found that with each marker studied, there was a universal association with lower IGF-1 levels. Click this hyperlink to read the full article, as published: http://circ.ahajournals.org/cgi/content/full/110/15/2260  ⁶⁹

In the first section of this module, the correlation between IGF-1 and growth hormone levels was reviewed. 

It is important to keep in mind that the insulin tolerance test has remained in popular use despite the more recent studies that appear to show IGF-1 to be a more reliable test. There is ample evidence in the utility of IGF-1 level use for determining, with a proper clinical context, whether or not a subject is likely to benefit from undertaking growth hormone modulation therapy for adult deficiency. 

Benefits of Growth Hormone

The benefits of growth hormone replacement in proven adult growth hormone deficiencies are essentially the inverse of the signs and symptoms associated with low growth hormone levels.  Studies have shown decreased body fat, increased bone density, increased aerobic performance, immune stimulation, positive changes in the nature of skin, improvement in lipid profiles, improvement in sleep patterns and increased reports of well-being.  

One of the first studies to show these pleiotropic effects of growth hormone was published by Rudman in the New England Journal of Medicine in 1990.  This study has been the basis for many of the claims made on behalf of growth hormone replacement therapy for adult growth hormone deficiencies.  Rudman found that in association with a rise in IGF-1 levels, there was an associated increase in lean mass, decline in fat mass, improvement in skin thickness and lumbar bone density.  Noted is the fact this was only a six-month trial and accomplished in the absence of nutritional or exercise counseling or support. ¹⁸ slide17

Blackman reported similar findings in a National Institute of Aging study.  Like Rudman, Blackman targeted IGF-1 levels, associated with normal range for approximately 20 to 25 year olds.  While there was no change in total body weight, lean body mass showed an increase with associated reductions in body fat.   

These two studies are important because they are the most often quoted in the popular press. However, both showed a high side effect incidence, with Blackman reporting approximately a 35% overall adverse reaction rate.  The two studies only used subjects above 60 years of age and, compared to what is now considered typical replacement dosing, were high-dose studies—both began at doses of approximately 21 units per week. ^{18 20} slide18

Although popular as a marketing tool, the results of these studies should give us pause with regard to using such high doses of growth hormone for adult growth hormone deficiencies when considering side-effect incidence and dosing targets.   

Given their adverse effect rate, short duration of study and lack of accompanying nutritional or exercise control, it could be concluded these studies yielded positive findings despite therapy. 

In a study published by Gibney in 1999, results of a 10-year study were reported, regarding growth hormone replacement in adult growth hormone deficient patients. Gibney found that increases in lean body mass, improved cholesterol profiles and reports of well-being were increased in association with growth hormone therapy and maintained over a long duration. At the end of the 10-year trial, it was found that carotid intimal thickness was greater in the placebo group than in the treatment group.  This measure is yet another independent marker of cardiovascular disease risk. Gibney’s study is much more clinically apt than the more popular Rudman and Blackman results, even though it is less mentioned. ²¹

Quality of Life and Well-being

For replacement therapy, the beneficial effect of GH replacement on psychologic well-being and QOL  in adults who have GHD is an important endpoint for replacement. The area of QOL to be affected by GHD was energy and vitality.  Some studies showed definite benefit after patients received GH replacement therapy but in othersimprovements were more limited or no improvement was seen.^{113 140 149 158} This aspect of treatment should be monitored clinically or by standardized self- administered questionnaires, or preferably both. ^{120 145 158}

GHD patients who had a subjectively low QOL on clinical interview and were treated  with GH were seen to improve using two questionnaires.  Strategy is to quantify the degree of psychologic impairment at baseline and use it in the monitoring of treatment. One third of patients did not have noticeable QOL improvements until GH had been administered for at least 6 months.¹²⁰ Some studies have shown that much of the improvement in quality of life occurs within the first 3 months of GH replacement. The implications are that once the decision has been made to initiate GH therapy, the therapy should be continued for an adequate period of time before judgements are made regarding its efficacy in improving QOL and psychologic well-being.  Improvements in QOL may be further delayed in some patient receiving individual dose titration after starting with a low dose of GH.

Glucose and Lipid Metabolism

Insulin sensitivity is reduced in adults who have GHD and following short-term GH replacement but later return to baseline values. ¹⁶⁵ The prevalence of an increase in the incidence of diabetes during GH replacement is more than what is expected in the background population.

The net effect on plamsa lipids during GH replacement is consistent reduction in total and LDL cholesterol and apoprotein B, and in some studies increases in HDL cholesterol concentration.¹³⁸ Most marked improvements occur in individuals in whom the most abnormal baseline values exist.¹²⁰

Baseline plasma lipids should be measured before GH treatment as an overall assessment of CV risk profile and continue to be monitored on a regular basis.  Assessment of glucose metabolism can be performed by using the oral glucose tolerance test or measuring fasting levels of glucose to monitor long-term trends.¹²⁰

Cardiovascular Health

In several large trials, GH replacement has resulted in a slight decrease in blood pressure.¹³⁸  Administration of GH reduces C-reactive protein concentrates, and this effect persists for as long as 18 months .  Most but not all studies have shown increase in high-density lipoprotein and decreases LDL and total cholesterol after institution of GH replacement therapy.^{76 92 125 138 140} 

A fourth CV parameter is insulin resistance.  GH replacement lowers fat mass, and increasing IGF-I improves insulin sensitivity. If high doses of GH are given, then sensitivity deteriorates acutely as a result of increased free fatty acid release)  However, low doses given for 6-12 months cause no change in insulin sensitivity. ^{165 105 161} Because individual patients have differential sensitivity in these parameter, it is not suprising that some show a worsening of insulin sensitivity after administration of GH, whereas others show little change. 

 Increased intimal-medial thickness (IMT) and abnormal arterial wall  dynamics have been documented in GHD. ^{135 148 163}  Administration of GH to GH–deficient adults resulted in decreased IMT.  In epidemiological studies , increases in IMT have predicted the development of symptomatic coronary disease occurring approximately eight years after the initial measurements. 

 Cardiac function may also be significantly impaired in GHD.  The most consistent  increases after GH administration were in LV mass, LV end diastolic volume, and stroke volumes. ¹³⁸ It is possible that changes in these parameters correlate with the reported subjective benefits in increased exercise tolerance and energy that have been reported by GH-deficient patients after replacement therapy 

Growth Hormone “Secretagogues” 

In the quest to deliver adequate growth hormone replacement for adult growth hormone deficiency in the most efficacious and efficient way possible, the question of growth hormone secretagogues is frequently raised.  There are many websites and retailers touting the benefits of growth hormone replacement therapy—then making claims that oral products are capable of achieving these results.  The good news with regard to these products is that most do nothing.  The bad news is that some of these products may do something.

Two commonly touted oral secretagogues are Ghrelin and Hexarelin. slide19 These are short-chain amino acid compounds that have shown some physiologic activity when administered orally. Given as an oral supplement, Ghrelin has been demonstrated to produce a 4-fold increase in growth hormone secreation versus growth hormone releasing hormone (GHRH).  Hexarelin has been demonstrated to have a 2.5 fold increase in growth hormone release versus a controlled dose of GHRH. ⁷⁰ As the graph points out, the upper curve (representing Ghrelin) and the middle curve (representing Hexarelin) demonstrate a substantial impact on growth hormone secretion after administration.  If the story ended there, these would be potentially useful products.   

However, Ghrelin and Hexarelin also have an impact on other pituitary hormones.  In this figure, the graph on the upper left represents the impact of these two supplements on ACTH production.  Both secretagogues cause a substantial increase in ACTH, which is the driving hormone for cortisol production.   

The curve on the upper right demonstrates their impact on prolactin secretion.  Increases in prolactin are associated with decreases in endogenous luteinizing hormone and testosterone levels.   

The graph slide20  on the lower left demonstrates the impact of these secretagogues on cortisol levels. As would have been suggested by the ACTH data, cortisol levels rise in response to secretagogue administration. Interventions that chronically raise cortisol levels are associated with long-term side effects, such as thinning of skin, loss of lean mass, gain in fat mass, increase in blood glucose, increase in intraocular pressure, increase in insulin levels and increased blood pressure—all are at odds with the desired outcomes of improving growth hormone metabolism.  ⁷¹

On the lower right, Ghrelin is associated with increasing aldosterone levels. Increased aldosterone levels are associated with increasing sodium retention and fluid volume.   

In summary, Ghrelin administration is associated with a seven-fold increase in ACTH, seven-fold increase in prolactin, a doubling of cortisol levels and a doubling of aldosterone levels. ⁷²

Hexarelin administration is associated with a greater than three-fold increase in ACTH, a four-and-a-half-fold increase in prolactin, and a near doubling of cortisol levels.  Hexarelin did not affect aldosterone levels. 

Although they cause increased growth hormone production, the overall impact of these molecules on hormone secretion patterns skews heavily toward a highly unfavorable hormone profile and should be avoided. 

Route of Administration and Dosing

Currently, the proper route of growth hormone delivery is only via subcutaneous injection. Growth hormone is a peptide hormone 191 amino acids in length.  Given its size and composition, it is not capable of being absorbed transdermally, sublingually or orally.  To maintain proper IGF-1 kinetics, current formulations of growth hormone require a daily injection. Typically this is well tolerated since it requires only a 30 or 31-guage needle, is a subcutaneous injection and is relatively independent of injection location, making for easy self-administration by a patient.   

Typical starting dose for growth hormone therapy for adult growth hormone deficient patients is expressed in units per week with an average of 7 to 8 units per week being a starting dose (1.15 to 1.25 international units per day).  This amount is divided into daily doses, six days per week. Given at this dosing interval, IGF-1 level responses are stable and well-maintained over time. Alternate day dosing has been associated with higher weekly dosage requirements to maintain adequate IGF-1 levels—i.e. higher weekly dose for the same clinical response. For the near term, growth hormone will continue to require a daily dose.  slide21

Growth hormone has a slightly sigmoid-shaped dose response curve. At sub-therapeutic doses, there may be no associated rise in IGF-1 levels; but with relatively small dosage changes within the therapeutic range, relatively large changes in IGF-1 values can be obtained. In general, when changing growth hormone doses, a one- or two-unit/per-week dosage change usually can be expected to yield a measurable result.  slide22

A 32-week study was conducted by Hartman et al ¹¹¹ to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen.  There were 29 patients in the study. The study compared an individualized GH dosing regimen (ID) with a fixed body weight-based dosing regimen. ^{111 146} In summary, GH replacement therapy in GH-deficient adults improved VO2 max( maximal oxygen comsumption) similarly with both dosing regimens, without any influence of physical activity.  There was no effect on submaximal exercise performance.  These results areclinically relevant because they demonstrate dosing regimens now recommended by consensus clinical guidelines will improve aerobic exercise capacity. ^{111 146}

Side Effects of Growth Hormone Therapy

The most common growth hormone related side effect for adult growth hormone deficient patients undergoing treatment is edema or subjective sensation of water retention. These patients may also report joint stiffness or a subjective sensation of higher resistance to movement in their joints, or even frank joint pain.  According to Cengenics Medical Institute’s unpublished treatment data, this is seen in approximately 9% of their patient population. Carpal tunnel syndrome symptoms may be noted in adult growth hormone deficient patients on growth hormone replacement therapy, occurring approximately 1%-2% incidence in the Cenegenics Medical Institute data. Side effects of growth hormone therapy for adult deficiency are minor, dose-related and totally reversible. Please review the 1999 article, published in the New England Journal of Medicine. ⁵⁸ 

In the literature, reports of hyperglycemia have been associated with growth hormone replacement studies, but these have all taken place without the context of nutritional or exercise counseling.  Again in Cenegenics Medical Institute unpublished data, a 0% incidence of hyperglycemia is noted in patients who are nutritionally compliant.   

Before starting any hormonal therapy, a comprehensive evaluation is essential.  In a cover story on growth hormone in a September 2003 issue of Newsweek, Dr. Pinchas Cohen, Director of Pediatric Endocrinology – UCLA, states “all the evidence shows that growth hormone is one of the safest drugs we have. Thousands of patients have been followed for the last sixteen years.” ⁵⁹ Appropriate focus on hormonal balance and careful monitoring minimizes the risk of experiencing these mild side effects. 

This illustration slide23  is a conceptual graph with regard to handling side effects in adult growth hormone deficient patients on growth hormone therapy. The vertical axis is growth hormone dose; the horizontal axis is time; the green line is growth hormone dose.  When starting patients on growth hormone, they are taken from a lower IGF-1 state to a higher IGF-1 state. This change—or “delta” (purple triangle)—may be associated with the previously mentioned side effects. When these side effects occur, discontinuation of growth hormone therapy is not required. If growth hormone therapy is decreased approximately 50%, total side-effect incidence falls to approximately 1% or less. Side effects are primarily related to the growth hormone level rate of change, rather than final growth hormone levels. As such—with reduction in dose and maintaining this reduced dose until side effects have been absent for approximately two weeks—the growth hormone dose can be advanced slowly. Then growth hormone dose can be titrated slowly upward with the expectation that eventual growth hormone doses for these patients will be maintained at a level sufficient to maintain proper IGF-1 levels.  Start at the expected final growth hormone dose and titrating dose downward only in the presence of side effects, achieving an eventual slow upward titration.   

For adult growth hormone deficient patients on multiple hormone replacement therapy, the only hormone-hormone interaction described is regarding the route of estrogen replacement therapy in female patients and their effect on IGF-1.   

In 1998, Ho described the effect of the estrogen delivery route on IGF-1 levels, revealing oral Estradiol replacement therapy was associated with a 20% decrease in IGF-1 versus transdermal delivery of similar dose. Additionally, on oral replacement therapy, fat mass was increased versus transdermal delivery; lean body mass was decreased versus transdermal delivery. ⁶⁰

An additional study by Janssen (2000) found similar outcomes with IGF-1 levels on oral estradiol replacement being approximately 24% below those receiving transdermal delivery of the same medication. ⁶¹

In women receiving female hormone replacement therapy, transdermal delivery has an advantage over oral therapy.

Other GH Replacement  Issues 

Growth Hormone and Cancer Incidence

In the popular press, there is much consternation about the impact of growth hormone and cancer incidence. However, growth hormone/IGF-1 levels and cancer incidence actually follow opposite tracks. Growth hormone levels are highest early in life and decline with age. Cancer incidence is lowest early in life and increases with age. There is an inverse association curve between growth hormone/IGF-1 levels and cancer incidence, with highest cancer incidence associated with the age IGF-1 is at its lowest. slide24

This has been documented specifically for breast cancer incidence in relation to IGF-1 levels.slide25  

In addition to IGF-1, insulin-like growth factor binding-protein-3 (IGFBP-3) is another physiologic product, resulting from metabolism of growth hormone.  IGFBP-3 has a strong negative correlation with cancer risk. In the accompanying figure, adapted from Ma in 1999, increasing IGF-1 levels are only associated with an increase in cancer risk, per association with declines in IGFBP-3. In fact, the lowest cancer risk category was seen in patients in the highest quartile of IGF-1 values in association with the highest cortile of IGFBP-3 values. IGF-1 levels were only associated with increased risk in patients who were simultaneously in the lowest quartile or for IGFBP-3 and the highest quartile for IGF-1 levels. ⁶⁶ slide26

When examining IGF-1 studies, it is important to evaluate risk in the context of IGFBP-3, as well. 

In addition to raising IGF-1 levels, administration of growth hormone raises IGFBP-3 levels.  Some studies have shown IGFBP-3 demonstrates an even higher percentage increase in level in response to growth hormone therapy than does IGF-1. Chihara and Strasburger are examples of literature, demonstrating this IGFBP-3 response to growth hormone administration. ^{47 48} slide27

IGF-1 and IGFBP-3 interact in a way that modulates the overall response of an organism to growth hormone. Given IGFBP-3 plays an important role in reducing cancer risk, IGF-1 as monotherapy would not be an effective intervention for patients with low IGF-1 levels.  While this product exists, at present, its primary clinical utility is for administrating to patients who are incapable of producing IGF-1 in response to growth hormone signaling.   

In discussing the impact of growth hormone on prostate cancer risk, an interesting opportunity arises to review how some medical literature is sometimes interpreted.  The following study made such an astounding claim, that an examination of the statistics applied to the results is in order. In the Journal of Clinical Oncology in 2004, Stattin authored an article concluding that higher levels of IGF-1 were associated with an increase in prostate cancer risk. ⁴⁹

In this study, they reviewed outcomes on 281 subjects who would subsequently develop prostate cancer over a four-year period. They also followed 562 controls who would remain cancer free. They stated that for patients who would subsequently develop prostate cancer, the average IGF-1 was 218 ng/ml at time of initial evaluation. For the control subjects, the average IGF-1 was 209 ng/ml. With only a 9 ng/ml difference in IGF-1 level, the study concluded “IGF-1 is an etiologic factor in prostate cancer.”   

Looking within the study, however, reveals that within intra-group variability of IGF-1 values was an 11% for one group of control sera and 8.6% for another. Additionally, no control samples were done for the IGF-1 concentrations, obtained from study subjects. This variability is less than claimed between cancer-developing subjects and negative controls. 

For between-batch variability, they found 13.8% and 15.2% variation, respectively.  The results for the prostate cancer and control groups were actually more similar to each other than batch-to-batch variability within the same group.   

The differences between the prostate cancer group and the control group were smaller than the variability of the test itself.   

Furthermore, given the age difference between the study groups—the average age of cancer patients at the start of the study was approximately nine months older than the non-cancer developing cohort—this in itself would have predicted a difference in IGF-1 levels of approximately 7 ng/ml, almost consistent with their findings. Additionally, the control groups were measured at different times than the prostate cancer group. The control group averaged an IGF-1 of 219ng/ml during one assay and averaged 202 ng/ml in another. The two control batches also varied more than the cancer subject versus control batching.   

The median PSA at time of initial evaluation for the patients who would “subsequently” develop prostate cancer was 4.7.  For control patients it was 1.2.  At the time of their initial evaluation, 80% of the subsequent prostate cancer developers had a PSA of greater than 2, with 58% having a value of greater than 4.0. And 28% of controls had a PSA of greater than 2.0 at uptake, but only 8% had a value greater than 4.0.  These results were ignored, and patients were followed over time for “subsequent” development of prostate cancer. 

No diagnostic evaluation was performed on any subject. Both subjects and controls were followed until patients presented with symptoms. Of the cancer subjects (again with a median PSA of 4.7), 85% were followed for more than one year before any diagnostic workup was obtained—77% were not diagnosed until more than two years after uptake and 47% were not evaluated until 4 years after their baseline evaluation.  What this study accomplished was this: researchers found a group of men with a median PSA value of 4.7 and did nothing. By the time of diagnosis, 90% of the cancer patients had a PSA of greater than 4.0 and more than half had a PSA of greater than 10.0. The mean PSA at time of cancer diagnosis was 11.0 with the 25^th percentile value being 6.8.   

Looking at this study’s IGF-1, and comparing IGF-1 levels between groups, there is no statistical correlation between control and cancer developing patients. However, there is a strong correlation between PSA and future cancer risk, which was ignored.  The title of this article should have been “High PSA is predictive of prostate cancer risk,” not “IGF-1 is a prostate cancer risk.”  

A better glimpse of the relationship between growth hormone and IGF-1 levels is seen in the previously mentioned study by Svensson, published in 2004. A large cohort of patients was followed prospectively for ten years. At the time of initial evaluation, IGF-1 values before treatment averaged 125 ng/ml. During treatment, IGF-1 for men averaged 289.6 ng/ml; for women, it averaged 210 ng/ml. ⁴⁶ 

Looking at outcomes for the Svensson study—consisting of a treated group, an untreated group and a control group with normal lab values—the treatment group had a relative risk for total mortality that was the same as normal control subjects with corresponding normal IGF-1 levels. The untreated group had a relative risk of 3.8, almost four times the risk of the control group for total mortality. slide28

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