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This module provides an overview and rationale for the reasoned use of growth hormone modulation therapy for adult onset growth hormone deficiency in the clinical setting when a comprehensive evaluation reveals an adult deficiency. The goals for this module are to enable a clinician’s ability (1) to evaluate a patient in the proper clinical context so informed treatment decisions can be made, regarding the use of growth hormone in adult deficiency; (2) to be able to measure appropriate objective markers of disease risk and outcome, including IGF-1; (3) to act appropriately upon the obtained data; and (4) to use objective criteria for monitoring disease risk markers and outcomes, both laboratory and clinical. This process is not a set-it-and-forget-it phenomenon—it requires continued diligence in a broad clinical setting. This module is really not about growth hormone alone, so much as about evaluation of growth hormone levels and their consideration as one clinical factor among many in a comprehensive adult patient-oriented diagnosis, prevention, and life-style alteration program. Growth hormone is a product of anterior pituitary gland. It is a 191-amino acid peptide hormone, which is pleiotropic in its effect. Growth hormone is technically a “pro hormone” since in liver and other peripheral tissue, it causes the production of the Insulin-like Growth Factor family of molecules. The predominant metabolically significant final hormone is Insulin-like Growth Factor 1, or IGF-1. In addition to IGF-1, other Insulin-like Growth Factor family molecules are produced. slide01 This module also covers a discussion on the impact of Insulin-like Growth Factor Binding Protein 3 (IGF-BP3) in the course of this review. The feedback loop for growth hormone secretion is multi-factorial. Growth hormone itself provides strong negative feedback on both the hypothalamus and the anterior pituitary to inhibit further release of growth hormone. As growth hormone is metabolized to IGF-1, IGF-1 provides only minor negative feedback on the hypothalamic pituitary axis; subsequent pulses of growth hormone can be generated readily in the presence of IGF-1. Additionally, growth hormone (strongly) and IGF-1 (weakly) exert positive feedback on the hypothalamus to generate the release of somatostatin, which also has inhibitory effect on the anterior pituitary with regard to growth hormone release. Homeostatsis of hormone production is maintained via both positive and negative feedback loops. slide02 Growth hormone is released in pulsatile fashion. Each secretion pulse can last between 20 and 60 minutes; the average person will produce four to six of these pulses per day. While the majority of growth hormone secretion pulses are random, there are relatively predictable growth hormone release pulses occurring after vigorous exercise and early in a subject’s nightly sleep pattern. The graph demonstrates the pulsatile nature of growth hormone release, pointing out one of the reasons that measuring growth hormone levels directly has low utility when evaluating a patient. Between pulses, growth hormone levels are essentially nil. If blood were drawn during this period, an incorrect assumption regarding low growth hormone levels would be made. Conversely, blood drawn during a growth hormone peak would give the impression of adequate or even high-growth hormone levels. IGF-1, however, is present at stable levels over the course of an average patient day. Given the relationship between growth hormone and IGF-1 noted in the previous slide—and with stable IGF-1 levels present at any given time—it has become the growth hormone marker of choice, presenting the clinician with a broad window regarding the examination timing for blood draws. The utility of IGF-1 measurement versus measurement of induced growth hormone secretion has been the subject of much discussion and debate. In the past, the insulin tolerance test was regarded as a requirement to adequately assess a subject’s growth hormone secretion abilities, but this has been called into question in recent years. The insulin tolerance test requires the medically supervised intravenous administration of insulin to achieve a blood glucose level of 40mg/Dl or less, with average blood glucose levels during this test at approximately 25mg/DL. The assumption with regard to this test is that under extreme hypoglycemic conditions, growth hormone (a counter-regulatory hormone) release will occur. Growth hormone levels are measured at baseline 30, 60 and, often, 90 minutes after insulin infusion. If, in the presence of this degree of hypoglycemia, growth hormone secretion occurs to levels of above 3 to 5ng/ml, a patient is judged “normal.” As noted in the slide, there is no connection between a patient’s state during an insulin infusion challenge versus a normal glucose state in the individual’s day-to-day life. The average subject will never have glucose levels as low as those seen in an insulin tolerance test—and this intervention may not adequately reflect a patient’s true physiologic state. The test has remained in the medical lexicon despite its lack of correlation to normal physiology. When the insulin tolerance test was developed, growth hormone was still harvested from cadavers and was made as an extract of human tissue. As such, it was quite limited in quantity and carried risk of disease transmission, especially prion diseases. Given its difficulty in acquisition and danger with regard to exposure, there was a strong rationale for rationing. The use of the insulin tolerance test was meant to guarantee that only patients with the least ability to secrete growth hormone would be treated. In the era before recombinant technology, this was a valid concern. Since 1986, growth hormone has been commercially produced in the laboratory with recombinant gene technology—a product no longer a human extract, but a pure synthetically produced bioidentical hormone. The change in production methods negated the previous rationale for rationing and disease transmission concerns. Despite this change in availability, there has been a persistence of the old diagnostic paradigm. Despite readily available recombinant forms of growth hormone, a slow accommodation in some circles exists, regarding diagnostic investigation—especially in the IGF-1 versus the insulin tolerance test (ITT) debate of which is the most useful in assessing growth hormone status. Data will be shown, demonstrating that IGF-1 is already accepted as a diagnostic and therapeutic marker in its own right. We will examine the independent and statistically significant use of IGF-1 as a marker of disease risk and will review some growth hormone intervention studies, which have been undertaken in the absence of “deficiency states” and their demonstrated clinical utility. The ITT is not a true indicator of a subject’s underlying hormonal state. As mentioned, it is not representative of a normal physiologic condition and does not reflect growth hormone secretion patterns in the absence of hypoglycemia. It is also far less reproducible than it is portrayed to be. Pandian, et al, concluded in 2004 that the ITT, like all growth hormone stimulation tests, suffered from statistical lack of reproducibility for a given individual and was deemed not an adequate test as a “gold standard” for the diagnosis of suboptimal growth hormone levels. (1) slide03 Vestergaard, in 1997, found a coefficient of variation in patients undergoing repeat ITT of 41% in men and 104% in women. Of note, approximately one-third of the patients had normal growth hormone release patterns on one test, but their second evaluation actually satisfied criteria for deficiency. (2) slide04 Hoeck, in 1995, examined normal male and female subjects with an average age of 31½. There were greater than 72 hours between insulin tolerance tests; this study generated glucose levels of less than 25mg/DL during the insulin challenge. One-fourth of normal female subjects met lab criteria for a deficiency state. If ITT had been used to make a treatment decision in these patients, they would have been inappropriately funneled for therapy, when in fact there was no underlying pathology. Hoeck noted no correlation between first and second test results, meaning from one test to another, there was no test reproducibility in his subjects. They also found that results did not correlate with the degree of hypoglycemia achieved. His conclusion: there was poor reproducibility during repeated testing and no correlation between the results of the two tests. (3) slide05 Biller, in 2002, demonstrated there was up to a six-fold difference in growth hormone secretion, either increased or decreased, when comparing adults undergoing repeat ITT. Her conclusion was that with the ITT, physicians would have to choose between high sensitivity versus high specificity when using the ITT, and in this context. Biller looked at the utility of using IGF-1 values and found that IGF-1 values were stable over time and highly reproducible, showing standard deviation scores and distribution of values, which dependably placed patients in the same diagnostic category with regard to IGF-1 value on repeat testing. In fact, no subjects were noted to have changed their diagnostic category on subsequent tests. Biller also observed an IGF-1 “cut point” for minimizing misclassification for the deficiency state was 127 mcg/L, but the 95% sensitivity value was set at 200mcg/L. The IGF-1 standard deviation score for 95% sensitivity was -0.12. (4) What this study shows is that in the clinical setting of evaluating the signs and symptoms of suboptimal growth hormone levels, a standard deviation score of only 0.12 standard deviations below the norm was required to achieve 95% sensitivity. Hoeck found a 97% degree of correlation between IGF-1 levels and subsequent result of growth hormone stimulation tests. (5) In 2003, Boquete pointed out further problems with insulin tolerance testing to evaluate growth hormone levels, demonstrating that insulin tolerance test levels varied with patient body mass index (BMI). He also found that 92% of patients could be properly categorized clinically using IGF-1 values. (6) Studies by Bonert and Biller showed similar variability with insulin tolerance testing and body mass index. (7,8) The most important thing to note with these studies is that IGF-1 values are independent of body mass index. Pandian endorsed the use of IGF-1 measurement on a routine basis and, most importantly, pointed out the importance of any growth hormone evaluation being placed in a clinical context in association with proper history and physical findings. (1) slide06 Pandian and Carroll as well as other authors have assembled clinical signs and symptoms, associated most frequently with suboptimal levels of growth hormone. These clinical signs and symptoms are consistent between studies. (9) slide07 The Growth Hormone Research Society published a position statement that was published in the Journal of Clinical Endocrinology and Metabolism. They concluded that in association with clinical signs and symptoms and in conjunction with proper laboratory evaluation, proper clinical diagnosis can be made in the absence of insulin tolerance testing and may be associated with normal range IGF-1 values. (9) slide08 The Growth Hormone Research Society’s conclusion properly places growth hormone evaluation in a clinical context with a focus on proper diagnosis and the subsequent long-term benefit of proper supplementation therapy. Even among clinicians who feel insulin tolerance testing is required in the diagnostic evaluation of suboptimal growth hormone levels, it is interesting to note within this group there is no controversy regarding the correlation between IGF-1 levels and growth hormone supplementation. Without a hint of irony, they conclude that the “gold standard” of following growth hormone supplementation therapy for adult deficiency involves the use of IGF-1 as a marker of supplementation dose and as a titration point for raising or lowering dose. The illustrated article by Drake is an example of this, pointing out the importance of using IGF-1 to properly titrate growth hormone supplementation. (10) It is interesting that on the one hand, IGF-1 is supposedly inadequate as a marker of growth hormone production for the purpose of diagnosis, but is transmuted from “lead” into “gold” as a standard for judging growth hormone dosing decisions. Drake also points out the utility of maintaining IGF-1 levels at between the normal average for a patient’s age and less than two standard deviations above that mean. This is regarded as typical of supplementation therapy. (10) Further demonstration of the almost 100% correlation between growth hormone dosage and IGF-1 levels is provided by these illustrations taken from Boer, 1996. (11) slide09 They demonstrate a dependable IGF-1 response with regard to dosing in the bar graph on the left. The horizontal axis represents daily growth hormone dose in units per day; the vertical axis represents corresponding IGF-1 levels in response. There is a direct linear relationship between IGF-1 levels and growth hormone dose. The illustration on the right points out that IGF-1 levels are dose responsive and well-maintained over time. The horizontal axis in these graphs represents a 12-month period, demonstrating a very stable IGF-1 level in response to a given growth hormone dose. Mukherjee looked at the IGF-1/Growth Hormone relationship from a different point of view. Instead of using IGF-1 to diagnose deficiency, she looked at what IGF-1 level would be sufficient to “avoid a deficiency state.” Her findings reinforced the currently accepted practice of treating IGF-1 levels to the upper half or quartile for normal age-related range and found that her 95% sensitivity measurement for “adequately” addressing a deficiency state with regard to growth hormone was IGF-1 levels, maintained above the age-related mean. (12) slide10 Looked at from both sides– diagnostic and the levels associated with adequate “avoidance” of deficiency—IGF-1 is a consistently useful (and used) measure. Even in articles criticizing growth hormone use without insulin tolerance testing to confirm a deficiency state (as published by Perls, et al in JAMA in 2005), the authors cannot avoid referencing articles, which undermine their insistence on insulin tolerance testing and point out the clinical utility of using IGF-1 assays for the diagnosis of adult growth hormone deficiency. (13) Again, Perls’ referenced article notes the well-accepted connection between growth hormone supplementation therapy dose and corresponding utility of monitoring resultant IGF-1 values. (13) slide10 slide12 – These slides are representative of the current state of the IGF-1 growth hormone discussion among clinicians who deny the utility of IGF-1 values as they relate to underlying growth hormone levels and insist on ITT to satisfy diagnostic criteria for diagnosis, but then abandon this paradigm in their subsequent use of IGF-1 to monitor therapy. 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) slide13 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: slide14 1) IGF-1 levels are, in fact, most likely adequate for the evaluation of a subject’s growth hormone status. 2) 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. 3) 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. |
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