Level Of Free Igf example essay topic

Acromegaly (Greek for "appendage enlargement") is a rare but very serious disease frequently referred to as "Gigantism" or "Giantism". It is the direct result of an overproduction and secretion of the adenohypophyseal growth hormone GH. True to its name, the disease is characterized by an enlargement of the organs, bones, and soft tissues, as well as a thickening of the skin and bodily membranes; and is frequently difficult to diagnose, as symptoms often do not appear until middle age. Typically the disease results in heart failure caused by an enlargement of the heart, organ failure due to pressure or thickening of the outer membrane of the organ, or brain hemorrhaging caused by a benign or malignant pituitary adenoma.

To date, there are three known forms of the disease: Cushing's disease, Nelson Syndrome, and Prolactinoma. Each is characterized by different phenotypic attributes commonly linked by an enlargement of all or some particular body parts. Prolactinoma is the most frequently recognized form of giantism. It is characterized by an overall enlargement of the body, and was brought to public attention nearly twenty years ago by pro-wrestler and actor Andre the Giant, who later died of heart failure in the early 1990's. Nelson's disease and Cushing Syndrome are similar to each other, however there is now controversy as to whether these two diseases are even linked to Prolactinoma since they are not commonly characterized by an overall enlargement of the body, but rather an extreme overproduction of soft and fatty tissue. These diseases cause thickening of the bones, skin, and soft tissue, but often appear after the person has finished growing, making the patient appear overweight and unable to speak and move with fluidity since the tongue and hands are hindered.

All three diseases tend to have the same outcome: organ failure or brain hemorrhaging. In the past twenty years, controversy has arisen as to whether there are in fact three forms of the disease, what characterizes differentiation between each one, and how should each be treated accordingly. The problem is until recently, scientists have based their diagnoses almost entirely upon phenotypic characteristics and what is known about pituitary adenomata; only now are scientists beginning to analyze the genes and hormones involved on the micro level. The following articles examine methods in which testing for the disease takes place. Recent studied tend to revolve mainly around the IGF-binding protein, the proposed cause of pituitary adenoma. However, it is not entirely known just how to test for this protein; whether to measure free IGF or total IGF-binding proteins.

Article Summaries: Note: there are ten articles attached to this document; the first five of which are primary and summarized below. The remaining five are not summarized here and are used for supplementary purposes. How and when to measure insulin-like growth factor-I and related growth hormone-dependent proteins: The IGF (insulin-like growth factor) -binding protein is a crucial structure to the ability of the body to produce the growth hormone GH. Patients who are GHD (growth hormone deficient) either secrete too much or too little GH.

In the case of Acromegaly, a massive influx of GH is produced by the pituitary gland leading to expansion of tissues and bone mass. GH affects the ability to not grow as well. Other patients who are GHD do not produce enough of the hormone, and therefore display little soft tissue, weak bones, and a generally small stature. This article examines the ability to determine GHD in a patient before irreversible damage is done to the body.

Though there are several forms of GHD, most are hereditary and caused by a number of factors including tumors and dysfunctional IGF-binding proteins. Typically, the amount of IGFs is not a contributor to GHD, though in some cases, it may be an indicator of problems involving the IGF type I receptor structure. On average, the body will produce IGFs at a constant rate but if they are not used, production slows, making it difficult to use the level of IGFs to indicate receptor obstructions. When the IGFs do not bond correctly, a negative feedback response causes the pituitary gland to cease secretion of GH, while overactive IGF receptors raise the level of GH dramatically.

The body produces IGFs to match the activity level of the receptors, leaving the amount at a fairly constant total. The question arises then how IGF type I receptors should be tested and measured. Only about 1% of IGF type I and type II receptors are unbound, so the hypothesis is that only free and unused IGF receptors should be measured for activity level to indicate a problem. Unfortunately, the binding process is not always constant and at any given second, up to 20% may be unbound and accessible to tissues. An oral glucose level test indicates free IGF receptors so many tests could be performed to take an average, however GHD is often coupled with hypoglycemia which skews the data since the body is already not processing glucose as expected. Recently, experiments have been conducted to test the levels of IGFBP-3, a newly discovered protein known as the "GH dependent IGF binding protein".

The amount of this protein tends to have more accurate results in that high levels are often found in children with early signs of acromegaly, while low levels tend to run in children of short stature. IGFBP-3 also tends to run at a sensitivity level about 83%, significantly higher and more accurate than IGF receptor testing. Acromegaly: the significance of serum total and free IGF-I and IGF-binding protein-3 in diagnosis: This article discusses a conflicting view with the previous document. The authors here argue that the levels of IGF receptors and IGFs in the body are crucial to the diagnosis of acromegaly, rather than the IGFBP-3 measurement which indicates only GHD instead of specific diseases. The van der Lely de Herder experiments indicate that acromegaliacs show no reliable correlation between the levels of IGF and the levels of IGFBP-3 proteins. The levels of IGFBP-3 and IGF in fact decrease with age at different rates so testing very early or very late in the patient's life may give inaccurate results.

When normal middle-aged (mean age 47) males and females were compared to acromegaliac middle-aged males and females, the results showed that the level of IGFs in the GH serum are much higher in the acromegaly patients. Specifically, the amount of free IGF-I differ the most from normal to diseased patients, followed by the total IGF-I with another dramatic differentiation. The IGFBP-3 levels, however, show two distinct clouds when plotted, with many overlapping portions. The scientists conclude that testing for the levels of IGFBP-3 is not completely without benefits.

These levels are very sensitive to GH and are a strong indicator of the severity of the disease, however they can only be used to diagnose acromegaly in severe cases. Acromegaly With Normal Basal Growth Hormone Levels: This very short article indicates that acromegaly cannot in fact be diagnosed based on IGF-I nor IGFBP-3 levels alone. The 42-year-old male patient observed in this experiment had been for five years a known acromegaliac. His diagnosis is based on a pituitary adenoma which crushes the pituitary gland, forcing the influx of GH production. This is not an uncommon form of acromegaly, often found in patients with prolactinoma specifically. The individual shows no visible signs of acromegaly; bone density and tissue size and sexual functionality have not visibly changed, nor has the patient developed gynecomastia nor galactorrhoea.

This stability in condition is also not uncommon in patients with acromegaly. Often visible physical changes do not occur for several years when adenomata are involved. What is striking about this patient however, is that the IGF-I and IGFBP-3 levels are liken to that of a normal person. The GH level is also completely within range of a normal person. Though the IFG-I free level is slightly elevated, there are almost no signs of acromegaly in the patient. The article concludes that this may not be as uncommon as previously thought and when GH levels are normal, acromegaly may still be present by means of adenomata.

The Role of Plasma Measurements of Growth Hormone and IGF-I in the Assessing Growth Hormone Secretion in Humans: This article summarizes how the peptide hormone GH controls the expression of the IGF-I complex then goes on to discuss ways in which the IGF levels are measured. The majority of the circulating IGFs exist in the liver where they bind to the IGF-I complex with a negative feedback response to the hypothalamus and pituitary gland. Complications with this structure result in excessively tall or short stature in children and possible acromegaly as adults. This article also argues that neither IGF levels nor IGFBP-3 levels should be measured in random plasma tests. This disputes the first two articles, which argue one method is better than the other.

The pituitary gland produces GH in a pulsatile manner, so at any given time, the hormone level may be very high or very low. However, if the plasma were tested for IGF levels while the pituitary gland was producing GH at the person's maximum level, more accurate comparisons can take place. The Christchurch Department of Endocrinology tested a method in which the levels are measured before the test and after a clonidine stimulus is applied, forcing the GH level to rise to its maximum production rate. Unfortunately, this testing method is reasonably new and appears to be only accurate in growth hormone disorders excluding acromegaly. Acromegaly patients can be diagnosed through this new manner of screening, however many acromegaliacs will have growth hormone levels consistently within the normal range, so testing for IGF levels in any situation may prove unreliable. Currently the Department of Endocrinology is continuing assessment of the benefits of this testing process.

When age and advancement of the disease is taken into account, these tests tend to lose the benchmark at which "diseased" and "healthy" may be determined. Guidelines for the diagnosis and treatment of acromegaly: a Canadian perspective: This abstract from the Canadian Medical Association discusses the general symptoms noted which are commonly used for the diagnosis of acromegaly. Here it mentions that acromegaly is often the result of an adenoma, however it can also be the cause of benign pituitary adenomata. Oftentimes, the disease is diagnosed after arthropathy diabetes, hypertension, cardiac dysfunction, obstructive sleep apnea, or colonic neoplasia occurs.

These symptoms are irreversible and typically result in death. Acromegaliacs are also two to three times more likely to die due to the complications mentioned above. With growth hormone secretion regulation, the death rate of acromegaliacs tends to return to the normal range, which is why it is so important to diagnose acromegaly specifically and begin immediate and specialized treatment. Discussion: The five articles presented each discuss either the three proposed methods of testing for acromegaly, background information on the disease, or exceptions to what is commonly believed about acromegaly. The third and final articles are background-based commentary which set the stage for the first, second, and fourth articles, all of which debate the method of testing for acromegaly and other GH disorders. Presently three methods exist in testing: IGF-I levels, IGFBP-3 levels, and stimulus-plasma levels.

Recent advancements have ruled out testing the amount of IGFs in the plasma, however the debate still continues as to whether IGF-I free or activated levels should be measured over IGFBP-3 or stimulated GH levels. Depending on the disease, one test appears to work better than the other. The recent German study indicates that IGFBP-3 levels do not correlate with acromegaliacs based on many limiting factors. Rather, the level of free IGF-I in the plasma for middle-aged persons shows the greatest differentiation. This directly contradicts the previous study which indicates that the level of IGFBP-3 is the only reliable system of measurement since IFG-I levels change because of the pulsing manner of the pituitary gland. The Christchurch study however argues that both methods of testing are inaccurate for that very reason; the pituitary gland does not function at a steady rate, so testing any level at any random time will not yield accurate results.

The three studies agree that there are a few limiting factors involved in all of the experiments. Age and sex affect the levels of IGF-I, IGFBP-3, and GH in the plasma, as does the advancement of the disease. This makes it difficult to establish benchmark levels based on age or gender; at any given moment the hormone level of a normal healthy person may fluctuate dramatically. Recently, research has been leaning towards difference studies where a level is tested before and after stimuli.

The difference between stimulated and normal pituitary function tends to be the more favorable test, though this method also has major drawbacks including the major issue of how can one know whether the pituitary gland is functioning at a minimum level. Using drugs which slow the GH production in the pituitary gland may be detrimental to a healthy person, so testing for acromegaly by these drugs is not safe nor recommended. The other problem with difference testing is that many patients with acromegaly do not have abnormal GH levels, as indicated in the Canadian study. Oftentimes, these patients have adenomata which can be removed through stereotactic radiosurgery, but not after major damage to the brain and gland have already occurred.

For these patients, an entirely new form of testing must take place where growth hormone levels alone are not the sole indicator of disease. Another problem with this testing is that if a minimum and maximum productivity level are found, what levels should be tested. This ties into the first two articles which discuss IGF-I free used levels versus IGFBP-3 level testing. Both of these levels are affected dramatically by age and sex, however it appears both levels may need to be tested for accurate results regardless. The German study indicates testing for IGFBP-3 is more acromegaly-specific, but IGF-I testing tends to determine GHD. These being the circumstances, research is being conducted where IGF-I levels are tested and followed up by IGFBP-3 testing for potential acromegaly-specific cases.

Conclusion: Since acromegaly is often difficult to diagnose until later in life, recent studies are focusing on the best and most efficient way to determine a problem before major irreversible damage occurs. Unfortunately, since the disease is so rare, major symptoms generally have to occur before the afflicted is even tested for the disease. However, it is also hereditary and with heredity comes early testing in patients where the disease is prevalent among the family. The problem arises then as to how to test early since growth hormone therapy performed on a patient who does not definitely have the disease may be more damaging than leaving the actual disease untreated. The rarity of the disease however, tends to limit the fund which go into the research, making early testing difficult to advance. Since it is known that age, sex, and advancement of the disease affect hormone and receptor levels, it is clear that more research must be done in order to establish what is "normal" for comparison with potentially diseased persons.

The majority of the acromegaly and GHD research funds are currently being poured into investigations on how to slow the pituitary gland without damaging it or the patient. GHD therapy includes medication which slows the pituitary gland, but in a healthy person, this type of treatment may even be fatal. Again, more research is being conducted to create a safe way to temporarily slow down pituitary function for this purpose. In addition, research is also being conducted as to whether IFG-I free or IGF-I total measurements should be taken since the values tend to fluctuate; also IF GBP-3 levels should be tested for acromegaly-specific cases. In both situations, further research must be conducted to establish average "healthy" and "abnormal" ranges in both levels.