OLYMPIC

Understanding IGF-1 By Bryan Haycock To understand how IGF-1 works you have to understand how muscles grow. The ability of muscle tissue to constantly regenerate in response to activity makes it unique. It’s ability to respond to physical/mechanical stimuli depends greatly on what are called satellite cells. Satellite cells are muscle precursor cells. You might think of them as "pro-muscle" cells. They are cells that reside on and around muscle cells. These cells sit dormant until called upon by growth factors such as IGF-1. Once this happens these cells divide and genetically change into cells that have nuclei identical to those of muscle cells. These new satellite cells with muscle nuclei are critical if not mandatory to muscle growth. Without the ability to increase the number of nuclei, a muscle cell will not grow larger and its ability to repair itself is limited. The explanation for this is quite simple. The nucleus of the cell is where all of the blue prints for new muscle come from. The larger the muscle, the more nuclei you need to maintain it. In fact there is a "nuclear to volume" ratio that cannot be overridden. Whenever a muscle grows in response to functional overload there is a positive correlation between the increase in the number of myonuclei and the increase in fiber cross sectional area (CSA). When satellite cells are prohibited from donating new nuclei, overloaded muscle will not grow (Rosenblatt,1992 & 1994; Phelan,1997). So you see, one important key to unnatural muscle growth is the activation of satellite cells by growth factors such as IGF-1. IGF-1 stimulates both proliferation (an increase in cell number) and differentiation (a conversion to muscle specific nuclei) in an autocrine-paracrine manner, although it induces differentiation to a much greater degree. This is in agreement with the Dual Effector theory. In fact, you can inject a muscle with IGF-1 and it will grow! Studies have shown that , when injected locally, IGF-1 increases satellite cell activity, muscle DNA content, muscle protein content, muscle weight and muscle cross sectional area (Adams,1998). On the very cutting edge of research scientists are now discovering the signaling pathway by which mechanical stimulation and IGF-1 activity leads to all of the above changes in satellite cells, muscle DNA content, muscle protein content, muscle weight and muscle cross sectional area just outlined above. This research is stemming from studies done to explain cardiac hypertrophy. It involves a muscle enzyme called calcineurin which is a phosphatase enzyme activated by high intracellular calcium ion concentrations (Dunn, 1999). Note that overloaded muscle is characterized by chronically elevated intracellular calcium ion concentrations. Other recent research has demonstrated that IGF-1 increases intracellular calcium ion concentrations leading to the activation of the signaling pathway, and subsequent muscle fiber hypertrophy (Semsarian, 1999; Musaro, 1999). I am by no means a geneticist so I hesitated even bringing this new research up. In summary the researchers involved in these studies have explained it this way, IGF-1 as well as activated calcineurin, induces expression of the transcription factor GATA-2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of the transcription factor nuclear factor of activated T cells or NF-ATc1. Thus, IGF-1 induces calcineurin-mediated signaling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs leading to increased contractile protein synthesis and muscle hypertrophy. Did you get all that? IGF-1 Usage By Author Unkown IGF stands for insulin-like growth factor. It is a natural substance that is produced in the human body and is at its highest natural levels during puberty. During puberty IGF is the most responsible for the natural muscle growth that occurs during these few years. There are many different things that IGF does in the human body; I will only mention the points that would be important for physical enhancement. Among the effects the most positive are increased amino acid transport to cells, increased glucose transport, increased protein synthesis, decreased protein degradation, and increased RNA synthesis. When IGF is active it behaves differently in different types of tissues. In muscle cells proteins and associated cell components are stimulated. Protein synthesis is increased along with amino acid absorption. As a source of energy, IGF mobilizes fat for use as energy in adipose tissue. In lean tissue, IGF prevents insulin from transporting glucose across cell membranes. As a result the cells have to switch to burning off fat as a source of energy. IGF also mimic's insulin in the human body. It makes muscles more sensitive to insulin's effects, so if you are a person that currently uses insulin you can lower your dosage by a decent margin to achieve the same effects, and as mentioned IGF will keep the insulin from making you fat. Perhaps the most interesting and potent effect IGF has on the human body is its ability to cause hyperplasia, which is an actual splitting of cells. Hypertrophy is what occurs during weight training and steroid use, it is simply an increase in the size of muscle cells. See, after puberty you have a set number of muscle cells, and all you are able to do is increase the size of these muscle cells, you don't actually gain more. But, with IGF use you are able to cause this hyperplasia which actually increases the number of muscle cells present in the tissue, and through weight training and steroid usage you are able to mature these new cells, in other words make them grow and become stronger. So in a way IGF can actually change your genetic capabilities in terms of muscle tissue and cell count. IGF proliferates and differentiates the number of types of cells present. At a genetic level it has the potential to alter an individuals capacity to build superior muscle density and size. There is a lot of talk about the similarity between IGF and growth hormone. The most often asked question is simply which is more effective. GH doesn't directly cause your muscles to grow, it works very indirectly by increasing protein synthesis capabilities, increasing the amount of insulin a person can use effectively, and increasing the amount of anabolic steroids a person can use effectively. GH also indirectly causes muscle growth by stimulating the release of IGF when it (the GH) is destroyed in the human body. So one way you could look at it as GH being a precursor to IGF. So to put it simple IGF is more effective at directly causing muscle growth and density increases. IGF is also much more cost effective. IGF can also be effectively used by itself and gains will still be easily noticeable. With growth hormone you need to use high amounts of anabolics and often insulin to see any gains at all, this is not the case with IGF. IGF can be used by itself and is often used by bodybuilders who bridge between cycles, during this bridge is a good time to use IGF since it has no effect on natural testosterone production so it will therefore allow you to return to normal in terms of hormone levels. A stack of IGF, PGF2a, HCG, and clomid would be a good bridge stack and would allow your body to return to normal and still allow you to retain and make new gains. IGF is a research drug, it hasn't been approved by the FDA for use as a pharmaceutical and it is currently being researched for nerve tissue repair, possible burn victims, and also as a possible aid in muscle wasting for AIDS patients. There are many different analogs of IGF available, instead of mentioning them all, I will simply mention the two most common and the most effective. Regular recombinant IGF is one of the two, it is also the more expensive and the least effective. Regular IGF only has a half-life of about 10-20 minutes in the human body and is quickly destroyed, it can be combined with certain binding proteins to extend the half-life, but it is not a very simple procedure and there is a more effective and less expensive version available. The most effective form of IGF is Long R3 IGF-1, it has been chemically altered and has had amino acid changes which cause it to avoid binding to proteins in the human body and allow it to have a much longer half life, around 20-30 hours. "Long R3 IGF-1 is an 83 amino acid analog of IGF-1 comprising the complete human IGF-1 sequence with the substition of an Arg(R) for the Glu(E) at position three, hence R3, and a 13 amino acid extension peptide at the N terminus. This analog of IGF-1 has been produced with the purpose of increasing the biological activity of the IGF peptide." "Long R3 IGF-1 is signifacantly more potent than IGF-1. The enhanced potency is due to the decreased binding of Long R3 IGF-1 to all known IGF binding proteins. These binding proteins normally inhibit the biological actions of IGF's." It is also not as expensive since a media grade version is available which is sufficient for bodybuilding use. There is also a receptor grade available but it is VERY expensive and the only noticeable difference between the two would only be able to be noticed in a laboratory setting. The price on the black market for Long R3 IGF-1 can be seen anywhere from $200-$500 per milligram depending on the source. The most effective length for a cycle of IGF is 50 days on and 20-40 days off. The most controversy surrounding Long R3 IGF-1 is the effective dosage. The most used dosages range between 20mcg/day to 120+mcg/day. IGF is only available by the milligram, one mg will give you a 50 day cycle at 20mcg/day, 2mg will give you a 50 day cycle at 40mcg/day, 3mg will give you a 50 day cycle at 60mcg/day, 4mg will give you a 50 day cycle at 80mcg/day and so on. The dosage issue mainly revolves around how much money you have to spend, plenty of people use the minimum dosage of 20mcg/day and are happy with the results, and in fact several top bodybuilders use the 20mcg/day dosage and are pleased with the results. IGF is most effective when administered subcutaneously and injected once or twice daily at your current dosage. The best time for injections is either in the morning and/or immediately after weight training. Another frequently asked question of IGF refers to the real world results, in terms of pure weight gain don't expect to gain 5 lbs. a week like you may off of anadrol or a similar steroid. The only weight you will gain from IGF use is pure lean muscle tissue, with steroids most of the weight gained is water weight. With an effective dosage you can expect to gain 1-2 lbs of new lean muscle tissue every 2-3 weeks and these effects can be increased with the use of testosterone, anabolic steroids, and insulin use. Increased vascularity is also very common, people report seeing veins appear where they never have before. And yet another effect reported is the ability to stay lean while bulking with heavy dosages of steroids and TONS of food while on an IGF cycle, this is perhaps the most pleasing effect. Increased pumps are also noticeable almost immediately, the pumps can almost become painful, pumps are even noticeable when doing cardio. Overall, IGF is a very exciting drug due to its ability to alter ones genetic capabilities. If you can find a trustworthy source and you use it correctly it can be a VERY useful tool in your bodybuilding drug arsenal.

Enjoy the read Northerners Proviron is a synthetic, orally effective androgen which does not have any anabolic characteristics. Proviron is used in school medicine to ease or cure disturbances caused by a deficiency of male sex hormones. Many athletes, for this reason, often use Proviron at the end of a steroid treatment in order to increase the reduced testosterone production. This, however is not a good idea since Proviron has no effect on the body's own testosterone production but-as mentioned in the beginning-only reduces or completely eliminates the dysfunctions caused by the testosterone deficiency. These are in particular impotence which is mostly caused by an androgen deficiency that can occur after the discontinuance of steroids, and infertility which manifests itself in a reduced sperm count and a reduced sperm quality. Proviron is therefore taken during a steroid administration or after discontinuing the use of the steroids, to eliminate a possible impotency or a reduced sexual interest. This, however does not contribute to the maintainance of strength and muscle mass after the treatment. There are other better suited compounds for this (see HCG and Clomid). For this reason Proviron is unfortunately cunsidered by many to be a useless and unnecessary compound. You should be aware that Proviron is also an estrogen antagonist which prevents the aromatization of steroids. Unlike the antiestrogen Nolvadex which only blocks the estrogen receptors (see Nolvadex) Proviron already prevents the aromatizing of steroids. Therefore gynecomastia and increased water retention are successfully blocked. Since Proviron strongly suppresses the forming of estrogens no rebound effect occurs after discontinuation of use of the compound as is the case with, for example, Nolvadex where an aromatization of the steroids is not prevented. One can say that Nolvadex cures the problem of aromatization at its root while Nolvadex simply cures the symptoms. For this reason male athletes should prefer Proviron to Nolvadex. With Proviron the athlete obtains more muscle hardness since the androgen level is increased and the estrogen concentration remains low. This, in particular, is noted positively during the preparation for a competition when used in combination with a diet. Female athletes who naturally have a higher estrogen level often supplement their steroid intake with Proviron resulting in an increased muscle hardness. In the past it was common for bodybuilders to take a daily dose of one 25 mg tablet over several weeks, sometimes even months, in order to appear hard all year round. This was especially important for athletes appearances at guest performances, seminars and photo sessions. Today Clenbuterol is usually taken over the entire year since possible virilization symptoms cannot occur which is not yet the case with Proviron. Since Proviron is very effective male athletes usually need only 50 mg/day which means that the athlete usually takes one 25 mg tablet in the morning and another 25 mg tablet in the evening. In some cases one 25 mg tablet per day is sufficient. When combining Proviron with Nolvadex (50 mg Proviron/day and 20 mg Nolvadex/day) this will lead to an almost complete suppression of estrogen. The side effects of Proviron in men are low at a dosage of 2-3 tablets/day so that Proviron, taken for example in combination with a steroid cycle, can be used comparatively without risk over several weeks. Since Proviron is well-tolerated by the liver liver dysfunctions do not occur in the given dosages. For athletes who are used to acting under the motto "more is better" the intake of Proviron could have a paradoxical effect. The most common side effect of Proviron-or in this case, secondary symptom- is in part a distinct sexual overstimulation and in some cases continuous penis erection. Since this condition can be painful and lead to possible damages, a lower dosage or discontinuing the compound are the only sensible solutions. Female athletes should use Proviron with caution since possible androgenic side effects cannot be excluded. Women who want to give Proviron a try should not take more than one 25 mg tablet per day. Higher dosages and periods of intake of more than four weeks considerably increase the risk of virilization symptoms. Female athletes who have no difficulties with Proviron obtain good results with 25 mg Proviron/day and 20 mg Nolvadex/day and, in combination with a diet, report an accelerated fat breakdown and continuously harder muscles.

It is so important not to chronically elevate GH and especially IGF-1. What follows is a summation of GH, how it acts, where it acts and its involvement in disease states. Derived in part from patent filings of GH-receptor antagonists. What is it? Growth hormone (GH) is in its major form, a 22-kDa (22 kilodalton) protein consisting of 191 amino acids (in humans), and in its equally anabolic minority isoform, a 20-kDa protein consisting of the same structure with the deletion of 15 amino acids at positions 32 to 46 as well as dimers of these two forms, released by the pituitary and a member of a cascade of hormones that regulate the growth of the body and its organs. Various Fragments of the GH chain are also released and may undergo further cleavage into yet other fragments. The biological activity for most of the fragments are known yet their significance and "modes of action" remain to be elucidated. Secretion of growth hormone into the bloodstream is followed by binding to growth hormone receptor (GHR) on many cell and organ types. Growth hormone signaling is initiated and mediated by this interaction. Growth hormone signaling brings about the production of another hormone, insulin-like growth factor-I (IGF-I or IGF-1), which is produced in the liver, adipose tissue and kidney and secreted into the bloodstream. About 75% of serum IGF-I is produced in the liver in response to growth hormone stimulation. Many disorders are caused by and/or associated with elevated growth hormone levels and/or elevated IGF-I levels in plasma and/or tissues including acromegaly, gigantism, retinopathy, macular degeneration, nephropathy, diabetes and cancers. The role of IGF-I in mediating many growth hormone effects is well recognized and the interrelationship is referred to as the growth hormone/insulin-like growth factor-I axis. In a normal feedback loop, IGF-I also causes the production of growth hormone by the pituitary to be reduced (i.e. negative feedback or inhibition). Growth hormone is produced and secreted by a set of specialized cells in the anterior pituitary. Growth hormone has direct and indirect effects on many tissues, such as stimulating bone and soft tissue growth and influencing carbohydrate, protein, and lipid metabolism. Direct biological activities of growth hormone include receptor binding, internalization of the hormone/receptor complex, and activation of proteins involved in signal transduction. GH Receptor Protein and RNA transcripts for receptors of growth hormone (GHR) have been detected in many of the tissues influenced by the hormone. It was determined that a single molecule of growth hormone binds sequentially to two receptor molecules, forming an active complex. This complex, in turn, signals stimulation of other genes, including IGF-I. IGF-I, produced and secreted by the liver and other target tissues, mediates some of the indirect effects of growth hormone on growth and development. Other intracellular events occurring after the growth hormone/growth hormone receptor interaction include activation of tyrosine kinases such as Janus kinase 2 (Jak-2), which leads to phosphorylation and activation of other proteins including signal transducer and activator of transcription 5A and 5B (STAT 5A and 5B) and mitogen activated protein (MAP) kinase that, in turn, activate other proteins and genes. The cDNA encoding the growth hormone receptor has been cloned from many species. The receptor consists of an extracellular hormone-binding region (exons 2-7), a single membrane spanning region (exon 8), and an intracellular region (exons 9-10). There are also multiple alternative 5' untranslated regions which are alternative first exons of the gene, in both the human and mouse transcripts. Growth hormone receptor has no intrinsic kinase domain, but the intracellular region plays a major role in the signal transduction process. A truncated form of the receptor, known as growth hormone binding protein (GHBP), lacks the transmembrane and intracellular regions of growth hormone receptor and is secreted into the serum. The truncated protein is produced by one of two different processes, depending on the animal species. In mice and rats, alternative splicing of growth hormone receptor precursor messenger RNA replaces the transmembrane and intracellular regions with a very short hydrophilic tail (encoded by exon 8A; 15, 16). In humans, cows, and pigs (among others), no alternative RNA splicing is apparent but instead the GHBP is produced by proteolysis of the growth hormone receptor. The function of the binding protein appears to be to modulate the level of circulating growth hormone. Growth hormone receptor is expressed in many organs and tissues including liver, adipose tissue, muscle, cartilage, bone, tooth, kidney, eye, cardiovascular system, gut, reproductive organs, skin, brain, endocrine system and immune system. The three-dimensional structure of the extracellular domain of growth hormone receptor has been established. It consists of two modules, each of about 100 amino acids, arranged as two sandwiches each with seven strands of beta-sheet. The secreted form of the extracellular domain of growth hormone receptor is the GHBP. The growth hormone receptor is biologically responsive to growth hormone stimulation. JAK2 is the primary effector molecule for growth hormone receptor signaling. JAK2 is activated post growth hormone receptor dimerisation. When the growth hormone dimerizes its receptors, the JAKs are brought close together, and with proper alignment transphosporylate each other, leading to full activation. The intracellular targets for the JAKs include tyrosine residues in the receptor cytoplasmic domain itself, which in turn activate SH2 domains (STATS, She and SHP2). These may go on to activate the MAP kinase pathway, which regulates cell proliferation. JAK2 also phosphorylates and activates other signaling molecules, such as IRS-1 and -2 and phosphatidyl 3-inositol kinase, which are important parts of the insulin signaling mechanism and may account for the insulin-like actions of growth hormone. Activated JAK2 also phosphorylates STATS, and when activated, is involved in the transcription of a number of genes. The Actions of GH Receptor Activation Growth hormone receptor activation leads to many actions in many organs including the following outcomes in the following organs: Liver: Increased secretion of insulin-like growth factor-I, synthesis of plasma proteins, regulation of nitrogen balance enzymes, increased carbohydrate synthesis/storage, and increased fat breakdown; Adipose Tissue: Breakdown of fat stores; Muscle: Increased protein synthesis, decreased protein breakdown; Cartilage: Increased height by increasing proliferation and differentiation of chondrocytes in growth plate; Bone & Tooth: Increased turnover of tissue, both synthesis and breakdown; Kidney: Increased sodium, bicarbonate and water retention; Eye: increased retinal neovascularization; Cardiovascular: Hypertrophy, increased contractility, stroke volume, cardiac output; Gut: Hypertrophy, increased amino acid, sodium, calcium, phosphate and B12 uptake; Reproductive System: Increased sperm production and motility, increased accessory gland secretion in male, increased number of follicles and ovulation rate, increased follicular maturation rate, increased milk production; Skin: Increased skin thickness and strength, increased hair growth and thickness; Brain: Increased neuron proliferation and connectivity prenatally, increased myelin formation, improved long-term memory; Endocrine System: Increased insulin synthesis and secretion, increased adrenal steroidogenesis; Immune System: Increased immune cell proliferation, increased killing by monocytes, macrophages and NK cells, increased antibody production IGF-1 Downstream from growth hormone receptor in the growth hormone signaling pathway are IGF-I and IGF-I receptor. The insulin-like growth factors (IGFs) are important in proliferation. In particular, IGF-I and IGF-2 are ubiquitous polypeptides each with potent mitogenic effects on a broad range of cells. Molecules of the insulin-like growth factor type are also known as "progression factors" promoting "competent" cells through DNA synthesis. The insulin-like growth factors act through a common receptor known as the Type I receptor or IGF-IR, which is tyrosine kinase linked. Particular proteins, referred to as insulin-like growth factor binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue insulinlike growth factor availability (Rechler and Brown, Growth Regulation, 1992,2,55-68). Six IGFBPs have so far been identified. The exact effects of the IGFBPs are not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed. There is some evidence, however, that certain IGFBPs are involved in targeting insulin-like growth factor-I to its cell surface receptor. Also expression of IGFBP-3 is regulated by growth hormone. The IGF-R is a tyrosine kinase linked cell surface receptor that regulates cell division, transformation and apoptosis in many cell types. Disease states related to GH/IGF-1 If feedback regulation of growth hormone production is lost and the pituitary continues to release aberrant amounts of growth hormone, the level of insulin-like growth factor-I continues to rise, leading to bone growth and organ enlargement. The excess growth hormone also causes changes in sugar and lipid metabolism, which may lead to diabetes. Defects in the growth hormone signalling pathway often lead to abnormalities of stature and body and/or organ size. Mutations in the growth hormone receptor gene result in extreme short stature (Laron's syndrome). Excessive production of growth hormone can lead to acromegaly or gigantism. Excess GH Acromegaly and gigantism are related growth disorders wherein growth hormone excess, sometimes caused by pituitary tumor, causes progressive cosmetic disfigurement and systemic organ manifestations. It affects 40-50 per million people worldwide with about 15,000 sufferers in each of the US and Europe and an annual incidence of about 4-5 per million. It is initially characterized by abnormal growth of the hands and feet and bony changes in the facial features. Patients have reduced quality of life with overgrowth of the jaw, enlargement of hands and feet, deepening of the voice, thickening of skin, offensive body odor, articular cartilage problems, hyperphosphatemia, peripheral neuropathies, higher blood pressure, diabetes, heart disease, and cancer, and have a reduced life expectancy if untreated. The mortality rate is about twice that of the normal population due to cardiorespiratory and cardiovascular diseases, diabetes and neoplasia, particularly colon cancer. The goal of current treatment is to reverse the effects of the hypersecretion of growth hormone and normalize production of IGF-I which is elevated by about 50% in these patients. When effective, treatment moderates disease symptoms and disease-associated mortality. Gigantism, the disease of excess growth hormone in children, is a rare disorder. In gigantism, excessive linear growth occurs whilst epiphyseal growth plates are open during childhood with growth hormone excess caused via a benign pituitary tumor. In both gigantism and acromegaly, all growth parameters are affected, although not necessarily symmetrically. Many of the growth related outcomes are mediated by elevated levels of serum IGF-I. Serum blood levels of IGF-I are elevated by about 50% in patients and reduction of serum IGF-I is used to monitor treatment Treatments for acromegaly and gigantism involve the ability to lower the elevated IGF-I in plasma. This may be achieved by surgical removal and radiation therapy of the benign pituitary tumor but this is effective in only 50% of patients. Dopamine agonists such as bromocriptine mesylate or cabergoline may be dosed orally which is convenient but they only reduce growth hormone production and associated IGF-I sufficiently in 10% of cases. They also produce significant gastrointestinal and central side effects in 20-30% of patients. Also used in treatment of acromegaly are the somatostatin analogues such as Sandostatin or octreotide, which inhibit the release of growth hormone releasing hormone (GHRH) from the hypothalamus, and/or pituitary and thereby reducing production of growth hormone in the pituitary. This compound is effective in 60-65% patients with acromegaly but it must be injected under the skin every 8 hours or intramuscularly for effective treatment. GHR Antagonist Recently a growth hormone receptor antagonist, Trovert, also known as Somavert, Pegvisomant and B2036PEG, was shown in clinical trials to be effective in 90-95% of patients. Clinical trial experience to date shows a 10% drop-out rate and adverse effects such as liver dysfunction. Trovert is a growth hormone molecule with a 9 amino acid substitution with 4-5 pegylations to increase half life. Like all modified proteins it is immunogenic, with antibodies being made to Trovert within 1 month of dosing. This can impact Trovert's short and long term utility and makes dosing difficult to predict. Trovert was initially dosed once per month by subcutaneous (sc) administration, but current clinical practice suggests dosing will need to be once/day sc. Trovert interferes with growth hormone binding to its receptor but not the Growth Hormone Binding Protein (GHBP) fragment of the growth hormone receptor. GHBP binds growth hormone prolonging its action, which can be disadvantageous in conditions involving excess growth hormone and/or excess IGF-I. Pegylation may also impact on Trovert's long term safety profile. Diabetes Diabetes and its life threatening complications such as diabetic retinopathy and nephropathy are also disorders associated with growth hormone and/or IGF-I levels. First line treatment of these conditions involves controlling hyperglycemia. Drugs that control diabetes reduce the incidence of nephropathy by 60% and also reduce the incidence of retinopathy. However, about half of all diabetics are unaware of disease and therefore remain untreated, so diabetic nephropathy and retinopathy are likely to remain a major condition requiring other treatments. In retinopathy surgical ablative treatments such as laser pan-retinal photocoagulation are used but these remain incompletely effective and destroy retinal tissue, causing partial vision field loss. In type I diabetics ACE and All inhibitors decrease albuminuria excretion by acting on the kidney and in Type II diabetics the same inhibitors act locally on kidney and also decrease blood pressure to reduce the risk of death from kidney failure by another 50%. However, 20-30% of patients remain resistant to treatment with current glycemic control drugs and ACE drugs. There is thus a need for better treatments. The underlying cause of diabetes, diabetic retinopathy and diabetic nephropathy may be insulin related hyperglycemia, but growth hormone and/or insulin-like growth factor-I excess is also important. Octreotide inhibitors of GHRH that decrease production of pituitary growth hormone, reducing systemic levels of growth hormone and IGF-I, and/or modulating local tissue levels show potential in the clinic. A study with octreotide by Grant et al., Diabetes Care, 2000, 2, 504-9) reducing sIGF-1 by 51% at maximally tolerated doses of octreotide 5000 ,Mg/day sc reduced the need for laser surgery in retinopathy patients to 1 patient out of 22 rather than 9/22 in placebo in a 15 month study. Also ocular disease was reduced to 27% vs placebo of 42% bordering on significance (P 0.06). Three human studies using octreotide at levels that reduced sIGFl 45%, about 20% and about 10% respectively were at least partly effective in clinical trials of nephropathy. The outcome reported by Serin et al. (JAMA, 1991, 265, 888-92) with 11 patients used high doses of octreotide in a 12 week study that reduced serum IGF-I by 45%. At the time it was stated to be the best effect observed on reducing glomerular filtration rate with a 22-33% reduction relative to placebo. This dose, however, was near maximally tolerated doses of octreotide. Animal pathology model studies with octreotide and Trovert also support the view that agents that modulate the growth hormone/insulin-like growth factor-I axis are beneficial in the treatment of these diabetic conditions. Growth hormone and its receptor are implicated in the induction of glomerular hypertrophy and sclerosis in partial nephrectomy and diabetic nephropathy with somatostatin inhibitors octreotide and PTR-3173 (Groenbaek et al., /. Endocrinol, 2002, 172, 637-643 and Landau et al, Kidney International, 2001, 60, 505-512) and growth hormone receptor antagonist, G120K-PEG, a weaker version of Trovert, preventing complications in type I and Type II diabetic mice (Chen et al, Endocrinology, 1996,137, 11, 5136-5165; Flyvbjerg et al, Diabetes, 1999, 40,377-382, and Segev et al., /. Am. Soc. Nephrol. 1999, 10,2374-81). Growth hormone and its receptor are implicated in the induction of retinal neovascularization through IGF-I with somatostatin inhibitors octreotide and growth hormone receptor antagonist MK678, inhibiting retinal neovascularization in mice. MK678 reduction of neovascularization correlated with low serum IGF-I (Smith et al, Science, 1997, 276, 1706-9). Oxygen induced retinopathy in the mouse was also responsive to octreotide as reported by Higgins et al.,Exp. Eye Res, 2002, 74,553-9. Macular Degeneration Macular degeneration is also associated with elevated growth hormone and/or IGF-I levels. Age-related macular degeneration (AMD) is caused by deterioration of the central part of the retina, the macula, resulting in loss of detailed vision. Wet AMD, the less common form, is caused by leakage from new blood vessels growing behind the retina. The growth hormone/IGF-I axis is involved in formation of new blood vessels relevant to this condition and to diabetic retinopathy. Cancer Various cancers are also associated with aberrant growth hormone and/or IGF-I levels. Reduction of serum IGF-I by 20-50% using Trovert decreased tumor volume in breast cancer in animal models and helped in colon cancer, liver metastasis, and meningiomas (Friend et al, Proceedings llth NCI EORTC. AACR Symposium and Friend, Growth Harm. IGF Res., 2001, Jun: 11 Suppl A: S121-3). The incidence of breast, colon, prostate, and lung cancer is increased in individuals in the high normal range of serum IGF-I. There have been no clinical studies with Trovert in cancers. However, octreotide is indicated for gastro-pancreatic cancers. Longevity Longevity may also be improved with modulation of growth hormone receptor (Coschigano et al., Endocrinology, 2000, 141, 2608-2613). There was a significant increase in lifespan of nearly a year in double knockout animals with low levels of IGF-I and high levels of growth hormone. Inhibition of Neuronal Differentiation Another application to modifying levels of growth hormone and/or IGF-I via the growth hormone receptor may enable stem cell differentiation towards neural cell production as growth hormone inhibits neuronal differentiation of neural progenitor cells (Turnley et al., Nature Neuroscience, 1 Oct. 2002, published online). Although the underlying roles in various disease or conditions may be different, the above conditions arise at least in part from incorrect levels of expression of local and/or systemic growth factors growth hormone and IGF-I and/or their receptors growth hormone receptor and IGF-R. In these situations, dopamine agonists, somatostatin antagonists, and growth hormone receptor antagonists targeting the proteins have been used and/or shown potenial In reference to DatbTrue

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