Growth Hormone Resistance

[DrMariano2]

@00slotiv 2957 wrote:

I have been using HGH for two years and my IGF-1 continues to slowly plummet. Three ius a day, every night.

Generally is around 170 but has hit 130 recently. I am 48. I started on it when I found my IGF-1 to be 122. Has hit the 200s when I was overeating. Recent fasting insulin was about 3.7. This was near the bottom of the range, which I believe to be good.

I think the HGH is working for fat loss and hopefully helping me out of osteopenia, but is there anything I can do to increase the IGF-1. I mean, it is low enough for treatment!

Am I just fine the way it is? I am 175 pounds and 6 foot 2, in good shape I think. On TRT with level of high 600s on 70 mg twice a week. Bio only in the low 300s. This too had been higher.

When growth hormone fails to increase IGF-1 signaling, a person has Growth Hormone Resistance. Growth Hormone Resistance has multiple possible causes. It is important to examine for each of those causes to help improve response to growth hormone.

The partial circuitry involved in IGF-1 production is as follows:
1. Growth Hormone Receptors are produced in Liver Cells.
2. Growth hormone from the pituitary or exogenous source stimulates Growth Hormone Receptors.
3. Stimulation of the Growth Hormone Receptor triggers within-cell signaling processes called signal transduction. Signal transduction includes activation of a protein called STAT5b.
4. STAT5b triggers the production of IGF-1.
5. Stimulation of the Growth Hormone Receptor also leads to the production of IGF Binding Protein 3 (IGFBP3) and Acid Labile Subunit (ALS).
6. In circulation, IGF-1 Binds to IGFBP3. The two then bind to ALS. This combination lengthens the half-life of IGF-1 to 12-hours.

If IGF-1 does not bind to proteins (free IGF-1), its half-life is 4.5 minutes. There are about 6 IGF Binding Proteins. 75-80 % of IGF-1 is bound to IGFBP3. About 1-2 % of IGF-1 is free. Growth Hormone triggers the production of IGF-1, IGFBP3, and ALS.

If there is any problem at any step of the circuitry described, the production of IGF-1 from Growth Hormone will be reduced and Growth Hormone Resistance occurs.

Some Conditions That Can Cause Growth Hormone Resistance:

* Alcohol. One drink is toxic enough to impair cellular metabolism in the liver such that growth hormone receptor production is reduced, inflammatory signaling is raised to the point production of IGF-1 and its binding proteins are reduced. One drink wastes an entire day’s worth of growth hormone.

* Fasting. Fasting inhibits growth hormone receptor production. Fasting also reduces production of IGF Binding Proteins.

* Nutritional Deficiencies. Nutrient deficiencies (such as in Vitamin A, iron, protein, etc.) directly or indirectly impair IGF-1 and IGFPB3 production.

* Hypoglycemia or low insulin levels can reduce IGF Binding Proteins other than IGFBP3. This can reduce the half-life of IGF-1, lowering blood levels.

* Hypothyroidism. Suboptimal thyroid hormone signaling impairs production of growth hormone receptors.

* Excessive Inflammatory Cytokine Signaling from the Immune System. Inflammatory cytokines (such as Tumor Necrosis Factor Alpha (TNF-alpha), InterLeukin 1a, 1b, and 6) can inhibit growth hormone receptor production, impair signal transduction, impair IGF-1 gene expression, leading to impaired IGF-1 production and impaired IGFBP3 and ALS production.

* Excess Estrogen. Excessive estrogen (e.g. estradiol and the numerous other estrogens.) binding to its receptor can directly reduce IGF-1 gene expression and hence IGF-1 production. Estrogen can increase inflammatory cytokine signaling and reduce thyroid hormone signaling. These can lead to reduced growth hormone receptor production and reduced IGF-1 production. Oral estrogen is particularly bad. It is a waste to use growth hormone when taking oral estrogens. Tamoxifen (Nolvadex) acts like estrogen in the liver, leading to a reduction in IGF-1. Arimidex may block estradiol production, but it doesn’t block the production of other estrogens. And, if the Arimidex dose is too high, even estradiol can be produced via alternative pathways.

* Liver Disease. Liver disease may involve impaired cellular metabolism and excessive inflammatory signaling which impairs IGF-1, IGFBP3, and ALS production.

* Renal Disease. Renal disease can cause multiple problems including nutritional, electrolyte, hormonal problems, and the production of inhibitors (including inflammatory signals) which lead to reduced growth hormone receptor production, impaired signal transduction and gene expression, which lead to decreased IGF-1. The ALS protein can also be lost from the kidney into the urine in protein-losing kidney diseases, leading to reduced half-life of IGF-1, leading to reduced IGF-1 level.

* Infections. Infections can cause excessive inflammatory cytokine production which decrease IGF-1. Some infections may not have obvious symptoms – such as periodontal disease, some gut infections, etc.

* Stress and trauma. Stress (either internal or external) increases norepinephrine signaling (the primary stress signal) and/or histamine signaling (another stress signal). These can increase inflammatory cytokine production which decrease IGF-1.

* Diabetes Type 2. Diabetes Type 2 and pre-diabetes have multiple pathophysiologies which can impair IGF-1 including increased stress/norepinephrine signaling, suboptimal thyroid signaling, increased immune system inflammatory signaling, cellular metabolic problems which impairs growth hormone receptor, IGF-1 and binding protein production.

* Autoimmune diseases, such as the inflammatory bowel diseases, can cause excessive production of inflammatory cytokines, which decrease IGF-1.

* Growth Hormone inhibiting antibodies. There is a rare condition where a person has a mutation in growth hormone which causes the immune system to recognize exogenous growth hormone as foreign. The body produces antibodies which inactivate growth hormone.

* Genetic Growth Hormone Resistance. Genetic defects can cause growth hormone receptor deficiency, impaired signal transduction, impaired gene expression and production of IGF-1, IGFBP3, and ALS, leading to low IGF-1 levels.

* Xenobiotics. Environmental toxins (including some plastics) can act like estrogen or lead to increased inflammatory cytokine signaling, leading to reduced IGF-1.

* Cancer. Some cancers increase inflammatory cytokine signaling.

* Etc., Etc., Etc.

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