The Myth of LR3 IGF-I ("IGF1-LR3")'s Long Half-Life

[Type-IIx]

LR3 IGF-I ("IGF1-LR3")'s biological half life is remarkably & profoundly short rather than long.

Its clearance from the blood depends primarily on IGFBP-3 levels, that are increased, probably dose-dependently, by rhGH. Nobody knows its estimated t1/2 in healthy adults, but it should be administered at least twice daily, if not more frequently.

From my notes (granted, it takes a bit more understanding that “it’s ‘Long’ R3, bro, lol”):

LR3 IGF-I is more potent than IGF-I when the peptides are given by injection, and particularly with twice daily injection due to its rapid clearance from plasma. [1]. The affinity for binding is four- to five- fold larger for LR3 IGF-I than IGF-I, and it is rapidly cleared from the plasma as a consequence of its resistance to binding to the IGFBPs. [1].

IGFBPs profiles & functions

- human skeletal muscle cells: abundant IGFBP-3; high affinity -BP-2 & -BP-4; -3, & -5 [3]

- fetal cells: <<IGFBP-3, -2 & no -4

- rat L6: IGFBP-4, -5, and -6

- rat C2: only IGFBP-5. [2].

IGFBPs modulate IGF activity by extending the half-life of the IGFs and by either potentiating or inhibiting binding of the IGFs to their receptors. [3].

From [3]:

Although muscle satellite cells were identified almost 40 years ago, little is known about the induction of their proliferation and differentiation in response to physiological/pathological stimuli or to growth factors/cytokines. In order to investigate the role of the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system in adult human myoblast differentiation we have developed a primary human skeletal muscle cell model. We show that under low serum media (LSM) differentiating conditions, the cells secrete IGF binding proteins-2, -3, -4 and -5. Intact IGFBP-5 was detected at days 1 and 2 but by day 7 in LSM it was removed by proteolysis. IGFBP-4 levels were also decreased at day 7 in the presence of IGF-I, potentially by proteolysis. In contrast, we observed that IGFBP-3 initially decreased on transfer of cells into LSM but then increased with myotube formation. Treatment with 20 ng/ml tumour necrosis factor-alpha (TNFalpha), which inhibits myoblast differentiation, blocked IGFBP-3 production and secretion whereas 30 ng/ml IGF-I, which stimulates myoblast differentiation, increased IGFBP-3 secretion. The TNFalpha-induced decrease in IGFBP-3 production and inhibition of differentiation could not be rescued by addition of IGF-I. LongR(3)IGF-I, which does not bind to the IGFBPs, had a similar effect on differentiation and IGFBP-3 secretion as IGF-I, both with and without TNFalpha, confirming that increased IGFBP-3 is not purely due to increased stability conferred by binding to IGF-I. Furthermore reduction of IGFBP-3 secretion using antisense oligonucleotides led to an inhibition of differentiation. Taken together these data indicate that IGFBP-3 supports myoblast differentiation.


From the INCRELEX pamphlet:

Clearance of [IGF-I and its analogues] is inversely proportional to IGF binding protein-3 (IGFBP-3) levels.

Normal (healthy) clearance is 0.01 L/hr/kg (because normal concentrations of IGFBP-3, to which clearance is inversely proportional, is 3 micrograms/mL IGFBP-3).

From [4]:

rats; protocol: continuous subcutaneous infusion ~1.5mg * kg⁻¹ daily * 28 days (0.125μL*h⁻¹)

No significant effect of LR3 IGF-I on muscle contractile properties, mass, force capacity, nor specific force!

↓IGF-I (serum), ↓median myofiber CSA, indicating that IGFBP interaction is needed to maintain or augment muscle myofiber size, oxidative capacity!

_______________________

References:

[1] Tomas, F. M., Lemmey, A. B., Read, L. C., & Ballard, F. J. (1996). Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection. Journal of Endocr inology, 150(1), 77–84. doi:10.1677/joe.0.1500077

[2] Crown, A. (2000). Characterisation of the IGF system in a primary adult human skeletal muscle cell model, and comparison of the effects of insulin and IGF-I on protein metabolism. Journal of Endocrinology, 167(3), 403–415. doi:10.1677/joe.0.1670403

[3] Foulstone, E. J., Savage, P. B., Crown, A. L., Holly, J. M. P., & Stewart, C. E. H. (2003). Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts. Journal of Cellular Physiology, 195(1), 70–79. doi:10.1002/jcp.10227

[4] Gehrig SM, Ryall JG, Schertzer JD, Lynch GS. Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage. Exp Physiol. 2008 Nov;93(11):1190-8. doi: 10.1113/expphysiol.2008.042838. Epub 2008 Jun 20.

 

[Performance Based]

Beyond fascinating thank you

 

[ZERaptor]

LR3 IGF-I ("IGF1-LR3")'s biological half life is remarkably & profoundly short rather than long.

Its clearance from the blood depends primarily on IGFBP-3 levels, that are increased, probably dose-dependently, by rhGH. Nobody knows its estimated t1/2 in healthy adults, but it should be administered at least twice daily, if not more frequently.

From my notes (granted, it takes a bit more understanding that “it’s ‘Long’ R3, bro, lol”):

LR3 IGF-I is more potent than IGF-I when the peptides are given by injection, and particularly with twice daily injection due to its rapid clearance from plasma. [1]. The affinity for binding is four- to five- fold larger for LR3 IGF-I than IGF-I, and it is rapidly cleared from the plasma as a consequence of its resistance to binding to the IGFBPs. [1].

IGFBPs profiles & functions

- human skeletal muscle cells: abundant IGFBP-3; high affinity -BP-2 & -BP-4; -3, & -5 [3]

- fetal cells: <<IGFBP-3, -2 & no -4

- rat L6: IGFBP-4, -5, and -6

- rat C2: only IGFBP-5. [2].

IGFBPs modulate IGF activity by extending the half-life of the IGFs and by either potentiating or inhibiting binding of the IGFs to their receptors. [3].

From [3]:

Although muscle satellite cells were identified almost 40 years ago, little is known about the induction of their proliferation and differentiation in response to physiological/pathological stimuli or to growth factors/cytokines. In order to investigate the role of the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system in adult human myoblast differentiation we have developed a primary human skeletal muscle cell model. We show that under low serum media (LSM) differentiating conditions, the cells secrete IGF binding proteins-2, -3, -4 and -5. Intact IGFBP-5 was detected at days 1 and 2 but by day 7 in LSM it was removed by proteolysis. IGFBP-4 levels were also decreased at day 7 in the presence of IGF-I, potentially by proteolysis. In contrast, we observed that IGFBP-3 initially decreased on transfer of cells into LSM but then increased with myotube formation. Treatment with 20 ng/ml tumour necrosis factor-alpha (TNFalpha), which inhibits myoblast differentiation, blocked IGFBP-3 production and secretion whereas 30 ng/ml IGF-I, which stimulates myoblast differentiation, increased IGFBP-3 secretion. The TNFalpha-induced decrease in IGFBP-3 production and inhibition of differentiation could not be rescued by addition of IGF-I. LongR(3)IGF-I, which does not bind to the IGFBPs, had a similar effect on differentiation and IGFBP-3 secretion as IGF-I, both with and without TNFalpha, confirming that increased IGFBP-3 is not purely due to increased stability conferred by binding to IGF-I. Furthermore reduction of IGFBP-3 secretion using antisense oligonucleotides led to an inhibition of differentiation. Taken together these data indicate that IGFBP-3 supports myoblast differentiation.


From the INCRELEX pamphlet:

Clearance of [IGF-I and its analogues] is inversely proportional to IGF binding protein-3 (IGFBP-3) levels.

Normal (healthy) clearance is 0.01 L/hr/kg (because normal concentrations of IGFBP-3, to which clearance is inversely proportional, is 3 micrograms/mL IGFBP-3).

From [4]:

rats; protocol: continuous subcutaneous infusion ~1.5mg * kg⁻¹ daily * 28 days (0.125μL*h⁻¹)

No significant effect of LR3 IGF-I on muscle contractile properties, mass, force capacity, nor specific force!

↓IGF-I (serum), ↓median myofiber CSA, indicating that IGFBP interaction is needed to maintain or augment muscle myofiber size, oxidative capacity!

_______________________

References:

[1] Tomas, F. M., Lemmey, A. B., Read, L. C., & Ballard, F. J. (1996). Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection. Journal of Endocr inology, 150(1), 77–84. doi:10.1677/joe.0.1500077

[2] Crown, A. (2000). Characterisation of the IGF system in a primary adult human skeletal muscle cell model, and comparison of the effects of insulin and IGF-I on protein metabolism. Journal of Endocrinology, 167(3), 403–415. doi:10.1677/joe.0.1670403

[3] Foulstone, E. J., Savage, P. B., Crown, A. L., Holly, J. M. P., & Stewart, C. E. H. (2003). Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts. Journal of Cellular Physiology, 195(1), 70–79. doi:10.1002/jcp.10227

[4] Gehrig SM, Ryall JG, Schertzer JD, Lynch GS. Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage. Exp Physiol. 2008 Nov;93(11):1190-8. doi: 10.1113/expphysiol.2008.042838. Epub 2008 Jun 20.

So how long would you say it lasts for rather than the 24-30 hour timeframe that's usually said?

 

[Type-IIx]

So how long would you say it lasts for rather than the 24-30 hour timeframe that's usually said?

Well, rhIGF-I (mecasermin; Increlex) has a mean biological half-life of 5.8 h. Since LR3 IGF-I is totally resistant to binding all IGFBPs, including IGFBP-3 that is inversely related to IGF-I clearance rate (0.01 L/hr/kg in healthy adults), I'd estimate that its half-life is at most 2 h.

 

[Type-IIx]

Well, rhIGF-I (mecasermin; Increlex) has a mean biological half-life of 5.8 h. Since LR3 IGF-I is totally resistant to binding all IGFBPs, including IGFBP-3 that is inversely related to IGF-I clearance rate (0.01 L/hr/kg in healthy adults), I'd estimate that its half-life is at most 2 h.

I should correct myself here. The biological half-life data for mecasermin (rhIGF-I; Increlex) is for children with severe primary IGF-I deficiency, that differ qualitatively from healthy adults by their blood IGFBP-3 levels and therefore clearance rate. Taking the published pharmacokinetic data for mecasermin and doing some math, Increlex half-life (t1/2) = 0.693 * Vd (L/kg) / CL (L/kg/hr), therefore in healthy adults, t1/2 (hr) = 0.693 * (0.257 L/14.1 kg) / (0.01 L/h/14.1 kg) ≈ 17.8 h.

I still intuitively believe that LR3 IGF-I's total resistance to binding the IGFBPs gives it a half-life considerably less than for moderately high dose rhIGF-I (4.92 mg) in severe primary IGFD. I stick by my 2 h approximation.

By the way, it's probably worth pointing out the very poor dose-response for rhIGF-I in healthy adults vs. rhGH oriented towards increasing blood IGF-I levels. For a 75 kg man, 3.8 IU/d rhGH ↑IGF-I (serum) from 162→439 μg/L, whereas 6 mg/d rhIGF-I ↑IGF-I (serum) merely from 156→342 μg/L.

 

[Performance Based]

@Type-IIx Without being overly nosey may I inquire as to what your educational background and profession are?

Your data points, ability to deduce and put forth information is unparalleled

 

[Type-IIx]

@Type-IIx Without being overly nosey may I inquire as to what your educational background and profession are?

Your data points, ability to deduce and put forth information is unparalleled

My profession frowns upon what it is I do here, discuss physique- and performance- enhancing drugs, so I am intentionally vague. I have advanced education and work in a related field.

 

[ZERaptor]

I should correct myself here. The biological half-life data for mecasermin (rhIGF-I; Increlex) is for children with severe primary IGF-I deficiency, that differ qualitatively from healthy adults by their blood IGFBP-3 levels and therefore clearance rate. Taking the published pharmacokinetic data for mecasermin and doing some math, Increlex half-life (t1/2) = 0.693 * Vd (L/kg) / CL (L/kg/hr), therefore in healthy adults, t1/2 (hr) = 0.693 * (0.257 L/14.1 kg) / (0.01 L/h/14.1 kg) ≈ 17.8 h.

I still intuitively believe that LR3 IGF-I's total resistance to binding the IGFBPs gives it a half-life considerably less than for moderately high dose rhIGF-I (4.92 mg) in severe primary IGFD. I stick by my 2 h approximation.

By the way, it's probably worth pointing out the very poor dose-response for rhIGF-I in healthy adults vs. rhGH oriented towards increasing blood IGF-I levels. For a 75 kg man, 3.8 IU/d rhGH ↑IGF-I (serum) from 162→439 μg/L, whereas 6 mg/d rhIGF-I ↑IGF-I (serum) merely from 156→342 μg/L.

That's interesting.

It is theorised that igf-1 LR3 is 'stronger' than the regular version (increlex), for whatever reason whether its for muscle building in there case here or treating short kids with deficiency, so would you say this is the case due to the lower binding affinity to the IGFBPs? (For dose equivalent manner)

 

[Type-IIx]

That's interesting.

It is theorised that igf-1 LR3 is 'stronger' than the regular version (increlex), for whatever reason whether its for muscle building in there case here or treating short kids with deficiency, so would you say this is the case due to the lower binding affinity to the IGFBPs? (For dose equivalent manner)

It has 4- to 5- fold greater affinity for the IGF-IR vs. rhIGF-I ("Increlex"), so presumably greater transactivation potency, as a consequence of this resistance/its structure. However, like all IGFs, it functions differently across tissues (with respect to mitogenic & metabolic effects, and most importantly to us, myogenic effects), and the IGFBPs, to which it is resistant, serve to extend the duration of activity and either potentiate or attenuate IGF activity tissue-dependently as well. As shown above, IGFBP-3 interaction with IGFs is particularly important in human skeletal muscle myogenic effects.

I use LR3 IGF-I in very advanced bodybuilders in a particular way that an astute reader might arrive at after reading and really mulling over the OP. Consider that, despite being less anabolic than insulin, it serves to increase the pool of available myofibers.

 

[ZERaptor]

It has 4- to 5- fold greater affinity for the IGF-IR vs. rhIGF-I ("Increlex"), so presumably greater transactivation potency, as a consequence of this resistance/its structure. However, like all IGFs, it functions differently across tissues (with respect to mitogenic & metabolic effects, and most importantly to us, myogenic effects), and the IGFBPs, to which it is resistant, serve to extend the duration of activity and either potentiate or attenuate IGF activity tissue-dependently as well. As shown above, IGFBP-3 interaction with IGFs is particularly important in human skeletal muscle myogenic effects.

I use LR3 IGF-I in very advanced bodybuilders in a particular way that an astute reader might arrive at after reading and really mulling over the OP. Consider that, despite being less anabolic than insulin, it serves to increase the pool of available myofibers.

Do you think both hgh and igf-1 LR3 can be taken together to get the 'best of both worlds' or would the igf-1 lr3 suppress the body from converting the injected gh into igf-1 through a feedback loop making the hgh less effective?

As you mentioned that lr3 may have a half life of 2 hours so they can both be taken together 12 hours apart (gh before bed and lr3 midday so they don't interfere with each other), I am assuming that this may be what most top bodybuilders are doing

 

[Type-IIx]

Do you think both hgh and igf-1 LR3 can be taken together to get the 'best of both worlds' or would the igf-1 lr3 suppress the body from converting the injected gh into igf-1 through a feedback loop making the hgh less effective?

As you mentioned that lr3 may have a half life of 2 hours so they can both be taken together 12 hours apart (gh before bed and lr3 midday so they don't interfere with each other), I am assuming that this may be what most top bodybuilders are doing

I think that you have to be very advanced, i.e., having totally maximally hypertrophied your available pool of myofibers, typically associated with at least vying for an IFBB pro card foreseeably in terms of months, for LR3 use to be justified, because it's not potently anabolic, it stimulates myoblast proliferation; and it's very expensive to administer at sufficient dose and frequency to elicit anything of substance.

If that is the case for you, then yes, they can be taken together rationally, rhGH & LR3 IGF-I.

I doubt most people use it rationally including top pros. I don't think many people have really thought about it with much sophistication, and certainly not many in bodybuilding.

 

[Performance Based]

My profession frowns upon what it is I do here, discuss physique- and performance- enhancing drugs, so I am intentionally vague. I have advanced education and work in a related field.

Without being overly nosey may I ask what tools, course works, frameworks you have utilized to write at a thesis level seemingly with ease?

I hold several masters degrees (non science based) and find myself articulate, when I want to be, however no where on the same level with your fluidity and seeming subject matter expertise.

I appreciate your time and do not mean to hijack nor distract from the original post - just something I have been sincerely curious about.

 

[Type-IIx]

Without being overly nosey may I ask what tools, course works, frameworks you have utilized to write at a thesis level seemingly with ease?

I hold several masters degrees (non science based) and find myself articulate, when I want to be, however no where on the same level with your fluidity and seeming subject matter expertise.

I appreciate your time and do not mean to hijack nor distract from the original post - just something I have been sincerely curious about.

Probably the technical writing, [professional] writing, and research methods courses.

 

[ZERaptor]

I think that you have to be very advanced, i.e., having totally maximally hypertrophied your available pool of myofibers, typically associated with at least vying for an IFBB pro card foreseeably in terms of months, for LR3 use to be justified, because it's not potently anabolic, it stimulates myoblast proliferation; and it's very expensive to administer at sufficient dose and frequency to elicit anything of substance.

If that is the case for you, then yes, they can be taken together rationally, rhGH & LR3 IGF-I.

I doubt most people use it rationally including top pros. I don't think many people have really thought about it with much sophistication, and certainly not many in bodybuilding.

Yes outside the top competitors I dont think most other bodybuilders use it regularly at all.

There is a second pool of people where igf is beneficial though for those with livers that don't respond well to any amount of injected hgh (which was why increlex was administered in humans I believe as there were short stature kids that had igf-1 levels that did not respond to injected gh sufficiently or at all).

 

[Type-IIx]

Yes outside the top competitors I dont think most other bodybuilders use it regularly at all.

There is a second pool of people where igf is beneficial though for those with livers that don't respond well to any amount of injected hgh (which was why increlex was administered in humans I believe as there were short stature kids that had igf-1 levels that did not respond to injected gh sufficiently or at all).

That's right, but I'd use rhIGF-I not LR3 in those cases, and in instances where GH response is low due to amenable health (e.g., liver, kidney disorders, prediabetes, obesity) or drug (e.g., trenbolone, estrogens) factors, try to ameliorate that first.

 

[dimethyl11]

so lr3 administration every 1-2hrs, check!

 

[Type-IIx]

so lr3 administration every 1-2hrs, check!

The major takeaway is that if you cannot afford it and are not very advanced (its purpose being primarily to increase # of myofibers), you're probably wasting your money on this drug.

 

[specter]

The major takeaway is that if you cannot afford it and are not very advanced (its purpose being primarily to increase # of myofibers), you're probably wasting your money on this drug.

So let me get this right, we are talkin IGF1-LR3 here not Increlex ? because when you mention cost, usually when i see lr3 its really cheap not like Increlex wich usually have a price right around the same as a kidney on the black market

 

[Type-IIx]

So let me get this right, we are talkin IGF1-LR3 here not Increlex ? because when you mention cost, usually when i see lr3 its really cheap not like Increlex wich usually have a price right around the same as a kidney on the black market

LR3, yes. It adds up at the doses & frequencies you need to use for any significant effects. It's WAY more expensive than a moderately-high pharma rhGH dose, that is going to give you severalfold the results of LR3 if you're healthy (i.e., GH responsive).

 

[xpoc]

The major takeaway is that if you cannot afford it and are not very advanced (its purpose being primarily to increase # of myofibers), you're probably wasting your money on this drug.

For us laymen... I would absolutely LOVE to read a bullet point list of peptides and your opinion on their effectiveness/safety/value (just as you have done with this post I am quoting). hGH, Sermorelin, BPC157, TB500 etc. I suspect it would generate more interaction than just about any thread posted on this msg board.