34 PEDs growth hormone

GH Indirect Effects on Muscle Growth • Potent stimulator of collagen synthesis in tendons and skeletal muscle, via autocrine IGF-1 mediated fibroblast stimulation.. AAS + GH+ Insulin Syn

PEDs

Human Growth Hormone

UNIVERSITY

Lesson Overview

What is GH/IGF-1 Role and Mechanism of Action

Regulation of GH/IGF-1 Axis

GH/IGF-1 effect on hypertrophy

Why do we retain fluid on HGH?

Gender Differences in HGH usage and role of estrogen

GH Indirect Actions

AAS and HGH synergy

Is there a ceiling dosage for HGH?

Why Autocrine GH/IGF-1 is Important

How should we time HGH?

What is the effect of HGH on endocrine production? Does HGH effect Insulin Resistance?

Does HGH effect the Thyroid?

Is there a maximum dosage for fat loss?

Hypertrophy Dosing Recommendations

Fat loss Dosing Recommendations

GH/IGF-1 Main Purpose

How Does it Carry out this Purpose?

GH is priming the body for growth by making energy substrate available, Growth is energy costly

How Does it Carry out this Purpose?

IGF-1 is taking the energy substrate made available by GH and using it for growth and repair IGF-1 Carries out most growth promoting

aspects

Regulation of GH/IGF-1 Axis

GH on Hypertrophy Numerous trials of exogenous GH administration in healthy subjects show no change in muscle protein synthesis or direct hypertrophy outcomes

“Effect of growth hormone and resistance exercise on muscle growth

in young men”( Yarasheski 1992)

Eighteen 21-34-year-old men, 12-week resistance training, 1.5g/kg protein /day; one group placebo, one group GH 0.04mg/kg 5 days per week post workout Plasma insulin and glucose not effected by GH After 5 days treatment water drop Serum GH peaked 2.5hrs post injection

“The combination of resistance training and GH administration is no more effective in increasing muscle size and strength and the rate of muscle protein synthesis than resistance training without GH.”

Why the Water Retention?

”Effects of growth hormone on renal

tubular handling of sodium in healthy

humans” (Hansen 2001)

6 day trial, 6IU GH vs control vs GH

+400mg Ibuprofen per day

GH Indirect Effects on Muscle Growth

• Potent stimulator of collagen synthesis in tendons and skeletal

muscle, via autocrine IGF-1 mediated fibroblast stimulation Positive application in athlete longevity

• Increased decorin gene expression Decorin is protein in skeletal muscle main role is growth and repair

• Cell cultures demonstrate GH promote satellite cell proliferation and differentiation into myofibers and provide increase myonuclei Again, not demonstrated in humans

• AAS increase satellite cell numbers, providing more raw material for

GH to take action on, this is key

So, GH alone has minimal impact on hypertrophy does combined AAS usage change this?

AAS + GH Synergy

“Growth Hormone and Sex Steroid Administration in Healthy Aged Women and Men”( Blackman 2002)

26 week Trial

57 women and 74 men 65-88 yrs old

Men: 0.03-0.02mg/kg GH 3x per week + test E 200mg/wk

Women: 0.03-0.02mg/kg GH 3x per week + estradiol 100mcg/d + medroxyprogesterone acetate 10mg/day PO

Continue normal activity

AAS + GH+ Insulin Synergy

AAS effects:

Testosterone alone increase GH/IGF-1 expression, while non/low aromatizing androgens causing much less of an impact (nandrolone/trenbolone)

AI and SERM usage attenuate the effects of testosterone on GH/IGF-1, AI is less impactful on

GH hepatic action than a SERM

Increased GH receptor expression in skeletal muscle

Increased local IGF-1 mRNA expression in skeletal muscle

Nearly 95% of all circulating IGF-1 exists in a bound state (most bound to IGFBP-3, 6 other isoforms) Binding proteins increase bioavailability, extend serum life Can inhibit or enhance IGF action AAS Decreased IGFBP-4 in local muscle, increase IGFBP-3 systemically

GH effects:

GH and AAS enhance collagen synthesis

GH stimulated JAK/STAT5 pathway direct relationship with local IGF-1, this pathway is also downstream target for androgen receptor gene expression So, GH increase AR expression (GH makes your current AAS more effective)

Insulin effects:

Insulin increases GHR, reverses IGF-1 desensitization, stimulates GH to IGF-1 expression

AAS + GH+ Insulin Synergy

Figure 1 Mechanisms of action of GH, IGF-1, and insulin in skeletal muscle AAT, amino

acid transporter Intramuscular anabolic mechanisms mediated by GH, IGF-1, and insulin providing the theoretical basis for use of these agents as PEDs (Anderson, 2017)

Ceiling Dosage for Systemic IGF-1

• Saturation point of GH/IGF-1 within 4-7 days (Tanaka 1999)

• Individual response to varying dosing patterns

• Advice don’t use more than needed to reach a peak level

Localized (Autocrine) GH to IGF-1

What we want is more localized IGF-1, not systemic

There is a celling dose for localized IGF-1 expression within the muscle

In human muscle studies, GH to IGF-1 mRNA expression occurs within 30-60min and peaks within 1-2 hours and last for 48hours (Frost et al)

The maximal dosage to stimulate mRNA expression was a dose between 7.5ng/mL and 30ng/mL, which is similar to levels seen in endogenous secretion post training

Local administration in animal models as shown increased local IGF-1 and localized growth with or without resistance exercise Even GH compared to IGF-1 injection IGF-1 injection likely less effective without binding proteins (IGF LR3, DES, etc)

Systemic IGF-1 works as a negative feedback for localized autocrine production of IGF-1

TAKE HOME POINT: Local IGF-1 is far more important for hypertrophy than systemic IGF-1 levels

Localized (Autocrine) IGF-1 Levels

Only pulsatile GH administration, and not continuous infusion, can maximally stimulate IGF-1 mRNA expression in skeletal muscle (Frost)

Pulsatile administration may also lead to comparable, or even

decreased, serum systemic IGF-1 levels (Bick)

For hypertrophy, peaking GH and getting it back to a baseline level with multiple injections seems ideal

There is also a desensitized refractory period within the JAK/STAT5 for

~5hours post GH administration where further administration does not cause same IGF-1 Response (Frost)

Insulin can resensitize the JAK/STAT5 pathway to GH A meal between

GH administration with an insulin increase would accomplish this

GH and Endocrine GH Suppression

18-month trial HIV patient's GH withdrawal effects ~0.018IU/kg/day (Lo 2010)

Single administration of

2IU GH and serum GH

levels 6 hours later at

onset of sleep

(Mendelson 1983)

GH and Insulin Resistance

“Effects of Growth Hormone on Glucose Metabolism and Insulin

Resistance In Human” (Kim 2017) review paper

High dose GH usage >0.01mg/kg/day increase fasting glucose and insulin levels and increased insulin resistance, A1c remained relatively unchanged

Low dose GH usage <0.01mg/kg/day show transient changes in fasting glucose levels and unchanged insulin resistance after long term usage

GH increases glucose production from liver and decrease uptake in peripheral tissue, FFA increase from adipose tissue, causes high serum glucose and FFA IGF-1 has opposing effects A genetic disposition to diabetes my be induced by GH therapy

GH and Thyroid Axis

GH increase T4 to T3

conversion in peripheral

tissue, lowering T4 and

reverse T3

This effect is transient and

stabilize with continued

HGH and Gender Differences

Females are less responsive to HGH to IGF-1 conversion compared to males

To achieve similar IGF-1 levels to males higher dosages of HGH are needed

In both men and women, local estrogens derived from the aromatization of androgens stimulate GH secretion in the hypothalamus Hence TRT therapy combined with Aromatase Inhibitors (AI) limits endocrine GH secretion

Oral estrogens shown to decrease GH to IGF-1 expression in liver and increase IGFBP-1 reducing bioactive IGF-1

Males treated with testosterone have an enhanced GH to IGF-1 expression and increase GH receptor expression

Selective Estrogen Receptor Agonist (SERM) has dual effect lowering GH and IGF1 via decreased liver IGF-1 expression and estrogen receptor antagonism at the hypothalamus

Males treated with testosterone have an enhanced GH to IGF-1 expression and increase GH receptor expression

Both GH and testosterone are required to exert full anabolic effects

With Exogenous HGH pituitary production is not an issue, so if estrogen control is needed an AI is the better option over a SERM

Note: limit oral estrogen-based birth control, use non oral route or IUD

Estrogen and Estrogen Antagonist GH Effects

Figure: Birzniece 2017

GH Hypertrophy Recommendations

1 Combined Stack of AAS and GH for females or males (GH alone

minimal effect)

2 Females non hormone-based birth control is ideal

3 AAS should have a testosterone base for estrogen positive role on GH/IGF-1 axis

4 FDA Pharm grade or validated generics with HPLC testing

5 Ceiling dosage around 4-8IU per day, monitor serum IFG-1 for peak levels obtained

6 Administer in pulses during day close to physiological norm, ~2IU per administration

7 Timing of injections less important as IGF-1 is elevated for days, I would time around normal physiological peaks (Pre bed >post

training>Am>pre training)

8 Have a carbohydrate-based meal between dosing for GH/IGF-1 axis resensitization

9 Limit AI, SERM, and thyroid hormone usage

10 Local IM injections can be considered for lagging body parts

11 There is no need for cycling on and off, lowering GH to physiological norm (2-3IU) during cruise periods would be advised for decreased systemic stress and restoring insulin sensitivity

12 Add to anabolic stack early within career to maximize all hypertrophy pathways and enhance current AAS usage, minimal 2IU as starting point

Immediate post training 1.5-2.0 GH

Meal 4 (post meal)

Meal 5

Meal 6

1.5-2IU pre bedtime

GH and Fat loss

GH Maximum Rate of Lipolysis?

Dose-dependent increase in FFA mobilization from no rHGH to

0.001mg/kg to 0.003mg/kg, no further increase with 0.006mg/kg This would be close to 1.2-1.5IU/100kg GH administered via IV (Hansen 2002)

FFA mobilization peak around 150-160min mark

Fat Loss Synergies

GH increase hormone sensitive lipase, decreases lipoprotein lipase, increased catecholamine sensitivity

AAS increase beta adrenergic receptor expression and direct action on the beta receptors

Ensure optimal thyroid levels for metabolic rate and beta receptor expression

Utilizing a beta-adrenergic receptor agonist like clenbuterol would maximize fat mobilization ability

Maximizing GH for Fat Loss

1 GH Dosage fasting for greatest fat loss effect, food does NOT completely blunt effect

2 Dosage of 1.5IU/100kg body weight

3 Perform low to moderate intensity fasted cardio, just water

4 Second GH dosage could be done pre bedtime

5 If choosing between AM or PM, I would choose PM for the enhanced

bioavailability

6 Utilize supraphysiological AAS with aromatizing compounds

7 Optimize thyroid function if needed

8 Clenbuterol for enhanced effect

9 Pre-contest drop GH 2 weeks prior to show for drop in water retention

10 For maximizing muscle retention apply recommendation from GH for

hypertrophy, dosing can go as high as 6-8IU

References

Hansen TK, Møller J, Thomsen K, Frandsen E, Dall R, Jørgensen JO, Christiansen JS Effects of growth hormone

on renal tubular handling of sodium in healthy humans Am J Physiol Endocrinol Metab 2001

Dec;281(6):E1326-32 doi: 10.1152/ajpendo.2001.281.6.E1326 PMID: 11701449

Ho KY, Weissberger AJ, Stuart MC, Day RO, Lazarus L The pharmacokinetics, safety and endocrine effects of authentic biosynthetic human growth hormone in normal subjects Clin Endocrinol (Oxf) 1989 Apr;30(4):335-

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Kimberly T Brill, Arthur L Weltman, Angela Gentili, James T Patrie, David A Fryburg, John B Hanks, Randall J Urban, Johannes D Veldhuis, Single and Combined Effects of Growth Hormone and Testosterone

Administration on Measures of Body Composition, Physical Performance, Mood, Sexual Function, Bone

Turnover, and Muscle Gene Expression in Healthy Older Men, The Journal of Clinical Endocrinology &

Metabolism, Volume 87, Issue 12, 1 December 2002, Pages 5649–5657, 020098

https://doi.org/10.1210/jc.2002-Hansen TK, Jørgensen JO, Christiansen JS Body composition and circulating levels of insulin, insulin-like growth factor-binding protein-1 and growth hormone (GH)-binding protein affect the pharmacokinetics of GH in adults independently of age J Clin Endocrinol Metab 2002 May;87(5):2185-93 doi: 10.1210/jcem.87.5.8473 PMID:

11994362

Meinhardt U, Nelson AE, Hansen JL, Birzniece V, Clifford D, Leung KC, Graham K, Ho KK The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial Ann Intern Med 2010 May 4;152(9):568-77 doi: 10.7326/0003-4819-152-9-201005040-00007 PMID: 20439575

Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR Systematic review: the effects of growth hormone on athletic performance Ann Intern Med

2008 May 20;148(10):747-58 doi: 10.7326/0003-4819-148-10-200805200-00215 Epub 2008 Mar 17 PMID:

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Monroy Guízar EA, García Benavides L, Ambriz Plascencia AR, Pascoe González S, Totsuka Sutto SE, Cardona Muñoz EG, Méndez-Del Villar M Effect of Alpha-Lipoic Acid on Clinical and Neurophysiologic Recovery of Carpal Tunnel Syndrome: A Double-Blind, Randomized Clinical Trial J Med Food 2018 May;21(5):521-526 doi: 10.1089/jmf.2017.0056 Epub 2018 Jan 22 PMID: 29356576

Troels Krarup Hansen, Claus Højbjerg Gravholt, Hans Ørskov, Michael Højby Rasmussen, Jens Sandahl

Christiansen, Jens Otto L Jørgensen, Dose Dependency of the Pharmacokinetics and Acute Lipolytic Actions of

Growth Hormone, The Journal of Clinical Endocrinology & Metabolism, Volume 87, Issue 10, 1 October 2002,

Pages 4691 –4698, https://doi.org/10.1210/jc.2002-020563

References

LIBBIE RUSSO, WAYNE V MOORE, A Comparison of Subcutaneous and Intramuscular Administration

of Human Growth Hormone in the Therapy of Growth Hormone Deficiency, The Journal of Clinical

Endocrinology & Metabolism, Volume 55, Issue 5, 1 November 1982, Pages 1003–

1006, https://doi.org/10.1210/jcem-55-5-1003

Yarasheski KE, Zachwieja JJ, Campbell JA, Bier DM Effect of growth hormone and resistance exercise

on muscle growth and strength in older men Am J Physiol 1995 Feb;268(2 Pt 1):E268-76 doi: 10.1152/ajpendo.1995.268.2.E268 PMID: 7864103

Karila T, Koistinen H, Seppälä M, Koistinen R, Seppälä T Growth hormone induced increase in serum IGFBP-3 level is reversed by anabolic steroids in substance abusing power athletes Clin Endocrinol (Oxf) 1998 Oct;49(4):459-63 doi: 10.1046/j.1365-2265.1998.00556.x PMID: 9876343

Aguirre, Gabriel & Gonzalez-Guerra, Jose-Luis & Espinosa, Luis & Castilla-Cortázar Larrea, Inma (2018) Insulin-Like Growth Factor 1 in the Cardiovascular System 10.1007/112_2017_8

Leroith, D., & Yakar, S (2007) Mechanisms of Disease: metabolic effects of growth hormone and

insulin-like growth factor 1 Nature Clinical Practice Endocrinology &Metabolism, 3, 302-310

Laron Z Interactions between the thyroid hormones and the hormones of the growth hormone axis Pediatr Endocrinol Rev 2003 Dec;1 Suppl 2:244-9-discussion 250 PMID: 16444165.Tanaka T, Seino

Y, Fujieda K, Igarashi Y, Yokoya S, Tachibana K, Ogawa Y Pharmacokinetics and metabolic effects of high-dose growth hormone administration in healthy adult men Endocr J 1999 Aug;46(4):605-12 doi: 10.1507/endocrj.46.605 PMID: 10580755

Frost RA, Nystrom GJ, Lang CH Regulation of IGF-I mRNA and signal transducers and activators of transcription-3 and -5 (Stat-3 and -5) by GH in C2C12 myoblasts Endocrinology 2002