UNIVERSITY Contest Prep PEDs Fat Loss Agents: Part Thyroid Hormones Lesson Overview Contest Prep Fat Loss Agents PART THYROID HORMONES • PED deployment overview • Mechanism of action • How are thyroid hormones regulated • Symptoms of hypothyroidism and lab interpretation • Safety of use • Contest prep effects on thyroid • Thyroid protocols for contest prep PART CLENBUTEROL • Mechanism of action • Skeletal muscle anabolism • Clenbuterol as a fat loss agent • Managing clenbuterol side effects and safety • Clenbuterol protocol for contest prep PART YOHIMBINE HCl • Mechanism of action • Yohimbine impact on adipose and skeletal muscle • Caffeine synergy • Gender differences • Side effects and safety • Yohimbine protocol for contest prep • Summary of Fat loss Agent in Contest Prep • Timing of Compounds for Contest Prep PED Deployment Anabolic Androgenic Steroids Ancillary Compounds Testosterone Based Testosterone Boldenone** Halotestin* Dianabol* Estrogen and Fertility Management Anastrozole* Extremestane* Nolvadex* Clomid* HCG Dihydrotestosterone Based Primobolan Masteron Anavar Proviron Winstrol* Anadrol* Nandrolone (19-Nor) Based Nandrolone Trenbolone* Peptide Hormones Growth Hormone Blood Glucose Metformin Slow and Fast Insulin* Blood Pressure ARBs PPAR y-agonist Telmisartan Fat Loss Agents Clenbuterol* T3/T4* Yohimbine HCl* No asterisk = frequent use allowable; and have been or currently in human clinical use *Phase Dependent Drug to deploy conditionally due to necessity, goal and/or safety risk, have been or currently in human clinical use **Not approved for Human Use, rare situation deployed Thyroid Actions • • • • • • • • Metabolic function for basal metabolic rate Generation of heat Increased oxygen uptake in tissues Increased sensitivity to catecholamines (heart) Carbohydrate absorption in gut Regulates protein and fat metabolism Regulates calcium and phosphorus metabolism (bone health) Synthesis and degradation of cholesterol and triglycerides (heart) Signs and Symptom of Low Thyroid Hormone • • • • • • • • • • • • • • Constipation Headaches Dry skin Menstrual irregularities Fluid retention Anxiety Lack of concentration Reduced heart rate and blood pressure Decrease sex drive Cold intolerance Insomnia Low Body temp Hair loss High CRP Hypothalamic Pituitary Thyroid Axis (Freitas, 2012) The Thyroid Hormones Thyroid Stimulating Hormone (TSH): Considered standard for evaluating thyroid function, poor measure for active thyroid hormone Released from Pituitary to stimulate thyroid gland production of T3 and T4 High TSH= low T3 and T4 levels Low TSH= high T3 and T4 levels Free T4(Thyroxine): active hormone not bound to protein carrier indicating thyroid response to TSH • T4 has little physiological activity • T4 must convert to T3 (takes place in liver(64%), GI (20%) and kidneys) Free T3 (Triiodothyronine): active hormone not bound to protein carrier indicating response to TSH and conversion of T4 to T3 • 90% of the thyroid hormone molecules that bind with the receptors are T3 and 10% are T4 Reverse T3: inactive isomer of T3 High normal or elevated reverse T3 is indicative of reduced thyroid transport, most common in chronic and acute dieting Thyroid peroxidase (TPO): Enzyme needed for thyroid production in thyroid gland 5’deiodinase: enzyme needed for conversion of T4 to T3, selenium dependent Thyroid Antibodies (anti-TPO, Antithyroglobulin, anitimicrosomal antibody) Thyroid binding globulin (produced by liver) estrogen increases Thyroid Dysfunction General hypothyroidism • Adrenal dysfunction can occur along with hypothyroidism • Thyroid antibodies can be present along with adrenal cortex antibodies (autoimmune driven hypothyroidism) • Cortisol levels may elevate to compensate for low T3 • Many disease states present to alter thyroid function • ~50% of hypothyroidism is related to autoimmune disorder Hashimoto’s thyroiditis • Focus for us is within a contest prep setting Thyroid Dysfunction Thyroid Dysfunction and Contest Prep Dieting • Calorie restriction decreases T3 up to 30%, likely related to energy availability (Calorie intake vs expenditure vs body fat level) • During low energy availability HPTA adapts to reduce energy expenditure • Caloric restriction increases proton leak across mitochondrial membrane via uncoupling proteins with thyroid hormone modulating the magnitude of proton leak, low TH decreased proton leak (Trexlar 2014) • Only days of low energy availability (30 vs 8kcal/kg FFM/day) can decrease free T3 by 18% and increase reverse T3 by 24% (Elliott-Sale 2018) • Athletes with amenorrhea show consistent decrease T3 levels, but T4 and TSH can range Stress • Increased thyroid binding protein, so T3 can not get in cells • Decrease T4 to T3 • Decreased sensitivity to thyroid hormones • Decreased immune barrier of GI tract via cortisol, resulting in inflammation and dysbiosis • Decreased HPTA communication to thyroid Natural Bodybuilding Competition Preparation and Recovery: A 12-Month Case Study (Rossow 2013) 6-month before and after drug free male bodybuilder competition Clenbuterol Protocol Consideration Timeline • Caloric restriction and expenditure is a first means to fat loss • Managing fatigue is high priority increased Stimulant fat agents can impeded sleep, which will impede recovery, muscle retention, and fat loss • Implement agents later stage of prep once cardio is high and food is low and need another tool to play Clenbuterol Dosing and Timing • 34-hour half life, stable levels with daily administration • Preferably first thing AM • Initiate 20mcg day, titrate dosage up as needed to 80mcg/day Discontinuing Usage • No taper is needed • days out remove to allow for fatigue management and enhanced sleep UNIVERSITY Contest Prep PEDs Fat Loss Agents: Part Yohimbine and Fat Loss Summary Lesson Overview Contest Prep Fat Loss Agents PART THYROID HORMONES • PED deployment overview • Mechanism of action • How are thyroid hormones regulated • Symptoms of hypothyroidism and lab interpretation • Safety of use • Contest prep effects on thyroid • Thyroid protocols for contest prep PART CLENBUTEROL • Mechanism of action • Skeletal muscle anabolism • Clenbuterol as a fat loss agent • Managing clenbuterol side effects and safety • Clenbuterol protocol for contest prep PART YOHIMBINE HCl • Mechanism of action • Yohimbine impact on adipose and skeletal muscle • Caffeine synergy • Gender differences • Side effects and safety • Yohimbine protocol for contest prep • Summary of Fat loss Agent in Contest Prep • Timing of Compounds for Contest Prep Yohimbine HCl What is it ? Naturally occurring alkaloid found in the yohimbe tree Alpha receptor antagonist main forms found in supplements: Yohimbe bark extract Concentrated powder of bark, with components of Yohimbine Yohimbine HCl Extracted Yohimbine molecule combined with a hydrochloric acid group Mechanisms of Action Beta receptor activation increases lipolysis Alpha-2 receptor activation prevents lipolysis Yohimbine is an Alpha-2 receptor antagonist Physiological Effects: • Elevates serum Free fatty acids (FFA), glycerol and norepinephrine • Potentiates exercise induced FFA and norepinephrine release during and following exercise • In subject ingesting yohimbine prior to 30min cardio, FFA levels 30 post exercise were doubled (Galitsky 1988) main mechanisms: Central activation of sympathetic tone (main action on beta receptors) Interference with the feedback mechanism whereby pre-synaptic Alpha-2 adrenoreceptors suppress further release of norepinephrine from sympathetic neurons Blockade of adipocyte alpha-2 adrenoreceptor that suppress lipolysis These receptors activate Gi proteins that inhibit adenyl cyclase, thus antagonizing the ability of beta-adrenoreceptors to boost cAMP generation Appetite suppression seen in mice studies; however, dosing was far higher than that found in human literature (Callahan 1984) Magnitude of Effect Yohimbine: The Effects on Body Composition and Exercise Performance in Soccer Players Research in Sports Medicine: An International Journal (Ostojic 2006) • 20mg per day for 21 days, 20 male soccer players • %body fat, 9.3 vs 7.1 in yohimbe group before and after • %body fat yohimbine vs control, 7.1 vs 9.2 • No alteration in muscle mass or performance indicators Caffeine Synergy • Potentiate norepinephrine release • Caffeine has Alpha-1 receptor antagonism preventing inhibition of further sympathetic norepinephrine release • Yohimbine with its alpha-2 receptor antagonism also prevents inhibition of further sympathetic norepinephrine release • Blockade of receptor (alpha or 2) can upregulate the other, decrease sympathetic Norepi release • Taking caffeine and yohimbine together synergistically will allow full action of yohimbine on norepinephrine release (mark 2002) Male vs Female Differences Greater expression of alpha-2 adrenoreceptors on the gynoid adipocytes of women could make them more responsive to yohimbine therapy Gynoid deposits (gluteofemoral subQ adipocytes) “Stubborn” glute and thigh body fat In a study with obese women on a 4-week very low-calorie diet • 14 of the women with greatest weight loss classified as “rapid losers” • others subjects termed “slow” losers • Metabolic properties of the adipocytes between groups showed similar beta receptor response, but the slow group was 10x more sensitive to alpha-2 receptor agonist (Hellstrom, 1997) Safety • Human FDA approved for treatment of erectile dysfunction (5.4mg 13x per day) • In dosing for erectile dysfunction (5.4mg 3x per day) nausea, abdominal pian, dizziness, nervousness • Moderate doses not produce anxiety or insomnia (McCarty 2002) • Single 15-20mg dose can cause tachycardia and hypertension • Can increase anxiety and panic attacks • Deaths have occurred in extreme dosing levels • case study: 37year old BBer, 5g ingestion loss of consciousness and seizure BP 259/107, acute neurotoxicity (Giampreti 2009) • cases studies of death occurring (Anderson 2013) Yohimbine Considerations and Implementation Considerations • During a fed state lipolytic action is completely suppressed (Galitzky 1988) • Can potentiate insulin response combined with carbohydrate • Peak levels in 30-60 min, and sustained for 3-4 hours (Berlan 1991) • During fasting state increased FFA, in fed state may increase insulin response and insulin resistance • Chronic administration of 12mg daily for 14 days, acute lipolytic action was blunted, but still occurred (Berlan 1991) • Upregulation of alpha-2 receptors is possible with frequent and chronic dosing, single daily dosing less likely to cause upregulation of Alpha receptors • 0.2mg/kg of body weight studied effective dose, taper up to this dosage Summary for usage: Yohimbine HCl 0.2mg/kg Fasted single dose 30 prior to cardio Delay meal for 1-2 hour post cardio session Combine with caffeine for added synergy No tapering off dosage needed Can be implemented last weeks of prep for ”stubborn” body fat, especially females Summary of Fat Loss Agents Synergy in Prep Use Multiple Pathways for fat loss • Anabolic Androgenic Steroids: Beta receptor sensitivity and density • Anabolic (test/primo) and Anticatabolic Compound (trenbolone) • • • • • • Growth Hormone: increased FFA mobilization Beta Agonist (Clenbuterol): increased adipose lipolysis Alpha-2 Antagonist (Yohimbine HCl): blockade of anti-lipolytic agents Catecholamines (caffeine): Increase BMR, norepinephrine Thyroid Hormone (Cytomel T3): Increased BMR PPAR Agonist (Telmisartan): gene regulator of lipid and glucose metabolism • Glucose Disposal Agent (Metformin and Berberine): CHO absorption blocking and increased glucose partitioning Timing of Compounds for Contest Prep • • • • • Remember caloric restriction is primary tool for fat loss Impl ement each fat l oss tool ”as needed” You Do NOT need all components You Do NOT i mplement all a gents a t same i tem a nd top dosage Get the MOST from the LEAST Hypothetical Timing of Fat loss Agents: At Bedtime Metformi n 500mg (6-hour half life) Upon Wa king T3 ba s ed on labs (~15-25mcg) (2.5 day half-life, timing irrelevant, need fasted) Cl enbuterol (20-80mcg) (half l ife 34 hours, ti ming i rrelevant) hour pri or to fasted ca rdio 1.5-2IU GH (1–2-hour peak concentration) Yohi mbine HCl (0.2mg/kg) Ca ffeine (100-200mg) Fa s ted Ca rdio Session (water only) 1-2 hours post cardio Mea l Tel misartan (20-80mg based on needs) (15 hour half life) References: Thyroid El l iott-Sale KJ, Tenforde AS, Pa rziale AL, Holtzman B, Ackerman KE Endocrine Effects of Relative Energy Deficiency i n Sport Int J Sport Nutr Exerc Metab 2018 Jul 1;28(4):335-349 doi: 10.1123/ijsnem.2018-0127 Epub 2018 Jul 14 PMID: 30008240 Cel i FS, Zemskova M, Li nderman JD, Smith S, Drinkard B, Sachdev V, Skarulis MC, Kozl osky M, Cs ako G, Costello R, Puci no F Meta bolic effects of liothyronine therapy i n hypothyroidism: a randomized, double-blind, crossover tri al of l iothyronine vers us l evothyroxine J Cl in Endocrinol Metab 2011 Nov;96(11):3466-74 doi: 10.1210/jc.2011-1329 Epub 2011 Aug 24 PMID: 21865366; PMCID: PMC3205882 Trexl er ET, Smith-Ryan AE, Norton LE Metabolic adaptation to weight l oss: implications for the athlete.J Int Soc Sports Nutr 2014;11(1):7 Publ ished 2014 Feb 27 doi:10.1186/1550-2783-11-7 Ros sow, Lindy M.; Fukuda, David H.; Fa hs, Christopher A.; Loenneke, Jeremy P.; Stout, Jeffrey R (2013) Natural Bodybuilding Competition Preparation and Recovery: A 12-Month Case Study International Journal of Sports Physiology and Performance, 8(5), 582–592 doi :10.1123/ijspp.8.5.582 Kel l y TF, Li eberman DZ Long term augmentation with T3 i n refractory ma jor depression J AffectDisord 2009 Ma y;115(12):230-3 doi : 10.1016/j.jad.2008.09.022 Epub 2008 Dec 23 PMID: 19108898 Lees e GP, Soto-Pedre E, Donnelly LA Li othyronine use in a 17 year observational population-based study - the tears study Cl i n Endocrinol (Oxf) 2016 Dec;85(6):918-925 doi: 10.1111/cen.13052 Epub 2016 Ma r 21 PMID: 26940864 Va genakis AG, Braverman LE, Azizi F, Portinay GI, Ingbar SH Recovery of pituitary thyrotropic function after withdrawal of prol onged thyroid-suppression therapy N Engl J Med 1975 Oct 2;293(14):681-4 doi: 10.1056/NEJM197510022931402 PMID: 808728 Aki rov A, Fa zelzad R, Ezzat S, Thabane L, Sawka AM A Sys tematic Review and Meta-Analysis of Pa tient Preferences for Combi nation Thyroid Hormone Treatment for Hypothyroidism Front Endocrinol (Lausanne) 2019;10:477 Publ ished 2019 Jul 24 doi :10.3389/fendo.2019.00477 Mi ot, Fra nỗoise & Dupuy, Cori nne & Thyroidienne, Oncogenese & Institut, Gustave & Roussy, & Dumont, Jacques & Rousset, Bernard (2021) Thyroid hormone synthesis and secretion Pa ns ini, F., “Effect of the hormonal contraception on serum reverse triiodothyronine l evels,”Gynecol Obstet Invest 1987; 23:133 Deys sig, R., et a l., “Ingestion of androgenic-anabolic steroids induces mild thyroidal impairment i n male body builders,” Jour Cl i n Endocrinol Metab 1993; 76(4):1069- 71 Wa rtofsky, L., et a l., “The evidence for a narrower thyrotropin reference nge is compelling,” Jour Clin Endo Met 2005; 90(9):5483-88 Mei er, C., et a l., “Serum TSH in assessment of s everity of ti ssue hypothyroidism i n patients with overt primary thyroi d fa i lure: cross sectional s urvey,” BMJ 2003; 326:311-12 Smi th, P., What You Must Know About Thyroid Disorders Garden Ci ty Pa rk, NY: Square One Publishers, 2016 Ll ewellyn W Anabolics Jupiter, FL: Molecular Nutrition LLC; 2017 References: Clenbuterol Jiang GL, Gu YD, Zhang LY, Shen LY, Yu C, Xu JG Randomized, double-blind, and placebo-controlled trial of clenbuterol in denervated muscle atrophy ISRN Pharm 2011;2011:981254 doi: 10.5402/2011/981254 Epub 2011 Aug 15 PMID: 22389867; PMCID: PMC3263717 Spiller, Henry A.; James, Kyla J.; Scholzen, Steven; Borys, Douglas J (2013) A Descriptive Study of Adverse Events from Clenbuterol Misuse and Abuse for Weight Loss and Bodybuilding Substance Abuse, 34(3), 306–312.doi:10.1080/08897077.2013.772083 Rothwell NJ, Stock MJ Effect of a selective beta 2-adrenergic agonist (clenbuterol) on energy balance and body composition in normal and protein deficient rats Biosci Rep 1987 Dec;7(12):933-40 doi: 10.1007/BF01122126 PMID: 3453750 Rothwell NJ, Stock MJ, Sudera DK Changes in tissue blood flow and beta-receptor density of skeletal muscle in rats treated with the beta2-adrenoceptor agonist clenbuterol Br J Pharmacol 1987 Mar;90(3):601-7 doi: 10.1111/j.1476-5381.1987.tb11211.x PMID: 3032321; PMCID: PMC1917183 Jessen S, Solheim SA, Jacobson GA, Eibye K, Bangsbo J, Nordsborg NB, Hostrup M Beta2 -adrenergic agonist clenbuterol increases energy expenditure and fat oxidation, and induces mTOR phosphorylation in skeletal muscle of young healthy men Drug Test Anal 2020 May;12(5):610-618 doi: 10.1002/dta.2755 Epub 2020 Jan 19 PMID: 31887249 Maltin CA, Delday MI, Watson JS, Heys SD, Nevison IM, Ritchie IK, Gibson PH Clenbuterol, a betaadrenoceptor agonist, increases relative muscle strength in orthopaedic patients Clin Sci (Lond) 1993 Jun;84(6):651-4 doi: 10.1042/cs0840651 PMID: 8334811 Jessen S, Onslev J, Lemminger A, Backer V, Bangsbo J, Hostrup M Hypertrophic effect of inhaled beta2 -agonist with and without concurrent exercise training: A randomized controlled trial Scand J Med Sci Sports 2018 Oct;28(10):2114-2122 doi: 10.1111/sms.13221 Epub 2018 Jun PMID: 29777633 Moratinos J, Reverte M Effects of catecholamines on plasma potassium: the role of alpha- and betaadrenoceptors Fundam Clin Pharmacol 1993;7(3-4):143-53 doi: 10.1111/j.14728206.1993.tb00228.x PMID: 8388847 Doheny MH, Waterfield CJ, Timbrell JA The effects of the beta 2-agonist drug clenbuterol on taurine levels in heart and other tissues in the rat Amino Acids 1998;15(1-2):13-25 doi: 10.1007/BF01345277 PMID: 9871484 Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure J Heart Lung Transplant 2008 Apr;27(4):457-61 doi: 10.1016/j.healun.2008.01.013 PMID: 18374884 References: Yohimbine Galitzky J., Taouis M., Berlan M., Riviere D., Garrigues M., Lafontan M Alpha 2-antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral yohimbine in healthy male volunteers Eur J Clin Invest 1988; IV: 587±594 Mark F McCarty (2002) Pre-exercise administration of yohimbine may enhance the efficacy of exercise training as a fat loss strategy by boosting lipolysis , 58(6), 0–495 doi:10.1054/mehy.2001.1459 Berlan M., Galitzky J., Riviere D et al Plasma catecholamine levels and lipid mobilization induced by yohimbine in obese and non- obese women Int J Obes 1991; IS: 305±315 Hellstrom L., Rossner S., Hagstrom-Toft E., Reynisdottir S Lipolytic catecholamine resistance linked to alpha 2adrenoceptor sensitivity ± a metabolic predictor of weight loss in obese subjects Int J Obes Relat Metab Disord 1997; PI: 314±320 Callahan MF, Beales M, Oltmans GA Yohimbine and rauwolscine reduce food intake of genetically obese (obob) and lean mice Pharmacol Biochem Behav 1984 Apr;20(4):591-9 doi: 10.1016/0091-3057(84)90309-5 PMID: 6145164 Colin Anderson, Dan Anderson, Nicole Harre, Norman Wade, Case Study: Two Fatal Case Reports of Acute Yohimbine Intoxication, Journal of Analytical Toxicology, Volume 37, Issue 8, October 2013, Pages 611– 614, https://doi.org/10.1093/jat/bkt057 Giampreti A, Lonati D, Locatelli C, Rocchi L, Campailla MT Acute neurotoxicity after yohimbine ingestion by a body builder Clinical Toxicology 2009;47(8):827–829 https://www.ncbi.nlm.nih.gov/pubmed/19640235 Ostojic, Sergej (2006) Yohimbine: The Effects on Body Composition and Exercise Performance in Soccer Players Research in Sports Medicine: An International Journal, 14(4), 289–299.doi:10.1080/15438620600987106 ... beta2-adrenoceptor agonist clenbuterol Br J Pharmacol 19 87 Mar;90(3):6 01- 7 doi: 10 .11 11/ j. 14 76 -53 81. 1987.tb 112 11. x PMID: 30323 21; PMCID: PMC1 917 183 Jessen S, Solheim SA, Jacobson GA, Eibye K, Bangsbo... ISRN Pharm 2 011 ;2 011 :9 812 54 doi: 10 .5402/2 011 /9 812 54 Epub 2 011 Aug 15 PMID: 22389867; PMCID: PMC3263 717 Spiller, Henry A.; James, Kyla J.; Scholzen, Steven; Borys, Douglas J (2 013 ) A Descriptive... remove to allow for fatigue management and enhanced sleep UNIVERSITY Contest Prep PEDs Fat Loss Agents: Part Yohimbine and Fat Loss Summary Lesson Overview Contest Prep Fat Loss Agents PART THYROID