UNIVERSITY PEDs Testosterone: A base of understanding to AAS action and cycle design Lesson Overview Testosterone, Estrogen, & DHT AAS Mechanism of Action Role of Hormone Receptor Androgen to Estrogen Ratio Role of Estrogen Role of DHT Why Testosterone as a Base/First Cycle? Dose Response Relationship of Testosterone How Long is a Cycle? Initial Cycle Progression Framework Testosterone, Estrogen, and DHT In males, testosterone is the primary sex hormone, ~510mg produced per day In females, estrogen is the primary sex hormone Testosterone ~0.5g per day In both sexes, testosterone can be aromatized into estrogen and/or 5alphareduced into Dihydrotestosterone (DHT) Androgen receptor activation & upregulation Decreased SHBG Aromatization to Estrogen AAS Mechanisms of Action Gh/Igf-1 increase IGF binding protein decrease Increase IGF1 receptors Increased Beta-adrenergic receptors on fat cells Increased Protein Synthesis Increase Satellite Cell # & differentiation Increased lipolysis 5-alpha reduced to DHT Increased creatine phosphate and glycogen stores Glucocorticoid receptor antagonist Increased Strength Decreased Protein Degradation Hormone Receptor Testosterone is a starting point to understand how our own natural androgen reacts in the body and lead to understanding other androgen derivatives Testosterone (T) and Estrogen (E) are similar in chemical structure and main mechanism of action is via the androgen (AR) or estrogen receptor (ER) in cells T and E can diffuse into cell Enzyme biotransformation may occur Binds to hormone receptor and forms complex Gene transcription occurs leading to specific actions to be carried out by cell Testosterone to Estrogen Ratio The AR complex will effect different genes than the ER complex and can have opposing roles Each hormone will react differently in its target tissue whether skeletal muscle, scalp, prostate, heart, or breast tissue The AR might upregulate a gene while the ER might downregulate it Examples: Skin: androgens increase sebum production while estrogens decrease it, hence more acne vulgaris with high dosed androgen cycles Breast tissue: Androgens oppose the effects of estrogens on breast tissue growth, hence why Drostanolone was used in breast cancer treatment Plasma Proteins: Androgens decrease SHBG, Estrogens increase it Hair: Androgenic alopecia, while estrogen promotes hair growth This gives us understanding of effects of altered ratios of androgens to estrogens as they balance one another Estrogen Neuroprotective Supraphysiological doses of T increase neurotoxicity, however physiological T is neuroprotective (Orlando 2007) If an aromatase inhibitor is given with low/normal T levels the neuroprotective effects are diminished Estrogen is neuroprotective when balanced with testosterone Nandrolone and Stanozolol given alone are neurotoxic likely due to lack of 17B-estradiol conversion Supraphysiological doses have shown high deposition of amyloid-beta plaque in brain tissue, same plaque associated with Alzheimer’s and Dementia (Kaufman, 2019) AAS induced oxidative stress reduces amyloid-beta elimination from brain Studies in humans have shown decreased cognitive attention in users on steroids vs off Estrogen Cardioprotective 12-week study (Freidel 1990) IM 280mg Test E + 250mg testolactone 4x daily IM 280mg Test E w/o AI PO 40mg Methyltestosteron e Serum Testosterone (ng/dl) 1155 1155 432 Serum Estradiol (pg/ml) 19 68 19 HDL reduction 25% Nonsignificant 35% Estrogen Libido and Erections and Body Fat Low and High estrogen can cause ED with estrogen modulating testosterone Penile tissue is dense with ER and stimulated can have an antiapoptotic effects on the endothelium cells Hypothalamus and pre-optic area are high in ER and aromatase and regulate libido Estrogen impacts serotonin levels (Finklestein 2013) found that the administration of testosterone with and without aromatase inhibitors markedly impaired sexual function when aromatization was inhibited Increasing testosterone in subjects decreased body fat, but the effect was negated with use of an aromatase inhibitor Estrogen and Muscle Mass Estrogen and Glucose Estrogen increases Glucose 6-phosphate dehydrogenase in skeletal muscle, G6PD increases post exercise to enhance glucose uptake and recovery This effect is diminished when an AI is used and estradiol is over suppressed Estrogen and GH/IGF-1 Axis Estrogen increases GH and IGF-1 levels In men given 300mg of test e vs 300mg test e + 20mg tamoxifen, the tamoxifen group IGF-1 was suppressed (Weissberger 1993) 300mg of test e vs 300mg of nandrolone decanoate showed the nandrolone to have less IGF1 levels likely due to the lack of aromatization into estrogen (Hobbs 1993) ”Steroid Fatigue” estrogen promotes wakefulness and alertness Estrogen Low or High? Testosterone normal range males: 300-1000 ng/dL Estradiol normal range males: 20-55pg/mL Signs of Low Estrogen: Fatigue No sex drive and erectile dysfunction Fat accumulation Depression and Irritability Forgetfulness Signs of High Estrogen: Libido present and erectile dysfunction Nipple sensitivity, breast swelling (gynecomastia) Water retention Elevated blood pressure Night sweats Saturation Point of Aromatase Enzyme Increasing dosages of testosterone lead to an increased T/E2 ratio Higher test dosages lead to higher estrogen levels, but to a lesser magnitude At a dosage that appears around 400-600mg of testosterone per week the aromatase is enzyme is highly saturated and the E2/T ratio is much less (Lakshman, 2010) Dihydrotesosterone (DHT) Testosterone is converted to DHT via alpha reductase enzyme and is 3-4x as potent as testosterone The enzyme is present in high amounts of the skin, scalp, prostate, liver, and nervous system This accounts largely for the androgenic side effects from AAS DHT being very androgenic is not very anabolic in skeletal muscle tissue Skeletal muscle contains the enzyme 3α -hydroxysteroid dehydrogenase (3α-HSD) which breaks down DHT to a much weaker androgen DHT Benefits Strong role in organization and function of nervous system Neuromuscular system is of primary importance for contraction of skeletal muscle and hence why many strength athletes are in favor of AAS that are DHT derivative for strength but not size Graded dosing of testosterone (25,50,125,300,600mg) with or without Dutasteride had not difference in fat free mass gain 600mg group 7.1kg vs 8.1kg (not significant, but still 2.2lbs of fat free mass) (Bhasin 2012) This interaction secondarily will impact muscle gain, as it impacts muscle performance alpha reductase inhibitors like dutasteride and finasteride increase occurrence of erectile dysfunction and low libido (Trost, 2013) DHT and metabolites modulate estrogen Antagonist of ER binding the to gene response element Offset androgen/estrogen ratio Why Testosterone First Cycle and Base? Main purpose is to maintain a physiological amount of estrogen and DHT that might otherwise by nonexistent using another AAS Testosterone allows for a bioidentical compound our bodies are used to managing with E2 and DHT levels in conjunction We know estrogen is protective for the brain, heart, penis, skin, and needed for muscle growth, a baseline amount needs to be present A non aromatizing DHT derivative (anavar, masteron, primobolan) although anabolic, will shutdown exogenous test levels and limit estrogen levels significantly (poor health and gains) An aromatizing drug like nandrolone, has low estrogen conversion and also alpha reduces to DHN, a weak version of DHT Many report sexual issues without a base of testosterone Also nandrolone is highly suppressive and not appropriate for a first cycle Testosterone Dosing There is a dose response relationship with testosterone and muscle gain 25,50,125,300 and 600mg of testosterone enanthate for 12 week in healthy young men, nonresistance trained The 125, 300, and 600mg group gained 3.4, 5.2, and 7.9kg of fat free mass, respectively (Bhasin 2001) 100-200mg testosterone is considered TRT levels This should be based on your initial baseline labs for: T, E2, LH, FSH A first starting cycle would start at 200-300mg of testosterone per week w/o Aromatase Inhibitor Remember we want to gain the biggest result from the smallest dose needed and least health impact before moving up in dosage How Long is a Cycle? Time course to maximize effect, but also limit detrimental effects Will depend on pharmacodynamics of test ester used, genomic and nongenomic effects, genetic polymorphisms and steroid metabolism We can gain insight looking at the time course of effect of test replacement in hypogonadal men (Saad 2011) Start of TRT wks wks 12 wks 20 wks 24wks 52 wks In literature we see maximal effects in muscle and strength at 12-20 weeks of testosterone therapy, giving validation to the idea of cycle length of 12 weeks This cycle duration should be based on your goal, level, health markers, and phase Also consideration for Blast/Cruise/PCT Initial Cycle Progression An initial cycle progression would be to increase testosterone dosages until you need to combat high estrogen levels For many this will depend on you on genetic predisposition to aromatization You can increase testosterone dosage 100-150mg per cycle as needed to continue making muscular gain up until an aromatize inhibitor would be needed This might be 300-600mg of testosterone per week for many At this point rather than an AI, it would be time add in other compounds to bring about anabolism and offset estrogen Some may also face more androgenic sides from DHT conversion, this might also need consideration for cycle design with compounds less effected by alpha reductase Summary The proper ratios of testosterone, estrogen and DHT are essential for optimal health Estrogen is not “bad” males need it for the brain, heart, penis and skeletal muscle We need a ratio in accordance with that of testosterone If testosterone is supraphysiological, estrogen can be as well, as long as no symptoms of high estrogen are present A first cycle should be a testosterone base and subsequent cycles should be a tapered-up testosterone dosage to a point estrogen control is needed Monitor labs and health markers and document to establish response to each dosage of testosterone used References Beck D, Kettler D Symptomkontrolle in der Palliativmedizin [Symptom control in palliative medicine] Schmerz 2001 Oct;15(5):320-32 German doi: 10.1007/s004820170005 PMID: 11810372 Orlando R, Caruso A, Molinaro G, Motolese M, Matrisciano F, Togna G, Melchiorri D, Nicoletti F, Bruno V Nanomolar concentrations of anabolic-androgenic steroids amplify excitotoxic neuronal death in mixed mouse cortical cultures Brain Res 2007 Aug 24;1165:21-9 doi: 10.1016/j.brainres.2007.06.047 Epub 2007 Jul 10 PMID: 17662261 Kaufman MJ, Kanayama G, Hudson JI, Pope HG Jr Supraphysiologic-dose anabolic-androgenic steroid use: A risk factor for dementia? 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Base/First Cycle? Dose Response Relationship of Testosterone How Long is a Cycle? Initial Cycle Progression Framework Testosterone, Estrogen, and DHT In males, testosterone is the primary sex hormone,... estrogen is the primary sex hormone Testosterone ~0.5g per day In both sexes, testosterone can be aromatized into estrogen and/or 5alphareduced into Dihydrotestosterone (DHT) Androgen receptor... issues without a base of testosterone Also nandrolone is highly suppressive and not appropriate for a first cycle Testosterone Dosing There is a dose response relationship with testosterone and muscle