Testosterone
Wirkstoff: Testosteron (Testosterone). Das Referenzandrogen, an dem alle anderen gemessen werden. Wirkt über den Androgen-Rezeptor im Zellkern, dosisabhängig und ohne Sättigung nach oben.
Auch bekannt als: Testo, Test E, Test C, Testosteron-Enantat, Testosteron-Cypionat, Testosteron, Testosterone
What it is
Testosterone is a steroid hormone with 19 carbon atoms. In men, around 95 percent come from the Leydig cells of the testicle, the rest from the adrenal cortex. In women it is produced in the ovaries and adrenal glands, in about a tenth of the amount, and is just as indispensable there.
How the body builds it
The starting material is cholesterol. The slowest and therefore crucial step is at the very beginning and is not a chemical reaction, but rather a transport: cholesterol has to be transported from the outer to the inner mitochondrial membrane. This is ensured by the StAR protein, which the Leydig cell only produces in quantity following the signal from LH. This is exactly where the regulation takes effect, not the enzymes behind it.
Inside, the enzyme CYP11A1 splits off the side chain of cholesterol, producing pregnenolone, the mother of all steroid hormones. From there, a short chain leads via 17-hydroxy intermediates to androstenedione, and 17-beta-hydroxysteroid dehydrogenase turns it into testosterone. All steroids, from cortisol to estradiol, branch from the same first steps. This is why disorders in this pathway are rarely limited to a single hormone.
How it is transported in the blood
Testosterone hardly floats freely. About 44 to 65 percent are firmly attached to sex hormone-binding globulin (SHBG), the majority are loosely attached to albumin, and only one to two percent are unbound. Practically only the free and loosely bound parts enter the cell.
That's why an overall value alone says little. Anyone who has a lot of SHBG, for example due to hyperthyroidism, liver disease or old age, can be biologically deficient if the overall value is normal. Conversely, excess weight and insulin resistance depress the SHBG, then the overall value looks worse than the situation is. More on this below Testosterone in the laboratory.
Rhythm and half-life
The hypothalamus releases GnRH in bursts, the pituitary gland responds with LH, and LH drives the Leydig cell. The distribution is therefore pulsatile and also follows a daily rhythm with the peak in the early morning. From around the fourth decade of life, the level drops slowly, on the order of one percent per year.
Free testosterone is only stable in the blood for minutes; it is in the Liver quickly dismantled. This is exactly why esters exist: If you attach a fatty acid to the 17-beta-hydroxy group, the molecule becomes more fat-soluble, remains in the muscle's oil depot and is slowly released from there. Esterases in the blood break down the fatty acid, leaving normal testosterone. The ester itself doesn't work, it just controls how quickly the active ingredient arrives. An enanthate has seven carbons and is effective for days, a propionate has three and is effective for a few days.
How it works
The genomic pathway
Testosterone is fat soluble and passes through the Cell membrane without transporter. Inside the cell it meets the Androgen receptor, which is held in position unbound by heat shock proteins. When the hormone binds, the receptor changes shape, detaches from the heat shock proteins, forms a pair with a second receptor and migrates to the cell nucleus.
There, this pair attaches itself to androgen-responsive elements in the DNA and switches on the reading of the underlying genes. More messenger RNA, more protein synthesis, more contractile material. This path takes hours to days. He is the reason why androgens work and at the same time the reason why they do not work immediately.
The quick way
There are also effects that occur within seconds to minutes and are far too fast for the detour via the cell nucleus. They cross membrane binding sites and trigger calcium influx and kinase cascades. This is proven in muscle, nerve and immune cells.
How much of these rapid effects contributes to hypertrophy is an open question. What matters most in practice is that the genomic pathway bears the brunt: That's why the timing of the injection within a week is indifferent, and that's why it takes weeks for anything to show up.
Two conversions that change everything
Testosterone is not only the active ingredient, but also the starting material for two other hormones, and both conversions determine the side effect profile.
- 5-alpha reductase turns it into dihydrotestosterone. DHT binds much more tightly to the androgen receptor and dissolves more slowly, so it has a stronger effect there. This enzyme is particularly active in the skin, prostate and hair follicles, but hardly active in skeletal muscle. That's why acne, prostate growth and androgenetic hair loss depend on DHT, while muscle building depends on testosterone itself.
- aromatase turns it into estradiol, especially in fatty tissue. Estradiol is not a disruptive factor in men, but is necessary: it closes the growth plates during puberty, protects the bones, and regulates libido and blood lipids.
Motif: Testosterone in the middle. To the left, 5-alpha-reductase leads to DHT, with skin, hair follicles and prostate as target tissues. To the right, aromatase leads to estradiol, with fatty tissue, bones and brain. The direct route downwards into the muscle fiber, without conversion. The three branches are visually clearly separated. Purpose: Assign the side effects to the metabolic pathway from which they originate instead of generally attributing them to testosterone. The entire side effects section of the article follows this division. Style: flat, factual vector graphic in the style of a textbook blackboard, clear contours, few flat colors, no photorealism, no textures, no drop shadows, no spatial lighting, calm monochrome background, no text in the image. Label: “Testosterone”, “DHT”, “Estradiol”, “5-alpha-reductase”, “aromatase”. Format: across, about 16:9
It is noteworthy that the negative feedback to the hypothalamus largely comes from estradiol, which is produced in the brain from testosterone. If you block aromatase, you also weaken the brakes and drive LH up. This is the reason why aromatase inhibitors play a role in the treatment of hypogonadism, and at the same time the reason why their careless use disrupts the structure.
Why the same dose has different effects
Two men with identical blood levels can react differently, and there are solid reasons for this.
- Enzyme content in the tissue. How much 5-alpha-reductase and aromatase a tissue has determines whether testosterone, DHT or estradiol plays the main role there. A high body fat percentage means more aromatase and therefore more estradiol from the same dose.
- Receptor sensitivity. The androgen receptor gene contains a repeat of the building block CAG, the length of which varies between people. Shorter repetitions are associated with a more sensitive receptor. The effects are small and inconsistent in studies, which is why testing for them is not clinically recommended, but they explain some of the variation.
- Receptor density in muscle. It is not the same in all muscles and can be influenced through training. This is one of the reasons why the same dose with training is significantly more effective than without.
From receptor signal to muscle
The muscle fiber is a cell with many nuclei, and each nucleus supplies only a limited volume of cytoplasm. If the fiber is to become permanently larger, it needs additional cores. These are supplied by the satellite cells, resting precursor cells at the edge of the fiber, which divide and fuse with it.
This is exactly where testosterone comes into play: under testosterone, the number of satellite cells and the number of muscle nuclei increase depending on the dose. In addition, it directs mesenchymal precursor cells towards muscle cells instead of fat cells. This explains the double movement that is visible in every study: muscle mass up, fat mass down.
It is also often claimed that testosterone has an anti-catabolic effect by displacing cortisol from the glucocorticoid receptor. This is a common explanation, but the direct evidence in humans is thin. It should be treated as a hypothesis, not as confirmed.
What the studies show
The attempt that ended the debate
In 1996, a trial appeared in the New England Journal of Medicine with 43 men in four groups: placebo without training, testosterone without training, placebo with training, testosterone with training. 600 milligrams of testosterone enanthate per week for ten weeks.
The group with testosterone without any training gained 9 kilograms in the bench press and 16 kilograms in the squat, and the cross-section of the triceps grew by 424 square millimeters. The placebo group with no training lost slightly. With training and testosterone, it was 22 kilograms in the bench press, 38 in the squat and 6.1 kilograms of fat-free mass.
This proved two things: androgens work even without stimulus, and they have a significantly stronger effect with training. Furthermore, neither mood nor behavior changed measurably.
How much brings how much
Five years later came the work that turned it into a curve. 61 men had their own production switched off with medication and then received one of five fixed doses for 20 weeks. Calories and protein were specified, there was no training.
Two things are notable about this. First, there is in this area no saturation: Fat-free mass continues to increase as the dose increases. Secondly, this doesn't apply to everything. Sexual function, spatial cognition and PSA did not change significantly over the entire dose range, while hemoglobin increased and HDL cholesterol decreased. Different androgen-dependent processes therefore have different dose-response curves. This is the key to the next section.
Side effects
Almost everything here is dose-dependent, and a lot also depends on the form of the substance or a predisposition. That's why every point states what actually happens and what it depends on, instead of a blanket warning.
Increase in red blood cells
Mechanism: Testosterone throttles hepcidin, the hormone that slows iron absorption and iron release from stores. Less hepcidin means more iron available for blood formation. In addition, testosterone shifts the set point at which the body releases erythropoietin.
Dependency: Clearly dose-dependent and more pronounced in old age than in young men.
Consequence: The Hematocrit belongs controlled. From around 54 percent onwards it is considered to require treatment, because the blood viscosity and thus the risk of thrombosis increases. The value returns after the dose is reduced.
What you can do: First the dose, then the interval: the same weekly amount divided into two or three injections keeps the peak level lower. Bloodletting or blood donation lowers it Hematocrit immediately, but it doesn't eliminate the cause and, when repeated, pulls the ferritin down, so it needs to be measured. Smoking and untreated sleep apnea have the same value and are the easier lever.
Drop in HDL cholesterol
Mechanism: Androgens increase the activity of hepatic lipase, the enzyme that breaks down HDL particles. In a controlled study, this increase was measurable after just three weeks, along with smaller HDL and LDL particles.
Dependency: Dose-dependent, but above all dependent on the form of the substance. Oral 17-alpha-alkylated steroids lower HDL many times more than injectable testosterone because they pass through the liver in high concentrations.
Consequence: Measure lipid profile before and during use. The effect largely diminishes after discontinuation. Together with the hematocrit, it forms the core of cardiovascular risk, see HDL cholesterol.
What you can do: The biggest lever is the choice of substance: no orally active 17-alpha-alkylated steroids, then the effect remains on the order of magnitude of what injectable testosterone does. Endurance sessions and a low body fat percentage raise the HDL slightly, but they cannot completely counteract the androgen effect. The second lever is the duration, because the value largely returns after discontinuation.
Shutting down your own production
Mechanism: The control circuit cannot distinguish where the hormone comes from. Supplied testosterone slows down GnRH and LH, the Leydig cell no longer receives a signal, and because FSH also falls, sperm production suffers.
Dependency: Already occurs in replacement doses and is not a question of amount, but of duration. The longer the suppression, the slower the recovery.
Consequence: For most people, the axis recovers after weaning, but slowly. A review of former users found that some had low values and complaints for years afterwards. If you want to have children, you should discuss this beforehand, see HPTA.
What you can do: The adjustment screw is the duration of use, not the height. There are protocols for the time after weaning hCG and SERMs like Clomiphene, which are supposed to push the axis again; Controlled data on this is sparse, the details are below HPTA. If you want to have children, the only reliable precaution is to have your seeds frozen beforehand.
What's going on about estradiol
Mechanism: More testosterone means more substrate for aromatase. If estradiol increases sharply, water retention and, if the ratio to testosterone is appropriate, growth of the mammary gland follows.
Dependency: Dose-dependent and also dependent on body fat percentage because the aromatase is located in fatty tissue. The same man at 20 percent body fat will get more estradiol from the same dose than at 12.
Consequence: Measure estradiol instead of blindly counteracting it. If estradiol is pressed too far, it causes joint problems, loss of libido and bone loss, i.e. the problems you wanted to avoid, only with a different sign.
What you can do: The first step is body fat, not drug: less adipose tissue means less aromatase and, from the same dose, less estradiol. If that's not enough, an aromatase inhibitor like this comes along Anastrozole in question, but only with measured and symptomatic excess and in the smallest effective dose. A SERM works against the beginning of gland growth Tamoxifen more targeted because it blocks the mammary gland without lowering estradiol throughout the body. Once the gland has hardened, the only option is surgery.
What runs through DHT
Mechanism: In the skin, hair follicles and prostate, 5-alpha reductase converts testosterone into the more potent DHT. It shortens the growth phase of the hair follicle and increases production of the sebaceous gland.
Dependency: Here the predisposition is more important than the dose. Hair loss only occurs in sensitive follicles, and this sensitivity is inherited. If you don't have it, you won't lose your hair even with high doses.
Consequence: Acne is usually manageable and goes away. It's not hair loss. There is one special thing about PSA: it did not change significantly over the entire dose range of the dose-response study. The widespread concern that testosterone causes prostate cancer has not been proven in this form.
What you can do: For acne, first use the usual external treatment. If the course is severe or scarring, isotretinoin is the most effective medication; it should be taken into the hands of a doctor because of its own side effects. A 5-alpha-reductase inhibitor like Finasteride to the very transformation that is at issue here; it only works as long as it is taken and has its own side effect profile. The following applies to PSA: measure once before starting so that there is a baseline value later.
Liver
Mechanism: A methyl group at position 17 protects the molecule from breakdown in the liver, making it orally effective. It is precisely this change that puts strain on the liver cell, resulting in the risk of cholestasis, peliosis hepatis and, in rare cases, tumors.
Dependency: This is almost entirely a question of the substance class, not the dose. Injectable testosterone is virtually non-toxic to the liver, orally active 17-alpha-alkylated substances are clearly so.
Consequence: In the case of injection preparations, elevated liver values are usually due to muscle origin and not liver damage, see OLD. When it comes to oral substances, they need to be taken seriously.
What you can do: The substance class is the whole answer. Anyone who omits oral 17-alpha-alkylated substances does not have this problem. Those who take it keep the duration short and, in addition to ALT, also measure bilirubin and bile duct values, because the damage here occurs through the flow of bile and not through cell destruction. TUDCA On the other hand, it is widely used and the data on it is more limited than its reputation.
Heart and vessels
Mechanism: High blood pressure due to water retention, unfavorable blood lipids, increased hematocrit and, after long-term use, thickening of the left ventricle all work together.
Dependency: The distinction between therapy and abuse is crucial here. A large safety study of over 5000 men with deficiency and cardiovascular risk found Replacement therapy no increased rate of heart attack, stroke or cardiac death compared to placebo, but more atrial fibrillation, pulmonary embolism and kidney stones.
Consequence: This is an all-clear for the treatment of a proven deficiency and expressly not for the doses of sport. These are many times higher and have never been examined in a controlled manner for years. The heart damage described there comes from observational studies on long-term users, see Heart and AAS.
What you can do: What can be measured can also be influenced: blood pressure at home and not just at the doctor's, as well as hematocrit and lipid profile at fixed intervals. Endurance sessions alongside strength training work on all three sizes at the same time. The strongest single factor remains the total duration over the years, and no one but the user decides that.
Psyche
Mechanism: Androgen receptors are also located in the amygdala and hippocampus, so an effect on drive and irritability is plausible.
Dependency: In the controlled trial with 600 milligrams per week, mood and behavior did not change measurably. Reports of severe irritability predominantly come from the environment of significantly higher doses and multiple combinations.
Consequence: The widespread image of the inevitable outburst of anger does not stand up to controlled testing in this dose range. That doesn't mean that there is nothing wrong with very high doses, but rather that the dose decides.
What you can do: If irritability occurs, dose is the first suspicion and sleep is the second. This can be checked by changing one of the two and then asking those around you instead of yourself: Self-assessment is exactly the part that becomes unreliable here.
Classification
Testosterone is the reference against which every other anabolic steroid is measured, by definition: its anabolic-androgenic ratio is set at 100:100. It is also the best-studied because it is approved as a drug and was therefore allowed to be tested on humans in a controlled manner, which does not apply to most other substances.
The anabolic effect is real, large and without saturation upwards in the examined range. The side effects follow the same dose but with different slopes, and part of them are due to things that cannot be changed. Anyone considering replacement therapy for a diagnosed deficiency is in well-researched territory. Those who use the sport's doses leave it, not because of a single dramatic danger, but because there is simply no controlled long-term data there.
All content is for informational purposes. The handling of prescription substances belongs in the hands of a doctor, including the laboratory controls that go with it.
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