Pure nonsense!
You were already running high-end/high FT from the get-go and constantly struggling.
You have numerous threads on here over the years and unfortunately, you are still chasing your tail.
www.excelmale.com
www.excelmale.com
As you very well know dysfunctional thyroid/adrenals, mental health disorders, quality of sleep, poor diet/lack of exercise can all have a negative impact on one's overall well-being.
Much more going on than just having healthy FT levels.
From your reply in post #5
*Only other issue I could possibly think my issue is adrenal exhaustion... I did have sleep study and I do have Sleep Apnea which started after I got on TRT. ( I tried Cpap and can't do it).... so just spinning my wheels that this point.
How many natty healthy young males hitting a peak TT 600-800 ng/dL let alone any outliers hitting 1000+ ng/dL even going back as far as the 70s when the first immunoassay to measure T was developed were running around with low SHBG?
Top it off that the peak is short-lived!
History of androgens and androgen action (2022)
David J. Handelsman
Invention
*This Golden Age also encompassed a third major but failed quest, that to invent a pure anabolic steroid, a synthetic androgen having purely anabolic effects but so devoid of any virilizing effects it could be used safely in women and children. Despite massive, invested effort, this failed quest left behind a legacy of thousands of synthetic androgens recorded in the expired patent literature, almost none ever tested in humans
*The comprehensive failure of this quest was ultimately due to its limited understanding of androgen physiology. These limitations included the subsequent discovery of a singular androgen receptor (AR), a final common pathway of androgen action that differs from other steroid receptors (estrogen progestin, glucocorticoid/mineralocorticoid) that feature complex dual receptor isoform control mechanisms
*More grievously, screening of steroid analogs was based on a misguided simplistic modification of the whole animal androgen bioassay. This purported to separate anabolic (represented by the levator ani muscle) from androgenic (represented by the ventral prostate) effects, an ad hoc refinement which made a false distinction where there was no difference
*This flawed approach is ultimately inconsistent with modern androgen physiology, findings rediscovered in more recent pharmaceutical research showing that the apparent differences between androgenic and anabolic endpoints in whole animal androgen bioassays reflected (a) whether the bioassay used maintenance or recovery of androgen effects and (b) differences in the speed of recovery from castration of androgen effects making the results depend on the timing of the endpoint [102]. Nevertheless, the term “anabolic” (or “androgenic-anabolic”) steroid persists in the common lexicon, serving largely as a journalistic pinata, long after it was known to be making a tautological distinction where there was no real difference e in reality, all androgens are anabolic, and all anabolic steroids are androgens [103]
*The next invention was that of the first non-steroidal androgen by Dalton et al. [111] in 1998, six decades after the first non-steroidal estrogen [112]. This creates a new class of non-steroidal synthetic androgen, often termed Specific Androgen Receptor Modulators (SARM), a misleading marketing term rather than an accurate pharmacological description [113,114], usurping a speculative but unsound analogy with Specific Estrogen Receptor Modulators (SERM). Non-steroidal androgens were developed by a rational drug design using computer-based structural modeling, an iterative approach exploiting a library of chemical substituents to optimize physicochemical interactions with the therapeutic target, in this case the androgen receptor using non-steroidal anti-androgens as lead compounds
*Nonsteroidal androgens are pharmacologically distinct from testosterone in being obligatorily pure androgens as they inherently lack testosterone's wider spectrum of activity. Pure (including nonsteroidal) androgens lack testosterone's capacity for amplification of androgenic potency by tissue-based 5a reduction to DHT as well as diversification by aromatization to estradiol to act upon estrogen receptors. Hence, while non-steroidal androgens may have potential roles in pharmacological androgen therapy, subject to rigorous efficacy, safety, and cost-effectiveness criteria, they could not replace testosterone for replacement therapy in men with pathologic hypogonadism due to their lack of testosterone's full spectrum of effects
*Nevertheless, although intended for pharmacological androgen therapy in indications such as prevention and treatment of muscle wasting in cancer [115], none of the non-steroidal androgens under development [116,117] are marketed by 2021. Yet hope springs eternal for this new attempt to separate anabolic from androgenic properties of androgens to facilitate marketing for muscle wasting and other selective effects of testosterone
Androgen pharmacology
*In replacement therapy, testosterone displays its full spectrum of effects including not just direct action via the androgen receptor, but also indirect effects via amplification by 5a reductase in some target tissues (prostate, skin, liver) as well as diversification of its effects via aromatization to estradiol to act on estrogen receptors in other target tissues (brain, bone). These effects are dose limited to replicate physiological androgen exposure intended to replicate the lifetime efficacy and safety of eugonadal men
*By contrast, synthetic androgens are exclusively pure androgens acting directly (or via metabolites) solely on the androgen receptor and are not suitable substitutes for testosterone in replacement therapy. However pharmacological androgen therapy uses synthetic androgens for their potent effects on muscle, liver, and other androgen target tissues aiming to modify the natural history of non-gonadal diseases [179]. In these applications, the dose and type of synthetic androgen are limited only by efficacy, safety, and cost-effectiveness of the androgen in placebo-controlled clinical trials
*Many such applications have been developed for synthetic androgens which remain cost-effective second-line alternatives even when more specific, purpose-designed therapeutics become available. For example, an oral alkylated androgens (stanozolol, danazol) can increase C1-inhibitor levels and reduce frequency of angioedema attacks; however, for prophylaxis, recombinant C1-inhibitor is more effective but costly [180]. Similarly, synthetic androgens are cost-effective at increasing hemoglobin in anemias due to renal or marrow failure [181] although recombinant erythropoietin or erythropoietin stimulating analogs are equally effective but higher cost
Androgen Physiology, Pharmacology, and Abuse (2020)
David J. Handelsman
View attachment 33073
*Testosterone is used clinically at physiologic doses for androgen replacement therapy, and, at typically higher doses, testosterone, or more usually synthetic androgens based on its structure, is also used for pharmacologic androgen therapy.
*The principal goal of androgen replacement therapy is to restore a physiologic pattern of androgen exposure to all the body’s tissues. Such treatment is usually restricted to the major natural androgen, testosterone, aiming to replicate physiologic circulating testosterone levels and the full spectrum (including prereceptor androgen activation) of endogenous androgen effects on tissues and recapitulating the natural history of efficacy and safety.5
*By contrast, pharmacologic androgen therapy exploits the anabolic or other effects of androgens on muscle, bone, and other tissues as hormonal drugs, which are judged on their efficacy, safety, and relative cost-effectiveness similar to any other therapeutic agents. Insight into the physiology of testosterone is a prerequisite for understanding and making the most effective use of androgen pharmacology.6,7
Practical Goals of Androgen Replacement Therapy
The goal of androgen replacement therapy is to replicate the physiologic actions of endogenous testosterone, usually for the remainder of life, as the pathological basis of hypogonadism usually involves irreversible disorders of the hypothalamus, pituitary, or testis. This requires rectifying the deficit and maintaining androgenic/anabolic effects on bone,132,482 muscle,357 blood-forming marrow,360,483 sexual function,484,485, and other androgen-responsive tissues. The ideal product for long-term androgen replacement therapy should be a safe, effective, convenient, and inexpensive form of testosterone with long-acting depot properties providing steady-state blood testosterone levels as a result of reproducible, zero-order release kinetics. Following the aim to maintain physiologic testosterone levels and resulting tissue androgen effects, androgen replacement therapy usually uses testosterone rather than synthetic androgens for reasons of safety, full-spectrum efficacy, and ease of monitoring. Synthetic steroidal and nonsteroidal androgens are likely to lack the full spectrum of testosterone tissue effects because of local amplification by 5α reductase to DHT and/or diversification to act on ERα by aromatization to estradiol.5,124 The practical goal of androgen replacement therapy is therefore to maintain stable, physiologic testosterone levels for prolonged periods using convenient depot testosterone formulations that facilitate compliance and avoid either supranormal or excessive fluctuation of androgen levels.
