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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
What is TRT and What is NOT TRT
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<blockquote data-quote="tareload" data-source="post: 195336"><p>Thought I'd share this well-written paragraph (last updated Oct 2020) attempting to describe state-of-the-art with respect to free hormone hypothesis. Unclear what the utility of "free T" actually is when trying to determine androgen sufficiency:</p><p></p><p><a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/" target="_blank">Androgen Physiology, Pharmacology, Use and Misuse</a></p><p></p><p>Transfer of hydrophobic steroids into tissues is presumed to occur passively according to physicochemical partitioning between the hydrophobic protein binding sites on circulating binding proteins, the hydrophilic aqueous extracellular fluid and the lipophilic cellular plasma membranes. According to the free hormone hypothesis (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">78</a>-<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">80</a>), recently restated and updated (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">62</a>), the free (non-protein bound) fraction of testosterone is the most biologically active with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir. The free hormone hypothesis derived from now outdated 1970’s pharmacological theory on the mechanism of drug-drug interactions as due to mutual protein binding displacement; however, this theory is long superseded in molecular pharmacology by well-established physiological mechanisms such as cytochrome P450 enzyme induction, drug transporter activity and cognate mechanisms unrelated to binding to circulating proteins (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">81</a>). As the free and/or bioavailable fractions would also have enhanced access to sites of testosterone inactivation by degradative metabolism that terminates androgen action, the free fractions may equally be considered the most evanescent and least active so that the net biological significance of the free or bioavailable fractions remains unclear and undermines a theoretical basis for the free hormone hypothesis. Furthermore empirical evidence indicates that, rather than being biologically inert, SHBG participates actively in cellular testosterone uptake via specific SHBG membrane receptors, uptake mechanisms and signaling via G protein and cyclic AMP (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">82</a>-<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">86</a>). These mechanisms include the megalin receptor, a multi-valent low-density lipoprotein endocytic receptor located on cell surface membranes that can mediate receptor-mediated cellular uptake of SHBG loaded with testosterone by endocytosis (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">87</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">88</a>) and might influence tissue androgen action (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">89</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">90</a>). Consequently, lacking a physiological basis for the free hormone hypothesis (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">91</a>) and with empirical evidence in its favor scarce and speculative, it is refuted by intensive, prospective clinical evaluation (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">92</a>). Hence, the biological significance of partitioning circulating testosterone into these derived fractions remains to be firmly established and its clinical application is unknown or possibly misleading. Furthermore, direct measurement of free testosterone requires laborious, manual methods only available in research or specialist pathology laboratories. Where available, they are costly and lack any external quality control programs or validated reference ranges. As a result, calculations purporting to replicate dialysis-based measurements are often substituted for direct measurements. These formulae come in two different formats – equilibrium binding equations requiring assumptions on testosterone binding stoichiometry and arbitrary plug-in binding affinity estimates (Sodergard (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">93</a>), Vermeulen (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">94</a>), Zakharov (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">95</a>)) or assumption-free empirical methods (Ly(<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">96</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">97</a>), Nanjee-Wheeler (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">98</a>)) calibrated directly to dialysis-based laboratory measurements. Direct comparison has proven that empirical equations are more accurate compared with laboratory dialysis-based measurements (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">95</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">96</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">99</a>, <a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">100</a>). Furthermore, calculations of free testosterone using any formula do not contribute significant to mortality or morbidity prognosis for older men’s health beyond accurate measurement of serum testosterone by liquid chromatography-mass spectrometry (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">92</a>).</p></blockquote><p></p>
[QUOTE="tareload, post: 195336"] Thought I'd share this well-written paragraph (last updated Oct 2020) attempting to describe state-of-the-art with respect to free hormone hypothesis. Unclear what the utility of "free T" actually is when trying to determine androgen sufficiency: [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/']Androgen Physiology, Pharmacology, Use and Misuse[/URL] Transfer of hydrophobic steroids into tissues is presumed to occur passively according to physicochemical partitioning between the hydrophobic protein binding sites on circulating binding proteins, the hydrophilic aqueous extracellular fluid and the lipophilic cellular plasma membranes. According to the free hormone hypothesis ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']78[/URL]-[URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']80[/URL]), recently restated and updated ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']62[/URL]), the free (non-protein bound) fraction of testosterone is the most biologically active with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir. The free hormone hypothesis derived from now outdated 1970’s pharmacological theory on the mechanism of drug-drug interactions as due to mutual protein binding displacement; however, this theory is long superseded in molecular pharmacology by well-established physiological mechanisms such as cytochrome P450 enzyme induction, drug transporter activity and cognate mechanisms unrelated to binding to circulating proteins ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']81[/URL]). As the free and/or bioavailable fractions would also have enhanced access to sites of testosterone inactivation by degradative metabolism that terminates androgen action, the free fractions may equally be considered the most evanescent and least active so that the net biological significance of the free or bioavailable fractions remains unclear and undermines a theoretical basis for the free hormone hypothesis. Furthermore empirical evidence indicates that, rather than being biologically inert, SHBG participates actively in cellular testosterone uptake via specific SHBG membrane receptors, uptake mechanisms and signaling via G protein and cyclic AMP ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']82[/URL]-[URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']86[/URL]). These mechanisms include the megalin receptor, a multi-valent low-density lipoprotein endocytic receptor located on cell surface membranes that can mediate receptor-mediated cellular uptake of SHBG loaded with testosterone by endocytosis ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']87[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']88[/URL]) and might influence tissue androgen action ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']89[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']90[/URL]). Consequently, lacking a physiological basis for the free hormone hypothesis ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']91[/URL]) and with empirical evidence in its favor scarce and speculative, it is refuted by intensive, prospective clinical evaluation ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']92[/URL]). Hence, the biological significance of partitioning circulating testosterone into these derived fractions remains to be firmly established and its clinical application is unknown or possibly misleading. Furthermore, direct measurement of free testosterone requires laborious, manual methods only available in research or specialist pathology laboratories. Where available, they are costly and lack any external quality control programs or validated reference ranges. As a result, calculations purporting to replicate dialysis-based measurements are often substituted for direct measurements. These formulae come in two different formats – equilibrium binding equations requiring assumptions on testosterone binding stoichiometry and arbitrary plug-in binding affinity estimates (Sodergard ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']93[/URL]), Vermeulen ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']94[/URL]), Zakharov ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']95[/URL])) or assumption-free empirical methods (Ly([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']96[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']97[/URL]), Nanjee-Wheeler ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']98[/URL])) calibrated directly to dialysis-based laboratory measurements. Direct comparison has proven that empirical equations are more accurate compared with laboratory dialysis-based measurements ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']95[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']96[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']99[/URL], [URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']100[/URL]). Furthermore, calculations of free testosterone using any formula do not contribute significant to mortality or morbidity prognosis for older men’s health beyond accurate measurement of serum testosterone by liquid chromatography-mass spectrometry ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']92[/URL]). [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
What is TRT and What is NOT TRT
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