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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
low shbg means high free E2 ?
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<blockquote data-quote="Cataceous" data-source="post: 214176" data-attributes="member: 38109"><p>Yes. The basic argument is that if you're introducing testosterone at a constant rate, as when absorbing testosterone from an injection site, then at steady state you must be metabolizing and eliminating testosterone at the same rate. If we can assume that the law of mass action is largely applicable in the clearance process then free testosterone must be proportional to the rate at which testosterone is introduced. Thus free testosterone is independent of SHBG/albumin/etc., and total testosterone should be viewed as the dependent variable. I've been putting forth this hypothesis for some time now and it hasn't been shot down yet. At least one or two formal studies have data that provide some indirect support. Until you brought up the subject I hadn't considered that the same principle should apply to the testosterone metabolites.</p><p></p><p>Very likely the latter. Let me quote "James" from over at PeakTestosterone.com, who wrote this in response to a question on why low SHBG is a problem:</p><p></p><p style="margin-left: 20px"><em>1.) Free SHBG plays a role in intracellular AR signalling. The rate of glucuronidation and time before effluxion of a free testosterone molecule that has entered a cell is mediated by intracellular SHBG brought into the cell via the megalin receptor. This phenomenon is tissue specific, and some cells produce their own SHBG internally to achieve this result. </em></p> <p style="margin-left: 20px"></p> <p style="margin-left: 20px"><em>2.) Free SHBG also plays a role in extracellular signalling. A receptor, known as SHBG-R, binds to free SHBG which then "catches" various steroid molecules to complete a signalling pathway believed to be related to C-AMP. There is a pinned post regarding this phenomenon, and Dr. Crisler wrote an article about it. </em></p><p></p><p>and in <a href="https://www.peaktestosterone.com/forum/index.php?topic=15554.msg140912#msg140912" target="_blank">another post</a>:</p><p></p><p style="margin-left: 20px"><em>First:</em></p> <p style="margin-left: 20px"><em>SHBG-R is a major regulator of cellular cAMP which upregulates AR production. If you have low AR expression, your T levels are entirely worthless. T cannot induce transcriptional changes without AR protien. </em></p> <p style="margin-left: 20px"></p> <p style="margin-left: 20px"><em>The extracellular SHBG-R receptor is responsible for upregulating cAMP and PKA. Studies have shown increases in cAMP by up to 600% when SHBG binds to extracellular SHBG-R and the SHBG glycoprotein then bonds with a free E2 molecule. (SHBG is a homodimer, with one dimer being able to bind to megalin and the second to a free steroid moleucle.) SHBG alone also triggers an effect at SHBG-R, but only 20-100%. Free hormones do not trigger any such cAMP increase. SHBG-DHT and SHBG-T do not trigger any increase. Only SHBG-E2.</em></p> <p style="margin-left: 20px"></p> <p style="margin-left: 20px"><em>Second:</em></p> <p style="margin-left: 20px"><em>SHBG bound T is actually active in certain tissue. SHBG-T binds to the extracellular megalin protien. The SHBG-T complex is then brought into cellular cytoplasm via endocytosis (the cell wall wraps itself around the complex.) Once in cytoplasm, the SHBG-T complex is degraded within organelles called lysosomes. The free T molecule may then bind with an AR protein and pass through the nuclear membrane into the nucleus where it will eventually bind to directly to DNA at HREs (hormone responsive elements), specifically AREs, and induce transcriptional changes.</em></p> <p style="margin-left: 20px"></p> <p style="margin-left: 20px"><em>Third:</em></p> <p style="margin-left: 20px"><em>Studies have shown that T-responsive tissue responds LESS to pure FT alone than it does when exposed to T+SHBG. The researchers note that when exposed to T without SHBG, T that enters the cell via passive diffusion is rapidly glucuronidated and effluxed. They surmise that SHBG (which enters the cell via megalin/endocytosis) prolongs the lifetime of T within the cell itself, and not just in serum.</em></p></blockquote><p></p>
[QUOTE="Cataceous, post: 214176, member: 38109"] Yes. The basic argument is that if you're introducing testosterone at a constant rate, as when absorbing testosterone from an injection site, then at steady state you must be metabolizing and eliminating testosterone at the same rate. If we can assume that the law of mass action is largely applicable in the clearance process then free testosterone must be proportional to the rate at which testosterone is introduced. Thus free testosterone is independent of SHBG/albumin/etc., and total testosterone should be viewed as the dependent variable. I've been putting forth this hypothesis for some time now and it hasn't been shot down yet. At least one or two formal studies have data that provide some indirect support. Until you brought up the subject I hadn't considered that the same principle should apply to the testosterone metabolites. Very likely the latter. Let me quote "James" from over at PeakTestosterone.com, who wrote this in response to a question on why low SHBG is a problem: [INDENT][I]1.) Free SHBG plays a role in intracellular AR signalling. The rate of glucuronidation and time before effluxion of a free testosterone molecule that has entered a cell is mediated by intracellular SHBG brought into the cell via the megalin receptor. This phenomenon is tissue specific, and some cells produce their own SHBG internally to achieve this result. [/I][/INDENT] [INDENT][I][/I][/INDENT] [INDENT][I]2.) Free SHBG also plays a role in extracellular signalling. A receptor, known as SHBG-R, binds to free SHBG which then "catches" various steroid molecules to complete a signalling pathway believed to be related to C-AMP. There is a pinned post regarding this phenomenon, and Dr. Crisler wrote an article about it. [/I][/INDENT] and in [URL='https://www.peaktestosterone.com/forum/index.php?topic=15554.msg140912#msg140912']another post[/URL]: [INDENT][I]First:[/I][/INDENT] [INDENT][I]SHBG-R is a major regulator of cellular cAMP which upregulates AR production. If you have low AR expression, your T levels are entirely worthless. T cannot induce transcriptional changes without AR protien. [/I][/INDENT] [INDENT][I][/I][/INDENT] [INDENT][I]The extracellular SHBG-R receptor is responsible for upregulating cAMP and PKA. Studies have shown increases in cAMP by up to 600% when SHBG binds to extracellular SHBG-R and the SHBG glycoprotein then bonds with a free E2 molecule. (SHBG is a homodimer, with one dimer being able to bind to megalin and the second to a free steroid moleucle.) SHBG alone also triggers an effect at SHBG-R, but only 20-100%. Free hormones do not trigger any such cAMP increase. SHBG-DHT and SHBG-T do not trigger any increase. Only SHBG-E2.[/I][/INDENT] [INDENT][I][/I][/INDENT] [INDENT][I]Second:[/I][/INDENT] [INDENT][I]SHBG bound T is actually active in certain tissue. SHBG-T binds to the extracellular megalin protien. The SHBG-T complex is then brought into cellular cytoplasm via endocytosis (the cell wall wraps itself around the complex.) Once in cytoplasm, the SHBG-T complex is degraded within organelles called lysosomes. The free T molecule may then bind with an AR protein and pass through the nuclear membrane into the nucleus where it will eventually bind to directly to DNA at HREs (hormone responsive elements), specifically AREs, and induce transcriptional changes.[/I][/INDENT] [INDENT][I][/I][/INDENT] [INDENT][I]Third:[/I][/INDENT] [INDENT][I]Studies have shown that T-responsive tissue responds LESS to pure FT alone than it does when exposed to T+SHBG. The researchers note that when exposed to T without SHBG, T that enters the cell via passive diffusion is rapidly glucuronidated and effluxed. They surmise that SHBG (which enters the cell via megalin/endocytosis) prolongs the lifetime of T within the cell itself, and not just in serum.[/I][/INDENT] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
low shbg means high free E2 ?
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