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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Shbg/free t?
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<blockquote data-quote="Cataceous" data-source="post: 211942" data-attributes="member: 38109"><p>SHBG should still be viewed primarily as a buffer or reservoir. Free testosterone remains the dominant driver of testosterone utilization: Yes, it is "floating around"—after dissociating from albumin or SHBG—and then being "picked up by androgen receptors". The transport mechanism involving SHBG and the megalin receptor is interesting, and apparently important for normal development[<a href="https://pubmed.ncbi.nlm.nih.gov/16143106/" target="_blank">R</a>]. But I've seen nothing so far to suggest that this pathway is large in a relative sense:</p><p></p><p style="margin-left: 20px"><em>There is considerable indirect and direct evidence in support of the free hormone hypothesis. Thus, in population studies, it is almost always <strong>the non-SHBG-bound fraction of testosterone or estradiol that has been most strongly associated with muscle mass, strength, and bone mineral density</strong> (BMD) (4). The non-SHBG-bound estradiol concentration has generally been the most robust predictor of BMD in men, with total estradiol and total or non-SHBG-bound testosterone usually showing weaker associations (reviewed in Ref. 5). Because SHBG concentrations more than double over life in men (3), this has led to the plausible hypothesis that the age-related increase in SHBG levels, by limiting the availability of sex steroids, contributes to the observed decline in bone mass in aging men (5).</em></p> <p style="margin-left: 20px"></p> <p style="margin-left: 20px"><em>There is also considerable direct evidence in favor of the free hormone hypothesis (summarized in Ref. 6). Thus, animal as well as in vitro studies have found that <strong>SHBG limits access of testosterone to some target tissues such as brain, liver, salivary gland, lymph node, and prostate</strong> (6, 7). SHBG also limits the bioavailability of estradiol, particularly in the brain and testis (6, 8, 9), although this effect may be less pronounced in other tissues such as the liver (6).</em></p> <p style="margin-left: 20px"><em>...</em></p> <p style="margin-left: 20px"><em>... <strong>The free hormone hypothesis, which has withstood the test of time, is likely still correct, at least under conditions of declining free hormone levels. On the other hand, the parallel pathway involving SHBG-mediated entry of sex steroids into cells may become more evident in the setting of sex steroid sufficiency. In the end, these apparent contradictory findings reflect the fact that biological processes rarely have absolute truths; it is only our artificial constructs of those truths that tend to be absolute.</strong></em></p> <p style="margin-left: 20px">[<a href="https://academic.oup.com/jcem/article/91/12/4764/2656257" target="_blank">R</a>]</p><p></p><p>Here's a more recent reference looking at the issue:</p><p></p><p style="margin-left: 20px"><em>... In this review, I will examine four hormone groups—vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)—that are bound to various degrees to their respective binding proteins—vitamin D-binding protein (DBP), thyroid-binding globulin (TBG), sex hormone-binding globulin (SHBG), and cortisol-binding globulin (CBG)—for which <strong>a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels</strong> under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. <strong>I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role.</strong> ...</em></p> <p style="margin-left: 20px">[<a href="https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbm4.10418" target="_blank">R</a>]</p></blockquote><p></p>
[QUOTE="Cataceous, post: 211942, member: 38109"] SHBG should still be viewed primarily as a buffer or reservoir. Free testosterone remains the dominant driver of testosterone utilization: Yes, it is "floating around"—after dissociating from albumin or SHBG—and then being "picked up by androgen receptors". The transport mechanism involving SHBG and the megalin receptor is interesting, and apparently important for normal development[[URL='https://pubmed.ncbi.nlm.nih.gov/16143106/']R[/URL]]. But I've seen nothing so far to suggest that this pathway is large in a relative sense: [INDENT][I]There is considerable indirect and direct evidence in support of the free hormone hypothesis. Thus, in population studies, it is almost always [B]the non-SHBG-bound fraction of testosterone or estradiol that has been most strongly associated with muscle mass, strength, and bone mineral density[/B] (BMD) (4). The non-SHBG-bound estradiol concentration has generally been the most robust predictor of BMD in men, with total estradiol and total or non-SHBG-bound testosterone usually showing weaker associations (reviewed in Ref. 5). Because SHBG concentrations more than double over life in men (3), this has led to the plausible hypothesis that the age-related increase in SHBG levels, by limiting the availability of sex steroids, contributes to the observed decline in bone mass in aging men (5).[/I][/INDENT] [INDENT][I][/I][/INDENT] [INDENT][I]There is also considerable direct evidence in favor of the free hormone hypothesis (summarized in Ref. 6). Thus, animal as well as in vitro studies have found that [B]SHBG limits access of testosterone to some target tissues such as brain, liver, salivary gland, lymph node, and prostate[/B] (6, 7). SHBG also limits the bioavailability of estradiol, particularly in the brain and testis (6, 8, 9), although this effect may be less pronounced in other tissues such as the liver (6).[/I][/INDENT] [INDENT][I]...[/I][/INDENT] [INDENT][I]... [B]The free hormone hypothesis, which has withstood the test of time, is likely still correct, at least under conditions of declining free hormone levels. On the other hand, the parallel pathway involving SHBG-mediated entry of sex steroids into cells may become more evident in the setting of sex steroid sufficiency. In the end, these apparent contradictory findings reflect the fact that biological processes rarely have absolute truths; it is only our artificial constructs of those truths that tend to be absolute.[/B][/I][/INDENT] [INDENT][[URL='https://academic.oup.com/jcem/article/91/12/4764/2656257']R[/URL]][/INDENT] Here's a more recent reference looking at the issue: [INDENT][I]... In this review, I will examine four hormone groups—vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)—that are bound to various degrees to their respective binding proteins—vitamin D-binding protein (DBP), thyroid-binding globulin (TBG), sex hormone-binding globulin (SHBG), and cortisol-binding globulin (CBG)—for which [B]a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels[/B] under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. [B]I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role.[/B] ...[/I][/INDENT] [INDENT][[URL='https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbm4.10418']R[/URL]][/INDENT] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Shbg/free t?
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