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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Side Effect Management
Beware of DHT
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<blockquote data-quote="madman" data-source="post: 196728" data-attributes="member: 13851"><p><strong>Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels (2017)</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>ABSTRACT</strong></p><p><strong></strong></p><p><strong><em>Benefits associated with lowered serum DHT levels after 5a-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate).</em></strong><em> Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. <strong>Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.</strong> (Endocrine Reviews 38: 220 – 254, 2017).</em></p><p><em></em></p><p><em></em></p><p></p><p></p><p><strong>ESSENTIAL POINTS</strong></p><p></p><p><em>· Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen-sensitive tissue (e.g., prostate, adipose, muscle) due to local regulatory mechanisms that tightly control intracellular androgen homeostasis. </em></p><p><em></em></p><p><em>· <strong>The modest increases observed in serum DHT and in the DHT/T ratio observed after TRT are unlikely to be a cause of clinical concern, particularly when viewed in the context of changes observed in these parameters for currently marketed T-replacement products and those under development for which DHT data are available. </strong></em></p><p><em></em></p><p><em>· While well-controlled, long-term studies designed to specifically examine the effects of androgen exposure on risk for the prostate need to be conducted, the current clinical database is relatively reassuring that circulating levels of androgens (or changes in such) apparently do not play as pivotal a role as once thought in the development of the prostate disease. </em></p><p><em></em></p><p><em>· <strong>Robust epidemiologic or clinical trial evidence of a deleterious DHT effect on CVD is lacking. There is some evidence that DHT therapy in men with CVD may improve clinical status—a finding that needs confirmation. Data from a longitudinal database of older normal (i.e., not hypogonadal) indicated an association between serum DHT and incident CV disease and mortality. Conversely, others have reported that higher DHT levels in older men were associated with decreased all-cause mortality and reduced ischemic heart disease mortality. Additional exploration in prospective, placebo-controlled intervention studies of TRT with CVD as the primary endpoint is needed to resolve the long-term effects of androgens on CVD risks.</strong> </em></p><p><em></em></p><p><em>· DHT does not play a substantive role in body composition compared to T under normal conditions. Thus, elevated levels of DHT in response to TRT are unlikely to appreciably impact lean or fat mass. Nonetheless, data from animals suggest a role for DHT in adipose tissue that inhibits biochemical pathways involved in lipid synthesis and promotes several transcripts associated with apoptosis of adipocytes. Whether these DHT-induced effects also occur in human adipose tissue remains an area for future study.</em></p><p><em></em></p><p><em>· There is very limited data available regarding DHT and its effects on cognition. Further research is needed, particularly in light of animal data where DHT positively modified synaptic structure and significantly delayed cognitive impairment in a well-regarded animal model for Alzheimer’s disease. · Recent data indicating that higher levels of DHT were inversely associated with insulin resistance and risk of diabetes merit further mechanistic investigation to understand whether this action is separate from that of T.</em></p><p></p><p></p><p></p><p></p><p><strong>Do Increases in Circulating Levels of DHT Increase Risk of CVD?</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Clinical data from DHT administration in supraphysiologic doses on CVD</strong></p><p><em>*Effect of DHT treatment in men with CAD</em></p><p><em>*Effect of oral TU and resultant elevated DHT in hypogonadal men with CAD</em></p><p></p><p></p><p><strong>Effects of DHT on various biomarkers of CVD risk</strong></p><p><em>*Vasodilatory effects of DHT in animal models and effects on endothelial nitric oxide synthase (eNOS) generation</em></p><p><em>*Evidence of DHT-mediated inhibition of macrophage foam cell formation</em></p><p><em>*Effects of DHT therapy on human inflammatory biomarkers</em></p><p><em>*Effects of DHT on EPCs</em></p><p><em>*Effects of DHT on platelet aggregation and thrombosis</em></p><p></p><p></p><p><strong>Effects of DHT on Various Other Biological Processes and Tissues</strong></p><p><em>*Erythropoiesis</em></p><p><em>*Lipids</em></p><p><em>*Skin</em></p><p><em></em></p><p><em>*Body composition</em></p><p>-Impact of exogenous DHT therapy on body composition</p><p>-Effects of 5a-reductase inhibition therapy and BMD on body composition</p><p></p><p><em>*Metabolic syndrome and type 2 diabetes</em></p><p><em>*Sexual function</em></p><p><em>*5a-reductase deficiency</em></p><p><em>*Gynecomastia</em></p><p><em>*Cognition</em></p><p><em>*Telomere length</em></p><p></p><p></p><p></p><p><strong><u><em>In summary, we have reviewed the evidence that slightly to moderately elevated DHT concentrations or an elevated DHT/T ratio during androgen therapy (most notably, TRT) are unlikely to pose either higher risk or a unique risk compared with T</em></u><em>.</em></strong> <strong><em>We acknowledge that the available published data are limited by the lack of large, well-controlled studies of the long duration that are sufficiently powered to expose subtle safety signals. <u>Nonetheless, the preponderance of available clinical data leads to the conclusion that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice</u>.</em></strong></p></blockquote><p></p>
[QUOTE="madman, post: 196728, member: 13851"] [B]Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels (2017) ABSTRACT [I]Benefits associated with lowered serum DHT levels after 5a-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate).[/I][/B][I] Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. [B]Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.[/B] (Endocrine Reviews 38: 220 – 254, 2017). [/I] [B]ESSENTIAL POINTS[/B] [I]· Circulating levels of DHT in response to testosterone replacement therapy (TRT) do not correlate with those found in androgen-sensitive tissue (e.g., prostate, adipose, muscle) due to local regulatory mechanisms that tightly control intracellular androgen homeostasis. · [B]The modest increases observed in serum DHT and in the DHT/T ratio observed after TRT are unlikely to be a cause of clinical concern, particularly when viewed in the context of changes observed in these parameters for currently marketed T-replacement products and those under development for which DHT data are available. [/B] · While well-controlled, long-term studies designed to specifically examine the effects of androgen exposure on risk for the prostate need to be conducted, the current clinical database is relatively reassuring that circulating levels of androgens (or changes in such) apparently do not play as pivotal a role as once thought in the development of the prostate disease. · [B]Robust epidemiologic or clinical trial evidence of a deleterious DHT effect on CVD is lacking. There is some evidence that DHT therapy in men with CVD may improve clinical status—a finding that needs confirmation. Data from a longitudinal database of older normal (i.e., not hypogonadal) indicated an association between serum DHT and incident CV disease and mortality. Conversely, others have reported that higher DHT levels in older men were associated with decreased all-cause mortality and reduced ischemic heart disease mortality. Additional exploration in prospective, placebo-controlled intervention studies of TRT with CVD as the primary endpoint is needed to resolve the long-term effects of androgens on CVD risks.[/B] · DHT does not play a substantive role in body composition compared to T under normal conditions. Thus, elevated levels of DHT in response to TRT are unlikely to appreciably impact lean or fat mass. Nonetheless, data from animals suggest a role for DHT in adipose tissue that inhibits biochemical pathways involved in lipid synthesis and promotes several transcripts associated with apoptosis of adipocytes. Whether these DHT-induced effects also occur in human adipose tissue remains an area for future study. · There is very limited data available regarding DHT and its effects on cognition. Further research is needed, particularly in light of animal data where DHT positively modified synaptic structure and significantly delayed cognitive impairment in a well-regarded animal model for Alzheimer’s disease. · Recent data indicating that higher levels of DHT were inversely associated with insulin resistance and risk of diabetes merit further mechanistic investigation to understand whether this action is separate from that of T.[/I] [B]Do Increases in Circulating Levels of DHT Increase Risk of CVD? Clinical data from DHT administration in supraphysiologic doses on CVD[/B] [I]*Effect of DHT treatment in men with CAD *Effect of oral TU and resultant elevated DHT in hypogonadal men with CAD[/I] [B]Effects of DHT on various biomarkers of CVD risk[/B] [I]*Vasodilatory effects of DHT in animal models and effects on endothelial nitric oxide synthase (eNOS) generation *Evidence of DHT-mediated inhibition of macrophage foam cell formation *Effects of DHT therapy on human inflammatory biomarkers *Effects of DHT on EPCs *Effects of DHT on platelet aggregation and thrombosis[/I] [B]Effects of DHT on Various Other Biological Processes and Tissues[/B] [I]*Erythropoiesis *Lipids *Skin *Body composition[/I] -Impact of exogenous DHT therapy on body composition -Effects of 5a-reductase inhibition therapy and BMD on body composition [I]*Metabolic syndrome and type 2 diabetes *Sexual function *5a-reductase deficiency *Gynecomastia *Cognition *Telomere length[/I] [B][U][I]In summary, we have reviewed the evidence that slightly to moderately elevated DHT concentrations or an elevated DHT/T ratio during androgen therapy (most notably, TRT) are unlikely to pose either higher risk or a unique risk compared with T[/I][/U][I].[/I][/B][I] [/I][B][I]We acknowledge that the available published data are limited by the lack of large, well-controlled studies of the long duration that are sufficiently powered to expose subtle safety signals. [U]Nonetheless, the preponderance of available clinical data leads to the conclusion that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice[/U].[/I][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Side Effect Management
Beware of DHT
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