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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Maximus: Oral TRT+ (native T + enclomiphene + pregnenolone)
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<blockquote data-quote="madman" data-source="post: 277504" data-attributes="member: 13851"><p>Not happening!</p><p></p><p></p><p><em><strong>*An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a <u>heavy load on liver metabolism</u>. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. <u>The capacity of this pathway is presumably very large</u>. <u>We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*There were no changes in <u>serum markers of liver or kidney function</u> or in the hematocrit or hemoglobin during the treatment phase or at follow-up.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*<strong>These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). <u>Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing</u>.</strong> <u>It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls</u> (32, 33).<strong> Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research.</strong></strong></em></p><p><em><strong><strong></strong></strong></em></p><p><em><strong><strong>*<em><strong>It is also important to note that previous studies of oral T administration <u>demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg</u> (21–23). <u>We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels</u> (data not shown),<u> implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T</u> levels seen in this study.</strong> </em></strong></strong></em></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/threads/my-experience-on-jatenzo-oral-trt-log.23595/page-5[/URL]</p><p></p><p></p><p><strong>THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE (1974)</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Discussion</strong></p><p><strong></strong></p><p><strong><em>Our results demonstrate that the effectiveness of micronized free testosterone by mouth depends on the dosage. <u>Our clinical double-blind trials in eunuchs showed that 100 mg. testosterone per day was ineffective, whereas 400 mg. per day was fully effective</u>.</em></strong></p><p><strong><em></em></strong></p><p><strong><em>These results accord with our finding that 200 mg. free testosterone given once orally can maintain a normal male serum-testosterone level for many hours in patients without testicular function.</em></strong></p><p><strong><em></em></strong></p><p><strong><em>The figure indicates that the <u>half-life of testosterone in serum after ingestion of tablets is about 5-7 hours</u>.</em></strong><em> This is surprising since the turnover of testosterone in the blood is very rapid.7,8 <strong>The reason why high testosterone levels are maintained in the blood for a considerable time after ingestion of testosterone tablets seems to be that <u>testosterone is absorbed very slowly from the intestine</u>.</strong> The fact that the tablets used to study serum testosterone contained a few large particles of testosterone can hardly explain the long effect since these large particles did not constitute more than about 10% of the surface area of testosterone. <strong>The extended effect is an advantage during therapy, and we intend to change our standard treatment with oral testosterone to tablets only twice a day.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>We recommend an oral testosterone dose in total testicular failure of 400 mg. per day (2 X 200 mg.). This dose in mg. substance is 3-4 times higher than that recommended for methyltestosterone or mesterolone.</strong> Free testosterone is reasonably cheap and 100- 200 mg. testosterone tablets made conventionally by hospital pharmacies will cost the same as commercial tablets containing patented artificial testosterone derivatives</em></p><p><em></em></p><p><em><strong>An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a <u>heavy load on liver metabolism</u>. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. <u>The capacity of this pathway is presumably very large</u>. <u>We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects</u>.</strong></em></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p><strong><strong>Oral Testosterone in Oil Plus Dutasteride in Men: A Pharmacokinetic Study (2005)</strong></strong></p><p></p><p></p><p><em><strong>Oral administration of unmodified T at doses up to 100 mg have little effect on serum T levels in T-deficient men (20, 21); however, <u>200-mg doses of oral T have been shown to elevate serum T levels to the low normal range for up to 8 h</u> (22, 23).</strong> <strong><u>At the time, these serum T levels were thought to be insufficient for clinical use, and research into using unmodified oral T was largely abandoned</u>.</strong></em></p><p><em></em></p><p><em>Testosterone undecanoate (TU) is a T ester currently given orally in oil and used clinically in Europe and Canada for the treatment of T deficiency. <strong>When administered orally, TU therapy results in therapeutic increases in serum T; however, it also results in <u>elevations in serum dihydrotestosterone (DHT) well above the normal range</u> (24 –27). </strong>Because DHT is required for cell growth within the prostate, concern has been raised about the potential for long-term harm associated with oral TU therapy from the elevated levels of serum DHT; however, no increased risk of prostate disease has been reported to date</em></p><p><em></em></p><p><em><strong>Because the androgen TU is absorbed well in oil, <u>we believed that other androgens such as T enanthate (TE) and potentially T itself might be well absorbed if also administered orally in oil</u>. </strong>Moreover, because the recently available 5-reductase inhibitor, dutasteride (D), lowers serum DHT levels more than 90% by inhibiting both isozymes of 5- reductase (28), <strong>we hypothesized that oral administration of the combination of <u>higher doses of unmodified T or the T ester, TE, in oil, when combined with D, would be safe and result in therapeutic serum T levels</u></strong>. <strong>In addition, we hypothesized that the concomitant administration of the 5-reductase inhibitor D with T or TE would further increase serum T levels while minimizing the elevations in serum DHT seen after oral administration of oral androgens such as TU.</strong> If effective, we believed that this novel means of T therapy would allow for selective androgen therapy in men with T deficiency. </em><strong><em>Therefore, we conducted a pilot study of the <u>oral administration of single doses of T and TE with and without concomitant administration of D</u> to determine the pharmacokinetics and safety of single high doses of oral T in oil in healthy men rendered temporarily hypogonadal with the GnRH antagonist acyline.</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Results</strong></p><p><strong></strong></p><p><strong>Subjects</strong></p><p></p><p><em><strong>Fourteen men were enrolled in the study; seven were randomized to the T group, and seven were randomized to the TE group, but one man assigned to the TE group failed to report for his acyline injection. Therefore, seven men completed the T arm, and six completed the TE arm of the study (Table 1). </strong>Except for the subject who failed to appear for his acyline injection, all subjects completed the drug exposure period. <strong>There were no serious adverse effects during the study.</strong> Nine of the subjects experienced transient mild pruritis at the site of the acyline injection, which resolved in all cases within 1 h of the injection. <strong>Eight subjects complained of mild, transient hot flash symptoms toward the end of the study period, presumably due to low T levels; however, no subject complained of feelings of anger, aggression, or irritability during treatment. <u>There were no adverse gastrointestinal symptoms associated with oral T or oral TE in oil</u>.</strong> One subject developed a small area of gynecomastia (1 1 cm) immediately under the nipple during the treatment period, but this resolved during follow-up.<strong> <u>There were no changes in serum markers of liver or kidney function or in the hematocrit or hemoglobin during the treatment phase or at follow-up</u>. <u>Furthermore, no significant changes in blood pressure or pulse were observed</u>. T and gonadotropin levels returned to baseline in all subjects during the follow-up period (data not shown). No subjects were lost to follow-up.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Serum T</strong></p><p></p><p><em>All subjects were suppressed to castrate levels of T by 24 h after acyline administration (d 0 T, 20.0 7.4; d 1 T, 2.3 0.5 nmol/liter; P 0.0001). There was no difference in serum T levels 24 h after acyline between groups [2.3 0.7 (T) vs. 2.3 0.8 (TE); P 0.9]. In addition, mean serum T levels before each dose of T were not significantly different from that 24 h after acyline administration.</em></p><p><em></em></p><p><em><strong><u>With the administration of both oral T and oral TE in oil, serum T was significantly increased in a dose-dependent fashion</u> (Fig. 2; P 0.01 for trend). In addition, the maximum concentrations of T, average concentrations of serum T, and area under the curve of serum T increased significantly in a dose-dependent fashion (Table 2 and Fig. 3A), <u>with the maximum concentration of T after oil dosing exceeding the normal range for the 800-mg dose of T and the 400- and 800-mg doses of oral TE in oil</u>. <u>The time of maximum concentration was between 2.5 and 4.5 h in all cases, and the calculated terminal t1/2 of oral T and TE in oil was between 7.5 and 11 h</u>. </strong>Coadministration of D with oral T or TE in oil significantly increased the resulting serum T levels compared with administration of T or TE alone (Fig. 2; P 0.01 for trend). The maximum concentration of T after oral treatment with the combination of T or TE and D exceeded the normal range for both the 400- and 800-mg doses of T and TE in oil. Similar to the administration of T or TE only, the time to maximum concentration remained between 2.5 and 4.5 h, and the calculated terminal t1/2 was between 8 and 10 h. The T area under the curve for the combination of T and D was significantly increased at all doses compared with that for T alone [200 mg, 124 28 nmol-h/liter (T alone) vs. 176 45 nmol-h/liter (T D); 400 mg, 208 74 nmol-h/liter (T alone) vs. 393 nmol-h/liter (T plus D); 800 mg, 328 82 nmol-h/liter (T alone) vs. 846 363 nmol-h/liter (T plus D); P 0.01 for all comparisons].</em></p><p></p><p></p><p></p><p></p><p><strong>Discussion</strong></p><p><strong></strong></p><p><strong><em>In this study, we have demonstrated that single doses of T or TE when administered orally in oil can result in serum T levels that would be useful for the treatment of T deficiency. </em></strong><em>Secondly, we have demonstrated that the addition of the 5- reductase inhibitor D to oral T in oil 1) significantly increases the serum T levels achieved after a given dose of T, and 2) attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T or T esters (e.g. TU) without concomitant 5-reductase inhibition.</em></p><p><em></em></p><p><em><strong>These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). <u>Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing</u>.</strong> It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls (32, 33).<strong> Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Previous studies of the oral administration of T may have found reduced levels of serum T in part due to 5-reductase activity in the intestine and liver (34). In this study using T or TE, and in the work of others with TU (24 –27), serum levels of DHT after oral administration are markedly elevated, <u>implying that a large fraction of the orally administered T dose may be metabolized in the liver and intestines to DHT</u>.</strong> Surprisingly, in this study, the coadministration of a 5-reductase inhibitor roughly doubles the average T concentration and the area under the curve for the serum T while reducing the elevations of serum DHT by approximately half. <strong>These marked elevations in serum T with concomitant 5-reductase inhibition are probably due to inhibition of the 5-reductase enzyme in the intestine and liver, which appears to account for approximately one-half of the metabolism of T after an oral dose. </strong>Importantly, the combination of elevated serum T without marked elevations in serum DHT may allow for selective oral androgen therapy, which may be useful in decreasing the risk for DHT-dependent diseases, such as benign prostate hyperplasia and prostate cancer.</em></p><p><em></em></p><p><em><strong><u>It is also important to note that previous studies of oral T administration demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg</u> (21–23). <u>We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels (data not shown), implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T levels seen in this study</u>.</strong> It has been previously shown that the absorption of oral TU is markedly affected by the concomitant intake of fatty foods (27, 30). This is probably due to the fact that much of the orally administered TU is absorbed via the lymphatics (35). In an animal model of TU absorption, more than 80% of the bioavailable T is thought to be absorbed via lymphatics (36). <strong><u>Whether food intake will affect the absorption of oral T in oil is unknown and probably depends on how much of the dose is absorbed via lymphatics vs. via the portal circulation</u>. <u>Because T was administered in oil in this study, some of the doses may have been absorbed via the lymphatics</u>. This might explain in part the unexpectedly long serum half-life of T seen with oral compared with iv administration of T, which has been reported to have a half-life of less than 1 h (31, 37). Another possibility is that there is some degree of enterohepatic circulation of the orally administered T, prolonging the apparent half-life in serum. </strong>Because of this uncertainty, the impact of food intake on the absorption and serum levels of T after the administration of oral high dose T will be the subject of future study.</em></p><p><em></em></p><p><em><strong><u>It is important to note that there was no evidence of either liver or kidney toxicity associated with the doses of oral T administered in this study</u>; however, additional long-term study of these doses combined with a 5-reductase inhibitor will be required to determine the safety of this approach to T therapy. </strong>Although one subject did report transient gynecomastia, this subject’s serum E2 level remained within the normal range. Additionally, no subject complained of impotence, decreased libido, or sexual dysfunction during the treatment period. These side effects have been reported when D is administered alone for benign prostate hyperplasia (38); however, in theory, they would be less likely when D is administered in combination with T. Additionally, the implication of long-term 5-reductase inhibition will need examination given the increase in high-grade prostate cancer (despite an overall decrease in prostate cancer incidence) seen with chronic finasteride administration in the prostate cancer prevention trial (39).</em></p><p><em></em></p><p><em><strong>There were slight, nonsignificant increases in serum E2 seen after oral dosing of T and TE in oil. <u>This implies that although orally administered T can undergo aromatization to E2, it does not do so at high levels, suggesting that there is probably little aromatase activity in the intestine and liver in man</u>. </strong>This finding is reassuring in showing that orally administered T is likely to allow for the important functions of estrogen in man, such as maintenance of bone density (40), but not lead to an increased risk of estrogen-related side effects such as gynecomastia.</em></p><p></p><p><strong><em>From a practical standpoint, a regimen using oral T in oil in the formulation used in this study may need to be administered twice daily; however, additional refinements of this approach, such as the use of slow-release capsules, may allow for more controlled release of T in the intestine and could lead to a formulation that could be administered orally once daily, a major improvement over current T replacement options.</em></strong></p><p><strong><em></em></strong></p><p><strong><em><u>In conclusion, we have demonstrated that single doses of T or TE, when administered orally in oil, can result in markedly elevated serum levels of T in normal men with induced hypogonadism; such levels would presumably be therapeutically effective in treating testicular failure</u>. In addition, we have demonstrated that the addition of the 5-reductase inhibitor D to oral T in oil significantly increases the serum T levels observed with a given dose of T and attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T alone. Combinations of oral T and 5-reductase inhibitors may allow for an oral, selective form of androgen therapy. Additional studies of the long-term safety, pharmacokinetics, and pharmacodynamics of this combination are warranted to determine whether it might be a clinically useful and attractive method of treating T deficiency.</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>FIG. 2. <u>Serum T concentrations (mean SEM) after oral administration of 200, 400, and 800 mg T in oil (A–C)</u> and TE in oil (D–F) with and without D for 24 h in normal men treated with the GnRH antagonist acyline to temporarily suspend T production. Note the larger y-axis for the 800-mg dose. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone.</strong></p><p><strong>[ATTACH=full]42310[/ATTACH]</strong></p><p><strong>[ATTACH=full]42311[/ATTACH]</strong></p><p><strong>[ATTACH=full]42312[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong><strong>FIG. 3. Average serum T (A) and DHT (B) concentrations (mean SD) over the 24-h interval after oral treatment. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone</strong></strong></p><p><strong><strong>[ATTACH=full]42313[/ATTACH]</strong></strong></p></blockquote><p></p>
[QUOTE="madman, post: 277504, member: 13851"] Not happening! [I][B]*An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a [U]heavy load on liver metabolism[/U]. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. [U]The capacity of this pathway is presumably very large[/U]. [U]We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects[/U]. *There were no changes in [U]serum markers of liver or kidney function[/U] or in the hematocrit or hemoglobin during the treatment phase or at follow-up. *[B]These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). [U]Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing[/U].[/B] [U]It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls[/U] (32, 33).[B] Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research. *[I][B]It is also important to note that previous studies of oral T administration [U]demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg[/U] (21–23). [U]We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels[/U] (data not shown),[U] implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T[/U] levels seen in this study.[/B] [/I][/B][/B][/I] [URL unfurl="true"]https://www.excelmale.com/threads/my-experience-on-jatenzo-oral-trt-log.23595/page-5[/URL] [B]THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE (1974) Discussion [I]Our results demonstrate that the effectiveness of micronized free testosterone by mouth depends on the dosage. [U]Our clinical double-blind trials in eunuchs showed that 100 mg. testosterone per day was ineffective, whereas 400 mg. per day was fully effective[/U]. These results accord with our finding that 200 mg. free testosterone given once orally can maintain a normal male serum-testosterone level for many hours in patients without testicular function. The figure indicates that the [U]half-life of testosterone in serum after ingestion of tablets is about 5-7 hours[/U].[/I][/B][I] This is surprising since the turnover of testosterone in the blood is very rapid.7,8 [B]The reason why high testosterone levels are maintained in the blood for a considerable time after ingestion of testosterone tablets seems to be that [U]testosterone is absorbed very slowly from the intestine[/U].[/B] The fact that the tablets used to study serum testosterone contained a few large particles of testosterone can hardly explain the long effect since these large particles did not constitute more than about 10% of the surface area of testosterone. [B]The extended effect is an advantage during therapy, and we intend to change our standard treatment with oral testosterone to tablets only twice a day. We recommend an oral testosterone dose in total testicular failure of 400 mg. per day (2 X 200 mg.). This dose in mg. substance is 3-4 times higher than that recommended for methyltestosterone or mesterolone.[/B] Free testosterone is reasonably cheap and 100- 200 mg. testosterone tablets made conventionally by hospital pharmacies will cost the same as commercial tablets containing patented artificial testosterone derivatives [B]An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a [U]heavy load on liver metabolism[/U]. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. [U]The capacity of this pathway is presumably very large[/U]. [U]We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects[/U].[/B][/I] [B][B]Oral Testosterone in Oil Plus Dutasteride in Men: A Pharmacokinetic Study (2005)[/B][/B] [I][B]Oral administration of unmodified T at doses up to 100 mg have little effect on serum T levels in T-deficient men (20, 21); however, [U]200-mg doses of oral T have been shown to elevate serum T levels to the low normal range for up to 8 h[/U] (22, 23).[/B] [B][U]At the time, these serum T levels were thought to be insufficient for clinical use, and research into using unmodified oral T was largely abandoned[/U].[/B] Testosterone undecanoate (TU) is a T ester currently given orally in oil and used clinically in Europe and Canada for the treatment of T deficiency. [B]When administered orally, TU therapy results in therapeutic increases in serum T; however, it also results in [U]elevations in serum dihydrotestosterone (DHT) well above the normal range[/U] (24 –27). [/B]Because DHT is required for cell growth within the prostate, concern has been raised about the potential for long-term harm associated with oral TU therapy from the elevated levels of serum DHT; however, no increased risk of prostate disease has been reported to date [B]Because the androgen TU is absorbed well in oil, [U]we believed that other androgens such as T enanthate (TE) and potentially T itself might be well absorbed if also administered orally in oil[/U]. [/B]Moreover, because the recently available 5-reductase inhibitor, dutasteride (D), lowers serum DHT levels more than 90% by inhibiting both isozymes of 5- reductase (28), [B]we hypothesized that oral administration of the combination of [U]higher doses of unmodified T or the T ester, TE, in oil, when combined with D, would be safe and result in therapeutic serum T levels[/U][/B]. [B]In addition, we hypothesized that the concomitant administration of the 5-reductase inhibitor D with T or TE would further increase serum T levels while minimizing the elevations in serum DHT seen after oral administration of oral androgens such as TU.[/B] If effective, we believed that this novel means of T therapy would allow for selective androgen therapy in men with T deficiency. [/I][B][I]Therefore, we conducted a pilot study of the [U]oral administration of single doses of T and TE with and without concomitant administration of D[/U] to determine the pharmacokinetics and safety of single high doses of oral T in oil in healthy men rendered temporarily hypogonadal with the GnRH antagonist acyline.[/I] Results Subjects[/B] [I][B]Fourteen men were enrolled in the study; seven were randomized to the T group, and seven were randomized to the TE group, but one man assigned to the TE group failed to report for his acyline injection. Therefore, seven men completed the T arm, and six completed the TE arm of the study (Table 1). [/B]Except for the subject who failed to appear for his acyline injection, all subjects completed the drug exposure period. [B]There were no serious adverse effects during the study.[/B] Nine of the subjects experienced transient mild pruritis at the site of the acyline injection, which resolved in all cases within 1 h of the injection. [B]Eight subjects complained of mild, transient hot flash symptoms toward the end of the study period, presumably due to low T levels; however, no subject complained of feelings of anger, aggression, or irritability during treatment. [U]There were no adverse gastrointestinal symptoms associated with oral T or oral TE in oil[/U].[/B] One subject developed a small area of gynecomastia (1 1 cm) immediately under the nipple during the treatment period, but this resolved during follow-up.[B] [U]There were no changes in serum markers of liver or kidney function or in the hematocrit or hemoglobin during the treatment phase or at follow-up[/U]. [U]Furthermore, no significant changes in blood pressure or pulse were observed[/U]. T and gonadotropin levels returned to baseline in all subjects during the follow-up period (data not shown). No subjects were lost to follow-up.[/B][/I] [B]Serum T[/B] [I]All subjects were suppressed to castrate levels of T by 24 h after acyline administration (d 0 T, 20.0 7.4; d 1 T, 2.3 0.5 nmol/liter; P 0.0001). There was no difference in serum T levels 24 h after acyline between groups [2.3 0.7 (T) vs. 2.3 0.8 (TE); P 0.9]. In addition, mean serum T levels before each dose of T were not significantly different from that 24 h after acyline administration. [B][U]With the administration of both oral T and oral TE in oil, serum T was significantly increased in a dose-dependent fashion[/U] (Fig. 2; P 0.01 for trend). In addition, the maximum concentrations of T, average concentrations of serum T, and area under the curve of serum T increased significantly in a dose-dependent fashion (Table 2 and Fig. 3A), [U]with the maximum concentration of T after oil dosing exceeding the normal range for the 800-mg dose of T and the 400- and 800-mg doses of oral TE in oil[/U]. [U]The time of maximum concentration was between 2.5 and 4.5 h in all cases, and the calculated terminal t1/2 of oral T and TE in oil was between 7.5 and 11 h[/U]. [/B]Coadministration of D with oral T or TE in oil significantly increased the resulting serum T levels compared with administration of T or TE alone (Fig. 2; P 0.01 for trend). The maximum concentration of T after oral treatment with the combination of T or TE and D exceeded the normal range for both the 400- and 800-mg doses of T and TE in oil. Similar to the administration of T or TE only, the time to maximum concentration remained between 2.5 and 4.5 h, and the calculated terminal t1/2 was between 8 and 10 h. The T area under the curve for the combination of T and D was significantly increased at all doses compared with that for T alone [200 mg, 124 28 nmol-h/liter (T alone) vs. 176 45 nmol-h/liter (T D); 400 mg, 208 74 nmol-h/liter (T alone) vs. 393 nmol-h/liter (T plus D); 800 mg, 328 82 nmol-h/liter (T alone) vs. 846 363 nmol-h/liter (T plus D); P 0.01 for all comparisons].[/I] [B]Discussion [I]In this study, we have demonstrated that single doses of T or TE when administered orally in oil can result in serum T levels that would be useful for the treatment of T deficiency. [/I][/B][I]Secondly, we have demonstrated that the addition of the 5- reductase inhibitor D to oral T in oil 1) significantly increases the serum T levels achieved after a given dose of T, and 2) attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T or T esters (e.g. TU) without concomitant 5-reductase inhibition. [B]These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). [U]Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing[/U].[/B] It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls (32, 33).[B] Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research. Previous studies of the oral administration of T may have found reduced levels of serum T in part due to 5-reductase activity in the intestine and liver (34). In this study using T or TE, and in the work of others with TU (24 –27), serum levels of DHT after oral administration are markedly elevated, [U]implying that a large fraction of the orally administered T dose may be metabolized in the liver and intestines to DHT[/U].[/B] Surprisingly, in this study, the coadministration of a 5-reductase inhibitor roughly doubles the average T concentration and the area under the curve for the serum T while reducing the elevations of serum DHT by approximately half. [B]These marked elevations in serum T with concomitant 5-reductase inhibition are probably due to inhibition of the 5-reductase enzyme in the intestine and liver, which appears to account for approximately one-half of the metabolism of T after an oral dose. [/B]Importantly, the combination of elevated serum T without marked elevations in serum DHT may allow for selective oral androgen therapy, which may be useful in decreasing the risk for DHT-dependent diseases, such as benign prostate hyperplasia and prostate cancer. [B][U]It is also important to note that previous studies of oral T administration demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg[/U] (21–23). [U]We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels (data not shown), implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T levels seen in this study[/U].[/B] It has been previously shown that the absorption of oral TU is markedly affected by the concomitant intake of fatty foods (27, 30). This is probably due to the fact that much of the orally administered TU is absorbed via the lymphatics (35). In an animal model of TU absorption, more than 80% of the bioavailable T is thought to be absorbed via lymphatics (36). [B][U]Whether food intake will affect the absorption of oral T in oil is unknown and probably depends on how much of the dose is absorbed via lymphatics vs. via the portal circulation[/U]. [U]Because T was administered in oil in this study, some of the doses may have been absorbed via the lymphatics[/U]. This might explain in part the unexpectedly long serum half-life of T seen with oral compared with iv administration of T, which has been reported to have a half-life of less than 1 h (31, 37). Another possibility is that there is some degree of enterohepatic circulation of the orally administered T, prolonging the apparent half-life in serum. [/B]Because of this uncertainty, the impact of food intake on the absorption and serum levels of T after the administration of oral high dose T will be the subject of future study. [B][U]It is important to note that there was no evidence of either liver or kidney toxicity associated with the doses of oral T administered in this study[/U]; however, additional long-term study of these doses combined with a 5-reductase inhibitor will be required to determine the safety of this approach to T therapy. [/B]Although one subject did report transient gynecomastia, this subject’s serum E2 level remained within the normal range. Additionally, no subject complained of impotence, decreased libido, or sexual dysfunction during the treatment period. These side effects have been reported when D is administered alone for benign prostate hyperplasia (38); however, in theory, they would be less likely when D is administered in combination with T. Additionally, the implication of long-term 5-reductase inhibition will need examination given the increase in high-grade prostate cancer (despite an overall decrease in prostate cancer incidence) seen with chronic finasteride administration in the prostate cancer prevention trial (39). [B]There were slight, nonsignificant increases in serum E2 seen after oral dosing of T and TE in oil. [U]This implies that although orally administered T can undergo aromatization to E2, it does not do so at high levels, suggesting that there is probably little aromatase activity in the intestine and liver in man[/U]. [/B]This finding is reassuring in showing that orally administered T is likely to allow for the important functions of estrogen in man, such as maintenance of bone density (40), but not lead to an increased risk of estrogen-related side effects such as gynecomastia.[/I] [B][I]From a practical standpoint, a regimen using oral T in oil in the formulation used in this study may need to be administered twice daily; however, additional refinements of this approach, such as the use of slow-release capsules, may allow for more controlled release of T in the intestine and could lead to a formulation that could be administered orally once daily, a major improvement over current T replacement options. [U]In conclusion, we have demonstrated that single doses of T or TE, when administered orally in oil, can result in markedly elevated serum levels of T in normal men with induced hypogonadism; such levels would presumably be therapeutically effective in treating testicular failure[/U]. In addition, we have demonstrated that the addition of the 5-reductase inhibitor D to oral T in oil significantly increases the serum T levels observed with a given dose of T and attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T alone. Combinations of oral T and 5-reductase inhibitors may allow for an oral, selective form of androgen therapy. Additional studies of the long-term safety, pharmacokinetics, and pharmacodynamics of this combination are warranted to determine whether it might be a clinically useful and attractive method of treating T deficiency.[/I] FIG. 2. [U]Serum T concentrations (mean SEM) after oral administration of 200, 400, and 800 mg T in oil (A–C)[/U] and TE in oil (D–F) with and without D for 24 h in normal men treated with the GnRH antagonist acyline to temporarily suspend T production. Note the larger y-axis for the 800-mg dose. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone. [ATTACH type="full" alt="Screenshot (33638).png"]42310[/ATTACH] [ATTACH type="full" alt="Screenshot (33639).png"]42311[/ATTACH] [ATTACH type="full" alt="Screenshot (33640).png"]42312[/ATTACH] [B]FIG. 3. Average serum T (A) and DHT (B) concentrations (mean SD) over the 24-h interval after oral treatment. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone [ATTACH type="full" alt="1710565977546.png"]42313[/ATTACH][/B][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Maximus: Oral TRT+ (native T + enclomiphene + pregnenolone)
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