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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: 277512" data-attributes="member: 13851"><p>The sole purpose of the ester is to control the release rate of T from the oily depot.</p><p></p><p>Esterified T is inert until it hits the bloodstream where the ester is rapidly hydrolyzed (esterase enzymes) and you are left with native/free T.</p><p></p><p></p><p></p><p></p><p><em><strong>*The purpose of the ester is to control the release rate of the steroid from the oily depot and it is cleaved as soon as it hits the bloodstream releasing free testosterone.</strong></em></p><p></p><h4><em><strong>*TU/TC/TE/TP (oily depot)----->ester cleaved (ECF)----->FREE TESTOSTERONE (blood)</strong></em></h4><p></p><p></p><p></p><p></p><p><strong><em>*"It is also important to stress the fact that<u> esters do not alter the activity of the parent steroid in any way</u>.</em></strong><em> <strong>They work only to <u>slow its release</u>"</strong></em></p><p><em><strong></strong></em></p><p><em><strong>The ester only <u>controls the release rate from the injection depot</u>.</strong></em></p><p></p><p><strong><em>"Once free in circulation, <u>enzymes will quickly remove the ester chain</u> and the <u>parent hormone will be free to exert its activity</u> (<u>while the ester is present the steroid is inert</u>)"</em></strong></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.ncbi.nlm.nih.gov/books/NBK279000/[/URL]</p><p></p><h4><strong>Injectable Testosterone</strong></h4><p><em><strong>The most widely used testosterone formulation for many decades has been an intramuscular injection of testosterone esters (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/figure/andro-phys-pharm-abs.F5/?report=objectonly" target="_blank">figure 5</a>), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">653</a>). <u>This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into circulation</u>. <u>The pharmacokinetics and pharmacodynamics of androgen esters are therefore primarily determined by ester side-chain length, the volume of the oil vehicle, and the site of injection via hydrophobic physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid</u> (<a href="https://www.ncbi.nlm.nih.gov/books/NBK279000/#" target="_blank">654</a>).</strong></em></p><p></p><p></p><p></p><h3>FIGURE 5.</h3><p><em><strong>Schematic overview of the pharmacology of testosterone esters. </strong>Testosterone is esterified through the 17 β hydroxyl group with fatty acid esters of different aliphatic or other chain lengths which is a biologically inactive pro-drug. <strong>The esterified testosterone in an oil vehicle is injected deeply into a muscle forming a local drug depot from which the testosterone ester is released at a slow rate determined by its Physico-chemical partitioning according to the testosterone ester’s hydrophobicity.</strong> <strong>Once the <u>testosterone ester exits the depot and enters the extracellular fluids, it is rapidly hydrolyzed by ubiquitous non-specific esterases thereby releasing the testosterone into the general circulation</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>[ATTACH=full]42316[/ATTACH]</strong></em></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/threads/short-acting-t-therapy-to-maintain-homeostasis-that-more-closely-reflects-normal-physiology.22083/[/URL]</p><p></p><p><em>*The various testosterone formulations have a wide range of dosing intervals including long-acting preparations: subcutaneous pellets (3 to 6 months), injectable IM testosterone undecanoate (10 weeks); intermediate-acting preparations: IM testosterone cypionate/enanthate (1 to 3 weeks); daily preparations: topical/transdermal formulations; and short-acting preparations: oral testosterone undecanoate (twice daily) and nasal testosterone (two to three times daily).</em> <em><strong>All formulations, with the exception of the short-acting ones, have a </strong><u><strong>target of long-term maintenance of sustained steady-state testosterone levels in the mid-normal range</strong></u><strong>, which leads to suppression of the endogenous activity of the HPG axis.</strong></em></p><p></p><p><strong><em>*As previously noted, testosterone levels in young healthy males follow a circadian rhythm. T levels are highest in the morning and lower in the evening hours. <u>There is significant change within a 24-h period</u>. Testosterone itself acts as a negative feedback molecule to the hypothalamus and anterior pituitary. </em></strong><em><u><strong>When T levels are high enough, they signal to reduce GnRH, LH, and FSH secretion, thereby also reducing endogenous testosterone production. This occurs regardless of whether the circulating testosterone is endogenous or exogenous</strong></u><strong>.</strong></em><strong><em><u> If high levels of testosterone are given exogenously for extended periods of time, this can result in negative feedback to the hypothalamus and anterior pituitary, disrupting normal HPG regulation</u>.</em></strong></p><p><strong></strong></p><p><strong>*</strong><em><strong>Topical gel formulations <u>achieve a sustained mid-normal T level with a once-daily application</u> (8). While the topical gel results in <u>less fluctuation of T levels between dosing intervals when compared to IM T, the sustained T levels result in inhibition of HPG axis activity</u> (9). T<u>he inhibition of HPG axis activity is evidenced by the nearly full suppression of gonadotropin levels following treatment with either IM injectable testosterone (10) or topical gel administration</u> (9).</strong> <strong><u>Nasal administration of T (4.5% testosterone nasal gel, Natesto) allows for rapid absorption through the nasal mucosa such that serum T levels reach a peak concentration in ∼40 min</u>. <u>Once in the circulation, the T is quickly metabolized, with a return to near baseline T levels in 3–6 h</u></strong> <strong>(11). Therefore, multiple administrations of nasal T throughout the day (three times daily) maintain normal mean serum T levels over 24 h. <u>The fluctuations in T levels potentially minimize the duration of exposure to exogenous T that is suppressive to the HPG axis, compared to other available T therapies</u>.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>FIGURE 1 | Percent change in mean gonadotropin levels (LH & FSH), from baseline through 6 months of testosterone treatment. </strong>Nasal testosterone (blue), dosed t.i.d., adapted from (15), n = 33. Topical testosterone (orange), dosed daily, adapted from (9), n = 123. IM injectable - 100 mg testosterone enanthate, (red), adapted from (10), n = 10. All changes from baseline were statistically significant. Nasal testosterone—FSH p = 0.03, all others p < 0.001. Standard error calculated using the delta method.</p><p>[ATTACH=full]42314[/ATTACH]</p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/threads/the-effect-of-longer-acting-vs-shorter-acting-trt-on-fsh-and-lh.21778/[/URL]</p><p></p><p><em>*Azoospermia and testicular atrophy result from exogenous T suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. In our prior work, a short-acting nasal gel T (Natesto, Food, and Drug Administration approved, May 2014) was shown to <strong>increase serum T, maintain gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), within the normal range, and not significantly affect semen parameters.</strong> <strong>8 <u>Unlike the dosing of other forms of exogenous T (subdermal pellets, injections, and trans-dermal gels) that provide steady delivery for 24 hours or more, </u></strong><u><strong><u>the</u> nasal gel is delivered either 2 or 3 times a day, providing discrete peaks (or pulses) in serum T levels with a return to baseline T levels between peaks. Pulsatile dosing, and more importantly, the existence of daily troughs between doses,</strong> <strong>may allow for reinitialization of the pulsatile release of gonadotropin-releasing hormone (GnRH) and therefore maintaining the production of LH and FSH. </strong></u>Because GnRH release cannot be directly measured in humans, FSH and LH are used as surrogates.9 We, therefore, hypothesized that short-acting T has a lesser effect on serum levels of gonadotropins (LH and FSH) than long-acting exogenous T.</em></p><p></p><p></p><p></p><p></p><p><strong>Table 1. Studies included in the analysis grouped by the duration of action</strong></p><p><em>[ATTACH=full]42315[/ATTACH]</em></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/threads/treating-low-testosterone-with-clomid-hcg-and-aromatase-inhibitors-a-review-of-the-data.20852/[/URL]</p><p></p><p></p><p>Some important points to keep in mind here!</p><p></p><p></p><p><strong><em>*<u>AAS can also bind the androgen receptor inside target cells</u> and bring into play the same negative feedback effects as endogenous testosterone.</em></strong></p><p></p><p><em><strong>*<u>Androgens, as well as estrogens and progestins,</u> in turn, cause negative feedback inhibition at the hypothalamus and pituitary, <u>lowering the output of gonadotropins and testosterone when too much hormone is present</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*<u>Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β </u>28. Therefore, the <u>HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis</u>, among other things.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Regulation of the secretion of GnRH, FSH, and LH occurs <u>partially by the negative feedback of testosterone and estradiol</u> at the level of the hypothalamo-pituitary. <u>Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion </u>[57–61].</strong></em></p><p><em></em></p><p><em><em><strong>*Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. <u><strong>M</strong>odalities of T therapy evolved to extend the dosing interval and maintain sustained “steady-state” T levels. Long-acting TTh can inhibit the HPG axis, which in turn suppresses pituitary LH and FSH secretion, reducing circulating levels of LH and FSH and endogenous T production</u></strong></em></em></p></blockquote><p></p>
[QUOTE="madman, post: 277512, member: 13851"] The sole purpose of the ester is to control the release rate of T from the oily depot. Esterified T is inert until it hits the bloodstream where the ester is rapidly hydrolyzed (esterase enzymes) and you are left with native/free T. [I][B]*The purpose of the ester is to control the release rate of the steroid from the oily depot and it is cleaved as soon as it hits the bloodstream releasing free testosterone.[/B][/I] [HEADING=3][I][B]*TU/TC/TE/TP (oily depot)----->ester cleaved (ECF)----->FREE TESTOSTERONE (blood)[/B][/I][/HEADING] [B][I]*"It is also important to stress the fact that[U] esters do not alter the activity of the parent steroid in any way[/U].[/I][/B][I] [B]They work only to [U]slow its release[/U]" The ester only [U]controls the release rate from the injection depot[/U].[/B][/I] [B][I]"Once free in circulation, [U]enzymes will quickly remove the ester chain[/U] and the [U]parent hormone will be free to exert its activity[/U] ([U]while the ester is present the steroid is inert[/U])"[/I][/B] [URL unfurl="true"]https://www.ncbi.nlm.nih.gov/books/NBK279000/[/URL] [HEADING=3][B]Injectable Testosterone[/B][/HEADING] [I][B]The most widely used testosterone formulation for many decades has been an intramuscular injection of testosterone esters ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/figure/andro-phys-pharm-abs.F5/?report=objectonly']figure 5[/URL]), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']653[/URL]). [U]This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into circulation[/U]. [U]The pharmacokinetics and pharmacodynamics of androgen esters are therefore primarily determined by ester side-chain length, the volume of the oil vehicle, and the site of injection via hydrophobic physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid[/U] ([URL='https://www.ncbi.nlm.nih.gov/books/NBK279000/#']654[/URL]).[/B][/I] [HEADING=2]FIGURE 5.[/HEADING] [I][B]Schematic overview of the pharmacology of testosterone esters. [/B]Testosterone is esterified through the 17 β hydroxyl group with fatty acid esters of different aliphatic or other chain lengths which is a biologically inactive pro-drug. [B]The esterified testosterone in an oil vehicle is injected deeply into a muscle forming a local drug depot from which the testosterone ester is released at a slow rate determined by its Physico-chemical partitioning according to the testosterone ester’s hydrophobicity.[/B] [B]Once the [U]testosterone ester exits the depot and enters the extracellular fluids, it is rapidly hydrolyzed by ubiquitous non-specific esterases thereby releasing the testosterone into the general circulation[/U]. [ATTACH type="full" alt="1710604039139.png"]42316[/ATTACH][/B][/I] [URL unfurl="true"]https://www.excelmale.com/threads/short-acting-t-therapy-to-maintain-homeostasis-that-more-closely-reflects-normal-physiology.22083/[/URL] [I]*The various testosterone formulations have a wide range of dosing intervals including long-acting preparations: subcutaneous pellets (3 to 6 months), injectable IM testosterone undecanoate (10 weeks); intermediate-acting preparations: IM testosterone cypionate/enanthate (1 to 3 weeks); daily preparations: topical/transdermal formulations; and short-acting preparations: oral testosterone undecanoate (twice daily) and nasal testosterone (two to three times daily).[/I] [I][B]All formulations, with the exception of the short-acting ones, have a [/B][U][B]target of long-term maintenance of sustained steady-state testosterone levels in the mid-normal range[/B][/U][B], which leads to suppression of the endogenous activity of the HPG axis.[/B][/I] [B][I]*As previously noted, testosterone levels in young healthy males follow a circadian rhythm. T levels are highest in the morning and lower in the evening hours. [U]There is significant change within a 24-h period[/U]. Testosterone itself acts as a negative feedback molecule to the hypothalamus and anterior pituitary. [/I][/B][I][U][B]When T levels are high enough, they signal to reduce GnRH, LH, and FSH secretion, thereby also reducing endogenous testosterone production. This occurs regardless of whether the circulating testosterone is endogenous or exogenous[/B][/U][B].[/B][/I][B][I][U] If high levels of testosterone are given exogenously for extended periods of time, this can result in negative feedback to the hypothalamus and anterior pituitary, disrupting normal HPG regulation[/U].[/I] *[/B][I][B]Topical gel formulations [U]achieve a sustained mid-normal T level with a once-daily application[/U] (8). While the topical gel results in [U]less fluctuation of T levels between dosing intervals when compared to IM T, the sustained T levels result in inhibition of HPG axis activity[/U] (9). T[U]he inhibition of HPG axis activity is evidenced by the nearly full suppression of gonadotropin levels following treatment with either IM injectable testosterone (10) or topical gel administration[/U] (9).[/B] [B][U]Nasal administration of T (4.5% testosterone nasal gel, Natesto) allows for rapid absorption through the nasal mucosa such that serum T levels reach a peak concentration in ∼40 min[/U]. [U]Once in the circulation, the T is quickly metabolized, with a return to near baseline T levels in 3–6 h[/U][/B] [B](11). Therefore, multiple administrations of nasal T throughout the day (three times daily) maintain normal mean serum T levels over 24 h. [U]The fluctuations in T levels potentially minimize the duration of exposure to exogenous T that is suppressive to the HPG axis, compared to other available T therapies[/U].[/B][/I] [B]FIGURE 1 | Percent change in mean gonadotropin levels (LH & FSH), from baseline through 6 months of testosterone treatment. [/B]Nasal testosterone (blue), dosed t.i.d., adapted from (15), n = 33. Topical testosterone (orange), dosed daily, adapted from (9), n = 123. IM injectable - 100 mg testosterone enanthate, (red), adapted from (10), n = 10. All changes from baseline were statistically significant. Nasal testosterone—FSH p = 0.03, all others p < 0.001. Standard error calculated using the delta method. [ATTACH type="full" alt="1710603241732.png"]42314[/ATTACH] [URL unfurl="true"]https://www.excelmale.com/threads/the-effect-of-longer-acting-vs-shorter-acting-trt-on-fsh-and-lh.21778/[/URL] [I]*Azoospermia and testicular atrophy result from exogenous T suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. In our prior work, a short-acting nasal gel T (Natesto, Food, and Drug Administration approved, May 2014) was shown to [B]increase serum T, maintain gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), within the normal range, and not significantly affect semen parameters.[/B] [B]8 [U]Unlike the dosing of other forms of exogenous T (subdermal pellets, injections, and trans-dermal gels) that provide steady delivery for 24 hours or more, [/U][/B][U][B][U]the[/U] nasal gel is delivered either 2 or 3 times a day, providing discrete peaks (or pulses) in serum T levels with a return to baseline T levels between peaks. Pulsatile dosing, and more importantly, the existence of daily troughs between doses,[/B] [B]may allow for reinitialization of the pulsatile release of gonadotropin-releasing hormone (GnRH) and therefore maintaining the production of LH and FSH. [/B][/U]Because GnRH release cannot be directly measured in humans, FSH and LH are used as surrogates.9 We, therefore, hypothesized that short-acting T has a lesser effect on serum levels of gonadotropins (LH and FSH) than long-acting exogenous T.[/I] [B]Table 1. Studies included in the analysis grouped by the duration of action[/B] [I][ATTACH type="full" alt="1710603515508.png"]42315[/ATTACH][/I] [URL unfurl="true"]https://www.excelmale.com/threads/treating-low-testosterone-with-clomid-hcg-and-aromatase-inhibitors-a-review-of-the-data.20852/[/URL] Some important points to keep in mind here! [B][I]*[U]AAS can also bind the androgen receptor inside target cells[/U] and bring into play the same negative feedback effects as endogenous testosterone.[/I][/B] [I][B]*[U]Androgens, as well as estrogens and progestins,[/U] in turn, cause negative feedback inhibition at the hypothalamus and pituitary, [U]lowering the output of gonadotropins and testosterone when too much hormone is present[/U]. *[U]Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β [/U]28. Therefore, the [U]HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis[/U], among other things. *Regulation of the secretion of GnRH, FSH, and LH occurs [U]partially by the negative feedback of testosterone and estradiol[/U] at the level of the hypothalamo-pituitary. [U]Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion [/U][57–61].[/B] [I][B]*Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. [U][B]M[/B]odalities of T therapy evolved to extend the dosing interval and maintain sustained “steady-state” T levels. Long-acting TTh can inhibit the HPG axis, which in turn suppresses pituitary LH and FSH secretion, reducing circulating levels of LH and FSH and endogenous T production[/U][/B][/I][/I] [/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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