ExcelMale
Menu
Home
What's new
Latest activity
Forums
New posts
Search forums
What's new
New posts
Latest activity
Videos
Lab Tests
Doctor Finder
Buy Books
About Us
Men’s Health Coaching
Log in
Register
What's new
Search
Search
Search titles only
By:
New posts
Search forums
Menu
Log in
Register
Navigation
Install the app
Install
More options
Contact us
Close Menu
Forums
Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Official Natesto Thread
JavaScript is disabled. For a better experience, please enable JavaScript in your browser before proceeding.
You are using an out of date browser. It may not display this or other websites correctly.
You should upgrade or use an
alternative browser
.
Reply to thread
Message
<blockquote data-quote="madman" data-source="post: 217751" data-attributes="member: 13851"><p>The main advantage of Natesto is that it will be the least suppressive on the HPGA due to its short-acting nature.</p><p></p><p>Short-lived peaks (60 min) with significant trough (4-6 hrs) time between doses.</p><p></p><p>Let alone there is no steady-state.</p><p></p><p>Much better chance of maintaining fertility let alone minimizing any potential side effects.</p><p></p><p>Injections result in sustained steady-state T levels and in most cases well beyond the mid-normal of the physiological range.</p><p></p><p>This will result in having a significant impact on suppression of the HPGA let alone increase RBCs/hemoglobin/hematocrit and can lead to various other side effects.</p><p></p><p></p><p></p><p><em><strong>*Compared with other routes of T delivery, <u>nasal T gel administration results in rather low Cavg and Cmax TT levels, as well as DHT and DHT: T ratios</u>, even with administering 11 mg three times daily</strong></em></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/short-acting-t-therapy-to-maintain-homeostasis-that-more-closely-reflects-normal-physiology.22083/[/URL]</p><p></p><p><strong>TESTOSTERONE PHARMACOKINETICS</strong></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).<strong> <em>All formulations, with the exception of the short-acting ones, have a target of long-term maintenance of sustained steady-state testosterone levels in the mid-normal range,</em></strong> <strong>which leads to suppression of the endogenous activity of the HPG axis.</strong></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><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. <strong>There is significant change within a 24-h period. </strong>Testosterone itself acts as a negative feedback molecule to the hypothalamus and anterior pituitary. <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> <strong>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.</strong></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em></em></p><p><em>Topical gel formulations achieve a sustained mid-normal T level with a once-daily application (8). While the topical gel results in less fluctuation of T levels between dosing intervals when compared to IM T, the sustained T levels result in inhibition of HPG axis activity (9). The 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 (9). <strong>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. Once in the circulation, the T is quickly metabolized, with a return to near baseline T levels in 3–6 h</strong> (11). Therefore, multiple administrations of nasal T throughout the day (three times daily) maintain normal mean serum T levels over 24 h. <strong>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.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>FINAL THOUGHTS</strong></p><p><strong></strong></p><p><strong><em>Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. Modalities 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 (Figure 1). </em></strong><em><strong><u>These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects</u>.</strong> The detrimental impact on sperm production from these long-acting testosterone therapies led to the use of many off-label products. The use of clomiphene citrate to stimulate gonadotropin production and subsequently increase testosterone levels is used to treat hypogonadism, while also trying to preserve fertility.</em></p><p><em></em></p><p><em><strong><u>Short-acting T therapy, consisting of several doses of T with a shorter half-life throughout the day, minimizes inhibition of the HPG axis and reduces the impairment of spermatogenesis</u>. Utilizing FDA approved, shorter-acting forms of T therapy to maintain homeostasis that more closely reflects normal physiology offers great promise for the treatment of men with hypogonadism—an advantage over long-acting formulations. </strong>This therapy would allow the use of FDA-approved testosterone supplementation exogenously as opposed to using off-label treatment strategies, while also preserving what fertility the treated subject has. Support of this hypothesis is needed from additional, longer-duration studies utilizing short-acting testosterone. However, it is encouraging that studies performed to date tend to support the hypothesis. <strong>The literature is well established that long-acting testosterone results in HPG suppression and resulting changes in physiology. Short-acting T therapy may be paradigm-changing for the treatment of T deficiency.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>[ATTACH=full]19791[/ATTACH]</strong></em></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/impact-of-short-acting-vs-long-acting-t-therapy-on-itt.23062/[/URL]</p><p></p><p><strong>Conclusions</strong></p><p><strong></strong></p><p><strong><em>Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T that is critical for maintaining spermatogenesis. The differential effects of TRT on intratesticular T based on their half-lives is novel and should be considered during the decision-making for hypogonadal men who wish to preserve fertility and/or testis size.</em></strong></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/the-effect-of-longer-acting-vs-shorter-acting-trt-on-fsh-and-lh.21778/[/URL]</p><p></p><p><strong>Conclusion</strong></p><p><strong></strong></p><p><strong><em>Our analyses support that long-acting Ts may have greater suppression of FSH and LH than shorter-acting formulations.</em></strong> <strong><em>However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into differences in side effects, such as fertility and testis volume.</em></strong></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/natesto-unique-approach-to-treating-low-t.23641/[/URL]</p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/pk-of-tth-and-diurnal-variation-of-testosterone.24117/[/URL]</p><p></p><p><em>A variety of exogenous TTh are available to increase serum T to physiologic levels in males with TD and may alleviate symptoms associated with TD.2<strong> Some T replacement options more closely mimic the circadian levels of T identified in older men, whereas other options seem to provide PK profiles closer to those of younger men (Fig. 1 [Please put figure as close as possible to this callout] and Table 1)</strong>. <strong>Some TTh options provide profiles that exceed the frequency of the natural T circadian rhythmicity.</strong></em></p><p><em></em></p><p><em>Once-weekly SC TE injections bring mean T levels into the physiologic range within 24 hours after the first dose, with a total T Cmax/Cmin ratio of 1.8. The PK profile appears to mimic the flatter profile of older males’ endogenous T.95 IM T injections can cause both supratherapeutic T levels post-injection and subtherapeutic levels during the dosing interval, and depending on the formulation and dosage, peak-to-trough ratios of IM TC and TE range between 2 and 5.3. Longer-lasting TU injections do not demonstrate the supratherapeutic peaks of other IM formulations, with trough levels occurring at later time points after each injection and a peak-to-trough ratio of approximately 2.6 to 2.8. All IM TTh preparations result in PK profiles that are unlike those of the normal diurnal variation of healthy young or older men.</em></p><p><em></em></p><p><em>Daily transdermal gels and solutions, and nasal and oral T products, provide a consistent serum T level within the physiologic range in most patients. The daily dosing frequency of the topical gel products results in a PK profile with a resemblance to that of endogenous T in younger males.</em></p><p><em></em></p><p><em><strong>Men using nasal and oral T products are able to achieve mean serum T levels that are within the normal range, but they experience several T peaks and troughs throughout the day because of the multiple daily dosing regimens required (2 or 3 times/day). <u>This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*No single formulation appears to provide an exposure profile that would resemble diurnal variation of both young and older men.</strong></em></p><p><em></em></p><p><em>*The importance of diurnal variation of endogenous T is not fully understood, but there may be additional factors (eg, sleep quality and duration) that may influence endogenous T levels.96 However, further clarification is needed for the association between the circadian timing of sleep loss and its effect on T levels.</em></p><p></p><p></p><p><strong>5. Conclusion</strong></p><p></p><p><em><strong>With TTh, serum T may be returned to levels within the normal physiologic range, and symptoms associated with low T may be improved. However, no TTh product precisely simulates the endogenous diurnal T variation observed in young and older men, and more clarification is needed on the impact of the variability in the range between peak and trough exposure with each different TTh.</strong></em></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/high-hematocrit-prevalence-with-intranasal-vs-intramuscular-testosterone.21467/[/URL]</p><p></p><p><strong>Conclusions</strong></p><p></p><p><em><strong>The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received testosterone cypionate injections.</strong></em><strong> <em>Given that the most frequent adverse effect of TRT is the resulting polycythemia, Natesto could be a potential option if this is a concern, although larger prospective studies with age-matched cohorts are needed to validate the finding in our cross-sectional study.</em></strong></p></blockquote><p></p>
[QUOTE="madman, post: 217751, member: 13851"] The main advantage of Natesto is that it will be the least suppressive on the HPGA due to its short-acting nature. Short-lived peaks (60 min) with significant trough (4-6 hrs) time between doses. Let alone there is no steady-state. Much better chance of maintaining fertility let alone minimizing any potential side effects. Injections result in sustained steady-state T levels and in most cases well beyond the mid-normal of the physiological range. This will result in having a significant impact on suppression of the HPGA let alone increase RBCs/hemoglobin/hematocrit and can lead to various other side effects. [I][B]*Compared with other routes of T delivery, [U]nasal T gel administration results in rather low Cavg and Cmax TT levels, as well as DHT and DHT: T ratios[/U], even with administering 11 mg three times daily[/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/short-acting-t-therapy-to-maintain-homeostasis-that-more-closely-reflects-normal-physiology.22083/[/URL] [B]TESTOSTERONE PHARMACOKINETICS[/B] [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).[B] [I]All formulations, with the exception of the short-acting ones, have a target of long-term maintenance of sustained steady-state testosterone levels in the mid-normal range,[/I][/B] [B]which leads to suppression of the endogenous activity of the HPG axis.[/B] *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. [B]There is significant change within a 24-h period. [/B]Testosterone itself acts as a negative feedback molecule to the hypothalamus and anterior pituitary. [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] [B]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.[/B] Topical gel formulations achieve a sustained mid-normal T level with a once-daily application (8). While the topical gel results in less fluctuation of T levels between dosing intervals when compared to IM T, the sustained T levels result in inhibition of HPG axis activity (9). The 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 (9). [B]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. Once in the circulation, the T is quickly metabolized, with a return to near baseline T levels in 3–6 h[/B] (11). Therefore, multiple administrations of nasal T throughout the day (three times daily) maintain normal mean serum T levels over 24 h. [B]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.[/B][/I] [B]FINAL THOUGHTS [I]Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. Modalities 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 (Figure 1). [/I][/B][I][B][U]These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects[/U].[/B] The detrimental impact on sperm production from these long-acting testosterone therapies led to the use of many off-label products. The use of clomiphene citrate to stimulate gonadotropin production and subsequently increase testosterone levels is used to treat hypogonadism, while also trying to preserve fertility. [B][U]Short-acting T therapy, consisting of several doses of T with a shorter half-life throughout the day, minimizes inhibition of the HPG axis and reduces the impairment of spermatogenesis[/U]. Utilizing FDA approved, shorter-acting forms of T therapy to maintain homeostasis that more closely reflects normal physiology offers great promise for the treatment of men with hypogonadism—an advantage over long-acting formulations. [/B]This therapy would allow the use of FDA-approved testosterone supplementation exogenously as opposed to using off-label treatment strategies, while also preserving what fertility the treated subject has. Support of this hypothesis is needed from additional, longer-duration studies utilizing short-acting testosterone. However, it is encouraging that studies performed to date tend to support the hypothesis. [B]The literature is well established that long-acting testosterone results in HPG suppression and resulting changes in physiology. Short-acting T therapy may be paradigm-changing for the treatment of T deficiency. [ATTACH type="full" alt="Screenshot (10992).png"]19791[/ATTACH][/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/impact-of-short-acting-vs-long-acting-t-therapy-on-itt.23062/[/URL] [B]Conclusions [I]Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T that is critical for maintaining spermatogenesis. The differential effects of TRT on intratesticular T based on their half-lives is novel and should be considered during the decision-making for hypogonadal men who wish to preserve fertility and/or testis size.[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/the-effect-of-longer-acting-vs-shorter-acting-trt-on-fsh-and-lh.21778/[/URL] [B]Conclusion [I]Our analyses support that long-acting Ts may have greater suppression of FSH and LH than shorter-acting formulations.[/I][/B] [B][I]However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into differences in side effects, such as fertility and testis volume.[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/natesto-unique-approach-to-treating-low-t.23641/[/URL] [URL unfurl="true"]https://www.excelmale.com/forum/threads/pk-of-tth-and-diurnal-variation-of-testosterone.24117/[/URL] [I]A variety of exogenous TTh are available to increase serum T to physiologic levels in males with TD and may alleviate symptoms associated with TD.2[B] Some T replacement options more closely mimic the circadian levels of T identified in older men, whereas other options seem to provide PK profiles closer to those of younger men (Fig. 1 [Please put figure as close as possible to this callout] and Table 1)[/B]. [B]Some TTh options provide profiles that exceed the frequency of the natural T circadian rhythmicity.[/B] Once-weekly SC TE injections bring mean T levels into the physiologic range within 24 hours after the first dose, with a total T Cmax/Cmin ratio of 1.8. The PK profile appears to mimic the flatter profile of older males’ endogenous T.95 IM T injections can cause both supratherapeutic T levels post-injection and subtherapeutic levels during the dosing interval, and depending on the formulation and dosage, peak-to-trough ratios of IM TC and TE range between 2 and 5.3. Longer-lasting TU injections do not demonstrate the supratherapeutic peaks of other IM formulations, with trough levels occurring at later time points after each injection and a peak-to-trough ratio of approximately 2.6 to 2.8. All IM TTh preparations result in PK profiles that are unlike those of the normal diurnal variation of healthy young or older men. Daily transdermal gels and solutions, and nasal and oral T products, provide a consistent serum T level within the physiologic range in most patients. The daily dosing frequency of the topical gel products results in a PK profile with a resemblance to that of endogenous T in younger males. [B]Men using nasal and oral T products are able to achieve mean serum T levels that are within the normal range, but they experience several T peaks and troughs throughout the day because of the multiple daily dosing regimens required (2 or 3 times/day). [U]This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients[/U]. *No single formulation appears to provide an exposure profile that would resemble diurnal variation of both young and older men.[/B] *The importance of diurnal variation of endogenous T is not fully understood, but there may be additional factors (eg, sleep quality and duration) that may influence endogenous T levels.96 However, further clarification is needed for the association between the circadian timing of sleep loss and its effect on T levels.[/I] [B]5. Conclusion[/B] [I][B]With TTh, serum T may be returned to levels within the normal physiologic range, and symptoms associated with low T may be improved. However, no TTh product precisely simulates the endogenous diurnal T variation observed in young and older men, and more clarification is needed on the impact of the variability in the range between peak and trough exposure with each different TTh.[/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/high-hematocrit-prevalence-with-intranasal-vs-intramuscular-testosterone.21467/[/URL] [B]Conclusions[/B] [I][B]The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received testosterone cypionate injections.[/B][/I][B] [I]Given that the most frequent adverse effect of TRT is the resulting polycythemia, Natesto could be a potential option if this is a concern, although larger prospective studies with age-matched cohorts are needed to validate the finding in our cross-sectional study.[/I][/B] [/QUOTE]
Insert quotes…
Verification
Post reply
Share this page
Facebook
X (Twitter)
Reddit
Pinterest
Tumblr
WhatsApp
Email
Share
Link
Sponsors
Forums
Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Official Natesto Thread
This site uses cookies to help personalise content, tailor your experience and to keep you logged in if you register.
By continuing to use this site, you are consenting to our use of cookies.
Accept
Learn more…
Top