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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Official Natesto Thread
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<blockquote data-quote="madman" data-source="post: 213539" data-attributes="member: 13851"><p>When it comes to dosing (BID/TID) it is critical that doses are taken 6 hours apart which would ensure a long enough trough time that minimizes suppression of the HPG-axis.</p><p></p><p>Keep in mind that most are hitting short-lived peaks in TT <1000 ng/dL.</p><p></p><p></p><p></p><p><strong>Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels (2019)</strong></p><p></p><p></p><p><em><strong>*TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period</strong></em></p><p></p><p><strong><em>*The 24-hour PK profile of testosterone for patients receiving TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur, on average, every 2 hours. <u>A maximal peak of testosterone appears at about 1 hour, followed by a return to endogenous, predose levels 4 to 6 hours later (half-life ∼1 hour)</u> [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib4" target="_blank">4</a>]. The nadir (trough) between doses correlates well with pretreatment endogenous levels at diagnosis</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*The unique, pulsatile PK profile is believed to have limited impact on the hypothalamic-pituitary-gonadal (HPG) axis, with <u>substantial trough time preserving LH, FSH, and endogenous testosterone production, and sperm counts</u> [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib16" target="_blank">16</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib17" target="_blank">17</a>], while also limiting excess red blood cell production, estradiol, DHT, and prostate-specific antigen levels in clinical trials [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib4" target="_blank">4</a>]</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*<u>TNG maintains the endogenous HPG axis</u>. This is clearly evident in single-dose PK profiles in healthy men and those with TDS for whom the predose value (t = 0), which corresponds to the patient’s endogenous TT level, was found again at the bottom of the trough between peaks and was maintained through 90 days of treatment (for twice- and thrice-daily doses). Additional evidence of active HPG when receiving TNG treatment is found in a recent trial showing unchanged sperm counts after 6 months of TNG treatment (thrice-daily dose only) [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib17" target="_blank">17</a>]. In larger trials, LH and FSH measurements were made proximal to a peak of TNG and were somewhat depressed, but they remained in the normal range [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib16" target="_blank">16</a>]. Our interpretation of these observations is that the <u>HPG axis is active and there is temporal suppression when TNG doses are administered</u>. <u>This suppression appears to recover completely, on the basis of consistent trough values over time</u></em></strong></p><p><strong><em></em></strong></p><p><strong><em>*<u>In fact, the observed PK profile after a TNG dose is a sum of all sources of testosterone</u> [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib20" target="_blank">20</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib21" target="_blank">21</a>]; exogenous and endogenous sources were not independently quantifiable in this study. <u>When exogenous testosterone was administered, there was a suppression of LH and testosterone production. Endogenous testosterone levels decreased as a result of ongoing elimination and reduced or halted production</u>. <u>Later (>1 hour after administration), as the exogenous testosterone absorption rate was reduced and elimination predominated, resulting in a drop in exogenous testosterone, the HPG recovered, reinitiating endogenous testosterone production</u> (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/figure/fig6/" target="_blank">Fig. 6a</a>). The degree of HPG suppression appeared to be proportional to the initial baseline TT. For patients with less severe hypogonadism with a supposedly more active HPG and higher baseline TT level, there was more endogenous testosterone suppression during each dose than for a patient with more severe hypogonadism with less HPG axis potential (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/figure/fig6/" target="_blank">Fig. 6b</a>). This model is supported by the larger decreases in LH in patients with higher baseline TT concentration seen in this study.<u> It should be noted that in the Rogol <em>et al.</em> study [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib15" target="_blank">15</a>], administration of TNG to healthy men with a predose TT baseline of 534 ng/dL (18.4 nmol/L) also showed Cmax peak levels in the same range as seen in this study and again a return to predose baseline nearly 6 hours after a dose</u></em></strong></p><p></p><p>[ATTACH=full]18559[/ATTACH]</p><p>[ATTACH=full]18560[/ATTACH]</p><p></p><p><strong><em>*Thus, <u>TNG’s ultradian profile is the means to maintain an active HPG</u>. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes</em></strong></p><p> </p><p><em><strong>*<u>Thus, an ultradian, pulsatile PK profile allows maintenance of the endogenous feedback mechanism when treated with TNG, which serves multiple purposes</u>. First, very high peaks of TT are only rarely observed [3.3% of patients had a Cmax of 1800 to 2500 ng/dL (63.0 to 87.0 nmol/L) in the phase 3 study], because the active feedback mechanism provides a control mechanism keeping the TT levels in check. <u>Second, troughs between peaks reduce overall exposure, helping to limit adverse effects of testosterone treatment, such as hematocrit overproduction (no patients had hematocrit values ≥54% in either the phase 3 or phase 4 studies)</u> [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib22" target="_blank">22</a>]. <u>Third, troughs allow for the secretion of gonadotropins that maintain active testicular testosterone production, as well as sperm</u>.<u> Last, as shown here, the combination of peaks and troughs is sufficient to achieve symptom efficacy even for patients with the most severe TDS in this study</u>. Overall, there are positive benefits to a treatment approach that is compatible with HPG physiology</strong></em></p><p></p><p><strong><em>*TNG treatment restores TT levels while preserving important aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels</em></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></p><p><strong></strong></p><p><strong></strong></p><p><strong>NATESTO® Product Monograph </strong></p><p><strong></strong></p><p><strong>Dosing Considerations </strong></p><p><em>NATESTO is a testosterone nasal gel available in a dispenser with a metered-dose pump. One pump actuation delivers 5.5 mg of testosterone per nostril. Each dose is applied as two actuations (one per nostril), for a total dose of 11.0 mg. <u>NATESTO is dosed either two or three times daily</u>. </em></p><p></p><p></p><p><strong>Recommended Dose and Dosage Adjustment </strong></p><p><em>The recommended starting dose of NATESTO (testosterone) is <u>11.0 mg of testosterone (1 actuation per nostril) administered intranasally twice daily for a total daily dose of 22.0 mg</u>.</em></p><p></p><p><strong>The NATESTO dose can be increased to a maximum recommended dose of 11.0 mg three times daily (33mg total daily dose) if either of the following conditions are met: </strong></p><p><strong></strong></p><p><strong>1)</strong> <em>a serum total testosterone from a single blood draw sample taken 20 minutes to 2 hours after a morning application of NATESTO is less than 300 ng/dL.</em></p><p></p><p><strong>2)</strong> <em>if symptoms are not adequately treated within 90 days.</em></p><p></p><p></p><p><strong>Serum total testosterone concentrations should be checked periodically: </strong></p><p></p><p>• <em>If the measured serum total testosterone concentration from the single morning blood draw is less than 300 ng/dL, the daily dose of NATESTO may be increased to 33.0 mg daily;</em></p><p></p><p>• <em>For patients on the maximum recommended dose and whose serum total testosterone concentration from the single morning blood draw is consistently less than 300 ng/dL and a desired clinical response is not achieved, NATESTO should be discontinued and an alternative treatment should be considered.</em></p><p></p><p><strong>If a post-dose morning total testosterone concentration consistently exceeds 1050 ng/dL, NATESTO should be discontinued.</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Missed Dose </strong></p><p><em>If a dose is missed, patients are instructed to skip the dose and take their next scheduled dose.</em></p><p></p><p><strong>Administration </strong></p><p><em><u>For twice daily, NATESTO is administered once in the morning and once in the evening (at least 6 hours from the prior dose and at least 1 hour before laying down for bed), preferably at the same time each day</u>. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose. <u>For three times daily, NATESTO is administered intranasally once in the morning, once in the afternoon and once in the evening (approximately 6-8 hours apart and at least 1 hour before laying down for bed), preferably at the same time each day</u>. Do not administer NATESTO to other parts of the body including the scrotum, penis, abdomen, shoulders, axilla, or upper arms.</em></p><p></p><p></p><p></p><p></p><p><strong>Figure 1: <u>Mean Serum Total Testosterone Concentrations on Day 90</u> in Patients Following NATESTO 22.0 mg Daily Administered at 9 p.m. and 7 a.m. (N=122) and 33.0 mg Daily Administered at 9 p.m., 7 a.m. and 1 p.m. (N=151)</strong></p><p>[ATTACH=full]18558[/ATTACH]</p><p></p><p></p><p></p><p></p><p><strong>Adult dose:</strong> <u><em>The recommended starting therapy is two doses (1 dose = 1 actuation per nostril) per day for a total of 22 mg</em></u><em>. Each actuation contains 5.5 mg of testosterone. Your dose may be increased by your healthcare professional to 33 mg/day applied in three doses (1 dose = 1 actuation per nostril). <u>Doses must be at least 6 hours apart</u>. The night dose should be taken at least 1 hour before laying down for bed.</em></p><p>[ATTACH=full]18557[/ATTACH]</p><p></p><p><em><strong>*</strong>TNG 4.5% testosterone nasal gel (Natesto®; Acerus Pharmaceuticals Corporation, Mississauga, Ontario, Canada) is a thixotropic gel that is applied in the nasal cavity [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib13" target="_blank">13</a>]. <strong>Testosterone levels or symptoms are used to guide titration decisions [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib13" target="_blank">13</a>] between either twice- or thrice-daily doses used to restore testosterone levels to the normal range. </strong>Surprisingly, patients report higher convenience with TNG than with once-daily topical gels [<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib14" target="_blank">14</a>].</em></p></blockquote><p></p>
[QUOTE="madman, post: 213539, member: 13851"] When it comes to dosing (BID/TID) it is critical that doses are taken 6 hours apart which would ensure a long enough trough time that minimizes suppression of the HPG-axis. Keep in mind that most are hitting short-lived peaks in TT <1000 ng/dL. [B]Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels (2019)[/B] [I][B]*TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period[/B][/I] [B][I]*The 24-hour PK profile of testosterone for patients receiving TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur, on average, every 2 hours. [U]A maximal peak of testosterone appears at about 1 hour, followed by a return to endogenous, predose levels 4 to 6 hours later (half-life ∼1 hour)[/U] [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib4']4[/URL]]. The nadir (trough) between doses correlates well with pretreatment endogenous levels at diagnosis *The unique, pulsatile PK profile is believed to have limited impact on the hypothalamic-pituitary-gonadal (HPG) axis, with [U]substantial trough time preserving LH, FSH, and endogenous testosterone production, and sperm counts[/U] [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib16']16[/URL], [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib17']17[/URL]], while also limiting excess red blood cell production, estradiol, DHT, and prostate-specific antigen levels in clinical trials [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib4']4[/URL]] *[U]TNG maintains the endogenous HPG axis[/U]. This is clearly evident in single-dose PK profiles in healthy men and those with TDS for whom the predose value (t = 0), which corresponds to the patient’s endogenous TT level, was found again at the bottom of the trough between peaks and was maintained through 90 days of treatment (for twice- and thrice-daily doses). Additional evidence of active HPG when receiving TNG treatment is found in a recent trial showing unchanged sperm counts after 6 months of TNG treatment (thrice-daily dose only) [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib17']17[/URL]]. In larger trials, LH and FSH measurements were made proximal to a peak of TNG and were somewhat depressed, but they remained in the normal range [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib16']16[/URL]]. Our interpretation of these observations is that the [U]HPG axis is active and there is temporal suppression when TNG doses are administered[/U]. [U]This suppression appears to recover completely, on the basis of consistent trough values over time[/U] *[U]In fact, the observed PK profile after a TNG dose is a sum of all sources of testosterone[/U] [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib20']20[/URL], [URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib21']21[/URL]]; exogenous and endogenous sources were not independently quantifiable in this study. [U]When exogenous testosterone was administered, there was a suppression of LH and testosterone production. Endogenous testosterone levels decreased as a result of ongoing elimination and reduced or halted production[/U]. [U]Later (>1 hour after administration), as the exogenous testosterone absorption rate was reduced and elimination predominated, resulting in a drop in exogenous testosterone, the HPG recovered, reinitiating endogenous testosterone production[/U] ([URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/figure/fig6/']Fig. 6a[/URL]). The degree of HPG suppression appeared to be proportional to the initial baseline TT. For patients with less severe hypogonadism with a supposedly more active HPG and higher baseline TT level, there was more endogenous testosterone suppression during each dose than for a patient with more severe hypogonadism with less HPG axis potential ([URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/figure/fig6/']Fig. 6b[/URL]). This model is supported by the larger decreases in LH in patients with higher baseline TT concentration seen in this study.[U] It should be noted that in the Rogol [I]et al.[/I] study [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib15']15[/URL]], administration of TNG to healthy men with a predose TT baseline of 534 ng/dL (18.4 nmol/L) also showed Cmax peak levels in the same range as seen in this study and again a return to predose baseline nearly 6 hours after a dose[/U][/I][/B] [ATTACH type="full" alt="1639591493335.png"]18559[/ATTACH] [ATTACH type="full" alt="1639591529599.png"]18560[/ATTACH] [B][I]*Thus, [U]TNG’s ultradian profile is the means to maintain an active HPG[/U]. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes[/I][/B] [I][B]*[U]Thus, an ultradian, pulsatile PK profile allows maintenance of the endogenous feedback mechanism when treated with TNG, which serves multiple purposes[/U]. First, very high peaks of TT are only rarely observed [3.3% of patients had a Cmax of 1800 to 2500 ng/dL (63.0 to 87.0 nmol/L) in the phase 3 study], because the active feedback mechanism provides a control mechanism keeping the TT levels in check. [U]Second, troughs between peaks reduce overall exposure, helping to limit adverse effects of testosterone treatment, such as hematocrit overproduction (no patients had hematocrit values ≥54% in either the phase 3 or phase 4 studies)[/U] [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib22']22[/URL]]. [U]Third, troughs allow for the secretion of gonadotropins that maintain active testicular testosterone production, as well as sperm[/U].[U] Last, as shown here, the combination of peaks and troughs is sufficient to achieve symptom efficacy even for patients with the most severe TDS in this study[/U]. Overall, there are positive benefits to a treatment approach that is compatible with HPG physiology[/B][/I] [B][I]*TNG treatment restores TT levels while preserving important aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels[/I] NATESTO® Product Monograph Dosing Considerations [/B] [I]NATESTO is a testosterone nasal gel available in a dispenser with a metered-dose pump. One pump actuation delivers 5.5 mg of testosterone per nostril. Each dose is applied as two actuations (one per nostril), for a total dose of 11.0 mg. [U]NATESTO is dosed either two or three times daily[/U]. [/I] [B]Recommended Dose and Dosage Adjustment [/B] [I]The recommended starting dose of NATESTO (testosterone) is [U]11.0 mg of testosterone (1 actuation per nostril) administered intranasally twice daily for a total daily dose of 22.0 mg[/U].[/I] [B]The NATESTO dose can be increased to a maximum recommended dose of 11.0 mg three times daily (33mg total daily dose) if either of the following conditions are met: 1)[/B] [I]a serum total testosterone from a single blood draw sample taken 20 minutes to 2 hours after a morning application of NATESTO is less than 300 ng/dL.[/I] [B]2)[/B] [I]if symptoms are not adequately treated within 90 days.[/I] [B]Serum total testosterone concentrations should be checked periodically: [/B] • [I]If the measured serum total testosterone concentration from the single morning blood draw is less than 300 ng/dL, the daily dose of NATESTO may be increased to 33.0 mg daily;[/I] • [I]For patients on the maximum recommended dose and whose serum total testosterone concentration from the single morning blood draw is consistently less than 300 ng/dL and a desired clinical response is not achieved, NATESTO should be discontinued and an alternative treatment should be considered.[/I] [B]If a post-dose morning total testosterone concentration consistently exceeds 1050 ng/dL, NATESTO should be discontinued. Missed Dose [/B] [I]If a dose is missed, patients are instructed to skip the dose and take their next scheduled dose.[/I] [B]Administration [/B] [I][U]For twice daily, NATESTO is administered once in the morning and once in the evening (at least 6 hours from the prior dose and at least 1 hour before laying down for bed), preferably at the same time each day[/U]. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose. [U]For three times daily, NATESTO is administered intranasally once in the morning, once in the afternoon and once in the evening (approximately 6-8 hours apart and at least 1 hour before laying down for bed), preferably at the same time each day[/U]. Do not administer NATESTO to other parts of the body including the scrotum, penis, abdomen, shoulders, axilla, or upper arms.[/I] [B]Figure 1: [U]Mean Serum Total Testosterone Concentrations on Day 90[/U] in Patients Following NATESTO 22.0 mg Daily Administered at 9 p.m. and 7 a.m. (N=122) and 33.0 mg Daily Administered at 9 p.m., 7 a.m. and 1 p.m. (N=151)[/B] [ATTACH type="full" alt="1639588804665.png"]18558[/ATTACH] [B]Adult dose:[/B] [U][I]The recommended starting therapy is two doses (1 dose = 1 actuation per nostril) per day for a total of 22 mg[/I][/U][I]. Each actuation contains 5.5 mg of testosterone. Your dose may be increased by your healthcare professional to 33 mg/day applied in three doses (1 dose = 1 actuation per nostril). [U]Doses must be at least 6 hours apart[/U]. The night dose should be taken at least 1 hour before laying down for bed.[/I] [ATTACH type="full" alt="1639588135830.png"]18557[/ATTACH] [I][B]*[/B]TNG 4.5% testosterone nasal gel (Natesto®; Acerus Pharmaceuticals Corporation, Mississauga, Ontario, Canada) is a thixotropic gel that is applied in the nasal cavity [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib13']13[/URL]]. [B]Testosterone levels or symptoms are used to guide titration decisions [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib13']13[/URL]] between either twice- or thrice-daily doses used to restore testosterone levels to the normal range. [/B]Surprisingly, patients report higher convenience with TNG than with once-daily topical gels [[URL='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694041/#bib14']14[/URL]].[/I] [/QUOTE]
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Official Natesto Thread
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