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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Who Started TRT w/ "Normal" Levels @ What Age?
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<blockquote data-quote="madman" data-source="post: 220324" data-attributes="member: 13851"><p>If anything that title would go to transdermal (T-patch) or topicals (once daily in the am).</p><p></p><p> <em>*<strong>In 34 men from a multicenter, phase 3 study of a transdermal T patch system for TD, nightly applications of 2 patches (5.0 mg/day) resulted in <u>peak levels occurring in the morning after application and decreasing slowly until system removal, mimicking the circadian patterns reported in healthy, young men</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Similar to the 2.5 mg/day and 5.0 mg/day systems, peak T levels occurred 8 hours post-application, mimicking diurnal variation when the patch is applied at night.</strong></em></p><p></p><p></p><p></p><p></p><p>Definitely not that oral T.</p><p></p><p><em><strong><em><strong>*As oral TU is given twice daily, there were <u>2 serum T peaks</u> between 20.8 and 24.3 nmol/L (600 and 700 ng/dL) approximately 4 hours after administration, <u>2 sub-therapeutic troughs</u> (<6.9 nmol/L or <200 ng/dL) 12 hours after administration, and a peak-to-trough ratio approaching 4</strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong>*Men using nasal and oral T products are able to achieve mean serum T levels that are within the normal range,<em><strong><em><strong> <u>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>. <u>This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients</u></strong></em></strong></em></strong></em></strong></em></p><p></p><p></p><p></p><p></p><p>Even then keep in mind many using transdermal tend to prefer the creams applied twice daily (am/pm) over the standard gels applied once daily in the am.</p><p></p><p><em><strong>*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</strong></em></p><p></p><p>Applying creams twice daily in no way mimics the natural 24 hr circadian rhythm of a healthy young male let alone even when applied once daily some men are still hitting really high FT levels post >12 hrs (look over Nelson's threads)!</p><p></p><p>Top it off that many using the creams are running absurdly high TT/FT levels well above what they were producing in their prime!</p><p></p><p></p><p></p><p></p><p><a href="https://www.excelmale.com/forum/threads/pk-of-tth-and-diurnal-variation-of-testosterone.24117/" target="_blank">PK of TTh and Diurnal Variation of Testosterone</a></p><p></p><p><strong>3.4 Transdermal T patch</strong></p><p></p><p><em><strong>The FDA originally approved ANDRODERM®, 51 a non-scrotal transdermal T patch, in 1995, with the 2.5 mg/day and 5.0 mg/day systems. </strong>This method of delivery allows T to be continually absorbed without dose accumulations for 24 hours. 52-56 In a 24-week, multicenter, randomized 1:1, parallel-group study comparing the PK, efficacy, and safety of a transdermal T system with IM TE injections in 66 men with TD, daily application of 2 transdermal T patches (5.0 mg/day total) resulted in morning T levels within the defined normal physiologic range (10.6–35.7 nmol/L, or 306–1,031 ng/dL) in 96% of patients over weeks 2 to 24. 54 At week 16, T Cavg was 17.9 ± 6.1 nmol/L (517 ± 176 ng/dL) compared with 1.9 ± 2.2 nmol/L (55.4 ± 62.8 ng/dL) at baseline. Peak T levels were reached approximately 8.2 hours after application, with a Cmax of 26.5 ± 9.6 nmol/L (765 ± 277 ng/dL). <strong>In 34 men from a multicenter, phase 3 study of a transdermal T patch system for TD, nightly applications of 2 patches (5.0 mg/day) resulted in <u>peak levels occurring in the morning after application and decreasing slowly until system removal, mimicking the circadian patterns reported in healthy, young men</u>.52</strong></em></p><p><em></em></p><p><em>A reduced dosing regimen for either 2.0 mg/day or 4.0 mg/day systems applied nightly was evaluated in an interventional study enrolling 40 men with TD for 4 weeks (Clinicaltrials.gov identifier: NCT01104246). This reduced dosing regimen was approved in 2011, and manufacturer data show that following 28 days of transdermal T application, 97% (34/35) men with TD were able to achieve Cavg within 10.4 to 35.7 nmol/L (300–1,030 ng/dL). 51 Mean Cmax values with 2.0 mg/day and 4.0 mg/day treatment were 22.5 ± 5.0 nmol/L (648 ± 145 ng/dL) and 24.1 ± 5.5 nmol/L (696 ± 158 ng/dL), respectively. <strong>Similar to the 2.5 mg/day and 5.0 mg/day systems, peak T levels occurred 8 hours post-application, mimicking diurnal variation when the patch is applied at night.</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong>3.8 Oral testosterone undecanoate (TU)</strong></em></p><p><em></em></p><p><em>Historically, oral TTh with non-esterified T has been unsuccessful in delivering physiological T due to first-pass hepatic metabolism; to overcome this, high doses were needed to achieve measurable serum T levels.86 A new, oral TU formulation delivered via a self-emulsifying drug delivery system was developed to promote solubilization and absorption of the lipophilic TU in the gastrointestinal tract, and in March 2019, became the first oral TTh approved by the FDA. In a phase 2 study, 200 mg oral TU administered twice a day resulted in 87% of men achieving average serum T levels within the physiological range (10.4–34.7 nmol/L, or 300–1,000 ng/dL), and none of the men had serum T levels >52 nmol/L (1,500 ng/dL). 87<strong><em><strong> Peak T levels were reached 4 to 5 hours after administration, and levels steadily decreased to baseline at approximately 12 hours unless a second dose was administered.</strong> </em></strong>As oral TU capsules are recommended to be taken with a meal, serum T levels appear to be modulated by dietary fat content. 88 Cavg and mean Cmax serum T levels were approximately 2-fold higher when 200 mg oral TU was administered with food compared with fasting. 87 Dietary fat was found to affect mean serum T levels achieved with oral TU; meals with higher fat content increased serum T concentrations. In a phase 3 study comparing the efficacy and safety of 237 mg oral TU given twice daily with once-daily 60 mg topical T solution, 87% (145/166) of men with TD treated with oral TU were able to achieve a mean Cavg within 8.7 to 31.4 nmol/L (252–907 ng/dL), meeting the primary objective.89 At the final study visit on day 105, the mean Cavg was 14.0 nmol/L (403 ng/dL) and Cmax was 34.9 nmol/L (1,008 ng/dL). <strong><em><strong>As oral TU is given twice daily, there were <u>2 serum T peaks</u> between 20.8 and 24.3 nmol/L (600 and 700 ng/dL) approximately 4 hours after administration, <u>2 sub-therapeutic troughs</u> (<6.9 nmol/L or <200 ng/dL) 12 hours after administration, and a peak-to-trough ratio approaching 4.</strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong>4. Diurnal Variation in Serum T Levels</strong></em></strong></em></p><p><em><strong><em><strong></strong></em></strong></em></p><p><em><strong><em><strong><em>Diurnal variation in endogenous serum T levels in healthy men is well documented, with the highest T levels in the morning and lowest values in the afternoon and early evening, although the amplitudes of peak and trough levels vary by age.</em></strong></em></strong> In 1983, a study by Bremner et al showed that there was a clear difference between serum T levels in normal young men (mean age 25.2 years) and older men (mean age 71.0 years).5<strong><em><strong><em> <strong>In young men, serum T levels were highest in the morning, falling to their lowest levels approximately 12 hours later and gradually increasing again to peak levels the next morning. Furthermore, a study to determine how endogenous T levels vary over clinic hours revealed that in 30- to 40-year-old men, morning total T levels are 30% to 35% higher than levels measured in the mid to late afternoon. This amplitude in daily endogenous T variation decreases with age, with a morning-to-afternoon difference of only 10% in 70-year-old men.90</strong></em></strong></em></strong> The morning-to-afternoon total T ratios in young and older men were approximately 1.3 and 1.1, respectively, similar to what was observed in the Bremner study. These observations have led to recommendations in various clinical guidelines, including those of the American Urology Association in 2018, to obtain early morning blood tests for the diagnosis of TD, a threshold defined as <10.4 nmol/L (300 ng/dL). 3<strong><em><strong><em> <strong>While endogenous serum T exhibits a clear diurnal pattern in young men that appears to be blunted naturally as men age, there does not appear to be much diurnal variation for DHT, SHBG, LH, FSH, or E2, regardless of age.90</strong></em></strong></em></strong></em></p><p><em><strong><em><strong><em></em></strong></em></strong></em></p><p><em><strong><em><strong><em>Diurnal variation appears to be absent in men with TD. Using a population mixed-effect analysis, Gupta et al showed that no circadian rhythm was detected in men with TD, and the mean endogenous T levels in men with TD (serum T levels <10.4 nmol/L, or 300 ng/dL) were much lower than in healthy young (mean age, 28 years) or older (mean age, 71 years) men. 91 Consistent with the literature, their modeling of circadian T in healthy young and older men revealed peak-to-trough ratios of 1.3 and 1.2, respectively. </em></strong></em></strong>Additionally, univariate analysis of cross-sectional data from 3,007 older men (≥40 years) showed that the proportion of men with serum T levels <10.4 nmol/L (300 ng/dL) did not significantly change during the day (P<0.11), further supporting that endogenous T diurnal variation is absent in men with TD.92 Results from a study by Shlykova et al evaluating endogenous T levels over a 24-hour period in 21 healthy male volunteers showed that men with baseline serum T levels <10.4 nmol/L (300 ng/dL) did not demonstrate diurnal variation within the 24-hour sampling period. 93 To understand the circadian rhythmicity of T levels in men with TD, a population kinetic model built by Gonzales-Sales et al, using baseline T profiles from 859 men with TD, predicted a base T value of 8.3 nmol/L (239 ng/dL), with the amplitude of oscillation estimated to be 1.1 nmol/L (32.4 ng/dL). 94 Their model also predicted that a stretched cosine function was more suitable to describe the circadian behavior of T levels of men with TD, as trough levels occurred approximately 5 hours after peak T levels, and levels then increased until the next peak occurred approximately 19 hours later.94</em></p><p><em></em></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><em><strong><em><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><u>Some TTh options provide profiles that exceed the frequency of the natural T circadian rhythmicity</u>.</strong></em></strong></em></strong></em></p><p><em><strong></strong></em></p><p><em><strong>Once-weekly SC TE injections</strong> 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. <strong><em><strong><em><strong><u>The PK profile appears to mimic the flatter profile of older males’ endogenous T</u>.95 </strong></em></strong></em></strong>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.<strong><em><strong><em><strong> <u>All IM TTh preparations result in PK profiles that are unlike those of the normal diurnal variation of healthy young or older men</u>.</strong></em></strong></em></strong></em></p><p><em><strong></strong></em></p><p><em><strong>Daily transdermal gels </strong>and solutions, and nasal and oral T products, provide a consistent serum T level within the physiologic range in most patients.<strong><em><strong><em><strong> <u>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</u>.</strong></em></strong></em></strong></em></p><p><em><strong></strong></em></p><p><em><strong>Men using nasal and oral T</strong> products are able to achieve mean serum T levels that are within the normal range,<strong><em><strong><em><strong> <u>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>. <u>This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients</u>.</strong></em></strong></em></strong></em></p><p><em><strong><em><strong><em><strong></strong></em></strong></em></strong></em></p><p><em><strong><em><strong><em><strong>*No single formulation appears to provide an exposure profile that would resemble diurnal variation of both young and older men.</strong></em></strong></em></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></p><p></p><p><strong>Figure 1. <u>Extrapolated mean steady-state serum total testosterone concentrations</u>. Estimated diurnal T in <u>young men</u> (<u>blue</u>, age range: 23-28 years) and <u>older men</u> (<u>yellow</u>, age range 58- 82 years). <u>Red arrows</u> indicate the time of T administration. <u>Dotted lines</u> indicate Cavg over the dosing interval of 168 hours. <u>Black lines</u> in each panel represent mean steady-state T profiles of</strong> <u>A</u>) weekly SC TE administration; <u>B</u>) average mean T profiles for IM TC, TE, and TU over 2 weeks; <u>C</u>) 900 mg subdermal T pellets; <strong>D) 4.0 mg daily transdermal patch; E) average mean T profiles of 100 mg TESTIM® /VOGELXO®, 40 mg FORTESTA®, 1.62% AndroGel®, and 2% AXIRON®; </strong>F) nasal gel T at day 90 three times daily; G) 30 mg buccal mucoadhesives applied twice daily, and<strong> H) twice daily 200 mg oral TU capsules.</strong></p><p><strong></strong></p><p><strong>*For products with ≥1 daily dose, we extrapolated data over 1 week to compare all PK profiles consistently.</strong> For products with dosing regimens of longer than a week (eg, IM injections and T pellet implantation), only the PK profile in the first week following dosing is presented; these data do not reflect average concentrations throughout the entire dosing interval.</p><p></p><p><strong>IM, intramuscular; SC, subcutaneous; T, testosterone; TC, testosterone cypionate; TE, testosterone enanthate; TU, testosterone undecanoate.</strong></p><p></p><p></p><p> </p><p><strong>D. Transdermal T-patch (<strong>4.0 mg daily transdermal patch)</strong></strong></p><p><strong>[ATTACH=full]20581[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>E. Topical gels and solutions (<strong>average mean T profiles of 100 mg TESTIM® /VOGELXO®, 40 mg FORTESTA®, 1.62% AndroGel®, and 2% AXIRON®)</strong></strong></p><p><strong>[ATTACH=full]20582[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>H. Oral capsule (<strong>twice daily 200 mg oral TU capsules)</strong></strong></p><p><strong>[ATTACH=full]20583[/ATTACH]</strong></p></blockquote><p></p>
[QUOTE="madman, post: 220324, member: 13851"] If anything that title would go to transdermal (T-patch) or topicals (once daily in the am). [I]*[B]In 34 men from a multicenter, phase 3 study of a transdermal T patch system for TD, nightly applications of 2 patches (5.0 mg/day) resulted in [U]peak levels occurring in the morning after application and decreasing slowly until system removal, mimicking the circadian patterns reported in healthy, young men[/U] *Similar to the 2.5 mg/day and 5.0 mg/day systems, peak T levels occurred 8 hours post-application, mimicking diurnal variation when the patch is applied at night.[/B][/I] Definitely not that oral T. [I][B][I][B]*As oral TU is given twice daily, there were [U]2 serum T peaks[/U] between 20.8 and 24.3 nmol/L (600 and 700 ng/dL) approximately 4 hours after administration, [U]2 sub-therapeutic troughs[/U] (<6.9 nmol/L or <200 ng/dL) 12 hours after administration, and a peak-to-trough ratio approaching 4 *Men using nasal and oral T products are able to achieve mean serum T levels that are within the normal range,[I][B][I][B] [U]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]. [U]This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients[/U][/B][/I][/B][/I][/B][/I][/B][/I] Even then keep in mind many using transdermal tend to prefer the creams applied twice daily (am/pm) over the standard gels applied once daily in the am. [I][B]*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][/I] Applying creams twice daily in no way mimics the natural 24 hr circadian rhythm of a healthy young male let alone even when applied once daily some men are still hitting really high FT levels post >12 hrs (look over Nelson's threads)! Top it off that many using the creams are running absurdly high TT/FT levels well above what they were producing in their prime! [URL='https://www.excelmale.com/forum/threads/pk-of-tth-and-diurnal-variation-of-testosterone.24117/']PK of TTh and Diurnal Variation of Testosterone[/URL] [B]3.4 Transdermal T patch[/B] [I][B]The FDA originally approved ANDRODERM®, 51 a non-scrotal transdermal T patch, in 1995, with the 2.5 mg/day and 5.0 mg/day systems. [/B]This method of delivery allows T to be continually absorbed without dose accumulations for 24 hours. 52-56 In a 24-week, multicenter, randomized 1:1, parallel-group study comparing the PK, efficacy, and safety of a transdermal T system with IM TE injections in 66 men with TD, daily application of 2 transdermal T patches (5.0 mg/day total) resulted in morning T levels within the defined normal physiologic range (10.6–35.7 nmol/L, or 306–1,031 ng/dL) in 96% of patients over weeks 2 to 24. 54 At week 16, T Cavg was 17.9 ± 6.1 nmol/L (517 ± 176 ng/dL) compared with 1.9 ± 2.2 nmol/L (55.4 ± 62.8 ng/dL) at baseline. Peak T levels were reached approximately 8.2 hours after application, with a Cmax of 26.5 ± 9.6 nmol/L (765 ± 277 ng/dL). [B]In 34 men from a multicenter, phase 3 study of a transdermal T patch system for TD, nightly applications of 2 patches (5.0 mg/day) resulted in [U]peak levels occurring in the morning after application and decreasing slowly until system removal, mimicking the circadian patterns reported in healthy, young men[/U].52[/B] A reduced dosing regimen for either 2.0 mg/day or 4.0 mg/day systems applied nightly was evaluated in an interventional study enrolling 40 men with TD for 4 weeks (Clinicaltrials.gov identifier: NCT01104246). This reduced dosing regimen was approved in 2011, and manufacturer data show that following 28 days of transdermal T application, 97% (34/35) men with TD were able to achieve Cavg within 10.4 to 35.7 nmol/L (300–1,030 ng/dL). 51 Mean Cmax values with 2.0 mg/day and 4.0 mg/day treatment were 22.5 ± 5.0 nmol/L (648 ± 145 ng/dL) and 24.1 ± 5.5 nmol/L (696 ± 158 ng/dL), respectively. [B]Similar to the 2.5 mg/day and 5.0 mg/day systems, peak T levels occurred 8 hours post-application, mimicking diurnal variation when the patch is applied at night. 3.8 Oral testosterone undecanoate (TU)[/B] Historically, oral TTh with non-esterified T has been unsuccessful in delivering physiological T due to first-pass hepatic metabolism; to overcome this, high doses were needed to achieve measurable serum T levels.86 A new, oral TU formulation delivered via a self-emulsifying drug delivery system was developed to promote solubilization and absorption of the lipophilic TU in the gastrointestinal tract, and in March 2019, became the first oral TTh approved by the FDA. In a phase 2 study, 200 mg oral TU administered twice a day resulted in 87% of men achieving average serum T levels within the physiological range (10.4–34.7 nmol/L, or 300–1,000 ng/dL), and none of the men had serum T levels >52 nmol/L (1,500 ng/dL). 87[B][I][B] Peak T levels were reached 4 to 5 hours after administration, and levels steadily decreased to baseline at approximately 12 hours unless a second dose was administered.[/B] [/I][/B]As oral TU capsules are recommended to be taken with a meal, serum T levels appear to be modulated by dietary fat content. 88 Cavg and mean Cmax serum T levels were approximately 2-fold higher when 200 mg oral TU was administered with food compared with fasting. 87 Dietary fat was found to affect mean serum T levels achieved with oral TU; meals with higher fat content increased serum T concentrations. In a phase 3 study comparing the efficacy and safety of 237 mg oral TU given twice daily with once-daily 60 mg topical T solution, 87% (145/166) of men with TD treated with oral TU were able to achieve a mean Cavg within 8.7 to 31.4 nmol/L (252–907 ng/dL), meeting the primary objective.89 At the final study visit on day 105, the mean Cavg was 14.0 nmol/L (403 ng/dL) and Cmax was 34.9 nmol/L (1,008 ng/dL). [B][I][B]As oral TU is given twice daily, there were [U]2 serum T peaks[/U] between 20.8 and 24.3 nmol/L (600 and 700 ng/dL) approximately 4 hours after administration, [U]2 sub-therapeutic troughs[/U] (<6.9 nmol/L or <200 ng/dL) 12 hours after administration, and a peak-to-trough ratio approaching 4. 4. Diurnal Variation in Serum T Levels [I]Diurnal variation in endogenous serum T levels in healthy men is well documented, with the highest T levels in the morning and lowest values in the afternoon and early evening, although the amplitudes of peak and trough levels vary by age.[/I][/B][/I][/B] In 1983, a study by Bremner et al showed that there was a clear difference between serum T levels in normal young men (mean age 25.2 years) and older men (mean age 71.0 years).5[B][I][B][I] [B]In young men, serum T levels were highest in the morning, falling to their lowest levels approximately 12 hours later and gradually increasing again to peak levels the next morning. Furthermore, a study to determine how endogenous T levels vary over clinic hours revealed that in 30- to 40-year-old men, morning total T levels are 30% to 35% higher than levels measured in the mid to late afternoon. This amplitude in daily endogenous T variation decreases with age, with a morning-to-afternoon difference of only 10% in 70-year-old men.90[/B][/I][/B][/I][/B] The morning-to-afternoon total T ratios in young and older men were approximately 1.3 and 1.1, respectively, similar to what was observed in the Bremner study. These observations have led to recommendations in various clinical guidelines, including those of the American Urology Association in 2018, to obtain early morning blood tests for the diagnosis of TD, a threshold defined as <10.4 nmol/L (300 ng/dL). 3[B][I][B][I] [B]While endogenous serum T exhibits a clear diurnal pattern in young men that appears to be blunted naturally as men age, there does not appear to be much diurnal variation for DHT, SHBG, LH, FSH, or E2, regardless of age.90[/B] Diurnal variation appears to be absent in men with TD. Using a population mixed-effect analysis, Gupta et al showed that no circadian rhythm was detected in men with TD, and the mean endogenous T levels in men with TD (serum T levels <10.4 nmol/L, or 300 ng/dL) were much lower than in healthy young (mean age, 28 years) or older (mean age, 71 years) men. 91 Consistent with the literature, their modeling of circadian T in healthy young and older men revealed peak-to-trough ratios of 1.3 and 1.2, respectively. [/I][/B][/I][/B]Additionally, univariate analysis of cross-sectional data from 3,007 older men (≥40 years) showed that the proportion of men with serum T levels <10.4 nmol/L (300 ng/dL) did not significantly change during the day (P<0.11), further supporting that endogenous T diurnal variation is absent in men with TD.92 Results from a study by Shlykova et al evaluating endogenous T levels over a 24-hour period in 21 healthy male volunteers showed that men with baseline serum T levels <10.4 nmol/L (300 ng/dL) did not demonstrate diurnal variation within the 24-hour sampling period. 93 To understand the circadian rhythmicity of T levels in men with TD, a population kinetic model built by Gonzales-Sales et al, using baseline T profiles from 859 men with TD, predicted a base T value of 8.3 nmol/L (239 ng/dL), with the amplitude of oscillation estimated to be 1.1 nmol/L (32.4 ng/dL). 94 Their model also predicted that a stretched cosine function was more suitable to describe the circadian behavior of T levels of men with TD, as trough levels occurred approximately 5 hours after peak T levels, and levels then increased until the next peak occurred approximately 19 hours later.94 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][I][B][I][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][U]Some TTh options provide profiles that exceed the frequency of the natural T circadian rhythmicity[/U].[/B][/I][/B][/I] Once-weekly SC TE injections[/B] 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. [B][I][B][I][B][U]The PK profile appears to mimic the flatter profile of older males’ endogenous T[/U].95 [/B][/I][/B][/I][/B]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.[B][I][B][I][B] [U]All IM TTh preparations result in PK profiles that are unlike those of the normal diurnal variation of healthy young or older men[/U].[/B][/I][/B][/I] Daily transdermal gels [/B]and solutions, and nasal and oral T products, provide a consistent serum T level within the physiologic range in most patients.[B][I][B][I][B] [U]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[/U].[/B][/I][/B][/I] Men using nasal and oral T[/B] products are able to achieve mean serum T levels that are within the normal range,[B][I][B][I][B] [U]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]. [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][/I][/B][/I][/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]Figure 1. [U]Extrapolated mean steady-state serum total testosterone concentrations[/U]. Estimated diurnal T in [U]young men[/U] ([U]blue[/U], age range: 23-28 years) and [U]older men[/U] ([U]yellow[/U], age range 58- 82 years). [U]Red arrows[/U] indicate the time of T administration. [U]Dotted lines[/U] indicate Cavg over the dosing interval of 168 hours. [U]Black lines[/U] in each panel represent mean steady-state T profiles of[/B] [U]A[/U]) weekly SC TE administration; [U]B[/U]) average mean T profiles for IM TC, TE, and TU over 2 weeks; [U]C[/U]) 900 mg subdermal T pellets; [B]D) 4.0 mg daily transdermal patch; E) average mean T profiles of 100 mg TESTIM® /VOGELXO®, 40 mg FORTESTA®, 1.62% AndroGel®, and 2% AXIRON®; [/B]F) nasal gel T at day 90 three times daily; G) 30 mg buccal mucoadhesives applied twice daily, and[B] H) twice daily 200 mg oral TU capsules. *For products with ≥1 daily dose, we extrapolated data over 1 week to compare all PK profiles consistently.[/B] For products with dosing regimens of longer than a week (eg, IM injections and T pellet implantation), only the PK profile in the first week following dosing is presented; these data do not reflect average concentrations throughout the entire dosing interval. [B]IM, intramuscular; SC, subcutaneous; T, testosterone; TC, testosterone cypionate; TE, testosterone enanthate; TU, testosterone undecanoate.[/B] [B]D. Transdermal T-patch ([B]4.0 mg daily transdermal patch)[/B] [ATTACH type="full" alt="Screenshot (11823).png"]20581[/ATTACH] E. Topical gels and solutions ([B]average mean T profiles of 100 mg TESTIM® /VOGELXO®, 40 mg FORTESTA®, 1.62% AndroGel®, and 2% AXIRON®)[/B] [ATTACH type="full" alt="Screenshot (11824).png"]20582[/ATTACH] H. Oral capsule ([B]twice daily 200 mg oral TU capsules)[/B] [ATTACH type="full" alt="Screenshot (11825).png"]20583[/ATTACH][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Who Started TRT w/ "Normal" Levels @ What Age?
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