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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: 218359" data-attributes="member: 13851"><p>Of course, there is going to be some suppression of the HPGA when using Natesto but it would be much less when compared to longer-acting formulations.</p><p></p><p>Natesto would be considered the least suppressive due to the short-lived peaks/significant trough times between doses.</p><p></p><p>Regardless of whether dosing 2-3 times daily, there is a short-lived peak Tmax 40-60 min with long trough times 6-8 hrs between doses.</p><p></p><p>The recommended <u>starting dose</u> in Canada is 2x/day and even then most in the know would push 3X daily if needed.</p><p></p><p>Comes down to the individual let alone no one needs to start on 3X daily.</p><p></p><p></p><p><strong>Natesto Effects on Reproductive Hormones and Semen Parameters: Results from an Ongoing Single-center, Investigator-initiated Phase IV Clinical Trial (2018)</strong></p><p></p><p></p><p><em>Natesto is a short-acting FDA-approved TRT that is delivered intranasally to men diagnosed with low T. Advantages to intranasal T include ease of delivery, no need for needles, and decreased risk of transference [11]. <strong>Recently, Natesto (125 ml/nostril, 11.0 mg T/dose) TID dosing was shown in a multi-institutional study to increase serum T while also maintaining serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [12].</strong> <strong><u>We hypothesized that the short half-life of Natesto likely preserves spermatogenesis by maintaining pulsatile release of gonadotropin-releasing hormone, thereby preventing the steep declines in serum LH and FSH routinely seen with other forms of TRT</u> (Fig. 1).</strong> <strong><u>Maintaining normal LH and FSH has the theoretical benefit of preserving normal semen parameters while on TRT with Natesto</u>. </strong>However, to date, no study has evaluated the effect of Natesto on semen parameters.</em></p><p><em></em></p><p><em><strong>We launched our clinical trial to evaluate the role of Natesto on semen parameters and reproductive hormones in November 2017 with the intent of enrolling 40 participants (<a href="https://www.clinicaltrials.gov/ct2/show/" target="_blank">Assessment of Autogenous Dentin Graft in Treatment of Infra-bony Defect - Full Text View - ClinicalTrials.gov</a> NCT03203681).</strong> It is an ongoing, single-institution, a prospective investigator-initiated study funded by Aytu Biosciences. Men eligible for the study are aged 18–55 yr, with at least two T levels <350 ng/dl (drawn before 10 AM) and have two semen analyses (SA) with total motile sperm count (TMSC) >5 million. All men are naïve to T therapy prior to enrolment.</em></p><p><em></em></p><p><em><strong>We collected baseline serum T, LH, FSH, two SA, 15- question International Index of Erectile Function Questionnaire (IIEF-Q15) and Short-Form Health Survey (SF-36) scores. After consent, patients were prescribed Natesto 4.5% nasal T. <u>Dosing includes two pumps, one per nostril for dosing of 11 mg, three times a day (33 mg delivery daily) as described on the label</u>. </strong>Serum reproductive hormones, SA, and questionnaires will be collected at 3 and 6 mo of therapy. The duration of this study is 6 mo.</em></p><p><em></em></p><p><em><strong>To date, we have enrolled 23 men.</strong> Their median age is 35 (interquartile range: 31.7–37.8) yr with a baseline T 228.8 (196.4–253.1) ng/dl, <strong><u>LH 3.3 (2.2–5.3) IU/ml, and FSH 3.9 (2.4–6.4) IU/ml</u>.</strong> <strong>Overall, six of the 23 men have dropped out of the study.</strong> <strong>T levels are available for 15 men at 1 mo. A total of six men have completed 3-mo follow-up, and five men have completed 6-mo follow-up</strong>. After 1 mo of therapy, T levels of 14 out of 15 men were above 300 ng/dl, with a median of 423.5 (350.0–870.0) ng/dl.</em></p><p><em></em></p><p><em>At 3 mo, T levels of four out of six men were above 300 ng/dl, median 374.3 (226.8–614.7) ng/dl (Fig. 2A),<strong> LH 1.6 (1.0–3.2) IU/ml, and FSH 1.5 (0.8–4.7) IU/ml (Fig. 2B). Median TMSC changed from 37.5 (17.0–63.9) million at baseline to 24.8 (7.1–52.0) million at 3 mo (Fig. 2C).</strong> At 6 mo, T levels of four out of five men were above 300 ng/dl, median 654.0 (389.5–810.3) ng/dl (Fig. 2A), <strong>LH 1.3 (1.1–2.6) IU/ml, and FSH 2.1 (0.9–4.9) IU/ml (Fig. 2B). Median TMSC changed to 32.5 (12.3–54.5) million at 6 mo (Fig. 2C).</strong> IIEF-Q15 and SF-36 scores remained statistically unchanged from baseline to 3 mo and 6 mo.</em></p><p></p><p><strong><em>We have accumulated promising initial data demonstrating that Natesto can not only increase serum T but also maintain FSH, LH, and importantly, semen parameters.</em></strong><em> Natesto has the potential to be “paradigm-shifting” in our approach to developing a safe and effective treatment for men with low T who wish to preserve fertility. </em><strong><em>Understanding factors that influence the preservation of spermatogenesis while taking T therapy can enable the development of a novel therapeutic strategy for men with low T.</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Fig. 1 – Short-acting nasal testosterone appears to preserve follicle-stimulating hormone and luteinizing hormone, thereby maintaining spermatogenesis. FSH = follicle-stimulating hormone; LH = luteinizing hormone; GnRH = gonadotropin-releasing hormone.</strong></p><p><strong>[ATTACH=full]19936[/ATTACH]</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Fig. 2 – (A) Median testosterone levels at baseline and at 1, 3, and 6 mo after therapy with Natesto TID dosing. Note that changes at 1, 3, and 6 mo are significantly increased from baseline. (B) <u>Median follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels</u> at baseline and at 3 and 6 mo after therapy with Natesto TID dosing. Note that the changes in FSH and LH are decreased, but nonsignificant. (C) <u>Median semen analysis concentration, motility, and total motile sperm count</u> at baseline and at 3 and 6 mo after therapy with Natesto TID dosing. Changes from baseline to 3 and 6 mo are all nonsignificant. FSH = follicle-stimulating hormone; LH = luteinizing hormone; TMSC = Total motile sperm count.</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>A</strong></p><p><strong>[ATTACH=full]19937[/ATTACH]</strong></p><p><strong></strong></p><p><strong>B</strong></p><p><strong>[ATTACH=full]19938[/ATTACH]</strong></p><p><strong></strong></p><p><strong>C</strong></p><p><strong>[ATTACH=full]19939[/ATTACH]</strong></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/nasal-spray-for-low-testosterone-preserves-fertility.18981/[/URL]</p><p></p><p><strong><em>*Interim results presented to date demonstrate that almost all subjects completing the six-month treatment period not only had serum testosterone levels return to the normal range, but all measures of semen parameters including sperm concentration, sperm motility, and total motile sperm count (TMSC) remained unchanged through three months and six months of therapy.</em></strong></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/acerus-announces-publication-of-study-results-demonstrating-effectiveness-of-natesto%C2%AE-regardless-of-baseline-symptom-severity.19173/[/URL]</p><p></p><p></p><p><strong><em>Take home points:</em></strong></p><p><strong><em></em></strong></p><p><strong><em><strong>*In between NATESTO® doses, all patients in the phase 3 study maintained their natural testosterone at the same levels they had prior to entry into the study, indicating that </strong><u>NATESTO® does not suppress natural testosterone production</u></em></strong></p><p><strong><em></em></strong></p><p><strong><em></em></strong></p><p><strong><em><strong>*Based on the data, Acerus believes that the mechanism of action of NATESTO® is unique whereby the <u>peaks in testosterone generated by NATESTO® dosing provide efficacy and improvement of symptoms, while the time between doses (4-8 hours) allows for the maintenance of testicular testosterone production and sperm production</u></strong></em></strong></p><p><strong><em><strong></strong></em></strong></p><p><strong><em><strong></strong></em></strong></p><p><strong><em><strong>*The release of testosterone with NATESTO® is pulsatile - closely matching the body's "natural" testosterone release. <u>Consequently, NATESTO® does not suppress a man's natural testosterone level, but simply adds to it to achieve a normal, safe level of testosterone</u></strong></em></strong></p><p><strong><em><strong></strong></em></strong></p><p><strong><em><strong></strong></em></strong></p><p><strong><em><strong>*Furthermore, NATESTO® has been shown to work even in severely testosterone deficient patients, suggesting that a wide range of testosterone deficient patients can be effectively treated</strong></em></strong></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></p><p><strong><strong>FINAL THOUGHTS</strong></strong></p><p><strong><strong></strong></strong></p><p><strong><strong><em>Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. <u>Modalities of T therapy evolved to extend the dosing interval and maintain sustained “steady-state” T levels</u>. <u>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)</u>. </em></strong><em><strong><u>These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects</u>.</strong></em> 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.</strong></p><p><strong></strong></p><p><strong><strong><em><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. </em></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. <u>Support of this hypothesis is needed from additional, longer-duration studies utilizing short-acting testosterone.</u> <u>However, it is encouraging that studies performed to date tend to support the hypothesis</u>. <em><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></strong></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><u><em>Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T which is critical for maintaining spermatogenesis</em></u><em>. 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></p><p></p><p></p><p></p><p></p><p></p><p>At least we have Lipschultz study to look forward to (end date 2023)!</p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/the-effects-of-natesto-for-treatment-of-hypogonadism.22799/[/URL]</p><p></p><p></p><p><strong>The Effects of Natesto For Treatment Of Hypogonadism (2021)</strong></p><p><strong></strong></p><p><strong></strong></p><p><strong><em>*In this prospective study, the investigators seek to confirm the role of Natesto to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional TTh.</em></strong></p></blockquote><p></p>
[QUOTE="madman, post: 218359, member: 13851"] Of course, there is going to be some suppression of the HPGA when using Natesto but it would be much less when compared to longer-acting formulations. Natesto would be considered the least suppressive due to the short-lived peaks/significant trough times between doses. Regardless of whether dosing 2-3 times daily, there is a short-lived peak Tmax 40-60 min with long trough times 6-8 hrs between doses. The recommended [U]starting dose[/U] in Canada is 2x/day and even then most in the know would push 3X daily if needed. Comes down to the individual let alone no one needs to start on 3X daily. [B]Natesto Effects on Reproductive Hormones and Semen Parameters: Results from an Ongoing Single-center, Investigator-initiated Phase IV Clinical Trial (2018)[/B] [I]Natesto is a short-acting FDA-approved TRT that is delivered intranasally to men diagnosed with low T. Advantages to intranasal T include ease of delivery, no need for needles, and decreased risk of transference [11]. [B]Recently, Natesto (125 ml/nostril, 11.0 mg T/dose) TID dosing was shown in a multi-institutional study to increase serum T while also maintaining serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [12].[/B] [B][U]We hypothesized that the short half-life of Natesto likely preserves spermatogenesis by maintaining pulsatile release of gonadotropin-releasing hormone, thereby preventing the steep declines in serum LH and FSH routinely seen with other forms of TRT[/U] (Fig. 1).[/B] [B][U]Maintaining normal LH and FSH has the theoretical benefit of preserving normal semen parameters while on TRT with Natesto[/U]. [/B]However, to date, no study has evaluated the effect of Natesto on semen parameters. [B]We launched our clinical trial to evaluate the role of Natesto on semen parameters and reproductive hormones in November 2017 with the intent of enrolling 40 participants ([URL='https://www.clinicaltrials.gov/ct2/show/']Assessment of Autogenous Dentin Graft in Treatment of Infra-bony Defect - Full Text View - ClinicalTrials.gov[/URL] NCT03203681).[/B] It is an ongoing, single-institution, a prospective investigator-initiated study funded by Aytu Biosciences. Men eligible for the study are aged 18–55 yr, with at least two T levels <350 ng/dl (drawn before 10 AM) and have two semen analyses (SA) with total motile sperm count (TMSC) >5 million. All men are naïve to T therapy prior to enrolment. [B]We collected baseline serum T, LH, FSH, two SA, 15- question International Index of Erectile Function Questionnaire (IIEF-Q15) and Short-Form Health Survey (SF-36) scores. After consent, patients were prescribed Natesto 4.5% nasal T. [U]Dosing includes two pumps, one per nostril for dosing of 11 mg, three times a day (33 mg delivery daily) as described on the label[/U]. [/B]Serum reproductive hormones, SA, and questionnaires will be collected at 3 and 6 mo of therapy. The duration of this study is 6 mo. [B]To date, we have enrolled 23 men.[/B] Their median age is 35 (interquartile range: 31.7–37.8) yr with a baseline T 228.8 (196.4–253.1) ng/dl, [B][U]LH 3.3 (2.2–5.3) IU/ml, and FSH 3.9 (2.4–6.4) IU/ml[/U].[/B] [B]Overall, six of the 23 men have dropped out of the study.[/B] [B]T levels are available for 15 men at 1 mo. A total of six men have completed 3-mo follow-up, and five men have completed 6-mo follow-up[/B]. After 1 mo of therapy, T levels of 14 out of 15 men were above 300 ng/dl, with a median of 423.5 (350.0–870.0) ng/dl. At 3 mo, T levels of four out of six men were above 300 ng/dl, median 374.3 (226.8–614.7) ng/dl (Fig. 2A),[B] LH 1.6 (1.0–3.2) IU/ml, and FSH 1.5 (0.8–4.7) IU/ml (Fig. 2B). Median TMSC changed from 37.5 (17.0–63.9) million at baseline to 24.8 (7.1–52.0) million at 3 mo (Fig. 2C).[/B] At 6 mo, T levels of four out of five men were above 300 ng/dl, median 654.0 (389.5–810.3) ng/dl (Fig. 2A), [B]LH 1.3 (1.1–2.6) IU/ml, and FSH 2.1 (0.9–4.9) IU/ml (Fig. 2B). Median TMSC changed to 32.5 (12.3–54.5) million at 6 mo (Fig. 2C).[/B] IIEF-Q15 and SF-36 scores remained statistically unchanged from baseline to 3 mo and 6 mo.[/I] [B][I]We have accumulated promising initial data demonstrating that Natesto can not only increase serum T but also maintain FSH, LH, and importantly, semen parameters.[/I][/B][I] Natesto has the potential to be “paradigm-shifting” in our approach to developing a safe and effective treatment for men with low T who wish to preserve fertility. [/I][B][I]Understanding factors that influence the preservation of spermatogenesis while taking T therapy can enable the development of a novel therapeutic strategy for men with low T.[/I] Fig. 1 – Short-acting nasal testosterone appears to preserve follicle-stimulating hormone and luteinizing hormone, thereby maintaining spermatogenesis. FSH = follicle-stimulating hormone; LH = luteinizing hormone; GnRH = gonadotropin-releasing hormone. [ATTACH type="full" alt="Screenshot (11128).png"]19936[/ATTACH] Fig. 2 – (A) Median testosterone levels at baseline and at 1, 3, and 6 mo after therapy with Natesto TID dosing. Note that changes at 1, 3, and 6 mo are significantly increased from baseline. (B) [U]Median follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels[/U] at baseline and at 3 and 6 mo after therapy with Natesto TID dosing. Note that the changes in FSH and LH are decreased, but nonsignificant. (C) [U]Median semen analysis concentration, motility, and total motile sperm count[/U] at baseline and at 3 and 6 mo after therapy with Natesto TID dosing. Changes from baseline to 3 and 6 mo are all nonsignificant. FSH = follicle-stimulating hormone; LH = luteinizing hormone; TMSC = Total motile sperm count. A [ATTACH type="full" alt="Screenshot (11129).png"]19937[/ATTACH] B [ATTACH type="full" alt="Screenshot (11130).png"]19938[/ATTACH] C [ATTACH type="full" alt="Screenshot (11131).png"]19939[/ATTACH][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/nasal-spray-for-low-testosterone-preserves-fertility.18981/[/URL] [B][I]*Interim results presented to date demonstrate that almost all subjects completing the six-month treatment period not only had serum testosterone levels return to the normal range, but all measures of semen parameters including sperm concentration, sperm motility, and total motile sperm count (TMSC) remained unchanged through three months and six months of therapy.[/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/acerus-announces-publication-of-study-results-demonstrating-effectiveness-of-natesto%C2%AE-regardless-of-baseline-symptom-severity.19173/[/URL] [B][I]Take home points: [B]*In between NATESTO® doses, all patients in the phase 3 study maintained their natural testosterone at the same levels they had prior to entry into the study, indicating that [/B][U]NATESTO® does not suppress natural testosterone production[/U] [B]*Based on the data, Acerus believes that the mechanism of action of NATESTO® is unique whereby the [U]peaks in testosterone generated by NATESTO® dosing provide efficacy and improvement of symptoms, while the time between doses (4-8 hours) allows for the maintenance of testicular testosterone production and sperm production[/U] *The release of testosterone with NATESTO® is pulsatile - closely matching the body's "natural" testosterone release. [U]Consequently, NATESTO® does not suppress a man's natural testosterone level, but simply adds to it to achieve a normal, safe level of testosterone[/U] *Furthermore, NATESTO® has been shown to work even in severely testosterone deficient patients, suggesting that a wide range of testosterone deficient patients can be effectively treated[/B][/I][/B] [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][B]FINAL THOUGHTS [I]Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. [U]Modalities of T therapy evolved to extend the dosing interval and maintain sustained “steady-state” T levels[/U]. [U]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)[/U]. [/I][/B][I][B][U]These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects[/U].[/B][/I] 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][I][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. [/I][/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. [U]Support of this hypothesis is needed from additional, longer-duration studies utilizing short-acting testosterone.[/U] [U]However, it is encouraging that studies performed to date tend to support the hypothesis[/U]. [I][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.[/B][/I][/B] [URL unfurl="true"]https://www.excelmale.com/forum/threads/impact-of-short-acting-vs-long-acting-t-therapy-on-itt.23062/[/URL] [B]Conclusions [U][I]Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T which is critical for maintaining spermatogenesis[/I][/U][I]. 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] At least we have Lipschultz study to look forward to (end date 2023)! [URL unfurl="true"]https://www.excelmale.com/forum/threads/the-effects-of-natesto-for-treatment-of-hypogonadism.22799/[/URL] [B]The Effects of Natesto For Treatment Of Hypogonadism (2021) [I]*In this prospective study, the investigators seek to confirm the role of Natesto to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional TTh.[/I][/B] [/QUOTE]
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Official Natesto Thread
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