Official Natesto Thread

[Fortunate]

Data point for anyone interested. Natesto has been the most tolerable form of TRT for me. Typically, I get headaches with other forms. I have also noticed a more forceful heartbeat than normal after injecting. I can even feel it in my abdominal aorta (I know, that sounds really weird).

I have been following my blood pressure more closely lately and have noticed a general increase while on injections. I started to wonder if the headaches and blood pressure are related (ie, does one cause the other, or does a common process cause both?).

I happen to be on a calcium channel blocker for migraine prevention. Have been for a while. I decided it would be a good idea to try a beta blocker for a few reasons. Beta blockers are first line migraine prevention drugs (check, good for me). And, I am starting to believe that Test has beta adrenergic activity that varies among individuals. Maybe I am more sensitive than others? If so, a beta blocker would blunt the effect.

Started propanol the other day. I have noticed a definite improvement in the "forceful" hearbeat phenomenon described above. I think I am also tolerating injections better - less headache. That said, I still sense a very minor, dull headache. It may not be related to the injection and I would have to observe for a longer period of time to make conclusions. On the other hand, although I still experience a very mild headache, I think I may have confirmed my theory that my headaches are in some way related to beta agonism and/or blood pressure.

Despite all this, I am once again thinking about going back to Natesto. I swing back and forth because while on injections or cream, I long for not getting headaches. I am still a huge proponent of Natesto, but while on it, I wonder if I am under treated a bit? I don't always feel this way. At times, I notice a significant boost in mood. I would even say libido is probably better on it.

So, I wanted to provide some input and check with others in this thread. Am I still the only one here interested in Natesto? I'd love for some more guys to give it a longer run so we can compare notes.

I would also encourage everyone to follow their blood pressure. It's a good idea in general, but I think it would be useful to see how common BP spikes are after injection. I bought an Omron and really like it. My wife and I both use it and can track our pressure separately by syncing to an app. I may even start a new thread to encourage guys to track BP.

 

[Willyt]

@Fortunate you may remember that I experimented with Natesto 1x per day. Have you ever compared 3x versus 2x versus 1x Natesto daily? If so, how did they feel different in terms of energy, sleep, libido, anxiety etc?

 

[Fortunate]

@Fortunate you may remember that I experimented with Natesto 1x per day. Have you ever compared 3x versus 2x versus 1x Natesto daily? If so, how did they feel different in terms of energy, sleep, libido, anxiety etc?

To be honest, I have pretty much been on 3x a day for years, so it's hard to say. I think when I started, I was told it could be used 2 or 3 times a day. I decided 3 was the way to go, and I've done that ever since. I don't think once a day would be very effective.

I don't take it exactly 6-8 hours apart - too hard to coordinate. So, I tend to take it after shower in AM, at lunch time and around 5PM. If I had to give one dose up, I'd give up 5PM. I suspect I would do OK without that one, but not sure.

How did your trial go?

For anyone interested, I recently (once again) did an injection trial. This time, I used Xyosted 50mg and spaced it out every 4-5 days. It's off label, but thought it made sense. I did it for several weeks and overall, I had a noticeable drop in libido. Mood has been poor. Energy OK. As of today, I am back on Natesto. It just works best for me. I have rendered some opinions on Natesto and libido before. My updated opinion on this matter is that Natesto is good for libido. I have experienced a few honeymoons (cream and injections), and during these times, libido is always strong. But, during this last trial, libido has been much worse than it is in general on Natesto.

In fairness, I started a beta blocker while I was on Xyosted. I get migraines and beta blockers are first line preventive drug. I reasoned that the beta blocker could reduce headaches, and blunt the cardiovascular effects of injected testosterone that I tend to feel (strong heartbeat, elevated blood pressure). I think the beta blocker made the ride smoother - less vigorous heartbeat and BP under better (but not perfect) control. But, I still got a headache every time I injected. Ended up not being worth it, and it is very possible that the beta blocker was responsible for some of my downward mood shift (a known side effect), as opposed to the test.

Will you keep me in the loop if you decide to go 2-3 times a day?

 

[Willyt]

To be honest, I have pretty much been on 3x a day for years, so it's hard to say. I think when I started, I was told it could be used 2 or 3 times a day. I decided 3 was the way to go, and I've done that ever since. I don't think once a day would be very effective.

I don't take it exactly 6-8 hours apart - too hard to coordinate. So, I tend to take it after shower in AM, at lunch time and around 5PM. If I had to give one dose up, I'd give up 5PM. I suspect I would do OK without that one, but not sure.

How did your trial go?

For anyone interested, I recently (once again) did an injection trial. This time, I used Xyosted 50mg and spaced it out every 4-5 days. It's off label, but thought it made sense. I did it for several weeks and overall, I had a noticeable drop in libido. Mood has been poor. Energy OK. As of today, I am back on Natesto. It just works best for me. I have rendered some opinions on Natesto and libido before. My updated opinion on this matter is that Natesto is good for libido. I have experienced a few honeymoons (cream and injections), and during these times, libido is always strong. But, during this last trial, libido has been much worse than it is in general on Natesto.

As I recall, the Canadian prescription is 2x daily versus US which is 3x.

If the half-life of Natesto is so short, how can multiple doses spaced throughout the day accumulate in the body to reach steady state levels? The only benefit of 3x that I could see is that you avoid whipsawing your T & E2 levels so much (i.e., from baseline to peak 600-800 TT).

 

[Fortunate]

As I recall, the Canadian prescription is 2x daily versus US which is 3x.

If the half-life of Natesto is so short, how can multiple doses spaced throughout the day accumulate in the body to reach steady state levels? The only benefit of 3x that I could see is that you avoid whipsawing your T & E2 levels so much (i.e., from baseline to peak 600-800 TT).

Natesto approaches TRT much differently than other forms. Instead of constant, high levels, like you said, you pulse your levels a few times during the day. As a result, you minimize suppression of the CNS signals, and therefore maintain some endogenous production. It also does not tend to elevate hematocrit or E2. My guess is that your levels simply aren't high enough for long enough to cause these side effects.

I don't think you are trying to reach a steady state with Natesto. You are simply pulsing T levels, thereby getting symptom relief and the subjective benefit of TRT. One upside is that, because you don't reach a steady state of constant high levels, you can stop using it and go back to your pre-treatment state and switch to something else if you want.

My subjective response to Natesto has been good. I think it's very useful for mood and, as above, I suspect it's good for libido. I have been jacking around so much for the last year, that I can't make a really good comment on what it does for body composition, but I am in decent shape. I suspect it's probably would not be an ideal choice for a body builder, though.

I did an experiment recently in which I checked my levels an hour after a dose. I was just below 500. Not terrible, but not as high as some studies report. However, I had stopped hCG for a few weeks just prior to doing this blood draw. Taking hCG doesn't make great sense while on Natesto, but I have been on it for years, and think I feel better on it. In any case, maybe this influenced my levels on the blood draw, assuming hCG has some CNS suppression of the axis.

Did you notice any benefit on it? Maybe you should try it twice a day.

 

[Fortunate]

Also, my theory, based on nothing, is that I have a "zone" in which I feel subjectively "good" on TRT. My guess is that with Natesto, I feel good on the way up and down within this zone, which is why I don't feel good for only an hour or so. Rather, I feel good most of the day.

It's obviously not perfect, otherwise, I would not have jacked around so much over the last year. But it is consistently the most tolerable forms of TRT for me. I have felt like total garbage on injections and creams (not on every trial, but enough for me to bail every time). I never feel like garbage on Natesto.

I am going to do some research on enclomiphene. I wonder if it would be a good alternative to hCG, as an option to bump up my baseline a little. I know it can raise levels, but I don't know if there are subjective benefits (mood, libido) compared with hCG. I also worry a lot about visual changes that have been reported with clomiphene. @Cataceous, do you know if enclomiphene carries this risk like clomiphene? Can you or anyone else comment on the subjective benefits? If it makes my numbers higher, but I don't "feel better", it's not worthwhile for me.

 

[Willyt]

Natesto approaches TRT much differently than other forms. Instead of constant, high levels, like you said, you pulse your levels a few times during the day. As a result, you minimize suppression of the CNS signals, and therefore maintain some endogenous production. It also does not tend to elevate hematocrit or E2. My guess is that your levels simply aren't high enough for long enough to cause these side effects.

From the graphs I have seen, there is a return to hypogonadal baseline between each peak - e.g., from 300 to 600 back to 300. So you are getting whipsawed 3x times per day versus 2x versus 1x. That is a big swing and is consistent with how I felt after a dose of Natesto.

I understand the pulsatile approach, but did not think it would be that extreme at 3x per day. Although from the graph below, it looks like there is some blunting of the 2nd and 3rd peaks.

 

[Fortunate]

From the graphs I have seen, there is a return to hypogonadal baseline between each peak - e.g., from 300 to 600 back to 300. So you are getting whipsawed 3x times per day versus 2x versus 1x. That is a big swing and is consistent with how I felt after a dose of Natesto.

I understand the pulsatile approach, but did not think it would be that extreme at 3x per day. Although from the graph below, it looks like there is some blunting of the 2nd and 3rd peaks.

Yeah, I know. The graphs suggest you'd feel whipsawed, but somehow that's now what the subjective experience has been for me.

Two possible explanations:

• my peaks aren't as high as the data suggests?
• or, my dose 2 and 3 are done a bit earlier than recommended, and maybe I am not fully hypo by the time I re-dose?

I don't know.

 

[Strengthandlibido]

I am trying the Empower version, and I'm feeling absolutely nothing so far. According to the pharmacy, one full rotation is 11 mg of testosterone, and I take that dose twice a day, right nostril in the a.m. and left nostril in the p.m..

I've tried to explain to Defy why I'm trying nasal gel monotherapy for now (injections seem to have killed libido entirely). But they still really want me to try hCG. That doesn't make much sense with nasal gel, but maybe I'll give it a go.

 

[Fortunate]

Maybe try Natesto for a month.

 

[Cataceous]

...
I am going to do some research on enclomiphene. I wonder if it would be a good alternative to hCG, as an option to bump up my baseline a little. I know it can raise levels, but I don't know if there are subjective benefits (mood, libido) compared with hCG. I also worry a lot about visual changes that have been reported with clomiphene. @Cataceous, do you know if enclomiphene carries this risk like clomiphene? Can you or anyone else comment on the subjective benefits? If it makes my numbers higher, but I don't "feel better", it's not worthwhile for me.

I think enclomiphene makes more sense than hCG if you're trying to keep the HPTA going. However, even though enclomiphene often yields great lab numbers, the subjective results vary widely. You just have to try it to see how it affects you. I expect that visual effects are possible with enclomiphene; it seems less likely to me that zuclomiphene causes them. However, I don't recall that any such issues were reported in the clinical trials for Androxal, even at 25 mg per day. The incidence at these relatively lower doses seems small enough that I don't worry about it. You can read Dr. Dach's page on the safety of clomiphene. He cites one report saying that the incidence of visual adverse events is 1.5%. But these likely pertain to doses in the range of 50-200 mg per day. If clomiphene is 60% enclomiphene then the enclomiphene exposure was 30-120 mg/day.

If you try it I suggest the low-and-slow approach. I might even start at 6.25 mg EOD, although that could be sub-therapeutic. Otherwise, 6.25 mg daily or 12.5 EOD would correspond to the lowest dose used in the clinical trials. The latter is my current dose.

 

[Willyt]

I am trying the Empower version, and I'm feeling absolutely nothing so far. According to the pharmacy, one full rotation is 11 mg of testosterone, and I take that dose twice a day, right nostril in the a.m. and left nostril in the p.m..

I've tried to explain to Defy why I'm trying nasal gel monotherapy for now (injections seem to have killed libido entirely). But they still really want me to try hCG. That doesn't make much sense with nasal gel, but maybe I'll give it a go.

Defy seems to view nasal gel as a way to top-off your injectables versus a monotherapy.

I am a bit wary of the 29 non-medicinal ingredients in the Empower nasal gel version:

High hematocrit prevalence with intranasal vs. intramuscular testosterone

Sperm parameters maintained in most men taking nasal testosterone gel 1:08/3:46

www.excelmale.com

Natesto is a lot more expensive, but at least the non-medicinal ingredients are minimal:

• Testosterone (4.5% concentration)
• Castor oil (solvent)
• Oleoyl polyoxylglyceride (wetting agent)
• Colloidal silicon dioxide (viscosity increasing agent)

 

[Fortunate]

Defy seems to view nasal gel as a way to top-off your injectables versus a monotherapy.

I am a bit wary of the 29 non-medicinal ingredients in the Empower nasal gel version:

High hematocrit prevalence with intranasal vs. intramuscular testosterone

Sperm parameters maintained in most men taking nasal testosterone gel 1:08/3:46

www.excelmale.com

Natesto is a lot more expensive, but at least the non-medicinal ingredients are minimal:

• Testosterone (4.5% concentration)
• Castor oil (solvent)
• Oleoyl polyoxylglyceride (wetting agent)
• Colloidal silicon dioxide (viscosity increasing agent)

I totally agree. I trust big Pharma on this one. I also think that more insurances cover Natesto now, possibly making it more affordable. If not, check with smaller pharmacies. Some of them have coupons/assistant programs available to make it more affordable.

 

[Dudley]

I am just starting Natesto 3x/day and am trying to compare how that compares in terms of delivered T to other options such as injection. Anyone know how I can compare apples to apples?

 

[madman]

I am just starting Natesto 3x/day and am trying to compare how that compares in terms of delivered T to other options such as injection. Anyone know how I can compare apples to apples?

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.



*Compared with other routes of T delivery, nasal T gel administration results in rather low Cavg and Cmax TT levels, as well as DHT and DHT: T ratios, even with administering 11 mg three times daily

Short-acting T therapy to maintain homeostasis that more closely reflects normal physiology

Short-Acting Testosterone: Physiologic? Gerwin Westfield, Ursula B Kaiser, Dolores J Lamb, Ranjith Ramasamy INTRODUCTION Pulsatile secretion of a hormone refers to the intermittent secretion of the hormone in a burst like or episodic manner rather than constantly, with the frequency...

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TESTOSTERONE PHARMACOKINETICS

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). 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, which leads to suppression of the endogenous activity of the HPG axis.




*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. There is significant change within a 24-h period. Testosterone itself acts as a negative feedback molecule to the hypothalamus and anterior pituitary. 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. 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.




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). 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 (11). Therefore, multiple administrations of nasal T throughout the day (three times daily) maintain normal mean serum T levels over 24 h. 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.




FINAL THOUGHTS

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). These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects. 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.

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. 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. 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. 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.

Impact of Short-Acting vs Long-Acting T Therapy on ITT

Abstract Introduction & Objective Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of the HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated...

www.excelmale.com

Conclusions

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.

The Effect of Longer-Acting vs Shorter-Acting TRT on FSH and LH

Abstract Introduction: Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to a decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH...

www.excelmale.com

Conclusion

Our analyses support that long-acting Ts may have greater suppression of FSH and LH than shorter-acting formulations. 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.

Natesto: Unique Approach to Treating Low-T

www.excelmale.com

Comparison of Testosterone Blood Concentrations from Different TRT Products Versus Normal Diurnal Variations

Abstract Background: To improve symptoms associated with testosterone deficiency (TD), many testosterone therapies (TTh) are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T...

www.excelmale.com

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 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). Some TTh options provide profiles that exceed the frequency of the natural T circadian rhythmicity.

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.

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). This results in a PK profile that significantly deviates from the endogenous PK profiles of both younger and older patients.

*No single formulation appears to provide an exposure profile that would resemble diurnal variation of both young and older men.

*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.


5. Conclusion

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.

High hematocrit prevalence with intranasal vs. intramuscular testosterone

A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate Abstract Introduction: Secondary polycythemia is a known adverse effect of testosterone replacement therapy (TRT). Different...

www.excelmale.com

Conclusions

The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received testosterone cypionate injections. 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.

 

[madman]

Comparison of Testosterone Blood Concentrations from Different TRT Products Versus Normal Diurnal Variations

Abstract Background: To improve symptoms associated with testosterone deficiency (TD), many testosterone therapies (TTh) are available that aim to restore serum testosterone (T) levels to the normal physiologic range. The magnitude, frequency, and duration between peak and trough T...

www.excelmale.com

3.6 Nasal administration

Approved by the FDA in May 2014, the nasal gel formulation of TTh (NATESTO® ) is a product using a metered-dose pump delivering 5.5 mg of T per pump actuation, with the recommended dosing of 2 pumps (11 mg; 1 actuation/nostril) administered intranasally 3 times daily (total 33 mg/day) 6 to 8 hours apart.77 Absorption occurs through the nasal mucosa, thereby avoiding hepatic first-pass metabolism, with approximately 75% of administered T entering the blood.78 Peak serum T levels were reached approximately 60 minutes post-application and declined to near baseline before the next dose. 79,80 In a randomized, dose-ranging, open-label phase 3 study of 306 men with TD (ClinicalTrials.gov NCT01446042), 11 mg nasal T dosed two times or three times daily resulted in between 71% and 91% of patients achieving serum TT concentrations within the defined range (10.4– 36.4 nmol/L; 300–1,050 ng/dL). At day 90, mean TT Cavg values were 13.0 and 14.6 nmol/L (375 and 421 ng/dL) for 11 mg dosed two or three times daily, respectively. 79 Compared with other routes of T delivery, nasal T gel administration results in rather low Cavg and Cmax TT levels, as well as DHT and DHT: T ratios, even with administering 11 mg three times daily. While patients experience 3 Cmax peaks in one day because of the required 3 daily doses, only 3.3% of patients had a Cmax between 62.4 and 86.7 nmol/L (1,800–2,500 ng/dL). At day 90, the Cmax and Cmin were 32.4 nmol/L (934.9 ng/dL) and 7.0 nmol/L (200.9 ng/dL), respectively, with a peak-to-trough ratio of 4.7. Furthermore, an ongoing phase 4 clinical trial suggests that not only can T nasal gel increases serum T over time, but it can also maintain FSH, LH, and semen parameters. 81




Figure 1. Extrapolated mean steady-state serum total testosterone concentrations. Estimated diurnal T in young men (blue, age range: 23-28 years) and older men (yellow, age range 58- 82 years). Red arrows indicate the time of T administration. Dotted lines indicate Cavg over the dosing interval of 168 hours. Black lines in each panel represent mean steady-state T profiles of A) weekly SC TE administration; B) average mean T profiles for IM TC, TE, and TU over 2 weeks; C) 900 mg subdermal T pellets; 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®; F) nasal gel T at day 90 three times daily; G) 30 mg buccal mucoadhesives applied twice daily, and 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. 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.

IM, intramuscular; SC, subcutaneous; T, testosterone; TC, testosterone cypionate; TE, testosterone enanthate; TU, testosterone undecanoate.


F. nasal gel

 

[Willyt]

Interesting side note on Empower's nasal gel. The folks at Defy included following comment with prescription of the 5mg gel: "(Note: Short-acting T nasal gel 1-2x/day will not suppress testosterone. 3x/day will)."

Natesto is same strength. The studies often cited by @madman were based on the 3x daily and showed minimal suppression of HPTA. Then again, the recommended Natesto dosing in USA is 3x per day versus Canada which is 2x.

 

[tareload]

Interesting side note on Empower's nasal gel. The folks at Defy included following comment with prescription of the 5mg gel: "(Note: Short-acting T nasal gel 1-2x/day will not suppress testosterone. 3x/day will)."

Natesto is same strength. The studies often cited by @madman were based on the 3x daily and showed minimal suppression of HPTA. Then again, the recommended Natesto dosing in USA is 3x per day versus Canada which is 2x.

Thanks for posting this. My personal discussion with the Brains of the operation over there included that if I was to try to recover my HPTA with Natesto or equivalent then I would pulse once per day with nasal gel or buccal troche. That's what I tentatively plan on trying at some point. Currently I've switched back exclusively to hCG monotherapy.

 

[madman]

Interesting side note on Empower's nasal gel. The folks at Defy included following comment with prescription of the 5mg gel: "(Note: Short-acting T nasal gel 1-2x/day will not suppress testosterone. 3x/day will)."

Natesto is same strength. The studies often cited by @madman were based on the 3x daily and showed minimal suppression of HPTA. Then again, the recommended Natesto dosing in USA is 3x per day versus Canada which is 2x.

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 starting dose 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.


Natesto Effects on Reproductive Hormones and Semen Parameters: Results from an Ongoing Single-center, Investigator-initiated Phase IV Clinical Trial (2018)


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]. 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]. 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 (Fig. 1). Maintaining normal LH and FSH has the theoretical benefit of preserving normal semen parameters while on TRT with Natesto. However, to date, no study has evaluated the effect of Natesto on semen parameters.

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 (Assessment of Autogenous Dentin Graft in Treatment of Infra-bony Defect - Full Text View - ClinicalTrials.gov NCT03203681). 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.

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. 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. Serum reproductive hormones, SA, and questionnaires will be collected at 3 and 6 mo of therapy. The duration of this study is 6 mo.

To date, we have enrolled 23 men. Their median age is 35 (interquartile range: 31.7–37.8) yr with a baseline T 228.8 (196.4–253.1) ng/dl, LH 3.3 (2.2–5.3) IU/ml, and FSH 3.9 (2.4–6.4) IU/ml. Overall, six of the 23 men have dropped out of the study. 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. 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), 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). 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), 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). IIEF-Q15 and SF-36 scores remained statistically unchanged from baseline to 3 mo and 6 mo.

We have accumulated promising initial data demonstrating that Natesto can not only increase serum T but also maintain FSH, LH, and importantly, semen parameters. 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. 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.


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.

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) Median follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels 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) Median semen analysis concentration, motility, and total motile sperm count 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

B

C

Nasal spray for low testosterone preserves fertility

CLICK2HOUSTON news Nasal spray for low testosterone preserves fertility

www.excelmale.com

*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.

Acerus Announces Publication of Study Results Demonstrating Effectiveness of NATESTO® Regardless of Baseline Symptom Severity

Acerus Announces Publication of Study Results Demonstrating Effectiveness of NATESTO® Regardless of Baseline Symptom Severity “Acerus continues to achieve important scientific milestones related to the global evolution of NATESTO®. With the publication of the study entitled Efficacy of...

www.excelmale.com

Take home points:

*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 NATESTO® does not suppress natural testosterone production


*Based on the data, Acerus believes that the mechanism of action of NATESTO® is unique whereby the 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


*The release of testosterone with NATESTO® is pulsatile - closely matching the body's "natural" testosterone release. Consequently, NATESTO® does not suppress a man's natural testosterone level, but simply adds to it to achieve a normal, safe level of testosterone


*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

Short-acting T therapy to maintain homeostasis that more closely reflects normal physiology

Short-Acting Testosterone: Physiologic? Gerwin Westfield, Ursula B Kaiser, Dolores J Lamb, Ranjith Ramasamy INTRODUCTION Pulsatile secretion of a hormone refers to the intermittent secretion of the hormone in a burst like or episodic manner rather than constantly, with the frequency...

www.excelmale.com

FINAL THOUGHTS

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). These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects. 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.

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. 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. 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. 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.

Impact of Short-Acting vs Long-Acting T Therapy on ITT

Abstract Introduction & Objective Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of the HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated...

www.excelmale.com

Conclusions

Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T which 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.








At least we have Lipschultz study to look forward to (end date 2023)!

The Effects of Natesto For Treatment Of Hypogonadism

https://clinicaltrials.gov/ct2/show/NCT04717362 Sponsor: Baylor College of Medicine Information provided by (Responsible Party): Larry I. Lipshultz, Baylor College of Medicine Detailed Description: Testosterone replacement therapy (TTh) is becoming increasingly common among men of...

www.excelmale.com

The Effects of Natesto For Treatment Of Hypogonadism (2021)


*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.

 

[Fortunate]

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 starting dose 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.


Natesto Effects on Reproductive Hormones and Semen Parameters: Results from an Ongoing Single-center, Investigator-initiated Phase IV Clinical Trial (2018)


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]. 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]. 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 (Fig. 1). Maintaining normal LH and FSH has the theoretical benefit of preserving normal semen parameters while on TRT with Natesto. However, to date, no study has evaluated the effect of Natesto on semen parameters.

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 (Assessment of Autogenous Dentin Graft in Treatment of Infra-bony Defect - Full Text View - ClinicalTrials.gov NCT03203681). 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.

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. 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. Serum reproductive hormones, SA, and questionnaires will be collected at 3 and 6 mo of therapy. The duration of this study is 6 mo.

To date, we have enrolled 23 men. Their median age is 35 (interquartile range: 31.7–37.8) yr with a baseline T 228.8 (196.4–253.1) ng/dl, LH 3.3 (2.2–5.3) IU/ml, and FSH 3.9 (2.4–6.4) IU/ml. Overall, six of the 23 men have dropped out of the study. 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. 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), 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). 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), 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). IIEF-Q15 and SF-36 scores remained statistically unchanged from baseline to 3 mo and 6 mo.

We have accumulated promising initial data demonstrating that Natesto can not only increase serum T but also maintain FSH, LH, and importantly, semen parameters. 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. 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.


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.
View attachment 19936




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) Median follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels 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) Median semen analysis concentration, motility, and total motile sperm count 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
View attachment 19937

B
View attachment 19938

C
View attachment 19939

Nasal spray for low testosterone preserves fertility

CLICK2HOUSTON news Nasal spray for low testosterone preserves fertility

www.excelmale.com

*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.

Acerus Announces Publication of Study Results Demonstrating Effectiveness of NATESTO® Regardless of Baseline Symptom Severity

Acerus Announces Publication of Study Results Demonstrating Effectiveness of NATESTO® Regardless of Baseline Symptom Severity “Acerus continues to achieve important scientific milestones related to the global evolution of NATESTO®. With the publication of the study entitled Efficacy of...

www.excelmale.com

Take home points:

*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 NATESTO® does not suppress natural testosterone production


*Based on the data, Acerus believes that the mechanism of action of NATESTO® is unique whereby the 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


*The release of testosterone with NATESTO® is pulsatile - closely matching the body's "natural" testosterone release. Consequently, NATESTO® does not suppress a man's natural testosterone level, but simply adds to it to achieve a normal, safe level of testosterone


*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

Short-acting T therapy to maintain homeostasis that more closely reflects normal physiology

Short-Acting Testosterone: Physiologic? Gerwin Westfield, Ursula B Kaiser, Dolores J Lamb, Ranjith Ramasamy INTRODUCTION Pulsatile secretion of a hormone refers to the intermittent secretion of the hormone in a burst like or episodic manner rather than constantly, with the frequency...

www.excelmale.com

FINAL THOUGHTS

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). These endocrine changes result in suppression of spermatogenesis and infertility, as well as having other side effects. 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.

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. 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. 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. 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.

Impact of Short-Acting vs Long-Acting T Therapy on ITT

Abstract Introduction & Objective Exogenous testosterone (T) replacement therapy (TRT) is typically long-acting and can potentially cause infertility in a majority of men due to suppression of the HPG axis. Intratesticular testosterone is vital for spermatogenesis and can be reliably evaluated...

www.excelmale.com

Conclusions

Natesto and other short-acting forms of TRT may help hypogonadal men maintain Intratesticular T which 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.








At least we have Lipschultz study to look forward to (end date 2023)!

The Effects of Natesto For Treatment Of Hypogonadism

https://clinicaltrials.gov/ct2/show/NCT04717362 Sponsor: Baylor College of Medicine Information provided by (Responsible Party): Larry I. Lipshultz, Baylor College of Medicine Detailed Description: Testosterone replacement therapy (TTh) is becoming increasingly common among men of...

www.excelmale.com

The Effects of Natesto For Treatment Of Hypogonadism (2021)


*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.

It's really interesting to see that the median T levels go up over six months. I would have to read the study to see who the population was. For example, where they guys who had suppression from prior TRT that then recovered some endogenous production while on Natesto? In any case, it's encouraging.