Official Natesto Thread

[Fortunate]

Welcome to the Natesto thread. I have used Natesto on an off for several years, but it seems to be one of the less popular TRT options here. That said, I have seen a few readers mention it, and I thought it would be good to start a dedicated thread on Natesto where people can share their thoughts and experiences.

Briefly, Natesto is a nasal gel used 2-3 times a day. It is by far the most inconvenient form of TRT. But, it has a lot of upsides, along with a few downsides. I have concluded:

UPSIDES:

• It works quickly. Within an hour or so
• It also wears off quickly
  • why is this an upside? If you are one who discovers you don't tolerate TRT, you don't have to live with unpleasant side effects for days (or even months with something like pellets)
• Your system sees T in pulsatile fashion, so it does not shut down endogenous production
• It tends not to elevate E2
• No needles
• No transfer to family members
• It seems to really help with mood
  • One of the primary reasons people seek TRT is to address the psychologic aspects of low T, such as mood, libido and energy (energy may fall into more than just the psychologic category). Natesto seems to be excellent with mood, but not as good with libido
• It tends not to elevate hematocrit

Downsides:

• Inconvenient for some (three times a day, nasal)
• Unpleasant application for some (nasal route, which I don't mind that much)
• Cost
  • somehow, it is pretty inexpensive for me. I think my pharmacy uses insurance and/or coupons
• I don't think there is very much of an anabolic benefit
  • this is hard thing to conclude, but I think it's safe to say it's less anabolic than just about any other form of TRT
• Does not seem to boost libido
  • I am likely going back to Natesto. I will track this and report back, but I am fairly certain that it does not help libido much at all (definitely not when compared to cream)
• Over time, rubbing your nose can cause skin irritation around the nose
  • Natesto requires brief rubbing of the nostrils to spread the medication
  • I break out easily and one of the things that can encourage a break out is skin to skin pressure. I think Natesto may cause some local skin irritation
• I sometimes I worry that the dosing may not be consistent
  • it can be hard to apply it the same way every time
• I wonder if nasal congestion can inhibit uptake
  • although, I did read that seasonal allergy related congestion does not alter absorption

For me, most forms of TRT help early on. Over time, TRT can become unpleasant, presumably from gradual elevation of average concentration levels and/or peak/trough levels. While I have not pinned down exactly what causes me to feel bad, possibilities included excess T, excess E2, excess DHT or some suboptimal ratio of these. The excesses cause some downstream events that translate into feeling bad.

Natesto simply does not do this. I never feel "over the top" on it. It is the gentlest form of TRT for me. On the other hand, it would be nice if it could help more with libido and body composition.

Ultimately, for me, it comes down to prioritizing. I would sacrifice some libido and body composition in order to feel mentally clear and emotionally content. But, it sure would be nice to figure out some way to "have it all".

The things I currently would like to know:

• Is there a way to boost libido while using Natesto?
• Empower compounds a nasal gel
  • how does it compare to Natesto?
    • easier to use?
    • cost?
  • there are two dosing options
    • does the higher dosing provide benefit over the standard dose, or is the extra T somehow superfluous?
• @Tester has mentioned his experience with a nasal spray. After learning a bit about this, it sounds interesting, but has to be applied very frequently (more than Natesto). Does anyone else have experience with a spray?

Questions or comments about Natesto? Feel free to leave feedback, ask questions or make suggestions.

 

[Cataceous]

...
For me, most forms of TRT help early on. Over time, TRT can become unpleasant, presumably from gradual elevation of average concentration levels and/or peak/trough levels. While I have not pinned down exactly what causes me to feel bad, possibilities included excess T, excess E2, excess DHT or some suboptimal ratio of these. The excesses cause some downstream events that translate into feeling bad.
...

Another possibility is TRT's disruption of upstream hormones: kisspeptin, GnRH, LH, FSH, progesterone, DHEA, pregenolone... I've found that "putting back" some of these makes me feel a lot closer to normal. In some cases TRT can also interfere with the adrenal and thyroid axes.

I would like to see greater awareness of Natesto and its equivalents. I think they should be the first-line treatment for hypogonadism. Conventional TRT is such a blunt instrument that at times it feels like the two steps forwards one makes in resolving symptoms are offset by at least a step backwards in the form of side effects.

 

[Fortunate]

Has anyone here used Empower's version of nasal gel? If so, what was your experience? How would you compare it to Natesto?

 

[Lucky Cat]

I've used the nasal gel by Empower. It's more like a cream, very easy to apply if you do it right. The gel comes in a 3ml pen-like syringe that's about the size of a magic marker. One full rotation will give you 8 clicks, and that's what you apply to each nostril (5mg + 5gm= 10mg). One syringe lasts 10 days if you apply it 3x/day, so you need 3 syringes per month. I think I was quoted $45 for a syringe. I haven't used the Natesto gel since it's very pricey, but their dosage is pretty much equivalent- 5.5mg + 5.5mg (each nostril)= 11mg per dosage.

 

[Nelson Vergel]

Natesto posts on ExcelMale.com

 

[Fortunate]

Natesto posts on ExcelMale.com

Thanks, Nelson. That's actually really helpful. I clearly need to get more facile at my search capabilities!

@stx359 made mention a few years ago about being on a combination of Natesto and cream. I have a question out to him to see if he is still doing this combo. I actually did this a few years ago and had good results. I am considering it again, but am wondering if anyone else has experience with this combination? Part of the benefit of Natesto is that it preserves endogenous production, but I believe it was @Cataceous that suggested this combo defeats the purpose of maintaining endogenous production, as it would shut it down. It's a good point. On the other hand, I think it worked for me, so I am considering it again. I also don't know where my endogenous production is. I was on hCG for years (100-150 IU/day), but recently stopped (feel better off it).

 

[stx359]

Thanks, Nelson. That's actually really helpful. I clearly need to get more facile at my search capabilities!

@stx359 made mention a few years ago about being on a combination of Natesto and cream. I have a question out to him to see if he is still doing this combo. I actually did this a few years ago and had good results. I am considering it again, but am wondering if anyone else has experience with this combination? Part of the benefit of Natesto is that it preserves endogenous production, but I believe it was @Cataceous that suggested this combo defeats the purpose of maintaining endogenous production, as it would shut it down. It's a good point. On the other hand, I think it worked for me, so I am considering it again. I also don't know where my endogenous production is. I was on hCG for years (100-150 IU/day), but recently stopped (feel better off it).

No I am not currently on this regimen. I even made a second attempt at it, this time in conjunction with Cataceous' HPTA restart protocol, which was successful, but the Natesto was not. My trough numbers were absurdly low, in the 200's, and even my sensitive E2 came back 14 which I don't believe to be a healthy number. Now I am on daily testosterone proprionate injections. Honestly I can't remember ever having a positive outcome from any topical testosterone application, either Natesto or cream, in several trials. It has never done a thing for me.

 

[Match]

Parte do benefício do Natesto é que ele preserva a produção endógena, mas acredito que foi [USUÁRIO = 38109] @Cataceous [/ USUÁRIO] que sugeriu que esta combinação anula o propósito de manter a produção endógena, pois iria desligá-la. É um bom ponto. Por outro lado, acho que funcionou para mim, então estou considerando novamente. Também não sei onde está minha produção endógena. Eu usei hCG por anos (100-150 UI / dia), mas parei recentemente (me sinto melhor com isso).

I wonder if Androgel blocks endogenproduction, HPA axis, or is similar to Natesto

 

[sammmy]

Natesto (nasal testosterone) is the least suppressive, Androgel (topical is more suppressive) and injectable are most suppressive.

Look at graphs in this post: suppression on various T forms

 

[Cataceous]

...
The things I currently would like to know:

• Empower compounds a nasal gel
  • how does it compare to Natesto?
    • easier to use?
    • cost?
  • ...

I happened to speak directly with an Empower pharmacist about this today. She said that while they do not perform their own pharmacokinetic studies, it is their intent for their testosterone nasal gel product to be comparable to Natesto, with similar dosing and pharmacokinetics.

Via Defy Medical the cost is currently $65 per 3 mL of 5 mg T/0.05 mL. This is 10 days worth at standard dosing of 30 mg per day, which puts the cost at about $200 per month. Empower has a double-strength product, $79 per 3 mL of 10 mg/0.05 mL. It's not clear if it only dispenses 10 mg doses, or if you can also dispense the normal 5 mg doses. If you can dispense the smaller doses then it's possible the cost to use it would be less.

 

[TLawyer]

I happened to speak directly with an Empower pharmacist about this today. She said that while they do not perform their own pharmacokinetic studies, it is their intent for their testosterone nasal gel product to be comparable to Natesto, with similar dosing and pharmacokinetics.

Via Defy Medical the cost is currently $65 per 3 mL of 5 mg T/0.05 mL. This is 10 days worth at standard dosing of 30 mg per day, which puts the cost at about $200 per month. Empower has a double-strength product, $79 per 3 mL of 10 mg/0.05 mL. It's not clear if it only dispenses 10 mg doses, or if you can also dispense the normal 5 mg doses. If you can dispense the smaller doses then it's possible the cost to use it would be less.

Is the 5 mg dose the same as the Natesto dose?

 

[Cataceous]

Is the 5 mg dose the same as the Natesto dose?

The Natesto dose is 5.5 mg, so close enough. In either case you apply one dose to each nostril two or three times a day.

 

[TLawyer]

The Natesto dose is 5.5 mg, so close enough. In either case you apply one dose to each nostril two or three times a day.

Is there a study that compares administering it twice per day versus three times per day?

 

[madman]

Is there a study that compares administering it twice per day versus three times per day?

NatestoTM, a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men (2015)


Study procedures

Randomization occurred on Day 1 via the ClinTrakTM Interactive Voice Response System (Medpace, Inc.; Cincinnati, OH), with subjects randomly assigned in a 3:1 ratio to the titration or the fixed-dose arm, respectively (Fig. 2). Following randomization, all subjects were instructed on the use of the medication dispenser and then received their first dose in the clinic at 2100 h. Subjects assigned to the titration arm were instructed to take 1 actuation (5.5 mg) per nostril of study medication at 0700 h and 2100 h (b.i.d., total dose 22 mg/day), while subjects assigned to the fixed-dose arm took 5.5 mg per nostril at 0700 h, 1300 h, and 2100 h (t.i.d, total dose 33 mg/ day). Subjects in the titration arm having an estimated serum total testosterone average concentration (Cavg) of <300 ng/dL (measured at Day 30) were up-titrated to t.i.d. on Day 45. Subjects continued treatment through the 90-day Treatment Period and, as applicable, through both Safety Extension Periods out to 1 year (Supplemental Data S1).


RESULTS

Figure 3 shows a plot of 24-h serum total testosterone concentration-time curves at Day 90 by treatment regimen. The mean total testosterone Cavg increased from 200.8 ng/dL at baseline into the normal range in all groups after 90 days of treatment (Table 3). Mean total testosterone Cavg were 375 and 421 ng/dL for b.i.d and t.i.d. regimens, respectively. Among subjects whose Cavg value was in the normal range, the mean values were 415 ng/dL for the b.i.d. and 428 ng/dL for the t.i.d. regimens. Geometric mean total testosterone Cmax values did not exceed the upper limit of normal (ULN) for the b.i.d. and t.i.d. regimens at Day 90.


DISCUSSION

In the case of testosterone nasal gel, 90% of hypogonadal subjects in the fixed-dose arm and 68% of subjects in the titration arm (ITT) were in the eugonadal range (300–1050 ng/dL) after 90 days of treatment with testosterone nasal gel. Subject’s mean total testosterone Cavg level after 90 days was 415 ng/dL when taking the b.i.d. dose and 428 ng/dL when receiving the t.i.d. dose. These levels are consistent with the mean Cavg (418 ng/dL) reported for a large, population-based epidemiological survey of healthy adult males aged 30–79 years (Litman et al., 2006). After considering the protocol violations, the PP percentage of subjects achieving normal serum testosterone is 91% in the fixed-dose arm and 71% in the titration arm. Protocol violations included failure to up-titrate subjects upon the direction of the physician or at patient request (b.i.d. being adequate for symptoms) despite estimated Cavg values <300 ng/dL. Notably, the percentage of PP subjects in the normal range on the b.i.d. dose of the titration arm was 75% (95% CI, 66–83%).

Each individual dose of nasal gel provides a reproducible short-acting peak that returns near to baseline by the time of the next dose. While there are up to three peaks per profile, Cmax values were consistently below 1500 mg/d and only 3.3% of subjects had values of 1800–2500 ng/dL. While one subject showed a Cmax >2500 ng/dL (3570 ng/dL); this subject would appear to have violated the protocol by continuing finasteride treatment. No safety concerns were identified for this subject

The peaks-and-troughs PK profile did not appear to have a negative impact on symptomatology. There were statistically significant improvements because of treatment in mean values for the erectile function and mood, and positive trends in improvement for body composition and BMD when compared to pretreatment baseline values.


*Some limitations of this study should be noted. The pharmacokinetic analysis is the key primary endpoint to determine the efficacy of testosterone therapies. The study was not blinded and did not include an active comparator or a placebo control limiting the usefulness of a variety of measures including secondary efficacy endpoints (IIEF, PANAS, and BMD) which were analyzed against baseline values and between the b.i.d. and t.i.d. regimens and are only indicators.

*Subjects with nasal disorders were excluded from the study (exclusion criteria). Single-dose pharmacokinetics of nasal testosterone administration was determined in subjects with active seasonal rhinitis (unpublished results) and treated with oxymetazoline; the results showed a relative decrease in testosterone absorption. It is recommended that patients consult their doctor when nasal inflammation occurs.




Table 2 Primary efficacy measure: percentage of testosterone nasal gel-treated subjects with serum total testosterone Cavg in the normal range at Day 90 of the treatment period by treatment and by population.

Figure 3 Plot of 24-h total testosterone concentration-time curves by treatment regimen and time point at Day 90 in the intent-to-treat population. Data are shown for the b.i.d. dosing (n = 141) (A), and the t.i.d. dosing (n = 77) (B).

Table 3 Pharmacokinetics of serum total testosterone by treatment regimen at Day 90 of the treatment period in the intent-to-treat population.

 

[madman]

When it comes to dosing (BID/TID) it is critical that doses are taken 6 hours apart which would ensure a long enough trough time that minimizes suppression of the HPG-axis.

Keep in mind that most are hitting short-lived peaks in TT <1000 ng/dL.



Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels (2019)


*TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period

*The 24-hour PK profile of testosterone for patients receiving TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur, on average, every 2 hours. A maximal peak of testosterone appears at about 1 hour, followed by a return to endogenous, predose levels 4 to 6 hours later (half-life ∼1 hour) [4]. The nadir (trough) between doses correlates well with pretreatment endogenous levels at diagnosis

*The unique, pulsatile PK profile is believed to have limited impact on the hypothalamic-pituitary-gonadal (HPG) axis, with substantial trough time preserving LH, FSH, and endogenous testosterone production, and sperm counts [16, 17], while also limiting excess red blood cell production, estradiol, DHT, and prostate-specific antigen levels in clinical trials [4]

*TNG maintains the endogenous HPG axis. This is clearly evident in single-dose PK profiles in healthy men and those with TDS for whom the predose value (t = 0), which corresponds to the patient’s endogenous TT level, was found again at the bottom of the trough between peaks and was maintained through 90 days of treatment (for twice- and thrice-daily doses). Additional evidence of active HPG when receiving TNG treatment is found in a recent trial showing unchanged sperm counts after 6 months of TNG treatment (thrice-daily dose only) [17]. In larger trials, LH and FSH measurements were made proximal to a peak of TNG and were somewhat depressed, but they remained in the normal range [16]. Our interpretation of these observations is that the HPG axis is active and there is temporal suppression when TNG doses are administered. This suppression appears to recover completely, on the basis of consistent trough values over time

*In fact, the observed PK profile after a TNG dose is a sum of all sources of testosterone [20, 21]; exogenous and endogenous sources were not independently quantifiable in this study. When exogenous testosterone was administered, there was a suppression of LH and testosterone production. Endogenous testosterone levels decreased as a result of ongoing elimination and reduced or halted production. Later (>1 hour after administration), as the exogenous testosterone absorption rate was reduced and elimination predominated, resulting in a drop in exogenous testosterone, the HPG recovered, reinitiating endogenous testosterone production (Fig. 6a). The degree of HPG suppression appeared to be proportional to the initial baseline TT. For patients with less severe hypogonadism with a supposedly more active HPG and higher baseline TT level, there was more endogenous testosterone suppression during each dose than for a patient with more severe hypogonadism with less HPG axis potential (Fig. 6b). This model is supported by the larger decreases in LH in patients with higher baseline TT concentration seen in this study. It should be noted that in the Rogol et al. study [15], administration of TNG to healthy men with a predose TT baseline of 534 ng/dL (18.4 nmol/L) also showed Cmax peak levels in the same range as seen in this study and again a return to predose baseline nearly 6 hours after a dose

*Thus, TNG’s ultradian profile is the means to maintain an active HPG. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes

*Thus, an ultradian, pulsatile PK profile allows maintenance of the endogenous feedback mechanism when treated with TNG, which serves multiple purposes. First, very high peaks of TT are only rarely observed [3.3% of patients had a Cmax of 1800 to 2500 ng/dL (63.0 to 87.0 nmol/L) in the phase 3 study], because the active feedback mechanism provides a control mechanism keeping the TT levels in check. Second, troughs between peaks reduce overall exposure, helping to limit adverse effects of testosterone treatment, such as hematocrit overproduction (no patients had hematocrit values ≥54% in either the phase 3 or phase 4 studies) [22]. Third, troughs allow for the secretion of gonadotropins that maintain active testicular testosterone production, as well as sperm. Last, as shown here, the combination of peaks and troughs is sufficient to achieve symptom efficacy even for patients with the most severe TDS in this study. Overall, there are positive benefits to a treatment approach that is compatible with HPG physiology

*TNG treatment restores TT levels while preserving important aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels








NATESTO® Product Monograph

Dosing Considerations
NATESTO is a testosterone nasal gel available in a dispenser with a metered-dose pump. One pump actuation delivers 5.5 mg of testosterone per nostril. Each dose is applied as two actuations (one per nostril), for a total dose of 11.0 mg. NATESTO is dosed either two or three times daily.


Recommended Dose and Dosage Adjustment
The recommended starting dose of NATESTO (testosterone) is 11.0 mg of testosterone (1 actuation per nostril) administered intranasally twice daily for a total daily dose of 22.0 mg.

The NATESTO dose can be increased to a maximum recommended dose of 11.0 mg three times daily (33mg total daily dose) if either of the following conditions are met:

1) a serum total testosterone from a single blood draw sample taken 20 minutes to 2 hours after a morning application of NATESTO is less than 300 ng/dL.

2) if symptoms are not adequately treated within 90 days.


Serum total testosterone concentrations should be checked periodically:

• If the measured serum total testosterone concentration from the single morning blood draw is less than 300 ng/dL, the daily dose of NATESTO may be increased to 33.0 mg daily;

• For patients on the maximum recommended dose and whose serum total testosterone concentration from the single morning blood draw is consistently less than 300 ng/dL and a desired clinical response is not achieved, NATESTO should be discontinued and an alternative treatment should be considered.

If a post-dose morning total testosterone concentration consistently exceeds 1050 ng/dL, NATESTO should be discontinued.


Missed Dose
If a dose is missed, patients are instructed to skip the dose and take their next scheduled dose.

Administration
For twice daily, NATESTO is administered once in the morning and once in the evening (at least 6 hours from the prior dose and at least 1 hour before laying down for bed), preferably at the same time each day. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose. For three times daily, NATESTO is administered intranasally once in the morning, once in the afternoon and once in the evening (approximately 6-8 hours apart and at least 1 hour before laying down for bed), preferably at the same time each day. Do not administer NATESTO to other parts of the body including the scrotum, penis, abdomen, shoulders, axilla, or upper arms.




Figure 1: Mean Serum Total Testosterone Concentrations on Day 90 in Patients Following NATESTO 22.0 mg Daily Administered at 9 p.m. and 7 a.m. (N=122) and 33.0 mg Daily Administered at 9 p.m., 7 a.m. and 1 p.m. (N=151)

Adult dose: The recommended starting therapy is two doses (1 dose = 1 actuation per nostril) per day for a total of 22 mg. Each actuation contains 5.5 mg of testosterone. Your dose may be increased by your healthcare professional to 33 mg/day applied in three doses (1 dose = 1 actuation per nostril). Doses must be at least 6 hours apart. The night dose should be taken at least 1 hour before laying down for bed.

*TNG 4.5% testosterone nasal gel (Natesto®; Acerus Pharmaceuticals Corporation, Mississauga, Ontario, Canada) is a thixotropic gel that is applied in the nasal cavity [13]. Testosterone levels or symptoms are used to guide titration decisions [13] between either twice- or thrice-daily doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than with once-daily topical gels [14].

 

[Willyt]

I happened to speak directly with an Empower pharmacist about this today. She said that while they do not perform their own pharmacokinetic studies, it is their intent for their testosterone nasal gel product to be comparable to Natesto, with similar dosing and pharmacokinetics.

Via Defy Medical the cost is currently $65 per 3 mL of 5 mg T/0.05 mL. This is 10 days worth at standard dosing of 30 mg per day, which puts the cost at about $200 per month. Empower has a double-strength product, $79 per 3 mL of 10 mg/0.05 mL. It's not clear if it only dispenses 10 mg doses, or if you can also dispense the normal 5 mg doses. If you can dispense the smaller doses then it's possible the cost to use it would be less.

I wonder if there are any practical differences between Natesto and Empowers version since there are a bunch of patents related to Natesto Good to know that Empower is more affordable

 

[Strengthandlibido]

Another possibility is TRT's disruption of upstream hormones: kisspeptin, GnRH, LH, FSH, progesterone, DHEA, pregenolone... I've found that "putting back" some of these makes me feel a lot closer to normal. In some cases TRT can also interfere with the adrenal and thyroid axes.

I would like to see greater awareness of Natesto and its equivalents. I think they should be the first-line treatment for hypogonadism. Conventional TRT is such a blunt instrument that at times it feels like the two steps forwards one makes in resolving symptoms are offset by at least a step backwards in the form of side effects.

So would I.

Do you think Natesto's relatively light shutdown effects are enough to allow for some recovery from traditional TRT? Or should one recover first, then try Natesto?

 

[Cataceous]

...
Do you think Natesto's relatively light shutdown effects are enough to allow for some recovery from traditional TRT? Or should one recover first, then try Natesto?

I've wondered about this. I think a recovery would eventually happen. It would be slower than when stopping testosterone totally. But it might also avoid most of the unpleasant side effects of immediately going without any exogenous testosterone. I expect you could speed up the process by taking enclomiphene for a few weeks.

 

[madman]

So would I.

Do you think Natesto's relatively light shutdown effects are enough to allow for some recovery from traditional TRT? Or should one recover first, then try Natesto?

post #27

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

 

[TLawyer]

When it comes to dosing (BID/TID) it is critical that doses are taken 6 hours apart which would ensure a long enough trough time that minimizes suppression of the HPG-axis.

Keep in mind that most are hitting short-lived peaks in TT <1000 ng/dL.



Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels (2019)


*TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period

*The 24-hour PK profile of testosterone for patients receiving TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur, on average, every 2 hours. A maximal peak of testosterone appears at about 1 hour, followed by a return to endogenous, predose levels 4 to 6 hours later (half-life ∼1 hour) [4]. The nadir (trough) between doses correlates well with pretreatment endogenous levels at diagnosis

*The unique, pulsatile PK profile is believed to have limited impact on the hypothalamic-pituitary-gonadal (HPG) axis, with substantial trough time preserving LH, FSH, and endogenous testosterone production, and sperm counts [16, 17], while also limiting excess red blood cell production, estradiol, DHT, and prostate-specific antigen levels in clinical trials [4]

*TNG maintains the endogenous HPG axis. This is clearly evident in single-dose PK profiles in healthy men and those with TDS for whom the predose value (t = 0), which corresponds to the patient’s endogenous TT level, was found again at the bottom of the trough between peaks and was maintained through 90 days of treatment (for twice- and thrice-daily doses). Additional evidence of active HPG when receiving TNG treatment is found in a recent trial showing unchanged sperm counts after 6 months of TNG treatment (thrice-daily dose only) [17]. In larger trials, LH and FSH measurements were made proximal to a peak of TNG and were somewhat depressed, but they remained in the normal range [16]. Our interpretation of these observations is that the HPG axis is active and there is temporal suppression when TNG doses are administered. This suppression appears to recover completely, on the basis of consistent trough values over time

*In fact, the observed PK profile after a TNG dose is a sum of all sources of testosterone [20, 21]; exogenous and endogenous sources were not independently quantifiable in this study. When exogenous testosterone was administered, there was a suppression of LH and testosterone production. Endogenous testosterone levels decreased as a result of ongoing elimination and reduced or halted production. Later (>1 hour after administration), as the exogenous testosterone absorption rate was reduced and elimination predominated, resulting in a drop in exogenous testosterone, the HPG recovered, reinitiating endogenous testosterone production (Fig. 6a). The degree of HPG suppression appeared to be proportional to the initial baseline TT. For patients with less severe hypogonadism with a supposedly more active HPG and higher baseline TT level, there was more endogenous testosterone suppression during each dose than for a patient with more severe hypogonadism with less HPG axis potential (Fig. 6b). This model is supported by the larger decreases in LH in patients with higher baseline TT concentration seen in this study. It should be noted that in the Rogol et al. study [15], administration of TNG to healthy men with a predose TT baseline of 534 ng/dL (18.4 nmol/L) also showed Cmax peak levels in the same range as seen in this study and again a return to predose baseline nearly 6 hours after a dose

View attachment 18559
View attachment 18560

*Thus, TNG’s ultradian profile is the means to maintain an active HPG. Despite modest Cavg, significant Cmax values may be sufficient for positive symptom outcomes

*Thus, an ultradian, pulsatile PK profile allows maintenance of the endogenous feedback mechanism when treated with TNG, which serves multiple purposes. First, very high peaks of TT are only rarely observed [3.3% of patients had a Cmax of 1800 to 2500 ng/dL (63.0 to 87.0 nmol/L) in the phase 3 study], because the active feedback mechanism provides a control mechanism keeping the TT levels in check. Second, troughs between peaks reduce overall exposure, helping to limit adverse effects of testosterone treatment, such as hematocrit overproduction (no patients had hematocrit values ≥54% in either the phase 3 or phase 4 studies) [22]. Third, troughs allow for the secretion of gonadotropins that maintain active testicular testosterone production, as well as sperm. Last, as shown here, the combination of peaks and troughs is sufficient to achieve symptom efficacy even for patients with the most severe TDS in this study. Overall, there are positive benefits to a treatment approach that is compatible with HPG physiology

*TNG treatment restores TT levels while preserving important aspects of HPG function, including the continued release of gonadotropins and production of endogenous testosterone, which allows maintenance of baseline levels








NATESTO® Product Monograph

Dosing Considerations
NATESTO is a testosterone nasal gel available in a dispenser with a metered-dose pump. One pump actuation delivers 5.5 mg of testosterone per nostril. Each dose is applied as two actuations (one per nostril), for a total dose of 11.0 mg. NATESTO is dosed either two or three times daily.


Recommended Dose and Dosage Adjustment
The recommended starting dose of NATESTO (testosterone) is 11.0 mg of testosterone (1 actuation per nostril) administered intranasally twice daily for a total daily dose of 22.0 mg.

The NATESTO dose can be increased to a maximum recommended dose of 11.0 mg three times daily (33mg total daily dose) if either of the following conditions are met:

1) a serum total testosterone from a single blood draw sample taken 20 minutes to 2 hours after a morning application of NATESTO is less than 300 ng/dL.

2) if symptoms are not adequately treated within 90 days.


Serum total testosterone concentrations should be checked periodically:

• If the measured serum total testosterone concentration from the single morning blood draw is less than 300 ng/dL, the daily dose of NATESTO may be increased to 33.0 mg daily;

• For patients on the maximum recommended dose and whose serum total testosterone concentration from the single morning blood draw is consistently less than 300 ng/dL and a desired clinical response is not achieved, NATESTO should be discontinued and an alternative treatment should be considered.

If a post-dose morning total testosterone concentration consistently exceeds 1050 ng/dL, NATESTO should be discontinued.


Missed Dose
If a dose is missed, patients are instructed to skip the dose and take their next scheduled dose.

Administration
For twice daily, NATESTO is administered once in the morning and once in the evening (at least 6 hours from the prior dose and at least 1 hour before laying down for bed), preferably at the same time each day. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose. For three times daily, NATESTO is administered intranasally once in the morning, once in the afternoon and once in the evening (approximately 6-8 hours apart and at least 1 hour before laying down for bed), preferably at the same time each day. Do not administer NATESTO to other parts of the body including the scrotum, penis, abdomen, shoulders, axilla, or upper arms.




Figure 1: Mean Serum Total Testosterone Concentrations on Day 90 in Patients Following NATESTO 22.0 mg Daily Administered at 9 p.m. and 7 a.m. (N=122) and 33.0 mg Daily Administered at 9 p.m., 7 a.m. and 1 p.m. (N=151)
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Adult dose: The recommended starting therapy is two doses (1 dose = 1 actuation per nostril) per day for a total of 22 mg. Each actuation contains 5.5 mg of testosterone. Your dose may be increased by your healthcare professional to 33 mg/day applied in three doses (1 dose = 1 actuation per nostril). Doses must be at least 6 hours apart. The night dose should be taken at least 1 hour before laying down for bed.
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*TNG 4.5% testosterone nasal gel (Natesto®; Acerus Pharmaceuticals Corporation, Mississauga, Ontario, Canada) is a thixotropic gel that is applied in the nasal cavity [13]. Testosterone levels or symptoms are used to guide titration decisions [13] between either twice- or thrice-daily doses used to restore testosterone levels to the normal range. Surprisingly, patients report higher convenience with TNG than with once-daily topical gels [14].

Just ordered the 5.0 mg dose from Defy. Their first instinct was to go with the 10 mg, but I want to try and mimic Natesto as much as possible. I figure I can always increase it after a few weeks if I am not getting results. Excited to give this is a try and compare to how I have felt on Enclomiphene. Hoping that it can help keep my E2 under better control.