Advice on low dose daily

sammmy

Active Member
I can attest to this. Last year I tried microdosing cypionate EOD out of curiosity. It suppressed my natural production and I ended up feeling worse than my pre-TRT baseline.
Natesto nasal gel is an example of testosterone microdosing. It causes some but not complete suppression and the achieved average daily total testosterone level is not very high. However, it uses pure testosterone base not esters, and doses 3 times daily.

Since the natural testosterone production is 6mg/day, I estimate that the testosterone absorbed from Natesto is 2 mg OR LESS at each dosing. It should be possible to imitate that by injecting testosterone base 3 times a day.
 

Cataceous

Well-Known Member
...
Since the natural testosterone production is 6mg/day, I estimate that the testosterone absorbed from Natesto is 2 mg OR LESS at each dosing. It should be possible to imitate that by injecting testosterone base 3 times a day.
We were speculating about this in another thread. Is there any solid pharmacokinetic data for testosterone base that would buttress the proposition?
 

camygod

Member
We were speculating about this in another thread. Is there any solid pharmacokinetic data for testosterone base that would buttress the proposition?
i have heard and im not saying its fact or true that its the ester with the tesosterone that can cause more of the shut down and issues and low dose of pure base on its own wont do this i havent tried it so dont quote me but the person who was claiming this did not seem a idiot so take it for whats it worth also if you are hypogonadal i guess it wont help any way its worth a try i want to experiment with test base but a number of facotrs have prevented me this last year
 

Willyt

Member
No surprise her
Natesto nasal gel is an example of testosterone microdosing. It causes some but not complete suppression and the achieved average daily total testosterone level is not very high. However, it uses pure testosterone base not esters, and doses 3 times daily.

Since the natural testosterone production is 6mg/day, I estimate that the testosterone absorbed from Natesto is 2 mg OR LESS at each dosing. It should be possible to imitate that by injecting testosterone base 3 times a day.
Yes, I tried microdosing with Natesto too with more success. The major downsides were nasal application and inability to boost libido. You can see results here:

Natesto is 11mg per dose so your estimate of 2mg seems low as that would be poor absorption rate.
 

sammmy

Active Member
We were speculating about this in another thread. Is there any solid pharmacokinetic data for testosterone base that would buttress the proposition?

To imitate Natesto, the testosterone suspension has to be absorbed fast in 30mins - 2 hours. It is not clear if intramuscular or subcutaneous injection can achieve that.

I can't find any pharmacokinetic data on testosterone suspension, except one study in horses that injected a huge dose for horses that persisted for 30 days:
Horses administered IM aqueous testosterone suspension had what appeared to be a very rapid absorption phase with Tmax for most horses appearing between 1 and 2 h following drug administration (Fig. 1). This was followed by a slow decrease in plasma testosterone concentrations and a second peak in plasma concentration between 4 and 17 daysafter administration.


If that fails, the Wikipedia article Pharmacokinetics of testosterone suggests that fast absorption is obtained with:
  • oral testosterone undecanoate. It is taken several times a day like Natesto.
  • sublingual testosterone Testoral. This was absorption enhanced by complexing with cyclodextrine around 1996 but is no longer available. The idea of Natesto is actually a remake of Testoral. Some compounding pharmacies have testosterone drops or troches but it is rather unclear how much of testosterone is absorbed without special enhancers like cyclodextrine.
  • scrotal application of testosterone gel or cream. The dose will have to be higher than nasal/sublingual and there are claims that scrotal leads to higher DHT, compared to transdermal or sublingual/intranasal.

I am not at all convinced in the popular claim that scrotal application leads to higher DHT than transdermal or sublingual/nasal. The sublingual Testoral link above shows DHT increases by a factor of 6 at the peak 30 mins after administration. However, in this scrotal vs transdermal vs patch study, 2 hours after gel application, DHT increased by a factor of 6.5 in the scrotal group and by a factor of 5 in the transdermal group. So in terms of keeping DHT low, these studies show no difference between scrotal, sublingual, and transdermal modes of administration. I looked for DHT studies for Natesto but could not find any - it should be similar to sublingual Testoral though.
 
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Cataceous

Well-Known Member
To imitate Natesto, the testosterone suspension has to be absorbed fast in 30mins - 2 hours. It is not clear if intramuscular or subcutaneous injection can achieve that.

I can't find any pharmacokinetic data on testosterone suspension, except one study in horses that injected a huge dose for horses that persisted for 30 days:
...
Because of that equine study I've been assuming the testosterone would have to be in oil, though I suppose smaller crystal sizes could keep suspensions in the running. It's disappointing not to have this kind of pharmacokinetic data; it shouldn't be so difficult to make these measurements. There's just not enough incentive to fund the studies.
 

Willyt

Member
To imitate Natesto, the testosterone suspension has to be absorbed fast in 30mins - 2 hours. It is not clear if intramuscular or subcutaneous injection can achieve that.
@sammmy - Why does it matter how fast the test supension is absorbed so long as the user can reliably estimate when it will peak?

For example, I have experimented with Natesto enough to know that it takes about 1 hour for me to feel the effects. I then time my workouts around this with much success. In theory, you could do the same with suspension, possibly to time a libido boost.

Nelson had posted an interview awhile back with a Dr talking about this “on-demand” testosterone concept similar to timing ED medications.

Also, why does there appear to be a medical bias against TNE? No one seems willing to prescribe it although I have yet to ask Defy.
 

sammmy

Active Member
Because of that equine study I've been assuming the testosterone would have to be in oil, though I suppose smaller crystal sizes could keep suspensions in the running. It's disappointing not to have this kind of pharmacokinetic data; it shouldn't be so difficult to make these measurements. There's just not enough incentive to fund the studies.
The horse study was done with water testo suspension but no specification of concentration or ingredients. I was quite shocked of their graph that it was still detectable after 30 days in horses.

I would go for water testo suspension with the highest available concentration. That should decrease the volume of the injected water and should decrease the absorption time (a drop of smaller volume will have a higher ratio of contact surface to volume). I am not sure if using an oil suspension will speed up the absorption. The injectable esters are in oil and they do not absorb fast but the injectable volume with them is much larger and it is not clear what effect is played by the oil - does it speed up or slow down absorption.
 

sammmy

Active Member
@sammmy - Why does it matter how fast the test supension is absorbed so long as the user can reliably estimate when it will peak?

For example, I have experimented with Natesto enough to know that it takes about 1 hour for me to feel the effects. I then time my workouts around this with much success. In theory, you could do the same with suspension, possibly to time a libido boost.

Nelson had posted an interview awhile back with a Dr talking about this “on-demand” testosterone concept similar to timing ED medications.

Also, why does there appear to be a medical bias against TNE? No one seems willing to prescribe it although I have yet to ask Defy.
Absorption time matters if you want to simulate Natesto with fast peaks and fast valleys. This reduces suppression or testosterone production in the body. If all of your testosterone comes from TRT, you would not care of that - you are already suppressed.

TNE (unmodified testosterone suspension) is not in current use, probably because it is absorbed too fast, requiring too many injections to maintain testosterone levels. Also, its absorption will depend on the size of the testosterone crystals in the suspension, which is hard to control, making it unreliable. Last, testo crystal suspensions in water cause local reactions lasting for days, which are less frequent with oil solutions: Wikipedia - testosterone phenylacetate water suspension

I could not find a contemporary pharmacokinetic study for TNE in humans. Probably these were done in the early years of discovering testosterone and then TNE was replaced by the esters in oil because of the above arguments. Everywhere, there is cited the same dumb statement that "unmodified testosterone has a half-life of only 10 minutes and would have to be injected very frequently". However this is surely talking about the half-life in blood. When the suspension is injected in the muscle, it forms a water depot and it is not released instantly into circulation. By the way, the half-life of testosterone propionate in blood is also about 10 minutes because it is converted to pure testosterone very fast. The prolonged half-life of the propionate is actually due to
the oil depot in the muscle from which it is slowly released with the oil.
 
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sammmy

Active Member
A nice summary of unmodified testosterone suspension (unesterified testosterone) Testosterone suspension (note that there are two authors and they contradict each other on some points like hepatotoxicity):

Testosterone suspension contains (free) testosterone in a water-based suspension, although oils are sometime also used as carriers. Without esterification, testosterone has a short halflife in the body. Testosterone suspension may require a minimum of 2-3 injections per week to maintain consistent hormone elevations.
Since it is in a water base, it gets in the blood in a matter of hours and has a life of around a day.
Testosterone has low water solubility, so the steroid will noticeably separate from a water-based solution when a vial or ampule is left to sit. A quick shake will temporarily place the drug back into suspension, so that the withdrawn dosage should always be consistent.
Testosterone suspension contains undissolved testosterone particles, which form a shortacting repository in the muscle following injection. Depending on the size of the particles and other agents present, injections of testosterone suspension may result in local irritation, pain, and redness. Veterinary testosterone suspensions may use large particles that require a needle as large as 21 gauge for injection, for example, and can be very uncomfortable to use. Modern testosterone suspension preparations made for human use often contain microcrystalline steroid particles. These crystals are highly refined, and are too small to see with the naked eye. This design provides significantly more patient comfort than less refined products, and is generally well tolerated.
Although this drug does require a frequent injection schedule, a well-refined suspension should pass through a needle as fine as 27 gauge (insulin). This allows the user more available injection sites, hitting the smaller muscle groups such as the deltoid, triceps, and calves.
Testosterone suspension has been unavailable in the United States for many years now. No old products should still be in circulation. Because the FDA never officially withdrew this drug from, it can be specially ordered through a small number of compounding pharmacies. Anything else bearing a U.S. manufacturer name is counterfeit. Testosterone suspension is still produced in India under the Aquaviron brand name, now by Piramal HC. It comes in the strength of 25 mg/mL, and is packaged in 1 mL ampules.
 

camygod

Member
heard you can take micronized test suspension sublinqualy too people may scoff but the famous russian steriod coctail the duchess was taken as oral soulation too so the idea that it wont absorb might by flawed
 

Willyt

Member
heard you can take micronized test suspension sublinqualy too people may scoff but the famous russian steriod coctail the duchess was taken as oral soulation too so the idea that it wont absorb might by flawed
So I had to look up the Dutchess cocktail. Fascinating story.

“Rodchenkov said his formula was exact: For very milliliter of alcohol, he used one milligram of the steroid blend. Rather than just downing the mixture, which would delay the absorption of the drugs until they could crossed the barrier of the stomach, the athletes "were instructed to swish the liquid around in their mouths, under the tongue,"
 

sammmy

Active Member
The Dutchess cocktail did not include pure testosterone (TNE), which is soluble in ethanol (drinking alcohol) at 0.5 mg/ml (according to Sigma - Aldrich quoted below). Just dropping water suspension of TNE sublingually is unlikely to result in significant absorption - they needed to complex it with cyclodextrin in 1996 to aid absorption:

Testosterone dissolves in chloroform at 100 mg/ml to yield a clear, colorless to very faint yellow solution. It is also soluble in methanol, absolute ethanol (0.5 mg/ml), 45 percent (w/v) aqueous 2-hydroxypropyl-b-cyclodextrin (18.2 mg/ml), vegetable oils and dioxane. It is slightly soluble in methyl oleate and insoluble in water.

I think though that the Sigma - Aldrich has a typo about the testosterone solubility in ethanol. Other sources site something like 160 mg/mL.
 
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camygod

Member
The Dutchess cocktail did not include pure testosterone (TNE), which is soluble in ethanol (drinking alcohol) at 0.5 mg/ml (according to Sigma - Aldrich quoted below). Just dropping water suspension of TNE sublingually is unlikely to result in significant absorption - they needed to complex it with cyclodextrin in 1996 to aid absorption:



I think though that the Sigma - Aldrich has a typo about the testosterone solubility in ethanol. Other sources site something like 160 mg/mL.
sorry i ment having the micronized base powder mixed with something like ethanol or dsmo or i heard vitamin e oil not just waster based suspesnion put in your mouth thats ment to be injected
 

madman

Member
i have heard and im not saying its fact or true that its the ester with the tesosterone that can cause more of the shut down and issues and low dose of pure base on its own wont do this i havent tried it so dont quote me but the person who was claiming this did not seem a idiot so take it for whats it worth also if you are hypogonadal i guess it wont help any way its worth a try i want to experiment with test base but a number of facotrs have prevented me this last year


False!

This is key: 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.





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.
 

madman

Member
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 varying from minutes to hours, determined in part by the half-life of the hormone.

T levels in a healthy male follow a diurnal variation and circadian rhythm, with levels highest early in the morning and subsequently declining as the day progresses, as a direct result of pulsatile LH secretion

A sustained steady-state level of T, however, differs from the normal circadian physiology of a healthy individual.


*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.




*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.
 

madman

Member
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.


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


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.
 

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