Maximus: Oral TRT+ (native T + enclomiphene + pregnenolone)

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Defy Medical TRT clinic doctor

Cataceous

Super Moderator
Look at this patient's bloodwork. You ever seen a Total T> 1500 and Free T> 350 with an LH of 5.4 and FSH of 8.9? Remarkable.

The clinical trial is being published on Monday on Maximus' website.
I'm concerned about this patient's relatively low estradiol and excessive vitamin D.

In terms of duration of action this product seems to lie between Natesto and oral testosterone undecanoate, perhaps better explaining why HPTA function can be preserved with the aid of enclomiphene.

On September 29, 2023, the FDA included enclomiphene on its 503A bulks list, which makes it clear that it is legal to compound.
...
That's good to know. I'm surprised I missed the news.

...
The point wasn't to fear monger but to dispel the myth that injectable testosterone is bioidentical, it is not. Native testosterone is true, bioidentical testosterone.
This still comes across as splitting hairs, because the esters do yield bioidentical testosterone. Not to mention that guys do regularly inject straight testosterone (suspension or oil base), although the pharmacokinetics make it less practical for TRT.
 

DixieWrecked

Well-Known Member
Bioavailability can be overridden by dose. The dosage is less relevant than the outcome: serum levels. When total testosterone can go above 1500 ng/dl (see screenshot above), it's plenty potent.

The enclomiphene/pregnenolone is sublingual. Because the oral testosterone need hundreds of mg, it requires a specially formualted tablet to get absorbed by the lymphatic system. Thus, it bypasses first pass liver metabolism and does not elevate liver markers significantly.
Is the pregnenolone and enclomiphene in the same troche? If so, why? Seems like pregnenolone wouldn't be necessary for a lot of guys if they aren't shut down.
 

Guided_by_Voices

Well-Known Member
The results are excellent (see my post above). There's no need to add Oxandrolone, given how effective the testosterone alone is. Enclomiphene is also far superior to Clomid in having less side effects.
My example of Oxandrolone was to point out that some of us on here seem to do better at lower T levels but also benefit from some more specific compounds. For example many of us benefit from the joint/injury tonic that the nandrolone family of compounds provides. Dixiewrecked mentioned proviron for DHT benefits although personally I don't find benefit there, but many people do. For those of us that need to maintain strength on a weekly workout schedule ( and hence have a 2-day recovery window at some point) the anabolic aspect is by no means unimportant. It will take a lot of crowdsourcing to figure out which compounds can be added in while maintaining decent LH levels and the degree to which the suppression is due to the compounds vs. dose vs. persistence in the body.

Also, while I haven't followed the enclomiphene/clomid debate too closely, my understanding is that clomid is cheaper and much easier to reliably source, so I assume that most people who are going to try this approach would go that route at least to start, if they can tolerate it. Personally, I responded well to very low doses of clomid (low in comparison to what Dr. Gordon or the PCT protocols use) so perhaps that is why I did not have issues.


As an aside, this approach (in general, combining a SERM and a short-acting AAS) has been something that many people reported to "work" and posted logic saying it should work, and were then shouted down, usually by those in the perma-blast community for whom everything has to be extreme, so it's heartening to see this approach getting some validation and traction, at least as an option.
 
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docc

New Member
I'm concerned about this patient's relatively low estradiol and excessive vitamin D.


In terms of duration of action this product seems to lie between Natesto and oral testosterone undecanoate, perhaps better explaining why HPTA function can be preserved with the aid of enclomiphene.


That's good to know. I'm surprised I missed the news.


This still comes across as splitting hairs, because the esters do yield bioidentical testosterone. Not to mention that guys do regularly inject straight testosterone (suspension or oil base), although the pharmacokinetics make it less practical for TRT.

Estradiol is easily increased by splitting the daily dosage in half, or lowering the dose. I'm just showing a peak level of 1500+ testosterone just to show how non-suppressive it is even at high levels.

Vitamin D toxicity is rare and does not happen until levels are 200+. 100 is perfectly safe.

If you want to split hairs, esters eventually yield bioidentical testosterone, but given the half-life, it does not behave the same in the body before the esters are cleaved, and are far more suppressive. Almost everyone injecting is using an ester. Only the topical guys are using native testosterone the majority of the time.
 

docc

New Member
My example of Oxandrolone was to point out that some of us on here seem to do better at lower T levels but also benefit from some more specific compounds. For example many of us benefit from the joint/injury tonic that the nandrolone family of compounds provides. Dixiewrecked mentioned proviron for DHT benefits although personally I don't find benefit there, but many people do. For those of us that need to maintain strength on a weekly workout schedule ( and hence have a 2-day recovery window at some point) the anabolic aspect is by no means unimportant. It will take a lot of crowdsourcing to figure out which compounds can be added in while maintaining decent LH levels and the degree to which the suppression is due to the compounds vs. dose vs. persistence in the body.

Also, while I haven't followed the enclomiphene/clomid debate too closely, my understanding is that clomid is cheaper and much easier to reliably source, so I assume that most people who are going to try this approach would go that route at least to start, if they can tolerate it. Personally, I responded well to very low doses of clomid (low in comparison to what Dr. Gordon or the PCT protocols use) so perhaps that is why I did not have issues.
Interesting, thanks for sharing. Its not as easy for clinics to prescribe Oxandrolone and Proviron, especially if you're talking about healthier individuals.

Clomid is actually more expensive now that one of the manufacturers shut down. There are now two published trials of enclomiphene and Clomid, with enclomiphene showing less side effects. Not to say guys can't do well on low doses of Clomid, but there's really no reason to use it now that enclomiphene is available.
 

madman

Super Moderator
Here i thought oral T has ultra low bioavailability and causes the most liver issues esp at 600mg a day im guessing they hope u absorb 1/12 of that or so?

neat but if it was me id make it all sublingual? T included

Not happening!


*An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a heavy load on liver metabolism. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. The capacity of this pathway is presumably very large. We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects.

*There were no changes in serum markers of liver or kidney function or in the hematocrit or hemoglobin during the treatment phase or at follow-up.

*These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing. It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls (32, 33). Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research.

*It is also important to note that previous studies of oral T administration demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg (21–23). We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels (data not shown), implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T levels seen in this study.








THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE (1974)


Discussion

Our results demonstrate that the effectiveness of micronized free testosterone by mouth depends on the dosage. Our clinical double-blind trials in eunuchs showed that 100 mg. testosterone per day was ineffective, whereas 400 mg. per day was fully effective.

These results accord with our finding that 200 mg. free testosterone given once orally can maintain a normal male serum-testosterone level for many hours in patients without testicular function.

The figure indicates that the half-life of testosterone in serum after ingestion of tablets is about 5-7 hours.
This is surprising since the turnover of testosterone in the blood is very rapid.7,8 The reason why high testosterone levels are maintained in the blood for a considerable time after ingestion of testosterone tablets seems to be that testosterone is absorbed very slowly from the intestine. The fact that the tablets used to study serum testosterone contained a few large particles of testosterone can hardly explain the long effect since these large particles did not constitute more than about 10% of the surface area of testosterone. The extended effect is an advantage during therapy, and we intend to change our standard treatment with oral testosterone to tablets only twice a day.

We recommend an oral testosterone dose in total testicular failure of 400 mg. per day (2 X 200 mg.). This dose in mg. substance is 3-4 times higher than that recommended for methyltestosterone or mesterolone.
Free testosterone is reasonably cheap and 100- 200 mg. testosterone tablets made conventionally by hospital pharmacies will cost the same as commercial tablets containing patented artificial testosterone derivatives

An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a heavy load on liver metabolism. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. The capacity of this pathway is presumably very large. We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side effects.









Oral Testosterone in Oil Plus Dutasteride in Men: A Pharmacokinetic Study (2005)


Oral administration of unmodified T at doses up to 100 mg have little effect on serum T levels in T-deficient men (20, 21); however, 200-mg doses of oral T have been shown to elevate serum T levels to the low normal range for up to 8 h (22, 23). At the time, these serum T levels were thought to be insufficient for clinical use, and research into using unmodified oral T was largely abandoned.

Testosterone undecanoate (TU) is a T ester currently given orally in oil and used clinically in Europe and Canada for the treatment of T deficiency. When administered orally, TU therapy results in therapeutic increases in serum T; however, it also results in elevations in serum dihydrotestosterone (DHT) well above the normal range (24 –27). Because DHT is required for cell growth within the prostate, concern has been raised about the potential for long-term harm associated with oral TU therapy from the elevated levels of serum DHT; however, no increased risk of prostate disease has been reported to date

Because the androgen TU is absorbed well in oil, we believed that other androgens such as T enanthate (TE) and potentially T itself might be well absorbed if also administered orally in oil. Moreover, because the recently available 5-reductase inhibitor, dutasteride (D), lowers serum DHT levels more than 90% by inhibiting both isozymes of 5- reductase (28), we hypothesized that oral administration of the combination of higher doses of unmodified T or the T ester, TE, in oil, when combined with D, would be safe and result in therapeutic serum T levels. In addition, we hypothesized that the concomitant administration of the 5-reductase inhibitor D with T or TE would further increase serum T levels while minimizing the elevations in serum DHT seen after oral administration of oral androgens such as TU. If effective, we believed that this novel means of T therapy would allow for selective androgen therapy in men with T deficiency.
Therefore, we conducted a pilot study of the oral administration of single doses of T and TE with and without concomitant administration of D to determine the pharmacokinetics and safety of single high doses of oral T in oil in healthy men rendered temporarily hypogonadal with the GnRH antagonist acyline.




Results

Subjects


Fourteen men were enrolled in the study; seven were randomized to the T group, and seven were randomized to the TE group, but one man assigned to the TE group failed to report for his acyline injection. Therefore, seven men completed the T arm, and six completed the TE arm of the study (Table 1). Except for the subject who failed to appear for his acyline injection, all subjects completed the drug exposure period. There were no serious adverse effects during the study. Nine of the subjects experienced transient mild pruritis at the site of the acyline injection, which resolved in all cases within 1 h of the injection. Eight subjects complained of mild, transient hot flash symptoms toward the end of the study period, presumably due to low T levels; however, no subject complained of feelings of anger, aggression, or irritability during treatment. There were no adverse gastrointestinal symptoms associated with oral T or oral TE in oil. One subject developed a small area of gynecomastia (1 1 cm) immediately under the nipple during the treatment period, but this resolved during follow-up. There were no changes in serum markers of liver or kidney function or in the hematocrit or hemoglobin during the treatment phase or at follow-up. Furthermore, no significant changes in blood pressure or pulse were observed. T and gonadotropin levels returned to baseline in all subjects during the follow-up period (data not shown). No subjects were lost to follow-up.




Serum T

All subjects were suppressed to castrate levels of T by 24 h after acyline administration (d 0 T, 20.0 7.4; d 1 T, 2.3 0.5 nmol/liter; P 0.0001). There was no difference in serum T levels 24 h after acyline between groups [2.3 0.7 (T) vs. 2.3 0.8 (TE); P 0.9]. In addition, mean serum T levels before each dose of T were not significantly different from that 24 h after acyline administration.

With the administration of both oral T and oral TE in oil, serum T was significantly increased in a dose-dependent fashion (Fig. 2; P 0.01 for trend). In addition, the maximum concentrations of T, average concentrations of serum T, and area under the curve of serum T increased significantly in a dose-dependent fashion (Table 2 and Fig. 3A), with the maximum concentration of T after oil dosing exceeding the normal range for the 800-mg dose of T and the 400- and 800-mg doses of oral TE in oil. The time of maximum concentration was between 2.5 and 4.5 h in all cases, and the calculated terminal t1/2 of oral T and TE in oil was between 7.5 and 11 h. Coadministration of D with oral T or TE in oil significantly increased the resulting serum T levels compared with administration of T or TE alone (Fig. 2; P 0.01 for trend). The maximum concentration of T after oral treatment with the combination of T or TE and D exceeded the normal range for both the 400- and 800-mg doses of T and TE in oil. Similar to the administration of T or TE only, the time to maximum concentration remained between 2.5 and 4.5 h, and the calculated terminal t1/2 was between 8 and 10 h. The T area under the curve for the combination of T and D was significantly increased at all doses compared with that for T alone [200 mg, 124 28 nmol-h/liter (T alone) vs. 176 45 nmol-h/liter (T D); 400 mg, 208 74 nmol-h/liter (T alone) vs. 393 nmol-h/liter (T plus D); 800 mg, 328 82 nmol-h/liter (T alone) vs. 846 363 nmol-h/liter (T plus D); P 0.01 for all comparisons].





Discussion

In this study, we have demonstrated that single doses of T or TE when administered orally in oil can result in serum T levels that would be useful for the treatment of T deficiency.
Secondly, we have demonstrated that the addition of the 5- reductase inhibitor D to oral T in oil 1) significantly increases the serum T levels achieved after a given dose of T, and 2) attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T or T esters (e.g. TU) without concomitant 5-reductase inhibition.

These data contradict the prevailing wisdom in the field, which states that the oral route for T delivery is impractical due to the near-complete hepatic first-pass metabolism of orally administered T (11). Although it is true that the bioavailability of orally administered T is very low, probably around 1% (30, 31), our work demonstrates that if sufficient T is administered orally in oil, potentially therapeutic levels of serum T can be achieved after oral dosing. It is likely that liver metabolism of orally dosed T is extensive because oral T administered to men with cirrhosis results in serum T levels that are markedly elevated compared with normal controls (32, 33). Whether long-term administration of oral T in oil would induce increased hepatic metabolism of oral T and therefore reduce T bioavailability will be the subject of future research.

Previous studies of the oral administration of T may have found reduced levels of serum T in part due to 5-reductase activity in the intestine and liver (34). In this study using T or TE, and in the work of others with TU (24 –27), serum levels of DHT after oral administration are markedly elevated, implying that a large fraction of the orally administered T dose may be metabolized in the liver and intestines to DHT.
Surprisingly, in this study, the coadministration of a 5-reductase inhibitor roughly doubles the average T concentration and the area under the curve for the serum T while reducing the elevations of serum DHT by approximately half. These marked elevations in serum T with concomitant 5-reductase inhibition are probably due to inhibition of the 5-reductase enzyme in the intestine and liver, which appears to account for approximately one-half of the metabolism of T after an oral dose. Importantly, the combination of elevated serum T without marked elevations in serum DHT may allow for selective oral androgen therapy, which may be useful in decreasing the risk for DHT-dependent diseases, such as benign prostate hyperplasia and prostate cancer.

It is also important to note that previous studies of oral T administration demonstrating poor oral bioavailability of T have used T in powder form at doses of 100 and 200 mg (21–23). We have tested oral T in powder form in doses as high as 400 mg without achieving therapeutic serum T levels (data not shown), implying that the administration of T in oil is crucial for the achievement of the therapeutic serum T levels seen in this study. It has been previously shown that the absorption of oral TU is markedly affected by the concomitant intake of fatty foods (27, 30). This is probably due to the fact that much of the orally administered TU is absorbed via the lymphatics (35). In an animal model of TU absorption, more than 80% of the bioavailable T is thought to be absorbed via lymphatics (36). Whether food intake will affect the absorption of oral T in oil is unknown and probably depends on how much of the dose is absorbed via lymphatics vs. via the portal circulation. Because T was administered in oil in this study, some of the doses may have been absorbed via the lymphatics. This might explain in part the unexpectedly long serum half-life of T seen with oral compared with iv administration of T, which has been reported to have a half-life of less than 1 h (31, 37). Another possibility is that there is some degree of enterohepatic circulation of the orally administered T, prolonging the apparent half-life in serum. Because of this uncertainty, the impact of food intake on the absorption and serum levels of T after the administration of oral high dose T will be the subject of future study.

It is important to note that there was no evidence of either liver or kidney toxicity associated with the doses of oral T administered in this study; however, additional long-term study of these doses combined with a 5-reductase inhibitor will be required to determine the safety of this approach to T therapy. Although one subject did report transient gynecomastia, this subject’s serum E2 level remained within the normal range. Additionally, no subject complained of impotence, decreased libido, or sexual dysfunction during the treatment period. These side effects have been reported when D is administered alone for benign prostate hyperplasia (38); however, in theory, they would be less likely when D is administered in combination with T. Additionally, the implication of long-term 5-reductase inhibition will need examination given the increase in high-grade prostate cancer (despite an overall decrease in prostate cancer incidence) seen with chronic finasteride administration in the prostate cancer prevention trial (39).

There were slight, nonsignificant increases in serum E2 seen after oral dosing of T and TE in oil. This implies that although orally administered T can undergo aromatization to E2, it does not do so at high levels, suggesting that there is probably little aromatase activity in the intestine and liver in man. This finding is reassuring in showing that orally administered T is likely to allow for the important functions of estrogen in man, such as maintenance of bone density (40), but not lead to an increased risk of estrogen-related side effects such as gynecomastia.


From a practical standpoint, a regimen using oral T in oil in the formulation used in this study may need to be administered twice daily; however, additional refinements of this approach, such as the use of slow-release capsules, may allow for more controlled release of T in the intestine and could lead to a formulation that could be administered orally once daily, a major improvement over current T replacement options.

In conclusion, we have demonstrated that single doses of T or TE, when administered orally in oil, can result in markedly elevated serum levels of T in normal men with induced hypogonadism; such levels would presumably be therapeutically effective in treating testicular failure. In addition, we have demonstrated that the addition of the 5-reductase inhibitor D to oral T in oil significantly increases the serum T levels observed with a given dose of T and attenuates the supraphysiological elevations in serum DHT seen with the administration of oral T alone. Combinations of oral T and 5-reductase inhibitors may allow for an oral, selective form of androgen therapy. Additional studies of the long-term safety, pharmacokinetics, and pharmacodynamics of this combination are warranted to determine whether it might be a clinically useful and attractive method of treating T deficiency.





FIG. 2. Serum T concentrations (mean SEM) after oral administration of 200, 400, and 800 mg T in oil (A–C) and TE in oil (D–F) with and without D for 24 h in normal men treated with the GnRH antagonist acyline to temporarily suspend T production. Note the larger y-axis for the 800-mg dose. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone.
Screenshot (33638).png

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FIG. 3. Average serum T (A) and DHT (B) concentrations (mean SD) over the 24-h interval after oral treatment. The dotted lines represent the upper and lower limits of the normal range for serum T. *, P 0.05 compared with T alone
1710565977546.png
 

madman

Super Moderator

Oral TRT Breakthrough! Maximus Testosterone Protocol​



TIMESTAMPS:

0:00 – Introductions and the Big Announcement
3:15 - Catching up on Enclomiphene
8:00 – The Drawbacks of Traditional TRT and other Oral Methods
11:45 - How Oral TRT Works
22:00 – Retaining the hormonal rhythm
30:15 – Misconceptions about enclomiphene
41:25Administration mechanics – take with a fat source
48:00Metabolism of oral testosterone… when’s the peak?
55:00 – Transitioning from injectable to oral TRT
1:08:00 – Personalized approach to hormone therapy
1:15:15 – SHBG and IGF-1
1:28:45 – Mike’s Hormone Panel
1:34:15 – Wrap Up
 

Cataceous

Super Moderator
...
Vitamin D toxicity is rare and does not happen until levels are 200+. 100 is perfectly safe.
...
Lack of acute toxicity does not imply long-term safety. Once you get north of 50 ng/mL there are negative correlations over time. Causality may not be firmly established, but why push upper limits without good reason? Interestingly, one study shows an inverted U-shaped curve for serum testosterone as a function of vitamin D levels. The peak for testosterone occurs when vitamin D is in the 30s ng/dL.

...
If you want to split hairs, esters eventually yield bioidentical testosterone, but given the half-life, it does not behave the same in the body before the esters are cleaved, and are far more suppressive. Almost everyone injecting is using an ester. Only the topical guys are using native testosterone the majority of the time.
The "topical guys" usually experience HPTA suppression and elevated DHT to boot. The duration of action appears to be the driving factor in the former. There's no reason to attack esters per se except for marketing purposes. This approach exposes the vulnerability in having enclomiphene in the protocol. It is decidedly non-bioidentical, and the safety of long-term use is not well-established. There are very likely some effects on non-target receptors, with uncertain consequences. These concerns are not enough to stop me from using enclomiphene, but I have to view it as a calculated risk.

These quibbles aside, I'm happy to see another option in the TRT marketplace, and you guys should be commended for making it happen.
 

madman

Super Moderator
The sole purpose of the ester is to control the release rate of T from the oily depot.

Esterified T is inert until it hits the bloodstream where the ester is rapidly hydrolyzed (esterase enzymes) and you are left with native/free T.




*The purpose of the ester is to control the release rate of the steroid from the oily depot and it is cleaved as soon as it hits the bloodstream releasing free testosterone.

*TU/TC/TE/TP (oily depot)----->ester cleaved (ECF)----->FREE TESTOSTERONE (blood)





*"It is also important to stress the fact that esters do not alter the activity of the parent steroid in any way. They work only to slow its release"

The ester only controls the release rate from the injection depot.


"Once free in circulation, enzymes will quickly remove the ester chain and the parent hormone will be free to exert its activity (while the ester is present the steroid is inert)"









Injectable Testosterone

The most widely used testosterone formulation for many decades has been an intramuscular injection of testosterone esters (figure 5), formed by 17β-esterification of testosterone with fatty acids of various aliphatic and/or aromatic chain lengths, injected in a vegetable oil vehicle (653). This depot product relies on retarded release of the testosterone ester from the oil vehicle injection depot because esters undergo rapid hydrolysis by ubiquitous esterases to liberate free testosterone into circulation. The pharmacokinetics and pharmacodynamics of androgen esters are therefore primarily determined by ester side-chain length, the volume of the oil vehicle, and the site of injection via hydrophobic physicochemical partitioning of the androgen ester between the hydrophobic oil vehicle and the aqueous extracellular fluid (654).



FIGURE 5.​

Schematic overview of the pharmacology of testosterone esters. Testosterone is esterified through the 17 β hydroxyl group with fatty acid esters of different aliphatic or other chain lengths which is a biologically inactive pro-drug. The esterified testosterone in an oil vehicle is injected deeply into a muscle forming a local drug depot from which the testosterone ester is released at a slow rate determined by its Physico-chemical partitioning according to the testosterone ester’s hydrophobicity. Once the testosterone ester exits the depot and enters the extracellular fluids, it is rapidly hydrolyzed by ubiquitous non-specific esterases thereby releasing the testosterone into the general circulation.

1710604039139.png










*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.




FIGURE 1 | Percent change in mean gonadotropin levels (LH & FSH), from baseline through 6 months of testosterone treatment. Nasal testosterone (blue), dosed t.i.d., adapted from (15), n = 33. Topical testosterone (orange), dosed daily, adapted from (9), n = 123. IM injectable - 100 mg testosterone enanthate, (red), adapted from (10), n = 10. All changes from baseline were statistically significant. Nasal testosterone—FSH p = 0.03, all others p < 0.001. Standard error calculated using the delta method.
1710603241732.png










*Azoospermia and testicular atrophy result from exogenous T suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. In our prior work, a short-acting nasal gel T (Natesto, Food, and Drug Administration approved, May 2014) was shown to increase serum T, maintain gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), within the normal range, and not significantly affect semen parameters. 8 Unlike the dosing of other forms of exogenous T (subdermal pellets, injections, and trans-dermal gels) that provide steady delivery for 24 hours or more, the nasal gel is delivered either 2 or 3 times a day, providing discrete peaks (or pulses) in serum T levels with a return to baseline T levels between peaks. Pulsatile dosing, and more importantly, the existence of daily troughs between doses, may allow for reinitialization of the pulsatile release of gonadotropin-releasing hormone (GnRH) and therefore maintaining the production of LH and FSH. Because GnRH release cannot be directly measured in humans, FSH and LH are used as surrogates.9 We, therefore, hypothesized that short-acting T has a lesser effect on serum levels of gonadotropins (LH and FSH) than long-acting exogenous T.




Table 1. Studies included in the analysis grouped by the duration of action
1710603515508.png











Some important points to keep in mind here!


*AAS can also bind the androgen receptor inside target cells and bring into play the same negative feedback effects as endogenous testosterone.

*Androgens, as well as estrogens and progestins, in turn, cause negative feedback inhibition at the hypothalamus and pituitary, lowering the output of gonadotropins and testosterone when too much hormone is present.

*Additional autocrine, paracrine, and endocrine factors within the hypothalamus, pituitary, and testis can function to further modulate the HPG axis in complex ways including endocannabinoids, GnRH, kisspeptin, norepinephrine, growth hormone, interleukins, and TGF-β 28. Therefore, the HPG axis represents a dynamic, but tightly regulated, system at multiple levels resulting in spermatogenesis, among other things.

*Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative feedback of testosterone and estradiol at the level of the hypothalamo-pituitary. Estradiol has a much larger, inhibitory effect than testosterone, being 200-fold more effective in suppressing LH secretion [57–61].


*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
 

docc

New Member
Lack of acute toxicity does not imply long-term safety. Once you get north of 50 ng/mL there are negative correlations over time. Causality may not be firmly established, but why push upper limits without good reason? Interestingly, one study shows an inverted U-shaped curve for serum testosterone as a function of vitamin D levels. The peak for testosterone occurs when vitamin D is in the 30s ng/dL.


The "topical guys" usually experience HPTA suppression and elevated DHT to boot. The duration of action appears to be the driving factor in the former. There's no reason to attack esters per se except for marketing purposes. This approach exposes the vulnerability in having enclomiphene in the protocol. It is decidedly non-bioidentical, and the safety of long-term use is not well-established. There are very likely some effects on non-target receptors, with uncertain consequences. These concerns are not enough to stop me from using enclomiphene, but I have to view it as a calculated risk.

These quibbles aside, I'm happy to see another option in the TRT marketplace, and you guys should be commended for making it happen.
Associational research is not very useful when it comes to Vit D. I suggest exploring the Vitamin D wiki’s studies. It’s not central to this discussion here, so let’s move on.

You can take Oral TRT alone if you’re a “T only” purist.

But adding a low dose of enclomiphene is generally worth maintaining the full function of your balls and brain.

Thank you. Having a cost effective oral T on the market, which can maintain testicular function and fertility is an important advancement.
 

madman

Super Moderator
Oral esterified T - Testosterone undecanoate (TU)








This study, LH/FSH levels were significantly depressed.

Oral TU (BID) resulted in a 70% decrease in LH/FSH.
Screenshot (33653).png

Screenshot (33652).png

Screenshot (33654).png

Screenshot (33655).png





 

granger

Member
Bioavailability can be overridden by dose. The dosage is less relevant than the outcome: serum levels. When total testosterone can go above 1500 ng/dl (see screenshot above), it's plenty potent.

The enclomiphene/pregnenolone is sublingual. Because the oral testosterone need hundreds of mg, it requires a specially formualted tablet to get absorbed by the lymphatic system. Thus, it bypasses first pass liver metabolism and does not elevate liver markers significantly.

right but dose would be 1/4 of what the oral dose if all was sublingual, less liver issues etc.

anyway, doesnt make much sense IMO as can get dosages far more dialed taking enclomophene pregnalone seperately and used as an add on to other test protocol.. OR perhaps enclomophene etc is all that is needed and no exogenous test required.

just interesting the common knowledge that oral test is bad now all of a sudden isnt a thing??? seems weird and imagine will show up even in undaconate post marketing, nevermind test plus lycethin and oil... me thinks its just a time thing and eventually markers will go up, 3-6 months obv isnt going to do a WHOLE lot but 3-5 years probably.... sorry just lost faith in folks and them making pretty big assumptions in their studies.
 

docc

New Member
right but dose would be 1/4 of what the oral dose if all was sublingual, less liver issues etc.

anyway, doesnt make much sense IMO as can get dosages far more dialed taking enclomophene pregnalone seperately and used as an add on to other test protocol.. OR perhaps enclomophene etc is all that is needed and no exogenous test required.

just interesting the common knowledge that oral test is bad now all of a sudden isnt a thing??? seems weird and imagine will show up even in undaconate post marketing, nevermind test plus lycethin and oil... me thinks its just a time thing and eventually markers will go up, 3-6 months obv isnt going to do a WHOLE lot but 3-5 years probably.... sorry just lost faith in folks and them making pretty big assumptions in their studies.
There's a physiological limit in how much you can absorb sublingually. Sublingual is just no a good delivery vehicle for testosterone. There's no need for "less liver issues," since there are no liver issues (per the research posted above).

We do offer enclomiphene/pregnenolone alone. It doesn't work in conjunction with injectable TRT.
 

MDavidW76

Active Member
Look at this patient's bloodwork. You ever seen a Total T> 1500 and Free T> 350 with an LH of 5.4 and FSH of 8.9? Remarkable.

The clinical trial is being published on Monday on Maximus' website.
There whole thing on their Facebook marketing was that you wouldn’t be at super physiological on TT, according to all the clinical ranges 1500 would be exactly that… Enclomifene is cheap, it’s half of clomid and was never FDA approved as Androxil…
 

granger

Member
i always assumed there was decades on why oral T was bad...and perhaps these "new" hypothesis dont have long enough data? or select obese people that get skinnier and liver gets better which is different than not causing liver issues partially from metabolites..

why wouldnt direct absorbtion via sublingual ACTUALLY bypassing liver be better? dosage is less is it not with troche?

clearly your body is doing something with that high of a dosage and its mostly not absorbed super quickly... so if its not near fully absorbed before liver obv most is making it past no? harmless metabolites in stomach acid?

oral t ~4% bioavailable, buccal test ~14% bioavailability.... in the literature i was able to find.
 
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