New thoughts on AI

[madman]

I'm having problems with this particular bit of conventional wisdom. First, are there any controlled studies demonstrating the effect? And second, what is the theoretical basis? From what I can see, the effective MCR influenced by SHBG ties into a half life on the order of at most a few hours. This has very little impact on the relatively long apparent half lives of the testosterone esters. Instead, everything is scaled accordingly. That is, double the MCR and get half the serum testosterone—but the peaks are still the same fraction of the troughs. What am I missing?

There are no RCTs looking into this.

Other factors aside from SHBG effect the individuals metabolic clearance rates.

I see your point.



VARIANCE IN PEAK AND TROUGH TESTOSTERONE LEVELS IN MEN USING INTRAMUSCULAR TESTOSTERONE

 

[sokaiya]

What side effects did you have on HCG? I am dropping my HCG to. I think the HCG is driving my E2 up to. They should start people off on test, without a ai. Then test E2. I know now if i dont use a Ai my e2 goes up to 160 on test and HCG. Now im doing subq 3 times a week and dropping HCG. We will see what happens.

HCG raised my E2, made me breakout and my mood just did not feel stable. I feel great on just 25mg EOD. As a matter of fact i may even bump it down to 20mg EOD. Right now i feel if it's not broke, don't fix it..

 

[Cataceous]

...
Other factors aside from SHBG effect the individuals metabolic clearance rates.
...

From a modeling perspective the key question is whether the MCR of T has a significant dependency on a related variable, such as T itself, or estradiol. If not it would seem that other MCR variations can be treated as noise. So not trying to put you on the spot, but are you agreeing that in isolation, changes in SHBG should affect neither the apparent half life of injected testosterone nor the relative size sizes of serum peaks and troughs?

 

[madman]

From a modeling perspective the key question is whether the MCR of T has a significant dependency on a related variable, such as T itself, or estradiol. If not it would seem that other MCR variations can be treated as noise. So not trying to put you on the spot, but are you agreeing that in isolation, changes in SHBG should affect neither the apparent half life of injected testosterone nor the relative size sizes of serum peaks and troughs?

Although it has been stated that the pharmacokinetics and pharmacodynamics of androgen esters are not only determined by the ester side-chain length but also the volume of oil vehicle and site of injection.


Once the ester is cleaved to what degree are other factors involved.






Differences in the Apparent Metabolic Clearance Rate of Testosterone in Young and Older Men with Gonadotropin Suppression Receiving Graded Doses of Testosterone

Andrea D. Coviello, Kishore Lakshman, Norman A. Mazer, and Shalender Bhasin






Background: Recently we found that testosterone levels are higher in older men than young men receiving exogenous testosterone. We hypothesized that older men have lower apparent testosterone metabolic clearance rates (aMCR-T) that contribute to higher testosterone levels.

Objective: The objective of the study was to compare aMCR-T in older and young men and identify predictors of aMCR-T.

Methods: Sixty-one younger (19 –35 yr) and 60 older (59 –75 yr) men were given a monthly GnRH agonist and weekly testosterone enanthate (TE) (25, 50, 125, 300, or 600 mg) for 5 months. Estimated aMCR-T was calculated from the amount of TE delivered weekly and trough serum testosterone concentrations, corrected for real-time absorption kinetics from the im testosterone depot.

Results: Older men had lower total (316 ± 13 vs. 585 ± 26 ng/dl, P <0.00001) and free testosterone (4 ± 0.1 vs. 6 ± 0.3 ng/dl, P <0.00001) and higher SHBG (52 ± 3 vs. 33 ± 2 nmol/liter, P <0.00001) than younger men at baseline. Total and free testosterones increased with TE dose and were higher in older men than young men in the 125-, 300-, and 600-mg dose groups. aMCR-T was lower in older men than young men (1390 ± 69 vs. 1821 ± 102 liter/d, P = 0.006). aMCR-T correlated negatively with age (P = 0.0007), SHBG (P = 0.046), and total testosterone during treatment (P = 0.02) and percent body fat at baseline (P = 0.01) and during treatment (P = 0.004). aMCR-T correlated positively with lean body mass at baseline (P = 0.03) and during treatment (P = 0.01). In multiple regression models, significant predictors of aMCR-T included lean body mass (P = 0.008), percent fat mass (P = 0.009), and SHBG (P = 0.001).

Conclusions: Higher testosterone levels in older men receiving TE were associated with an age-related decrease in apparent testosterone metabolic clearance rates. Body composition and SHBG were significant predictors of aMCR-T.





The purpose of this analysis was to compare the metabolic clearance rate in the group of older men with that in younger men who participated in a study in which graded doses of testosterone enanthate were administered to healthy young and older men in whom suppression of endogenous gonadotropin and testosterone production was achieved by administration of a long-acting GnRH agonist. We sought to determine whether differences in metabolic clearance rates of testosterone coincided with differences in circulating testosterone levels in young and older men receiving the same dose. A secondary aim was to determine physiological predictors of testosterone metabolic clearance rates.



Outcome measures

The apparent metabolic clearance rate of testosterone (aMCR-T) was estimated for each subject in analogy with the standard clearance formula for multiple dosing (19): aMCR-T = (dose/dosing interval)/ (Cavg), where dose corresponds to the absorbed dose of unesterified testosterone, the dosing interval is 7 d, and Cavg is the time-average steady-state serum T concentration. We further assumed that all of the injected TE was absorbed into the bloodstream and deesterified (20). As such, dose was set equal to (288.4/400.6) x TE dose, where the ratio corresponds to the molecular weight of T divided by the molecular weight of TE. Lastly, Cavg was estimated from the measured trough concentration (Cmin) obtained 7 d after the prior injection based on the assumption that the absorption kinetics of the TE was similar to that reported by Dobs et al. (20) and was the same for all subjects, independent of the TE dose or age of the subject. From the mean pharmacokinetic profile reported in that paper, the apparent first-order rate constant for TE absorption was estimated to be 0.096 d-1 . Taking the elimination half-life for circulating testosterone as 1.29 h (21), the ratio Cavg/Cmin, corresponding to a steady-state dosing interval of 7 d, was calculated from pharmacokinetic theory to be 1.415 (19). Combining these relationships into a single result, the estimated value of aMCR-T (liters per day) was calculated from the ratio of the TE dose (milligrams) and Cmin (nanograms per deciliter), as aMCR-T (liters per day) = 7268 x [TE dose (milligrams)/Cmin (nanograms per deciliter)].






Discussion

Older men, in whom endogenous T production had been suppressed by pharmacologically induced hypogonadotropism, had significantly higher total and free T levels than young men given equivalent doses of im TE. The mean aMCR-T in healthy older men was significantly lower than in young men, by approximately 24%. Age-related differences in clearance may have contributed to the higher circulating T levels observed in older men in comparison with young men in this study.

Older men had a higher frequency of adverse events as well as more serious adverse events than younger men, especially polycythemia, which appeared to be dose related (17). The higher adverse event rate observed in older men may be related to their higher circulating T levels, compared with young men (Fig. 2). The potential explanations for the higher T levels in older men in comparison with young men include age-related differences in metabolic clearance, absorption from TE im injection depot, or differences in circulating SHBG levels. We assumed that the bioavailability of T from an im depot of TE is similar in young and older men, although this assumption has not been tested.

Our data are consistent with a small study of six young men (21– 49 yr) and five older men (62–77 yr) that found that older men had lower clearance rates than young men (23). Another small study in young and middle-age men also reported lower plasma T clearance rates in middle-aged men, compared with young men (24). In remarkable concordance with our data, this study found that the mean aMCR-T was about 33% lower in middle-aged men than young men, in parallel with a decrease in the endogenous T production rates (24). In our study, differences in production rates were eliminated by clamping the pituitary with a GnRH agonist and then treating older and younger men with graded doses of TE.Whereas there was no difference in aMCR-T within age groups across TE doses, suggesting no significant dose effect, the difference in aMCR-T between younger and older men was statistically significant at physiological and supraphysiological doses, suggesting a significant age effect.

The metabolic clearance of T and other steroid hormones can be conceptualized as consisting of two parts: hepatic clearance and clearance from other tissues or extrahepatic clearance (23, 25, 26). The observed differences in aMCR-T between older and younger men could be due to age-related changes in hepatic clearance or extrahepatic clearance. Hepatic clearance accounts for 50 – 65% of aMCR-T in men (23, 25).

Hepatic clearance is a function of hepatic blood flow and hepatic extraction from the splanchnic vascular bed, both of which decrease with age. Hepatic blood flow decreases with age and is about 15% lower in people in their 60s and 70s, compared with those under the age of 45 yr (27). Hepatic extraction is also lower in older men (45%) than young men (65%) (28). The decrease in hepatic extraction with aging is presumably related to the increase in SHBG seen with aging because the non-SHBG-bound fraction of T is presumed to approximate its hepatic extraction (26). The greater SHBG levels found in older men may be a contributing factor in the lower aMCR-T observed in this study, compared with young men. This effect would be more important at the higher doses of TE when SHBG binding of T could become saturated in the younger men with lower SHBG levels. Extrahepatic clearance has also been found to be lower in older men, compared with young men (26).

Age-related differences in serum SHBG concentrations may contribute in multiple ways to the age-related changes in aMCR-T. SHBG increases with age but decreases with increasing adiposity (1, 29 –32). The higher SHBG levels in the older men in this study (Fig. 4A) may have contributed to lower aMCR-T and the higher total T levels observed in older men in comparison with the younger men. However, free T levels were also significantly higher in older than young men; the higher SHBG levels cannot account fully for the higher free T levels (Fig. 2). SHBG levels declined in a dose-dependent manner in younger men in response to TE, whereas the magnitude of change in SHBG levels during T treatment was lesser in older men. The greater magnitude of decrease in SHBG in young men may be reflected in their higher aMCR-T. aMCR-T correlated negatively with SHBG in this analysis.

Another possible explanation of the lower aMCR-T in older men may be differences in body composition between young and older men. Older men had a higher percent body fat than younger men at baseline (17). aMCR-T estimates were negatively correlated with total fat mass and percent body fat at baseline and during treatment. Whereas both total fat mass and percent body fat were predictive of aMCR-T, percent change in fat mass was not correlated with or predictive of aMCR-T. SHBG decreases with increasing adiposity, which would be expected to increase T clearance; therefore, it is surprising that fat mass was negatively correlated with aMCR-T in this study. aMCR-T estimates were associated positively with LBM at baseline and during treatment but not with percent change in LBM. Muscle mass is presumably a large contributor to the extrahepatic clearance of T. This observation is consistent with the positive correlation we observed between aMCR-T and LBM. These observations suggest that the etiology of age-related differences in aMCR-T is likely multifactorial and that a complex interaction of factors, including age-related changes in body composition, SHBG, hepatic blood flow, and other unknown factors, contribute to the age-related changes in aMCR-T.

 

[Cataceous]

Although it has been stated that the pharmacokinetics and pharmacodynamics of androgen esters are not only determined by the ester side-chain length but also the volume of oil vehicle and site of injection.


Once the ester is cleaved to what degree are other factors involved.
...

These factors are a matter of selecting the appropriate constants for the model, unless there's evidence they vary relatively quickly or as a function of one of our variables. I'm going to start a new thread on the question of SHBG and apparent ester half life. It's really bugging me that in models with only SHBG lowered, all that happens is free T goes up and total T goes down—in proportion.

 

[[email protected]]

I don’t take an AI. My TRT is 200mg/wk. my estrogen is 20-25 as long as I stay well hydrated (excess converted estrogen is peed out), closer to 40 if dehydrated, and I get swollen painful joints above 30.

 

[Gman86]

I don’t take an AI. My TRT is 200mg/wk. my estrogen is 20-25 as long as I stay well hydrated (excess converted estrogen is peed out), closer to 40 if dehydrated, and I get swollen painful joints above 30.

Holy sht, 20-25 on 200mg/ week?? So lucky lol. Interesting about E2 being higher when dehydrated. Never heard that. Something to consider. Are you injecting once per week? And are these E2 values your levels at trough?

Do you have a very low SHBG?

And you get joint pain from elevated E2? Never heard that before. I’ve only heard of guys having joint pain from low E2.

 

[Robotics]

Holy sht, 20-25 on 200mg/ week?? So lucky lol. Interesting about E2 being higher when dehydrated. Never heard that. Something to consider.

Do you have a very low SHBG?

And you get joint pain from elevated E2? Never heard that before. I’ve only heard of guys having joint pain from low E2.

He must have high shbg not low.

 

[Gman86]

He must have high shbg not low.

How do you figure? Not saying you’re wrong or anything, just curious.

 

[Robotics]

How do you figure? Not saying you’re wrong or anything, just curious.

you need a lot of shbg to bind up such a large dose, and not have a super high free testosterone that aromatises into E2

 

[Gman86]

you need a lot of shbg to bind up such a large dose, and not have a super high free testosterone that aromatises into E2

Interesting. Kind of makes sense. Has it been proven though that E2 is based off of free T? Are we positive E2 isn’t based off of total T?

 

[Cataceous]

...Has it been proven though that E2 is based off of free T? Are we positive E2 isn’t based off of total T?

I believe that bound testosterone won't aromatize, so this part is probably right. However, if you look at calculated free T for fixed SHBG and total T in a normal range, like 400 to 800 ng/dL, then you see that there's a fairly linear relationship between free T and T. The equation for estradiol production from T can be modeled pretty well by E2 = k1 * T / (k2 + T), where k1 and k2 are constants that vary somewhat between individuals.

 

[edward]

That line of thinking has not been really well received on this forum and those individuals that are on that "roundtable", the youtube doctors, have been well criticized here. In fact they don't come near this forum or have otherwise been banned.

You need to spend some time with the search feature...I doubt that there is going to be any new discussion on this allowed.

I saw a post by you I believe Vince advocating the use of an AI (anastrazole) 24 hours after a T-cyp injecition so that the AI and T-cyp would peak at the same time. It’s my understanding that the T-max or peak blood level for anastrazole is at ~1 hr. with a half-life of ~50 hours and that T-cyp peaks in ~3 days with a half-life of 8 days. So, if someone were to take the AI 24 hours after the T-cyp injection wouldn’t the peak T-cyp level coincide with the AI level at half the initial dose instead of its peak level? I’m referring to SQ T-cyp btw. What is your latest recommendation as to the timing of the AI after a SQ T-cyp injection? Thanks!

 

[fifty]

That’s what a lot of forums say. My doc always says to take ai and test at the same time. I don’t believe test cyp takes 3 days to peak. I believe it peaks in ~24hrs at least for me.

However the ai a day after still makes sense to me on paper though I don’t do that.

 

[edward]

That’s what a lot of forums say. My doc always says to take ai and test at the same time. I don’t believe test cyp takes 3 days to peak. I believe it peaks in ~24hrs at least for me.

However the ai a day after still makes sense to me on paper though I don’t do that.

I think that SQ T-cyp takes longer to peak than IM. What type of injection do you use? Also, do you take anastrazole and if so when relative to the T shot?

 

[fifty]

IM and i would take ai and shot same time.

 

[edward]

IM and i would take ai and shot same time.

Thanks again. I’m on SQ T-cyp which takes longer to be absorbed than IM so I suspect that the peak blood level takes somewhat longer to achieve. I’ll likely continue taking the AI 24 hrs. after my shot and see what the labs show; then do a new post.

 

[seb288]

I believe that bound testosterone won't aromatize, so this part is probably right. However, if you look at calculated free T for fixed SHBG and total T in a normal range, like 400 to 800 ng/dL, then you see that there's a fairly linear relationship between free T and T. The equation for estradiol production from T can be modeled pretty well by E2 = k1 * T / (k2 + T), where k1 and k2 are constants that vary somewhat between individuals.

Interesting that you've found this relationship, I've found from T=200-10,000ng/dl that E2 = (T)^1/2 for males under 30 and E2 = (1+k/50)T^1/2 for men over 30 where k = age minus 30. There is also some variance between individuals.

 

[Cataceous]

Interesting that you've found this relationship, I've found from T=200-10,000ng/dl that E2 = (T)^1/2 for males under 30 and E2 = (1+k/50)T^1/2 for men over 30 where k = age minus 30. There is also some variance between individuals.

Here's the reference. They found that the constants do vary significantly between young and old men—see Table 3. The work shows the same general form applies to DHT conversion.

In all cases, the combined data exhibited curvilinear relationships that were well described by a rectangular hyperbolae, Y = A X/ (B + X), consistent with a saturable conversion of testosterone to metabolite governed by Michaelis-Menten kinetics ...

 

[Vitamin_C]

Its really up to how you feel and what the labs are telling you. Some men will aromatize more than others, particularly obese men. AI's should be used if there are overtly high E2 symptoms in conjunction with grossly elevated E2 numbers. Elevated estrogen is harmful to men and women, but the problem is many men are so afraid of high E2 effects on the body they will go overzealous with the Adex. If your sensitive E2 comes back 80-90 but you feel great, I wouldn't mess with your protocol, maybe add some DIM. If you don't feel good, try 0.25mg of Adex and assess how you feel. I haven't listened to the TOT guys but I'm assuming they aren't talking about men with extremely high E2's?