Pituitary restart while on TRT: promising initial results with GnRH plus enclomiphene

Cataceous

Well-Known Member
TL;DR: Over a period of seven weeks, treatment with GnRH and enclomiphene raised LH and FSH from around 0.1 mIU/mL to about 1.0 mIU/mL, even though TRT and hCG dosing were continued. Subjective results have been encouraging.

I had written previously on the subject of GnRH suppression on TRT. This got me thinking about the possibility of replacing the missing GnRH. That led to the next question: if you take GnRH with TRT will you make LH and FSH? If so, will it be enough that you could stop taking hCG? Research suggests that TRT should suppress pituitary stimulation via estradiol:

From these data, we conclude that in the human male, estrogen has dual sites of negative feedback, acting at the hypothalamus to decrease GnRH pulse frequency and at the pituitary to decrease responsiveness to GnRH.

If there’s a glimmer of hope that the suppression isn’t severe it is in this work. The authors present results of GnRH pulses given at various intervals, with trials of men both on and off TRT. However, the subjects were not on long-term TRT, so it may simply be that the duration of the experiment was not long enough for suppression to develop fully.

Is it possible to work around the problem of suppression at the pituitary? Fortunately, it appears there is not significant negative feedback from androgens at this location. Therefore it’s only necessary to antagonize the estrogen receptors there, which can be achieved with various SERMs. In this case enclomiphene was used. It’s generally believed that SERMs are not strong enough to overcome the suppressive effects of TRT, at least in most cases. However, the premise here is that this is due to the strong negative feedback of androgens at the hypothalamus. In administering GnRH directly the hypothalamus is bypassed, so its continued suppression doesn’t matter.

The minimum GnRH dosing schedule needed to “awaken” the pituitary is unknown. Normal males make pulses every couple hours or so. Various studies have found that using infusion pumps to deliver subcutaneous pulses of GnRH at regular intervals results in normal levels of gonadotropins, testosterone, etc. Without an infusion pump, the idea is to inject as often as one can tolerate to give the restart the best chance of working. In this case dose frequency was increased over a period of three weeks to six per day. Typical pulsed doses in the literature range from 2-20 mcg.

Timeline and quantitative results:

Prior baseline: LH is 0.1 mIU/mL
Week 1 to week 3: Start GnRH SQ injections, gradually increase dose and frequency to five per day @20 mcg, one at 10 mcg.
Week 4: Start enclomiphene @12.5 mg per day
Week 5: Intermediate lab work, LH is 0.2 mIU/mL, FSH is 0.3 mIU/mL
Week 7: Lab work, LH is 1.1 mIU/mL, FSH is 1.0 mIU/mL, peak T is 800 ng/dL, peak E2 is 50 pg/mL, SHBG is 30 nMol/L

Subjective observations:

1. Unusual and brief flare of libido on day of first GnRH dose, better than in years. Coincidence? Placebo?
2. Enhanced testicular volume; uncertain without quantitation
3. Enhanced ejaculate volume and overall seminal fluid release; pretty evident but also not quantified
4. Improved mental clarity; confounding factors include higher dietary protein and some dopamine system tinkering

What's next? It will be interesting to see if LH and FSH continue to rise, as is seen after long-term suppression. The increases seen so far are in line with the data from this study, which go as follows:

Months after off Tx

Average LH (mIU/ml)

0

0.5

1

1.3

3

5.9

6

7.2

12

10.3


Alternatively, the irregularity of the GnRH pulses may limit progress. If LH continues to rise will it be sufficient to make hCG unnecessary? Even if LH is sufficient, is this procedure practical? To this I’d say the answer is “no” for most. But some would find two or three daily injections doable. The six used in this trial would be harder to manage indefinitely.


Are there other practical uses for this procedure? One possibility is to use it to ease the transition when ending long-term TRT. Additionally, one could envision men on steroid cycles using this approach to avoid a complete HPTA shutdown, if they’re not already doing so.
 
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Cataceous

Well-Known Member
A quick update on this experiment after 12 weeks of GnRH and 10 weeks of enclomiphene: Doses as above, except that the last GnRH dose each day was lowered to 5 mcg. Only small increases were seen in LH and FSH, about 10%, to 1.1 and 1.2 mIU/mL respectively. It's a little disappointing not to have them higher at this point, but it's good that pituitary activity was maintained, and confirms the previous results.

Here are thoughts on what may help to raise the gonadotropins into their normal ranges:

• More time on the current protocol
• Lower serum estradiol (still over 40 pg/mL at this trough measurement)
• Higher enclomiphene dose
• More frequent GnRH doses
• GnRH doses throughout day and night

Going forward, a possible direction for this experiment is a trial period without hCG use. This would accomplish the first two points above: more time, and serum estradiol reduced by 15-20 pg/mL. It would also be interesting to know if gonadotropins at these levels can provide the same benefits as hCG use.
 

Nelson Vergel

Founder, ExcelMale.com
Great posts. Thanks for sharing. I am confused. What is the protocol? TRT with it? Where did you get GnRH and at what cost?
 

Cataceous

Well-Known Member
Great posts. Thanks for sharing. I am confused. What is the protocol? TRT with it? Where did you get GnRH and at what cost?
The pituitary stimulation protocol is 12.5 mg enclomiphene PO daily along with 20 mcg GnRH subQ at 7a, 9a, 12p, 3p, 6p and 5 mcg at 11p.

The TRT protocol is 3 mg T propionate ED, 12 mg T enanthate E3D and 200 IU hCG E3D. This results in daily peak testosterone around 800 ng/dL and a trough around 500, roughly approximating a diurnal rhythm.

GnRH is also known as gonadorelin, which can be obtained via prescription, or for research purposes via Peptide Sciences (10 mg/$50).
 

Nelson Vergel

Founder, ExcelMale.com
So, you stopped the TRT protocol and then started the HPTA reset one. How long have you been on the later? Thanks
 

Cataceous

Well-Known Member
So, you stopped the TRT protocol and then started the HPTA reset one. How long have you been on the later? Thanks
No, these are simultaneous protocols. That's what makes this interesting: there's pituitary activation in spite of the suppressive effects of TRT. The sequence was:

1) Be on TRT protocol for quite a while
2) Start gonadorelin, continue TRT
3) After a couple weeks add enclomiphene, continue gonadorelin, continue TRT

The most recent test results came 12 weeks after step 2).
 

swoops36

Active Member
No, these are simultaneous protocols. That's what makes this interesting: there's pituitary activation in spite of the suppressive effects of TRT. The sequence was:

1) Be on TRT protocol for quite a while
2) Start gonadorelin, continue TRT
3) After a couple weeks add enclomiphene, continue gonadorelin, continue TRT

The most recent test results came 12 weeks after step 2).
Very interesting, but what is the end goal? Was TRT just not working for you?
 

Cataceous

Well-Known Member
Very interesting, but what is the end goal? Was TRT just not working for you?
I mention a few possibilities in the first post. What's of significant interest is a way to get the benefits of hCG without the excessive aromatization. And while TRT is working well in many respects, there are certain shortcomings that have become more pronounced as time goes by. Substandard libido is one, and appears to be a common complaint. Consider this work as part of exploring how TRT may cause problems as well as fix them.
 

swoops36

Active Member
I mention a few possibilities in the first post. What's of significant interest is a way to get the benefits of hCG without the excessive aromatization. And while TRT is working well in many respects, there are certain shortcomings that have become more pronounced as time goes by. Substandard libido is one, and appears to be a common complaint. Consider this work as part of exploring how TRT may cause problems as well as fix them.
Gotcha, I’ll be following along. Good luck!
 

Cataceous

Well-Known Member
The latest update: Possibly aided by two weeks without hCG and an 8% reduction in TRT dose, LH jumped to 2.1 mIU/mL. This is officially in the normal range of 1.7-8.6, an important milestone. FSH inched up to 1.4 mIU/mL.
Screen Shot 2020-05-31 at 9.31.34 PM.png

Subjective results have been mixed. The cessation of hCG was followed initially by a decline in libido, though recently there has been some recovery. Testicular volume may have slightly decreased, but remains healthy in the 20-25 mL range, well above what’s expected in atrophy. This suggests that this protocol may be partially succeeding as an hCG replacement. However, it must be noted that the process of testicular atrophy takes longer than two weeks. Thus only time will tell whether or not atrophy is prevented by having low-normal LH for two-thirds of the day and zero LH for the remainder. Mental acuity is the best in years, though correlation does not prove causality.
 
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DorianGray

Active Member
Very thoughtful progression of treatment and followup. I would be particularly interested in how LH, FSH, Estradiol and Estrogen levels stabilize and at what point.
 

Cataceous

Well-Known Member
... I would be particularly interested in how LH, FSH, Estradiol and Estrogen levels stabilize and at what point.
The estradiol readings during this period have been a little erratic, but generally moving in the expected directions. With daily injections of a blend of testosterone enanthate and testosterone propionate, serum testosterone varies by about +/-24% about the mean. Corresponding to the last three data points in the above graph, estradiol has been 54 (peak), 41 (trough) and 41 (peak) pg/mL. Ostensibly the cessation of hCG led to a drop of 13 pg/mL in peak estradiol. It seems as though this drop should have been bigger, as previous data suggest that hCG is contributing close to 20 pg/mL of estradiol to total. In addition the TRT dose was a little lower.
 

Willyt

Member
Fascinating Cataceous. You got me thinking from another thread about the potential impact of GnRH suppression on libido and emotions (specifically, the somewhat common side effects of lack of libido and flat emotions).

I am taking a different tact by trying to take advantage of the natural troughs associated with nasal T (Natesto) which clears the body within hours and presumably results in less suppression of GnRH. It’s for another thread, but similar end goal.

Watching your progress closely!
 

Cataceous

Well-Known Member
...
I am taking a different tact by trying to take advantage of the natural troughs associated with nasal T (Natesto) which clears the body within hours and presumably results in less suppression of GnRH. It’s for another thread, but similar end goal.
...
I've also been intrigued by the Natesto results and their implication that HPTA suppression is perhaps more a function of trough or average serum testosterone than of peak. I'm interested in reading about your experience.
 

Cataceous

Well-Known Member
It's now safer to call this phase of the experiment a success: After one month without hCG there's been no loss of testicular volume. It's also very likely that testicular volume is higher than during use of only testosterone and hCG. Therefore GnRH and enclomiphene can be used in place of hCG while on TRT. The subjective results are also very encouraging, with improved libido compared to baseline and a much better sense of wellbeing. The improvements are such that it's hard to envision returning to a standard protocol, in spite of the tedium of the GnRH protocol.

There's at least the perception of a cyclical effect from the lack of nocturnal GnRH administration. This takes the form of a very subtle testicular ache early in the morning, and also a gradual improvement in mood as the day progresses. However, there's no guarantee these are real phenomena as opposed to a "nocebo" effect stemming from the knowledge that gonadotropins are dropping to low levels each night. If they are real then the only solution is to seriously consider use of an infusion pump to deliver GnRH pulses all day and all night. The significant expense is the primary deterrent.

More practically, the TRT community needs to know whether or not less frequent GnRH injections can provide benefits beyond the production of gonadotropins. That is, if you're already taking hCG with your TRT then you wouldn't bother with the enclomiphene. Instead you'd just add gonadorelin to your daily or EOD injections. Will you feel better than without? It's uncertain, because one GnRH pulse a day is a long way from the natural 16 or so. But because six pulses a day seem to work, there's at least hope. Anybody wanting to experiment should of course do it under a doctor's supervision.
 
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Willyt

Member
Thanks again for the experimentation. I would be very curious to see if 1xEOD would still have a positive impact. Will you continue to experiment?

Unfortunately, I doubt that I could convince my doc to write the prescription.
 

Cataceous

Well-Known Member
Thanks again for the experimentation. I would be very curious to see if 1xEOD would still have a positive impact. Will you continue to experiment?

Unfortunately, I doubt that I could convince my doc to write the prescription.
The experiment will continue. In one to two months we'll see if there are any more gains in LH or FSH. It would also be useful to know if there's production of non-negligible amounts of endogenous testosterone. For unknown reasons, previous measurements with and without hCG use have failed to clearly detect an endogenous contribution to total testosterone caused by hCG, even at up to 300 IU EOD.

I expect most doctors would need to learn more before they'd be willing to prescribe this therapy. Of course guys who are already buying and "researching" peptides from places like Peptide Sciences might find that avenue acceptable.
 

SSHSSA74

Member
I mention a few possibilities in the first post. What's of significant interest is a way to get the benefits of hCG without the excessive aromatization. And while TRT is working well in many respects, there are certain shortcomings that have become more pronounced as time goes by. Substandard libido is one, and appears to be a common complaint. Consider this work as part of exploring how TRT may cause problems as well as fix them.
Besides the first day jump in libido, did you notice any sustained increases in libido?
 

Cataceous

Well-Known Member
Besides the first day jump in libido, did you notice any sustained increases in libido?
I'm enthusiastic about the overall results, but I don't want to create excessive expectations. The outcome of any particular protocol can be quite dependent on the individual, and all too often just when you think you've figured something out, things change.

Nonetheless, in the case of libido there's been some return of that visceral excitement about sex. It's the kind of thing where without it you know something's missing, but you're not quite sure what. Then it comes back and you say "That's it!" So the answer is: Yes, there has been a sustained increase in libido for some weeks now.

Other sustained correlations:
Improved—mental sharpness, mood, motivation, orgasm quality, ease attaining orgasm, testicular volume, ejaculate volume
Stayed the same—erection quality (good), penile sensitivity (mediocre)
Worse—Ease in attaining erection (still pretty good, but a small reduction)

There's currently an experiment within the experiment: this marks two weeks since a switch to using gonadorelin that had been frozen after hydration, then thawed. There is concern about a loss of potency, but so far there's no indication that this is a significant problem.

A quick recap of the current protocol with respect to sex hormones: 3.7 mg T enanthate ED, 2.8 mg T propionate ED, 20 mcg gonadorelin 5.25x daily, 0.5 mg progesterone ED—all as subcutaneous injections. In addition is the 12.5 mg ED enclomiphene, taken orally
 
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SSHSSA74

Member
I'm enthusiastic about the overall results, but I don't want to create excessive expectations. The outcome of any particular protocol can be quite dependent on the individual, and all too often just when you think you've figured something out, things change.

Nonetheless, in the case of libido there's been some return of that visceral excitement about sex. It's the kind of thing where without it you know something's missing, but you're not quite sure what. Then it comes back and you say "That's it!" So the answer is: Yes, there has been a sustained increase in libido for some weeks now.

Other sustained correlations:
Improved—mental sharpness, mood, motivation, orgasm quality, ease attaining orgasm, testicular volume, ejaculate volume
Stayed the same—erection quality (good), penile sensitivity (mediocre)
Worse—Ease in attaining erection (still pretty good, but a small reduction)

There's currently an experiment within the experiment: this marks two weeks since a switch to using gonadorelin that had been frozen after hydration, then thawed. There is concern about a loss of potency, but so far there's no indication that this is a significant problem.

A quick recap of the current protocol with respect to sex hormones: 3.7 mg T enanthate ED, 2.8 mg T propionate ED, 20 mcg gonadorelin 5.25x daily, 0.5 mg progesterone ED—all as subcutaneous injections. In addition is the 12.5 mg ED enclomiphene, taken orally
Thank you for all the GREAT information. I appreciate you taking the time. I'm sure you probably stated this somewhere already but where do you get the gonadorelin, progesterone and enclomiphene? And no hcg for you it looks like...
 
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