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:
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:
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.
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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