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

[Jntsrgn]

Just want to add my protocol.... I take 20mg of Test Cyp on MWF (down from 60mg) along with 250 IU of HCG and 75 IU of HMG. My total T last draw was 1100 and Free T 244. E2 is always 60-70 without symptoms and I do not take any Anastrozole. Adding the HCG and HMG brought me from a completely absent sperm count to 15 million fully functional swimmers on my last analysis. I was able to become fertile without stopping TRT.

 

[Mastodont]

Is there anyone who has tried infrequent large doses of gonadorelin? Curious if gonadorelin is enough to prevent testicular shrinkage if taken daily or even eod-e3d.
In my country it's only available for cows, dont know if i could identify as one and get it prescribed, but it is 50micrograms per ml, larger doses might be problematic subq.

 

[Cataceous]

Is there anyone who has tried infrequent large doses of gonadorelin? Curious if gonadorelin is enough to prevent testicular shrinkage if taken daily or even eod-e3d.
In my country it's only available for cows, dont know if i could identify as one and get it prescribed, but it is 50micrograms per ml, larger doses might be problematic subq.

As mentioned later in this post on the previous page, Royal Medical Center is or was using such protocols. I haven't noticed patients of theirs making comments here, but it's possible there are reports elsewhere. It would be good to know if the relatively infrequent, but robust pulses of LH and FSH are sufficient to prevent testicular atrophy. I don't recall if we nailed down the exact protocol, but I believe it was either 50 or 100 mcg taken once or twice a week.

 

[KNDyMan]

I've been looking for people who have discovered pulsatile GnRH as an adjunct to TRT to keep the HPG axis running as I recently discovered this protocol which makes me feel worlds better on TRT. It was important to me to try to keep the factory running as I may want to discontinue TRT at some point in the future.

So I started looking for solutions and discovered hCG and GnRH thanks to some forum posts like these, and dove into the literature around hypogonadism and fertility treatments and compared them to the protocols from TRT clinics (which I am not convinced are evidence-based, the weekly high-dose GnRH does not seem like it would be very effective, IDK though). I wanted to avoid AIs and SERMs as well.

I found the hCG (500 IU q4d or 1000 IU q7d) with TRT (50mg q2d) seemed to increase my aromatization sides (acne, nipple swelling, tight prostate/slow urination, etc) but GnRH substantially decreased them. My theory is that the real LH/FSH in a pulsatile fashion diverts most of your aromatization to your testicles where it belongs instead of secondary tissues (why did this not happen with hCG? keep in mind hCG has a really long half-life so your leydig cells are constantly activated instead of pulsed like natural LH release - maybe that has something to do with it?).

Unfortunately the pulsatile GnRH protocol is really inconvenient - 10 mcg q2h, which is a lot of pokes per day, and overnight, your FSH producing mRNA will decay. Commercial fertility treatment pulsatile GnRH solutions like LutrePulse - which is based on the OmniPod insulin pump (looking into the open source artificial pancreas community to see what they have in this vein) - use gonadarelin _acetate_ in solution, not just gonadarelin. GnRH without the acetate is unstable and will hydrolize, oxidize, and break down in water within a couple of days and lose potency quickly. Many fertility clinics seem to prepare GnRH for pulsatile injection with a sterile 0.1M sodium acetate buffer at pH 5.0 and that seems to maintain potency for weeks or months, but still maintains short serum half-life needed for pulsatility (unlike modified GnRH like triptorelin).

I had also looked into kisspeptins, but like SERMs I was afraid of some of the cardiovascular possibilities seen in studies, and I also think based on my amateur endocrinologist understanding, stimulating the KNDy network directly with kisspeptins might be redundant with the pulsatile GnRH. I feel like based on the side reduction so far, I could potentially increase my TRT dose without getting into AI territory.

Anyways, sorry for necro-ing the thread, this is my first post on this forum so I'm not sure what the etiquette is but it looks like this thread was posted to several times over the years so hopefully I'm not committing a major faux pas and this information is useful to someone out there.

 

[Cataceous]

@KNDyMan: Your contributions are welcome.

A few comments:

I am also skeptical of the weekly, high-dose gonadorelin protocols. I have not seen reports on what the subjective results are like. Royal Medical Center did demonstrate high levels of the gonadotropins shortly after the injections.

Most commercially available gonadorelin is actually the acetate salt even when not explicitly stated. This is the case with Peptide Sciences, for example.

The protocol is indeed inconvenient. It might be marginally less so with use of a nose spray instead of injections.

The Grok AI disputes your assertion that "your FSH producing mRNA will decay" overnight.

An 8–12 hour overnight break from gonadorelin injections does not cause meaningful decay of FSH-producing mRNA or loss of HPTA stimulation in the context of pulsatile therapy.​

It is perfectly compatible with maintaining upstream signaling, normal intratesticular testosterone, and fertility on TRT.​

I have been shifting away from conventional TRT in favor of faster-acting testosterone, which is more permissive of continued HPTA function. In particular I am experimenting with a water-based testosterone solution. Testosterone nasal gel would be a more proven treatment. The newer oral formulations may also qualify. One motivation in this is to get away from enclomiphene use, which I don't entirely trust to be benign in the long-term. I am still pulsing gonadorelin and kisspeptin-10, however.

One other thing: In my experience, and as suggested in the literature, kisspeptin may offer some benefits that are independent of the stimulation of GnRH production.

 

[KNDyMan]

@KNDyMan: Your contributions are welcome.

Thank you, it's so nice to find like-minded people, your commitment to knowledge is inspiring and I've learned a lot reading your threads! It looks like I might have to break this post into parts because I'm getting flagged for spam..

A few comments:

I am also skeptical of the weekly, high-dose gonadorelin protocols. I have not seen reports on what the subjective results are like. Royal Medical Center did demonstrate high levels of the gonadotropins shortly after the injections.

Most commercially available gonadorelin is actually the acetate salt even when not explicitly stated. This is the case with Peptide Sciences, for example.

The protocol is indeed inconvenient. It might be marginally less so with use of a nose spray instead of injections.

I am sure Royal Medical Center could demonstrate high levels of LH after a single dose, LH is kept in depot in the pituitary and released immediately upon activation. However the half-life of LH is relatively short so it would be a single burst of LH, single burst of T. Might be effective as a HPG restart but not for maintaining high intra-testicular testosterone levels during TRT (my theory about what's reducing side effects for me).

You are right that some gonadarelin is likely to already be acetated - but a lot of it is free base (this was the case for me). So it's good to check with your vendor to be sure.

I have been considering nasal spray, but AFAIK it's a bit harder to accurately dose a nasal spray, and my concern is over- or under-saturating the GnRH receptors, and also, I'll expand on why I think the insulin pump approach would be most effective..

It seems like exercise and eating both blunt the response from GnRH. I don't have quantitative data for this, but physiologically it makes sense - insulin, glucose, cortisol, adrenaline, leptin, etc all blunt the KNDy network upstream which would reduce GnRH pulse _amplitude_, to the point where it does not activate the pituitary to release LH. I also think that these conditions also seem to blunt the release of LH from the pituitary even given a higher amplitude exogenous GnRH dose, I certainly _feel_ the LH/T rush far less if I'm digesting or working out. There are a lot of studies showing that more LH/T production happens overnight, so this indicates to me that conditions are more favorable at rest and while not digesting and I don't think the effect is limited to the KNDy, I think the pituitary is also impacted by these conditions.

 

[KNDyMan]

The Grok AI disputes your assertion that "your FSH producing mRNA will decay" overnight.

An 8–12 hour overnight break from gonadorelin injections does not cause meaningful decay of FSH-producing mRNA or loss of HPTA stimulation in the context of pulsatile therapy.​

It is perfectly compatible with maintaining upstream signaling, normal intratesticular testosterone, and fertility on TRT.​

It's impossible to know for sure, I couldn't find any studies directly measuring FSHB mRNA in vivo (hard to study ofc), but my understanding is typical median half-life for mRNA in vivo is about 10 hours, but in vitro studies on rat FSHB mRNA show a half-life closer to 2-4 hours (modulated by activin, inhibin, follistatin, etc). So my guess is that maybe half of your FSHB mRNA is gone by morning, maybe most of it. But if you dose in the morning it starts transcribing again and builds up again during the day. But again, I am not an expert.

 

[KNDyMan]

I have been shifting away from conventional TRT in favor of faster-acting testosterone, which is more permissive of continued HPTA function. In particular I am experimenting with a water-based testosterone solution. Testosterone nasal gel would be a more proven treatment. The newer oral formulations may also qualify. One motivation in this is to get away from enclomiphene use, which I don't entirely trust to be benign in the long-term. I am still pulsing gonadorelin and kisspeptin-10, however.

One other thing: In my experience, and as suggested in the literature, kisspeptin may offer some benefits that are independent of the stimulation of GnRH production.

I'm going to keep looking into kisspeptin, but my main concern (besides the poorly understood potential risk of CV issues because of limited trial data - not an issue with GnRH because it's been widely used for fertility treatments and hypogonadism for decades) is having both my KNDy network active and producing GnRH as well as adding exogenous GnRH, my understanding is if the GnRH pulses come too frequently (less than 30-60 minutes?) you're risking overstimulating the GnRH receptors and ending up with a triptorelin-like response where you shut down the pituitary, or at the very least, blunting FSH transcription. It seems like this isn't happening to you, though, so I am probably misunderstanding the role of kisspeptin. Interesting notes about impact on libido, definitely something to keep researching.

I strongly agree with your approach to mimic physiologic patterns (e.g. natural testosterone has a half-life of only 30-60 minutes wheras test C is like 8 days). I feel like most protocols are designed for compliance and convenience rather than efficacy and we deal with the side effects by adding more drugs. I think if it were easier to administer hormones regularly, everyone would do it this way.

 

[Guided_by_Voices]

- insulin, glucose, cortisol, adrenaline, leptin, etc all blunt the KNDy network upstream which would reduce GnRH pulse _amplitude_, to the point where it does not activate the pituitary to release LH.

This is very interesting and could explain a lot of why people in poor metabolic health do not produce enough T. Avoiding chronically elevated insulin and glucose is something we've talked about elsewhere but not in the context of this mechanism IIRC. However, since activity, especially moderate weightlifting is a strong promoter of insulin sensitivity, I would think that on meaningful timeframes exercise would be a net good thing. Exercising (or using pre-workout stimulants) to the point of chronically elevated cortisol would not be good.

 

[Cataceous]

It's impossible to know for sure, I couldn't find any studies directly measuring FSHB mRNA in vivo (hard to study ofc), but my understanding is typical median half-life for mRNA in vivo is about 10 hours, but in vitro studies on rat FSHB mRNA show a half-life closer to 2-4 hours (modulated by activin, inhibin, follistatin, etc). So my guess is that maybe half of your FSHB mRNA is gone by morning, maybe most of it. But if you dose in the morning it starts transcribing again and builds up again during the day. But again, I am not an expert.

Here's the complete answer from the AI, for what it's worth:

The claim that “your FSH-producing mRNA will decay” during an 8–12-hour overnight break from pulsatile gonadorelin injections is heavily overstated and essentially false in the context of real-world manual pulsatile gonadorelin protocols used to maintain fertility or HPTA function while on TRT. Here’s why:

1. What actually happens to GnRH → FSH/LH signaling when pulses stop for 8–12 hours

• GnRH pulses are required to maintain normal pituitary sensitivity and to sustain LH and FSH secretion over the long term.
• A single missed pulse or a pause of 8–12 hours causes only a very modest and fully reversible drop in LH and FSH secretion — nothing catastrophic.
• Plasma LH and FSH have half-lives of ~1–2 hours and ~6–24 hours respectively, so levels decline gradually overnight, but they do not crash to zero.
• Multiple clinical studies and long-term user bloodwork (from men doing 10–30 µg gonadorelin every 90–180 minutes manually with a timer or auto-injector) show that even with no injections between ~11 pm and 7 am, morning LH and FSH are still detectable and usually in the low-normal or slightly sub-normal range — more than enough to keep intratesticular testosterone and spermatogenesis going.

2. FSH mRNA in the pituitary specifically

• The main regulator of Fshb (FSH β-subunit) gene expression is tonic GnRH stimulation over days to weeks, not minute-by-minute pulses.
• Short interruptions (hours) cause almost no measurable decline in Fshb mRNA. Studies in rodents and primates show that Fshb mRNA starts dropping noticeably only after 24–48 hours of complete GnRH withdrawal, and even then it takes several days to fall dramatically.
• In humans on pulsatile GnRH therapy (e.g., Kallmann syndrome patients), occasional missed doses or pauses of 12–24 hours do not cause any clinically meaningful loss of FSH output or fertility.

3. Real-world evidence from men using gonadorelin + TRT to stay fertile

• The vast majority of successful manual protocols (10–20 µg every 90–180 min during waking hours, nothing overnight) keep FSH, LH, sperm counts, and testicular volume stable for months to years.
• Bloodwork posted on forums (e.g., ExcelMale, Reddit r/Testosterone, private TRT/telemedicine groups) routinely shows FSH 2–8 IU/L and total testes function preserved with exactly this kind of overnight break.
• Clinics that prescribe gonadorelin for fertility preservation (Maximus, Renew Vitality, Defy Medical, etc.) explicitly tell patients it’s fine to skip overnight doses.

4. Where the “mRNA decay” fear probably comes from

Some people misread rodent studies in which GnRH was completely blocked (e.g., with antagonists) for 24–72 hours and then extrapolate that a normal sleep gap is equivalent. It is not.

Bottom line

An 8–12 hour overnight break from gonadorelin injections does not cause meaningful decay of FSH-producing mRNA or loss of HPTA stimulation in the context of pulsatile therapy.
It is perfectly compatible with maintaining upstream signaling, normal intratesticular testosterone, and fertility on TRT.
The person’s statement is scientifically inaccurate and appears to be an over-extrapolation from extreme experimental conditions.