The GH Axis, Explained

There are a lot of GH peptides. They all claim to raise growth hormone. They have overlapping names, confusing abbreviations, and they stack together in combinations that seem arbitrary. Why do people run CJC-1295 with ipamorelin instead of just one or the other? Why does sermorelin need to be dosed at night? Why does tesamorelin exist if we already have sermorelin?

These questions all have the same answer: the GH axis isn't a single switch. It's a cascade with multiple control points, and different peptides work on different points.

The cascade in plain English

Your growth hormone system has three floors:

1. Hypothalamus — decides when to turn GH release on or off.
2. Pituitary — actually releases the growth hormone.
3. Liver and tissues — convert that signal into the downstream hormone (IGF-1) and the actual biological effects.

Each floor has its own controls, and peptides exist that act on each one.

HYPOTHALAMUS
    |
    | (sends GHRH "go" signal)
    | (sends somatostatin "stop" signal)
    | (responds to ghrelin from the stomach)
    v
PITUITARY (somatotroph cells)
    |
    | (releases growth hormone in pulses)
    v
LIVER + TISSUES
    |
    | (produces IGF-1)
    v
ACTUAL EFFECTS:
fat burning, tissue repair, muscle protein synthesis,
bone density, collagen turnover, recovery

Floor 1: The hypothalamus (decides to release)

Your hypothalamus is the general in charge. It sends two opposing signals down to the pituitary:

• GHRH (Growth Hormone Releasing Hormone): "release GH now."
• Somatostatin: "don't release GH."

These oscillate. GHRH spikes, somatostatin drops, and you get a GH pulse. Then somatostatin rises, and the pulse ends. This is why GH release is pulsatile — it comes in bursts throughout the day, with the biggest burst happening during deep sleep.

A third input comes from below: ghrelin, the hunger hormone released from your stomach. Ghrelin also triggers GH release through a different receptor on the pituitary (the "growth hormone secretagogue receptor," or GHS-R). This is why fasting and deep sleep both produce GH pulses — both raise ghrelin tone relative to insulin.

Floor 2: The pituitary (actually releases)

The somatotroph cells in the anterior pituitary are the GH factories. They've spent all day making GH and storing it in little granules. When the right signals hit, they dump those granules into the blood.

Two receptor types trigger the dump:

• GHRH-R — responds to GHRH from above
• GHS-R — responds to ghrelin from below

Both pathways converge on the same output (GH release), but they do it through different mechanisms. That's why hitting both at once produces more GH than either alone — they're two different on-switches wired in parallel.

Floor 3: The liver and tissues (produce IGF-1)

GH itself has some direct effects — it's lipolytic (breaks down fat), it antagonizes insulin (can raise blood sugar), and it stimulates cell proliferation. But most of what people associate with "GH effects" actually comes from IGF-1 (insulin-like growth factor 1), which the liver produces in response to GH.

IGF-1 is a peptide itself. It drives most of the anabolic effects — muscle protein synthesis, collagen production, bone density, tissue repair. It also has a much longer half-life than GH (~12–15 hours bound to its carrier protein vs. minutes for free GH), which is why blood IGF-1 is the marker people actually track.

Where each peptide acts

Now the peptide landscape makes sense:

Peptide	Floor	Receptor	Effect
Sermorelin	1→2	GHRH-R	Short GHRH analog, triggers natural pulse, very short half-life
CJC-1295 (no DAC)	1→2	GHRH-R	Slightly stabilized GHRH, ~30 min half-life
CJC-1295 with DAC	1→2	GHRH-R	Same, but albumin-bound; 6–8 day half-life = constant GHRH stimulus
Tesamorelin	1→2	GHRH-R	FDA-approved GHRH analog for visceral fat (lipodystrophy)
Ipamorelin	2	GHS-R (ghrelin)	Selective ghrelin mimetic, minimal cortisol/prolactin effect
GHRP-2, GHRP-6	2	GHS-R	Older ghrelin mimetics, more appetite + cortisol effects
Hexarelin	2	GHS-R	Strongest GH pulse, but desensitizes receptors fastest
MK-677 (Ibutamoren)	2	GHS-R	Oral small-molecule ghrelin mimetic, 24-hour GH/IGF-1 elevation
Recombinant GH (somatropin)	3	GH receptor	The actual hormone, bypasses the upstream entirely
IGF-1 LR3	Below	IGF-1R	Bypasses everything above, directly stimulates downstream growth

Why people stack GHRH + GHRP

A common protocol pairs a GHRH analog (like CJC-1295 no-DAC) with a GHRP (like ipamorelin). This is the reason:

The GHRH analog sets the amplitude of the GH pulse — how big the wave is. The GHRP sets the frequency and synergy — it amplifies that pulse and suppresses somatostatin somewhat. Together they produce more GH than either one alone, and they do it through a pattern that resembles natural physiology.

Running just GHRP-2 alone, by contrast, will also raise cortisol and prolactin. Running just a GHRH analog alone is fine but less potent. The combination hits the sweet spot most protocols aim for.

Why timing matters

Because the axis has a built-in "stop" signal (somatostatin) that fluctuates throughout the day, when you inject matters as much as what you inject. Somatostatin tone is highest after meals — your body doesn't want to raise GH when insulin is high. It's lowest during fasting and deep sleep, which is why nighttime GH pulses are naturally the biggest.

The standard advice for GH peptides:

• Inject on an empty stomach (at least 2 hours after a meal, no food for 30–60 minutes after)
• Dose before bed to layer on top of your natural nighttime pulse
• For multi-daily protocols, additional doses pre-workout or mid-afternoon

A GHRH analog injected 20 minutes after a high-carb meal produces a fraction of the GH response it would on an empty stomach.

Why feedback limits what you can do

IGF-1 feeds back to the hypothalamus and pituitary and suppresses further GH release. This is the built-in ceiling. More peptide doesn't produce proportionally more IGF-1 past a certain point — the axis clamps itself. This is usually framed as a safety feature: with GHRH and GHRP peptides, you can't really overshoot the way you can with injected recombinant GH, because the feedback loop still works.

Where to go next

• For the full neuroendocrine detail, the Pepperpedia entry on the growth hormone axis has the receptor biology, feedback loops, and clinical context.
• For the basic signaling model underneath all of this, see How Peptides Signal in the Body.
• If you're looking at a specific protocol, start with the Sermorelin guide.
• For how to read those "~30 minutes" and "6–8 days" numbers, Half-Life and Why It Matters.