The growth-hormone secretagogue category encompasses a large and sometimes confusing set of peptides that all share one goal: stimulate the pituitary to release endogenous growth hormone. But "stimulate" can happen in multiple ways, and the differences matter enormously for outcomes, side effects, and stacking logic. Unlike exogenous HGH (which floods the system with supraphysiologic hormone), secretagogues work through the native feedback loop—they amplify the body's own signaling, not replace it.
The two axes: GHRH and GHRP
Growth-hormone secretagogues divide into two mechanistic classes based on which receptor they activate.
GHRH analogues (Growth-Hormone-Releasing Hormone) include Sermorelin, Tesamorelin (Egrifta), and the CJC family (CJC-1295 without DAC, CJC-1295 with DAC/CJC-1295 (DAC)). These peptides bind the GHRH receptor on the anterior pituitary and directly stimulate GH synthesis and release. Sermorelin is a truncated GHRH(1-14) analogue. CJC-1295 is a tetra-substituted GHRH(1-29) analogue engineered to resist DPP-4 cleavage, extending its half-life. Tesamorelin is similar—a GHRH analogue approved by the FDA for HIV-associated lipodystrophy, one of the few peptide hormones with direct regulatory approval for human clinical use.
GHRPs (Growth-Hormone-Releasing Peptides) take a different path. They bind the ghrelin receptor (GHSR1a) and trigger GH release through a distinct neural pathway. This class includes Ipamorelin, GHRP-2, GHRP-6, and Hexarelin. The original GHRP compounds were discovered in the 1990s through peptide screening and were synthesized without a natural counterpart; ghrelin itself was identified later as the endogenous ligand. This matters: the synthetic GHRPs aren't replacing a hormone, they're mimicking a hunger signal.
Mechanism and feedback
Here's the crucial distinction from exogenous HGH. When you inject growth hormone directly, you suppress your own somatostatin (the GH-inhibiting hormone) to zero—you've flooded the system. The feedback loop goes silent. With secretagogues, the native somatostatin and IGF-1 inhibition remain active. Your pituitary still "knows" how much GH is in circulation and can still dampen release if levels get too high.
This has real consequences. Secretagogue protocols preserve the pulsatile architecture of GH secretion. Exogenous HGH suppresses it entirely, replacing endogenous pulses with a constant bath of hormone. The literature increasingly suggests that GH pulses, not chronic elevation, drive most of the adaptations researchers care about—skeletal protein synthesis, lean-mass accretion, and metabolic remodeling. This is a key reason why secretagogue-based research often outperforms exogenous HGH protocols when endpoints are carefully matched.
Selectivity within the GHRP family
Not all GHRPs are created equal. Ipamorelin is GH-selective—it binds GHSR1a with minimal off-target engagement, so GH release is relatively clean. The side-effect profile is mild. GHRP-2 and GHRP-6 are less selective. GHRP-2 triggers significant cortisol and prolactin spikes alongside GH, which can be beneficial (cortisol drives mobilization) or undesirable (prolactin elevation has reproductive implications). GHRP-6 is notorious for hunger stimulation—it activates appetite centers in the hypothalamus as a secondary effect. Hexarelin is potent but has a well-documented desensitization problem—the pituitary response fades with repeated dosing if the peptide is dosed continuously.
Researchers routinely exploit these differences. If appetite stimulation is desired (for athletes in a bulk phase), GHRP-6 becomes the choice compound. If a cortisol co-release is useful (for metabolic remodeling), GHRP-2. If selectivity for GH alone is paramount, Ipamorelin. And if the research question is about receptor-independent signaling or synergistic effects with other axes, Hexarelin despite its desensitization profile.
Stacking: GHRH + GHRP synergy
Here's where the two classes get interesting together. A GHRH analogue (CJC-1295, Sermorelin, Tesamorelin) and a GHRP (Ipamorelin, GHRP-2) hit different receptors and trigger different branches of the GH-release pathway. When combined, they produce a GH pulse substantially larger than either alone. This isn't additive; it's synergistic. The pituitary has two independent stimuli firing, and the result is a much more robust secretion event.
The classic stack for lean-tissue research is CJC-1295 without DAC (short-acting) plus Ipamorelin, dosed twice or three times daily. The pulsatile pattern is preserved, the pituitary gets clean stimuli to both receptors, and the magnitude of GH release per pulse can exceed what either peptide generates alone. The trade-off is injection frequency—you're committing to multiple daily injections, not the weekly schedule of long-acting secretagogues.
DAC and the pulsatile-versus-bleed trade-off
CJC-1295 with DAC extends the half-life from ~30 minutes to ~8 days, converting a pulsatile secretagogue into a long-acting, bleed-style agent. The pharmaceutical advantage is obvious: one injection per week instead of two to three daily. The biological cost is less obvious but real. With DAC, you get a continuous background GH elevation rather than discrete pulses. This flattens the pituitary's natural rhythm.
The debate in the literature is whether pulsatile or continuous is superior for lean-mass gains. Current evidence favors pulsatile—the receptor and transcriptional machinery downstream of GH signaling seem to respond better to repeated pulses than to constant elevation. But the practical advantage of weekly dosing keeps DAC versions popular in compliance-conscious research.
Research-protocol implications
A researcher choosing within this category needs to answer three questions: (1) Do I want pulsatile or continuous GH elevation? (2) Do I want GHRP selectivity for GH alone, or do I want off-target effects (cortisol, appetite)? (3) How many injections per week can I sustain?
Pulsatile + selective for GH alone = CJC-1295 no-DAC + Ipamorelin, twice daily. Pulsatile + wanting cortisol engagement = CJC-1295 no-DAC + GHRP-2, twice daily. Continuous + maximal convenience = CJC-1295 with DAC, once weekly. Each has merit; the choice depends on whether your endpoint favors rhythm, amplitude, or simplicity.
Should you stack GHRH and GHRP together?
Yes. They hit different receptors and produce synergistic GH pulses substantially larger than either alone. CJC-1295 without DAC + Ipamorelin is the classic pulsatile stack for lean-tissue research.
What's the difference between Ipamorelin, GHRP-2, and GHRP-6?
Ipamorelin is GH-selective with mild side effects. GHRP-2 triggers cortisol and prolactin spikes. GHRP-6 drives appetite stimulation. Choose based on whether you want clean GH or specific off-target effects.
Why is DAC on CJC-1295 a big deal?
DAC extends half-life from ~30 min to ~8 days, converting pulsatile dosing to once-weekly. The trade-off: once-weekly convenience vs loss of pulsatile GH rhythm, which some literature suggests drives better lean-mass gains.
Can you use a long-acting secretagogue with a short-acting one?
Yes, though less common. CJC-1295 with DAC + a GHRP creates a hybrid pattern (continuous baseline + acute pulses), which is less well-characterized in literature than pure pulsatile stacks.
