RFRP-3 (GnIH)
The brain's brake on reproduction — the opposite of kisspeptin — that links stress and season to fertility. A research peptide, not a drug
RFRP-3 (RFamide-related peptide-3) is the mammalian version of a bird hormone called gonadotropin-inhibitory hormone, or GnIH — the first peptide ever found that puts a brake on the reproductive axis. If kisspeptin is the accelerator that switches puberty and fertility on, RFRP-3 is the brake: made by a small group of neurons in the hypothalamus, it inhibits the GnRH neurons that drive the reproductive system and lowers the release of luteinizing hormone from the pituitary. It is the messenger through which stress and the changing seasons turn fertility down — its levels rise with psychological and immune stress (via glucocorticoids) and track day length through melatonin. Beyond reproduction it stimulates feeding and influences energy balance, and it acts directly on the ovary. RFRP-3 signals through the receptor GPR147. It is studied as a research tool and a potential handle on fertility and stress; it is not an approved medicine and has not been given to people as a treatment.
No established human dose Details ↓
Recommended Dosing
No established human dose
RFRP-3 is an endogenous human peptide that has never been given to people as a treatment. The human evidence is its identification in brain tissue; the functional studies are in animals and cells, where RFRP-3 is injected into the brain or applied to cells at experimental amounts that do not carry over to people.
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What is it?
For decades the reproductive axis was thought to have only an accelerator — gonadotropin-releasing hormone (GnRH), which drives the pituitary to make the gonadotropins that run the ovaries and testes. Then in 2000 a peptide was discovered in quail that did the opposite: gonadotropin-inhibitory hormone (GnIH), the first known brake on the system. Its mammalian counterpart is RFRP-3, RFamide-related peptide-3, a short RFamide peptide (human sequence VPNLPQRF-amide) cut, together with RFRP-1, from the product of the NPVF gene. It signals through the receptor GPR147.
RFRP-3 is made by a small, discrete group of neurons in the dorsomedial hypothalamus whose fibres reach the GnRH neurons and the pituitary. Working at both sites, RFRP-3 inhibits GnRH neurons directly and reduces luteinizing-hormone release — the mirror image of kisspeptin, the peptide that switches the reproductive axis on. Electrophysiology in brain slices shows RFRP-3 hyperpolarizes and silences GnRH neurons, including kisspeptin-activated ones, through a direct membrane mechanism.
What makes RFRP-3 compelling is that it is a transducer — a way for the body and the environment to dial fertility up or down. Its expression rises with psychological and immune stress, an effect carried by the stress hormone cortisol acting on the RFRP neurons, so RFRP-3 is now implicated in stress-induced suppression of fertility and sexual behaviour; silencing it in animals restores both. In seasonally breeding species its expression tracks day length through melatonin, timing reproduction to the right part of the year.
RFRP-3’s reach extends past the brain. Human studies identified RFRP-1 and RFRP-3 and their GPR147 receptor in the hypothalamus and pituitary, confirming the system exists in people. The peptide also stimulates feeding and interacts with energy balance and glucose handling, and it acts directly on the gonads — in ovarian cells it can arrest the cell cycle and change steroid output — so the reproductive brake is wired to metabolic state as well.
RFRP-3 is an endogenous human peptide and a research tool, not a medicine. No published study has given RFRP-3 to people as a treatment — the human side is its identification in tissue, and the functional work is in animals and cells — it is approved nowhere, and material sold online as ‘RFRP-3’ or ‘GnIH’ is an unregulated research chemical. Nothing here is a dose or a therapy; this page records what the published science says about the peptide.
Mechanism of Action
RFRP-3 is the mammalian gonadotropin-inhibitory hormone — an RFamide peptide signalling through GPR147 that brakes the reproductive axis, transduces stress and seasonal signals into fertility, stimulates feeding, and acts directly on the gonads.
Reproductive brake (opposite of kisspeptin)
Through GPR147, RFRP-3 directly hyperpolarizes and silences GnRH neurons and reduces luteinizing-hormone release (PMIDs 19204051, 26063871) — the functional opposite of kisspeptin, acting at both the brain and the pituitary (PMID 20027225).
Stress- and season-transducer
RFRP-3 expression rises with psychological and immune stress via glucocorticoids and tracks day length via melatonin, making it the messenger that turns fertility and sexual behaviour down under stress and off-season (PMID 25511257).
Feeding, metabolism and direct gonadal action
RFRP-3 stimulates feeding and links to energy balance and glucose handling (PMID 33566226), and acts directly on the ovary — arresting granulosa-cell proliferation and altering steroid output (PMID 29337271).
Published Research
These are studies of RFRP-3 read from their PubMed abstracts on November 6, 2026. They include two reviews — on the seasonal control of GnIH and on RFRP-3 in energy homeostasis and reproduction — an animal study of RFRP-3 suppressing luteinizing hormone, the identification of RFRP-1/RFRP-3 and their receptor in the human hypothalamus, a brain-slice study of its direct inhibition of GnRH neurons, and a cell study of its effect on ovarian cells. RFRP-3 has not been given to people as a treatment in any published study; the human evidence is its identification in tissue.
Seasonal control of GnIH in birds and mammals
A review of gonadotropin-inhibitory hormone (GnIH/RFRP-3) as a key component of the circuitry that phases reproduction with the seasons. Transducing photoperiod (day-length) information, it adjusts reproductive state and sexual motivation across species, and can also drive acute changes in reproductive status — surveying the similarities and differences in how GnIH works across photoperiodic birds and mammals.
RFRP-3 in energy, metabolism and reproduction
A review of RFRP-3 as a neuroendocrine regulator that links energy balance and reproduction. Through GPR147 it inhibits the reproductive axis, and it also has an orexigenic (feeding-stimulating) action; its expression rises in metabolically deficient states, suggesting RFRP-3 integrates energy balance with reproduction, and the review considers its possible relevance to type-2 diabetes, aging and subfertility.
RFRP-3 suppresses LH in female mice
In female mice, RFRP-3 appeared to act as an endogenous brake on the reproductive axis before puberty, and centrally administered RFRP-3 suppressed plasma luteinizing hormone. In prepubertal mice this suppression depended on estradiol (it was lost after ovariectomy and restored by estradiol), whereas in adults it was independent of estradiol — RFRP-3 reducing GnRH expression at the mRNA and protein level (a preclinical result).
RFRP-3 and its receptor identified in human brain
Human GnIH homologs were isolated from the human hypothalamus and identified by mass spectrometry as RFRP-1 (MPHSFANLPLRF-amide) and RFRP-3 (VPNLPQRF-amide), with GnIH-immunoreactive neurons in the dorsomedial hypothalamus projecting to GnRH neurons and the median eminence. The receptor GPR147 was found in the hypothalamus and in pituitary gonadotropes — establishing the GnIH/RFRP system in people (a human-tissue identification study).
RFRP-3 directly inhibits GnRH neurons
In mouse brain slices, GnIH and RFRP-3 produced an almost identical, non-desensitizing hyperpolarization of GnRH neurons — including kisspeptin-activated ones — through a direct postsynaptic potassium-current mechanism, and could prevent or interrupt kisspeptin-induced activation. This showed RFRP-3 can silence GnRH neurons directly, reducing GnRH and glutamate release (an electrophysiology result in animal tissue).
RFRP-3 arrests ovarian-cell cycle
In pig ovarian granulosa cells, RFRP-3 reduced cell viability and induced G2/M cell-cycle arrest, lowering Cyclin B1 and CDK1 and raising the inhibitory regulators Myt1 and phospho-Wee1 — evidence that RFRP-3 acts directly on the ovary to restrain granulosa-cell proliferation, beyond its central effects on the reproductive axis (a cell-culture result).
No Established Human Dose
RFRP-3 is an endogenous human peptide that has never been given to people as a treatment. The human evidence is its identification in brain tissue; the functional studies are in animals and cells, where RFRP-3 is injected into the brain or applied to cells at experimental amounts that do not carry over to people. No regulator has approved any dose, and no published human dose exists, so no amount is printed here.
What this rests on: PMID 26063871, PMID 20027225, PMID 25511257.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes RFRP-3 (GnIH) is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
Unknown: no human dose of RFRP-3 (GnIH) has been established (see No Established Human Dose below), so there is no amount to work out. The reconstitution calculator does the arithmetic for any vial, water and dose.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store RFRP-3 (GnIH), before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long RFRP-3 (GnIH) stays intact once mixed.
How it is taken
Unknown: with no established human dose, there is no established way of taking RFRP-3 (GnIH). What the human studies gave and how is set out under No Established Human Dose.
What to expect, and when
How long it stays in the body: a half-life of not established for humans as a drug; an endogenous signalling peptide. After about five half-lives almost none is left.
When effects appear: unknown; no source on this page gives a time to effect for RFRP-3 (GnIH). Results reported in the studies are under Published Research.
Source: half-life: PMID 25511257.
Side effects, and when to stop or get help
From the Side Effects section: No human adverse-event data exist: no published study has administered RFRP-3 to people; In animals, RFRP-3 suppresses the reproductive axis and luteinizing hormone (PMIDs 26063871, 19204051) and mediates stress-induced loss of fertility and sexual behaviour (PMID 25511257) — effects of a signalling peptide, not a safety profile; It stimulates feeding and acts directly on the ovary (PMIDs 33566226, 29337271), so reproductive and metabolic effects would be expected if it were administered; Material sold online as ‘RFRP-3’ or ‘GnIH’ is an unregulated research chemical of unverified content. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping RFRP-3 (GnIH). Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“RFRP-3 is an endogenous peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status”).
Interactions
Unknown: a PubMed search for human interaction studies of RFRP-3 (GnIH) (reviewed 2026-11-06) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of RFRP-3 (GnIH) products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a drug: Drugs@FDA and the openFDA label endpoint hold no record, and FDA GSRS and ChEMBL hold no substance record for RFRP-3 / gonadotropin-inhibitory hormone (searched November 6, 2026)). Sport: Not on the 2026 List.
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Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
RFRP-3 is an endogenous peptide that has not been given to people as a drug, so there is no human safety profile; the points below reflect that research status.
Contraindications & Cautions
RFRP-3 has no approved use and no label. These points reflect its endogenous, research status.
Legal Status
RFRP-3 (gonadotropin-inhibitory hormone) is an endogenous human peptide studied as a research compound; it is not a drug and is not approved in any country.
Frequently Asked Questions
?What is RFRP-3?
An endogenous human peptide, RFamide-related peptide-3 — the mammalian version of the bird hormone gonadotropin-inhibitory hormone (GnIH). Cut with RFRP-1 from the NPVF-gene precursor (human sequence VPNLPQRF-amide), it signals through the receptor GPR147 and acts as a brake on the reproductive axis.
?What does it do?
It inhibits GnRH neurons and luteinizing-hormone release — the opposite of kisspeptin (PMIDs 19204051, 26063871) — and is the messenger through which stress and the seasons turn fertility down (PMID 25511257). It also stimulates feeding and acts directly on the ovary (PMIDs 33566226, 29337271).
?Is it a treatment for anything?
No. RFRP-3 is a research peptide used to study the reproductive axis, stress and fertility; its receptor GPR147 is a potential drug target. No human trial has administered RFRP-3, and it is approved nowhere.
?Is it approved or available to buy?
No. RFRP-3 is not a medicine, has no FDA application or label, and is approved nowhere. Material sold online as RFRP-3 or GnIH is an unregulated research chemical. Grey Peptides lists no sellers and recommends no source; this page records the published science.
References
- [review] Kriegsfeld LJ, et al. "Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals." Front Neuroendocrinol, 2015;37:65-75. PMID: 25511257.
- [review] Anjum S, et al. "RF-amide related peptide-3 (RFRP-3): a novel neuroendocrine regulator of energy homeostasis, metabolism, and reproduction." Mol Biol Rep, 2021;48(2):1837-1852. PMID: 33566226.
- [animal] Xiang W, et al. "The Inhibitory Effects of RFamide-Related Peptide 3 on Luteinizing Hormone Release Involves an Estradiol-Dependent Manner in Prepubertal but Not in Adult Female Mice." Biol Reprod, 2015;93(2):30. PMID: 26063871.
- [mechanism] Ubuka T, et al. "Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis." PLoS One, 2009;4(12):e8400. PMID: 20027225.
- [mechanism] Wu M, et al. "Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism." J Physiol, 2009;587(Pt 7):1401-11. PMID: 19204051.
- [mechanism] Wang X, et al. "RFRP-3, the mammalian ortholog of GnIH, induces cell cycle arrest at G2/M in porcine ovarian granulosa cells." Peptides, 2018;101:106-111. PMID: 29337271.
- [other] UniProt Q9HCQ7 (NPVF_HUMAN), read November 6, 2026: RFRP-3 is one of the peptides (with RFRP-1) cut from the neuropeptide VF precursor, the product of the NPVF gene; human RFRP-3 is VPNLPQRF-amide and signals through the receptor GPR147 (NPFFR1). https://www.uniprot.org/uniprotkb/Q9HCQ7/entry
- [other] Gonadotropin-inhibitory hormone (GnIH) was discovered in quail in 2000 as an inhibitor of gonadotropin release; its mammalian ortholog is RFamide-related peptide-3 (RFRP-3), an LPXRF-amide RFamide peptide, and the human RFRP-1/RFRP-3 peptides and their GPR147 receptor were identified in the human hypothalamus in the study carded on this page (read November 6, 2026).
- [other] US FDA, Drugs@FDA and the drug label endpoint (openFDA), searched November 6, 2026: no application and no label record for RFRP-3 / gonadotropin-inhibitory hormone. It is an endogenous human peptide, not a registered drug; FDA GSRS and ChEMBL hold no substance record for it.
Sources & Citations
The six studies carded above were read from their PubMed records on November 6, 2026. Identity comes from UniProt (Q9HCQ7, gene NPVF); RFRP-3’s status as the mammalian GnIH ortholog, its VPNLPQRF-amide sequence, its GPR147 receptor and its roles in inhibiting the reproductive axis and transducing stress and season are from the reviews and studies carded here, including the human-tissue identification; the absence of US approval and of a drug substance record from Drugs@FDA, openFDA, FDA GSRS and ChEMBL was checked the same day. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.