Kisspeptin-10 (mouse/rat): reproductive-hormone trigger peptide
A natural brain peptide fragment that signals the body to start releasing reproductive hormones; used only as a lab research tool.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Kisspeptin-10 is the ten-residue active C-terminal fragment of kisspeptin, an endogenous neuropeptide produced in the hypothalamus that sits at the very top of the reproductive hormone cascade. This card covers the mouse and rat form (sequence YNWNSFGLRY, C-terminally amidated) — distinct from the human form, Kisspeptin-10 (human), which ends in phenylalanine (YNWNSFGLRF) at the final position. Both species variants bind the same receptor — KISS1R, formerly called GPR54 — and trigger the same downstream cascade: KISS1R activation on GnRH neurons drives GnRH release, which drives LH and FSH release from the pituitary, which drives sex hormone production in the gonads. The rodent decapeptide is the standard tool compound used in laboratory studies of the hypothalamic-pituitary-gonadal (HPG) axis in mice and rats. The C-terminal amidation (–NH₂ on the final tyrosine) is not visible in the raw 10-letter sequence shown here, but is present in the endogenous and synthetic forms; the amide protects the C-terminus from carboxypeptidases and is part of the canonical RFamide-related signature shared with the broader kisspeptin family (Kirby and colleagues, Pharmacological Reviews 2010).
History
Kisspeptin was discovered in 1996 at the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, as a metastasis-suppressor cDNA encoded by the gene the discoverers named KISS1 — the "kiss" was a nod to the town's Hershey's Kisses (programme context: Beck and colleagues, European Journal of Cancer 2010). The peptide's reproductive function was not recognised for another seven years. In 2003, two independent groups reported that humans with inactivating mutations in the kisspeptin receptor (then GPR54, now KISS1R) failed to undergo puberty, establishing kisspeptin as the master upstream regulator of the reproductive axis (Mead and colleagues, British Journal of Pharmacology 2007, reviewing the original finding).
The kisspeptin decapeptide was identified as the minimal active fragment shortly thereafter and became the standard probe of HPG-axis biology. Rodent studies through the late 2000s mapped the central role of kisspeptin neurons in the arcuate and anteroventral periventricular nuclei in gating pulsatile GnRH release, and direct hypothalamic injection of kisspeptin was shown to potently raise LH and testosterone in adult male rats (Patterson and colleagues, Journal of Neuroendocrinology 2006). Subsequent reviews charted the evolutionary conservation of the kisspeptin/KISS1R system across vertebrates (Tsutsui and colleagues, Journal of Neuroendocrinology 2010; Pasquier and colleagues, Frontiers in Endocrinology 2012; Akazome and colleagues, Journal of Fish Biology 2010; Okamura and colleagues, Animal Science Journal 2013).
What it does
In intact animals, a single kisspeptin-10 injection raises LH within minutes and drives a downstream rise in testosterone or estradiol over the following hours. The effect is robust enough that kisspeptin-10 is used as a pharmacological "challenge" to test whether the GnRH–pituitary–gonadal axis of a given animal (or person) is intact. The peptide's plasma half-life is short (on the order of minutes), so the response is brisk and self-limiting; continuous infusion eventually causes receptor desensitisation (tachyphylaxis), making kisspeptin unsuited to chronic continuous dosing in any species (Jayasena and colleagues, JCEM 2009, characterising tachyphylaxis with the longer kisspeptin-54).
Beyond the reproductive cascade, kisspeptin signalling has been linked to direct modulation of brain regions involved in sexual and emotional processing in humans, observed by fMRI under intravenous kisspeptin administration (Comninos and colleagues, JCI Insight 2018). Those central effects appear to be partly independent of the downstream gonadal-steroid rise.
Evidence
- Human: Jayasena and colleagues (JCEM 2011) administered intravenous kisspeptin-10 to healthy men and women across the menstrual cycle and observed sexually dimorphic responses — robust LH stimulation in men, weaker and cycle-phase-dependent responses in women — establishing kisspeptin-10 itself as a tool to probe HPG-axis physiology in humans. Resting-state fMRI changes in sexual and emotional brain networks have been documented under intravenous kisspeptin (Comninos and colleagues, JCI Insight 2018). The high-profile efficacy trials in hypoactive sexual desire disorder (HSDD) (Mills and colleagues, JAMA Network Open 2023; Thurston and colleagues, JAMA Network Open 2022) used the longer kisspeptin-54, not kisspeptin-10 — these results are programme context, not direct kisspeptin-10 evidence. There are no Phase 3 trials of kisspeptin-10 in any indication.
- Animal: Rodent studies established the HPG-axis-stimulating activity of kisspeptin and mapped the central role of kisspeptin neurons in driving pulsatile GnRH release (Patterson and colleagues, Journal of Neuroendocrinology 2006; Rønnekleiv and colleagues, Advances in Experimental Medicine and Biology 2013). Comparative work across vertebrates documented conservation of the kisspeptin/KISS1R system and species variation in the active peptide ending (Akazome and colleagues, Journal of Fish Biology 2010; Pasquier and colleagues, Frontiers in Endocrinology 2012; Okamura and colleagues, Animal Science Journal 2013).
- In vitro: The murine kisspeptin-10 decapeptide is a random coil in solution but undergoes a conformational change at membranes and forms β-sheet aggregates in the presence of heparin — an effect blocked by amphiphilic surfactants (Nielsen and colleagues, Biopolymers 2010). Independent of this aggregation behaviour, kisspeptin-10 retains full KISS1R binding activity; the broader pharmacology of KISS1R agonism is reviewed in Kirby and colleagues (Pharmacological Reviews 2010).
Mechanism
Kisspeptin-10 is a Gq/11-coupled KISS1R agonist. Receptor activation on GnRH neurons in the hypothalamus drives phospholipase C signalling and intracellular calcium mobilisation, producing pulsatile GnRH release into the hypothalamo-pituitary portal vessels. GnRH then drives LH and FSH release from anterior-pituitary gonadotrophs, which stimulates gonadal steroidogenesis — testosterone in males and oestrogen/progesterone in females (Kirby and colleagues, Pharmacological Reviews 2010; Xie and colleagues, Frontiers in Endocrinology 2022). The genetic loss-of-function evidence in humans — people without functional KISS1R do not undergo puberty — directly establishes KISS1R agonism as the obligate upstream gate of HPG-axis activation (Mead and colleagues, British Journal of Pharmacology 2007, reviewing the 2003 human genetics).
Kisspeptin-10 itself is the minimal active fragment of the kisspeptin-54 precursor and retains essentially full KISS1R binding affinity. Compared with the longer kisspeptin-54, kisspeptin-10 has a shorter plasma half-life (minutes), which is why longer-acting fertility-trigger applications (IVF oocyte maturation) were developed using kisspeptin-54 rather than kisspeptin-10 (Jayasena and colleagues, Clinical Pharmacology & Therapeutics 2010; Dhillo and colleagues, JCEM 2005, 2007). The arcuate "KNDy" population that co-expresses kisspeptin, neurokinin B and dynorphin is now understood as the central pulse-generator network that translates kisspeptin signalling into the rhythmic GnRH output the pituitary requires (Xie and colleagues, Frontiers in Endocrinology 2022).
The peripheral role of kisspeptin/KISS1R signalling outside the hypothalamus — in gonads, placenta and other reproductive tissues — has also been mapped (Cao and colleagues, Reproductive Biology and Endocrinology 2019), and the conformational and aggregation behaviour of the bare decapeptide in the presence of heparin and surfactants (Nielsen and colleagues, Biopolymers 2010) is relevant for storage and formulation but not for the physiological mechanism at receptor.
Known effects
- HPG-axis stimulation (LH, FSH, downstream testosterone or oestradiol) — established in rodents and humans, with sexual dimorphism in the human response (Jayasena and colleagues, JCEM 2011; Patterson and colleagues, Journal of Neuroendocrinology 2006).
- Modulation of brain regions involved in sexual and emotional processing — observed in humans by fMRI under intravenous kisspeptin (Comninos and colleagues, JCI Insight 2018). The HSDD efficacy programme has used kisspeptin-54, not kisspeptin-10.
- Tachyphylaxis on continuous administration — receptor desensitisation has been documented with chronic kisspeptin-54 dosing (Jayasena and colleagues, JCEM 2009) and is a general feature of KISS1R pharmacology that constrains chronic-use strategies for any kisspeptin form.
Safety signals
There is no Phase 3 kisspeptin-10 safety database. Phase 1–2 work with intravenous kisspeptin (both -10 and -54) at academic centres has reported a generally favourable acute safety profile: transient flushing is the most commonly reported effect, with occasional mild headache and IV injection-site reactions; no serious adverse events have been reported across the published programme (Mead and colleagues, British Journal of Pharmacology 2007, reviewing the early trials; Xie and colleagues, Frontiers in Endocrinology 2022). The published exposures are small (n ≤ 32 per trial), acute or short-term, and concentrated at a single academic centre, so the safety claim is bounded by those limits.
The chief pharmacological concern is downstream HPG-axis over-stimulation rather than direct toxicity of the peptide. KISS1 also has a documented role as a metastasis-suppressor gene in some tumour models (Beck and colleagues, European Journal of Cancer 2010), and the net effect of repeated exogenous kisspeptin administration on cancer risk has not been characterised. Long-term safety of repeated kisspeptin-10 exposure in humans is not established — all published human exposures are acute or short-term.
Regulatory status
- US (FDA): Not approved for any indication. Kisspeptin-10 has no marketing authorisation and remains an investigational research compound.
- EU (EMA): Not approved.
- UK: Investigational use only at academic centres (Imperial College London and collaborators) under investigator protocols; not a commercially approved product.
- WADA: Kisspeptin's mechanism (stimulating endogenous LH and testosterone release) falls within the spirit of S2 (peptide hormones) and S4 (hormone and metabolic modulators) categories that prohibit HPG-axis stimulants in competitive sport; athletes should treat it as prohibited.
Open questions
- Independent replication of the human kisspeptin-54 sexual-processing findings using kisspeptin-10 itself — the HSDD imaging trials used kisspeptin-54; whether kisspeptin-10 (with its shorter half-life) produces comparable central effects has not been directly demonstrated.
- Phase 3 efficacy in any indication — no Phase 3 trial exists for kisspeptin-10.
- Route equivalence — published human work uses intravenous administration; whether subcutaneous or intranasal routes give comparable HPG-axis effects for kisspeptin-10 specifically is not established.
- Chronic exposure — KISS1R tachyphylaxis on continuous administration constrains chronic-use strategies; what pulsatile dosing schedules (if any) could sustain efficacy without desensitisation remains uncharacterised.
- Species equivalence — the mouse/rat form ending in Y and the human form ending in F both bind KISS1R; direct head-to-head pharmacology between the two decapeptides in matched assays has not been individually characterised in the references on file.
Related peptides
- Kisspeptin-10 (human) — the human-sequence decapeptide (YNWNSFGLRF), the form used in most human clinical studies labelled simply as "kisspeptin-10".
- Kisspeptin-13 (human) — a 13-residue extension of kisspeptin-10 from the human KISS1 precursor.
- Kisspeptin-54 (27–54, human) — the longer 54-residue form used in most clinical HSDD and IVF-trigger trials; longer plasma half-life than kisspeptin-10.
- Kisspeptin (zebrafish) — a non-mammalian KISS1R-active kisspeptin from a paralogous fish kisspeptin gene system.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does kisspeptin-10 form an amyloid-like structure in the hypothalamus that acts as a local reservoir, releasing active peptide gradually to keep reproductive hormone levels stable between pulses?
If true, it would reveal a completely new way the brain maintains reproductive hormone balance and could explain why some fertility disorders involve altered proteoglycan environments, pointing to new targets beyond the kisspeptin receptor itself.
In women whose reproductive hormones have shut down due to extreme stress or low body weight, can kisspeptin-10 restart the natural hormonal pulse rhythm rather than just imposing an artificial one?
If true, kisspeptin-based treatment could help athletes, women with anorexia, or others with stress-related infertility restore natural fertility cycles with better hormonal balance than existing pulsatile GnRH pump therapy.
Is the C-terminal tyrosine of kisspeptin-10 the critical anchor for receptor activation, with the tryptophan at position 3 providing only secondary contact?
If true, researchers could design much shorter, more stable versions of kisspeptin for treating infertility, making potential future treatments cheaper and easier to administer.
Does the tyrosine at the end of mouse kisspeptin-10, which has a hydroxyl group absent in the human version's phenylalanine, allow the rodent peptide to also activate NPFF pain-modulating receptors?
If true, decades of rodent experiments using this peptide to study reproduction might need reinterpretation, and the human version of kisspeptin-10 would be a more specific research tool, improving the reliability of preclinical fertility drug development.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.9377373456954956 | boltz-2 |
| ranking score | 0.757849395275116 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10711,
sequence = {YNWNSFGLRY},
target = {kiss1r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}