Research Dossier on KissPeptin

(Reproductive Peptide)

Classification & Molecular Identity

Amino-acid sequence, molecular weight, structural motifs

“Kisspeptin” denotes a family of KISS1-derived peptides that share a conserved C-terminal RF-amide motif and activate the KISS1 receptor (KISS1R/GPR54), a class-A GPCR. The human KISS1 precursor (~145 aa) can be processed into multiple biologically active fragments, of which kisspeptin-54 (KP-54) (54 aa) and kisspeptin-10 (KP-10) (decapeptide YNWNSFGLRF-NH₂) are most used in research. All active fragments contain the C-terminal decapeptide sequence necessary and sufficient for KISS1R activation.PMC

Physicochemical properties differ by length: KP-54 is larger and circulates longer than KP-10 (see Pharmacokinetics). Structural studies and pharmacology indicate that amidation of the C-terminus enhances receptor affinity, and that shorter fragments (e.g., KP-10) retain intrinsic bioactivity but are cleared more rapidly.Oxford Academic+1

Discovery history (lab, year, species)

KISS1 was originally identified as a metastasis-suppressor gene (“KiSS-1”) in melanoma; later, its receptor GPR54 (KISS1R) was cloned and de-orphanized. Discoveries that loss-of-function mutations in KISS1R (and, later, KISS1) cause congenital hypogonadotropic hypogonadism established kisspeptin/KISS1R as a master upstream regulator of GnRH neurons, puberty onset, and reproductive endocrine function.PMC+2PNAS+2

Endogenous vs synthetic origin

Endogenous kisspeptins are produced from the KISS1 gene and act on KISS1R in hypothalamic circuits to stimulate GnRH release. For research, synthetic KP-54 and KP-10 are manufactured by peptide synthesis and used as research agonists of KISS1R.PMC

Homologs, analogs, derivatives

• Endogenous fragments: KP-54, KP-14/13, KP-10 (all share RF-amide motif).PMC

• Analogs: Modified KP-10 analogs with greater in vivo bioactivity and/or enhanced stability have been reported; these aim to address short plasma half-life of native peptides.PMC

• Functional comparators: GnRH (GNRH1) and GHRH are upstream/lateral hypothalamic peptides in reproduction but target distinct receptors and circuits; kisspeptin acts primarily upstream of GnRH neuron activation.PMC

Historical Development & Research Trajectory

Key milestones

• 1996–2001. Identification of KISS1 as a metastasis suppressor and cloning/de-orphanization of GPR54 (KISS1R).PMC

• 2003–2012. Human genetics (GPR54 and later KISS1 mutations) link the pathway to puberty and GnRH function; central role in human reproduction becomes clear.PNAS+1

• 2007–2014. Human translational studies show that KP-54 (and KP-10) can increase LH/FSH secretion in men and women; tachyphylaxis with sustained or repeated dosing is observed in hypothalamic amenorrhea (HA).PubMed+2PMC+2

• 2014–2017. Proof-of-concept IVF studies: KP-54 used to trigger oocyte maturation (including a registered trial NCT01667406); dosing strategies (single vs second dose) explored.JCI+2PMC+2

• 2018–2025. Emerging psychosexual research (neuroimaging/behavioral) and, most recently, intranasal KP-54 in humans demonstrates rapid gonadotropin stimulation across healthy and HA cohorts (2025).NIHR Imperial Biomedical Research Centre+2Imperial College London+2

Paradigm shifts & controversies

1. Reproductive “gatekeeper.” Kisspeptin/KISS1R is indispensable for pubertal initiation and GnRH pulse generation, reframing it as a master regulator rather than a peripheral modulator.PNAS

2. Beyond reproduction. Ongoing work examines psychosexual, behavioral, and cancer-biology roles (KISS1 as metastasis suppressor), but translation outside reproductive endocrinology remains developing.ScienceDirect

3. Clinical realities. While acute studies show robust endocrine responses, tachyphylaxis with repeated administration and short peptide half-lives complicate chronic use paradigms (see Pharmacokinetics & Human Evidence).PubMed

Evolution of scientific interest

After rapid growth in neuroendocrine research, attention diversified to assisted reproduction, functional hypothalamic amenorrhea, puberty disorders, and psychosexual neuroscience. The field increasingly explores formulation/route(e.g., intranasal) to navigate PK constraints while probing physiology.Bioscientifica+1

Mechanisms of Action

Primary and secondary receptor interactions

Kisspeptin peptides are high-affinity agonists at KISS1R (GPR54). In the hypothalamus, KISS1R activation stimulates GnRH neurons, increasing GnRH release into the portal circulation and thereby elevating pituitary LH and FSH. Some evidence also suggests direct pituitary actions in certain species/contexts, but the dominant effect in humans is upstream at GnRH neurons.PMC

Intracellular signaling pathways

KISS1R couples primarily to Gq/11–PLCβ–IP₃/Ca²⁺ signaling; downstream, GnRH neuron depolarization and intracellular Ca²⁺ transients trigger GnRH exocytosis. In pituitary gonadotrophs, GnRH activates Gq/11–PKC–MAPKcascades driving LH/FSH secretion; kisspeptin’s precipitating role is GnRH pulse generation.PMC

CNS vs peripheral effects

• CNS: Kisspeptin neurons in arcuate nucleus (KNDy network) and anteroventral periventricular nucleusintegrate steroid feedback and metabolic cues to pace GnRH/LH pulsatility. Human neuroimaging and behavioral studies implicate kisspeptin in psychosexual processing, though mechanisms remain under investigation.PMC+1

• Peripheral: KISS1/KISS1R are expressed in placenta, gonads, and some peripheral tissues; roles include placental function and potential metastasis suppression (KISS1), but clinical significance in peripheral sites is variable and sometimes controversial.PMC+1

Hormonal, metabolic, immune interactions

Kisspeptin orchestrates the GnRH–LH/FSH–gonadal steroid axis. Interactions with leptin, energy balance, and stresshave been reported in preclinical models; in humans, metabolic–kisspeptin interactions are plausible but not fully defined. On the immune side, direct effects are unclear/Not established.PMC

Evidence grading (A–C)

• A (replicated, foundational): KISS1R mutations → hypogonadotropic hypogonadism; kisspeptin stimulation of GnRH and gonadotropins in animals and humans; conserved Gq–PLC–IP₃/Ca²⁺ signaling.PNAS+1

• B (translational): Acute human studies across sexes and cycles; use as oocyte-maturation trigger in IVF; intranasal KP-54 rapidly stimulates gonadotropins.JCI+2PMC+2

• C (hypothesis/uncertain): Chronic therapeutic paradigms limited by tachyphylaxis; psychosexual indications promising but require larger trials; non-reproductive systemic roles debated.PubMed+1

Pharmacokinetics & Stability

ADME profile

Absorption depends on route (IV/SC/IN). Distribution is typical of peptides (limited volume close to extracellular fluid). Metabolism via peptidases is rapid, with short plasma half-lives. Excretion pathways are peptidic (renal/hepatic peptide catabolism); detailed human metabolite mapping is Not established.

Comparative half-life. Multiple studies show KP-54 persists longer than KP-10 in circulation:

• KP-54 t½ ~28–32 min (human/animal; method-dependent; reports extend to ~1.8 h).

• KP-10 t½ ~3–4 min (very rapid clearance).PMC+3PMC+3ScienceDirect+3

Direct comparisons confirm that KP-54 achieves higher/longer plasma exposure; KP-10 bioactivity is comparable at the receptor but limited by fast clearance.PMC

Plasma half-life & degradation pathways

• KP-54: Post-infusion mono-exponential decline with t½ ≈ 28–32 min reported; variability exists across preparations/assays.ScienceDirect+1

• KP-10: t½ ≈ 3–4 min; rapid decline limits steady-state levels (even at matched infusion rates vs KP-54).PMC

Stability in vitro & in vivo

In human plasma in vitro, reported half-lives can be very short for RF-amide peptides; amidation and longer fragments(KP-54) improve apparent stability/in vivo exposure. Precise stability is assay-dependent and Not standardized across labs.Karger

Storage/reconstitution considerations

Peer-reviewed literature does not provide universal, product-agnostic reconstitution/stability curves for research vials; standard peptide handling (cold chain, minimize freeze–thaw, protect from light) applies. Validated shelf-life in specific formulations is Not established in the public domain.

Preclinical Evidence

Animal & in vitro studies (selected domains)

GnRH/Gonadotropin stimulation.
Kisspeptin robustly activates GnRH neurons, increasing LH/FSH in rodents and primates. Central administration and systemic dosing both stimulate gonadotropin release, with cycle stage modulating magnitude (preovulatory > follicular).Oxford Academic+1

KP-54 vs KP-10 potency.
Receptor-level bioactivity is similar, but KP-54 has longer t½ and greater area under the curve, yielding stronger or more sustained endocrine responses than equimolar KP-10 infusions. Mechanistic work points to kinetic, not intrinsic efficacy, differences.PMC+1

Reproductive neurobiology.
Kisspeptin neurons (KNDy) coordinate GnRH pulses via reciprocal interactions with neurokinin B and dynorphin; kisspeptin is a final common excitatory driver onto GnRH neurons. (KNDy details mainly from animal models; in humans, functional homology is strongly inferred.)PMC

Representative investigational dose ranges (preclinical).

• Rats/swine: nmol·kg⁻¹ ranges for acute LH responses; detailed ED₅₀ values vary by species/route/fragment. (See human dosing below for translational ranges.)Oxford Academic

Limitations.
Species differences in steroid milieu, cycle stage, and feedback complicate cross-study pooling; dose, route, and peptide length critically influence outcomes.

Human Clinical Evidence

Summary: Robust acute endocrine responses are documented in healthy volunteers and targeted patient groups; route/formulation and dosing schedule strongly influence outcomes. Several proof-of-concept trials explore IVF triggering and hypothalamic amenorrhea; intranasal delivery (2025) shows rapid gonadotropin stimulation. Chronic paradigms can show tachyphylaxis.

Acute endocrine studies (healthy adults; women & men)

• Cycle-phase dependence in women (KP-54, IV bolus). In a classic randomized study across menstrual phases, KP-54 caused dose-dependent LH rises (0.2–6.4 nmol·kg⁻¹ IV bolus; investigational doses used in study Dhillo 2007). Responses were largest preovulatory and smallest follicular.PubMed

• KP-10 in men (IV bolus). KP-10 acutely increased LH and LH pulse frequency in healthy men; higher bolus dosing showed diminished returns, suggesting rapid desensitization at short intervals in some paradigms (investigational doses used in study George 2011/J Clin Endocrinol Metab).PMC

• Direct comparison (IV infusions). KP-54 produced higher steady-state plasma levels and longer effects than KP-10 at matched infusion rates, attributed to longer half-life; GnRH itself remained the most potent acutely on a molar basis in that paradigm.PMC

Functional hypothalamic amenorrhea (HA)

• SC KP-54 (acute vs chronic). In women with HA, single SC KP-54 doses acutely stimulated LH; however, chronic twice-daily administration resulted in tachyphylaxis (blunted LH) over two weeks (investigational SC regimen used in study Jayasena 2009).PubMed

• Continuous IV infusion (pulsatility restoration). In a small proof-of-concept study, constant IV KP-54 infusion(0.01–1.00 nmol·kg⁻¹·h⁻¹) temporarily increased LH pulsatility in women with HA (investigational infusion rates used in study Jayasena 2014).PubMed

IVF / Oocyte maturation

• Single-dose KP-54 trigger (IVF). A prospective trial showed that a single KP-54 injection could trigger oocyte maturation in subfertile women undergoing IVF; fertilization and pregnancies occurred. NCT01667406 registered this program (investigational dose in study Jayasena 2014; JCI).JCI+1

• Second-dose strategy. A randomized study reported that a second KP-54 dose 10 h after the first (each 9.6 nmol·kg⁻¹) improved oocyte yield in women at high risk of OHSS, compared to a single dose (investigational dosing used in study Abbara 2017).PMC+1

• Evidence synthesis. Recent reviews summarize three clinical trials of KP-54 as an IVF trigger, discussing efficacy and safety across dose regimens. (Exploratory/translational; not equivalent to licensing-grade Phase 3.)Frontiers

Intranasal delivery (2025)

• IN KP-54 (healthy & HA). A 2025 human study reported that intranasal KP-54 (12.8 nmol·kg⁻¹ investigational dose used in study Mills 2025) rapidly stimulated gonadotropin release in healthy men/women and in HA patients, with no adverse events reported in the study. (First peer-reviewed, controlled demonstration of intranasalkisspeptin stimulating endocrine output.)PubMed+1

Psychosexual/behavioral research (proof-of-concept)

Small controlled trials with functional MRI and behavioral endpoints suggest kisspeptin can modulate sexual processing networks and (in one men’s study) penile rigidity; these are early-phase signals requiring larger confirmatory trials and rely partly on institutional reports and peer-reviewed articles from the same centers.Imperial College London+1

Selected investigational human doses and designs (illustrative)

• KP-54 IV bolus: 0.2–6.4 nmol·kg⁻¹ across cycle phases → LH↑ (Dhillo 2007).PubMed

• KP-54 SC: acute LH↑ in HA; twice-daily for 2 w → tachyphylaxis (Jayasena 2009).PubMed

• KP-54 continuous IV infusion (HA): 0.01–1.00 nmol·kg⁻¹·h⁻¹ → LH pulsatility↑ (Jayasena 2014).PubMed

• KP-54 IVF trigger: single or two doses of 9.6 nmol·kg⁻¹ 10 h apart (Abbara 2017; linked to NCT01667406).PMC+1

• IN KP-54: 12.8 nmol·kg⁻¹ intranasal → LH↑ in healthy & HA cohorts (Mills 2025).PubMed+1

Safety signals/adverse events

Across acute studies, tolerability has generally been acceptable, with no serious adverse events typically reported in small samples. However, tachyphylaxis with repeated dosing (HA study), short half-life, and dose-/context-dependent variability are notable. Long-term safety, immunogenicity, and broad drug–drug interaction profiles are Not established.PubMed

ClinicalTrials.gov IDs (illustrative)

• NCT01667406 (IVF/oocyte maturation; results published).ClinicalTrials.gov

• NCT05633966 (SC kisspeptin in reproductive disorders; ongoing/registry snapshot).ClinicalTrials.gov

Comparative Context

Related peptides/approaches

• GnRH: downstream effector; direct GnRH agonists bypass hypothalamic gating but differ in tachyphylaxisprofiles and clinical use.

• GHRH/GHSR agonists: regulate GH axis (distinct from kisspeptin/GnRH).

• Neurokinin B/dynorphin: co-modulators in KNDy circuitry shaping GnRH pulses; act in concert with kisspeptin.PMC

Advantages (research perspective)

• Physiologic “upstream” trigger of the HPG axis with robust, immediate gonadotropin responses in acute settings.

• Multiple active fragments enable probing PK/PD differences (KP-54 vs KP-10).

• Emerging IN route broadens experimental paradigms.The Lancet

Disadvantages/constraints

• Short plasma half-lives (especially KP-10).

• Tachyphylaxis under sustained or repeated dosing (HA).

• Heterogeneous responses by sex/cycle-phase, steroid milieu, and disease context.PubMed

Research category placement

• Neuroendocrine tool peptide for dissecting GnRH/LH/FSH physiology, probing puberty, hypothalamic amenorrhea, and testing assisted reproduction mechanisms (e.g., oocyte maturation trigger).PMC

Research Highlights

• Causal genetics: KISS1R and KISS1 loss-of-function mutations → isolated hypogonadotropic hypogonadism(IHH), anchoring kisspeptin’s pivotal role in human reproduction.PNAS+1

• Acute human pharmacology: KP-54/KP-10 reliably increase LH/FSH; magnitude modulated by cycle-phaseand dose.PubMed+1

• PK contrast: KP-54 t½ ~28–32 min vs KP-10 ~3–4 min, explaining stronger sustained effects with KP-54 at equivalent infusion rates.PMC+2ScienceDirect+2

• IVF proof-of-concept: Kisspeptin-triggered oocyte maturation in IVF including second-dose strategy (two 9.6 nmol·kg⁻¹ doses, 10 h apart) to increase oocyte yield in high-risk OHSS patients.JCI+1

• Novel delivery: Intranasal KP-54 (2025) rapidly stimulates gonadotropins in healthy and HA cohorts, with no reported AEs in that study.PubMed+1

Conflicting/uncertain areas

• Durable therapeutic windows: Repeated dosing can lead to tachyphylaxis; chronic efficacy remains Not established.PubMed

• Psychosexual indications: Early studies suggest benefit, but evidence remains limited to small trials; broader efficacy and dosing windows are Unknown.Imperial College London

• Peripheral oncology roles: KISS1 as metastasis suppressor is well-documented in models; translational relevance across tumor types remains heterogeneous.ScienceDirect

Potential Research Applications (no clinical claims; research-use framing)

1. GnRH pulsatility mapping.
   Use acute KP-54/KP-10 challenges to interrogate GnRH/LH pulse generators, quantify steroid-feedback sensitivity, and model KNDy interactions using frequent-sampling deconvolution in controlled physiology studies.PMC

2. Route/formulation innovation.
   Explore intranasal and pulsatile paradigms to test whether specific exposure patterns can minimize tachyphylaxiswhile achieving targeted gonadotropin dynamics (first evidence reported for IN KP-54 in 2025).The Lancet

3. Assisted reproduction mechanisms.
   Examine how kisspeptin-triggered cascades differ from hCG or GnRH agonist triggers (downstream ovarian signaling, oocyte competence), and whether dose-splitting strategies improve maturation metrics in defined populations.PMC

4. Psychosexual neuroendocrinology.
   Combine kisspeptin challenges with fMRI/EEG to chart limbic and hypothalamic network responses, linking endocrine outputs to behavioral indices in controlled experimental settings. (Exploratory; not efficacy claims.)NIHR Imperial Biomedical Research Centre

5. Comparative peptide kinetics.
   Directly compare KP-54 vs KP-10 vs optimized analogs for PK/PD, receptor bias, and desensitization metrics, guiding design of next-gen KISS1R agonists with longer half-life and reduced tachyphylaxis.PMC

Safety & Toxicology

Preclinical toxicity

Standard GLP-style, long-term toxicology packages specific to KP-54/KP-10 are not broadly available in the public domain. In animals and acute human studies, kisspeptin was generally well-tolerated, but systematic repeat-dose tox, immunogenicity, genotoxicity, and carcinogenicity datasets for chronic exposure are Not established.

Known/theoretical molecular risks

• Desensitization/tachyphylaxis: Repeated or sustained exposure can blunt LH responses, particularly in HA cohorts.PubMed

• Endocrine variability: Responses depend on sex, cycle-phase, steroid milieu, and disease state; inappropriate exposure timing may yield suboptimal or variable effects.PubMed

• Off-target/peripheral actions: KISS1/KISS1R in non-hypothalamic tissues (e.g., placenta, tumors) suggest potential context-specific effects; clinical relevance for exogenous peptides remains uncertain.PMC+1

Human safety observations

Acute dosing studies and small experimental trials report no serious adverse events, including the recent intranasalstudy. However, long-term safety, DDIs, and population-level risk assessments remain Not established and require larger, controlled programs.The Lancet

Limitations & Controversies

• Short half-life & delivery challenges: Especially for KP-10, limiting steady-state exposure without infusion strategies.PMC

• Tachyphylaxis with chronic exposure: Demonstrated in HA with repeated SC dosing; undermines sustained endocrine goals without optimized regimens.PubMed

• Heterogeneous translational evidence: IVF trigger data exist but remain limited in scale; psychosexual findings promising yet early; standardized endpoints and multicenter replication are needed.Frontiers+1

Future Directions

• Route-optimized paradigms: Further intranasal and pulsatile delivery studies to balance efficacy vs desensitization; define exposure–response surfaces across sexes and cycle stages.The Lancet

• Analogs with enhanced PK. Develop longer-acting or biased KISS1R agonists to sustain GnRH drive with less tachyphylaxis, guided by comparative KP-54/KP-10 data and novel analog screens.PMC

• Mechanistic integration. Systems-level mapping of KNDy–GnRH circuitry with kisspeptin stimuli (multi-omics, in-human neuroimaging) to refine models of pulse generation and steroid feedback.PMC

• Clinical scaling. Larger, controlled trials to assess IVF outcomes, HA management strategies, and psychosexualendpoints; harmonize dosing, timing, and safety monitoring across centers.Frontiers+1

References (selected peer-reviewed & registries)

1. Dhillo WS, et al. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase in women. J Clin Endocrinol Metab. 2007. (KP-54 0.2–6.4 nmol·kg⁻¹ IV bolus; cycle-dependent LH response.) PubMed

2. George JT, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011. (Acute KP-10 effects; desensitization with higher bolus intervals discussed.) PMC

3. Chan YM, et al. Direct comparison of IV kisspeptin-10, kisspeptin-54, and GnRH on gonadotropins in men. J Clin Endocrinol Metab. 2015. (KP-54 > KP-10 exposure; GnRH most potent acutely.) PMC

4. Zhang C, et al. Mechanistic insights: KP-54 vs KP-10 potency; KP-54 t½ ≈32 min vs KP-10 ≈4 min.Endocrinology. 2017. PMC

5. Jayasena CN, et al. SC KP-54 acutely stimulates gonadotropins in HA; chronic dosing causes tachyphylaxis. J Clin Endocrinol Metab. 2009. PubMed

6. Jayasena CN, et al. Continuous IV KP-54 increases LH pulsatility in HA. J Clin Endocrinol Metab. 2014. (0.01–1.00 nmol·kg⁻¹·h⁻¹; deconvolution.) PubMed

7. Jayasena CN, et al. Kisspeptin-54 triggers egg maturation in IVF. J Clin Invest. 2014. NCT01667406. JCI+1

8. Abbara A, et al. Second KP-54 dose 10 h later improves oocyte yield in high-risk OHSS women. J Clin Endocrinol Metab. 2017. (Two 9.6 nmol·kg⁻¹ doses.) PMC

9. Mills EG, et al. Intranasal KP-54 rapidly stimulates gonadotropins in healthy adults and HA patients.EBioMedicine/The Lancet Discovery Science. 2025. (12.8 nmol·kg⁻¹ IN; no AEs reported in study.) PubMed+1

10. Skorupskaite K, et al. Kisspeptin–GnRH pathway in human reproductive health. Hum Reprod Update. 2014. (Mechanistic overview; human data synthesis.) PMC

11. de Roux N, et al. Loss-of-function GPR54 causes IHH. PNAS. 2003. (Causal genetics.) PNAS

12. Topaloglu AK, et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012. (Human KISS1 LOF mutation.) New England Journal of Medicine

13. Gottsch ML, et al. From KISS1 to kisspeptins: historical perspective and future. Endocrinology. 2009. (Historical/biological overview.) PMC

14. Nash KT, Welch DR. The KISS1 metastasis suppressor: mechanistic insights. Cancer Res. 2006. (Cancer biology context.) PMC

15. Sharma B, et al. Use of kisspeptin to trigger oocyte maturation—evidence synthesis. Front Endocrinol. 2022. (Trial summary table.) Frontiers

16. LC–MS/MS KP-10 and KP-54 t½ reports: analytical/pharmacokinetic measurements supporting KP-54 ~28 mint½ in humans. J Chromatogr B. 2013. ScienceDirect

Additional registry references: NCT05633966 (SC kisspeptin in reproductive disorders); see also associated protocol/SAP documents for NCT01667406 (IVF program). ClinicalTrials.gov+2Clinical Trials+2

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.