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Kisspeptin-10

Tier 2 · Preclinical
Also known as KP-10 · Kisspeptin-112-121 · Metastin 45-54

Multiple randomized/controlled human trials of kisspeptin-10 (and the parent kisspeptin-54) exist, establishing Tier 1 evidence for gonadotropin-stimulating effects. However, the strongest reproductive outcome data (e.g., the Phase 2 IVF live-birth trial) pertain to kisspeptin-54, and no Phase 3 trial has been completed for any kisspeptin. Human trials are small (n=4-12 in several key studies). Many non-reproductive mechanistic and therapeutic claims (bone, atherosclerosis, airway, neuroprotection, cardiac fibrosis, OHSS prevention, cancer) rest only on in vitro or animal data. Anecdotal single-user and fasted-state dosing claims are Tier 3.

Half-life
~0.0667 h
Routes
Intravenous (bolus and infusion) · Subcutaneous · Intracerebroventricular (research, animal)
Goals
sexual health
Cost / mg
Not recorded

How it works

Kisspeptin-10 is a short 10-amino-acid fragment of the natural kisspeptin hormone that acts as a full activator (agonist) of the KISS1R receptor (also called GPR54) found on the GnRH neurons of the hypothalamus. By switching on these neurons, it triggers release of GnRH, which in turn prompts the pituitary to secrete the reproductive hormones LH and FSH. LH then stimulates testosterone production in men and progesterone/estradiol in women, while FSH supports sperm and egg development. In short, kisspeptin-10 sits at the top of the reproductive hormone cascade and 'kick-starts' it. Its effect depends heavily on how it is given: brief pulses stimulate the system, whereas continuous over-stimulation can, according to some sources, desensitize the receptor and instead suppress hormone output. Its effects also differ between the sexes and across the menstrual cycle.

Overview

Overview

Kisspeptin-10 (KP-10; kisspeptin-112-121; metastin 45-54) is the C-terminal decapeptide fragment of the endogenous neuropeptide kisspeptin. It comprises the ten C-terminal amino acids (Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2) of kisspeptin-54, corresponding to residues 45-54 of the precursor, with a molecular weight of approximately 1302.5 g/mol. All kisspeptin peptides share this decapeptide and its Arg-Phe-NH2 (RF-amide) motif, the minimum pharmacophore required for receptor binding and biological activity.

History

The KISS1 gene was originally identified in 1996 as a metastasis suppressor gene in melanoma cells. In 2001, two independent groups identified kisspeptin-54 and its shorter fragments as endogenous ligands for the orphan G protein-coupled receptor GPR54, now designated KISS1R. The KISS1 gene encodes a biologically inactive 145-amino-acid pre-pro-peptide that is processed into four active peptides: kisspeptin-54, -14, -13 and -10, all of which bind KISS1R with similar low-nanomolar affinity.

Role in reproductive physiology

Kisspeptin peptides are critical regulators of mammalian and human reproductive physiology. Kisspeptin neurons in the arcuate and anteroventral periventricular (AVPV) nuclei of the hypothalamus are the primary upstream regulators of GnRH neurons and the HPG axis. Kisspeptin-10 stimulates GnRH release, which drives pituitary secretion of LH and FSH; LH stimulates testosterone in Leydig cells and progesterone/estradiol in the ovary, while FSH drives spermatogenesis and follicular development. The effect on gonadotropins is abolished by GnRH-antagonist pretreatment, confirming an upstream mechanism. The genetic evidence is striking: inactivating mutations in KISS1R/GPR54 or KISS1 cause absent puberty, congenital hypogonadotropic hypogonadism and infertility, while activating mutations can cause precocious puberty; GPR54-knockout mice reproduce isolated hypogonadotropic hypogonadism while retaining normal GnRH content and responsiveness.

Human evidence

Central or peripheral administration potently stimulates gonadotropin release across mammalian species. In healthy men, serum LH and FSH rose after IV bolus doses as low as 0.3 and 1.0 nmol/kg. A notable sexual dimorphism exists: kisspeptin-10 stimulates gonadotropins in men and in preovulatory-phase women but fails to do so in follicular-phase women. Bolus injection increases LH dose-dependently (P<0.0001) and FSH (P=0.012), and it dose-dependently increases LH pulse frequency in men. GnRH itself is roughly 2-3 fold more potent than kisspeptin isoforms. The strongest reproductive outcome data pertain to the parent molecule kisspeptin-54, not KP-10: a Phase 2 IVF trial in 60 high-risk women using kisspeptin-54 as an oocyte-maturation trigger achieved a 45% live birth rate with zero moderate, severe or critical OHSS cases. No Phase 3 trial has been completed for any kisspeptin.

Uses under investigation

Kisspeptin-10 has been used primarily as a research and diagnostic tool to probe the kisspeptin-GnRH axis, where a brisk LH response confirms intact GnRH and pituitary function. It and its axis are investigated for infertility, amenorrhea, pubertal delay, diagnostic evaluation of hypogonadotropic hypogonadism, ovulation/oocyte-maturation triggering in IVF (potentially substituting for hCG), and as an adjunct to testosterone replacement. Intravenous kisspeptin has also been proposed as a provocative test for oxytocin-deficient states in males. Its shorter sequence makes it simpler and cheaper to synthesize than kisspeptin-54, and it is functionally equivalent at the receptor in vitro and in animals; longer-acting analogs such as MVT-602 extend the pharmacological duration.

Broader biology (preclinical)

Beyond reproduction, largely in vitro and animal studies report metabolic and multi-organ effects (cardiovascular, respiratory, musculoskeletal), sexually dimorphic metabolic responses, increased oxytocin and vasopressin, bone-protective effects via suppression of osteoclast activity, pro-atherosclerotic vascular effects, inhibition of airway smooth muscle proliferation, neuroprotection in cellular models, cardiac collagen deposition, prevention of OHSS-associated vascular permeability, and metastasis-suppressor roles of the parent KISS1 protein. These non-reproductive findings have not been validated in humans and sometimes point in opposing directions across models.

What the research shows

150 findings extracted from the 22 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 17 human trial findings, 4 human study findings, 8 animal findings and 1 in vitro finding.

  • human trialBolus injection of kisspeptin-10 was found to increase LH in a dose-dependent manner1

  • human trialKisspeptin-10 increases FSH1

  • human trialKisspeptin-10 does not increase testosterone1

  • human trialKisspeptin-10 is a potent stimulator of LH (luteinizing hormone)2

  • human trialKisspeptin-10 increases pulse frequency in men2

  • human trialIn healthy men, serum LH and FSH were elevated after iv bolus kisspeptin-10 at doses as low as 0.3 and 1.0 nmol/kg, respectively3

  • human trialIn healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after iv bolus, sc bolus, or iv infusion of kisspeptin-103

  • human trialIn women during the preovulatory phase, serum LH and FSH were elevated after iv bolus kisspeptin-10 (10 nmol/kg)3

Show 22 more findings

  • human trialKisspeptin-10 shows sexual dimorphism in its effects on gonadotropin release in humans3

  • human trialIntravenous kisspeptin administration increases peripheral OXT levels post-injection in healthy adults4

  • human trialTen minutes after kisspeptin, OXT increased by 18.8% from baseline4

  • human trialMales showed greater OXT increase than females (31.9% vs 5.7%) after kisspeptin administration4

  • human trialIn healthy men, serum LH and FSH were elevated after i.v. bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively6

  • human trialIn healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after i.v. bolus, s.c. bolus, or i.v. infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720 pmol/kg/min, respectively6

  • human trialIn women during the preovulatory phase, serum LH and FSH were elevated after i.v. bolus kisspeptin-10 (10 nmol/kg)6

  • human trialKisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase6

  • human trialPeripheral exogenous kisspeptin administration stimulates gonadotrophin release in healthy adults and in patients with certain forms of infertility7

  • human studyKisspeptin-10 is capable of increasing circulating follicle-stimulating hormone, luteinizing hormone and testosterone levels in humans5

  • human studyLoss of kisspeptin signaling causes hypogonadotrophic hypogonadism in humans and other mammals7

  • human studyInactivating mutations in the gene encoding kisspeptin and its receptor cause infertility7

  • human studyLoss-of-function mutations of the GPR54 gene are linked to absence of puberty onset and hypogonadotrophic hypogonadism in humans21

  • animalCentral or peripheral administration of kisspeptin-10 stimulates gonadotropin release in several mammalian species3

  • animalKisspeptin-10 stimulates gonadotropin release in both male and female rodents3

  • animalKisspeptin-10 stimulates gonadotropin release in both male and female rodents6

  • animalICV administration of kisspeptin-10 increased plasma vasopressin concentration in anesthetized male rats8

  • animalSerum concentrations of Kisspeptin-10 were significantly higher in cows with follicular cysts compared with healthy cows10

  • animalKp-10 abrogated bone loss by suppressing osteoclast activity in vivo12

  • animalKp-10 prevents the increased vascular permeability of OHSS by the activation of KISS1R and the inhibition of VEGF20

  • animalMetastin and kisspeptin-10 have been demonstrated as very potent stimulators of the gonadotrophic axis in a number of species and through different routes of administration21

  • in vitroExogenously administered KP-10 (0.1 µM) substantially suppressed wild-type and E46K mutant α-syn-mediated apoptosis and mitochondrial depolarization in cholinergic differentiated SH-SY5Y neurons14

How it works

Based on 1 human trial finding, 10 human study findings, 30 animal findings, 42 in vitro findings, 5 expert opinion findings and 11 theoretical findings.

  • human trialSexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction6

  • human studyInactivating mutations of the kisspeptin receptor (KISS1R) cause pubertal failure in humans3

  • human studyActivating mutations of kisspeptin receptor can lead to precocious puberty3

  • human studyKisspeptin, acting centrally via the kisspeptin receptor, stimulates secretion of gonadotrophin releasing hormone (GnRH)7

  • human studyKisspeptin interacts with other neuropeptides such as neurokinin B and dynorphin, to regulate GnRH pulse generation7

  • human studyKisspeptin signaling be regulated by nutritional status and stress7

  • human studyKisspeptin may have direct gonadal effects and interact with metabolic pathways7

  • human studyKisspeptin (Kp) and KISS1R are expressed in human airways, especially in airway smooth muscle (ASM)15

Show 91 more findings

  • human studyExpression of Kp and KISS1R is lower in ASM from women compared with men15

  • human studyExpression of Kp and KISS1R is lower in patients with asthma compared with people without asthma15

  • human studyKiss1r mRNA decreased in the luteinized human granulosa cells of high-risk OHSS patients20

  • animalThe effect of kisspeptin-10 on gonadotropin release is abolished by preadministration of a GnRH antagonist3

  • animalKisspeptin administration increases plasma OXT in animals4

  • animalKisspeptins play crucial roles in regulating reproductive functions9

  • animalKisspeptins have effects on cardiovascular, respiratory, and musculoskeletal systems9

  • animalKisspeptin signaling has been investigated in endocrine-metabolic regulation9

  • animalKisspeptin modulates the release of hormones from hypothalamus, pituitary, gonadal, adrenal, and pancreatic glands9

  • animalKisspeptin metabolic effects exhibit sexual dimorphism with increase in metabolic activity and decrease in body weight in females9

  • animalKisspeptin metabolic effects exhibit sexual dimorphism with increase in weight gain in males9

  • animalGene expression analysis showed a reduction in GPR54 mRNA levels in follicular cysts compared to preovulatory follicles10

  • animalNo expression of the GPR147 receptor was detected in follicular cyst and preovulatory follicles10

  • animalLower presence of GPR54 in follicular cysts compared to preovulatory follicles can be determined by down-receptor regulation induced by elevated serum concentrations of Kisspeptin-1010

  • animalEndocrine imbalances of the hypothalamic-pituitary-ovarian axis in follicular cysts may reflect altered patterns of Kisspeptin-10 and GnIH secretion10

  • animalKisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416 via GPR54 activation12

  • animalGpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus12

  • animalKp-10 binding to Gpr54 leads to up-regulation of Dusp1812

  • animalKiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss12

  • animalKiSS-10 increases the level of propeptides of procollagen type I (PICP) and III (PIIICP) in fibroblast culture medium and mouse PIIICP in serum13

  • animalFour-week infusion of KP-10 into Apoe mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation17

  • animalFour-week KP-10 infusion in Apoe mice decreases intraplaque vascular smooth muscle cell content17

  • animalP234, a GPR54 antagonist, completely attenuated proatherosclerotic effects of endogenous and exogenous KP-10 in Apoe mice17

  • animalKisspeptin-10 stimulated GnRH release in males and females at the prepubertal and pubertal stages19

  • animalFemales are much more sensitive to kisspeptin signaling than males19

  • animalThroughout the progress of puberty, major remodeling of kisspeptin and NKB signaling pathways for the regulation of GnRH release takes place19

  • animalIn females during puberty, reciprocal pathways (kisspeptin signaling mediated through NKB neurons and NKB signaling mediated through kisspeptin neurons) are established19

  • animalIn males during puberty, reciprocal pathways are consolidated to a simpler kisspeptin-dominant signaling pathway19

  • animalIn primates, both kisspeptin and NKB signaling are contributing factors for the pubertal increase in GnRH release, rather than initiating puberty19

  • animalDecreased expression of Kiss1r was observed in both ovaries and lung tissue of OHSS rats20

  • animalInjection of exogenous Kp-10 inhibited the increase of vascular permeability and VEGF while promoting the expression of Kiss1r in both the ovarian and lung tissue of OHSS rats20

  • animalGPR54-null mice reproduce the phenotype of absent puberty onset and hypogonadotrophic hypogonadism21

  • animalThe hypothalamic KiSS-1/GPR54 system is an essential gatekeeper of GnRH neurons, involved in their activation at puberty and their regulation by gonadal steroids and metabolic factors21

  • in vitroAll kisspeptin peptides share the C-terminal decapeptide sequence, kisspeptin-10, which is required for biological activity in vitro3

  • in vitroFour metabolites corresponding to peptide fragments y9, y8, y7 and y5 were found after kisspeptin-10 incubation in human serum5

  • in vitroA degradation product was probably caused by oxidation of the tryptophan residue into a kynurenine residue5

  • in vitroKisspeptin is a family of peptides derived from the KISS1/kiss1 gene with structural similarity, forming from differential proteolysis of a common precursor, prepro-kisspeptin7

  • in vitroKisspeptin is an endogenous ligand of GPCR54 and stimulates GnRH release8

  • in vitroIn the brain slice preparation in vitro, bath application of kisspeptin-10 potentiated mEPSCs in MNCs of the rat SON by a mechanism that involved the kisspeptin receptor8

  • in vitroIn vitro, kisspeptins were found to favor oocyte maturation8

  • in vitroKisspeptins were found to induce the production of progesterone in cultured rat luteal cells8

  • in vitroKisspeptin-10 challenge of Fluo-4 loaded sperm was found to promote an increase in intracellular calcium indicating that these highly specialized cells express a functional Kiss1R8

  • in vitroKisspeptin-10 significantly increases the content of intracellular collagen in the myocardium13

  • in vitroKiSS-10 elevates the level of phosphorylated focal adhesion kinase (FAK) in human cardiac fibroblasts13

  • in vitroInhibition of FAK negates the stimulatory effect of KiSS-10 on collagen deposition in vitro13

  • in vitroKiSS-10 inhibits the release of metalloproteinases (MMP-1,-2,-9)13

  • in vitroKiSS-10 elevates the secretion of tissue inhibitors of metalloproteinases (TIMP-1,-2,-4)13

  • in vitroKiSS-10 enhances the expression of α1 chains of procollagen type I and III in vitro13

  • in vitroKiSS-10 augmentation of collagen deposition is dependent on protein synthesis elevation, inhibition of MMPs activity, and increase of TIMPs release13

  • in vitroThe profibrotic activity of KiSS-10 is mediated by FAK and is not dependent on TGF-β113

  • in vitroKisspeptin-10 (KP-10) is a hypothalamic neurohormone implicated in cholinergic pathologies when aberrant fluctuations of expression patterns and receptor densities occur in neurodegenerative micromilieus14

  • in vitroKP-10 is biologically governed by its cognate G-protein-coupled receptor, GPR5414

  • in vitroKP-10 attenuated the progressive demise of α-synuclein (α-syn)-rich cholinergic-like neurons14

  • in vitroCo-administration of KP-10 with GPR54 antagonist kisspeptin-234 (KP-234) failed to abrogate the neuroprotection elicited by KP-10, signifying a GPR54 dispensable mechanism of action14

  • in vitroKP-10 treatment diminished α-syn and ChAT immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn14

  • in vitroCleaved forms of Kp, particularly Kp-10, mitigated PDGF-induced ASM proliferation15

  • in vitroPharmacological inhibition of KISS1R increased basal ASM proliferation15

  • in vitroKISS1R knockdown increased basal ASM proliferation, which was further amplified by PDGF15

  • in vitroThe antiproliferative effect of Kp-10 in ASM was mediated by inhibition of MAPK/ERK/Akt pathways15

  • in vitroKp-10 treatment led to altered expression of PCNA, C/EBP-α, Ki-67, cyclin D1, and cyclin E15

  • in vitroKp-10 induced cell cycle arrest at G0/G1 phase in ASM15

  • in vitroKP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury17

  • in vitroKP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs)17

  • in vitroKP-10 induces senescence in HUVECs17

  • in vitroKP-10 increases adhesion of human monocytes to HUVECs17

  • in vitroKP-10 stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs17

  • in vitroKP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages17

  • in vitroIn human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation17

  • in vitroKP-10 enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3 in human aortic smooth muscle cells17

  • in vitroKISS1 is a metastasis suppressor protein whose expression is commonly downregulated in the metastatic tumors of various origins18

  • in vitroKISS1 has the ability to suppress colonization of disseminated cancer cells in distant organs critical for the formation of secondary tumor foci18

  • in vitroKISS1 is involved in the mechanisms of tumor angiogenesis, autophagy and apoptosis regulation18

  • in vitroKISS1 may have a role in both restricting and promoting cancer cell invasion18

  • in vitroA high level of 17-β estradiol suppressed the expression of KISS1R and increased VEGF and nitric oxide through estrogen receptors (ESR2) in HUVECs20

  • in vitroKisspeptins are the peptide products of the KiSS-1 gene, identified in 2001 as natural ligands of the previously orphan G protein-coupled receptor, GPR5421

  • expert opinionKisspeptin peptides are critical regulators of mammalian reproductive physiology3

  • expert opinionKisspeptin peptides are critical in human reproductive physiology3

  • expert opinionKisspeptin receptors are found on oxytocinergic neurons4

  • expert opinionKisspeptin-10 is a potent vasoconstrictor and inhibitor of angiogenesis17

  • expert opinionKisspeptins play a crucial role in the normal functioning of the reproductive axis in both humans and animals by stimulating the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus22

  • theoreticalKisspeptin-10 is thought to stimulate the release of GnRH from the hypothalamus, which then stimulates gonadotropin release from the pituitary gland3

  • theoreticalKisspeptin-10 is a biologically active peptide that is a product of the KISS1 gene, consisting of a conserved C-terminal 10-amino acid sequence, which is crucial for its receptor binding activity to the G protein-coupled receptor GPR548

  • theoreticalThe KISS1 gene encodes the 145 amino acid pre-pro-peptide which is biologically inactive8

  • theoreticalPost-translational modification produces four biologically active peptides designated kisspeptin-54, -14, -13 and -10, on the basis of their total amino acid number8

  • theoreticalThe four kisspeptins share a common C-terminal Arg-Phe-NH2 motif8

  • theoreticalThe four kisspeptins bind with similar affinity to the KISS1R indicating the C-terminal motif is important in binding and activating KISS1R8

  • theoreticalHuman KISS1R is a 398 amino acid class A GPCR present on chromosome 19p138

  • theoreticalHuman KISS1R signals predominantly to the Gq/11 pathway, with very little coupling to other subfamilies8

  • theoreticalIn silico algorithms demonstrated surface complementarities between KP-10 and α-syn, with KP-10 accommodated in the C-terminal binding pockets of α-syn14

  • theoreticalKisspeptin-10 is an active fragment of the endogenous full-length kisspeptin-14516

  • theoreticalKISS1 is a precursor for several shorter peptides, known as metastin (Kisspeptin-54), Kisspeptin-14, Kisspeptin-13 and Kisspeptin-1018

How the body handles it

Based on 3 animal findings.

  • animalRapid elimination time of only 30 min after injection in rats5

  • animalLH response reached a maximum concentration at 5 minutes post-dose and remained relatively unchanged for at least 30 minutes after dosing with no gender effect16

  • animalLH concentrations on Day 1 were generally greater than on day 1416

Safety and side effects

Based on 1 human study finding and 2 animal findings.

  • human studyKisspeptin-10 is included in the 2024 World Anti-Doping Agency Prohibited List5

  • animalNo overt signs of drug-related toxicity observed in clinical signs, body weights, food consumption, clinical pathology, histopathology, urinalysis, electrocardiogram, or respiratory rate in dogs at doses of 30, 100, and 1,000 μg/kg IV once daily for 14 days16

  • animalKP-10 demonstrated favorable safety profile in dog where 1,000 μg/kg dose was considered as a no-observed-adverse-effect level dose when administered IV once daily for 14 days16

What people use it for

Based on 1 human trial finding, 2 animal findings, 7 expert opinion findings and 2 theoretical findings.

  • human trialKisspeptin is a candidate for a provocative test to identify oxytocin-deficient state in males4

  • animalKisspeptins have possible therapeutic effects on gestational hypothyroidism, diabetes mellitus, and neoplasms9

  • animalKp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation12

  • expert opinionKisspeptin-10 effects suggest its use as a treatment for infertility5

  • expert opinionKisspeptin-10 testosterone-increasing effect indicates potential misuse in sports5

  • expert opinionKisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility6

  • expert opinionKisspeptin-10 is a potential therapeutic agent for reproductive disorders such as infertility, amenorrhea, and pubertal delay16

  • expert opinionKP-10 may contribute to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques17

Show 4 more findings

  • expert opinionGPR54 antagonist may be useful for the prevention and treatment of atherosclerosis17

  • expert opinionRecent studies have investigated the association of kisspeptins to infertility of diverse causes and the therapeutic potential22

  • theoreticalKISS1 has potential use as a diagnostic marker for cancer progression18

  • theoreticalKISS1 has potential use as a new anti-cancer therapeutic18

Other findings

Based on 1 in vitro finding, 1 expert opinion finding and 1 theoretical finding.

  • in vitroKisspeptin was first discovered in 1996 as a metastasis inhibitor in melanoma cell lines7

  • expert opinionThe shorter amino acid sequence of kisspeptin-10 makes it simpler and cheaper to synthesize than kisspeptin-543

  • theoreticalKisspeptins include metastin and kisspeptin-1021

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Limited evidence

Human trials are small and no Phase 3 has been completed

The pivotal human reproductive studies involved very small samples (e.g., n=4-5 per group in The Effects of Kisspeptin-10 on Reproductive Hormone Release ...; n=6 men in Kisspeptin: The Upstream GnRH-Stimulating Neuropeptide ...; n=12 in Sex-dependent increases in oxytocin levels in response to intravenous kisspeptin in humans.), and Kisspeptin-10: Research, Evidence, Dosing & Safety | Peptidings/Kisspeptin-10: HPG-Axis & Fertility Guide (2026) note the most rigorous clinical work used the parent molecule kisspeptin-54 (not KP-10) and that no Phase 3 trial has been completed for kisspeptin.

Other

Landmark IVF efficacy data are for kisspeptin-54, not kisspeptin-10

The 45% live birth rate and zero moderate/severe OHSS in a Phase 2 trial of 60 women (Kisspeptin-10: Research, Evidence, Dosing & Safety | Peptidings) and much of the strongest clinical trigger data (Kisspeptin-10: HPG-Axis & Fertility Guide (2026), Kisspeptin: The Upstream GnRH-Stimulating Neuropeptide ...) pertain to kisspeptin-54, the longer parent fragment; extrapolation to kisspeptin-10 rests on shared receptor pharmacology rather than direct KP-10 outcome trials.

Single source

Anecdotal single-user results and fasted-state dosing claims come from one low-tier source

The individual case (LH 1.2→6.8 mIU/mL, testosterone 285→612 ng/dL over four weeks) and the 50-60 fold greater fasted-state LH release are reported only in How Long Does Kisspeptin-10 Take to Work? Full Timeline, a tier-3 web source flagged as anecdotal, and are not corroborated by clinical-trial sources.

Other

KP-10 has opposing vascular/tissue effects across models

Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis. reports KP-10 is pro-atherosclerotic and pro-inflammatory in vascular cells and Apoe mice, while Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity. reports profibrotic collagen-deposition effects in cardiac tissue and Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner. reports neuroprotective effects; these are non-reproductive, mostly in vitro/animal effects with unclear human relevance.

Limited evidence

Many mechanistic and therapeutic claims rest on in vitro or animal data only

Claims about bone loss (Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.), atherosclerosis (Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis.), airway smooth muscle (Kisspeptins inhibit human airway smooth muscle proliferation.), neuroprotection (Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.), cardiac fibrosis (Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity.), OHSS prevention (Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion.), and cancer (KISS1 in breast cancer progression and autophagy.) derive from in vitro or animal studies and have not been validated in humans.

Other

Discovery date for GPR54/KISS1R loss-of-function mutations is stated inconsistently

Kisspeptin-10: Research, Evidence, Dosing & Safety | Peptidings gives 2003 as the year loss-of-function mutations in GPR54/KISS1R were discovered, while Comprehensive Review on Kisspeptin and Its Role in ... refers to inactivating mutations identified '11 years ago' relative to a 2015 review (≈2004); the sources are roughly consistent but not identical.

Using it with other compounds

Check a stack
  • TriptorelinStack with caution

    Research does not support combining these

    These work against each other. Kisspeptin-10 stimulates GnRH release to raise LH/FSH and testosterone, while triptorelin — given as a continuous depot — first flares then chronically SUPPRESSES the axis to castration-level testosterone by desensitizing the pituitary. Combining them means one is trying to turn the reproductive axis on while the other turns it off, so the effects largely cancel or conflict.

    Tier 4Theoretical — not established

    Shares testosterone axis

  • OxytocinComplementary

    Worth caution

    Kisspeptin-10 has been reported to increase plasma oxytocin (greater in males), meaning giving kisspeptin can raise the body's own oxytocin levels. This makes them mechanistically linked: kisspeptin sits upstream and can amplify oxytocinergic signaling, so their prosocial/reproductive effects may overlap even though they hit different receptors.

    Tier 4Theoretical — not established
    What the research doesn't establish
    That kisspeptin-10 raises plasma oxytocin is an observed correlation only; it is not shown whether this rise is direct or indirect, nor that kisspeptin acts upstream to amplify oxytocin signaling. The two act through separate receptors (KISS1R/GPR54 versus OXTR), and any overlap in prosocial or reproductive effects has not been demonstrated to result from one potentiating the other.
  • GonadorelinSame downstream effect

    Worth caution

    Kisspeptin-10 acts one step upstream, telling the hypothalamus's GnRH neurons to release their own GnRH, whereas gonadorelin IS GnRH acting directly on the pituitary. Both funnel into the same output — LH and FSH secretion and the resulting rise in sex steroids. Because they converge on the same HPG endpoint, combining them is largely redundant rather than additive, and both share the receptor desensitization risk if pulsatility isn't preserved.

    Tier 4Theoretical — not established

    Timing If ever used together, maintain pulsatile (not continuous) dosing to avoid gonadotroph desensitization.

    Shares testosterone axis

  • HCGSame downstream effect

    Worth caution

    Kisspeptin-10 works one step further upstream than gonadorelin \it triggers GnRH neurons, which release GnRH, which drives pituitary LH/FSH, which stimulate the gonads. HCG bypasses all of that and directly activates the gonadal LH receptor. Both ultimately raise gonadal sex hormones, so they target the same physiological endpoint by different routes. Stacking is more redundant than synergistic and warrants hormone monitoring.

    Tier 3Largely anecdotal — commonly discussed

    Shares testosterone axis

Safety and side effects

Safety and regulatory status

Kisspeptin-10 is not FDA-approved for any clinical indication, and its use outside research settings is investigational. As of April 2026 it remained non-approved but available through licensed compounding pharmacies by prescription and used in hospital-based research and diagnostic protocols in the UK and US.

Tolerability

In a 14-day repeat-dose study in dogs at 30, 100 and 1,000 μg/kg IV once daily, no overt signs of drug-related toxicity were observed across clinical signs, body weights, food consumption, clinical pathology, histopathology, urinalysis, ECG or respiratory rate; the 1,000 μg/kg dose was the no-observed-adverse-effect level. Notably, LH responses on Day 1 were generally greater than on Day 14, consistent with possible attenuation over repeated dosing.

Dosing-pattern considerations

The direction of effect depends on the administration pattern. Acute bolus or pulsatile dosing stimulates gonadotropin release, whereas some sources note that continuous or sustained KISS1R activation causes receptor desensitization and downregulation, resulting in suppression rather than stimulation. However, at least one clinical report found continuous infusion increased LH pulse frequency without desensitization, so the desensitization threshold remains uncertain.

Anti-doping

Kisspeptin-10 is included in the 2024 World Anti-Doping Agency Prohibited List; its testosterone-increasing potential indicates a risk of misuse in sport.

Evidence limitations

  • Human trials are small (e.g., n=4-5 per group, n=6 men, n=12 adults in several key studies) and no Phase 3 has been completed.
  • Whether KP-10 raises testosterone in humans is contested: a Tier-1 lifespan review reports it increases LH and FSH but not testosterone, while other sources report dose-dependent testosterone increases; the discrepancy may relate to acute single-dose versus sustained/pulsatile dosing.
  • Landmark IVF efficacy data (45% live birth rate, zero moderate/severe OHSS) are for kisspeptin-54, not KP-10.
  • Anecdotal single-user results (e.g., LH 1.2→6.8 mIU/mL and testosterone 285→612 ng/dL over four weeks, with cleared mental fog and no mood swings or water retention) and the claim of 50-60 fold greater LH release in a fasted state derive from a single low-tier source and are not corroborated by clinical trials.
  • Non-reproductive effects reported in vitro/animal include pro-atherosclerotic and pro-inflammatory vascular actions, vasoconstriction and profibrotic cardiac collagen deposition; human relevance is unclear.

Reconstitution and handling

Supply and reconstitution

No dose has been established for this compound. No regulatory label exists for it, so the figures below are what sources report — not guidance.

Kisspeptin-10 is supplied as a lyophilized white powder, typically in 5 mg vials, and is reconstituted with bacteriostatic water. A typical reported research dose is 1 mg (1000 mcg) subcutaneously daily.

Storage

  • Refrigerate lyophilized product at 2-8°C.
  • Store at -20°C for long-term storage.
  • Reconstituted shelf life is approximately 2-4 weeks.

Reported research dosing

Dosing in the literature spans several routes and regimens:

  • Clinical trials: 0.01-1.0 nmol/kg intravenously and 6.4-12.8 nmol/kg subcutaneously.
  • IV bolus: 0.24-12 nmol/kg (single dose).
  • Continuous IV infusion: 1-10 nmol/kg/hour over 4-48 hours.
  • Subcutaneous single bolus: 3-10 nmol/kg.

Because of the very short plasma half-life (~4 minutes), pulsatile or repeat dosing is generally required to maintain pituitary stimulation. LH and FSH typically rise within 10-60 minutes of an IV bolus in subjects with a normal reproductive axis; in responsive men, testosterone rises over the following 2-8 hours. Anecdotal reports describe a detectable LH rise within 10-15 minutes, peak LH at 30-45 minutes, and peak FSH at 45-150 minutes.

Notes

An anecdotal claim that fasted-state administration produces a 50-60 fold greater LH response, and an individual case using 100 mcg subcutaneously every three days over eight weeks, come from a single low-tier source and are not clinical-trial validated. All dosing figures above are reported research parameters, not clinical recommendations; kisspeptin-10 is investigational and not FDA-approved.

Sources

Ordered by evidence quality — the strongest first.

  1. Kisspeptin across the human lifespan:evidence from animal studies and ...(opens in a new tab)
    Tier 1Web · journals.bioscientifica.com
  2. Kisspeptin-10 Is a Potent Stimulator of LH and Increases Pulse Frequency in Men - PMC(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  3. The Effects of Kisspeptin-10 on Reproductive Hormone Release ...(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  4. Sex-dependent increases in oxytocin levels in response to intravenous kisspeptin in humans.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  5. [Not Available].(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  6. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans - ICH GCP(opens in a new tab)
    Tier 1Web · ichgcp.net · 2023
  7. Comprehensive Review on Kisspeptin and Its Role in ...(opens in a new tab)
    Tier 1Web · e-enm.org · 2015
  8. Kisspeptin 10 - an overview(opens in a new tab)
    Tier 2Web · sciencedirect.com
  9. Endocrine-metabolic effects of kisspeptin in mammals.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  10. New Insights in Bovine Follicular Cysts.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  11. Author Correction: Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  12. Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  13. Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  14. Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  15. Kisspeptins inhibit human airway smooth muscle proliferation.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  16. Safety Evaluation of KP-10 (Metastin 45-54) Following once Daily Intravenous Administration for 14 Days in Dog.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  17. Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  18. KISS1 in breast cancer progression and autophagy.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2019
  19. Role of Kisspeptin and NKB in Puberty in Nonhuman Primates: Sex Differences.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2019
  20. Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2017
  21. GPR54 and kisspeptin in reproduction.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2006
  22. Kisspeptins Regulating Fertility: Potential Future Therapeutic Approach in Infertility Treatment(opens in a new tab)
    Tier 3Web · mdpi.com

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