Peerless Peptides

Kisspeptin-10

C-terminal decapeptide YNWNSFGLRF-NH2 of the KISS1 gene product; GPR54 / KISS1R ligand

Kisspeptin-10 (Kp-10) is the synthetic C-terminal decapeptide YNWNSFGLRF-NH2 of the 145-amino-acid KISS1 preprotein (UniProt Q15726, chromosome 1q32.1), the cognate ligand of the GPR54 / KISS1R receptor. The KISS1 gene was isolated in 1996 at Penn State College of Medicine in Hershey, Pennsylvania as a melanoma metastasis-suppressor gene; in 2003, GPR54 loss-of-function mutations were identified as a cause of hypogonadotropic hypogonadism, reframing the gene as the upstream master regulator of the HPG axis. The dominant clinical thread runs through the Imperial College London / Hammersmith Hospital program led by Waljit Dhillo.

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Biochemical Profile

CAS Number
374675-21-5
Molecular Formula
C63H83N17O14
Molecular Weight
1302.45 g/mol
Purity
≥99% (HPLC-UV (220 and 280 nm))
PubChem CID
25240297
Amino Acid Sequence
Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2

Receptor Targets and Signaling Pathway Context

Kisspeptin-10 is the minimal active C-terminal fragment of the KISS1 gene product. All processed kisspeptin forms (Kp-54, Kp-14, Kp-13, Kp-10) share the identical YNWNSFGLRF-NH2 sequence and the conserved C-terminal Arg-Phe-amide (RFamide) motif, which is load-bearing for receptor binding. Three independent laboratories in 2001 (Kotani, Ohtaki, Muir) identified the kisspeptins as the natural ligands of the orphan receptor GPR54[1].

GPR54 (also called KISS1R, AXOR12) is a Class A rhodopsin-like seven-transmembrane G-protein coupled receptor encoded on chromosome 19p13.3. The receptor couples primarily to Gαq/11, generating inositol-1,4,5-trisphosphate, mobilizing intracellular calcium via PIP2 hydrolysis, and driving downstream ERK1/2 and p38 MAPK phosphorylation. Kp-10 binds rat and human GPR54 with low nanomolar affinity (Kd ~1 nM). On sustained agonist exposure, the receptor undergoes beta-arrestin-mediated internalization. This is the molecular basis for the tachyphylaxis observed in continuous-infusion human studies.

In the hypothalamus, kisspeptin neurons cluster in the arcuate nucleus and anteroventral periventricular nucleus and project to GnRH neurons. The arcuate population co-expresses neurokinin B and dynorphin and is referred to as the KNDy neuron group. Direct evidence positions the KNDy population as the GnRH pulse generator: calcium signals in arcuate kisspeptin neurons are temporally correlated with LH pulses, and optogenetic activation of these neurons elicits LH pulses comparable to spontaneous ones.

The pulse-generator framing operationalizes the 2003 hypogonadotropic-hypogonadism findings reported simultaneously by de Roux in PNAS and Seminara in NEJM[2][3]. Loss-of-function in GPR54 abolishes kisspeptin-driven activation of GnRH neurons, eliminates the pulsatile GnRH signal, and produces isolated hypogonadotropic hypogonadism in consanguineous human families and in engineered knockout mice. Exogenous kisspeptin administered to healthy human males produces dose-dependent increases in plasma LH, FSH, and testosterone, first reported by Dhillo and colleagues at Imperial College London in 2005[4] and extended by the Edinburgh Anderson/Millar group in 2011 using the Kp-10 form in men[5].

The plasma half-life of Kp-10 in humans is approximately 4 minutes after intravenous bolus. This short half-life is the dominant pharmacokinetic constraint shaping the entire clinical-development arc. Continuous infusion is required to maintain receptor occupancy; continuous exposure triggers desensitization. The Imperial program has therefore favored the longer-persistent Kp-54 form in clinical work, and industrial development has moved toward metabolically stabilized long-acting analogs (TAK-448, MVT-602).

Research Applications

Reproductive Endocrinology and the HPG Axis

The KISS1-GPR54 signaling axis has been characterized as the upstream regulator of GnRH neuron activity. The 2003 dual identification by de Roux (PNAS) and Seminara (NEJM) that loss-of-function mutations in GPR54 cause isolated hypogonadotropic hypogonadism in consanguineous human families is the foundational human-genetics finding for the entire reproductive-axis biology[2][3]. The Seminara NEJM paper combined human-mutation analysis with mouse-knockout phenotyping; the de Roux paper identified a homozygous 155-nucleotide deletion in GPR54 segregating with isolated hypogonadotropic hypogonadism.

Rodent and non-human primate studies have established that exogenous kisspeptin administration stimulates LH and FSH release, advances pubertal timing in juvenile females, and disrupts estrous cyclicity if administered continuously. The Plant and Terasawa primate work positioned kisspeptin as the central node for primate pubertal initiation. Restraint of kisspeptin-receptor signaling delays puberty; release of restraint initiates it.

In humans, the first kisspeptin administration was conducted by Dhillo and colleagues in 2005 at Imperial College London, with a 90-minute intravenous infusion of Kp-54 producing dose-dependent increases in plasma LH, FSH, and testosterone in healthy male volunteers[4]. George et al. (2011) extended the work with the Kp-10 form in men, reporting peak LH stimulation at intravenous bolus doses on the order of 1 microgram per kilogram and an increase in LH pulse frequency during low-dose continuous infusion[5].

Kisspeptin in Assisted Reproduction (IVF Triggering)

The strongest clinical efficacy signal in the kisspeptin literature comes from the Imperial College London Phase 2 IVF triggering program led by Ali Abbara and Waljit Dhillo. Abbara et al. (2015) reported a Phase 2 randomized adaptive-design trial (NCT01667406, n=60) in women at high risk of ovarian hyperstimulation syndrome (OHSS), in which a single subcutaneous Kp-54 trigger replaced the conventional hCG trigger 36 hours before oocyte retrieval[6]. The trial reported oocyte maturation in 95% of women, clinical pregnancy rate 52.9% per transfer, live-birth rate 45.1% per transfer, and no moderate or severe OHSS in any subject. Abbara et al. (2017) reported a follow-on Phase 2 randomized trial in which two Kp-54 doses administered 10 hours apart improved mature-oocyte yield over a single dose, with continued absence of moderate/severe OHSS[7].

The rationale is mechanism-anchored: kisspeptin triggers an endogenous LH surge dependent on the patient's individual GnRH and gonadotropin reserves rather than imposing a long-acting exogenous hCG signal. As of May 2026, more than 30 babies have been born in the Imperial College Healthcare NHS Trust IVF program using kisspeptin as the maturation trigger. No Phase 3 trial has been published. The Phase 2 efficacy data have not been advanced to a regulatory submission.

Hypoactive Sexual Desire Disorder Mechanism Studies

Two Phase 2 mechanism-of-action trials at Imperial College London have examined kisspeptin in adults with hypoactive sexual desire disorder. Comninos et al. (2022) reported a randomized double-masked placebo-controlled 2-way crossover trial (ISRCTN17271094, n=32 premenopausal women), in which Kp-54 administered by 75-minute intravenous infusion was compared with placebo[8]. The primary endpoint was BOLD fMRI response across whole brain and pre-specified regions of interest during erotic-video and facial-attraction stimuli. The reported regional findings were mixed and direction-dependent: deactivation in left inferior frontal gyrus, activation in right postcentral and supramarginal gyrus, deactivation in right temporoparietal junction.

Mills et al. (2023) reported the parallel trial in 32 men with HSDD[9]. The same Kp-54 infusion protocol was used. The reported outcomes included modulation of brain activity in sexual-processing network structures and an increase in penile tumescence over placebo during the long sexual video task.

Both trials are Phase 2 mechanism-of-action studies with neuroimaging and physiological-arousal endpoints, not Phase 3 efficacy trials with standardized HSDD outcome instruments and chronic dosing. The Comninos/Mills group framed the findings as a basis for further clinical development. As of May 2026, no chronic-dosing efficacy trial in HSDD has been published.

Hypothalamic Amenorrhea and HPG Restoration Research

Hypothalamic amenorrhea has been a sustained research focus for the Imperial College London Reproductive and Investigative Endocrinology Group. Jayasena et al. (2010) reported that twice-weekly Kp-54 administration for 8 weeks stimulated reproductive hormone release across the full study period in women with hypothalamic amenorrhea, in contrast to twice-daily dosing which produced tachyphylaxis within days[10]. The acute-versus-chronic dichotomy was first characterized in this program and has shaped subsequent kisspeptin protocol design: pulsatile or intermittent dosing preserves response, while continuous or daily dosing produces desensitization through GPR54 beta-arrestin internalization.

Jayasena et al. (2014) reported the use of intravenous Kp-54 infusion to increase LH pulsatility in women with hypothalamic amenorrhea, with response magnitude correlated with basal estradiol[11]. The underlying hypothalamic-pituitary reserve is the rate-limiting determinant of the kisspeptin response in this population.

No large-scale efficacy trial showing restoration of regular menses or fertility in hypothalamic-amenorrhea patients has been published as of May 2026. The published evidence is Phase 2 mechanism and feasibility data.

KISS1 in Cancer Metastasis Biology

The KISS1 gene was first characterized in cancer biology, not reproductive endocrinology. Lee, Miele, Hicks, Phillips, Trent, Weissman, and Welch (J Natl Cancer Inst 1996) isolated a cDNA from a melanoma-cell hybrid that had been suppressed for metastatic potential by introduction of chromosome 6[12]. Re-expression of the cloned cDNA in metastatic C8161 melanoma cells suppressed metastasis to lung in athymic nude mice in a dose-dependent fashion. The gene was named KiSS-1 in reference to Hershey's Chocolate Kisses, manufactured in the same Pennsylvania town. The original paper made no mention of reproduction, of GPR54, or of a secreted active peptide. West et al. (1998) confirmed the 1q32.1 chromosomal localization[13].

Thirty years of cancer-metastasis research has not produced an approved clinical asset. The Ly, Harihar, and Welch 2020 review (Cancer Metastasis Rev, PMID 32152912) catalogs contradictory tissue-context findings: KISS1 expression has been reported to suppress metastasis in melanoma, prostate, ovarian, and pancreatic cancer while paradoxically associating with poorer prognosis or pro-tumorigenic phenotypes in some studies of liver, breast, and thyroid cancer. The Ly review notes that canonical KISS1-KISS1R signaling has been called into question on the cancer side.

The Takeda industrial program tested the long-acting analog TAK-448 in a Phase 1 prostate-cancer study, reporting testosterone downregulation into the castration range via paradoxical agonism: initial gonadotropin stimulation, then HPG suppression via GPR54 desensitization (MacLean 2014)[14]. The Phase 2 cancer program was not pursued; the asset later moved to Myovant Sciences as MVT-602 and was redirected to reproductive-medicine indications.

Replication and Clinical Status

The kisspeptin field has a structural pharmacokinetic problem: the plasma half-life of Kp-10 in humans is approximately 4 minutes. Continuous infusion is required to maintain receptor occupancy, but continuous exposure triggers GPR54 beta-arrestin internalization and tachyphylaxis. This has driven three field-level adaptations. The Imperial College program has preferentially used Kp-54 (longer in vivo persistence than Kp-10, identical in vitro receptor affinity) in clinical work. Single-bolus dosing has been used where feasible (the Abbara IVF triggering protocol initiates an endogenous LH surge that proceeds without further exogenous input). Industrial development has converged on metabolically stabilized long-acting analogs (TAK-448, MVT-602)[14][15].

As of May 2026, no Phase 3 efficacy trial of native kisspeptin (Kp-10 or Kp-54) has been completed or published for any indication. The strongest data are Phase 2: IVF triggering (Abbara 2015, 2017)[6][7], HSDD mechanism studies (Comninos 2022, Mills 2023)[8][9], and hypothalamic amenorrhea (Jayasena 2010, 2014)[10][11]. The cancer-metastasis program has not produced a clinical asset. The two-biology problem is not interchangeable: cancer-metastasis findings should not be cited as support for reproductive-axis applications, and reproductive-axis trials should not be cited as evidence for cancer indications.

The regulatory status of kisspeptin-10 is the major operational fact. On October 29, 2024, the FDA Pharmacy Compounding Advisory Committee voted against adding kisspeptin-10 to the 503A bulks list. The FDA briefing-document rationale cited insufficient physicochemical characterization (peptide-related impurities, aggregates, variants), significant immunogenicity risk on injection, insufficient evidence of effectiveness for the nominated indication (secondary hypogonadism in men), and availability of FDA-approved alternative therapies. The FDA subsequently proposed not to add kisspeptin-10 to the bulks list. No reopening of the decision is on the public docket. Kisspeptin is also banned at all times under WADA Prohibited List class S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics), with kisspeptin named as an example on the 2024 list and carried forward to 2026[16].

Reconstitution & Storage

Recommended Diluent
Bacteriostatic water (0.9% benzyl alcohol) or sterile saline
Storage (lyophilized)
-20°C, dry, dark, in sealed amber vials with desiccant
Storage (reconstituted)
2-8°C, prepare immediately prior to experimental use; use within 24-48 hours
Shelf Life
24+ months lyophilized at -20°C

Research References

  1. [1] Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276(37):34631-34636. doi:10.1074/jbc.M104847200PMID:11457843
  2. [2] de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100(19):10972-10976. doi:10.1073/pnas.1834399100PMID:12944565
  3. [3] Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614-1627. doi:10.1056/NEJMoa035322PMID:14573733
  4. [4] Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90(12):6609-6615. doi:10.1210/jc.2005-1468PMID:16174713
  5. [5] George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011;96(8):E1228-E1236. doi:10.1210/jc.2011-0089PMID:21689260
  6. [6] Abbara A, Jayasena CN, Christopoulos G, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab. 2015;100(9):3322-3331. doi:10.1210/jc.2015-2332PMID:26192876
  7. [7] Abbara A, Jayasena CN, Comninos AN, et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod. 2017;32(9):1915-1924. doi:10.1093/humrep/dex253PMID:28854728
  8. [8] Comninos AN, Demetriou L, Wall MB, et al. Effects of kisspeptin administration in women with hypoactive sexual desire disorder: a randomized clinical trial. JAMA Netw Open. 2022;5(10):e2236131. doi:10.1001/jamanetworkopen.2022.36131PMID:36287566
  9. [9] Mills EG, Ertl N, Wall MB, et al. Effects of kisspeptin on sexual brain processing and penile tumescence in men with hypoactive sexual desire disorder: a randomized clinical trial. JAMA Netw Open. 2023;6(2):e2254313. doi:10.1001/jamanetworkopen.2022.54313PMID:36735255
  10. [10] Jayasena CN, Nijher GMK, Abbara A, et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther. 2010;88(6):840-847. doi:10.1038/clpt.2010.204PMID:20980998
  11. [11] Jayasena CN, Abbara A, Veldhuis JD, et al. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54. J Clin Endocrinol Metab. 2014;99(6):E953-E961. doi:10.1210/jc.2013-1569PMID:24517142
  12. [12] Lee J-H, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88(23):1731-1737. doi:10.1093/jnci/88.23.1731PMID:8944003
  13. [13] West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998;54(1):145-148. doi:10.1006/geno.1998.5566PMID:9806840
  14. [14] MacLean DB, Matsui H, Suri A, Neuwirth R, Colombel M. Sustained exposure to the investigational kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two Phase 1 studies. J Clin Endocrinol Metab. 2014;99(8):E1445-E1453. doi:10.1210/jc.2013-4236PMID:24762108
  15. [15] Mills EG, Abbara A, Dhillo WS, Comninos AN, et al. Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical trials. Fertil Steril. 2024. PMID:37925096
  16. [16] World Anti-Doping Agency. 2024 Prohibited List, class S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics). Kisspeptin named as an explicit example of a prohibited substance alongside the GnRH agonist analogs (buserelin, deslorelin, goserelin, histrelin, leuprorelin, nafarelin, triptorelin). Status carried forward to the 2026 Prohibited List.
  17. [17] Ly T, Harihar S, Welch DR. KISS1 in metastatic cancer research and treatment: potential and paradoxes. Cancer Metastasis Rev. 2020;39(3):739-754. doi:10.1007/s10555-020-09868-9PMID:32152912
  18. [18] U.S. Food and Drug Administration, Pharmacy Compounding Advisory Committee. Meeting documents on the kisspeptin-10 nomination for the 503A bulks list. October 29, 2024. Vote outcome: against inclusion. FDA subsequently proposed not to add kisspeptin-10 to the 503A bulks list.

Scientific Journal Author

Waljit S. Dhillo, FRCP, FRCPath, FMedSci, PhD

Section of Endocrinology and Investigative Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London / Hammersmith Hospital, NIHR Senior Investigator, Consultant Endocrinologist

Landmark Publications

  • Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90(12):6609-6615. (PMID 16174713) — first human administration of kisspeptin.
  • Abbara A, Jayasena CN, Christopoulos G, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab. 2015;100(9):3322-3331. (PMID 26192876) — Phase 2 IVF triggering trial.
  • Comninos AN, Demetriou L, Wall MB, et al. Effects of kisspeptin administration in women with hypoactive sexual desire disorder: a randomized clinical trial. JAMA Netw Open. 2022;5(10):e2236131. (PMID 36287566) — Phase 2 HSDD mechanism study.

Professor Dhillo is independently cited here as the principal investigator of the Imperial College London / Hammersmith Hospital Reproductive and Investigative Endocrinology Group, which has produced the dominant share of the world's published human kisspeptin clinical data since 2005. There is no affiliation or commercial relationship between Professor Dhillo, Imperial College London, the Imperial College Healthcare NHS Trust, or any associated entity, and Peerless Peptides.

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