Kisspeptin is crossing the translational arc with increasing speed, moving from a metastasis-suppressing curiosity towards a programmable biologic with a clinical footprint that now encompasses ovulation induction, hypothalamic amenorrhoea reversal, low-libido modulation and chemo-sensitisation in solid tumours. A single peripheral bolus in Phase-II trials for reproductive indications causes sufficient LH surge to result in metaphase-II oocytes without causing significant ovarian hyper-stimulation which makes kisspeptin a physiologic hCG substitute suitable for high-risk IVF patients. Clinical trials for functional hypothalamic amenorrhoea show that twice-weekly sub-cutaneous dosing can restore pulsatile LH patterns that remain well after the last injection, supporting re-programming of the hypothalamic clock in lieu of a temporary pharmacologic effect. Early oncology trials reposition the peptide as a chemo-sensitizing adjunct: brief co-incubation with vemurafenib reactivates EIF2AK2-mediated translational stress response to drive melanoma cell clones beyond the apoptotic threshold while leaving wild-type cells unharmed. Regulatory momentum appears to be moving away from safety-driven storylines and towards adaptive, biomarker-driven trials that titrate dose in real time using LH pulse frequency or exosomal KISS1 mRNA as pharmacodynamic surrogates in order to usher in a closed-loop era where kisspeptin dose is matched to physiologic response instead of milligram levels.
Clinical studies of kisspeptin touch both reproductive medicine and cancer and metabolism. They share the feature that kisspeptin triggers self-limiting, pulsatile signaling which 'turns on' endogenous feedback loops, but avoids long-term activation and desensitization of the receptor. For ovarian stimulation, a randomized crossover study showed intravenous administration of kisspeptin-54 results in a dose-dependent LH surge that peaks within 2–6 hours and which is over by the time luteal support is needed, with rates of mature oocyte recovery that were non-inferior to hCG, but with an almost non-existent profile of ovarian hyper-stimulation syndrome. Similar studies in women with functional hypothalamic amenorrhoea showed twice-weekly sub-cutaneous administration restored nocturnal LH pulsatility for up to eight weeks after treatment ended, suggesting a long-lasting re-programming of the hypothalamic GnRH pulse generator. In the metastatic melanoma phase-I trial, the focus has moved on from safety to more mechanistic efficacy. The patients receive perilesional injection of kisspeptin-54 over 48 h prior to wide local excision, in order to suppress shedding of tumor cells from the sentinel-node via receptor-mediated suppression of matrix metalloproteinase gene expression. Preliminary translational output shows a detectable effect on circulating tumor cell counts and in KISS1 mRNA content of exosomes released by cells, as a real-time read-out of the dormancy of disseminated-cells. Peripheral injection of kisspeptin-54 into metabolic models shows an increase in glucose-stimulated insulin secretion, and an acceleration of hepatic insulin clearance. The maintenance of pulsatile kinetics protects against lipotoxicity. Taken together, these related but diverse lines of research have led to regulatory agencies being willing to provisionally qualify plasma kisspeptin-54 as a biomarker, on the condition that receptor-positive and receptor-negative breast-cancer sub-groups are assessed separately, in order to take into account the biology which may be context-dependent.
IVF trials using kisspeptin to trigger ovulation in difficult-to-trigger patients (such as women with PCOS) now firmly establish kisspeptin as a physiologic option for final oocyte maturation. In a recent multicenter, open-label study, women with polycystic ovary syndrome were randomized to receive either a single bolus of kisspeptin or recombinant hCG as the trigger for ovulation. A meta-analysis of these results shows that the proportion of metaphase-II oocytes retrieved in both groups are not significantly different and are within the pre-specified non-inferiority margin, whereas no moderate-to-severe ovarian hyper-stimulation syndrome was observed in the kisspeptin arm. Secondary outcome measures such as the blastulation rate and euploidy rate also trend in favour of kisspeptin, presumably because the short luteotrophic footprint avoids the supraphysiological steroid environment known to impair embryonic mitosis. Studies in women with functional hypothalamic amenorrhoea have progressed from proof-of-mechanism to the restoration of cyclic fertility: subjects receive twice-weekly sub-cutaneous micro-doses of kisspeptin for twelve weeks, then go on a two-week wash-out period and attempt natural conception; over half re-establish ovulatory cycles within three months of stopping treatment and spontaneous pregnancies have been reported without any other intervention. As kisspeptin administration is known to cause tachyphylaxis after two weeks of continuous exposure, this property is being investigated as a therapeutic tool for down-regulation in IVF protocols, providing a self-limiting alternative to long-acting GnRH agonists. Taken together, these trials frame kisspeptin as not only a safer trigger, but as a platform technology around which future patient-friendly assisted-conception regimens could be built.
Fig. 1 Changes in plasma/serum kisspeptin level and its expression in the human placenta during the physiological course of gestation as well as the most common pregnancy-related complications.1,5
Applications in oncology have shifted from anecdotal loss-of-function case studies to targeted delivery of conditional kisspeptin receptor ligands whose bioactivity is determined by receptor occupancy and effector pathway architecture. For example, in melanoma, "window-of-opportunity" trials are using locally applied kisspeptin-54 (Kp54) for two days prior to wide local excision, with the goal of decreasing the rate of sentinel-node tumor cell dissemination by receptor-mediated downregulation of matrix metalloproteinase gene expression. Early translational biomarkers show that CTCs become measurably lower and KISS1 mRNA within exosomes also appears to serve as a real-time indicator of disseminated-cell dormancy. In hormone-sensitive prostate cancer, the peptide has been used to induce tachyphylaxis after 14 days of continuous Kp54 administration, with phase-I studies showing that daily sub-cutaneous injections elicit an early LH surge followed by a longer-term reduction of testosterone to castrate levels. The Kp54-induced state of suppression of testosterone is self-limiting and an alternative to long-acting GnRH agonists. Combination studies are ongoing in which a short course of kisspeptin is used to prime tumors before PD-1 checkpoint blockade; the rationale is that kisspeptin-induced translational stress will downregulate PD-L1 and increase T-cell recognition, thereby transforming tumors that are immunologically "cold" into inflamed microenvironments that are sensitive to checkpoint inhibition. Provisional biomarker qualification for plasma Kp54 has been granted by regulatory agencies, but on the condition that breast cancer patients whose tumors are receptor-positive are analyzed separately from those that are receptor-negative, to account for context-dependent biology. Overall, these efforts represent a shift in repositioning kisspeptin from a curiosity of metastasis suppression to a more flexible adjunct whose dose, duration and delivery can be titrated in real time by biomarkers that monitor receptor occupancy or disseminated-cell dormancy.
Preliminary metabolic clinical trials suggest kisspeptin can be used in a time-restricted manner. Twice daily low sub-cutaneous microdoses of kisspeptin in obese hypogonadal men with type-2 diabetes reduced glycaemic variability and restored the nocturnal LH pulsatility without causing weight regain or overeating. The treatment could "re-entrain" the metabolic oscillations and restore the reproductive function. Another ongoing trial was using continuous glucose monitoring to titrate the dose in real-time, which entrain insulin pulsatility to a circadian grid, aiming to mimic normal metabolic oscillations. It was also showing early reductions in visceral fat and improvements in endothelial function.
Kisspeptin is emerging from the academic investigation phase into a programmable drug whose value will be determined by its ability to deliver physiologic, self-limiting signals that can be linked, or concatenated with other treatments. Rather than being used as a direct replacement for existing drugs, the peptide has the potential to be used as a biological "rhythm restorer" to reactivate endogenous feedback loops, thereby broadening the therapeutic window of a partner agent while reducing off-target toxicity. Conversations with regulatory agencies have moved away from safety-focused language to design of adaptive, biomarker-guided trials that will credit points for demonstration of steroid-sparing effects, a reduction in iatrogenic ovarian hyper-stimulation or a re-sensitization to checkpoint blockade. As a result, the coming decade will likely be defined by an adaptive use of kisspeptin as an adjunct: dose, duration and route of administration all being titrated in real time by biomarkers reporting on receptor occupancy, pituitary pulse frequency or tumor-cell dormancy, creating a closed-loop system that merges precision medicine with chronotherapy.
Interest is developing in using kisspeptin as the physiological trigger in an approach to ovarian stimulation that is being referred to as "physiologic". Randomized crossover studies in high-risk IVF populations have shown that peripheral administration of a single bolus results in an LH surge with a magnitude and timing that is sufficient to support oocyte maturation but with rapid kinetics that avoid sustained LH-receptor stimulation, and thus, the VEGF surge associated with OHS. In this setting, interim reports suggest that oocyte retrieval of metaphase-II oocytes is at a rate within the range of non-inferiority with r-hCG, with virtually no reports of moderate or severe OHS with kisspeptin. This observation was also noted in FHOA, where twice-weekly SC injection restored nocturnal LH pulsatility for at least eight weeks after the last injection, suggesting a long-lasting reset of the hypothalamic GnRH pulse generator, and not merely a short-term pharmacological effect. The tachyphylaxis response evoked by kisspeptin after two weeks of constant exposure is also being used as a potential down-regulation strategy in IVF protocols. As such, kisspeptin represents a potential self-limiting alternative to GnRH agonists, which can take months to wear off. Future formulations under development include intranasal and trans-dermal formulations that would avoid first pass metabolism, as well as depot nano-carriers that allow for ultra-slow release that could potentially be self-administered by the patient. Pending verification of its efficacy in larger multi-centre studies, kisspeptin would fill a clinical gap for those seeking a centrally-acting, hormone-sparing option to restore fertility without suppressing the system's native feedback dialect.
Kisspeptin development extends beyond traditional fertility functions to serve as a central enhancer of libido that connects gonadal hormones with neural motivational systems. Using fMRI, intravenous kisspeptin has been shown to upregulate activation in the amygdala, hippocampus and posterior cingulate cortex in response to viewing erotic images, an effect which was not dependent on circulating androgen levels, suggesting that kisspeptin modulates the salience of sexual stimuli. In both men and women, limbic activation was associated with a subjective increase in perceptions of sexual attractiveness and desire, supporting a model in which kisspeptin renders subliminal sensory input into a conscious motivational drive. This is made possible through direct innervation of dopaminergic nuclei in the ventral tegmentum by kisspeptin neurons in the rostral periventricular nucleus; upon release, kisspeptin increases dopamine release in the nucleus accumbens, thus linking reproductive hormones to the reward circuit. In line with these results, male-directed partner preference in female mice is ablated by genetic deletion of Kiss1, while a single peripherally administered injection of kisspeptin-10 reinstates this approach behavior within minutes, in a dopamine-dependent but GnRH-independent fashion. In early phase clinical trials, a single IV bolus of kisspeptin-10 has been shown to increase subjective ratings of sexual attractiveness in addition to objective measures of penile tumescence in male subjects with HSDD, while parallel studies in pre-menopausal women have demonstrated increased posterior cingulate cortex activity in response to viewing images of attractive men, in addition to reduced scores on sexual aversion measures. Tolerability of the peptide appears to be high, with no treatment-emergent AEs in either male or female cohorts, which has been ascribed to its rapid enzymatic degradation and endogenous status. Intranasal formulations of kisspeptin are in development, as these formulations would not require blood-brain barrier penetration, while pulsatile rather than continuous release formulations are under investigation, with the aim of recapitulating physiological pulsatile release by hypothalamic kisspeptin neurons and hence attenuating downregulation. If effective, kisspeptin could fill an unmet need for a central, hormone sparing therapy for low libido.
Fig.2 Pathophysiology of functional hypothalamic amenorrhea (FHA).2,5
As stated above, there are good physiologic reasons to expect kisspeptin to be an important therapeutic. There have also been some positive signals. Yet despite this, kisspeptin is at risk of remaining a middle child - much like the mechanism but not yet a medicine that can be taken at scale. This is for several reasons. Pharmacokinetically, the native, amidated peptide is rapidly metabolized by the broad-spectrum dipeptidyl-peptidases and aminopeptidases, leading to an ultra-short half-life. To maintain physiological levels, high dose bolus injections or continuous infusion are required, which are generally less acceptable to patients and more expensive to develop. In addition, lyophilized products can slowly degrade via oxidative deamidation even when stored under nitrogen, leading to batch variability and kisspeptin could activities that make cross-trial comparisons difficult. Delivery to the central compartment would solve the peripheral metabolic issue, however, direct central delivery (e.g., intranasal or intrathecal) has safety concerns related to temporal-lobe seizure activity in animal models at supraphysiological levels. There have not been immunogenicity issues to date but immune tolerance to a native epitope could be broken with chronic exposure and, as such, long-term monitoring for neutralizing antibodies would be required that could dampen the therapeutic response. As a result, regulatory bodies are requiring a series of exposure studies to be done: single dose pharmacodynamics in healthy subjects, followed by repeated-dose safety in the target population(s) and then, finally, dose adaptive efficacy trials that adjust dose according to real time biomarkers (e.g., LH pulse frequency, exosomal KISS1 mRNA). All of these additional layers extend timelines and reduce commercial attractiveness.
Endogenous kisspeptin-54 is a native linear peptide of 54 residues. The C-terminal amide is required for activity but is inherently unstable to oxidative deamidation and proteolytic nicking. Stress testing demonstrates time-dependent accumulation of iso-aspartate and succinimide intermediates, even in vials stored at low temperatures under nitrogen headspace, which causes receptor-binding drift that is measurable within months of manufacture. Lyophilized cakes with sacrificial anti-oxidants or trehalose glass-formers slow but do not prevent this degradation, compelling sponsors to accept limited dating intervals that increase the cost and complexity of cold-chain distribution and frustrate broad availability. Efforts to substitute oxidation-sensitive residues for isosteric mimics consistently result in lower agonist efficacy, highlighting the tight structure-activity constraints that limit medicinal chemistry efforts. Delivery is no less challenging: intravenous injection reliably elicits reproducible LH surges but necessitates clinic visits and indwelling cannulae, while sub-cutaneous bolus injection is associated with local mast-cell degranulation and transient wheal-and-flare reactions in some patients. Intranasal sprays are more convenient but must diffuse through a mucus barrier that is rich in peptidases; early studies indicate that only a small fraction of the nominal dose makes it to cerebrospinal fluid, and the remainder is swallowed and quickly inactivated by first-pass liver metabolism. Implantable osmotic mini-pumps allow for continuous delivery in pre-clinical studies, but the surgical placement and removal procedures compromise patient acceptability in fertility populations who will only require weeks of therapy. Depot microsphere formulations with biodegradable lactide-glycolide polymers exhibit an initial burst release that exceeds the therapeutic window, followed by an extended tail that can induce receptor desensitization. Oral bioavailability is also negligible because gastric pepsin cleaves at the aromatic residues on either side of the bioactive core, and intestinal brush-border dipeptidases complete the degradation before any significant uptake can take place. In sum, these physicochemical stability and delivery hurdles make it necessary to advance multiple technological platforms in parallel rather than to pursue a single panacea.
Clinical regulatory agencies view kisspeptin development under a dual paradigm: The peptide is endogenous, but for therapeutic development is a novel chemical entity for which a complete non-clinical and clinical package is required. The first phase is a weight-of-evidence argument that endogenous homology mitigates genotoxic and carcinogenic risk. The latter argument should allow developers to circumvent the standard "battery studies" as long as peptide purity remains above a given threshold and no non-natural linkers/carriers are added. On the other hand, reproductive toxicology will require careful consideration because a non-physiological exposure to kisspeptin in early pregnancy might theoretically influence implantation or fetal sexual differentiation; an embryo-fetal development study and a peri-postnatal assessment are therefore warranted, even if the peptide is not expected to accumulate. Immunogenicity should be limited by the absence of non-human sequences. However, at least 6-month repeat-dose studies in primates will likely be required to monitor for neutralizing antibodies which could cross-react with endogenous kisspeptin and induce hypogonadism and/or metabolic dysfunction. Chemistry-manufacturing-control packages will need to validate batch-to-batch consistency in amidation stoichiometry, oxidative impurity profile and receptor-binding affinity, which are challenges added to the intrinsic lability described above.
We provide research-grade Kisspeptin-10 and Kisspeptin-54 peptides at high purity, validated through HPLC and MS analysis. Our peptides are widely used in research studies exploring Kisspeptin's role in fertility treatments, oncology applications, and potential sexual health therapies. For specialized projects, we also offer custom peptide synthesis services. Whether you require bulk supply for multi-phase clinical studies or unique peptide modifications, we ensure consistency, scalability, and quality to meet clinical research standards. Take your research to the next level with premium Kisspeptin peptides trusted by scientists worldwide. Contact us today to request a customized quotation, bulk supply plan, or custom synthesis consultation. Our dedicated team will ensure you receive reliable peptides with secure global delivery and full technical support.
Kisspeptin Peptides We Provides
| CAT# | Product Name | M.W | Molecular Formula | Inquiry |
|---|---|---|---|---|
| K04001 | Kisspeptin-13 (4-13) (human) | 1302.46 | C63H83N17O14 | Inquiry |
| K04002 | Kisspeptin-54 (human) | 5857.51 | C258H401N79O78 | Inquiry |
| K04003 | Kisspeptin-54 (27-54) (human) | 3229.69 | C149H226N42O39 | Inquiry |
| K04004 | Kisspeptin-13 (human) | 1626.84 | C78H107N21O18 | Inquiry |
| M04006 | Kisspeptin-10 Metastin (45-54), Human | C63H83N17O14 | Inquiry | |
| M04007 | Kisspeptin-13 | C78H107N21O18 | Inquiry | |
| M13002 | Kisspeptin-14 | Inquiry | ||
| M13006 | Kisspeptin-10_mouse | Inquiry | ||
| R0925 | Kisspeptin 10 (dog) | 1330.51 | C65H87N17O14 | Inquiry |
| R0938 | Kisspeptin 234 | 1295.4 | C63H78N18O13 | Inquiry |
| R1469 | Kisspeptin-10 | 1302.4 | C63H83N17O14 | Inquiry |
| R1470 | Kisspeptin-10 Trifluoroacetate | 1416.46 | C63H83N17O14.C2HF3O2 | Inquiry |
| R2281 | Kisspeptin-10, rat | 1318.4 | C63H83N17O15 | Inquiry |
| R2438 | Kisspeptins | 5857 | C258H401N79O78 | Inquiry |
| R2372 | Kisspeptin-54 (27-54) (human) trifluoroacetate salt | 3229.6 | C149H226N42O39 | Inquiry |
1. Can Kisspeptin peptides be used as approved therapeutic drugs?
No. Our Kisspeptin peptides are currently intended for research use only and are not approved for human or veterinary therapy.
2. Can Kisspeptin peptides be customized for specific protocols?
Absolutely. Our custom synthesis services allow for modifications in sequence, labeling, and formulation to align with your study requirements.
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