Kisspeptin-10

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5mg vial · vial

Kisspeptin-10 signals through a single G-protein-coupled receptor, KISS1R (formerly GPR54), expressed prominently on GnRH neurons in the hypothalamus and at lower levels in multiple peripheral tissues including placenta, gonads, and the central nervous system reward circuitry. The pharmacology is elegant and relatively simple in mechanism but drives a complex downstream physiology:

Primary Hypothalamic Effect — GnRH Release: KISS1R activation is coupled predominantly to Gαq/11, which activates phospholipase C, generates inositol trisphosphate (IP3) and diacylglycerol (DAG), raises intracellular calcium, and triggers GnRH release from GnRH neuron terminals in the median eminence. Kisspeptin is currently understood to be the obligate upstream driver of pulsatile GnRH release — the GnRH neurons themselves generate the pulse timing, but kisspeptin input controls whether and how strongly they fire. Under physiological conditions, kisspeptin neurons in the arcuate nucleus (the "KNDy" neurons, which also express neurokinin B and dynorphin) fire synchronously to generate GnRH pulses, while kisspeptin neurons in the preoptic area (AVPV) drive the GnRH surge responsible for the mid-cycle LH surge in females.

Downstream HPG Axis Activation: GnRH released from the median eminence travels through the hypophyseal portal circulation to the anterior pituitary, where it stimulates gonadotroph cells to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates gonadal testosterone or estrogen production and triggers ovulation in females; FSH drives spermatogenesis in males and follicular development in females. The entire cascade — KP-10 → GnRH → LH/FSH → gonadal steroids → gametogenesis — takes roughly 20-60 minutes from IV or SC kisspeptin administration to measurable LH/FSH rise in plasma.

Selectivity and Signaling Bias: KP-10 is a high-affinity full agonist at KISS1R with IC50 in the low-nanomolar range. There is no significant cross-reactivity with other GPCRs. Signaling bias studies suggest that kisspeptin preferentially engages Gαq pathways over β-arrestin recruitment, which may contribute to its relatively favorable desensitization profile compared to GnRH analogs. Continuous high-dose kisspeptin exposure does eventually produce GnRH-axis downregulation, but pulsatile or intermittent dosing appears to maintain responsiveness.

Extrapituitary Effects:

• Limbic system (amygdala, hippocampus, cingulate cortex): KISS1R expression in limbic structures mediates kisspeptin's effects on sexual desire, emotional processing, and mood. Comninos and colleagues at Imperial College have shown using fMRI that kisspeptin administration in men enhances brain activity in reward/arousal circuits in response to sexual and romantic cues, and attenuates activity in regions associated with negative mood and anxiety (Comninos et al., 2017).
• Gonads (direct): KISS1R is expressed on theca and granulosa cells of the ovary and on Leydig cells of the testis; direct local kisspeptin signaling may modulate steroidogenesis and gamete maturation, though the physiological significance of these peripheral actions in kisspeptin-treated subjects is uncertain.
• Placenta: Kisspeptin is produced in large amounts by trophoblasts and is thought to regulate trophoblast invasion and placental development. This is why plasma kisspeptin concentrations rise dramatically in pregnancy.

Pharmacokinetics: KP-10 administered subcutaneously or intravenously has a plasma half-life of approximately 4 minutes — extremely short, reflecting rapid peptidase degradation. Despite this short half-life, the downstream LH/FSH response lasts 1-2 hours because the pituitary gonadotrophs require time to transcribe and secrete the hormones triggered by the initial GnRH pulse. Continuous infusion or repeated boluses produce sustained axis activation; single doses produce a single pulse-like LH/FSH rise. This short half-life is why kisspeptin preparations are usually administered either as continuous subcutaneous infusions (for ovulation induction or sustained axis stimulation) or as frequent bolus doses (for pulsatile stimulation mimicking endogenous physiology).

Longer-Acting Forms: Researchers have developed both KP-54 (which has slightly longer half-life but still on the order of 30 minutes) and engineered kisspeptin analogs with PEGylation or other half-life-extending modifications. MVT-602 (from Myovant Sciences) is a kisspeptin analog with an approximate 60-90 minute half-life being investigated for clinical use. For most peptide-community use, plain KP-10 remains the most accessible form.

Kisspeptin-10 (KP-10, metastin 45-54) is the C-terminal decapeptide fragment of kisspeptin, a neuropeptide product of the KISS1 gene that has emerged over the past two decades as the master regulator of reproductive endocrinology in humans and all other vertebrates studied to date. The KISS1 gene was originally cloned in 1996 in Hershey, Pennsylvania (and named after the town's iconic Hershey Kiss), initially as a metastasis-suppressor gene in melanoma cell lines. Its true reproductive function wasn't understood until 2003, when two independent research groups — one led by Nicolas de Roux in Paris and another by Stephanie Seminara at Massachusetts General Hospital — discovered that loss-of-function mutations in the G-protein-coupled receptor GPR54 (now named KISS1R) caused hypogonadotropic hypogonadism with failure of puberty. This finding transformed kisspeptin from an obscure tumor-biology gene into the gatekeeper of the entire hypothalamic-pituitary-gonadal (HPG) axis (de Roux et al., 2003, Seminara et al., 2003).

Kisspeptin is synthesized as a 145-amino-acid precursor prohormone that is processed into several bioactive peptides: kisspeptin-54 (KP-54, the longest form), kisspeptin-14, kisspeptin-13, and kisspeptin-10. KP-10 retains essentially all of the biological potency of the parent molecule at the KISS1R receptor, making it the most practical form for research and therapeutic exploration — it is smaller, more stable, easier to synthesize, and equally efficacious. Kisspeptin neurons in the hypothalamus (located in the arcuate nucleus and the preoptic area / AVPV) project to GnRH neurons and release kisspeptin as the essential upstream stimulus that drives GnRH release. Without kisspeptin signaling, GnRH neurons fire infrequently or not at all, and the entire reproductive axis — LH, FSH, testosterone, estrogen, ovulation, spermatogenesis — shuts down. This is why congenital KISS1R mutations cause such a dramatic reproductive phenotype despite the rest of the HPG axis being intact (Messager et al., 2005).

In current clinical and research practice, kisspeptin (usually as KP-10 or KP-54) is being investigated for a range of reproductive applications: as a diagnostic probe for the integrity of the HPG axis (an alternative to or supplement to GnRH stimulation testing), as an ovulation trigger in in-vitro fertilization cycles (where it may reduce ovarian hyperstimulation syndrome risk compared to hCG), as a therapy for hypothalamic amenorrhea and functional hypothalamic hypogonadism, and as an investigational treatment for hypoactive sexual desire disorder (HSDD), with emerging work on mood and anxiety effects as well. Kisspeptin is not currently approved for any indication in the United States, but Phase II data from Imperial College London and other centers have been promising enough that pharmaceutical development is underway (Dhillo et al., 2005, Abbara et al., 2015).

Off-label and peptide-community interest in KP-10 centers on two use cases. First, men using suppressive regimens — testosterone replacement therapy, anabolic steroid cycles, or GnRH-axis-affecting drugs — sometimes use KP-10 during "post-cycle" recovery phases on the theory that stimulating endogenous GnRH release may accelerate HPG axis recovery faster than the conventional Gonadorelin (GnRH) or HCG (Human Chorionic Gonadotropin) approaches. The evidence base for this use is thin — kisspeptin's efficacy in restoring suppressed axes after exogenous androgens has not been formally studied — but mechanistically plausible. Second, some researchers and a small community of users are interested in kisspeptin's effects on sexual desire and mood, which appear to be separable from its reproductive effects and mediated by kisspeptin receptor expression in limbic structures like the amygdala (Comninos et al., 2017).

KP-10 is a legitimate research tool with meaningful clinical promise and an unusually well-characterized physiological mechanism. Unlike many grey-market peptides, the clinical evidence base is growing and the safety profile in short-term human trials at reproductive-axis doses has been clean. This entry covers KP-10's known biology, its current and investigational uses, and the considerable uncertainties that remain — particularly around long-term dosing, optimal regimens for axis recovery, and whether peripheral KP-10 administration reproduces the physiological effects of endogenous kisspeptin neuron firing.

IUPAC Name

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2

CAS Number

374683-28-0

Molecular Formula

C63H83N17O13

Molecular Mass

1302.46 g/mol

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