Kisspeptin: Safety Profile & Research Summary
30 PubMed CitationsExpert ReviewedGMP CertifiedLast Reviewed: February 2026
Preclinical Research Summary
Key Preclinical Studies
| Study | Model | Key Findings | Ref |
|---|---|---|---|
| Mills et al. (2025) | C57BL/6J mice — intranasal Kp-54 | 12.8–50 nM intranasal: dose-dependent LH to 3.6 ng/mL at 25 min (p < 0.001); GnRH neurons activated in olfactory bulb → novel extra-hypothalamic pathway | [19] |
| Izarraras et al. (2025) | DIAMOND mice — TAK-448 MASLD | 0.3 nmol/h × 6 weeks: reduced liver triglycerides, serum FFA, ALT (p < 0.05); downregulated CIDEA via AMPK-SREBP-1c | [18] |
| Seminara/Ramaswamy (2006/07) | Juvenile rhesus monkeys — IV KP-10 | 200–400 µg/h × 98h: maximal LH at 3h, desensitization by 12h; GnRH bolus still effective but KP-10 bolus was not | [23] |
| Terse et al. (2021) | Dogs — KP-10 1000 µg/kg IV × 14d | NOAEL at 1000 µg/kg; peak LH at 5 min post-dose; no toxicity signs | [24] |
| Thompson et al. (2006) | Adult male rats — chronic SC KP-54 | Chronic SC → testicular degeneration; HPG axis suppression via receptor desensitization | [25] |
| Dinh et al. (2023) | Wistar rats — KP-13 CKD model | 13–26 µg/day IP × 10d: increased BP, exacerbated CKD markers and uremic cardiomyopathy | [26] |
Human Clinical Data (>1,000 Participants)
| Trial | Population | Dose/Route | Key Results | Ref |
|---|---|---|---|---|
| Dhillo et al. (2005) | n=6 healthy men | IV Kp-54 4 pmol/kg/min × 90 min | 2.6-fold LH increase; first-in-human; no AEs | [5] |
| Dhillo et al. (2007) | n=8 healthy women | SC 0.4 nmol/kg | Preovulatory LH rise 20.64 IU/L vs follicular 0.12 IU/L | [6] |
| Abbara et al. (2015) | n=60 IVF, high OHSS risk | SC Kp-54 3.2–12.8 nmol/kg | 95% mature oocytes, 52.9% pregnancy rate, 45.1% live birth rate, no clinically significant OHSS | [10] |
| Abbara et al. (2017) | n=62 IVF RCT | SC 9.6 nmol/kg × 2 doses | 30% live birth rate; 1 case mild OHSS only | [11] |
| Jayasena et al. (2009) | n=10 women with HA | SC 6.4 nmol/kg 2x daily × 2 wk | Acute LH ~24 IU/L; tachyphylaxis to 1.5 IU/L | [12] |
| Jayasena et al. (2010) | n=20 women with HA | SC 6.4 nmol/kg 2x/week × 8 wk | Sustained LH ~9 IU/L without complete desensitization | [13] |
| Mills et al. (2023) | n=32 men with HSDD | IV Kp-54 | Penile tumescence ↑55%; enhanced sexual brain processing | [17] |
| Abbara et al. (2020) | n=21 (HV, HA, PCOS) | SC MVT-602 0.01–0.03 nmol/kg | Peak LH at 21h (vs 4.7h Kp-54); >4x AUC; prolonged action | [9] |
| Mills et al. (2025) | n=34 (men, women, HA) | Intranasal Kp-54 12.8 nmol/kg | Rapid LH ↑4.4 IU/L men; no AEs; non-invasive delivery validated | [19] |
| Izzi-Engbeaya et al. (2018) | n=15 healthy men | IV Kp-54 | Glucose-stimulated insulin secretion ↑35% | [22] |
| Comninos et al. (2022) | n=26 healthy men | Acute Kp-54 | Osteocalcin ↑24% (bone formation marker) | [21] |
Safety Summary: >1,000 Human Exposures
| Parameter | Finding |
|---|---|
| Common AEs | Mild/transient: injection site reactions, headache, nausea, bloating |
| Cardiotoxicity | None — no changes in HR, BP, or ECG |
| Tachyphylaxis | Continuous high-dose → β-arrestin recruitment → receptor internalization → HPG suppression (physiological, not toxic) |
| Dog NOAEL | 1000 µg/kg IV × 14 days — no toxicity |
| Metabolism | Cleaved by MMP-2, MMP-9, furin; C-terminal cleavage inactivates |
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References
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- 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. Journal of Biological Chemistry. 2001;276(37):34631-34636.
- Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. New England Journal of Medicine. 2003;349(17):1614-1627.
- Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. Journal of Clinical Endocrinology & Metabolism. 2005;90(12):6609-6615.
- Dhillo WS, Chaudhri OB, Thompson EL, et al. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. Journal of Clinical Endocrinology & Metabolism. 2007;92(10):3958-3966.
- World Anti-Doping Agency. The Prohibited List. S2 Peptide Hormones, Growth Factors, Related Substances, and Mimetics. WADA. Updated 2025.
- de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proceedings of the National Academy of Sciences. 2003;100(19):10972-10976.
- Abbara A, Eng PC, Phylactou M, et al. Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. Journal of Clinical Investigation. 2020;130(12):6739-6753.
- Abbara A, Jayasena CN, Christopoulos G, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of OHSS during IVF therapy. Journal of Clinical Endocrinology & Metabolism. 2015;100(9):3322-3331.
- Abbara A, Clarke S, Islam R, et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of OHSS: a phase 2 randomized controlled trial. Human Reproduction. 2017;32(9):1915-1924.
- Jayasena CN, Nijher GM, Chaudhri OB, et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. Journal of Clinical Endocrinology & Metabolism. 2009;94(11):4315-4323.
- Jayasena CN, Nijher GM, Abbara A, et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clinical Pharmacology & Therapeutics. 2010;88(6):840-847.
- 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. Journal of Clinical Endocrinology & Metabolism. 2014;99(8):E1445-E1453.
- Skorupskaite K, et al. KP-10 infusion in PCOS women. Human Reproduction. 2020.
- Comninos AN, Wall MB, Demetriou L, et al. Kisspeptin modulates sexual and emotional brain processing in humans. Journal of Clinical Investigation. 2017;127(2):709-719.
- Mills EG, et al. HSDD in men — kisspeptin increases penile tumescence and sexual brain processing. JAMA Network Open. 2023.
- Izarraras L, et al. Kisspeptin agonist reduces hepatic de novo lipogenesis in MASLD via AMPK-SREBP-1c-CIDEA. 2025.
- Mills EG, et al. Intranasal kisspeptin-54 rapidly stimulates gonadotropin release in humans: a non-invasive delivery route. eBioMedicine. 2025.
- Jayasena CN, Abbara A, et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. Journal of Clinical Investigation. 2014;124(8):3667-3677.
- Comninos AN, et al. Acute kisspeptin administration increases osteocalcin in healthy men. Journal of Clinical Endocrinology & Metabolism. 2022.
- Izzi-Engbeaya C, et al. Kisspeptin increases glucose-stimulated insulin secretion in healthy men. Diabetes, Obesity and Metabolism. 2018.
- Seminara SB, et al. Continuous human metastin 45-54 infusion desensitizes GPR54-induced GnRH release in juvenile male rhesus monkeys. 2006.
- Terse PS, et al. Kisspeptin-10 toxicology studies in dogs — NOAEL at 1000 µg/kg IV × 14 days. 2021.
- Thompson EL, et al. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. 2006.
- Dinh TO, et al. Kisspeptin-13 exacerbates chronic kidney disease and uremic cardiomyopathy in rats. 2023.
- George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. Journal of Clinical Endocrinology & Metabolism. 2011;96(8):E1228-E1236.
- Thurston L, et al. Kisspeptin modulates brain activity in sexual desire regions in women with HSDD. JAMA Network Open. 2022.
- Nishizawa N, Takatsu Y, et al. Design and synthesis of TAK-448, an investigational nonapeptide KISS1R agonist. Journal of Medicinal Chemistry. 2016;59(19):8804-8811.
- Chan YM, Butler JP, Pinnell NE, et al. Kisspeptin resets the hypothalamic GnRH clock in men. Journal of Clinical Endocrinology & Metabolism. 2011;96(6):E908-E915.
Related Research Questions
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This content is provided for educational and informational purposes only. Products are furnished for in-vitro studies only and are not medicines, drugs, or supplements. Not approved by the FDA to prevent, treat, or cure any condition.