KISSPEPTIN (KISS1-GENE)

Mechanism of Action
Kisspeptin is a family of peptides (e.g., kisspeptin-54, also known as metastin) derived from the KISS1 gene. It was initially discovered for its role in cancer biology: KISS1 was identified in 1996 as a metastasis-suppressor gene capable of inhibiting the spread of melanoma and breast carcinoma. Its essential function in the reproductive endocrine system was clarified later.
Kisspeptins bind to the G-protein–coupled receptor GPR54 (KISS1R) on hypothalamic neurons, triggering the release of gonadotropin-releasing hormone (GnRH). Hypothalamic GnRH then stimulates the pituitary to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn drive sex steroid production (testosterone/estrogens) and sexual maturation (puberty). Inactivating mutations of GPR54 cause congenital hypogonadotropic hypogonadism (failure to initiate puberty due to GnRH deficiency) in humans and animal models, demonstrating that kisspeptin signaling is indispensable for normal pubertal development.
Beyond its central role in the reproductive axis, kisspeptin and its receptor are expressed in other tissues (e.g., limbic cortex, placenta), suggesting additional modulatory roles in sexual behavior, metabolism, and placental function—areas that remain under active investigation.
 
Clinical or Therapeutic Uses
Kisspeptin has emerged as a potential therapeutic agent in reproductive and sexual disorders. Because of its ability to induce GnRH release, it has been used experimentally to treat hypothalamic dysfunctions. For example, in women with hypothalamic amenorrhea (loss of menstruation due to stress or low body weight), kisspeptin administration reactivated GnRH/LH release and restored ovarian function in pilot studies. It is also being explored for hyperprolactinemia and obesity-associated hypogonadism, where it may help re-establish deficient hormonal pulsatility.
In assisted reproduction (IVF), kisspeptin-54 has been tested as a hormonal trigger to induce final oocyte maturation. Early clinical trials showed that a single kisspeptin injection can replace hCG to trigger ovulation in women undergoing IVF, without causing ovarian hyperstimulation syndrome (OHSS)—a serious complication associated with hCG. This suggests kisspeptin could offer a safer alternative for ovulation induction in fertility treatments.
Kisspeptin has also attracted interest in sexual medicine, particularly for hypoactive sexual desire disorder (HSDD). Recent clinical studies in men and women with very low sexual desire demonstrated that kisspeptin infusions enhanced brain activation related to sexual stimuli and increased sexual desire compared with placebo. In men, pro-erectile effects were also observed. These findings (Imperial College London, 2022–2023) open the door to potential treatments for psychogenic sexual dysfunction.
Additionally, preliminary data suggest possible skeletal and metabolic benefits: kisspeptin signaling has been linked to bone mineral density (via interactions with osteoblasts) and to modulation of non-alcoholic fatty liver disease, although these applications are at a very early research stage. Overall, kisspeptin is shaping up as a novel therapeutic candidate for infertility (as an ovulation trigger), certain forms of central hypogonadism, and disorders of sexual desire.
 
Side Effects or Associated Risks
As an endogenous hormone, kisspeptin administered under controlled conditions has shown good tolerability. In clinical trials using intravenous infusion (e.g., HSDD studies), no serious adverse events or clinically meaningful changes in vital signs were reported compared with placebo. Both women and men received kisspeptin under monitoring without allergic reactions or significant alterations in blood pressure or heart rate.
Some participants reported transient facial flushing or a sensation of warmth during infusion, consistent with acute hormonal activation (similar to LH-related hot flashes), but these effects were mild and short-lived. Overall, short-term administration of kisspeptin appears safe. For example, a study in 32 men receiving kisspeptin-54 infusion found no anxiogenic effects and no significant adverse events versus placebo.
Potential risks: Because there is no approved commercial kisspeptin product, use outside clinical trials carries uncertainty. Synthetic formulations (such as the decapeptide kisspeptin-10) could theoretically induce antibody formation or immune reactions with repeated use. Indeed, the FDA has listed kisspeptin-10 among unapproved substances that may pose immunogenicity risks and lack sufficient safety data. Therefore, any application of kisspeptin should be confined to monitored research settings.
To date, available studies suggest a favorable safety profile, but longer-term data are needed—particularly regarding effects on other hormonal systems and potential risks during pregnancy or fetal development.