Inside the body with Kisspeptin

Two kisspeptin neuron populations project to GnRH neurons. Infundibular (arcuate in rodents) neurons co-express neurokinin B and dynorphin (KNDy neurons) and are thought to shape pulsatile GnRH release. In rodents, a second population in the rostral periventricular area (AVPV) drives the pre-ovulatory LH surge through oestrogen positive feedback; in the human hypothalamus only sparse kisspeptin neurons have been found in the preoptic area. The KNDy picture is also less clear-cut in humans, with little overlap of the three peptides reported in young men. Kisspeptin-54, first isolated from placenta, is the major circulating isoform in humans. Much of the detailed circuitry comes from rodent and primate work, with human data mainly from imaging, genetics and hormone responses.[src][src][src]

Kisspeptin binds KISS1R (GPR54), a Gq/11-coupled receptor, and depolarises GnRH neurons. In adult mice kisspeptin depolarised more than 90% of GnRH neurons (Han 2005), and GPR54 mRNA colocalises with GnRH neurons; kisspeptin raised LH and FSH in wild-type but not Gpr54-null mice, and given into the brain of sheep it released GnRH into cerebrospinal fluid (Messager 2005). These direct-action data are from animals. In humans, biallelic inactivating KISS1R variants cause hypogonadotropic hypogonadism (Seminara 2003; de Roux 2003), and cryo-EM structures of KISS1R with kisspeptin-54 and kisspeptin-10 bound to Gq show the binding pocket (Science Advances 2024; Cell Reports 2024).[src][src][src][src][src][src]

Pulsatile GnRH secretion into the hypophyseal portal circulation sets the pattern of LH and FSH secretion from pituitary gonadotropes. In healthy men, an intravenous kisspeptin-54 infusion raised mean 90-minute LH from 4.2 to 10.8 U/L and FSH from 3.2 to 3.9 U/L versus saline (Dhillo 2005). Consistent with an action above the pituitary, women with hypothalamic amenorrhoea still responded to GnRH after two weeks of kisspeptin-54 had blunted their response to kisspeptin (Jayasena 2009). GnRH itself gave a larger LH rise than kisspeptin-10 or -54 in healthy men (Jayasena 2015, as summarised by FDA).[src][src][src]

Plasma kisspeptin-54 had a half-life of 27.6 +/- 1.1 min, a metabolic clearance rate of 3.2 +/- 0.2 mL/kg/min and a volume of distribution of 128.9 +/- 12.5 mL/kg in healthy men (Dhillo 2005). Kisspeptin-10 half-life was about 4 minutes in men and women (Jayasena 2011, summarised in FDA's briefing). In women the LH response depends on cycle phase: it is largest in the pre-ovulatory phase and near zero in the follicular phase (Dhillo 2007). Rapid enzymatic breakdown and short half-lives are one reason synthetic analogues such as MVT-602 (previously TAK-448) were developed (FDA 2024).[src][src][src]

In healthy men, kisspeptin-54 infusion raised mean 180-minute testosterone from 21.7 to 24.9 nmol/L (Dhillo 2005). In IVF, a single subcutaneous kisspeptin-54 injection after ovarian stimulation induced an LH surge and egg maturation in all dose groups of a 53-woman study, with clinical pregnancy in 12 of 53 (Jayasena 2014). In 60 women at high risk of OHSS, oocyte maturation occurred in 95% and no woman developed moderate, severe or critical OHSS (Abbara 2015). Adding a second injection raised the share with at least 60% oocyte yield from 45% to 71% (Abbara 2017). The analogue MVT-602 (previously TAK-448) produced LH surges of similar size and length to the natural mid-cycle surge in women (Abbara 2024). In men, sustained exposure to the same analogue (as TAK-448) suppressed testosterone to the castration range in phase 1 studies (MacLean 2014). Comparisons with established triggers were not part of these trials.[src][src][src][src][src][src][src]

In three agonadal juvenile male rhesus monkeys, continuous infusion of metastin 45-54 (kisspeptin-10) produced an LH rise for about 3 h followed by a drop despite continued infusion, and a later bolus no longer raised LH while GnRH and NMDA boluses still did (Seminara 2006, animal data). In women with hypothalamic amenorrhoea, twice-daily kisspeptin-54 for two weeks reduced the maximal LH increment from 24.0 to 2.5 IU/L (Jayasena 2009). In healthy women, a week of follicular-phase dosing did not abolish cyclicity but shortened the cycle (Jayasena 2013). In monkeys, hourly low-dose pulses of kisspeptin-10 kept producing consistent LH responses over 48 h (Plant 2006, as summarised by FDA; animal data).[src][src][src][src]

In a double-blind crossover imaging study of 29 healthy men, kisspeptin-54 enhanced limbic activity in response to sexual and couple-bonding stimuli and attenuated negative mood (Comninos 2017). In a randomised crossover trial in premenopausal women with hypoactive sexual desire disorder (40 randomised, 32 completed), kisspeptin-54 infusion modulated brain responses to erotic videos and face attraction (Thurston 2022). These are small, mechanistic neuroimaging studies rather than trials of clinical benefit, and neither led to any approval or recommended use.[src][src]