Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans

E.G. Mills; M.S.B. Silva; V. Delli; L. Decoster; G. Ternier; J. Tsoutsouki; L. Thurston; M. Phylactou; B. Patel; L. Yang; S.A. Clarke; M. Young; E.C. Alexander; S. Nyunt; A.C. Yeung; M. Choudhury; A. Newman; P. Bech; A. Abbara; M. Swedrowska; B. Forbes; V. Prevot; K. Chachlaki; P. Giacobini; A.N. Comninos; W.S. Dhillo

doi:10.1530/ey.22.1.11

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 1.11 | DOI: 10.1530/ey.22.1.11

ESPEYB25 1. Pituitary and Neuroendocrinology New Treatments and Hopes (5 abstracts)

1.11. Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans

E.G. Mills , M.S.B. Silva , V. Delli , L. Decoster , G. Ternier , J. Tsoutsouki , L. Thurston , M. Phylactou , B. Patel , L. Yang , S.A. Clarke , M. Young , E.C. Alexander , S. Nyunt , A.C. Yeung , M. Choudhury , A. Newman , P. Bech , A. Abbara , M. Swedrowska , B. Forbes , V. Prevot , K. Chachlaki , P. Giacobini , A.N. Comninos & W.S. Dhillo

EBioMedicine 115 (2025) 105689.PMID: 40215751

Brief Summary: This study shows that intranasal administration of kisspeptin rapidly and effectively stimulates the release of gonadotropins (LH and FSH) in humans. The findings provide evidence for the potential therapeutic use of kisspeptin in the management of reproductive disorders.

The authors examined a novel, non-invasive delivery route for kisspeptin in humans and rodents. Kisspeptin is neuropeptide critical for the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. By demonstrating that intranasal administration of kisspeptin (12.8 nmol/kg) can rapidly and effectively stimulate the release of gonadotropins (LH and FSH) in humans, the authors provide clinical evidence for a new therapeutic avenue that may change the management of reproductive disorders.

The authors conducted human trial to directly assess the physiological impact of kisspeptin delivered via the nasal mucosa. Hormone profiles were measured after intranasal administration both in healthy and patients with reproductive disorders. The observed rapid rise in circulating gonadotropins highlights both the bioavailability and biological potency of intranasal kisspeptin. This route of administration could circumvent the need for injectable therapies, offering increased patient compliance and broader accessibility.

The findings hold promise for clinical conditions such as hypogonadotropic hypogonadism, delayed puberty, and potentially infertility due to hypothalamic dysfunction. The fast-acting nature of the response suggests that kisspeptin could also be used diagnostically, in a manner analogous to GnRH stimulation testing, to assess pituitary responsiveness in real time. The authors go one step further and use rodents to administer kisspeptin-54 fluorescently tagged and demonstrate the same hormonal response that in humans. The rodent studies allow them to show that tagged-kisspeptin binds to GnRH neurons from the olfactory bulbs (OB) triggering physiological response. The authors show that OB neurons express kisspeptin receptor hence postulating a mode of action of nasal kisspeptin treatment by acting on the OB GnRH neurons.

Unlike exogenous gonadotropin injections, kisspeptin acts upstream of LH/FSH, triggering a more physiologically regulated release of endogenous hormones. This could reduce the risk of ovarian hyperstimulation syndrome (OHSS), a serious complication of fertility treatments.

There are questions that warrant further exploration. For example, the duration of the gonadotropin response, the effects of repeated dosing, interindividual variability, and the efficacy in populations with reproductive pathology remain to be fully characterized. Additionally, while the intranasal route appears effective, future studies should assess its pharmacokinetics and optimal dosing regimens across sexes, age groups, and clinical conditions.