Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans.

Mills EG, Silva MSB, Delli V, Decoster L, Ternier G, Tsoutsouki J, Thurston L, Phylactou M, Patel B, Yang L, Clarke SA, Young M and 14 more

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Alexander EC, Nyunt S, Yeung AC, Choudhury M, Newman A, Bech P, Abbara A, Swedrowska M, Forbes B, Prévot V, Chachlaki K, Giacobini P, Comninos AN, Dhillo WS

EBioMedicine11 Apr 2025Cited by 5 (Europe PMC)

PMID40215751PMCIDPMC12018048DOI10.1016/j.ebiom.2025.105689PepBankPUB-40215751

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Summary

BackgroundKisspeptin administration by intravenous or subcutaneous routes activates hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is being developed to treat reproductive disorders. However, these invasive routes markedly limit patient acceptability and clinical use. Recent rodent data has identified a large GnRH population within the olfactory system communicating directly with hypothalamic GnRH neurons. Intranasal kisspeptin administration may be able to capitalise on this novel pathway and thus offer a potential non-invasive approach to stimulate reproductive hormones. Herein, we examine intranasal kisspeptin using human, pharmaceutical, and rodent studies.MethodsReproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study. Pharmaceutical testing evaluated the chemical stability and nasal kisspeptin delivery, and rodent studies provided mechanistic insight.FindingsIntranasal kisspeptin-54 rapidly stimulates gonadotropin release in healthy men and women, and in patients with a common reproductive disorder (hypothalamic amenorrhoea), without any side effects or adverse events encountered. Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone in all study groups: 4.4 ± 0.6 IU/L (mean difference = 3.1 IU/L [95% CI, 1.2-4.9], P = 0.002 vs. placebo) in healthy men; 1.4 ± 0.3 IU/L (mean difference = 1.0 IU/L [95% CI, 0.4-1.7], P = 0.004 vs. placebo) in healthy women; 4.4 ± 0.2 IU/L (mean difference = 4.3 IU/L [95% CI, 2.7-6.0], P < 0.001 vs. placebo) in patients with hypothalamic amenorrhoea. Kisspeptin-54 was delivered effectively via nasal spray and was stable for up to 60 days at 4 °C. Mirroring the human effects, intranasal kisspeptin-54 in adult C57BL/6J male mice stimulates luteinising hormone release. Further mechanistic insights reveal the accumulation of fluorescently-tagged kisspeptin in the olfactory epithelium, as well as the presence of kisspeptin receptors in olfactory bulb GnRH neurons, implicating the involvement of these extra-hypothalamic GnRH neurons in the pathway mediating intranasal kisspeptin's effects on reproductive hormones.InterpretationWe demonstrate the clinical potential for intranasal kisspeptin delivery as the first non-invasive method to robustly and safely stimulate gonadotropins with kisspeptin and potentially transform the management of reproductive disorders.FundingNational Institute for Health and Care Research (NIHR)/NIHR Imperial Biomedical Research Centre/Medical Research Council (MRC).

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

5 results from studies that gave the peptide. 4 results from people.

01HumanRandomized controlled trialSafety outcome
In healthy men and women and in patients with hypothalamic amenorrhoea, intranasal kisspeptin‑54 caused no side effects or adverse events.
In plain wordsIn healthy adults and women with hypothalamic amenorrhoea, nasal kisspeptin‑54 caused no side effects or adverse events.
Peptide
Kisspeptin-54 (metastin)
Outcome
No significant changeSide effects and adverse events
Study
n: not reported in source
Comparator
Placebo
Outcome group
Adverse events · Whole body
Studied dose
12.8 nmol/kg · intranasalAs given in this study (human).
Source sentences
Summary
Intranasal kisspeptin-54 rapidly stimulates gonadotropin release in healthy men and women, and in patients with a common reproductive disorder (hypothalamic amenorrhoea), without any side effects or adverse events encountered.
1 context sentence(design, population, supporting numbers)
Summary · context
Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study.
Show in the study text Report a problemFND-4021575101
02HumanRandomized controlled trialEfficacy outcome
In healthy men, intranasal kisspeptin raised the maximal serum LH above baseline more than placebo.
In plain wordsIn healthy men, nasal kisspeptin raised luteinising hormone more than placebo.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseMaximal LH increase in healthy men
Study
n: not reported in source
Comparator
Placebo
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
12.8 nmol/kg · intranasalAs given in this study (human).
Measurements
Maximal LH increase above baseline
4.4 IU/L
healthy men
Mean difference versus placebo
3.1 IU/L
healthy men
Source sentences
Summary
Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone in all study groups: 4.4 ± 0.6 IU/L (mean difference = 3.1 IU/L [95% CI, 1.2-4.9], P = 0.002 vs. placebo) in healthy men
1 context sentence(design, population, supporting numbers)
Summary · context
Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study.
Show in the study text Report a problemFND-4021575102
03HumanRandomized controlled trialEfficacy outcome
In healthy women, intranasal kisspeptin raised the maximal serum LH above baseline more than placebo.
In plain wordsIn healthy women, nasal kisspeptin raised luteinising hormone more than placebo.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseMaximal LH increase in healthy women
Study
n: not reported in source
Comparator
Placebo
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
12.8 nmol/kg · intranasalAs given in this study (human).
Measurements
Maximal LH increase above baseline
1.4 IU/L
healthy women
Mean difference versus placebo
1 IU/L
healthy women
Source sentences
Summary
Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone
2 context sentences(design, population, supporting numbers)
Summary · context
1.4 ± 0.3 IU/L (mean difference = 1.0 IU/L [95% CI, 0.4-1.7], P = 0.004 vs. placebo) in healthy women
Summary · context
Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study.
Show in the study text Report a problemFND-4021575103
04HumanRandomized controlled trialEfficacy outcome
In patients with hypothalamic amenorrhoea, intranasal kisspeptin raised the maximal serum LH above baseline more than placebo.
In plain wordsIn women with hypothalamic amenorrhoea, nasal kisspeptin raised luteinising hormone more than placebo.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseMaximal LH increase in hypothalamic amenorrhoea
Study
n: not reported in source
Comparator
Placebo
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
12.8 nmol/kg · intranasalAs given in this study (human).
Measurements
Maximal LH increase above baseline
4.4 IU/L
hypothalamic amenorrhoea
Mean difference versus placebo
4.3 IU/L
hypothalamic amenorrhoea
Source sentences
Summary
Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone
2 context sentences(design, population, supporting numbers)
Summary · context
4.4 ± 0.2 IU/L (mean difference = 4.3 IU/L [95% CI, 2.7-6.0], P < 0.001 vs. placebo) in patients with hypothalamic amenorrhoea
Summary · context
Reproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study.
Show in the study text Report a problemFND-4021575104
05AnimalAnimal study (in vivo)Efficacy outcome
In adult male C57BL/6J mice, intranasal kisspeptin‑54 stimulated luteinising hormone release.
In plain wordsIn male mice, nasal kisspeptin‑54 triggered release of luteinising hormone.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseLuteinising hormone release in mice
Study
mousen: not reported in source
adult C57BL/6J male mice
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
Dose not stated · intranasalAs given in this study (mouse).
Source sentences
Summary
Mirroring the human effects, intranasal kisspeptin-54 in adult C57BL/6J male mice stimulates luteinising hormone release.
Show in the study text Report a problemFND-4021575107

Studies that did not test the peptide alone3

In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Kisspeptin-54 (metastin).

06AnimalNot a test of Kisspeptin-54 (metastin) aloneAnimal study (in vivo)Mechanism
In rodents, fluorescently-tagged kisspeptin accumulated in the olfactory epithelium.
In plain wordsIn rodents, a fluorescent-tagged kisspeptin built up in the nose lining that senses smell.
Peptide
Kisspeptin-54 (metastin)
Outcome
IncreaseAccumulation of fluorescently-tagged kisspeptin in the olfactory epithelium
Study
rodentn: not reported in source
rodent
Outcome group
Receptor activity and mechanism · Reproductive and sexual health
Source sentences
Summary
accumulation of fluorescently-tagged kisspeptin in the olfactory epithelium
1 context sentence(design, population, supporting numbers)
Summary · context
Pharmaceutical testing evaluated the chemical stability and nasal kisspeptin delivery, and rodent studies provided mechanistic insight.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-4021575108
07LabNot a test of Kisspeptin-54 (metastin) aloneIn vitro (cell-free)Other
Kisspeptin‑54 nasal spray was stable for up to 60 days at 4 °C.
In plain wordsIn lab tests, kisspeptin‑54 nasal spray stayed stable for up to 60 days at 4 °C.
Peptide
Kisspeptin-54 (metastin)
Outcome
Not applicableChemical stability of kisspeptin-54 nasal spray
Study
n: not reported in source
Outcome group
Formulation, delivery and stability · Pharmacology
Measurements
Stability duration
60 days
4 °C
Source sentences
Summary
was stable for up to 60 days at 4 °C.
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-4021575105
08LabNot a test of Kisspeptin-54 (metastin) aloneIn vitro (cell-free)Other
Kisspeptin‑54 was delivered effectively via nasal spray in pharmaceutical testing.
In plain wordsIn lab tests, a nasal spray delivered kisspeptin‑54 effectively.
Peptide
Kisspeptin-54 (metastin)
Outcome
Not applicableNasal spray delivery of kisspeptin-54
Study
n: not reported in source
Outcome group
Formulation, delivery and stability · Pharmacology
Source sentences
Summary
Kisspeptin-54 was delivered effectively via nasal spray
In this study, Kisspeptin-54 (metastin) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Kisspeptin-54 (metastin).
Show in the study text Report a problemFND-4021575106

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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