SFEBES2023 Oral Communications Reproductive Endocrinology (6 abstracts)
Intranasal kisspeptin: a novel, effective and non-invasive approach to stimulate reproductive hormones in patients with reproductive disorders
Edouard. G Mills 1,2 , Virginia Delli 3 , Konstantina Chachlaki 3 , Mauro SB. Silva 3 , Laurine Decoster 3 , Gaetan Ternier 3 , Layla Thurston 1 , Maria Phylactou 1,2 , Bijal Patel 1 , Lisa Yang 1 , Sophie A. Clarke 1,2 , Emma Alexander 1 , Muhammad Choudhury 1 , Paul Bech 1 , Ali Abbara 1,2 , Magda Swedrowska 4 , Ben Forbes 4 , Paolo Giacobini 3 , Vincent Prevot 3 , Alexander N. Comninos 1,2 & Waljit S. Dhillo 1,2
1Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom. 2Department of Endocrinology, Imperial College Healthcare NHS Trust, London, United Kingdom. 3Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, University of Lille, Inserm, Lille, France. 4Institute of Pharmaceutical Science, King’s College London, London, United Kingdom
Background: Kisspeptin is a potent regulator of GnRH neurons with potential to treat reproductive and psychosexual disorders. However, administration is limited to the subcutaneous or intravenous routes. These invasive routes limit clinical development. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first-time using rodent, human and pharmaceutical studies.
Methods: First, we conducted rodent studies in adult mice to investigate whether intranasal kisspeptin-54 administration could stimulate reproductive hormone release, as well as experiments to elucidate possible mechanisms. Thereafter, we sought to translate these findings into humans: healthy men (n =12) and a patient group of women with hypothalamic amenorrhoea (HA) (n =5) completed a randomised, double-blinded, crossover, placebo-controlled study investigating the effects of intranasal kisspeptin-54 (doses: 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs placebo) on reproductive hormone secretion over 4hrs. Finally, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery.
Results: Rodent studies: we demonstrate that intranasal kisspeptin-54 robustly and dose-dependently stimulates LH release in mice. To provide mechanistic insight, we show that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium and that GnRH neurons located in the olfactory bulb express kisspeptin receptors. Human studies: in healthy men, intranasal kisspeptin dose-dependently increased serum LH at doses 6.4-25.6nmol/kg (P<0.01 all doses vs placebo) with maximal rises at 30mins. Likewise, in women with HA, intranasal kisspeptin acutely increased serum LH (P=0.004 vs placebo) with maximal stimulation from 30mins. Pharmaceutical studies: Kisspeptin-54 in solution remained within pharmaceutically accepted limits for stability for 60days at 4°C, demonstrating realistic pharmaceutical potential.
Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive and effective kisspeptin administration route for the management of reproductive disorders that would likely be preferable to patients and clinicians alike.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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