SFEBES2015 Early Career Prize Lectures (1) (2 abstracts)
Kisspeptin- A ‘key regulator’ of reproductive physiology, integrating limbic circuits with the regulation of reproductive hormones
Alexander Comninos 1 , Jelena Anastasovska 1 , Amar Shah 1 , Matthew Wall 3 , Channa Jayasena 1 , Xiaofeng Li 2 , Ali Abbara 1 , Shaku Narayanaswamy 1 , Gurjinder Nijher 1 , Chioma Izzi-Engbeaya 1 , Lysia Demetriou 3 , Sophie Clarke 1 , Mohammad Ghatei 1 , Jimmy Bell 1 , Paul Matthews 1 , Stephen Bloom 1 , Kevin O’Byrne 2 & Waljit Dhillo 1
1Imperial College, London, UK; 2King’s College, London, UK; 3Imanova Imaging, London, UK.
Kisspeptin is a recently identified reproductive hormone which serves as a crucial activator of the Hypothalamic–Pituitary–Gonadal (HPG) axis via stimulation of GnRH neurones. We have previously observed that a single kisspeptin injection increases LH pulsatility while twice daily kisspeptin injections can even advance the menstrual cycle. Furthermore, we have demonstrated that kisspeptin restores LH pulsatility in women with hypothalamic amenorrhoea and can potently stimulate egg maturation in women undergoing IVF, thereby unveiling novel therapeutic actions.
However, the effects of kisspeptin are not limited to the HPG axis, yet there is paucity of data in this regard. Kisspeptin and its cognate receptor are also expressed within the amygdala, a key limbic brain structure with important roles in social and reproductive behaviours. In addition, the amygdala exerts an ‘inhibitory brake’ on reproduction via inhibitory neuronal projections to hypothalamic centres involved in reproductive hormone release. By mapping brain neuronal activity (using Manganese-Enhanced MRI) in adult rodents we demonstrated a marked decrease in neuronal activity within the amygdala following kisspeptin administration. Subsequently, we investigated functional relevance by assessing the LH response to direct intra-amygdala administration of kisspeptin or kisspeptin antagonist in adult rodents. This revealed that direct intra-amygdala administration of kisspeptin elicited a dose-dependent increase in LH secretion. In addition, blocking endogenous kisspeptin signalling specifically within the amygdala by administering intra-amygdala kisspeptin antagonist decreased LH secretion as well as LH pulse frequency. This provides the first evidence for a novel pathway in which kisspeptin inhibits neuronal activity in the amygdala, thereby releasing the amygdala’s ‘inhibitory brake’ on reproduction, resulting in stimulation of gonadotrophin secretion and pulsatility. Furthermore, these studies suggest that kisspeptin can integrate limbic circuits with the regulation of reproductive hormones. We now translate this work into humans, employing functional MRI to interrogate human brain activity in response to kisspeptin.
Volume 38
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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