Kevin O'Byrne

Kevin O’Byrne is Professor of Reproductive Neuroendocrinology in the Department of Women and Children’s Health.  Graduate of Physiology, Chelsea College London (1980) and PhD, University of Bristol (1984).  Joined the MRC Reproductive Biology Unit, Edinburgh, as Non-Clinical Scientist (1986-1988).  Assistant Professor, Department of Physiology, University of Texas, Houston to 1994 before joining the Department of Anatomy at King’s College London.

Selected recent PUBLICATIONS

https://www.researchgate.net/profile/Kevin-Obyrne-3

1. Adekunbi DA, Li XF, Li S, Adegoke OA, Iranloye BO, Morakinyo AO, Lightman SL, Taylor PD, Poston L, O'Byrne KT. Role of amygdala kisspeptin in pubertal timing in female rats. PLoS One. 2017; 12:e0183596.
2. He W, Li XF, Adekunbi D, Liu Y, Long H, Wang L, Lyu Q, Kuang Y, O'Byrne KT. Hypothalamic effects of progesterone on regulation of the pulsatile and surge release of luteinising hormone in female rats. Scientific Reports. 2017; 7:8096.
3. Adekunbi DA, Li XF, Lass G, Shetty K, Adegoke OA, Yeo SH, Colledge WH, Lightman SL, O'Byrne KT. Kisspeptin neurones in the posterodorsal medial amygdala modulate sexual partner preference and anxiety in male mice. J Neuroendocrinol. 2018; 30:e12572.
4. Mills EGA, O'Byrne KT, Comninos AN. Semin Reprod Med. The Roles of the Amygdala Kisspeptin System. 2019; 37:64-70.
5. Mills EGA, O'Byrne KT, Comninos AN. Kisspeptin as a Behavioral Hormone. Semin Reprod Med. 2019; 37:56-63.
6. Li XF, Adekunbi DA, Alobaid HM, Li SY, Pilot M, Lightman SL, O’Byrne KT. Role of the posterodorsal medial amygdala in predator odour stress induced puberty delay in female rats. J Neuroendocrinol. 2019; 31:e12719.
7. Lee CY, Li S, Li XF, Stalker DAE, Cooke C, Shao B, Kelestimur H, Henry BA, Conductier G, O Byrne KT, Clarke IJ. Lipopolysaccharide reduces gonadotrophin-releasing hormone (GnRH) gene expression: role of RFamide-related peptide-3 and kisspeptin. Reprod Fertil Dev. 2019; 31:1134-1143.
8. Lin XH, Wu DD, Li C, Xu YJ, Gao L, Lass G, Zhang J, Tian S, Ivanova D, Tang L, Chen L, Ding R, Liu XM, Han M, Fan JX, Li XF, Sheng JZ, O'Byrne KT, Huang HF. Maternal High Triglyceride Levels During Early Pregnancy and Risk of Preterm Delivery: A Retrospective Cohort Study. J Clin Endocrinol Metab. 2019; 104:1249-1258.
9. Voliotis M, Li XF, De Burgh R, Lass G, Lightman SL, O’Byrne KT, Tsaneva-Atanasova K. Mathematical modelling elucidates core mechanisms underpinning GnRH pulse generation.  J Neuroscience. 2019; pii: 0828-19. doi: 10.1523/JNEUROSCI.0828-19.2019.
10. Lass G, Li XF, de Burgh RA, He W, Kang Y, Hwa-Yeo S, Sinnett-Smith LC, Manchishi SM, Colledge WH, Lightman SL, O’Byrne KT. Optogenetic stimulation of kisspeptin neurones within the posterodorsal medial amygdala increases luteinising hormone pulse frequency in female mice. J Neuroendocrinol. 2020; 32: e12823.
11. Liu Y, Li X, Ivanova D, Lass G, He W, Chen Q, Yu S, Wang Y, Long H, Wang L, Lyu Q, Kuang Y, O’Byrne KT. Dynorphin and GABAA Receptor Signaling Contribute to Progesterone's Inhibition of the LH Surge in Female Mice.  Endocrinology.  2020; 161:bqaa036. doi: 10.1210/endocr/bqaa036.
12. Zavala E, Voliotis M, Zerenner T, Tabak J, Walker JJ, Li XF, Terry JR, Lightman SL, O'Byrne K T, Tsaneva-Atanasova K. Dynamic Hormone Control of Stress and Fertility. Front Physiol. 2020 Nov 17;11:598845. doi: 10.3389/fphys.2020.598845.
13. Ivanova D, Li XF, McIntyre C, Liu Y, Kong L, O’Byrne KT. Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice. Endocrinology. 2021 Dec;162(12):bqab206.
14. Voliotis M, Li XF, De Burgh RA, Lass G, Ivanova D, McIntyre C, O'Byrne KT, Tsaneva-Atanasova K. Modulation of pulsatile GnRH dynamics across the ovarian cycle via changes in the network excitability and basal activity of the arcuate kisspeptin network. Elife. 2021 Nov 17;10: e71252.
15. Voliotis M, Plain Z, Li XF, McArdle CA, O'Byrne KT, Tsaneva-Atanasova K. Mathematical models in GnRH research. J Neuroendocrinol. 2021 Dec 30: e13085.
16. Lin XH, Lass G, Kong LS, Wang H, Li XF, Huang HF, O'Byrne KT. Optogenetic Activation of Arcuate Kisspeptin Neurons Generates a Luteinizing Hormone Surge-Like Secretion in an Estradiol-Dependent Manner. Front Endocrinol. 2021;12:775233.
17. McCosh RB, O'Bryne KT, Karsch FJ, Breen Regulation of the gonadotropin-releasing hormone neuron during stress. J Neuroendocrinol. 2022 Jan 21. doi.org/10.1111/jne.13098.
18. Ivanova D, Li X, Liu Y, McIntyre C, Fernandes C, Lass G, Kong L, O'Byrne KT. Front Endocrinol (Lausanne). 2022 May 17;13:893029. doi: 10.3389/fendo.2022.893029.
19. Lass G, Li XF, Voliotis M, Wall E, de Burgh RA, Ivanova D, McIntyre C, Lin XH, Colledge WH, Lightman SL, Tsaneva-Atanasova K, O'Byrne KT. GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice.  J Neuroendocrinol. 2022 Nov;34(11):e13207. doi: 10.1111/jne.13207.
20. Ivanova D, Li XF, McIntyre C, O'Byrne KT. Posterodorsal Medial Amygdala Urocortin-3, GABA, and Glutamate Mediate Suppression of LH Pulsatility in Female Mice.  2022 Dec 19;164(2):bqac196. doi: 10.1210/endocr/bqac196.
21. McIntyre C, Li XF, de Burgh R, Ivanova D, Lass G, O'Byrne KT. GABA Signaling in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice.  2022 Nov 14;164(1):bqac197. doi: 10.1210/endocr/bqac197.
22. Shen X, Liu Y, Li XF, Long H, Wang L, Lyu Q, Kuang Y, O'Byrne KT. Optogenetic stimulation of Kiss1^ARC terminals in the AVPV induces surge-like luteinizing hormone secretion via glutamate release in mice.  Front Endocrinol (Lausanne). 2022 Nov 8;13:1036235. doi: 10.3389/fendo.2022.1036235.
23. Ludwig M, Newton C, Pieters A, Homer NZM, Feng Li X, O'Byrne KT, Millar RP. Provocative tests with Kisspeptin-10 and GnRH set the scene for determining social status and environmental impacts on reproductive capacity in male African lions (Panthera leo).  Gen Comp Endocrinol. 2022 Dec 1;329:114127. doi: 10.1016/j.ygcen.2022.114127.
24. Ivanova D, O'Byrne KT. Optogenetics studies of kisspeptin neurons. 2023 Apr;162:170961. doi: 10.1016/j.peptides.2023.170961.
25. McIntyre C, Li XF, Ivanova D, Wang J, O'Byrne KT. Hypothalamic PVN CRH neurons signal through PVN GABA neurons to suppress GnRH pulse generator frequency in female mice. 2023 May 29;164(6):bqad075. doi: 10.1210/endocr/bqad075.

Stress and Infertility

The GnRH pulse generator

Research effort is directed at the operation of a neural oscillator, or pulse generator, located in the hypothalamus that controls the pulsatile secretion of gonadotrophin-releasing hormone (GnRH) into the pituitary portal circulation.  This, in turn, governs the secretion of luteinising hormone (LH) and follicle stimulating hormone from the pituitary gland and, therefore, all of reproduction.  Deviations from the normal physiological frequency range of this pulse generator are commonly associated with major disruptions in follicular development and ovulation resulting in infertility.  

The discovery that humans and rodents with an inactivating mutation in kisspeptin or its receptor fail to progress through puberty or show normal pulsatile LH secretion, suggested that kisspeptin is a key regulator of pulsatile GnRH secretion.  Attention has focused on the kisspeptin expressing neuronal population in the hypothalamic arcuate nucleus (ARC), the location of the GnRH pulse generator. These neurones, known as KNDy, because they co-express neurokinin B (NKB) and dynorphin A (Dyn), innervate the distal processes of the GnRH neurones at the level of the median eminence, and were recently shown to display calcium oscillations in synchrony with LH pulses. It is hypothesised that NKB acting on its receptor (NK₃R) functions as an excitatory signal to depolarise KNDy cells postsynaptically in the network, resulting in kisspeptin output to the GnRH neurones to initiate each GnRH pulse. The co-released Dyn functions as an inhibitory signal within the KNDy network, acting presynaptically on kappa opioid receptors (KOR) to inhibit the release of NKB, thus terminating kisspeptin release and ceasing the signal for GnRH secretion. There is unequivocal evidence that the KNDy neural network comprises the major component of the hypothalamic GnRH pulse generator, and we are interrogating this with a unique combination of world class in-vitro experimentalists (Martin Kelly, Oline Ronnekleiv, Jian Qui and colleagues at OHSU, USA), computational mathematical modellers (Krasimira Tsaneva-Atanosova and Margaritis Voliotis, University of Exeter) and the in-vivo experimentalist team at King’s. We have developed the first ever mathematical model of the KNDy network.

The Amygdala, a key upstream regulator of the GnRH pulse generator

The amygdala, a key limbic brain structure commonly known for its role in higher-order emotional processing, is implicated in reproduction and we have shown the medial amygdala underlies psychological stress-induced suppression of pulsatile LH secretion.  The finding of extra-hypothalamic kisspeptin and its receptor in the medial amygdala, and more specifically its posterodorsal subnucleus (MePD) has opened up new possibilities concerning its role as an upstream regulator of the GnRH pulse generator. Indeed, we have recently shown that kisspeptin signalling in the MePD is a key regulator of pubertal timing, sexual motivation behaviour and anxiety. Critically, in collaboration with Waljit Dhillo and colleagues at Imperial, we have discovered that kisspeptin signalling in the MePD per se, robustly regulates hypothalamic GnRH pulse generator frequency, but the underlying mechanisms and pathways are well understood.  The MePD comprises primarily GABAergic but also prominent glutamatergic neuronal populations and we have shown an interaction with amygdala kisspeptin to control the GnRH pulse generator via projections to the hypothalamus.  The MePD is also rich in the stress neuropeptide urocortin-3, which is activated by psychological stress.

Using an integrative neuroscience approach, including the latest cutting-edge technologies of combined targeted optogenetic manipulations with in-vivo gradient-index (GRIN) lens microendoscopic systems to monitor in real time neurone calcium dynamics, a proxy for neuronal activity, of selective GCaMP-expressing neurones, we are primarily interested in establishing the neural basis of the GnRH pulse generator and stress-induced infertility.

Early life programming and Puberty

Puberty is a key event in development and its onset is governed by a complex neuronal and glial network within the hypothalamus that regulates the secretion of GnRH, more specifically increasing GnRH pulse generator frequency, driving gonadotrophic hormone secretion, promoting gonadal steroidogenesis and sexual maturation.  Despite the recent unprecedented progress in our understanding of the neural control of puberty, especially the critical role of hypothalamic kisspeptin, there has been very little advancement in our understanding of the actual timing mechanism of puberty and the mechanism underlying its modulation by stress.  Although the essential role of hypothalamic kisspeptin in GnRH secretion and therefore puberty is unequivocal, the finding of extra-hypothalamic kisspeptin and its receptor in the MePD opens up new possibilities concerning the central control of puberty.  Our recent discovery that this population is developmentally upregulated at puberty raises the possibility that MePD kisspeptin is key to triggering accelerated pulsatile GnRH release to drive puberty onset.  Critically, this novel hypothesis is supported by our recent data showing that (i) endogenous kisspeptin signalling within the MePD per se regulates hypothalamic GnRH pulse generator frequency and (ii) that selective optogenetic activation of MePD kisspeptin neurones accelerated LH pulse frequency and advanced puberty.

Although genetic factors are considered to explain 50-80% of the variance of age at puberty, links between environmental factors and the genetic control of pubertal timing, where epigenetic mechanisms play a crucial role, are increasingly realised.  We are interested in the neural systems susceptible to programming by early life stressors and the neural mechanisms that underlie vulnerability to stress-induced disruption of pubertal development.  Much attention has focused on the impact of nutritional status on pubertal timing, in particular the rising problem of childhood obesity as a major risk factor for early onset of puberty.  However, there is an emerging realisation that psychosocial stressors can unequivocally advance or delay puberty independent of adiposity, which is disconcerting since both ends of the puberty timing-spectrum appear to have a profound impact on later health in men and women.  Familial stressors such as absence of a father, parental conflict and mother-daughter conflict accelerate pubertal development, and there are striking parallels in animal models of weak parent-offspring bonding.  However, childhood psychological abuse, neglect and post-traumatic stress disorder (eg. After hurricanes Katrina and Rita) are associated with delayed puberty. Psychosocial stress can also delay puberty in animal models; eg. social subordination in monkeys and exposure to predator odour in rats.  Despite this substantial evidence, the underlying mechanisms are unknown.  Although we have shown that overexpression of CRF in the central nucleus of the amygdala, a model of chronic stress, advances puberty, intracerebro-ventricular administration of CRF delays puberty in the rat.  Moreover, CRF receptor antagonism advances puberty, suggesting a key endogenous CRF inhibitory tone.  We are currently investigating the role of the stress neuropeptide Unocrotin-3, which is extensively expressed within the MePD, on pubertal timing and have recently shown that chemogenetic activation of this population suppresses LH pulse frequency and delays puberty.

Feeding and Sex Behaviour

Stress-induced feeding or ‘comfort eating’ is common and characterised by an increase in food intake when faced with emotionally or physically challenging events.  It is a likely contributor to the increased prevalence of obesity in those suffering from stress.  Major depressive disorder and generalised anxiety disorder in adolescence are linked to an increased risk of obesity in adulthood.  Despite the commonality of comfort eating, the responsible mediators remain elusive.  The amygdala plays a central role in higher-order emotional processing and the MePD, in particular, is involved in food intake.  Extra-hypothalamic CRF is well recognised for mediating behavioural responses to stress.  We have shown that endogenous CRF signalling in the MePD is involved in stress-induced food intake and thus the amygdala CRF system may be a mediator of comfort eating.

The medial amygdala is also crucial for sexual behaviour.  Kisspeptin receptor knockout mice display no sexual behavior.  With the recent discovery of kisspeptin and its receptor in the MePD, we hypothesised it may influence male sexual behaviour. We have recently shown that intra-MePD infusion of kisspeptin caused multiple erections in rats; an effect specific to kisspeptin receptor activation.  Thus kisspeptin plays a key role in male sexual behavior, which may be specific to the MePD.

Hot flushes

Hot flushes are one of the most distressing symptoms of the menopausal syndrome, affecting over 80% of women, many of whom require medical treatment because their severity greatly impact on their quality of life. With our ageing population in the UK and increased retirement age for women, the health, social and economic implications of this menopausal symptom are enormous. Although HRT is the mainstay of treatment for this symptom, contraindication, such as breast cancer, stroke and thrombo-embolism have raised serious concerns and anxiety, and dictate the need for continued search for non-hormonal therapies to alleviate hot flushes. We are studying the central and peripheral effects of oestrogen receptor alpha and beta analogues, and kisspeptins on the vasomotor disturbances that underlie hot flushes. We are also interested in the potential use of plant derived or phytoestrogens as “alternative” therapies for hot flushes.

Research colleagues

Senior Research Fellows

Xiao Feng Li (MD, PhD)

PhD Students

Lin, Yanyan (MD)

Women & Children's Health

First/primary/lead supervisor

1/10/2022 → …

Ye, Jinbin (MD)

Women & Children's Health

First/primary/lead supervisor

1/10/2022 → …

Hollings, Owen (BSc, MSc)

Women & Children's Health

First/primary/lead supervisor

1/07/2022 → …

Yu, Junru (MD)

Women & Children's Health

First/primary/lead supervisor

1/10/2021 → …

Batool, Sadia (BSc) – Commonwealth Commission Split-site Ph.D. Studentship