Kevin O’Byrne King’s College London
Kevin O’Byrne King’s College London
Professor Kevin O’Byrne
Kevin O’Byrne is Professor of Reproductive Neuroendocrinology in the Division of Women’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.
Stress and Infertility
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. Using an integrative neuroscience approach, including optogenetics, we are primarily interested in establishing the neural basis of the GnRH pulse generator and stress-induced infertility.
With the use of selective antagonists for the major stress neuropeptide, corticotrophin-releasing factor (CRF), we reported for the first time a differential role for CRF receptor types 1 and 2 in stress-induced suppression of LH pulses. Further, we have identified a novel site of action for CRF in the locus coeruleus, the principal noradrenergic nucleus with strong limbic (emotional) connections, in the aetiology of psychological stress responses and stress-induced infertility. In addition, a previously unrecognised interaction between CRF and kisspeptin signalling underlying stress-induced reproductive dysfunction has been demonstrated. Hypothalamic arcuate nuclear (ARC) kisspeptin neurones are a key integral component of the GnRH pulse generator and we are at the forefront of characterising the unique contribution of ARC Kisspeptin neurones, which co-localise Neurokinin-B and Dynorphin (KNDy), in fertility regulation.
We have identified a novel inhibitory role for the amygdala, a key emotional brain structure, in stress-induced suppression of the GnRH pulse generator in adult rats. More recently we have discovered that endogenous kisspeptin signalling within the posterodorsal subnucleus of the medial amygdala (MePD) is a major stimulant of LH secretion and indeed regulates hypothalamic GnRH pulse generator frequency (Figure 1).
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 (Figure 1) and (ii) that kisspeptin antagonism within the MePD delays 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 site(s) of action, including the MePD, and CRF receptor subtypes involved.
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 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.
Senior Research Fellows
Xiao Feng Li (MD, PhD)
Xian Hua Lin (MD, PhD) – KC Wong Foundation Fellow
Geffen Lass (BSc)
Wen He (MD)
Daniel Adekunbi (BSc) – Commonwealth Commission Split-site Ph.D. Studentship