Investigating hypothalamic kisspeptin neuronal dysfunction as a key mediator of the pathophysiology of PCOS and HA

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Problem: Polycystic Ovary Syndrome (PCOS) and Hypothalamic Amenorrhoea (HA) are the two commonest reproductive disorders affecting young women, being found in 2-13% and 1-2% of pre-menopausal women, respectively. PCOS is characterised by menstrual irregularity, hyperandrogenism and polycystic ovarian morphology on ultrasound (PCOM), whereas HA by low body-weight, excessive exercise and psychological stress. A key abnormality in both of these reproductive disorders is the alteration in hypothalamic gonadotrophin releasing hormone (GnRH) pulsatility. Specifically, women with PCOS have increased GnRH pulsatility, whereas women with HA have reduced GnRH pulsatility. Kisspeptin (KP) neurons in the arcuate (ARC) nucleus of the hypothalamus (infundibular nucleus in humans) are thought to be the 'GnRH pulse generator'. Although ARC kisspeptin expression is increased in most PCOS-like models eg prenatal androgenised model, it is not known whether this alteration is causal in the aetiology of the reproductive phenotype. Furthermore, it is not known whether attenuating kisspeptin neuronal overactivity in an established model of PCOS (ie prenatal androgenised model) can attenuate the PCOS-like phenotype. Conversely, although ARC kisspeptin expression is reduced in HA-like models, it is not known whether increasing ARC kisspeptin neuronal activation can rescue reproductive health in the face of undernutrition.Furthermore, the diagnosis of both conditions can be challenging. Whilst the diagnosis of both conditions is supported by guidelines, both conditions are diagnoses of exclusion and up to 86% of women diagnosed as HA also meet diagnostic criteria for PCOS. Thus, even clinicians with specialist expertise may be faced with diagnostic uncertainty in women presenting with oligo/amenorrhoea. As the alteration in hypothalamic function is a key but divergent abnormality in these conditions, I will evaluate whether assessment of hypothalamic dysfunction using a KP test could represent an objective method to classify the cause of menstrual disturbance in women presenting with oligo/amenorrhoea.Aims:1. Determine whether restoring ARC kisspeptin-neuronal activation can rescue estrus cyclicity in a mouse model of HA.2. Determine whether increased ARC kisspeptin-neuronal activity is responsible for PCOS 2a: Establish whether reducing ARC kisspeptin-neuronal overactivity in an established mouse model of PCOS (prenatal androgenised) can resolve the reproductive phenotype. 2b: Determine whether increasing ARC kisspeptin-neuronal activation in healthy adult female mice induces a PCOS-like phenotype.3. Evaluate the discriminatory performance of the endocrine response to an intravenous bolus of KP as a diagnostic test to differentiate PCOS and HA in oligo/amenorrhoeic women.Applications and Benefits: This proposal will establish the extent to which alterations in the activity of ARC kisspeptin neurons are directly responsible for the phenotype observed in PCOS and HA. Moreover, these data will establish the therapeutic relevance of targeting these neurons by determining whether attenuating their overactivity in a prenatal androgenised PCOS-like model, or increasing it in a HA model, can resolve the disturbance in reproductive health.KP is a potent stimulator of hypothalamic GnRH secretion, and thus can be used to assess hypothalamic function. My pilot data demonstrates that the luteinising hormone (LH) response is exaggerated in women with HA, compared to those with PCOS. Thus, a KP test of hypothalamic function could be developed into an objective test to identify the cause in women presenting with oligo/amenorrhoea.Summary:The overall aim of this proposal is to investigate the role of hypothalamic arcuate kisspeptin neuronal activity in the aetiology of PCOS and HA, and to determine the utility of KP as a diagnostic test in women presenting with menstrual disturbance.