Endocrine Abstracts

Background: Placentation (invasion of the placenta into the maternal endometrium) is hypothesised to be critical for healthy placental function and is abnormal in two thirds of miscarriages. Kisspeptin has emerged as a putative regulator of physiological placentation; it is highly expressed in placental syncytiotrophoblasts and could play an important paracrine role in the regulation of placentation. Circulating kisspeptin levels are considerably raised during healthy pregnanc...

Introduction: Hypothalamic amenorrhoea (HA) is a condition characterised by reduced GnRH pulsatility and is a common cause of anovulatory subfertility. Kisspeptin is an endogenous neuropeptide that regulates hypothalamic GnRH function. Hypothalamic kisspeptin expression is reduced, and kisspeptin receptor expression is increased, in a rodent model of HA. The kisspeptin analogue MVT-602 has a 3-4-fold longer half-life than native kisspeptin-54 (t1/2 0.5 h). We invest...

Background: Hot flushes affect 70% of menopausal women, can be long-lasting, and often severely impact on physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but not without risk. Neurokinin B is an important mediator of hot flushes in rodents and elevated hypothalamic expression occurs in menopausal women. Neurokinin B acts via the neurokinin 3 receptor. We therefore hypothesised that neurokinin 3 receptor antagonism could be a nove...

Background: Hypothalamic KNDy neurons have recently been identified as key regulators of reproductive function by releasing three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin. Animal studies show they interact to control pulsatile GnRH release, which is vital for fertility. In animals, kisspeptin stimulates, NKB modulates and the opioid dynorphin inhibits GnRH pulsatility. However, the interaction of these peptides has never been studied in humans. To inve...

Background: In vitro fertilisation is an effective therapy for infertility, but can result in the potentially life-threatening complication, Ovarian Hyper-Stimulation Syndrome (OHSS). We have previously reported that a single injection of kisspeptin results in an LH surge of ~12–14 hrs duration, sufficient to safely induce oocyte maturation, but eliminate OHSS. However, the physiological LH surge in a normal menstrual cycle has a plateaux lasting 24–28 hrs. ...

As the nation gets fatter, the incidence of diabetes is also rising. The brain is now emerging as a critical mediator of blood sugar control, re-directing focus away from the traditional pancreas-centred model. The enzyme glucokinase (GK) acts as a glucose sensor in many tissues including glucose-sensitive neurones within the hypothalamic arcuate nucleus. However, the role of GK here is unclear. We investigated the role of arcuate GK in glucose homeostasis in both healthy and ...

Background: Hypogonadotrophic Hypogonadism (HH) is characterised by hypogonadism in the context of low gonadotrophin levels, frequently due to a defect in hypothalamic function e.g. Kallman’s syndrome. However, no direct test of hypothalamic function currently exists. Kisspeptin is a hypothalamic neuropeptide that stimulates endogenous GnRH release. Thus, we investigated whether kisspeptin could be used to interrogate hypothalamic function in men with HH.<p class="abs...

Background: Kisspeptin-54 (KP54) stimulates hypothalamic GnRH release. The kisspeptin analogue, MVT-602, has a longer half-life (t1/2108min) than KP54 (t1/228mins). MVT-602 potently stimulates gonadotrophin release in men. We sought to determine for the first time the effect of MVT-602 on gonadotrophin release in healthy women.Methods: A two-phase dose-finding study was carried out in 9 healthy women, 18–35 yrs with regular men...

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...

Context: IVF treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication ‘ovarian hyperstimulation syndrome’ (OHSS).Objective: To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.Design: Phase 2 multi-dose open label randomised clinical trial.<p class...