Over the last 15−20 years, textbooks outlining the hormonal control of the reproductive system have had to be rewritten, as novel research studies have identified the role of a population of hypothalamic ‘KNDy’ neurones, which co-express the neuropeptides kisspeptin, neurokinin B (NKB) and dynorphin, in regulating gonadotrophin-releasing hormone (GnRH), gonadotrophin and sex steroid secretion.1
Furthermore, over the same period, Naomi Rance, a pathologist in Arizona, USA, and her colleagues were researching the role of NKB, together with its receptor (the neurokinin 3 receptor; NK3R), in the generation of menopausal hot flushes.
They had initially noted hypertrophy and increased activity of NKB neurones, with increased NKB gene expression, in the brain tissue of post-menopausal women when compared with pre-menopausal subjects at post-mortem. Their subsequent work in monkey and rat models confirmed neuronal plasticity in response to oestrogen status, just as is seen in the menopause and with hormone replacement therapy (HRT). They identified that NKB/NK3R signalling is critical in the autonomic thermoregulatory pathway via the median pre-optic nucleus.2
‘This was the first report of an oral NK3R antagonist effectively attenuating menopausal hot flushes in humans, without the need for oestrogen exposure, by preventing NKB/NK3R-mediated activation of the thermoregulatory pathway.’
Commensurate with this, a randomised, placebo-controlled, study demonstrated that peripheral intravenous infusion of NKB induced hot flushes in pre-menopausal women similar to those described by menopausal women.3 In pre-menopausal women, this physiological signalling pathway achieves co-ordination of reproductive hormone status and thermoregulation throughout the menstrual cycle, to improve fertility and success of pregnancy, but becomes pathological when reproductive potential is subsequently lost.
In response to falling circulating oestrogen levels, 70% of women experience menopausal flushes over a long period of time (median 7.4 years);4 these typically impact on all aspects of their daily life. Many women have a contraindication or aversion to HRT. Consequently, a novel therapeutic that could safely attenuate such flushes should benefit a huge number of women (estimated to be 10 million individuals in the UK alone5).
We were keen to try and investigate this unmet clinical need. In the context of the pre-existing literature, we hypothesised that an oral NK3R antagonist would attenuate menopausal flushes. Our investigator-initiated and investigator-led randomised, double-blind, placebo-controlled, crossover trial tested this hypothesis in a proof of concept study.6
We recruited women aged 40−62 years, who had been amenorrhoeic for at least 12 months, and were having at least seven hot flushes per 24-hour period, of which some were bothersome or severe. Participants received 4 weeks of treatment with an oral NK3R antagonist twice daily (MLE4901; Millendo Therapeutics, Inc., Ann Arbor, MI, USA) and 4 weeks of treatment with an exact-match placebo twice daily, in random order, separated by a 2-week washout period.
Participants recorded their symptoms in real-time and completed daily questionnaires. For the first 48 hours of each week they wore a sternal skin conductance monitor, to objectively measure their flushes. They also attended a weekly clinical review, where blood samples were taken to measure hormone concentrations and renal/liver function for safety monitoring.
MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points when compared with placebo. The treatment effect size was similar, irrespective of drug order. Furthermore, compared with baseline, hot flush frequency reduced by 73%, severity by 45%, bother by 51% and interference by 72% after 4 weeks of treatment with the oral NK3R antagonist. Good concordance was shown between subjective reporting and objective measurement of hot flushes.
This was, therefore, the first report of an oral NK3R antagonist effectively attenuating menopausal hot flushes in humans, without the need for oestrogen exposure, by preventing NKB/NK3R-mediated activation of the thermoregulatory pathway.6 Further post-hoc analysis showed that the therapeutic time-to-onset of MLE4901 was rapid (by day 3 of treatment) and sustained throughout the 4-week treatment period, with an additional therapeutic benefit on sleep.7
Our next focus of investigation was to examine the impact of our oral NK3R antagonist on luteinizing hormone (LH) pulsatility. We were intrigued that the pre-existing literature (two seminal papers from 1979) concluded that the menopausal flush synchronised with the LH pulse, and that this had since been widely accepted.
‘Our findings suggest great promise for this therapeutic class in the treatment of menopausal flushes … such agents may also be a potential therapeutic for cancer patients.’
Using a modern, commercially available, LH immunoassay and mathematical modelling we investigated whether we would find the same relationship. Using two validated mathematical models to analyse LH pulsatility, together with self-reporting of flushes during an 8-hour clinical study, we found that the probability that the two event intervals (hot flush and LH pulse) matched was low in the majority of participants (mean P=0.24; where P=1 reflects perfect association).8
This, therefore, challenges the previously accepted dogma, and suggests that the KNDy neurones regulate LH pulsatility and hot flushes by different signalling pathways, which has therapeutic and mechanistic implications.
Our findings suggest great promise for this therapeutic class in the treatment of menopausal flushes in the future.9 Furthermore, as the aetiology of hot flushes in women taking oestrogen deprivation therapy for breast cancer, and for men taking androgen deprivation therapy for prostate cancer, is likely to be the same as in the menopause, such agents may also be a potential therapeutic for cancer patients, as they do not require sex steroid exposure to yield their effect.
Further larger and longer studies in menopausal women, and subsequently in cancer patients, are required to ensure that efficacy and safety are confirmed, and the pharmaceutical industry is already heavily involved in taking this forward.10 If these studies are successful, then NK3R antagonists could be practice-changing, and will serve as an important reminder to us all of the absolute importance of good basic science in successful translational research, and the debt we owe to those individuals who agree to participate in clinical trials.
I would like to acknowledge Professor Waljit Dhillo as my PhD supervisor.
Julia Prague, MRC Fellow, Department of Investigative Medicine, Imperial College, London
- Navarro VM et al. 2009 Journal of Neuroscience 29 11859−11866.
- Rance NE et al. 2013 Frontiers in Neuroendocrinology 34 211−227.
- Jayasena CN et al. 2015 Scientific Reports 5 8466.
- Avis NE et al. 2015 JAMA Internal Medicine 175 531−539.
- Office for National Statistics 2011 UK Census www.ons.gov.uk/ census/2011census.
- Prague JK et al. 2017 Lancet 389 1809−1820.
- Prague JK et al. 2018 Menopause 25 862−869.
- Prague JK et al. 2019 Journal of Clinical Endocrinology & Metabolism 104 3628–3636.
- Greenhill G 2017 Nature Reviews Endocrinology 13 314.
- Fraser G et al. 2019 Journal of the Endocrine Society 3 Suppl 1 OR33–36.
EARLY CAREER PRIZE LECTURES
The Society’s Early Career Prize Lectures help Clinicians-in-Training and Scientists-in-Training have their work recognised across the wider endocrine community. Successful applicants present a 20-minute lecture at the Society for Endocrinology BES conference each November and receive an honorarium of £750, as well as having an article published in The Endocrinologist.
To find out more see www.endocrinology.org/grants-and-awards/prizes-and-awards/early-career-prize-lectures.