Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial

Prague, Julia; Roberts, Rachel; Comninos, Alexander N; Clarke, Sophie; Jayasena, Channa N.; Nash, Zachary; Doyle, Chedie; Papadopoulou, Deborah; Bloom, Stephen R.; Mohideen, Pharis; Panay, Nicholas; Hunter, Myra; Veldhuis, Johannes D.; Webber, Lorraine; Huson, Les; Dhillo, Waljit

doi:10.1530/endoabs.49.gp131

Cited by 25 publications

(43 citation statements)

References 14 publications

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“…These change dramatically in postmenopausal women, in whom they can generate hot flushes [39]. In this subpopulation of neurons, in particular, neurokinin B and its receptor NK3R have been implicated in the induction of hot flushes in healthy women that are typical in location and duration of postmenopausal hot flushes [40,41]. In order to gain more insights into the mechanism of action of Serelys V R on neurons, the effect of PureCyTonin V R on the uptake of [ 3 H]-serotonin into rat cortical synaptosomes was analyzed.…”

Section: Mechanism Of Action Of Serelys V Rmentioning

confidence: 99%

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms

Genazzani

Panay

Simoncini

et al. 2020

Gynecological Endocrinology

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Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin V R. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin V R in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin V R , an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin V R may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

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Section: Mechanism Of Action Of Serelys V Rmentioning

confidence: 99%

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms

Genazzani

Panay

Simoncini

et al. 2020

Gynecological Endocrinology

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“…Of these, 330 were excluded; 59 included fewer than 20 women per study arm and 54 were not an RCT; 126 did not clearly state a sample size calculation; 52 did not measure vasomotor symptoms as the primary outcome; 39 were secondary analysis. Following these exclusions, 214 RCT were included…”

Section: Resultsmentioning

confidence: 99%

“…Other subjective vasomotor symptoms measurement tools included a 20‐item structured symptom checklist; two of the items asking about the presence of hot flushes and cold/night sweats, a 5‐point (from none to very severe) scoring system about the severity of hot flushes and night sweats, Interactive Voice Response System to record the number and severity of the hot flushes, and self‐reported surveys . Objective measures of vasomotor symptoms such as skin conductance were used in five trials in addition to subjective measures (Table ).…”

Section: Resultsmentioning

confidence: 99%

Variation in menopausal vasomotor symptoms outcomes in clinical trials: a systematic review

Iliodromiti

Wang

Lumsden

et al. 2019

BJOG

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Background There is substantial variation in how menopausal vasomotor symptoms are reported and measured among intervention studies. This has prevented meaningful comparisons between treatments and limited data synthesis. Objectives To review systematically the outcome reporting and measures used to assess menopausal vasomotor symptoms from randomised controlled trials of treatments. Search strategy We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to May 2018. Selection criteria Randomised controlled trials with a primary outcome of menopausal vasomotor symptoms in women and a sample size of at least 20 women per study arm. Data collection and analysis Data about study characteristics, primary vasomotor‐related outcomes and methods of measuring them. Main results The search identified 5591 studies, 214 of which were included. Forty‐nine different primary reported outcomes were identified for vasomotor symptoms and 16 different tools had been used to measure these outcomes. The most commonly reported outcomes were frequency (97/214), severity (116/214), and intensity (28/114) of vasomotor symptoms or a composite of these outcomes (68/214). There was little consistency in how the frequency and severity/intensity of vasomotor symptoms were defined. Conclusions There is substantial variation in how menopausal vasomotor symptoms have been reported and measured in treatment trials. Future studies should include standardised outcome measures which reflect the priorities of patients, clinicians, and researchers. This is most effectively achieved through the development of a Core Outcome Set. This systematic review is the first step towards development of a Core Outcome Set for menopausal vasomotor symptoms. Tweetable summary Menopausal hot flushes and night sweats have been reported in 49 different ways in clinical research. A core outcome set is urgently required.

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“…45 Following this, NK3R antagonists have been developed as a novel therapy for menopausal flushing, reducing the total number and severity of flushes by 41 to 45%. 46 Thus, these promising agents could revolutionize the treatment of women with hot flushes, especially those at risk of side effects from sex-steroid-based therapies, and several compounds are now in late-phase development.…”

Section: Nkb Administration In Humansmentioning

confidence: 99%

Clinical Translational Studies of Kisspeptin and Neurokinin B

Hunjan

Abbara

2019

Semin Reprod Med

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Kisspeptin and neurokinin B (NKB) are hypothalamic neuropeptides that are vital for reproductive health. An absence of either kisspeptin or NKB signaling results in hypogonadotrophic hypogonadism and a failure to proceed through puberty. In recent years, several studies have demonstrated potential avenues for the clinical utility of medications that act through these pathways in the assessment and treatment of reproductive disorders. Kisspeptin acts to stimulate hypothalamic gonadotrophic-releasing hormone (GnRH) secretion from the hypothalamus. Kisspeptin induces gonadotrophin secretion in both healthy men and women, and in women with reproductive disorders such as hypothalamic amenorrhea (HA). Kisspeptin-based treatments hold promise for use during in vitro fertilization (IVF) treatment; a bolus of kisspeptin-54 induces an LH surge of 12 to 14 hours of duration sufficient to induce oocyte maturation, but with markedly reduced rates of the most significant complication of IVF treatment, ovarian hyperstimulation syndrome (OHSS). Kisspeptin could also be used chronically to restore reproductive health in patients with functional hypogonadism, such as those with HA. Furthermore, kisspeptin has potential as a diagnostic test of hypothalamic function; a “kisspeptin test” could be used in children with delayed puberty to identify the subset with genetically determined deficits in hypothalamic pathways (congenital hypogonadotrophic hypogonadism [CHH]). In addition to its role in hypothalamic GnRH pulse generation, NKB plays a critical role in the occurrence of one of the most troubling symptoms of the menopause, the “hot flush.” Neurokinin-3 receptor (NK3R) antagonists are highly effective as treatments for hot flushes in postmenopausal women, with several compounds now in late-phase development. Furthermore, NK3R antagonism leads to a reduction in LH secretion by reducing GnRH pulsatility in the hypothalamus and has been shown to reduce androgen levels in women with polycystic ovary syndrome (PCOS) (in whom GnRH pulsatility is often increased). In summary, although further detailed evaluation in several clinical settings is ongoing, medications based on kisspeptin and NKB pathways have prodigious potential in the assessment and treatment of reproductive disorders.

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Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial

Cited by 25 publications

References 14 publications

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms

Variation in menopausal vasomotor symptoms outcomes in clinical trials: a systematic review

Clinical Translational Studies of Kisspeptin and Neurokinin B

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