New pathways in the treatment for menopausal hot flushes

Within the next 25 years, an estimated 1 billion women worldwide will be older than 50 years, and therefore likely to be nearing menopause or postmenopausal. Hot flushes (vasomotor symptoms) are experienced by approximately 73% of postmenopausal women, and the associated sleep disturbances, fatigue, and decreased cognitive function lead to a reduction in their quality of life and an increased use of medical resources. A hypothalamic mechanism is well established in the understanding of hot flushes, but the pathways involved have been unclear, thus reducing therapeutic options. Novel hypothalamic neuropeptide-signalling pathways have shed light on the central regulation of both reproductive and thermoregulatory systems and the links between them, and might now lead to specific therapies. The menopause results in oestrogen deficiency, with loss of feedback regulation of hypothalamic gonadotropinreleasing hormone (GnRH). The kisspeptin–neurokinin B (NKB)–dynorphin (KNDy) signalling system in the hypothalamus is the proximate and obligate stimulus of GnRH secretion, and is hypertrophied after the menopause. Hypothalamic NKB neurons also project to the medial preoptic area, the hypothalamic site of thermoregulatory neuronal pathways, and evidence exists that these NKB neurons are a key link between the endocrine changes of the menopause and vasomotor symptoms. Flushing, like thermoregulation, is controlled centrally but effected peripherally, and blood flow to the skin is also increased in postmenopausal women with severe flushing. NKB neurons might also facilitate cutaneous vasodilatation and contribute to oestrogenic modulation of body temperature. In The Lancet, Julia Prague and colleagues report the findings from their phase 2, randomised, doubleblind, placebo-controlled trial investigating the oral neurokinin 3 receptor (NK3R) antagonist MLE4901 as a new therapy for menopausal hot flushes. In 28 healthy women aged 40–62 years, oral administration of a 40 mg dose twice per day for 4 weeks reduced the number of hot flushes during week 4 by 45 percentage points (95% CI 22–67) compared with placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87]; p<0·0001). This finding was also supported by an objective assessment of flushes, using the Bahr sternal skin conductance monitor. Reductions in the number of flushes might be less important to women than measures of quality of life, thus it is of interest that the authors found hot flush severity, bother, and interference to be significantly reduced during treatment with MLE4901. However, in Prague and colleagues’ study, no improvements occurred in the sexual symptoms commonly reported after menopause (MENQOL sexual domain score adjusted means: placebo 2·15 [95% CI 1·84–2·51] vs MLE4901 1·98 [1·68-2·30]; p=0·24). As an index of GnRH secretion, luteinising hormone pulse frequency was unchanged in the treatment group, although other measures of pulsatile secretion altered with increases in amplitude and orderliness of luteinising hormone pulse. Thus, although NKB pathways regulate both the vasomotor and reproductive systems, separate effects can be identified, and these might vary with the endocrine environment. Most withdrawals from the study were for reasons unrelated to treatment, and no serious adverse events occurred with MLE4901, although three women developed liver enzyme elevations (alanine aminotransferase was 4·5–5·9 times the upper limit of normal), which normalised within 90 days. The limitations of the trial include its small size (of 68 women screened, only 28 completed the trial and were included in the per-protocol analysis) and short duration of treatment. The current gold-standard treatment for menopausal Published Online April 3, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30886-3