Neurokinin B administration induces hot flushes in women

Abstract

Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms), and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

Figure 1. Participant-reported hot flush symptoms during 30 minute intravenous infusion of neurokinin B (Study 1).

Five healthy women were monitored for 180 minutes in a Clinical Research Unit. They were administered an intravenous infusion of neurokinin B (NKB, 5.12 nmol/kg/h) between 90–120 minutes. Red ovals represent timings and duration of participant-reported hot flush symptoms. Hot flush symptoms were reported by four out of five participants.

Figure 2. Participant-reported hot flush symptoms during double-blinded administration of vehicle and neurokinin B (Study 2).

The order of infusions was randomised by an independent investigator. (a) Participants 1,2,5,7 and 9 received vehicle infusion first and NKB infusion second. (b) Participants 3,4,6,8 and 10 received NKB infusion first then vehicle infusion second. Red ovals represent timings and duration of participant-reported hot flush symptoms. Hot flush symptoms were reported by eight out of ten participants. There were a total of thirteen separate flushing episodes.

Figure 3. Physiological changes associated with hot flush episodes in healthy women.

Mean heart rate (a), skin temperature by skin probe (c), skin temperature by thermal imaging (e) and mean arterial pressure (MAP) (g), during 5 minute period pre-symptom onset (Pre-symp) and during symptom period (Symp) using the minutely recordings. Parts b, d, f and h represent change in respective physiological parameter when compared with pre-symptom level. As MAP was recorded every 5 minutes (rather than minutely so as to avoid discomfort), the MAP measurement immediately prior to symptoms was compared to that at symptom onset or closest after symptom onset. Data presented as mean ± SEM. *P < 0.05.

Figure 4. Reproductive hormone changes during neurokinin B and vehicle infusion.

Serum luteinizing hormone (LH) (a), serum follicle stimulating hormone (FSH) (c) and serum estradiol (e) levels during neurokinin B (NKB) and vehicle infusion. Parts b, d and f represent change in respective parameter when compared with vehicle. Data presented as mean ± SEM.