Perimenopausal vasomotor symptoms are triggered by a fall in circulating levels of estrogen and other sex steroids. It has been hypothesized that thermoregulatory centres in the hypothalamus play a crucial role in mediating the hot flash response. However, exactly how do hormonal changes bring about these changes in the hypothalamus? If we could understand this connection, we might be able to devise new non-hormonal strategies for the management of menopausal symptoms.
Researchers have recently looked at the hypothalamic hormone, neurokinin B (NKB), as a possible mediator linking estrogen deficiency to hot flashes. NKB is a decapeptide and a member of the tachykinin family of peptides. In humans, NKB is encoded by the TAC3 gene and binds preferentially to the neurokinin 3 receptor (NK3R, encoded by the TAC3R gene). Hypothalamic NKB expression is elevated in postmenopausal women, and animal studies have indicated that levels of NKB expression return to normal levels with estrogen replacement.
In a randomized, double-blinded, placebo-controlled, 2-way crossover study, ten healthy women were admitted to a temperature and humidity-controlled research unit. After an intravenous infusion of NKB, 8 of the 10 women developed symptoms consistent with menopausal hot flashes, including elevations in heart rate and skin temperature. After the placebo infusion, none of the women reported flushing. This finding supports the hypothesis that increased NKB levels can cause hot flashes in women. Further studies will be conducted to determine if pharmacological blockade of NKB signalling could inhibit hot flushes in menopausal women.
Interestingly the NK3 receptor, to which NKB binds, has received significant attention of late as a possible target for psychotropic drugs. This receptor has a discrete pattern of expression in the brain and it appears that binding of NKB to these receptors modulates various neurotransmitter systems in the CNS. These novel agents are now being explored for the treatment of psychiatric illness, primarily schizophrenia, and sex hormone-related disorders. Stay tuned.
Further supporting a role for NKB in the etiology of menopausal vasomotor symptoms in the recent finding that there may be a genetic predisposition to hot flashes. Researchers from UCLA found a link between single nucleotide polymorphisms (SNPs) in the NK3 receptor locus and an increased predisposition to vasomotor symptoms (VMS) for menopausal women. The analysis included data from 17,695 participants (ages 50 to 79) collected at 40 U.S. health centers from the Women’s Health Initiative Observational Study (WHI-OS) and Clinical Trials (WHI-CT). Crandall and colleagues identified 14 SNPs which were associated specifically with hot flashes in menopausal women. There was a 1.20- to 1.83-fold greater likelihood of VMS in menopausal women associated with each SNP examined. All SNPs were located on chromosome 4 in the region of the NK3 (also called the TAC3) gene.
Pretty cool. It will be interesting to see what comes next. Will some of the NK3 receptor antagonists currently being developed be of use in the treatment of menopausal vasomotor (and mood?) symptoms?
Ruta Nonacs, MD
Crandall CJ, Manson JE, Hohensee C, Horvath S, Wactawski-Wende J, LeBlanc ES, Vitolins MZ, Nassir R, Sinsheimer JS. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women’s Health Initiative Study. Menopause: The Journal of The North American Menopause Society. Vol. 24, No. 3, pp. 000-000 DOI: 10.1097/GME.0000000000000763
Jayasena, C. N., Comninos, A. N., Stefanopoulou, E., Buckley, A., Narayanaswamy, S., Izzi-Engbeaya, C., … Dhillo, W. S. (2015). Neurokinin B Administration Induces Hot Flushes in Women. Scientific Reports, 5, 8466. doi: 10.1038/srep08466
Simonsen KB, Juhl K, Steiniger-Brach B, Nielsen SM. Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications. Curr Opin Drug Discov Devel. 2010 Jul;13(4):379-88.