Hot flushes, which are among the most frequent symptoms of menopause, are considered to be the result of the changes in the sex hormone milieu and tissue exposure at midlife and beyond. However, modern medicine tries also to tie physiological processes with the individual gene profile. This was also done in regard to vasomotor symptoms (VMS) in the WHI study, in search of potential associations between VMS and certain genetic variations and single nucleotide polymorphisms (SNPs). After adjustment for bilateral oophorectomy, age, smoking, alcohol intake, physical activity, population structure, body mass index, education, income, and menopausal hormone therapy use, 14 SNPs were associated with increased odds of VMS at a p value threshold < 5 × 10-8 . These 14 SNPs are located within the same region of chromosome 4, the gene which encodes tachykinin receptor 3 (TACR3), and neurokinin B (NKB), a member of the tachykinin family of peptides, preferentially binds to NK3R. NKB mRNA-expressing neurons are located predominantly in the infundibular nucleus and the anterior hypothalamic area. In humans, NKB neurons co-localize with the gonadotropin releasing hormone tract in the infundibular stalk, and the NKB pathway is implicated in pubertal development and hypogonadatropic hypogonadism. Another study showed that the expression of tachykinins and their receptors in the mouse uterus are tightly and differentially regulated by ovarian steroids . Estrogen effects are mainly mediated by estrogen receptor alpha, supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus. Furthermore, menopause and/or oophorectomy are associated with changes in NKB gene expression: in the human infundibular nucleus it increases after menopause, and in monkeys and rats ovariectomy induces similar increases in NKB gene expression that are reversed by estradiol therapy .
You may ask at this point why these data should be of interest for us menopause clinicians. Well, the WHI study released its data in 2009, and some smart guys thought there might be a commercial potential for the association between VMS and the tachykinin pathway. Fezolinetant is an oral neurokinin-3 receptor antagonist which has been optimized for use in women’s health, and is being developed for sex hormone-related disorders such as endometriosis, polycystic ovary syndrome and uterine fibroids. Also, because of its estrogen-mimicking properties, fezolinetant is being tested as a non-hormonal therapy for VMS . It was recently announced that it reduced frequency of moderate to severe hot flushes from baseline to weeks 4 and 12 by 88% and 93%, respectively, vs. 38% and 54% for placebo (p < 0.001 for both) in a Phase IIa trial. Fezolinetant also reduced hot flush severity by 60% at week 4 and 70% at week 12, compared with 12% and 23% for placebo (p < 0.001 for both). So here is a very good example of how pure scientific results transform with time into a potential new therapy for a very common clinical problem.
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Crandall CJ, Manson JE, Hohensee C, et al. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women’s Health Initiative Study. Menopause 2017;24:252-61
Pinto FM, Pintado CO, Pennefather JN, Patak E, Candenas L. Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus. Reprod Biol Endocrinol 2009;7:77
Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA. Neurokinin B and the hypothalamic regulation of reproduction. Brain Res 2010;1364:116-28
Ogeda announces positive data from phase IIa trial of fezolinetant in the treatment of menopausal hot flashes.